41ST Annual Intensive Review of Internal Medicine PDF

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41ST ANNUAL
INTENSIVE REVIEW OF
INTERNAL MEDICINE
41st Annual
Intensive Review of Internal Medicine
Provided by:
Brigham and Women’s Hospital
The Department of Medicine
Harvard Medical School
Postgraduate Medical Education
______________________________________________________________________________
Date of Original Release: October 1, 2018

Termination Date: January 31, 2021
(Please note that AMA PRA Category 1 Credits™ will no longer be issued for the activity after this date)
Estimated Time to Complete the Activity: 85 hours
Media: This educational activity is in the form of an online video and MP4 and/or Audio MP3
PROGRAM DESCRIPTION
The Intensive Review of Internal Medicine course is designed to enhance internal medicine
knowledge by offering a comprehensive update in internal medicine and its subspecialties. It will
consist of a case-based review of challenging clinical problems and review of literature to guide
evidence-based practice. This course can also serve to prepare attendees for the ABIM Board
Examinations (Certification/Recertification).
LEARNING OBJECTIVES
Upon completion of this activity, participants will be able to:
• Apply current/recommended guidelines in clinical practice
• Perform differential diagnosis of complex clinical presentations
• Identify/integrate current therapeutic options for specific disorders,
including end-of-life care
• Review and interpret up-to-date literature relevant to clinical practice
• Describe pathophysiology as it applies to management of clinical problems
• Apply knowledge gained to the ABIM certification/recertification examinations
ACGME Competencies:
This course is designed to meet one or more of the following Accreditation Council for
Graduate Medical Education competencies:
• Patient Care and Procedural Skills
• Medical Knowledge
• Practice-Based Learning and Improvement
TARGET AUDIENCE
The target audience for the Intensive Review of Internal Medicine course is clinical and
academic internists, pediatricians, and primary care physicians/trainees preparing for ABIM
internal medicine certification/recertification examinations and/or seeking a comprehensive
update in internal medicine and its subspecialties.
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METHOD OF PARTICIPATION:
Review audio/video program of conference sessions, complete the comprehensive activity
evaluation and score 70% or greater on the required post-test to assess the knowledge gained
from reviewing the program.
• Go to www.myoakstone.com and log in using your user ID and password

• Click on your program to take your exam
ACCREDITATION
The Harvard Medical School is accredited by the Accreditation Council for Continuing Medical
Education (ACCME) to provide continuing medical education for physicians.
AMA CREDIT DESIGNATION STATEMENT

The Harvard Medical School designates this enduring material for a maximum of 85 AMA PRA
Category 1 Credits™. Physicians should claim only the credit commensurate with the extent of
their participation in the activity.
RISK MANAGEMENT CREDIT

This activity meets the criteria of the Massachusetts Board of Registration in Medicine for 2.75
credits of Risk Management Study. This includes:
.75 Credits of Opioid Education and Pain Management Training

.75 Credits of End-of-Life Care Studies
Please check your individual state licensing board requirements before claiming these credits.
ABIM MOC MEDICAL KNOWLEDGE MOC POINTS

Successful completion of this CME activity enables the participant to earn up to 85 MOC points
in the American Board of Internal Medicine’s (ABIM) Maintenance of Certification (MOC)
program. Participants will earn MOC points equivalent to the amount of CME credits claimed
for the activity. It is the CME activity provider’s responsibility to submit participant completion
information to ACCME for the purpose of granting ABIM MOC points.
On the course evaluation page please indicate “Yes” when asked if you would like to receive
ABIM MOC points for your participation in this enduring activity. You will then be required to
provide your ABIM ID # and your Date of Birth. Points earned will equal the amount of AMA
PRA Category 1 CreditsTM claimed.
HMS will upload the participant data, including the points earned, directly to the ABIM so that it
will appear on the ABIM diplomates transcript. These points will not appear on your certificate
provided at the end of this enduring activity.
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DISCLOSURE POLICY
Harvard Medical School (HMS) adheres to all ACCME Essential Areas, Standards, and Policies.
It is HMS’s policy that those who have influenced the content of a CME activity (e.g. planners,
faculty, authors, reviewers and others) disclose all relevant financial relationships with
commercial entities so that HMS may identify and resolve any conflicts of interest prior to the
activity. These disclosures will be provided in the activity materials along with disclosure of any
commercial support received for the activity. Additionally, faculty members have been instructed
to disclose any limitations of data and unlabeled or investigational uses of products during their
presentations.
Disclosure information for all individuals in control of the content of the activity is located
on the disclosure statement in the PDF and printed syllabus.
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(http://www.videolan.org/).
If you experience technical difficulties, you can contact our Customer Service hotline at
1-800-284-8433.
Disclaimer:
CME activities sponsored by Harvard Medical School are offered solely for educational
purposes and do not constitute any form of certification of competency. Practitioners
should always consult additional sources of information and exercise their best professional
judgment before making clinical decisions of any kind.
WARNING:
The copyright proprietor has licensed the picture contained on this recording for private
home use only and prohibits any other use, copying, reproduction, or performance in
public, in whole or in part (Title 17 USC Section 501 506).
CMEinfo is not responsible in any way for the accuracy, medical or legal content of this
recording. You should be aware that substantive developments in the medical field covered
by this recording may have occurred since the date of original release.
© 2018 Ebix, Inc. DBA Oakstone Publishing. LLC.

CMEinfo is a registered trademark of Oakstone Publishing, LLC.
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ACTIVITY DISCLOSURE STATEMENT
41st Annual Intensive Review of Internal Medicine
Course Number: 732046-1901
Date of Original Release: October 1, 2018 / Termination Date: January 31, 2021
The Harvard Medical School is accredited by the Accreditation Council for Continuing Medical Education (ACCME) to provide
continuing medical education for physicians.
The Harvard Medical School designates this enduring material for a maximum of 85 AMA PRA Category 1 Credits™. Physicians
should claim only the credit commensurate with the extent of their participation in the activity.
This activity meets the criteria of the Massachusetts Board of Registration in Medicine for 2.75 credits of Risk Management Study.
This includes .75 Credits of Opioid Education and Pain Management Training and .75 Credits of End-of-Life Care Studies. Please
check your individual state licensing board requirements before claiming these credits.
Harvard Medical School has long held the standard that its continuing medical education courses be free of commercial bias.
In accord with the disclosure policy of the Medical School as well as standards set forth by the Accreditation Council for Continuing
Medical Education, course planners, speakers, and content reviewers have been asked to disclose any relevant relationship they, or
their spouse or partner, have to companies producing, marketing, re-selling or distributing health care goods or services consumed by,
or used on, patients. In addition, faculty have been asked to list any off-label uses of pharmaceuticals and/or devices for
investigational or non-FDA approved purposes that they plan to discuss.
Such disclosure is not intended to suggest or condone bias in any presentation, but is elicited to provide the course director and
participants with information that might be of potential importance to their evaluation of a given presentation.
The following planners, speakers, and content reviewers, on behalf of themselves and their spouse or partner, have reported financial
relationships with an entity producing, marketing, re-selling, or distributing health care goods or services (relevant to the content of
the activity) consumed by, or used on, patients:
NAME COMPANY RELATIONSHIP

Course Planners and Faculty:
Ajay K. Singh, MBBS, FRCP (UK) GlaxoSmithKline Consultant
MBA
Course Faculty:
Maureen Achebe, MD, MPH AMAG Pharmaceuticals Advisory Board
Luitpold Pharmaceuticals Consultant
Elizabeth M. Battinelli, MD PhD Sanofi Consultant
Carolyn Bernstein, MD Palmer Chiropractic Grant Support

Amgen Consultant
Marc P. Bonaca, MD, MPH Amgen Grant Support, Consultant

AstraZeneca Grant Support, Consultant
Merck Grant Support, Consultant
MedImmune Grant Support
Pfizer Grant Support
Aralez Consultant
Bayer Consultant
Janssen Consultant
Sanofi Consultant
Barry Brenner, MD Janssen Consultant

Jean M. Connors, MD Bristol-Myers Squibb Consultant/Scientific Advisory Board
Boehringer Ingelheim Scientific Advisory Board
Dova Pharmaceuticals Consultant
Pfizer Consultant
Portola Scientific Advisory Board
Unum Therapeutics Data Safety Monitoring Board
Paul Dellaripa, MD Genentech Principal Investigator

Bristol-Myers Squibb Principal Investigator
Akshay Desai, MD, MPH Abbott/St. Jude Medical Consultant

Amgen Consultant
AstraZeneca Consultant
Boehringer Ingelheim Consultant
DalCor Pharmaceuticals Consultant
Janssen Consultant
Novartis Consultant, Research Grants
Relypsa Consultant
Joerg Ermann, MD Boehringer Ingelheim Research Grant, Consulting

Pfizer Research Grant
Eli Lilly Scientific Advisory Board
Novartis Scientific Advisory Board
Hilary J. Goldberg, MD Genentech Member of Clinical Coordinating Center for

Industry-Sponsored Study
Samuel Z. Goldhaber, MD Boehringer Ingelheim Research Support, Consultant

Bristol-Myers Squibb Research Support, Consultant
BTG EKOS Research Support
Daiichi Research Support, Consultant
Janssen Research Support, Consultant
Thrombosis Research Institute Research Support
Agile Consultant
Bayer Consultant
Portola Consultant
Soleno Consultant
Sarah Hammond, MD Merck Research Support
Lauren Harshman, MD Bayer Advisor/Research to the Institution/Travel

Exelixis Advisor
Genentech Advisor/Research to the Institution
Dendreon/Valient Advisor/Research to the Institution
Pfizer Advisor/Research to the Institution
Medivation/Astellas Advisor/Research to the Institution
Kew Group Advisor
Theragene Advisor
Corvus Advisor
Merck Advisor/Research to the Institution
Bristol-Myers Squibb Research to the Institution
Janssen Research to the Institution
Sotio Research to the Institution
Takeda Research to the Institution
Sanofi Travel
Novartis Advisor
Craig Hersh, MD Boehringer Ingelheim Grant
Novartis Grant
23andMe Consultant
Elliot Israel, MD AstraZeneca Consultant

Entrinsic Health Solutions Consultant
GlaxoSmithKline Consultant
Merck Consultant
Novartis Consultant
4D Pharma Consultant
Pneuma Respiratory Consultant
Regeneron Consultant
Sanofi Consultant
Vorso Corp Consultant
Genentech Clinical Research Trial (BWH)
Novartis Clinical Research Trial (BWH)
Sanofi Clinical Research Trial (BWH)
David Jackman, MD AstraZeneca Consultant

CVS Caremark Consultant
More Health Consultant
Ursula Kaiser, MD Novo Nordisk Consultant
Scott Kinlay, MBBS, PhD Colorado Prevention Center Data Safety Monitoring Board
Ann LaCasce, MD Bristol-Myers Squibb Consulting

Seattle Genetics Consulting
Ming V. Lin, MD Gilead Advisory Board
James Maguire, MD Bayer Advisory Committee
Jeffrey Meyerhardt, MD Chugai Pharmaceuticals Consultant

Ignyta Consultant
Samia Mora, MD Atherotech Diagnostics Research Grant to Institution
Anju Nohria, MD Amgen Research Support

Takeda Oncology Consultant
Paul M. Ridker, MD AstraZeneca Research Support, Co-Inventor on Licensed

Patents
Novartis Research Support, Research Consultant
Pfizer Research Support
Kowa Research Support
Amgen Research Support
Siemens Co-Inventor on Licensed Patents
Quintiles Research Consultant
Corvida Research Consultant
Inflazome Research Consultant
Eisai Research Consultant
Sanofi Research Consultant
Janssen Research Consultant
Susan Ritter, MD Pfizer Spouse – Employee

Marc S. Sabatine, MD Amgen Research Grant Support, Consulting
AstraZeneca Research Grant Support, Consulting
Daiichi-Sankyo Research Grant Support
Eisai Research Grant Support
GlaxoSmithKline Research Grant Support
Intarcia Research Grant Support, Consulting
Janssen Research and Dev. Research Grant Support, Consulting
Medicines Company Research Grant Support, Consulting
MedImmune Research Grant Support, Consulting
Merck Research Grant Support, Consulting
Novartis Research Grant Support, Consulting
Pfizer Research Grant Support
Poxel Research Grant Support
Takeda Research Grant Support
Bristol-Myers Squibb Consulting
CVS Caremark Consulting
Dyrnamix Consulting
Esperion Consulting
Robert C. Stanton, MD Janssen Pharmaceuticals Consultant
Usha Tedrow, MD Abbott Medical Honorarium/Faculty, Fellows’ Course

Biosense Webster Honorarium/Faculty, Fellows’ Course
Medtronic Honorarium/Faculty, Fellows’ Course
Derrick Todd, MD Optum Consultant
Alexander Turchin, MD Merck Consultant

Monarch Medical Technologies Consultant
Eli Lilly Research Support
Brio Systems Consultant
All other individuals including course directors, planners, reviewers, faculty, staff, etc., who are in a position to control the content of
this educational activity have, on behalf of themselves and their spouse or partner, reported no financial relationships related to the
content of this activity.
Faculty List
____________________________________________________
COURSE DIRECTORS:
Ajay K. Singh, MBBS, FRCP (UK), MBA Carolyn B. Becker, MD

Senior Associate Dean for Postgraduate Associate Professor of Medicine,
Medical Education, Harvard Medical School,
Director, Master in Medical Sciences in Division of Endocrinology,
Clinical Investigation (MMSCI) Program Diabetes and Hypertension,
Harvard Medical School, Department of Medicine,
Director, Office of Postgraduate Brigham and Women’s Hospital
Medical Education, Joseph Loscalzo, MD, PhD
Brigham and Women’s Hospital Hersey Professor of the Theory and
Nancy Berliner, MD Practice of Medicine,
Professor of Medicine, Harvard Medical School,
Harvard Medical School, Division of Cardiovascular Medicine,
Chief, Division of Hematology, Chairman, Department of Medicine,
Department of Medicine, Brigham and Women's Hospital
Brigham and Women's Hospital
FACULTY:
Maureen M. Achebe, MD, MBBS Lindsey R. Baden, MD

Assistant Professor of Medicine, Associate Professor of Medicine,
Harvard Medical School, Harvard Medical School,
Division of Hematology, Division of Infectious Diseases,
Department of Medicine, Department of Medicine,
Brigham and Women's Hospital Brigham and Women’s Hospital
Dale S. Adler, MD Rebecca M. Baron, MD

Associate Professor of Medicine, Assistant Professor of Medicine,
Division of Cardiovascular Medicine, Division of Pulmonary and Critical Care
Department of Medicine, Medicine, Department of Medicine,
Brigham and Women’s Hospital Brigham and Women’s Hospital
Edwin P. Alyea, III, MD Elisabeth M. Battinelli, MD

Medical Oncology, Division of Hematology,
Dana-Farber Cancer Institute, Department of Medicine,
Department of Medicine, Brigham and Women's Hospital
____________________________________________________
David D. Berg, MD Wendy Y. Chen, MD, MPH
Clinical Fellow in Medicine, Assistant Professor of Medicine,
Chief Medical Resident, Medical Oncology,
Department of Medicine, Dana-Farber Cancer Institute,
Brigham and Women’s Hospital Department of Medicine,
Carolyn A. Bernstein, MD
Assistant Professor of Neurology, Cheryl R. Clark, MD
Harvard Medical School, Assistant Professor of Medicine,
Department of Neurology, Harvard Medical School,
Brigham and Women's Hospital Director,
Health Equity Research & Intervention
Marc P. Bonaca, MD Center for Community Health and
Assistant Professor of Medicine, Health Equity,
Harvard Medical School, Division of General Internal Medicine
Division of Cardiovascular Medicine, and Primary Care,
Kari P. Braaten, MD, MPH Nathan T. Connell, MD, MPH

Instructor in Obstetrics, Assistant Professor of Medicine,
Gynecology and Reproductive Biology, Harvard Medical School,
Harvard Medical School, Division of Hematology,
Department of Obstetrics and Gynecology, Department of Medicine,
Brigham and Women's Hospital Brigham and Women's Hospital
Barry M. Brenner, MD Jean M. Connors, MD

Samuel A. Levine Distinguished Assistant Professor of Medicine,
Professor of Medicine, Harvard Medical School,
Harvard Medical School, Division of Hematology,
Renal Division, Department of Medicine, Department of Medicine,
Brigham and Women's Hospital Brigham and Women’s Hospital
Julie E. Buring, ScD Paul F. Dellaripa, MD

Professor of Medicine, Associate Professor of Medicine,
Department of Medicine, Division of Rheumatology,
Brigham and Women's Hospital Immunology and Allergy,
Department of Medicine,
Walter W. Chan, MD, MPH Brigham and Women’s Hospital
Assistant Professor of Medicine,
Harvard Medical School, Bradley M. Denker, MD
Division of Gastroenterology, Associate Professor of Medicine,
Hepatology and Endoscopy, Harvard Medical School,
Department of Medicine, Renal Division,
Brigham and Women's Hospital Department of Medicine,
Beth Israel Deaconess Medical Center
____________________________________________________
Akshay S. Desai, MD, MPH Christopher H. Fanta, MD
Associate Professor of Medicine, Professor of Medicine,
Division of Cardiovascular Medicine, Division of Pulmonary and
Department of Medicine, Critical Care Medicine,
Sanjay Divakaran, MD
Clinical Fellow in Medicine, Sonia Friedman, MD
Harvard Medical School, Associate Professor of Medicine,
Division of Cardiovascular Medicine, Harvard Medical School,
Department of Medicine, Division of Gastroenterology,
Brigham and Women’s Hospital Hepatology and Endoscopy,
Todd B. Ellerin, MD Brigham and Women’s Hospital
Instructor in Medicine,
Harvard Medical School, Elizabeth B. Gay, MD
Division of Infectious Disease, Assistant Professor of Medicine,
Department of Medicine, Harvard Medical School,
South Shore Hospital Division of Pulmonary and
Critical Care Medicine,
Lawrence J. Epstein, MD Department of Medicine,
Instructor in Medicine, Part-Time, Brigham and Women’s Hospital
Harvard Medical School,
Division of Sleep Medicine, Hilary J. Goldberg, MD
Department of Medicine, Assistant Professor of Medicine,
Brigham and Women’s Hospital Harvard Medical School,
Division of Pulmonary and
Joerg Ermann, MD Critical Care Medicine,
Instructor in Medicine, Department of Medicine,
Harvard Medical School, Brigham and Women’s Hospital
Division of Rheumatology,
Immunology and Allergy, Samuel Z. Goldhaber, MD
Department of Medicine, Professor of Medicine,
Division of Cardiovascular Medicine,
Brendan M. Everett, MD, MPH Department of Medicine,
Assistant Professor of Medicine, Brigham and Women’s Hospital
Division of Cardiovascular Medicine, Annekathryn Goodman, MD
Department of Medicine, Associate Professor of Obstetrics,
Brigham and Women’s Hospital Gynecology, and Reproductive Biology,
Department of Obstetrics and Gynecology,
Massachusetts General Hospital
____________________________________________________
Kathleen J. Haley, MD Elliot Israel, MD
Assistant Professor of Medicine, Professor of Medicine,
Division of Pulmonary and Critical Care Division of Pulmonary and
Medicine Department of Medicine, Critical Care Medicine,
Florencia Halperin, MD
Instructor in Medicine, David M. Jackman, MD
Division of Endocrinology, Diabetes Harvard Medical School,
and Hypertension, Medical Oncology,
Department of Medicine, Dana-Farber Cancer Institute,
Sarah P. Hammond, MD
Assistant Professor of Medicine, Kunal Jajoo, MD
Division of Infectious Diseases, Harvard Medical School,
Lauren C. Harshman, MD Brigham and Women’s Hospital
Harvard Medical School, Jennifer A. Johnson, MD
Medical Oncology, Assistant Professor of Medicine,
Dana-Farber Cancer Institute, Harvard Medical School,
Department of Medicine, Division of Infectious Diseases,
Galen V. Henderson, MD
Assistant Professor of Neurology, Ursula B. Kaiser, MD
Harvard Medical School, Professor of Medicine,
Brigham and Women’s Hospital Division of Endocrinology,
Diabetes and Hypertension,
Craig P. Hersh, MD Department of Medicine,
Assistant Professor of Medicine, Brigham and Women’s Hospital
Division of Pulmonary and Sunil Kapur, MD
Critical Care Medicine, Instructor in Medicine,
Brigham and Women's Hospital Division of Cardiovascular Medicine,
____________________________________________________
Matthew I. Kim, MD Ming Valerie Lin, MD
Assistant Professor of Medicine, Instructor in Medicine,
Division of Endocrinology, Division of Transplantation,
Diabetes and Hypertension, Department of Surgery
Department of Medicine, Lahey Hospital and Medical Center
James H. Maguire, MD
Scott Kinlay, MBBS, PhD Professor of Medicine,
Associate Professor of Medicine, Harvard Medical School,
Harvard Medical School, Division of Infectious Diseases,
Division of Cardiovascular Medicine, Department of Medicine,
Department of Medicine, Brigham and Women’s Hospital
Kathryn A. Martin, MD
Michael Klompas, MD Assistant Professor of Medicine,
Associate Professor of Population Medicine, Part-time, Harvard Medical School, Division
Harvard Medical School, of Women’s Health,
Division of Infectious Diseases, Department of Medicine,
Department of Medicine, Massachusetts General Hospital
Julia Y. McNabb-Baltar, MD
Ann S. LaCasce, MD Instructor in Medicine,
Harvard Medical School, Division of Gastroenterology,
Medical Oncology, Hepatology and Endoscopy,
Dana-Farber Cancer Institute, Department of Medicine,
Jeffrey A. Meyerhardt, MD
Lisa S. Lehmann, MD, PhD Associate Professor of Medicine,
Part-time, Harvard Medical School, Division Medical Oncology
of General Internal Medicine & Primary Dana-Farber Cancer Institute,
Care, Department of Medicine, Department of Medicine,
Leonard S. Lilly, MD Tracey A. Milligan, MD

Professor of Medicine, Assistant Professor of Neurology,
Division of Cardiovascular Medicine, Department of Neurology,
____________________________________________________
Elinor A. Mody, MD Kathryn M. Rexrode, MD
Chief, Division of Rheumatology, Division of Women’s Health,
Reliant Medical Group Department of Medicine,
Samia Mora, MD
Associate Professor of Medicine, Paul M. Ridker, MD
Harvard Medical School, Eugene Braunwald Professor of Medicine,
Department of Medicine, Division of Cardiovascular
Brigham and Women’s Hospital Medicine, Department of Medicine,
Muthoka L. Mutinga, MD
Assistant Professor of Medicine, Susan Y. Ritter, MD
Harvard Medical School, Instructor in Medicine,
Division of Gastroenterology, Harvard Medical School,
Hepatology and Endoscopy Division of Rheumatology,
Department of Medicine, Immunology and Allergy,
Anju Nohria, MD
Assistant Professor of Medicine, Christopher L. Roy, MD
Department of Medicine, Hospitalist Services,
M. Angela O'Neal, MD
Assistant Professor of Neurology, Anna E. Rutherford, MD, MPH
Brigham and Women's Hospital Division of Gastroenterology,
Hepatology and Endoscopy,
Ann L. Pinto, MD, PhD Department of Medicine,
Instructor in Medicine, Brigham and Women's Hospital
Division of General Internal Medicine & Marc S. Sabatine, MD, MPH
Primary Care, Professor of Medicine,
Brigham and Women’s Hospital Division of Cardiovascular Medicine,
____________________________________________________
Suzanne E. Salamon, MD David E. Sloane, MD
Assistant Professor of Medicine, Instructor in Medicine,
Associate Chief for Clinical Geriatrics, Division of Rheumatology,
Beth Israel Deaconess Medical Center Immunology and Allergy,
John R. Saltzman, MD Brigham and Women’s Hospital
Professor of Medicine,
Harvard Medical School, Benjamin N. Smith, MD
Division of Gastroenterology, Assistant Professor of Medicine,
Hepatology and Endoscopy, Harvard Medical School,
Adam Schaffer, MD Brigham and Women’s Hospital
Harvard Medical School, Caren G. Solomon, MD
Department of Medicine, Associate Professor of Medicine,
Brigham and Women's Hospital Harvard Medical School,
Division of Women’s Health,
Gordon Schiff, MD Department of Medicine,
Assistant Professor of Medicine, Brigham and Women's Hospital
Division of General Internal Medicine & Robert C. Stanton, MD
Primary Care, Department of Medicine, Associate Professor of Medicine,
Chief, Kidney & Hypertension Section,
Scott L. Schissel, MD, PhD, DPhil Joslin Diabetes Center;
Assistant Professor of Medicine, Division of Nephrology,
Harvard Medical School, Department of Medicine,
Division of Pulmonary and Beth Israel Deaconess Medical Center
Chief of the Department of Medicine, Garrick C. Stewart, MD
Brigham and Women’s Hospital Faulkner Instructor in Medicine,
Ellen W. Seely, MD Division of Cardiovascular Medicine,
Professor of Medicine, Department of Medicine,
Harvard Medical School, Brigham and Women’s Hospital
Division of Endocrinology,
Diabetes and Hypertension, David M. Systrom, MD
Department of Medicine, Assistant Professor of Medicine,
Division of Pulmonary and
____________________________________________________
Laura L. Tarter, MD Alexander Turchin, MD
Harvard Medical School Harvard Medical School,
Division of Rheumatology, Division of Endocrinology, Diabetes and
Immunology and Allergy, Hypertension,
Usha B. Tedrow, MD, MS Anand Vaidya, MD, MMSc

Division of Cardiovascular Medicine, Division of Endocrinology,
Department of Medicine, Diabetes and Hypertension,
Manisha Thakuria, MD
Instructor in Dermatology, Anne M. Valente, MD
Harvard Medical School, Associate Professor of Pediatrics,
Department of Dermatology, Harvard Medical School,
Brigham and Women’s Hospital Division of Cardiovascular Medicine,
Lori W. Tishler, MD Boston Children’s Hospital
Assistant Professor of Medicine, Part-Time
Harvard Medical School, Russell G. Vasile, MD
Vice President, Medical Affairs Associate Professor of Psychiatry,
Commonwealth Care Alliance Harvard Medical School,
Department of Psychiatry,
Derrick J. Todd, MD, PhD Beth Israel Medical Deaconess Hospital
Harvard Medical School, Gustavo E. Velasquez, MD, MPH
Division of Rheumatology, Instructor in Medicine,
Immunology and Allergy, Harvard Medical School,
Department of Medicine, Division of Infectious Disease
J. Kevin Tucker, MD
Assistant Professor of Medicine, Sushrut S. Waikar, MD
Harvard Medical School, Associate Professor of Medicine,
Renal Division, Harvard Medical School,
Department of Medicine, Renal Division,
Brigham and Women’s Hospital Department of Medicine, Brigham and
Women’s Hospital
____________________________________________________
Sarah E. Wakeman, MD, FASM
Medical Director, Mass General Hospital
Substance Use Disorder Initiative,
Division of General Internal Medicine &
Primary Care,
Gerald L. Weinhouse, MD
Division of Pulmonary and Critical Care
Medicine
Department of Medicine, Brigham and
Women’s Hospital
Maria A. Yialamas, MD
Division of Endocrinology,
Diabetes and Hypertension,
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>ŝŶŐt͘:EĞƵƌŽŝŵŵƵŶĞ WŚĂƌŵĂĐŽů ;ϮϬϭϲͿϭϭ͗ϯϵϰʹϰϬϬ
± dW///͘:D͘ϮϬϬϭ͖Ϯϴϱ͗ϮϰϴϲͲϮϰϴϳ͘'ƌƵŶĚǇ^͕ĞƚĂů͘ ŝƌĐƵůĂƚŝŽŶϮϬϬϰ͖ϭϭϬ͗
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Global and Continuing Education
Book
Topic/Speaker Page #
NEPHROLOGY
Acute Kidney Injury
1
Sushrut S. Waikar, MD
Chronic Kidney Disease
20
Ajay K. Singh, MBBS, FRCP (UK), MBA
Revisiting Electrolytes and Acid-Base Basics
34
Bradley M. Denker, MD
Proteinuria, Hematuria, and Glomerular Disease
75
Questions and Answers
NA
Nephrology Faculty
Electrolytes and Acid-Base: Challenging Q&A
92
Dialysis and Transplantation
152
J. Kevin Tucker, MD
NA
Nephrology Faculty
Nephrology: Take-Home Messages and Clinical Pearls
189
Nephrology Board Review
205
HEMATOLOGY
Anemia
240
Maureen M. Achebe, MD, MBBS
Hypercoagulable States and New Anticoagulants
271
Jean M. Connors, MD
Bleeding Disorders
297
Elisabeth M. Battinelli, MD, PhD
NA
Hematology Faculty
Hematology Cases: Common, Complex, Rare
335
Nancy Berliner, MD
NA
Hematology Faculty
Board Review in Hematology
364
Nathan T. Connell, MD, MPH
and
Book
HEMATOLOGY
Board Review Practice - 1 - - Images Part I
402
GASTROENTEROLOGY
Esophageal Disorders
424
Walter W. Chan, MD, MPH
Peptic Ulcer Disease
457
John R. Saltzman, MD
Acute and Chronic Pancreatitis
486
Julia Y. McNabb-Baltar, MD
Hepatitis B and C
511
Ming Valerie Lin, MBChB
Chronic Liver Disease and Its Complications
532
Anna E. Rutherford, MD, MPH
NA
Gastroenterology Faculty
Inflammatory Bowel Disease
553
Sonia Friedman, MD
Diarrhea
585
Benjamin N. Smith, MD
Gastroenterology: Take-Home Messages and Clinical Pearls
615
Kunal Jajoo, MD
GI Board Review
627
ONCOLOGY
Oncology: Clinical Pearls
675
Wendy Y. Chen, MD
Leukemia and Myelodysplastic Syndrome
712
Edwin P. Alyea, III, MD
Prostate and Bladder Cancer
737
Lauren C. Harshman, MD
Lung Cancer
772
David M. Jackman, MD
Breast Cancer
794
Wendy Y. Chen, MD
NA
Oncology Faculty
and
Book
ONCOLOGY
Lymphoma and Multiple Myeloma
829
Ann S. LaCasce, MD
Gastrointestinal Cancers
858
Jeffrey A. Meyerhardt, MD
NA
Oncology Faculty
Oncology: Take-Home Messages and Clinical Pearls
891
Ann S. LaCasce, MD
Board Review in Oncology
925
Ann S. LaCasce, MD
CARDIOVASCULAR MEDICINE
2018 Cardiology Overview
946
Leonard S. Lilly, MD
CV Prevention
964
Samia Mora, MD
Acute Coronary Syndrome Management
1008
Marc S. Sabatine, MD
NA
Cardiovascular Faculty
Pulmonary Embolism, DVT and Anticoagulation
1035
Samuel Z. Goldhaber, MD
Valvular Heart Disease
1067
Brendan M. Everett, MD, MPH
Peripheral, Aortic and Carotid Disease
1103
Marc P. Bonaca, MD
NA
Congestive Heart Failure
1133
Anju Nohria, MD
Congenital Heart Disease
1157
Ann M. Valente, MD
NA
Must-Not-Miss ECG Diagnoses
1178
Dale S. Adler, MD
and
Book
CARDIOVASCULAR MEDICINE
Atrial Fibrillation and Common Supraventricular
Tachycardias 1246
Sunil Kapur, MD
NA
Bradycardias, Syncope and Sudden Death
1267
Usha B. Tedrow, MD, MS
Inflammation and CVD
1293
Paul M Ridker, MD
Cardiology: Take-Home Messages and Clinical Pearls
1318
Akshay S. Desai, MD, MPH
Board Review in Cardiology
1344
Garrick C. Stewart, MD
INFECTIOUS DISEASE
Infection in the Immunocompromised Host
1404
Sarah P. Hammond, MD
Tropical Medicine and Parasitology
1428
Tuberculosis for the Non-ID Specialist
1461
Gustavo E. Velasquez, MD, MPH
NA
Infectious Diseases Faculty
Adult Immunization
1493
Lindsey R. Baden, MD
HIV Disease: An Overview
1518
Jennifer A. Johnson, MD
Pneumonia and Other Respiratory Tract Infections
1539
Michael Klompas, MD, MPH
NA
Infectious Diseases Faculty
Infectious Disease: Take-Home Messages and Clinical Pearls
1569
Sexually Transmitted Diseases
1587
Todd B. Ellerin, MD
Infectious Disease Board Review
1617
Todd B. Ellerin, MD
and
Book
WOMEN’S HEALTH
Contraception: An Update
1647
Kari P. Braaten, MD
Medical Complications of Pregnancy
1676
Ellen W. Seely, MD
Screening for and Preventing HPV and Cervical CA
1697
Annekathryn Goodman, MD
NA
Women’s Health Faculty
Menopause
1734
Kathryn A. Martin, MD
Evaluation of the Patient with Menstrual Irregularities
1756
Osteoporosis and Metabolic Bone Disease
1782
Carolyn B. Becker, MD
Women’s Health: Take-Home Messages and Clinical Pearls
1818
Caren G. Solomon, MD
Women’s Health Board Review
1835
Kathryn M. Rexrode, MD
Board Review Practice - 2
1869
David D. Berg, MD
PULMONARY MEDICINE
Pulmonary Overview
1895
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Psychiatry Overview
Acute Kidney Injury
Sushrut S. Waikar, MD, MPH
Constantine L. Hampers, MD Distinguished Chair in Renal Medicine
Associate Professor
Disclosures
None relevant
1
Goals
• Introduction to new terminology, definition
• Incidence, mortality, costs of AKI
• Approach to the patient with AKI
• Specific clinical scenarios
Case
• 64 year old man with HTN, DM, osteoarthritis, BPH
• Presents to ED complaining of nausea, vomiting
• Meds: lisinopril 40 mg/d, metformin 1gm bid, ibuprofen
800 mg tid
• Exam: BP 100/60, HR 104, RR 16
– Lungs clear; CV RRR nl s1 s2, no rub, no JVD
– Abd soft
– Ext no edema
• Labs
134 100 84
5.6 18 3.2*
*283 µmol/L
2
Acute Kidney Injury

or the syndrome formerly known as “Acute Renal Failure”
• “Acute”
Happening within hours to days
• “Kidney”
(more familiar than “Renal”)
• “Injury”
Not always “failure.” Refers to
organ damage…
Defining AKI
“Sudden” rise of > 2.0 mg/dL
> 0.3 mg/dL increase

0.5 mg/dL if < 1.9
1.0 mg/dL if 2.0 – 4.9
1.5 mg/dL if > 4.9
25% increase to at least 2.0 mg/dL within 48h

50% increase to at least 1.4 mg/dL
3
Defining AKI
“Sudden” rise of > 2.0 mg/dL

> 0.3 mg/dL increase
0.5 mg/dL if < 1.9
> 30 different 1.0 mg/dL if 2.0 – 4.9
1.5 mg/dL if > 4.9
definitions in the
nephrology literature
25% increase to at least 2.0 mg/dL within 48h
New consensus definition
• Increase in creatinine
of > 0.3* mg/dL in 48h
OR
• 1.5x baseline in 7d
OR
• Oliguria < 0.5ml/kg/h
x 6h
*26.5 µmol/L
4
AKI is deadly
70% increased odds of death
Chertow, G. M. et al. J Am Soc Nephrol 2005;16:3365-3370
AKI is increasingly common

• 5 to 7% of
admissions, up to
AKI incidence (/100,000 py)
50% of ICU pts

• Between 1988 and
2002: Four-fold
increase in AKI,
six-fold increase in
AKI-D (Waikar JASN 2006)
1Hsu Kidney Int 2007 • Community-based
estimate1: 522 AKI,
30 AKI-D per
100,000
5
AKI is expensive
• 60% increase1 in cost with post-CABG AKI
defined as 50% increase in SCr
• Additional $50002 when SCr increases by

> 0.3 mg/dL (26.5 µmol/L)
• $10 billion annually2
1Dasta et al. Nephrol Dial Transp 2008 2Chertow et al. JASN 2005
Approach to the
patient with AKI
6
Waikar & Bonventre, AKI chapter in Harrison’s Principles of Internal Medicine, 18th ed.
Approach to the
patient with AKI
• Pre-renal
• Intrinsic renal
• Post-renal
7
Check bladder scan,

insert Foley
Renal sonogram or CT
Pearl:
False negative u/s:
• Early obstruction
• Retroperitoneal fibrosis
or tumor (consider
retrograde pyelogram)
Waikar & Bonventre, AKI chapter in Harrison’s Principles of Internal Medicine , 18th edition
Pre-renal azotemia
• Serum creatinine increases due to
renal hypoperfusion
• No structural injury to kidney
• Recovery with restoration of
hemodynamics
Causes
• Hypovolemia
• Decreased cardiac output
• Decreased effective circ. volume
– Congestive heart failure, cirrhosis
• Impaired renal hemodynamics
– NSAIDs, ACE, ARB
Pearl: all NSAIDs including Cox-2 inhibitors;

Both ACE and ARB’s
8
Tubules Intratubular
Small vessels Ischemic ATN, sepsis, Myeloma
endogenous toxins proteins, uric
Glomerulonephritis, vasculitis,
(rhabdo, hemolysis), acid, debris,
TTP/HUS, DIC, atheroemboli,
exogenous toxins acyclovir, MTX.
HTN, sepsis
(contrast, cisplatin,
gent)
Interstitium
Large vessels Allergic (PCN, rifampin)
Renal artery embolus, Infection (severe pyelo,
dissection, vasculitis, Legionella, sepsis)
renal vein thrombosis,
Infiltration (lymphoma,
abdominal compartment
leukemia)
syndrome
Inflammatory (Sjogren’s,
sepsis, tubulointerstitial
nephritis with uveitis)
Waikar & Bonventre, AKI chapter in Harrison’s Principles of Internal Medicine , 18the
Common causes of AKI

Outpatient Inpatient International
• Pre-renal • Medical ICU: • Sub-Saharan
•ACE-I when ATN from sepsis, Africa
vomiting drugs • Malaria (1% of
•ACE-I + NSAID severe cases)
• Cardiac floor: • Diarrhea
• Obstruction contrast, cardiac
• BPH, stones surgery, cardio- • Tropics
renal • Leptospirosis
• SICU: • Others
rhabdomyolysis, • Post-strep GN
sepsis, postop ATN • Crush
syndrome
9
First steps
64M with HTN, DM, OA, BPH.
• Is this acute or chronic In ED with N/V.
Meds: ACE, NSAID, metformin
– Baseline SCr (if available)
Exam: BP 100/60, HR 104,
– Chronic RR 16; unrevealing exam
• Anemia (non-specific)
Labs: BUN 84, Creat 3.2 (283
• Small kidneys (< 8cm) umol/L), K 5.6, Bicarb 18
• “Increased echogenicity”
• How urgent is this?
– Hyperkalemia (K > 6.0, or rising fast)
– Anuria
– Severe hypoxemic respiratory failure
– Intoxication: methanol, ethylene glycol, salicylates,
lithium
Physical examination
• Pre-renal
– Orthostatic hypotension, tachycardia, decreased skin turgor, etc
– Hepato-renal: stigmata of liver disease
– Cardio-renal: signs of heart failure
• Post-renal GFR = 6000 ml/hour
– Palpable bladder. Pearl: normal urine output does not rule it out
• Intrinsic renal UFR = 100 ml/hour
– ATN: nonspecific (volume overload if present)
– Glomerulonephritis: (variable)
– Vasculitis: palpable purpura
– Atheroembolic disease: livedo reticularis, blue toes
– Interstitial nephritis: rash, fever (eos)—only 10% of cases
10
Studies
• Chem 7, BUN, creatinine, Ca, Phos, uric acid, CPK
• CBC with diff
• Renal ultrasound or computed tomography
• Urinalysis
• Urine sediment
• Fractional excretion of Na – pearl… BEWARE exceptions

– Traditional teaching: ATN > 1 or 2%; pre-renal < 1%
– Non-pre-renal with low FeNa: contrast, rhabdo, early sepsis,
obstruction, acute glomerulonephritis
– Pre-renal with high FeNa: diuretic use, pre-existing CKD
Case
64M with HTN, DM, OA, BPH. In ED with N/V.
Meds: ACE, NSAID, metformin
Exam: BP 100/60, HR 104, RR 16; unrevealing exam
Labs: BUN 84, Creat 3.2 (283 µmol/L), K 5.6, Bicarb 18
• Obtain baseline labs: creatinine 1.0 baseline

• Risk stratify: not emergent, but urgent
• Immediate considerations:
– Pre-renal azotemia (NSAID, ACE-I)
– Obstruction (history of BPH)
– Stop the metformin (note gap acidosis)
• Volume challenge, d/c ACE-I and NSAIDs, further evaluation of
obstruction and labs [U/A, urine sediment, FeNa]
• New appreciation of longer-term risks following an episode of AKI, even
if complete recovery
11
Further lab evaluation of

intrinsic AKI
• Pre-renal thought to be unlikely
• Post-renal ruled out
• No good cause for ATN
– No sepsis, surgery, nephrotoxin exposures,
contrast, rhabdomyolysis, tumor lysis,
ingestion, etc.
Further lab evaluation of

intrinsic AKI
• Pre-renal thought to be unlikely
• Post-renal ruled out
• No good cause for ATN
– No sepsis, surgery, nephrotoxin exposures,
contrast, rhabdomyolysis, tumor lysis,
ingestion, etc.
C3, C4 : depressed complements in diffuse GN (post-strep, lupus, cryo)
(also: atheromboli, TTP/HUS, sepsis, liver disease)
ANCA, antiGBM: time is nephrons.
ANA: lupus
LDH, haptoglobin: hemolysis, thrombotic microangiopathy
BIOPSY
12
Patterns of creatinine elevation

• Return to baseline after 48-72 hrs of fluid
replacement: pre-renal azotemia
• Rapid (> 2mg/dL per day) rise:
rhabdomyolysis [anecdotal]
• Rise within 24h, peak within 3-5d, return to
baseline ~1 wk: contrast nephropathy (note
typically non-oliguric)
• Aminoglycosides: rise after 5d therapy (can
be after discontinuation), return towards
baseline over 2-3 weeks (note, nonoliguric)
Complications of AKI
• Volume overload
• Hyperkalemia
• Metabolic acidosis
– GAP: retained anions (phosphate, urate, hippurate,
sulfate)
– NON-GAP: impaired distal H+ excretion
• Hypocalcemia, hyperphosphatemia
• Bleeding from uremic platelets
• Pericarditis
• Long term: increased risk of CKD, ESRD
13
Preventing AKI
• Avoidance of nephrotoxins
• Adequate intravascular volume
• N-acetylcysteine: no evidence for benefit
• Bicarbonate IVF: no benefit for contrast
nephropathy, conflicting data in septic shock
• Furosemide: observational studies suggest
harm, RCT suggests no benefit
– Clinical experience: widespread use
Treating AKI
• Pre-renal: improve hemodynamics
• Post-renal: relieve obstruction
• Intrinsic renal:
– Acute tubular necrosis: no proven therapies
• Specifically, no evidence for dopamine
– Acute interstitial nephritis: withdrawal of
suspected drug, ? Steroids
– Acute glomerulonephritis: (depends on type)
– Scleroderma renal crisis: ACE-inhibitors
14
Renal replacement for AKI

• “Indications”
–A
–E
–I
–O
–U
Renal replacement for AKI

• “Indications”
– Acidosis
– Electrolytes (K+)
– Ingestions (NOT digoxin)
– Overload (fluid)
– Uremia (pericarditis, encephalopathy)
15
Take home
• AKI is common, often deadly
• Pre-renal Post-renal Intrinsic renal
• Indications for dialysis
–A E I O U
• Patterns of creatinine elevation
– Pre-renal, contrast, rhabdo, aminoglycosides
• Beware the common exceptions to FeNa
Case 1
1. A 66-year-old previously healthy man is admitted to the hospital for crushing
substernal chest pain. Vital signs on admission were: blood pressure
126/78, pulse 102 beats per minute, respiratory rate 20 per minute.
Electrocardiogram reveals ST-segment elevation in leads II, III, and avf. He
is treated with aspirin, unfractionated heparin, metoprolol, nitroglycerin, and
captopril, and then taken to the cardiac catheterization laboratory where he
undergoes successful percutaneous coronary intervention of an acutely
occluded right circumflex artery. During the procedure the blood pressure
remained above 120/70, and he remained hemodynamically stable
thereafter. The serum creatinine concentration was 0.7 mg/dL (62 µmol/L)
on admission and rose to 1.4 mg/dL (124 µmol/L) on hospital day 3, when
captopril was discontinued. The serum creatinine rose to 7.8 mg/dL (690
µmol/L) by hospital day 9, when hemodialysis was initiated. Skin
examination was notable for livedo reticularis.
The renal vessels most likely involved in the pathophysiology of his acute
kidney injury are the:
• A) afferent arterioles
• B) efferent arterioles
• C) interlobular veins
• D) interlobar veins
16
Explanation
• This patient’s presentation is consistent with renal
atheroemboli. Angiography is the most common
triggering event, and anticoagulation is also a risk factor.
The clinical course is variable and includes subacute
kidney injury weeks later or severe acute kidney injury.
Urinary findings are relatively non-specific, and heavy
proteinuria is not common. Eosinophilia and
hypocomplementemia may be seen. Cholesterol crystals
lodge in small arteries of 150-200 mm in diameter
(arcuate; interlobular; occasionally afferent arterioles or
glomeruli). The answer is A. The other answers are
post-glomerular vessels which are not involved in
cholesterol embolization.
Case 2
2. A 75 year old man is admitted to the hospital for severe diarrhea for the
past four days. The past medical history is notable for hypertension and
osteoarthritis. His medications included lisinopril 40 mg daily, ibuprofen
800 mg three times daily, and metoprolol 50 mg daily. The physical
examination is notable for BP 100/60, pulse 120 beats per minute, and
decreased skin turgor. Labs show serum creatinine of 4.6 mg/dL (407
µmol/L), potassium 5.8 meq/L, and fractional excretion of Na of 0.4%.
In addition to pre-renal azotemia, the following causes of acute kidney
injury can be associated with a fractional excretion of sodium below
1.0%:
• A) rapidly progressive glomerulonephritis
• B) rhabdomyolysis
• C) contrast nephropathy
• D) none of the above
• E) All of the above (A, B, and C)
17
Explanation
• The answer is E. Although the fractional excretion of
sodium is one of the most commonly ordered tests for
the differential diagnosis of acute kidney injury and is
often presumed to denote pre-renal azotemia, low FeNa
can be seen in a number of other clinical settings. These
include rapdily progressive glomerulonephritis,
rhabdomyolysis, and contrast nephropathy.
References
• Chertow, GM, Burdick, E, Honour, M, Bonventre, JV & Bates, DW:
Acute kidney injury, mortality, length of stay, and costs in
hospitalized patients. J Am Soc Nephrol, 16: 3365-70, 2005.
• Wald, R, Quinn, RR, Luo, J, Li, P, Scales, DC, Mamdani, MM & Ray,
JG: Chronic dialysis and death among survivors of acute kidney
injury requiring dialysis. Jama, 302: 1179-85, 2009.
• Blantz, RC: Pathophysiology of pre-renal azotemia. Kidney Int, 53:
512-23, 1998.
• Friedrich, JO, Adhikari, N, Herridge, MS & Beyene, J: Meta-analysis:
low-dose dopamine increases urine output but does not prevent
renal dysfunction or death. Ann Intern Med, 142: 510-24, 2005.
• Steiner, RW: Interpreting the fractional excretion of sodium. Am J
Med, 77: 699-702, 1984
18
Disclosures
None relevant
19
CKD:
The Story of
my Seventy-Eight Year
Old Patient
Ajay K. Singh, MB, FRCP
Renal Division
Senior Associate Dean,
Postgraduate Medical
Education,
Disclosures
GSK - Consultant
20
Case History
• 78 year old African American man T2D, HTN
• Scr of 1.32 mg/dL. eGFR is >60
ml/min/1.73m2.
• He is otherwise healthy.
• Past medical history - hypertension ≈15
years duration, type 2 diabetes mellitus for
8 year; Hypercholesterolemia treated with
atorvastatin.
• BP-- in the 150-160 mmHg range.
• Medications: lisinopril, ASA,
hydrochlorthiazide, atorvastatin, metformin,
glipizide.
Case History
• PE: BP 152/68 mmHg, HR 72 bpm. Weight
120 kg JVP 8 cm. Rest of the examination
negative.
• Lab values
• Dipstick urinalysis shows SG 1015, pH 6.0, trace
to 1+ alb, rest is negative
• BUN 28, Serum creatinine 1.32 mg/dL, HbA1C
7.8
• Does he have kidney disease?
21
We don’t want to call something a

disease when it isn’t
x
x
Lindeman, R. D., J. D. Tobin, and N. W. Shock. Longitudinal
studies on the rate of decline in renal function with age. J.
Am. Geriatr. Soc. 33: 278–285, 1985.
1. Does he have risk factors for CKD?

• Susceptibility Risk Factors
• Diabetes
• Hypertension
• Older age
• Family history of CKD
• Racial or ethnic minority
• Other: low income, minimal education, kidney-mass
reduction, known kidney disease
Levey et al. Ann Intern Med. 2003;139:137-147..

6
22
The Risk of Kidney Failure Is Not Uniform
Relative risks compared to Whites:
African Americans 4.45 X

Native Americans 3.57 X
Asians 1.59 X
Xue, et al., 2000
2. Obtain laboratory Data

a.) UA dipstick /Sediment
b.) Renal US
23
Is there Proteinuria-Albuminuria?
• Urine Dip a commonly used screening test
• Use ACR for quantification
Result Significance
Negative Unlikely to be proteinuria present
Trace 15-30mg/dL
1+ 30-100mg/dL
2+ 100-300mg/dL
3+ 300-1000mg/dL
4+ >1000mg/dL
Assess albuminuria – ACR
Risk for progression

or CVD
24
3. Evaluate Risk of Kidney Failure

Kidney Failure Risk Equation (KFRE)
Tangri’s laboratory based equation to predict
CKD progression
Accurately predicts CKD stage 3-5 progression
over 5 years (C statistic 0.84-0.91)
3 variable KFRE – Age, Sex, eGFR

4 variable KFRE – Age, Sex, eGFR, ACR
8 variable KFRE + Ca, Phos, Bicarb, alb
Tangri et al JAMA 2011, 2016
Rate of GFR Decline in Normals and CKD

Patients
0 10 20 30 40 50 60 70 80 90 100
1ml/min/year starting at age 45yrs

(normal ageing)
GFR ml/min
≈ 2-3 ml/min/year
ESRD
25 35 45 55 65 75
Age, years
Collister D, http://www.sciencedirect.com/science/article/pii/S027092951630033X
25
Manage Progression factors for CKD?

• Susceptibility • Progression
Risk Factors Factors
• Diabetes • Higher level of
albuminuria
• Hypertension
• Higher BP
• Older age
• Poor glycemic
• Family history of CKD control
• Racial or ethnic • Smoking
minority
• Hyperlipidemia
• Other: low income,
minimal education, • Drug use
kidney-mass reduction,
known kidney disease
Levey et al. Ann Intern Med. 2003;139:137-147.
Algorithm for this 78 year old man

eGFR ml/min/1.73m2
Does he have risk factors?

HTN, DM
High risk group
UA and sediment?
Renal US ACR
Does he have CKD? = YES

NEXT STEPS>>>>
26
Keys to managing patients with CKD
• Screen patients at high risk

• Patients with specific conditions (diabetics, HTN,
metabolic syndrome), Specific populations
(African Americans, Latinos)
• Estimate kidney function, by converting Scr
to eGFR; use UACR to stratify risk
• Treat BP, Manage diabetes
• Use ACEI/ARB, SGLT2 inhibitor (T2D)
• Consider other interventions: low protein
diet, statin
ACEi and ARBs; CCBs

• ACEi and ARB have similar antiproteinuric
effects
• Combination of ACEi and ARB: 20% reduction in
albuminuria – over and above either agent alone
(Addition of Aliskiren to maximum dose of ARB
reduces further albuminuria by 20%)
• Dual blockade not recommended
• CCBs - Strong antihypertensive agents.
• Dihydropyridine CaCBs: No effect on CKD
progression ( in absence of RAAS blockade) eg
amlodipine
• Non-dihydropyridine CaCBs: Reduce albuminuria
(use if RAAS are not tolerated) eg diltiazem
27
What about Combo therapy:

ACEi+ARB? NO…..ONTARGET
• 25,620 patients with either pre-existing vascular disease or
diabetes randomly assigned ramipril, telmisartan, or the
combination of the two
• No hint of benefit for CV endpoint with combination therapy
• Trend toward increased risk of death, 1.07 (0.98-1.16), with
combination therapy
• Many more adverse events
New Eng J Med 2008; 358:1547
•Secondary analysis in 5623 patients with eGFR<60 and/or

albuminuria
•Combination therapy reduced albuminuria over
monotherapy
•Combination therapy significantly increased ESRD or
doubling of Scr (0.79 vs. 0.56 % per year)
Circulation 2011; 123:1098
Nevertheless, multiple BP agents

required
No. of Antihypertensive Agents
Trial Target BP, mm Hg 1 2 3 4
UKPDS DBP <85

ABCD DBP <75
MDRD MAP <92
HOT DBP <80
AASK MAP <92
IDNT <135/ <85
ALLHAT <140/ <90
ABCD=Appropriate Blood Pressure Control in Diabetes; MDRD=Modification of Diet in Renal

Disease; HOT=Hypertension Optimal Treatment ; IDNT=Irbesartan Diabetic Nephropathy Trial;
DBP=diastolic blood pressure; MAP=mean arterial pressure; SBP=systolic blood pressure.
Bakris et al Am J Kidney Dis. 2000;36:646-661; Lewis et al N Engl J Med. 2001;345:851-860;

Cushman et al J Clin Hypertens. 2002;4:393-404.
28
Therapy for Hypertension based on JNC 8

Implement lifestyle interventions
No diabetes and/or CKD Diabetes and/or CKD
Age >60 Age <60 All ages
BP Goal BP Goal BP Goal

<150/90 <140/90 <140/90
Only diabetes Only CKD
Blacks <75 y >75 y

Non-Blacks
Thiazide, ACEi, ARB or CCB Thiazide or CCB ACEi or ARB CCB or Thiazide
alone or in combination alone or in combination
Source: Singh et al, Brigham Intensive Review of Internal Medicine, Oxford University Press 2014
Adapted from James PA et al: Report from the panel members appointed to the Eighth Joint National Committee (JNC 8).
JAMA 2014; DOI:10.1001/jama.2013.284427.
72.2m
32%
103.3m
46%
29
Guideline not based on RCTs

Updates JNC7 not JNC 8
Creates “disease” in ≈30 million Americans
• 32% to 46% of Americans now have HTN
• Those with “pre-hypertension, now hypertension
Integrates cardiovascular risk assessment into BP
management
BP goal same in age>65
SOURCE: Bakris G and Sorrentino M, NEJM Feb 8 2018
Muntner P, Carey RM, Gidding S, et al. Potential US population impact of the 2017
ACC/AHA high blood pressure guideline. Circulation 2018;137:109-118.
Does the SPRINT Study apply to this

patient?....No because SPRINT excluded
diabetics • RCT, N=9361, median FU
3.26 y
• Study population: pts with
SBP>130 and increased
CVD risk but not diabetic
• SBP<120 vs. <140 mmGH
• Cardiovascular composite
(MI, other coronary
syndromes, CHF,
stroke, CVD death)
30
Newer therapy for renal progression in

T2 Diabetics: YES… SGLT2 inhibitors
In clinical trials
• Average baseline HbA1c of about 7.5-8.5%, SGLT2 inhibitors reduced HbA1c by 0.5-1.5%
without inducing hypoglycaemia
• Accompanied by weight loss of 2-3kg, reflecting calorie loss via renal glucose excretion
(loss of 80-85g glucose per day) with initial changes due to altered fluid balance
plateauing at around 6 months
• SGLT2 inhibitor treatment induces an osmotic diuresis – voiding up to an extra
400ml/day, with unchanged natraemia – and a decrease in systolic blood pressure (2-
5mmHg).r
NEJM June 14, 2016

• RCT, N=7020, 590 sites, 42 countries
• Patients with T2D eGFR >30 ml/min/1.73m2
• Empagliflozin (10 or 25 mg/d) or placebo
• 39% reduction in incident or worsening nephropathy (HR 0.61,
P<0.001)
• 44% risk reduction in doubling of serum creatinine
• 55% lower relative risk of initating renal replacement therapy
31
A Change in eGFR over 192 Wk

78
Adjusted Mean eGFR (ml/ min/ 1.73 m2)

76
74
Empagliflozin, 10 mg
72
Empagliflozin, 25 mg
70
Placebo
68
66
Baseline 4 12 28 52 66 80 94 108 122 136 150 164 178 192
Week
No. at Risk
Placebo 2323 2295 2267 2205 2121 2064 1927 1981 1763 1479 1262 1123 977 731 448
Empagliflozin, 10 mg 2322 2290 2264 2235 2162 2114 2012 2064 1839 1540 1314 1180 1024 785 513
Empagliflozin, 25 mg 2322 2288 2269 2216 2156 2111 2006 2067 1871 1563 1340 1207 1063 838 524
No. in Follow-up
Analysis
Total 7020 7020 6996 6931 6864 6765 6696 6651 6068 5114 4443 3961 3488 2707 1703
Wanner C, Inzucchi SE, Lachin JM, et al. Empagliflozin and

progression of kidney disease in type 2 diabetes. N Engl J
Med. DOI: 10.1056/NEJMoa1515920.
Summary
- Use GFR equations and albuminuria to

make diagnosis of CKD
- Use a kidney failure risk equation
- Use ACEi/ARB, but not in combination
- Consider adding SGLT2 inhibitor for T2DN,
but with modest-to-well preserved GFR
- Use multiple agents for BP control
32
References
Wanner C, Inzucchi SE, Lachin JM, et al.
Empagliflozin and progression of kidney
disease in type 2 diabetes. N Engl J Med. DOI:
10.1056/NEJMoa1515920.
Lindeman, R. D., J. D. Tobin, and N. W. Shock.
Longitudinal studies on the rate of decline in
renal function with age. J. Am. Geriatr. Soc. 33:
278–285, 1985.
Levey et al. Ann Intern Med. 2003;139:137-
147..
Collister D,
http://www.sciencedirect.com/science/article/pii
/S027092951630033X
33
Revisiting Electrolytes and Acid-

Base Basics
Bradley M. Denker, MD.
Clinical Chief,
Renal Division, Department of Medicine
Beth Israel Deaconess Medical Center and
Harvard Vanguard Medical Associates
Associate Professor of Medicine
Financial disclosures
No conflict of interest to disclose.
34
Outline
I. Na+ disorders
- Hyper- and hyponatremia
II. K+ disorders
- Hyper- and hypokalemia
III. Acid-base disorders
- General approach
- Metabolic acidosis & alkalosis
Na+ disorders
[Na+]= Amount of Na+/Amount of H2O
Renin/Angiotensin/Aldo ADH
(RAS)
Plasma Osmolality ~ 2x [Na+]

Intracellular: Extracellular (plasma/interstitial):
[K+]=145mEq/L [Na+]=145mEq/L
[Na+]=5mEq/L [K+]=5mEq/L
35
Hypernatremia
Na+/H2O
or
Na+/ H2O
Renal water loss versus other sources
Hypernatremia
UOsm
< 800 mOsm/kg > 800 mOsm/kg

• Renal H2O loss • Insensible H2O loss
• GI H2O loss
+
Diabetes Osmotic
insipidus diuresis ↓ Water intake
• Na+ Intake
CDI NDI Glucose, urea,
ADH ADH mannitol
Deficiency Resistance
36
Nephrogenic diabetes insipidus

Hypokalemia
Hypercalcemia
Tubulointerstitial nephropathies
Sickle cell disease
Myeloma
Obstructive uropathy
Recovery from ATN or obstruction
Lithium
Chronic renal failure
Distinguishing central from nephrogenic DI
Water deprivation test
DDAVP (desmopressin)
↑UOsm No ∆ in UOsm
CDI NDI
37
Management of hypernatremia
Replace free water deficit (50% in first 24 hr,
no more than 0.5 mM/hr)
0.4-0.5 x BW(kg) x (SNa/140-1)
Replace ongoing free water losses

Treat underlying cause
Desmopressin for CDI
No specific Rx for NDI (attempt to reduce urine
output with Na restriction, thiazides or give
supratherapeutic dose of desmopressin)
Hyponatremia
Na+/H2O - Volume Depletion

or
Na+/ H2O - Water Excess;
or Euvolemic
Na+/ H2O - Volume Depletion

+ Hypotonic Fluids
RAS ADH
38
Hyponatremia
Posm
> 290 mOsm/kg Normal < 275 mOsm/kg

“Pseudohyponatremia”
↑Glucose* Lipid ↑ Hypoosmolal

Mannitol hyponatremia*
Protein ↑
*Requires ADH+
*Correct serum Na+ by 1.6
for every 100 mg/dL ∆ in glucose Water Intake
Next Slide
Hypoosmolal hyponatremia
Volume status
Hypovolemic Euvolemic Edematous

Dehydration* Psych. polydipsia† CHF*
Addison’s SIADH Liver failure*
Diuretics Hypothyroid
* UNa < 20 = Extrarenal cause of ECV depletion

†U < 100 = ADH appropriately suppressed
Osm
39
Plasma ADH (pg/mL)
Plasma Osmolality Blood Vol Depletion (%)
Rx of hyponatremia
Hypovolemia Isotonic saline
Polydipsia Water restriction
SIADH Water restriction

Hypertonic saline / Na tablets
Furosemide
Aquaretics (“vaptans”)
40
Rate of correction of hyponatremia

Acute (< 48 hr, usually due to hypotonic fluid
intake) or severely symptomatic
100 mL of 3% saline bolus to increase SNa by
2-3 mEq/L
Chronic (> 48 hr) including SIADH and

asymptomatic
0.5 mEq/l per hour
Do not exceed ∆6-8 mEq/L in 1st day
Osmotic demyelination syndrome

Central and extrapontine myelinolysis
Risk factors :
Excessive rate or amount of correction of serum Na+
Classic CPM presents with dysphagia,

quadriparesis, locked-in syndrome
Can be permanent or fatal
41
Sample board review question 1

A 26 yr-old otherwise healthy male presents with
seizure.
Na 115, K 3.5, Cl 88, CO2 23, BUN 5, Cr 0.7

Urine: Na 30 mEq/L, Osm 45 mOsm/kg
What is the most likely diagnosis:

A. SIADH
B. Hypothyroidism
C. Psychogenic polydipsia
D. Hepatic cirrhosis
E. Adrenal insufficiency
Volume status


Osm
42
K+ disorders
Hyperkalemia
43
Pseudohyperkalemia
Hemolysed blood sample
Leukocytosis/thrombocytosis
Check EKG, whole blood potassium (e.g. blood gas
analyzer)
Hyperkalemia
↑ Intake Cell shift

Metabolic acidosis
Decreased urinary Hyperglycemia
K+ excretion β-blocker
24 hr urine K+ < 40 mEq Digitalis
Hyperkalemic
Next Slide periodic paralysis
Cell lysis
44
Decreased urinary K+ excretion
↓GFR ↓CCD [K+]

Renal
failure Next Slide
Cortical Collecting Duct (CCD)
Lumen Blood
45
↓GFR ↓CCD [K+]

Renal
failure Meds Adrenal Hyporenin
insufficiency hypoaldo
NSAIDs
ACEI/ARB Addison’s
Block Heparin
RAAS Spironolactone Next Slide
Cyclosporine
Block Na+ Amiloride

channel Trimethoprim
Pentamidine
Type IV RTA (hyporeninemic

hypoaldosteronism)
Hyperkalemia (disproportionate to level of GFR)

Non-gap metabolic acidosis with normal urine
acidifying ability
Mild CKD
Often underlying tubulointerstitial disease:
- DM
- SLE, obstruction, myeloma/amyloid, HIV etc.
- NSAIDs
46
Treatment of hyperkalemia
Stabilize membrane excitability
Calcium chloride or gluconate, 1 g IV
Increase K+ entry into cells
Glucose 25 g and insulin 10 U
β2-adrenergic agonist (albuterol 10-20 mg inh)
NaHCO3
Removal of excess K+
Cation exchange resin (Kayexalate)
Diuretics
Dialysis
Dietary K+ restriction
Hypokalemia
47
DDX of hypokalemia
Cellular shift GI cause Urinary K wasting

Alkalemia
Insulin
β-agonist
Hypokalemic periodic
paralysis
Next Slide
Features suggestive of hypokalemic

periodic paralysis
+FH or Asian male with thyrotoxicosis
Precipitated by meal or exercise
Repetitive episodes of acute profound hypokalemia
Recovery of serum K+ within hrs after each episode

without repletion, either spontaneously or with
propanolol
Low urine K+
48
DDX of hypokalemia

Alkalemia Vomiting 24 hr UK > 25 mEq
Insulin Diarrhea Random UK/Creat <
β-agonist 13 mEq/g
paralysis
DDX of hypokalemia

Alkalemia Diarrhea 24 hr UK > 25 mEq
Insulin
β-agonist Vomiting
paralysis
49
Hypokalemia/Renal K+
wasting & hypertension
Renin
AI AII Aldosterone
Substrate Renin Conv Enz
Na+ Abs
K+ Excretion
Renal Hypo-perfusion
HYPERTENSION
Aldosterone
High Low
Renin
High Low
Renal artery Primary Cushing’s

stenosis hyperaldosteronism Liddle's
Reninoma Liquorice ingestion
(very rare)
Renin
AI AII Aldosterone
Substrate
Renin Conv Enz
50
Renal K wasting with normal or low BP
Osmotic Drugs Vomiting RTA Inherited

diuresis tubulopathy
Diuretics Proximal Bartter
Loop & thiazide Classic distal Gitelman
Cisplatin
Aminoglycosides
Ticarcillin Renal NaCl wasting
Amphotericin
Toluene
Use of the urine chloride

In the setting of metabolic alkalosis, urine Cl-
is a more reliable marker of hypovolemia than
urine Na+
Low urine Cl- indicates hypovolemia due to
extrarenal (GI) cause
High urine Cl- in the setting of
hypovolemia/euvolemia suggests renal salt
wasting
51
Cryptogenic hypokalemic metabolic

alkalosis
Volume Urine
Urine Cl-
status/BP diuretics
Hyperaldosteronism ↑ > 40 mEq/L -
Surreptitious
Nl or ↓ < 25 mEq/L -
vomiting
Diuretic abuse Nl or ↓ > 40 mEq/L +
Bartter/Gitelman
Nl or ↓ > 40 mEq/L -
syndrome
Sample board review question 2

A 75 yr-old male with known coronary and peripheral
vascular disease presents with worsening hypertension
despite treatment with HCTZ, amlodipine and
candesartan.
Na 141, K 3.0, Cl 108, CO2 29, BUN 25, Cr 1.9
Which diagnostic test is most likely to be useful?

A. Urine diuretic screen
B. Genetic test for mutations in NKCC2
C. CT scan of the adrenal glands
D. Urine metanephrines
E. Doppler ultrasound of the renal arteries
52
Renin
AI AII Aldosterone
Na+ Abs
K+ Excretion
HYPERTENSION
Acid-base disorders
53
General approach
Approach
1. Is there acidemia or alkalemia?
2. What is the primary process (metabolic

or respiratory, acidosis or alkalosis)?
3. Is there an appropriate compensatory

response?
54
1. Is there acidemia or alkalemia?
Acidemia pH < 7.35
Alkalemia pH > 7.45
2. What is the primary process?

Metabolic
processes
HCO3-
pH = 6.1 + log 0.03 x PCO
2
CO2 + H2O ↔H2CO3 ↔ H+ + HCO3–

Respiratory
processes
55
-
pH HCO3 ; PCO2 Primary disorder
Acidemia ↓ HCO3- Metabolic acidosis
↑ PCO2 Respiratory acidosis
↑ HCO3
-
Alkalemia Metabolic alkalosis
↓ PCO2 Respiratory alkalosis
HCO3-
pH = 6.1 + log 0.03 x PCO
2
3. Is there an appropriate
compensatory response?
Metabolic processes Respiratory processes

Metabolic
acidosis
↓ HCO3-
“Respiratory
alkalosis”
↓ PCO2
56

“Metabolic
acidosis”
↓ HCO3-
Respiratory
alkalosis
↓ PCO2

“Respiratory
acidosis”
↑ PCO2
Metabolic
alkalosis
↑ HCO3-
57

Respiratory
acidosis
↑ PCO2
“Metabolic
alkalosis”
↑ HCO3-
Compensatory mechanisms
Remember the direction of compensation

Remember that compensation is almost
never complete
58
Metabolic acidosis
Metabolic acidosis
Ingestion Endogenous Defective acid Loss of

of acid generation excretion alkali
of acid
59
Metabolic acidosis

of acid
Ethylene glycol Oxalic acid/glycolic acid

Methanol Formic acid
Toluene Hippuric acid
Salicylic acid
Metabolic acidosis

of acid
Lactic acidosis Diabetes mellitus

Ketoacidosis
Alcohol
Rhabdomyolysis
60
Metabolic acidosis

of acid
Renal failure
Distal renal tubular acidosis
Metabolic acidosis

of acid
Diarrhea
Proximal RTA
61
Serum anion gap

[Na+] - ([Cl-] + [HCO3-])
= Unmeasured anions - Unmeasured cations
(Normal range: 8 - 12)
Serum anion gap

[Na+] - ([Cl-] + [HCO3-])
= Unmeasured anions - Unmeasured cations
(Normal range: 8 - 12)
62
High anion gap metabolic acidosis

Glycols (ethylene, propylene (lorazepam)
Oxyproline – paracetamol/women
L-Lactate
D-Lactate – short bowel syndrome
Methanol Mehta et.al,
The Lancet, Volume 372, Issue 9642,
Aspirin
Page 892, 13 September 2008
Renal Failure
Ketosis – starvation, alcohol, diabetic
Anion and osmolal gap in

diagnosis of intoxications
Anion gap
acidosis Osmolal gap
+ Normal Salicylates
Ethanol
Ethylene glycol
+ High
Propylene glycol
Methanol
- High Isopropanol
63
Serum osmolal gap

Osmolal gap = Measured Sosm - Calc Sosm
Calculated Sosm :
2 [Na+] + [glucose]/18 + [BUN]/2.8
Clues to high anion gap acidosis

syndromes
Alcoholic fetor
Papilledema
Osmolar gap
Undetectable serum ethanol
Methanol intoxication
64

syndromes
No fetor
Osmolar gap
Calcium oxalate dihydrate (envelope-
shaped) crystalluria
Urine fluoresces under Wood's (UV) lamp
Ethylene glycol intoxication

syndromes
Tinnitus/deafness
Fever, tachycardia, hyperventilation
Associated respiratory alkalosis and
metabolic acidosis
Salicylate intoxication
65

syndromes
Normal glucose
Serum Acetest/acetoacetate negative or
borderline
Serum β-hydroxybutyrate positive
Serum ethanol may or may not be present
Alcoholic ketoacidosis

syndromes
Didanosine or stavudine use

2 mth - 2 yr after start of Rx
± concurrent tenofovir use
Lactic acid elevated
Type B lactic acidosis 2° to NRTI
66

syndromes
Short bowel syndrome

Episodes of ∆MS associated with AG
metabolic acidosis, after CHO intake
Spontaneous resolution if NPO
Serum lactic acid level negative
D-lactic acidosis

syndromes
ICU patient sedated with high dose

intravenous infusion of lorazepam
Osmolar gap
Elevated serum lactic acid level
Propylene glycol intoxication
67
DDx of a non-gap metabolic acidosis
Diarrhea RTA
(bicarb loss)
I II IV
Classic distal Proximal Hyporeninemic
(bicarb loss) hypoaldosteronism
68
DDx of RTA
Proximal Classic distal Hyporenin
hypoaldo
Serum K Low Low High
Urine pH Variable > 5.5 < 5.5
Other Fanconi (low Nephrocalcinosis
features PO4, glycosuria) ± CaPO4 stones
Causes and Rx of RTA

hypoaldo
Common Ifosfamide Sjogren’s CKD plus:
causes NRTI (tenofovir, SLE DbM
adefovir, cidofovir) Amphotericin Obstruction
Myeloma Sickle cell dz
SLE
NSAIDs
Rx Bicarbonate (lots) Bicarbonate K+ lowering Rx:
(1 mEq/kg/day) Diuretics
Kayexalate
Low K diet
Mineralocorticoid
69
Metabolic alkalosis
Induction of metabolic alkalosis
Ingestion Loss of acid Cellular

of alkali shift
Antacids ↓ K+
GI loss Renal loss
Blood Tx
Vomiting Diuretics
NG suction Bartter/Gitelman
Hyperaldosteronism
70
Maintenance of alkalosis
Requires impairment of renal excretion of
excess bicarbonate:
• Volume contraction (e.g. vomiting, diuretics)

• Hypokalemia
• Renal failure
• Hyperaldosteronism
Changes with Metabolic Alkalosis

Excreted Bicarb exceeds reabsorption
obligate Na/K wasting in the urine
Increased Aldosterone stimulates Na+
reabsorption until no Cl- remaining in urine
Aldo stimulates K+ /H+ ATPase exacerbating
hypokalemia and metabolic alkalosis
71
Changes with Metabolic Alkalosis
UNa+ UK+ UCl- pH

(bicarb)
Day 1-3
>3 days
Correction of Alkalosis Requires Cl-

to Allow HCO3- Excretion
72

alkalosis
Volume Urine
Urine Cl-
status/BP diuretics
Surreptitious
vomiting
Bartter/Gitelman
syndrome
Take Home Messages (1)

Hypo- and Hyper-Natremia are usually water
imbalances;
Volume depletion (Na loss) stimulates RAS
Water depletion (hypersomolality) stimulates
ADH
Potassium Disorders
Most K is intracellular (intake/cellular shift)
Renal K excretion is regulated by GFR; Aldo
and UNa
73
Take Home Messages (2)

Assess pH (emia), PCO2 (Resp) and HCO3-
(metabolic)
Compensation is opposite process and direction
but not to normal pH.
Metabolic Acidosis
Elevated AG; addition of H+ with non-Cl- anion
Normal AG; addition of H+Cl- OR Bicarb loss
(GI or Renal)
Metabolic Alkalosis-vomiting and diuretics
Suggested reading
Rennke, H.G., Denker, B.M., Renal Pathophysiology – The
Essentials, 4th Edition, Lippincott Williams & Wilkins, 2014
Mount, D.B., Fluid and Electrolyte Distrubances. In Harrison's

Principles of Internal Medicine, 18th Edition, Eds. Longo, Fauci, et
al., McGraw-Hill, p. 341-359
DuBose, T.D.,Jr. Acidosis and Alkalosis. In Harrison's Principles of

Internal Medicine, 18th Edition, Eds. Longo, Fauci, et al., McGraw-
Hill,p. 363-373
74
Approach to Proteinuria
and Hematuria
5 Clinical Scenarios Common to the Boards
Ajay K. Singh, MB., FRCP

Physician, Renal Division,
Brigham and Women’s Hospital,
Senior Associate Dean
for Postgraduate Medical Education,
Disclosures
• GSK - Consultant
75
Why Are Proteinuria and

Hematuria Important?
• As markers of kidney disease
• Insight into causality
• Prognostic indicator
Proteinuria
• Albuminuria
– Normal excretion <150 mg/24 h
• 60% is filtered plasma protein (20-40 mg of albumin)
• 40% are glycoproteins -- IgA, uromodulin
– Detected by urine dipsticks (Albustix; Ames or Miles etc)
– Detects >10-15 mg/dL; almost always (+) if urine alb > 30
mg/dL
Dip for protein
– Read-out is colorimetric; false (+) in highly alkaline urine Dip scale
tr 10 -20 mg/dl
– Microalbuminuria = 30-300 mg/24h, or 20-200 µg/min 1+ 30 mg/dl
2+ 100 mg/dl
3+ 300 mg/dl
• Quantitative assays 4+ 1000 mg/dl
poor correlation with
24° urine
– Sulfosalicylic method
• Acid precipitation, detects all proteins, sensitivity 5-10
mg/dL
76
Hematuria
• Presence of three or more red blood cells per high-power field visible
in a properly collected urine specimen without evidence of infection.
• Microscopic hematuria detected incidentally with a prevalence of 2-
31%
• Occurring along with proteinuria – strongly suggests glomerular
process
Hematuria – Major Causes

• Infection • Glomerular
– Pyelo, cystitis – GN eg IgA
• Malignancy – Hereditary
– Renal cell Ca – Thin basement membrane
– Transitional cell Ca – Alport’s
– Prostatic Ca – Vaculitis
• Metabolic/Other – Exercise
– Calculi • Interstitial
– Hypercalciuria – AIN
– Hyperuricosurua – PKD
– Coagulopathy – Papillary necrosis
– Cytoxan • Vascular
– Renal vein thrombosis,
Atheroemboli, Malignant HTN
77
#1 Young patient with routine

dipstick positivity of protein in urine
• A 14-year old young girl is noted to have

proteinuria on dipstick after a urine is sent for
urinalysis and urine c and s.
• The young girl is asymptomatic, except for some
mild frequency, has no past medical history and is
completely normal on physical examination. Wt
52 Kg, BSA 1.0 m2, BP 78/62 mmHg, no edema
• The urine culture is negative. Recheck of UA
shows 2+ protein. Spot protein to creatinine 0.8 g
prot/gram creat
Urine positive for protein
Repeat Twice
Urine transiently Urine remains

Positive for protein positive for protein
Check labs
(esp. BUN/Cr, Alb, UPCR
Routine UA and sed
F/U
Abnormal labs Normal labs Normal labs

>1g UPCR <1g UPCR
Refer to Pediatric Neg Check for Orthostatic

Nephrologist proteinuria
Check complement
ANA, antiDS DNA
Viral serologies, ASLO titer Pos
Renal US
Kidney Biopsy Trial of steroids Annual F/U
78
Orthostatic (Postural) proteinuria

– May be present normally
– Proteinuria < 1g / 24 h
– Commonly seen in adolescents; prevalence 0.6 to 6.3%
(Finish study)
– rare > age 30
– In both sexes, proteinuria increases with age.
– 90% of young men with isolated proteinuria have
“orthostatic” proteinuria; entirely benign
– Most children who test positive for proteinuria on initial
evaluation “lose” the proteinuria at follow-up.
– ≈10 percent of children have persistent proteinuria >6
months
Source: MAHMOUD LOGHMAN-ADHAM M., Am Fam
Physician. 1998 Oct 1;58(5):1145-1152. VEHASKARI VM, Archives of Disease in
Childhood, 1982, 57, 729-730
#2 Middle age person, type 1 diabetic

(x12 years), noticed to have
albuminuria
Ms. R is a 39-year old African American woman
with T1DM, HTN, atrial fibrillation on Coumadin.
Asymptomatic.
ROS- patient active, feels energetic
Medications: Coumadin, amlodipine, atorvostatin
BP 112/65 mmHg, HR 97 bpm,
NA 144, K 3.9, CL 110, CO2 24, BUN 17, CRE
0.70, EGFR 128 ml/min/1.73m2,
mAb 80 mg/g cre; Trace to 1+ prot in UA dip.
79
Natural History
Diabetic Nephropathy: KW nodules
80
Diabetic Kidney Disease

• Commonest cause of ESRD in West
• 45% of all U.S. patients with ESRD
• Screen annually for microalbuminuria in:
Type 1 diabetic patients who have had diabetes >5
years
Type 2 diabetic patients when diagnosis made.
– Test for urinary albumin excretion
Albumin to creatinine ratio (ACR)
Timed collection (e.g., 12 or 24 h) of albumin
concentration
• To reduce risk and/or slow progression of nephropathy
– optimize glucose control.
– optimize blood pressure control
– Use ARB or ACEi
Screen for MA in Diabetic Patient is positive

(repeat twice)
Urine transiently >30 mg AB

Positive for protein on UACR
Routine
F/U
MAB 30-300 mg AB >300 mg
NL Cr
Glycemic control
Manage BP
1. Glycemic control ACEi/ARB
HbA1C<7.5% T1DM age<19 or elderly AND REFER TO NEPHROLOGY
HbA1C<7% for adults
2. Manage BP <140/90 Work up
3. ACEi or ARB Typical Atypical
Manage as High Risk Patient Kidney Biopsy
81
#3 Patient with hematuria, RBC casts

and rapid loss in kidney function
• A 24-year old hairdresser from Cape Cod is
admitted with oliguria. Has a 2 day history of tea
colored urine, headaches, and feelling unwell. 1-
day history of coughing up blood and dyspnea.
• Examination 150/95 mmHg, HR 110 bpm,
afebrile, O2 sat 91% on air, reduced air entry in
lung bases.
• Labs: BUN 58 mg/dL, creatinine 2.9 mg/dL, Hb
10.2 g/dL, WBC 6.2, plats 286,000. UA 4+ bl 2+
prot, no leuks; sediment 30-60 dysmporhic RBCs,
1-2 RBC casts, 2-4 WBCs/HPF.
Glomerular Syndromes
• Nephritis: Hypertension, Azotemia,
proteinuria, hematuria, RBC casts /
dysmorphic RBCs
• Nephrosis: edema, proteinuria,
hypoalbuminemia, lipid abnormalities
• RPGN: rapid renal failure, crescents on
renal biopsy + nephritis
• Isolated urinary abnormalities: hematuria /
proteinuria
82
Pulmonary Renal Syndrome
• Main Causes
– Anti GBM Disease: Goodpasture’s
– ANCA associated vasculitis
• Granulomatosus with polyangiitis (Wegener’s)
• Microscopic polyarteritis (MPA)
• Churg Strauss
– Immune complex mediated
• Lupus nephritis
• Cryoglobulinemia
• HSP nephritis
Dysmorphic RBCs and Red Cell Cast
83
Anti-GBM Nephritis
Goodpasture’s Syndrome
• Uncommon: incidence 0.1 cases/million
• 1-2% of renal biopsy specimens
• Slight preponderance in males
• Age 1st to 9th decade
• More common in whites over African-American’s
• Year-round presentation, ? Spring and summer
• 50-75% have upper respiratory prodrome,
– plus fever, rash, myalgias, malaise, headache, weight
loss
• Renal presentation with RPGN - proteinuria but usually not
nephrotic, hypertension uncommon
• US - normal size kidneys
Pathologic Features of
Anti-GBM Nephritis
84
Treatment
• Treatment without methylprednisone and plasmaphereis
– 89% progress to death or dialysis; only 10% improved
• Treatment with pulse steroids, plasmapheresis, and Cytoxan
– standard-of-care
– 50% improve
– Protocol
– Pulse methylpred 1 g QD x 3 d, 1-1.5 mg/Kg prednisone
– Cyclophosphamide 3 mg/Kg/d (reduced dose in older patients, or
if GFR < 10) > 2 months
– Plasma exchange daily 4 L with albumin replacement (or FFP if
pulmonary hemorrage present) x 14 d or until ab goes away
• Patients with serum creat of >7.0 respond to treatment
– 75% with Scr <7 respond, 8% with Scr > 7 respond
– Generally no improvement in patients on dialysis
#4 19-year old white male and his military

physical
• 19-year white male is evaluated as part of health

screening for his military physical.
• Healthy asymptomatic
• One prior episode of gross hematuria, resolved
spontaneously after 3 or 4 days. Not referred
• PE normal
• UA 2+ blood, no protein, 5-10 red cells (dysmorphic) in
urine microscopy
• Biopsy considered – done
– IgA nephropathy
85
IgA nephropathy
• Epidemiology
– Most common cause of nephritis in the world (15 to 40% of
primary GN in world, 20% of primary GN in USA)
– Males > Females (2:1)
– Peak occurrence in 2nd & 3rd decades
– Asian predominance (up to 40% of biopsies compared with 20%
in European/U.S. registries)
• Clinical
– Synpharyngitic (24 to 48 hrs after URI or GI infection -- in
contrast with post-infectious nephritis 1 to 3 weeks)
– Low grade fever, loin pain
– Serum IgA levels elevated in ~50% (Test for elevated serum IgA
not diagnostic)
– Spectrum of microscopic hematuria + albuminuria to RPGN
– Can be with or w/o Henoch-Schonlein Purpura (HSP)
• Children: gross hematuria after URI
• Adults: microscopic hematuria and/or proteinuria
IgA: Therapeutic Options
• No Treatment
• Treatment
– ACEi/ARB
– Glucocorticoids
– Fish Oils
– Tonsillectomy
– Immunosuppressives
• Azathioprine + steroids
• Cyclophosphamide + steroids
• Mycophenolate mofetil
86
#5 Teenager with sudden onset face

swelling, LE edema and nephrotic
proteinuria
• 17-year white male high school student develops sudden
onset of facial swelling, LE swelling, frothy urine.
Otherwise completely asymptomatic. One week before
presentation he had a bee sting on his forearm.
Examination normal BP. 2 Kg increase in weight, swollen
eye-lids, lips, face, anasarca
• Renal function Bun 14 mg/dL, Creat 0.5 mg/dL,. serum
albumin 2.8 g/dl, total cholesterol 315 mg/dl, triglycerides
68 mg/dl, LDL cholesterol 228 mg/dl.
• UACR - 16 g alb/g cre.
Nephrotic Syndrome
• Proteinuria (> 3.5g/d) (>2 g/d is usually

glomerular origin proteinuria)
• Hypoalbuminemia (< 3 g/dL)
• Hyperlipidemia
• Lipiduria
• Edema
• Bland urine or fatty casts/ free fat / oval fat
bodies
87
Urinalysis: key features
NS: Etiology
Primary Causes Secondary Causes
• Medications
• Membranous – Gold, NSAIDs, Interferon -
alfa, Heroin, Captopril,
• Focal Segmental GS • Allergens
(FSGS) – Bee Sting, Pollen
• Minimal Change Disease • Infections
– Bacterial, Viral, Helminth
• IgA • Cancer
– Solid: Lung, colon, stomach
– Leukemia, Hodgkins,
ovarian
• Autoimmune Diseases
• Metabolic Diseases
• Pregnancy
88
Normal and Minimal Change Disease

A: Normal B: MCD
Minimal changes of glomeruli

– basic characteristics
1. Full blown nephrotic syndrome with selective
proteinuria
2. Rarely presence of hematuria, hypertension,
or renal insufficiency
3. Absence of glomerular abnormalities on LM
an IF.
4. Typical picture of damage of epithelial cells
(fusion of foot processes) in EM
89
Swelling/edema/UA pos for protein
Check labs
esp. BUN/Cr, Alb, UA,
UACR
Abnormal labs
Refer to
Nephrology
>2 g UACR
Abnormal labs Otherwise Normal labs
Further W/U Trial of steroids

For MCD
Partial response or
No response Remission
Kidney Biopsy Or remission-then-relapse
after 16 w therapy Routine F/U
Summary/Conclusion
• 6 clinical scenarios
• Proteinuria and Hematuria - GN of different
causes and different age groups
Painting by Sir Luke Fildes.
90
References
• Source: MAHMOUD LOGHMAN-ADHAM M.,
Am Fam Physician. 1998 Oct 1;58(5):1145-
1152. VEHASKARI VM, Archives of Disease in
Childhood, 1982, 57, 729-730
91
ELECTROLYTE AND ACID BASE:

Challenging Questions and Answers
Bradley M. Denker, MD.
Clinical Chief,
Renal Division, Department of Medicine
Beth Israel Deaconess Medical Center and
Harvard Vanguard Medical Associates
Bradley M. Denker
No conflict of interest to disclose.
92
Case 1
A 35 year-old man with bipolar disorder treated on lithium,
is referred to you for chronic polyuria and polydipsia. He
complains that he has to void once every hour.
Laboratory studies:
Serum sodium 146 mEq/L
Blood urea nitrogen 35 mg/dL
Serum creatinine 1.9 mg/dL
Serum osmolality 305 mOsm/kg
24-hr urine volume 5L
Urine sodium 28 mEq/L
Urine osmolality 190mOsm/kg
Case 1
Which of the following might be appropriate in the
management of this patient?
(A) Discontinue lithium
(B) Demeclocycline
(C) Vasopressin V2 receptor antagonist
(D) Fluid restriction
(E) Furosemide
Choices B-E are all potential treatment options for

Hyponatremia but will worsen hypernatremia
93
Hypernatremia
UOsm

• GI H2O loss
• Na+ intake
DI Osmotic
diuresis +
CDI NDI Glucose, urea, ↓ Water intake
mannitol
Nephrogenic diabetes insipidus

Hypokalemia
Hypercalcemia
Tubulointerstitial nephropathies
Sickle cell disease
Myeloma
Obstructive uropathy
Recovery from ATN or obstruction
Lithium
Chronic renal failure
94
Distinguishing central from nephrogenic DI
Water deprivation test
DDAVP (desmopressin)
↑UOsm No ∆ in UOsm
CDI NDI
Replace free water deficit (50% in first 24 hr,
no more than 0.5 mM/hr)
0.4-0.5 x BW(kg) x (SNa/140-1)

No specific Rx for NDI (attempt to reduce urine
output with Na restriction, thiazides or give
supratherapeutic dose of desmopressin)
95
Case 1
Which of the following might be appropriate in the
(A) Discontinue lithium
(B) Demeclocycline; interferes with ADH action in
collecting duct-increased water excretion
(C) Vasopressin V2 receptor antagonist-blocks

V2 receptor and ADH action in collecting duct-
increased water excretion
(D) Fluid restriction; more free water needed

(E) Furosemide; blocks ability to concentrate urine;
dilute urine output
Case 2
An 85 year-old woman, who lives alone, fell in her bedroom and
broke her hip. She was unable to get up and had no access to
water. She was found 2 days later and brought into the ER. On
examination, she is drowsy but responsive. The blood pressure
is 103/51 mm Hg, pulse rate 90 per minute, weight 70 kg,
mucous membranes are very dry and skin turgor is decreased.
Laboratory studies:
Hematocrit 56%
Urine osmolality 820 mOsm/kg
96
Case 2
All of the following statements are correct except:
A. She has intracellular fluid volume depletion
B. Appropriate initial fluids would be 0.45% NaCl
C. Her serum Na+ should be lowered to a target of 152
mEq/L in the next 24 hours
D. Overly rapid correction of her hypernatremia could
cause osmotic demyelination syndrome
E. Correction of her hypernatremia could cause
cerebral edema
Hypernatremia
UOsm

• GI H2O loss
• Na+ intake
DI Osmotic
diuresis
+
CDI NDI Glucose, urea, ↓ Water intake
mannitol
97
Replace free water deficit (50% in first 24 hr, no
more than 0.5 mM/hr)
Risk is cerebral edema due to synthesis of organic
osmolytes; CPM seen with rapid increase in Na+

No specific Rx for NDI (attempt to reduce urine output
with Na restriction, thiazides or give supratherapeutic
dose of desmopressin)
Rapid Increased Rapid Decreased

Na Na
Osmotic Demyelination Cerebral Edema

160
120
H2O H2O
Sterns, N Engl J Med 2015;372:55-65.
98
Case 2
All of the following statements are correct except:
A. She has intracellular fluid volume depletion-Yes,
appears volume and water depleted
B. Appropriate initial fluids would be 0.45% NaCl-Yes,
both salt and water depleted; water>Na so
hypotonic replacement
C. Her serum Na+ should be lowered to a target of 152
mEq/L in the next 24 hours-Ok; 0.5mEq/h~12
D. Overly rapid correction of her hypernatremia could
cause osmotic demyelination syndrome - Incorrect
E. Correction of her hypernatremia could cause
cerebral edema – Correct
Case 3
A 64 year-old woman with coronary artery disease, multiple prior
MI and ischemic cardiomyopathy, with a LV EF of 15%, is
admitted with pulmonary edema. Her medications include
aspirin, metoprolol, furosemide, spironolactone, digoxin,
isosorbide dinitrate, and lisinopril. On examination, the blood
pressure is 97/54 mm Hg, pulse rate 85 per minute, jugular
venous pressure 9 cm, moist mucous membranes, lungs with
diffuse inspiratory crackles, heart with an S3 gallop, and cool,
clammy extremities with 1+ peripheral edema.
Serum sodium 128 mEq/L Blood urea nitrogen 46 mg/dL

Serum potassium 3.6 mEq/L Serum creatinine 1.2 mg/dL
Arterial pH 7.48
Serum chloride 87 mEq/L
Serum bicarbonate 34 mEq/L
99
Case 3
Urine electrolytes (6 hrs after last diuretic dose):
Urine chloride < 5 mEq/L
Case 3
All of the following might be appropriate in the
management of this patient EXCEPT:
(A) Intravenous 0.9% saline
(B) Restriction of free water intake
(C) Dietary sodium restriction
(D) Dobutamine
(E) Acetazolamide
100
Hyponatremia
Posm


Mannitol Protein ↑ hyponatremia
*Correct serum Na+ by 1.6 for every 100 mg/dL ∆ in glucose

Next Slide
Volume status

Dehydration* CHF*
Addison’s UOsm Nephrotic*
Diuretics Liver failure*
> 100 < 100 Renal failure
SIADH Polydipsia
Hypothyroid
101
Intravascular Volume Depletion Will

Predominate Over Hypo-osmolality
Underfilled Arterial
Circulation
Case 3
All of the following might be appropriate in the
(A) Intravenous 0.9% saline; NO will worsen CHF
(B) Restriction of free water intake; Yes, will reduce
hypo-osmolar hyponatremia
(C) Dietary sodium restriction; Yes, will reduce volume

expansion and reduce LVEDP
(D) Dobutamine; Yes, Β-agonist will increase C.O.

(E) Acetazolamide; Yes, CA inhibitor; Prox Tubule
inhibition of Na reabsorption
102
Case 4
A 45 year-old male smoker presents with confusion and
drowsiness. His only medications are bronchodilator and
steroid inhalers. On examination, his BP is 125/86, HR 78,
moist mucous membranes, good skin turgor, jugular venous
pressure 4 cm, lung fields clear to auscultation, no peripheral
edema. Chest radiograph shows emphysematous changes
but is otherwise normal. Laboratory studies:
Urine potassium 78 mEq/L
Case 4
Appropriate steps in the management of this
patient might include:
(A) Order serum protein and lipid panel
(B) Computed tomography scan of the chest
(C) Psychiatry consult for psychogenic
polydipsia
(D) Administer thiazide diuretic
(E) Order echocardiogram
103
Hyponatremia
Posm


Mannitol Protein ↑ hyponatremia

Next Slide
Volume status

Dehydration* CHF*
SIADH Polydipsia
Hypothyroid
104
Case 4
Appropriate steps in the management of this patient
might include:
(A) Order serum protein and lipid panel; this is
pseudohyponatremia
(B) Computed tomography scan of the chest

(C) Psychiatry consult for psychogenic
polydipsia; would expect appropriately dilute
urine
(D) Administer thiazide diuretic; no effect on urine

dilution; Na loss will worsen hyponat
(E) Order echocardiogram; No evidence for CHF
Case 5
A 45 year-old woman with hypertension and type 2
diabetes mellitus presents with leg swelling. Her
medications are insulin, amlodipine, enalapril,
furosemide, aspirin.
Laboratory studies:
Serum potassium 6.2 mEq/L
24 hr urine total protein 4.8 g
105
Case 5
All of the following could be contributing to this
patient's hyperkalemia EXCEPT:
(A) Enalapril
(B) Decreased glomerular filtration rate
(C) Type 4 renal tubular acidosis
(D) Renal artery stenosis
(E) Excess dietary K intake
Renin
AI AII Aldosterone
Na+ Abs
K+ Excretion - Hypokal
HYPERTENSION
106
Aldosterone
High Low
Renin
High Low

Liquorice ingestion
Hyperkalemia

Metabolic acidosis
Hyperkalemic
periodic paralysis
Cell lysis
107
↓Tubular flow ↓CCD [K+]
Renal ↓ECV Meds Adrenal Hyporenin

failure insufficiency hypoaldo
NSAIDs
Block Heparin 1° hypoaldo
RAAS Spironolactone
Cyclosporine
Amiloride
Block Na+
Trimethoprim
channel
Pentamidine
Type IV RTA (hyporeninemic

hypoaldosteronism)
Hyperkalemia (disproportionate to level of GFR)

Non-gap metabolic acidosis with normal urine
acidifying ability
Mild CRF
Often underlying tubulointerstitial disease:
- DM
- SLE, obstruction, myeloma/amyloid, HIV etc.
- NSAIDs
108
Case 5
All of the following could be contributing to this
patient's hyperkalemia EXCEPT:
(A) Enalapril; RAS inhibitor, increased K

(B) Decreased glomerular filtration rate;K
excretion depends on GFR
(C) Type 4 renal tubular acidosis
(D) Renal artery stenosis; causes HypoK; activated
RAS
(E) Excess dietary K intake; major cause of
increased K; Total Intracellular K ~
145x28L~4000mEq; Total Extracellular~14Lx4~60
2gms K ~ 50mEq
Case 6
A 20 year-old man, with no past medical history and on no
medications, presents with a one week history of fatigue,
nausea, vomiting, diarrhea and acute abdominal pain. On
examination, BP is 80/60, HR 110, temperature 99.8°F.
The abdomen was diffusely mildly tender.
Laboratory studies:
Serum glucose 52 mg/dL
24 hr urine potassium 5 mEq/L
109
Case 6
Which one of the following tests would be most
likely to reveal the underlying cause of the
hyperkalemia?
(A) Blood digoxin level

(B) Serum creatine kinase
(C) ACTH stimulation test
(D) Blood glycosylated hemoglobin level
(E) Iothalamate GFR test
Hyperkalemia

Metabolic acidosis
Hyperkalemic
periodic paralysis
Cell lysis
110
↓Tubular flow ↓CCD [K+]
Renal ↓ECV Meds Adrenal Hyporenin

failure insufficiency hypoaldo
NSAIDs
Block Heparin
RAAS 1° hypoaldo
Spironolactone
Cyclosporine
Block Na+ Amiloride

Pentamidine
Volume status


Osm
111
Case 6
Which one of the following tests would be most
likely to reveal the underlying cause of the
hyperkalemia?
(A) Blood digoxin level; inhibits Na/K ATPase and

can lead to increased K
(B) Serum creatine kinase; elevated levels seen
with rhabdomyolysis and increased K
(C) ACTH stimulation test
(D) Blood glycosylated hemoglobin level;
hyperglycemia associated with K shift out of cells
(E) Iothalamate GFR test; reduced GFR
predisposes to hyperkalemia
Case 7
An 18 year-old female presents with acute muscle
weakness. She has had several previous episodes that
resolved spontaneously. BP 96/54. Rest of the exam was
unremarkable.
Laboratory studies:
Serum sodium 135 mEq/L 24 hr urine studies:
Serum potassium 2.9 mEq/L Sodium 80 mEq/d
Serum chloride 99 mEq/L (range 50-150mEq)
Serum bicarbonate 28 mEq/L Potassium 105 mEq/d
Blood urea nitrogen 8 mg/dL (range 50-100mEq/d)
Serum creatinine 0.5 mg/dL Chloride 150 mEq/Ld
112
Case 7
Which one of the following diagnoses are
compatible with this clinical picture?
(A) Gitelman’s syndrome

(B) Primary hyperaldosteronism
(C) Surreptitious amiloride use
(D) Surreptitious laxative abuse
(E) Hypokalemic periodic paralysis
DDX of hypokalemia
Cellular shift GI loss Urinary K wasting

Alkalemia Vomiting* 24 hr UK > 25 mEq
Insulin Diarrhea
β-agonist
paralysis
*Also renal K+ wasting
113

Cisplatin
Aminoglycosides
Ticarcillin
Amphotericin
Toluene

alkalosis
Volume Urine
Urine Cl-
status/BP diuretics
Surreptitous
vomiting
Bartter/Gitelman
syndrome
114
Case 7
Which one of the following diagnoses are
compatible with this clinical picture?
(A) Gitelman’s syndrome

(B) Primary hyperaldosteronism; Hypokalemia +
HTN
(C) Surreptitious amiloride use; K sparing diuretic;
expect low urine K and high serum K
(D) Surreptitious laxative abuse; causes low K but
urine K should be very low
(E) Hypokalemic periodic paralysis; cellular K
shifts, urine K not elevated
Case 8
A 74 year-old woman diagnosed with hypertension at the
age of 40 presents with worsening blood pressure control
over the past 3 years. She is now on amlodipine, lisinopril,
hydrochlorothiazide, atenolol and clonidine. Her current BP
is 156/78.
Laboratory studies:
Plasma renin activity 8.5 ng/mL/hr (Normal range 1-6)
Plasma aldosterone 24 ng/dl (Normal range 5-20)
115
Case 8
Which of the following tests would be the most
appropriate next step?
(A) Computed tomography scan of the adrenal

glands
(B) Dexamethasone suppression test
(C) Urine diuretic screen
(D) Doppler ultrasound of the renal arteries
Aldosterone
High Low
Renin
High Low

Reninoma Liquorice ingestion
(very rare)
Renin
AI AII Aldosterone
Substrate
Renin Conv Enz
116
Case 8
(A) Computed tomography scan of the adrenal

glands; hyperaldo causes HTN and low K but
renin should be suppressed
(B) Dexamethasone suppression test; Rule out
Cushing’s but aldo usually normal/low
(C) Urine diuretic screen; not typical scenario/
taking diruetic
(D) Doppler ultrasound of the renal arteries
Case 9
A 28 year-old man is found unconscious in the street and
brought into the emergency room. No medical history is
available. His blood pressure is 120/75 mm Hg, respiratory
rate 12 per minute. He appears dishevelled and is comatose
and responsive only to pain. His pupils are reactive to light
and he has a non-focal neurological examination. No fetor is
noted. He is intubated, undergoes gastric lavage, and
activated charcoal is adminstered via a nasogastric tube.
Serum glucose 75 mg/dL Next page →
117
Case 9
Serum ethanol None detected

Acetest Negative
Serum β-hydroxybutyrate Negative
Serum lactate < 1 mmol/L
Serum salicylate None detected
Serum creatine kinase 10 mU/mL
Arterial blood studies on room air:

pH 7.22
PCO2 24 mm Hg
Case 9
The most appropriate next step in the
management of this patient is:
(A) Dopamine
(B) Hemodialysis
(C) Forced alkaline diuresis
(D) Thiamine
(E) Fomepizole
Blocks alcohol dehdyrogenase
which normally converts ethylene
glycol to glycolic acid and
methanol to formic acid
118
Brent; NEJM 360;21, 2009
Case 9
pH 7.22, PCO2 24 mm Hg, HCO3 10 mEq/L
Primary metabolic acidosis
Predicted PCO2 from Winter's formula = (1. 5 x {HCO3-}) + 8

= 23
Respiratory compensation is appropriate
Na 132 mEq/L, Cl 98 mEq/L
Anion gap = 132 - 98 - 10 = 24 (normal 8-12)
Anion gap metabolic acidosis
∆AG = 24 - 10 = 14
∆HCO3 = 24 - 10 = 14
∆/∆ = 14/14 = 1
Pure anion gap metabolic acidosis
119
Serum osmolal gap

Calculated Sosm :
2 [Na+] + [glucose]/18 + [BUN]/2.8
(2 x 132) + (75/18) + (32/2.8) = 280

Osmolal gap = 308 - 280 = 28 (normal < 10)
Anion and osmolar gap in diagnosis

of intoxications
Anion gap
Ethanol
Ethylene glycol
+ High
Propylene glycol
Methanol
- High Isopropanol
120

syndromes
Alcoholic fetor
Papilledema
Osmolar gap
Undetectable serum ethanol
Methanol intoxication

syndromes
No fetor
Osmolar gap
Calcium oxalate dihydrate (envelope-
shaped) crystalluria
Urine fluoresces under Wood's (UV) lamp
Ethylene glycol intoxication
121
Case 9
The most appropriate next step in the
management of this patient is:
(A) Dopamine; not indicated

(B) Hemodialysis; likely will be needed; takes time to
initiate
(C) Forced alkaline diuresis; indicated for
salicylates; no utility for alcohol toxicities
(D) Thiamine; Vitamin B1; deficient in alcoholics
(E) Fomepizole; inhibits alcohol dehdyrogenase to
reduce toxic producsts
Case 10
An 18 year-old female is brought in with change in
mental status and suspected toxic ingestion. Her blood
pressure is 100/73 mm Hg, pulse rate 89, respiratory
rate 40, temperature 100.5°C. She vomited once in
the emergency room and is poorly responsive.
Laboratory studies:
Serum glucose 62 mg/dL Next page →
122
Case 10
Acetest Negative
Serum lactate 1.8 mmol/L

pH 7.39
PCO2 25 mm Hg
Case 10
Which of the following treatments would be most
likely to be effective in the management of this
patient?
(A) Breathe into a bag

(B) Insulin drip
(D) 5% dextrose
(E) Fomepizole
123

syndromes
Tinnitus/deafness
Fever, tachycardia, hyperventilation
Associated respiratory alkalosis and
metabolic acidosis
Salicylate intoxication
Case 10
Primary metabolic acidosis, & probably respiratory alkalosis
Predicted PCO2 from Winter's formula = (1. 5 x 16) + 8 = 32

Concomitant respiratory alkalosis

Anion gap = 142 - 102 - 16 = 24 (normal 8-12)
Anion gap metabolic acidosis
∆AG = 24 - 10 = 14
∆HCO3 = 24 - 16 = 8
∆/∆ = 14/8 = 1.8
Vomiting induced metabolic alkalosis:bicarb higher
than expected for degree of elevation of AG
124
Serum osmolal gap

Calculated Sosm :
2 [Na+] + [glucose]/18 + [BUN]/2.8
(2 x 142) + (62/18) + (21/2.8) = 295

Osmolal gap = 295 - 295 = 0
Anion and osmolar gap in diagnosis

of intoxications
Anion gap
Ethanol
Ethylene glycol
+ High
Propylene glycol
Methanol
- High Isopropanol
125
Lipid
Permeable
Two benefits of alkalinization:

Increasing pH favors HS moving out of brain cell
Increasing urine pH favors salicylate excretion into the urine
(Increase urine pH from 6.5 to 8.1; 5x greater excretion)
Case 10
Which of the following treatments would be most
likely to be effective in the management of this
patient?
(A) Breathe into a bag; increasing PCO2 will

worsen acidosis
(B) Insulin drip; used for DKA
(D) 5% dextrose; no benefit
(E) Fomepizole; inhibits alcohol dehydrogenase
126
Case 11
A 35 year-old male with HIV infection is maintained on
HAART therapy, with his most recent regimen being
raltegravir (INSTI), tenofovir (NRTI) and emtricitabine
NRTI). He has been doing well, but on a routine clinic visit
was found to have abnormal chemistries.

Serum potassium 2.8 mEq/L Serum glucose 91 mg/dL
Serum chloride 109 mEq/L Serum calcium 8.8 mg/dL
Serum bicarbonate 18 mEq/L Serum phosphate 1.8 mg/dL
Urinalysis: Specific gravity 1.015, pH 6, trace protein, 3+

glucose, no blood, leukocyte esterase negative
Case 11
Which of the following would be the most
appropriate next step in the management of this
patient?
(A) Stool microbiology and colonoscopy

(B) Discontinue tenofovir
(C) Discontinue raltegravir
(D) Send autoantibody panel
(E) Magnetic resonance imaging of the adrenal
glands
127
Case 11
HCO3 18 mEq/L, no ABG
Probable metabolic acidosis

Anion gap = 135 - 109 - 18 = 8 (normal 8-12)
Non-gap metabolic acidosis
128
Diarrhea RTA
(bicarb loss)
I II IV
Classic distal Proximal Hyporeninemic
(bicarb loss) hypoaldosteronism
Case 11
HCO3 18 mEq/L, no ABG
Probable metabolic acidosis

Anion gap = 135 - 109 - 18 = 8 (normal 8-12)
Non-gap metabolic acidosis
Urine pH 6 is inappropriately high

Renal tubular acidosis, Type I or II
Hypokalemia, hypophosphatemia, glycosuria with

normoglycemia
Fanconi syndrome, most likely with Type II (proximal) RTA
129
DDx of RTA
hypoaldo
Serum K Low Low High
Urine pH Variable > 5.5 < 5.5
Other Fanconi (low Nephrocalcinosis
features PO4, glycosuria) ± CaPO4 stones
Causes and Rx of RTA

hypoaldo
Common Ifosfamide Sjogren’s CKD plus:
causes NRTI (tenofovir, SLE DbM
adefovir, cidofovir) Amphotericin Obstruction
Myeloma Sickle cell dz
SLE
NSAIDs
Rx Bicarbonate (lots) Bicarbonate K+ lowering Rx:
(1 mEq/kg/day) Diuretics
-tenofovir disoproxil fumarate
Kayexalate
(TDF); newer alafenamide (TAF) is
Low K diet
effective at 1/30th dose so less renal
toxicity anticipated Mineralocorticoid
130
Case 11
appropriate next step in the management of this
patient?
(A) Stool microbiology and colonoscopy;

diarrhea leads to non-gap acidosis but intact
renal acidification (urine pH-6)
(B) Discontinue tenofovir
(C) Discontinue raltegravir; not associated with
RTA
(D) Send autoantibody panel; consider for distal RTA
and Sjogren’s syndrome
(E) Magnetic resonance imaging of the adrenal
glands; hyperaldo should cause HTN
Case 12
A 47 year-old female with known peptic ulcer disease
presents with a 3 day history of epigastric pain, profuse
vomiting and inability to tolerate oral fluids. On examination,
she is in moderate pain. Blood pressure is 88/42, pulse rate
97, and mucous membranes are dry.
Serum lactate 8.3 mmol/L
pH 7.65 PCO2 38 mm Hg
131
Case 12
Which of the following best describes the acid-
base disorder in this patient?
(A) Metabolic alkalosis and respiratory acidosis

(B) Metabolic alkalosis and respiratory alkalosis
(C) Metabolic alkalosis, respiratory acidosis and
respiratory alkalosis
(D) Metabolic alkalosis, respiratory alkalosis and
metabolic acidosis
(E) None of the above
Case 12
Metabolic Alkalosis
132
Induction of metabolic alkalosis
Ingestion Loss of acid Cellular

of alkali shift
Antacids ↓ K+
GI loss Renal loss
Blood Tx
Vomiting Diuretics
NG suction Bartter/Gitelman
Hyperaldosteronism
Case 12
Metabolic Alkalosis
PCO2 - 0.6-0.7mm/1Meq change in bicarb or
16(0.6)=9.6 so predicted PCO2~50mmHg
Lack of respiratory compensation indicates
Respiratory Alkalosis:
Anion gap = 124 - 65 - 40 = 19 (normal 8-12)
Lactate level = 8.3 mmol/L
Superimposed anion gap Metabolic Acidosis (lactic

acidosis)
133
Case 12
Which of the following best describes the acid-
base disorder in this patient?
(A) Metabolic alkalosis and respiratory acidosis

(B) Metabolic alkalosis and respiratory alkalosis
(C) Metabolic alkalosis, respiratory acidosis and
respiratory alkalosis
(D) Metabolic alkalosis, respiratory alkalosis and
metabolic acidosis
(E) None of the above
Case 13
22 year-old male with no past medical history
presents with confusion. His serum sodium is 106
mEq/L, serum osmolality 240 mOsm/kg, urine sodium
45 mEq/L and urine osmolality 40 mOsm/kg.
Select the best option (A-E) for treatment of the

serum sodium.
(A) 0.9% NaCl

(B) 3% NaCl
(C) Free water restriction
(D) Hydrocortisone
(E) No treatment
134
Volume status

Dehydration* CHF*
< 100 Renal failure
> 100
SIADH Polydipsia
Hypothyroid
Case 14
52 year-old female with chronic obstructive pulmonary
disease and 2 month history of worsening dyspnea
presents with a seizure. On examination she appears
confused. BP 125/90, HR 74, mucous membranes moist,
no peripheral edema. Her serum sodium is 110 mEq/L,
serum osmolality 251 mOsm/kg, urine sodium 150 mEq/L
and urine osmolality 710 mOsm/kg.
Select the best option (A-E) for treatment of the serum
sodium.
(A) 0.9% NaCl
(B) 3% NaCl
(D) Hydrocortisone
(E) No treatment
135
Volume status

Dehydration* CHF*
< 100 Renal failure
> 100
SIADH Polydipsia
Hypothyroid
Rate of correction of hyponatremia

Acute (< 48 hr, usually due to hypotonic fluid
intake) or severely symptomatic (seizures)
100 mL of 3% saline bolus to increase SNa by
2-3 mEq/L
Chronic (> 48 hr) including SIADH and

asymptomatic
0.5 mEq/l per hour
Do not exceed ∆8-10 mEq/L in 1st day
136
Case 15
67 year-old male with fatigue and low back pain. Serum
values were: sodium 124 mEq/L, glucose 76 mg/dL, total
protein 13 g/dL, albumin 3.6 g/dL, hemoglobin 9 g/dL.

sodium.
(A) 0.9% NaCl

(B) 3% NaCl
(D) Hydrocortisone
(E) No treatment
Hyponatremia
Posm


Mannitol hyponatremia*
Protein ↑
* Requires
ADH+ Water
Intake
137
Case 16
45 year-old male with diabetes mellitus, hypertension and
ischemic cardiomyopathy maintained on aspirin, carvedilol,
captopril, glipizide and furosemide. On examination, BP is
135/94, HR 80, mucous membranes moist, jugular venous
pulsations are visible to the angle of the jaw, and there is 3+
pitting edema of the legs and thighs. His serum sodium is
123 mEq/L, urine sodium 10 mEq/L and urine osmolality
570 mOsm/kg.
sodium.
(A) 0.9% NaCl
(B) 3% NaCl
(D) Hydrocortisone
(E) No treatment
Volume status

Dehydration* CHF*
SIADH Polydipsia
Hypothyroid
138
Case 17
43-year-old man with Type II diabetes mellitus,
hypertension, congestive cardiac failure, nephrotic-range
proteinuria, peripheral edema and a serum creatinine of
1.6 mg/dl. His serum potassium has been in the range of
5.3-5.6 mEq/L since starting captopril, despite adhering to a
potassium-restricted diet.

potassium.
(A) Thiazide diuretic

(B) Hydrocortisone
(C) Insulin
(D) Hemodialysis
(E) Sodium polystyrene sulfonate
Sites of action of natriuretics

Distal convoluted tubule (5-10%)
Thiazide diuretics
Proximal tubule Cortical collecting duct

(60-70%) (1-3%)
Osmotic diuretics K+-sparing diuretics
Carbonic anhydrase inhibitors
Thick ascending limb
(20-30%)
Loop diuretics
139
Loop and thiazide diuretics cause K+

wasting and alkalosis
↑NaCl
↓TALH Na+ ↑ Na+ ↑ K+ & H+
delivery to
reabsorption reabsorption secretion
CCD
Case 18
88-year-old woman who had partial sigmoid colectomy for
perforated diverticular abscess and septicemia two days
previously, and has been anuric since the operation. Her
serum potassium is 6.5 mg/dL but there are no
electrocardiographic changes.
Select the best option (A-E) for treatment of their serum

potassium.

(B) Hydrocortisone
(C) Insulin
(D) Hemodialysis
140
Hyperkalemia

Metabolic acidosis
Hyperkalemic
periodic paralysis
Cell lysis
↓GFR ↓CCD [K+]

Renal
NSAIDs
Block Heparin
RAAS Spironolactone
Cyclosporine
Block Na+ Amiloride

Pentamidine
141
Treatment of hyperkalemia
Stabilize membrane excitability
Calcium chloride or gluconate, 1 g IV
Increase K+ entry into cells
Glucose 25 g and insulin 10 U
β2-adrenergic agonist (albuterol 10-20 mg inh)
NaHCO3
Removal of excess K+
Cation exchange resin (Kayexalate)
Diuretics
Dialysis
Dietary K+ restriction
Case 19
18-year-old man with no prior medical history who presents
with one week of polyuria and polydipsia.
Labs:
Na 132, K 5.9, Cl 91, HCO3 16, BUN 30, Cr 1.2, glucose 330

potassium.

(B) Hydrocortisone
(C) Insulin
(D) Hemodialysis
142
Hyperkalemia

Metabolic acidosis
Hyperkalemic
periodic paralysis
Cell lysis
Case 20
26-year-old woman with acquired immune deficiency
syndrome, fatigue, weight loss, low-grade fever, and
orthostatic hypotension. Na-129; K-5.9
Serum cortisol level:
Baseline at 8 a.m. 7 µg/dL (nl 5-24 µg/dL)
30 minutes after 250 µg cosyntropin i.m. 10 µg/dL
60 minutes after 250 µg cosyntropin i.m. 11 µg/dL
potassium.
(B) Hydrocortisone
(C) Insulin
(D) Hemodialysis
143
↓GFR ↓CCD [K+]

Renal
NSAIDs
Block Heparin
RAAS Spironolactone
Cyclosporine
Block Na+ Amiloride

Pentamidine
Case 21
For the following cases of hypokalemic metabolic alkalosis,
select the most likely cause (A-E):
16-year-old girl with amenorrhea, body mass index of 13,

and a urine chloride concentration of 5 mEq/L.
(A) Diuretic use

(B) Surreptitious vomiting
(C) Hypokalemic periodic paralysis
(D) Gitelman’s syndrome
(E) Conn’s syndrome
144

alkalosis
Volume Urine
Urine Cl-
status/BP diuretics
Surreptitious
vomiting
Bartter/Gitelman
syndrome
Case 22
35-year-old man presenting for the first time with new-onset

hypertension.
(A) Diuretic use

(E) Conn’s syndrome (hyperaldosteronism)
145
Aldosterone
High Low
Renin
High Low

Liquorice ingestion
Cortical Collecting Duct (CCD)
H+
Lumen Blood
146
Case 23
32-year-old woman with a history of bulimia. Random urine

chloride concentrations on three separate clinic visits were
40, 67 and 26 mEq/L.
(A) Diuretic use


alkalosis
Volume Urine
Urine Cl-
status/BP diuretics
Surreptitious
vomiting
Bartter/Gitelman
syndrome
147
Case 24
15-year-old girl with recurrent episodes of muscle weakness

since childhood and a urine chloride concentration is
65 mEq/L and 24 hour urine K+ is 60 mEq. Her brother has
had similar symptoms.
(A) Diuretic use


Cisplatin
Aminoglycosides
Ticarcillin
Amphotericin
Toluene
How Can One Distinguish Bartter/Gitelman?
Urinary Calcium is Low with Na+Cl-
Cotransporter Inhibition (Thiazides)
148
Case 25
For the following cases of hypokalemia, select the most
likely cause (A-E):
20-year-old man with thyrotoxicosis and recurrent episodes

of muscle weakness after meals.
(A) Diuretic use

Features suggestive of hypokalemic

periodic paralysis
+FH or Asian male with thyrotoxicosis
Precipitated by meal or exercise
Repetitive episodes of acute profound hypokalemia
Recovery of serum K+ within hrs after each episode

without repletion, either spontaneously or with
propanolol
Low urine K+
149
Case 26
All of the following drugs can result in
Hypomagnesemia EXCEPT:
A. Ranitidine
B. Furosemide
C. Hydrocholorthiazide
D. Omeprazole
E. Gentamicin
PPI’s and Hypomag

Several large studies show association of
Hypomag with long-term PPI use (>1 year) or
If concurrently taking diuretics
GI mechanism of inhibition of GI TRP channel;
Renal losses low (FeMg<2%) consisent with non-
renal losses
Safety warning issued by FDA in 2011
Resolves with discontinuation of drug
Danziger et al., Kidney Int 2013; 83:692.
150
Suggested reading
Rennke, H.G., Denker, B.M., Renal Pathophysiology – The
Essentials, 4th Edition, Lippincott Williams & Wilkins, 2014
Mount, D.B., Fluid and Electrolyte Distrubances. In Harrison's

Principles of Internal Medicine, 18th Edition, Eds. Longo, Fauci, et
al., McGraw-Hill, p. 341-359
DuBose, T.D.,Jr. Acidosis and Alkalosis. In Harrison's Principles of

Internal Medicine, 18th Edition, Eds. Longo, Fauci, et al., McGraw-
Hill,p. 363-373
151
Dialysis and Transplantation

J. Kevin Tucker, M.D.
Chief of Nephrology
Brigham and Women’s/Faulkner
Hospital
Disclosures
• None
152
Outline
• Scope of the problem
– Demographics
• Preparing the patient for renal
replacement
• Hemodialysis
• Peritoneal dialysis
• Transplantation
Renal replacement therapy

• General nomenclature used to
designate the forms of therapy to
replace kidneys that no longer are
adequate to maintain life
– Hemodialysis
– Peritoneal dialysis
– Transplantation
153
Trends in the incidence rates of ESRD in the U.S. population
Data Source: Reference Table A.2(2) and special analyses, USRDS ESRD Database
2017 Annual Data Report

Volume 2, Chapter 1
Trends in the number of ESRD prevalent cases by

modality
Data Source: Reference Table D.1. Abbreviation: ESRD, end-stage renal disease

Volume 2, Chapter 1
154
Trends in adjusted prevalence of ESRD by race
Data Source: Reference Table B.2(2) and special analyses, USRDS ESRD Database

Volume 2, Chapter 1
Indications for dialysis

• Acid-base disturbances
• Electrolyte abnormalities
• Ingestions
• Fluid Overload
• Uremia
– Nausea/Vomiting
– Anorexia
– Dysgeusia
– Pruritus
– Pericarditis
155
Renal replacement decision tree
RRT No RRT
Transplant
Dialysis
Home Incenter
Renal replacement decision tree
Home
Incenter
PD Home
hemo
156
If dialysis is chosen
• Conservative (non-dialysis) therapy may
be appropriate in some patients
– No increase in survival and no
improvement in quality of life in frail elderly
who are started on dialysis
• Create a vascular access or place a
peritoneal dialysis catheter
• Manage metabolic complications
• Manage nutrition
What is the ideal time to initiate

dialysis?
• Trend towards earlier dialysis start, i.e.,
at a higher GFR through 1990’s and mid
2000’s
– Are outcomes better with earlier starts?
– Earlier starts driven by a factor that is not
GFR-dependent, for example, volume
control?
157
Trends in initiation of dialysis:

Dialysis initiated at higher GFRs over period of
1997-2007
O’Hare AM et al Arch Intern Med. 2011;171(18):1663-1669
The IDEAL Study
Cooper BA et al. N Engl J Med 2010;363:609-619
158
Kaplan–Meier Curves for Time to the Initiation of

Dialysis and for Time to Death
Cooper BA et al. N Engl J Med 2010;363:609-619
Incremental Dialysis
• Does every patient need the same
dialysis prescription irrespective of
residual kidney function?
• An incremental approach to dialysis
initiation takes into account residual
kidney function
– 1-2 days per week of HD
– 1-2 exchanges per day with CAPD
159
Putative benefits of incremental

initiation
• Better quality of life
• Preservation of residual kidney function
– Fewer hypotensive events and less
ultrafiltration lead to prolonged
preservation of native kidney function
– Native kidney function confers a survival
benefit
Hemodialysis
160
Essential Components of
Hemodialysis Procedure
• Dialyzer
• Dialysate
• Access to circulation
Hemodialysis
• Hemodialysis is a two-step procedure:
– Diffusion/Convection
– Ultrafiltration
161
Diffusion and Ultrafiltration
Dialyzers
• Most commonly used
dialyzers in the US are
hollow-fiber dialyzers.
• Dialyzer shell is a tube with
four ports.
• Two ports communicate with
the blood compartment, and
two ports communicate with
the dialysate compartment.
• Blood flows through the
fibers, and dialysate around
the outside.
162
Dialysate Composition (mEq/L)

Sodium 135-145
Potassium 0-4.0
Calcium 2.5-3.5
Magnesium 0.5-0.75
Chloride 98-124
Acetate 2-4
Bicarbonate 30-40
Dextrose 11
Hemodialysis vascular access types
• AV fistula
• AV graft
• Catheter
– Tunneled
– Non-tunneled
163
AV fistula
• The preferred vascular access
• Fewer interventions needed to maintain
patency
• Fewer infectious complications
• Tradeoff:
– More primary failures
– More patients initiating with catheters
AV grafts
• More interventions required to maintain
patency
• Higher infection rates
164
AV fistula
The AV Graft
165
Fistula First Initiative
Catheters
• Least desirable
vascular access
• Greater infection
risk
• Pro-inflammatory
166
Outpatient hemodialysis
• Once the patient is started on HD, he/she is
referred to an outpatient unit, usually closet to
his/her home.
167
Complications of hemodialysis
• Vascular access complications
– Thrombosis
– Infection
• Hypotension
• Cramping
• Air embolism
• Hemolysis
Vascular access infection

• Infection is the second leading cause of
death in ESRD patients.
• Catheters are the vascular access type
most associated with infections.
• Catheter-related bacteremia may be
due to Gram positive or Gram negative
organisms.
• Nasal carriage of Staph aureus is a risk
factor.
168
Catheter-associated bacteremia
treatment
• Removal of the catheter and treatment
with systemic antibiotics is the gold
standard
• Other approaches
– Catheter exchange with guidewire plus
systemic antibiotics
– Systemic antibiotics plus an antibiotic lock
Knowledge Check (Audience

Response)
The preferred vascular access for
hemodialysis in a 26-year-old man with
ESRD due to glomerulonephritis is:
A) AV graft
B) Tunneled catheter
C) AV fistula
D) Non-tunneled catheter
169
Peritoneal dialysis
Physiology of PD
• The peritoneal membrane can serve as
a diffusive surface for solutes to move
from areas of high concentration to low
concentration
• An osmotic gradient for fluid removal
(ultrafiltration) is provided by glucose.
170
Composition of dialysate
Volume 2, 2.5, 3L most commonly for CAPD
6L for APD
Sodium 132 mEq/L
Potassium 0
Glucose 1.5, 2.5, 4.25 g/dL
Calcium 2.5, 3.5 mEq/L
Magnesium 0.5-1.5 mEq/L
Lactate 35-40 mEq/L
171
Types of PD
• CAPD = Continuous ambulatory
peritoneal dialysis
– Manual exchanges
• CCPD = Continuous cycling peritoneal
dialysis
– Use of an automated cycler with a long
daytime dwell
Education affects Choice

National Average Patients’ Choice after
Thorough Education
100% 60%
80% 50%
40%
60%
30%
40%
20%
20% 10%
0% 0%
PD HD PD HD
Patients more likely to choose PD when provided thorough

education on treatment options.
4. Renal Data Review, Nephrology News and Issues, Sept. 1997
5. Stephenson, Kerry RN and Rosalie Villano, “Results of a Pre-
Dialysis Education Program,” Dialysis and Transplantation, Sept. 1993
172
Utilization of PD in the United

States
• PD is underutilized in the United States
– About 8% of all dialysis patients
• When pre-dialysis modality education is
provided, more patients will choose PD.
• PD patients report greater quality of life
and greater satisfaction with therapy
Barriers to utilization of PD
• Patient factors
– Lack of knowledge about PD
– “I’m afraid.”
– Poor social supports
– Technical problems, e.g., limited
manual dexterity
– Aging patient population
173
Barriers to utilization of PD
• Physician factors
– Lack of knowledge
– Concerns about
• Adequacy
• Infection
• Ultrafiltration
• Mortality
Complications of PD
• Peritonitis
– The leading cause of transfer from PD to
HD.
• Hydrothorax
• Hemoperitoneum
• Encapsulating peritoneal sclerosis
174
Clinical Signs and Symptoms

of Peritonitis
• Fever
• Abdominal pain
• Abdominal tenderness/rebound
• Cloudy effluent
• Nausea/vomiting
Laboratory studies
• Effluent cell count
– WBC > 100/uL with 50% PMNs
• Effluent Gram stain
• Effluent culture
• Blood cultures
175
Treatment of peritonitis
• Bacterial peritonitis
– Intraperitoneal antibiotics (vancomycin +
ceftazidime, for example)
– Catheter removal if infection does not clear
• Fungal peritonitis
– Prompt catheter removal
– Systemic anti-fungals
Prevention of peritonitis
factor.
• Daily application of a topical antibiotic
reduces episodes of peritonitis and exit-
site infection
– Mupirocin
– Gentamicin
176
Knowledge check (Audience

Response)
Which of the following is the leading
cause of modality change from peritoneal
dialysis to hemodialysis?
A) Exit site infection
B) Membrane failure
C) Peritonitis
D) Encapsulating peritoneal sclerosis
Kidney transplantation
• The optimal form of renal replacement
• Limited by organ availability
• Organ sources:
– Living related donors
– Living unrelated donors
– Deceased donors
• Extended criteria donors
177
Medical evaluation of the transplant

recipient
• Kidney recipients require
multidisciplinary team evaluation:
– Surgeon
– Nephrologist
– Social worker
– Pharmacist
– Psychiatrist
Medical evaluation
• Cardiovascular disease
• Malignancies
• Infections
– HIV
– Hepatitis B
– Hepatitis C
– Syphilis
– CMV
– EBV
178
Immunosuppression for
kidney transplantation
Glucocorticoids Block cytokine synthesis
Weight gain, hyperglycemia,
cataracts osteoporosis
Azathioprine Inhibits purine biosynthesis
Major interaction with allopurinol
Mycophenolate Selective effect on lymphocyte
replication
GI side effects
Cyclosporine Calcineurin inhibitor
Gingival hyperplasia
Hypertension
Hirsutism
Tacrolimus Calcineuin inhibitor
Diabetes
Hypertension
Neurotoxicity
Immunosuppression for
kidney transplantation
Sirolimus mTOR inhibitor
Bone marrow
suppression
Hyperlipidemia
Monoclonal antibodies Block activated T-cells
(basiliximab and expressing IL2 receptor
daclizumab)
Polyclonal antibodies Non-specifically block T-
(ATGAM and cells
thymoglobulin)
179
Drugs/susbtances that alter

cyclosporine metabolism
Increase level of cyclosporine Decrease level of cyclosporine
Diltiazem Barbiturates
Verapamil Phenytoin
Nicardipine Carbemazepine
Amlodipine Isoniazid
Ketoconazole Rifampin
Fluconazole
Erythromycin
Clarithromycin
Grapefruit juice
Infectious complications post-

transplant
• First month
– Surgical wound infections
– Urinary tract infections
– Catheter-related bacteremia
180

transplant
• 1-6 months
– CMV
– EBV
– Pneumocystis jiroveci
– Nocardia
– Listeria monocytogenes
– Prophylaxis with TMP-SMX, dapsone,
valgancyclovir

transplant
• After 6 months
– Infectious risk decreases as
immunosuppression is reduced.
– CMV disease may occur late
• Fever
• Leukopenia
• Malaise
• Allograft dysfunction
181
Non-infectious complications
of kidney transplantation
• Cardiovascular disease
• NODAT
• Malignancies
– Skin cancer
– Cervical cancer
• Post-transplant lymphoproliferative
disorder
Knowledge check (Audience

Response)
Pneumocystis jiroveci infection occurs most
commonly in kidney transplant patients during
which time period?
A) The first month post-transplant
B) 1-6 months post-transplant
C) 6-12 months post-transplant
D) 5-10 years post-transplant
182
Summary
• Renal replacement options for the patient
with advanced CKD include transplantation,
hemodialysis, and peritoneal dialysis.
• Conservative (non-dialytic) treatment may be
appropriate for some patients with advanced
CKD.
• Preparation for renal replacement shoud
include the timely placement of a vascular
access or PD catheter.
Summary
• The AV fistula is the preferred vascular
access for hemodialysis.
factor for infectious complications in
both hemodialysis and peritoneal
dialysis.
• Peritonitis is the leading cause of
transfer from HD to PD.
183
Summary
• Kidney transplantation is the optimal
form of renal replacement but limited by
organ availability.
• Infections, cardiovascular disease,
diabetes, and malignancies are
complications of transplantation for
which patient should be monitored.
Question 1
• A 52-year-old man with ESRD
secondary to diabetes is maintained on
an immunosuppressive regimen of
cyclosporine, mycophenolate mofetil,
and prednisone. He develops post-
transplant hypertension. Which of the
following antihypertensive medications
may affect cyclosporine levels?
184
Question 1
• A. Losartan
• B. Enalapril
• C. Amlodipine
• D. Hydrochlorothiazide
Question 1
• The correct answer is C. Of the choices
given, amlodipine is the only one that
increases cyclosporine levels.
185
Question 2
• A 23-year-old woman with lupus
nephritis has progressed to stage 4
CKD despite aggressive treatment with
cytotoxic agents. A recent kidney
biopsy has shown advanced fibrosis.
Her BMI is 30 kg/m2. All of the following
are true with respect to renal
replacement options EXCEPT:
Question 2
• A. She should be educated regarding
hemodialysis, peritoneal dialysis, and
transplantation.
• B. She should be encouraged to lose weight
prior to renal transplantation.
• C. Her obesity excludes her as a candidate
for peritoneal dialysis.
• D. She should be referred to a vascular
surgeon for immediate creation of an AV
fistula is her renal replacement choice is HD.
186
Question 2
• The correct answer is C. She should be
educated regarding all renal
replacement options. If HD is her
choice, she needs an AVF. She should
be encouraged to lose weight since
weight gain and diabetes are common
after transplantation. However, obesity
is not a contraindication to PD.
References
• Bernardini et al 2005, J Am Soc Nephrol
16:539-545
• Konner K et al 2003, J Am Soc Nephrol
14: 1669-1680
• Mehrotra et al 2006, Kidney Int 68: 378-
390
• Silkensen 2000, J Am Soc Nephrol 11:
582-588
187
Disclosures
• None
188
Take Home Messages

IRIM 2018
Ajay K. Singh, MB., FRCP

Physician, Renal Division,
Brigham and Women’s Hospital,
Senior Associate Dean for Postgraduate
Medical Education,
Disclosures
GSK - Consultant
189
Clinical Scenarios In General Nephrology

• #1 CKD-Anemia
– 62-year-old woman with CKD and anemia
• #2 CKD-Hyperkalemia
– A 44-year old patient with CKD who has a K of 7.2
mEq/L
• #3 ADPKD
– 42-year old patient with known ADPKD inquiring
about ways to slow progression of PKD
• #4 Kidney Stones
– 37-year-old man. After a few twinges over past 2
months, presents with 2 hours of excruciating pain in
left groin
#1 62-year-old woman with CKD and

anemia
62-yo white woman with 10-year history of CKD

from diabetes; slowly worsening renal function.
Past medical history of a right CVA stroke. She
sees you in the office. Feels great. Working,
exercising, eating well. Lab data shows BUN 48
mg/dL, Cr 4.2 mg/dL, eGFR 18 ml/min/1.73m2, Hb
9.1 g/dL, Tsat 30%, ferritin 282.
190
Anemia Treatment in Dialysis

and Non-Dialysis Patients
• Target range - Hb 10-11 g/dL
• Make sure patient is iron replete
• TSAT >20%, Ferritin >100
• Use an ESA (2 ESA’s in US – Epo or
Darbepoietin
• Be cautious with ESA treatment in patients with
a history of stroke and/or cancer
TREAT Composite Endpoints
Pfeffer MA et al. N Engl J Med. 2009;361:2019-2032.
191
Fatal and Nonfatal Stroke

50
Darbepoetin alfa 101 (5.0%)
Patients With Events (%)
Risk of stroke doubles among

40 Placebo 53 (2.6%)
Patients on ESA with a h/o prior
Stroke (Skali, et al Circulation 2011)
30
HR: 1.92 (1.38–2.68)
20 P<0.001
10
0
0 6 12 18 24 30 36 42 48
Months
Pfeffer MA et al. N Engl J Med. 2009;361:2019-2032.
CHOIR Study: Hb 13 vs. 11.3 g/dL

in non-dialysis CKD patients
30%
125
Randomized Treatment
Hemoglobin Target 13.5 g/dL
Hemoglobin Target 11.3 g/dL
25%
97
Kaplan-Meier Failure Estimate (%)
Hazard ratio 1.337 (1.025, 1.743)

20% P= 0.0312
15%
10%
5%
0%
0 6 12 18 24 30 36
Months from Randomization
715 587 457 270 101 55 0
717 594 499 293 107 44 3
Primary Composite Endpoint:
Death, MI, CHF hosp (no RRT) and/or stroke
Singh AK et al. N Engl J Med. 2006;355:2085-2098.
192
CHOIR: Higher risk of Death

and CHF
Death 65 deaths CHF Hospitalization (where RRT
20% 20%
did not occur)
p = 0.0674
Hazard ratio 1.483 p = 0.0727
15% 15%
(0.969, 2.268) Hazard ratio 1.409
(0.967, 2.054)
10% 10%
5% 5%
0% 0%
0 6 12 18 24 30 36 0 6 12 18 24 30 36
Stroke Myocardial Infarction

20% 20%
p = 0.9803 p = 0.7836
15% Hazard ratio 1.010 15% Hazard ratio 0.915
(0.454, 2.249) (0.484, 1.729)
10% 10%
5% 5%
0% 0%
0 6 12 18 24 30 36 0 6 12 18 24 30 36
Months from Randomization Months from Randomization
Randomized Treatment Hemoglobin Target 13.5 g/dL Hemoglobin Target 11.3 g/dL
Singh AK et al. N Engl J Med. 2006;355:2085-2098.
ESAs Currently in Use in the U.S.
Source: Fishbane S et al, 2013

http://www.nephrologynews.com/articles/109496-choice-of-erythropoiesis-stimulating-agent-in-esrd
193
#2 A 44-year old patient with CKD who

has a K of 7.2 mEq/L
• A 44-year old woman with a history of stage 4

CKD is noted to have a serum K of 7.2 mEq/L.
She denies N, V and diarrhea. No new
medications
• On physical examination. Wt 72 Kg, BP 141/62
mmHg, Heart and lung examination normal,
no edema.
• EKC – see next slide….
ECG Changes of hyperkalemia
http://www.aafp.org/afp/2006/0115/p283.html
Peaked T waves
P wave wide and flat
Prolonged QRS interval with bizarre QRS morphology, High-grade AV block with slow
junctional and ventricular escape rhythms, Conduction block (bundle branch blocks,
fascicular blocks)
(Development of a sine wave appearance (a pre-terminal rhythm))
194
Causes of Hyperkalemia
• Increased intake
– K+ supplements, diet, transfusions, iatrogenic
• Decreased renal excretion
– Renal disease, particularly with type IV RTA
– DRUGS (e.g., potassium-sparing diuretics (eg,
spironolactone, triamterene, amiloride; NSAIDs)
– Adrenal insufficiency
• Intra → extracellular shifts
– Hyperosmolarity
– Insulinopenia
– Metabolic acidemia
– DRUGS (e.g., beta-blockade)
• Artifactual
– in vitro hemolysis, leukocytosis, thrombocytosis
– “pseudohyperkalemia”
Management of Hyperkalemia as an
Outpatient
K< 5.5 mEq/L K 5.5-6.0 mEq/L K>6.0 mEq/L
No structural CVD disease Do EKG Emergency treatment

Chronically on high side Hold K raising meds
Hold K raising meds Do EKG
Treat with resin If EKG changes
Recheck Ca gluconate
Then Insulin/Dex/resin
Structural CVD disease dialysis
Do EKG No EKG Changes

Hold K raising meds Recheck K
Diet Insulin/dextrose/resin
Treat with resin Diet
195
Treatment of Hyperkalemia
Mechanism Therapy Dose Onset Duration
Stabilize membrane Calcium 10% Ca-gluconate, 1-3 min. 30-60
potential 10 ml over 10 min. min
Cellular K+ uptake Insulin 10 U R with 50 ml 30 min. 4-6 h
of D50, if BS<250
β2-agonist nebulized albuterol, 30 min. 2-4 h

10 mg
+
K removal Kayexalate 30-60 g PO hours ?
ZS9 5-10 g PO hours
Hemodialysis Immediate
• ZS-9 is an inorganic cation exchanger with a high
selectivity for potassium
• Binds nine times as much potassium as Kayexalate, an
organic polymer resin.
• ZS-9 comes as a fine powder that dissolves in water
and is tasteless.
Bicarb
Blumberg et al, Am J Med, 85, 1988
196
Changes in plasma K during IV infusion of

bicarbonate in HD patients
Values= means + SE
*P<0.5, + P<0..01 vs. baseline
Blumberg et al KI, 41: 369-374, 1992
Kayexalate/SPS Complications
• Ischemic colitis and colonic necrosis
- ↑risk in enema form
- often fatal
- ↑ risk with sorbitol - but can occur without sorbitol and is
associated with intestinal SPS crystals
- post-transplant and post-op patients at ↑ risk
• Volume overload
• Reduction in serum calcium
• Iatrogenic hypokalemia
197
#3 42-year old patient with known ADPKD

inquiring about ways to slow progression of
PKD.
• A 42-year old woman with a history of ADPKD
diagnosed in her 20s with a strong family
history wants to know about treatments for
ADPKD
• On physical examination. Wt 74 Kg
(unchanged from 2 weeks back), BP 141/62
mmHg, HR 82 bpm, otherwise normal exxcept
abdominal fullness in flanks bilaterally
• BUN 34, Cre 1.5
ADPKD
• Most common genetic disease
– Incidence 1:500 – 1:1000 live births
• Mutation in ~70% located on short arm of chromosome 16p
(PKD1 locus)
• ~30% of mutation is located on chromosome 4q21-q23 milder
phenotype with PKD2 locus.
• Clinical Manifestations
– abdominal mass
– chronic flank or back pain
– gross hematuria
– recurrent UTI
– nephrolithiasis (uric acid stones)
198
Ultrasound Criteria for Diagnosis

of PKD1 in At-Risk Individuals
Positive and negative predictive values 97-100%
Ravine et al, Lancet 343:824, 1994
• Age < 30: at least 2 cysts (unilateral or bilateral)
• Age 30-59: at least 2 cysts/kidney
• Age > 60: at least 4 cysts/kidney
• For PKD2 age 30-59, use 4 or more cysts in both

kidneys for sensitivity of 96%
Pei et al, JASN 14:107A, 2003
Progressive Loss of Kidney Function

• Rate of decline of GFR
(data from MDRD study,
starting at GFR <55
ml/min)
Males 5 - 6 ml/min/year
Females 4 - 5
ml/min/year
– GFR stable for many
years, despite
progressive increase
in total kidney volume
– GFR decrease not
detected until total
kidney volume
exceeds 1500 ml
199
Treatment of ADPKD
• Progressive kidney insufficiency
– Lack of proven benefit of low protein diets or RAAS blockade
• Rigorous blood-pressure control in early PKD (Schrier
RW et al NEJM 2014)
– slower increase in total kidney volume
– no overall change in the estimated GFR
– greater decline in the left-ventricular-mass index
– greater reduction in urinary albumin excretion.
• High water intake
• Extrarenal manifestations
– Intervene as needed for symptoms
– Screen for cerebral aneurysms with + family history;
antibiotic prophylaxis for valvular regurgitation
– Avoid estrogen/progesterone in women (effect on liver cyst
disease)
#4 37-year-old man. After a few twinges

over past 2 months, presents with 2 hours of
excruciating pain in left groin
• A 37-year old man presents with 2 hrs of excrcating
pain in the left groin. Started in left flank. Episode of
gross hematuria. PMH of rt flank twinges.
• On physical examination. Looked in pain (writing,
sweaty), Wt 72 Kg, BP 155/80 mmHg, HR 105 bpm,
afebrile, JVP 8 cm, normal skin turgor, moist mucous
membranes, lungs clear, mild tenderness left flank, no
guarding, no edema.
• Na 140, K 4.2, Cl 100, BUN 24, Cre 1.1, BG 98 mg/dL.
UA SG 1015, pH 5.0, 4+ blood, 1+ leuks, rest neg. Sed
TNTC RBCs not dysmorphic, ocass WBC
200
Acute Management of a Stone Episode

Stone NO Probably uric acid
Radiopaque stone
YES
Fluid and pain Fluid and pain

medication Medication
Alkalinize urine
YES K citrate
Stone >5 mm Percutaneous
NO Lithotomy
Staghorn calculus Plus
Strain urine ESWL
Continue hydration Urologic NO
Evaluation Calyceal or upper
Ureter calculus ESWL
Stone passes
YES NO
Uretroscopy
Renal US in 2 weeks if Distal uretral or
Hydronephrosis or calcuus ESWL
Multiple stones
SOURCE: Adapted from Uptodate
Work-up
• Imaging
– Non-Contrast helical CT with Stone protocol is gold
std (detects stones not visible by KUB/IVP and has
significantly better sensitivity/specificity)
– Ultrasound: For patients needing avoidance of
radiation (pregnant, childbearing age)
– IVP: No longer favored due to lower sensitivity,
HIGHER radiation exposure
– KUB: Will miss radiolucent uric acid stones, small
stones, stones with overlying bony structures.
201
What stones don’t show up on imaging
• 85% of stones are radio-opaque

– Ca containing
– Cystine
• 15% radiolucent
– Uric acid
– Indinavir
Treatment
• Urologic Intervention?
– X<5mm : most pass spontaneously. Possible
observation and pain control
– X>5mm : less than 20% chance of passage and may
need urologic intervention
• So when to consult urology?
– If > 5mm
– For ANY size with ….
• Urosepsis, AKI, anuria, unyielding N/V/Pain ->
Inpatient consult
• Failed conservative management and stone did not
pass spontaneously -> Inpatient or Outpatient
consult depending on severity
202
Risk Factors for Stone Formation

• Dehydration
– concentrates stone forming constituents
• Anatomic abnormalities
– promote stasis, infection and/or crystal adhesion
• Changes in urinary pH
– e.g. calcium oxalate less soluble in alkaline urine
• Diet
– high protein / salt intake promotes hypercalciuria
– diet high in oxalate promotes oxaluria
• Medications
– furosemide /ca wasting; acetozolamide /bicarb
Stones
• Calcium oxalate
– 70-80%
• Uric Acid
– 10-15%
• Magnesium ammonium phosphate (struvite infection
related)
– 10-15%
• Cystine
– <1%
• Others (eg Indinavir, Triamterene)
– <1%
203
References
• N Engl J Med 2000; 342:1581-1589
• Blumberg et al KI, 41: 369-374, 1992
• N Engl J Med 2015; 372:222-231
• JASN 14:107A, 2003
• N Engl J Med 2014; 371:2267-2276
• N Engl J Med 2014; 371:2255-2266
• Clin J Am Soc Nephrol. 2009 Jul; 4(7): 1183–1189.
• MED ARH 2011; 65(4): 213-215
• Am Fam Physician. 2011 Dec 1;84(11):1234-1242.
• Ann Intern Med. 2003;139:137-147
204
Renal Board Review

2018
Ajay K. Singh MBBS, FRCP, MBA
Renal Division
Brigham and Women’s Hospital Senior Associate
Dean, Postgraduate Medical Education
Disclosures
• Consultant
GSK
205
Question 1
A 78 year old woman with DM, CAD, and CKD (Cre=2.4 mg/dL),
has persistent HTN, despite being treated with 5 medications
(lisinopril 40 mg, amlodipine 10 mg, furosemide 40 mg bid,
metoprolol 50 mg, and diltiazem 120 mg). She is asymptomatic.
She tells you that she is often dizzy when she wakes up in the
morning. She checks her BP at home, and says it is typically 100
– 120 systolic. On exam, her BP is 164/70 mmHg, non-
orthostatic, HR 54 bpm, but otherwise unremarkable. Her UA
shows 2+ albumin. BUN=42, Cre=2.38, K=4.1.
- Which one of the following next steps is most appropriate?
A.) Increase the dose of her diltiazem to achieve better BP
control
B.) Ask her to continue to do home BP measurements and see
her again in 3 months time.
C.) Do a screen for furosemide in her urine to see if she is being
adherent with her medications
D.) Set her up for ambulatory BP monitoring
E.) Start her on a clonidine patch.
Question 1
A 78 year old woman with DM, CAD, and CKD (Cre=2.4 mg/dL),
has persistent HTN, despite being treated with 5 medications
(lisinopril 40 mg, amlodipine 10 mg, furosemide 40 mg bid,
metoprolol 50 mg, and diltiazem 120 mg). She is asymptomatic.
She tells you that she is often dizzy when she wakes up in the
morning. She checks her BP at home, and says it is typically 100 –
120 systolic. On exam, her BP is 164/70 mmHg, non-orthostatic,
HR 54 bpm, but otherwise unremarkable. Her UA shows 2+
albumin. BUN=42, Cre=2.38, K=4.1.
- Which one of the following next steps is most appropriate?
A.) Increase the dose of her diltiazem to achieve better BP control
B.) Ask her to continue to do home BP measurements and see her again
in 3 months time.
C.) Do a screen for furosemide in her urine to see if she is being adherent
with her medications
√ D.) Set her up for ambulatory BP monitoring
E.) Start her on a clonidine patch.
206
Clinic 10-40%
Pressure White Coat Sustained

Hypertension Hypertension
140/90
120/80
True Masked
Normotension Hypertension
5-20%
MH officeblood pressure (BP) level is 135/85

‘normal” but ambulatory or home BP 120/80 Ambulatory Pressure
readings are in the hypertensive range
Recommendations for Clinical Use of

ABPM: JNC 7 & WHO-ISH
JNC 7
WHO-ISH
ABPM endorsed Yes Yes
Indications:
White Coat HTN Yes Yes
Labile BP Yes Yes
R/O hypotensive episodes Yes Yes
Resistant HTN Yes Yes
Autonomic dysfunction Yes No
207
SOURCE: http://visualmed.org/relationship-between-clinic-and-ambulatory-
blood-pressure-measurements-and-mortality/
208
Question 2
A 52 year old American of Asian origin sees you for
routine follow-up. She says her blood pressure is running
in the 135-140 mmHg systolic. She feels well.
Asymptomatic.
Medications: Lisinopril 20 mg/d, HCTZ 25 mg BID,
Amlodipine 10 mg QD, atorvostatin, metformin, glipizide
PE: Looks well. BP 138/72 mmHg, HR 80 bpm, soft left
and right carotid bruit. Soft SEM aortic area. No rales. No
edema. No peripheral pulses.
UA SG 1015, pH 5.5, 1+ protein otherwise neg
Scr 1.5 mg/dL, BUN 20, K 4.4 mEq/L.
What do You do?

• A.) Add a beta blocker (atenolol) and aim for
a BP of 120/80 mmHg
• B) Add a beta blocker and aim for the JNC8
goal of 140/90
• C) Add a beta blocker and aim for <140/90
mmHg
• D) Make no changes and reassure the patient
209
Question 2
What do You do?
A.) Add a beta blocker (atenolol) and aim for
a BP of 120/80 mmHg
• B) Add a beta blocker and aim for the JNC8
goal of 140/90
• C) Add a beta blocker and aim for <140/90
mmHg
• D) Make no changes and reassure the patient
Whelton PK, et al 2017

ACC/AHA/AAPA/ABC/ACPM/AGS/APhA/ASH/ASPC/NMA/
PCNA guideline for the prevention, detection, evaluation,
and management of high blood pressure in adults: a report
of the American College of Cardiology/American Heart
Association Task Force on Clinical Practice Guidelines.
Hypertension. 2017;
Taler SJ, Initial Treatment of Hypertension, Feb 15 NEJM
NEJM 2018; 378; 636-44
210
72.2m
32%
103.3m
46%
Guideline not based on RCTs

Updates JNC7 not JNC 8
Creates “disease” in ≈30 million Americans
• 32% to 46% of Americans now have HTN
• Those with “pre-hypertension, now hypertension
Integrates cardiovascular risk assessment into BP management
BP goal same in age>65
SOURCE: Bakris G and Sorrentino M, NEJM Feb 8 2018
Muntner P, Carey RM, Gidding S, et al. Potential US population impact of the 2017 ACC/AHA
high blood pressure guideline. Circulation 2018;137:109-118.
211
Therapy for Hypertension based on JNC 8

Implement lifestyle interventions
No diabetes and/or CKD Diabetes and/or CKD
Age >60 Age <60 All ages
BP Goal BP Goal BP Goal

<150/90 <140/90 <140/90
Only diabetes Only CKD
Blacks <75 y >75 y

Non-Blacks
Thiazide, ACEi, ARB or CCB Thiazide or CCB ACEi or ARB CCB or Thiazide
alone or in combination alone or in combination
Source: Singh et al, Brigham Intensive Review of Internal Medicine, Oxford University Press 2014
Adapted from James PA et al: Report from the panel members appointed to the Eighth Joint National Committee (JNC 8). JAMA
2014; DOI:10.1001/jama.2013.284427.
Question 3
• A 22 year-old woman is admitted with a
diagnosis of Goodpasture’s syndrome. This
diagnosis is confirmed by an ELISA and
Western blot analysis demonstrating anti-
GBM antibodies. A preliminary reading of the
renal biopsy confirms the diagnosis of anti-
GBM nephritis. Her serum creatinine is 3.2
mg/dL. 2 weeks previously her serum
creatinine was 0.7 mg/dL. Which of the
following therapeutic options would be most
appropriate for her:
212
– A.) Prednisone 60 mg/day for 1 month followed by

a gradual weaning of her prednisone dose.
– B.) Pulse methylprednisone accompanied by daily
plasmapheresis with exchange, followed by high
dose oral prednisone coupled with
cyclophosphamide, until her anti-GBM titer is
undetectable.
– C.) Pulse methylprednisone followed by high dose
oral prednisone coupled with cyclophosphamide,
until her anti-GBM titer is undetectable.
– D.) Prednisone 60 mg/day plus cyclophoshamide
3 mg/Kg/day
– E.) Plasmapheresis alone
– A.) Prednisone 60 mg/day for 1 month followed by

a gradual weaning of her prednisone dose.
B.) Pulse methylprednisone accompanied by daily
plasmapheresis with exchange, followed by high
dose oral prednisone coupled with
cyclophosphamide, until her anti-GBM titer is
undetectable.
– C.) Pulse methylprednisone followed by high dose
oral prednisone coupled with cyclophosphamide,
until her anti-GBM titer is undetectable.
– D.) Prednisone 60 mg/day plus cyclophoshamide
3 mg/Kg/day
– E.) Plasmapheresis alone
213
• Ernest Goodpasture, joined the Brigham and Women’s Hospital/HMS in

1912 as a pathologist.
• In 1919 Goodpasture, while studying the influenza pandemic, described a
progressive and usually fatal disease in which glomerulonephritis was
associated with coughing of blood. Most of the patients died of kidney
failure. This has been known since as Goodpasture's syndrome.
• In 1924 he was invited to return to Vanderbilt as professor and chairman
of the Department of Pathology in the reorganized Vanderbilt University
School of Medicine.
• Uncommon: incidence 0.1 cases/million

• 1-2% of renal biopsy specimens
• Slight preponderance in males
• Age 1st to 9th decade
• More common in whites over African-
American’s
• Year-round presentation, ? Spring and
summer
• 50-75% have upper respiratory prodrome,
– plus fever, rash, myalgias, malaise,
headache, weight loss
214
Pathologic Features of
Anti-GBM Nephritis
• Renal presentation with RPGN
• proteinuria but usually not nephrotic
• Hypertension uncommon
• US - normal size kidneys
• Renal function declines rapidly
215
Treatment
• Treatment without methylprednisone and
plasmaphereis
– 89% progress to death or dialysis; only 10% improved
• Treatment with pulse steroids, plasmapheresis, and
Cyclophosphamide
– standard-of-care
– 50% improve
• Patients with serum creat of >7.0 respond to
treatment
– 75% with Scr <7 respond, 8% with Scr > 7 respond
– No improvement in 58 patients on dialysis
Treatment
• Protocol
– Pulse methyl prednisone (solumedrol) 1 g
QD x 3 d, 1-1.5 mg/Kg prednisone
– Cyclophosphamide 3 mg/Kg/d (reduced
dose in older patients, or if GFR < 10) > 2
months
– Plasma exchange daily 4 L with albumin
replacement (or FFP if pulmonary
hemorrhage present) x 14 d or until
antibody dissapears
216
Question 4
• In all of the following conditions an increase

in serum creatinine can be explained by a
reduction in GFR EXCEPT
– A.) Bilateral hydronephrosis
– B.) Severe extracellular volume contraction
caused by diarrhea
– C.) Severe congestive heart failure
– D.) Increase in serum creatinine 1 day post
arteriogram
– E.) Cimetidine treatment of peptic ulcer disease
• In all of the following conditions an

increase in serum creatinine can be
explained by a reduction in GFR
EXCEPT
– A.) Bilateral hydronephrosis
– B.) Severe extracellular volume contraction
caused by diarrhea
– C.) Severe congestive heart failure
– D.) Increase in serum creatinine 1 day post
arteriogram
E.) Cimetidine treatment of peptic ulcer
disease
217
Limitations of serum
creatinine
• Creatinine - freely filtered, secreted,

extra-renal degradation
• secretion and extra-renal elimination
increases as GFR falls
• Scr dependent on muscle mass and
meat intake
• Sensitivity of creatinine as GFR
measure approx 60%
Creatinine metabolism
• creatinine production proportional to muscle
mass
– males 20-25 mg/Kg/24h
– females 15 to 20 mg/Kg/24h
• Expected creat excretion (male) = (28-0.2[age
years](weight[kg])
• Expected creat excretion (female) = (24-
0.17[age years](weight[kg])
• Secreted by organic cation exchanger
• Drugs that interfere with proximal secretion
– Cimetidine
– Trimethoprim
– Dapsone
– Probenicid
218
SOURCE:
http://www2.kidney.org/professionals/kdoqi/guidelines
_ckd/p5_lab_g4.htm
Question 5
• You are asked to consult on a 62 year old African-
American male with acute on chronic renal
insufficiency secondary to diabetes mellitus ascribed
to contrast nephrotoxicity. Routine chemistry labs
show a potassium of 8.2 mg/dL. All of the following
would be changes seen on the EKG compatible with
hyperkalemia, except:
– A.) Peaked T waves
– B.) Prolonged QRS
– C.) Flattened p wave
– D.) Sine-wave appearing QRS complex
– E.) U wave
219
Question 5
• You are asked to consult on a 62 year old African-
American male with acute on chronic renal
insufficiency secondary to diabetes mellitus ascribed
to contrast nephrotoxicity. Routine chemistry labs
show a potassium of 8.2 mg/dL. All of the following
would be changes seen on the EKG compatible with
hyperkalemia, except:
– A.) Peaked T waves
– B.) Prolonged QRS
– C.) Flattened p wave
– D.) Sine-wave appearing QRS complex
E.) U wave
EKG changes in hyperkalemia
• Early: tenting of T waves “pinch-bottomed T

waves”; precordial leads
• Prolonged P-R interval
• ST segment depression and lengthening of
QRS
• P wave disappears, further widening of QRS
• Ventricular fibrillation
220
EKG changes in Hyperkalemia
Question 6
• 48 year old male ESRD patient presents to

the ED with a K= 7.8 mEq/L, HC03 of 22. His
EKG shows peaked T waves. Recommended
initial treatment include all of the following
EXCEPT:
– A.) Calcium gluconate 10 mls, IV
– B.) Insulin 10 units and 1 amp of 50% dextrose
– C.) Albuterol nebulizer (10-20 mg)
– D.) IV bicarbonate 8.4%, 1 to 2 amps IV
– E.) Emergent dialysis
221
• 48 year old male ESRD patient presents to

the ED with a K= 7.8 mEq/L, HC03 of 22. His
EKG shows peaked T waves. Recommended
initial treatment include all of the following
EXCEPT:
– A.) Calcium gluconate 10 mls, IV
– B.) Insulin 10 units and 1 amp of 50% dextrose
– C.) Albuterol nebulizer (10-20 mg)
D.) IV bicarbonate 8.4%, 1 to 2 amps IV
– E.) Emergent dialysis
Changes in plasma K
8.4% bicarb, epinephrine, insulin/dextrose, or HD
Blumberg et al
Am J. Med 88:507-512, 1988
222
Changes in plasma K during IV

infusion of bicarbonate in HD patients
Values= means + SE
*P<0.5, + P<0..01 vs. baseline
Blumberg et al KI, 41: 369-374, 1992
Question 7
• The most common type of kidney stone

observed in the United States is:
– A.) Cystine stone
– B.) Triple phosphate stone
– C.) Struvite stone
– D.) Calcium oxalate stone
– E.) Uric acid stone
223
• The most common type of kidney stone

observed in the United States is:
– A.) Cystine stone
– B.) Triple phosphate stone
– C.) Struvite stone
D.) Calcium oxalate stone
– E.) Uric acid stone
Nephrolithiasis
• 12% of US population affected
• Incidence rate (age 30-65)
– Male: 3/1000/yr
– Female: 1/1000/yr
• Calcium oxalate > 75%
– Hypercalciuria,hyperoxaluria, hypocitrituria,
hyperuricosuria
• Infection stone/Magnesium ammonium
phosphate/struvite/triple phosphate 7-15%
• Uric acid 2%
• Calcium phosphate 2%
• Cystine <1%
224
Common Crystals
Source: www:medstat.med.utah.edu/WebPath
Question 8
• A 60-year old man who has been previously in good

health and on no medications develops the nephrotic
syndrome. No systemic causes are identified and
serologic work up is completely negative. The most
likely histologic lesion of percutaneous renal biopsy
is:
– A.) Light chain nephropathy
– B.) Membranous glomerulopathy
– C.) Myeloma kidney
– D.) Membranoproliferative glomerulonephritis
– E.) IgA nephropathy
225
Question 8
• A 60-year old man who has been previously in good

health and on no medications develops the nephrotic
syndrome. No systemic causes are identified and
serologic work up is completely negative. The most
likely histologic lesion of percutaneous renal biopsy
is:
– A.) Light chain nephropathy
B.) Membranous glomerulopathy
– C.) Myeloma kidney
– D.) Membranoproliferative glomerulonephritis
– E.) IgA nephropathy
MN points
• Idiopathic
• Insidious onset
• M>F 2-3:1
• 80% NS at presentation
• 20% asymptomatic non-nephrotic
proteinuria
• 50% have hematuria
• HTN not common (30%)
• Increased risk of thromboembolism (15-
40%)
• Insidious decline in GFR
226
Membranous nephropathy
Primary Secondary
(Idiopathic) - Lupus
- Hepatitis B
75% 25% - NSAIDs
- Malignancy
- Toxins (Hg)
anti-PLA2R - Others
??
associated
M-type phospholipase A2 receptor

• 185 kDa type I transmembrane glycoprotein
• Expressed in human kidney, lung, placenta, WBC
• Member of the mannose receptor family

– Mannose Receptor (CD206)
– Endo180 (uPAR-associated protein or CD280)
– DEC-205 (CD205), dendritic cell receptor
– M-type phospholipase A2 receptor
– FcRY = avian yolk sac IgY receptor
• Binds certain sPLA2s, but exact function is not known
• May play a role in cellular replicative senescence
Source: Beck, et al
227
Association of anti-PLA2R with clinical status

Anti-PLA2R level
correlates with
proteinuria
Hofstra JM, Beck LH et al. (2011) Clin J Am Soc Nephrol 6: 1286-91
Question 9
• A 16-year old woman who presents with a history of a
sore throat 2 weeks previously has edema, mild
hypertension, hematuria and red cell casts on her
urine sediment. Her complements are low. The most
likely diagnosis is:
– A.)Minimal change disease
– B.)Post-infectious glomerulonephritis
– C.)IgA nephropathy
– D.)Acute interstitial nephritis
– E.) Light chain deposition disease
228
• A 16-year old woman who presents with a

history of a sore throat 2 weeks previously
has edema, mild hypertension, hematuria and
red cell casts on her urine sediment. Her
complements are low. The most likely
diagnosis is:
– A.) Minimal change disease
B.) Post-infectious glomerulonephritis
– C.) IgA nephropathy
– D.) Acute interstitial nephritis
– E.) Light chain deposition disease
Infectious agents and GN

• Bacterial • Parasitic
– Gp A-beta strep – Plasmodium malariae
– Staph aureus – Toxoplasma
– Staph epi – Filaria
– Gram neg bacilli – Schistosomia
– Strep pneumoniae – Trichenella
– Treponema pallidum – Trypanosome
– Salmonella typhi
• Rickettsial
– Meningococcus
– Scrub typhus
– Leptospirosis
• Fungal
• Viral
• Coccidioides
– Hep B and C
immites
– CMV
– Enterovirus
– Measles
– Parvovirus
– Oncovirus
– Mumps virus
– Rubella
– Varicella
229
PSGN points
• Follows pharyngeal and skin infection
• Nephritogenic strains M types Serotype 49
commonest
• Primarily disease of children, age 5 –15, rare <2 y
and > 40 y.
• Latent period 7-14 d pharyngeal, 14-28 d pyoderma
• Presentation: hematuria (70%), periorbital edema,
weight gain, HTN, oliguria
• UA: proteinuria (usually < 2g/24h), RBCs, RBC casts,
WCCs, WC casts
• FENA usually < 0.5% in acute phase
• Serology: Antistreptolysin ab (ASO),
Antistreptokinase, antideoxyribosenuclease B, and
antinicotyladenine dinucleaotidase
– Titers rise 10-14 d post strep pharyngitis, peak at 3-4 wks
– No relationship with development of nephritis or its severity
Question 10
– A 52 year old African-American female presents to
the emergency room with unstable angina. She is
noted to have a past medical history of mild chronic
renal insufficiency ( creatinine of 1.8 mg/dL). She is
transferred to the coronary care unit and therapy for
her unstable angina is initiated. A cardiac
catheterization is planned for the next day. Risk
factors that would predispose this woman to contrast
nephrotoxicty include all of the following except:
– A.) Diabetes mellitus
– B.) Pre-existing renal insufficiency
– C.) The volume of IV contrast utilized in the
procedure
– D.) Presence of extracellular volume contraction
– E.) A history of coronary artery disease
230
– A 52 year old African-American female presents to

the emergency room with unstable angina. She is
noted to have a past medical history of mild chronic
renal insufficiency ( creatinine of 1.8 mg/dL). She is
transferred to the coronary care unit and therapy for
her unstable angina is initiated. A cardiac
catheterization is planned for the next day. Risk
factors that would predispose this woman to contrast
nephrotoxicty include all of the following except:
– A.) Diabetes mellitus
– B.) Pre-existing renal insufficiency
– C.) The volume of IV contrast utilized in the
procedure
– D.) Presence of extracellular volume contraction
E.) A history of coronary artery disease
Question 11
• Her cardiologist asks you for an estimate of
her risk of developing contrast nephrotoxicity.
Which one of the following would be the
closest estimate:
– A.) 60%
– B.) <5%
– C.) 20%
– D.) >80%
– E.) >95%
231
Question 11
• Her cardiologist asks you for an estimate of

her risk of developing contrast nephrotoxicity.
Which one of the following would be the
closest estimate:
– A.) 60%
– B.) <5%
C.) 20%
– D.) >80%
– E.) >95%
Contrast Nephrotoxicity
• ARF and oliguria within 24-48 hours

• Peak serum creatininine on days 3-5
• Low fractional excretion of sodium
• Benign sediment or granular casts
• Resolution usual within 1 week
• Risk factors: CRI, diabetic nephropathy,
dose>120 cc, multiple myeloma, volume
• Prevention: hydration 75 cc 0.45% saline,
non-ionic for high risk patients
232
Contrast Nephropathy
• 12% of hospital-acquired ARF due to contrast

(Hou et al)
• Mortality of CN with Scr > 2.0, 48 h post
angiography > 34%
• 0.7% of diagnostic cath patients develop CN
– 10.9% with Scr > 1.2 mg/dL
• Overall Risk
– CRI patients 10-30%, Diabetes mellitus 24-50%
233
Contrast Nephropathy
Risk Factors
• Pre-existing renal insufficiency

• Diabetes mellitus
• CHF
• Volume Depletion
• Dose of Contrast agent
Prophylaxis for CIN
• Volume repletion – yes

• N-acetyl cysteine – no
NO
• Sodium bicarbonate - no
234
SOURCE: http://www.nephjc.com/news/2017/11/26/visual-abstracts-for-preserve
Question 12
• A 42 year otherwise healthy white male runs the
Boston Marathon in 4 hours and 4 minutes. He
complains of severe body cramps immediately after
the race and then after he returns to his hotel room.
At night, on voiding, he notices that the volume is
small and it is dark red in color. His spouse insists he
goes to the emergency room, where a blood test
shows that his serum creatinine is 4 mg/dL and his
BUN is 18. His urine shows a positive dipstick for
blood but virtually no red blood cells in the sediment.
The next step in management should be:
– A.) 800 mg indomethacin 3 times a day and return if not improved.
– B.) Starting the patient on pulse methylprednisone 500 mg/day (for
3 consecutive days).
– C.) Immediate initiation of hemodialysis
– D.) Aggressive hydration with normal saline and mannitol
– E.) Intravenous furosemide to initiate a diuresis
235
• A 42 year otherwise healthy white male runs the

Boston Marathon in 4 hours and 4 minutes. He
complains of severe body cramps immediately after
the race and then after he returns to his hotel room.
At night, on voiding, he notices that the volume is
small and it is dark red in color. His spouse insists he
goes to the emergency room, where a blood test
shows that his serum creatinine is 4 mg/dL and his
BUN is 18. His urine shows a positive dipstick for
blood but virtually no red blood cells in the sediment.
The next step in management should be:
– A.) 800 mg indomethacin 3 times a day and return if not improved.
– B.) Starting the patient on pulse methylprednisone 500 mg/day (for
3 consecutive days).
– C.) Immediate initiation of hemodialysis
D.) Aggressive hydration with normal saline and mannitol
– E.) Intravenous furosemide to initiate a diuresis
236
Epidemiology of Rhabdo
• Eighty-five percent of victims of traumatic injuries
develop rhabdomyolysis.[2]
• Of those patients with rhabdomyolysis 10-50% of
those patients will develop acute renal failure.[2]
• It is also suggested that victims of severe injury that
develop rhabdomyolysis and later acute renal failure
have a mortality of 20%.[2] An estimated 26,000
cases of rhabdomyolysis are reported annually in the
US.[2]
1Huerta-Alardin AL, Varon J, Marik P. Bench-to-beside review: Rhabdomyolysis
- an overview for clinicians. Critical Care 2005; 9: 158-169
2Harriston S. A review of rhabdomyolysis. Dimensions Of Critical Care Nursing:
DCCN [serial online]. July 2004;23(4):155-161. Available from: MEDLINE,

Ipswich, MA. Accessed March 23, 2014.
Features of Rhabdomyolysis
• Muscle pain and dark urine “Coca-Cola” color

• Orthotoludine-positive urine without RBCs
• Elevated CPK and myoglobin
• Increased K, Phos, urate, decreased Ca
• Rapid increase in serum creatinine
• Mechanism: free radicals, ferrihemate, reduced nitric
oxide
• Treatment: saline repletion, alkaline diuresis,
mannitol. Dialysis once ARF established
237
Causes of Rhabdomyolysis
• Excessive muscle activity

– seizures, delerium tremens, sport
• Direct of ischemic muscle injury
– trauma, compression syndrome, vascular occlusion
• Metabolic disorders
– hypokalemia, hyponatremia, hypophosphatemia
• Drugs or toxins
– ethanol, isopropyl alcohol, heroin, methadone
• Infections
– tetanus, legionaires, influenza
• Under normal conditions, CK levels are 45-260 U/L.

• After rhabdomyolysis, the levels of CK can be raised to 10,000-
200,000 U/L.
• No other condition except rhabdomyolysis can cause such extreme
CK elevation
SOURCE: Efstratiadis G, Voulgaridou A, Nikiforou D, et al. Rhabdomyolysis

updated. Hippokratia 2007; 11(3): 129-13
238
Disclosures
• Research Grants
GSK
239
ANEMIA
Maureen M. Achebe, MD, MPH

Division of Hematology
Assistant Professor, Harvard Medical School
Commercial/Faculty Disclosures
• AMAG Pharmaceuticals – Scientific advisory

board
• Luitpold Pharmaceuticals - Consulting
240
Anemia
• Hemoglobin or hematocrit below the normal
range for age and gender
• Anemia can be due to:

- ↓ red cell production (low retic count)
- ↑ red cell destruction (high retic count)
- Red cell (blood) loss (high retic count)
Evaluation of Anemia
1. Size of RBCs – MCV

2. Reticulocyte count
3. Peripheral smear
Other Labs in Evaluation
}
• LDH
+ Retics Hemolysis
• Indirect Bilirubin
• /absent Haptoglobin + Retics Ineffective
Erythropoesis
241
RDW
Normal RDW AI, thal trait, aplastic anemia, renal

disease, acute blood loss
Elevated Iron deficiency, folate & B12 def,

RDW myelodysplasia, sickle cell disease
Reticulocyte count
Corrected Reticulocyte Count/Reticulocyte Index
Reticulocyte Index = Retic count X Hematocrit

Normal Hct (45)
Reticulocyte Index in a normal healthy adult is between

1 and 2
242
Reticulocyte Index and MCV
Iron deficiency
Anemia of inflammation Low MCV
Sideroblastic anemia
Thalassemias
Renal failure
Aplastic anemia Normal MCV
Low retic index
Hypothyroidism
B12/folate deficiency
MDS
High MCV
Alcohol liver disease
Hemolytic anemias
High retic index Blood loss
Reticulocyte Index and MCV
Iron deficiency
Anemia of inflammation Low MCV
Sideroblastic anemia
Thalassemias
Renal failure
Normal MCV
Aplastic anemia
Low retic index
Hypothyroidism
High MCV
MDS
Hemolytic anemias
High retic index Blood loss
243
Case 1
58 y o woman w/ SLE, HTN and GERD presents with
intermittent headaches and fatigue.
WBC 4.7, Hgb 8, Hct 25, MCV 74, platelets 544,000,
retic count 1.5%, iron : 45, TIBC : 520, ferritin 20.
Soluble transferrin receptor is 4.2 (0.8 – 3 mg/L).
microcytic hypochromic RBCs
lymphocyte
Case 1
58 y o woman w/ SLE, HTN and GERD presents with
intermittent headaches and fatigue.
WBC 4.7, Hgb 8, Hct 25, MCV 74, platelets 544,000,
Soluble transferrin receptor is 4.2 (0.8 – 3 mg/L).
Which of the following would be of most benefit?
a) Epo stimulating agent therapy
b) Better control of SLE
c) 1 unit packed RBCs
d) Intravenous iron
e) Proton pump inhibitor therapy
244
Case 2
60 y o woman w/ SLE, HTN and GERD presents 2 years
later with fatigue and dyspnea on exertion.
WBC 4.7, Hgb 7.8, Hct 23, MCV 76, platelets 267,000,
Soluble transferin receptor is 0.9 (0.8 – 3 mg/L).
Case 2
60 y o woman w/ SLE, HTN and GERD presents 2 years
later with fatigue and dyspnea on exertion.
WBC 4.7, Hgb 7.8, Hct 23, MCV 76, platelets 267,000,
Soluble transferin receptor is 0.9 (0.8 – 3 mg/L).
What is the most likely cause of her anemia:
a) Iron deficiency
b) Anemia of inflammation
c) Iron deficiency and Anemia of inflammation
d) None of the above
245
Iron Deficiency Anemia
http://www.cdc.gov/
Iron Homeostasis
246
Iron Homeostasis
Iron Homeostasis
247
Iron Homeostasis
Anemia of Inflammation
Iron Sequestration Syndromes
• Characterized by inappropriately high serum hepcidin
Inflammation
IL-6
Hepcidin
macrophage
248
Anemia of Inflammation
Iron Sequestration Syndromes
• Iron deficiency may exacerbate chronic diseases
leading to accelerated clinical deterioration
– Inflammatory bowel disease
– CHF
– CKD
– Rheumatologic diseases
– Infections
– Critical illness
– Malignancies
Diagnosis Iron Deficiency Anemia of

Anemia Inflammation
Iron Anemia of
deficiency Inflammation
Serum Fe Low Low
TIBC High Low
Transferrin Low Low

saturation
Ferritin Very low N/High
249
Serum Transferrin Receptor

Punnonen et al. Blood 89 (3) 1997:1052
No stainable iron n=48
129 adult patients
Hb <12.8g.dL or BM Asp/biopsy Stainable Fe + chronic infl n=64
<11.7g/dL
No stainable Fe + inflam process n=17
Management of Iron Deficiency Anemia

• Estimated to affect 2 billion people worldwide
• Oral repletion - Ferrous sulfate/gluconate PO

• Intravenous repletion
• Expected Response to Fe Treatment

Reticulocytosis – 5-7 days
Increase in Hb – 2 weeks
Ferritin repletion – 6 months
• If not, seek other cause.
250
• Retrospective comparison of safety of IV irons used at

our institution.
• 619 patients over 2 yrs : 32 adverse events (AEs), ranging
from urticaria to chest pain.
• No serious AEs or anaphylactic-type rxns.
• AE rates: LMW Dextran ≈ ferric gluconate equivalent
• Iron sucrose had higher OR of AEs (OR= 5.7; 95% CI 1.6–21.3).
• AE rates with IV iron are acceptable

Am J Hematol. 2012 Nov;87(11):E123-4.
Management of Anemia of Inflammation

• Identify specific cause.
• Epo stimulating agents (ESA) are beneficial in pts with

normal or elevated serum creatinine.1,2,3
• IV iron increases ESAs efficacy in select patient
populations.4
• Goal Hgb 10 -11 g/dL.5,6
• New therapeutic strategies – target hepcidin-

ferroportin axis.
1. Littlewood et al. JCO 2001;19:2865-74. 4. Coyne et al. J Am Soc Nephrol. 2007;18:975-84
2. Adamson, Hematol ASH Educ Prog 2008(1):159-165 5. Singh et al. N Engl J Med 2006; 255:2085-2098.
3. Hertel et al. Am J Nephrol 2006;26:149-156 6. Pfeffer et al. N Engl J Med 2009;361:2019-2032
251
Case 3
40 y o instructor at a firing range with no medical history
presents with fatigue, irritability, dyspepsia & arthralgias.
On exam: BP 145/90, pale, hearing loss and peripheral
neuropathy.
Labs: WBC 6.2, Hgb 9.3, ↑RBC protoporphyrin level.
Smear: RBCs show basophilic stippling.
Which would expect to see?
a) BM aspirate with ringed sideroblasts
b) Peripheral smear with teardrops
c) Megaloblastic RBCs & elevated methylmalonic acid
d) Elevated hepcidin level
Sideroblastic Anemias
• Heterogenous group of anemias
• Characterized by Ineffective erythropoiesis
Common Causes Clinical Associations
Myelodysplastic Syndrome Elderly person
Lead intoxication Construction workers,
Auto repairers, Scrap metal
recyclers, painters
INH without vit B6 Tuberculosis
Alcohol intoxication Alcohol abuse history
252
Sideroblastic Anemia
RBCs containing Pappenheimer bodies Ringed sideroblasts in Bone Marrow
Courtesy Arthur Skarin, MD.
Case 4
• 70 y o woman with diabetes is brought to PCP by her
family for progressive dementia. Labs are reported as
normal. Donepezil (Aricept) started. Six months f/u, no
improvement. Gait is unsteady. WBC 2.9, hgb 8.3,
platelets 85,000, retic ct 0.9%.
She is diagnosed with vitamin B12 deficiency.
Peripheral blood smear Bone marrow aspirate
Nuclear-cytoplamic asynchrony
253
Case 4
• 70 y o woman with diabetes diagnosed with vitamin B12
deficiency
Which of the following results is she likely to have?

a) ↑ folate, ↓ B12, normal MMA,↓ homocysteine
b) normal folate, ↓ B12, ↑ MMA,↓ homocysteine
c) normal folate, ↓ B12, normal MMA, ↑ homocysteine
d) normal folate, low normal B12, ↑ MMA, ↑ homocysteine
e) ↑ folate, normal B12, ↓ MMA, ↑ homocysteine
Biochemistry of Megaloblastic Anemia -

Impaired DNA Synthesis
DNA
dGTP dCTP dATP dTTP
dTDP
DHF-PG dTMP
THF-PG Thymidylate synthase

5-10-methylene
THF-PG dUMP
THF
methionine
methionine synthase
homocysteine
B12 5-Methyl THF
Cell membrane
methylTHF plasma
Dietary folate Dietary B12 Small intestine
254
Physiology of Vitamin B12
Cbl III Cobalamin II

in tissues
adenosylCbl Succinyl CoA

methylCbl
B12 Methylmalonyl CoA mutase

B12 THF
methionine
methionine synthase
homocysteine Methylmalonic acid
5-Methyl THF
DNA Synthesis for the TCA cycle
Folate vs B12 Deficiency

Folic Acid def Vitamin B12 def
Diet history EtOH, poor Vegan diet
overall intake
Neurological deficits No Paresthesias, dementia,
madness
Homocysteine High High
Methylmalonic acid Normal High
Other buzzwords pregnancy, hx of bariatric surgery

growing child fish tapeworm
255
When to get homocysteine and

methylmalonic acid levels
Cobalamin Serum folate Check
(200 – 900 pg/ml) (normal >2ng/ml) homocysteine and
MMA
200-300 >4 Yes, to R/O B12
deficiency
<200 <2 Yes, to distinguish

folate deficiency from a
combined deficiency
>300 2-4 Yes, to confirm folate
deficiency
Case 5
• 60 y o woman with Rheumatoid Arthritis presents with a
2 wk history of worsening weakness and dizziness.
• Labs: WBC 4.7, Hgb 7.3, Hct 25%, MCV 92, MCHC 39
platelet count 177,000. T bil 3.1, retic 23%, LDH 636,
direct Coombs (+) for IgG and complement.
Smear shows spherocytes
256
Case 5
• 60 y o woman with Rheumatoid Arthritis presents with a
2 wk history of worsening weakness and dizziness.
• Labs: WBC 4.7, Hgb 7.3, Hct 25%, MCV 92, MCHC 39
platelet count 177,000. T bil 3.1, retic 23%, LDH 636,
direct Coombs (+) for IgG and complement.
What would you expect?
a) Eosin-5-maleimide to be abnormal
b) Treatment with steroids to be beneficial
c) Sputum culture positive for Mycoplasma pneumonia
d) Osmotic fragility to be normal
e) Splenomegaly
Hemolytic Anemias
Hereditary Acquired
1. Defects in RBC membrane 1. Immune HA

2. Defects in RBC metabolism 2. Non-immune HA
(enzymopathies)
3. Defects in Hemoglobin
(hemoglobinopathies)
257
Autoimmune Hemolytic Anemia

Warm AIHA Cold AIHA
IgG
IgM
MAC
Splenic macrophages Intravascular hemolysis

Warm AIHA Cold AIHA
Courtesy ASH Image bank
258

Warm AIHA Cold AIHA
Direct IgG or IgG & C3 C3 only
Coombs
Antibody IgG IgM
Etiology 1. Drugs: Methyldopa, 1. Drugs: Quinidine
PCN, 2. Malignancy: NHL
Sulfa 3. Infection:
2. Malignancy: CLL, Mycoplasma
NHL 4. Paroxysmal cold
3. Infection hemoglobinuria
Treatment of Warm AIHA

• First line therapy –
Corticosteroids.1,2 No specific dose. Prednisone 1 mg/kg/day
• Second line
Rituximab 375 mg/m2 weekly for 4 weeks – CR in 29 - 55% pts, PR
in 50% pts. 3,4,5
Splenectomy - some response in 59 - 100% patients.6
Supportive Care
• RBC transfusions – Cross-matching is difficult because of pan-
agglutinating Abs. Use closest match possible
1. Allgood et al. Am J Med 1967;43(2):254-273 4. Bussone. Am J Hematol 2009;84(3):153-157

2. Zupanska at al. Haematologia 1981;14(4):425-433. 5. D’Arena. Eur J Haematol 2007;79(1):53-58
3. Dierickx et al. J Intern Med 2009;266(5):484-491 6.Crowther et al. Blood 2011;118 (15) 4036-4040
259
Case 6
32 y o woman presents with 3 day history of colicky
abdominal pain and fatigue.
Labs: WBC 2.9, Hct 22% MCV 78, platelets 60,000, retic
count 9%, direct and indirect Coombs (-), ferritin 10.
Abdominal USS shows portal vein thrombosis.
U/A – hemosiderin (+).
The most likely diagnosis is:

A) Factor V Leidin mutation
B) Paroxysmal cold hemoglobinuria
C) Warm autoimmune hemolytic anemia
D) Aplastic anemia
E) Paroxysmal nocturnal hemoglobinuria
Paroxysmal Nocturnal Hemoglobinuria
PIG A
GPI anchors C′ activation
C′ activation
loss of anchors
PIG A MAC
mutation CD55
260
Paroxysmal Nocturnal Hemoglobinuria

Features:
• Chronic hemolysis urine hemosiderin Fe def.
• Thrombocytopenia
• Thrombosis in unusual sites – hepatic, mesenteric,
cerebral veins.
Diagnosis: flow cytometry for absence of CD55 & CD59
Treatment: Eculizumab
Steroids
Allogeneic BM transplant
Eculizumab
Brodsky Blood 2014;124:2804-2811

©2014 by American Society of Hematology
261
Case 7
34 yr old Hispanic woman who is 20 weeks pregnant
presents with generalized aches and fatigue. She’s had
an episode once in her life before. Her pulse is 102,
temp 101, BP 120/80. She’s jaundiced. Her labs show:
Hct 22, WBC 14, platelets 420,000. LDH 574, retics 15%
What diagnostic test is most appropriate?

34 yr old Hispanic woman who is 20 weeks pregnant
presents with generalized aches and fatigue. She’s had
an episode once in her life before. Her pulse is 102,
temp 101, BP 120/80. She’s jaundiced. Her labs show:
Hct 22, WBC 14, platelets 420,000. LDH 374, retics 15%
A) Full liver function tests
B) Hemoglobin electrophoresis
C) Bone marrow biopsy
D) Rapid strep test
E) Osmotic fragility
262
Case 7 continues
8 hrs later, patient is SOB, chest pain, tachycardic, diaphoretic,
Rm air O2 sat is 83%. CXR shows bilateral lower lobe
infiltrates. What is the most appropriate next step?
A) Continue current antibiotics and exchange RBC transfusion,
send sputum cultures
B) Continue current antibiotic, IV pain medication and deliver
baby as soon as possible
C) Continue current antibiotics, send for V/Q scan, initiate
anticoagulation
D) Expand antibiotic coverage for atypicals and monitor
patient closely
E) Expand antibiotic coverage for atypicals, exchange RBC
transfusion immediately.
Sickle Cell Syndromes (Qualitative Defect)

• Due to a point mutation in β-globin chain : β6 Glu Val
Bunn, NEJM 1997;337:762
263
Sickle Cell Anemia

• Homozygous inheritance of S β-globin
• Hb electrophoresis: HbS -75-95%, HbF 2-20%, HbA2<4%
• Functional asplenia, vaso-occlusive crises
Common Complications:
• Acute chest syndrome – major cause of mortality
• Aseptic necrosis of bone
• Priaprism
• Retinopathy
Acute Chest Syndrome (ACS)

• characterized by fever, chest pain, shortness of
breath, hypoxia and a new infiltrate(s) on CXR.
Vichinsky et al. NEJM 2000; 342:1855-1865
264
Acute Chest Syndrome (ACS)

• Treatment for acute chest syndrome includes:
antibiotic coverage for typical and atypical orgs.
RBC exchange transfusion to a goal HbS <30%
Aggressive supportive care
Rx of Bone pain crisis – Fluid repletion and

liberal pain medication as needed
Rx to prevent frequent crises – Hydroxyurea

Vichinsky et al. N Eng J M 2000; 342:1855-1865
Sickle Cell Trait

• Not considered a disease state
• Vast majority are asymptomatic
• Heterozygous inheritance of HbS:
Hb electrophoresis : <50% HbS, >50% HbA
Rarely present with
• renal papillary necrosis

• painless hematuria
Ryan T Clark
• isothenuria Pittsburgh Steeler
• splenic infarcts
265
Case 8
An 18-year old woman is referred for the evaluation of
mild jaundice. She thinks she has had it intermittently
for years. She has always tired more easily than her
friends, and she has been told several times that she
was anemic. She has been treated on several occasions
with iron pills, but not in the past two years.
On physical exam, scleral icterus and a spleen tip
palpable.
Her WBC – 6,500,Hgb -11.6 g/dl, hematocrit 31%, MCV
83, retics 7%, platelets 220,000.
Blood smear: Spherocytes, increased retics
Case 8
Coombs test was negative.
The patient is most likely to respond to which of

the following:
A. Corticosteroids
B. Intravenous iron
C. Splenectomy
D. Eculizumab
266
Hereditary Spherocytosis
Courtesy Sam Lux
Hereditary Spherocytosis
• loss of RBC membrane in spleen spherocytes
• Chronic hemolysis early gall stones
• >65% are autosomal dominant – (+) family hx
• MCHC ≥ 36 in 50% patients
Diagnosis : Eosin-5-maleimide binding test by

flow cytometry.
Treatment : Folic acid
Splenectomy - limits hemolysis
267
Summary on Anemias
Iron deficiency
Anemia of chronic dx
Sideroblastic anemia Low MCV
Thalassemias
Renal failure
Low retic Aplastic anemia Normal MCV
index
Hypothyroidism
MDS High MCV
High retic Hemolytic anemias

Blood loss
index
Summary on Anemias
Diagnosis and Treatment of Iron Deficiency & AI
• Differentiating Fe Deficiency – High TIBC, low ferritin
vs. Anemia of Inflammation – Low TIBC, high ferritin
Soluble transferrin receptor – normal in AI

Bone marrow iron – normal in AI
Differentiating folate vs B12 deficiency

↑ Methylmalonic acid & neurological deficits in B12 def.
Intrinsic factor Ab - ∼99% specificity for pernicious
anemia
268
Summary on Anemias
Hemolytic anemias - ↑LDH, ↑ retic count
Spherocytes – AIHA or hereditary spherocytosis
Diagnosis AIHA – (+) direct Coombs test
Diagnosis of HS – Eosin-5-maleimide testing
Sickle Cell Disease

Urgent exchange RBC transfusion for Acute chest
syndrome. Target HbS<30%
Diagnosis and Treatment of PNH

Gold standard for diagnosis : Flow cytometry for
absence of CD55 &CD59
Treatment : with monoclonal Ab, Eculizumab
Commercial/Faculty Disclosures
• AMAG Pharmaceuticals – Scientific advisory

board
• Luitpold Pharmaceuticals - Consulting
269
References
1. Bain, BJ. Diagnosis from the Blood smear. N Engl J Med. 2005;353:498-507.
2. Weiss, G, Goodnought, LT. Anemia of chronic disease. N Engl J Med.
2005;352:1011-23.
3. Go, S,. Winters, J. How I treat autoimmune hemolytic anemia. Blood 2017;
129:2971-2979.
4. Young, N. Acquired Aplastic Anemia. JAMA 1999 July 21;282(3):271-278.
5. The Management of Sickle Cell Disease. National Institutes of Health.
National Heart, Lung and Blood Institute, Division of Blood Diseases and
Resources. NIH publication No. 02-2117. Fourth edition.
6. Ballas, S. Beyond the Definition of the Phenotypic complications of Sickle
Cell Disease: an Update of Management. The Scientific World Journal 2012;
Article ID 949535.
7. Rund, D. β-Thalassemia. N Engl J Med. 2005;353:1135-46.
270
Thrombophilia Testing
Jean M Connors MD
Medical Director, Anticoagulation Management and Stewardship Services

Hematology Division
Brigham and Women’s Hospital/Dana Farber Cancer Institute
Associate Professor, Harvard Medical School
Conflicts of Interest
Proteostasis
Consultant
Pfizer/Bristol-Meyers Squibb
Independent Review Committee
Scientific Ad Boards
Consultant
Unum Therapeutics
DSMB
Portola
Advisory Board
Dova Pharmaceuticals
Consultant
CSL Behring
Research funding to the institution
271
Agenda
• Brief overview of risks for VTE
• Thrombophilia testing
– Tests, timing, patient selection
• Inherited thrombophilias
• Antiphospholipid antibody syndrome testing
– Will not cover thrombophilia and pregnancy
Virchow's triad
Not just inherited

Kyrle P A , Eichinger S Blood 2009;114:1138-1139 factors
272
Seasonal
Seasonal Variation
variation ininVTE
VTE
Boulay BMJ 2001
VTE
Risks for hypercoagulable states
– Inherited
– Acquired: more common
• 35% US adults are obese, OR of 2.3 for VTE
• <10% have an inherited thrombophilia
– Mixed: all are additive or synergistic
“Provoked” vs “Unprovoked”
– Clear precipitating factor vs idiopathic or
unidentified risk factor
• Transient vs persistent provoking factor
• Unprovoked = idiopathic
273
Annual incidence of venous thromboembolism by age and sex.
Heit J A Hematology 2007;2007:127-135
Acquired Risk Factors for VTE

Transient/Provoked Idiopathic/
Persistent
Unprovoked
Surgery Obesity
Trauma (major trauma or Increasing Age ?????
lower-extremity injury)
Chronic Medical
Acute medical illness Illnesses
Immobilization Cancer and its
therapy
Estrogen-containing
-thalidomide
contraceptives or derivatives
hormone replacement
-Tamoxifen
therapy (drospirenone)
Inflammatory bowel
Pregnancy/puerperium disease
HIT Nephrotic syndrome
Myeloproliferative
Prolonged air travel neoplasms/PNH
Sickle cell disease
274
Acquired Deficiency
ANTITHROMBIN PROTEIN C PROTEIN S
Pregnancy Pregnancy
Liver Disease Liver Disease Liver Disease
DIC DIC DIC
Nephrotic syndrome
Major surgery Inflammation
Acute thrombosis Acute thrombosis Acute thrombosis
Treatment with:
Heparin Warfarin Warfarin
Estrogens Estrogens
• Levels decrease in the setting of above factors.

• Results drawn at initial presentation of VTE or while on anticoagulants
including DOAC often not valid.
• Abnormal results must be confirmed after discontinuation of
anticoagulation, at least 2 or more weeks after stopping warfarin, longer
for other factors such as estrogen
Established Inherited Thrombophilias

• Mutations create coagulation imbalance:
• Increased procoagulant activity
– Factor V Leiden mutation
• APC “resistance”
– Prothrombin gene G20210A mutation
• Increased prothrombin levels
– FVL and PTG comprise 50-60% of cases
• Decreased anticoagulant activity
– Multiple mutations lead to decreased level or altered
function (quantitative vs qualitative)
– Protein C: inactivates FVIII and FV
– Protein S: cofactor for protein C
– Antithrombin: inactivates thrombin, Xa
275
The “Hypercoagulable Workup”
Test for Factor V Leiden mutation

• APCR standard screen
• Genetic PCR confirm
PCR for Prothrombin G20210A mutation
Functional assay of Antithrombin

Functional assay of Protein C
Functional assay of Protein S
• Free Protein S Antigen
• Total Protein S Antigen (free + bound to C4bp)
Inherited Thrombophilias
• Extremely rare
– Dysfibrinogenemia
– Cystathionine beta synthase deficiency(homocysteinuria)
• WHAT NOT to test:

– Homocysteine and MHTFR polymophisms
• Decreased levels with B vitamins had no impact on recurrent
VTE or MI
• NORVIT (NEJM 2006) HOPE2 (NEJM 2006, Ann Int Med 2007)
VITRO (Blood 2007)
– FVIII
– XIII polymorphisms, IX, XI,XII
– PAI-1 4G/5G promoter, PAI-1
276
Thrombophilia Tests and Prevalence of Risk Factors.
Connors
Connors JM. N Engl J Med ;377:1177-1187 NEJM 2017
APLA work-up
Tests for Antiphospholipid Antibodies
• Lupus anticoagulant:
• Screen: functional clotting assays
• Sensitive PTT
• DRVVT
• Kaolin clotting time
• Confirmatory: remove APLA
• Platelet neutralization test
• Hexagonal phase phospholipids
• Anti-Cardiolipin and β2-glycoprotein I
antibodies
• IgG and IgM only
• No diagnostic role for other tests
277
Diagnostic Criteria for the Antiphospholipid Syndrome
Connors JM. N Engl J Med ;377:1177-1187
Connors NEJM 2017
Thrombophilias
• Indiscriminant testing in the inpatient or ER
setting should be avoided
• Results affected by
• Drugs—anticoagulants: heparin, warfarin, DOACS
• Acute setting—clot, inflammation, miscarriage
• Lab quality
• There is no need to know immediately—require at least
3 months anticoagulation for VTE regardless of
thrombophilia status
• Ravi Sarode at UTSW stewardship program: 63% of

inpatient thrombophilia panels cancelled after electronic
consult
278
Connors JM. N Engl J Med 2017;377:1177-1187
279
Thrombophilia Testing
• Why the controversy?
– Profound controversy over the utility of testing
• No data that results should affect care
– ASH Choosing Wisely Campaign 2013: “do not test
in the setting of provoked VTE due to strong risks”
– NICE, SIGN, ACCP—no recommendations
“It is not possible to give a validated recommendation as to how such
patients (and families) should be selected.” BJH 2010
• Misinterpretation of the significance of results
– Over treatment in the case of positive results
– False sense of security with negative results
• Studies demonstrate increased VTE risk for patients with a
family history of VTE despite negative results
VTE Recurrence Risk
Leiden Thrombophilia Study
N = 474
provoked and unprovoked 1st VTE
HR = 1.3 (95% CI, 0.8 – 2.0)
Christiansen JAMA 2005
280
VTE Recurrence Risk
ELATE Trial Sub-study

661 patients unprovoked
VTE tested for
thrombophilia.
Randomized to 2 INR
ranges after initial rx.
Events are while on
warfarin therapy.
Kearon Blood 2008
Inherited Thrombophilia Testing: Why Test?
Role of testing not well defined

– Lack of studies on utility of testing
– Lack of studies on efficacy/safety of prophylaxis
When does it change care?

– Explain etiology—patients have a lower threshold for first VTE
– Prophylaxis
– Pregnancy
– OCP/hormone therapy
– Family members
When does it not change care?

– Duration of anticoagulation therapy in most provoked VTE cases
– Antiphospholipid syndrome
– Malignancy
281
Algorithm for Selecting Patients with a First Venous

Thromboembolism (VTE) for Thrombophilia Testing.
Connors NEJM 2017
Summary
• The “hypercoagulable state” is a spectrum of
risk, with many patients having multiple additive
risk factors.
• Environment and acquired events add to
baseline genetic risk and are more common
than inherited thrombophilias.
• Inherited thrombophilias provide variable
baseline risk; testing is easy, whom to test and
what to do with results more complex. No
guidelines have been established.
282
Summary
• No data for efficacy or safety for VTE prophylaxis
based on thrombophilia status alone
• Toughest decision is duration of anticoagulation in

patients with unprovoked VTE. No risk prediction
scores incorporate inherited thrombophilia
status—Vienna, DASH, HERDOO2
• No available data support different treatment for

patients with vs without inherited thrombophilia
– Data demonstrate no difference in recurrence rates
– Clinical factors more important than test results
• Consult with a specialist can be helpful
DOAC:
Paradigm shift in Secondary VTE
Prevention Strategies
Jean M Connors MD
Medical Director, Anticoagulation Management and Stewardship Services
Hematology Division
Brigham and Women’s Hospital/Dana Farber Cancer Institute
283
Duration of Anticoagulation
• What factors impact the decision for how long
to treat with anticoagulation after a venous
thromboembolic event?
• Most significant factor is etiology:
– Provoked VTE with transient risk factor
– Unprovoked or idiopathic, with no obvious risk factors
• The extremes are easy (at first)

– Provoked: 3-6 months
– Unprovoked: indefinite
The presence of an inherited thrombophilia does not
mandate indefinite duration anticoagulation.
• Treatment duration is more difficult to

determine in patients with VTE that don’t
fall neatly into the provoked or unprovoked
category, or occur in patients with
continually present/non-modifiable VTE
risk factors.
• These patients may be viewed as having

VTE as a “chronic disease”
284
Provoked
– 3 months sufficient if risk Idiopathic
gone
– 1% risk per year of
recurrence, not changed by 3 Secondary
vs 6 months
Unprovoked/Idiopathic
– Recurrence rate highest in Prandoni Haematologica 2007
first 2 years
• 10% per year in 1st 2
years
• 40% at 5 years
VTE Recurrence Risk
A= post-op within 6 weeks

B= pregnancy VTE: 0 recurrence
C= unprovoked C
D= non-surgical risks
570 patients treated for

24-26 weeks, then followed A
for 2 years.
Baglin Lancet 2003
285
VTE Recurrence Risk
Recurrence of VTE according to site of first event

and sex
male, PE or proximal DVT

male, distal DVT
female, PE or proximal DVT
female, distal DVT
Delluc ASH 2016
Unprovoked VTE
Is longer duration better?
>90% risk reduction if continue anticoagulation

(full intensity warfarin)
Reduction in risk disappears when

anticoagulation is stopped, ie not modifying
underlying risk
At 5 years, 60% will have had unnecessary

treatment
286
Duration of Treatment
Need to consider
– Patient preference and lifestyle
– Recurrence risk
– Bleeding risk: case fatality rates similar for recurrent
VTE vs bleeding: with warfarin
• Recurrent VTE case fatality rate 0.3-1%
• Major bleeds 1-3%/yr fatal bleeds 0.4-0.8%
– Alternatives? ASA, risk modification
DOAC are changing the treatment paradigm for

patients with unprovoked VTE or need for
extended secondary VTE prophylaxis.
AMPLIFY-EXTENSION
• 2468 patients with VTE treated for 6-12 months in

randomized double blind study:
– Placebo, Apixaban 2.5 mg bid, Apixaban 5 mg bid
• Followed for 12 months for recurrent VTE and
bleeding
Placebo APIX 2.5 APIX 5
Recurrent p<0.001
VTE 8.8% 1.7% I.7%
Major 0.5% 0.2% 0.1%
Bleed
CRNM 2.3% 3.0% 4.2%
Bleed
Agnelli NEJM 2013
287
Kaplan–Meier Cumulative Event Rates AMPLIFY- EXT
AMPLIFY-EXT
90-93% unprovoked
7-10% provoked
Agnelli G et al. N Engl J Med 2013;368:699-708
Agnelli NEJM 2013
EINSTEIN-CHOICE
• 3365 patients with VTE treated for 6-12 months

randomized in double blind study to:
– Asa 81, Rivaroxaban 10 mg qd, Rivaroxaban 20 mg qd
• Followed for 12 months for recurrent VTE and
bleeding
ASA RIVA 10 RIVA 20

Recurrent p<0.001
VTE 4.4% 1.2% 1.5%
Major 0.3% 0.4% 0.5%
Bleed
CRNM 1.8% 2.0% 2.7%
Bleed
Weitz NEJM 2017
288
Kaplan–Meier Rates Cumulative Event Rates EINSTEIN-CHOICE
EINSTEIN Choice
60% provoked
40% unprovoked
Patients in equipoise for

need to continue
anticoagulation
Weitz JI et al. N Engl J Med 2017;376:1211-1222
Weitz NEJM 2017
Extended Duration Anticoagulation

Summary
• The benefit-risk profile is improved with reduced dose
or prophylactic dose apixaban and rivaroxaban,
bleeding rates are similar to aspirin or placebo.
• With follow-up of one year, reduced dose appears to
confer similar decreased risk of recurrent VTE as full
dose, with better efficacy than ASA or placebo.
• Both full and reduced dose have similar low risk of
major bleeding, although event rates in all groups
were low.
• CRNM bleeding is lower with reduced dose compared
to full dose.
289
My Approach:
Extended Duration Anticoagulation
• After full intensity anticoagulation for unprovoked VTE
consider change to reduced dose apixaban or
rivaroxaban
• For provoked VTE with persistent risks and for
patients in equipoise, switch to reduced dose
apixaban or rivaroxaban
– Unclear provoking factors
– Post thrombotic syndrome or significant persistent residual
vein thrombosis
– Obesity, heart failure, immobile
• Patients who should not be on reduced dose
– Antiphospholipid syndrome
– Mechanical heart valves (should not be on a DOAC)
– Atrial fibrillation Cancer
DOAC Related Bleeding

The basics:
– Stop anticoagulant
– Assess severity
– Baseline coag tests, CBC, creatinine
– When was the last dose of drug--short half life
T ½ 10-12 hours for all DOAC with normal renal function
– Standard supportive measures

• IV fluid, RBC, platelets, fibrinogen, antifibrinolytics
– Massive hemorrhage or trauma protocols
• Localization and management of specific site
Is immediate reversal of anticoagulation needed?
290
Idarucizumab
• PRAXBIND = idarucizumab
– Humanized monoclonal antibody fragment
that binds dabigatran
– 350 x higher affinity for dabigatran than
dabigatran has for thrombin
• FDA approved Oct 16, 2015

– RE-VERSE AD: “real world” study
– 5 gram dose IV bolus
– immediate and sustained reversal of
dabigatran activity over 24 hours
– Approved for bleeding and urgent surgery
Andexanet alfa
“AndexXa”
• “decoy” recombinant FXa
molecule with mutation in
catalytic site, lacks Gla
domain
• “universal” FXai antidote
• Bolus followed by 2 hour CI
• FDA approved May 3, 2018
– For reversal of apixaban and
rivaroxaban in patients with
major bleeding
291
Use of Antidotes
idarucizumab
How should targeted reversal agents be used?
Life-threatening bleeding
Emergency Surgery
Anticipated delayed clearance and bleeding
Not for use in:

Elective surgery or surgery that can be delayed
Elevated coagulation tests but no bleeding
Bleeding managed with routine supportive care
Jean M. Connors MD
jconnors@bwh.harvard.edu
292
Question 1
Question 1
A 67 year old man is seen by his PCP for advice about
duration of anticoagulation. Two months ago he had had
urgent cholecystectomy with the development of a left
calf vein DVT. The diligent surgery intern sent a
hypercoagulable work up which revealed heterozygous
Factor V Leiden. The patient was told he requires
lifelong anticoagulation. You advise:
A. Aspirin 81 mg once daily

B. Warfarin target INR 1.5-2.0
C. Apixaban 2.5 mg twice daily
D. Continue anticoagulation for one more month
Question 1
Question 1
ANSWER: D
This patient had a clear cut surgically provoked VTE.

The presence of factor V Leiden does not affect risk of
recurrent VTE and is not a reseaon to continue life-long
anticoagulation even with Factor V Leiden mutation.
Limited duration anticoagulation of 3 months is sufficient,
unless there is significant post-thrombotic syndrome or
other indications for anticoagulation.
293
Question 2
Question 1
A 42 year old man is seeing you for a second opinion. He
has been on warfarin for 11 months for an unprovoked VTE.
He reports that he was writing a novel at the time of the PE
and would sit for 6-8 hours writing. He weighs 125 kg with a
BMI of 39.5. renal function is normal. You decide to:
A. Continue warfarin with target INR 2.0-3.0 as he has been

doing well on this and is young with low bleeding risk
B. Stop anticoagulation completely as he has had adequate
treatment for acute VTE
C. Transition to rivaroxaban 10 mg once daily
D. Transition to edoxaban 30 mg once daily
Question 2
Question 1
Answer C
This 42 yo man is at high risk for recurrent VTE, especially
PE, given age, gender, and BMI, as well as duration of
treatment of only 11 months as risk for recurrence is highest
in the first 2 years. Although he reports sitting for extended
periods of time this is really not a recognized risk factor and
he should be classified as having an unprovoked VTE
Although he could continue with warfarin, reduced dose

rivaroxaban is an attractive alternative with less lifestyle
burden. Risk of bleeding should be lower although there has
been no head to head comparison with warfarin. Edoxaban
and dabigatran have not been studied at reduced dose in
this setting.
294
References
Thrombophilia testing and venous thrombosis.
Connors JM. N Engl J Med. 2017 Sep 21;377(12):1177-1187.
Apixaban for extened treatment of venous thromboembolism

Agnelli G, Buller HR, Cohen A, Curto M, Gallus AS, Johnson M, Porcari A,
Raskob GE, Weitz JI; AMPLIFY-EXT Investigators.
N Engl J Med. 2013 Feb 21;368(8):699-708.
Rivaroxaban or Aspirin for Extended Treatment of Venous

Thromboembolism.
Weitz JI, Lensing AWA, Prins MH, Bauersachs R, Beyer-Westendorf J,
Bounameaux H, Brighton TA, Cohen AT, Davidson BL, Decousus H, Freitas
MCS, Holberg G, Kakkar AK, Haskell L, van Bellen B, Pap AF, Berkowitz
SD, Verhamme P, Wells PS, Prandoni P; EINSTEIN CHOICE Investigators.
N Engl J Med. 2017 Mar 30;376(13):1211-1222.
References
Idarucizumab for Dabigatran Reversal--full cohort analysis.
Pollack CV Jr, Reilly PA, van Ryn J, Eikelboom JW, Glund S, Bernstein
RA,Dubiel R, Huisman MV, Hylek EM, Kam CW, Kamphuisen PW,
Kreuzer J, Levy JH, Royle G, Sellke FW, Stangier J, Steiner T,
Verhamme P, Wang B, Young L, Weitz JI.
N Engl J Med 2017; 377:431-441
Andexanet Alfa for Acute Major Bleeding Associated with Factor Xa

inhibitors. Connolly SJ, Milling TJ Jr, Eikelboom JW, Gibson CM, Curnutte
JT, Gold A, Bronson MD, Lu G, Conley PB, Verhamme P, Schmidt J,
Middeldorp S, Cohen AT, Beyer-Westendorf J, Albaladejo P, Lopez-Sendon
J, Goodman S, Leeds J, Wiens BL, Siegal DM, Zotova E, Meeks B,
Nakamya J, Lim WT, Crowther M; ANNEXA-4 Investigators. N Engl J Med.
2016 Sep 22;375(12):1131-41
295
Thrombophilia Tests and Prevalence of Risk Factors.
Diagnostic Criteria for the Antiphospholipid Syndrome
296
Bleeding Disorders 2018
Elisabeth M. Battinelli, M.D./Ph.D.

Assistant Professor of Medicine
Associate Physician
Hematology Division

Associate Physician
Disclosures
Sanofi, Consultant
297
http://medicinembbs.blogspot.com/2011/02/normal-hemostasis.html
Primary Hemostasis
Durkan, CVC 2008
298
Secondary Hemostasis: Coagulation

(exposed TF)
XIa
IX TF
Phospholipid
IXa VIIa
Phospholipid
X
VIIIa VII
VIII
Xa
Phospholipid
Va V
II
IIa
Fibrinogen Fibrin
Coagulation Cascade Screening Tests

Endothelial Injury
aPTT PT
TT
Soluble fibrinogen
Fibrin stabilizes platelet plug
299
Case 1: Pregnancy Panic

• A 32 yo woman from another state, pregnant with
her first child, is visiting friends and unexpectedly
goes into labor.
• She tells the covering obstetrician and OB
anesthetist at your hospital that she has von
Willebrand’s Disease and wants to know if it is
okay for her to have an epidural.
• You are asked to see her and provide advice re the
advisability of an epidural and possible treatment
for the von Willebrand’s disease.
Laboratory results
• Chemistries including BUN, creatinine and
glucose are normal
• CBC:
– Hb is 12.3 gm/dl
– Hct 35.5%
– WBC 9500
– Platelet count 450,000
– Differential is reported as normal
• Coagulation Parameters:
– PT 11.5 seconds (INR 1.1)
– PTT 28 seconds (nl < 35)
300
Your consultation
• She tells you that she has had occassional
nosebleeds since she was a child and has had
menorrhagia, also she bled a lot when she had her
wisdom teeth extracted.
• She is usually treated with the intravenous or intra-
nasal administration of ddavp for bleeding or
before surgeries.
• Her mother and one sister have similar symptoms
and respond to the same medication regimen.
• You try but are not able to reach her primary
hematologist.
301
Mannucci, 2004
Coagulation in Pregnancy
Increase Decrease
•Fibrinogen •Protein S
•vWF •Acquired resistance to
•VIII activated protein C
•VII •Fibrinolysis
•X (inhibition)
•IX •Platelet Count
•XII
302
vWF
• Large multimeric protein
– Synthesized in endothelial cells, megakaryocytes
– Stored in Weibel-Palade bodies of endothelial
cells, alpha granules of platelets
• 3 main functions
– Bind to collagen on subendothelial matrix
– Bind to platelet GPIb receptor
– Prolong half life of factor VIII from 24 mins to
12 hours
vWD
• Most common inherited hemostatic disorder,
prevalence up to 1%
• Mucocutaneous bleeding
• Epistaxis
• Easy bruising
• GI bleeding
• Post-op
• Surgery--immediately
• Dental procedures
• “Women’s health issue
• 75% women with vWD have menorrhagia
• often dx with first menstrual period or PPH
303
vWF: Laboratory Evaluation

• aPTT
• FVIII:C
• vWF:Ag
• vWF:RCo Ristocetin cofactor activity
• Multimer gel electrophoresis
vWD
• Mild vWD can be difficult to diagnose
• Levels vary and are affected by:
– Blood type
– Estrogen
– Inflammation
– Stress
– Smoking
304
vWD: Classification
– Type I: autosomal dominant, quantitative
decrease in vWF and concordant decrease in
all functions
• 70-80% of vWD cases
– Type III: homozygous recessive, almost no

detectable vWD
• Very Rare
vWD: Classification
Type II: Qualitative Abnormalities
A: decreased large mw multimers
10-15% of VWD
B: gain of function mutations, increased binding to

gpIb
M: loss of function mutations, decreased binding to
gpIb
N: loss of function mutations, decreased FVIII
binding
305
TYPE 1 vWD
• Quantitative deficiency
• Autosomal dominant trait
• 85% of patients
• Mis-sense mutations detected in some
but not all patients
vWD and Pregnancy

• Antigen levels increase with increased
estrogen
• Function does not change
• Increased risk of bleeding
– Miscarriage?
– 1st trimester
– Perineal hematomas
• 3/49 vaginal deliveries vs
• 2.2/1000 from 26,187 cohort study
306
vWD and Pregnancy

• Increased risk of post-partum hemorrhage
– Levels return to baseline over 7-21 days
– 20-25% patients with vWD have delayed PPH
– Mean onset 15.7 + 5.2 days
vWD: Treatment
DDAVP
• Release of stored vWF from Weibel-Palade bodies
• Onset of action within 30 mins
• Watch for Tachyphylaxis with repeated dosing
• Side effects include:
– Headache, HTN, flushing,N/V, hyponatremia and
seizures, uterine contractions
• Pre-procedure DDAVP challenge test to monitor
response
307
vWD:Treatment
vWF containing concentrates
• plasma derived pathogen-inactivated.
• Dose by FVIII or vWF levels.
– Humate-P
– Alphanate
Cryoprecipitate
• Pooled product from 10 donors*
• Only as last resort
Next steps
• Assume she has von Willebrand’s as
suggested by her history?
• Administer DDAVP to treat her
presumed vWD?
• Tell the patient and her doctors that you
are not certain what she has and how to
treat it and she must not have epidural
anesthesia?
308
What happens next?

• At 3 am your patient delivers a 7 lb 4 oz baby boy without
any bleeding
• You reach primary hematologist and learn that she indeed

has Type I vWD.
• Labs prior to pregnancy vWF Ag 30%, activity 35%, VIII

activity 45%
• Values two weeks before delivery vWF Ag 105%, activity

120%, VIII activity 150%
And then ….
• 48 hours after delivery you are making
rounds at the hospital and are paged by her
obstetrician because she has developed
uterine hemorrhage.
• What has happened?
309
VON WILLEBRAND’S DISEASE AND

PREGNANCY
• SELF CORRECTION IN (MOST) TYPE 1

PATIENTS
• POSTPARTUM BLEEDING IN 25% OF
PATIENTS
• INCREASED THROMBOCYTOPENIA IN
TYPE 2B PATIENTS
vWD: NHLBI Guidelines

• “We suggest that VWF ristocetin cofactor
activity and factor VIII levels of at least 50
IU/dL be achieved before delivery and
maintained for three to five days afterward (Grade
2C).”
• For patients who do not have this degree and
length of response on their own or following the
use of DDAVP, we suggest the use of VWF
concentrates (Grade 2C).”
NHLBI Guidelines for vWD 2008
310

“In patients who are known to adequately
respond to DDAVP, we suggest that
DDAVP be given after the beginning of
labor and as close to the time of delivery as
can be estimated (Grade 2C).”

“We suggest that regional anesthesia can be
considered if vWF and FVIII levels can be
maintained above 50 IU/dl (Grade 2C).”
311
Case 2: Can’t Stop Bleeding

• 23 year old female who presents with bleeding after wisdom tooth
removal. Patient has been referred to ED from dental clinic after the
dentist could not control the bleeding.
• Pt. has no history of epistaxis, gingival bleeding but does report that at
onset of menses her period was very heavy prompting her to regulate
menses with OCPs.
• No history of any other tooth extractions or surgical procedures.
• Family Hx: Mother with von Willebrand disease per report of patient.
No other bleeding history in the Family.
Can’t Stop the Bleeding: Labs

• WBC 8.6
• Hct 38
• Plt 235, normal appearance on smear
• PT 1.1
• PTT 32.5
• Fibrinogen 365
• von Willebrand Panel is normal
• Platelet Aggregation studies: Abnormal
312
Can’t Stop the Bleeding:

Platelet Aggregation Studies
• Absent platelet aggregation in response
to multiple agonists:
– ADP
– Thrombin
– Collagen
– Arachadonic Acid
• Normal Aggregation to Ristocetin
Signs of Thrombocytopathies
• Prolonged bleeding times
• Defective clot formation
• Bleeding tendency from childhood
• Low prevalence of these disorders but high

percentage of patients with unclassified
platelet dysfunction.
313
Classify platelet disorders by platelet

functionality
• Adhesion/Aggregation
• Activation/Signal Transduction
• Storage Granule Disorder/Release
• Aggregation
Platelet aggregation studies

• Aggregation
– Light transmission aggregometry using Chrono-
Log instrument
– ADP, arachidonic acid, collagen, epinephrine,
ristocetin
• ATP secretion
– Luciferin-Luciferase assay
– ADP, arachidonic acid, collagen,
epinephrine, ristocetin, thrombin
314
Platelet aggregation studies

• Requirements:
– Platelet count minimum 100K/uL
– 8 blue-top (citrate) tubes
• Common interferences:
– EDTA
– NSAIDs (e.g., aspirin, ibuprofen, indomethacin, COX-2
inhibitors)
– ADP receptor antagonists (e.g., clopidogrel, ticlopidine)
– GPIIb/IIIa antagonists (e.g., abciximab, eptifibatide,
tirofiban)
– Various other drugs (see Arch Pathol Lab Med.
2002;126:133–146)
Problems with Platelet Aggregation

Studies
• Numerous variables affect aggregation:

• Anticoagulant (sodium citrate best)
• Plt count in PRP
• Plt size distribution
• Time of day
• Temporal relation to meals and physical activity
315
Aggregometry
•Platelets shift from disc-like to a rounded form with

pseudopods transiently decreasing light transmission.
•Then they aggregate into clumps, increasing light
transmission.
The Aggregometer Tracings
Secondary wave (Dense granule

release, thromboxane A2
production)
Primary wave (Agonist

interacts with receptor)
316
Disorders in Platelet Aggregation
http://medicinembbs.blogspot.com/2011/02/normal-hemostasis.html
Aggregation Disorders: Glanzmann’s

Thrombasthenia
• History of muco-cutaneous bleeding
• Autosomal Recessive Inheritance
• Deficiency of GPIIb/GPIIIa complex
317
Diagnosis
• Platelet count and morphology is normal
• Bleeding time prolonged
• The hallmark of the disease is severely
reduced or absent platelet aggregation
in response to multiple agonists ie ADP,
thrombin, or collagen (except
Ristocetin)
• Flow cytometry: decreased mAb
expression of CD41 (GPIIb) and CD61
(GPIIIa)
Can’t Stop the Bleeding:

Management
• Platelet transfusions
• Supportive care: ddavp and amicar
• She improved after transfusions of platelets.
318
Case 3: Is it safe to operate?

• 75 y.o. female comes to you for pre-op
clearance for cardiac surgery.
• She is referred to your clinic for a prolonged
PTT.
• She has not seen a physician in 40 years.
• No bleeding history per the patient
Laboratory testing
• Factor XIII screen is normal

• Factor VIII level is 102%
• Factor IX level is 89%
• Factor XI level is 22%
319
Factor XI Deficiency
• Rare bleeding disorder

• Inherited as Autosomal Recessive
• Prolongs the PTT
• Characterized by variable bleeding history
• Incidence is 1 in 450 in the Ashkenazi
Jewish population and 1 in a million in non-
Jewish population.
Factor XI deficiency
• Usual sights of bleeding:

– Skin and mucousa
– Genitourinary tract
– Gastrointestinal tract
320
Factor XI deficiency
• Bleeding manifestations do not correlate with factor XI
levels
• Most bleeding episodes in patients with severe deficiency
are injury-related
• Spontaneous bleeding is rare
• May be associated with bruising, epistaxis, menorrhagia,
GI/GU bleeding, umbilical stump bleeding or bleeding
after surgery, trauma, dental procedures, pregnancy or
circumcision
• Up to 33% of patients with severe deficiency develop
inhibitors after replacement therapy
321
Treatment for Factor XI

Deficiency
• 10-20 ml fresh frozen plasma/kg, then 5-10 ml/kg
every 24 hours as necessary
• Antifibrinolytic therapy has been used in women
with factor XI deficiency and menorrhagia
• Patients with inhibitors have been treated
successfully with plasma, prothrombin complex
concentrates, and recombinant activated factor VII
• Note: factor XI concentrates available in Europe
monitor for thromboembolic complications
CASE 4
25 yo healthy woman
• CC: rash on lower
extremities
• PE:
• skin: rash
• HEENT: hemorrhagic bullae
in mouth
• Otherwise normal
• Labs:
• WBC 3.9 with normal diff; Hct 35
with normal MCV; Plts 14K
• PT/PTT normal
• electrolytes, LFTs normal
322
Thrombocytopenia
DECREASED PRODUCTION
• Marrow Failure
• Drugs
• Myelophthysis
• Nutritional deficiency (megaloblastic anemia)
SEQUESTRATION
• Splenomegaly (rarely <50,000)
INCREASED DESTRUCTION
• ITP
• TTP
• DIC
Evaluation of Thrombocytopenia
History
• Intercurrent illnesses
• Medication history
• History of autoimmune disease, LPD
Physical
• Bleeding manifestations (purpura, petechiae)
• Splenomegaly
• Adenopathy
Laboratory
• Examination of the peripheral smear
• Platelet reticulocyte count
• Antiplatelet antibodies??
• Bone marrow examination??
323
Laboratory Evaluation for

Thrombocytopenia
• CBC
• Peripheral Blood Smear
• Liver Function tests
• Thyroid Function tests
• Quantitative immunoglobulin levels
• Direct antiglobulin test
• Antiphospholipid antibodies
• ANA
• H pylori testing
• HIV, HCV, HBV
• VWD type IIb testing
ITP Therapy: Initial Treatment

Agents used for initial therapy of ITP:
• Corticosteroids
• High dose methylprednisolone
• Prednisone
• Dexamethasone
• IV Immunoglobulin
• Anti-D
324
“Standard of care”
• Prednisone 1mg/kg/day
• Taper—schedules undefined
• Response: 65-90%
• Long term response: 5-30%
• Of note, study that reported 30% assessed at
6 months.
• Most studies with longer follow-up report <10%
long term response to prednisone

Dexamethasone:
• Single course, 40mg/day X 4 (NEJM 2003; 349: 831)
• Initial response: 85%
• Relapse: 50%; 2nd course response: 100%
• Sustained: 42%
• Persistent response after D/C maintenance: 18%
• Multiple course, 40mg/day X 4 (BLOOD 2007;109: 1401)
• Two protocols: 6 cycles q28 days/4 cycles q14 days
• Initial response: 89%/86%
• RFS at 15 mos: 90% /81%
• Long term response:
• median 26mos with 6 cycles: 68%
• median 8 mos with 4 cycles: 74%
• Randomized trial Dex vs Prednisone (BLOOD 2016;127: 296)
• Durable responses with less toxicity
• Only a single course, so still need a trial of repeated courses of
dexamethasone
325

100 100
Patients achieving a remission (%)
Patients in ongoing remission (%)

75 75
p = 0.40 p = 0.007
50 50
25 25
Prednisone, n = 12
Dexamethasone, n = 14
0 0
0 1 2 3 0 30 60 90 120 150
a Months b Months
100 100

75 75
p = 0.55 p = 0.014
50 50
25 25
Prednisone, n = 9
0 0
0 1 2 3 0 30 60 90 120 150
c Months d Months
100 100

75 75
p = 0.18 p = 0.053
50 50
25 25
Prednisone, n = 7
0 0
0 1 2 3 0 30 60 90 120 150
e Months f Months
Matshke et al Acta Haem. 2016: 136:101-107
Therapy: Relapsed or Refractory ITP

Response Time to Duration of
Therapy Rate Response Toxicity Response
Splenectomy 80% 1-24 days Surgical 2/3 with no
complications, further Rx
thrombosis
Rituximab 60% response 1-8 weeks Allergic rxns; 15-20%

40% complete immune supp. sustained
Can be retreated
TPO Mimetics >80% response 2-3 weeks Unknown long- Up to 1.5-4 yrs
(plts >50K) term toxicity with continuous
Increased reticulin drug
Rapid fall of plts
with D/C of drug
Adapted from Blood. 2010;115:168-186
326
TPO Response to Thrombocytopenia
Hematol Oncol Clin North Am.23:1193, 2009.
Thrombopoietin Mimetics
Romiplostim Eltrombopag
• Fc-peptide fusion • Small molecule, oral TPO
protein (peptibody)
receptor agonist
• Binds to and activates the
TPO receptor to increase • Increases platelet
platelet counts production by increasing
• Approved for treatment of megakaryocyte growth
chronic ITP in US, EU,
Canada and Australia
TPOr binding
Fc Domain domain
Both approved for the treatment of chronic ITP
327
Take Home Messages: Case 4

• The treatment of ITP continues to be somewhat
controversial
• First-line therapy is corticosteroids—my
recommendation is pulse dexamethasone
• Second line therapy is probably still splenectomy
• However, rituximab is effective in many patients, is
probably the third most likely to give a long
remission, and can be repeated
• TPO mimetics work but have some known and
many possible unknown downsides.
Summary
• In bleeding disorders you must think about
primary and secondary hemostasis to
understand etiology.
Primary: Platelets disorder and vWD
Secondary: Coagulation factors and
fibrinolysis
History is Key for diagnosis and management.
328
Board Review Questions
Question 1
• You are asked to see a 37 yo woman
with history of vWD for consultation.
She asks: “Is it safe for me to have
elective knee surgery?”
• Pt. never had an surgery. She had
frequent epistaxis as a child and heavy
menses.
• FH: Mother has hx vWD but died young
(trauma). 5 uncles, one with bleeding
disorder.
329
Question 1
– F VIII:C 27
– vWF:ag 89
– vWF:RCo 75
– PTT 46 sec
• What type of vWD does this patient have?
Question 1
• A. Types I vWD. Treat with ddavp prior to
surgery.
• B. She does not have vWD because her
VWF:ag and :Rco are normal.
• C. You need more info. She could have type
2N or be a hemophilia A carrier.
330
2N vs. Hemophilia A carrier

• 2N should be consider in AR inheritance
with disproportionately low FVIII:C levels
compared with VWF levels.
• To prove 2N, a FVIII-VWF binding assay is
required.
• VWF gene mutation screening:R854Q at
amino-terminus of VWF subunit is most
frequent
2N vs. Hemophilia A carrier

• Treatment Plan?
• Hemophilia A carrier
– Low production FVIII
– Normal vWF
– Treat with recombinant FVIII
– Maintain levels in postop period
• vWD Type II N
– Normal FVIII production
– Endogenous vWF does not bind FVIII
– Treat with Humate-P
– Monitor levels in postop period
331
Question 1
• A. Types I vWD. Treat with ddavp at

delivery and postpartum.
• B. She does not have vWD because her

VWFag and Rco are normal.
• C. You need more info. She could have type

2N or be a hemophilia A carrier.
Question 2
• 38 y.o. Female is seen in the ER for
bleeding gums after a dental procedure.
She tells you that she has essential
thrombocytosis and takes daily
hydroxyurea and aspirin.
• A CBC is drawn and her platelet count
is 1600 X109/L million.
The ER team asks why this patient is

bleeding
332
Possible Answers
• A. The patient is on aspirin and

bleeding due to its anti-platelet effects.
• B. The patient has developed an
acquired von willebrand disease.
• C. This is a laboratory error and the
platelet count should be repeated.
Question 2
• This patient has developed an
acquired von willebrand disease in
the setting of thrombocytosis.
• Diagnosis is confirmed by von
Willebrand panel demonstrates low
ristocetin cofactor activity with normal
antigen levels.
• Aspirin should be used cautiously in
patients with platelets >1000 x 109/L
333
References
Mannucci, PM. Treatment of von Willebrand’s Disease. N Engl J Med. 2004 Aug 12;351(7):683-94.
Giuseppe L Diego A, Roberto Q, and Gianfranco C. Urgent monitoring of direct oral anticoagulants in
patients with atrial fibrillation: a tentative approach based on routine laboratory tests. Journal of Thrombosi
and Thrombolysis, May 2014 (epub).
Conolly, S. et al. Dabigatran versus Warfarin in Patients with Atrial Fibrillation. N Engl
J Med 2009; 361: 1139-1151.
Duga, S., Salomon O., Congenital Factor XI deficiency: an update. Semin Thromb Hemost. 2013
Sep;39(6):621-31. doi: 10.1055/s-0033-1353420. Epub 2013 Aug 8.
Gernsheimer, T., James, AH, and Stasi, R. How I treat thrombocytopenia in pregnancy. Blood. 2013 Jan
3;121(1):38-47. doi: 10.1182/blood-2012-08-448944. Epub 2012 Nov 13.

Associate Physician
No Disclosures
334
Hematology Cases:
Common, Complex, and Rare
Nancy Berliner, M.D.
H. Franklin Bunn Professor of Medicine
Chief, Division of Hematology
Professor of Medicine
DISCLOSURES
Nothing to disclose
Discussion of experimental drug:

Emapalumab (Novimmune, NI-0501)
335
CASE 1
• 30 year-old woman with no significant past

medical history
• 10 days prior to admission:
– mild URI
– 1-2 days of “loose stools” (non-bloody)
• 1-2 days prior to admission:
– progressive debilitating fatigue, exertional
dyspnea, and some easy bruising
Labs
134 96 88 4.0 15.0 32.0

92 9.60 111
3.5 21 12.31 1.2
11.8
U/A:
LDH: 1566 hCG: negative
Glucose: negative
Tbili: 1.3 DAT: negative
Bili: negative
ALT/AST: 29/35 C3: 79 (normal 90-180)
Ketones: 1+
TP: 4.2 C4: 11 (10-40)
Blood: 3+
Alb: 3.0 Stool culture negative;
Protein: 3+
including E. coli O157:H7
Nitrite: negative
Leuk Est: neg
RBC: 4-10
WBC: 0-4
336
Peripheral Blood Smear
Laboratory features in TTP vs. HUS
Furlan M et al. N Engl J Med 1998;339:1578-1584.
337
Atypical HUS: Overview
• Arises through dysregulation of the alternative

complement pathway
• Multiple loss-of-function and gain-of-function
mutations in multiple complement pathway
genes are known to predispose
– Factor H, factor I, MCP, thrombomodulin, factor B, C3
– ~50% of patients have heterozygous mutations
– ~10% have more than one mutation
– Penetrance is 50%; additional genetic/environmental
modulators likely to be at play
• Renal involvement is predominant
Rosove, Sem Arthritis & Rheumatism, 2013
aHUS: The Alternative complement pathway
338
Atypical HUS: Complement Factor Mutations
Complement levels
are variable
Nester, ASH Book, 2012
Atypical HUS: Serum complement levels
Loirat et al., Ped Nephrol, 2008
339
Treatment Prior to Eculizumab for aHUS

• Plasma Exchange
– Recommended treatment prior to Eculizumab based on case
series
– No RCTs. Loirat et al. (Ped Neph 1988) showed no benefit of
plasma infusion, but did not distinguish HUS and atypical HUS
• Transplant
– High rate of recurrence with renal transplant alone unless MCP
mutation.
– Case reports of liver and renal transplant shows proof of
principle, but 2 cases with bad outcomes (Remuzzi et al. Lancet
2002)
Kim et al. Pediatric Neph 2011
Treatment of aHUS: Plasma infusion/pheresis

• No prospective controlled trials of plasmapheresis
• Plasma infusion may correct defects in patients with
quantitative complement factor deficiencies
• Plasma exchange may be required in patients with
antibodies (i.e. anti-H) or in patients with mutations
causing protein dysfunction
• Certain complement proteins (i.e. MCP) are membrane
bound and defects cannot be corrected by plasma therapy
• 2009 European Study Group guidelines for aHUS: “consensus”
– Plasmapheresis within 24 hrs of diagnosis
• Repeat daily x 5 days, then 5x weekly x 2 weeks
• With this “standard” treatment:
– ~60% initial response
– ~25 mortality rate
– ~ 50% left with CKD
– Outcomes vary by mutation type
340
Prognosis in Atypical HUS

• Prognosis
– Overall 5 year survival-52% children, 33% adults (Fremeaux-Bacchi et
al. J Am Soc Neph 2013.)
– Based on data pre-eculizumab therapy
– Genotype is predictive of outcome
• MCP-better prognosis. Only 35% with ESRD at 5 years
• CFH-worse prognosis. 77% with ESRD or died.
Treatment of aHUS: Use of eculizumab
• Humanized monoclonal antibody against C5

• First-in-class terminal complement inhibitor
• Approved for PNH in 2007
• Approved for aHUS in 2011
• World’s most expensive drug - $409,500 per year
• Requires meningococcal vaccination prior to initiation
and long-term antibiotic prophylaxis
• Has been reported to be effective for aHUS in multiple
case reports and a recent prospective trial
• No randomized trial of eculizumab vs. plasma exchange
has been conducted
Kavanagh, Semin Nephrol, 2013
341
Eculizumab blocks C5, inhibiting terminal

complement activation
Edwin et al. Molecular Immunology 2013
Treatment of aHUS: Use of eculizumab

• Two separate 26-week Phase II studies
– Trial 1: patients with aHUS and progressing TMA
– Trial 2: patients with aHUS of long duration, CKD, and on
prolonged plasmaphersis/infusion treatment
Outcomes were similar in patients in which a

complement mutation was not identified
Legendre et al., NEJM, 2013
342
Treatment of aHUS: How long?
Originally suggested that lifelong therapy should be continued

….especially by the company that makes eculizumab
But…
Study of 17 patients with aHUS treated with eculizumab
Taken off eculizumab and monitored
13/17 patients did not require further therapy
Those that recurred were successfully treated
Blood 2017 130:368
Take Home Points: Case 1

TTP
– Hereditary (Upshaw-Schulman syndrome)-ADAMTS13 deficiency
– Acquired: Antibody to ADAMTS13
• Idiopathic--usually IgG inhibitor to ADAMTS13
• May be associated with pregnancy, malignancy, lupus
• Response to plasma exchange in 90+%
• Relapse rate 10-30%
HUS
• Shiga toxin producing E. Coli
• Seen almost entirely in children
• Excellent prognosis with no therapy
Atypical HUS
• Genetic mutations, and rarely antibodies that cause inappropriate
activation of alternative complement cascade
• Grim prognosis in the pre-eculizumab era
• Prognosis with eculizumab still being defined
George et al. Am Soc Hematology 2012
343
CASE 2
48 y.o. male w/ CAD, thrombocytosis
w/ LLE extremity DVT worsening on warfarin
HPI:
• 13 yrs. PTA: RLE DVT post-vein stripping (warfarin × 6 mo)
• 10 yrs. ago RLE DVT s/p angioplasty (warfarin × 5 yr)
• off anti-coagulation × 5 yr
• 3 weeks PTA: to outside hospital w/LLE swelling, no precipitant
• Dx: LLE DVT; Rx heparin → warfarin
• D/C’d home
• Represents with pain, discoloration, and increased LLE
swelling.
PMH
• LLE DVT X1; RLE DVT X2
• s/p venous stripping
• CAD s/p angioplasty
• Hypertension
• Thrombocytosis; known JAK2 +
• MEDS: warfarin, ASA, metoprolol
CASE 2
PE
BP 112/60 HR 74 RR 16 Temp 98°F
Exam benign with exception of LLLE
LLE >> RLE; tender to deep palp, + erythema
Pulses intact
Labs
14 PT/INR 24/3.9
12 678
44 PTT 50
Electrolytes, BUN, Creatinine normal
344
CASE 2
Radiographic Studies
US:
• New occlusive thrombus L ext iliac vein to popliteal vein
• Old non-occlusive thrombus R femoral to popliteal
CT Scan:
• New DVT L ext iliac vein to femoral vein; also hypogastric
• Old DVT R ext iliac to fem
• Infra-renal IVC occlusion with collaterals
• Dilated inferior mesenteric veins
• Calcifications within the pelvic veins
CASE 2
Hospital Course
• Diagnosed as warfarin failure
• Heparin begun and tPA thrombolysis
• Initially improved, then worsened
• Transferred to MICU, Hematology consulted
Hypercoagulable workup
• JAK2 positive
• Factor V Leiden positive (homozygous)
• Bone marrow normal
345
What happened??
CAUSES OF THROMBOPHILIA
Congenital Disorders Acquired Disorders

• ATIII deficiency • Pregnancy, estrogen
• Protein C deficiency • Immobilization
• Protein S deficiency • Trauma,
• Factor V Leiden • Antiphospholipid syndrome
• Prothrombin 20210 • Malignancy
• Hyperhomocysteinemia • Nephrotic syndrome
• HIT
• Myeloproliferative Dx
• PNH
• Hyperhomocysteinemia
346
MPN: Pro-thrombotic
Thrombosis at diagnosis:
• 40% PV
• 30% ET
Arterial > venous thrombosis
Microcirculatory disorders: platelet thrombi
• Erythromelalagia
• Visual symptoms—occular migraines
• Neurologic symptoms: TIA like
Risk stratification:
• PV and ET patients at HIGH risk for thrombosis:
• Prior thrombosis
• Age > 60
• Cardiovascular risk factors? (DM, HTN, cholesterol, smoking) difficult
to distinguish disease-specific risk vs these
Venous clots respond to anticoagulation
What causes poor response to adequate anticoagulation?
Consider direct thrombin activation
347
Hematology 2006 The American Society of Hematology
Heparin-Induced Thrombocytopenia (HIT)
Diagnosis:
• HIT is more common in surgical patients, where platelet
counts typically rise postoperatively
• Typically seen at 1-2 weeks of prophylaxis or Rx with
heparin
• HIT: Relative fall to below 50% of the peak platelet count
• Rarely if ever occurs within the first five days of heparin
therapy, except with recent exposure to heparin
• Less common with LMWH, but once a patient has HIT,
antibodies are cross-reactive
• No absolute platelet number is diagnostic of HIT; more
important to consider in the appropriate clinical setting
348
HIT: Pre-test clinical score: “4 T’s”

Thrombocytopenia
• <30% drop in platelet count: 0 points
• 30-50% drop in platelet count: 1 point
• >50% drop in platelet count: 2 points
Timing
• < 4days with no prior exposure in last 100 days: 0 points
• >10 days or <1 day with exposure in last 30-100 days: 1 point
• 5-10 days after heparin exposure: 2 points
Thrombosis
• None: 0 points
• Suspected or non-necrotizing skin lesions: 1 point
• Confirmed thrombosis, skin necrosis: 2 points
oTher Likely Cause
• None: 2 points
• Possible: 1 point
• Definite: 0 points
< 3: Low; 3-5 Intermediate; >5 High Suspicion
J Thromb Haemost 2006; 4: 759–65.
HIT: Timing of Low Platelets and Thrombosis
Warkentin, T. E. Hematology 2006;2006:408-414
349
HIT
Immune mediated IgG Ab response to heparin/PF4

complex
• CVS > surgical > medical patients
• UFH (bovine>porcine) >> LMWH
8% of heparin treated patients develop Ab
1-5% develop HIT thrombocytopenia
• 30-50% of these develop thrombosis
• 20-30% morbidity and mortality rate
HIT Pathogenesis Patient makes

IgG Antibody
against the complex
Heparin then binds

to PF4,
Fc portion of this antibody
forming complex
binds to platelet receptor,
activating platelets
Heparin stimulates
PF4 release from -Thrombin generation
platelet granules -EC activation
Activated platelets
aggregate and release PF4
Images.md
350
Warfarin does NOT inhibit coagulation!
• Warfarin inhibits γ-carboxylation of clotting

factors and Proteins S and C
• It lowers the levels of factors, but does not
inhibit coagulation
• Clearly shown not to prevent thrombosis in HIT
• Can predispose to coumadin skin necrosis in the
setting of thrombin activation of any sort-
including, but not restricted to, HIT.
Heparin-Induced Thrombocytopenia
Treatment:
• STOP HEPARIN
• STOP WARFARIN
• If patient on warfarin, administer Vitamin K to reverse it
• Treatment with direct thrombin inhibitors until clinically
improved and plt count has returned to (near) normal
• Overlap warfarin and DTI X at least 5 days
• Warfarin to INR of 3-4 (depends on DTI), and overlap at
least 2 days with therapeutic INR
• Warfarin for 3-6 months in the setting of thrombosis
• Duration in the absence of thrombosis…no data
351

• Venous thrombosis usually responds to
anticoagulation
• If you see recurrent thrombosis, think of
malignancy, anti-phospholipid syndrome, or HIT
• Thrombosis in HIT may PRECEDE the
development of thrombocytopenia
• Treatment with direct thrombin inhibitor
• Therapy in patients on warfarin includes reversal
of warfarin
CASE 3
39 y/o female home maker, wife and mother of three with no
significant past medical history
• 12/12/04 – fevers, chills, rigors

– WBC 3.9, Hct 34.8, plt 148
– Fevers resolved after a 10 day course of doxycycline
• 1/05— recurrent fevers

– CBC and chemistries - normal
– bone marrow biopsy: normocellular w/small, poorly formed
granulomas
• 2/12/05 – presented with fever and back pain

– ROS – fevers, chills, rigors, back pain, generalized fatigue
352
CASE 3
Outside Hospital:
• WBC 1.1 (ANC 600), Hct 23.5, platelets 77
• ESR 9
• Blood cultures negative
• CXR normal
Transferred on vancomycin, ceftazadime, doxycycline
On arrival:
• WBC 0.9 with 18 segs, 42 bands, 26 lymphocytes, 9 monocytes, 5
metamyelocytes, 1 nucleated RBC
• Hct 22.8 with reticulocyte count of 2.3%, platelets 73
• Na+ 134, K+ 3.4 Cl- 102, HCO3- 25, BUN 12, Cr 0.8
• Tbili 0.58, ALT 55, AST 128, AP 97, alb 3.2, LDH 1350
• INR 1.47, PTT 30.5, D-dimer >1.0, FSP >40, fibrinogen 176
• Iron 50, IBC 245, % iron saturation 20, ferritin 1460
• CRP 5.3
Bone Marrow Aspirate

This image cannot currently be display ed.
353
Hemophagocytic Lymphohistiocytosis
• Related to impaired cytolytic activity of T cells and NK

cells
• Uncontrolled T-cell activation with increased secretion of
TH1 cytokines, including IFNγ, IL-12, and IL-18, which
activate macrophages
• Results in proliferation and activation of benign
macrophages, and is associated with phagocytosis of
hematopoietic elements throughout the RE system
• Familial HLH is associated with identified defects in
cytotoxic T cells and NK cells
• Mechanism of acquired forms of HLH is unknown
HLH: Diagnostic Criteria

Molecular Diagnosis consistent with HLH
OR
Clinical and laboratory criteria (5/8)
• Fever
• Splenomegaly
• Cytopenia
• Hypertriglyceridemia and/or hypofibrinogenemia
• Fasting triglycerides > 3mmol/l
• Fibrinogen < 1.5 g/l
• Ferritin > 500
• sCD25 > 2400U/ml
• Decreased or absent NK-cell activity
• Hemophagocytosis in bone marrow, CSF, or nodes
These criteria are entirely based on PEDIATRIC patients
354
Adult HLH: A newly recognized epidemic?
• In the last 10-15 years, there has been an explosion of

reports and studies of adult HLH
• Apparent increase in HLH in adults is unexplained
• Newly-prevalent vs newly-recognized
• Either way, is an increasingly common diagnosis
• Despite this, the diagnosis continues to be driven by
criteria developed in the pediatric population
• Diagnosis and treatment in adults is evolving
Hemophagocytic Lymphohistiocytosis
Genetic HLH
• Familial HLH
• Known gene defects (perforin, munc 13-4, syntaxin 11)
• Unknown gene defects
• Immune deficiency syndromes
• Chediak-Higashi syndrome
• Griscelli syndrome
• X-linked lymphoproliferative syndrome
Acquired HLH
• Infection associated hemophagocytic syndrome
• Autoimmune disease (macrophage activation syndrome)
• Malignancy (T cell lymphoma)
• Drug hypersensitivity reaction (?)
355
CTL Killing of Target Cells

• Perforin resides within the granules
Figure 12-10 of NK cells and CTLs
• Granules are released into the
“immunological synapse” at the site
of contact between a CTL and a
target cell
• The granule membrane fuses with
the cell membrane, and releases the
contents of the granules
Copyright © 2005 Elsevier Inc. (USA) All rights reserved.
• Perforin binds to and makes “pores”
in the target cell membrane.
• May allow entry of granzymes,
important mediators of apoptosis of
the target cell. Alternatively, it may
be necessary for the release of
granzymes from the endocytic
vesicle.
• Results in killing of the target cell.
Perforin in T Cell Homeostasis
• During acute T cell responses, T cells interact with

APCs, and cells may be activated, remain silent, or die
(activation-induced cell death).
• Deletion is promoted by high affinity interactions, high
dosage, and long duration of antigen stimulation.
• Perforin is required for activation-induced T cell death
Curr Opin Hematol 15: 359-67, 2008
356
Surveys of adult HLH

• 103 adult HLH patients from single hospital in China:
– 48% hematologic malignancy
– 14% autoimmune disease
– 23% infectious disease
– 23% unknown
Li et al, Medicine 2014; 93: 100
• 73 adult HLH patients from WUSL, St Louis
– 40% infectious disease
– 29% hematologic maliginancies
– 18% unknown
Otrock and Eby AmJHematol 2015; 90:220
• 68 patients in Partners hospitals, Boston
– 49% malignancy
– 33% infectious
– 15% unknown
Schram et al, BrJHaematol 2015; in press
• 62 patients at Mayo Clinic

– 62% malignancy
– 34% infectious
– 6% unknown
Parikh et al, Mayo Clinic Proc 2014; 89:484
HLH-94 Protocol
357
Therapy for Adult HLH

• Treatment in adults generally follow HLH-94
- Exception: MAS; usually respond to steroids + IST alone
- Some protocols modify the dose of etoposide in adults
- We generally use tacrolimus rather than CsA for less renal
toxicity
• Adults do less well than children
– May be delay in diagnosis and therapy
– May be more complex etiology
– Affected by much higher rate of associated malignancy
Treatment/outcome of adult HLH
Schram et al, BrJHaematol 2015; in press
358
Salvage Therapy for Adult HLH

1) Alemtuzumab (anti-CD52):
– Retrospective study of 22 pts (all ages) receiving alemtuzumab after prior
induction therapy
– 77% of pts made it to SCT
– Long term probability of survival estimated at 64%
Marsh RA et al, Pediatr Blood Cancer, 2013
2) DEP regimen:
– Multi-center, prospective study of Doxil/Etoposide/Methylpred for adult
refractory HLH
– 29 lymphoma, 22 EBV, 4 FHLH, 8 unknown
– CR in 27%, PR in 49%; 29/48 with CR/PR survived to chemo or SCT
Wang Y et al, Blood, 2015
3) Emapalumab (Novimmune, NI-0501)
– Anti IFNγ antibody
– Highly successful treatment of children with relapsed/refractory HLH with 75%
reaching transplant
– Awaiting trials in adults
HSCT for Adult HLH

• Lack of large prospective studies
• CIBMTR Query:
– 47 adults with HSCT from 2001-2012
• 37 with FHLH or acquired HLH
– Mostly MRD/MURD (1 haplo, 1 CBT)
– 56% with MAC; 44% with RIC
– Estimated 2 yr OS was 57%
Nikiforow S et al, BBMT, 2014:S243
359
Principles of Therapy for HLH
(1) Combination of immunosuppressive and cytotoxic

therapy to control hyperinflammatory state, plus
(2) disease-specific therapy, followed by
(3) Allo-SCT for familial or recurrent HLH
Schram, Berliner, Blood, 2015

• Diagnosis of HLH in adults is still based on pediatric
diagnostic criteria
• Etiology of HLH in adults is more skewed toward
malignancy-associated disease
• Treatment of HLH in adults still parallels the approach
to pediatric patients. There is increasing evidence that
most patients should undergo HSCT
• MOST IMPORTANT: It is more common than you think;
if you don’t consider the diagnosis, you won’t make it!
360
DISCLOSURES
Nothing to disclose
QUESTION 1
A 43-year old man with no past medical history presents to the
hospital with a two month history of fevers and night sweats.
Repeated cultures by his PCP have been negative, and despite three
admissions to the hospital, his illness has evaded diagnosis. He has
lost 20 pounds, and he has been unable to work for 6 weeks.
Physical examination reveals a cachectic appearing young man with a
palpable liver and spleen. He has no adenopathy. Laboratory
studies reveal pancytopenia with an ANC of 726 and a platelet
count of 15,000, elevated transaminases, and diffuse infiltrates on
chest CT. He is begun on empiric antibiotics. Which of the following
tests is LEAST likely to be helpful in making a diagnosis:
A. Bone marrow aspirate and biopsy

B. Liver biopsy
C. Serum soluble CD25
D. Serum ferritin
361
QUESTION 1
Which of the following tests is LEAST likely to be helpful in making a
diagnosis:
A. Bone marrow aspirate and biopsy
B. Liver biopsy
C. Serum soluble CD25
D. Serum ferritin
ANSWER: B
This patient almost certainly has hemophagocytic
lymphohistiocytosis (HLH). He has pancytopenia,
splenomegaly, and fever, with no obvious infectious source.
Other diagnostic features that would support the diagnosis
would be the finding of hemophagocytosis on bone marrow,
an elevated serum ferritin, an elevated soluble CD25, elevated
triglycerides, and low fibrinogen. A liver biopsy, while it might
show hemophagocytosis, is likely to be dangerous in someone
with this low a platelet count, and is not considered a
particularly helpful diagnostic procedure.
QUESTION 2
A 60 year old man undergoes coronary artery bypass grafting. He
has a history of chronic atrial fibrillation treated with warfarin.
Following surgery he is placed on a heparin bridge and restarted on
his home dose of warfarin. On the sixth postoperative day, his INR is
2.5, his heparin is stopped, and he is preparing for discharge.
However, he complains of R leg pain and swelling and is found to
have a deep vein thrombosis in the R superficial femoral vein. His
platelet count is noted to have fallen from 240K on admission to
120K. Most appropriate therapy is:
A. Restart heparin as he is a warfarin failure

B. Start low molecular weight heparin and continue the
warfarin with a longer period of bridging
C. Start a direct thrombin inhibitor
D. Give 5 mg IV Vitamin K and start a direct thrombin inhibitor
362
QUESTION 2
Most appropriate therapy is:
A. Restart heparin as he is a warfarin failure
B. Start low molecular weight heparin and continue the warfarin
with a longer period of bridging
C. Start a direct thrombin inhibitor
D. Give 5 mg IV Vitamin K and start a direct thrombin inhibitor
ANSWER: D
The patient has heparin induced thrombocytopenia with
thrombosis (HITT). Even though he is off heparin, patients
with untreated HIT can have thrombotic complications for up
to 6 weeks after discontinuing heparin. His warfarin should be
discontinued until after he has been treated with a direct
thrombin inhibitor (DTI) and his platelet count has recovered;
furthermore, the warfarin should be reversed to prevent
warfarin skin necrosis and to prevent undertreatment with
the DTI. He can then be restarted on warfarin while remaining
on the DTI until he has a therapeutic INR.
REFERENCES
George JN, Al-Nouri ZL. Diagnostic and therapeutic challenges in the
thrombotic thrombocytopenic purpura and hemolytic uremic syndromes.
Hematology / the Education Program of the American Society of
Hematology American Society of Hematology Education Program
2012;2012:604-9.
Legendre CM, Licht C, Muus P, et al. Terminal complement inhibitor
eculizumab in atypical hemolytic-uremic syndrome. The New England
journal of medicine 2013;368:2169-81.
Schram AM, Berliner N. How I treat hemophagocytic lymphohistiocytosis in
the adult patient. Blood 2015;125:2908-14
Warkentin TE. Think of HIT. Hematology / the Education Program of the
American Society of Hematology American Society of Hematology
Education Program 2006:408-14.
Wei Y, Ji XB, Wang YW, et al. High-dose dexamethasone vs prednisone for
treatment of adult immune thrombocytopenia: a prospective multicenter
randomized trial. Blood 2016;127:296-302.
363
Board Review in Hematology
Nathan T. Connell, M.D., M.P.H.

Associate Physician
Hematology Division, Department of Medicine

Disclosures
• No disclosures
364
Question 1
A 35 year-old woman comes to the emergency room

complaining of exertional dyspnea over the past several
days. Her past medical history is unremarkable. She
takes no medications and denies any other systemic
symptoms. She is afebrile and her vital signs are stable.
Physical examination is only remarkable for a few small
ecchymoses on the upper and lower extremities, mild
scleral icterus, and a grade I/VI holosystolic murmur.
Question 1
Laboratory studies reveal:

White blood cell count 9,600/mm3 (4,000-10,000)
Hematocrit 23% (36-48)
Platelets 36,000/mm3 (150,000-450,000)
PT 12 s (11-13)
PTT 26 s (22-34)
Fibrinogen 450 mg/dL (200-400)
Creatinine 0.8 mg/dL (0.7-1.3)
LDH 1535 (107-231)
Peripheral blood smear reveals decreased platelets and moderate
schistocytes.
365
Question 1
Which of the following is the appropriate next step:

A. Send serum toxicology panel and stool studies for
E. coli 0157:H7
B. Initiate therapeutic plasma exchange as soon as

possible
C. Observation for now, initiate plasma exchange if

the platelet count < 20,000/mm3
D. Observation for now, initiate plasma exchange if

the patient becomes febrile or the creatinine rises
Question 1
What are the key clinical data provided?
Thrombocytopenia, anemia, and schistocytes
366
Question 1
The following therapy is now most appropriate:

A. Send serum toxicology panel and stool studies for
E. coli 0157:H7
B. Initiate therapeutic plasma exchange as soon

as possible
C. Observation for now, initiate plasma exchange if

the platelet count < 20,000/mm3
D. Observation for now, initiate plasma exchange if

the patient becomes febrile or the creatinine rises
TTP smear: schistocytes
367
Diagnosis of TTP
Two major characteristics of the classic pentad

are enough to diagnose TTP:
Microangiopathic hemolytic anemia
Thrombocytopenia
Others are secondary manifestations of the basic
pathophysiology and may or not be present
Fever
Neurologic symptoms
Renal Insufficiency/Failure
Pathophysiology of TTP: ADAMTS13
Moake, J. L. N Engl J Med 2002;347:589-600
368
Course of TTP
About 90% of cases of TTP improve with
plasma exchange
About 30% of these patients relapse, may
respond to another course of plasma
exchange
About 10% of patients have refractory
disease after a prolonged course of
pheresis – consider rituximab, splenectomy,
cytotoxic agents
Question 2
A 54 year-old man of Greek ancestry is seen for follow-up

3 days after completing treatment for an upper respiratory
tract infection with a course of
trimethoprim/sulfamethoxazole. On review he notes that
during the past week his cough has improved, although
he now feels somewhat more short of breath with exertion
and is more fatigued than one week ago.

Reticulocyte count 11% (1-1.5%)
MCV 101 fL (80-95)
Platelets 3
175,000/mm (150,000-
450,000)
369
Question 2
The most appropriate course of action at this time is:
A. Obtain folate and vitamin B12 levels
B. Observation, return visit in a few weeks for further

laboratory studies
C. Test for glucose-6-phosphate dehydrogenase

deficiency
D. Bone marrow aspirate and biopsy
Question 2
What are the key clinical data

provided?
Anemia, with reticulocytosis, following a
course of antibiotics, in a man of Greek
ancestry
370
Question 2
The most appropriate course of action at this time is:
A. Obtain folate and vitamin B12 levels
B. Observation, return visit in a few weeks for further

laboratory studies
C. Test for glucose-6-phosphate dehydrogenase

deficiency
D. Bone marrow aspirate and biopsy
Abnormal G-6-PD Variants
A- isoform
G6PD activity declines due to enzyme instability
during the red cell life-span
present in 10% of African-American males
G6PD levels in reticulocytes are normal
May require Heinz Body identification to diagnose
during acute hemolytic episode
Mediterranean Isoform
essentially no G6PD activity in RBC
present in 5% of Mediterranean people
Can always be diagnosed
371
Heinz body prep
Heinz bodies: oxidized, denatured precipitates of hemoglobin
Oxidant Stressors in G-6-PD Deficiency

• Antibacterials • Miscellaneous
– Dapsone – Doxorubicin
– Nalidixic acid – Methylene blue
– Nitrofurantoin – Phenazopyridine
– Sulfamethoxasole (PYRIDIUM)
– Sulfapyridine – Phenylhydrazine
• Antimalarials – Probenacid
– Primaquine • Environmental/Food
– Pamaquine – Fava beans
– Naphthalene (moth
balls)
– Toluene blue
372
Physiology of G6PD Deficiency
Toxicity of Oxidative Stress in G6PD Deficiency
2H2O H2O2 Hemoglobin
Sulf-hemoglobin
GSSG 2GSH
Heinz bodies
NADPH NADP
6-PG G6P Hemolysis

G6PD
Question 3
A 35 year-old woman originally from the Dominican

Republic comes to clinic for her first visit. She has no
significant medical problems and has had two children.
After the birth of her second child three years ago she was
told to take iron tablets twice daily. Aside from an oral
contraceptive, this is her only medication.

MCV 66 fL (80-95)
Platelets 3
256,000/mm (150,000-450,000)
Fe 150 µg/dL (40-159)
TIBC 275 µg/dL (250-400)
373
Question 3
The most appropriate next steps are:
A. Phlebotomy for hemochromatosis

B. Continue current iron therapy, initiate work-
up for chronic inflammatory process
C. Switch therapy from oral iron sulfate to
intravenous ferric gluconate
D. Discontinue iron therapy, send ferritin and
hemoglobin electrophoresis
Question 3
Key Laboratory studies reveal:
MCV 66 fL (80-95)
Fe 150 µg/dL (40-159)

TIBC 275 µg/dL (250-400)
374
Question 3
The most appropriate next steps are:
A. Phlebotomy for hemochromatosis

B. Continue current iron therapy, initiate work-
up for chronic inflammatory process
C. Switch therapy from oral iron sulfate to
intravenous ferric gluconate
D. Discontinue iron therapy, send ferritin and
hemoglobin electrophoresis
Smear: thalassemia
Hypochromia, microcytosis
375
Question 4
A 74 year-old man with diabetes mellitus controlled with an

oral agent presents for routine follow-up. His other medical
problems include hypertension, for which he takes an ACE
inhibitor, and benign prostatic hypertrophy. On review of his
records you note that his hematocrit has been gradually
declining over the past three years. On his visit today
laboratories reveal:

MCV 84 fL (80-95)
Platelets 340,000/mm3 (150,000-450,000)
BUN 35 mg/dL (9-25)
Creatinine 1.9 mg/dL (0.7-1.3)
LDH 230 (107-231)
Question 4
The most likely etiology of his anemia is:
A. Combined iron and B12 deficiency
B. Medication effect from the ACE inhibitor
C. Erythropoietin deficiency
D. Anemia due to marrow replacement by

metastatic prostate cancer
376
Question 4
CLINICAL SCENARIO
Progressive anemia, with a high creatinine
Question 4
The most likely etiology of his anemia is:
A. Combined iron and B12 deficiency
B. Medication effect from the ACE inhibitor
C. Erythropoietin deficiency
D. Anemia due to marrow replacement by

metastatic prostate cancer
377
Regulation of Erythropoietin
Renal/Hepatic Epo production
Hypoxia
Iron
Folate
B12
Increased Red Cell Production
Anemia of Renal Disease

Decline in renal function is associated with decreased
erythropoietin production
Anemic patients with diabetes mellitus and even modestly
abnormal renal function are often erythropoietin deficient
The normal range for erythropoietin values is for patients
who are not anemic
Anemia of any significant degree should lead to a rise in the
erythropoietin level out of the normal range
normal response to moderately severe anemia is a rise in
the epo level
378
Question 5
A 23 year-old man with sickle cell anemia is admitted for

management of pneumonia. He presented with a two-day
history of a dry non productive cough, fever to 101°F and
was found to have a right lower lobe infiltrate. On admission
his oxygen saturation was 94% on room air, and he was not
short of breath. He is placed on cefuroxime and given IV
hydration along with 1 unit of red blood cell transfusion.
Question 5
CBC on admission:
Platelets 247,000/mm3 (150,000-
450,000)
One day later he complains of increasing shortness of breath

and is found to have an oxygen saturation of 86% on room
air. Chest radiograph reveals bilateral lower lobe opacities.
379
Question 5
In addition to supplemental oxygen, the

appropriate next step is to:
A. Obtain V/Q scan
B. Administer furosemide
C. Transfuse RBCs
D. Add coverage for atypical organisms and
transfuse RBCs
E. Add coverage for atypical organisms, perform
exchange transfusion
Acute Chest Syndrome
Clinical syndrome of fever, hypoxia, and pulmonary

infiltrates
Often associated with infection with atypical
organisms such as chlamydia or mycoplasma
Blood transfusion-simple or exchange- may be life-
saving
Exchange transfusion:
demonstrated to improve outcome in acute chest syndrome
in adults
Indications for exchange: stroke, acute chest syndrome,
priapism
380
Question 5
In addition to supplemental oxygen, the

appropriate next step is to:
A. Obtain V/Q scan

B. Administer furosemide
C. Transfuse RBCs
D. Add coverage for atypical organisms and
transfuse RBCs
E. Add coverage for atypical organisms, perform
exchange transfusion
Question 6
A 76 year-old woman on warfarin for chronic atrial fibrillation

normally anticoagulated to an INR of 2.5 is found to have an INR
of 5.8 on routine testing. She is otherwise asymptomatic. The
most appropriate next step is:
A. Decrease dose of warfarin by 50%

B. Hold warfarin, administer 1 mg vitamin K subcutaneously
C. Hold warfarin, administer 2.5 mg vitamin K orally
D. Hold warfarin, recheck INR in 1 to 2 days prior to
restarting therapy
E. Hold warfarin for one day, restart at 50% of previous dose
the next day
381
Question 6
A 76 year-old woman on warfarin for chronic atrial fibrillation

normally anticoagulated to an INR of 2.5 is found to have an INR
of 5.8 on routine testing. She is otherwise asymptomatic. The
most appropriate next step is:
A. Decrease dose of warfarin by 50%

B. Hold warfarin, administer 1 mg vitamin K subcutaneously
C. Hold warfarin, administer 2.5 mg vitamin K orally
D. Hold warfarin, recheck INR in 1 to 2 days prior to
restarting therapy
E. Hold warfarin for one day, restart at 50% of previous dose
the next day
Warfarin (COUMADIN, JANTOVEN)
• Inhibits Vitamin K dependent gamma- carboxylation of

coagulation Factors II, VII, IX, and X
• Half life is 40 hours (highly variable)
• Duration of effect is 2-5 days
382
Non-urgent warfarin reversal

Administration of vitamin K
Oral:
Poorly bioavailable in some patients
Takes 12-24 hours to take effect
SC:
Variable absorption (not recommended)
IV:
Takes effect in 4 to 6 hours
Anaphylactic risk is very small
Urgent Warfarin Reversal

Prothrombin complex concentrate 4-factor
(US: KCENTRA; Canada: BERIPLEX and OCTAPLEX)
Indicated for acute major bleeding or urgent surgery
Dosing is based on the INR
Repeat dosing not indicated.

Administer Vitamin K concurrently
383
Direct Oral Anticoaguants (DOACs)
Dabigatran (PRADAXA)
Rivaroxaban (XARELTO)
Apixaban (ELIQUIS)
Edoxaban (SAVAYSA)
Reversing DOAC-Associated Bleeding

FFP: No benefit
PCCs Possible benefit
Factor VIIa Possible benefit
Idarucizumab Dabigatran (PRADAXA)

(PRAXBIND)
Andexanet alfa Direct Xa inhibitors

(ANDEXXA)
384
Question 7
A 24 year-old Caucasian female is found to

have a right popliteal deep venous thrombosis
while taking oral contraceptives.
Of the following heritable conditions, which is
most likely to be found on diagnostic evaluation:
A. Antithrombin III deficiency

B. Protein C deficiency
C. Homocysteinemia
D. Factor V Leiden
E. Prothrombin gene mutation (G20210A)
Question 7
A 24 year-old Caucasian female is found to

have a right popliteal deep venous thrombosis
while taking oral contraceptives.
Of the following heritable conditions, which is
most likely to be found on diagnostic evaluation:
A. Antithrombin III deficiency

B. Protein C deficiency
C. Homocysteinemia
D. Factor V Leiden
E. Prothrombin gene mutation (G20210A)
385
Common Inherited Thrombophilias

Factor V Leiden
G1691A mutation (arg to glu amino acid 506)
Prevents inactivation of factor V
Present in 4-6% of Caucasian population, 0.05% of
Asians and Africans
Prothrombin Gene Mutation
G20210A mutation (3’-untranslated region)
Leads to elevated levels of prothrombin
Present in 2-3% of Caucasians, 0.0% of Asians and
Africans
Other Inherited Causes of Thrombophilia
Rare (<1% of population combined)

Antithrombin deficiency
Protein C deficiency
Protein S deficiency
Very Rare
Dysfibrinogenemia
Homozygous homocystinuria
Possibly Inherited
Elevated factor VIII, IX, XI levels
386
Clinical Frequency of Thrombophilia
In patients with VTE who are:

less than age 50 years
have a family history of thrombosis
a history of recurrent events
no acquired risk factors except for pregnancy or oral
contraceptive:
Factor V Leiden 40%

Prothrombin Gene Mutation 16%
Protein C, S, or Antithrombin 13%
Question 8
Which of the following statements is true regarding oral

replacement with Vitamin B12?
A. It is only effective in patients who possess intrinsic

factor
B. Since it costs more than parenteral replacement, it
should be discouraged
C. It is generally effective, though requires monitoring
for compliance
D. When used in appropriate situations, the dose and
frequency are similar to parenteral B12
E. Methylmalonate and homocysteine levels cannot
be used for the monitoring of therapy
387
Question 8
Which of the following statements is true regarding oral

replacement with Vitamin B12?
A. It is only effective in patients who possess intrinsic

factor
B. Since it costs more than parenteral replacement, it
should be discouraged
C. It is generally effective, though requires monitoring
for compliance
D. When used in appropriate situations, the dose and
frequency are similar to parenteral B12
E. Methylmalonate and homocysteine levels cannot
be used for the monitoring of therapy
Cobalamin (Vitamin B12) Deficiency

Diagnosis:
Levels of less than 200 pg/mL diagnostic
homocysteine and methylmalonate levels can
be helpful in such situations (both are elevated
in B12 deficiency)
Clinical Features:
Hematopoiesis: pancytopenia
Neurological: peripheral neuropathy>posterior
column > dementia
388
Cobalamin (Vitamin B12) Deficiency

Pathophysiology:
Malabsorption
Intrinsic factor deficiency: gastric bypass
Resection of distal ilieum; celiac disease, ileitis
Competition from parasites: blind loop,
intestinal divericulum
Dietary deficiency is extremely rare
Treatment
Parenteral: 1000 mg/month IM; no need to
monitor
Oral: daily, absorbed by mass action
Folic acid deficiency

Clinical Features:
No neurologic sequelae
Hematopoietic and GI manifestations same as
cobalamin
Pathophysiology:
Decreased intake:
poor diet, alcoholism, infancy
Impaired absorption: gastric by-pass; sprue, etc.
Increased requirements:
growth spurts: infancy, adolescence
pregnancy
Hemolysis
marrow hyperplasia, bulky tumors
389
Question 9
An asymptomatic 35 year-old woman is seen in the office and is found

to have the following CBC:
Platelets 758,000/mm3 (150,000-450,000)
Which of the following statements is true:
A. Therapy with hydroxyurea is indicated

B. Warfarin therapy is indicated to prevent thrombotic
complications
C. The possibility of iron deficiency, an inflammatory state or
CML should be investigated
D. The patient has a very high risk of thrombosis or
hemorrhage during the next five years
Question 9
An asymptomatic 35 year-old woman is seen in the office and is found

to have the following CBC:
Platelets 758,000/mm3 (150,000-450,000)
Which of the following statements is true:
A. Therapy with hydroxyurea is indicated

B. Warfarin therapy is indicated to prevent thrombotic
complications
C. The possibility of iron deficiency, an inflammatory state or
CML should be investigated
D. The patient has a very high risk of thrombosis or
hemorrhage during the next five years
390
Thrombocytosis
Reactive Thrombocytosis
Infection
Inflammation
Rebound
Iron Deficiency
Myeloproliferative Disorders
Myelodysplasia (5q- syndrome)
Smear: Myeloproliferative disorders
CML: neutrophilia, CML: increased basophils

myeloid precursors
Essential thrombocythemia
391
Essential thrombocytosis
No platelet lowering treatment necessary in

asymptomatic individuals, age < 60, with platelet
counts of < 1,500,000/mm3
Older individuals, those with a history of

complications, and those with higher counts may
benefit from hydroxyurea
Low-dose aspirin (81 mg daily) is generally

recommended
Question 10
A 67 year-old man with a history of unstable angina is admitted to the
coronary care unit for further management of chest pain. His complete
blood count is normal on admission and he is started on unfractionated
heparin. On hospital day 5 his platelet count is noted have drifted down to
80,000/mm3. An ELISA assay for antibodies to the heparin-PF4 complex is
sent.
What is the appropriate next step:
A. Continue unfractionated heparin pending the ELISA results

B. Switch to a low molecular weight heparin pending the ELISA
results
C. Discontinue unfractionated heparin and begin anticoagulation with
a direct thrombin inhibitor pending ELISA results
D. Discontinue unfractionated heparin and begin warfarin to target an
INR 2-3 pending the ELISA results
392
Question 10
A 67 year-old man with a history of unstable angina is admitted to the
coronary care unit for further management of chest pain. His complete
blood count is normal on admission and he is started on unfractionated
heparin. On hospital day 5 his platelet count is noted have drifted down to
80,000/mm3. An ELISA assay for antibodies to the heparin-PF4 complex is
sent.
What is the appropriate next step:
A. Continue unfractionated heparin pending the ELISA results

B. Switch to a low molecular weight heparin pending the ELISA
results
C. Discontinue unfractionated heparin and begin anticoagulation with
a direct thrombin inhibitor pending ELISA results
D. Discontinue unfractionated heparin and begin warfarin to target an
INR 2-3 pending the ELISA results
Heparin-Induced Thrombocytopenia
Relative fall to below 50% of the peak platelet
count
Rarely if ever occurs within the first five days of

heparin unless there has been a recent pre-
exposure to heparin
Less common with LMWH, but once a patient has

HIT, antibodies may be cross-reactive
There is no absolute platelet number that is

diagnostic of HIT, and is more important to consider
in the appropriate clinical setting
393
HIT MANAGEMENT
STOP HEPARIN
BEGIN A DIRECT THROMBIN

INHIBITOR
HIT MANAGEMENT
If patient was on warfarin, administer Vitamin K
When platelet count has returned to normal overlap

warfarin and DTI for at least 5 days
Continue the overlap at least 24-48 hours with

therapeutic INR (DTI may artificially elevate the INR)
Continue warfarin for 3-6 months in the setting of

thrombosis
Duration in the absence of thrombosis…no data
394
Heparin-Induced Thrombocytopenia (HIT)

Pathophysiology:
Anti-PF4/heparin antibodies:
Activation of platelets
formation of platelet
microparticles
neutralization of heparin
increased thrombin generation
• Activation of endothelium and
monocytes
cell surface TF expression
Indirect through platelet
activation.
Can lead to arterial as well as
venous thrombosis
Semin Thromb Hemost 2004; 30: 273-283
Question 11
A 28 year-old woman is seen for preconception counseling. Her past

medical history is notable for significant bleeding after extraction of her
wisdom teeth. She takes no medications. Her family history is notable for
the fact that her mother required blood transfusions several days after the
birth of each of her two children. Her sister also had major bleeding
several days after the birth of her child.
An appropriate evaluation at this time would include:
A. Thrombin and reptilase times

B. Von Willebrand antigen level, ristocetin cofactor levels, and factor
VIII activity level
C. Factor XIII screen
D. Euglobulin clot lysis time
E. Factor XI activity level
395
Question 11
A 28 year-old woman is seen for preconception counseling. Her past

medical history is notable for significant bleeding after extraction of her
wisdom teeth. She takes no medications. Her family history is notable for
the fact that her mother required blood transfusions several days after the
birth of each of her two children. Her sister also had major bleeding
several days after the birth of her child.
An appropriate evaluation at this time would include:
A. Thrombin and reptilase times

B. Von Willebrand antigen level, ristocetin cofactor levels, and factor
VIII activity level
C. Factor XIII screen
D. Euglobulin clot lysis time
E. Factor XI activity level
Von Willebrand Disease Screening Panel
von Willebrand Antigen
Factor VIII activity
Ristocetin cofactor activity level
Note: Those with Type O blood have a

VW:Ag level ~25% lower
396
Von Willebrand Factor

A 270 kD monomer that assembles into multimers ranging
from 600 kD to 20,000 kD in size
vWF binds to subendothelial collagen and to platelets via

GPIb and GPIIb/IIIa receptors
Facilitates platelet-platelet interactions
Acts as a carrier for Factor VIII, protecting it from proteolysis

and prolonging its half life
The ristocetin co-factor assay measures the functional

activity of vWF binding to platelets: causes a conformational
change in vWF so that it can bind to the GPIb on platelets
vWD Genetic Mutations
Type 1: partial vWF deficiency

Type 2: qualitative defects in vWF
2A: decreased platelet dependent
function
2B: increased affinity of vWF for platelets
2N: defective factor VIII binding site
Type 3: complete vWF deficiency
397
Question 12
A 67 year-old man with a history of hypertension is seen for routine physical

examination. Physical exam is notable for a ruddy complexion and a grade
II/VI systolic flow murmur. CBC is notable for:

Platelets 430,000/mm3 (150,000-450,000)
The serum erythropoietin level is low. Which of the following is the most
appropriate next step in evaluation:
A. Serum iron panel with HFE gene mutation analysis

B. JAK2 V617F mutation analysis
C. Polysomnography (sleep study)
D. Hemoglobin electrophoresis with p50 dissociation curve
Question 12
A 67 year-old man with a history of hypertension is seen for routine physical

examination. Physical exam is notable for a ruddy complexion and a grade
II/VI systolic flow murmur. CBC is notable for:

Platelets 430,000/mm3 (150,000-450,000)
The serum erythropoietin level is low. Which of the following is the most
appropriate next step in evaluation:
A. Serum iron panel with HFE gene mutation analysis

B. JAK2 V617F mutation analysis
C. Polysomnography (sleep study)
D. Hemoglobin electrophoresis with p50 dissociation curve
398
Causes of an Elevated Hematocrit
Polycythemia Vera
~95% of cases have a JAK2 V617F mutation
Relative or spurious erythrocytosis
Absolute Erythrocytosis from Hypoxia
Renal Disease
Tumors
Hemoglobinopathies
Epo receptor mutations
Question 13
A 28-year-old man with no significant past medical history
presents with several weeks of worsening fatigue and darkened
urine. On exam, he is tachycardic (130 beats/min), tachypneic
(24/minute), and jaundiced. His CBC shows:

Platelets 430,000/mm3 (150,000-450,000)
MCV 106 fL (80-100)
The peripheral blood smear shows numerous spherocytes and

his Direct Coombs (DAT) is positive for IgG. The patient’s
antibody screen is reactive to all cells tested. The blood bank
says that it may be 4-6 hours before a fully compatible cross-
match unit is available.
399
Question 13
In addition to supportive care with folic acid and initiation

of corticosteroids, which of the following is the next
appropriate step in management:
A. Transfusion of emergency release AB-negative red cell

units until fully crossmatch compatible red cell units
are available
B. Transfusion with the least incompatible type-specific
red cell units
C. Observation until fully compatible type-specific red
cells units are available
D. Red cell exchange transfusion with concurrent
plasmapheresis
Question 13
What are the key clinical data provided?
Immune-mediated hemolysis with hemodynamic

instability and difficulty with crossmatch
400
Due to antibody mediated destruction of red

cells leading to shortened RBC survival
Compensation by the bone marrow (retics)
Corticosteroids
Decrease removal by reticuloendothalial system
Decrease antibody production
Supportive Care:
Folic Acid
Transfusion support
Question 13
In addition to supportive care with folic acid and initiation

of corticosteroids, which of the following is the next
appropriate step in management:
A. Transfusion of emergency release AB-negative red cell

units until fully crossmatch compatible red cell units
are available
B. Transfusion with the least incompatible type-specific
red cell units
C. Observation until fully compatible type-specific red
cells units are available
D. Red cell exchange transfusion with concurrent
plasmapheresis
401
Board Review Practice

Images
Part 1
2018
Ajay K. Singh, MBBS, FRCP
Disclosures
• GSK - Consultant
402
Question 1
A 52 year old homeless man
on chronic dialysis with a
history of non-compliance
presents with chest pain. CXR
and EKG show the following.
The next step should be:
A. Administer predinisone 60
mg/day tapered over 1 month.
B. Emergency
pericardiocentesis and
initiate heparin-free daily
hemodialysis
C. Anticoagulate the patient
immediately with heparin
D. Administer colchicine
E. Administer vitamin B6
B. Emergency pericardiocentesis
and initiate heparin-free daily
hemodialysis
Uremic pericarditis w/ tamponade
• inflammation of the visceral and parietal
membranes of the pericardial sac.
• BUN is usually >60 mg/dL
• Risk factors: inadequate dialysis and/or fluid
overload .
• Fever and pleuritic chest pain - worse in the
recumbent position. pericardial rub is generally
audible, but is frequently transient.
•Signs of cardiac tamponade may be seen,
particularly in patients with rapid pericardial fluid
accumulation.
Electrical alternans Sinus Tachy w/ • EKG does not show the typical diffuse ST and T
beat to beat variation in QRS wave elevations observed with other causes of acute
appearance (best seen V2 and V4) pericarditis. This results from the lack of penetration
Source: Ary Goldberger, MD of the inflammatory cells into the myocardium
cmbi.bjmu.edu.cn
403
Question 2
A 68 year old woman has
a long history of
rheumatoid arthritis (RA).
Which one of the
following deformities is
not characteristically
seen in RA?
A. Boutonnière deformity
B. swan- neck deformity
C. Ulnar deviation of the
metacarpophalangeal
joints
D. Bouchard’s nodes
E. Mallett Finger
SOURCE: https://www.cedars-sinai.edu/Patients/Health-Conditions/Arthritis---Rheumatoid-
Arthritis-Osteoarthritis-and-Spinal-Arthritis.aspx
Question A 68 year old woman has

a long history of
rheumatoid arthritis (RA).
Which one of the
following deformities is
not characteristically
seen in RA?
A. Boutonnière deformity
B. Swan- neck deformity
C. Ulnar deviation of the
metacarpophalangeal
joints
D. Bouchard’s nodes
E. Mallett Finger
SOURCE: https://www.cedars-sinai.edu/Patients/Health-Conditions/Arthritis---Rheumatoid-
Arthritis-Osteoarthritis-and-Spinal-Arthritis.aspx
404
Osteoarthritis (OA) hand abnormalities
http://www.womens-health-
advice.com/photos/osteoarthritis.html
RA hand abnormalities
SOURCE:
http://morphopedics.wikidot.com/rheumatoid-
arthritis
405
Question 3
Serum levels of which one
of the following laboratory
tests would be expected to
be most abnormal in this
patient?
A. 17-hydroxyprogesterone
B. Angiotensin-converting
enzyme
Q: C. Anti-tissue
transglutaminase antibody
D. Prolactin
E. Vitamin B6
SOURCE:Graham McMahon and

http://emedicine.medscape.com/article/361490-
overview
Question
B. Angiotensin-converting
enzyme
Lupus pernio is a manifestation of

sarcoidosis that involves the
nasal bridge and cheeks. The
CXR shows bilateral hilar
lymphadenopathy. Serum levels
of the angiotensin-converting
Q:
enzyme are elevated in the
majority of patients with untreated
sarcoidosis.
SOURCE:Graham McMahon and

http://emedicine.medscape.com/article/361490-
overview
406
ACE Levels
• ACE levels may be elevated in ≈ 60% of patients at the time of
diagnosis.
• Non-caseating granulomas (NCGs) secrete ACE: the enzyme is
secreted by epithelioid cells at the periphery of the granulomas,
and the level is usually elevated in patients with “active”
sarcoidosis
• Serum ACE levels may correlate with total body granuloma load.
• Levels may be increased in fluid from bronchoalveolar lavage or
in cerebrospinal fluid.
Also in pts with miliary tuberculosis, silicosis, asbestosis, biliary cirrhosis,
leprosy, histoplasmosis, hepatitis, lymphoma, berylliosis, diabetic
retinopathy and hyperthyroidism.
• Sensitivity and specificity as a diagnostic test is limited (60% and
70%, respectively). There is no clear prognostic value.
• Serum ACE levels may decline in response to therapy.
• Decisions on treatment should not be based on the ACE level
alone.
Question 4
What is the most likely
diagnosis?
A. Amyloidosis
B. Celiac disease
C. Hypothyroidism
D. Kawasaki disease
E. Type 2 diabetes
Q:
Pastore L, et al, N Engl J Med 2007; 356:2547

http://www.nejm.org/doi/full/10.1056/NEJMc070
200#t=article
407
B. Celiac disease
Atrophic glossitis is a
typical manifestation of
celiac disease.
The tongue was the most

frequently affected site in
a series of 128 patients
with celiac disease who
were examined for oral
mucosal lesions and
symptoms, with 29.6% of
Pastore L, et al, N Engl J Med 2007; 356:2547 the patients describing
http://www.nejm.org/doi/full/10.1056/NEJMc070 soreness or a burning
200#t=article
sensation and 8.6%
having erythema or
atrophy. 1
1R.
Docimo, M. Costacurta, P. Maturo, L. Di Iorio, F.M. Paone. (2009) Malattia celiaca e
manifestazioni intraorali. Prevenzione & Assistenza Dentale 35, 26-33
Other Manifestations of Celiac Disease

in the Oral Cavity1
• Dental enamel defects with a various degree of advancement:
discolorations, horizontal groves and pits, and structural
destruction causing the change of the dental crown.
• Symmetric location of defects within all dentition sections, and
within the same anatomic groups of teeth (the most
frequently: incisors and first permanent molars), is specific for
celiac disease.
• Recurrent aphthae and other disorders of the oral mucosa
such as ulceration, erythema, atrophic glossitis, as well as
dryness and a burning sensation (particularly of the tongue)
• Delayed tooth eruption may also be a consequence of
alimentary deficiency in celiac disease.
1Krzywicka B, Herman K, Kowalczyk-Zając M, Pytrus T. Celiac disease and its

impact on the oral health status - review of the literature. Adv Clin Exp Med.
2014 Sep-Oct;23(5):675-81.
408
Leffler, DA et al Extraintestinal manifestations of coeliac disease

Nature Reviews Gastroenterology & Hepatology 12, 561–571 (2015)
Question 5
• This 53-year-old college
professor could no longer
lecture because her tongue
kept getting in the way. Her
tongue was enlarged and
had serrations, reflecting
imprints of her teeth. Her
upper-torso muscles were
grossly hypertrophied and
hard as wood
A. Acromegaly
B. Hypothyroidism
C. Amyloidosis
D. Pernicious anemia
E. An allergic reaction to
toothpaste
Source: http://cnx.org/content/m14953/latest/
409
Question
C. Amyloidosis
An enlarged, serrated tongue

suggests amyloidosis,
acromegaly, or hypothyroidism.
The “shoulder pad” sign,
however, is relatively specific for
amyloid disease. Thus, the
combination of an enlarged,
serrated tongue with the
"shoulder pad" sign is
pathognomonic of systemic
amyloidosis.
Source: http://cnx.org/content/m14953/latest/
Localized Amyloidosis
• Tongue is most frequently affected site in forms of

localised amyloidosis
• Tongue biopsy possess a highly diagnostic value for
amyloidosis.
• No consensus regarding the management of lingual
amyloidosis, although numerous therapies have
been proposed, including surgical excision and
pharmacological treatment. However lesions often
persist or recur.
Angiero F, et al Amyloid deposition in the tongue: clinical and histopathological

profile. Anticancer Res. 2010 Jul;30(7):3009-14.
410
Question 6
What is the diagnosis?
A. Central retinal artery

occlusion
B. Diabetic retinopathy
C. Ocular toxoplasmosis
D. Optic neuritis
E. Malignant
hypertension
Q:
Source: http://www.aoa.org/diabetic-retinopathy.xml
B. Diabetic retinopathy
The fundus photograph

shows findings consistent
with a diagnosis of
diabetic retinopathy.
Features
• Microaneurysms
• Dot and blot hemorrhages
• Flame-shaped hemorrhages
• Retinal edema and hard
exudates
• Cotton-wool spots
• Venous loops and venous
beading
• Intraretinal microvascular
abnormalities
• Macular edema
Source: http://www.aoa.org/diabetic-retinopathy.xml
411
Microaneurysms: The earliest clinical sign of diabetic retinopathy; these occur

secondary to capillary wall outpouching due to pericyte loss; they appear as small, red
dots in the superficial retinal layers
Dot and blot hemorrhages: Appear similar to microaneurysms if they are small; they
occur as microaneurysms rupture in the deeper layers of the retina, such as the inner
nuclear and outer plexiform layers
Flame-shaped hemorrhages: Splinter hemorrhages that occur in the more superficial

nerve fiber layer
Retinal edema and hard exudates: Caused by the breakdown of the blood-retina
barrier, allowing leakage of serum proteins, lipids, and protein from the vessels
Cotton-wool spots: Nerve fiber layer infarctions from occlusion of precapillary arterioles;
they are frequently bordered by microaneurysms and vascular hyperpermeability
Venous loops and venous beading: Frequently occur adjacent to areas of

nonperfusion - reflect increasing retinal ischemia, and their occurrence is the most
significant predictor of progression to proliferative diabetic retinopathy (PDR).
Intraretinal microvascular abnormalities: Remodeled capillary beds without

proliferative changes; can usually be found on the borders of the nonperfused retina
Macular edema: Leading cause of visual impairment in patients with
Source: Medscape.com/article/1225122-overview
Question 7
The urine sediment
shows what form of
crystals?
A. Oxalate crystals
B. Cystine crystals
C. Uric acid crystals
D. Struvite crystals
E. Acyclovir crystals
412
B. Cystine crystals
• The crystals are usually hexagonal,

translucent, white.
• Cystinuria is an autosomal recessive
disorder caused by mutations in the
SLC3A1 and SLC7A9 genes.
• These genes encode two parts of a
transporter protein in the kidneys.
•Under normal circumstances, this
protein allows certain amino acids,
including cysteine, to be reabsorbed into
the blood from the filtered fluid that will
become urine.
•As the levels of cystine in the urine
increase, the crystals typical of
cystinuria are able to form, resulting in
kidney stones.
Source: http://en.wikipedia.org/wiki/Cystinuria
Question 8
A 22-year old woman
presents with joint and
abdominal pain and a
rash. Rectal exam is
positive for occult
blood. Urine shows
hematuria. What is the
most likely diagnosis?
A. Renal cell cancer

B. Renal infarction
C. Kidney stone
D. Goodpasture’s
syndrome
E. Henoch-Schonlein
purpura
413
E. Henoch-Schonlein
purpura
The patient has palpable

purpura and hematuria. The
the red cells appear crenated -
- dysmorphic red cells. The
combination of the clinical
presentation and the hematuria
makes HSP nephritis the most
likely etiology.
HSP is an IgA-mediated, small-
vessel vasculitis that
predominantly affects children
but also is seen in adults. HSP
is a subset of necrotizing
vasculitis characterized by
fibrinoid destruction of blood
vessels and leukocytoclasis.
Glomerular Syndromes
• Nephritis: Hypertension, Azotemia,

proteinuria, hematuria, RBC casts /
dysmorphic RBCs
• Nephrosis: edema, proteinuria,
hypoalbuminemia, lipid abnormalities
• RPGN: rapid renal failure, crescents on
renal biopsy + nephritis
• Isolated urinary abnormalities:
hematuria / proteinuria
414
Pathology of IgAN/HSP nephritis
HSP nephritis
Clinical Features
Dermal Renal
Purple, nonblanching, 33% children, 63% adults
urticarial, purpuric papules Hematuria, macroscopic / microscopic
may become confluent Proteinuria
Bx: leukocytoclastic vasculitis Azotemia
GI
Abd pain (2/3rds of cases)
may precede rash Joints
Vomiting Arthralgias and periarticular edema (2/3)
Diarrhea knees, ankles, elbows, wrists
Periumbilical pain
Major complications (5%)
intussusception
bowel ischemia
necrosis
415
Question 9
What is the most likely
diagnosis?
A. Renal tubular acidosis

B. Primary
hypoparathyroidism
C. Familial hypocalciuric
hypercalcemia
D. Salicylate overdose
Q: E. Paget's disease
Slide courtesy of Graham McMahon, BWH
A. Renal tubular acidosis
The film reveals bilateral

Answer:
symmetric calcification of the
renal parenchyma, sparing
only the renal pelvis. This
patient had been diagnosed
with renal tubular acidosis at
9 years of age, but did not
undergo medical follow-up for
20 years. The other listed
choices are not common
causes of nephrocalcinosis.
416
Distal RTA
1. Classical form of RTA (described first)
2. Failure of alfa intercalated cells to secrete H+ and K+
3. Hypokalemia, hypocalecemia, hyperchloremia
4. Urinary stone formation (related to alkaline urine,
hypercalciuria and low urine citrate
5. Nephrocalcinosis
6. Bone demineralization 9rickets in children, osteomalacia in
adults)
Question 10 A 78-year-old male

presented with headache
of 4 weeks' duration.
Pain was excruciating,
constant and
predominantly over the
right hemicranium, with
the maximum being over
the right temple. There
was jaw and tongue
claudication. The patient
felt weak and there was
SOURCE:
https://www.google.com/search?q=temporal+arteritis&biw=132 low grade fever. He also
7&bih=661&source=lnms&tbm=isch&sa=X&sqi=2&ved=0ahUK complained of proximal
EwjdyPjXmufNAhUCDT4KHWfWD9kQ_AUIBigB#imgrc=1Boe
GCHqqtZAPM%3A
and axial joint arthralgias.
He had tenderness
tenderness over his
superficial temporal
artery and over his scalp.
SOURCE: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2771971/
417
A diagnosis of giant cell arteritis (GCA) was confirmed

by a superficial temporal artery (STA) biopsy. Which
one of the following is atypical of GCA?
A.) Jaw claudication

B.) Small-Medium vessel involvement
C.) Tongue claudication
D.) Proximal and axial joint arthralgias suggesting
polymyalgia rheumatica (PMR)
E.) Scalp tenderness
A diagnosis of giant cell arteritis (GCA) was confirmed

by a superficial temporal artery (STA) biopsy. Which
one of the following is atypical of GCA in this
presentation?
A.) Jaw claudication

B.) Small-Medium vessel involvement
C.) Tongue claudication
D.) Proximal and axial joint arthralgias suggesting
polymyalgia rheumatica (PMR)
E.) Scalp tenderness
418
• Most common vasculitis

GCA
• Elderly women
• Small, medium size arteries
• Cranial Arteritis: temporal, facial, ophthalmic arteries. Also aortic
arch (giant cell aortitis, uncommon)
• Throbbing headache that doesn’t respond to NSAIDs, tender
temporal area, firm & nodular temporal artery
• Facial pain, loss of taste, tongue pain/claudication, scalp
tenderness
• Jaw claudication
• Visual abnormailities: amaurosis fugax, blurred vision, double
vision, blindness
• 50% cases => Polymyalgia Rheumatica
• Necrotizing vasculitis with granulomas: fragementation of the
internal elastic lamina due to the presence of multinucleated Giant
Cells & intimal fribrosis.
GCA Treatment
Stone JH et al N Engl J Med 2017; 377:317-328July 27, 2017
N=251
Pred (26 w course) + tocilizumab (162 mg SC weekly/QOW)
vs.
Pred (26 w or 52 w course) +placebo
Outcome: Rate of remission
At 52 weeks: ≈56% remission in combination therapy group
versus 18% in the prednisone alone
More side-effects in the prednisone alone group
419
Question 11
This 26-year old patient
presented with a facial rash
and diffuse arthralgias. She is
not on any drug treatment.
Which one of the following
tests would confirm the
diagnosis?
A. ESR
B. CRP
C. Anti-ds DNA ab
D. Anti-microsomal antibody
measurement
E. Anti-RNP ab measurement
C. Anti-ds DNA ab
DDx
• SLE
• Pellagra
• Bloom syndrome (BLM)
Bloom = autosomal recessive

characterized by short stature and a
butterfly facial rash that develops shortly
after first exposure to sun. Other clinical
features include a high-pitched voice;
distinct facial features, such as a long,
narrow face, pigmentation (hypo/hyper),
moderate immune deficiency, sub-fertility
in females.
Pellagra most commonly caused by a

chronic lack of niacin (vitamin B3).
Characterized by 4 D’s: diarrhea,
dermatitis, dementia, and death
Source cure4lupus.org
420
Anti-ds DNA Antibodies

• Group of anti-nulcear Abs that target double stranded DNA
• Low sensitivity for SLE, high specificity (absence of the
antibodies does not rule out the disease)
• Anti-dsDNA antibodies are highly associated with lupus
nephritis
• Some patients with high titers of anti-dsDNA antibodies do not
develop renal disease -most likely because anti-dsDNA are a
heterogeneous population and some non-pathogenic.
• Patients with rheumatoid arthritis can develop anti-dsDNA
antibodies, however they are usually treatment related. Anti-
TNFα biological therapies, such as adalimumab, infliximab,
etanercept.
• Infection with viral pathogens can induce anti-dsDNA
antibodies transiently e.g., HIV, human parvovirus B19, BK
virus.
Question 12
A 46-year-old woman with
metastatic sarcoma who had
been treated with five cycles of
doxorubicin, ifosfamide, and
mesna chemotherapy
presented with two
symmetrical, horizontal white
lines on all of her fingernails
but not on her toenails. Which
Q: one of the following is the
SOURCE: Morrison-Bryant M, Gradon JD. A. Chronic renal failure

N Engl J Med. 2007 Aug 30;357(9):917 B. Iron deficiency
C. Graves' disease
D. Chemotherapy treatment
E. Psoriasis
421
D. Chemotherapy treatment
• A diagnosis of Muehrcke's lines related to chemotherapy

treatment.
• Muehrcke's lines are the two smooth white bands that run parallel
to the lunula across the width of the nail.
• The lines are nonpalpable and, unlike Beau's lines, do not indent
the nail itself.
• Muehrcke's lines are a nonspecific finding that may be associated
with periods of metabolic stress, which transiently impairs protein
synthesis. Muehrcke's lines are also caused by infections and
trauma.
Question 13
A 56-year-old woman with
hypertension presented
with a sudden onset
painless impaired vision in
the right eye. On the
previous day, she
had undergone cardiac
catheterization for
evaluation of hypertensive
Q: emergency. On physical
examination, the visual
acuity in the right eye was
20/100 with significant
visual-field defect in the
inferior temporal quadrant.
SOURCE: Meyer CH, Holz FG. Images in clinical medicine. Blurred vision after cardiac
catheterization. N Engl J Med. 2009 Dec 10;361(24):2366.
422
Q: What is the diagnosis? B. Cholesterol embolism
The image demonstrates

Answer: cholesterol emboli with surrounding
white lucency representing retinal
edema. Fluorescein angiography
confirmed occlusion of the
cilioretinal artery with nonperfusion
of the tissue bed in the
hypofluorescent areas. Cholesterol
emboli are crystals that are released
in the arterial bloodstream from
ulcerated or disrupted
atherosclerotic plaques and can be
an initial sign of vascular disease.
• Cholesterol embolism syndrome should be suspected in a

patient who develops worsening renal function, hypertension,
distal ischemia or acute multisystem dysfunction after an
invasive procedure.
• middle-aged to elderly Step wise rise in Scr
• men >women Bland urine classic
cholesterol embolus in a medium sized artery of the kidney
SOURCE: https://en.wikipedia.org/wiki/Cholesterol_embolism
423
Center for Gastrointestinal Motility
Esophageal Disorders
Walter W. Chan, MD, MPH
Director, Center for Gastrointestinal Motility

Division of Gastroenterology, Hepatology and Endoscopy
Assistant Professor of Medicine, Harvard Medical School
Disclosures
No relevant disclosure.
424
Outline
Clinical presentations of esophageal disorders
Diagnostic tests for esophageal and swallowing
symptoms
Esophageal disorders
– Gastroesophageal reflux disease and complications
– Esophageal motility disorders
– Eosinophilic esophagitis
– Other esophagitis (infectious, pill-induced)
CLINICAL PRESENTATION OF
ESOPHAGEAL DISORDERS
425
Clinical Presentation
Symptoms
– Dysphagia
• Mucosal inflammation, mechanical obstruction, dysmotility
• Solids only: suggests mechanical obstruction
• Solids + liquids: suggests dysmotility
– Odynophagia
• Inflammation (infectious, caustic), ulceration
– Chest pain
– Heartburn
– Regurgitation
– Others:
• Weight loss, cough, choking, hoarseness, dyspnea
Physical Examination
– Often normal
– Signs of dehydration or malnutrition
• Hypotension, tachycardia, dry skin/mucousa, poor skin
turgor, etc.
• Electrolytes derangement
– Symptoms/signs associated with underlying primary
illness
• Oropharyngeal or dental (erythema, edema, erosions,
plaques, halitosis, etc.)
• Pulmonary/airway (wheezing, dyspnea, cough, hoarseness)
• Skin (rash, scales, hardened skins, etc.)
• Muscoloskeletal (joint pain, swelling)
426
Etiologies of
Esophageal Dysphagia
Mechanical / Mucosal Motility Functional

Obstructive
• Mass or • GERD / reflux • Achalasia • Visceral

malignancy esophagitis • GERD hypersensitivity
• Stricture • Eosinophilic • DES • Functional
• Ring esophagitis • Nutcracker dysphagia
• Web • Infection • Hypomotility /
• Diverticulum • Caustic injury / IEM
• Fistula pills • Scleroderma /
• External • Radiation connective
compression • Autoimmune tissue disorders
DIAGNOSTICS FOR
ESOPHAGEAL AND
SWALLOWING DISORDERS
427
Imaging
Videofluoroscopic swallow
study/modified barium swallow
– Assess oropharyngeal bolus transport
– Evaluate structural abnormalities of
oropharynx and upper esophagus
Barium swallow
– Evaluate for high-grade esophageal
obstructive lesion, strictures, diverticuli,
or retained foreign body
– May demonstrate characteristic changes
of certain motility disorders, hiatal
hernia, or reflux
Endoscopy
Rule out mechanical
obstruction
– Malignancy
– Foreign body
– Stricture, ring, web
Assess and biopsy abnormal

mucosa
– Infection (viral, fungal)
– Inflammation (GERD, caustic)
– Eosinophilic esophagitis
428
Esophageal Manometry
Transnasal passage of catheter
with pressure sensors into the
esophagus and stomach
Indications
– Assess esophageal contractile
activity and anatomical landmarks
=> diagnosis of motility disorders
– Assist in placement of pH probe
– Pre-operative evaluation for anti-
reflux surgery or other
esophageal/chest surgeries
Ambulatory pH Monitoring
Continuously records the distal esophageal pH to
quantify acid reflux over study period (24-48 hrs)
Two modalities:
– Transnasal probe with pH sensor
– Endoscopically placed pill-sized capsule (Bravo)
A battery-powered device records data from the

probe/capsule and patient-reported symptoms
Allows correlation between patient-reported

symptoms and reflux events
429
Intraluminal Impedance
Multichannel intraluminal
impedance detects bolus
movement in the esophagus
– Impedance = resistance to
changing electrical current from
transit of bolus
• Liquid: ↓ impedance
– Combined with manometry or pH
probe
• EM-MII: Measures bolus transit
• pH-MII: Measures bolus reflux
ESOPHAGEAL DISORDERS:
GASTROESOPHAGEAL
REFLUX DISEASE
430
GERD
25-40% healthy adult Americans experience GERD
symptoms at least once per month
– 7-10% of adults experience symptoms daily
– Likely underestimated due to self-treatment/OTC PPI
Gender: Male ≈ Female

– Reflux esophagitis: 2-3:1 (M:F)
– Barrett’s esophagus: 10:1 (M:F)
GERD prevalence increases with age

– Mean ≈ 40 years old
– Intensity of symptoms may decrease after age 50, but
prevalence of erosive esophagitis increases with age
Richter et al. N Engl J Med 1992.
GERD: Pathophysiology
Gastroesophageal reflux is physiologically normal
– Normally with meals
– Refluxate
• Gastric acid, bile, pancreatic secretion, food matter
– Pathologic reflux results when irritation of the
esophagus (symptom ± inflammation) occurs from
refluxate exposure
• Increased acid/refluxate exposure
• Decreased barrier to irritation
Areas of dysfunction: esophagus, lower

esophageal sphincter (LES), or stomach
431
GERD: Pathophysiology
Factors associated with GERD
– Esophagus: Impaired esophageal motility or epithelial
barrier function
– LES: Weak LES or inappropriate relaxation
– Stomach: Delayed emptying, increased acid
production, hiatal hernia
– Others:
• Obesity
• Pregnancy / hormonal changes
• Medications
• Ingestions: Food, alcohol, tobacco
GERD: Clinical Presentation

Esophageal Symptoms Extraesophageal
– Typical Manifestations
• Heartburn – ENT
• Regurgitation • Hoarseness, sorethroat,
– Atypical cough, post-nasal drip
• Chest pain – Pulmonary
• Dysphagia • Asthma
• Odynophagia • COPD
• Nausea • Interstitial lung disease
• Globus sensation – Dental erosions
• Epigastric pain
– Waterbrash
432
GERD: Management
Lifestyle modification
– Dietary modification
• Avoid trigger food items
– Spicy food, citrus food, chocolate, caffeine, carbonated rinks,
alcohol, peppermint
• Multiple, small meals
– Avoid recumbency for 2-3 hours after eating
– Tobacco cessation
– Elevating the head of bed Strategies with the best
evidence for improving
– Weight loss
GERD symptoms
GERD: Management
Empiric acid suppression therapy
– Trial x 8 weeks and titrate dose to severity of symptoms
– Administer 15-30 min before meals
– Always try to taper dose when symptoms respond
• Goal: manage symptoms with lowest possible dose
Risk factors for PPI failure: longer duration of

disease, hiatal hernia, extraesophageal symtoms,
low compliance
Pregnancy: Antacids, H2 receptor antagonists, PPI

(except omeprazole – category C) are safe to use
433
GERD: Management
PPI Adverse Effects
– Acute side effects in <2%
• Headache, diarrhea, constipation, abdominal pain
– Increased risk for community-acquired pneumonia in
elderly with short term usage (upon initiation)
– Chronic PPI use:
• Malabsorption of B12 (elderly), calcium, magnesium
• Osteoporosis and hip fractures in high risk groups
• Bacterial gastroenteritis and C. difficile
• Small intestinal bacterial overgrowth
– Suggested association
• Cardiovascular events?? => no evidence on further investigation
• Chronic renal insufficiency?? => further investigation needed
• Dementia?? => no evidence on multiple subsequent studies
GERD: Management
When should endoscopy and further diagnostic
testing be performed to evaluate GERD?
– Alarming features
• Dysphagia / odynophagia
• Weight loss
• Signs of GI bleeding/anemia
• Vomiting
• Abnormal imaging
• Family history of upper GI malignancy
– Age > 50
– Nonresponder to medical therapy
434
GERD: Management
Limited options for PPI nonresponders:
– Optimize timing of PPI and compliance
– Esophageal function testing (manometry, pH monitor)
– Addition of H2 blockers for nocturnal symptoms
• Most beneficial if pH testing shows overnight acid reflux
– No role for metoclopramide without gastroparesis
– Neuromodulator for hypersensitivity: TCA, Trazodone
– Consider GABA-B receptor agonists as reflux inhibitors
• Baclofen 5-20 mg tid (not FDA approved for GERD)
– Decreases acid exposure, reflux episodes, symptoms, and TLESR
– Side effects: dizziness, somnolence, constipation
Van Herwaarden et al. Aliment Pharmacol Ther 2002

Shaheen et al. Gut 2012
GERD: Management
Anti-reflux Surgery
– Indications
• Failed/intolerant of medical therapy, medication dependence
– Fundoplication
• Relieves GERD symptoms in over 90% of patients
• Laparoscopy has comparable 10-year outcome to laparotomy
• Adverse events: gas-bloat syndrome (15-20%), dysphagia
– Bariatric surgery may be more effective than
fundoplication among obese patients
• RYGB >> adjustable gastric band and sleeve gastectomy
• Gastric banding has also previously been shown to cause or
worsen GERD in some patients, and should be avoided in
obese patients with GERD
Broeders et al. Ann Surg. 2009
Pallati et al. Surg Obes Relat Dis. 2014
435
Non-Cardiac Chest Pain

Esophageal
Etiologies Motor
Disorders
(10-18%) Esophageal motility
disorder or spasm
only accounts for a
GERD
Functional
(29-60%)
small minority of
Chest Pain patients with non-
(32-60%)
cardiac chest pain!
Evaluation:
• RULE OUT CARDIAC CAUSE
• Lifestyle modification, empiric PPI
• EGD, pH study, manometry
Fass et al. Neurogastroenterol Motil 2006

Barret et al. Neurogastroenterol Motil 2016
BARRETT’S ESOPHAGUS
436
Barrett’s Esophagus
Replacement of normal distal esophageal squamous
epithelium by specialized intestinal metaplasia
Chronic GERD -> esophagitis -> metaplastic change
Overall prevalence in US: ~5.6%

– Patients with GERD: ~5-10%
Risk factors:
– Caucasian, age, male, obesity, tobacco, alcohol
Increased risk of esophageal adenocarcinoma

El-Serag et al. Gastrointest Endosc. 2006
Hayeck et al. Dis Esophagus. 2010
Barrett’s screening
– No screening recommended for general population
– Screening indicated in patients with multiple risk
factors associated with Barrett’s (AGA
recommendations):
• Age 50 or older
• Male sex
• White race
• Chronic GERD
• Hiatal hernia
• Elevated BMI
• Intra-abdominal distribution of body fat
Spechler et al. Gastroenterol. 2011
437
Barrett’s surveillance
– Endoscopic surveillance with biopsies is indicated for
signs of dysplastic progression
– All biopsies should be examined by pathologists with
expertise in esophageal histopathology
No Dysplasia Low-grade Dysplasia High-grade Dysplasia
Surveillance every 3-5 * Referral for endoscopic * Referral for endoscopic
years therapy therapy
or or
Surveillance every 6-12 Referral for surgery
months if therapy not or
performed Surveillance every 3
months if therapy not
performed
Treatment
– Endoscopic therapy
• Endoscopic mucosal resection
• Radiofrequency ablation
• Indication: Dysplastic Barrett’s
– All post-endoscopic therapy patients require
continued surveillance to ensure eradication of
Barrett’s tissues and to monitor for recurrence
– Chemoprevention
• PPI has been shown to reduce neoplastic progression in
patients with Barrett’s
• Aspirin and NSAIDs are associated with reduced risk for
esophageal cancer
Kastelein et al. Clin Gastroenterol Hepatol. 2013
438
MOTILITY DISORDERS
Esophageal Motility
Disorders
Disorders of Inhibitory Disorders of Excitatory

Innervation Innervation and Smooth
Muscle
Decreased Increased Hypotensive Hypertensive
Achalasia Transient lower Hypotensive Hypertensive

esophageal peristalsis (IEM) peristalsis
Diffuse sphincter (nutcracker,
esophageal relaxation Hypotensive LES jackhammer)
spasm (DES) (TLESR)
Scleroderma Hypertensive
LES
439
Achalasia
Preferential degeneration of post-ganglionic
inhibitory neurons in myenteric plexus
– Insufficient lower esophageal sphincter relaxation with
swallowing and aperistalsis
Annual Incidence: 1 in 100,000
Most commonly between ages 25-50
Prevalence: Male = Female
16-fold increase in risk of squamous cell carcinoma

– Average of 14 years after achalasia diagnosis
– Routine surveillance endoscopy not recommended
Achalasia
Primary achalasia: Idiopathic, ? viral, ? Autoimmune
– Gradual onset and insidious progression
– Mean duration of symptoms -> diagnosis = 4.7 years
Secondary achalasia: Chagas disease, malignancy,

amyloidosis, sarcoidosis, eosinophilic gastroenteritis,
neurofibromatosis
– Often acute onset and more rapidly progressive
Signs/symptoms
– Dysphagia (nearly 100%), regurgitation (60-90%)
– Difficulty belching (85%), chest pain/heartburn (40%),
weight loss, pulmonary/ENT symptoms (especially when
recumbent)
440
Achalasia Diagnosis
Laboratory studies
– Anti-neuronal antibodies, T cruzi assay
Endoscopy
– Rule out mechanical obstruction
Barium swallow
– Bird’s beak
– Dilated esophagus
– No peristalsis
– Poor esophageal emptying
Manometry
– Abnormal relaxation of the LES with
swallowing
– Aperistalsis of the esophageal body
Source: Fox et al. Gut 2008.
Achalasia Treatment
Pneumatic Surgicalmyotomy POEM Botulinum toxin CCB / Nitrates
dilation injection
Response 60-90% at 1 yr 90-93% at 1 yr 98% at 1 yr 90% at 1 mo 50-70% initial
86% at 2 yrs 90% at 2 yrs 91% at 2 yrs 60% at 1 yr <50% at 1 yr
82% at 5 yrs 85% at 5 yrs
Complications 2-5% 10% symptomatic 37% increased reflux 20% rash, transient 30% headache,
perforation reflux; on 24-hr pH; chest pain hypotension
11% mucosal tear 18% reflux
esophagitis
Advantages Good response Excellent, Excellent response; Low morbidity Rapidly initiated
rates prolonged Less invasive than
response; surgery;
Laparoscopic Long myotomy
Disadvantages Risk of Surgical risk Lack of controlled Frequent repeat; Poor effect on
perforation; and long-term data Loss of response; esophageal
~25% require Fibroinflammatory emptying;
re-treatment reaction at LES Tachphylaxis
441
Achalasia Treatment
Low Surgical High Surgical

Risk Risk
Pneumatic
Myotomy Botox Injection
Dilation Failure
Failure
Nitrates
Repeat myotomy or dilation
Calcium channel
Esophagectomy
blockers
Diffuse Esophageal Spasm

Impairment of inhibitory innervation in the
esophageal body
– Excessive simultaneous or premature contractions
– Normal LES relaxation
Symptoms and Signs

– Chest pain (at rest, with eating, stress)
– Dysphagia, regurgitation
Imaging
– Barium swallow
• Non-propagated (tertiary) contractions
• “corkscrew” appearance
442
Diffuse Esophageal Spasm

Manometry
– Spastic esophageal body contractions
with normal LES relaxation
Treatment
– Acid suppression: PPI or H2 Blockers
– Smooth muscle relaxants: nitrates,
CCB
– Anticholinergics
– Pain modulators: TCA
– Dilation, botox injection, myotomy
Clinical course/Prognosis
Source: Zerbib et al. J Clin Gastroenterol 2015. – Intermittent and non-progressive
– 3-5% transition to achalasia
Other Motility Disorders

Motor Pathology Etiologies Clinical Study Treatment
Disorders Presentation Findings
Hypomotility Impaired • Idiopathic • GERD • Decreased • Anti-reflux
Disorders excitatory • Medications - Esophagitis contraction therapy
• Hypotensive LES innervation - Anticholinergic - Stricture • Increased • Avoid
• Absent or muscle - Smooth • Dysphagia failed offending
contractility contractility muscle • Chest pain peristalsis meds
• Ineffective relaxant • Impaired • Baclofen
Esophageal - Hormone
Motility (IEM)
esophageal • Bethanechol
• Pregnancy
clearance
• CTD (Scl)
• GERD
Hypermotility Overactive • CNS stress • Chest pain • Increased • Anti-reflux
Disorders excitatory • GERD • Dysphagia contraction therapy
• Hypertensive LES nerves or • Normal • Anticholinergic
• Hypercontractile smooth peristalsis • Smooth
LES muscle • Nutcracker muscle
• Nutcracker/ response esophagus relaxant
Jackhammer
• Elevated • TCA
LES • Cognitive-
pressure behavioral
therapy
443
EOSINOPHILIC ESOPHAGITIS
Eosinophilic Esophagitis
Clinically characterized by symptoms related
to esophageal dysfunction
Pathologically, ≥ 1 biopsy specimens must
show eosinophil-predominant inflammation
– ≥15 eos/hpf on esophageal biopsies
Disease is isolated to the esophagus and
other causes of esophageal eosinophilia are
excluded
Liacouras et al. J Allergy Clin Immunol 2011
444
Mean age: 37 years Symptoms:
Gender: 72% Male – Dysphagia 82%
– Heartburn: 29%
Mean symptom
duration: 5 years – Chest pain: 8%
Atopic history: 74%

Food allergy history:
19%
Food impaction
– EoE found in 11-55% of
adult with food impaction
– 30-55% of EoE patients
experience food impaction
Endoscopy
– Ringed esophagus
– Longitudinal furrows
– White patches
– Small caliber esophagus
– Strictures
445
PPI-REE/PPI-Responsive EoE
25-50% of patients with EGD + biopsies
esophageal eosinophilia
have histologic resolution ≥15 eos/hpf
of eosinophilia with PPI
Twice daily PPI for
8-12 weeks
Clinically indistinguishable
from PPI-non-responsive
EoE EGD + biopsies
≥15 eos/hpf <15 eos/hpf

? underlying GERD vs anti-
inflammatory properties of EoE PPI-REE/
PPI (EoE variant) PPI-REoE
Treatment for PPI-Non-

Responsive EoE
Elimination diet
– Empiric vs allergy test-directed
Topical therapy
– Swallowed fluticasone, budesonide slurry
Systemic therapy
– Steroids
– ? Biologics
Endoscopic dilation of strictures
446
OTHER ESOPHAGITIS
Infectious Esophagitis
Odynophagia is the most common
symptoms
Most often develops in immunosuppressed
patients
– HIV infection, chemotherapy, organ
transplantation, chronic immunosuppressive
medication use
447
Candidial esophagitis
– Most frequent cause of infectious esophagitis
– Often associated with oral candidiasis
– Upper endoscopy with biopsy is the most sensitive
and specific test
• Characteristic appearance: whitish plaques
– Treatment typically involves systemically active
oral azoles (e.g. fluconazole)
Viral esophagitis
– Herpes simplex virus, cytomegalovirus
– Most often seen in transplant recipients
– Diagnosis requires upper endoscopy with
esophageal brushing, viral culture, or biopsies
• Characteristic appearances: mucosal ulcerations
– Treatment:
• HSV: acyclovir, foscarnet
• CMV: gangiclovir, foscarnet, cidofovir
448
Pill Esophagitis
Dysphagia or odynophagia
Most common drugs:
– Antibiotics, NSAIDs, bisphophonates, potassium
choloride, quinidine, ferrous sulfate
Most patients have normal underlying
esophageal structure and function
Risk factors: advanced age, esophageal
dysmotility, extrinsic esophageal compression,
large pill size, swallowing pills without water
and in supine position
Summary
The main symptoms of esophageal disorders
include dysphagia, odynophagia, heartburn,
chest pain, and regurgitation.
Barium esophogram, endoscopy, esophageal

manometry, and ambulatory pH monitoring are
the primary diagnostic modalities for esophageal
disorders.
449
Summary
Lifestyle modification and empiric acid
suppression trial are first-line approach to
uncomplicated GERD.
In management of GERD symptoms, endoscopy

and other diagnostic studies should be reserved
for patients with alarm features, older age
individuals (>50), or those who fail medical
therapy.
Summary
Dose tapering of PPI should always be
attempted once symptom response is achieved.
The most common cause of non-cardiac chest

pain is gastroesophageal reflux disease.
Management strategies for GERD should be
followed once cardiac cause has been ruled out.
450
Summary
Secondary or pseudoachalasia should be ruled
out in patients diagnosed with achalasia.
Management strategy of primary achalasia

depends on the patient’s surgical risk.
– Low surgical risk patients should undergo pneumatic
dilation or myotomy (surgical or endoscopic).
Summary
Esophageal biopsies to assess for eosinophilia
should be performed for work-up of dysphagia.
When esophageal eosinophilia is found, an 8-12-

week trial of high-dose PPI followed by repeat
biopsies should be performed to determine
responsiveness to PPI
Management of PPI-non-responsive EoE mainly

involves elimination diet or steroid therapy.
451
Summary
Odynophagia is the most common symptom for
infectious esophagitis.
Infectious esophagitis usually occur in

immunosuppressed patients, with candida being
the most common agent.
Medications at highest risk for causing pill

esophagitis include NSAID, antibiotics,
bisphosphonate, potassium tablets.
Question 1
A 40 year-old woman with no significant past medical
history presented to the Emergency Department with
chest pain episodes over the past week. She described
a sharp pain in her substernal region, with no
association with exertion, positional changes, or eating.
She was admitted for management and cardiac
evaluation, including an exercise stress test, which were
all negative. Her symptoms were felt to most likely be
of an esophageal origin. However, she denied any
dysphagia, odynophagia, nausea, vomiting, heartburn,
reflux, or regurgitation symptoms. Her other laboratory
evaluations were unremarkable and she had no other
complaints.
452
Question 1
What is the most appropriate next step for the
A. Barium swallow.
B. Empiric trial of proton pump inhibitor.
C. Upper endoscopy with mucosal biopsies.
D. Esophageal manometry with impedance study.
E. Empiric trial of smooth muscle relaxant (calcium
channel blockers).
Question 1: Answer
B. Empiric trial of proton pump inhibitor.
The patient in question presented with chest pain symptoms and
her cardiac evaluation was unremarkable. The most common
cause of non-cardiac chest pain is gastroesophageal reflux disease
(GERD), which should be evaluated/treated next. In a young and
healthy patient without alarming signs/symptoms, the initial steps
of GERD management include lifestyle modification and an empiric
trial of proton pump inhibitor (PPI). Diagnostic studies (answers A,
C, D) should be considered only after the patient fails her PPI trial
or if she has any alarming signs/symptoms. An empiric trial of
smooth muscle relaxant (answer E) would not be appropriate
without an objective diagnosis of hypercontractile motility disorder,
as GERD is a significantly more common cause of non-cardiac
chest pain than esophageal dysmotility, and smooth muscle
relaxants would worsen reflux.
453
Question 2
A 20 year-old man with a history of eczema and chronic
dysphagia presents for follow-up after an incidence of food
impaction for which he underwent urgent upper endoscopy in
the emergency department. A repeat upper endoscopy was
performed :
Mucosal biopsies obtained revealed >80 eosinophils/hpf. He

continues to report intermittent dysphagia symptoms when
eating solid food, but no further food impaction episode. He
denies any chest pain, heartburn, reflux, or regurgitation.
Question 2
What is the most appropriate next step in management?
A. Start six-food elimination diet.

B. Schedule esophageal manometry.
C. Initiate treatment with swallowed fluticasone
D. Start twice daily proton pump inhibitor.
E. Repeat upper endoscopy for biopsies.
454
Question 2: Answer
D. Start twice daily proton pump inhibitor.
The patient in question (young man with a history of atopy)
presented with intermittent dysphagia and a history of food
impaction, raising suspicion for eosinophilic esophagitis. His upper
endoscopy revealed ringed esophagus and esophageal biopsies
showed an increase in eosinophilic infiltration. The initial step of
management after diagnosis of esophageal eosinophilia is a trial of
twice daily proton pump inhibitor (PPI) for 8-12 weeks, followed by
repeat upper endoscopy with biopsies to assess histologic response
(E). This allows differentiation between PPI-responsive esophageal
eosinophilia if eosinophilic infiltration resolves and non-PPI
responsive eosinophilic esophagitis (EoE) if eosinophilia persists.
Elimination diet (A) and steroids (C) should be considered only
after post-PPI biopsies confirm lack of responsiveness. Esophageal
manometry (B) is not part of the management algorithm for
esophageal eosinophilia.
References
Liacouras et al. J Allergy Clin Immunol
2011
Source: Fox et al. Gut 2008.
Richter et al. N Engl J Med 1992
Fass et al. Neurogastroenterol Motil 2006
Barret et al. Neurogastroenterol Motil
2016
455
Thank You
Center for Gastrointestinal Motility
456
PEPTIC ULCER DISEASE

• JOHN R SALTZMAN, MD
• Director of Endoscopy
• Brigham and Women’s Hospital
• Professor of Medicine
• Harvard Medical School
Disclosures
• No disclosures
457
Overview
• Causes of peptic ulcer disease
• Clinical manifestations
• Current diagnostic tests
• Recommended therapies
• New strategies to treat H. pylori
• Complications including GI bleeding
Peptic ulcer disease

• Ulcers are defects in gastrointestinal mucosa that
extend beyond muscularis mucosa
• Arise when mucosal defenses are impaired in
presence of gastric acid and pepsin
• Overall incidence declining worldwide
• Lifetime prevalence 5-10%
• Complications
– GI bleeding (10-20%)
– Perforation (5%)
– Obstruction (2%)
458
Causes of peptic ulcers

• Helicobacter pylori infection
• Aspirin and NSAIDs
• Rare causes:
– Neoplasia (carcinoma, lymphoma, leiomyosarcoma)
– Acid hypersecretion (Zollinger-Ellison syndrome)
– Granulomatous disease (Crohn’s, sarcoidosis)
– Systemic mastocytosis
– Infectious (CMV, HSV, TB)
– Familial
• Idiopathic (No H. pylori, NSAID or other identifiable
cause)
Additional Risk Factors

• Older age
• Prior history of peptic ulcers
• Smoking – proportional to amount
smoked
• Medications in combination with NSAIDs
– Corticosteroids, anticoagulants, anti-
platelets, SSRIs, bisphosphonates
459
Helicobacter pylori
• Gram-neg spiral, urease producing bacteria
• H. pylori is the most common chronic bacterial
infection in humans
• Infection mainly acquired in childhood (<10 years)
• Risk factors include
– Low socioeconomic status
– Household crowding
– Country of origin and ethnicity
Cover TL, Blaser MJ. Gastroenterology 2009;136(6):1863-73;

Bruce MG Epidemiol Infect 2015;143(6):1236-4
H. pylori and peptic ulcers
• H. pylori associated with up to 50% to

80% duodenal ulcers
• H. pylori associated with up to 60% to
70% gastric ulcers
• Prevalence of H. pylori
– Undeveloped countries 80% by age 20
– Developed countries 10% by age 20
• Incidence of peptic ulcers declining in
developed countries due to less H. pylori
460
H. pylori eradication results in long-term

remission of peptic ulcer disease
Duodenal ulcer Gastric ulcer
% Patients in remission % Patients in remission
100 100
H. pylori eradicated H. pylori eradicated
75 75
50 50
H. pylori-positive
25 25
H. pylori-positive
0 0
0 0.5 1 1.5 2 0 2 4 6 8 10 12
Years after termination Months after termination
of treatment of treatment
Miehlke S. Eur J Gastroenterol Hepatol 1995;7(10):975-8;

Axon AT. BMJ 1997;314(7080):565-8
NSAIDs and peptic ulcers

• Responsible for majority of ulcers not due to H. pylori
(>100,000 hospitalizations/year)
• Increased risk for significant GI event (bleeding,
perforation and obstruction) and “silent” ulcers
• Surreptitious NSAID use is common, especially in
refractory / complicated ulcers
• Co-therapy of NSAIDs with corticosteroids,
anticoagulants, other NSAIDs, low dose aspirin,
selective serotonin reuptake inhibitors (SSRIs) and
alendronate increases the risk of ulcers
461
Risk of ulcer complications with

ASA and NSAIDs
ASA + ASA + ASA +

NSAIDs > COX-2 inhibitor > placebo
• ASA alone causes a 2-3 fold increase in ulcer bleeding

• Long term ASA use does not reduce risk of ASA-induced
ulcer bleed (Meta-analysis of 24 RCTs)
• Enteric coated or buffered ASA does not protect against
ulcers due to systemic effects
Garcia Rodriguez LA. Gastroenterology 2007;132(2):498-506;

Derry S, Loke YK. BMJ 2000;321(7270):1183-7
Risk factors for NSAID-

induced peptic ulcers
Risk Factor Relative Risk 95 Percent CI
Overall 2.74 2.54-2.97
Anticoagulants 12.7 6.3-25.7
High dosage 10.1 4.6-22.0
(>2x normal)
Age (>60) 5.52 4.63-6.60
Prior PUD 4.76 4.05-5.59
Corticosteroids 4.4 2.0-9.7
462
Other causes of peptic ulcers

• Gastric acid hypersecretion
– Zollinger-Ellison syndrome
• Cigarette smoking
– Increased rate of ulcers in patients with H.
pylori
– More difficult to treat ulcers
• Neoplasia (carcinoma, lymphoma)
• Familial (polygenic inheritance)
Zollinger-Ellison Syndrome
• Neuroendocrine tumor (duodenum, pancreas)
• Hypergastrinemia ↑ acid secreLon
• PUD (duodenum, jejunum), diarrhea, GERD
• Usually sporadic
– MEN1 syndrome in 25% of cases
• Diagnosis – gastrin, cross-sectional imaging
– Ddx hypergastrinemia – hypochlorhydria from PPI or
atrophic gastritis
463
Clinical manifestations of
peptic ulcer disease
• Dyspepsia: epigastric pain most common
• Duodenal ulcer symptoms
– Epigastric pain (burning, gnawing or hunger-like), 2 to 5
hours after meal or on empty stomach (without a food
buffer)
– Nocturnal between 11 PM and 2 AM (circadian
stimulation of acid maximal)
– Symptom relief with food or antacids
• Gastric ulcer symptoms: Pain soon after meals
with less relief by food or antacids
• Ulcers can be asymptomatic (up to 70%)
Differential diagnosis of
peptic ulcer disease
• Functional nonulcer dyspepsia

• Gastroesophageal reflux disease
• Gastric cancer
• Pancreatic and biliary diseases
464
Alarm symptoms
• Weight loss
• Persistent vomiting
• Dysphagia
• Anemia
• Hematemesis
• Palpable abdominal mass
• Family H/O upper GI carcinoma
• Previous gastric surgery
Diagnosis of peptic ulcer disease

• Suspect by symptoms and history
• Ask about alarm symptoms
• Consider blood tests
– CBC, LFT’s, calcium and lipase
• Test for H. pylori infection
• Consider endoscopy
465
Upper endoscopy for PUD

• Upper endoscopy gold standard test
• Best in patients over the age of 45 years or
with alarm symptoms
• Allows biopsy (for H. pylori or to R/O
cancer)
• Sensitive, specific and safe
• Best initial test in most patients
Gastric ulcer
466
Antisecretory therapy for PUD

• H2-blockers 90% effective after 8 weeks
• Proton pump inhibitors
– More rapid healing than H2-blockers
– 90% effective at 4 weeks
• Large ulcers (>2 cm) take longer to heal
• Gastric ulcers—confirm healing and exclude
malignancy in 8 to 12 weeks
• Continue maintenance PPIs in patients with non H.
pylori, non NSAID ulcers
Diagnostic tests for H. pylori infection
467
Endoscopy-based methods of
detecting H. pylori
Method of Sensitivity Specificity
Diagnosis Main Indication (%) (%)
Histology Diagnosis 90 90-95
Culture H. pylori antibiotic 80-90 95-100

sensitivities
Rapid urease Rapid results in 90 90

test (CLO) endoscopy room
Gastric biopsies with H. pylori
468
Noninvasive methods of
detecting H. pylori
Method of Sensitivity Specificity
Diagnosis Main Indication (%) (%)
Serology Screening 85 79
Urea breath Screening and confirm 95 96

test eradication
Stool antigen Screening and confirm 93 94

test eradication
Principle of 13C + 14C-urea breath test
469
General principles of treating PUD

Heal ulcer by decreasing gastric
acid using PPIs or H2RAs
Treat the underlying cause:

• Test and eradicate H. pylori infection
• For NSAID-related ulcers
- Discontinue or switch to non-NSAID analgesic
- For patients who require chronic NSAIDs, consider
co-therapy with PPI (or misoprostol)
Established recommendations
for H. pylori eradication
• Strong evidence to treat
– Gastric or duodenal ulcers
(current or H/O untreated H. pylori)
– MALT lymphoma
• Also recommended (limited evidence of benefit)
– Atrophic gastritis / intestinal metaplasia
– Gastric adenocarcinoma in early stages
– 1st degree relatives of patients with gastric cancer
Maastricht IV Consensus Report. Gut 2012;61(5):646-64;
Liang X. Clin Gastroenterol Hepatol 2013;11(7):802-7
470
New recommendations for

H. pylori eradication
• Any patient with a positive test not previously treated
• Non-ulcer dyspepsia
– Under the age of 60 years without alarm features who undergo non-
endoscopic testing and found to have H. pylori
– Those who undergo endoscopy and are found to have H. pylori
• Prior to long-term NSAID or ASA use to reduce risk of bleeding
(in patients with H. pylori)
• Patients with unexplained iron deficiency anemia despite an
appropriate evaluation (in patients with H. pylori)
• Adults with idiopathic thrombocytopenic purpura (ITP) should
be tested for and treated if H. pylori present
Chey WD. Am J Gastroenterol 2017;112:212–238
Treatment of H. pylori
• Multiple regimens and durations evaluated
• Treatment must be effective, have acceptable costs,
side effects and ease of administration
• Commonly used regimens have frequent side effects
(usually mild) including metallic taste, diarrhea and
allergic reactions
• Be aware of clarithromycin and metronidazole
resistance and do not repeat Rx with these drugs
• Best regimens eradicate organism > 90%
471
H. pylori eradication therapies

• Clarithromycin triple therapy
• PPI BID+ 2 antibiotics including clarithromycin
– Determine if patient had previous macrolide exposure
– Clarithromycin may be used if local resistance low
(resistance <15%)
• Bismuth quadruple therapy
– PPI BID+ Bismuth salt + 2 antibiotics
• Other first line regimens
• Salvage therapy
– Avoid initial antibiotics and offer to those with persistent
infection after initial therapy
Liang X. Clin Gastroenterol Hepatol 2013;11(7):802-7;

Clarithromycin triple therapy
• Proton pump inhibitor twice daily

• Amoxicillin 1 gram twice daily
• Clarithromycin 500 mg twice daily
• All given for 14 days
• Can substitute Metronidazole 500 mg twice
daily if penicillin allergic
472
Bismuth quadruple therapy

• Bismuth subcitrate or subsalicylate
2 tablets 4 times daily
• Tetracycline 500 mg 4 times daily
• Metronidazole 250-500 mg 4 times daily
• All given with meals for 10-14 days
• First line therapy if prior macrolide exposure
or penicillin allergy
2017
H. pylori
Treatment
Guidelines
American College of
Gastroenterology (ACG)
Chey WD. Am J Gastroenterol 2017;112:212-238
473
Levofloxacin triple therapy

• Levofloxacin 500 mg once daily
• All given for 10-14 days
Concomitant therapy
• Clarithromycin 500 mg twice daily
• Nitroimidazole (metronidazole or
tinidazole) 500 mg twice daily
• All given for 10-14 days
474
Confirmation of H. pylori eradication
• Recommended for all treated patients

– Serologic testing not useful
– Urea breath testing or stool antigen testing
• Repeat testing 4-6 weeks after therapy

– Patients need to avoid using antibiotics, bismuth compounds and PPIs
(for 1-2 weeks) which can cause false negative results
Salvage regimens
• Use for recurrent or persistent H. pylori
• If clarithromycin used as first line therapy
– Bismuth quadruple therapy x 14 days
– Levofloxacin triple therapy x 14 days
• If Bismuth used as first line therapy
– Clarithromycin triple therapy x 14 days
– Levofloxacin triple therapy x 14 days
• Concomitant therapy alternative option
475
Treatment recommendations for

NSAID-related peptic ulcers
Heal ulcer with acid lowering medications
Test and eradicate any H. pylori infection
Discontinue or For patients requiring chronic

switch to NSAIDs consider strategies
non-NSAID analgesic to prevent recurrent ulcers
Preventing recurrent ulcers in patients

requiring chronic NSAIDs
• Use lowest dose of NSAID and provide co-
therapy with either PPI or misoprostol
(prostaglandin E1 analogue)
• Switch to a selective COX-2 inhibitor
• Effective anti-inflammatory agents
• Less ulcer complications than nonselective NSAIDs
– Increases cardiovascular events (RR =1.42)
Sung JJ. Gut 2011;60(9):1170-7;

Laine L. Aliment Pharmacol Ther 2009;30(7):767-74
476
Complications of peptic ulcers

• Gastrointestinal bleeding 10-20%
• Gastric outlet obstruction 2%
• Perforation/fistulalization 5%
• Usually occur in chronic peptic ulcers
• May develop in days - weeks of NSAIDs
• May occur heralded by symptoms or may
occur in “silent” ulcers
Bleeding peptic ulcers

• Accounts for over 50% severe UGI bleeding
• Overall mortality rate 2-14%
• Resuscitation is critical
• Restrictive transfusion strategy (Hgb < 7 g/dL)
• Acid suppression with PPIs
• Endoscopy within 24 hours
Crooks C. Gastroenterology 2011;141(1):62-70;

Villanueva C. N Engl J Med 2013;368(1):11-21
477
Restrictive vs. liberal transfusion strategy
921 patients with acute upper GI bleeding
Restrictive: Transfuse Liberal: Transfuse

when Hgb < 7 g/dL when Hgb < 9 g/dL
Further GI bleed 10% 16% (P=0.01)
Adverse events 40% 48% (P=0.02)
Hazard ratio: 0.55

Survival at 6 weeks 95% 91% (95%CI:0.33 to 0.92 ; P=0.02)
Villanueva C. N Engl J Med 2013;368(1):11-21
Survival according to
transfusion strategy
Overall Survival (%)
Days
478
RCT of aspirin vs. placebo after

peptic ulcer bleed
Event rate (%)
Sung JJ. Ann Intern Med 2010;152:1-9
Resumption of aspirin after

upper GI bleeding
American College of Gastroenterology Guidelines
“If given for secondary prevention (i.e. established

CV disease) then aspirin should be resumed as soon
as possible after bleeding ceases in most patients:
ideally within 1-3 days and certainly within 7 days”
Laine L, Jensen DM. Am J Gastroenterol 2012;107:345-60
479
Summary
• NSAIDs/ASA and H. pylori are the major causes
of peptic ulcers
• Test for and eradicate H. pylori using
established treatments regimens
• For ulcer patients requiring chronic NSAIDs
– Treat with PPI (misoprostol) or COX2 NSAID
• For bleeding ulcer patients requiring ASA
– Restart ASA within 7 days with a PPI
Questions
480
Question 1
A 47 year old man presents with a bleeding gastric ulcer with
biopsies showing H. pylori infection. He is treated with
clarithromycin triple therapy including a PPI, amoxicillin and
clarithromycin. At 8 weeks repeat upper endoscopy shows that the
ulcer has healed but H. pylori is still present. His next course of H.
pylori treatment should avoid use of the following medication:
a) Proton pump inhibitors

b) Amoxicillin
c) Clarithromycin
d) Metronidazole
e) Bismuth subsalicylate
Question 1
A 47 year old man presents with a bleeding gastric ulcer with
biopsies showing H. pylori infection. He is treated with
clarithromycin triple therapy including a PPI, amoxicillin and
clarithromycin. At 8 weeks repeat upper endoscopy shows that the
ulcer has healed but H. pylori is still present. His next course of H.
pylori treatment should avoid use of the following medication:
a) Proton pump inhibitors

b) Amoxicillin
c) Clarithromycin
d) Metronidazole
e) Bismuth subsalicylate
481
The answer is C
• Commonly used regimes to treat H. pylori include
clarithromycin triple therapy (PPI BID + 2 antibiotics
including clarithromycin) and Bismuth quadruple
therapy (PPI BID, Bismuth + 2 antibiotics)
• Clinicians need to be aware of clarithromycin and
metronidazole resistance
• If a patient is previously treated with clarithromycin or
metronidazole, a repeat treatment for H. pylori should
not use these drugs
Maastricht IV Consensus Report. Gut 2012;61(5):646-64;
Question 2
A 62 year old male presents with abdominal pain, nausea, and
passage of dark black stools. He has diabetes, hypertension, and
coronary artery disease and takes aspirin daily for secondary
prophylaxis. An upper endoscopy shows a duodenal ulcer with a
visible vessel that is treated with endoscopic hemostasis. Biopsies of
the stomach show no H. pylori present. He remains stable for 3 days
and starts treatment with oral PPI therapy. What are your
recommendations about further antiplatelet therapy?
a) Discontinue aspirin therapy

b) Switch aspirin therapy to clopidogrel
c) Continue an oral PPI and restart aspirin at this time
d) Continue an oral PPI and restart aspirin therapy after 4 weeks
482
Question 2
A 62 year old male presents with abdominal pain, nausea, and
passage of dark black stools. He has diabetes, hypertension, and
coronary artery disease and takes aspirin daily for secondary
prophylaxis. An upper endoscopy shows a duodenal ulcer with a
visible vessel that is treated with endoscopic hemostasis. Biopsies of
the stomach show no H. pylori present. He remains stable for 3 days
and starts treatment with oral PPI therapy. What are your
recommendations about further antiplatelet therapy?
a) Discontinue aspirin therapy

b) Switch aspirin therapy to clopidogrel
c) Continue an oral PPI and restart aspirin at this time
d) Continue an oral PPI and restart aspirin therapy after 4 weeks
The answer is C
• The patient has significant cardiovascular disease
requiring continued anti-platelet therapy
• The use of a PPI given with aspirin is superior to
switching to clopidogrel alone in reducing
recurrent ulcer bleeding
• He should continue oral PPI therapy and restart
aspirin as soon as possible
• This strategy significantly reduces mortality as
compared to restarting aspirin several weeks later
Sung JJ. Ann Intern Med 2010;152:1-9
483
Disclosures
• No disclosures
References
• Chey ED. ACG Clinical Guideline: Treatment of Helicobacter pylori
Infection. Am J Gastroenterol 2017;112:212–238
• Graham DY. History of Helicobacter pylori, duodenal ulcer, gastric
ulcer and gastric cancer. World J Gastroenterol 2014;20:5191-204
• Kumar NL. Initial management and timing of endoscopy in
nonvariceal upper GI bleeding. Gastrointest Endosc 2016;84(1):10-7
• Lau JY. Challenges in the management of acute peptic ulcer
bleeding. Lancet 2013;381:2033-43
• Malfertheiner P. Management of Helicobacter pylori infection-the
Maastricht IV/ Florence Consensus Report. Gut 2012;61(5):646-64
• Laine L Jensen DM. Am J Gastroenterol 2012;107:345-60
• Villanueva C. Transfusion strategies for acute upper gastrointestinal
bleeding. N Engl J Med 2013;368(1):11-21
484
485
ACUTE AND CHRONIC PANCREATITIS

Julia Y McNabb-Baltar, MD, MPH
Associate Physician
Co-Director Center for Pancreatic Disease
Instructor of Medicine
Disclosure
I have no disclosures
486
Outline
Acute Pancreatitis
– Epidemiology
– Diagnosis
– Etiology
– Severity
– Treatment
– Complications
Chronic Pancreatitis
– Etiology
– Diagnosis
– Etiology
– Treatment
– Complications
ACUTE PANCREATITIS
487
Epidemiology
>275,000 patients are hospitalized for AP
annually
Aggregate cost of >$2.6 billion per year
Incidence 5-30 / 100,000
Case fatality is 5 % overall
Diagnosis
2 of the 3 following criteria:
1) Abdominal pain consistent with the

disease
2) Serum amylase and/or lipase > 3 times
ULN
3) Characteristic findings on abdominal
imaging
Tenner, Baillie, DeWitt. American College of Gastroenterology
Guideline: Management of Acute Pancreatitis. Am J Gastro. 30 july 2013
488
Abdominal Imaging
CECT: 90% Sn, Sp
– Routine use of CT unwarranted
CT or MRI recommended if unclear dx or
patient fail to improve within 48-72h, to
assess local complications
– Guideline recommendation: Strong
recommendation, low quality of evidence
MRCP may help detect CBD stones and
PD disruption
Tenner. Am J Gastro. 2013
Stimac. Am J Gastro 2007
Imaging
Abdominal
ultrasound should
be performed in all
patients to assess
gallstone
pancreatitis
Guideline
recommendation:
Strong
recommendation,
low quality of
evidence

http://upload.wikimedia.org/wikipedia/commons/8/8a/Gallstone_0414092027109.jpg
489
Etiology
Common Uncommon/Rare
Gallstone Vascular/vasculitis
Alcohol CTD, PPT
Hypertriglyceridemia Cancer
ERCP Hypercalcemia
Trauma Pancreas Divisum
Drugs (AZA, 6-MP, Hereditary pancreatitis
sulfonamide, estrogen, Infections (mumps, coxsackie
tetracycline, valproic acid, virus, CMV, echovirus,
HAART) parasites)
SOD Autoimmune (Sjogren, AIP)

Yadav. J Clin Gastroenterol. 2003
Severity -Mild
75-80%
Absence of organ failure and pancreatic
necrosis
Substantial improvement by 48 hours
Banks, Bollen, Dervenis. Classification of acute pancreatitis- 2012: revision of the

Atlanta classification and definitions by international consensus. Gut. 2012.
490
Moderately Severe AP
Local or systemic complications without
persistent organ failure
– Necrotizing Pancreatitis
– Acute Peripancreatic Fluid Collection (APFC)
– Acute Necrotic Collection (ANC)
Transient organ failure (<48h)

Severe AP
Persistent organ failure (>48h)
– Single organ failure
– Multiple organ failure

491
Risk Stratification
Serial bedside evaluation
– Vitals, orthostatics
– Volume overload, ARDS
RANSON > 3
APACHE II > 8
HAPS
CRP : 48- 72h to become accurate
– CRP > 150
BISAP
PASS
Lankisch. Clin Gastro Hep. 2009

Initial Assessment
• Goal directed therapy using isotonic crystalloid solution (
LR or NS)
– Conditional recommendation, low quality of evidence
• Crystalloid replacement fluid is prefered over
colloid
– Conditional recommendation, low quality of evidence
• Early aggressive IV hydration is most beneficial in the first
12-24h, and may be of little benefit beyond
– Conditional recommendation, moderate quality of evidence
Crocketts. Gastro. 2018
492
Nutrition
In AP, AGA recommends early oral feeding ( within 24h)
– Strong recommendation, moderate quality (AGA 2018)
In mild AP initiation of diet with low-fat diet appears as safe
as clear liquid diet
– Conditional recommendation, moderate quality (ACG 2013)
If oral intake not tolerated, enteral nutrition is recommended.
Parenteral nutrition should be avoided unless EN is not
available, not tolerated, or not meeting the caloric
requirements
NG and NJ delivery of enteral feeding appear comparable in
efficacy and safety

PYTHON trial
Multicentric, RC superiority T early enteral
feed vs. oral diet at 72 hour.
N=208 with APACHE II score ≥8
Outcome: composite outcome of major
infection or death at 6 month
30% enteral feeding vs. 27% in on
demand group
– ( OR=1.07 CI: 0.79-1.44)
– Mortality 11 EN vs. 7 on demand % (p=0.33)
Bakker. NEJM. 2014
493
ERCP in AP
Patients with AP and concomitant cholangitis
should undergo ERCP within 24h of admission
– Strong recommendation, moderate quality
ERCP is not needed in most patients with gallstone
pancreatitis who lack laboratory or clinical
evidence of ongoing biliary obstruction
– Conditional recommendation, low quality
In absence of cholangitis and/or jaundice, MRCP
or EUS should be used to screen for CBD stone if
highly suspected
Role of Antibiotics
Should be given for an extrapancreatic
infection such as cholangitis
– Strong recommendation, high quality
Routine use of prophylactic antibiotics in
patients with predicted severe acute
pancreatitis is not recommended

494
Infected Necrosis
Infected necrosis should be considered in patients
with necrosis who deteriorate or fail to improve after
7-10 days. CT-FNA should be done prior to ATBx if
possible
– Strong recommendation, low quality
In infected necrosis, the use of antibiotics known to
penetrate pancreatic necrosis, such as carbapenem,
quinolones, and metronidazole, may be useful in
delaying or avoiding intervention
Routine administration of antifungal along with
prophylactic or therapeutic ATBx is not recommended
Role of Surgery
In biliary AP, cholecystectomy should be performed
before discharge to prevent recurrent AP
In patients with necrotizing gallstone pancreatitis, in
order to prevent infection, cholecystectomy should be
deferred until active inflammation subsides and fluid
collections resolve or stabilize
– Strong recommendation, moderate quality (ACG 2013)
The presence of asymptomatic pseudocysts and
pancreatic, or extrapancreatic necrosis do not warrant
intervention, regardless of the size, location, extension
– Strong recommendation, moderate quality (ACG 2013)

495
Infected Necrosis
Randomized prospective trial – 19 hospitals, 88
patients
– primary open necrosectomy
– step-up approach
• percutaneous or endoscopic drainage
• minimally invasive retroperitoneal necrosectomy
Advantages of step-up approach
– 35% - did not require retroperitoneal necrosectomy
– less new-onset multiple organ failure
– less diabetes
– less need for pancreatic enzymes
– less costly
No decreased mortality (19% vs. 16%)
van Santvoort et al. NEJM 2010; 362: 1491-1502
Acute Alcoholic Acute

Pancreatitis
AGA recommends brief alcohol
intervention during admission
(AGA 2018)
– RCT comparing repeated-6 months interval
intervention for 2 years vs single intervention
during admission.
– No statistical significant difference but a trend
towards reduction in hospitalization
Nordback. Gastro. 2009
496
CHRONIC PANCREATITIS
Definition
Irreversible damage to the pancreas and
development of histologic evidence of
inflammation and fibrosis with eventual
loss of pancreatic exocrine and endocrine
tissue
Calcifications
Fibrosis
Inflammation
497
Epidemiology
Incidence 3-12/100,000
Prevalence 50/100,000
Men > Women
Median age of diagnosis 30-40 years
old
80,000 yearly admission in US
10 year survival : 70%
Bloating, Diabetes
cramping Recurrent
pancreatitis
Gas, foul
smelling,
oily stool Nausea,
Chronic Vomiting
Pancreatitis
Stool
frequency Abdominal
pain
Weight
Back
loss
pain
498
Pain Pattern
No Pain
Usually pain
16%
free, but
episodes of
mild to
moderate pain
Constant 13%
severe pain
Constant mild
4%
to moderate
pain
Constant mild 4%
to moderate [CATEGORY
pain with NAME]
epsiodes of [PERCENTAGE]
severe pain
44%
C. Mel Wilcox, Clin Gastro Hep. 2015
Laboratory
IgG4 in
Autoimmune
Pancreatitis
Low fecal
Lipase elastase
Chronic
Pancreatitis
Elevated
Low albumin Hba1c
499
STEP 1: CT scan
D Conwell, Pancreas 2014
Differential diagnosis
Calcifications Atrophy
– Islet cell tumor - NET – Aging
– Serous cystadenoma – Prior necrotizing
– Mucinous cystic pancreatitis
neoplasm – Cystic Fibrosis
– Solid pseudopapillary – Shwachman-
neoplasm Diamond syndrome
– Granulomatous – Hemochromatosis
infection
– Hyperparathyroidism
500
STEP 2: MRI/MRCP with or without secretin
STEP 3: EUS
EUS criteria
Clin Gastro Hep,
D Conwell, 2012
Parenchymal Abnormalities Ductal Abnormalities

– Hyperechoic foci (C) – Main duct dilation
– Hyperechoic stranding (A) – Duct irregularities (D)
– Cysts – Side branch dilation
– Lobularity of contour of – Stones (E)
gland – Hyperechoic duct margins
(B)
501
STEP 4: Pancreatic Function Test
Direct pancreas function test.

A cholecystokinin B secretin
Clin Gastro Hep, D Conwell, 2012
Conditions associated with

pancreatic exocrine insufficiency
Condition Presumed mechanism
Chronic pancreatitis Acinar cell loss or injury
Severe acute pancreatitis Acinar cell loss
Shwachman-Diamond syndrome Acinar cell dysfunction
Pancreatic surgery Acinar cell removal
Intestinal surgery Asynchronous delivery of
enzymes with meals
Ductal dysfunction Cystic fibrosis
Duct blockage Ductal carcinoma, IPMN,
stricture
Zollinger-Ellison syndrome Enzyme destruction
C.E. Forsmark, Gastroenterology. 2013
502
Determination of Etiology
TIGAR-O
Toxic-Metabolic
Idiopathic
Genetic
Autoimmune
Recurrent/severe AP
Obstructive
Whitcomb. Gastroenterology, 2001
Hereditary factors
TRYPSINOGEN TRYPSIN SPINK-1

PRSS-1
TAP
Trypsinogen Trypsin
503
Autoimmune Pancreatitis
Diffusely enlarged pancreas
Featureless borders: Sausage-shape
Delayed enhancement w/w/o capsule-like rim
Courtesy Dr Sainani
Assess complications
Pancreatic cancer
Overall lifetime risk is 4%, increased if smoke,
coexisting diabetes and in hereditary pancreatitis
Pseudocyst
Pancreatic ascites and pleural effusion
Bile duct obstruction
– From inflammatory mass in the head
Duodenal obstruction
Osteopenia / Osteoporosis
– similar risk as IBD, in exocrine insufficiency
504
Assess for complications

Gastroparesis
Small Bowel Bacterial Overgrowth
– Multifactorial: intestinal motility from pain and
opioids, inflammatory changes, obstruction,
surgically altered anatomy
Variceal bleed and splenic vein
thrombosis
Pseudoaneurysm
Therapy
Measure pain, quality of life
Counsel smoking and alcohol cessation
Nutrition counselling, Calcium and Vitamin D
supplement, baseline Bone Mineral Density
Analgesia- start tylenol, NSAIDS, tramadol
Adjunctive therapy for those with worsening
pain, increasing requirements
– Pregabalin, Gabapentin, SSRI, SNRI
Assess exocrine and endocrine function: fecal
elastase or serum trypsin, Hb1ac , GTT
505
Pancreatic Enzymes
Replacement Therapy
Normal pancreas produces 900 K per
meal, 10% needed for normal
digestion
Start 50-75 K /meal and 20-35 K/
snack
Temperature-sensitive
Enzyme degradation over time
Limited time of effect
Side Effects of Pancreatic

Enzymes Replacement
Abdominal pain, gas
Headache
Mouth ulcers possible
Hypersensitivity to porcine product
Hyperuricemia
Bowel perforation and obstruction
Fibrosing colonopathy
– Theoretical risk : concern > 6,000 IU/kg/day
506
Endoscopic and surgical

treatment
Inflammatory mass in pancreatic head
Assess anatomy
Whipple operation, Berger, Frey or Berne operation
Dilated pancreatic duct

Endoscopic therapy: Pancreatic and biliary sphincterotomy,
Stricture dilation and stenting, lithotripsy, stone extraction
Surgical Therapy: Modified Puestow
Small duct disease

Medical management
Surgical options: V-plasty, total pancreatectomy with islet
cell auto transplantation
Take Home Points

Acute Pancreatitis
– 2/3 criteria for diagnosis
– Ultrasound to assess for gallstones
– Wait after initial 48-72h to obtain a CT scan because necrosis
can take longer to appear
– Favor enteral route
Chronic Pancreatitis
– Think of the etiology as it is not just caused by alcohol
– Autoimmune pancreatitis can be treated with steroids
– Remember the diagnostic and treatment approach according to
the anatomy
– Monitor for complication and treat accordingly
507
Question 1
You are admitting a patient with acute
necrotizing alcoholic pancreatitis. What
nutrition do you prescribe?
a) Parenteral nutrition in 1 week
b) Enteral nutrition via nasogastric tube now
c) Oral feeding as tolerated using low fat
diet
d) Enteral nutrition via nasojejunal tube in 3
days
Question 1
c ) Oral feeding as tolerated using low fat
diet
Python trial and AGA recommendation
508
Question 2
What gene is most associated with
hereditary pancreatitis and what genetic
inheritance pattern does it follow
(depicted below)
a) PRSS1, autosomal dominant
with incomplete penetrance
b) CTRC, autosomal recessive
c) CFTR, mitochondrial
inheritance
d) SPINK1, X-linked recessive
Question 2
a) PRSS1, autosomal dominant
with incomplete penetrance
509
References
Crockett, SD. American Gastroenterological
Association Institute Guideline on Initial
Management of Acute Pancreatitis.
Gastroenterology 2018;154:1096-1101
Ito, T. Evidence-based clinical practice
guidelines for chronic pancreatitis 2015. J
Gastroenterol 2016;51:85-92
Majumder, S. Chronic Pancreatitis. Lancet
2016, May7; 387 (10031): 1957-66
510
Psychiatry Overview
Hepatitis B and C
M. Valerie Lin, MD
Transplant Hepatologist
Division of Transplantation, Department of Surgery
Lahey Hospital and Medical Center
Tufts University School of Medicine
Disclosure
• Gilead HBV advisory board
511
HEPATITIS B
Learning Objectives
• Understand the natural history (phases of
infection) of chronic HBV
• Recognize when to initiate treatment for HBV
• Identify currently approved drugs for HBV and
their efficacy
• Describe the novel drug targets and inhibitors
currently in pipeline
512
Case
34 year old Asian male who was tested positive
for HBsAg. Additional labs showed positive anti-
HBc, positive HBeAg, HBV DNA > 170m IU/mL
and normal LFT. Clinically asymptomatic.
1) Which phase of HBV infection?

2) Is treatment indicated?
Serological Tests for HBV and

Interpretation
Source: AASLD – LiverLearning
513
Phases of Chronic Hepatitis B
Immune Tolerant CHB
514
HBeAg Positive “Active” CHB
Immune Inactive CHB
515
HBeAg Negative “Active” CHB
Resolved CHB
516
Interpretation of HBV Serology

Status HBsAg HBeAg HBc IgM HBc IgG HBs Ab HBe DNA LFT
Ab
Immune Tolerance + + - + - - +++ N
Active infection + + + (acute) - (acute) - - +++

- (chronic) + (chronic)
Carrier + - - + - +/- + or UD N
E-Ag neg chronic HBV + - - + - - ++
Resolution - - - + + - UD N
Window Period - - + - - - +++
Immunization - - - - + - - N
Algorithm to Identify HBV

Treatment Candidates
AASLD Practice Guidelines
517
Current Available HBV Treatment

Medication Administration Dosing Effectiveness* Risk of
Resistance
First line
Entecavir Oral 0.5mg daily >90% in naïve <1% in naïve
patients 30% at 5 yrs in lam-
experienced pts
Tenofovir Oral 25mg or 300mg >90% <1%

daily
Peg-interferon Injectable 180ug weekly 30% None
Second line
Lamivudine Oral 100mg daily <50% 70% at 5 years
Adefovir Oral 10mg daily <50% 30-40%
Telbivudine Oral 600mg daily <70% 30% at 5 years
Responses to HBV Treatment

• Virologic/Serologic Response
– Decrease in HBV DNA
– HBeAg loss and sero-conversion to anti-Hbe
– HBsAg loss
• Biochemical response
– Normalization of ALT
• Histological response
– Decrease in hepatic inflammation
518
HBV DNA Reduction After 1 Year

of Treatment
Scaglione SJ, Lok AS. Gastro 2012; 142: 1360-1368
Rate of HBeAg Seroconversion and

HBsAg Loss after 1 to 5 years of Rx
HBeAg Seroconversion HBsAg Loss
519
Novel Drug Targets and Inhibitors
Liver International 2017; 37(Suppl. 1): 33–39
Case
34 year old Asian male who was tested positive
for HBsAg. Additional labs showed positive anti-
HBc, positive HBeAg, HBV DNA > 170m IU/mL
and normal LFT. Clinically asymptomatic.
1) Which phase of HBV infection? Immune

Tolerant
2) Is treatment indicated? No
520
Take Home Points

• Age of infection influences natural history
• The phases of HBV disease help determine treatment
needs
• There are 8 approved HBV treatments - 2 types of
interferons and 6 nucleos/tide analogues
• Currently available HBV treatment are effective in
HBV suppression but not eradication
• Entecavir and tenofovir are the preferred treatment
because of low risk of drug resistance
HEPATITIS C
521
Learning Objectives
• Describe the recommendations for HCV
testing
• Understand the nature history of HCV
• Describe the goal of HCV treatment
• Understand the general concept of prescribing
HCV therapy
CDC and USPSTF

Recommendations for HCV Testing
• Risk-based
– Injection or intranasal drug users
– Received blood products prior to 1992
– Exposure to hemodialysis
– Infants born to HCV-infected mothers
– Unregulated tattoo
– History of incarceration
• Medical Indications
– Persistently elevated ALT
– HIV
• Birth Cohort
– One-time test for persons born 1945-1965
Ly et al. Ann Int Med 2012
522
Testing Sequence For Identifying

Active HCV Infection
CDC. Testing for HCV infection: MMWR 2013;62(18)
HCV Natural History

Acute hepatitis C
55 - 85%
Chronic infection
70%
Chronic hepatitis 1 - 4%/yr
20% HCC
Cirrhosis
Decompensation
Time 4 - 5%/yr
(yr)
10 20 30
523
Factors Associated with Faster

Fibrosis Progression
Non-modifiable Modifiable
HCV Can Be Cured

• Cure is defined by
HCV Life Cycle
sustained virological
response (SVR)
• I.e. undetectable HCV
RNA at least 3 months
post-Rx
• SVR is associated with:
– ALT normalization
– Disease progression
– Improved mortality
524
FDA Approved Oral HCV Direct

Acting Anti-virals (DAAs)
AASLD HCV modules
Case
50 year old man with history of hyperlipidemia (on
simvastatin) and GERD (on omeprazole) presented to
discuss treatment for chronic HCV. He is treatment
naïve. Lab showed genotype 1a, HCV RNA 1 million
IU/ml. Liver elastography showed stage 1 fibrosis.
1) Which HCV Rx would you recommend? And for how

long?
2) What if he has stage 3-4 fibrosis?
525
General Principles of Prescribing Oral

DAAs
• Regimen selection
• Drug-drug interaction Genotype • 1 to 6
• Monitoring
– Side effects
– Labs Prior Rx • Naïve
Experience • Rx Experienced
Fibrosis • Stage 1-3

Stage • Cirrhosis
Commonly Used DAA

Combinations
Generic Type of inhibitor Brand Name
Ledipasvir + Sofosbuvir NS5A + NS5B Harvoni

Velpatasvir + Sofosbuvir NS5A + NS5B Epclusa
Velpastasvir + Sofosbuvir + Voxilaprevir NS5A + NS5B + PI Vosevi
Elbasvir + Grazoprevir NS5A + PI Zepatier
Pibrentasvir + Glecaprevir NS5A + PI Mavyret
NS5A = NS5A inhibitor

NS5B = NS5B Nucleoside inhibitor
PI = Protease inhibitor
AASLD HCV modules
526
Case
50 year old man with history of hyperlipidemia (on
simvastatin) and GERD (on omeprazole) presented to
discuss treatment for chronic HCV. He is treatment
naïve. Lab showed genotype 1a, HCV RNA 1 million
IU/ml. Liver elastography showed stage 1 fibrosis.
1) Which HCV Rx would you recommend? And for how
long? All the DAAs listed in the table for either 8 or
12 weeks
2) What if he has stage 4 fibrosis? Extend Rx duration
to 12 weeks
Things to Note When Prescribing HCV

DAAs
• Drug-drug interaction
• Monitoring
– Side effects
– Labs
527

DAAs
• Drug-drug interaction
• Monitoring CNS GI
Headache Nausea
– Side effects
– Labs
Fatigue Diarrhea
Insomnia

DAAs
• Regimen selection • CBC, LFTs, Cr/GFR
• Drug-drug interaction Pre-Rx • HCV RNA and Genotype
• HBsAg and HBcAb
• Monitoring
– Side effects During
• CBC, LFT, Cr/GFR
– Labs Rx • HCV RNA
(week 4)
• HCV RNA at end of Rx

Post- Rx • HCV RNA at 12 weeks
post-Rx
528
Post-Marketing HBV Reactivation

with DAA Regimens
• 29 cases identified
• Occurred within 4-8 weeks (mean 53 days)
• Heterogeneous in HCV genotype, DAA received and
baseline HBV parameters
• Outcomes:
– 2 fatalities and 1 liver transplant
– 16 pts received HBV treatment (usually delayed)
• FDA advised to screen HBV pre-therapy and monitor
during and post- therapy
Bersoff-Matcha SJ, et al. Ann Int Med June 2017
Take Home Messages

• Chronic HCV infection leads to cirrhosis and HCC
• HCV direct-acting antivirals (DAAs) are highly
effective and well-tolerated
• The main hurdle for HCV treatment is linkage of care
• When selecting HCV regimen, consider genotype,
prior treatment experience and fibrosis stage
• HBV reactivation could occur in patients with HBV
coinfection, and these patients needs to be
monitored closely or prophylactically treated
• Refer to HCV Guidelines ww.hcvguidelines.org
529
Question 1
Which of the following is an indication for
stopping HBV treatment?
A. After completing 6 months interferon and serum HBV DNA is
undetectable
B. When serum HBV DNA becomes undetectable in patients receiving
nucleos/tide analogue
C. When HBsAg is cleared (HBsAg-) in a non-cirrhotic patients receiving
D. After completing 5 years nucleos/tide analogue treatment
regardless of response
E. After completing 5 years interferon treatment regardless of
response
Question 1
Which of the following is an indication for
stopping HBV treatment?
A. After completing 6 months interferon and serum HBV DNA is
undetectable
B. When serum HBV DNA becomes undetectable in patients receiving
C. When HBsAg is cleared (HBsAg-) in a non-cirrhotic patients receiving
D. After completing 5 years nucleos/tide analogue treatment
regardless of response
E. After completing 5 years interferon treatment regardless of
response
530
Question 2
Which of the following is associated with the
higher risk for liver-related complications
secondary to HCV?
A. HCV genotype 2
B. Obesity
C. Immune compromise
D. Histology with advanced fibrosis
Question 2
Which of the following is associated with a
higher risk for liver-related complications
secondary to HCV?
A. HCV genotype 2
B. Obesity
C. Immune compromise
D. Histology with advanced fibrosis
531
CHRONIC LIVER DISEASE AND ITS

COMPLICATIONS
Anna Rutherford, MD, MPH

Clinical Director of Hepatology
Division of Gastronterology, Hepatology & Endoscopy
I have no disclosures relevant to this presentation.
532
Learning Objectives
• Natural history and outcome of cirrhosis
• Initial management of complications of cirrhosis
• Appropriate timing of referral for liver transplant
Chronic Liver Compensated Decompensated Death

Disease Cirrhosis Cirrhosis
Ascites
Jaundice
Encephalopathy
Variceal Hemorrhage
533
Probability of Hepatic Decompensation:

58% over 10 years
Ascites
Jaundice
Encephalopathy
Variceal bleeding
Hepatology 1987; 7: 122-128
Risk Factors for Hepatic Decompensation
• GI Bleeding
• Infection
• Alcohol intake
• Medications
• Dehydration
• Constipation
• Obesity (Hepatology 2011; 54: 555)
534
Hepatic Decompensation Reduces Survival
9 years
1.6 years
Hepatology 1987; 7: 122-128
Prediction of 3-Month Survival in Cirrhotics
MELD score = 3.8 ln (bilirubin) + 11.2 ln (INR) + 9.6 ln (creatinine) + 6
535
Prediction of 1 Year Survival in Cirrhotics:

Child Turcotte Pugh Score
Points 1 2 3
Encephalopathy None 1 and 2 3 and 4
Ascites Absent Slight Moderate

Bilirubin (mg/dL) 1-2 2-3 >3
Albumin (g/dL) 3.5 2.8-3.5 <2.8
INR <1.7 1.7-2.3 >2.3
5-6 A 100% 1 year survival

7-9 B 80% 1 year survival
10-15 C 45% 1 year survival
Natural History of Cirrhotic Ascites

Portal Hypertension
No Ascites
Uncomplicated
Ascites
Ascites +
Hyponatremia
Refractory Ascites
536
Management of Ascites
• 50% of compensated cirrhotics will develop ascites 10 years
from diagnosis
• Ascites most common complication of cirrhosis that leads
to hospital admission
• 15% 1 year mortality, 44% 5 year mortality after first
appearance of ascites
• New-onset ascites requires diagnostic paracentesis
• Bleeding complications in less 1/1,000 who require
paracentesis
• Use of blood products (FFP/platelets) not data supported
• SAAG of ≥ 1.1 is 97% accurate for portal hypertension
AASLD Guidelines: Hepatology 2013; 57: 1651–1653.
Treatment Options for Cirrhotics with Ascites

• Cessation of Alcohol use
• Sodium restricted diet (2000mg/day) and education
• Dual diuretics: Spironolactone and Furosemide, orally with single daily dosing
• Most patients do not need fluid restriction
• Ratio Spironolactone 100mg: Furosemide 40mg, increase every 3-5 days
• Maximum doses are Spironolactone 400mg: Furosemide 160mg
• Amiloride 10-40mg substituted for Spironolactone for tender gynecomastia
• Consider stopping NSAIDS, ACE Inhibitors, Angiotensin Receptor blockers,
Propranolol
• Liver transplant evaluation
537
Management of Refractory Ascites
• 10% of cirrhotics with ascites
• Unresponsive to 2g sodium diet and high dose diuretics

OR
Clinically significant complications of diuretics (encephalopathy, creatinine > 2g/dL,
sodium < 120 mmol/L, potassium > 6 mmol/L)
• Options include serial LVPs vs. TIPS liver transplant
• In LVP ≥ 5L, albumin infusion of 6-8g/L removed improves survival and prevents post-
paracentesis circulatory dysfunction
• Use of nonselective beta blockers may be associated with increased mortality in

patients with refractory ascites
Hepatology 2012; 55: 1172-1181.

J Hepatology 2014; 60: 643.
Large Scale Randomized Controlled Trials of TIPS

vs. LVP for Refractory Ascites
N Control of Ascites Survival Encephalopathy
60 61% vs. 18% (p=.006) 69% vs. 52% (p=.11) 58% vs. 48%*
70 51% vs. 17% (p=.003) 41% vs. 35% (p=.29) 77% vs. 66%
109 58% vs. 16% (p<.001) 40% vs. 37%* 60% vs. 34% (p=.058)
66 79% vs. 42% (p=.001) 77% vs. 52% (p=.021) Severe (p=0.39)
* P value not significant.
AASLD Guidelines: Hepatology 2013; 57: 1651–1653
538

Portal Hypertension
No Ascites
Uncomplicated
Ascites
Ascites +
Hyponatremia
Refractory Ascites
Hepatorenal
Syndrome
Hepatorenal Syndrome – clinical features
• Cirrhosis with ascites

• Serum creatinine > 1.5mg/dL
• No creatinine improvement after 2 days diuretic
withdrawal
• No creatinine improvement after volume expansion
with albumin (1g/kg up to 100g)
• Absence of shock, nephrotoxins
• Bland urine sediment/no parenchymal kidney
disease
AASLD Guidelines: Hepatology 2013; 57: 1651–1653.
539
Natural History of Hepatorenal Syndrome

6
Type 2 HRS SBP Type 1 HRS
5
4
Therapeutic
Creatinine paracenteses Cefotaxime
(mg/dL) 3
0
0 -6 -4 -2 0 1 2 3
Months Weeks
Gastroenterology 2002; 122:1658.
Hepatorenal Syndrome – management
• Treatment of underlying liver disease (alcoholic hepatitis, HBV)

• Prevention with albumin infusion in SBP
• Cessation of nonselective beta blockers in SBP
• Albumin/Octreotide/Midodrine
• In ICU, Norepinephrine (or Vasopressin) + Albumin
• Terlipressin – not approved in U.S.
• Hemodialysis as bridge to liver recovery or transplant
• TIPS
• Liver transplantation
540

Portal Hypertension
No Ascites
Uncomplicated
Ascites
Ascites + SBP
Hyponatremia
Refractory Ascites
Hepatorenal
Syndrome
Spontaneous Bacterial Peritonitis:

Treatment
Systemic antibiotics for Community Acquired SBP
• Ceftriaxone or Cefotaxime
• Beta lactam/beta-lactamase inhibitor combination
• Avoid aminoglycosides
• Most patients will respond to 5 day course of treatment
Cessation of nonselective beta blockers
Albumin IV on Day 1 and Day 3 with any of following:

• BUN > 30mg/dL
• Creatinine > 1.0 mg/dL
• Serum bilirubin > 4mg/dL
Best Pract Res Clin Gastroenterol 2007; 21: 77-93.
Gastroenterology 2014; 146: 1680-1690.
541
Spontaneous Bacterial Peritonitis:

Primary & Secondary Prophylaxis
• Prior episode of SBP
• Ascites total protein <1.5/dL AND

Creatinine ≥ 1.2, BUN ≥ 25 or serum Na ≤130
• Child score ≥ 9 or Bilirubin ≥ 3
Gastroenterology 2007; 133: 818-824.
Treatment of Hepatic Encephalopathy
• Determine precipitant of hepatic encephalopathy and treat

(Infection, Electrolytes, GI Bleeding, Constipation, Dehydration, Sedatives)
• Lower ammonia level (only if elevated in setting of altered
mental status): Lactulose Rifaximin
• No need to follow blood ammonia levels
• Do not restrict protein: Maintain dietary protein intake of 1.2
to 1.5g/kg/day
• Probiotics may be as effective as Lactulose in treatment of
chronic hepatic encephalopathy
542
Management of Gastroesophageal Varices
• GEV present in 50% cirrhotics: 30-40% compensated, 85% decompensated

• In compensated cirrhotics, varices develop at rate of 7-8%/year
• LS < 20kPA and platelet count > 150,000 very unlikely to have GE varices
• EGD to screen for gastroesophageal varices recommended in anyone with
new diagnosis of cirrhosis
• If no varices on original EGD, repeat every 2 years with ongoing liver injury
(obesity, alcohol) or 3 years (abstinence, viral elimination)
• Small varices (grade 1) on original EGD repeat 1-2 years
• EGD at time of other clinical decompensation (ascites, encephalopathy)
• If cirrhosis but no varices prevent clinical decompensation
• Grade 1 varices Non-selective beta blocker
• Grade 2-3 varices Non-selective beta blocker or variceal ligation (not both)
Hepatology 2017; 65: 310-332.
Management of Acute Variceal Hemorrhage

• Admit to ICU
• Blood volume resuscitation
Hemoglobin ~7 g/dL > 9g/dL: Risk of Rebleeding 11% vs. 22% in Cirrhotics (p=0.02)
NEJM 2013; 368: 11-21
• Short-term antibiotic prophylaxis (maximum 7 days)

Decreases rebleeding and improves survival
IV Ceftriaxone 1g/day >> Norfloxacin 500mg BID in Childs B/C
Gastroenterology 2006; 131: 1049-1056
• Somatastatin, Octreotide, Vapreotide for 3-5 days

• Upper endoscopy within 12 hours
• TIPS
AASLD Guidelines: Hepatology 2007; 46: 922-938.
543
Early TIPS An Option for Variceal Hemorrhage
• 63 Child B/C cirrhotics with acute variceal bleeding

• All had vasoactive drugs and endoscopic therapy, then
randomized:
• 32 underwent TIPS within 72 hours of admission
• 31 continued vasoactive drugs for 3-5 days
Nadolol/Propranolol and continued banding
• 7/31 needed rescue TIPS
• Median follow-up 16 months
• At 1 year, episodes of encephalopathy 18% TIPS vs.
10% pharmacologic (p=.80)
• No significant differences in adverse events
NEJM 2010; 362: 2370-2379.
Transjugular Intrahepatic Portosystemic Shunt
Hepatic Vein
TIPS
Splenic
Portal Vein Vein
Superior Mesenteric
Vein
544
Early TIPS An Option for Variceal Hemorrhage
Rebleeding Survival
97% vs. 50% 86% vs. 61%
NEJM 2010; 362: 2370-

2379.
Management of Bleeding Gastric Varices
• Vasoactive drugs, restrictive transfusion, antibiotic prophylaxis

• Banding gastric varices can be technically difficult (IGV1> GOV2>
GOV1)
• Cyanoacrylate glue injection
-Polymerizes into firm clot within varix
- Risk of distal embolization
- Not approved by FDA for use in US, center dependent expertise
• TIPS
• Balloon-occluded retrograde obliteration (BRTO)
- Balloon catheter in draining vessel then instill sclerosant/sponge
- 90% long-term bleeding control
- Can increase portal pressure: worsen esophageal varices, ascites
545
Balloon Retrograde Transcatheter Obliteration
Optimal Timing of Referral for LT

Clinical Decompensation + Biochemical Decompensation (MELD >15)
- Encephalopathy
- Ascites
- Variceal Hemorrhage or chronic GI bleed from portal hypertensive gastropathy
- Hepatocellular Carcinoma
- Hepatorenal syndrome
- Hepatopulmonary syndrome or Portopulmonary Hypertension
Other considerations:
- Acute Liver Failure
- Poor quality of life or Recurrent, resistant infections in PSC/PLD
- Liver based metabolic conditions with systemic manifestations
546
Timing: What is MELD?
• Model for End-stage Liver Disease

• Originally created to predict short term mortality
post TIPS
• Basis for liver allocation in U.S. since 2/2002
• MELD-Sodium used since 1/2016
• 4 objective lab tests (Sodium, Total bilirubin, Creatinine, INR)
• Highly predictive of 3-month mortality in cirrhotics
• MELD of 15 is threshold patient survival with
transplantation > survival without transplantation
Liver Disease Etiology of Adult Transplant Recipients
HCV
Malignancy
Alcohol
Others
Cholestatic
ALF
SRTR.transplant.hrsa.gov 2012
547
Exclusions for Liver Transplantation

MELD Score <15
Severe cardiac or pulmonary disease
AIDS
Ongoing alcohol or illicit substance abuse
HCC with metastatic spread
Uncontrolled sepsis
Anatomic abnormality that precludes liver transplant
Intrahepatic cholangiocarcinoma
Extrahepatic malignancy
Persistent non-compliance
Lack of adequate social support system
Hepatology 2014; 59: 1144-1165.
Living Donor Liver Transplantation

• ~4% of liver transplants in U.S. in 2017
• Patient must be listed for deceased donor transplant
• Anticipated prolonged time on wait list with MELD >15
• Recipients of LDLT are less sick: MELD 15-20
• Has family member or acquaintance with close
relationship – no coercion
• In adult, take the right lobe (2/3 mass of liver) from donor
recipient
• Pediatric cases use left lobe living donor transplant
548
Liver Transplants in 2017 in 11 UNOS Regions

REGION 2017
1 336
2 997
3 1251
4 815
5 1235
6 228
7 670
8 535
9 420
10 773
11 822
SUMMARY
• Hepatic decompensation reduces survival
• MELD and CTP scores predict 3-month and 1-year mortality
in hospitalized cirrhotics
• TIPS > LVP in management of refractory ascites
• Prevention of HRS includes antibiotics in UGI bleeding, IV
albumin in SBP/LVP
• Nonselective beta blocker cessation in SBP
• Consider early TIPS in Childs B/C variceal bleeds
• Gastric varices: cyanoacrylate glue, TIPS, BRTO in select
patients
• Refer for liver transplantation: MELD ≥ 15 + clinical
decompensation
549
SELECT REFERENCES
• G Garcia-Tsao et al. Portal Hypertensive Bleeding in Cirrhosis: Risk Stratification, Diagnosis and
Management: 2016 Practice Guidance from AASLD. Hepatology 2017; 65: 310-335.
• M Mandorfer et al. Nonselective B Blockers Increase Risk for Hepatorenal Syndrome and Death in Patients
with Cirrhosis and Spontaneous Bacterial Peritonitis. Gastroenterology 2014; 146: 1680-1690.
• P Martin et al. Evaluation for Liver Transplantation in Adults: 2013 Practice Guideline by American
Association for the Study of Liver Diseases and American Society of Transplantation. Hepatology 2014; 59:
1144-1165.
• B Runyon. Management of Adult Patients with Ascites Due to Cirrhosis. Hepatology 2013; 57: 1651-1653.
• H Vilstrup et al. Hepatic Encephalopathy in Chronic Liver Disease: 2014 Practice Guidelines by the
American Association for the Study of Liver Diseases and the European Association for the Study of the
Liver. Hepatology 2014; 60: 715-735.
A 61 year old HCV cirrhotic is admitted with

abdominal pain and confusion. His admission
creatinine is 2.1 (baseline 1.0), and he has evidence
of SBP on tap (>250 PMNs). In addition starting
Ceftriaxone, your next steps in management
should include all except:
A) Stop Nadolol
B) Albumin infusion 1.5mg/kg IV
C) Check urinalysis
D) Start Pentoxyfylline 300mg TID
550
A 61 year old HCV cirrhotic is admitted with

abdominal pain and confusion. His admission
creatinine is 2.1 (baseline 1.0), and he has evidence
of SBP on tap (>250 PMNs). In addition starting
Ceftriaxone, your next steps in management
should include all except:
A) Stop Nadolol
B) Albumin infusion 1.5mg/kg IV
C) Check urinalysis
D) Start Pentoxyfylline 300mg TID
The correct answer is D. This cirrhotic man has what appears to be acute kidney injury in the setting of spontaneous bacterial
peritonitis (SBP). The urinalysis is recommended to evaluate the acute kidney injury, which could be hepatorenal syndrome (HRS)
or something else. In SBP there is data to support cessation of non-selective beta blockers while the infection is being treatment,
as well as giving albumin infusion of 1.5 mg/kg of body weight to prevent HRS on the first day of treatment. There is no data to
support the use of Pentoxyfylline in cirrhotics with acute kidney injury or SBP.
On hospital day #2, this patient has massive hematemesis.

Urgent endoscopy shows grade III esophageal varices with red
wale signs. He has 3 bands placed. Next steps should include:
A) Octreotide IV for 72 hours

B) Consider BRTO before he rebleeds
C) Transfuse to keep hemoglobin > 10g/dL
D) Referral for urgent liver transplantation
551
On hospital day #2, this patient has massive hematemesis.

Urgent endoscopy shows grade III esophageal varices with red
wale signs. He has 3 bands placed. Next steps should include:
A) Octreotide IV for 72 hours

B) Consider BRTO before he rebleeds
C) Transfuse to keep hemoglobin > 10g/dL
D) Referral for urgent liver transplantation
The correct answer is A. Management of an acute esophageal variceal bleeding includes upper endoscopy within 12 hours,
vasoactive medications such as Octreotide for 72 hours and antibiotic prophylaxis. A hemoglobin threshold of > 7g/dL reduces the
risk of rebleeding when compared to a transfusion threshold of > 9g/dL. BRTO is used in management of isolated gastric variceal
bleeding. Acute variceal bleeding is not an indication for urgent liver transplantation, and it does not give additional points to the
MELD score.
552
Psychiatry Overview
Inflammatory Bowel Disease

Sonia Friedman MD
Associate Physician, Brigham and Women’s Hospital
Division of Gastroenterology, Department of Medicine
Conflict of Interest
• No conflicts of interest
553
Overview of Inflammatory Bowel Disease

(IBD)
IBD
>1.4 million persons in US
ULCERATIVE1 INDETERMINATE CROHN’S

COLITIS COLITIS2 DISEASE3
10%-20% of IBD patients
Proctitis Pancolitis Ileitis Colitis

28% 47% % at time 22% 32%
of diagnosis
Left-sided Ileocolitis
disease 45%
25%
1. Loftus EV, et al. Gut. 2000;46:336-343; 2. Marion JF, et al. In: Kirsner JB, ed.
Inflammatory Bowel Disease. 5th ed. Philadelphia, Pa: WB Saunders Co; 2000:315-
325; 3. Loftus EV, et al. Gastroenterology. 1998;14:1161-1168.
Age-Specific Incidence of IBD*

Ulcerative Colitis Crohn’s Disease
10 10
8 8
6 6
4 4
2 2
0 0
0 20 40 60 80 0 20 40 60 80
Age (yrs) Age (yrs)
*Per 100,000 population
Reprinted with permission from Lashner BA. In: Stein SH and Rood RP, eds. Inflammatory Bowel
Disease: A Guide for Patients and Their Families. Philadelphia, Pa: Lippincott-Raven Publishers;
1999:23-29.
554
UC: Presenting Symptoms

• Bloody diarrhea
• Abdominal cramping
• Tenesmus
• Weight loss
• Fevers
• Symptoms depend upon extent
and severity of inflammation
Endoscopic Spectrum of Severity

UC – Spectrum of Disease
Normal Mild
Moderate Severe
Reprinted with permission from AGA Clinical Teaching Project. IBD. 3rd ed. 2002.
555
Classification of UC Severity
FULMINANT
SEVERE • >10 stools/day
• >6 bloody • Continuous bleeding
stools/day • Toxicity
MODERATE • Fever • Abdominal
• ≥4
• Tachycardia tenderness/distension
stools/day
• Anemia or • Transfusion requirement
± blood
MILD
• Minimal ↑ ESR • Colonic dilation on x-ray
• <4
signs of
stools/day
toxicity
± blood
• Normal ESR
• No signs of
toxicity
Truelove SC, Witts LJ. Br Med J. 1955;2(4947):1041-8;

Kornbluth A, Sachar DB. Am J Gastroenterol. 2010;105(3):501-23.
CD: Presentation
• Diarrhea
• Chronic abdominal pain and
tenderness
• Weight loss
• Fever
• Perianal disease
• Symptoms vary with location of
disease
556
CD: Clinical Features

Inflammation Obstruction Fistulization
Abdominal pain Cramps Diarrhea

Tenderness Distention Pain
Diarrhea Vomiting Air/feces in urine
Weight loss Types
– Enteroenteric
– Enterovesical
– Retroperitoneal
– Enterocutaneous
Adapted with permission from AGA Gastroenterology Teaching Project. 3rd ed. 2002.
Crohn’s Disease: Severity

• Remission: Asymptomatic either spontaneously or after medical or
surgical intervention and not on steroids.
• Mild to moderate: Ambulatory and able to tolerate an oral diet, no
dehydration, toxicity, abdominal tenderness, mass, obstruction, or
> 10 percent weight loss.
• Moderate to severe: Failed treatment for mild to moderate or
prominent symptoms such as fever, weight loss, abdominal pain
and tenderness, intermittent nausea or vomiting, or anemia.
• Severe-fulminant disease: Persisting symptoms despite
conventional glucocorticoids or biologics as outpatients or
individuals presenting with high fevers, persistent vomiting,
intestinal obstruction, significant peritoneal signs, cachexia or
evidence or an abscess
557
AGA Clinical Pathway for Crohn’s Disease:

Characterizing Risk
Low Risk High Risk
>30 years Age at diagnosis <30 years
Limited Anatomic involvement Extensive

Perianal and/or
No severe Yes
rectal disease
Superficial Ulcers Deep
Prior surgical
No Yes
resection
Stricturing and/or
No Yes
penetrating behavior
Sandborn WJ. Gastroenterology. 2014;147(3):702-5.
558
The image demonstrates a new gastrocolic fistula (solid white

arrows). Multifocal involvement of the small bowel and
terminal ileum is also present (dashed white arrows).
559
Treatment of inflammatory bowel disease

(IBD) 20 - 5 years ago
Surgery
• Biological therapy was

Severe
considered only for Biological
those who have a Therapy
moderate-severe disease Immunomodulators

Moderate
or failed other (thiopurines/
medications methotrexate)
• It was introduced for Prednisone/Budesonide
treatment of IBD in the Mild
late 90s Anti-inflammatory drugs (5-ASA)
Treatment of moderate to severe IBD

in 2018
Surgery
Total Parenteral Nutrition (Crohn’s

disease only)
Small molecules (UC only)
Prednisone/Budesonide
Biologics + Immunomodulators
560
Goals of IBD Management

• Clarify disease and severity
• Induce Remission
– Defined by both patient reported
outcomes as well as biological
parameters
• Maintain a steroid-free remission
• Change the natural course of IBD

– Avoid hospitalization and surgery
– Avoid disease-related
complications
– Reduce costs of care Rubin DT, et al. Am J Gastroenterol Suppl. 2016;3:4‐7.
Peyrin‐Biroulet L, et al. Am J Gastroenterol.
2015;110(9):1324‐38.
Newer Management Concepts For

Moderate to Severe IBD
• Treat early in disease
• Treat aggressively with “top down”
biologics
• Check drug levels
• Dual therapy (immunomodulator +
biologic)
• Aim for deep remission (histologic and
endoscopic remission)
561
Pharmacology of
Thiopurines
Azathioprine 6-MP
2:1
2.5 – 3.0 mg/kg 1.0 – 1.5 mg/kg

100mg 50mg
Cuffari C, et al. Aliment Pharmacol Ther. 2000;14:1009-1014.
What are the data on efficacy and

safety of biologic agents?
562
Currently Approved Biologics for

IBD
Certolizumab Ustekinumab
Pegol approved approved for
for Crohn’s Crohn’s
disease (2008) Disease (2017)
Infliximab Adalimumab Natalizumab Vedolizumab
Initial cA2 approved for approved for approved for approved for
(Infliximab) Crohn’s disease Crohn’s disease Crohn’s disease Crohn’s
NEJM (1997) (1998) (2007) (2008) Disease (2014)
Infliximab Adalimumab Golimumab Vedolizumab

approved for approved for approved for approved for
ulcerative colitis ulcerative ulcerative ulcerative
(2005) colitis (2012) colitis (2013) colitis (2014)
Currently Approved Small Molecule

Therapy for IBD
Tofacitinib
approved for
ulcerative
colitis (2018)
563
Anti-TNF Therapies – Approved

for IBD
CD and UC CD UC
• Infliximab (IFX): chimeric mouse/human anti-TNF-⍺ antibody
• 75% human IgG1 isotype
• Adalimumab (ADL)/Golimumab (GOL): fully human monoclonal anti-TNF-⍺ antibodies
• Certolizumab pegol (CIMZIA): antigen-binding fragment (Fab') of a humanized
monoclonal antibody coupled to polyethylene glycol (No Fc portion)
Clinical Remission in UC
Patients failing 5-ASA/Steroids/Immunomodulators
ACT: Infliximab 8 Weeks1 ULTRA 2 Adalimumab PURSUIT: Golimumab

40% ** 40% 8 Weeks2 40% 6 Weeks3
30%
** 30% 30%
20% 20% * 20% ** **
10% 10% 10%
0% 0% 0%
Infliximab Infliximab Placebo Adalimumab Placebo Golimumab Golimumab Placebo
10 mg/kg 5 mg/kg 400/200 mg 200/100 mg
ACT: Infliximab 54 Weeks1 ULTRA 2: Adalimumab PURSUIT: Golimumab

40% ** 40% 52 Weeks2 40% 54 Weeks4
**
30% 30% 30% **
20% 20% ** 20%
10% 10% 10%
0% 0% 0%
Infliximab Infliximab Placebo Adalimumab Placebo Golimumab Golimumab Placebo
10 mg/kg 5 mg/kg 100 mg 50 mg
1Rutgeerts P,et al. N Engl J Med. 2005;353(23):2462-76; 2Sandborn WJ, et al. Gastroenterology. *P<.05 vs. placebo;
2012;142(2):257-65; 3Sandborn WJ, et al. Gastroenterology. 2014;146(1):85-95; 4Sandborn WJ, et al.
Gastroenterology. 2014;146(1):96-109. **P <.01 vs. placebo
564
Vedolizumab for UC
Induction Week 6
60
53 N=374
Proportion of Patients
50 47*
* P<.0001
40 ** P=.001
30 26
23
20 17 **
10 5
0
Remission Response
Vedo Anti-TNF Naïve - Vedo Placebo
Feagan BG, et al. N Engl J Med. 2013;369(8):699-710.
Vedolizumab for UC
Maintenance Week 52
60 57*
52* N=373
Proportion of Patients
50 45*
42* * P<.0001
40
30
24
20 16
10
0
Remission Response
Vedo q 4 weeks Vedo q 8 weeks Placebo
565
Cyclosporine vs. Infliximab for UC
There were no significant differences between IFX and cyclosporine in

adverse drug-related events, post-operative complications, or mortality.
Narula N, et al. Am J Gastroenterol. 2016;111(4):477-91.
UC Success Trial: Week 16 Results

Concomitant Immunomodulators in Patients with UC
*P<.05 compared to IFX
#P<.05 compared to AZA
100
#
# 77
80
69 #
# 63
60 55
50
*40#
37
40
24 22
20
0
Steroid-free remission Response Mucosal healing
AZA N=76 IFX N=77 IFX+AZA N=76
Panaccione R. Gastroenterology. 2011;140 (5 Suppl 1):S134.
566
Efficacy of Anti-TNF Therapies for Crohn’s Disease

ACCENT I*
(infliximab)2
80
58.5
Patients (%)
60
CHARM** 39.0
40
(adalimumab)1 22.8
80 60 20
Patients (%)
60 40 0
24 Week 2 Response Week 30 Remission Overall Remission
40
Week 30
20
0
Week 4 Response Week 26 Overall Remission PRECISE 2
Remission Week 26 (certolizumab)3
80
64.1
Patients (%)
60 47.9
40 30.7
20
0
*5 mg/kg dose. Week 6 Response Week 26 Overall Remission
**Maintenance trial with 80/40 mg induction dosing. Randomized Remission Week 26
responders = CR-70 at week 4. 1Colombel JF, et al. Gastroenterology. 2007;132(1):52-65;
Week 26 remission among randomized responders on 40 mg every 2Hanauer SB, et al. Lancet. 2002;359(9317):1541-9;
other week dosing. 3Schreiber S, et al. N Engl J Med. 2007;357(3):239-50.
Crohn’s Disease: SONIC Study Design

Randomization of Patients
Azathioprine 2.5 mg/kg Infliximab 5 mg/kg Infliximab 5 mg/kg
+ placebo infusions + placebo capsules + Azathioprine
2.5 mg/kg
Visits
Week 0* • • •
Week 2 • • •
Week 6 • • •
Week 10
Main
Week 14 • • •
Week 18
Week 22 • • •
Week 26* Primary Endpoint (Corticosteroid-free Remission at Week 26)
Week 30 • • •
Week 34
Extension
Week 38 • • •
Week 42
Week 46 • • •
Week 50 Secondary Endpoint (Week 50)
Week 54 • Infusions
* Endoscopy performed at Weeks 0 & 26 Colombel JF, et al. N Engl J Med. 2010;362(15):1383-95.
567
Crohn’s Disease: SONIC Clinical Remission

Without Corticosteroids: Week 26
100
p<0.001
Proportion of Patients (%)
80
p=0.009 p=0.022
60 57
45
40
30
20
52/170 75/169 96/169
0
AZA + placebo IFX + placebo IFX+ AZA
Colombel JF, et al. N Engl J Med. 2010;362(15):1383-95.
GEMINI 3:
Week 10 Results Vedolizumab in CD
TNF Failure TNF-naive
100 (Secondary Endpoint) 100 (Exploratory Endpoint)
Patients with Clinical
Patients with Clinical
80 80
Remission (%)
P=0.0012b
Remission (%)
60 60
27 35
40 40 16
12
20 20
0 0
Placebo Vedolizumab Placebo Vedolizumab
N=157 N=158 N=50 N=51
A 95% CI for difference from placebo.
BP value vs. placebo.
Clinical remission was defined as CDAI score ≤150.

Sands BE, et al. Gastroenterology. 2014;1479(3):618-627.
568
Vedolizumab: Maintenance in Crohn’s
GEMINI II
100% Vedolizumab q 4w
Week 52
Vedolizumab q 8w
Placebo
75%
P=.005
P=.004
P<.001
50% 45.5% 43.5% P=.04
P=.02
36.4% 39.0%
30.1% 28.8% 31.7%
25% 21.6%
15.9%
0%
Clinical Response Clinical Remission Steroid-Free Remission
P values vs. placebo
Infections and Mortality in the TREAT

Registry: 15,000 Patient-Years of Experience
Multivariate Analysis
4.5
4.0 Mortality Serious infections

3.5
Adjusted Odds Ratio
Steroids
3.0
2.5
AZA
AZA IFX 6-MP Steroids
2.0
6-MP MTX
1.5 IFX MTX
1.0
P<.001 P=.006 P=.002
0.5
0.0
AZA = azathioprine; IFX = infliximab; MTX = methotrexate.
Lichtenstein GR, et al. Am J Gastroenterol. 2012;107(9):1409-22.
569
Minimizing Toxicity for Anti-TNF Therapy

• Rule out evidence for TB prior to initiation
– If immunocompromised, PPD and Quantiferon may be
negative
• Rule out active infection prior to initiation
– Abscess, C. difficile, CMV
• Check serology for Hepatitis B
• Vaccination for age-appropriate disease
– Influenza, Hepatitis A and B, pneumococcal pneumonia,
herpes zoster
• Assess for signs/symptoms of:
– Uncontrolled heart failure
– Demyelinating disorders
– Skin cancers/suspicious moles
Kane S. Curr Gastroenterol Rep. 2010;12(6):502-6.
Vedolizumab: Safety
• Safety data from 6 studies in 2,830 patients (4,811 patient-years of

exposure)
• Adverse events and serious adverse events not higher than placebo
• No cases of progressive multifocal leukoencephalopathy (PML)
• Most frequent AEs were GI events and infections (more frequent in
placebo groups)
• Immunogenicity (anti-vedolizumab antibody): 4-18%
• Infusion reactions: <5% of patients (3 serious)
• Malignancies: 18 in all studies (including 11 open label studies)
Colombel JF, et al. Gut. 2016. pii: gutjnl-2015-311079.
570
Ustekinumab: Induction
Clinical Remission
UNITI-1 UNITI-2
Patients in Clinical Remission (%)
Ustekinumab: Maintenance
Primary and Major Secondary End Points in IM-UNITI
Patients (%)
571
Ustekinumab: Adverse Events

• Ustekinumab and Malignancy
– Rate of Malignancy: 0.2% prevalence in the
UNITI trials (similar to general population)
• Serious Infection (SI)

– UNITI Trials: 2.3% (UST q8) vs. 5.3% (UST q12)
and 2.3% in the placebo group
– Psoriasis Longitudinal Assessment (PSOLAR)
Registry
• 2.3% (12,093 patient) had co-diagnosis of
IBD
• Numerically lower rates of SI in patients
treated with UST compared to IFX: 1.38 vs
5.75
• Reversible Posterior Leukoencephalopathy Syndrome

(RPLS)
– Characterized by headaches, altered
consciousness, and seizures
– Self-limited with supportive care
• Limited data in IBD, but low risk of increased serious

infection or risk of malignancy in UST Feagan BG, et al. N Engl J Med. 2016;375(20):1946-60
Loftus EV et al. Gastoenterology, 2016;150(4):S805
Gratton D et al. JAMA Dermatology, 2017 Feb 1;16(2):177-179
Advantages of Small Molecules in IBD

• Low-molecular weight
• Oral administration
• Resist gastric degradation
• Rapidly enter the systemic circulation
• Short half-life
• Lack immunogenicity
• Easier to manufacture than biologics, which may
improve cost effectiveness
• Bind to specific intracellular targets.
572
Tofacitinib in UC: OCTAVE Phase 3 Trial

Clinical Response and Remission: Week 8
OCTAVE 1 OCTAVE 2
Clinical Clinical Clinical Clinical
Response Remission Response Remission
80 P<.00 80 P<.00
1 1
59.
60 60 55
9 P<.01 P<.001
40 40
32.
8 25. 29 22.
20 2 20 1
12. 12
8.2 4
6
0 0
Placebo 10 mg Placebo TNF TNF Placebo 10 mg Placebo TNF TNF
BID Naive Rxed BID Naive Rxed
Tofacitinib Tofacitinib
10 mg BID 10 mg BID
Sandborn WF, et al. NEJM. May 2017.
Phase 3 OCTAVE Tofacitinib Trial: Safety
OCTAVE Induction 1 OCTAVE Induction 2
Tofacitinib Tofacitinib
Placebo Placebo
10 mg BID 10 mg BID
N=122 N=112
N=476 N=429
Treatment –emergent AEs, N(%) 269 (56.6) 73 (59.8 232 (54.1) 59 (52.7)
Treatment –emergent SAEs, N(%) 16 (3.4) 5 (4.1) 18 (4.2) 9 (8.0)
Discontinuation due to AEs, N(%) 18 (3.8) 2 (1.6) 17 (4.0) 8 (7.1)
Infections, N(%) 111 (23.3) 19 (15.6) 78 (18.2) 17 (15.2)
Serious infections N(%) 6 (1.3) 0 (0.0) 1 (0.2) 0 (0.0)
573
Phase 3 OCTAVE Tofacitinib Trial

Maintenance Week 52
100 Placebo
P<.001 vs. placebo, all comparisons Tofacitinib 5 mg
80 Tofacitinib 10 mg
Percent of Patients
59
60
47 49
40 33 35
25 28
22 19
20
5 7 5
0
Sustained remission Sustained mucosal Sustained steroid- Sustained clinical
healing free remission* response
*Among remitters at baseline;
Placebo N=59, Tofacitinib 5 mg N=65, Tofacitinib 10 mg N=55
Biosimilars
• Biosimilar is highly similar to the reference product with
minor differences in clinically inactive components
• Price reductions up to 80%
• No clinically meaningful differences between the biological
product and the reference product in terms of biological
activity, safety, efficacy, purity, and potency
• Same strength, dosage form, and route of administration as
original
• Can be alternated with original without loss of efficacy or
change in risk
• Can be substituted at the pharmacy without intervention of
healthcare provider
574
Non-response: Definitions
• Primary non-response: A patient does not respond to a
loading dose of a biological agent when he/she receives it for
the first time. Is this patient a non-responder to all drugs
targeting the same pathway?
• Secondary non-response: A patient has responded to

biological therapy at onset, but loses response or becomes
intolerant to the molecule. This patient may respond to dose
adjustment or is likely to benefit from other agents targeting
the same pathway. If antibodies to initial drug, can switch
within class.
Reactive Testing Algorithm: Anti-TNF

Therapy
Secondary loss of response
(disease activity confirmed)
Sub-therapeutic
Infliximab/Adalimumab
Therapeutic concentration
infliximab/adalimumab
concentration Drug antibody
Drug antibody
positive
negative
Low level of antibody High level of antibody
Change drug class or Dose escalate

surgery Consider dose Change to
escalation, addition of different
immunomodulator, or anti-TNF
change anti-TNF
Modified from Khanna R, et al. Aliment Pharmacol Ther. 2013;38(5):447-59.
575
Changing Class More Efficacious Than Dose

Escalation in Patients with Adequate ADA
Levels
Yanai H, Clin Gastroenterol Hepatol. 2015 Mar;13(3):522-530
Proactive Monitoring
• Outcomes of patients who
had proactive therapeutic
Probability on Infliximab
concentration monitoring
(TCM) of IFX (N=48), and
those without (N=78) TCM
No TCM
• Target 5 to 10 µg/mL IFX
• Pts with IFX <3 fell from 27%
to 10%
• 86% of TCM group remained Weeks
on IFX, versus 52% without
monitoring
Vaughn BP, et al. Inflamm Bowel Dis. 2014;20(11):1996-2003.
576
IBD: Systemic Complications

Growth failure
Eye
in children
inflammation*
Lower Kidney
bone density* stones
Liver and Subfertility*

bile duct
inflammation Ovaries
Uterus
Gallstones
Arthritis and
joint pains
Skin lesions
*Higher incidence in women.
577
578
Musculoskeletal Disorders in IBD

• Peripheral arthritis
Reprinted with permission
from Berens DL. Roentgen
Features of Ankylosing
• Sacroiliitis Spondylitis. Clin Ortho.
1971;74:20-33.
Reprinted from the Clinical

Slide Collection on the
Rheumatic Diseases,
• Ankylosing copyright 1991, 1995, 1997.
Used by permission of
spondylitis the American College of
Rheumatology.
579
AGA Recommendations
for Managing Osteoporosis
Basic Prevention:
-Ca/Vit D
-exercise
T score >-1 -smoking cessation
-avoid alcohol
IBD patient: -minimize
Any of: corticosteroids
-Prolonged steroid use T score -2.5 to -1 -treat hypogonadism
(>3mo consec or recurrent
courses) Prevention and:
-Low trauma, fragility fracture DXA -repeat DXA 2 years
-Postmenopausal or male age -Prolonged CS consider BP
>50 and DXA 1 year
-Hypogonadism
T score <-2.5
Prevention and:
-Screen other causes low BMD
Vert Fracture -Bisphosphonate therapy or
Regardless of DXA -Refer to bone specialist
Gastroenterology 2003;124:795-841
Relative Risk of Colon Cancer Based on

Extent of UC (and Crohn’s colitis)
20
18
16
14
12
10
8
6
0
All Cases Proctitis Left-Sided Pan-colitis
Ekbom A, et al. N Engl J Med. 1990;323:1228-1233.
580
Risk Factors for Colon Cancer in IBD
• Strictures that cannot be passed

• Extensive colitis
• Long duration of disease
• Active disease
• Primary sclerosing cholangitis
• Family history of colon CA
Take Home Messages

• Treat early
• Treat aggressively for moderate to severe IBD
• Use dual therapy
• Use drug levels to guide therapy
• Treat to endoscopic and histologic remission
• The risk of a serious side effect is much less than
the risk of a complication from the IBD itself
581
Question
Which of the therapies for IBD has the highest
risk for immunogenicity (drug antibody
development)?
A. Vedolizumab
B. Ustekinumab
C. Infliximab
D. Adalimumab
E. Golimumab
Question
Which of the therapies for IBD has the highest
risk for immunogenicity (drug antibody
development)?
A. Vedolizumab
B. Ustekinumab
C. Infliximab
D. Adalimumab
E. Golimumab
Infliximab is 25% mouse protein and thus has the highest immunogenicity
582
Question
A 38 year old man with a medical history notable for Crohn’s
Disease, currently on Infliximab at 5mg/kg every 8 weeks, presents
in follow up with worsening abdominal pain, frequent bowel
movements up to 15 daily, to discuss next options. Serum CRP is
56mg/dL. Infliximab trough level obtained prior to his last infusion
was 12μg/mL (adequate therapeutic level is >5μg/mL); no antibody
level detected.
After providing induction therapy, what would be the next best

therapeutic option in managing his disease?
A. Start azathioprine
B. Increase the infliximab dose to 10mg/kg
C. Discontinue infliximab and start the biosimilar: inflectra
D. Discontinue infliximab and start ustekinumab
E. Decrease interval between infliximab infusions to every 4 weeks
Question
A 38 year old man with a medical history notable for Crohn’s
Disease, currently on Infliximab at 5mg/kg every 8 weeks, presents
in follow up with worsening abdominal pain, frequent bowel
movements up to 15 daily, to discuss next options. Serum CRP is
56mg/dL. Infliximab trough level obtained prior to his last infusion
was 12μg/mL (adequate therapeutic level is >5μg/mL); no antibody
level detected.
After providing induction therapy, what would be the next best

therapeutic option in managing his disease?
A. Start azathioprine
B. Increase the infliximab dose to 10mg/kg
C. Discontinue infliximab and start the biosimilar: inflectra
D. Discontinue infliximab and start ustekinumab
E. Decrease interval between infliximab infusions to every 4 weeks
IFX does not work here even when the level is therapeutic so it is
necessary to switch drug class
583
References
1. Bonovas S: Biologic therapies and risk of infection and malignancy in
patients with inflammatory bowel disease: a systemic review and network
meta-analysis. Clin Gastroenetrol Hepatol 14:1385, 2016.
2. Ha C, Kornbluth A. A Critical Review of Biosimilars in IBD: The Confluence
of Biologic Drug Development, Regulatory Requirements, Clinical
Outcomes, and Big Business. Inflamm Bowel Dis 22:2513, 2016.
3. Julsgaard M: Concentrations of adalimumab and infliximab in mothers
and newborns and effects on infection. Gastroenterology 151:110, 2016.
4. Ng SC: Geographical variability and environmental risk factors in
inflammatory bowel disease. Gut 62:630, 2013.
5. Regueiro M: Infliximab Reduces Endoscopic, but Not Clinical, Recurrence
of Crohn's Disease After Ileocolonic Resection. Gastroenterology
150:1568, 2016.
584
Acute and Chronic Diarrhea
Benjamin Smith, MD
Assistant Professor, Harvard Medical School
Attending Physician: Brigham & Womens, Faulkner and
VAMC GI Fellowship Training Program
Commercial/Faculty
Disclosures
None
585
Goals
• Acute and Chronic Diarrhea
• Focus on essentials
• New developments
Topics Covered
• Definitions
• Approach to acute diarrhea
– Differential diagnosis
– Diagnostic approach
• When to watch
• When to test
• When to treat
• Approach to chronic diarrhea
– Mechanisms
– Diagnostic evaluation
• Initial testing
• Follow-up testing
586
Diarrhea: Definitions
• Objective definition
– Excessive stool weight: >200gm/day
• Subjective definition
– Excessive frequency of defecation (>3 stools)
– Less-than-normal form and consistency
• Acute diarrhea: < 4 weeks duration
• Chronic diarrhea: > 4 weeks duration
• Persistent diarrhea: 2-4 weeks duration
Normal Intestinal Physiology
• 10 L of fluid enters the jejunum daily

– 2 L: Food and drink
– 8L: Salivary, gastric, biliary, pancreatic,
intestinal secretions
• 1L enters the colon
• 80-100 mL excreted daily
587
Abnormal Intestinal Physiology
• Loosening of stools: 50-60mL increase daily

fecal water
• Diarrhea: 100mL (1-2%) increase in fecal water
• Many disorders disrupt intestinal fluid and
electrolyte absorption by at least this amount
– Frequent event
– Extensive differential diagnosis
Acute Diarrhea: Major Causes
• Infectious: Most common

– Viral: Noroviruses , Rotavirus
– Bacterial: Food poisoning, C. difficile
– Parasitic/protozoal
• Noninfectious
– Medications
– Consumption of poorly absorbed sugars (e.g.
sorbitol)
– Enteral feeding
– Ischemic colitis
– Fecal impaction: “paradoxical diarrhea”
588
Diagnostic Evaluation
• Majority of cases are mild and self-

limited
• 90% of cases need no diagnostic
evaluation
Situations Requiring Additional Testing
– Bloody diarrhea
– Profuse diarrhea leading to dehydration
– Duration >48 hrs or > 6 unformed stools/24
hrs
– Severe abdominal pain: Over age 50
– Temperature > 38.5°C (101.3°F)
– Immunocompromised or elderly (>70 yrs)
589
Initial Diagnostic Evaluation
• Stool assessment:
Wright’s stain
– Fecal leukocytes
– Occult blood
Fecal lactoferrin assay
• Presence of both: Dysentery
– Supports a bacterial etiology for acute diarrhea
– Campylobacter, Salmonella > E.Coli 0157:H7, Shigella
• Exception: Nosocomial diarrhea

– Testing for C. difficile toxin higher yield than fecal leukocytes
Stools Negative for FOBT and

Leukocytes
• Not severely ill

• Treat symptomatically for several days
• Likely etiologies:
– Viral (>75%)
• Noroviruses (71%), Rotavirus,
– Bacteria elaborating preformed toxin
• S. aureus, B. cereus, C. perfringens
• Stool culture positive: 1.5-5.6%
590
Further Testing: Stool Culture

• Sick/bloody diarrhea
– Stool culture positive: Up to 87%
• Food handlers
• Patients with IBD
• Routine culture:
– Campylobacter, Salmonella, Shigella
• Notify lab:
– E. Coli O157:H7, Yersinia, Aeromonas
• Single specimen: Bacteria shed continuously
• Clostridium difficile toxin assay
– Antibiotic/Chemotherapy within preceding 2 weeks
– Hospital-acquired diarrhea
Stool For Ova and Parasites

• Cost-effective in high risk groups
– Persistent diarrhea (>14 days)
– Community waterborne outbreak
– Exposure to untreated water (e.g.
streams)
– Daycare center exposure
– Travel to Russia, Nepal
• Giardia, Cryptosporidia
– Homosexual men (Giardia, E.histolytica)
– Patients with AIDS (Giardia, E.histolytica
and others)
• Intermittent shedding
– 3 specimens on consecutive days
591
Who needs Endoscopic Evaluation?
• Bloody diarrhea
– IBD versus infectious diarrhea
– Suspected ischemic colitis
• Pseudomembranous colitis
• Immunocompromised or other high-risk patients:
Look for CMV
• Flexible sigmoidoscopy versus colonoscopy
Supportive Therapy
• Rehydration: Glucose-NA+ co transporter
– WHO oral rehydration solution (per liter of water)
• 20gm glucose or 40gm sucrose, NaCl, NaHCO3, KCL
– Alternative rehydration solution (per liter of water)
• 4 tablespoon sugar
• ½ teaspoon salt
• ½ teaspoon baking soda
– Rice-based oral rehydration solution (e.g. Cera-lyte)
• Fluids for sweat replacement (e.g. Gatorade,
Powerade, Propel)
– Not equivalent to ORS. Sufficient for mild cases
– Diluted fruit juice plus saltine crackers
• Dietary modification
– Lactose free diet for several weeks
– Avoid food with high fat content
– Boiled starches or cereals with salt
– BRAT diet: Bananas, rice, apple sauce, toast
592
Supportive Therapy: Other Measures
• Stop all sugar substitutes

• Review medications
• Assess for fecal impaction and treat
• Adjust tube feeds: Dilute, decrease rate or add
fiber
Antidiarrheal agents
• Stools nonbloody and fever low-grade
• Antimotility agents: Decrease peristalsis
– Loperamide (Imodium)
• 4mg initially, then 2mg after each loose movement
• Maximum: 16mg/day for 2 days
– Diphenoxylate atropine (Lomotil)
• Central opiate and anti-cholinergic side-effects (atropine)
• 1-2 tabs tid/qid
• Other agents
– Pepto-Bismol: 2 tabs every 30 minutes; Can also help
vomiting
– Kaopectate
593
Empiric Antibiotic Therapy

• Severely ill immunocompetent individuals
– Fever, bloody diarrhea
– Dehydration
– >8 stools/day or symptoms for > 1 week
• Immunocompromised patients
– AIDS, malignancy, transplant recipients
• Drugs of choice
– Quinolone: Ciprofloxacin, levofloxacin, norfloxacin (3-5 days)
– Alternatives: Azithromycin (3 days) and erythromycin (5 days)
• Suspect fluoroquinolone resistance
• Campylobacter infection
– Metronidazole: C. difficile suspected
Probiotics: Mixed Results

• Prevention of travelers diarrhea
– Supportive studies/meta-analysis
– Lactobacillus GG and acidophilus
– Saccaromyces boulardii: N. Africa, Turkey
• Infectious diarrhea
– Mixed data: Lactobacillus species
– Reduce duration of diarrhea: about 24 hours
– 10 billion CFU within first 48 hours
• Antibiotic associated diarrhea: Need more
studies
594
Acute Diarrhea
Select Infectious Causes
Salmonella
• Most common
• 1.2 million illnesses
• 23,000 hospitalizations
• 450 deaths in US each year
• Single species: Salmonella cholerasuis
– 2200 different serotypes
– Nontyphoidal serotypes
• S. enteritidis, S. typhimurium, S. heidelberg
– Typhoidal serotypes
• S. typhi, S. paratyphi CDC 2018
595
Salmonella Gastroenteritis
• Source: Contaminated eggs and poultry
• Leukocytosis: Predominant mononuclear cells
• Achlorhydric individuals at increased risk
• Should not receive antibiotics
– Do not alter rate of clinical recovery
– Increases incidence and duration of intestinal
carriage
Salmonella Complications
• Bacteremia (5%): Risk of endovascular invasion
– Risk factors:
• Aortic aneurysm
• Vascular graft
• Prosthetic heart valve
• Osteomyelitis
– Risk factors:
• Orthopedic prosthetics
• Sickle cell disease
• These patients should receive antibiotics
– Ciprofloxacin 500mg BID for 10-14 days
– Multi-drug resistant: Chloramphenicol
596
Typhoid Fever
• Caused by Salmonella typhi or paratyphi

• Uncommon: 500 cases/yr in the U.S.
• Spiking fever
– Relative bradycardia,
• “Rose spot” rash: upper anterior trunk
• Hepatosplenomegaly
• RLQ abdominal pain
• Diarrhea: Varies in severity
• Duration 3-5 weeks
Campylobacter jejuni
• A leading cause of bacterial

diarrhea: 4-11%
• Source - Contaminated poultry:
50-70%
• Relapsing course: 15-20%
• Drugs of choice:
– Fluoroquinolones
– Azithromycin
– Rising rates of resistance
• Check sensitivities
597
Campylobacter: Complications
• Reactive arthritis/Reiter’s Syndrome: 1%

– 1-2 weeks after diarrhea onset
– Self-limited: several months
• Guillain-Barré Syndrome
– Responsible for 25% cases
– Symptoms within 3 months of diarrhea onset
– May be Culture negative but serology positive
• Antibiotics do not prevent these complications
Enterohemorrhagic E. coli (EHEC)
• Most prevalent in U.S.: E. coli 0157: H7

– Undercooked meat ingestion
– Predisposing factors: Age < 10 or > 50
– Watery diarrhea bloody diarrhea
– Often afebrile
– April 2017: Local food establishment that serves
chicken and rice
• 15 reported cases, 10 hospitalized
• May elaborate 2 proteins:

– Shiga toxin = verotoxine
– Intimin= Adhesine protein
598
EHEC Infections: Complications

• EHEC with both proteins
– Potentially lethal
– Increase risk of Hemolytic-uremic Syndrome
(HUS)
• Acute renal failure
• Microangiopathic hemolytic anemia
– Selective culture required
– Avoid Antibiotics: Increased risk of HUS
Chronic Diarrhea:
A Systematic Approach
599
Chronic Diarrhea
• Afflicts 5% of the population

• Myriad of disorders
• Order of prevalence varies
– Practice setting
• Optimum evaluation strategy
– Not established
– Expert opinion
MAJOR CAUSES IN DEVELOPED

COUNTRIES
• Irritable bowel syndrome
• Inflammatory bowel disease
– Ulcerative colitis, Crohn’s disease
– Microscopic colitis
• Malabsorption syndromes
– Lactose intolerance
– Celiac disease
• Medications
• Chronic infections
– Immunocompromised
– Bacterial, parasitic
600
Categorization of Diarrhea
Osmotic
• Watery
Secretory
• Inflammatory
• Fatty
• Several mechanisms may coexist
Osmotic Diarrhea
• Hallmarks
– Diarrhea stops with fasting
– Large osmotic gap: > 125 mOsm/kg
• Mechanism
– Ingestion of osmotically active solutes
– Retention of water in intestinal lumen
– Electrolyte absorption (Na+, K+) is normal
– Large osmotic gap between expected (290mOsm)
and calculated
• Stool osmotic gap = 290 – 2([Na+] + [K+])
601
Osmotic or Malabsorptive Diarrhea

• Exogenous Causes:
– Antacids: Mg+
– Laxatives:
• Polyethylene glycol (PEG)
• Poorly absorbed anion (PO4-3, SO4-2, citrate)
– Sugar substitutes: Sugar-free candy/gum or medication
elixirs:
• Sorbitol, mannitol, Splenda, lactulose
– Nonabsorbable fats: Olestra
• Endogenous Causes:
– Congenital: Disaccharide deficiencies: Lactose intolerance
– Acquired
• Post-enteritis: Lactose intolerance
• Pancreatic insufficiency
• Celiac disease
Secretory Diarrhea
• Hallmarks
– Persists with fasting
– Nocturnal diarrhea
– Large volume, watery
– Small stool osmolar gap < 50 mOsm/kg
602
Secretory Diarrhea
• Exogenous:
– Stimulant laxatives: Bisacodyl, senna
– Prostaglandins, theophylline, colchicine
– Dietary secretagogues: Ethanol, caffeine, colas
• Endogenous:
– Bile acid malabsorption:
• Crohn’s ileitis, SB resection, bacterial
overgrowth, cholecystectomy
– Hormone-producing tumors: VIPoma, gastrinoma
Bile Acid Diarrhea

• IBS-D: up to 50% with bile acid malabsorption
• Post cholecystectomy: 5-12%; Often improves over
weeks to months
• Bile acids: Stimulate colonic motility and secretion
• Treatment: Bile acid sequestrants
– Colestipol (tablet): 1 gm twice daily
– Cholestyramine (powder): 4 gms daily
– Colesevelam/Welchol (tablet): 1.875gm twice daily
• Average delay in transit time of 4 hours c/w placebo
• Potential side effects: Bloating, flatulence, abdominal
discomfort and constipation
– Need to be separated from other medication by > 2 hours.
603
Inflammatory Diarrhea
• Hallmarks
– Mucoid, bloody stool
– Tenesmus, abdominal pain, fever
– FOBT positive
– Fecal leukocytes:
• Low sensitivity (70%) /specificity (50%)
• Fecal calprotectin: Zn/Ca binding protein
– Derived from neutrophils & monocytes
– Levels increased in intestinal inflammation
– Distinguish inflammatory from noninflammatory causes
of chronic diarrhea
Inflammatory Diarrhea
• Chronic infections
– C. difficile, amebiasis, TB, parasitic pathogens
• IBD: Crohn’s, ulcerative colitis
• Radiation or chemo-induced mucositis
• Colonic ischemia
604
Fatty Diarrhea
• Oil droplets in stool, floating stool
• Diagnosis
– Positive Sudan III stain: Qualitative
– 72 hour stool collection
• Abnormal: > 7gm fat/day
• Rarely done (limited reproducibility)
– Stool acid steatocrit
• Acidify stool
• Separate fecal homogenate into lipid, water, solid phases;
Measure lipid
• Good correlation with quantitative fecal fat
– NIRA: Near infrared reflectance analysis
• Simultaneous measurement of fecal fat, carbohydrates,
nitrogen
• Expanding use in Europe, starting in U.S.
Fatty Diarrhea: Causes
• Pancreatic insufficiency
• Crohn’s disease
• Short bowel syndrome
• Bacterial overgrowth
605
History
• Stool characteristics: Watery, bloody, oily
• Epidemiological factors: Travel, sick contacts
• Aggravating/mitigating factors: Diet, stress
• Presence or absence:
– Fecal incontinence, abdominal pain, weight loss
• Past history:
– Diabetes, Hyperthyroidism, surgery, XRT, CAD
• Medication history
• Sexual history: Risk factors for AIDS
• Family history: IBD, neoplasm, celiac disease
• Markers of eating disorder, malingering
PHYSICAL EXAM
• Extent of fluid and nutritional depletion
• Skin rashes or flushing
• Mouth ulcers
• Thyroid masses or exophthalmos
• Arthritis
• Hepatomegaly or abdominal masses
• Anorectal exam: sphincter tone, perianal
fistula/abscess
• Scars (suggesting prior abdominal surgery)
606
Initial Laboratory Testing

• Minimum
– CBC with differential
– Electrolyte panel
– Total protein & albumin
– Thyroid function tests
– ESR
• Strongly consider
– Iron studies, vitamin B12, Folate, Prothrombin time
– Sprue serology: TTG IgA and IgA level
Initial Stool Testing
• Fecal occult blood testing

• Fecal leukocytes
• C. difficile toxin: Antibiotic history
• Stool culture
• Stool examination for O & P: Three samples
• ELISA for Giardia antigen
607
Endoscopic Evaluation
• Required for evaluation of many patients
• Flexible Sigmoidoscopy
– Reasonable exam for some patients
• Colonoscopy
– Patients with iron deficiency anemia
– Older patients: >50 yrs
– Patients with suspected Crohn’s disease
– Biopsy normal-appearing mucosa
• Collagenous/lymphocytic colitis
• 10% right-sided only
• Upper Endoscopy
– May be useful to rule-out sprue or Whipple’s
Difficult to Diagnose Cases
• Common problems overlooked

– Lactose intolerance
– Fecal incontinence
– Review medications again
• Stool culture: Aeromonas and pleisiomonas
• O&P: Cryptosporidium, Microsporidia
• Breath test for bacterial overgrowth
• Calculate the osmotic gap
608
Difficult Cases: Osmotic
• Laxative screen
– Inadvertent or surreptitious laxative use
• Stool pH < 5.3
– Carbohydrate malabsorption (e.g. lactulose, sorbitol)
Difficult Cases: Secretory
• Plasma peptides:
– VIP, gastrin, glucagon, calcitonin, tryptase
• 24 hour urine collection: 5-HIAA
• Imaging: CT scan:
– Pancreatic neoplasm, intestinal lymphoma,
TB
609
Difficult Cases: Inflammatory and Fatty

• Fecal fat assessment
– Stool sudan stain
• Suspect pancreatic insufficiency
– Pancreatic imaging: Chronic pancreatitis
• MRI/MRCP
– Stool: Fecal elastase, chymotrypsin
• Reliable only in moderate to severe insufficiency
– Urine collection: Pancreolauryl test
– Trial of pancreatic enzymes
• Small bowel follow through, MR enterography
– Rule-out IBD
• Small bowel biopsies for sprue, Whipple’s
• Breath test for SIBO
– Trial of antibiotics
SYMPTOMATIC THERAPY
• Therapeutic Options:
– Opiates: most effective
– Empiric trial of antimicrobial therapy
– Cholestyramine and colestipol
– Octreotide
610
Summary: Acute Diarrhea

• Infections: Most common cause of acute diarrhea
– Viral more common than bacterial etiology
– 90% self-limited, require no further evaluation
• Further evaluation: Sick, bloody diarrhea
– Sick: Stool for Fecal leukocytes, occult blood
– Bloody diarrhea: Stool culture
– Exception: Antibiotic exposure, hospitalized C. Diff. Toxin
• Empiric Antibiotics: Severely ill, immunocompromised
– Quinolone
– Second line: Azithromycin or erythromycin
– Metronidazole: C. difficile suspected
• Avoid antibiotics: E. coli 0157:H7
Summary (2): Chronic Diarrhea
• Broad differential diagnosis

• Evaluation assisted by:
– Careful history and physical
– Categorize the diarrhea:
• Watery, Inflammatory or Fatty
• Keep in mind possibility of fecal incontinence
• Many patients with chronic diarrhea require endoscopic
evaluation
• Acute and chronic diarrhea:
– Supportive measures: Rehydration, antidiarrheal agents
611
Question 1:
All of the following may cause chronic
inflammatory diarrhea except:
a. Ulcerative Colitis
b. Radiation
c. Clostridia difficile infection
d. Bacterial overgrowth
e. Chemotherapy
Question 1: Answer d
• Bacterial overgrowth
– Bile acid malabsorption
• Watery secretory diarrhea
• Fatty diarrhea
– Not inflammatory diarrhea
612
Question 2:
In patients with acute diarrhea, empiric
antibiotic therapy should be considered in all
but one of the following contexts:
a. Fever and bloody diarrhea

b. Moderate to severe travelers diarrhea
c. Known or suspected E. coli 0157: H7
d. Elderly and immunocompromised
e. Hospitalization under consideration
Question 2: Answer C
• Known or suspected E. coli 0157: H7
• Most common EHEC infection
• Avoid antibiotics:
• Increases production of shiga toxin
• Increases risk of Hemolytic-uremic Syndrome (HUS)
• Acute renal failure
• Microangiopathic hemolytic anemia
613
References
1. LaRoque R, Harris JB , Approach to the adult with acute diarrhea in
resource-rich settings In: UpToDate, Post TW (Ed), UpToDate, Waltham,
MA (accessed on April 7th 2018).
2. American gastroenterological association medical position statement:

guidelines for the evaluation and management of chronic diarrhea.
Gastroenterology 1999;116: 1461-1464.
3. Bonis PA, LaMont JT, Approach to the patient with chronic diarrhea in
resource rich settings In: UpToDate, Post TW (Ed), UpToDate, Waltham,
MA (accessed on May 28th 2017).
4. Centers for Disease Control and Prevention: www.cdc.gov
Commercial/Faculty
Disclosures
None
614
GI TAKE HOME MESSAGES and CLINICAL PEARLS
Kunal Jajoo, MD
Clinical Director
Disclosures
• None relevant to this presentation
615
GI Take Home Messages

• Whopping dose of GI information
• How will you metabolize this?
• Acronyms?
• Pathways?
• Clinical vignettes?
• Systems-based approach
GI Take Home Messages

• Whopping dose of GI information
• How will you metabolize all this?
• Acronyms?
• Pathways?
• Clinical vignettes?
• Systems-based approach
616
Esophagus
• GERD is quite common
• Treatment includes lifestyle changes and acid
suppression (H2RA / PPI) or sometimes
surgery
• EGD and pH testing (alarm / new symptoms,
treatment failure)
• Longterm effects of PPI need further
investigation
Esophagus
• Barrett’s esophagus is a result of GERD and a
precursor of adenocarcinoma
• Progression rate is much lower than initially
thought
• Screening indicated when multiple risk factors
present
• Surveillance indicated as treatment for
dysplasia is effective
617
Esophagus
• Eosinophilic esophagitis is an increasingly
recognized allergic disorder most commonly
presenting as dysphagia
• PPI therapy, elimination diet, food allergy
testing and swallowed steroids are mainstays
of therapy
Esophagus
• Motility disorders can be difficult to diagnose
• Must rule out structural causes of dysphagia
• High resolution manometry can distinguish
amongst the dysmotility disorders and direct
therapy
618
Peptic Diseases
• PUD most commonly caused by NSAIDs or H
pylori (or both - synergistic)
• NSAIDs often under-reported in the history
• PPIs have a more rapid response in healing
peptic ulcers than H2RAs
• Restrictive transfusion regimen for bleeding
PUD
• 2° ASA should be re-started within one week
Peptic Diseases
• Newest H pylori guidelines favor a test and
treat strategy for non-ulcer dyspepsia, ITP, iron
deficiency anemia and prior to long-term
NSAID use
• Treatment algorithm for H pylori hinges upon
macrolide exposure / PCN allergy
• Bismuth, clartihro, levofloxacin based
regimens; sequential regimens
619
IBD
• UC and Crohn’s
• Clinical parameters to define severity of
disease
• Goals of therapy
– Induce remission (clinical and biologic)
– Steroid free therapies
– Avoid surgery/hospital
IBD
• Paradigm shift: step-up therapy replaced by
top-down
• Treat early in moderate to severe disease
• Dual therapy – immunomodulator and
biologic mAb
• Be aware of longterm complicatons –
osteoporosis, cancer risk (highest in pan-
colitis), need for surveillance
620
Liver
• HBV • HCV
– Phases of Hep B – Risk based testing
determine treatment • Baby boomers should be
need: treat when tested
evidence of – progression to cirrhosis,
inflammation (ALT 2x), HCC
replication or fibrosis – Direct acting anti-virals
– Multiple treatment high sustained virologic
regimens: suppression response
– Entecavir / Tenofovir – Risk of re-activation HBV
preferred
Liver
• Decompensation occurs in the majority of
patients with cirrhosis
• Ascites>jaundice > encephalopathy > variceal
bleeding
• New ascites warrants paracentesis (SAAG > 1.1
= pHTN)
• Treatment – Na restriction,
furosemide/spironolactone; LVP/TIPS
621
Liver
• Hepatorenal syndrome
– Renal impairment that does not respond to
holding diuretics or volume expansion
– Type 1: acute precipated by SBP, alc hep, surgery
– Type 2: chronic, refractory ascites, Cr > 1.5
– Poor prognosis
– Albumin/Octreotide/Midodrine
– TIPS
Liver
• Varices
– Screening indicated; if seen, then non-selective
beta blocker or banding for esophageal
– Acute hemorrhage managed in ICU, banding, early
TIPS for CPT B/C
– Gastric variceal hemorrhage: BRTO (IR),
coiling/glue (GI)
622
Liver
• Transplant
– MELD score
• Highly predictive of 3 month mortality, used to triage
transplantation, MELD > 15
– OLT at MELD > 15 and decompensation
– Allocation is regional – variation
– LDLT
– Exclusions
Pancreas
– Acute Pancreatitis
• Most commonly due to gallstones or alcohol
• 2/3 criteria: typical pain, amylase/lipase > 3 x normal,
imaging
• Severity graded on presence of local complications and
degree of organ failure
• Early, aggressive fluid hydration, colloid
• Oral feeding > enteral feeding, avoid TPN; NGT ≈ NJT
623
Pancreas
– Acute Pancreatitis
• ERCP only in patients with concomitant cholangitis or
evidence of ongoing biliary obstruction
• Antibiotics for cholangitis, but not for prophylaxis of
severe AP
• Cholecystectomy in the same hospitalization if biliary
AP without necrosis
Pancreas
– Chronic Pancreatitis
• Toxic/Metabolic, Idiopathic, Genetic, Auto-Immune,
Recurrent, Obstructive
• Exocrine pancreatic insufficiency treated with
pancrealipase
• Opioid sparing pain regimen
• Steroids for AIP
624
Diarrhea
• Acute
– Viral > bacterial
– Norovirus, Rotavirus
– Salmonella (avoid abx), Campylobacter, C Diff,
EHEC (avoid abx)
– O&P only with > 14 days of symptoms, travel or
exposure
Diarrhea
• Chronic
– Inflammatory
– Medications
– EPI
– Celiac disease
– Microscopic colitis
625
GI - Take Home
626
GI BOARD REVIEW
Associate Physician
Department of Medicine
DISCLOSURES
• Muthoka Mutinga, MD- No disclosures
627
1. A 22 year old woman whose medical history is

only notable for moderate to severe acne, presents
for evaluation of worsening and persistent moderate
to severe retrosternal pain for the past two days. She
has had no similar symptoms in the past and does not
use illicit drugs. She has no personal or family
history of cardiovascular disease.
Which of the following is her likely diagnosis?
A. Dissecting aortic aneurysm
B. Esophageal spasms
C. Pill esophagitis
D. Reflux esophagitis
628
1. The answer is C
• Persistent retrosternal pain in a patient who may be taking
doxycycline for moderate to severe acne is highly
suggestive of pill induced esophagitis
• Other symptoms associated with pill esophagitis include

heartburn, odynophagia, dysphagia
• A discrete esophageal ulcer with normal surrounding

mucosa is typically seen endoscopically
2. A 20 year old man with ileocolonic Crohn’s disease

managed with 6-mercaptopurine presents for urgent
evaluation of anal pain and rectal bleeding. He is recovering
from a recent exacerbation of Crohn’s disease associated with
frequent non-bloody, watery stools. He reports acute onset of
sharp pain with defecation two days ago and also noticed a
small amount of bright red blood when wiping after
defecation. He has not been using suppositories or enemas to
manage the Crohn’s disease flare and reports no anal trauma,
fever, chills or abdominal pain.
629
Which of the following would you recommend for initial

management of his likely diagnosis?
A. Lateral internal sphincterotomy
B. Stool softener
C. Botulinum toxin injection
D. Sitz bath
2. The answer is D
• Patients with symptomatic anorectal disease, such as an anal fissure in
this case, often have elevated anal sphincter tone
• A warm sitz bath relaxes the internal anal sphincters and would be an
appropriate initial nonsurgical therapy for this patient
• Other nonsurgical approaches to manage anal fissures in Crohn’s
disease patients include measures to decrease diarrhea and bulk the
stools as well as topical medications such as nitrates and calcium
channel blockers to relax the internal sphincter
• The majority of acute anal fissures resolve without requiring surgical
therapy
630
3. A 41 year old man recently diagnosed with acute

uncomplicated sigmoid diverticulitis is referred for a follow-
up colonoscopy six weeks after completion of antibiotic
therapy. The colonoscopy exam is only notable for mild
sigmoid diverticulosis without evidence of inflammation.
Which of the following is associated with increased

risk of diverticulitis in men?
A. Tobacco use
B. Consumption of seeds and nuts
C. High fiber diet
D. Vigorous physical activity
631
3. The answer is A
• The incidence of diverticulitis has risen dramatically in the
United States
• Smoking is associated with increased risk of diverticulitis
• Consumption of seeds and nuts have not been shown to
increase the risk of diverticulitis contrary to popular belief
• Other lifestyle factors associated with a lower risk of
diverticulitis include:
– Low red meat consumption (<4 servings/week)
– Normal body weight (BMI 18.5-24.9)
– High dietary fiber intake (>23gm/day)
4. A 48 year-old man with a long history of

gastroesophageal reflux disease undergoes an
EGD which reveals a 5 centimeter long
segment of salmon-colored mucosa extending
proximally from the gastroesophageal junction.
Biopsies reveal Barrett’s esophagus without
dysplasia. Another endoscopy one year later
notes similar findings.
632
What is the proper subsequent surveillance

protocol for this patient?
A. Biopsy of the Barrett’s segment every 3-6

months
B. Biopsy of the Barrett’s segment annually
C. Biopsy of the Barrett’s segment every 3-5
years
D. No further surveillance is necessary
4. The answer is C.
• Barrett’s esophagus
– Intestinal metaplasia of the esophagus
– Associated with an increased risk of esophageal adenocarcinoma
• No dysplasia: repeat EGD in 3-5 years
• Indefinite for dysplasia: intensify acid suppressive therapy

and repeat EGD in 3-6 months
• Low grade dysplasia: confirm with 2nd pathologist and do

ablation therapy (preferred) or repeat EGD annually
• High grade dysplasia: confirm with 2nd pathologist and do

ablation therapy and endoscopic mucosal resection (EMR)
for discrete nodules.
633
5. A 21 year old college student is referred for evaluation of

rectal bleeding and intermittent loose stools associated with
urgency. His weight is stable and he reports no abdominal
pain. Stool culture do not reveal infection. The symptoms
have been ongoing for 1 month, but he delayed seeking
medical attention thinking symptoms would resolve. A
colonoscopy is performed and reveal inflammation localized
to the rectum. Biopsies reveal chronic active proctitis and
normal mucosa in all other regions of the colon.
Which of the following is associated with a poor

outcome in patients with ulcerative colitis?
A. Pancolitis
B. Older age
C. Normal c-reactive protein (CRP) level
D. Current smoker
E. Normal hemoglobin level
634
5. The answer is A.
• Extensive or pancolitis is associated with a higher risk of colectomy
• Younger age is associated with more severe disease, shorter time to
relapse and increased risk of colectomy
• Elevated inflammatory markers such as CRP and the erythrocyte
sedimentation rate (ESR) are associated with a higher risk of
colectomy
• Current smokers typically have a lower rate of relapse and fewer
hospitalizations
• On the other hand, nonsmokers and ex-smokers typically have more
extensive disease and a lower likelihood of disease regression
• Low hemoglobin or fibrinogen levels are independently associated
with treatment failure in patients with severe colitis.
6. A patient with hepatic cirrhosis due to

alcohol abuse is found to have large
esophageal varices on upper endoscopy,
but has no history of gastrointestinal
bleeding.
635
What is the appropriate therapy to

prevent future variceal bleeding?
A. Ursodiol
B. Sucralfate
C. Nonselective β-blocker
D. Endoscopic sclerotherapy
E. Proton pump inhibitor
6. The answer is C.
• Patients with portal hypertension and large esophageal
varices benefit from pharmacological prophylaxis (non-
selective β-blockers such as propranolol, nadolol and
timolol)
• Endoscopic sclerotherapy has been shown to be ineffective
and possibly harmful for prophylaxis of variceal
hemorrhage
• Sucralfate, ursodiol and acid inhibition therapy have no
role for prophylaxis of variceal hemorrhage
• Variceal band ligation has shown initial promise in patients
with large varices and may be considered in patients with
contraindications for nonselective β-blocker therapy
636
7. A 67 year-old man with a history of

congestive heart failure and peripheral
vascular disease presents with 48 hours of
left lower quadrant abdominal pain,
diarrhea with intermittent bleeding, and
low grade fever. Stool cultures reveal no
infection and ischemic colitis is
considered as a possible cause of his
symptoms.
Which of the following is true of this

disorder?
A. Digoxin may predispose patients to bowel
ischemia
B. Urgent angiography is indicated in order to
identify a culprit blood vessel
C. This disorder has the highest mortality rate of
the ischemic intestinal disorders
D. The diagnosis can be made on CT scan.
E. Serum lactate levels are markedly elevated in
this disorder
637
7. The answer is A.
• Ischemic colitis is a form of intestinal ischemia most often affecting
the descending and sigmoid colon (“watershed area”)
• Usually results from low vascular flow to a colonic segment, rather
than emboli or large vessel thrombosis
• Generally associated with low mortality
• Digoxin, a splanchnic vasoconstrictor, can predispose to both
mesenteric ischemia and ischemic colitis
• CT scan- may show colonic thickening, but can’t distinguish this from
other inflammatory processes
• Angiography- useful for suspected mesenteric ischemia, but of limited
value in ischemic colitis
• Serum lactate elevation- uncommon and usually associated with bowel
infarction and necrosis
8. A 58 year old man with no history of alcoholism,

chronic viral hepatitis or obesity is seen by his
primary care provider for evaluation of increased
abdominal girth as well as scrotal and lower
extremity edema. Abdominal ultrasound imaging is
notable for moderate ascites, patent hepatic and
portal veins and a normal appearing liver. Lab tests
to evaluate for chronic viral hepatitis and other forms
of chronic liver disease are unrevealing.
Arrangements are made for a diagnostic
paracentesis.
638
Ascites is classified via the serum-ascites albumin

gradient (SAAG), which is obtained by subtracting
the albumin level in ascites from that in the serum.
Which of these conditions will cause ascites with a
low SAAG gradient (<1.1mg/dL)?
A. Budd-Chiari Syndrome
B. Cirrhosis due to chronic hepatitis C
C. Peritoneal carcinomatosis
D. Congestive heart failure
E. Acute alcoholic hepatitis
8. The answer is C.
• The serum-ascites albumin gradient (SAAG)
differentiates between ascites due to portal
hypertension (SAAG>1.1) and that due to non-
portal hypertensive states (SAAG<1.1), with 97%
accuracy.
• Low gradient ascites (SAAG<1.1) can be seen in
conditions such as peritoneal carcinomatosis,
tuberculous peritonitis and fungal infections of the
peritoneum.
639
9. A 47 year-old woman presents with a 4-

month history of watery diarrhea and weight
loss of 25 pounds. Laboratory examination
reveals a mild iron deficiency anemia and a low
serum calcium. Stool cultures and examination
for ova and parasites are unremarkable. A
colonoscopy with random biopsies is normal. A
tissue transglutaminase (tTG) antibody is
strongly positive.
Which of the following statements

regarding this disorder is true?
A. Adherence to a gluten-free diet may reduce the risk of

developing risk of small intestinal lymphoma
B. This disease is more common in patients with
Type II diabetes mellitus
C. This disease is seen most commonly in patients of
Mediterranean background
D. Small intestinal biopsy in those who are compliant with a gluten
free diet typically reveals villous atrophy, deepened crypts and
intraepithelial lymphocytes
E. There is no association between this disease and
autoimmune thyroid disorders
640
9. The answer is A.
• The constellation of symptoms, evidence of nutrient
malabsorption and positive tissue transglutaminase (tTG)
antibody are consistent with celiac sprue.
• Primarily affects people of Northern European descent,
though it has worldwide distribution.
• May be associated with other autoimmune disorders such
as Type I diabetes mellitus and autoimmune thyroid
disease (e.g. Hashimoto’s thryoiditis).
• Treatment-- gluten free diet; this eliminates symptoms in
most people and decreases cancer risk, such as small
intestinal lymphoma and adenocarcinoma.
• Histological abnormalities also typically resolve with
adherence to a gluten free diet.
10. A 35 year-old woman is found to

have the following iron studies:
• Serum iron: 186
• Total iron binding capacity: 255
• Serum ferritin: 280 (normal 25-240)
• Transferrin saturation: 73%
Her liver function tests are normal, she

is asymptomatic, and has a normal physical
examination
641

ideal to obtain to confirm her diagnosis?
A. Percutaneous liver biopsy

B. Serum B12 and folate levels
C. Glucose tolerance testing
D. Testing for hereditary hemochromatosis
gene mutation
E. Abdominal CT scan with IV contrast
10. The answer is D.

• A transferrin saturation >55% is suggestive of an iron
overload syndrome.
• Transferrin saturation= serum iron/TIBC
• The ferritin may also be elevated in patients with
hemochromatosis-- less likely in menstruating women
• HFE gene analysis (hemochromatosis genetic test) would
be the next test to obtain; can detect 2 of the most common
mutations (C282Y & H63D)
• CT scanning is not sensitive enough to determine degree of
iron overload.
• A liver biopsy is not needed in a young, asymptomatic
patient.
642
11. A 28 year old woman with recent onset of moderate upper

abdominal pain exacerbated by eating and associated with
mild nausea and early satiety is seen for further evaluation by
her primary care provider. She also reports mild weight loss
associated with the symptoms. She does not take aspirin or
NSAIDs. She uses an inhaler for mild asthma and does not
take any other medications. Laboratory testing including a
complete blood count, liver function tests and TSH are
normal and the H. pylori breath test is negative.
Subsequently an esophagogastroduodenoscopy is performed.
Mild gastric mucosal erythema is noted, but biopsies are
histologically normal as are duodenal biopsies.
Which of the following would you order next to

establish her diagnosis?
A. Breath test to evaluate for small intestinal

bacterial overgrowth
B. Gastric emptying study
C. Abdominal ultrasound
D. Magnetic resonance cholangiopancreatography
(MRCP)
643
11. The answer is B

• Upper abdominal pain is often overlooked as a
symptom associated with gastroparesis
• In this case the symptoms of nausea and early
satiety in the absence of a mechanical cause of or
explanation on upper endoscopic examination
further favors the diagnosis of gastroparesis
• A solid phase gastric emptying study would help
to establish the diagnosis
12. A 42 year old presents to a travel clinic

requesting advice about reducing risk of
exposure to Hepatitis E. He is planning to
travel to an endemic area.
644
Which of the following statements regarding

Hepatitis E is true?
A. The virus is endemic in Southeast Asia

B. The clinical features of hepatitis E are similar to those
of hepatitis B
C. The virus is transmitted primarily via percutaneous
blood exposure
D. Hepatitis E is associated with a high rate of fulminant
hepatic failure in most people who acquire the
infection.
12. The answer is A.
• Hepatitis E is endemic in Southeast Asia, Africa,

the Middle East and Central America.
• It is transmitted via the fecal-oral route
• The infection is generally associated with a self-
limited icteric illness, with course similar to
Hepatitis A.
• Pregnant women have a high rate of fulminant
hepatic failure- up to 25%.
• A Hepatitis E vaccine is in development.
645
13. A 34 year old woman is seen by an ENT

specialist for evaluation of a chronic sore
throat. A diagnosis of gastroesophageal
reflux (GERD) is suspected.
Which of the following is another atypical

manifestations of GERD?
A. Exertional asthma
B. Hemoptysis
C. Hoarseness
D. Chronic diarrhea
646
13. The answer is C.
• A variety of clinical syndromes have been associated with

GERD such as hoarseness, chronic laryngitis, chronic non-
productive cough, nocturnal asthma and non-cardiac chest
pain.
• A 24-hour intraesophageal pH monitor can be used to
confirm the presence of acid reflux.
• Alternatively an empiric trial of a proton pump inhibitor
could be tried.
• There is no association between simple GERD and
exertional asthma, hemoptysis and chronic diarrhea.
14. A 62 year old man with recently diagnosed

compensated cirrhosis due to nonalcoholic
steatohepatitis (NASH) is advised to discontinue
statin therapy by his primary care provider due to
concerns about possible hepatoxicity. He is obese,
has hypertension and dyslipidemia, but does not
have diabetes mellitus or coronary heart disease.
647
Which of the following is believed to be true

concerning the effects of statin therapy in patient
with chronic liver disease?
A. Statins may decrease overall survival

B. Statins may increase the risk of hepatic
decompensation
C. Statins may decrease the risk of developing
hepatocellular carcinoma
D. Statins may retard the progress and/or
development of cirrhosis
14. The answer is D

• Recent data shows no evidence that statins are deleterious
in patients with chronic liver disease including
compensated cirrhosis
• In fact, statins appear to retard the progression and/or
development of cirrhosis, likely by inhibiting profibrotic
cytokines
• Statins appear to improve overall survival in patients with
chronic liver disease and decrease the risk of hepatic
decompensation
• Statins are not known to have any direct effect on the
development of hepatocellular carcinoma
648
15. A 62 year old man is referred for upper

endoscopy for evaluation of persistent
epigastric pain. He does not take aspirin or
NSAIDs and has not experienced melena or
weight loss. He does an internet search and is
worried that he may have a H. pylori infection.
Which of the following is a potential sequela of

chronic H. pylori infection?
A. Gastric varices
B. Gastric fundic gland polyps
C. Gastric MALT lymphoma
D. Duodenal adenocarcinoma
649
• H. pylori is a gram-negative, urease-producing bacterium that

colonizes the gastric mucosa.
• There is an association between MALT lymphoma and chronic H.
pylori infection. In addition, chronic H. pylori infection can be
associated with a risk for developing gastric adenocarcinoma
• There is a clear association between H. pylori infection and duodenal
ulcer disease eradication reduces ulcer recurrence by 80%.
• Chronic H. pylori infection does not increase the risk of developing
gastric varices, fundic gland polyps or duodenal adenocarcinoma
• Duodenal adenocarcinomas typically arise from adenomatous polyps
in the duodenum
16. A 64 year old woman with COPD presents for evaluation

of recurrent diarrhea and mild diffuse abdominal pain. Of
note was diagnosed and treated for C. difficile infection three
months ago. This first episode occurred after receiving
antibiotic therapy for acute bronchitis. She had a confirmed
recurrence of C. difficile infection six weeks later from which
she promptly recovered after antibiotic therapy. She was well
until the current presentation and had not received other
antibiotics in the interim. Stool testing is again positive for C.
difficile toxin, and no other pathogens are identified. Of note,
the first episode of C. difficile infection was treated with oral
metronidazole for 10 days and the second with oral
vancomycin for 10 days.
650
…continued
Her labs are normal except for a white blood count of 16,000
cells/mm3. She is afebrile, normotensive and not tachycardic.
She is unwilling to consider a fecal microbiota transplantation
after treatment of the current C. difficile infection.

appropriate treatment for this second recurrence of
C. difficile infection?
A. Oral vancomycin for 14 days
B. Rifaximin for 14 days
C. Fidaxomicin for 10 days
D. Metronidazole for 14 days
651
16. The answer is C

• A second recurrence of C. difficile infection should be treated with
Fidaxomicin 200mg orally BID for 10 days or a pulsed or tapering
dose of oral vancomycin
• Fidaxomicin has the advantage of being associated with a lower risk of
recurrence of C. difficile infection compared to currently available
antimicrobial agents, but it is also very expensive
• Fecal microbiota transplantation is a reasonable consideration after a
second recurrence of C. difficile infection
• Oral metronidazole (500mg TID for 10- 14 days) or oral vancomycin
(125mg QID for 10-14 days) are the preferred treatment for mild to
moderate initial C. difficile infection and can be repeated for the first
recurrence.
17. An 86 year-old man develops abdominal

cramps, watery diarrhea and low grade fevers.
Within two days, his stools become bloody, and
he feels weak and light-headed. He is seen in
the office and is noted to have a temperature of
100.8 and is normotensive but mildly
orthostatic. He has a diffusely tender abdomen
with no peritoneal signs, and bloody stool in the
rectal vault. He also has a fine petechial rash
on his lower extremities. Labs are notable for
hematocrit of 27%, platelet count of 48K/µL,
and creatinine of 3.5mg/dL. Of note, his prior
labs 6 months ago were all normal.
652
Which of the following statements

regarding this disorder is true?
A. The hematologic and renal complications of
this disorder are seen most often in middle-aged
adults
B. The illness is primarily transmitted through
the ingestion of poorly-cooked meat products
C. Antibiotics are effective in preventing
complications in this illness
D. In general, the diarrheal illness is severe
E. The disease is caused by Gram-positive
bacteria
17. The answer is B.

• Hemolytic-uremic syndrome (HUS) is a sequela of
E. coli O157:H7 infection (EHEC), a gram
negative bacterium.
• Transmitted via poorly cooked meat products.
• Generally self limited, except in the very young
and in the elderly.
• Antibiotics have not been shown to prevent HUS,
and in fact, may promote the development of
HUS.
653
18.A screening colonoscopy on a 50 year

old man with no family history of colon
cancer reveals two small, flat polyps in
the ascending colon which are removed.
The pathology report indicates that they
are sessile serrated adenomas.
Which statement regarding serrated

adenomas is true?
A. They are not associated with an increased risk
of metachronous colon cancer
B. The prevalence of serrated polyps is very low
(<1%)
C. They disproportionally contribute to interval
colon cancers
D. They are easily detected on colonoscopic
examination
654

• Serrated polyps are:
– Characterized histologically by serrated (saw-tooth) appearance of
crypt epithelium
– More easily missed on colonoscopic exam due to their flat
morphology and ambiguous color, especially in the proximal colon
• A recent metanalysis of data published between 2009-2014

estimate that the prevalence of serrated polyps ranged
from 5.6-28.7%
• Serrated polyps are associated with an increased risk of

metachrounous cancer and certain types are also
associated with increased risk of synchronous advanced
neoplasia
• They also disproportionally contribute to interval colon

cancers
19. A 52 year old man with cirrhosis due to chronic

hepatitis C, genotype 3, recently had confirmed
sustained virologic response (SVR) after completion
of direct acting antiviral therapy. He is seen for an
annual physical exam and reports no interval
symptoms. He has no history of complications
related to cirrhosis. He is concerned about his future
risk of developing hepatocellular cancer (HCC).
655
Which of the following statements concerning

HCC is true?
A. Alcohol induced cirrhosis is the leading risk factor for

HCC in the U.S.
B. Following SVR, cirrhotic patients’ risk for developing

HCC is similar to non-cirrhotic patients
C. Hepatocellular cancer is the fastest growing cause of

cancer death in the U.S.
D. Direct acting antiviral therapy eliminates subsequent risk

of developing HCC in patients who achieve SVR
The answer is C.
• Hepatocellular cancer (HCC) is the fastest growing cause of cancer

death in the U.S.
• Chronic hepatitis C is the leading risk factor for HCC in the U.S., not
alcohol induced cirrhosis
• Cirrhotic patients who achieve SVR after receiving direct acting
antiviral therapy for chronic hepatitis C, still have a >4 fold greater
incidence of HCC compared to non-cirrhotic patients
• The cumulative incidence of HCC is lower in patients with chronic
hepatitis C who achieve SVR following therapy with direct acting
antivirals compared to those who fail to achieve SVR
656
20. A 31 year old with recently diagnosed

ulcerative colitis is concerned about the
long term risk of developing colon cancer.
He is experiencing a mild exacerbation of
ulcerative colitis and requests and
appointment for evaluation and to discuss
his concerns about colon cancer risk.
Which one of the following factors in patients with Crohn’s

or ulcerative colitis is associated with a low risk of
developing colorectal cancer?
A. Extensive and active colonic disease
B. Isolated proctitis
C. Primary sclerosing cholangitis (PSC)
D. Prior dysplasia or colonic stricture
657

• Isolated proctitis is associated with a low risk of
colorectal cancer.
• Current guidelines recommend annual surveillance
colonoscopy in patients with inflammatory bowel
disease who are at high risk of developing
colorectal cancer.
• These high risk groups include patients with:
– Prior dysplasia or colonic stricture
– Family history of colorectal cancer in a first-degree
relative age <50
– Primary sclerosing cholangitis (PSC), regardless of
duration of inflammatory bowel disease
– Extensive, active disease
21. A 58 year old presents with a 5 year history of

progressive dysphagia for liquids and solids. She
describes occasional nocturnal regurgitation of food. A
barium esophagram reveals a dilated esophagus with
beak-like narrowing at the level of the
gastroesophageal junction. An upper endoscopy
reveals no masses. High resolution esophageal
manometry confirms that she has type II achalasia.
658
Which therapy would likely result in the highest

likelihood of relief of dysphagia symptoms?
A. Pneumatic dilation
B. Isosorbide mononitrate
C. Botulinum toxin injection of the LES
D. Nifedipine
21. The answer is A.

• Achalasia results from progressive loss of ganglion cells in the
myenteric plexus.
• Treatment that disrupts the muscles of the lower esophageal sphincter

such as pneumatic dilation and surgical myotomy provide the greatest
symptom relief in patients with type II achalasia (achalasia with
pressurization of the esophageal body).
• Medical therapy such as botulinum toxin injections of the lower

esophageal sphincter, nitrates and calcium channel blockers are less
effective in reducing dysphagia symptoms.
• Role of esophagogastroduodenoscopy (EGD) is to rule out causes of

pseudoachalasia such as adenocarcinoma of the stomach or distal
esophagus.
659
22. A 35 year old with mild Crohn’s disease

presents with symptoms of intense epigastric
pain. He doesn’t drink alcohol. His only
medication is oral mesalamine. Laboratory
studies are notable for lipase of 2500 U/L (nl
<60 U/L), total bilirubin 2.5mg/dL (nl: 0.2-
1.2mg/dL), direct bilirubin 0.5 mg/dL, AST
17 U/L, ALT 25 U/L, alkaline phosphatase 72
U/L, creatinine 0.7mg/dL and hematocrit is
38% after hydration. He does not meet any
systemic inflammatory response syndrome
(SIRS) criteria .
Which of the following imaging tests would

be the most appropriate at this time?
A. ERCP
B. Abdominal ultrasound
C. MRCP
D. KUB
660

• Patients with Crohn’s disease are at increased risk of
developing gallstones.
• Since he has no definite cause for pancreatitis, an
abdominal ultrasound to assess for gallstones is appropriate
at this time.
• Mesalamine infrequently causes acute pancreatitis.
• ERCP is indicated in patients with suspected ascending
cholangitis or high grade biliary obstruction.
• The patient’s indirect hyperbilirubinemia is suggestive of
Gilbert’s syndrome rather than an obstructive biliary
process, hence MRCP is not indicated.
23. A 42 year old man is found to have occult blood

in the stool on routine digital rectal exam during an
physical exam. He has no upper or lower
gastrointestinal symptoms and does not take aspirin
or NSAIDs. There is no family history of
gastrointestinal malignancy and his hematocrit is
normal.
661
Which of the following could potentially cause

occult gastrointestinal blood loss?
A. Meckel’s diverticulum
B. Barrett’s esophagus
C. Colonic diverticulosis
D. Cameron lesions

• Cameron lesions are erosions or ulcers that develop on the lower
margin of a large hiatal hernia sac and may be associated with acute
and chronic blood loss as well as iron deficiency anemia
• A Meckel’s diverticulum is a congenital vestigial remnant of the
omphalomesenteric duct, located in the ileum, usually within 2 feet of
the ileocecal valve. Most are asymptomatic, but they can occasional
cause overt bleeding, rather than occult blood loss
• Colonic diverticulosis are a fairly common cause of overt lower
gastrointestinal hemorrhage, but are associated with occult blood loss
• Barrett’s esophagus, characterized by intestinal metaplasia of the
esophagus, is a non-inflammatory lesion and is not associated with
occult blood loss
662
24. A 42 year old woman with hypertension, type II diabetes

mellitus, dyslipidemia and obesity is noted to have multiple
small gallstones on ultrasound imaging performed to evaluate
transaminase elevation (ALT and AST <100 IU/L). The
common bile duct measures 3mm and there is no intrahepatic
ductal dilation. She reports no history of episodic, severe
upper abdominal pain. She is very anxious about the
possibility of developing symptoms or complications from the
gallstones especially since she has diabetes mellitus.
What is the recommended course of action for this

patient?
A. Elective cholecystectomy
B. Ursodeoxycholic acid
C. Lithotripsy
D. No intervention
663
24. The answer is D

• The risk of gallstone related complications
in a person with asymptomatic cholelithiasis
is approximately 20% over 15 years of
follow-up
• The risk of cholecystectomy outweighs the
benefits, even in diabetic patients
25. A 32 year old man who is new to your practice

is seen for follow-up after hospitalization for asthma
exacerbation. He recently found out that his 58 year
old father was diagnosed with Stage II colon cancer.
There are no other first or second degree relatives
with colon cancer or polyps. He seeks your advise
regarding when he should commence colorectal
cancer screening. He is asymptomatic.
664
At what age should he begin colorectal cancer

screening?
A. Age 35
B. Age 40
C. Age 48
D. Age 50
25. The answer is B

• Colorectal cancer screening for individuals
with a first degree relative with colorectal
cancer should begin at age 40, or 10 years
before the age of diagnosis of the youngest
affected relative, whichever is earlier.
665
26. A 33 year old man with no significant past

medical history presents to emergency department
for evaluation of persistent right lower quadrant
pain associated with anorexia, nausea and subjective
fever. His symptoms began acutely the night before
and he initially had generalized lower abdominal
pain. He has a low grade fever and is not ill
appearing. A clinical suspicion of acute appendicitis
is confirmed with ultrasound imaging. He is fearful
of surgery and insists on nonoperative management.
Which one of the following statements is true regarding

nonoperative management of acute uncomplicated
appendicitis?
A. It is the optimal strategy for patients with multiple

medical comorbidities
B. Very few patients who pursue this option require

subsequent appendectomy
C. It is a safe option for patients with fecaliths seen on

imaging
D. After recovery, colonoscopy should be performed on

patients >40 years old, who have had no prior exam
666
26. The answer is D

• Timely open or laparoscopic surgery remains the recommended
treatment of choice for adults with uncomplicated appendicitis
• Colonic neoplasms can mimic appendicitis, therefore colonoscopy
screening should be performed on those age 40 or above, after
recovery
• Patients with multiple medical comorbidities were excluded from trials
of nonoperative management of acute appendicitis, thus the efficacy of
this strategy is unknown in these patients
• Up to 30% of patients who were initially successfully treated with
antibiotics require appendectomy for recurrent appendicitis or for pain
• Up to 40% of patients with fecaliths seen on imaging have complicated
appendicitis
27. A 44 year old man with poorly controlled type II diabetes

mellitus and morbid obesity presents to the Emergency
Department for evaluation of severe acute epigastric pain
radiating to his back for the past 3 hours. He is afebrile, heart
rate is 92 beats/minute, BP 154/90 mm Hg, respiratory rate of
16 breaths/min, and oxygen saturation is 98% on room air .
His exam is notable for hypoactive bowel sounds and
moderate epigastric tenderness with light palpation. His
sclera are anicteric. He has no occult blood in his stool.
667
LABS:
White blood count: 14,000 mm3 (nl: 4,500-11,000 mm3)
Hematocrit: 43%
ALT: 84 U/L (nl: 7-56 U/L)
AST: 55 U/L (nl: 0-40 U/L)
ALK: 99 IU/L
Total bilirubin: 0.4 mg/dL
Sodium: 126 mEq/L (nl: 135-145 mEq/L)
Glucose: 95mg/dL
Amylase: 55 U/L (nl: 23-85 U/L)
Lipase: 4589 U/L (nl: 0-160 U/L).
An abdominal ultrasound is notable for increased echogenicity of the

liver suggestive of fatty deposits, normal gallbladder without stones or
sludge, common bile duct measures 3mm in diameter and there is no
intrahepatic duct dilation. An abdominal/pelvic CT scan confirms
interstitial pancreatitis with peripancreatic fat stranding and no necrosis.
He does not consume alcohol.
What is the likely case of the acute pancreatitis?
A. Gallstones
B. Pancreatic mucinous neoplasm
C. Hypertriglyceridemia
D. Sphincter of Oddi dysfunction
668
27. The answer is C

• Hypertriglyceridemia is an important risk factor for acute
pancreatitis when levels exceed 1000mg/dL
• Hypertriglyceridemia-induced acute pancreatitis is the
third most common cause of acute pancreatitis after
alcohol and gallstones.
• Excess triglyceride in serum can displace water containing
sodium and cause pseudo-hyponatremia, a clue in this case
• Serum triglyceride levels >500mg/dL may interfere with
colorimetric reading resulting in falsely normal amylase,
another clue in this case. Lipase results are unaffected.
• Secondary causes of hypertriglyceridemia include poorly
controlled diabetes mellitus, medications, pregnancy,
alcohol and hypothyroidism.
28. A busy Gastroenterology practice begins

providing quarterly reports of adenoma detection
rates (ADR) to each provider, in an effort to
motivate providers to improve their adenoma
detection rates
669
28. Which of the following statements is true

regarding the adenoma detection rate (ADR)?
A. The bowel preparation quality has little bearing on the

ADR
B. ADR in the proximal colon is higher than in the distal

colon
C. ADR increases with procedures performed late in an

Endoscopist’s schedule
D. Short colonoscopy withdrawal time (< 6 minutes) is

associated with lower ADR

• Adenoma detection rate (ADR), defined as the percent of
colonoscopies in which one or more adenomas are
detected, increases with longer colonoscopy withdrawal
time
• The optimal colonoscopy withdrawal time is unknown, but
some studies suggest at least 6 minutes is optimal
• Serrated adenomas are more likely to be located in the
proximal colon, may be quite flat, and thus may be more
difficult to detect
• Optimal cleansing of the colon enhances the adenoma
detection rate
• Fatigue may contribute to lower adenoma detection rates
for later procedures in a Endoscopist’s schedule
670
29. A 23 year old returning foreign traveler is seen

in urgent care with complaints of unilateral knee
pain and swelling. She reports no trauma and is not
sexually active. She had a self-limited diarrheal
illness during her trip. She is well appearing and lab
tests are unrevealing.
Which one of the statements regarding reactive

arthritis following an enteric infection is true?
A. Intestinal infection with ameba has been

associated with this syndrome
B. Many affected people are HLA DQ2 and DQ8

antigen-positive
C. There is a high female to male ratio
D. It may be associated with a triad of arthritis,

conjunctivitis and urethritis
671
29. The answer is D

• Post-enteric reactive arthritis, formerly known as Reiter’s syndrome,
usually develops 2-4 weeks after an acute diarrheal illness
• It is more common in men than women and many affected patients are
HLA B27 antigen positive
• It may be associated with a triad of arthritis, conjunctivitis and

urethritis
• Shigella sp. is the most commonly associated enteric organism,

although Salmonella sp, Campylobacter jejuni, Yersinia enterocolitica
and even Clostridium difficile have been implicated.
• Amebic intestinal infections are not typically associated with reactive

arthritis
30. A 36 year old woman is seen in the office for

evaluation of a sensation of a lump in her throat
ongoing for several months. She reports no
dysphagia or odynophagia. Her head and neck exam
is unremarkable.
672
Which one of the following is a common cause of a

globus sensation?
A. Parathyroid adenoma
B. Gastroesophageal reflux disease
C. Depression
D. Myasthenia gravis

• Globus refers to the sensation of a lump or foreign body in
the throat in the absence of dysphagia and odynophagia
• Gastroesophageal reflux, goiter, early hypopharyngeal
cancer and anxiety disorders can all be associated with the
globus sensation
• Myasthenia gravis can result in oropharyngeal dysphagia,
but not the globus sensation
• Parathyroid adenomas are generally very small and
unlikely to cause a globus sensation
673
DISCLOSURES
• Muthoka Mutinga, MD – No disclosures
Selected References
1. Beaty JS and Shashidharan M. Anal fissure. Clin Colon Rectal Surg 2016
Mar;29(1):30-37.
2. Liu P-H, Cao Y, Keeley B, et al. Adherence to a Healthy Lifestyle is
Associated With a Lower Risk of Diverticulitis Among Men. Am J
Gastrenterol 2017;112:1868-1876.
3. Kamal S, Khan M, Seth A, et al. Beneficial Effects of Statins on the Rate of
Hepatic Fibrosis , Hepatic Decompensation and Mortality in Chronic Liver
Disease: A Systematic Review and Meta-Analysis. Am J Gastroenterol
2017;112: 1495-1505.
4. Kanwal F, Kramer J, Asch S, et al. Risk of Hepatocellular Cancer in HCV
Patients Treated With Direct-Acting Antiviral Agents. Gastroenterol
2017;153:996-1005.
5. Rex DK, Boland CR, Dominitz JA, et al. Colorectal Cancer Screening:
Recommendations for Physicians and Patients from the U.S. Multi-Society
Task Force on Colorectal Cancer. Am J Gastroenterol 2017 Jul;112(7):1016-
1030
674
Oncology Pearls for the Boards

Wendy Y. Chen, MD MPH
Senior Physician
Department of Medical Oncology
Psychiatry Overview
Dana Farber Cancer Institute
DISCLOSURE
None related to this lecture
675
“Pearl” - a beautiful thing produced as the

result of a long, irritating process which seems
pointless at the time it is being endured
Oncology Pearls
• Oncologic emergencies
• Important issues for common cancers
• Screening in different populations
• Oncology issues in primary care
676
Case #1
60 y.o. man with 80 pack-yr smoking hx c/o 1

week history of facial swelling and cough
Physical examination: distended neck veins,
prominent chest wall venous distention,
facial edema
Chest CT: bulky right hilar/mediastinal
lymphadenopathy
Case #1
A. Proceed with mediastinoscopy or bronchoscopy
to obtain tissue diagnosis
B. Initiate heparin and radiation with plan to biopsy
when swelling improves
C. Initiate steroids and heparin with plan for biopsy
when swelling improves
D. Initiate heparin and emergent stent placement
then biopsy once swelling improves
E. Explain to patient this is metastatic cancer and
he should consider hospice
677
Oncology pearl
• Describe the signs and symptoms of
and optimal treatment for superior vena
cava syndrome.
– Ref. Wilson LD et al. SVC syndrome with

malignant causes. N Engl J Med 2007;
356: 1862-9.
Superior Vena Cava Syndrome

• Majority due to malignancy
• External compression -mediastinal mass
– Most common malignancies – lung cancer
(both NSCLC and small cell) and lymphoma
• Thrombosis
– More common now with catheters
678
Signs and symptoms

• Physical examination
– Facial edema and plethora
– Jugular venous distension
– Venous distension of superficial veins on
chest
• Symptoms
– Shortness of breath
– Cough
– Hoarseness
Management of SVC syndrome

• Tissue diagnosis critical for Rx decisions
– Prognosis depends on underlying disease
• Treatment plan depends on tumor histology
– Chemo-insensitive cancers (e.g. NSCLS)
treated with upfront XRT
– Chemo-sensitive tumors (e.g. small cell,
lymphoma) treated with upfront chemo
– Stent placement not usually done 1st line in
cancers that may respond to chemo/RT
=> Rarely fatal
679
Case #2:
64 y.o. male with metastatic prostate

cancer to bone with metastases to ribs,
pelvis, and multiple vertebrae. Currently
on docetaxel chemo. Calls c/o of 1-2
weeks increasing mid-back pain. He has
no weakness, radicular pain, bowel or
bladder difficulties. Neurologic exam is
normal.
Case #2:
A. Order a bone scan and CT scan to
look for disease progression.
B. Prescribe NSAIDs and oxycodone as
needed for pain.
C. Obtain an MRI of the spine.
D. Recommend radiation to the spine.
680
Oncology pearl
• Describe the signs and symptoms and
optimal management of spinal cord
compression.
– Ref: Ropper AE and Ropper AH. Acute
spinal cord compression. N Engl J Med
2017; 376: 1358-69
Spinal Cord Compression

• Initiate treatment earlier to prevent
neurologic deficits
– Once neurologic deficits occur, often
irreversible
• Usually from epidural compression from
vertebral body metastases
– Most common tumors: lung, breast, prostate,
myeloma, lymphoma, renal cell
– Thoracic spine most common location (60%)
– Intramedullary metastases less common
681
Ropper N Engl J Med 2017
Symptoms
• BACK PAIN!
– New or worsening back pain with known
vertebral mets mandates further evaluation
– Pain may be radicular, but not always
• Weakness
– Motor deficits more common than sensory
• Bowel and bladder symptoms occur late
• Neurologic exam may be normal
– Key is early diagnosis
• MRI is imaging of choice
682
Treatment
• Corticosteroids to ↓ edema
– Only short-term benefit
• Should not be used if diagnosis unknown
– Typically 10 mg IV load then 4 mg po q 6hrs
• Radiation 1st line treatment for most
• Upfront surgery reserved for:
– Unknown diagnosis
– Progression during or after radiation
– Spinal instability
– One RCT showed improved function with
immediate surgery for less radiosensitive tumors
with single area of compression
Case #3:
62 y.o. man presents to ER with temperature

of 101.4°F, malaise, and cough 15 days
after receiving chemotherapy for refractory
lymphoma. Physical exam is unrevealing
for source. WBC is 640 cells/mm3 with 45%
polys. CXR is negative. Cultures are
obtained.
683
Case #3:
A. Admit patient and start cefepime

B. Admit patient, start cefepime and G-
CSF
C. Admit patient and observe
D. Discharge patient home on oral
quinolone and G-CSF
E. Discharge patient home on oral quinolone
Oncology pearl
• Describe the optimal management of
febrile neutropenia.
– Ref: Freifeld AG et al. Executive summary:

clinical practice guideline for the use of
antimicrobial agents in neutropenic
patients with cancer: 2010 update by the
Infectious Diseases Society of America.
Clin Infect Dis 2011; 427-31
684
Fever and Neutropenia

Fever
• Oral temperature > 38.3°C (101°F) or
38.0 °C (100.4 °F) for > 1 hr
Neutropenia
• Absolute neutrophil count < 500 cells/µL
or ANC < 1,000 with predicted nadir of <
500 in next 48 hrs
Fever and Neutropenia

• Risk for occult infection and mortality ↑ as
ANC falls below 1,000/mm3
– Greatest risk with ANC < 500/mm3
– Mortality rate for solid tumors less than heme
malignancies
• Growth factors (GCSF)
– Modestly ↓ duration of neutropenia and
hospitalization
⇒No impact on mortality
⇒No significant benefit to empiric use of GCSF in
uncomplicated F & N
685
Risk Factors for F&N
• Rapid decline in ANC

• Prolonged duration of neutropenia (>7-10d)
• Leukemic induction
• Uncontrolled cancer
• Hematologic cancers
Typical infectious sources of F&N
• Catheters
• Skin
• Respiratory tract
• Sinuses
• GI tract
=>Source identified in less than 30% of
cases
– Endogenous flora in 80% of cases
686
Likely Organisms
• Gram-positive infections (50-60%)
– Staph epidermidis
– Streptococcus
– Enterococcus faecalis/faecium
• Gram-negative rods (more likely to
cause death)
– Enterbacteriaceae (E. coli, Klebsiella)
– Pseudomonas aeruginosa
Routine evaluation
• History
• Physical exam
• CBC, chemistries, LFTs, urine analysis
• Blood/sputum/urine cultures
• CXR
• Consider directed radiology:
chest/abd/sinus CT if warranted by
symptoms
687
Treatment
Empiric antibiotics: broad spectrum with gram positive
and gram negative coverage (especially
Pseudomonas)
• 3rd generation cephalosporin (cefepime or ceftaz)
– May depend upon local hospital bacteriology
• Alternatives:
– Imipenem cilastatin or meropenem
• Higher rate C.diff colitis than cephalospoin
– Beta-lactam allergy: cipro+clinda or aztreonam+vanco
• <1% cross-reactivity between 3rd generation ceph and PCN/1st gen
cephalosporin
Vancomycin for F & N
• Empiric initial use does not improve

morbidity or mortality
• Encourages development of vancomycin

resistant Enterococuus
• Reserve for high suspicion of line/skin

infection, mucositis, h/o MRSA, severe PCN
allergy along with quinolone or aztreonam
688
“Low risk” F & N

• Outpatient antibiotic treatment reasonable
for low risk (Cipro/levo + Amox/Clav)
– anticipated duration of neutropenia < 7 days
– solid tumor
– clinically stable
– no major morbidities
– adequate oral intake and social supports
– malignancy responding to current treatment
– observe for a few hours
Case #4:
45 y.o. female with mantle cell lymphoma
admitted day 9 after chemotherapy with
F & N. Her fever resolved promptly with
institution of empiric antibiotics. One
day later, blood cultures grow E. coli
sensitive to amoxicillin. ANC is
currently 246.
689
Case #4:
A. Stop IV antibiotics and discharge her
on p.o. amoxicillin.
B. Continue IV antibiotics until ANC > 500.
C. Obtain echocardiogram to evaluate for
endocarditis
D. Stop IV antibiotics and start amoxicillin,
but continue to observe her for 48 hours
in hospital.
F & N – part 2
• When can antibiotics be stopped or
changed?
– Only when BOTH fever and neutropenia
have resolved
– If ANC > 500 and afebrile and source
isolated => complete course of abx for
infection
– If ANC>500 and afebrile and no source
isolated=> discontinue abx
690
Case #5:
57-year-old woman with metastatic lung

cancer is brought to the emergency room
with confusion. Serum calcium is 17.2
mg/dl and creatinine is 1.5 mg/dl. Four
liters of normal saline and IV furosemide
are administered. What is the next most
appropriate therapeutic intervention that
should be undertaken first?
Case #5:
A. Another 2 liters normal saline infusion IV

and furosemide
B. Denosumab 120 mg IV
C. Zoledronate 4 mg IV
D. Chemotherapy for lung cancer
691
Oncology pearl
• Describe optimal management of
hypercalcemia.
– Ref: Stewart AF. Hypercalcemia

associated with cancer. N Engl J Med
2005; 352: 373-9.
Hypercalcemia
• Occurs in up to 20% of cancer patients

– Both solid tumors and leukemia
– Most common: breast, lung, myeloma
• Incidence ↓↓ among metastatic breast and
myeloma pts with routine bisphophonate use
• Urgent rx for hypercalcemia important for
palliation, but long-term control requires
effective anti-cancer therapy
692
Causes of Hypercalcemia
• Humoral hypercalcemia of malignancy
– Tumors secrete PTHrP
– Most common cause
• Local osteolytic hypercalcemia
– Mainly in breast, myeloma, and lymphoma
• 1,25 (OH)2D-production by tumor
– Rare and occurs only in lymphoma
• Ectopic PTH
– Extremely rare – isolated case reports
Drug therapy for hypercalcemia

• Inhibit osteoclastic bone resorption
– Bisphosphonates (2-4 days for max effect)
– Calcitonin (immediate; tachyphylaxis in 2-3d)
• Increase urinary calcium excretion
– Normal saline to volume replete
• Loop diuretic can be added as needed to manage volume
• Antibody to RANKL inhibits osteoclast activity
– Denosumab
• Dialysis
– Only in rare circumstances – e.g. CHF does not allow
aggressive volume repletion or oliguric renal failure
693
Bisphosphonates vs denosumab
• 1st line treatment after volume repletion
– Oral agents much less potent so not used for
hypercalcemia Rx
• Zolendronate vs. Denosumab
– Have not been directly compared for
hypercalcemia
• Both associated with osteonecrosis of jaw
– Denosumab not approved for hypercalcemia
• Much more expensive (given SQ not IV)
• Can be associated with refractory hypocalcemia
• Can be used in severe renal impairment
Case #6
Which of the following pairs a proven cancer
prevention action and the cancer it
prevents?
A. Tobacco cessation and bladder cancer

B. Hepatitis C vaccine and hepatocellular
carcinoma
C. Decreasing soy consumption and breast
cancer
D. Human papilloma virus and uterine
cancer
694
Oncology pearl
• Recognize important epidemiologic
associations for cancer
Important associations
Tobacco Ionizing Radiation
• Head and neck • Thyroid
• Pancreas • Hodgkin's
• Bladder • Breast
• Lung • Lung
• Esophagus • Leukemia
• Kidney
Infectious causes
• Hepatitis B and C => hepatocellular cancer
• Epstein-Barr virus =>post-transplant lymphoma and
nasopharyngeal cancer
• Human papilloma virus => cervical and anal cancer
695
Case #7:
53 y.o man with Burkitt’s lymphoma

begins induction chemotherapy. He
starts on allopurinol and hydration.
Four days later, his creatinine has
increased from 1.0 to 5.4 mg/dL. Urine
output is 20 cc over the last 24 hours.
Labs include K+ 6.0, Ca 6.1, PO4 8.3,
uric acid 15.0. He complains of muscle
cramps and paresthesias.
Case #7:
A. Rasburicase, aggressive IV
hydration, alkalinize urine, kayexalate
(sodium polystyrene sulfonate)
B. Aggressive IV hydration, alkalinize
urine, kayexelate, IV calcium.
C. Dialysis
D. Rasburicase, furosemide, kayexelate,
oral calcium.
696
Oncology pearl
• To recognize and treat tumor lysis
syndrome.
– Ref: Howard SC et al. Tumor lysis

syndrome. N Engl J Med 2011; 364: 1844-
54
Tumor lysis syndrome

• Large tumor burden with rapid cell kill
• More common with aggressive leukemia
and lymphomas, e.g Burkitt’s
– Uncommon with solid tumors
– Risk highest during induction chemo when
tumor burden greatest
• Fatal complications include arrhythmias
and renal failure
• Oliguria poor prognostic sign
697
Laboratory abnormalities
• Serum potassium > 6.0 mg/dL
• Serum uric acid > 8 mg/dL
• Serum phosphate ≥ 4.5 mg/dL
• Serum calcium < 7 mg/dL
Management
• Prophylaxis/prevention key
– Aggressive hydration to maintain urine output
– Rasburicase vs allopurinal for prevention
• Treatment
– Rasburicase - recombinant urate oxidase
• Converts uric acid to allantoin which is more
soluble in urine than uric acid
• Contraindicated in G6PDH deficiency
• Dialysis if oliguric or persistent metabolic
abnormalities or severe symptoms
698
Case #8:
32 y.o. man in good health presents for
routine physical exam. His mother died
of colon cancer at 37, and his 39 y.o.
brother was just diagnosed with colon
cancer. Physical examination and fecal
occult blood test are negative. Labs are
normal.
What do you recommend?
A. Colonoscopy now and, if negative,

every 10 years.
B. Sigmoidoscopy now and, if negative,
every 5 years.
C. Annual fecal occult blood testing
D. Prophylactic colectomy
E. Genetic counseling with screening
recommendations to take place after
that has been performed.
699
Oncology pearl
• Identify different populations for
colorectal cancer screening.
– Wolf AMD et al. Colorectal cancer

screening for average‐risk adults: 2018
guideline update from the American
Cancer Society. CA J Clin 2018
Screening for Colorectal Cancer

• Risk assessment to determine screening
– Average risk
• Age 50 or older without personal or family history of
colorectal cancer or adenoma
– Increased risk
• Personal history of polyps or colorectal cancer
• Family history of polyps or colorectal cancer
• History of inflammatory bowel disease
• Known hereditary syndrome (e.g. Lynch, familial
adenomatous polyposis
700
Screening for average risk

Age 50 to 75 (could consider starting age 45)
• Annual Fecal Occult Blood Test or Fecal
Immunochemical or Stool DNA Test
• Flex sig q 5 yrs +/- FOBT/FIT q 1-3 yrs
• Colonoscopy q 10 yrs
• CT colonography q 5 yrs
USPTF, ACS
Screening if family history

• Increased risk: One 1st degree relative
with history of colorectal cancer > age
50 or 2 or more 2nd degree relatives with
colon cancer
– Begin screening at age 40 or 10 years
before youngest age of diagnosis then
follow standard screening intervals
701
High risk for screening (HNPCC)

• Amsterdam criteria (all criteria)
– At least 3 relatives (2 must be FDR) with
history of colorectal cancer
– At least one relative <50 at diagnosis
– At least 2 successive generations affected
• Bethesda criteria
– FDR with colon cancer < 45 or adenoma < 40
– Two HNPCC-related cancer (endometrial,
small intestine, ovarian, gastric)
Screening for high risk

• Familial adenomatous polyposis
– Consideration of colectomy
• Hereditary non-polyposis colorectal cancer
– Colonoscopy q1-2 yrs beginning age 20-25
• Personal history of colorectal cancer
– Colonoscopy at 1, 3, then q 5 yrs
– Modified for rectal cancer
• Personal history of polyps
– Depends upon number and type of polyps
(tubular vs villous, high grade vs low grade)
702
Case #9:
Which of the following patients has resectable non-small cell
lung cancer?
A. 10 cm RLL mass with ipsilateral mediastinal and
subcarinal LN involvement.
B. 2 cm LUL mass with ipsilateral hilar and
supraclavicular LN involvement.
C. 2 cm RUL mass with ipsilateral hilar LN
involvement and small malignant pleural effusion.
D. 4 cm RLL mass with positive ipsilateral
mediastinal LN and invasion of carina
E. 2 cm LLL mass with positive contralateral hilar LN,
but negative contralateral mediastinal LN
Oncology pearl
• Identify which patients with non-small
cell lung cancer are operable.
703
Lung cancer staging
Stage IIIB and IV and any T4 unresectable

N0 N1 N2 N3 M1
T1
IIIB IV
T2
T3
T4 IIIB
Lung cancer staging - nodes
• N1 – ipsilateral peribronchial or hilar
• N2 – ipsilateral mediastinal or subcarinal
• N3- contralateral mediastinal or hilar,

ipsilateral or contralateral scalene, or
supraclavicular LN
704
Lung cancer staging - tumor

• T3 – Tumor of any size extending into chest
wall, diaphragm, mediastinal pleura, or
pericaridum without involving heart, great
vessels, trachea, esophagus, vertebrae,
main stem bronchus, or carina; separate
tumor nodule in same lobe
• T4 – Tumor of any size involving heart,
trachea, esophagus, vertebrae, or carina;
separate tumor nodule in different ipsilateral
lobe
• Malignant pleural/pericardial effusion M1
Case #10
65 y.o. male notes worsening back and
hip pain. Bone scan and CAP CT scan
show widespread blastic bone
metastases without a clear primary.
Which of the following blood tests would
be most helpful to identify the primary
site?
705
Case #10
A. PSA (prostate specific antigen)
B. CEA (carcinoembryonic antigen)
C. AFP (alphafetoprotein)
D. hCG (human chorionic gonadotropin)
Oncology pearl
• How to evaluate cancer of unknown
primary
– Ref: Varadhachary GR and Raber MN,
Cancer of unknown primary site. N Engl J
Med 2014; 371:757-765
706
Approach to unknown primary

• Chest/abdominal/pelvic CT with contrast
– Unclear if PET-CT superior
• Focused tumor markers
– Often non-specifically elevated
– Man with adenocarcinoma and bone mets
• PSA
– Man with mediastinal/midline carcinoma
• hCG and AFP for germ cell tumor
• Immunhistochemistry vs tissue of origin
molecular profiling
Histology of unknown primary

• Adenocarcinoma (70%)
– Lung, hepatobiliary, pancreatic, renal most common
• Poorly differentiated cancer (25%)
– Lymphoma, melanoma, sarcoma, germ cell
• Squamous cell carcinoma (5%)
– Cervical => head and neck primary
– Inguinal => genital or anorectal primary
• Neuroendocrine tumors (1%)
707
Find non-metastatic cancers

• Woman with axillary lymph nodes
– Node positive breast cancer
• Neck nodes with squamous cell ca
– Locally advanced head and neck
• Young man with
mediastinal/retroperitoneal LN
– Germ cell tumor
• Woman with peritoneal disease
– Stage III ovarian cancer
Find treatable metastatic cancer
• Breast
• Ovarian
• Prostate
• Germ cell
• Lymphoma
• Melanoma
• Head and neck
• Colorectal
708
Case #11
45 y.o. premenopausal women has
severe hot flashes during the day and
frequent night sweats. She has a
history of a stage I ER negative breast
cancer diagnosed two years ago treated
with lumpectomy and radiation. She is
not on hormonal therapy. Which of the
following is the best choice for treating
her hot flashes?
Case #11
A. Amitriptyline
B. Lorazepam
C. Soy protein
D. Paroxetine
E. Conjugated estrogens without
progesterone
709
Oncology pearl
• Counsel cancer survivors regarding hot
flash treatment
– Ref: Fisher MA et al. Risk factors,
pathophysiology, and treatment of hot
flashes in cancer. CA Cancer J Clin 2013;
63: 167-92.
Hot flash treatment

• Placebo-controlled RCT key since placebo
has 25-30% response rate
• RCTs show 30-50% ↓ in frequency and
intensity of hot flashes with:
– SSRI’s (paroxetine, fluoxetine)
– SNRI’s (venlafexine)
– Gabapentin
– Clonidine
=> No consistent effect of soy protein, black
cohosh
710
HT for breast cancer survivors

• Menopausal symptoms common among
breast ca survivors
– Treatment induced menopause and side effects
of treatments
• Two RCT among breast cancer survivors
– Both showed ↑ recurrence risk
– Results similar regardless of ER status
=>No systemic HT for br ca survivors
=> Limited vaginal HT (e.g. ring, suppositoryk
or cream) OK JCNI 2008, Lancet Oncol 2009
Summary
• Study what is important for the internist to
know (and a little bit of trivia)
– Know your oncologic emergencies
– Cancer risk assessment
– Screening recommendations
– Common issues among common cancers
711
Leukemia and MDS
Edwin P, Alyea, MD
Medical Oncology
Leukemia and MDS

Edwin P. Alyea
• Chronic Lymphocytic Leukemia

• Acute Lymphocytic Leukemia
• Myelodysplastic Syndromes
• Acute Myeloid Leukemia
• Chronic Myelogeneous Leukemia
712
Disclosures
Edwin P. Alyea
• None
Objectives
• Incidence
• Diagnosis
– Histology
– Immunophenotyping
– Cytogenetics
– Molecular genetics
– Minimal Residual Disease
• Prognosis/Risk Stratification
• Treatment Options
– New agents
713
Chronic Lymphocytic Leukemia

• Most common form of leukemia
• Heterogeneous disease
• median age at diagnosis is 65
• involves the bone marrow, lymph nodes and spleen at
diagnosis
• malignant cell is a B lymphocyte-CD19, dimCD20, CD5,
CD23
• common complications include autoimmune hemolytic
anemia and hypogammaglobulinemia
• increased risk of secondary malignancies
Prognostic Factors: CLL-

International Prognostic Index (IPI)
Variable Adverse Factor Grading
TP53(17p) Del and/or 4
mutated
IGHV Unmutated 2
Beta-2 >3.5 2
microglobulin
Clinical Stage Binet B/C 1

Age >65 1
a a GE
Lancet Oncology, 2016
714
Who to treat and when?

Risk Group Score Treatment 5 yrs Overall
Recommendations survival
Low 0-1 Do not treat 93%
Intermediate 2-3 No treat unless 79%

symptoms
High 4-6 Treat unless 63%

asymptomatic
Very High 7-10 Novel inhibitor or 23%

clinical trial
Lancet Oncology, 2016
-No improvement in survival with early treatment (IWCLL 2008)
Frontline Treatment for CLL

Under 65
• Ibrutinib
• FCR if healthy; BR is a reasonable alternative
• Del 17p –treatment naïve- ibrutinib. Role of RIC
allogeneic stem cell transplant unclear.
• Unmutated IGHV – consider ibrutinib or FCR
Over 65
• Del 17p/TP53 mut, del 11q, unmutated IGHV:
ibrutinib
• Others:
Bendamustine/Rituximab; CLB + obinutuzumab, CLB +
ofatumumab; ibrutinib
715
Fludarabine Ibrutinib
• Purine analogue
• BTK inhibitor
• higher response rate with • oral
combination chemotherapy • Combinations
– Fludarabine, being explored
Cyclophosphamide and • Lymphocyte count
Rituxan (FCR) often rises when
• Side Effects therapy initiated
– myelosuppression
– tumor lysis syndrome Side Effects
– hemolytic anemia • Myelosuppression
– opportunistic infections • infections
• should not combine • A fib (6%)
with Prednisone • Bleeding (6%)
• PCP prophylaxis
should be given
Ibrutinib prolongs PFS/OS in frontline CLL

PFS OS
• 18-month PFS rate: 90% with ibrutinib vs. 52% with chlorambucil
• 24-month OS rate: 98% with ibrutinib and 85% with chlorambucil
• Median follow-up: 18.4 months
Burger et al., N Eng J Med, 2016
716
Venetoclax therapy has durable benefits in CLL
FDA approved
for patients
with 17p and
as second line
therapy
11
Roberts AW , Davids MS et al. N Engl J Med 2015
Infectious Complications in CLL

• Hypogammaglobulinemia common
– infections with encapsulated organisms
– replacement therapy indicated for patients with recurrent
infections
• Progressive granulocytopenia
• Severe T cell immune suppression

– infections with listeria, PCP, etc.
– Fludarabine leads to reduction in CD4+ T cell counts
– need PCP prophylaxis
– CMV reactivation with alemtuzumab
– Fungal infections seen in patients with ibrutinib
717
Other Complications of CLL

• Autoimmune Complications
Hemolytic anemia
– treat with steroids, IvIg
– seen after treatment with fludarabine
ITP
– steroids, IvIg
• secondary malignancies- increased risk
• risk of transformation to more aggressive disease
– rapidly enlarging nodes, rapid increase in LDH, B symptoms
Acute Lymphocytic Leukemia
• Most common form of childhood cancer

• peak incidence 3-5 years, bimodal peak at 50
• increased incidence in patients with Down’s
syndrome, Bloom’s Syndrome and Ataxia-
Telangiectasia
• represents about 15% of leukemia in adults
718
Adverse Prognostic Features in ALL

Adverse Feature
Age >35-40
Clinical Features WBC >25,000
ETP T-ALL
25% of adults
Cytogenetics Ph+ (9;22), Ph-Like >40% in patients
4:11, complex over 60
Delayed Response >4-6 weeks to

to induction therapy obtain remission
Minimal Residual Disease defined milestones
NCCN Guidelines, March 2018
Treatment of ALL
• Induction Therapy- multiagent chemotherapy

– (e.g. cytoxan, adriamycin, L-aspariginase, vincristine
and prednisone)
• Consolidation therapy-
– CNS prophylaxis
– Maintenance chemotherapy extends for about 2 years
• 5 year leukemia free survival: 30%- 55%
719
Risk Adapted Therapy

First Complete Remission
• High Risk Patients
– Poor Risk Cytogenetic Abnormalities (i.e. 9;22)
– Adverse features (MRD positive)
– Allogeneic Bone Marrow Transplantation in first
remission
• Standard Risk (T cell or No adverse features)
• chemotherapy
Relapse
• Bone Marrow Transplantation
•CAR T cells
Ph+ ALL
• Incidence: 25% of adults, >40% -50% of patients over 60
• Diagnosis: FISH or cytogenetics
• Minimal residual disease monitoring by PCR
• 9;22 translocation
– Bcr-abl; chromosome 9-ABL and chromosome 22 BCR
– p190 in 70%
– p210 in 30%
• Treatment
– Chemotherapy plus TKI
– TKI plus steroids
– Stem Cell Transplantation
– If PCR negative—TKI alone? (Data to support this in young patients)
720
Chimeric Antigen Receptor (CAR)
Abbreviations: CAR, chimeric antigen receptor; GMP, good manufacturing practice; TCR, T-cell receptor Barrett et al, 2014
Anti-CD19 CARs in ALL

2015 Co-stim Age Clinical Outcomes Toxicity
Abstract# Domain
Author
682 – Park CD28 Adults 82% CR Severe CRS
MSKCC n-=46 6mo OS >65% 24%, Neuro
Phase 2 28%
681-Grupp 41BB Age <24 93% CR 88% CRS, 1
UPENN N=59 1yr OS 78% Grade 4, 27%
Phase 2 tx’d
684 – Lee CD28 Kids and 59% CR 6% Gr ¾ CRS
NIH young LFS 17.7 mos if MRD after CTX
Phase 2 adults neg CR stratification
N=39
FDA Approved: Tisagenlecleucel.
Patients up to age 25 with B-cell precursor acute lymphoblastic leukemia that
is refractory or in second or later relapse
721
Special Issues in ALL

• Infections
– use of prednisone increases risk for infections such
as PCP. PCP prophylaxis should be given.
• Avascular Necrosis
– related to prior steroid therapy
• Sites of Relapse
– Both the CNS and testicles are potential sites of
relapse.
Myelodysplastic Syndrome
Heterogenous group of clonal disorders characterized
by inadequate and dysmorphic hematopoiesis
• Stem cell disorder

• Increased incidence with age
• Increased risk with prior chemotherapy or
radiation
• Cytopenias present at diagnosis
– Anemia 45-90%
– Thrombocytopenia 20-40%
– Neutropenia 25-40%
722
Bone Marrow
Findings in MDS
-hypercellular marrow
-trilineage dysplasia
-irregular nuclear
formations in red cell
precursors
From Heaney, NEJM 1999
Differential Diagnosis of MDS

• Anemia of chronic disease
• marrow infiltration
• drug toxicity (ETOH, chemotherapy, INH)
• viral infections (HIV)
• vitamin deficiency (B12, folate)
The MCV is often elevated in patients with MDS
723
IPSS-R calculation
Parameter Categories and Associated Scores
Cytogenetic risk Very good Good Intermediate Poor Very Poor

group 0 1 2 3 4
Marrow blast ≤2% >2 - <5% 5 - 10% >10%

proportion 0 1 2 3
≥10 g/dL 8 - <10 g/dL <8 g/dL

Hemoglobin
0 1 1.5
≥0.8 x 109/L <0.8 x 109/L
Absolute
neutrophil count 0 0.5
≥100 x 109/L 50 - 100 x 109/L <50 x 109/L

Platelet count
0 0.5 1
Possible range of summed scores: 0-10

Steensma D Hematologist 2013; from Greenberg P et al Blood 2012 Sep 20;120(12):2454-65. Epub 2012 Jun 27
IPSS-R (see: http://www.mds-foundation.org/ipss-r-calculator/)

Time until
% patients Median
25% of
(n=7,012; Median survival for
Risk group Points patients
AML data on survival, years pts under 60
develop AML,
6,485) years
years
Very low 0-1.5 19% 8.8 Not reached Not reached
Low 2.0-3.0 38% 5.3 8.8 10.8
Intermediate 3.5-4.5 20% 3.0 5.2 3.2
High 5.0-6.0 13% 1.5 2.1 1.4
Very high >6.0 10% 0.8 0.9 0.7
Only valid for:

Adults
De novo disease
Treated with supportive care
At the time of diagnosis
From: Greenberg P et al Blood 2012 Sep 20;120(12):2454-65. Epub

2012 Jun 27
724
Mutations and Outcome

in Patients with MDS
Prognostic Genes:
TP53, EZH2, ETV6, RUNX1,

or ASXL1
Behar et al., N Engl J Med. 2011
Treatment of MDS
• Treatment: Age, Performance status and IPSS
• Supportive Care
– Chelation therapy for iron overload
• RARS-may respond to pyridoxine
• Growth Factors:
– EPO-helpful if EPO level is less than 500
– G-CSF for patients with recurrent infections
• Chemotherapy
– 5-azacytidine-hypomethylation agent
– Decitibine-inhibits DNA methylation
– Lenalidomide (5q-)
• Allogeneic Bone Marrow Transplant
– only curative option
725
AZA-001 Survival Study (Higher risk MDS):

Azacitidine vs “Conventional Care”
1.0 Log-Rank p=0.0001
0.9 HR = 0.58 [95% CI: 0.43, 0.77]
0.8 Deaths: Aza = 82, Control = 113
Proportion surviving
0.7
Difference: 9.4 months
0.6
0.5
24.4 months
0.4
15 months
0.3 Azacitidine
0.2
0.1 Control arm
0.0 (BSC, 3&7, LDAC)
0 5 10 15 20 25 30 35 40
Time (months) from randomization
Probably better to give 7 days than <7 days

IV same as SC Fenaux P, et al. Lancet Oncology 2009 10: 223–232
Special Issues in MDS

• 5q- syndrome
– older women with anemia and high platelet counts
– SF3B1 mutation
– prolonged course
– Lenolidomide associated with response
• Hypoplastic MDS
– hypocelluar bone marrow
– DDX with aplastic anemia. Cytogenetics are helpful.
• Therapy related MDS
– prior radiation and chemotherapy exposure
– 11q23 abnormalities associated with epipodophylotoxins
(VP-16)
726
Acute Myelogenous Leukemia
• Incidence of 2.4/100,000
• median age of 65-70
• most common acute leukemia in adults
• associated with prior radiation and toxin
exposure
• may arise from prior MDS
Bone Marrow
Findings in AML
Histology
-large blasts
-nucleoli often visible
- granules often present
-Auer rods may be
present
Immunophenotyping
demonstrates myeloid
makers
CD13, CD33, CD11
From Lowenberg, NEJM 1999
727
Cytogenetics in AML
• Favorable outcomes
– t(8;21), t(15;17), inversion 16
– t(8;21) and inv16 involve AML1-CBFb
• Adverse outcomes:
– -5, -7, 11q23, trisomies 8 and 13, 6;9 translocation
– >3 cytogenetic abnormalities
• Cytogenetic abnormalities have the most significant

impact on prognosis and are used to guide therapy
Current Risk Assessment in AML

Key Prognostic Data in AML in 2016
Patient age
Cytogenetics / karyotype
Primary versus secondary disease
(secondary = post-antecedent hematologic disorder, or therapy-related)
Molecular studies:
• FLT3 ITD (internal tandem duplication) mutation Unfavorable

• NPM1 mutation Favorable
• CEBPA biallelic mutation Favorable
• KIT mutation [in ~25% of t(8;21) or inv(16) AML] Unfavorable
Of Future Importance: mutation status of IDH1/2, DNMT3A, TET2, etc.
728
Treatment of AML
• Induction Therapy-
– anthracycline and Ara-C. Complete remission rate 60%-
80%.
– Complete remission lower in older adults, high toxicity
– Low intensity regimens used in older adults and those with
P53 defects
• Consolidation therapy- chemotherapy or BMT
– High dose Ara- C most commonly used
– randomized trial has shown no significant difference in
overall survival between consolidation chemotherapy,
allogeneic BMT, and autologous BMT
Risk Adapted Therapy for AML

1st complete remission
• Favorable cytogenetics/Molecular Profile
– t(8;21), t(15;17) and inv16
– Positive for NPM1 or CEBPA
– chemotherapy
• Unfavorable cytogenetics/Molecular Profile/MRD+
– t(9;22), -7, -5, 11q23
– FLT 3 ITD (not TKD), other high risk markers
– Allogeneic BMT
• Intermediate risk- normal cytogenetics
– chemotherapy or BMT
– Meta analysis favors BMT (Koreth et al, JAMA 2009)
729
APML- M3
t(15;17)
• All trans-retinoic acid (Atra) is combined with

induction therapy
• Atra improves complete remission rate
• Atra reduces the complications associated with
DIC
• Arsenic trioxide is used to treat relapsed patients
• Atra + Arsenic associated with >85% CR
Issues in AML
Hyperleukocytosis
• associated with very high blast count
• manifestations can include respiratory
compromise and/or altered mental status
• medical emergency
• treatment:
– IV hydration
– rapid initiation of chemotherapy
– leukopheresis
– radiation therapy
730
Chronic Myelogenous Leukemia
A myeloproliferative disease characterized

by the 9;22 chromosomal translocation
• median age at diagnosis of 53
• sex ratio of 1:1
• increased risk associated with prior radiation
exposure
• median survival is approximately 5 years
CML
clinical presentation
• ~50% asymptomatic at presentation

• fatigue (80%)
• weight loss (60%)
• abdominal discomfort (40%)
• easy bruising (35%)
• leukostasis, priapism and thrombosis are
rare
731
Ph Chromosome
• 90% of patients with hematologically

acceptable CML have the Ph chromosome
• 5% have a variant of the Ph chromosome
• 5% are Ph chromosome negative
– 40% of these patients will have the bcr-abl
translocation detected by PCR
Imatinib (STI571)
Gleevec
• BCR-ABL tyrosine kinase inhibitor (TKI) inhibits

proliferation of bcr-abl containing cells
• oral
• minimal side effects
– nausea (55%), myalgias (49%), edema (60%), rash (32%),
diarrhea (29%)
732
CML Treatment Options

• Chronic Phase Low Risk/Intermediate:
– Determine Risk Score:
– Imatinib or 2nd generation TKI
– 95% 5 year survival
– Assess Response Milestones (PCR log reduction)
– May be able to stop TKI in some patients
• Accelerated/ Blast Crisis

• Evaluate for BMT
• Chemotherapy + TKI for blast crisis in some cases
NCCN guidelines Jan 2018 ; Lancet Hematology 2015; Blood 2017
Question 1
42 yo female presents with a high white blood cell count (>100K)and
is found to have ALL. Her cytogenetics return 2 weeks later and she
has a 9;22 translocation.
The treatment associated with the best chance of long term survival is:
• Gleevec
• Dasatinib
• Intensive Consolidation Chemotherapy
• Allogeneic Stem Cell Transplantation
733
Question 2
64 yo physician is found to have an elevated lymphocyte count, HCT and Plts
normal. Flow cytometry demonstrates the lymphocytes to be CD20+, CD23+
and CD5+. The patient is observed. After developing anemia, therapy with
ibrutinib is started. His nodes decline but he has rapid rise in his WBC. He is
concerned about his rising WBC and wants to change therapy. What option
would you recommend?
a) Change to Venetoclax
b) Re-check FISH studies
c) Change to Fludarabine
d) Continue ibrutinib
Question 2a
The patient remains on ibrutinib and has an excellent response.
He complains of easy bruising. He is planning to have his hip
replaced. What would you suggest regarding his treatment for
CLL.
• Continue ibrutinib
• Stop ibrutinib and change to Venetoclax
• Hold ibrutinib for 3-7 days before and after surgery
• Continue ibrutinib and add warfarin after surgery to
prevent DVT
734
Summary
• Cytogenetics/Molecular Profiles predict outcome
• Risk adapted approach used to guide therapy
• New approaches using targeted therapies
Disclosures
Edwin P. Alyea
• None
735
Selected References
• Dohner H, Stilgenbauer S, Benner A, et al. Genomic aberrations and
survival in chronic lymphocytic leukemia. N Engl J Med.
2000;343:1910-1916.
• Greenberg P, Cox C, LeBeau MM, et al. International scoring system
for evaluating prognosis in myelodysplastic syndromes [see comments]
[published erratum appears in Blood 1998 Feb 1;91(3):1100]. Blood.
1997;89:2079-2088.
• Fenaux P, Mufti GJ, Hellstrom-Lindberg E, et al. Efficacy of
azacitidine compared with that of conventional care regimens in the
treatment of higher-risk myelodysplastic syndromes: a randomised,
open-label, phase III study. Lancet Oncol. 2009;10:223-232.
• Saglio G, Kim DW, Issaragrisil S, et al. Nilotinib versus imatinib for
newly diagnosed chronic myeloid leukemia. N Engl J Med;362:2251-
2259.
• Kantarjian H, Shah NP, Hochhaus A, et al. Dasatinib versus imatinib in
newly diagnosed chronic-phase chronic myeloid leukemia. N Engl J
Med;362:2260-2270.
736
Prostate and Bladder Cancer:

What the Internist Needs to Know
Lauren C. Harshman MD
Senior Physician, Dana-Farber Cancer Institute
July 23, 2018
Confluence of Interests
• Advisory: Bayer, Genentech, Dendreon, Pfizer,
Medivation/Astellas, Kew Group, Theragene, Corvus,
Merck, Exelixis, Novartis
• Research to the institution: Bayer, Sotio, Bristol-Myers

Squib, Merck, Takeda, Dendreon/Valient, Jannsen,
Medivation/Astellas, Genentech, Pfizer
737
Prostate Cancer in the US

• Incidence: 220,800 in 2015
161, 360 in 2017 to 164,690 in 2018
• Mortality: 29, 430
• 2nd cause of cancer death in 2018 up
from #3 in 2017
• 1 in 7 men
• Risk Factors:
- Age
- Family history
- Race: African American
- Genetic syndromes
• BRCA 1/2, Lynch syndrome
Siegel J CA Cancer Statistics 2018, www.cancer.org (ACS)
The Spectrum of Prostate Cancer

Organ Confined Organ Confined Metastatic Castration Resistant
Low Risk - Risk of Mets Disease Prostate Cancer
Prostate Cancer
Risk of cancer Rising PSA no mets Rising PSA no/min mets
Varied spectrum from low volume, low grade disease that would never
kill the patient to intermediate risk disease to high risk, high volume
localized disease to frank metastatic disease that is incurable.
Treatment decisions require balancing the risk of progression and

morbidity secondary to treatment toxicity with life expectancy.
738
Randomized Screening Studies for Prostate Cancer

• Rationale: identify cancer early increase chances of cure
• Screening tests: PSA (FDA 1994), digital rectal exam (DRE)
PLCO (US)** European Goteborg
Sample size 150,000 162,243 20,000
Median F/u 13 yrs 13 yrs 14 yrs
Prostate cancer No difference 21% reduction 44% reduction,
mortality p=0.001 p=0.0002
NNT* 37 12
*NNT: number needed to treat to prevent 1 death; **52% contamination
Why not screen?
Risks of Biopsy Risk of Overdiagnosis & Tx Toxicity

• Infection
• Pain
• Anxiety
Sanda et al, NEJM 2008

www.auanet.org/content/health-policy/quality/pdf/AUA-SUNA-PNBWhitePaper.pdf
739
Screenshot June 2016 & June 2017
For the C recommendation for men aged 55 to 69 years, the USPSTF’s

Screenshot
intention is to convey that each man’s values may shift June to
the balance 2017
a
net benefit of screening and to promote the importance of informed
decision making prior to screening.
The USPSTF continues to find that the benefits of screening do not

outweigh the harms in men 70 years and older and recommends against
screening in these men.
https://screeningforprostatecancer.org
Recommendations 2013 on…

American Urologic Association (AUA)
•No PSA screening in men under age 40. No routine screening in men between ages
40 to 54 years at average risk
•“For men ages 55 to 69 years the Panel recognizes that the decision to undergo PSA screening involves
weighing the benefits of preventing prostate cancer mortality in 1 man for every 1,000 men screened over a
decade against the known potential harms associated with screening and treatment. For this reason, the
Panel strongly recommends shared decision-making for men age 55 to 69 years that are considering PSA
screening, and proceeding based on a man’s values and preferences”
•To reduce harms of routine screening, prefer interval of two years or more
•No PSA screening: >age 70 OR any man with < 10 -15 year life expectancy
American Cancer Society (ACS)

• All men >50 with 10 yr life expectancy
• Discuss age >45 for African Americans and men with first degree relative
diagnosed <65 yo
• Discuss age >40 for those with multiple family members diagnosed young
• Screen yearly for PSA >2.5, every other year for <2.5
Auanet.org; cancer.org
740
≥ 50
Effects of 2012 USPTF
Recommendations
• Decreased PSA testing
• Significant decrease in prostate cancer incidence
• Too short follow-up to know effects on mortality 50-74
rate
• Pendulum still swinging…
≥75
Sammons JAMA 2015, Jemal JAMA 2015, Penson JAMA 2015
Grading and Staging Prostate Cancer

• Gleason Score (GS):
• Most prominent pattern +
Next most prominent pattern
- GS: 3 + 3 = 6
- GS: 4 + 3 = 7
- GS: 4 + 5 = 9
• PSA: <10, 10-20, >20
• TNM clinical staging

- Staging of bones
and nodes
741
Treatment Options for Early Stage Prostate Cancer
Radical Radiation Therapy

Prostatectomy +/-ADT
Active Surveillance Watchful Waiting
Overview: Treatment Options by Stage

Low Risk Intermediate Risk High Risk
GS 6 GS 7 GS 8-10
PSA <10 PSA 10-20 PSA >20
T1 T2 T3-4
Active surveillance Radical prostatectomy Radiation + 2-3 yrs CAB
Radical prostatectomy Radiation + 6 mo. CAB Radical prostatectomy +/-
Radiation: external beam, adjuvant radiation
brachytherapy
Stage: CT/MRI pelvis,
Bone scan
• Life expectancy <10 yrs: consider watchful waiting

• Surgery and radiation prevent PC deaths and increase overall survival in men
with clinically significant tumors and reasonable life expectancy
• Weigh side effect profiles, comorbidities, and risk of overtreatment
• Adding CAB to radiation improves outcomes but at expense of toxicity
GS: Gleason Score; CAB: combined androgen blockade (e.g., Lupron + bicalutamide)
742
Active Surveillance for Low Risk Prostate Cancer

• No initial treatment; treat only those men who need it
• Close monitoring: PSA, physical exam, serial re-biopsy
• Treat to cure at a sign of more aggressive disease
– e.g., Increase in Gleason score, PSADT
• Cons: anxiety, chance of progression to non-curative state
• Grey: death to other cancer

• Black: death due to PC
• GS <7: few deaths from PC
• GS ≥7 and >10 yr LE: no AS
Parker et al, BJC 2006
Outcome of Surgically Treated Patients

• Gleason 8-10: 10% of all cases
– 49% 15-year PCSM G8-10
– 45% of all cancer deaths
• Gleason 7: 40% of all cases
– 8% 15-year PCSM
– 50% of all cancer deaths G4+3
• Gleason 6: 50% of all cases G3+4
– <1% 15-year PCSM G3+3
– 1 of 3756 patients with
organ-confined, Gleason 6
cancer died from prostate
Stephenson et al J. Clin Onc 2009
cancer
• Surgery induces high cure rate in GS ≤7
• Surgery for select cases of GS 8-10
PCSM: prostate-cancer specific mortality
743
Prostate Cancer Exquisitely Dependent on Androgens

…Initially Orchiectomy
Brain LH
FSH
Testosterone
(LHRH) DHT
Lupron
Antiandrogens Prostate
Abiraterone Cancer
•Medical or surgical castration: testosterone suppression

DHT: dihydrotestosterone
Intermediate Risk: Radiation plus 4 - 6 mo ADT
• RTOG Trial
- Enrolled all risk patients
- XRT +/- Short term ADT
- Intermediate risk
• Decrease PC mortality
• Increase OS
- No benefit for low risk
- High risk likely need longer
course ADT
• Two other trials with similar

results
- TROG Lancet 2011
- DFCI JAMA 2008
Jones NEJM 2011
744
High Risk Disease: Radiation plus Longterm

Testosterone Suppression
36 months versus 6 months ADT

• all deaths (increased OS)
• Prostate Ca deaths
• 5 yr mortality: 19% vs. 15.2%
HR: 1.42 (95.7% CI 1.79, p0.65
Bolla et al NEJM 2009
ProtecT Trial
• Evaluated the effectiveness of
surgery, radiation or active
monitoring (AM) on PC mortality
• PSA detected clinically localized
cancers (n=1643)
• Outcomes equivalent: high cure rates
• Death from PC ~1% at 10 years
irrespective of treatment
• Treatment over AM 50% less:
– Rate of disease progression
– Development of metastatic disease
• 25% of men on AM went on to
receive radical therapy within 3 yrs
and 50% by 10 yrs
AM = active monitoring Hamdy NEJM 2016
745
Weighing Toxicity
Surgery Radiation ADT
• Surgical complications • Irritative urinary Sx • Hot flashes
- Wound healing • Bowel dysfunction • Fatigue
- Infection • Erectile dysfunction • Weight gain
- Anesthesia risks • Risk of second cancer • Bone density loss
• Erectile dysfunction • Loss of libido
• Urinary Incontinence • Emotional changes
• Metabolic insults:
insulin resistance
• ?Cardiac toxicity
• ?Dementia
• Surgery: radical prostatectomy (robotic, open, laparoscopic)

• Radiation: external beam, brachytherapy
• ADT: GnRH agonist or antagonist +/- antiandrogen
Sanda NEJM 2008, Resnick NEJM 2013
Summary: Treatment of localized disease
• Low risk disease:

– Active surveillance for > 70 yrs with low risk disease
– Shared decision making re: surgery vs. radiation for younger men
• Intermediate risk disease:

– Surgery or Radiation plus 4-6 months androgen suppression
• High grade but localized cancer:

– Radiation plus long course androgen suppression (2-3 yrs) OR
– Radical prostatectomy (+/- adjuvant radiation)
746
The spectrum of prostate cancer

Prostate Cancer
• Biochemical Recurrence: Rising PSA after local therapy

- Post prostatectomy: >0.2
- Post-radiation: nadir + 2 (still have normal prostate tissue making PSA)
Natural History of Prostate Cancer: deferred ADT
Makarov et al J. Urol; 2008, 179 (156-162)
747
ADT for Biochemical relapse

• Non-inferiority Phase 3 Study:
• Post XRT as primary or local Rx
• 8 month ADT, hold and restart
with PSA rise vs. continuous
• Intermittent not inferior, better QOL
Overall survival by Treatment Arm

10 0
P e rce n ta g e of P a tie n ts
75
Crook NEJM 2012

50
• TOAD trial: early vs. delayed ADT

25
Treatment = A:Delayed
- Early use = increase OS (HR 0.55)
Treatment = B:Immediate
- Median OS not reached at 8 yrs
0
0 2 4 6 8
Years
Duchesne ASCO 2015, Lancet 2016
Hormone Sensitive Metastatic Prostate Cancer

Prostate Cancer
748
Metastatic Prostate Cancer Starting ADT: Prognosis
Hussain et al. J Clin Oncol 2006
Eisenberger et al. S8894 NEJM
• Worse prognosis: high volume bone or

liver/lung metastases Harshman et al J Clin Oncol 2017
• Better prognosis: node only or < 4 • Patients with deeper PSA nadir
bone metastases have improved survival by years
Metastatic Disease: Intermittent vs. Continuous ADT

• Men with metastatic prostate
cancer starting ADT (n=3040)
• PSA < 4 in 1535 men =
selected group
• Randomized to continuous vs.

intermittent ADT
• Median 6 mo survival benefit with

continuous testo suppression
• HR for death with intermittent
tx: 1.10; 90% CI - 0.99 to 1.23
• Exceeded the upper boundary
for noninferiority
• Thus, “not non-inferior” Hussain et al NEJM 2013
Standard Remains Continuous ADT… in those that can tolerate it
749
Adding Docetaxel to ADT Increases Survival

High Volume Metastases Low Volume Metastases
1.0 1.0
0.9 0.9
0.8 0.8
0.7 0.7
0.6 0.6
0.5 0.5
p=0.0006
Probability
Probability
p=0.1398
0.4 HR=0.60 (0.45-0.81) 0.4
HR=0.63 (0.34-1.17)
Median OS: Median OS:
0.3 0.3
ADT + D: 49.2 months ADT + D: Not reached
0.2
ADT alone: 32.2 months 0.2 ADT alone: Not reached
0.1 0.1
0.0 0.0
0 12 24 36 48 60 72 84 0 12 24 36 48 60 72 84
OS (Months) OS (Months)
Arm TOTAL DEAD ALIVE MEDIAN
• Overall: 57.6 vs. 44 mo, HR:0.61, 95% CI: 0.47-0.80, p <0.001
• High volume = liver, lung, > 4 bone with one beyond spine and pelvis
• High volume metastatic dz: 17 month OS benefit: 32.2 mo 49.2 mo
Sweeney ASCO 2014, NEJM 2015
Hormone therapy works….for a While
Flare!
• Ultimately almost all patients become “castration-resistant”

• CRPC = rising PSA/progression despite testosterone <50
750
Progression of Prostate Cancer Despite

Testosterone Suppression:
Castration-resistant Disease

Prostate Cancer
Current Treatment of Castration-resistant Prostate Cancer
Bone-targeted:
Second line • Radium-223
Androgen blockade: • Antiresorptives
• Abiraterone
• Enzalutamide
• (nilutamide, flutamide,
ketoconazole/HC)
Chemotherapy
• Docetaxel
Immunotherapy: • Cabazitaxel
Sipuleucel-T
• Median overall survival from time of second line agent: 18-35 months
• Clinical trials remain imperative as there are no cures!
751
Take Home Messages:

Castration Resistant Prostate Cancer
• 6 agents that improve survival after progression on initial
androgen deprivation therapy
• Range from immunotherapy to second line antiandrogens to
chemotherapy to bone metastasis homing agents
• Incremental improvements in survival: median 2-5 months
each (these add up when given sequentially!)
• Best sequence unclear: consider tolerability, toxicity, co-
morbidities (e.g., seizures; diabetes given need for steroids)
• Clinical trials imperative as still no cure!
Summary of Prostate Cancer

• Prostate cancer mortality has decreased significantly in the PSA era
– Screening appears most beneficial in the 55-69 age group with life
expectancy >10 yrs (shared decision making is key)
– Overtreatment is a valid concern, but diagnosis does not equate to
definite need to treat
• Active surveillance reasonable in low risk disease—goal: delay or prevent
toxicity
• Both surgery and radiation + ADT can improve outcomes in younger
patients with intermediate or high risk disease
• Wealth of agents that improve survival in metastatic disease but no cures
– ADT +/- docetaxel chemotherapy
– 2nd line hormone suppression: abiraterone, enzalutamide
– Immunotherapy: first anticancer vaccine sipuleucel-T
– Bone homing agents like Radium-223
– Clinical trials remain imperative to improve outcomes
752
Slides for Reference on Advanced

Treatments for Castration-Resistant
Prostate Cancer That Your Patients May
Receive
Extinguishing AR axis after Androgen Suppression

Abiraterone *Steroid biosynthesis
Pregnenolone
*Intratumoral
CYP17 & Systemic
Enzalutamide
17-OH-Pregnenolone
CYP17
DHEA
Hormone regulated
AR
genes
* AR upregulated in CRPC tissue
plus
* Tumors make own androgens
=
Rationale for 2nd Line Hormonal Rx
753
Abiraterone/Prednisone & Enzalutamide in CRPC
• First approved in docetaxel-refractory setting

- 4-5 month overall survival benefit
• Later tested pre-chemotherapy with even greater benefit over
placebo in progression-free and overall survival
deBono NEJM 2011, Scher NEJM 2012, Ryan NEJM 2013, Beer NEJM 2014
Docetaxel Chemotherapy Increases Overall Survival
• Cabazitaxel (2nd gen taxane) vs. mitoxantrone:

- Median OS: 15.1 vs. 12.7 mo, HR 0.7, p<0.0001
754
Sipuleucel-T: First Anticancer Treatment Vaccine
Antigen (PAP-
GMCSF) is
exposed to an Antigen is Fully activated,
Antigen APC takes up processed and the APC is now
Presenting the antigen presented on sipuleucel-T
Cell (APC) surface of the and is collected
APC
INFUSE
PATIENT
T-cells proliferate and attack sipuleucel-T activates T-

cancer cells cells in the body
IMPACT Trial: Sipuleucel-T Improves Overall Survival

36.5 mo median f/u
HR = 0.759 (95% CI, 0.606, 0.951)
P = 0.017 (Cox model)
Median survival benefit = 4.1 mo
Sipuleucel-T (n = 341)
Median survival: 25.8 mo.
36 mo. survival: 32.1%
Placebo (n = 171)
Median survival: 21.7 mo.
36 mo. survival: 23.0%
No. at Risk
Sipuleucel-T 341 274 142 56 18 3

Placebo 171 123 59 22 5 2 Kantoff et al NEJM 2010
755
Bone Metastases & Radium-223

• >90% of patients with mCRPC have bone metastases
• Most frequent cause of morbidity and mortality
• Incur high treatment-related costs in this disease
• Radium-223 dichloride: radiotherapeutic

– Calcium mimetic: hones in on bone metastases due to their high rate
of bone turnover
– Short path length alpha particles limits toxicity to surrounding healthy
tissue
– Well tolerated with the most frequently observed adverse events:
low grade myelosuppression, GI toxicity, and fatigue
– Compared to placebo, radium-223 significantly :
• Median overall survival: 11.3 14.9 mo; HR 0.70
• Median time first symptomatic skeletal events
Parker N Engl J Med 2013
100
ALSYMPCA Overall Survival
90 HR 0.695; 95% CI, 0.552-0.875
80 P = 0.00185
70
60
Radium-223, n = 541
% 50 Median OS: 14.0 months
40
30
20
Placebo, n = 268
Median OS: 11.2 months
10
0
Month 0 3 6 9 12 15 18 21 24 27
Radium- 223 541 450 330 213 120 72 30 15 3 0

Placebo 268 218 147 89 49 28 15 7 3 0
Benefit in patients with and without prior chemotherapy
756
Bladder Cancer for Internists: A to Z
Bladder Cancer US Statistics in 2018

• 81,190 cases will be diagnosed
– 62,3800 males/ 18,810 females (3:1)
– #4 cancer in incidence
– 50-60% superficial disease
– Median age: 73-74 yrs
• 17,240 estimated deaths

– 10% present with metastatic disease
– 4% of all cancer deaths
Siegel CA Cancer Stat 2012, 2018
757
Risk Factors
Types of Bladder Cancer
TCC 90%
Squamous (6-8%)
Adenocarcinoma(2%)
Other (3%)
Urothelium
• Urothelial cell or transitional cell-carcinoma (TCC) (90%) •Renal pelvis
• Squamous (6-8%) •Ureters
– Schistosomiasis •Bladder
– Non-schistosomiasis cases: chronic catheterization patients •Urethra
• Adenocarcinoma (2%)
– Urachal
– Non-urachal (chronically irritated transitional epithelium)
• Small cell (<1%, treat like lung cancer)
758
Diagnosis: Internist Often First To See

• Hematuria: gross or microscopic
• UTI like or irritative symptoms: frequency, dysuria, blood
– Patients are often treated with 2-3 courses of antibiotics before they
are referred to a urologist
• If not clearly a UTI on UA or culture:

– Refer to urology for cystoscopy and
upper tract evaluation
– Send urine cytology
– Consider CT abdomen/pelvis
Staging of Bladder Cancer: TNM
• T1 = superficial, non-invasive
• T2 = muscle invasion
• T3 = into/through perivesciular fat
• T4b = invasion of pelvic/abdom wall
• N1 = Involved regional lymph nodes
• M1 = Distant metastasis
Critical that TURBT samples the

muscle layer!
Harshman et al Surg Pathol Clin 2015
759
Spectrum of Bladder Cancer

Bladder Cancer
Non-muscle Muscle Invasive Metastatic

Invasive (60%) (30%) (10%)
Recur
• TURBT • Radical cystectomy +/- • Chemotherapy

• Intravesical tx neo/adjuvant chemo • Immunotherapy
if high grade OR
• Chemoradiation
Non-Muscle Invasive Urothelial Cancer

• Most common stage (60%)
• Risk of progression to muscle invasive
– High grade, T1a - 48% rate of progression
– Low grade Ta - 2% rate of progression
• Managed by cystoscopy and TURBT Webmd.com
– Transurethral resection of bladder tumor
– BCG instillations weekly x 6 then q 3 months for “high risk” lesions
• Improved disease free survival compared with no therapy
• Decreases need for “salvage” cystectomy
• No improvement in overall survival because often cured with
cystectomy
760
Muscle Invasive Disease: Outcomes after Cystectomy
Overall survival
Can adding chemotherapy improve surgical outcomes??
• Organ confined (T2, ~35%): 5 yr OS: 74%, median OS ~15 yrs

• Extravesicular (>T2): 5 yr OS: 37%, median OS ~4.5 yrs
• Regional nodal disease: 5 yr OS: 31%, median: OS ~2 yrs
OS: overall survival Stein J Clin Oncol 2001
SWOG 8710: Cystectomy +/- Neoadjuvant MVAC
T2-4aN0M0 disease
Median Alive at 5 yrs p-value

n=307
Survival (2-sided)
RC 46 mos 43%
.06
MVAC +RC 77 mos 57%
• Disease-Specific Survival: 1.66 in favor of chemotherapy (p= 0.002)

• Overall Survival: 1.33 in favor of chemotherapy (p=0.06)
• Clinically significant increase in median overall survival
• Supported by meta-analyses
MVAC: methotrexate, vinblastine, adriamycin, cisplatin Grossman NEJM 2003
RC: radical cystectomy ABC Collaboration Eur Urol 2005
761
Adjuvant Chemo: Immediate vs. Delayed

Phase 3 EORTC Trial: pT3-4 or Node + Urothelial Cancer
100 5 yr PFS: 46.8% vs. 39.5% 100 5 yr OS: 53.6% vs. 47.7%
90
90
80
HR 0.52, p<0.0001 80
HR 0.78, p =0.13
70 Median: 2.9 vs. 0.9 yrs 70 Median: 6.8 vs. 4.6 yrs
60 60
PFS 50 OS 50
40
40
30
30
20
20
10
10
0 (years)
0 (years)
0 2 4 6 8 10 12
0 2 4 6 8 10 12
O N Number of patients at risk : Treatment
O N Number of patients at risk : Treatment 66 141 95 70 44 25 3 Immediate
73 141 71 56 39 21 3 Immediate 82 143 83 67 42 21 4 Deferred
103 143 50 43 30 18 4 Deferred
• Largest randomized adjuvant study to date but closed early

• Immediate cisplatin-based chemo improves PFS and non-significant 22.2%
reduction in risk of death (underpowered)
• Multiple meta-analyses suggest DFS and OS benefit to cisplatin-based chemo
• Clinical Practice: consider if pT3-T4 or node positive and cisplatin eligible
Sternberg ASCO 2014, Leow Eur Urol 2013
Trimodality Bladder Preservation Therapy:

Maximal TURBT + Chemoradiation
• Optimal candidates: small solitary lesions <5cm, T2 or
T3 disease, no hydronephrosis, ability to perform a
complete TURBT, and minimal to no CIS
• Bladder preservation approach:

– Maximal TURBT to remove all residual disease
– Radiation: 64-65 Gy bladder, 44-45 Gy adj pelvic nodes
– Cisplatin based therapy: weekly vs. every 3 wks
– Cisplatin unfit: 5FU/Mitomycin, carbo/taxol
– Repeat TURBT: if residual cancer salvage cystectomy
• Outcomes
– ~50% of patients long term control with intact bladder
Shipley et al Cancer 2003
– 20-30% require salvage cystectomy Mak JCO 2009
762
Chemoradiation in Patients with Muscle

Invasive UC Unfit for Surgery or Cisplatin
• 2001-2008: 360 T2-4aN0 patients
– Majority T2 (82%)
– Median age: 72 yrs
• TURBT: complete only in 55%
• XRT 55 Gy in 20 fx or 64 Gy in 32 fx
• +/- Chemo: 5-FU plus Mitomycin C
• Addition of chemo to XRT:

– 43% reduction in risk of
locoregional relapse
– Trend to benefit in OS
James et al NEJM 2012
Metastatic Disease: MVAC vs. Gem/Cis (GC)
mOS ~14-15 mo.

PFS: ~8 mo.
RR: 46-49%
• Cisplatin is the best drug for urothelial cancer

• Non-inferiority trial (not equivalency or superiority)
• GC was not inferior to MVAC in all respects
• GC probably superior in terms of toxicity: less mucositis, neutr. fever/sepsis
MVAC: methotrexate, vinblastine, adriamycin, cisplatin, GC: gemcitabine/cisplatin Von der Maase JCO 2000, & JCO 2005
763
Some Metastatic disease is CURABLE with Chemotherapy
# Factors % pts CR (%) Med. Surv 5-yr 10 yr
0 32 38 33 mo 33% 24%
1 45 25 13.4 mo 11% 6%
2 23 5 9.3 mo 0% 0%
• N = 203 patients
• Risk factor: KPS < 80; any visceral metastasis - lung, liver, bone
• ~20% of patients can have longevity/durable responses to chemo
Bajorin; JCO 1999
Cisplatin Unfit Patients

• Up to 50% of patients are “unfit” for cisplatin
– Performance status, renal dysfunction, neuropathy, heart failure
• No standard therapy in this setting: carboplatin, gemcitabine, taxanes
• Carboplatin based regimens:

- ORR: 30-40%
- CRs: 10% or less
Galsky J Clin Oncol 2011
764
Second line Chemotherapy
• Before 2016: No standard

– Doublets/Triplets likely not better than single agents
– Increased response rates but not necessarily OS
– General outcomes from many trials of different chemos:
• Progression-free survival: 3-5 months
• Overall survival: 5-9 months
• 2016 New Standard—Immunotherapy with PD-1 pathway

blockade
PD-1 Blockade: Reinvigorate the CTLs
Killer T cell
Increased
cytokine
IFN-γ
PD-1 Increased
TCR killing
mAb
Pembrolizumab PD-L1 MHC
Atezolizumab
Nivolumab
Durvalumab
Avelumab Tumor cell
G. Freeman
765
Boon of Checkpoint Inhibitor Immunotherapy

Approvals for Urothelial Cancer
Durvalumab
1108 Trial
2L mUC
Avelumab
JAVELIN Trial
2L mUC
Atezolizumab Pembrolizumab
ImVigor211 (-) KeyNote-052
2L mUC 1L Cis-Inel mUC
Pembro
MVAC Pembrolizumab
KeyNote-052
Improves OS KeyNote-045
1L Cis-Inel
1L mUC 2L mUC
mUC
Atezolizumab
CG Atezolizumab Nivolumab Pembro Nivolumab Atezolizumab
ImVigor210
Less toxic than ImVigor210 CheckMate275 KeyNote-045 CheckMate275 ImVigor210/211 2L
1L Cis-Inel
MVAC 1L mUC 2L mUC 2L mUC 2L mUC 2L mUC mUC
mUC
1992 - 2000 May 2016 Feb 2017 April 2017 May 2017 June 2017 Sept 2017
Figure N. Hahn
KEYNOTE-045: Open-Label, Phase 3 Study of Pembrolizumab vs

Investigator’s Choice of Paclitaxel, Docetaxel, or Vinflunine for
Overall Survival: Total
Previously Treated Advanced Urothelial Cancer
100
90 Events HR (95% CI) P
80 Pembro 155 0.73 0.0022
70 Chemo 179 (0.59-0.91)
43.9%
O S, %
60 30.7%
50
40
30
Median (95% CI)
20 10.3 mo (8.0-11.8)
10 7.4 mo (6.1-8.3)
0
0 2 4 6 8 10 12 14 16 18 20 22 24
Time, months
No. at risk
270 226 194 169 147 131 87 54 27 13 4 0 0
272 232 171 138 109 89 55 27 14 3 0 0 0
Data cutoff date: Sep 7, 2016. Bellmunt J et al, NEJM 2017

Data cutoff date: Sep 7, 2016.
766
2017: Atezolizumab & Pembrolizumab Approved Plimack ASCO 2016
Multiple First line trials exploring IO/IO or chemo-IO
767
Multiple First line trials exploring IO/IO or chemo-IO
Conclusions
• Multidisciplinary approach essential to cure
• MIBC: can be highly sensitive to chemotherapy and immunotherapy

– Cisplatin remains gold standard first line agent in fit/eligible patients
– PD-1/PD-L1 blockade in first line cisplatin-ineligible or platinum-refractory
disease (2nd line +)…but maybe only if PD-L1+…evolving story
• Cure/long term control possible in node positive (St IV) disease
• Modest but real survival benefit to neoadjuvant cisplatin-based

chemotherapy
• Novel therapies imperative to improve outcomes: SUPPORT TRIALS
768
Board Review Question 1

• Which pairing of treatment and clinical scenario is incorrect?
A. Prostatectomy for 57 yo with T1c (no nodule on DRE), Gleason score
7 disease in 4 of 6 cores and PSA 5
B. Active surveillance for 73 yo with Gleason score 6 in 5% of 1 core
out of 12 cores and PSA 4.5, T1c (no nodule on DRE)
C. 2-3 years of androgen suppression and radiation for 65 yo with 6 of
12 cores with Gleason score 8 and T2b (nodule on DRE)
D. Radiation alone for 60 yo with Gleason score 4+3 =7 disease in 8 of
12 cores, PSA 8, and T2a (small nodule) disease

A. Prostatectomy for 57 yo with T1c (no nodule on DRE), Gleason
score 7 disease in 4 of 6 cores and PSA 5
B. Active surveillance for 73 yo with Gleason score 6 in 5% of 1 core
out of 12 cores and PSA 4.5, T1c (no nodule on DRE)
C. 2-3 years of androgen suppression and radiation for 65 yo with 6 of
12 cores with Gleason score 8 and T2b (nodule on DRE)
D. Radiation alone for 60 yo with Gleason score 4+3 =7 disease in 8 of
12 cores, PSA 8, and T2a (small nodule) disease
Answer:
– D is incorrect: Radiation plus short term testosterone suppression
alone for intermediate risk prostate cancer results in superior
prostate cancer specific and superior overall survival compared to
radiation alone.
769

A. Neoadjuvant cisplatin combination therapy followed by cystectomy
for muscle invasive urothelial bladder cancer in a “fit” 60 yo
B. Transurethral resection of bladder tumor (TURBT) alone for grade 1
Ta solitary papillary urothelial cancer
C. Concurrent mitomycin plus 5-FU with radiation for multifocal high
grade T1 (lamina propria invasion but not muscle) urothelial cancer
D. Mitomycin plus 5FU plus XRT for 78 yo female with muscle invasion
and not “fit” for cystectomy

A. Neoadjuvant cisplatin combination therapy followed by cystectomy
for muscle invasive urothelial bladder cancer in a “fit” 60 yo
B. Transurethral resection of bladder tumor (TURBT) alone for grade 1
Ta solitary papillary urothelial cancer
C. Concurrent mitomycin plus 5-FU with radiation for multifocal high
grade T1 (lamina propria invasion but not muscle) urothelial cancer
D. Mitomycin plus 5FU plus XRT for 78 yo female with muscle invasion
and not “fit” for cystectomy
• Answer:
– C is incorrect: TURBT with intravesical therapy (most commonly
BCG to decrease risk of recurrence) is appropriate management for
non-muscle cancers at high risk for recurrence. Radiation is not
appropriate for T1 (superficial) disease outside of a clinical trial.
770
Selected References
• Bill-Axelson A, Holmberg L, Ruutu M et al. Radical prostatectomy versus watchful
waiting in early prostate cancer. The New England journal of medicine.
2011;364(18):1708-17.
• Bolla M, de Reijke TM, Van Tienhoven G, et al. Duration of androgen suppression in the
treatment of prostate cancer. The New England journal of medicine.
2009;360(24):2516-27.
• Hussain M, Tangen CM, Berry DL, et al. Intermittent versus continuous androgen
deprivation in prostate cancer. N Engl J Med. 2013 Apr 4;368(14):1314-25.
• von der Maase H, Sengelov L, Roberts JT, et al. Long-term survival results of a
randomized trial comparing gemcitabine plus cisplatin, with methotrexate, vinblastine,
doxorubicin, plus cisplatin in patients with bladder cancer. Journal of Clinical Oncology.
2005;23(21):4602-8.
• Grossman HB, Natale RB, Tangen CM, et al. Neoadjuvant chemotherapy plus
cystectomy compared with cystectomy alone for locally advanced bladder cancer. The
New England journal of medicine. 2003;349(9):859-66.
• Bellmunt j, de Wit R, Vaughn D et al. Pembrolizumab as second-line therapy for
advanced urothelial carcinoma. N Engl J Med 2017; 376(11): 1015-1026.
Extra Slides For Reference
771
Lung Cancer
David Jackman, MD
Medical Director of Clinical Pathways, Dana-Farber Cancer Institute
Disclosures
• Consultant:
– AstraZeneca
– CVS Caremark
– MOREHealth
772
Question 1
Which of the following statements is true?

A. Lung cancer is the third most common cause of cancer death, after
breast and colon cancer.
B. For former smokers, it takes ~ 10 years for the risk of lung cancer to
decrease to that of a nonsmoker.
C. More than half of new lung cancers are already metastatic at the time of
diagnosis.
D. Tumor grade (based on appearance under the microscope) is a more
important predictor than tumor stage (extent of disease on scans)
E. Small cell lung cancer is both more aggressive and more common than
non-small cell lung cancer.
Question 1

A. Lung cancer is the third most common cause of cancer death, after
breast and colon cancer.
B. For former smokers, it takes ~ 10 years for the risk of lung cancer to
decrease to that of a nonsmoker.
C. More than half of new lung cancers are already metastatic at the time
of diagnosis.
D. Tumor grade (based on appearance under the microscope) is a more
important predictor than tumor stage (extent of disease on scans)
E. Small cell lung cancer is both more aggressive and more common than
non-small cell lung cancer.
773
5 things to know about … Lung Cancer Epidemiology
Topics to Address
Overview and
1
Epidemiology
2 CT Screening U.S. Deaths/year
3 Diagnosis and
Staging
1. Lung Cancer: 154,050
4 Treatment Overview
2. Colon Cancer: 50,630
A Localized Disease
3. Pancreatic Cancer: 44,330
Locally Advanced
B Disease 4. Breast Cancer: 41,400
Metastatic Disease
5. Prostate Cancer: 29,430
C
Total: 165,790
Siegel et al, CA: A Cancer Journal for Clinicians, 2018 5
Topics to Address
Overview and
2
1
Epidemiology
3
2 Diagnosis and
CT Screening
Staging
4 Diagnosis and
3 Treatment
Staging Overview
5
4 Treatment
CT Screening
Overview • 85% of lung cancers in the U.S. occur in
smokers.
B Localized Disease
• Risk increases with number of cigs/day and
C
Locally Advanced
Disease
number of years smoking.
• Smokers have a 15-30-fold higher risk of lung
Metastatic Disease
C
cancer compared to nonsmokers.
• Quitting decreases risk, but it never normalizes.
774
Topics to Address
Overview and
2
1
Epidemiology
3
2 Diagnosis and
CT Screening
Staging
4 Diagnosis and
3 Treatment
Staging Overview
5
4 Treatment
CT Screening
Overview
B Localized Disease
Locally Advanced
C Disease Unknown Early
(8%) (15%)
C Metastatic Disease Locally Advanced
Metastatic (22%)
(55%)
SEER 2000
7
Topics to Address Stage 5-year survival

Overview and Localized 55%
2
1
Epidemiology
3
2 Diagnosis and
CT Screening
Staging Regional 28%
4 Diagnosis and
3 Treatment
Staging Overview
Distant 4%
5
4 Treatment
CT Screening
Overview
B Localized Disease
Locally Advanced
C Disease
C Metastatic Disease
SEER Cancer Statistics Review, 1975-2013

8
775
Topics to Address
Overview and
2
1
Epidemiology
3
2 Diagnosis and
CT Screening
Staging
4
3
Diagnosis and
Treatment
Staging Overview 88% 12%
Non-small Cell
5
Small Cell
4 Treatment
CT Screening
Overview
B Localized Disease
Locally Advanced
C Disease
C Metastatic Disease
DIAGNOSIS AND STAGING
10
776
5 things to know about …Diagnosis and Staging
Topics to Address
1. Stage and Approach
Overview and
1
Epidemiology NSCLC SCLC
Treatment Approach
2 Diagnosis and Stage Stage
Staging
IA,
Surgical resection
3 Treatment Overview IB (< 4cm)
IB (> 4cm), Surgical resection,
4 CT Screening
IIA, IIB +/- chemotherapy
IIIA Multimodality approach
IIIB Limited Chemotherapy and Radiation
IV Extensive Chemotherapy
11
5 things to know about …Diagnosis, Staging and

Screening
Topics to Address 2. Initial Staging Workup
Overview and
1
Epidemiology Which of the following is not indicated in
Diagnosis and
2
Staging
the initial workup of EVERY new lung
cancer patient?
4 CT Screening A. Abdominal imaging
B. Bone imaging (PET/CT or bone scan)
C. Brain imaging (MRI or CT) without
contrast
D. Chest CT with IV contrast
E. All are indicated
12
777
5 things to know about …Diagnosis, Staging and

Screening
Topics to Address 2. Initial Staging Workup
Overview and
1
Epidemiology Which of the following is not indicated in
Diagnosis and
2
Staging
the initial workup of EVERY new lung
cancer patient?
4 CT Screening A. Abdominal imaging
B. Bone imaging (PET/CT or bone scan)
C. Brain imaging (MRI or CT) without
contrast
D. Chest CT with IV contrast
E. All are indicated
13
Topics to Address Common Sites of Metastasis
Overview and Liver

1
Epidemiology Bone
2 Diagnosis and Adrenals
Staging
Brain
Brain MRI w/ gadolinium (preferred), or
4 CT Screening CT head with and without contrast
CT chest with contrast, specified for lung cancer
PET-CT (preferred) or
bone scan
14
778
Topics to Address
3. The Value of Mediastinal Staging
Overview and
1
Epidemiology • Appropriateness of resection
Diagnosis and
2
Staging
• Guiding radiation therapy
• Ways and means:
4 CT Screening • Mediastinoscopy
• Endobronchial ultrasound
• Surgical lymph node dissection
15
Topics to Address
4. Making a Diagnosis
Overview and
1
Epidemiology GET AS MUCH TISSUE AS YOU
Diagnosis and
2
Staging SAFELY CAN
3 Treatment Overview • Diagnosis
4 CT Screening
• Genomic analysis
• Immunotherapy assessment
• Clinical trial eligibility
Caveats:
• Core over FNA
• Non-bone over bone
16
779
Topics to Address 5. Paraneoplastic syndromes

Overview and
1
Epidemiology Match the paraneoplastic syndrome
2 Diagnosis and with the most likely corresponding
Staging
thoracic tumor histology.
Hyponatremia (SIADH) Small cell lung cancer
4 CT Screening
Cushing syndrome Squamous cell lung cancer
Lambert-Eaton Adenocarcinoma of lung
Hypercalcemia Mesothelioma
Myasthenia Gravis Thymoma
17
Topics to Address 5. Paraneoplastic syndromes

Overview and
1
Epidemiology Match the paraneoplastic syndrome
2 Diagnosis and with the most likely corresponding
Staging
thoracic tumor histology.
Hyponatremia (SIADH) Small cell lung cancer
4 CT Screening
Cushing syndrome Squamous cell lung cancer
Lambert-Eaton Adenocarcinoma of lung
Hypercalcemia Mesothelioma
Myasthenia Gravis Thymoma
18
780
Topics to Address 5. Paraneoplastic Syndromes

Overview and Endocrine/ Mechanism Symptoms
1
Epidemiology Paracrine
2 Diagnosis and Hypercalcemia Multiple Altered mental status, ataxia.
Staging Cardiac concerns
3 Treatment Overview SIADH ADH/aVP Symptomatic hyponatremia
Cushing’s ACTH Muscle weakness, hyperglycemia,
4 CT Screening syndrome hylokalemia. Infection.
Neurologic Mechanism Symptoms

Lambert-Eaton Anti-voltage gated Fatigue, large muscle
calcium channels weakness
Paraneoplastic Anti-Hu Ataxia, diplopia,
cerebellar Anti-Yo dysphagia
degeneration
Myasthenia gravis Anti-Acetylcholine Fatigable weakness of
receptor voluntary muscles
Pelosof et al. Mayo Clin Proc 2010. 85(9): 838-854 19
MANAGEMENT OF LUNG
CANCER
20
781
5 things to know about …Lung Cancer Treatment
NSCLC SCLC Treatment 1. Anatomic Resection

Stage Stage Approach
IA,
remains the Gold
IB (< 4cm) Surgical resection Standard
IB (> 4cm), Surgical resection, Alternatives include:
• Wedge resection
IIIA Multimodality • Radiation
approach
• Ablation
IIIB Limited Chemotherapy and
Radiation
Chemotherapy /
IV Extensive Targeted Therapy /
Immunotherapy
21
2. Role of Radiation
Radiation is appropriate for all but which of the following?
A. Curative therapy for a localized lung cancer in a patient with poor
operative risk
B. Combined with chemotherapy as part of a multimodality strategy
for a right upper lobe mass with hilar and mediastinal nodal
involvement.
C. Whole lung irradiation for a patient with multiple lung lesions
throughout the left lung.
D. Palliative therapy for brain metastases
E. Palliative therapy for SVC syndrome
22
782
2. Role of Radiation
Radiation is appropriate for all but which of the following?
A. Curative therapy for a localized lung cancer in a patient with poor
operative risk
B. Combined with chemotherapy as part of a multimodality strategy
for a right upper lobe mass with hilar and mediastinal nodal
involvement.
C. Whole lung irradiation for a patient with multiple lung lesions
throughout the left lung.
D. Palliative therapy for brain metastases
E. Palliative therapy for SVC syndrome
23
NSCLC SCLC Treatment

Stage Stage Approach
IA,
IB (< 4cm) Surgical resection

IIIA Multimodality
approach 3. Genomically
IIIB Limited Chemotherapy and targeted therapy
Radiation has been a major
Chemotherapy /
IV Extensive Targeted Therapy / advance in non-
Immunotherapy small cell lung
cancer
24
783
5 things to know about … Lung Cancer Treatment
Moving beyond Chemo Targeted

therapies
chemotherapy
Response rate 20-30%
100 Median 8-12 months
80 survival
Percent Alive
60
40
20
0
0 5 10 15 20 25 30
Months
Schiller et al. N Engl J Med. 2002;346:92.
25

Chemo Targeted
Moving beyond therapies
chemotherapy Response rate 20-30% 60-80%
Median 8-12 months 2-3 years
100 survival
80
Percent Alive
60
40
20
0
0 5 10 15 20 25 30
Months

26
Rosell R, et al. Lancet Oncol. 2012;13:239-246.
784
Also:
ROS1
RET
NTRK
MET
Johnson BE, et al.

ASCO 2013.
27
4. Immunotherapy
Ribas, NEJM 2012
For metastatic non-small cell lung cancer patients treated with

nivolumab, a PD-1 inhibitor, the 5-yr survival: 15% !
Gettinger S, Horn L, Jackman D, et al. J Clin Onco 2018

28
785
5 things to know about …Treating Local Disease
5. What’s the current standard of care for additional testing at

time of diagnosis?
Genomic, Immunohisto- Coming?
approved chemical,
approved
Non-small cell, non- EGFR, BRAF, PD-L1 MET, NTRK,
squamous ALK, ROS1 RET, HER2
TMB
NSCLC, squamous - PD-L1 TMB
SCLC - - TMB
29
CT SCREENING
30
786
5 things to know about … Lung Cancer Screening
Topics to Address 1. Does it save lives?
Overview and • 20% decrease in lung

1
Epidemiology cancer mortality
2 Diagnosis and
Staging • 6.7% decrease in all
cause mortality
4 CT Screening
NLST investigators, NEJM 2011. 365: 395-409 31
Topics to Address 1. Does it save lives? 2. Whom to screen?

• 20% decrease in lung • Ages 55-80
Overview and
1
cancer mortality • Smokers, heavy and
Epidemiology
recent:
Diagnosis and
2
• 6.7% decrease in all • > 30 pack-yrs
Staging
cause mortality • Quit within last
3 Treatment Overview 15 yrs
4 CT Screening
Uspreventiveservicestaskforce.org. Lung Cancer:Screening, Release Date Dec 2013 32
787

Overview and
1
Epidemiology
recent:
Diagnosis and
2
Staging
4 CT Screening
3. How and
•when?
Annual LD-CT until:
• > 15 yrs since smoking
cessation, or
• Age 80, or
• Unwilling or too ill to
undergo curative
resection for detected CA
Uspreventiveservicestaskforce.org. Lung Cancer:Screening, Release Date Dec 2013 33

Overview and
1
Epidemiology
recent:
Diagnosis and
2
Staging
4 CT Screening
3. How and 4. Is it cost-
•when?
Annual LD-CT until: effective?
cessation, or • Estimates of $80K/QALY
• Age 80, or gained
• Unwilling or too ill to • Cost-effectiveness
undergo curative improves if tied to effective
resection for detected CA smoking cessation
program
34
788

Overview and
1
Epidemiology
recent:
Diagnosis and
2
Staging
5. Follow-up
4 CT Screening for detected
3. How and lesions 4. Is it cost-
•when?
Annual LD-CT until: effective?
cessation, or • Estimates of $80K/QALY
• Age 80, or gained
• Unwilling or too ill to • Cost-effectiveness
undergo curative improves if tied to effective
resection for detected CA smoking cessation
program
35
Topics to Address Incidental Solid Pulmonary Nodules found on

Overview and
Non-Screening CT: Fleischner Guidelines
1
Epidemiology
Nodule Size Low Risk Pt High Risk Pt
2 Diagnosis and
< 4 mm No follow-up needed Follow-up CT at 12
Staging
mo; if unchanged, no
3 further follow-up
Treatment Overview
> 4 – 6 mm Follow-up CT at 12 Initial follow-up CT at
mo; if unchanged, no 6-12 mo, then at 18-24
4 CT Screening further follow-up mo if no change
> 6 – 8 mm Initial follow-up CT at Initial follow-up CT at
6-12 mo, then at 18-24 3-16 mo, then at 9-12
mo if no change and 24 mo if no
change
> 8 mm Follow-up CT at Same as for low-risk
around 3, 9, and 24 patient
mo, dynamic contrast-
enhanced CT, PET,
and/or biopsy
MacMahon et al, Radiology 2005. 237(2): 395-400 36
789

Incidental Subsolid Pulmonary Nodules found on Non-Screening CT:
Topics to Address
Fleischner Guidelines
Nodule
Overview and
Size Management Recommendations Additional Remarks
2
Epidemiology
Solitary Pure GGNs
3 < 5CT
mmScreening No CT follow-up required Obtain contiguous 1 mm-thick sections
to confirm that nodule is truly a pure
GGN
4 Diagnosis and
> 5Staging
mm Initial follow-up CT at 3 mo to confirm persistence, then FDG-PET is of limited value, potentially
annual surveillance CT for a minimum of 3 yrs misleading, and not recommended.
5 Treatment
Solitary part-solid nodules
OverviewInitial follow-up CT at 3 mo to confirm persistence. If Consider PET-CT for part-solid nodules
persistent and solid component < 5 mm, then yearly > 10 mm.
surveillance CT for minimum of 3 yrs. If persistent and
B Localized Disease solid component > 5 mm, then biopsy or surgical resection
Multiple Subsolid nodules

Locally Advanced
Pure CGGNs < 5 mm
Disease Obtain follow-up CT at 2 and 4 years Consider alternate causes for multiple
GGNs < 5 mm
Pure C
GGNs > 5 mm DiseaseInitial follow-up CT at 3 months to confirm persistence and
Metastatic FDG-PET is of limited value, potentially
without a dominant then annual surveillance CT for a minimum of 3 yrs misleading, and not recommended.
nodule
Dominant nodule(s) with Initial follow-up CT at 3 mo to confirm persistence. If Consider lung-sparing surgery for
part-solid or solid persistent, biopsy or surgical resection is recommended, patients with dominant lesion(s)
component especially for lesions with > 5 mm solid component suspicious for lung cancer.
Naidich et al, Radiology 2013. 266(1): 304-17 37
NCCN Guidelines for Solid Nodule on

Initial screening LDCT
38
790
NCCN Guidelines for solid nodules found on follow-up

scans or annual LDCT
39
NCCN Guidelines for Part-Solid Nodules on

Initial screening LDCT
40
791
NCCN Guidelines for Part-Solid Nodules on

Follow-up or Annual LDCT
41
Summary Points
Topics to Address
5 Key Points for Boards:
Overview and
1
Epidemiology
2 Diagnosis and • Smoking cessation
Staging
• Importance of Stage
• Staging tests to get
4 CT Screening
• Paraneoplastic Syndromes
• Who Should be screened
42
792
Summary Points
Topics to Address
5 Key Points for Practice:
Overview and
1
Epidemiology
2 Diagnosis and • Common confusion in staging tests:
Staging • PET/CT doesn’t obviate need for
3 Treatment Overview dedicated brain imaging
• Brain imaging needs contrast
4 CT Screening
• Get enough tissue the first time
• Refer to oncology for evaluation and
consideration of therapy
• Start appropriate CT screening
43
References
• Gettinger S, Horn L, Jackman D, et al. J Clin Onco 2018

• NLST investigators, NEJM 2011. 365: 395-409
• Naidich et al, Radiology 2013. 266(1): 304-17
• Pelosof et al. Mayo Clin Proc 2010. 85(9): 838-854
• SEER Cancer Statistics Review, 1975-2013
44
793
Breast Cancer Update

“A buffet of breast cancer topics”

Dana-Farber Cancer Institute

• Disclosures:
– None related to this presentation
794
Breast Cancer
• Epidemiology and Genetics
• Screening
• Prevention
• Primary (non-metastatic) breast cancer
• Metastatic breast cancer
Cancer cases
Cancer deaths
Siegel et al, CA Cancer

J Clin 2018
795
Established breast cancer risk factors
• Age
• Overweight
• Alcohol use
• Physical activity
• Menopausal hormone use
• Late age at first birth (> 30 y.o.)
• Early age at menarche
• Late age at menopause
• BRCA1/2 and Family history
Established breast cancer risk factors
• Age
• Overweight
• Alcohol use
• Menopausal hormone use
• Late age at first birth (> 30 y.o.)
• Early age at menarche
• Late age at menopause
• BRCA1/2 and Family history
796
Modifiable breast cancer risk factors
Body mass index
797
Body mass index

• ↑↑ Postmenopausal breast cancer risk
– 20-30% higher with BMI > 30
– No increase in premenopausal breast ca
• Main source of estrogen after
menopause = peripheral conversion of
androgens into estrogens by aromatase
in adipose tissue
Body mass index and sex steroid levels

60
50
40
Estradiol
30
SHBG
20
10
0
<22.5 22.5-24.9 25-27.4 27.5-29.9 30+
Body Mass Index
798
Physical activity
Physical activity and breast cancer
• ↓↓ breast cancer risk with physical

activity
– Prevent weight gain and ↓ body fat
– ↓ estradiol, estrone, and free estradiol
and ↑ sex hormone binding globulin
– ↓ insulin levels
McTiernan, JAMA 2003; Canc Res 2004
799
Exercise and postmenopausal breast ca
1.25
P for trend =.03
=> No strong
association
1
with
moderate or
strenuous
activity
0.75
0.5
0 <=5 5.1-10 10.1-20 20.1-40 >40
met-hours of recreational physical activity McTiernan, JAMA 2003
Alcohol
800
Alcohol Intake and Breast Cancer

1.8
1.6
Relative Risk
1.4
1.2
0.8
0 5 10 15 20 25 30 35 40 45 50 55 60
Alcohol Intake (g/d)
Alcohol and estrogen levels

20
P for trend= 0.001
18 0g
1-4 g
16
5-15 g
15 -24 g
14
25+ g
12 P for trend= 0.03

10
8
Estrone Estradiol
Onland-Mouret 2006,
J Clin Endocrinol Metab
801
Family History/Genetics
Who should get BRCA1/2 testing?

Risk for BRCA1/2 mutation is greater if:
Age < 50 at diagnosis
Bilateral breast cancer
Male breast cancer
Triple negative breast cancer < age 60
=> Person with cancer should be tested first
802
BRCA 1 & 2
• ↑↑ risk of breast and ovarian cancer
– BRCA1 : 55-70% breast , 40-50% ovarian ca
– BRCA2 : 45-70% breast , 15-20% ovarian ca
– ↑↑ male breast cancer with BRCA2
– ↑ pancreatic and prostate cancer
– Explains 5-10% of breast cancers
• Multigene/expanded panel testing

– CDH1, ATM, p53, PALB2, CHK2, pTEN, NBN,
NF1, STK11, etc
– Clinical recommendations unclear
Screening mammography
To screen or not to screen?
803
Screening question
A 55 y.o. woman wants to know more about breast cancer
screening. You would advise her that:
1. Mammograms do not reduce mortality for women aged
40-49
2. MRI reduce breast cancer mortality more than

mammograms do
3. Virtually all DCIS found on mammography will turn into

invasive cancer if not removed
4. Mammographically detected lesions can be accurately

evaluated by core needle biopsy
Answer to screening question

A 55 y.o. woman wants to know more about breast cancer
screening. You would advise her that:
1. Mammograms DO reduce mortality for women aged 40-
49.
2. MRI has NOT been shown to reduce breast cancer

mortality
3. Only 15-40% of DCIS will become invasive.
4. Mammographically detected lesions can be accurately

evaluated by core needle biopsy
804
What we know about screening

Women aged 50-74 should get routine
screening mammogram
– Randomized controlled trials and meta-

analyses => 15-20% ↓↓ mortality
– Recommended screening interval 1-2 years
Mammography for women 40-49

Arguments AGAINST Arguments FOR
• Large RCT’s (100,000+) • Although individual trials
=>15-25% ↓↓ mortality but not significant, meta-
not statistically significant analyses => 7-23%
significant ↓↓ mortality
• Absolute benefits smaller • Relative benefits similar to
because breast cancer less women 50+
common < age 50
• Older studies done before • Older studies used outdated

modern treatments so not techniques, so older RCT’s
applicable to present underestimated benefit
• More false positives in • Breast cancer leading cause

women 40-40 of death age 40-49
805
False positive mammograms –

provider perspective
Definition varies: additional mammo to
biopsy
– ~5% of mammograms “false positive”

• 20-50% cumulative risk over 10 mammograms
– More common in women younger than 50
=> Problem from population and health care

cost perspective
Elmore, NEJM 2004
False-positive mammograms –
patient perspective
806
Overdiagnosis
Detection of disease that would not be
clinically apparent during life
– Overdiagnosis => Overtreatment!!
– Difficult to determine in individual
• Ideally estimated from control arm of RCT
• Estimated at 5-50%
– Can be DCIS or small invasive cancers
=> Focus on increasingly sensitive radiologic

techniques worsens problem
Ductal Carcinoma In-Situ (DCIS)

• Rare before screening mammography
– 60,290 cases in 2015
– ~20% of all mammographically detected lesions
• Uncertainty re: natural history of DCIS

– 14-40% estimated to recur if untreated
• Largest study = 80 women (Eusebi 1994)
– Cannot identify those that recur so treat all
• Mastectomy/lumpectomy +/- RT +/-tamoxifen
– Is it really cancer? Confusing nomenclature
• Cells look similar to invasive disease, but do not
invade basement membrane
• Cervical carcinoma in situ => CIN III
807
Lobular Carcinoma in Situ (LCIS)

• Often incidental finding
• ↑ risk of invasive carcinoma bilaterally

without predictable location - ~1%/yr
– Generally does not need surgical excision
• Management options
– observation
– tamoxifen
Breast density
Fatty breast Dense breast
808
Breast Density
• Breast density associated with ↑
breast cancer risk => unclear what
screening modality best
– 34 states have mandatory notification
– Ultrasound best for targeted areas, not
whole breast
– MRI high rate of false positives and not
necessarily covered by insurance
Breast tomosynthesis (3-D mammogram)

Breast stays in place and x-ray
machine moves to take multiple
images of breast
Park, 2007
Radiographics,
809
Breast MRI
• More sensitive – especially in young women
– Does not replace mammograms
– Many more false positives
– Impractical as screening tool
• Current indications for MRI from ACS
• Recommended for:
BRCA1/2, Li-Fraumeni (p53), Cowden’s (pTEN)
Radiation to chest between ages 10 and 30
Lifetime risk of >20-25%
• Insufficient evidence for or against:

Personal history of breast cancer
Dense breasts on mammography
= >Never been shown to reduce mortality!
Saslow CA J Clinic 2007
3D (tomo) vs 2D
• No randomized trial data
• Prospective comparison trials

– ↓↓ recall rate
– ↑↑ cancer detection rate
– Unclear if superior in dense breasts
• Already widely adopted

Friedenwald JAMA 2014; Ciatto Lancet Oncol 2013
810
Prevention
Prevention question
A healthy 45 y.o. premenopausal woman has
a mother who was diagnosed with breast
cancer at age 60 and passed away at 65 with
metastatic disease. She would like to
discuss breast cancer prevention. You
recommend that she consider:
A. Aromatase inhibitor
B. Raloxifene
C. Tamoxifen
D. All of the above depending upon side
effects
811
Breast cancer chemoprevention
• Age 60 or older
• Personal history of lobular carcinoma
in situ or atypical hyperplasia
• Age 35-59 with 5 yr predicted risk of
breast cancer >1.66% (Gail model)
http://www.cancer.gov/bcrisktool/
=>Both tamoxifen and raloxifene FDA

approved for chemoprevention
Randomized placebo controlled

prevention trials
• Tamoxifen, raloxifene, aromatase

inhibitors – 40-60% ↓↓ breast ca risk
– Only prevents ER+ breast cancer
– No survival benefit seen
– Raloxifene and AI’s only after menopause
Why isn’t breast cancer chemoprevention done
more?
Absolute risk of breast cancer low
Side effects
Screening available for breast cancer
812
Tamoxifen vs Raloxifene vs AI
Tamoxifen Raloxifene Aromatase

inhibitors
Hot Flashes Yes Yes No
Uterine effects Yes No No
Bone Density ↑↑ ↑↑ ↓↓
Thrombotic risk Yes Yes No
Premenopaual Yes No No
use
Breast Cancer Treatment
813
Treatment question
A 60 y.o. woman was diagnosed with a 1.5
cm, node negative, ER positive, HER2
negative breast cancer and had a
mastectomy. What will have the biggest
impact on 10 year overall survival?
1. Hormonal therapy
2. Radiation
3. Chemotherapy
4. Trastuzumab
Treatment of Non-metastatic breast cancer
• Surgery
• Radiation
• Systemic therapy
– Adjuvant chemotherapy
– Hormonal therapy
– HER2 based therapy
814
Breast cancer surgery - 2018
• Sentinel node biopsy routinely done

– Axillary dissection only for palpable
lymph nodes at diagnosis
• Bilateral mastectomy more common
– No impact on survival (except BRCA/12)
– More preoperative MRI => occult disease
– Celebrities having bilateral mastectomies
Rationale for radiation

More recurrences with Lumpectomy + RT or
lumpectomy alone mastectomy survival same
Fisher, N Engl J Med 2002
815
Primary Breast Cancer – Systemic Rx

• Patients with disease confined to breast and
axilla can be cured by surgery/RT alone, but
some may develop distant metastases
• Decision for adjuvant treatment based on:

– Tumor characteristics and likelihood of
developing metastases
– Overall life expectancy
Risk factors for developing metastatic

breast cancer
• Biology of tumor
– ER status
– HER status
• Tumor size and grade
• Axillary lymph node involvement
816
Breast Cancer is More than 1 Disease
1. ER positive + HER2 negative (Luminal A)

Hormonal therapy +/- chemo
2. ER positive + HER2 positive (Luminal B)

Hormonal therapy +/- trastuzumab + chemo
3. ER negative + HER2 positive (HER2 enriched)

Chemo + trastuzumab
4. Triple negative (Basaloid)

No targeted therapies
Gene expression profiling of tumor
Sorlie, PNAS, 2001
817
OncotypeDX®
• RT-PCR gene expression array of 21 genes
– To estimate recurrence risk - compare pattern to 668 women
treated with tamoxifen in 1980’s on NSABP B-14
• ER positive tumors
– Strongest data for node-negative and 1-3 positive lymph node
• Generally covered by insurance if medically indicated
Paik
NEJM
2004
Risk of distant recurrence by OncotypeDX®
• Low score is good!

• Node negative
– TailoRx: 5 yr Distant met 0.7%
– SEER: 5 yr Br Ca death 0.4%
– TransATAC: 9 yr Distant met
4%
• Node positive
– PlanB: 3 yrs DFS 98%
– SEER: 5 yr Br Ca death 1.0%
– TransATAC : 9 yr distant emt
17%
Paik ,,
New Engl
J Med
2004 Sparano, N Engl J Med 2015; Petkov NPJ
Breast Cancer 2016; Gluz, J Clin Oncol 2016
818
OncotypeDX® and chemotherapy benefit
Paik J Clin Oncol 2006

Paik, JCO 2006
TAILORx study
• Randomized 10,273 ER positive, node negative
with OncotypeDX 11-25 to hormonal rx +/- chemo
– Overall survival 93.9 vs 93.8% (median f/u 8 yrs)
⇒ ? Benefit to chemo for women < age 50

⇒ ? Node positive patients
Sparano N Engl J Med 2018
819
Adjuvant breast cancer chemotherapy
• Improves cure rate and overall

survival in appropriate populations
– Triple negative
– HER2 positive when given with
trastuzumab
– ER positive if poorly differentiated or
multiple involved lymph nodes
Flavors of Adjuvant Chemotherapy

• AC – doxorubicin (Adriamycin) +
cyclophosphamide
• AC + T – AC + Taxane (paclitaxel or docetaxel)
• TAC - docetaxel (Taxotere) + AC
• TC – doctaxel + cyclophosphamide
• CAF – AC + 5-FU
• CMF –cyclophosphamide +methotrexate + 5-FU
820
HER2/neu and Trastuzumab

• HER2/neu (c-erbB2) proto-oncogene - 185-kd
transmembrane factor receptor
– 20-25% of breast cancers overexpress HER2
– Immunohistochemistry (+3) or FISH assay (ratio > 2.0)
• Trastuzumab - monoclonal antibody to HER2

– Can cause congestive heart failure
– Not administered with an anthracycline
• HER2+ tumors have worse prognosis, if not

treated with trastuzumab
– With treatment, prognosis similar to HER2 negative
AC + paclitaxel +/- Trastuzumab
50% Reduction in Recurrence
Perez, NEJM, 2005
821
pertuzumab
Trastuzumab/
T-DM1
lapatinib
Hudis, NEJM, 2007
Tyrosine kinase needs homo or heterodimerization for activation
Adjuvant Hormonal therapy

• 1st targeted therapy!
– ↓↓ breast cancer mortality by 1/3
– ↓↓ contralateral breast cancer by 1/2
– 5 yrs for stage I, 10 yrs for node positive
• Tamoxifen
– Can be used for both pre and postmenopausal
– No data for raloxifene in adjuvant setting
• Aromatase inhibitors
– Preferred for postmenopaual women
• Ovarian suppression
– Considered for high risk
822
Metastatic Breast Cancer
Metastatic Breast Cancer Treatment Decision Tree
Luminal A Luminal B HER2 enriched Triple negative
ER +, HER2 - ER +, HER2 + ER -, HER2 + ER -, HER2 -
Hormonal Rx Hormonal Rx Chemo + pertuz

Trastuzumab + Trastuzumab
TDM1
Chemo +
Chemotherapy Chemo + ?novel agents
Trastuzumab Chemo +
Trastuzumab
or lapatinib
823
Metastatic breast cancer – Hormonal Rx
• 1st line except for visceral crisis

– AI +/- palbociclib for postmenopausal
– Tamoxifen + ovarian suppression for premenopausal
• Aromatase inhibitor
– Anastrozole, letrozole, exemestane
• Fulvestrant
– Pure estrogen receptor antagonist
Targeted therapy
• Palbociclib, ribociclib, and abemaciclib
– Oral Cyclin D Kinase (CDK) 4/6 inhibitor
• Everolimus Improve PFS,
– Oral mTOR inhibitor
but not OS,
add toxicity
• Immunotherapy
– PDL1/PD1 inhibitors in clinical trials
– Some activity in triple negative, but still
unclear how to maximize response
824
Chemotherapy for Metastatic Breast Cancer

• Doxorubicin • 5-fluorouracil
• Paclitaxel • Capecitabine
• Docetaxel • Vinorelbine
• Cyclophosphamide • Gemcitabine
• Methotrexate • Liposomal
• Eribulin doxorubicin
• Ixabepilone
Principles of metastatic breast cancer
• Chemotherapy => modest improvements in

overall survival
– Main goal of treatment = symptom control/
palliation
• Single agent chemotherapy less toxic than
doublet with similar efficacy
• Targeted therapy (ER and HER2) changed
natural history of metastatic breast cancer
– 20-30% survive > 5 years with metastatic disease
– Wide variation in survival for metastatic breast
cancer
825
Bisphopshonates for bone metastases
• 70-75% of women with metastatic breast

cancer will develop bone mets
• Complications of bone metastases
– Pain
– Hypercalcemia
– Pathologic fracture
– Cord/nerve compression
=> Routine bisphosphonate use for bone
metastases has significantly improved
quality of life for metastatic pts
Precision or personalized medicine
Breast cancer treatment already targets

several known pathways
– Examples: ER, HER2, mTOR, CDK4/6
826
Precision medicine
Promises Pitfalls
• Large amount of tumor- • Available target ≠ anti-tumor
specific personalized effect
genetic information – e.g. Hormonal therapy
ineffective for ER+ lung cancer
• Some mutations
already have FDA • Multiple mutations
approved treatments – Pathways have multiple
redundancies, which one is
rate limiting?
• Many mutations do not
currently have effective
targeted therapy
Breast Cancer Summary

• Epidemiology –Overweight and alcohol use increase
breast ca risk, physical activity decreases risk
• Prevention – Tamoxifen , raloxifene, and AI reduce

breast ca risk, but no effect on mortality
• Screening – Mammography leads to early diagnosis of

breast ca, but overdiagnosis a problem
• Primary, non-metastatic, breast cancer –Biologic

subtypes of breast cancer drive appropriate therapy
• Metastatic breast cancer – New biologic agents offer

hope for better survival
827
Thank You!
References
1. Manson JE et al. Menopausal hormone therapy and health outcomes
during the intervention and extended poststopping phases of the Women’s
Health Initiative randomized trials. JAMA 2013; 310: 11353-68.
2. Moyer VA et al. Medications to decrease the risk for breast cancer in

women: recommendations from the U.S. Preventive Services Task Force
recommendation statement. Ann Intern Med 2013; 159: 698-708
3. Perez EA and Spano JP. Current and emerging targeted therapies for
metastatic breast cancer. Cancer 2012; 118: 3014-25.
http://onlinelibrary.wiley.com/doi/10.1002/cncr.26356/full
4. World Cancer Research Fund International/American Institute for Cancer
Research Continuous Update Project Report: Diet, nutrition, physical
activity and breast cancer. 2017.
http://wcrf.org/breast-cancer-2017
828
Lymphoma
Multiple Myeloma
Ann S. LaCasce, MD, MMSc
Institute Physician
Disclosures for
Ann S. LaCasce, MD
No relevant conflicts of interest to declare
Research Support/P.I.

Employee

Consultant

Major Stockholder

Speakers Bureau

Honoraria
Membership in Advisory Seattle Genetics, BMS

Board
Presentation includes a No relevant conflicts of interest to declare
description of the following
off-label use of a drug or
medical device
829
Agenda
• Classification of lymphoid malignancies
• Presentation
• Work- up and staging
• Serious complications
• Non-Hodgkin lymphoma
– Diffuse large B-cell lymphoma
– Follicular lymphoma
• Hodgkin lymphoma
– Therapy
– Complications of therapy
• Multiple Myeloma
Classification of lymphoma
• Malignancies of normal lymphoid cells which reside
predominantly in lymphoid tissues (nodes, spleen, marrow)
• WHO classification based on morphology,
immunophenotype, cytogenetics and clinical factors
• Non-Hodgkin lymphoma
– B-cell
• Precursor vs mature
– T and NK-cell
• Precursor vs mature
• Hodgkin lymphoma
– Classical (nodular sclerosis, mixed cellularity, lymphocyte
rich, lymphocyte delpleted)
– Nodular lymphocyte predominant Hodgkin lymphoma
830
Lymphocyte maturation and lymphoma

subtypes
Jaffe. Blood. 2008
Presentation
• Lymphadenopathy (2/3)
• B symptoms - fever (>38), drenching night sweats,

weight loss > 10% in 6 months
• Extra nodal sites - GI tract, skin, bone
• Rare - kidney, bladder, adrenal, heart, lungs, breast,

testes, thyroid
831
Differential diagnosis of
lymphadenopathy
• Infection
• Medication (dilantin, sulfonamides, penicillin,

hydralazine)
• Rheumatologic (Lupus, RA, Still’s disease, Churg-

Strauss)
• Other (sarcoid, Kikuchi disease, amyloidosis, chronic

granulomatous disease, Castleman’s disease)
Biopsy
• Supraclavicular > cervical/axillary > inguinal
• Excisional biopsy when possible
• CT guided core needle
• Send for pathology, immunohistochemisty/flow

cytometry
832
Work-up
• CT scans chest/abdomen/pelvis
• PET scan
• Bone marrow biopsy
• CBC/diff
• BUN/creatinine
• LFTs
• Uric acid
• Electrolytes/calcium
• B2 microglobulin (indolent)
• LDH
• SPEP (CLL/SLL/waldenstrom’s/lymphoplasmacytoid)
Staging
A – asymptomatic; B- fever, night sweats, 10% wt loss
833
Serious complications
• Cord compression
• Pericardial disease/tamponade
• Hypercalcemia
• SVC/airway compromise
• Hyperviscosity
• Intestinal obstruction
• Ureteral obstruction
• Tumor lysis syndrome
• ITP/AIHA
Risk factors
Exposures: Immune dysfunction:
Occupational Autoimmune disease

Environmental Immunodeficiency
Prior RT, chemotherapy Immune suppression
Genetics:
Exposures:
Occupational
Environmental
Prior RT, chemotherapy
834
Infectious associations
EBV:
Burkitt lymphoma
DLBCL
NK-T cell lymphoma
Hodgkin lymphoma
Plasmablastic lymphoma
HTLV-1:
Adult T-cell leukemia/lymphoma Marginal zone lymphoma :
H pylori
HHV-8: B burgdorferi
Primary effusion lymphoma C jejuni
Large B cell lymphoma associated Hepatitis C
with Castlemans
Non-Hodgkin Lymphoma
835
Clinical behavior of non-Hodgkin

lymphoma
Indolent Aggressive Highly

aggressive
Survival Years Months Weeks
untreated
Response to Not curable Curable Curable
chemotherapy
Example Follicular Diffuse large Burkitt
lymphoma B-cell lymphoma
lymphoma
Indolent lymphomas
• B-cell lymphomas • T-cell lymphomas

- B-cell CLL/SLL - T-cell LGL leukemia
- lymphoplasmacytic - Mycosis fungoides
- Hairy cell leukemia
- Follicular (gr 1-2)
- Marginal zone
- Nodal
- Extranodal (MALT)
- Splenic
- Mantle cell*
- Plasma cell myeloma
836
Aggressive lymphomas
• Diffuse large B-cell lymphoma
• Follicular lymphoma (grade 3)
• Peripheral T-cell lymphoma
• Anaplastic large cell lymphoma
• NK/T cell lymphoma
Highly aggressive lymphomas
Burkitt Lymphoma
Precursor B lymphoblastic lymphoma
Precursor T lymphoblastic lymphoma
Adult T-cell lymphoma/leukemia
837
Diffuse large B-cell lymphoma
•Most common subtype NHL – 25%

• Median age 65
• Male predominance
Therapy for DLBCL

• 1970’s - CHOP (cyclophosphamide, doxorubicin,
vincristine, prednisone)
• 1980’s – 2nd and 3rd generation regimens (addition

of other active agents, modification of doses and
schedules) with improved CR rates and survivals in
pilot studies
838
Therapy for large cell lymphoma 1990’s
CHOP
Fisher et al. NEJM 1993
Rituximab – anti CD20 monoclonal antibody

NK- NK-
cell cell
NK-
CD20 CD20 cell
ADCC
CDC
B-cell
CD20
direct killing
839
Overall
CHOP vs RCHOP Survival patients with
in older
DLBCL
Coiffier, B. et al. N Engl J Med 2002;346:235-242
International Prognostic Index
Pre-Rituxan Era Rituxan Era

Risk 5 yr Risk 4 yr 4 yr
factors OS factors DFS OS
0-1 73% 0 94% 94%
2 51% 1-2 80% 79%

3 42%
3-5 53% 55%
4-5 26%
Risk factors: age > 60, stage III/IV, >1 EN site, PS, LDH
840
Gene expression profiling in DLBCL
Dunleavy and Wilson. Oncology. 2014 Lenz et al. NEJM. 2008
Follicular lymphoma
• Second most common NHL (20%)
• Median age at presentation - 60
• Male to Female – 1:1.7
841
Indolent B-cell lymphoma:

clinical management
Localized Advanced Advanced

Low tumor High tumor
burden burden
Involved Field Observation Therapy
RT
Observation vs early therapy

• Prospective randomized and retrospective studies
• No survival disadvantage
• 3 year median progression to treatment

• Grade 1: 48 months
• Grade 2: 16.5 months
• Same rate of histological transformation

• Is an active process, requires periodic monitoring
• Spontaneous remissions can occur
842
Indications for therapy
• Cytopenias secondary to BM infiltration

• Threatened end-organ function
• Symptoms attributable to disease
• Bulk at presentation
• Steady progression during a period of observation
>6 months
• Presentation with concurrent histologic
transformation
• Massive splenomegaly
Therapy follicular lymphoma

• Not curable with conventional therapy
• Rituximab +/- chemotherapy:
– Bendamustine
– CHOP
• Maintenance
• Novel agents (lenalidomide, idelalisib)
• Stem cell transplants may be curative in subset of
patients with relapsed/refractory disease
843
Hodgkin lymphoma
Epidemiology
Increased incidence in
industrialized countries
NS subtype associated
with high standard of
living
MC/LD in economically
disadvantaged
countries (EBV
associated)
844
Clinical presentation
• Fever including classic Pel-Ebstein

• Drenching night sweats (25%)
• Pruritus (10-15%)
• Abdominal/groin pain from retroperitoneal disease
• Alcohol induced pain
• Rarely jaundice
• Adenopathy – neck/mediastinum most common
Competing risks in Hodgkin lymphoma
Minimize
late effects
Maximize
cure
Armitage JO. N Engl J Med 2010
845
HL complications of therapy
• Fertility
– ABVD low risk of infertility
• Pulmonary Toxicity
– Bleomycin
– Mediastinal RT
• Cardiac toxicity
– Mediastinal RT – pericardial, valvular and CAD
– Doxorubicin - cardiomyopathy
• Second malignancies
– solid tumors from radiation - breast, lung, etc
Hodgkin lymphoma
• Chemotherapy: ABVD developed (adriamycin, bleomycin,
vinblastine, dacarbazine)
• RT: involved site radiotherapy
• Stage I and II Disease

– Chemotherapy with or without radiation
– Approximately 85%-90% cured with initial chemotherapy
• Stage III and IV Disease
– Chemotherapy always required
– Role of radiation therapy to sites of bulky disease
uncertain
– 75% cured with initial therapy depending on risk
846
Brentuximab Vedotin
ORR 75% (34% CR) with 96% disease control in relapsed HL
Monomethyl auristatin E (MMAE), microtubule-disrupting agent

Protease-cleavable linker
Anti-CD30 monoclonal antibody
CD-30
ADC binds to CD30
ADC-CD30 complex
is internalized and
traffics to lysosome
MMAE is released G2/M cell
MMAE disrupts cycle arrest
microtubule network
Apoptosis
BV+AVD associated with 5% improvement in PFS with

more toxicity
Connors et al.
NEJM 2017
847
Immunotherapy and Hodgkin lymphoma

Classical HL (cHL) is characterized pathologically by a
failed immune response.
Near uniform amplification at 9p24.1
leading to overexpression of PD-L1 and PD-L2
cHL has a genetically driven vulnerability to
PD-1 blockade.
PD-L1 expression in cHL
Chen et al. Clin Cancer Res. 2013

Ansell et al. N Engl J Med. 2014
On-going research in early HL

• Early stage disease:
– Given excellent prognosis, focus on preventing
long-term complications
– Less chemotherapy
– Less radiation
– Chemotherapy only
• Advanced stage disease:
– Incorporation of upfront brentuximab vedotin,
PD-1 inhibitors
• Risk adapted therapy using PET scans
848
Multiple Myeloma
Multiple Myeloma
High incidence in
African Americans,
Pacific Islanders
Etiology: MGUS,
irradiation,
exposures
849
Criteria for Diagnosis of MM
• Monoclonal plasma cells in bone marrow and/or presence of

biopsy-proven plasmacytoma
• Myeloma-related organ dysfunction (1 or more)

(C) serum calcium >10.5 mg/L or ULN
(R) Renal insufficiency (SCr >2 mg/dL)
(A) Anemia (hemoglobin <10 g/dL or 2g <normal)
(B) Lytic bone lesions or osteoporosis
Durie BGM et al. Hematol J.

2003;4:379
Initial diagnostic evaluation

Blood:
CBC with diff and platelet counts
BUN, SCr
Electrolytes, calcium, albumin
Quantitative immunoglobulins
Serum protein electrophoresis (SPEP) and immunofixation
β2-microglobulin
Serum free light chain
Urine:
24-hr protein electrophoresis (UPEP) and immunofixation
Other
Skeletal survey
Bone marrow aspirate and biopsy with cytogenetics
PET in selected situations
850
International Staging System

Stage Criteria Median Survival
Serum β2M <3.5 g/dL
I 62 mo
Serum albumin ≥3.5 g/dL
II Serum β2M <3.5 g/dL 44 mo
Serum albumin <3.5 g/dL
OR
Serum β2M 3.5 to <5.5 mg/dL*
III Serum β2M ≥5.5 g/dL 29 mo
Complications
• Bone disease/hypercalcemia
• Hyperviscosity-IgM, IgG3, IgA
• Recurrent infections
• Renal failure: hypercalcemia, myeloma kidney,
hyperuricemia, IV urography, dehydration, plasma
cell infiltration, pyelonephritis, amyloidosis
• Cardiac failure: amyloid, hyperviscosity, anemia
• Anemia: BM tumors, renal dysfunction,
myelosuppression, low endogenous erythropoietin
• Neuropathy: sensory ±motor, amyloid, anti-myelin
Ab
851
MM initial therapy
Non-transplant: Transplant:
• dexamethasone/bortezomib/ • 3 drug combinations*:
cyclophosphamide – dexamethasone/
• dexamethasone/bortezomib/ bortezomib
lenalidomide Plus:
• dexamethasone/ – Lenalidomide or
lenalidomide – cyclophosphamide or
– doxorubicin
Bisphosphonates for bony disease
Stem cell transplantation
• Autologous transplant:
– Survival benefit compared with standard therapy
• Maintenance with lenalidomide improves outcome

but increased secondary malignancies
• Myeloablative allo-transplant rarely performed due

to treatment related mortality
852
Targeting the hallmarks
Hanahan and Weinberg Cell 2011
Summary
Non-Hodgkin lymphoma:
– Often presents with lymphadenopathy but any
organ may be involved
– Excisional or core biopsy to determine subtype
– Staging with CT +/- PET and bone marrow biopsy
– Aggressive lymphoma is curable in > half of
patients with combination chemotherapy
– Indolent lymphoma is not curable with standard
chemotherapy, but patients may have long
remissions and survival
853
Hodgkin lymphoma:
– Often presents in neck and mediastinum
– High cure rates
– Early stage disease treated with combined
modality therapy, advanced disease treated with
chemotherapy
– Significant long term toxicities of therapy
Multiple myeloma:
– Diagnosis requires malignant plasma cells in
marrow or plasmacytoma + CRAB criteria
– Initial therapy includes IMIDS/proteasome
inhibitors/steroids with upfront consolidation
with ASCT
Question #1
26 year old college student presents with cough, night
sweats and 20 lb weight loss. On exam she has bilateral
cervical and left supraclavicular lymphadenopathy.
Chest CT scan confirms a 4 cm left supraclavicular node
and a large mediastinal mass.
a. Follicular lymphoma
b. T-cell LGL
c. Hodgkin lymphoma
d. Small lymphocytic lymphoma
e. Burkitt’s lymphoma
854
Question #1
a. Follicular lymphoma commonly presents in older
adults with asymptomatic lymphadenopathy.
b. T-cell LGL presents with cytopenias and
splenomegaly.
c. Hodgkin lymphoma affects young adults and
presents with adenopathy in the neck and chest. B
symptoms are common.
d. Small lymphocytic lymphoma also presents with
asymptomatic adenopathy with frequent spleomegaly
in older adults.
e. Burkitt’s lymphoma typically presents with rapidly
progressive adenopathy and high LDH.
Question #2
Which of the following are indications for therapy in
the indolent lymphomas?
a. thrombocytopenia
b. bulky lymphadenopathy
c. weight loss
d. transformation to diffuse large B-cell lymphoma
e. all of the above
855
Question #2
All of the above are indications for initiating therapy
in follicular lymphoma. Early therapy in the
absence of symptoms has not been shown to
prolong overall survival.
References
• Swerdlow et al. The 2016 revision of the World Health

Organization classification of lymphoid neoplasms.
Blood 2016.
• NCCN Clinical Practice Guidelines in Oncology.

www.nccn.org
• Evans LS, Hancock BW. Non-Hodgkin lymphoma. Lancet.

2003 362:139-46.
856
Disclosures for
Ann S. LaCasce, MD

Employee

Consultant

Major Stockholder

Speakers Bureau

Honoraria

Board
medical device
857
GI Cancers for the Boards

Jeffrey Meyerhardt, MD, MPH
Clinical Director, Gastrointestinal Cancer Center
Deputy Clinical Research Officer

Disclosures
• Advisory board: Ignyta

• Consultant: Chugai Pharmaceutical
858
Common GI Malignancies:
Esophageal Cancer
Gastric Cancer
Pancreatic Cancer
Colorectal Cancer
Hepatocellular Carcinoma
Less Common GI Malignancies:

Biliary Cancer/Gallbladder
Pancreatic Islet Cell/Carcinoid Tumors
Anal Cancer
Small bowel
Total Annual Cases in US 310,440
Total Deaths in US 157,700
CA Cancer J Clin 2018;68:7‐30
Annual Incidence and Mortality of

Gastrointestinal Malignancies
United States (2017) Worldwide (2012)
Siegel et al CA Cancer J Clin 2017 Globocan2012 WHO
Cancer New Cases Deaths New Cases Death

Esophageal 17,290 15,850 455,784 400,169
Gastric 26,240 10,800 951,594 723,073
Pancreas 55,440 44,30 337,872 330,391
Colorectal 140,250 50,630 1,360,602 693,933
Liver 42,220 30,200 782,451 745,533
Breast 268,670 41,400 1,671,149 521,907
Lung 253,290 158,770 1,824,701 1,589,925
859
Esophageal Cancer
Esophageal Cancer: Risk Factors

Risk Factor Squamous-Cell Carcinoma Adenocarcinoma
Tobacco use +++ ++
Alcohol use +++ —
Barrett’s esophagus — ++++
Weekly reflux symptoms — +++
Obesity — ++
Poverty ++ —
Achalasia +++ —
Caustic injury to the esophagus ++++ —
Nonepidermolytic palmoplantar keratoderma
(tylosis) ++++ —
Plummer–Vinson syndrome ++++ —
History of head and neck cancer ++++ —
History of breast cancer treated with XRT +++ +++
Adapted from Enzinger and Mayer, N Engl J Med. 2003 Dec 4;349(23):2241-52
860
* Per 100,000 persons
5
*
4.5
4
3.5
3
2.5 ADC/Esophagus
2 SCC
1.5
1
0.5
0
1972 80 88 1996
Per Capita Cigarette Consumption, Major Smoking & Health Events,

and Incidence of Esophageal Cancer - United States
Temporal Trends in Incidence Rates and Survival Rates for Esophageal

Adenocarcinoma.
Rustgi AK, El-Serag HB. N Engl J Med 2014;371:2499-2509.
861
Neoplastic Progression of Barrett’s Esophagus
GERD 0.005%/yr
1:7 Americans 0.5%/yr
1%/yr
4% 5%
Squamous 10% /yr Low- ? High- /yr 85+%
epithelium
Metaplasia Grade Grade ADC METS
Dysplasia Dysplasia
Early Genetic Events: c-erbB2

Oxidative stress
Inflammation
17pLOH p53; 9pLOH p16
cyclin D1 E-cadherin-
G1&G2 catenin
2nd Tier Genetic Events:
COX-2 p53 mutation; p16 mutation/methylation
BCL-2 EGF(R), telomerase RNA
Late Genetic Events:
4 N (G2) aneuploidy of 5q/13q
and LOH of 5q/13q(Rb)/18q
Local Esophageal Cancer:

Treatment Options
• Surgery alone
– Resectability rates 54-69%
– Perioperative mortality 4-10%
– Perioperative complications (cardiac,
infection, anastomotic leaks) 26-41%
– 2 year survival 35-42%

– 5 year survival 15-24%
862
Local Esophageal Cancer:

Treatment Options
• At least 3 randomized trials have shown no
benefit to postoperative radiation or
postoperative chemotherapy
(Fok Surgery 1997, Tenier Surg Gyn Onc 1991, Ando J Thor Cardiovasc Surg 1997)
• Not standard practice in US – postoperative

therapy reserved for R1 resections
• 2 neoadjuvant chemotherapy trials with

conflicting results
(Kelson NEJM 1998; MRC Lancet 2002)
Radiation Therapy vs. Chemotherapy + Radiation

Therapy for Localized SCC or ADC of the Esophagus
Herskovic. N Engl J Med 1992, Al-Sarraf. J Clin Oncol 1997
863
Preoperative Chemoradiation followed by Surgery

versus Surgery Alone in Esophageal Cancer
Sjoquist Lancet
Oncology. 2011.
12 (7), p 681–692
Esophageal Cancer:
Treatment Algorithm
Early stage disease (T1-2, N0) Surgery
Preoperative
Locally advanced disease chemoradiation
regimen followed
(T3, N0-1)
by surgery
Palliation of local
Metastatic Disease symptoms
Palliative chemo if
appropriate
864
Esophageal Cancer: Survival

Stage Tumor Node Mets 5 year
survival
0 Tis N0 M0 > 95%
1 T1 N0 M0 50-80%
IIA T2-3 N0 M0 30-40%
III T3 N1 M0 10-25%
T4 Any N M0
IVA Any T Any N M1a <5%
IVB Any T Any N M1b < 1%
Adapted from Enzinger and Mayer, N Engl J Med. 2003 Dec 4;349(23):2241-52
Chemotherapy for Metastatic Esophageal

and Gastric Cancer
• No standard therapy for metastatic

disease – typically platinum based
combination regimen
• Expectations of current treatment options
– Response rates 30-60%
– Relief of dysphagia (without XRT) up to 80%
– Median overall survival 7-10 months
865
Gastric Cancer
Incidence of Gastric Cancer

(Cases per 100,000 population)
35
30
25
20
Men
15 Women
10
5
0
1930 1990
866
Risk Factors for Gastric Adenocarcinoma

Nutritional
Low fat or protein consumption
Salted meat or fish
High nitrate consumption
Environmental
Poor food preparation (smoked)
Lack of refrigeration
Poor drinking water (well water)
Occupation (rubber, coal workers)
Smoking (1.6x)
Low social class
Medical
Prior gastric surgery
Helicobacter pylori infection (2x)
Gastric atrophy and gastritis
Hereditary
E cadherin mutation families
Gastric Cancer Survival by Stage

National Cancer Data Base 1985-1996
1
0.9
0.8 IA
0.7
Survival (%)
0.6 IB
0.5
0.4 II
0.3
IIIA
0.2
IIIB
0.1
IV
0
0 1 2 3 4 5
Time, years
867
Proportion of H.pylori-Positive and H.pylori-Negative Patients who

Remained Free of Gastric Cancer
Uemura et al, N Engl J Med,345,2001; 345: 784-789
Chemoradiotherapy After Surgery Compared with Surgery

Alone for Adenocarcinoma of the Stomach or
Gastroesophageal Junction
MacDonald et al, N Engl J Med, 2001;345: 784-9
868
CALGB 80101: Overall Survival
O ve ra ll S u rviv al b y Arm
1.0
ECF
0.8
5 -F U
Proportion Surviving
0.6
0.4
0.2
P, log rank = 0.80

0.0
0 1 2 3 4 5 6 7
Y e a rs fro m S tu d y E n try
Fuchs et al J Clin Oncol 29(suppl):256s, abstr 4003.
MAGIC: Peri-operative Chemotherapy

R A
A ECF Surgery only ECF
Deemed surgically
N
resectable gastric
D
cancer
O
N=503 M
I Surgery only
Z B
E
36% v 23% at
5 years
Notes: 88% of patients randomized to chemotherapy arm had surgery but only 42% of
patients completed all protocol treatment
Cunningham N Engl J Med. 2006 Jul 6;355(1):11-20
869
Chemotherapy for Metastatic Esophageal

and Gastric Cancer
• No standard therapy for metastatic
disease – typically platinum based
combination regimen
• Expectations of current treatment options
– Response rates 30-60%
– Relief of dysphagia (without XRT) up to 80%
– Median overall survival 7-10 months
Trastuzumab + Chemotherapy Versus

Chemotherapy only for HER2-positive
Advanced Gastric or GEJ Junction cancer
Overall Survival Progression-free Survival
Bang et al The Lancet, Volume 376, Issue 9742, 2010, 687 - 697
870
Ramucirumab in Previously Treated

Advanced Gastric or GEJ adenocarcinoma
Overall Survival Progression-Free Survival
Ramucirumab Placebo
Median Overall Survival 5.2 months 3.8 months
Median Progression Free Survival 2.1 months 1.3 months
Fuchs et al. The Lancet, Volume 383, Issue 9911, 2014, 31 - 39
Checkpoint Inhibitors in Gastric Cancer
Fuchs et al. JAMA Oncol. 2018;4(5):e180013. doi:10.1001/jamaoncol.2018.0013
871
Take Home Points of Gastric Cancer
• Gastric cancer decreasing incidence in

past few decades
• ~50% of patients diagnosed will pass
away from gastric cancer
• Standard of care for localized disease is
surgery and often chemoRT
postoperatively
• Metastatic disease median survival < 1 yr
Board Question #1
Your patient is a 72 year old carpenter who presents with several
month history of difficulty swallowing, primarily just certain
foods. He has lost approximately 10 pounds in the past
month, but he claims that he was trying to diet. You order an
EGD and there is a mass in his midesophagus. Biopsies
demonstrate squamous cell carcinoma. He consults a
thoracic surgeon who performs an esophagectomy and final
pathology reveals invasion through the muscle to subserosa
(T3) and 2 positive lymph nodes. Margins were all negative.
You now recommend:
A. Adjuvant chemotherapy
B. Adjuvant radiation
C. Combined chemotherapy and radiation
D. Observation and intermittent surveillance
872
Board Question #1
A. Adjuvant chemotherapy
B. Adjuvant radiation
C. Combined chemotherapy and radiation
D. Observation and intermittent surveillance
Since patient has esophageal cancer, no role for adjuvant therapy

based on multiple trials of either modality
If tumor was GE junction, adjuvant therapy would be reasonable
to offer
Pancreas Cancer
873
Pancreatic Cancer: Survival

Data from National Cancer Database 1985-1990
Relative %
at each time
point
Niederhuber et al. (2006) Cancer. 76 (9): 1671-7
Risk Factors for Pancreatic

Adenocarcinoma
• Hereditary
– Hereditary chronic pancreatitis
– Peutz-Jeghers syndrome
– Ataxia-telangiectasia
• Chronic pancreatitis – mixed data
• Diabetes (relative risk 2)
• Smoking
• Obesity
• History of partial gastrectomy
874
Pancreatic Cancer: Treatments
• Local disease: Surgery + adjuvant therapy
• Borderline resectable: Neoadjuvant

chemotherapy, reassess, +/- radiation,
reassess, surgery if resectable
• Locally advanced: Chemotherapy +/-

chemoradiation
• Metastatic: Chemotherapy
Pancreatic Cancer: Local Disease
• Curative-intent resection possible in only 15%

of all patients with pancreatic cancer
• 15% of resected patients survive 5 years
• Adjuvant Therapy trials
– ChemoRT after surgery beneficial in 1 trial of 43
patients in US; not beneficial in 2 European trials
– Chemotherapy beneficial in 2 trials in European
– Nonetheless improvements are modest
Yang et al. CA Cancer J Clin. 2005 55(6):352-67.
875
Pancreatic Cancer: Borderline Resectable
P R R R
E F
R E E E
Patient with N m GEM O
E- S 50.4g S S
BLR PDAC R FOLFIRINOX L
RE T EBRT T SURGERY T
(Intergroup O 2 L
GI A + CAPE A A
Definition) ST
L 2 months months O
G G G
ER L W
E E E
• 27% RECIST response
• R0 operations possible in 64% patients
• 33% resections <5% viable cells, 13% pCR
• median OS of all enrolled patients: 22 months
Katz et al JAMA Surg. 2016 Aug 17; 151(8): e161137.
Pancreatic Cancer: Metastatic Disease
Response rate 5% 0%
Burris HA, et al J Clin Oncol 1997;15:2403-2413.
876
Metastatic Pancreatic Cancer: FOLFIRINOX

R
A
Gemcitabine
N
D
O
M FOLFIRINOX
I
(5-FU, LV, Irinotecan, Oxaliplatin)
Z N = 842
E
Response Median Median 1 year OS Grade 3/4 Grade 3/4

Rate PFS OS WBC Emesis
Gemcitabine 9% 3.3 m 6.8 m 21 % 19 % 5%
FOLFIRINOX 33 % 6.4 m 11.1 m 48 % 46 % 15 %
P value 0.0001 <0.0001 <0.0001 <0.0001 0.0001 0.002

Conroy et N Engl J Med. 2011 May 12;364(19):1817-25.
Metastatic Pancreatic Cancer:

Gemcitabine + nab Paclitaxel
R
A
Gemcitabine
N
D
O
M
I
Gem-nab Paclitaxel
Z N = 861
E
Response Median Median 1 year Grade 3/4 Grade 3/4

Rate PFS OS OS WBC Neuropathy
Gemcitabine 7% 3.7 m 6.7 m 22 % 27 % 1%
Gemcitabine- 23 % 5.5 m 8.5 m 35 % 38% 17 %

nab Paclitaxel
P value <0.0001 <0.0001 <0.0001 0.0002 0.001 0.001
Von Hoff N Engl J Med 2013 Oct 31;369(18):1691-703
877
Take Home Points of Pancreatic Cancer
• Only 15% of patients diagnosed are

eligible for surgery and only 15% of those
patients will be cured (cure rate 2-3%)
• Locally advanced disease chemoRT
• Metastatic disease treated with
chemotherapy and median survival 6-11
months – some increased choices but
more toxic
• Yet to find “targeted” therapy options
Colorectal Cancer
878
Risk Factors for Developing Colorectal Cancer
Decrease Risk Increase Risk Uncertain Impact

Screening Family history Statins
Exercise IBD Fiber
Vitamin D Diabetes Glycemic index
Aspirin / NSAIDs Obesity Fruits/Vegetables
Post-menopausal Red meat Folic Acid
estrogen Western diet
Calcium Alcohol
Smoking
Colorectal Cancer: Risk Factors

• Hereditary
– Familial syndromes (~5% of CRC)
• Familial adenomatous polyposis
• Hereditary nonpolyposis cancer syndrome
– Family history (or personal history) (~10-15%)

• ~ 2 x risk of developing CRC
• Depending on age of relative at dx and # of relatives
879
Colorectal Cancer: Screening

• Why screen?
Winawer, S. J. et al. N Engl J Med 1993;329:1977-1981

• American Cancer Society recommendations for
average risk patients (updated 2008)
Tests that find polyps and cancer

• Flexible sigmoidoscopy every 5 years *
• Colonoscopy every 10 years
• Double contrast barium enema every 5 years *
• CT colonography (virtual colonoscopy) every 5 years *
Tests that mainly find cancer
• Fecal occult blood test (FOBT) every year *
• Fecal immunochemical test (FIT) every year *
• Stool DNA test (sDNA), interval uncertain *
*Colonoscopy should be done if test results are positive.

Levin et al CA Cancer J Clin 2008; 58:130-160
880

• Screening still not universal enough
– Any screening 54% in 2002 65% in 2010
– 23 million Americans age 50-75 never screened
Centers for Disease Control and Prevention (CDC). Behavioral Risk Factor Surveillance System Survey Data. Atlanta,
Georgia: U.S. Department of Health and Human Services, Centers for Disease Control and Prevention, 2010.
Colorectal Cancer: AJCC 8

Primary tumor (T)
Tx Primary tumor cannot be assessed

Tis Carcinoma in situ
T1 Tumor invades submucosa
T2 Tumor invades muscularis propia
T3 Tumor invades through the muscularis propia into the subserosa
T4 Tumor directly invades other organs or structures, and/or perforates
Nodal status (N)

N1a = 1 node
N1b = 2-3 nodes
Nx Regional lymph nodes cannot be assessed N1c = tumor deposits in
N0 No regional lymph node metastases subserosa or mesentery
N1 Metastases in 1 to 3 regional lymph nodes
N2 Metastases in 4 or more regional lymph nodes
N2a = 4-6 nodes
N2b = 7+ nodes
Distance Metastases (M)
Mx Distant metastases cannot assessed M1a = single organ

M0 No distant metastases detected M1b = more than 1 organ
M1 Presence of distant metastases M1c = peritoneal mets (with or without
other organs)
881
Colorectal Cancer: Staging
Stage 5 year survival

Stage I > 90%
Stage II 70-85%
Stage III 30-70%
Stage IV 8-10 %
Colorectal Cancer:
Standard Therapy Algorithm
Stage Colon Rectal
I (T1-T2, N0, M0) Surgery only Surgery only
Surgery +/- Chemoradiation
II (T3-T4, N0, M0)
Chemotherapy Surgery
Chemotherapy
OR
Surgery
III (Tany, N+, M0) Surgery
Chemotherapy
Chemoradiation &
Chemotherapy
Chemotherapy +/- Chemotherapy +/-
IV (Tany, Nany, M1)
Surgery Surgery
National Comprehensive Cancer Network. NCCN Clinical Practice

Guidelines in Oncology: Colon Cancer V3.2012. Available at:
www.nccn.org. Accessed April 12, 2012.
882
Colorectal Cancer: Surgery

• Surgical resection cures a large number of patients
with early disease
– 80% of patients present without detectable mets
• Colon cancer
– At least 12-14 nodes should be included in sample
– Increasing evidence for equivalent outcomes with
laparoscopic colectomy
• Rectal cancer
– Low anterior resection – maintains sphincter
– Abdominoperineal resection – low tumors permanent
colostomy
Colorectal Cancer: Radiation

• Why beneficial in rectal and not colon?
– Related to risk of local recurrence (radiation is a

local treatment)
• In colon cancer – <2% risk of local recurrence

• In rectal cancer – up to 30% local recurrence
rate with surgery alone
883
Colorectal Cancer: Chemotherapy

• Stage III colon cancer
– Adjuvant 5-FU/LV reduces the risk of disease
recurrence by 40% and overall mortality by 33%.
– 1990 consensus statement from NCI committee
recommended adjuvant 5-FU and leucovorin for
stage III patients
– 3 trials demonstrated improvements with adding
oxaliplatin to fluoropyrimidine
• Downside: Neurotoxicity
• Ongoing studies testing 3 v 6 months therapy
Sun W, Haller DG. Seminars in Oncology. 2005;32(1):95-102.
Andre T, et al. N Engl J Med 2004;350(23):2343-2351.

• 5 yr overall survival for stage III colon cancer
surgery surgery w/chemo
Stage IIIA 52% 71%

Stage IIIB 37% 51%
Stage IIIC 21% 32% using AJCC 6
Surgery only Surgery + Adjuvant 5-FU

Greene FL, et al. Ann Surg. 2002;236:416
884
FOLFOX Adjuvant Therapy –

Duration Based on Risk Groups
T1-3 N1 (58.7%) T4 or N2 (41.3%)
100 100
Duration Duration
90 3 Months 3 Months
90
6 Months 6 Months
80 80
70 70
Percent Without Event
Percent Without Event

60 60
3-yr DFS% (95%
Duration HR (95% CI)
50 CI) 50
Duration 3-yr DFS% (95% CI) HR (95% CI)
40 1.01 (0.90 – 40
3m 83.1 (81.8 – 84.4)
1.12) 3m 62.7 (60.8 – 64.6) 1.12 (1.03 – 1.23)
30 30
20 6m 83.3 (82.1 – 84.6) Ref 20 6m 64.4 (62.6 – 66.4) Ref

10 10
3-yr DFS diff. = -0.2%, 95% CI, (-1.9 to 1.5%) 3-yr DFS diff. = -1.7%, 95% CI, (-4.3 to 0.9%)
0
0
0 1 2 3 4 5 6
0 1 2 3 4 5 6
Years from Randomization

Years from Randomization
3744 3313 2796 1934 1064 527 211
2634 2099 1640 1044 531 292 107
3727 3336 2788 1949 1081 566 221
2622 2151 1655 1094 586 301 110
Interaction p-value = 0.11
Shi et al N Engl J Med 2018; 378:1177-1188

• Stage II colon cancer
– No randomized trials with enough stage II patients to

draw definitive recommendations.
– 2 meta-analyses give conflicting results
– ASCO Consensus panel concluded that based on
available evidence, benefit would not exceed 5% - a
benefit between 0-5% possible (JCO 2004)
– High risk patients may be appropriate – T4 lesions,
obstruction or perforation, few lymph nodes in sample.
– Various molecular marker panels are prognostic but not
predictive
885

• Metastatic disease
– In general, not curable
• Patients with isolated metastases that can be
surgically resected – up to 30% long term
survival.
– Chemotherapy known to prolong life and
improves symptoms
• Median survival without therapy ~ 6 months

1998
• FDA approved chemotherapy option for
metastatic colorectal cancer
5-FU
Median survival with therapy 10-12 months
886
Colorectal Cancer: Chemotherapy options for

Metastatic Colorectal Cancer 2018
– First line – Previously treated with irinotecan
• 5-FU +/- bevacizumab • Cetuximab (RAS wildtype)
• Capecitabine • Cetuximab + Irinotecan (RAS
• FOLFIRI or IFL +/- wildtype)
bevacizumab or cetuximab • Panitumumab (RAS wildtype)
(RAS wildtype) or
panitumumab (RAS wildtype) – All prior therapies
• FOLFOX +/- bevacizumab or • Regorafenib
cetuximab (RAS wildtype) or
panitumumab (RAS wildtype) • TAS102
– Second-line – MSI-H tumors

• Irinotecan (5-FU progression) • Pembrolizumab
• FOLFOX (Irinotecan • Nivolumab
progression)
• FOLFIRI with ziv-aflibercept – BRAF mutated
• FOLFIRI with ramucirumab • Vemurafenib/Irinotecan
/Cetuximab
Le DT et al. N Engl J Med 2015;372:2509-2520.
887
Colorectal Cancer: Progress
Prior to any active chemotherapy 6 months
Fluoropyrimidine only 10-12 months
Fluoropyrimidine + 1 other active cytotoxic 14-16 months

chemotherapy (irinotecan or oxaliplatin)
Fluoropyrimidine + irinotecan + oxaliplatin 20-22

(at some point in course of treatment) months
All three cytotoxic chemotherapy during

course of treatment with exposure
to VEGF and EGFR inhibitors 2+ years
Adapted from Meyerhardt and Mayer, NEJM 2005
Take Home Points of Colorectal Cancer

• Disease common – some risk factors modifiable
• 80% patients without detectable mets at diagnosis
• Treatment depends on stage of disease – surgery is

considered in all patients
• Stage III colon cancer adjuvant chemo

Stage II and III rectal neoadj chemoRT or post op
chemoRT and chemo adjuvant either way
Stage II colon ? Chemo adjuvant?
• Metastatic disease treatment mainly palliative but

median survival > 2 years
888
Board Question #2
Your patient is a 56 year old school teacher who presented with
about 2 months of intermittent blood in the toilet bowl with
bowel movements. A colonoscopy is performed which
demonstrates a mass in the mid sigmoid and biopsy confirm
adenocarcinoma. He undergoes laparoscopic hemicolectomy
and final pathology reveals a 3 cm, moderately differentiated
adenocarcinoma through the muscle layer into the serosa
with 2 of 9 lymph nodes positive. The next step would be:
A. Re-operate for more complete lymph node dissection
B. Referral to medical oncologist for consideration of
chemotherapy
C. Followup colonoscopy in one year
D. Referral to radiation oncologist for postoperative radiation
Board Question #2
A. Re-operate for more complete lymph node dissection
B. Referral to medical oncologist for consideration of
chemotherapy
C. Followup colonoscopy in one year
D. Referral to radiation oncologist for postoperative radiation
• Patient has stage III colon cancer

• Lymph node sampling is not ideal (12 is preferred #) – can
request pathologist to further search
• Patient should be considered / offered chemotherapy
• Colonoscopy in 1 yr is appropriate surveillance but not next
step
• Radiation reserved for rectal and rarely colon (T4)
889
Selected References
• Rustgi A and El-Serag. Esophageal Cancer. N Engl J Med 2014;371:2499-509.
• Cohen and Leichman. Controversies in the Treatment of Local and Locally

Advanced Gastric and Esophageal Cancers. Journal of Clinical Oncology 33,
no. 16 (June 2015) 1754-1759.
• Shah and Kelsen. Gastric cancer: A primer on the epidemiology and biology of the
disease and an overview of the medical management of advanced disease. J Natl
Compr Canc Netw. 2010; 8: 437-47.
• Heestand, Murphy and Lowy. Approach to Patients With Pancreatic Cancer

Without Detectable Metastases. Journal of Clinical Oncology 33, no. 16 (June
2015) 1770-1778.
• Ko. Progress in the Treatment of Metastatic Pancreatic Cancer and the Search for
Next Opportunities. Journal of Clinical Oncology 33, no. 16 (June 2015) 1779-
1786.
• Fakih. Metastatic Colorectal Cancer: Current State and Future Directions. Journal
of Clinical Oncology 33, no. 16 (June 2015) 1809-1824.
Disclosures
• Advisory board: Ignyta

• Consultant: Chugai Pharmaceutical
890
Take Home Points

Institute Physician
Disclosures for
Ann S. LaCasce, MD

Employee

Consultant

Major Stockholder

Speakers Bureau

Honoraria

Board
medical device
891
Management of SVC syndrome
• Tissue diagnosis critical for Rx decisions

– Prognosis depends on underlying disease
• Treatment plan depends on tumor histology
– Chemo-insensitive cancers (e.g. NSCLS) treated
with upfront XRT
– Chemo-sensitive tumors (e.g. small cell,
lymphoma) treated with upfront chemo
– Stent placement not usually done 1st line in
cancers that may respond to chemo/RT
=> Rarely fatal
Spinal Cord Compression
• Initiate treatment earlier to prevent neurologic deficits

– Once neurologic deficits occur, often irreversible
• Usually from epidural compression from vertebral body
metastases
– Most common tumors: lung, breast, prostate,
myeloma, lymphoma
– Thoracic spine most common location
– Intramedullary metastases less common
892
Treatment
• Corticosteroids to decrease edema
– Only short-term benefit
– Caution if diagnosis unknown
– Typically 10 mg load then 4 mg q 6hrs
• Radiation 1st line treatment for most
• Upfront surgery reserved for:
– Unknown diagnosis
– Progression during or after radiation
– Spinal instability
– One RCT showed improved function with immediate surgery
for less radiosensitive tumors with single area of
compression
F+N likely organisms
• Gram-positive infections (60-75%)

– Staph epidermidis
– Streptococcus
– Enterococcus faecalis/faecium
• Gram-negative rods (more likely to cause death)
– Pseudomonas aeruginosa
– E. coli
– Klebsiella pneumonia
893
Treatment
Empiric antibiotics: broad spectrum with gram positive and
gram negative coverage (especially Pseudomonas)
• 3rd generation cephalosporin (ceftaz or cefepime)
– May depend upon local hospital bacteriology
• Alternatives:
– Imipenem cilastatin or meropenem
• Higher rate C.diff colitis than cephalospoin
– Beta-lactam allergy: Quinolone with gram pos
• <1% cross-reactivity between 3rd generation ceph
and PCN/1st gen cephalosporin
Hypercalcemia
• Tumor secretion of PTHrP
• Local osteolytic hypercalcemia
• 1,25 (OH)2D-production by tumor (lymphoma)
• Ectopic PTH (very rare)
• Increase urinary calcium excretion
– Normal saline to volume replete then add loop
diuretic (immediate effect)
• Inhibit osteoclastic bone resorption
– Bisphosphonates (2-4 days for max effect)
– Calcitonin (immediate; tachyphylaxis in 2-3d)
894
Tumor lysis syndrome

• Large tumor burden with rapid cell kill
• More common with aggressive leukemia and lymphomas, e.g
Burkitt’s
• Occurs during first cycle
• Fatal complications include arrhythmias and renal failure
• High uric acid does not equal TLS
• Prophylaxis/prevention key
– Allopurinol and aggressive hydration to maintain urine output
• Treatment
– Rasburicase - recombinant urate oxidase
• Converts uric acid to allantoin which is more soluble in
urine than uric acid
• Dialysis if oliguric or persistent metabolic abnormalities or severe
symptoms
Breast cancer
• Risk factors:
– Age
– Obesity/sedentary lifestyle
– Alcohol
– Exposure to hormones
– BRCA 1/2
• BRCA 1/2
– Responsible for 5-10% breast CA
– BRCA1: 50-70% risk breast and 40-50% ovarian
– BRCA2: 40-60% breast (including male) and 10-25% ovarian
• Prevention
– Tamoxifen , raloxifene, and AI reduce breast ca risk, but no effect on
mortality
• Screening
– Women aged 50-74 should get routine screening mammogram every
1-2 years
895
Primary Breast Cancer
• Patients with disease confined to breast and axilla can

be cured by surgery/RT alone, but some may develop
distant metastases
• Decision for adjuvant treatment based on:

– Size of tumor
– Tumor grade
– Axillary nodal involvement
– ER status
– HER2/neu status
– Overall life expectancy
Breast cancer subtypes dictate therapy

• ER positive + HER2 negative (Luminal A)
Hormonal therapy +/- chemo
• ER positive + HER2 positive (Luminal B)

Hormonal therapy +/- trastuzumab + chemo
• ER negative + HER2 positive (HER2 enriched)

Chemo + trastuzumab
• Triple negative (Basaloid)

No targeted therapies
896
Risk of distant recurrence by OncotypeDX®
RCT Oncotype Dx 11-25
Paik ,,
New Engl
J Med
2004 Sparano NEJM 2018
Adjuvant breast cancer therapy

• Chemotherapy improves overall survival in:
– Triple negative
– HER2 positive when given along with trastuzumab
– ER positive if poorly differentiated or multiple involved lymph
nodes
• Hormonal therapy:
– 1st targeted therapy!
– ↓↓ breast cancer mortality by 1/3
– ↓↓ contralateral breast cancer by 1/2
• Tamoxifen
– Selective estrogen receptor modulator – 5 vs10 yrs
– No data for raloxifene in adjuvant setting
• Aromatase inhibitors
– Preferred for postmenopaual women
• Ovarian suppression
– Considered for high risk
897
Metastatic Breast Cancer Treatment Decision Tree
Luminal A Luminal B HER2 enriched Triple negative
ER +, HER2 - ER +, HER2 + ER -, HER2 + ER -, HER2 -
Hormonal Rx Hormonal Rx Chemo + pertuz

Trastuzumab + Trastuzumab
TDM1
Chemotherapy Chemo +
Chemo + ?novel agents
Trastuzumab Chemo +
Trastuzumab
or lapatinib
Lung cancer epidemiology
• Leading cause of cancer deaths at 154,000/yr

• Smoking:
– 85% of cases in smokers
– 15 – 30 risk of developing lung ca
– Quitting reduces risk but not to baseline
• More than half of patients diagnosed with lung ca
have metastatic disease
• 90% of cases are non-small cell lung cancer
898
Survival correlates with stage
Stage 5-year survival

(Clinical)
Localized 55%
Regional 28%
Distant 4%
Lung cancer screening
• 20% decrease in lung cancer mortality

• Data supports annual low dose CT screening
– Ages 55-80
– > 30 pack years
– Quit within the last 15 years
• Fleischner guidelines for f/u imaging lung nodules
• NCCN guidelines for management of lung nodules on
screening CT
899
Presenting symptoms
Endocrine/Parac Mechanism Symptoms
rine
Hypercalcemia Multiple Altered mental status, ataxia. Cardiac
Local Symptoms concerns
Cough SIADH ADH/aVP Symptomatic hyponatremia
Hemoptysis Cushing’s ACTH Muscle weakness, hyperglycemia,

syndrome hylokalemia. Infection.
Chest Pain
Dyspnea
Hoarseness Neurologic Mechanism Symptoms
Pleural involvement Lambert-Eaton Anti-voltage gated Fatigue, large muscle

calcium channels weakness
SVC syndrome
Paraneoplastic Anti-Hu Ataxia, diplopia, dysphagia
Pancoast syndrome cerebellar Anti-Yo
degeneration
Myasthenia gravis Anti-Acetylcholine Fatigable weakness of
receptor voluntary muscles
Biopsy/staging
• Tissue:
– More is better
– Genomic anaylsis
– Core preferred to FNA
– Non-bone sites preferred
• Staging
– mediastinoscopy
– Chest CT with contrast
– PET/CT
– Brain MRI with gadolinium (in selected cases)
900
Treatment dictated by stage
NSCLC SCLC
Treatment Approach
Stage Stage
IA,
Surgical resection
IB (< 4cm)
IIIA Multimodality approach
IIIB Limited Chemotherapy and Radiation
Chemotherapy, Targeted
IV Extensive
therapy, Immunotherapy
Primary therapy
• Localized disease
– Anatomic resection gold standard
– Steriotactic radiosurgery in selected cases
• Locally advanced disease
– Surgery and radiation: sequential or concurrent
901
Standard
5 things chemotherapy
to know in met
about …Treating lungDisease
Local cancer
Chemo Targeted
therapies
Rosell R, et al. Lancet Oncol. 2012
Response rate 20-30% 60-80%
Median survival 8-12 months 2-3 years
100
80
Percent Alive
60
40
20
0
0 5 10 15 20 25 30
Months
5 things to know about …Treating Local Disease

Genomics in lung cancer
Johnson BE, et al. ASCO 2013.
902
Novel approaches in lung cancer
Ribas, NEJM 2012
Genomic Immunohisto- Coming

chemical
staining
Non-small cell, EGFR, ALK, (PD-L1) BRAF, MET,
non-squamous ROS1 RET, NTRK,
HER2
NSCLC, - (PD-L1)
squamous
SCLC - - DLL3
Prostate cancer epidemiology
• 221,000 new cases per year (1 in 7 men)

• 28,000 deaths per year
• Risk factors:
– Age
– Family history
– African American
– BRCA 1/2, Lynch syndrome
903
The Spectrum of Prostate Cancer

Prostate Cancer
Varied spectrum from low volume, low grade disease that would never
kill the patient to intermediate risk disease to high risk, high volume
localized disease to frank metastatic disease that is incurable.
Treatment decisions require balancing the risk of progression and

morbidity secondary to treatment toxicity with life expectancy.
Prostate cancer screening

PLCO (US)** European Goteborg
Sample size 150,000 162,243 20,000
Median F/u 13 yrs 13 yrs 14 yrs
Prostate cancer No difference 21% reduction 44% reduction,
mortality p=0.001 p=0.0002
NNT* 37 12
American Urologic Association (AUA)

•No PSA screening in men under age 40. No routine screening in men between ages
40 to 54 years at average risk
•Routine screening interval of two years or more may be preferred
•No PSA screening: >age 70; any man with < 10 -15 year life expectancy
American Cancer Society (ACS)

• All men >50 with 10 yr life expectancy
• Discuss age >45 for African Americans and men with family history at < age 65
• Discuss age >40 for those with multiple family members diagnosed young
• Screen yearly for PSA >2.5, every other year for <2.5
904
Grading and Staging Prostate Cancer

• PSA:
– <10, 10-20, >20
• TNM clinical staging
– Staging of bones and nodes
• Gleason Score (GS):

• Most prominent grade + next most
prominent
- GS: 3 + 3 = 6
- GS: 4 + 3 = 7
- GS: 4 + 5 = 9
Overview: Treatment Options by Stage

Low Risk Intermediate Risk High Risk
GS 6 GS 7 GS 8-10
PSA <10 PSA 10-20 PSA >20
T1 T2 T3-4
Active surveillance Radical prostatectomy Radiation + 2-3 yrs CAB
Radical prostatectomy Radiation + 6 mo. CAB Radical prostatectomy +/-
Radiation: external beam, adjuvant radiation
brachytherapy
Stage: CT/MRI pelvis,
Bone scan
• Life expectancy <10 yrs: consider watchful waiting

• Surgery and radiation prevent PC deaths and increase overall survival in men
with clinically significant tumors and reasonable life expectancy
- No head to head trials: radiation vs. surgery
• Weigh side effect profiles, comorbidities, and risk of overtreatment
• Adding CAB to radiation likely improves outcomes but at expense of toxicity
GS: Gleason Score; CAB: combined androgen blockade (e.g., Lupron + bicalutamide)
905
Weighing Toxicity
Surgery Radiation ADT

• Surgical complications • Irritative urinary Sx • Hot flashes
- Wound healing • Bowel dysfunction • Fatigue
- Infection • Erectile dysfunction • Weight gain
- Anesthesia risks • Risk of second cancer • Bone density loss
• Erectile dysfunction • Loss of libido
• Urinary Incontinence • Emotional changes
• Metabolic insults:
insulin resistance
• ?Cardiac toxicity
• Surgery: radical prostatectomy (robotic, open, laparoscopic)

• Radiation: external beam, brachytherapy
• ADT: GnRH agonist or antagonist +/- antiandrogen
Sanda NEJM 2008, Resnick NEJM 2013
Metastatic prostate cancer
• Continuous androgen deprivation therapy

with better outcomes than intermittent
• Adding docetaxel improves overall survival
906
Current Treatment of Castration-resistant

Prostate Cancer
Bone-targeted:
Second line • Radium-223
Androgen blockade: • Antiresorptives
• Abiraterone
• Enzalutamide
• (nilutamide, flutamide,
ketoconazole/HC)
Chemotherapy
• Docetaxel
Immunotherapy: • Cabazitaxel
Sipuleucel-T
• Median overall survival from time of second line agent: 18-35 months
• Clinical trials remain imperative as there are no cures!
Bladder cancer epidemiology

• 81,000 cases per year in the US (3 to 1 M/F)
• Median age in 70’s
• 17,000 deaths per year
• Risk factors
– Age
– Tobacco
– Occupational exposures
– Parasitic infection of bladder
– Cyclophosphamide
– Male
– More common in whites
– Family history
• 90% of cases urothelial or transitional cell
• Rare squamous (schistosomiasis, chronic catheter), adeno, small cell
907
Presentation
• Hematuria
• UTI type symptoms
• If no infection:
– Refer for cystoscopy
– Urine cytology
– Possible imaging with CT
Staging of Bladder Cancer
• T1 = superficial, non-invasive
• T2 = muscle invasion; path
specimen must have muscularis
propria
• Stage IV encompasses any of
these factors:
- T4b = invasion of
pelvic/abdominal wall
- Involved regional lymph
nodes
- Distant metastasis
Harshman Surg Pathol Clin 2015
908
Spectrum of Bladder Cancer
Bladder Cancer
Non-muscle Muscle Invasive Metastatic

Invasive (60%) (30%) (10%)
Recur
• TURBT • Radical cystectomy +/- • Chemotherapy

• Intravesical tx neo/adjuvant chemo
if high grade OR
• Chemoradiation
Non-muscle invasive urothelial cancer
• 60% of cases
• Risk of progression to muscle invasive
– High grade, T1a - 48% rate of progression
– Low grade Ta - 2% rate of progression
• Managed by cystoscopy and TURBT
– Transurethral resection of bladder tumor
– BCG instillations weekly x 6 then q 3 months for
“high risk” lesions
909
Muscle invasive disease

• Organ confined: 5 yr OS: 74%,
• Extravesicular: 5 yr OS: 37%
• Regional nodal disease: 5 yr OS: 31%
• Adjuvant therapy:
• Multiple meta-analyses suggest
survival benefit to cisplatin-based
chemo
• Clinical Practice: consider if T3-T4
or nodes + and cisplatin eligible
• Bladder preservation:
• small lesions without CIS, T2 and
T3
• maximal TURBT
• cisplatin plus RT
• 50% long term control
• 20-30% require cystectomy
Metastatic urothelial cancer
• Cisplatin is the most active drug
• Gemcitabine plus cisplatin most commonly used
• Second line or first line in patients not eligible for

platin – immunotherapy with PD-1/PDL-1 inhibitor
910
Annual Incidence and Mortality of

Gastrointestinal Malignancies
United States (2017) Worldwide (2012)
Siegel et al CA Cancer J Clin 2017 Globocan2012 WHO
Cancer New Cases Deaths New Cases Death

Esophageal 17,290 15,850 455,784 400,169
Gastric 26,240 10,800 951,594 723,073
Pancreas 55,440 44,30 337,872 330,391
Colorectal 140,250 50,630 1,360,602 693,933
Liver 42,220 30,200 782,451 745,533
Breast 268,670 41,400 1,671,149 521,907
Lung 253,290 158,770 1,824,701 1,589,925
Esophageal cancer
• Risk factors:
– SCC: etoh, tbco, prior RT
– Adeno: Barretts’s, reflux, obesity
• Localized disease
– Surgery alone (5 year survival 15-24%)
– No benefit to post-op chemo or RT
– 2 neo-adjuvant studies with conflicting results
• Metastatic disease
– Survival less than one year
– Palliative RT
– Palliative chemo (platinum based, Her2 directed therapy
if over-expressed)
911
Gastric cancer
• Risk factors: H.pylori, salted meats, nitrates,
lack of refrigeration, occupation, E cadherin
mutation
• Standard for localized disease is surgery often
plus post-op chemotherapy/RT
• Palliative chemo for metastatic disease
(platins most active)
Pancreatic cancer
• Risk factors: hereditary, DM, obesity, tbco

• Localized disease (15% of patients):
– surgery with adjuvant chemo/RT
– 15% survive 5 years
• Locally advanced:
– Chemotherapy + RT
• Metastatic disease:
– Chemotherapy (FOLFIRINOX, gemcitabine/nab-
paclitaxel)
912
Colorectal cancer
• Risk factors:
– Increase risk: family hx, IBD, DM, tbco, obesity,
western diet
– Decrease risk: screening, exercise, vit D, ASA,
NSAIDS, calcium
• Hereditary (5% cases):
– FAP
– HNPCC

• American Cancer Society recommendations for average risk patients
(updated 2008)
Tests that find polyps and cancer
• Flexible sigmoidoscopy every 5 years *
• Colonoscopy every 10 years
• Double contrast barium enema every 5 years *
• CT colonography (virtual colonoscopy) every 5 years *
Tests that mainly find cancer
• Fecal occult blood test (FOBT) every year *
• Fecal immunochemical test (FIT) every year *
• Stool DNA test (sDNA), interval uncertain *
*Colonoscopy should be done if test results are positive.
Levin et al CA Cancer J Clin 2008; 58:130-160
913
Stage predicts 5 year survival
Stage I > 90%

Stage II 70-85%
Stage III 30-70%
Stage IV 8-10 %
Therapeutic approach CRC
Stage Colon Rectal

I (T1-T2, N0, M0) Surgery only Surgery only
Surgery +/- Chemoradiation
II (T3-T4, N0, M0)
Chemotherapy Surgery
Chemotherapy
OR
Surgery
III (Tany, N+, M0) Surgery
Chemotherapy
Chemoradiation &
Chemotherapy
Chemotherapy +/- Chemotherapy +/-
IV (Tany, Nany, M1)
Surgery Surgery
National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in

Oncology: Colon Cancer V3.2012. Available at: www.nccn.org. Accessed April 12,
2012.
914
CLL
• most common form of leukemia
• mature B-cell lymphoma
– CLL > 5000 circulating tumor cells
– SLL < 5000 circulating cells
• median age at diagnosis is 65
• commonly involves nodes diffusely, spleen, liver
• common complications include autoimmune
hemolytic anemia and hypogammaglobulinemia
• increased risk of secondary malignancies
Risk factors CLL
• cytogenetics
– 13q favorable
– 11q unfavorable
– 17p most unfavorable
• IGVH
• stage
915
Therapy for CLL

• No benefit to early treatment
• Indications – anemia, thrombocytopenia, bulky LAN or
splenomegaly, Richter’s
• Initial therapy:
– Chemo-immunotherapy: FCR (younger with unmutated
IGVH), BR (not for high risk cytogenetics or unmutated
disease), obinituzumab + chlorambucil, ibrutinib
– Ibrutinib for 17p and selected others (afib, bleeding)
• Relapsed disease:
– Inbrutinib
– Idelalisib + rituximab
– Vanetoclax (17p)
ALL
• Most common childhood cancer

• 15% of adult leukemias
• Prognostic factors:
– Philadelphia chromosome
– Other cytogenetics/molecular profiles
– high white cell count at diagnosis
916
Treatment of ALL
• Induction/consolidation/CNS
prophylaxis/maintenance
• Pediatric regimens in younger adults
• Ph+ patients with TKI plus steroids
• Transplant in first remission in Ph+ and other
high risk patients
• Relapsed disease
– Novel drugs blinatumomab, antibody drug
conjugates
– Chimeric antigen T cells (treatment related toxicity)
MDS
• heterogeneous diseases or stem cells
• incidence increases with age
• Prior chemo/RT predisposing factor
• Presents wit cytopenias (anemia most common)
• Marrow hypercellular with dysplasia
• Prognosis – IPSS
– % blasts
– Cytogenetics
– Number of cytopenias
• Numerous genetic mutations recently identified
• Can transform to AML
917
Treatment MDS
• Supportive care
• Growth factors
• Hypomethylating agents (decitabine and

azacytidine)
• Allogeneic stem cell transplant only curative

approach
AML
• 2.4 cases/100,000
• Median age late 60’s-70
• Associated with prior chemo/RT/toxin
• Pre-existing MDS
• Prognosis:
– Age
– Cytogenetics (ie t(15;17)
– Complex chromosomes adverse
– Mutations (ie FLT-3, NPM-1)
918
Therapy AML
• Induction with anthracycline plus cytarabine

• APML atra plus arsenic or chemotherapy
depending on risk
• Consolidation with chemotherapy or
allogeneic transplant depending on risk
CML
• Myeloproliferative disorder characterized by t(9;22)

• Median age 53
• Presents with leukocytosis and splenomegaly
• Therapy with imatinib or other tyrosine kinase
inhibitors
• Risk for transformation to AML or ALL (blast crisis)
919
Non-Hodgkin's Lymphoma
• Most common hematologic malignancy

• 75,000 cases/year in the US
• 5th most common cause of cancer deaths
• 2nd fasting growing malignancy in terms of
mortality
• 85% are of B-cell origin
Non-Hodgkin’s lymphoma
Indolent Aggressive Highly

aggressive
Survival Years Months Weeks
untreated
Response to Not curable Curable Curable
chemotherapy
Example Follicular Diffuse large Burkitt
lymphoma B-cell lymphoma
lymphoma
920
Biopsy
• Supraclavicular > cervical/axillary > inguinal
• Excisional biopsy when possible
• CT guided core needle
• FNA
• Send for pathology, immunohistochemisty/flow

cytometry
Indolent B-cell lymphoma:

clinical management
Localized Advanced Advanced

Low tumor High tumor
burden burden
Involved Field Observation Therapy
RT
921
Hodgkin lymphoma
• Stage I and II Disease
– Combined modality therapy with chemotherapy and
radiation
– Increasing role for chemotherapy alone
– Approximately 85%-90% cured with initial chemotherapy
• Stage III and IV Disease

– Chemotherapy always required
– Role of radiation therapy to sites of bulky disease
uncertain
– 75% cured with initial therapy depending on risk
HL complications of therapy
• Fertility
– ABVD low risk of infertility
• Pulmonary Toxicity
– Bleomycin
– Mediastinal RT
• Cardiac toxicity
– Mediastinal RT – pericardial, valvular and CAD
– Doxorubicin - cardiomyopathy
• Second malignancies
– solid tumors from radiation - breast, lung, etc
922
Multiple Myeloma
• 20,000 new cases per year
• Risk factors: African Americans, RT, MGUS
• Mean age 65
• Diagnosis:
Monoclonal plasma cells in bone marrow and/or

presence of biopsy-proven plasmacytoma
Myeloma-related organ dysfunction (1 or more)

(C) serum calcium >10.5 mg/L or ULN
(R) Renal insufficiency (SCr >2 mg/dL)
(A) Anemia (hemoglobin <10 g/dL or 2g <normal)
(B) Lytic bone lesions or osteoporosis
Complications
• Bone disease/hypercalcemia
• Hyperviscosity-IgM, IgG3, IgA
• Recurrent infections
• Renal failure: hypercalcemia, myeloma kidney,
hyperuricemia, IV urography, dehydration, plasma
cell infiltration, pyelonephritis, amyloidosis
• Cardiac failure: amyloid, hyperviscosity, anemia
• Anemia: BM tumors, renal dysfunction,
myelosuppression, low endogenous erythropoietin
• Neuropathy: sensory ±motor, amyloid, anti-myelin
Ab
923
MM initial therapy
Non-transplant: Transplant:
• dexamethasone/bortezomib/ • 3 drug combinations*:
cyclophosphamide – dexamethasone/
• dexamethasone/bortezomib/ bortezomib
lenalidomide Plus:
• dexamethasone/ – Lenalidomide or
lenalidomide – cyclophosphamide or
– doxorubicin
Bisphosphonates for bony disease
924
Oncology Board Review

Institute Physician
Question 1
63 year old woman has completed 5 years of tamoxifen following
lumpectomy and RT for a 1.5 cm, ER +, node negative breast
cancer. She presents to your office with severe, localized back
pain. Physical examination is normal including the neurologic
exam. The alkaline phosphatase is 330 (elevated) and the CA27.29
is 156 (elevated). A bone scan is positive in several areas of the
thoracic and lumbar spine, as well as in several ribs. The course
of action at this point should be:
A. Combination chemotherapy
B. Tamoxifen therapy
C. MRI scan of the spine
D. Radiation therapy to areas of localized disease
E. Stem cell transplantation
925
Question 1 - Answers
A. Combination chemotherapy – might be appropriate at some time
but not initially
B. Tamoxifen therapy – might be appropriate some time but not

initially
C. MRI scan of the spine – you must rule out or in spinal cord
compression – and outcome is best if it is discovered prior to
the onset of neurologic findings
D. Radiation therapy to areas of localized disease – the might be

appropriate at some time, and would be for spinal cord
compression if that is present on MRI
E. Stem cell transplantation – unfortunately doesn’t work for patients

with metastatic breast cancer
Question 2
68 year old male presents with back pain, anemia and fevers. The
patient has no lymphadenopathy or splenomegaly. Laboratory
studies are notable for HCT of 34% total protein of 9.8 gm/dl,
creatinine of 3.2 mg/dl, and calcium of 12.3 mg/dl. Plain x-rays of
the spine show generalized osteoporosis, without focal defects.
Which of the following is true:
A. Fever is a worrisome sign and infection is a life threatening risk in

this disease
B. Renal failure is likely a consequence of dehydration
C. The patient should undergo CT scans with contrast to evaluate

source of fever
D. The lack of lytic lesion argues against an underlying diagnosis of

myeloma
E. IgA and IgG paraproteins have similar serum viscosities
926
A. Fever is a worrisome sign and infection is a life threatening
risk – for myeloma patients and infection is the most common
cause of death
B. Renal failure is a common complication of myeloma due to

myeloma kidney, hypercalcemia and can be acutely and
irreversibly worsened by dehydration.
C. Patients with myeloma should not receive IV contrast even in the

setting of apparently normal renal function
D. The most common bone lesion seen in patients with myeloma is

generalized osteoporosis, not lytic bone lesions
E. IgA and IgG paraproteins have different serum viscosities – IgA

paraproteins have an unpredictable but higher viscosity than IgG
paraproteins.
Question 3
46 year old woman presents to your office for routine health care.
She is concerned about the possibility of developing breast
cancer, and asks you about her risk factors. Which statement is
correct:
A. A previous history of LCIS does not substantially increase
her risk of developing breast cancer
B. Presence of a BRCA-1 germ line mutation will substantially

increase her risk of developing breast cancer
C. A maternal aunt with post-menopausal breast cancer will

substantially increase her risk of developing breast cancer
D. The majority of women with breast cancer have identifiable

risk factors for the development of breast cancer
E. Duration and degree of estrogen (endogenous and

exogenous) exposure is not associated with increased of
developing breast cancer
927
A. A previous bx which revealed LCIS will substantially increase her risk of
developing breast cancer – LCIS substantially increases the likelihood of
future breast cancer, with an incidence of about 1% per year.
B. BRCA 1 and 2 mutations are associated with an increased risk of

breast cancer
C. A maternal aunt with post-menopausal breast cancer will substantially

increase your risk of developing breast cancer – it is first degree relatives
and relatives who develop breast cancer an a younger age who confer
the greatest risk on family members
D. 80-85% of patients have no identifiable risk factors other than being a

woman
E. Duration and degree of estrogen (endogenous and exogenous) exposure

will increase your risk of developing breast cancer – early menarche,
HRT, etc
Question 4
67 year old male smoker presents headaches, forgetfulness, and
poor coordination. Several times over the past few weeks he has
had periods of confusion and urinary incontinence. Head CT scan
reveals multiple round enhancing lesions. Chest x-ray shows a 2
cm lesion in the right mid lung field. The most likely diagnosis is:
A. Prostate cancer metastatic to lung and brain
B. Pneumonia with brain abscesses
C. Colon cancer with lung and brain metastases
D. Adenocarcinoma of the lung with brain metastases
E. Gastric cancer with lung and brain metastases
928
A. Prostate cancer commonly metastasizes to bone, and
rarely to lung and brain
B. Pneumonia with brain abscesses – possible, rare, and

this is an oncology review session
C. Brain metastases are an uncommon complication of

colon cancer
D. Brain metastases are very common in patients with

adenocarcinoma of the lung, at presentation and
later in the course of illness
E. Brain metastases are less common with gastric cancer
Question 5
26 year old woman with Hodgkin lymphoma and bulky
mediastinal disease is treated with ABVD (doxorubicin,
bleomycin, vinblastine, dacarbazine) and radiation to the
mediastinum. Which of the following is most true:
A. She is more likely to die of causes other then HL
B. Given she is over 20, she is not at increased risk of breast

cancer
C. She has an increased risk of leukemia
D. She is likely to have difficulty with fertility in the future
E. She is not at increased risk for heart disease
929
A. HD is highly curable but there is increased mortality from
other diseases and she is more likely to die of other
causes, including heart disease and second cancers
B. She has an increased risk of breast cancer – women under 30

who receive chest radiation have an increased risk of breast
cancer
C. ABVD does not increase the risk of leukemia as MOPP did
D. She is likely to remain fertile without increased risk of children

with birth defects – ABVD and chest radiation do not impair
fertility or decrease the likelihood of having a normal child
E. She is at increased risk for heart disease – she is at increased

risk for cardiomyopathy from doxorubicin and coronary artery
disease from radiation
Question 6
46 year old Asian woman, who never smoked, is diagnosed
with stage IV non-small cell lung cancer, metastatic to
liver and bone. Which of the following is correct:
A. She is potentially curable with intensive modern

chemotherapy
B. The likelihood of responding to an EGFR kinase inhibitor

is related to the presence of a mutation in the kinase
region
C. The likelihood of having a mutation of the kinase region

of EGFR is random and not related to gender or ethnic
background
D. Cytotoxic chemotherapy is the only potentially beneficial

treatment
E. Resistance to kinase inhibitors is rare
930
A. She is incurable and modern therapy has not changed this
fact
B. The likelihood of responding to an EGFR kinase inhibitor

is related to the presence of a mutation in the kinase
region
C. The likelihood of having a mutation of the kinase region of

EGFR is related to being a woman, a non-smoker and Asian
D. If her tumor has a EGFR kinase mutation she has a good

chance of responding to an inhibitor
E. Development of resistance to EGFR kinase inhibitors is

related to further acquired mutations in the tumor
Question 7
22 year old man presents with left a supraclavicular mass, and an
otherwise normal physical examination. Chest x-ray shows a
widened mediastinum. Aspiration cytology of the supraclavicular
mass demonstrates undifferentiated carcinoma. The next clinical
action should be:
A. Institution of multi-agent chemotherapy
B. MRI scan of the chest
C. Mediastinoscopy and biopsy of the para-tracheal nodes
D. Testicular ultrasound
E. Institution of radiation therapy to the mediastinum and

supraclavicular areas
931
A. Institution of multi-agent chemotherapy – always better to
know what you are treating and to identify potentially curable
diseases
B. MRI scan of the chest – will not add helpful information
C. Mediastinoscopy and biopsy of the para-tracheal nodes – will

not add helpful information since you already have pathology
D. Testicular ultrasound – this is correct – you can see

occult testicular cancers with this pattern of spread and
they are highly curable and relatively common in this age
group – so the burden of proof is on you to find curable
diseases
E. Institution of radiation therapy to the mediastinum and

supraclavicular areas – better to know what you are treating –
this would be clearly palliative
Question 8
Which of the following is true about the epidemiology of
lung cancer:
A. Adenocarcinoma has become the most common histologic

subtype of lung cancer.
B. Women who smoke, develop lung cancer with a similar

incidence and at a similar age as men who smoke.
C. Asbestos does not add to the risk of developing lung cancer

in smokers
D. Cigarette filters reduce the carcinogenic effect of cigarettes.
E. 90% of patients diagnosed with stage I non-small cell lung

cancer will survive their cancer.
932
A. Adenocarcinoma has become the most common histologic
subtype of lung cancer
B. Women who smoke, develop lung cancer at an earlier age than

men who smoke
C. Asbestos and smoking are additive risk factors for lung cancer
D. Cigarette filters do not reduce the carcinogenic effect of

cigarettes – and they apparently increase the risk of
adenocarcinomas in the lung periphery.
E. Only slightly more than half the patients diagnosed with stage I
non-small cell lung cancer will survive their cancer – even
apparently localized lung cancer has a high recurrence rate and
mortality.
Question 9
28 year old man is admitted to the hospital with newly
diagnosed acute lymphoblastic leukemia. Which of
the following clinical characteristics would convey the
worst prognosis:
A. Peripheral blood blast count of 200,000/mm3
B. T-cell phenotype
C. Mediastinal mass
D. Philadelphia chromosome t(9;22)
E. Thrombocytopenia
933
A. A high peripheral blood blast count does not decrease
chance of cure
B. T-cell phenotype – with modern therapy this is a very

treatable and potentially curable disease
C. Mediastinal mass – most of these patients have T-cell

phenotype and are potentially curable as above
D. Philadelphia chromosome t(9;22) – this is a poor

prognostic finding requiring more intensive
therapy
E. Thrombocytopenia – does not predict outcome
Question 10
51 year old man underwent surgical resection for rectal cancer. On
pathology evaluation the tumor penetrates the serosa of the bowel
and one regional lymph node shows involvement with metastatic
carcinoma. There is no evidence of distant metastases. Optimal
therapy should include:
A. No post-operative therapy
B. Re-resection of pelvic tissue surrounding the area of the

original tumor
C. Radiation therapy to the pelvis
D. Systemic chemotherapy
E. Both radiation to the pelvis, and chemotherapy
934
A. Post-operative therapy is indicated as in E
B. Maximal tissue is usually resected during primary

surgery but because of the tight area and surrounding
structures this is limited
C. Radiation therapy to the pelvis will decrease local but

not systemic recurrence
D. Systemic chemotherapy will reduce systemic

recurrence but not local recurrence
E. Both radiation to the pelvis, and chemotherapy –

will reduce both local and systemic recurrence
Question 11
46 year old woman with epithelial ovarian cancer at surgical
debulking is found to have billateral ovarian masses with multiple
peritoneal and omental nodules, as well as ascitic fluid. All tumor
that can be removed is removed, but tumor masses of 2-3 cm
remain. There is no evidence of disease outside of the peritoneal
cavity. Postoperatively, the patient is treated with paclitaxel and
carboplatin for 6 cycles. Which of the following is true:
A. A very low chance of response to chemotherapy and a very low

chance of cure.
B. A high chance of complete clinical response, but a low chance for

cure.
C. A high chance of response and a high chance for cure.
D. The need for radiation therapy delivered to the whole abdomen.
E. The need for localized radiation therapy to the pelvis.
935
A. Ovarian cancer is a tumor that responds to many
chemotherapy agents but has a high recurrence and
death rate
B. A high chance of complete clinical response, but a

low chance for cure – as above
C. As in “B”
D. Whole abdominal radiation is very toxic, limits ability to

give chemotherapy, and does not improve outcome
E. Localized radiation therapy to the pelvis limits ability to

give chemotherapy and does not improve outcome
Question 12
A 72 year old man presents with hematuria. Cystoscopy reveals
multiple bladder nodules which are biopsied and reveal
transitional cell carcinoma. The likelihood of developing
metastatic bladder cancer is most closely related to:
A. The size of the tumors in the bladder.
B. The number of tumors in the bladder.
C. History of smoking.
D. Family history.
E. Bladder wall muscle invasion by the tumor.
936
A. Tumors without muscle invasion can be large and not
metastasize.
B. The number of tumors in the bladder can be a “pain” to remove

and treat, but does not affect outcome.
C. History of smoking – this is a risk factor for developing bladder

cancer but does not determine likelihood of developing
metastases.
D. Family history – weak risk factor for developing bladder cancer but
does not affect risk of metastases.
E. Bladder wall muscle invasion by the tumor – this is an

important risk factor for the development of metastases.
Question 13
A 32 year old man presents with acute myelogenous leukemia.

Allogeneic bone marrow transplantation will most likely be
recommended if a suitable donor can be found if:
A. His initial blast count > 100,000/mm3
B. He is septic at presentation
C. He has M3/Acute promyelocytic leukemia and has DIC
D. His leukemic blasts have a 7q- chromosomal deletion
E. His leukemic blasts have a t(8;21) chromosomal translocation
937
A. His initial blast count of > 100,000/mm3 does not affect outcome
B. Being septic at presentation affects initial mortality but not ultimate

response to chemotherapy
C. M3/Acute promyelocytic leukemia with DIC affects initial mortality

but not ultimate response to chemotherapy and in fact thse
patients ultimately have a better prognosis than average
D. Leukemic blasts wth a 7q- chromosomal deletion portend a

poor prognosis with standard chemotherapy
E. Patients whose leukemic blasts have a t(8;21) chromosomal

translocation have a better prognosis than average
Question 14
You are evaluating a 52 year old man with newly
diagnosed non-small-cell carcinoma of the right lung.
In which of the following scenarios is the patient
resectable?
A. Contralateral (N3) mediastinal adenopathy.
B. Enlarged (4 cm) left adrenal gland.
C. Ipsilateral pleural effusion.
D. Ipsilateral (N2) mediastinal adenopathy.
E. Enlarged supraclavicular lymph nodes.
938
A. Patients with contralateral (N3) mediastinal adenopathy are not

resectable.
B. 25% of pts with NSCLC will have adrenal metastases early on,
and these pts are not helped by resection – and an adrenal mass
of this size is more likely malignant than representing a benign
adenoma.
C. Pleural effusions make resection unsuccessful.
D. Patients with ipsilateral (N2) mediastinal adenopathy are

potentially resectable, and curable, particularly after
preoperative chemotherapy and radiation.
E. Enlarged supraclavicular lymph nodes are indicative of metastatic

disease, and these patients are not helped by resection.
Question 15
Which of the following is true regarding tamoxifen and

raloxifene?
A. Raloxifene is a bone strengthening agent but

tamoxifen is not
B. Both increase the risk of endometrial cancer.
C. Both decrease the risk of developing a future breast

cancer
D. Tamoxifen increases risk of hot flashes, but

raloxifene doesn’t
939
A. Both increased bone density
B. Tamoxifen increases the risk of endometrial

cancer, but raloxifene does not
C. Both decrease the risk developing breast

cancer
D. Both increase the likelihood of hot flashes
Question 16
42 year old woman presents with a 3 cm poorly differentiated
breast, ER/PR negative, HER2 positive cancer with 5 involved
axillary lymph nodes. Which of the following is true:
A. The presence of HER2 on breast cancer cells does not affect

prognosis
B. Adjuvant chemotherapy is not effective in reducing the

subsequently development of metastatic breast cancer
C. Trastuzumab, when added to chemotherapy, substantially

reduces the risk of developing metastatic disease in the
future.
D. Letrozole, an aromatase inhibitor, would further improve the

cure rate for this patient.
E. The addition of trastuzumab to chemotherapy is safe, without

short and long-term complications.
940
A. Tumors which overexpress HER2 are more likely to metastasize
B. Adjuvant chemotherapy substantially reduces the risk of her

subsequently developing metastatic breast cancer for both HER2
positive and negative tumors.
C. Trastuzumab, when added to chemotherapy, further reduces

the risk of developing metastatic disease in the future
D. Letrozole, an aromatase inhibitor, is not effective for pts with

estrogen receptor negative tumors
E. Trastuzumab, when administered after doxorubicin, is associated

with increased risk of cardiomyopathy
Question 17
56 year old man with a history of a primary melanoma
on the right forearm 3 years ago, presents with
hepatomegaly and is found to have metastatic
melanoma in the liver. Which of the following is the
best treatment option:
A. Dacarbazine and tamoxifen
B. No therapy is effective or warranted and the patient

should be place in hospice care
C. Nivolumab plus ipilimumab.
D. Prophylactic brain irradiation
941
A. Dacarbazine and tamoxifen was a favored treatment in the
past, but tamoxifen was shown to be ineffective, and the
benefit from dacarbazine is marginal
B. Metastatic melanoma is a bad disease, and in the past

placement on hospice as initial treatment could be considered
appropriate
C. Nivolumab plus ipilimumab has been shown to be highly

active in this disaease
D. Patients with metastatic melanoma do frequently develop

brain metastases but prophylactic brain radiation has not
been shown to improve outcome
Question 18
64 yo woman has a routine CBC showing a WBC of 14,500/mm3
with 75% mature-appearing lymphocytes, Hct 41%, and Plt of
180,000/mm3. She has no adenopathy or splenomegaly and feels
well. Which of the following is true:
A. The diagnosis of CLL can only be made on a bone marrow

aspirate and biopsy
B. She is at increased risk for infection
C. She is in need of urgent chemotherapy
D. She is likely to die of CLL before her 70th birthday
E. Splenomegaly is rare in patients such as this one
942
A. The diagnosis of CLL can be made on testing of the
peripheral blood, by flow cytometry, looking for the co-
expression of CD20 and CD5
B. She is at increased risk for infection, from decreased

antibody production in response to infection, and infection
is the leading cause of death for patients with CLL
C. Many people live with CLL without therapy for years and
reasons to treat include severe anemia, thrombocytopenia,
bulky adenopathy, or systemic symptoms and she has none of
these
D. Statistically she is likely to be alive at age 75
E. Splenomegaly is a common finding in patients with CLL
Questions 19-23 - Answers

A. Bevacizumab
B. Cyclophosphamide
C. Paclitaxel
D. Trastuzumab
E. Ipilimumab
19. Stabilization of microtubule assembly

20. Inhibition of HER2
21. Inhibition of VEGF
22. Alkylation of DNA
23. Increase T cell response versus tumor
943

A. Bevacizumab - 21
B. Cyclophosphamide - 22
C. Paclitaxel - 19
D. Trastuzumab - 20
E. Ipilimumab- 23
19. Stabilization of microtubule assembly

20. Inhibition of HER2
21. Inhibition of VEGF
22. Alkylation of DNA
23. Increase T cell response versus tumor

A. Bevacizumab
B. Cyclophosphamide
C. Paclitaxel
D. Trastuzumab
E. Ipiliumumab
24. Congestive heart failure
25. Hypertension
26. Colitis, pneumonitis, hypophysitis
27. Acute hypotensive and bronchospasm
28. Hematuria
944

A. Bevacizumab - 25
B. Cyclophosphamide - 28
C. Paclitaxel - 27
D. Trastuzumab - 24
E. Ipiliumumab- 26
24. Congestive heart failure
25. Hypertension
26. Colitis, pneumonitis, hypophysitis
27. Acute hypotensive and bronchospasm
28. Hematuria
Oncology Board Review
Ann S. LaCasce, MD

• Disclosures:
– No relevant conflicts of interest to declare
945
Cardiology Overview
Leonard S. Lilly, M.D.
Chief, Brigham/Faulkner Cardiology
BRIGHAM AND HARVARD

WOMEN’S HOSPITAL MEDICAL SCHOOL
Faculty Disclosure/Conflicts
None
946
Recent Cardiology Highlights

• 2017 Hypertension Guidelines: new treatment
strategies and goals
• PCSK9 inhibitor reduces cardiovascular events
in 2nd major outcomes trial (ODYSSEY Outcomes)
• PCI no better than sham procedure for
improving symptoms or exercise capacity in
single vessel CAD and stable angina (ORBITA)
• Anti-inflammatory therapy with canakinumab
(IL-1β inhibitor) reduced cardiac events in patients
with prior MI and hsCRP > 2 mg/L (CANTOS)
• FDA approves new DOAC reversal agent
2017 Hypertension Guidelines
947
• 56 year old black businessman presents to

office for annual evaluation.
• Blood pressure is 138/84, similar to other
recent office visits and at home.
• He doesn’t smoke and is not diabetic. There is
a strong family history of hypertension. He
consumes 3-4 alcoholic beverages per week.
BMI is 28.
• Medication: Atorvastatin 10 mg daily.
• Predicted 10-year risk for first cardiovascular
event is 12% using ACC/AHA pooled cohort
equations.
Which recommendation is consistent with

current hypertension guidelines?
A. His blood pressure is not in a range that
requires intervention; continue routine
monitoring of BP
B. Recommend life style modifications, including
weight loss, but antihypertensive drug therapy
should not yet be initiated
C. He should follow life style modifications and
begin drug therapy using a beta-blocker or an
ACE inhibitor
D. His target on-therapy blood pressure should be
< 130/80
948

Category Systolic Pressure Diastolic Pressure
(mmHg) (mmHg)
Normal < 120 and <80
Elevated 120-129 and <80
Stage 1 Hypertension 130-139 or 80-89
Stage 2 Hypertension ≥140 or ≥90
Class I recommendation in primary prevention:

Initiate BP-lowering meds for:
• SBP ≥140 mm Hg or DBP ≥90 mm Hg
• SBP ≥130 mm Hg or DBP ≥80, if 10-year ASCVD risk ≥10%
On-therapy BP target: < 130/80

Whelton PK, et al. 2017 Guideline for the prevention,
detection, evaluation, and management of high blood
pressure in adults. J Am Coll Cardiol 2018; 71:2199.
First line drug therapies for Stage 1 hypertension:

• Diuretics (thiazide or chlorthalidone)
• Calcium channel blockers
• ACE inhibitors
• Angiotensin receptor blockers
In patients with CAD or HFrEF:
• Beta-blockers
For black patients, without HFrEF or chronic kidney

disease, initial therapy should include:
• Diuretic (thiazide or chlorthalidone) and/or
• Calcium channel blocker
Whelton PK, et al. 2017 Guideline for the prevention,

detection, evaluation, and management of high blood
pressure in adults. J Am Coll Cardiol 2018; 71:2199.
949
DOAC Reversal Agents
• 62 year old woman with chronic

nonvalvular atrial fibrillation takes
dabigatran 150 mg twice daily.
• 30 minutes ago she sustained trauma as
passenger in a motor vehicle collision.
• In the Emergency Department she is
intubated, unresponsive and hypotensive.
CT imaging shows small intracranial
subdural hematoma and retroperitoneal
hemorrhage that requires urgent
exploratory laparotomy.
950
Which is the most appropriate

anticoagulation reversal agent for this
patient on dabigatran with life-threatening
bleeding in need of emergency surgery?
A. Vitamin K
B. Protamine
C. Idarucizumab
D. Andexanet alfa
Direct Oral Anticoagulants (DOACs)

Compared to warfarin:
• At least as effective in nonvalvular AF
and venous thromboembolism, with
fewer bleeding complications
• Predictable anticoagulation
• Do not require routine blood test
monitoring / more convenient
• Shorter half-lives – usually sufficient to
simply withhold drug for minor bleeding
• Vitamin K is ineffective for reversal
951
DOAC Emergency Reversal of Anticoagulation

Rapid Reversal Agent Alternatives
Direct Thrombin Inhibitor
• 4 Factor prothrombin
Idarucizumab 1
• Dabigatran complex concentrate
(Fab monoclonal antibody fragment
directed at dabigatran) • Hemodialysis
Factor Xa Inhibitors
• Apixaban Andexanet alfa 2 • 4 Factor prothrombin
• Rivaroxaban (Recombinant factor Xa complex concentrate
decoy protein)
• Edoxaban
1N Eng J Med 2017;377:431.

2N Eng J Med 2016;375:1131.
Heart Failure
952
Switching to sacubitril/valsartan in place of an ACE

inhibitor or ARB would be most appropriate for which of
the following heart failure patients?
A. 72 y.o. man hospitalized for heart failure decompensation,

LVEF 35% and severe (NYHA class IV) symptoms despite
ACE inhibitor, beta-blocker and spironolactone
B. 64-year-old man with nonischemic cardiomyopathy, LVEF
38%, NYHA class II symptoms, comes for routine office
visit on torsemide and optimal doses of metoprolol
succinate and lisinopril
C. 62-year-old woman with ischemic cardiomyopathy, LVEF
40%, NYHA class II symptoms who developed
angioedema previously on an ACE inhibitor
D. 76-year-old woman with heart failure and preserved
ejection fraction (HFpEF), LVEF 50%, NYHA class III
symptoms, taking metoprolol, valsartan, and furosemide
AHA/ACC 2017 Heart Failure Guidelines1

Class I indication:
For patients with chronic HFrEF with
class II-III symptoms who tolerate an
ACE inhibitor or ARB, replacement with
an angiotensin receptor neprilysin
inhibitor (e.g., sacubitril/valsartan) is
recommended to further reduce
morbidity and mortality
1J Am Coll Cardiol 2017;70:776.
953
PARADIGM-HF: Cardiovascular Death or Heart Failure

Hospitalization (Primary Endpoint)
40
1117
32 Enalapril
Cumulative Rates (%)
(n=4212) 914
24
Sacubitril / Valsartan
(n=4187)
16
HR = 0.80 (0.73-0.87)
P = 0.0000002
8 Number needed to treat = 21
0
0 180 360 540 720 900 1080 1260
Days After Randomization
Stopped early (27 m)
because of marked benefit
N Eng J Med 2014;371:993.
Candidates for Sacubitril/valsartan

Chronic symptomatic HFeF (EF≤ 40%)
Not hospitalized with acute decompensated failure
NYHA Class I IV
II-III
Tolerating
ACEi/ARB
Safety Screen
K ≤ 5.4 mmol/L
eGFR ≥ 30 mL/min/m2
SBP ≥ 95 mm Hg
Yes No
Candidate for
Valsartan/sacubitril
Contraindications:
• History of angioedema on
ACEI
• Pregnancy
J Am Coll Cardiol 70:776-803, 2017.
954
ECG Interpretation
52 year old malpractice attorney presents to

the Emergency Department with left-sided
chest pain since awakening. Pain is less
intense sitting upright.
• No history of angina
• Father sustained MI at age 56
• Had URI 3 weeks ago
An electrocardiogram is obtained
immediately...
955
What is most appropriate immediate action?

A. Send directly to cardiac cath lab, if can achieve
door-to-coronary intervention time < 90 min
B. Administer fibrinolytic therapy if < 6 hours since
onset of pain
C. Administer calcium channel blocker and nitrates
D. Administer aspirin and obtain echocardiogram
ST Which ST-T PR
Coving Leads? Evolution Segment
Pericarditis Diffuse Days- ↓

weeks
(STE < 5 mm)
Acute Localized Hours Normal

STEMI
956
Management of Idiopathic Acute

Pericarditis
• Aspirin (e.g., 650 mg q 4-6 h)

• NSAIAs (e.g., ibuprofen 400-800 mg q 6-8 h)
• Colchicine (off-label: 0.5 mg BID;
0.5 mg daily if weight ≤70 kg)
ICAP Trial. N Engl J Med 2013; 369:1522.
CORP Trial. Ann Int Med 2011;155:409.
• Prednisone 0.25-0.5 mg/kg/d (last resort)

1. Send directly to cardiac cath lab, if can achieve
2. Administer fibrinolytic therapy if < 6 hours since
onset of pain
3. Administer calcium channel blocker and nitrates
4. Administer aspirin and obtain echocardiogram
957

1. Send directly to cardiac cath lab, if can achieve
2. Administer fibrinolytic therapy if < 6 hours since
onset of pain
3. Administer calcium channel blocker and nitrates
4. Administer aspirin and obtain echocardiogram
STEMI – Initial Management
Invasive Strategy Preferred Fibrinolysis Acceptable

• Skilled PCI lab available • Non-PCI hospital, and delay
• Can achieve PCI within to transfer for PCI > 120 min
90 min of medical contact • No contraindications to
• STEMI with cardiogenic fibrinolysis
shock, regardless of timing • Should be administered
< 30 min after arrival
N Engl J Med 2017; 376:2053.
958
Endocarditis Prophylaxis
36 y.o. woman is scheduled for a tooth

extraction. She has a history of a heart murmur
and her dentist calls to determine if
premedication is needed. For which one of the
following conditions is antibiotic prophylaxis
recommended?
A. Atrial septal defect with surgical repair 8 years ago
B. Hypertrophic cardiomyopathy with outflow tract
obstruction
C. Bicuspid aortic valve with severe aortic regurgitation
D. History of MVP, s/p mitral valve repair (annuloplasty
ring), with no residual regurgitation
959
Antibiotic Prophylaxis in Endocarditis

American Heart Association Guidelines
“recommended only for patients with underlying cardiac
conditions associated with the highest risk of adverse outcome”
1. Prosthetic heart valve (including TAVR) or valve

repair with prosthetic material
2. Prior occurrence of endocarditis
3. Certain congenital heart diseases:
• Unrepaired cyanotic lesions (e.g., Tetralogy of Fallot)
• Prior repair with residual defects adjacent to prosthetic material
• Complete repair with prosthetic material, for first 6 months
4. Valve abnormality after heart transplant
J Am Coll Cardiol 2017; 70:252.

Circulation 2007; 116:1736-1754.
Antibiotic Prophylaxis in Endocarditis

American Heart Association 2007 Guideline
• Recommended for invasive dental procedures
• Not recommended for upper respiratory tract
procedures, unless involves incision or biopsy of
mucosa (e.g., tonsillectomy, bronchoscopy with biopsy)
• Not recommended for GU or GI procedures in
absence of infection
Standard regimen: Amoxacillin 2 g 30-60 min prior
If allergy: Clindamycin, azithromycin, clarithromycin, cephalexin
If parenteral required: Ampicillin, cefazolin, ceftriaxone, clindamycin
Circulation 2007;116:1736-1754.
960
Statins and Muscle Injury
A 62 year old woman with history of

hypertension, diabetes and dyslipidemia takes
simvastatin 40 mg daily.
Which one of the following medications would
not be expected to increase the risk of muscle
toxicity if added to her regimen?
A. Gemfibrozil
B. Ketoconazole
C. Azithromycin
D. Diltiazem
E. Amiodarone
961
Statin Muscle Side Effects

CK Incidence
Myalgia Normal 1-20%
Myositis Elevated < 0.5%
Rhabdomyolysis >10-40 x < 0.01%
ULN
Related to:
• Drug metabolism
• Dose of drug
• Concurrent medications
Commonly Used Statins

Metabolism
Atorvastatin CYP3A4
Lovastatin CYP3A4
Simvastatin CYP3A4
Fluvastatin CYP2C9
Rosuvastatin CYP2C9
Pitavastatin CYP2C9
Pravastatin Neither
962
Increased Risk of Myopathy

Potent inhibitors of CYP3A4:
⋅ cyclosporine ⋅ ketoconazole
⋅ erythromycin ⋅ protease inhibitors
⋅ clarithromycin ⋅ grapefruit juice
Moderate inhibitors of CYP3A4:

⋅ amiodarone
⋅ verapamil
⋅ diltiazem
Gemfibrozil
Additional Reading
1. Whelton PK, Carey RM, Aronow WS, et al. 2017 ACC/AHA/AAPA/
ABC/ACPM/AGS/APhA/ASH/ASPC/NMA/PCNA Guideline for the prevention,
detection, evaluation, and management of high blood pressure in adults: Executive
summary. J Am Coll Cardiol 2018; 71:2199.
2. Tomaselli GF, Mahaffey KW, Cuker A, et al. 2017 ACC expert consensus decision
pathway on management of bleeding in patients on oral anticoagulants. J Am Coll
Cardiol 2017; 70:3042.
3. Yancy CW, Jessup M, Bozkurt B, et al. 2017 ACC/AHA/HFSA focused update of
the 2013 ACCF/AHA guideline for the management of heart failure. J Am Coll
Cardiol 2017;70:776.
4. 2015 ESC Guidelines for the diagnosis and management of pericardial diseases. Eur
Heart J 2015; 6:2921.
5. Anderson JL and Morrow DA. Acute myocardial infarction. N Engl J Med 2017;
376:2053.
6. 2017 AHA/ACC focused update of the 2014 AHA/ACC guideline for the
management of patients with valvular heart disease. J Am Coll Cardiol 2017;
70:252.
963
CV Prevention
Samia Mora, MD, MHS
Associate Physician
Divisions of Preventive and Cardiovascular Medicine
Name)
Disclosures
• Dr. Mora has received institutional research support
from Atherotech Diagnostics. NIDDK, FDA, Roche,
Abbott
964
Objectives
1. To review current challenges for CVD prevention
2. To review (briefly) recent evidence / guidelines on:
• CV risk assessment
• Cholesterol
• Blood pressure
• Aspirin
• Lifestyle
Take-home messages
• Lifestyle interventions should underlie

all preventive efforts
• The intensity of preventive interventions

should match baseline cardiovascular
risk
965
Primordial, Primary, Secondary Prevention
Vaduganathan et al JACC 2015
Trends In Cardiovascular Death Rates Over Time
Nabel E, Braunwald E. NEJM 2012;366:54-63.
966
Impact of CVD in Women

1. More strokes in women, more coronary heart
disease (CHD) in men
2. Impact of obesity is greater in women than men
3. Gestational diabetes (2-10% of pregnancies)
increases risk of future diabetes by ~ 50% (30-60%)
3. Unique risk factors for stroke in women:
Pregnancy; Hormone Therapy
More hypertension after age 65
Objectives
• Cholesterol
• Blood pressure
• Aspirin
• Lifestyle
967
Risk stratification is the key to prevention

High Risk Individuals
Established CHD
Cerebrovascular disease
Peripheral arterial disease
Abdominal aortic aneurysm
End-stage or CKD
Diabetes mellitus
(10 year Framingham risk > 20%)
10 year ASCVD risk (Pooled Cohorts) ≥ 7.5% *
* http://my.americanheart.org/cvriskcalculator
The information required to estimate ASCVD risk includes:

age, sex, race, TC, HDL-C, SBP, BP Rx, diabetes, smoking
10-yr risk of MI, fatal or nonfatal stroke, CHD death
lifetime risk
968
ASCVD Risk Calculator
http://tools.acc.org/ascvd-risk-estimator-plus/#!/calculate/estimate/
Importance of disease prevalence in applying

clinical risk scores
• Clinical prediction scores are developed to help clinicians
make more accurate probability estimates
• Caveat: clinical risk scores may not perform as well in a new

setting as they did in the setting in which they were
developed due to differences in disease prevalence in
different populations
969
Importance of disease prevalence in applying risk

scores
• To adjust for differences in disease prevalence in
clinical settings, Bayes’ Theorem can be applied
to risk scores (similar to diagnostic tests)
“High risk” score
“Low risk” score
13
Mora AHA 2015
Pooled Cohort Risk Equations

• Since the publication of the PCE, numerous
studies reported apparent overestimation of
risk with PCE (i.e. predicted > observed risk)
• Potential explanations:
– Differences in study populations
– Increasing use of statins and aspirin
– Decreasing ASCVD event rates
– Under-ascertainment of event rates in studies that
rely mainly on self-report
Mora et al AHA 2017
970
Pooled Cohort Risk Equations in the Women’s Health Initiative (WHI)

Observed vs predicted risk in women ≥65 years
before and after adding CMS events
20
15
Percent
10
5 Observed, unadjusted
Observed adj. asa, statin, CMS
0 Predicted
<7.5% 7.5 - <10% ≥ 10%
10-year risk category
Without including surveillance for ASCVD events using CMS, observed risks in
the WHI were lower than predicted by PCE as noted in several other US cohorts
Adjustment for time-dependent changes in statin and aspirin use resulted in small
increases in observed risks
Mora et al AHA 2017
Objectives
• Cholesterol
• Blood pressure
• Aspirin
• Lifestyle
971
4 Statin Benefit Groups

( 1-3) High Risk:
1. Clinical ASCVD*
2. LDL–c >190 mg/dL, Age >21 years
3. Primary prevention – Diabetes:
Age 40-75 years, LDL–c 70-189 mg/dL
(4) Primary prevention† 4. No Diabetes:
≥7.5% 10-year risk, Age 40-75 years, LDL–c 70-189 mg/dL
* ACS, MI, angina, coronary or other arterial revascularization, stroke,
TIA, atherosclerotic PAD
† Requires risk discussion between clinician and patient
Stone et al JACC 2014;63:2889-934
Individuals Not in a Statin Benefit Group

Additional factors may inform clinical decision making
• Family history of premature ASCVD*

• High lifetime risk
• LDL–c ≥160 mg/dL
• hs-CRP ≥ 2 mg/L
• CAC score ≥ 300 or ≥75th percentile
• Ankle brachial index (ABI) < 0.9
* onset <55 y first degree male or <65 first degree female
Stone et al JACC 2014;63:2889-934
972
Statins and CVD Prevention by Baseline Risk
Cholesterol Treatment Trialists CTT Collaborators. Lancet. 2012;380:581–590.
PCSK9i lower LDL-c by ~ 60%
Robinson NEJM 2015

Sabatine NEJM 2015
973
PCSK9i Clinical Outcomes Studies

Alirocumab
n=18,000; Post-acute MI or hospitalized UA w/in 12 months
Rx w/ atorva 40/80 mg/d, rosuva 20/40 mg/d or max tolerated; LDL >
ODYSSEY Outcomes 70, nonHDL > 100, or apo B > 80
Randomized to alirocumab 75-150 mg SC Q2W
Completion ~ December 2017
Bococizumab
High risk CVD event; LDL 70-100 or nonHDL 100-130; on LLRx;
SPIRE-1 Randomized to Boco 150 mg SC Q2W vs placebo; n=17,000
SPIRE-2 Same as above except LDL > 100 or nonHDL > 130; n=9000
Evolocumab
N=27,564; History of MI, CVA, or PAD + RF;
Rx with atorva ≥ 20 mg or equivalent;
FOURIER LDL > 70 or nonHDL > 100;
Rx w/ evo 140 Q2W or 420 mg QM vs placebo
FOURIER: Eligibility Criteria

Clinical ASCVD (MI or stroke) within 5 years plus additional
risk factors:
Sabatine et al AHJ 2016; 173: 94
974
FOURIER: Primary Endpoint
Sabatine et al NEJM 2017; 376: 1713
FOURIER Trial—Key Efficacy and Safety End Points
Binding and neutralizing antibody rates for evolocumab of 0.35 and 0.0%, respectively
Sabatine MS et al. NEJM. 2017
975
FOURIER – PRIOR MI
Outcomes by High Risk Features
≥1 High Risk Feature No High Risk Feature
• 67% of FOURIER • 37% of FOURIER

• 22% RRR • 6% RRR
• 2.5% ARR • 0.5% ARR
SPIRE: Bococizumab
Trials stopped due to immunogenicity
Ridker et al NEJM 2017 376: 1522
976
Alirocumab
ODYSSEY-Outcomes Study Design
• Patient population: • Primary endpoint:
• Recent ACS (1-12 mo before randomization) – CHD death
• Lipids not optimally controlled on optimal statin: – Non-fatal MI
LDL-C ≥70 mg/dL, non-HDL-C ≥100 mg/dL, or apo B – Ischemic stroke
≥80
– Unstable angina requiring hospitalization
Run-In Period Double-Blind Treatment Period

(~ 2 to 5 years)
At Month 2 and beyond:

75 mg or 150 mg
every 2w adjusted in blinded fashion to
Adjust statin, achieve LDL-C<50 mg/dl
Check lipids
Alirocumab (n=9000)
R
Randomization
Index ACS Placebo (n=9000)
event
Schwartz GG et al., Am Heart J 2014; 168:682-689
Stegg G et al., ACC 2018
977
Guidance on Use of Nonstatin Therapy

4 statin benefit groups
• Adherence and lifestyle

• Statin intolerance
• All patients
Control with
of other risk ASCVD
factors
• Discussion about non-statin
• Primary
therapies
• Choosing
• >50% alternative goalsinofLDL-C
reduction
therapy
•• Secondary (may consider)
Monitoring response to therapy
• • LDL-C
Referral <70 mg/dL
to a specialist/nutritionist
• Ezetimibe
• Non-HDL-C <100 mg/dL
• Bile acid sequestrant
• PCSK9 inhibitor
• Other therapies (LDL apheresis,
lomitapide, mipomersen)
PCSK9, proprotein convertase subtilisin/kexin type 9 serine protease.

Lloyd-Jones DM, et al. JACC. 2017;70(14):1785-1822.
2016 ESC/EAS Guidelines on the Management

of Dyslipidemias: Pharmacological Treatment
of Hypercholesterolemia
Task Force for the Management of Dyslipidaemias of the ESC and EAS. Eur Heart J. 2016 prepub.
978
AACE 2017 Lipid Goals
ENDOCRINE PRACTICE Rapid Electronic Article in Press DOI:10.4158/EP171764.GL
2017
R 20. Lipids, including TG, can be measured

in the non-fasting state if fasting
determinations are impractical
32
Jellinger et al. Endocrine Practice 2017;Epub ahead of print Feb 3
979
Take-home messages
• Statins are the most effective traditional LDL-cholesterol lowering medication
and should be used at the maximally tolerated intensity in those at highest
risk (e.g. clinical ASCVD)
• Currently approved PCSK9 inhibitors (alirocumab and evolocumab) achieve

significant reductions in LDL-cholesterol to previously unseen levels
• The PCSK9 inhibitors significantly and safely reduce the rate of adverse events
when added to statin therapy in high risk secondary prevention patients with
additional risk factors
• Incremental benefit for ASCVD (but not mortality) associated with lowering of
LDL-cholesterol levels well below current targets
Objectives
• Cholesterol
• Blood pressure
• Aspirin
• Lifestyle
980
2017 Guideline for the Prevention, Detection, Evaluation

and Management of High Blood Pressure in Adults
BP Classification (JNC 7 and ACC/AHA Guidelines)
SBP DBP 2003 JNC7 2017 ACC/AHA
<120 and <80 Normal BP Normal BP
120–129 and <80 Prehypertension Elevated BP
130–139 or 80–89 Prehypertension Stage 1 hypertension
140–159 or 90-99 Stage 1 hypertension Stage 2 hypertension
≥160 or ≥100 Stage 2 hypertension Stage 2 hypertension
• Blood Pressure should be based on an average of ≥2 careful readings on ≥2 occasions

• Adults with SBP or DBP in two categories should be designated to the higher BP category
Whelton PK et al. Hypertension. 10.1161/HYP.0000000000000065. [Epub ahead of print].
Whelton PK et al. J Am Coll Cardiol. 2017; doi: 10.1016/j.jacc.2017.11.006. [Epub ahead of print].
Direct relationship of CVD with urinary Sodium

2,275 individuals with Prehypertension
Cook et al, Circulation 2014:129:981
981

BP Thresholds for Treatment
SBP DBP CVD Risk/other circumstances Recommended Treatment
<120 and <80 N/A Healthy Lifestyle
120–129 and <80 N/A Nonpharmacological therapy
130-139 or 80-89 No CVD/10-yr ASCVD risk <10%* Nonpharmacological therapy
130–139 or 80–89 CVD/10-year ASCVD risk ≥ 10%
≥130 or ≥80 Diabetes or CKD Antihypertensive drug therapy

(plus nonpharmacological therapy)
≥130 Age ≥65 years
≥140 or ≥90 N/A
Whelton PK et al. Hypertension. 10.1161/HYP.0000000000000065. [Epub ahead of print]. * AHA/ACC 2013 Pooled
Whelton PK et al. J Am Coll Cardiol. 2017; doi: 10.1016/j.jacc.2017.11.006. [Epub ahead of print]. Cohort CVD Risk Equations

High BP Treatment Target
SBP DBP CVD Risk Recommended Treatment
<120 and <80 N/A N/A
120–129 and <80 N/A N/A
130-139 or 80-89 No CVD and 10-year

ASCVD risk <10%
130–139 or 80–89 Clinical CVD or 10-year
ASCVD risk ≥ 10%
SBP <130 and DBP <80 mm Hg
≥130 or ≥80 Diabetes or CKD
≥140 or ≥90 N/A
≥130 Age ≥65 years SBP <130 mm Hg
Whelton PK et al. Hypertension. 10.1161/HYP.0000000000000065. [Epub ahead of print].

Whelton PK et al. J Am Coll Cardiol. 2017; doi: 10.1016/j.jacc.2017.11.006. [Epub ahead of print].
982
Lifestyle Modifications for BP Control
Modification Recommendation Approximate SBP

Reduction Range
Weight Maintain normal body weight 5-20 mmHg/10 kg

reduction (BMI=18.5-25) weight lost
DASH eating Diet rich in fruits, vegetables, low 8-14 mmHg

plan fat dairy and reduced in fat
Restrict sodium <2.4 grams of sodium per day 2-8 mmHg

intake
Physical Regular aerobic exercise for at 4-10 mmHg

activity least 30 minutes at least 5 days of
the week
Moderate <2 drinks/day for men and <1 2-4 mmHg
alcohol drink/day for women
Chobanian AV et al. JAMA 2003;289:2560-2572
Included: SBP 130-180

Age >50 plus one CVD risk factor
SPRINT Excluded: Diabetes, CVA, HF
Target Systolic BP
Intensive Treatment Standard Treatment

Goal SBP < 120 mm Hg Goal SBP < 140 mm Hg
Screened
(n=14,692)
Randomized
(n=9,361)
Intensive treatment Standard treatment

SPRINT trialists. NEJM 2015;737:2103-16.
(n=4,678) (n=4,683)
983
SPRINT: Change in Blood Pressure
134.6 mmHg
(1.8 medications)
121.5 mmHg
(2.8 medications)
DBP: 66 vs. 75 mmHg

SPRINT
Median f/u = 3.3 yrs
Number needed to treat = 61
984
Summary of SPRINT Findings

• Difference of 13 mmHg SBP between Rx groups
• 3 vs. 2 BP meds
• 25% reduction primary outcome
• NNT 61
• 27% reduction all-cause mortality
• NNT 90
• Rx effect similar across all 6 pre-specified subgroups
• Patients >75 y/o with benefit
• 28% >75 yrs of age (mean age 80)
• No overall difference in serious adverse events
• Increased hypotension, electrolyte abnormalities, AKI, but not injurious falls
HOPE-3
~12K pts
No CVD
Annual risk ~1%
(10-yr risk ~ 10%)
Avg SBP ~138
Randomized:
Placebo vs
Canda 16 + HCTZ 12.5
~5.6 yrs f/u
Primary outcome:
CV death, MI, CVA
Upper BP tertile
benefit
HOPE-3 NEJM 2016
985
HOPE-3
HOPE-3 NEJM 2016
Causes of Secondary Hypertension
Medical Conditions Drugs

Chronic kidney disease NSAIDS
Primary hyperaldosteronism Oral contraceptives
Renovascular disease Adrenal steroids
Chronic steroid therapy Sympathomimetics
Cushing’s syndrome Cyclosporine or tacrolimus
Pheochromocytoma Erythropoietin
Aortic coarctation Ephedra, mu huang, bitter orange
Thyroid or parathyroid disease Cocaine or amphetamines
Sleep apnea Alcohol
Chobanian et al. JAMA 2003;289:2560-2572
986
Take-home messages
1. Risk-based assessment*
2. For most patients, goal is <130/ <80
3. Use any of: CCB, thiazides, ACE/ ARB, BB, taking into
account CKD, CAD, HF, aortopathy
*ACC/AHA Pooled Cohort Equations (http://tools.acc.org/ASCVD-

Risk-Estimator/) to estimate 10-year risk of atherosclerotic CVD.
Objectives
• Cholesterol
• Blood pressure
• Aspirin
• Lifestyle
987
What about Aspirin?

• Aspirin for CVD prevention
• Review overall estimates of benefit
• Review estimates in men, women
• Review the 2016 USPSTF guidelines
Aspirin: Mechanism of Action
Membrane Phospholipids
Arachadonic Acid
COX-1 Aspirin
Prostaglandin H2
Thromboxane A2 Prostacyclin
↑ Platelet Aggregation ↓ Platelet Aggregation
Vasoconstriction Vasodilation
Spite, Serhan Circulation Research 2010; 107:1170-1184
988
2016 U.S. Preventive Task Force Services

updated meta-analysis
Outcome No. trials No. individuals Summary Relative

Risk
Nonfatal MI 10 114,734 0.78 (0.71-0.87)
8 (≤100 mg) 87,524 0.83 (0.74-0.94)
Nonfatal stroke 10 99,655 0.95 (0.85-1.06)
7 (≤100 mg) 68,734 0.86 (0.76-0.98)
CVD mortality 11 118,445 0.94 (0.86-1.03)
8 (≤100 mg) 87,524 0.97 (0.85-1.10)
Total mortality 11 118,445 0.94(0.89-0.99)
8 (≤100 mg) 87,524 0.95 (0.89-1.01)
Guiruis-Blake JM et al. 2016 www.uspreventiveservicestaskforce.org
Aspirin in Primary Prevention:

Sex differences?
Mora, Manson. JAMA Internal Med 2016; 176

Antithrombotic Trialist Collaboration. Lancet 2009;373:1849
989
2016 U.S. Preventive Services Task Force

Recommendations for low dose aspirin
Population Recommendation Grade
Adults age 50-59 yrs For primary prevention of ASCVD and colorectal B (Moderate)
cancer if:
- ≥ 10% ASCVD risk *
- Not at increased risk of bleeding
- Life expectancy of at least 10 yrs
- Willing to take aspirin for at least 10 yrs
Adults age 60-69 yrs Individualize the decision if: C

- ≥ 10% ASCVD risk,
- Not at increased risk of bleeding
- Life expectancy of at least 10 yrs
- Willing to take aspirin for at least 10 yrs
Adults < 50 yrs Insufficient evidence I

Adults ≥ 70 yrs Insufficient evidence I
Guiruis-Blake JM et al. 2016 www.uspreventiveservicestaskforce.org
2016 ADA Aspirin Recommendations for Patients with Diabetes

• Aspirin 75 to 162 mg/day for primary ASCVD prevention
in diabetic patients at increased ASCVD risk and not
increased risk of bleeding
– Those at risk for ASCVD (10-year risk >10%)—men >50 yrs,
women >50 yrs, with >1 additional risk factor
– Family history of premature ASCVD
– HTN
– Smoking
– Dyslipidemia
– Albuminuria
• Not recommended for primary prevention in low risk
groups (10-year risk <5%)
• Clinical judgement for intermediate risk (5 to 10%) or
<50 yrs and risk factors
ADA Diabetes Care 2016;39:S1-S106
990
Longterm low-dose aspirin reduces cancer incidence and

metastasis, in particular for gastrointestinal cancers (colorectal)
Cancer incidence Cancer metastasis
Placebo
Aspirin
HR 0.88 (0.80-0.98), P=0.017 HR 0.81 (0.70-0.93), P=0.003
Years to Notification Years to Notification
Rothwell PM. et al. 2012 Lancet 13:518
Bleeding risks with aspirin

Risk factors for bleeding
Proton Pump Inhibitors (PPIs) may
Age
decrease risk of GI bleeding on aspirin
Male sex
GI hospitalization
Excess alcohol use
Current smoking
Hypertension
Diabetes
Liver / renal disease
Concomitant meds Tran-Duy A. et al. 2015 Int J Clin Pract doi:10.1111/ijcp.12634

(NSAIDs, anticoagulants)
Whitlock E et al. 2015 www.uspreventiveservicestaskforce.org

GI: Gastrointestinal
991
Primary Prevention with Aspirin:

Tipping the Scales
www.aspiringuide.com
Nonfatal GI or Intracranial
CVA/MI Bleed
Older age
ASCVD Risk Male
NSAID/anticoag
Ulcers
Prior GIB
Mora et al JAMA 2016; 316:709

Mora and Manson JAMA Internal Med 2016; 176
Aspirin-Guide
www.
aspiringuide.com
JAMA 2016; 316:709

JAMA Internal Med 2016; 176
992
Objectives
• Cholesterol
• Blood pressure
• Aspirin
• Lifestyle
Preventability of
Heart Disease, Stroke, and Diabetes
With lifestyle
modifications*
-83% -79% -91%
* Physical activity, not smoking, weight control, healthy diet (high in whole grains, fiber,
fruit/veg, fish, low in saturated and trans fats), moderate alcohol.
Stampfer, et al. NEJM 2000; Chiuve, et al. Circulation 2008; Hu, et al. NEJM 2001.
993
AHA Life’s Simple 7

1. ≥150 minutes moderate activity /week
or ≥75 minutes vigorous activity/week
2. Eat a healthy diet (4-5 components of
healthy diet score*)
3. Have a normal body weight (BMI < 25)
4. Never smoked or quit >1 year ago
5. Total cholesterol <200 mg/dL
6. Blood pressure <120/80 mm Hg
7. Fasting blood glucose <100 mg/dL
* 1) 4.5 cups or more of fruits and vegetables per day 2)
two or more 3.5-oz servings of fish per week 3) three
servings per day of whole grains 4) less than 1500 mg of
sodium per day 5) 36 ounces or less of sugar-sweetened
beverages per week
Lloyd-Jones et al. Circulation 2010; 121:586-613
AHA Life’s Simple 7 predicts mortality
Yang et al. JAMA 2012; 307:1273-83
994
Activity Recommendations for CV/General Health

• Goal: 30 minutes 7 days per week (minimum 5 days
per week)
• Assess risk with history and/or exercise test: I (B)
• 30-60 min moderate aerobic + increase in daily
activities: I (B)
• Encourage resistance training 2/week: IIb (C)
• Medically supervised programs for high-risk (ACS,
revascularization, heart failure): I (B)
Courtesy of Donna Polk, MD
Physical Activity Recommendations for LDL and BP
3 to 4 sessions a week, lasting on average 40

minutes per session, and involving moderate-to-
vigorous intensity physical activity.
Eckel RH et al. Circulation 2013: 10.1161/01.cir.0000437740.48606.d1
995
2014 ACC/AHA/TPC Obesity Guideline Goals
• BMI 18.5 to 24.9 kg/m2
• Women: WC <35 inches

• Men: WC <40 inches
• 3 to 5% sustained weight reduction in

overweight/obese individuals with CVD risk
factors
Jensen et al. Circulation 2014: 129: S102
Diet Recommendations for Weight Reduction

I IIa IIb III
Prescribe a diet to achieve reduced calorie intake for obese or
overweight individuals who would benefit from weight loss, as part
of a comprehensive lifestyle intervention. Any one of the following
methods can be used to reduce food and calorie intake:
a. Prescribe 1,200–1,500 kcal/d for women and 1,500–1,800
kcal/d for men (kilocalorie levels are usually adjusted for the
individual’s body eight);
b. Prescribe a 500-kcal/d or 750-kcal/d energy deficit; or
c. Prescribe one of the evidence-based diets that restricts
certain food types (such as high-carbohydrate foods, low-
fiber foods, or high-fat foods) in order to create an energy
deficit by reduced food intake.
996
Scientific Report of the 2015 Dietary Guidelines

Advisory Committee (Key Recommendations)
Three beneficial dietary patterns
1. Healthy US-style pattern

2. Healthy Mediterranean-style pattern
3. Healthy Vegetarian pattern
https://health.gov/dietaryguidelines/2015-scientific-report/pdfs/scientific-report-of-the-2015-dietary-guidelines-advisory-committee.pdf
Dietary Priorities
Mozaffarian Circulation 2016: 129: S102
997
Women’s Health Initiative (WHI)
Howard et al JAMA 2006;295:655
998
Lyon Diet Heart Study
De Lorgeril M et al. Arch Intern Med 1998;158:1161 De Lorgeril M et al. Circ 1999;99:779-785
PREDIMED STUDY
N=7447
57% women
High CVD risk
No prior CVD
RRR of Mediterranean diet (EVVO or raw nuts)

reduced CVD by 30% compared with control diet
Estruch et al NEJM 2013;368:1279
999
Statins
Cholesterol Treatment Trialists CTT Collaborators. Lancet. 2012;380:581–590.
PREDIMED Study Design. Participants
Men: 55-80 y 1. Smoking

2. Hypertension
Women: 60-80 y
3. ↑ LDL-C
High risk without CVD 4. ↓ HDL-C
with type 2 diabetes or 5. Overweight / obesity
3+ CVD risk factors 6. Family history of early-onset CHD
Random
N=7447
1000
PREDIMED: 3 Randomized Groups

Mediterranean diet + Extra-Virgin Olive Oil
Advice on MeDiet + EVOO ≥ 50 ml/day (~4 Tbsp/d)
(1 gallon/m)
Mediterranean diet + Nuts

Advice on MeDiet +
3 whole walnuts (15 g)
+ 30 g of raw nuts
8 hazelnuts (7.5 g) per day
+
6 almonds (7.5 g)
Control group: Advice on a low-fat diet (Reduce fat, discourage

use of nuts and olive oil; Non-food items)
PREDIMED: Compliance with Mediterranean Diet
Estruch R. et. al. N Engl J Med 2013;368:1279-90
1001
Food Differences between Mediterranean

and Control Diets
KEY FOODS MeDiet + EVOO MeDiet + nuts Control P value
diet
Grams/day
Virgin olive oil 29 10 3 < 0.001
Refined-mixed olive oil - 17 -6 -4 < 0.001
Nuts 0 18 -3 < 0.001
Legumes 2.4 2.4 0 < 0.001
Fish or Seafood 1.25 2.50 -4 ≤ 0.01
The change is follow-up minus baseline; the last available follow-up FFQ of each
participant was used.
Differences in consumption of other key foods were not statistically significant.
Topics discussed
• Cholesterol
• Blood pressure
• Aspirin
• Lifestyle
1002
Summary Slide Take-home messages

1. First step in prevention is to assess ASCVD risk
(risk factors, global risk score)
2. Lifestyle improvement is the most important component of ASCVD
prevention and risk factor treatment (Life’s Simple 7)
3. Statins added to lifestyle to reduce risk of ASCVD in higher risk
individuals (4 statin benefit groups); PCSK9i in the very highest
risk patients
4. Blood pressure control: Target BP for most patients <130/80
mmHg; risk-based assessment
5. Aspirin (81-162 mg/d) in higher risk individuals if benefit outweighs
risk of bleeding (avoid in low risk individuals and elderly)
Question
According to the 2013 ACC/AHA guideline on treatment of blood
cholesterol to reduce ASCVD risk in adults, what is the
definition of high-intensity statin therapy? (select the best
answer) A. Daily dose lowers LDLC by ≥75%
B. Daily dose lowers LDLC by ≥50%

C. Daily dose lowers LDLC by 30 to 50 %
D. Daily dose lowers LDLC by 25%
1003
Answer / Discussion
According to the 2013 ACC/AHA guideline on treatment of blood cholesterol to reduce
ASCVD risk in adults, what is the definition of high-intensity statin therapy? (select
the best answer) Discussion:
• High intensity statin usually
A. Daily dose lowers LDLC by ≥75%
lowers LDLC by 50%
B. Daily dose lowers LDLC by ≥50% • Moderate intensity statin
daily dose lowers LDLC by
C. Daily dose lowers LDLC by 30 to 50 % 30-50%
D. Daily dose lowers LDLC by 25% • Low intensity statin daily
dose lowers LDLC by <30%
Statin Intensity
High: Moderate: Low: Lowers LDL-C
Lowers LDL-C by ≥50% Lowers LDL-C 30 to <30%
<50%
Atorvastatin 40, 80 Atorvastatin 10, 20
Rosuvastatin 20, 40 Rosuvastatin 5, 10
Simvastatin 20, 40 Simvastatin 10
Pravastatin 40, 80 Pravastatin 10, 20
Lovastatin 40 Lovastatin 20
Fluvastatin XL 40 BID Fluvastatin 20, 40
Pitavastatin 2, 4 Pitavastatin 1
Stone et al JACC 2014;63:2889-934
1004
Question / Case
26 yo Hispanic M, smoker, multiple borderline risk factors,
BMI 33, Lp(a) 70 (uln 30 mg/dL) - one day prior to ACS:
• Does he have any of the other factors that the 2013
ACC/AHA guidelines recommend can be considered if a
risk decision is not certain? (select the best answer)
A. Smoking
B. Obesity (his BMI 33)
C. High lifetime risk
D. High Lp(a) (his Lp(a) 70 mg/dL)
Answer / Case Discussion

yo Hispanic M, smoker, multiple borderline risk factors, BMI 33, Lp(a) 70 (uln 30 mg/dL) -
one day prior to ACS:
• Does he have any of the other factors that the 2013
ACC/AHA guidelines recommend can be considered if a
risk decision is not certain? Discussion:
A. Smoking • High lifetime risk is
a factor that the
B. Obesity (his BMI 33) guidelines say can
C. High lifetime risk inform treatment
decision (2013
D. High Lp(a) guidelines would
support moderate
statin Rx here)
1005
One day prior to his ACS, what was his risk?

According to the 2013 ACC/AHA guidelines
60
Predicted Risk (%)
40
20
0
10-yr risk Lifetime risk
Jose Optimal RF
* Optimal risk factors: TC 170, HDL-c 50, SBP 110, No DM, No HTN or Rx
*
http://my.americanheart.org/cvriskcalculator 85
Question
The 2016 USPSTF recommend considering aspirin for primary
prevention of ASCVD for individuals 50-69 years who are not
at increased risk of bleeding if (select the best answer)
A. 10-yr ASCVD ≥7.5%
B. 10-yr ASCVD ≥10%
C. 10-yr ASCVD ≥10% AND age >70 y
D. None of the above
1006
Answer / Discussion
The 2016 USPSTF recommend considering aspirin for primary
prevention of ASCVD for individuals 50-69 years who are not
at increased risk of bleeding if
Discussion:
A. 10-yr ASCVD ≥7.5% • 7.5% is the threshold for the
cholesterol guidelines
B. 10-yr ASCVD ≥10%
• Age > 70 Grade I (Insufficient
C. 10-yr ASCVD ≥10% AND age >70 y evidence) [also increased
risk bleeding]
Supplemental References
1. Risk assessment guidelines. Goff et al JACC
2014;63:2935-59
2. Cholesterol guidelines. Stone et al JACC
2014;63:2889-934
3. Lifestyle guidelines. Eckel et al Circulation
2014;129:S76-99
4. Obesity guidelines. Jensen et al Circulation
2014;129:S102
5. 2017 ACC/AHA BP guidelines. Whelton PK et al. JACC
2017 ; doi: 10.1016/j.jacc.2017.11.006.
6. 2016 USPSTF aspirin guidelines.
www.uspreventiveservicestaskforce.org
1007
Acute Coronary Syndrome Management
HMS & BWH

Marc S. Sabatine, MD, MPH

Chairman, TIMI Study Group
Lewis Dexter, MD, Distinguished Chair in Cardiovascular Medicine, BWH
Professor of Medicine, Harvard Medical School
Disclosures
Research Grant Support through BWH:
Amgen; AstraZeneca; Daiichi-Sankyo; Eisai; GlaxoSmithKline; Intarcia; Janssen Research and
Development; Medicines Company; MedImmune; Merck; Novartis; Pfizer; Poxel; Takeda
Scientific Advisory Boards & Consulting:

Consulting for: Amgen; AstraZeneca, Bristol-Myers Squibb; CVS Caremark; Dyrnamix; Esperion;
Intarcia; Janssen Research and Development; Medicines Company; MedImmune; Merck; Novartis
An Academic Research Organization of

Brigham and Women’s Hospital and Harvard Medical School
1008
ACUTE CORONARY SYNDROMES
Non-ST elevation ACS ST elevation ACS

CK-MB
Tn
UA NSTEMI STEMI
UA NQWMI QwMI
ACS: ECG
• What to look for
– STE or LBBB not known to be old
– ST depression ≥0.5 mm; TWI >1 mm
– Coronary distribution
• What else to look for
– Q waves or poor R wave progression (PRWP)
• How to look for it
– 12-lead ECG w/in 10 mins of presentation
– Compare to prior ECGs
– Obtain serial ECGs (initial ⊕ in <50% ACS Pts)
1009
ACS: Biomarkers
Era Assay Measure at presentation
+…
Ancient Historsy CK-MB q8 hrs × 3

(1980s)
Dawn of modern Troponin q8 hrs × 3

cardiac markers
(1990s)
Recent past Troponin 3-6 hrs after sx onset

Now hs-Troponin 1 (to 3) hours later
(If presentation ≥3 h after sx onset)
Examine absolute and ∆
Other Causes of ⊕ Troponin

• Very rarely “false positive” (ie, no true
myocardial injury - ? renal failure)
• “Type 2 MI” = myocyte injury not due to ACS
– Supply-demand mismatch not due to ∆ in CAD
• HoTN, tachycardia or HTN crisis
• HCM, severe AS
• Coronary spasm
– Non-ischemic injury: myocarditis, contusion
– Multi-factorial
• CHF exacerbation
• PE, ARDS, severe pneumonia
• Sepsis, stroke
1010
“Minor” Elevations of cTn in ACS

and Clinical Outcomes
99th %ile AMI per CK-MB
16
Normal "Leaklet” AMI
12.1
D/MI/ACS thru 30 days
12 11.3
10.5
8
5.5
4
n=734 n=181 n=213 n=693

0
<0.1 0.1-0.4 0.4-1.5 >=1.5

Brigham and Women’s Hospital and Harvard Medical School Troponin I Morrow DA et al. JAMA 2001;286:2405
ACS Likelihood
Feature High Intermediate Low
History • Chest or L arm pain or • Chest or L arm pain or • Prob ischemic sx w/o
discomfort as chief sx ≈ discomfort as chief sx intermed-likelihood
prior doc angina • Age >70 y characteristics
• Known h/o CAD • Male sex • Recent cocaine use
Exam • Transient MR murmur, HoTN, • Extracardiac vascular • Chest discomfort

diaphoresis, pulm edema, or disease reproduced by palp
rales
ECG • New, or presumably new, • Fixed Q waves • Tw flattening or

transient ST deviation • ST depression 0.5-1 mm inversion <0.1 mV in
(≥1 mm) or TWI (≥2 mm) in or TWI >1 mm leads w/ dominant R
multiple precordial leads waves
• Normal ECG
Biomarkers • Elevated • Normal • Normal
ACC/AHA 2007 UA/NSTEMI Guidelines. Circulation 2007;116:e148

1011
CCTA vs Perfusion Imaging

Parameter Standard of Care
CCTA
N 501 449 P
Cost Effectiveness
Median Time to dx (hr, IQR) 5.8 (4.0-9.0) 21.0 (8.5-23.8) <.001
Length of stay (hr, IQR) 8.6 (6.4-27.6) 26.7 (21.4-30.6) <.001
Mean Total Cost $4026 ± 6792 $3874 ± 5298 .75
Procedures
Angiography 11% 7% .06
Revasc (PCI or CABG) 6% 4% .14
Safety
MACE 2 6 .18
Radiation exposure (mSv/pt) 13.9 ± 10.4 4.7 ± 8.4 <.001
Hoffmann et al. NEJM 2012;367:299
ST-Elevation MI (STEMI)
• Consider immediate reperfusion therapy
• In whom?
– Within 12 hrs of sx onset, or
– 12-24 hrs after sx onset if clinical or ECG evidence of
ongoing ischemia
• How?
– Primary PCI (including transfer to PCI-capable hosp
if door-in to door-out time will be <30 min &
1st med contact to PCI anticipated <120 min)
– Fibrinolytic (barring contraindications*)
*Absolute: prior ICH; intracranial neoplasm, aneurysm, or AVM; stroke or head trauma w/in 3 mos; active
internal bleeding or diathesis; suspected AoD
*Relative: severe HTN; stroke; prolonged CPR; recent bleed, surgery or trauma; noncompressible vasc
puncture; pregnancy; current use of anticoagulants
1012
Preventive PCI in STEMI

PRAMI: 465 Pts w/ STEMI CvLPRIT: 296 Pts w/ STEMI
Immediate PCI of all other lesions >50% PCI of all other lesions >70% during index hosp.
25
Cardiac death, MI, refractory angina (%)
Death, reMI, HF, IDR (%)

20
P=0.009
15
10
0
Culprit only Complete
NEJM 2013;369:1115 JACC 2015;65:963

What To Do after Fibrinolysis?

• If it fails (persistent STE [<50% resolution] or sx, development of
shock, evidence of infarct-related artery reocclusion): PCI
• If it succeeds:
• Non-invasive ischemia testing (ie, stress test), OR
• Transfer high-risk pts w/in 3-24 hrs for elective PCI
(high-risk = anterior MI, inferior MI w/ low EF or RV infarct,
extensive STE or LBBB, HF, hypotension or tachycardia)
D, MI, RI, CHF/shock
88.7% cath
• 1059 high-risk STEMI median time 32.5 h (1/3 w/in 12 h) P=0.004
Pts Rx’d with lytic 67.4% PCI, 22.7 h from lytic
• Rand. to immed transfer 98.5% cath

w/ PCI w/in 6 h or rec for median time 2.8 h
cath w/in 2 wks (earlier 84.9% PCI; 3.9 h from lytic
if needed)
Transfer-AMI, NEJM
2009;360:2705-18
1013
Anti-Ischemic Therapy
• Nitrates
– Sx relief; no mort benefit (GISSI-3 & ISIS-4)
• Beta-blockers
– ↓ ischemia, ↓ D/MI (in AMI trials)
• Calcium channel blockers
– If ischemia despite max βB or βB contra.
• Morphine
– Pain, CHF, agitation; don’t mask angina
• Oxygen
Beta-Blockers Acutely in ACS

Class I
Oral βB should be initiated in the first 24 hrs if w/o any of following:
1) heart failure,
2) low output state,
3) ↑ risk for cardiogenic shock, or
4) other relative contraindications (PR >0.24 sec, 2° or 3° AVB,
active asthma, or reactive airways disease)
Class III Harm

IV βB at time of presentation if risk factors for shock
Risk factors for cardiogenic shock (the greater the number of risk factors present, the higher the risk)
are age >70 yrs, SBP <120 mm Hg, HR >110 bpm or <60 bpm, and ↑ time since onset of symptoms.
Circ 2013;127:e362
1014
Management Strategy in NSTEACS

INVASIVE
(ie, angiography for all in ~48 hrs)
PCI / CABG
NSTEACS
anatomy
Long-term
Initial Med Rx
Med Rx
high-risk low-risk
recurrent
angina
Cont’d
Med Rx
CONSERVATIVE
(ie, selective angiography)
Benefit of INV vs CONS Strategy

Brigham and Women’s Hospital and Harvard Medical School O’Donoghue M, et al. JAMA 2008;300:71-80
1015
Troponin Treatment Interaction

CONS INV
OR=0.41
30
D/MI/ACS at 30 days (%)
Interaction (0.28-0.61)
25 P<0.001 p<0.001
20 17.6
OR=1.60 16.5 15.6
15 (0.83-3.0)
P=NS 8.8
10
6.6
4.3 4.4 5.4
5
0
<0.1 0.1-0.4 0.4-1.5 >=1.5
N=734 N=181 N=213 N=693
TnI Level at Presentation
Brigham and Women’s Hospital and Harvard Medical School Cannon CP et al. NEJM 2001;344:1879
TIMACS
3031 Patients with NSTEACS
Cath w/in 24 h (median 14 h) or >36 h (median 50 h)
D, MI, refract ischemia
D, MI, stroke
Mehta SR et al. NEJM 2009;360:2165-75
1016
2014 ACC/AHA NSTEACS Guidelines:

Early Invasive
Immediate Early Invasive Delayed Invasive Ischemia-Guided
(w/in 2 h) (w/in 24 h) (w/in 25-72 h)
• Refractory angina • GRACE score >140 • TIMI Risk Score ≥2 • TIMI Risk Score 0-1
• Signs or symptoms • Temporal ∆ in Tn • GRACE score >109- • GRACE score <109
of HF or new or • New or presumably 140 • Low-risk Tn-neg
worsening MR new ST depression • Diabetes female patient
• Recurrent angina or • GFR <60 • Patient or clinician
ischemia at rest or mL/min/1.73m2 preference in
with low-level activity absence of high-risk
despite intensive • EF <0.40
features
med Rx • Early postinfarction
angina
• PCI w/in 6 mo
• Prior CABG

Brigham and Women’s Hospital and Harvard Medical School Circulation 2014;130:2354-94
Antithrombotics
• Antiplatelet drugs
– Start with COX Inhibitor (ie, aspirin)
– Almost always add: P2Y12 ADP Receptor Blocker (eg, clopidogrel,
prasugrel, ticagrelor)
– Sometimes also add: glycoprotein IIb/IIIa inhibitors (eg, abciximab,
eptifibatide, tirofiban)
• Anticoagulants (one of the following)

– Unfractionated heparin (UFH)
– Low-molecular-weight heparin: enoxaparin or dalteparin
– Direct thrombin inhibitors: bivalirudin
– Pentasaccharide blockers: fondaparinux

1017
Antiplatelet Therapy
Clopidogrel
Prasugrel
Ticagrelor
ADP Receptor (P2Y12)
Abciximab
Eptifibatide Ticlopidine
Tirofiban ADP
ADP
GP IIb/IIIa
receptor
Collagen
Activation Thrombin
TXA2
Fibrinogen COX
TXA2
Aspirin
Give ASA 162-325 mg PO to all patients w/ ACS

(barring contraindication)
ADP = adenosine diphosphate, TXA2 = thromboxane A2, COX = cyclooxygenase.
Adapted from Schafer AI. Am J Med. 1996;101:199-209.
Clopidogrel in Acute Coronary Syndromes

CURE CLARITY-TIMI 28
12,563 Pts w/ NSTEACS 3,491 Pts w/ STEMI
Predominantly managed conservatively Fibrinolytic therapy
14
15
Placebo Placebo
CV Death, MI, or Urg Revasc (%)
12
CV Death, MI, Stroke (%)
10
10
Clopidogrel
8 Clopidogrel
6
Odds Ratio 0.80
5
RR 0.80
4 (95% CI 0.65-0.97)
P=0.001 P=0.026
2
0
0
0 3 6 9 12 0 5 10 15 20 25 30
months days
Yusuf et al. NEJM 2001;345:494 Sabatine MS et al. NEJM 2005;352:1179
1018
13,608 Patients with ACS and Planned

PCI Randomized to Prasugrel (60/10)
vs. Clopidogrel (300/75)
15
Clopidogrel
12.1 HR 0.81
CV Death / MI / Stroke (0.73-0.90)
10 9.9 P=0.0004
Endpoint (%)
Prasugrel
5
TIMI Major Prasugrel
Non-CABG Bleeds HR 1.32
2.4
(1.03-1.68)
1.8
P=0.03
Clopidogrel
0
0 30 60 90 180 270 360 450
Days
Wiviott SD et al. NEJM 2007;357:2001-15
Primary efficacy endpoint: CV death, MI or stroke

18,624 Patients w/in 24 hrs of onset of ACS
13
12 HR 0.84
Clopidogrel 11.7
11 (95% CI 0.77–0.92)
Cumulative incidence (%)
10 P=0.0003 9.8
9
Ticagrelor
8
7
6
5
4
3 Cardiovascular Death: 4.0% vs. 5.1%, HR 0.79 (0.69-0.91), P=0.001
2 All-cause Mortality: 4.5% vs. 5.9%, HR 0.78 (0.69-0.89), P<0.001
1
0
0 60 120 180 240 300 360
Days after randomisation
No. at risk
Ticagrelor 9,333 8,628 8,460 8,219 6,743 5,161 4,147
Clopidogrel 9,291 8,521 8,362 8,124 6,743 5,096 4,047
K-M = Kaplan-Meier; HR = hazard ratio; CI = confidence interval

Wallentin L, et al. NEJM 2009;361:1045-57
1019
Bleeding
13 NS
Ticagrelor
12 11.6 Clopidogrel
11.2
11
NS
K-M estimated rate (% per year)
10
NS 8.9 8.9
9
7.9
8 7.7
7 NS
5.8 5.8
6
5
4 p=0.025
2.8
3
2.2
2
NS
1 0.3 0.3
0
PLATO major TIMI major Non-CABG Red cell PLATO life- Fatal bleeding
bleeding bleeding TIMI major transfusion* threatening/
bleeding fatal bleeding
Major bleeding and major or minor bleeding according to TIMI criteria refer to non-adjudicated events analysed with the use
of a statistically programmed analysis in accordance with definition described in Wiviott SD et al. NEJM 2007;357:2001–15;
*Proportion of patients (%); NS = not significant
2014 ACC/AHA NSTEACS Guidelines:

P2Y12 Inhibitors
Recommendation COR LOE
Clopidogrel 300-600 mg load (latter preferred before PCI) → 75 mg/d I B
Prasugrel 60 mg loading dose → 10 mg/d (PCI only) I B
Ticagrelor 180 mg loading dose → 90 mg/bid (initial Rx or PCI) I B
Reasonable to use ticagrelor in preference to clopidogrel (initial Rx IIa B

or PCI)
Reasonable to use prasugrel in preference to clopidogrel (PCI only) IIa B
Prasugrel should not be given if prior stroke or TIA III: Harm B

Brigham and Women’s Hospital and Harvard Medical School Circulation 2014;130:2354-94
1020
Glycoprotein IIb/IIIa Inhibitors

• Potent intravenous antiplatelet drugs
• Typically consider giving at time of PCI
• UA/NSTEMI
– INV Strategy: give at time of PCI; upstream use (ie, prior to
angiography) w/o clear efficacy and increases risk of bleeding
– CONS Strategy: usually no role unless Pt goes for PCI
• STEMI
– Primary PCI: give at time of PCI (not before)
– Fibrinolysis: CONTRAINDICATED
Coagulation Cascade & Anticoagulants

AMPLIFICATION (“Intrinsic”) INITIATION (“Extrinsic”)
(FXII, FXI, platelet membrane) (Tissue Factor, FVIIa, Ca2+) Warfarin
Intrinsic Extrinsic
IX Tissue Factor IXa Tenase Tenase Rivaroxaban (PO)
Apixaban (PO)
Edoxaban (PO)
VIII Thrombin VIIIa
V Thrombin Va
V X Xa ATIII Fondaparinux
Prothrombinase
ATIII LMWH
ATIII UFH
Prothrombin Thrombin Fibrin Formation
Bivalirudin (IV)
Platelet Dabigatran (PO)
Activation
1021
Anticoagulants Acutely
• Unfractionated heparin (UFH)
– Most commonly used; fast on & fast off; reversible
– Wt-based dosing; unpredictable PD, requiring PTT
– Compared with no anticoagulation: D/MI by ~33%
• Low-molecular weight heparin (LMWH)

– More predictable PD; not as reliably reversed
– Compared with UFH: 9% D/MI, may bleeding
– Consider in conservatively managed patients
• Bivalirudin
– Fast on & fast off
– Compared with heparin: 9% MACE, 38% stent thrombosis,
bleeding (especially if compared with UFH+GP Iib/IIIa inhibitor)
– Consider in invasively managed Pts, espec if at high risk for bleeding
Oler et al. JAMA 1996;276:811; JAMA 2004; 292: 45, 55, & 89
Cavender MA and Sabatine MS. Lancet 2014;384:599-606
CURE: Long-term benefit of clopidogrel

12,562 Patients with NSTEACS (mostly conservatively managed)
CV Death, MI, or Stroke CV Death, MI, or Stroke

First 30 Days >30 Days–1 Year
1.00 1.00
Proportion Event-Free
Proportion Event-Free
Clopidogrel .98 Clopidogrel

.98
.96 .96
Placebo Placebo
.94 .94
RRR: 21% RRR: 18%
.92 95% CI, 0.67–0.92 .92 95% CI, 0.70–0.95
P=.003 P=.009
.90 .90
Week 0 1 2 3 4 Month 1 4 6 8 10 12
No. at Risk No. at Risk
Clopidogrel 6259 6145 6070 6026 5990 5981 5481 4742 4004 3180 2418
Placebo 6303 6159 6048 5993 5965 5954 5390 4639 3929 3159 2388
Yusuf S, et al. Circulation. 2003;107:966-972.
1022
Continued Divergence of Event Curves With

More Potent Long-Term P2Y12 Inhibition
8 8
6.9
6.6
Clopidogrel Clopidogrel
CV Death, MI, or Stroke (%)

6 6
5.6 5.3
4
4
Ticagrelor
Prasugrel
2
2 HR 0.80 HR 0.80
P=0.003 P<0.001
1
0
0
3 30 60 90 180 270 360 450 31 90 150 210 270 330
Days after randomisation Days after randomisation
Wiviott SD et al. NEJM 2007;357:2001-15 Wallentin L, et al. NEJM 2009;361:1045-57
Ticagrelor in Patients w/ Prior MI

10
21,162 Patients w/ MI 1-3 years prior
9 All on low-dose ASA Placebo (9.0%)
Median follow-up 33 months
8 Ticagrelor 90 (7.8%)
Ticagrelor 60 (7.8%)
7
Ticagrelor 90 mg
4
HR 0.85 (95% CI 0.75 – 0.96)
3 P=0.008
Ticagrelor 60 mg
2
HR 0.84 (95% CI 0.74 – 0.95)
1 P=0.004
0
0 3 6 9 12 15 18 21 24 27 30 33 36
Months from Randomization

Brigham and Women’s Hospital and Harvard Medical School Bonaca MP et al. and Sabatine MS. NEJM 2015; 372:179
1023
Efficacy of Adding Low-dose NOAC to

DAPT post-ACS
CV Death / MI / Stroke Cardiovascular Death All Cause Death

5% 5%
HR 0.85 HR 0.62 HR 0.64
12% Placebo Placebo Placebo
Estimated Cumulative incidence (%)
mITT 10.4% mITT mITT 4.5%

p=0.04 p<0.001 4.2% p<0.001
9.0%
ITT ITT ITT
p=0.01 p<0.001 p<0.001
2.7%
2.5%
Rivaroxaban Rivaroxaban Rivaroxaban

2.5 mg BID 2.5 mg BID 2.5 mg BID
NNT = 71 NNT = 59 NNT = 56
0 12 24 0 12 24 0 12 24
Months Months Months
Mega JL et al. NEJM 2012;366:9-19
Long-term Low-Dose Anticoagulation
COMPASS Trial: 27,395 patients with stable ASCVD
5 mg bid
2.5 mg bid
Years
An Academic Research Organization of NEJM 2017;377:1319

1024
“Triple Therapy” (DAPT + OAC)

Favors less intensive antithrombotic Rx Favors more intensive
(eg, dose NOAC and/or antiplt monoRx) antithrombotic Rx
Coronary Risk Acute MI

Elective PCI
Multiple, long, narrow (antiplt)
Single next gen DES
stents
Stroke Risk Prior stroke or high CHA2DS2-VASc

CHA2DS2-VASc = 1 LV thrombus
(anticoag)
Large VTE
HAS-BLED ≥3 Bleed Risk

(esp. h/o bleed, ICH, HAS-BLED ≤2
elderly, renal dysfxn)

Beta-Blockers: Clinical Data

1884 Patients 1-4 weeks after acute MI
Randomized to β-blocker vs. placebo
45% risk reduction 28% risk reduction

P=0.0001 P=0.0006
Norwegian Multicenter Study Group. NEJM 1981;304:801.
1025
PROVE IT – TIMI 22
4162 patients hospitalized w/in prior 10 d for ACS
30 Pravastatin 40 mg
Death or Major CV Events (%)
(avg achieved LDL = 95 mg/dl)

25
20
Atorvastatin 80 mg
15 (avg achieved LDL = 62 mg/dl)
10
16% RR
5
(P = 0.005)
0
0 3 6 9 12 15 18 21 24 27 30
Months of Follow-up
Cannon et al. NEJM 2003; 350: 1495
Primary Endpoint — ITT

Cardiovascular death, MI, documented unstable angina requiring
rehospitalization, coronary revascularization (≥30 days), or stroke
HR 0.936 CI (0.887, 0.988) Simva alone
p=0.016 (achieved LDL-C 34.7%
69.5 mg/dL) NNT= 50
32.7%
EZE + Simva
(achieved LDL-C
53.7 mg/dL)
7-year event rates

NEJM 2015;372:2387-97
1026
IMPROVE-IT vs. CTT:

Ezetimibe vs. Statin Benefit
. IMPROVE-IT
CTT Collaboration.
Lancet 2005; 366:1267-78; Using CTT methods: LDL difference between groups using baseline LDL for Pts without blood
Lancet 2010;376:1670-81. samples. Endpoint of CV Death, MI, stroke or revasc >30days post Rand. Cox HR reported.
Summary of Effects of
PCSK9i Evolocumab
• ↓ LDL-C by 59% down to a median of 30 mg/dl
• ↓ CV outcomes in patients on statin
• Safe and well-tolerated HR 0.85 (0.79-0.92)
100
Placebo P<0.0001
15 14.6
80 12.6 HR 0.80 (0.73-0.88)
LDL Cholesterol (mg/dl)
59% reduction P<0.0001

KM Rate (%) at 3 Years
P<0.00001
60 9.9
10
Absolute 56 mg/dl 7.9
40
5
20 Evolocumab
(median 30 mg/dl, IQR 19-46 mg/dl)
0 0
0 24 48 72 96 120 144 168 CVD, MI, stroke CVD, MI, stroke
Weeks after randomization UA, cor revasc
Sabatine MS et al. NEJM 2017;376:1713-22
1027
ACC 2018
Non-Statin Therapy
1028
LDL Cholesterol
2034 patients w/ baseline LDL-C<70 mg/dL
100
90
Placebo
80 (median 66 mg/dl, IQR 56-78 mg/dl)
(median 1.7 mmol/L, IQR 1.4-2.0 mmol/L)
LDL Cholesterol (mg/dl)
70
60
50
66% mean reduction (95%CI 62-69), P<0.00001
40
30
20
Evolocumab
10 (median 21 mg/dl, IQR 11.5-37 mg/dl)
(median 0.5 mmol/L, IQR 0.3-1.0 mmol/L)
0
0 12 24 36 48 60 72 84 96 108 120 132 144
Weeks
Giugliano RP et al. and Sabatine MS. JAMA Cardiol 2017;2:1385-91
Clinical Outcomes
by Baseline LDL-C
CVD, MI, stroke, UA, or cor revasc HR (95% CI) Pinteraction
All Patients 0.85 (0.79-0.92)
Baseline LDL-C <70 mg/dL 0.80 (0.60-1.07)

0.65
Baseline LDL-C ≥70 mg/dL 0.86 (0.79-0.92)
0.4 1.0 2.5

CVD, MI, or stroke
All Patients 0.80 (0.73-0.88)
Baseline LDL-C <70 mg/dL 0.70 (0.48-1.01)

0.44
Baseline LDL-C ≥70 mg/dL 0.81 (0.73-0.89)
0.4 1.0 2.5

EvoMab better Pbo better

Giugliano RP et al. and Sabatine MS. JAMA Cardiol 2017;2:1385-91
1029
CV Death, MI, Stroke
P = 0.0001
mM
19 39 58 77 97 116 135 155 174 mg/dL

LDL-C at 4 weeks
Giugliano RP et al. & Sabatine MS. Lancet 2017;309:1962-71
ACE Inhibitors Post-MI with EF <40% but asx
19% Reduction in
Mortality
Pfeffer MA et al. NEJM 1992;327:669-677.
1030
ACE Inhibitors in All Acute MI
Greater apparent benefit

7% Reduction in
Mortality in anterior STEMI
than in inferior STEMI or
NSTEACS
ISIS-4. Lancet 1995;345:669.
Aldosterone Antagonists
6632 patients with recent MI and EF <40% w/ either HF sx or diabetes
All-cause mortality
Pitt B et al. NEJM 2003;348:1309-1321.
1031
Summary
• Diagnose ACS using H&P, 12-lead ECG, troponin
• For STEMI: select Primary PCI vs Lytic
• For UA/NSTEMI: select Invasive (eg, ⊕ Tn) vs. Conservative Strategy
• Anti-ischemic Rx: beta-blocker, nitrates
• Select Antiplatelet Regimen
– ASA
– + P2Y12 Inhibitor: ticagrelor, prasugrel, or clopidogrel
– ? + GP IIb/IIIa inhibitor (typically at time of PCI)
• Select Anticoagulant: UFH, LMWH, or bivalirudin (or fondaparinux)
• Long-term therapy
– ASA, P2Y12 inhibitor (at least 12 mos, if not longer)
– β-blocker, statin (+ EZE + PCSK9i)
– ? ACEI, ? Aldo inhibitor
Question #1
A 67 year old diabetic woman presents with substernal chest pain
at rest for 15 minutes that, after beta-blocker and nitrates, has
partially but not completely resolved. A 12-lead ECG reveals
inferior ST-segment depressions. Cardiac troponin is elevated.
In addition to ASA, the most appropriate treatment strategy would

be:
a. UFH, GP 2b/3a inhibitor, stress test in 24-48 hrs

b. Clopidogrel, bivalirudin, stress test in 24-48 hrs
c. Enoxaparin, cardiac catheterization in 48 hrs
d. UFH, cardiac cath w/in 12-24 h, ticagrelor ± GP 2b/3a if PCI
1032
Question #1
A 67 year old diabetic woman presents with substernal chest pain at rest for 15
minutes that, after beta-blocker and nitrates, has partially but not completely
resolved. A 12-lead ECG reveals inferior ST-segment depressions. Cardiac
troponin is elevated. In addition to ASA, the most appropriate treatment strategy
would be:
a. UFH, GP 2b/3a inhibitor, stress test in 24-48 hrs

[no, GP 2b/3a for INV managed patients]
b. Clopidogrel, bivalirudin, stress test in 24-48 hrs
[no, bival for INV managed patients]
c. Enoxaparin, cardiac catheterization in 48 hrs
[no, need to add P2Y12 inhib]
d. UFH, cardiac cath w/in 12-24 h, ticagrelor ± GP 2b/3a if PCI
[yes, approp antiplt, anticoag, and management]
Question #2
You are considering the optimal lipid management in this same 67
year old diabetic woman.
LDL-C on admission (not on any lipid-lowering Rx) was 180 mg/dL.
She was started on atorva 80 mg.
What else would you recommend?
a. Target LDL-C reduction of 50%

b. Target LDL-C of 70 mg/dL
c. Add ezetimibe
d. Add PCSK9 inhibitor
e. Add ezetimibe and a PCSK9 inhibitor
1033
Question #2
You are considering the optimal lipid management in this same 67 year old
diabetic woman.
LDL-C on admission (not on any lipid-lowering Rx) was 180 mg/dL.
She was started on atorva 80 mg.
What else would you recommend?
a. Target LDL-C reduction of 50%

[OK, but after A80, LDL-C still likely >70 mg/dL]
b. Target LDL-C of 70 mg/dL
[OK, but we know clinical benefit to adding EZE or PCSK9i in
those with LDL-C <70]
c. Add ezetimibe
[yes, but only ~24% LDL-C reduction beyond statin]
d. Add PCSK9 inhibitor
[yes, ~60% LDL-C reduction & ~20% MACE reduction]
e. Add ezetimibe and a PCSK9 inhibitor
[yes, cannot be too low!]
Key References
• O’Gara et al. Circulation 2013;127:e362
• Amsterdam et al. Circulation 2014;130:2354
• Bonaca et al. N Engl J Med 2015;372:179
• Sabatine et al. N Engl J Med 2017;376:1713
1034
PE, DVT, ANTICOAGULATION

Samuel Z. Goldhaber, MD
Interim Chief, Division of
Cardiovascular Medicine
Section Head, Vascular Medicine
DISCLOSURES
Research Support:
Boehringer-Ingelheim; BMS; BTG
EKOS; Daiichi; Janssen; NHLBI;
Thrombosis Research Institute
Consultant:
Agile; Bayer; Boehringer-Ingelheim;
BMS; Daiichi; Janssen; Portola;
Soleno
1035
LEARNING OBJECTIVES
• Optimal duration and intensity of
anticoagulation after provoked or
unprovoked PE/ DVT
• Anticoagulation Rx of patients with
cancer and VTE—role of edoxaban
• Advanced Rx for acute PE beyond
anticoagulation—low-dose TPA
• Prevention of VTE in hospitalized
medically ill patients--betrixaban
EXTENDED DURATION
ANTICOAGULATION
• A 44 y.o. obese (BMI=32) man suffered
a flare of ulcerative colitis requiring
hospitalization. He suffered acute
submassive PE and was treated with
rivaroxaban for 6 months. Negative
hypercoag workup.
• At his 6-month visit in the office, he asks:
“May I discontinue anticoagulation?”
“Can you switch me to ‘baby aspirin’?”
1036
VOTING CASE #1:

Based on the EINSTEIN-CHOICE
Trial (NEJM 2017), you advise:
A.Rivaroxaban 20 mg with dinner

B.Rivaroxaban 10 mg with dinner
C.Aspirin 81 mg daily
D.No further medical therapy
E.Obtain a D-dimer to help decide
EINSTEIN CHOICE: 60%

PROVOKED and 40% UNPROVOKED
VTE—PREVENTING RECURRENCE
N=3,396
(Weitz JI. Thromb Haemost 2015; 114: 645-650)
1037
RECURRENT VTE:
PROVOKED vs UNPROVOKED
Riva 20 Riva 10 mg ASA 100
mg mg
Provoked 1.4% 0.9% 3.6%
Unprovoked 1.8% 1.5% 5.6%
(Weitz JI. NEJM 2017; March 17)
EFFICACY: RIVAROXABAN
20 MG VERSUS 10 MG
1038
SAFETY: RIVAROXABAN 20 MG
VERSUS 10 MG
PROVOKED, MINOR PERSISTING

RISK FACTORS PREDISPOSE TO
RECURRENCE
• Inflammatory bowel disease
• Lower limb paresis or paralysis
• Congestive heart failure
• Obesity
• Family history of VTE
• Hereditary thrombophilia
1039
PROVOKED, MINOR TRANSIENT

RISK FACTORS PREDISPOSE TO
RECURRENCE
• Immobilization
• Travel > 8 hours
• Estrogen, pregnancy
• Leg injury with impaired mobility
RECURRENT VTE:
EINSTEIN CHOICE/ EXTENSION
Riva 10/20 Placebo/ ASA
mg, N=2,832 100 mg, N=1,721
Unprovoked 1.6% 6.5%
Cancer 0% 4.6%
Minor 1.5% 4.9%

Persisting
Min. Transient 0.4% 4.5%
Major Surgery 0% 0%
(Prins MH, ISTH 2017)
1040
High VTE
(Prandoni. Recurrence
Haematolo- Rate
gica 2007;
92: 199-
205)
(N=1,626
DVT
patients)
CHEST ACCP GUIDELINES 2016:

DURATION OF RX
If unprovoked with low to moderate
bleeding risk, we suggest extended
anticoagulant therapy (no
scheduled stop date) over 3 months
of therapy (Grade 2B).
If provoked by surgery or a
nonsurgical transient risk factor,
anticoagulate for 3 months (Grade
1B).
(CHEST 2016; 149: 315-352)
1041
PE: FILLED WITH WBCs and

PLATELETS—INFLAMMATION
(Savchenko AS.
J Thromb Haemostas
2014; 12: 860-870)
THROMBIN-
INDUCED
INFLAMMATION
LEADS TO Aspirin
THROMBOSIS
(Croce K, Libby P.
Intertwining of
thrombosis and
inflammation in
atherosclerosis.
Curr Opin Hematol
2007;14: 55)
1042
ASPIRE & WARFASA: 32% LESS

VTE WITH LOW-DOSE ASPIRIN!
(N=1,224)
(Brighton TA et al. NEJM 2012; 367: 1979-1987)
D-DIMER DISAPPOINTS re:

EXCLUDING RECURRENT VTE:
Unprovoked VTE; 5 months warfarin;
Average 2.2 years follow-up (N=319)
Gender Negative D-dimer: Positive D-dimer:
Recurrence Recurrence
Men 8% per year 16% per year
Women 5% per year 10% per year
(Kearon C. Ann Intern Med 2015; 162: 27-34)
1043
NOACS FOR EXTENDED

TREATMENT OF VTE
RE- Dabigatran vs. ↓93%
SONATE placebo
RE-MEDY Dabigatran vs. Non-inferior

warfarin, INR 2-3
EINSTEIN Rivaroxaban vs. ↓82%
-EXT placebo
AMPLIFY- Apixaban vs. placebo ↓81%
EXT
CORE EXPLANATIONS: HIGH

VTE RECURRENCE RATE
• Persistent VTE risk factors (such as
obesity, diabetes, metabolic
syndrome, sedentary lifestyle)
• Persistent inflammation (that may
wax and wane in intensity)
• Persistent hypercoagulability:
genetic or acquired (e.g.,
anticardiolipin antibodies)
1044
EINSTEIN CHOICE LESSONS

1. VTE: chronic inflammatory
disease, high recurrence rate
after discontinuing
anticoagulation
2. For extended duration
anticoagulation, Rivaroxaban:
70% more effective and as safe
as aspirin to prevent recurrent
provoked/ unprovoked VTE
VOTING CASE #1:

Based on the EINSTEIN-CHOICE

C.Aspirin 81 mg daily
D.No further medical therapy
E.Obtain a D-dimer to help decide
1045
CAN DOACS REPLACE

LMWH IN CANCER
PATIENTS WITH VTE?
CANCER AND ACUTE VTE

• A 65 y.o. woman with esophageal
cancer was hospitalized with difficulty
swallowing and newly discovered lung
nodules. She had a 40 PPD cigarette
smoking history and had quit 2 years
ago.
• During hospitalization, she became
SOB and was diagnosed with
submassive PE.
1046
VOTING CASE #2:

Based on the HOKUSAI VTE Cancer
C.Enoxaparin as monotherapy
D.Warfarin (after enoxaparin bridge)
E.Edoxaban (after enoxaparin
bridge)
CLOT TRIAL for cancer pts:

Reduction in Recurrent VTE
25
Risk
Recurrent VTE, %
Recurrent reduction =
20
VTE 52% WARFARIN
15
p-value =
10 0.0017
DALTEPARIN
5
0
Lee et al.
NEJM 2003; 0 30 60 90 120 150 180 210
349: 146 Days Post Randomization
1047
HOKUSAI VTE CANCER

TREATMENT TRIAL
(Van Es N. Thromb Haemost 2015; 114: 1268-

76)
HOKUSAI VTE CANCER:

EDOXABAN vs. DALTEPARIN
(N=1046)
• Primary outcome: Recurrent VTE or major
bleeding 12 months after randomization
• Edoxaban had more major bleeding
(especially upper GI) and fewer recurrent
VTE events.
• Edoxaban was noninferior to dalteparin
with respect to the primary outcome.
(Raskob GE. NEJM 2017; epubl December 12)
1048
PRIMARY OUTCOME
RECURRENT VTE
1049
MAJOR BLEEDING
HOKUSAI VTE CANCER:

EDOXABAN vs. DALTEPARIN
• The increase in upper GI bleeding
occurred mainly in patients with GI
cancer.
• These data provide clinicians and
cancer/ VTE patients with a rationale to
discuss prescription of oral edoxaban
rather than LMWH monotherapy
injections.
1050
VOTING CASE #2:

Based on the HOKUSAI VTE Cancer
C.Enoxaparin as monotherapy
D.Warfarin (after enoxaparin bridge)
E.Edoxaban (after enoxaparin
bridge)
ADVANCED MANAGEMENT
OF PE:
WHEN ANTICOAGULATION
ALONE MIGHT NOT SUFFICE
1051
62 y.o. woman; BP=102/60; HR=134

RR=30; Oxygen saturation=89%;
Thrombolysis or Heparin Alone?
1052
VOTING CASE #3:
A.Continue IV heparin monotherapy

B.Switch to enoxaparin monotherapy
C.TPA 100 mg/ 2h—peripheral vein
D.TPA 50 mg/ 2h—peripheral vein
E.Ultrasound-facilitated catheter-
directed thrombolysis—24 mg TPA
or lower OPTALYSE dose
WHAT ABOUT PE DEATH RATE

AFTER HOSPITAL DISCHARGE?
• 8% die within 30 days (mostly of

recurrent PE)
• 20% die within 6 months
(Minges KE. Am J Cardiol 2015; 116: 1436-1442)
1053
HIGH PE MORTALITY at 30d

and 6 months; HIGH 30d
READMISSION RATES
(Minges KE. Am J Cardiol 2015; 116: 1436-1442)
PE THROMBOLYSIS: TREND
TOWARD LOWER DOSES
OVER THE PAST 30 YEARS
• Lower doses: associated with less
major and less minor bleeding
• Lower doses and lower durations of
infusion: lower the cost of therapy
and lower the hospital length of stay
1054
PE THROMBOLYSIS
1. Systemic thrombolysis:
a) 100 mg/2h (“full dose”) TPA
(FDA Approved 1990)
b) 50 mg TPA (“half-dose”)
(MOPETT (AJC 2013; 111: 273)
2. Catheter-directed, Ultrasound-facilitated
TPA 24 mg (“1/4 dose”)
(FDA Approved 2014)
3. OPTALYSE-PE Dose: TPA 8 mg/2h
(“< one-tenth dose”)
(JACC Cardiovasc Interventions 2018)
LYSIS IN SUBMASSIVE PE:

MORTALITY META-ANALYSIS
(JAMA 2014; 311: 2414-2421)
1055
SUBMASSIVE PE: 50 mg TPA

versus heparin (MOPETT) (N=121)
TPA 10mg/1 min followed by 40 mg/2 h
No bleeding complications/ no ICH
PA Pressure (ECHO) lower with TPA
TPA PA systolic Controls P value
Admission 50 51 0.4
Within 48h 34 41 < 0.001
6 months 31 49 < 0.001
28 months 28 43 < 0.001
(Am J Cardiology 2013; 111: 273-277)
1056
TPA 24 mg/12h = total TPA

dose
TPA 12 mg TPA 12 mg
ULTRASOUND-FACILITATED CDT:
Improves Blood Flow in Distal Pulmonary
Arteries (Microvasculature)
(Piazza G, et al. AHA 2017)
1057
CDT VS. HEPARIN: SUBMASSIVE PE

CDT HEPARIN
Lyse PE Yes No
Rapidly reverse Yes No

pulmonary
hypertension
Rapidly reduce RV Yes No
size
Clean out Probably No
pulmonary
microvasculature
1058
IVC FILTERS VS. CONTROLS
(Bikdeli B. JACC 2017; 70: 1587-97)
1059
VOTING CASE #3:
A.Continue IV heparin monotherapy

B.Switch to enoxaparin monotherapy
C.TPA 100 mg/ 2h—peripheral vein
D.TPA 50 mg/ 2h—peripheral vein
E.Ultrasound-facilitated catheter-
directed thrombolysis—24 mg TPA
or lower OPTALYSE dose
AN OUNCE OF
PREVENTION IS
WORTH A POUND
OF CURE
1060
53
VTE AFTER HOSPITAL DISCHARGE

• Despite in-hospital VTE prophylaxis
with UFH or LMWH, > 400,000 VTE
events occur in this patient population
annually.
• About half occur within 6 weeks of

discharge. Prior to betrixaban, no
agents were FDA approved for
extended duration prophylaxis.
BWH: READMISSION with NEW VTE within

30 DAYS OF HOSPITAL DISCHARGE
1061
BETRIXABAN
• Factor Xa inhibitor
• 19-25 hour half life
• Low peak-to-trough ratio
• 17% renal clearance
• Antidote (Andexanet)
APEX STUDY DESIGN

Standard
Prophylaxis Extended Prophylaxis
10 ± 4 days 35 – 42 days Evaluation
Enoxaparin
Subjects enrolled
Placebo Ultrasound Follow-up

40 mg & Visit 3 safety visit
(N=7,513)
Double blind, double dummy

1:1
R
30 Days
Day 35 After Visit 3
Betrixaban Betrixaban
(+7 days) (+5 days)
80 mg 80 mg
Loading dose
160 mg
(NEJM 2016; 375: 534-544)
1062
Baseline Characteristics:
Primary Admission Diagnoses
Enoxaparin Betrixaban
(n=3,754) (n=3,759)
44.6%
Acute CHF NYHA III-IV, % (n) 44.5% (1,672)
(1,677)
29.6%
Acute infection, % (n) 28.2% (1,058)
(1,112)
Acute respiratory failure, % (n) 12.6% (474) 11.9% (448)
Acute ischemic stroke w/ immobilization,
% (n) 11.5% (432) 10.9% (411)
Acute rheumatic disorder, % (n) 3.1% (117) 2.9% (109)
(NEJM 2016; 375: 534-544)
SUMMARY: BETRIXABAN vs
ENOXAPARIN
• 24% reduction in VTE

• 46% reduction in symptomatic VTE
• 30% reduction fatal, irreversible
events
• 56% reduction VTE-related
rehospitalization
• 56% reduction in stroke
• No increase in major or fatal bleeding
1063
TAKE HOME POINTS

1. For extended duration therapy,
Rivaroxaban: 70% more effective and
as safe as aspirin to prevent recurrent
provoked/ unprovoked VTE
2. Edoxaban is an alternative to LMWH in
non-GI cancer patients.
3. Critically ill PE patients warrant
thrombolysis or embolectomy.
4. Betrixaban: a new paradigm for VTE
prevention during/ after hospitalization
What parameters are used to

determine advanced PE therapy?
A. Clinical assessment
B. Right ventricular size
C. Right ventricular function
D. Troponin elevation
E. All of the above
1064
What parameters are used to

determine advanced PE therapy?
A. Clinical assessment
B. Right ventricular size
C. Right ventricular function
D. Troponin elevation
E. All of the above
After completing 6 months of full

anticoagulation for acute VTE,
A. Aspirin is no more effective than
placebo.
B. Aspirin has significantly fewer major
bleeding complications than NOACs.
C. Aspirin is as effective as NOACs.
D. Aspirin is more effective than placebo
E. Aspirin does not cause major
bleeding
1065
References
• (NEJM 2016; 375: 534-544)
• (NEJM 2016; 375: 534-544)
• (Am J Cardiology 2013; 111: 273-277)
• (Van Es N. Thromb Haemost 2015; 114:
1268-76)
• (Prins MH, ISTH 2017)
1066
Valvular and Congenital Heart

Disease
Brendan M. Everett, MD, MPH

Disclosures
• I have no financial disclosures relevant
to the topics of valvular and congenital
heart disease
1067
Aortic Stenosis
Aortic Stenosis
1068
Aortic Stenosis
Obstruction
Afterload Hypertrophy Cor flow
Diastolic O2
dysfunction mismatch
Natural History of Aortic Stenosis

Onset severe
Angina
symptoms
100 Syncope
Failure
80 period
Latent period,
(increasing
increasing obstruction,
60 myocardial overload) 0 2 4 6
hypertrophy
Avg
Yrs survival (yr)
after onset
40
Average death
20
age ( )
0
0 40 50 60 70 80
Age (yr)
Ross J Jr. and Braunwald E: Circ 38(Suppl 5):61, 1968
CP1061785-6
1069
Aortic Stenosis
Classification of Severity
MILD MODERATE SEVERE
Jet Velocity (m/s) < 3.0 3.0 - 4.0 > 4.0
Mean Gradient (mmHg) < 25 25-40 > 40
Valve Area (cm2) > 1.5 1.0-1.5 ≤ 1.0
Valve Area Index (cm2/m2) ≤ 0.6
Zoghbi W et al. J Am Soc Echocardiogr 2003; 16:777.
Severe Aortic Stenosis

Indications for Replacement
Indication ACC/AHA1 ESC2

2014 2012
Symptoms I(B) I(B)

Need for CABG/Ao Surgery I(B) I(C)
LVEF < 0.50 I(B) I(C)
Abnormal ETT IIa(B) IIa or IIb(C)

Rapid Progression/Delay IIb(C) IIa(C)
Very severe AS IIa(B) IIa(C)
Severe LVH (≥15mm) ----- IIb(C)
1. Nishimura 2014 ACC/AHA guidelines JACC 2014
2. Vahanian A et al. European Heart Journal 2012
1070
Surgery in Asymptomatic Severe AS

Class LOE
LVEF <0.50 not due to another cause I C
Symptoms on ETT due to AS I C
Fall in BP on ETT IIa C
Very severe AS (Vmax>5.5m/s); rapid IIa C

progression (>0.3m/s/y) & severe
calcification
Markedly elevated BNP; exercise increase in IIb C
gradient >20mm Hg; excessive LVH
ESC 2012 VHD Guidelines. Euro Heart J. 2012; 33: 2451-2496
TAVR has not been evaluated for asymptomatic patients with severe AS. These
patients should have SAVR if at low or intermediate surgical risk.
Severe AS (AVA < 1cm2)
High-Gradient AS Low-Gradient AS
Mean gradient > 40 mm Hg AVA < 1.0 cm2

Peak velocity > 4 m/s
AVR Reduced EF Preserved EF
Clinical question: Clinical question:

Is the EF low because Am I ignoring AS
of the AS? Or is AVA because the gradients
small because of the are low? Is this low-
low EF? gradient, low-flow AS?
Otto CM, et al J Am Coll Cardiol. 2017 Mar 14;69(10):1313–46.
1071
Severe AS with Low EF

Look at the Valve!
Dobutamine Stress Echo (DSE)
↑ CO ↑ CO ↔ CO
↑ Gradient ↑ Gradient ↔ Gradient
↑ AVA > 1.0 cm2 AVA < 1.0 cm2 AVA < 1.0 cm2
CR ?
AVR, TAVR ?
Paradoxical Low Flow Aortic Stenosis
1. Look at the valve!
2. Look at the SVi!
Stroke Volume Stroke Volume

index > 35 mL/m2 index ≤ 35 mL/m2
Pibarot P et al. J Am Coll Cardiol Img 2009;2:400-403
1072
AVR in Low-Flow/Low-Gradient AS
Recommendations Class LOE
AVR is reasonable in symptomatic patients IIa C

with low-flow/low-gradient severe AS with
reduced LVEF when low-dose dobutamine
stress shows AV velocity ≥ 4 m/s (or mean
gradient ≥ 40 mm Hg) with an AVA ≤1.0 cm2
at any dobutamine dose
AVR is reasonable in symptomatic patients IIa C

with low-flow/low-gradient severe AS,who
are normotensive and have LVEF ≥ 50%
ACC/AHA Guideline: J Am Coll Cardiol. 2014 Mar 3;63(22):2438–88.
PARTNER Cohort B: Medical Therapy vs. TAVR

All Cause Mortality
Standard Rx
TAVR
HR [95% CI] =
100 0.54 [0.38, 0.78]
All-cause mortality (%)
P (log rank) < 0.0001

80
60
40
20
0
0 6 12 18 24
Months
Numbers at Risk
TAVR 179 138 122 67 26
Standard Rx 179 121 83 41 12
1073
TAVR vs. SAVR:

Partner A and CoreValve
A: Sapien 3 (Partner A)
B: CoreValve (U.S. Pivotal Trial)
Vahl TP, et al.. J Am Coll Cardiol. 2016;67:1472–1487.
TAVR or SAVR? 2017 Guidelines

Nishimura, et al.
2017 VHD Focused Update
Figure 1. Choice of TAVR Versus Surgical AVR in the Patient With Severe Symptomatic AS
3 to <15% 15 to < 50%

T
30 day mort 30 day mort

≥50% 30
P
day mort
C RI
US
AS indicates aortic stenosis; AVR, aortic valve replacement; and TAVR, transcatheter aortic valve replacement.
1. Nishimura RA, et al. 2017 AHA/ACC Focused Update of the 2014 AHA/ACC Guideline for the Management of Patients
With Valvular Heart Disease. J Am Coll Cardiol. 2017;
2. Risk calculator available at the ACC or STS websites.
1074
Aortic Regurgitation
Etiology
VALVE ROOT
• BAV DISEASE • CT DISORDER
• RHEUMATIC • DISSECTION
• IE • IE
• MYXOMATOUS • AORTITIS
• APLA • HTN
• FEN-PHEN ? • OTHER
• TRAUMA (Congenital)
1075
Acute Severe AR

ANGIO GRADE 1+ 2+ 3-4+
DOPPLER JET AREA < 25% LVOT > MILD > 65% LVOT
VENA CONTR (cm) < 0.3 0.3-0.6 > 0.6
REGURG VOL (ml/b) < 30 30-59 > 60
REGURG FRAC (%) < 30 30-49 > 50
EROA (cm2) < 0.10 0.10-0.29 > 0.30
Am Soc Echocardiography 2003
1076
Vasodilator Therapy
100
Aortic Valve Replacement (%)
80
P=0.29 Enalapril
60
Nifedipine
40
Control
20
0
0 1 2 3 4 5 6 7 8 9 10
Years
Mean SBP 142-147

Evangelista A et al. NEJM 2005; 353:1342-9
Severe Aortic Regurgitation

Indications for Surgery
Class I Class II
• Symptoms • LVESD > 50 mm or
• EF < 0.50 > 25 mm/m2
• Need for Ao surgery • LVEDD > 65 mm if
surgical risk low
• LVESD > 50 mm or
LVEDD > 70 mm and
progressively ↑
ESC Valve Guidelines 2012

ACC/AHA Valve Guidelines 2014
1077
BAV Aortopathy

BAV with Dilated Aortic Root
Class I
• Maximal dimension > 5.5 cm or annual
increase in size > 0.5 cm / year.*
• Maximal dimension > 4.5 cm and
surgery indicated for severe AS or AR.*
* Consider lower threshold values for patients of small

stature of either gender
ACC/AHA Valve Guidelines 2014
1078
Mitral Regurgitation
Mitral Regurgitation Etiology

Acute MR Chronic MR
• Acute MI (Inf-Post) • Myxomatous
• Endocarditis • Ischemic
• Trauma • DCM
• “Acute on chronic” • Rheumatic
• MAC
• HOCM
• Other (APLS, etc.)
1079
Symptomatic Primary MR
• If Primary MR
• AND Severe
– Vena contracta ≥ 0.7 cm
– Regurgitant volume ≥ 60 mL
– Regurgitant fraction ≥ 50%
– Effective regurgitant orifice ≥ 0.4 cm2
– LV dilation
• LVEF > 30% or LVESD ≥ 40mm: MV surg (Class I)
• LVEF ≤ 30%: MV Surgery (Class IIB)
• Progressive increase in LVESD or decrease in EF:
MV surgery (Class IIA)
ACC/AHA VHD guidelines 2014
Asymptomatic Primary MR
1080
Chronic MR
Medical Therapy
•No
ABx prophylaxis
role when and if indicated
for vasodilator therapy in
asymptomatic,
• Management of AF normotensive
•patients
Managementwith chronic severe MR
of CAD
and
• ACE-I normal
or ARB LVreduced
for HTN, function
EF
Surgery in Asymptomatic Severe Primary MR

Class LOE
LVEF <0.60 or LVSD >45mm – ESC I C
LVEF 0.30-0.60 and/or LVESD ≥ 40 mm - AHA
Preserved EF and new onset AF or PA HTN at rest (>50 mm IIa C
Hg)
Preserved EF, high likelihood durable repair, low risk and IIa C
flail leaflet, LVESD >40mm (AHA/ACC < 40 mm)
LVEF ≥60 but progressive decease or LVESD ≥ 40 but IIa C
progressive increase
Preserved EF, high likelihood durable repair, low risk, and IIb C
LASVI >60mL/m2 or exercise PA HTN (>60 mmHg)
LVEF ≤ 30% IIb C
ESC 2012 VHD Guidelines. Euro Heart J. 2012; 33: 2451-2496

ACC/AHA VHD guidelines 2014 and 2017
1081
Ischemic MR
Mitral regurgitation
Indications for mitral valve surgery
for functional MR:
• Severe MR, persistent

symptoms despite optimal class IIb
medical therapy, including
CRT
1082
Mitral Stenosis
1083
Mitral Stenosis
Diastolic Filling Period
Mitral Stenosis
Anticoagulation
• AF: paroxysmal, persistent, permanent
• Hx TIA/CVA, systemic embolus
• Presence of LA thrombus
• LA > 5.5cm or spontaneous contrast
1084
POP QUIZ!
What would you recommend for
anticoagulation for someone with
PAF and mitral stenosis?
a. Apixaban
b. Dabigatran
c. Warfarin
d. Rivaroxaban
e. Edoxaban
POP QUIZ!
What would you recommend for
anticoagulation for someone with
PAF and mitral stenosis?
a. Apixaban
b. Dabigatran
c. Warfarin
d. Rivaroxaban
e. Edoxaban
1085
PMBV
CLASS 1 Indications
• Symptoms
• PA HTN (PA > 50 rest, > 60 ex)
Predicated on:
1. Favorable morphology
2. Operator and Lab experience
Absent:
1. Moderate to severe MR
2. LA thrombus
3. Inability to perform trans-septal puncture
PMBV
MVA = 1.5 cm2 MVA = 3.5 cm2

Mean Gradient = 8.0 mm Hg Mean Gradient = 4.0 mm Hg
PCWP = 16-18 mm Hg PCWP = 9 mm Hg
1086
Tricuspid Regurgitation
Tricuspid Regurgitation
Etiology
• Primary
– Congenital: Ebstein’s
– Carcinoid (metastatic)
– Rheumatic
– Myxomatous
– Radiation
– Trauma
– Infectious endocarditis
• Secondary
– TV annular dilation
– PA HTN
1087
Prosthetic Valves
Prosthetic Valves
Tissue Mechanical
1088
Prosthetic Heart Valves

Complications
• Structural valve deterioration
• Para-valvular regurgitation
• Hemolytic anemia
• Infective endocarditis
• PV thrombosis
• Thromboembolism; bleeding
• Pannus formation
• Prosthesis-patient mismatch
Anti-Thrombotic Therapy
Aspirin Warfarin Warfarin Bridge
75-100mg INR 2.0-3.0 INR 2.5-3.5
Mechanical Valve
1. AVR- low risk* Class I Class I None needed
2. AVR- high risk* Class I Class I UFH or SC

LMWH
3. MVR Class I Class I UFH or SC
LMWH
* These recommendations apply to bileaflet mechanical valves

Class III: oral direct thrombin inhibitors or anti-Xa agents should NOT be
used in patients with mechanical prostheses
Risk Factors: AF, previous thromboembolism, LV dysfunction,
hypercoagulable condition, older generation mechanical AVR
ACC/AHA VHD guidelines 2014, 2017
1089
Aspirin Clopidogrel Warfarin Warfarin No
75-100 mg 75 mg INR 2.0- INR 2.5- Warfarin
3.0 3.5
Biological Valve
1. AVR
< 3 months Class IIa Class IIb
> 3 months Class IIa
2. MVR
< 3 months Class IIa Class IIa
3. TAVR
< 6 months Class IIa Class IIb
ACC/AHA VHD guidelines 2014, 2017
Endocarditis Prophylaxis Recommend- Level of
ation Evidence
Prosthetic cardiac valve or prosthetic material IIa C-LD
for valve repair (including TAVR)
Previous infective endocarditis IIa C-LD
Unrepaired cyanotic congenital heart disease IIa C-LD
(CHD)
Repaired CHD with prosthetic material, first 6 IIa C-LD
months
Repaired CHD with residual defects at site of IIa C-LD
patch or device
Cardiac transplant with valve regurgitation IIa C-LD
due to structurally abnormal valve
For dental procedures that involve manipulation of either gingival tissue or the
periapical region of teeth or perforation of the oral mucosa.
1090
Antibiotic Regimens
Situation Agent Single Dose 30-60 min
before procedure
Oral Amoxicillin 2g
Cannot take oral Ampicillin 2 g IM or IV
Allergic to PCN or AMP Cephalexin 2g
Clindamycin 600 mg
Azithro or clarithro 500 mg
Allergic to PCN or AMP Cefazolin or ceftriaxone 1 g IM or IV
and unable to take oral
Clindamycin 600 mg IM or IV
Bonow RO et al. JACC. 2008;52:e1–e142.
https://www.nytimes.com/2018/04/29/health/drugs-opioids-addiction-heart-endocarditis.html
1091
ATRIAL SEPTAL DEFECT
1. Secundum
2. Primum
3. Sinus venosus
4. Coronary sinus

• Types: secundum, primum , sinus venosus,
coronary sinus
• Exam: Grade 2 MSM, fixed splitting S2
• ECG: IRBB. Left axis deviation = primum.
• ECHO: RV volume overload, shunt flow,

associated findings (MVP, cleft MV, APVD)
1092
SECUNDUM ASD
PATENT FORAMEN OVALE

• Present in 25-30% of population
• Sometimes associated with interatrial
septal aneurysm
• Implied role in
– Cryptogenic stroke
– Migraine
– Platypnea-orthodeoxia
– Decompression sickness
1093
TETRALOGY OF FALLOT
1. VSD
2. Overriding Ao
3. RVOT
obstruction
4. RVH
TETRALOGY OF FALLOT
• VSD (NON-RESTRICTIVE, LARGE)
• OVERRIDING AORTA
• RVOT OBSTRUCTION
• RVH
1094
COARCTATION
BAV DISEASE
Lembeke A et al.Circulation 2003;107:e80
Question 1
A 70 year old woman presents with
mild dyspnea on exertion.
HR 72 reg, BP 156/80. Grade 3 late
peaking murmur of aortic stenosis.
ECG: NSR. LVH
TTE: Calcified aortic valve, mean
gradient 50 mm Hg, AVA=0.8cm2. Wall
thickness 1.5 cm. LVEF 0.75.
1095
Question 1
Which of the following treatments would
you recommend?
a. Diuretic and ACE-inhibitor with close
follow-up
b. Bioprosthetic aortic valve
replacement
c. Mechanical aortic valve replacement
Question 1
you recommend?
follow-up
replacement
1096
Answer: This woman has symptomatic AS, with a mean

gradient and valve area in the severe range. Diuretics could
Question 1
well be harmful, and an ACEI is not going to alter her fixed
stenosis. She will require elective AVR. Given her age of 70,
the guidelines suggest a bioprosthetic aortic valve would be
appropriate. Without significant comorbidity, the AVR should
you recommend?
be performed via an open surgical route.
follow-up
replacement
Question 2
A previously asymptomatic 50 yr old
woman with mitral valve prolapse and
mild mitral regurgitation presents with
NYHA Function Class II dyspnea of 6
months duration. She had dental work
done 2 weeks before symptom onset
without antibiotic prophylaxis.
HR 84 reg, BP 102/76. T 98.2. Grade 3

systolic murmur at the apex.
1097
Question 2
Echocardiography now shows

moderate-severe MR with a
partially flail posterior leaflet.
LVEF is 65%. 6 blood cultures are
negative.
Question 2
Which of the following strategies

would you pursue?
• Careful clinical follow-up with

echo studies at 3-month intervals
• ACE inhibitor therapy
• Mitral valve replacement
• Mitral valve repair
1098
Question 2

would you pursue?

Answer: This woman has chronic mitral valve prolapse and

Question 2
myxomatous MV disease and has ruptured a chord. This is
what caused her mitral regurgitation to worsen and led to her
symptoms. She has symptomatic severe MR and will require
surgery. Mitral valve repair is the preferred operation.

would you pursue?

1099
Question 3
• A 71 year old woman with a St. Jude
MVR and AF is scheduled for
laparoscopic cholecystectomy. She
had a TIA 2 years ago. She takes
warfarin, low dose aspirin, metoprolol
succinate, and furosemide. Labs
include INR 3.4, BUN 42, serum
creatinine 2.1 (CrCl 27 mL/min).
Question 3
• Which of the following strategies for
anticoagulation management would
you advise?
– a. Taper warfarin and operate when INR 2.0
– b. Hold warfarin for 5 days and operate
– c. Hold warfarin, admit for IV UFH when
INR < 2.5
– d. Hold warfarin, bridge with enoxaparin, 1
mg/kg bid
1100
Question 3
• Which of the following strategies for
anticoagulation management would
you advise?
– a. Taper warfarin and operate when INR 2.0
– b. Hold warfarin for 5 days and operate
– c. Hold warfarin, admit for IV UFH when
INR < 2.5
– d. Hold warfarin, bridge with enoxaparin, 1
mg/kg bid
Answer: This woman has a mechanical mitral valve prosthesis and atrial
fibrillation, a high risk feature for thromboembolism. Her INR goal is 2.5-3.5.
While recommendations vary, ACC/AHA and ESC guidelines would suggest
UFH for someone with mechanical MVR + one other risk factor for
thromboembolism. Her eGFR precludes the use of LMWH.
Aspirin Warfarin Warfarin Bridge
75-100mg INR 2.0-3.0 INR 2.5-3.5
Mechanical Valve
1. AVR- low risk Class I Class I None needed
2. AVR- high risk Class I Class I UFH or SC

LMWH
3. MVR Class I Class I UFH or SC
LMWH
Class III: oral direct thrombin inhibitors or anti-Xa agents should NOT be
used in patients with mechanical prostheses
Risk Factors: AF, previous thromboembolism, LV dysfunction,

hypercoagulable condition, older generation mechanical AVR
1101
References
• ACC/AHA 2008 Valvular Heart Disease
Guidelines. www.acc.org/guidelines
• ACC/AHA 2014 and 2017 Valvular Heart
Disease Guidelines. www.acc.org/guidelines
• ESC 2012 Valvular Heart Disease Guidelines.
www.esc.org/guidelines
• ACC/AHA 2009 Adult Congenital Heart Disease
Guidelines. www.acc.org/guidelines
1102
Peripheral, Aortic and Carotid Disease
Marc P. Bonaca, MD, MPH

Medical Director Aortic Center
Vascular Medicine, Cardiology
Disclosures
Research Grant Support to TIMI Study

Group: Amgen, AstraZeneca, MedImmune,
Merck
Consulting: Aralez, AstraZeneca, Merck,

Bayer, Janssen, Sanofi
1103
Peripheral Artery Disease (PAD)
• The presence of a stenosis

or occlusion in the aorta or
arteries of the limbs
• Usually caused by
atherosclerosis
• Associated with an
increased risk of death,
myocardial infarction, and
stroke
• May impair walking or
cause critical limb
ischemia
3
Clinical Presentation of PAD

~15%
Typical
Claudication
50%
Asymptomatic
~ 33%
Atypical
Limb Symptoms
2-3%
Critical
Limb Ischemia
4
1104
Physical Findings in PAD
• Absent or diminished peripheral pulses

• Absent posterior tibial pulse > 90% specific
for diagnosis of PAD
• Bruits
• Hair loss
• Dystrophic nail changes
• Rapid elevation pallor or dependent rubor
of the limb
• Evidence of tissue loss (ulceration,
gangrene)
Diagnostic Testing for Suspected PAD
Colors correspond to Class of

Recommendation in Table 1.
ABI indicates ankle-brachial index; CLI,

critical limb ischemia; CTA, computed
tomography angiography; GDMT, guideline-
directed management and therapy; MRA,
magnetic resonance angiography; PAD,
peripheral artery disease; and TBI, toe-
brachial index.
Gerhard-Herman et al. Circulation 2016
1105
Imaging Tests for PAD
• Duplex ultrasonography
• Magnetic resonance angiography
• Computed tomographic angiography
• Conventional contrast angiography
1106
PAD Risk-reduction Therapies
• Lifestyle modifications
– Weight maintenance/reduction
• Smoking
– Complete cessation
– HbA1c goal, target specific agents
• Dyslipidemia
– High intensity statin + other agents (lower is better)
• Hypertension
– Therapies to achieve target, ACE inhibitors (HOPE Trial)
• Antithrombotic therapy
Summary of Effects of
PCSK9i Evolocumab
• ↓ LDL-C by 59% to a median of 30 mg/dL
• ↓ CV outcomes in patients on statin
• Safe and well-tolerated HR 0.85 (0.79-0.92)
Placebo P<0.0001
15 14.6
12.6 HR 0.80 (0.73-0.88)
59% reduction P<0.0001
KM Rate (%) at 3 Years
P<0.00001
9.9
10
Absolute 56 mg/dl 7.9
5
Evolocumab
(median 30 mg/dl, IQR 19-46 mg/dl)
0
CVD, MI, stroke CVD, MI, stroke
UA, cor revasc
Sabatine MS et al. NEJM 2017;376:1713-22
1107
Major Adverse Limb Events in Patients

with PAD and no MI or Stroke
Placebo PAD
Evolocumab (no MI/stroke, N=1505)
3.0%
57% RRR
2.6%
Major Adverse Limb Events
2.5% HR 0.43
(0.19 – 0.99)
P=0.042
2.0% 1.3% ARR
1.5%
1.3%
1.0%
0.5%
0.0%
0 90 180 270 360 450 540 630 720 810 900
Days from Randomization
Achieved LDL-C and Major

Adverse Limb Events
P=0.026 for beta coefficient
adjusted for significant (p<0.05) predictors of LDL-C cholesterol at 1 month after randomization including age,
BMI, LDL-C at baseline, male sex, race, randomized in North America, current smoker, high intensity statin.
1108
MACE or MALE
In Patients with PAD and no MI or Stroke
Placebo
Evolocumab
PAD
(no MI/stroke, N=1505)
14% 48% RRR 12.8%
12% HR 0.52
PAD
(0.35 – 0.76)
6.3% ARR
MACE or MALE
10% P=0.0006
NNT2.5y 16
8%
6.5%
6%
4%
2%
0%
0 90 180 270 360 450 540 630 720 810 900

Targets for Antithrombotic Therapy
Marc P. Bonaca, and Mark A. Creager Circulation

Research. 2015;116:1579-1598
Copyright © American Heart Association, Inc. All rights reserved.
1109
New Guidelines!
For “Symptomatic PAD”
• Similar to 2005 COR Therapy Comment

Guideline LOE
I Monotherapy CAPRIE showed
A clopidogrel
• Recommendations ASA 75-325 mg superior to ASA
for therapy to or Clopidogrel
reduce MACE based IIb DAPT Refer to the

on presence of B-R DAPT guideline
ASA+ for CAD
claudication (not Clopidogrel
MACE risk factors)
IIb DAPT or TAPT Benefit for
B-R MACE and ALI
Vorapaxar but increase in
bleeding so
(added to ASA overall benefit
and/or clopi) uncertain
Therapies Approved by the US FDA for PAD in BLUE
Gerhard-Herman et al. Circulation 2016 15
COMPASS Trial
Reductions in CV Death
Mortality
HR for Major Bleeding 1.70

Adapted from: N Engl J Med 2007;357:217-27.
(1.40 – 2.05), p<0.001
>90% with CAD, large subgroup with

Concomitant PAD, consistent benefits for both
1110
Anand et al. Lancet 2017
COMPASS PAD – Limb Risk By PAD History
4% 3.80%
Incidence of MALE (%)
3%
2%
1.37%
1%
0.50%
N=86 N=37 N=5
0%
Prior Revascularization or Claudication but no Asymtomatic low ABI
Amputation History of (<=0.90)
Revascularization or
Amputation
N=2264 N=2705 N=1422

36% of Population 42% of Population 22% of Population
1111
ASA+Ticagrelor in PAD with Prior MI
Placebo
25%
Ticagrelor 60 mg BID
PAD
20% 19.3%
ARR 5.2% Absolute Risk
HR
NNT 20 Difference at
(95% CI)
3 Years
15% 14.1% 0.69
CVD / MI / Stroke – 5.2 (0.47 – 0.99)
P=0.045
0.47
CV Death – 5.4 (0.25 – 0.86)
10% No PAD P=0.014
0.52
Mortality – 5.7 (0.32 – 0.84)
P=0.0074
5% TIMI Major Bleeding 1.18
0.02 (0.29 – 4.70)
P-interaction NS
P=0.82
0% 0.1 Ticagrelor Better Placebo Better 10

1.0
Brigham and Women’s Hospital and Harvard Medical School Bonaca MP et al. JACC 2016
A Framework for Optimizing Antithrombotic Intensity in PAD
Symptomatic PAD
High MACE Risk?

• Prior MI (mortality benefit)
High Bleeding Risk? • Severe CAD
• Recent major bleeding • Others (eg, DM)
• Prior stroke/ICH No
High MALE Risk?
• Indication for AC (e.g. AF)
• Prior bypass/stenting
• Others (eg, frailty, anemia)
• Prior thrombotic complication
• Undergoing intervention
• Others*(eg, severe disease)
Yes
Yes
No
(either)
Consider a More
Intensive
Monotherapy Antithrombotic
Strategy
*Risk scores may be helpful!
1112
Intermittent Claudication:
Exercise Therapy
• Frequency: 3–5 supervised sessions/week

• Duration: 35–50 minutes of exercise/session
• Type of exercise: treadmill or track walking
to near-maximal claudication pain
• Length: ≥6 months
• Results: 100%–150% improvement in maximal
walking distance
• Improvement in QoL
NOW COVERED BY CMS!
Stewart KJ et al. N Eng J Med. 2002;347:1941-1951.
21
Exercise in PAD
P<0.001
Change in Pain Free Walking Time (Minutes) From
P<0.04
7
5.8
Baseline to Six Months
6
Mean Difference P=0.02
5 1.01 Minutes
95% CI 0.07 – 1.95
4 P=0.04 3.7
2
1.43
1.2
1
0.42
0
Control Home Based Optimal Medical Stent Supervised
Exercise Care Revascularization Exercise
McDermott et al. JAMA 2013 Murphy et al. Circulation 2012
1113
Structured Exercise Therapy
COR LOE Recommendations

In patients with claudication, a supervised exercise
I A program is recommended to improve functional status and
QoL and to reduce leg symptoms.
A supervised exercise program should be discussed as a
I B-R treatment option for claudication before possible
revascularization.
In patients with PAD, a structured community- or home-
based exercise program with behavioral change
IIa A
techniques, can be beneficial to improve walking ability
and functional status.
In patients with claudication, alternative strategies of
exercise therapy, including upper-body ergometry, cycling,
IIa A and pain-free or low-intensity walking that avoids
moderate-to-maximum claudication while walking, can be
beneficial to improve walking ability and functional status.
Gerhard-Herman et al. Circulation 2016
Pharmacotherapy for Claudication

FDA Approved Drugs
Pentoxifylline
• Methylxanthine
• Approved August 1984
• Decreases plasma viscosity, improves RBC deformability,
some vasodilation
Cilostazol
• Phosphodiesterase III inhibitor derivative
• Approved January 1999
• Platelet inhibitor, vasodilation, ↑HDL-cholesterol,
↓triglycerides
• Contraindicated if history of CHF of any severity
24
1114
Indications and Options for

Revascularization
• Persistent, lifestyle-limiting claudication
despite maximal medical therapy
• Rest pain
• Nonhealing ulcer, gangrene
• Endovascular reconstruction options

• Angioplasty / Stenting
• Surgical reconstruction options
• Bypass
Gerhard-Herman et al. Circulation 2016 25
Endovascular Revascularization and Supervised

Exercise (ERASE) for Claudication Study
N = 212 patients with aorto-iliac and/or femoral-popliteal artery disease randomized
to supervised exercise training (SET) or SET plus endovascular revascualrization
Fakhry et al. Presented at 2013 AHA Scientific Sessions,

26
1115

Therapies for MACE Reduction in all Patients
• Lifestyle Modification
• Tobacco Cessation Therapies
• Targeting blood pressure goals with preference for ACEi
• LDL-C lowering with statin ± ezetimibe and/or PCSK9i
• Antiplatelet monotherapy (symptomatic), preference for P2Y12 inhibition
Therapies for MACE Reduction in Selected Patients
Diabetes
• Glucose lowering to reduce microvascular risk
• GLP-1 , SGLT2 inhibitors but caution with canagliflozin
Prior MI or CAD (Polyvascular Disease) and low bleeding risk

• ASA + rivaroxaban 2.5 BID (broad polyvascular definition)
• ASA + ticagrelor 60 mg BID (prior MI or other need for DAPT)
• ASA and/or clopidogrel with vorapaxar (prior MI or diabetes)
Therapies for MALE Reduction in all Patients

• LDL-C lowering with statin ± ezetimibe and/or PCSK9i
Therapies for MALE Reduction in Selected Patients
Prior peripheral revascularization & low bleeding risk
• ASA + rivaroxaban 2.5 BID
• ASA + ticagrelor 60 mg BID (prior MI or other need for DAPT)
• ASA and/or clopidogrel with vorapaxar
Therapies for Claudication

Symptomatic Patients
• Cilostazol 100 mg BID (only if no history of heart failure)
Abdominal Aortic Aneurysms

• Annual incidence 40.6 to 49.3 per 100,000
men and 6.8 to 12 per 100,000 women
• Accounts for ~16,000 deaths annually in
U.S., 13th leading cause of death in US
• Majority of pts asymptomatic with AAA
incidentally found
• Primary complication is rupture which is
associated with high mortality (~50% reach
hospital, 30-50% who reach hospital die)
• Rupture is predictable by size and rate of
change
• Medical therapy is targeted at reducing
overall cardiovascular risk and reducing the
rate of expansion
2011 ACCF/AHA Focused Update of the Management of Patients With Peripheral Artery Disease Guideline (Updating the 2005 Guideline) 28
1116
Risk of AAA Rupture

Relation to Size
Maximum Diameter (cm) 5-Year Rupture Rate (%)
<4.0 2
4.0–4.9 3–12
5.0–5.9 25
6.0–6.9 35
>7.0 75
Lederle FA, et al. Arch Intern Med 2000;160:1425.

29
Screening for AAA

ACC/AHA Guidelines
I IIa IIb III • Men 60 years of age or older who are

either the siblings or offspring of
patients with AAAs should undergo
physical examination and ultrasound
screening for detection of aortic
aneurysms
I IIa IIb III • Men who are 65-75 years of age who
have ever smoked should undergo a
physicial examination and 1- time
ultrasound screening for detection of
AAAS
Rooke TW, Hirsch AT, et al. JACC, 2013; 61:1555-70.
30
1117
Aortic Aneurysm
AAA – Medical / Lifestyle Therapy
Primary goal to reduce overall cardiovascular risk
• Aspirin
• Statin therapy
• Blood pressure control

• Beta-blockers in patients planned for repair
• ACEi/ARB, diuretics, CCB
• Lifestyle counseling
• Smoking Cessation
• Exercise is ok! (moderate activity)
Surgical Repair for Infrarenal AAA
Creager, MA ed. Atlas of Vascular Medicine, Current Science, 2002 32
1118
Endovascular Repair Technique and

Devices
Components of endograft device:

• Delivery system to allow placement via femoral artery approach
• Attachment system that forms a blood tight seal between graft and abdominal aorta
• Graft excludes aneurysm from flow and minimizes rupture risk
Infra-renal attachment Deliver contralateral

Device delivery
iliac endoleg Complete deployment
33
Abdominal Aortic Aneurysm

ACC/AHA Guidelines
I IIa IIb III • Patients with AAA >5.5 cm in diameter should
undergo repair to eliminate the risk of rupture.
I IIa IIb III • Patients with AAA 4.0 to 5.4 cm in diameter

should be monitored by ultrasound or CT scans
every 6-12 months to detect expansion
I IIa IIb III
• For AAA <4.0 cm in diameter, monitor by
ultrasound every 2-3 years.
I IIa IIb III
• In patients with symptomatic aortic aneurysms,
repair is indicated regardless of diameter.

34
1119
Abdominal Aortic Aneurysm

ACC/AHA Guidelines
I IIa IIb III • Open or endovascular repair of

infrarenal AAAs is indicated in
patients who are good surgical
candidates.
• Periodic long-term surveillance

I IIa IIb III imaging should be performed to
monitor for endoleak, confirm
graft position, and document
shrinkage or stability of the
excluded aneurysm sac
35
Thoracic Aortic Aneurysm

Epidemiology
• Degenerative disease (cystic medial necrosis)
• Incidence 10.4 cases / 100,000 pt-yrs, 2:1 male:female
• Risk factors: HTN, smoking, COPD
• Associated with genetic syndromes, bicuspid AV, inflammatory

diseases, infection, prior trauma
• Most common site is descending thoracic aorta (>50%)
• Peak incidence occurs at age 70 in men and age 80 in women,

infrequent in persons <50 years
• Most asymptomatic but if large it may present with heart failure

(if AI), dysphagia, hoarseness, chest pain, cough or wheezing
Hiratzka et. al: 2010 Consensus Guidelines – Thoracic Aortic Disease
1120

Screening
• Marfan Syndrome – TTE every 6 months
• Loeys-Dietz – complete aortic imaging every 6 months
• Turner Syndrome – imaging of heart and aorta every 5-10 yrs
• Bicuspid aortic valve – valve, aortic root, ascending aorta
• Anyone with a 1st degree relative with thoracic aortic aneurysm

or dissection
• If the mutant gene (FBN1, TGFBR1, TGFBR2, COL3A1, ACTA2, MYH11)

associated with aortic aneurysm and/or dissection is identified in a
patient, first degree relatives should undergo counseling and testing.
Then, only the relatives with the genetic mutation should undergo aortic
imaging.
Thoracic Aortic Disease

`
When to Intervene?
• Generally 5.5 cm, or growth > 0.5 cm/y

including bicuspid AoV (unless RF for
dissection such as FH)
• For genetic syndrome (MFS, LDS, EDS,

familial syndrome) may undergo at smaller
diameters (4.0-5.0) – for MFS
contemplating pregnancy > 4.0 cm
• If aortic valve surgery and > 4.5 cm

2010 ACCF/AHA/AATS/ACR/ASA/
SCA/SCAI/SIR/STS/SVM Guidelines for the Diagnosis and Management of Patients with Thoracic Aortic Disease
1121

Diameter and Risk of Complication
Pathogenesis of Stroke
Ischemic Stroke (80%) Hemorrhagic Stroke (20%)
Atherothrombotic
Cerebrovascular Intracerebral
Disease (20%) Cryptogenic (30%) Hemorrhage (70%)
?
Lacunar (25%)
(small vessel disease) Cardioembolic (20%) Subarachnoid Hemorrhage (30%)
Albers GW et al. Chest. 1998;119:683S-698S.

Albers GW Personal communication. February 27, 2003.
Rosamond WD et al. Stroke. 1999;30:736-743.
40
1122
Risk Factors and Newer Therapies

Modify Risk
Risk Factor Increased Risk Bosch J. BMJ
2002; 324:699
ACE Inhibitors / ARBs 25-34% PROGRESS
Hypertension 2X Collaborative
reduction in stroke Group. Lancet
2001:358; 1033
B Dahlof et al.
High Cholesterol 2X Statins 25% reduction in stroke Lancet
2002;359:995-1003
MRC/BHF HPS
Investigators
IGT / DM 2X / 3X Weight loss, diet, meformin Lancet 2002; 360
(9326): 7
UKPDS 10-year
NOACs as effective as warfarin with less outcomes
Atrial Fibrillation 5X
bleeding – broader population for rx
Smoking 2-4 X Reductions in prevalence of smoking
OSA 2X Increased identification and treatment
Lloyd-Jones et al. Circulation Heart Disease and Stroke Statistics 2012
Mechanisms of Stroke in Patients with

Carotid Artery Stenosis
42
1123
Stroke Attributable
Asymptomatic Carotid Disease
In the Current Era
Proportion of ischemic stroke Population Attributable Risk for Stroke
subtypes: NOMASS
< 15% due to asymptomatic carotid disease
White, H. Circ 2005;111:1327 Lloyd-Jones et al. Circulation Heart Disease and

Stroke Statistics 2012
Duplex Ultrasonography:
Internal Carotid Artery Stenosis
44
1124
Carotid Duplex Ultrasonography (DUS)

ACC/AHA Guidelines
I IIa IIb III

• DUS is recommended as the initial diagnostic test
to detect hemodynamically significant carotid
stenosis in asymptomatic patients with known or
suspected carotid stenosis.
I IIa IIb III • DUS is recommended to detect carotid stenosis in

patients who develop focal neurological symptoms
corresponding to the territory supplied by the left or
right internal carotid artery.
I IIa IIb III
• DUS is not recommended for routine screening of
asymptomatic patients who have no clinical
manifestations of or risk factors for atherosclerosis.
Medical Therapy for Carotid Stenosis
• Goal to Reduce Overall Cardiovascular Risk

• Lifestyle modification
• Antiplatelet therapy
• Lipid lowering (high-intensity statin)
• Antihypertensive therapy
46
1125
Symptomatic Carotid Disease
• Focal neurologic symptoms, retinal artery embolization

on fundoscopic exam, amaurosis fugax
• Imaging (CUS, CTA/MRA)
• Revascularization for stenosis of 50% or greater (CEA

vs. CAS) time sensitive
• Within 6 hours urgent revasc
• Fixed deficit >6 hours within 2 weeks once stable
• Antiplatelet therapy
47
Medical Intervention for Prevention of Ipsilateral Stroke

With Asymptomatic Severe Carotid Stenosis
Average annual stroke (+/-TIA) rates decreased by later publication years
Abbott, A. L. Stroke 2009;40:e573-e583

48
1126
Carotid Revascularization Endarterectomy

vs. Stenting Trial (CREST)
2522 symptomatic and asymptomatic

patients randomly assigned to
CEA or stent. >50% stenosis for
symptomatic and >60% for
asymptomatic
Results for Asymptomatic Patients

CAS CEA p
MI 7 (1.2%) 13 (2.2%) 0.2
All Stroke 15 (2.5%) 8 (1.4%) 0.15
Stroke/Death/MI 21 (3.5%) 21 (3.5%) 0.96
Brott TG et al. N Engl J Med 2010;363:11-23. Silver, FL. Stroke 2011, 42:675-680

Medical Therapy is Improving – Should we Revasc?
• Stroke rates are decreasing due to medical therapy
• % stroke due to asymp. CAS is small and shrinking
• Asymptomatic CAS is a potent predictor of MI and

Death (and not a very good predictor of stroke)
• Trials of CEA show benefit (for stroke) in era of high

rates and no medical therapy…lack of benefit for
women, high risk patients, broad endpoints, etc.
• No one knows if CEA provides additional benefit on

top of optimal medical therapy…but there is risk
(ACST 3.1% risk of peri-op stroke or death at 30 days)
1127
Management Choices for Patients with

Unilateral Asymptomatic Carotid Stenosis
At Least Everyone is Confused…
Klein, A. NEJM 2008, 358:e23

Considerations for Revascularization
• Patient Factors
• Life expectancy (>5 years)
• Comorbidities
• Treatment of concomitant risk factors
• Anatomic Factors
• High risk plaque characteristics, grade of stenosis
• TCD – is there active embolization?
• Anatomic issues informing procedural risk (hostile neck)
• Procedural Factors
• Volume, local outcomes (procedural risk < 3%)
• CEA (generally preferred especially in >70 YO) vs. Stenting (if
high surgical risk but must take DAPT for at least 30 days).
1128
Indications for Carotid Revascularization

ACC/AHA Guidelines
I IIa IIb III
• Patients at average or low surgical risk who
experience nondisabling ischemic stroke or TIA within
6 months should undergo CEA if the ipsilateral ICA
I IIa IIb III stenosis is >70%.
• CAS is indicated as an alternative to CEA for
symptomatic patients at average or low risk of
complications.
I IIa IIb III
• It is reasonable to perform CEA in asymptomatic
patients who have >70% stenosis of the ICA if the risk
of perioperative stroke, MI, and death is low.
I IIa IIb III • It is reasonable to choose CAS over CEA when
revascularization is indicated in patients with neck
anatomy unfavorable for CEA
Brott et a. JACC. 2011;57:1002-44
Question 1
A 64 year old man has been experiencing left calf discomfort for the past
three months. It occurs whenever he walks a distance of more than three
blocks. The physical examination reveals a blood pressure in each arm of
152/88 mm Hg. Both femoral pulses are present. The right dorsalis pedis
and posterior tibial pulses are present; the left dorsalis pedis and posterior
tibial are not palpable. The right ankle systolic pressure, measured with a
Doppler instrument, is 158 mm Hg; the left ankle pressure is 120 mm Hg.
Which of the following treatments should be considered next to improve

walking distance?
(A) Clopidogrel
(B) Supervised walking program
(C) Left iliac-femoral artery bypass graft
(D) Left iliac PTA/stent
1129
Question 1
(A) Clopidogrel
(B) Supervised walking program
(C) Left iliac-femoral artery bypass graft
(D) Left iliac PTA/stent
The ACC/AHA PAD guidelines recommend supervised exercise training

as an initial treatment modality for intermittent claudication. Clopidogrel
reduces the risk of adverse cardiovascular events but does not improve
walking time in PAD. Revascularization is indicated for life-style limiting
claudication despite optimal medical therapy. Moreover, the patient’s
physical examination suggests infra-inguinal disease, so it is unlikely
that iliac artery revascularization would be helpful.
Question 2
• A 78 year old woman presents with
a 5 minute episode of left arm
weakness. Her medications include
aspirin and atorvastatin. Her
angiogram is shown. Which of the
following additional treatments is
recommended?
A) Heparin
B) Dipyridamole
C) Carotid endarterectomy Right carotid artery
D) Carotid-subclavian bypass
1130
Question 2
A) Heparin
B) Dipyridamole
C) Carotid endarterectomy
D) Carotid-subclavian bypass
Carotid endarterectomy is indicated to treat symptomatic hemodynamically

significant carotid artery stenosis. The patient is already taking an
antiplatelet drug, and although addition of dipyridamole may be more
effective than aspirin alone in reducing recurrent stroke, it should not replace
carotid endarterectomy in this patient. There is no evidence that heparin
reduces risk of stroke in patients with symptomatic carotid artery stenosis.
Carotid-subclavian artery bypass is not a surgical procedure used in lieu of
carotid endarterectomy to treat internal carotid artery stenosis.
References
Aboyans et al: Measurement and interpretation of the ankle-brachial index: a
scientific statement from the American Heart Association. Circulation 126: 2890,
2012
Gerhard-Herman et al: ACC/AHA 2016 guidelines for the management of

patients with peripheral artery disease
Rooke et al: 2011 ACCF/AHA Focused Update of the Guideline for the
Management of Patients With Peripheral Artery Disease (updating the 2005
guideline): a report of the American College of Cardiology Foundation/American
Heart Association Task Force on Practice Guidelines." J Am Coll Cardiol 58:
2020, 2011.
Brott et al: 2011 ASA/ACCF/AHA Guideline on the Management of Patients With

Extracranial Carotid and Vertebral Artery Disease A Report of the American
College of Cardiology Foundation/American Heart Association Task Force on
Practice Guidelines. J Am Coll Cardiol 57: e16-9, 2011
1131
References
2010 ACCF/AHA/AATS/ACR/ASA/SCA/SCAI/SIR/STS/SVM Guidelines for the

Diagnosis and Management of Patients With Thoracic Aortic Disease
2011 ACCF/AHA Focused Update of the Guideline for the Management of Patients
With Peripheral Artery Disease (Updating the 2005 Guideline) : A Report of the
American College of Cardiology Foundation/American Heart Association Task
Force on Practice Guidelines
ACCF/AHA/ACR/SCAI/SIR/SVM/SVN/SVS 2010 Performance Measures for Adults

With Peripheral Artery Disease
Fleming C, Whitlock EP, Beil TL, Lederle FA. Screening for abdominal aortic
aneurysm: a best-evidence systematic review for the U.S. Preventive Services Task
Force. Ann Intern Med 2005;142:203-11.
1132
Heart Failure
Anju Nohria, MD
Assistant Professor
Advanced Heart Disease Section
Cardiovascular Division
Disclosures
• Amgen: research funding
• Takeda Oncology: consultant
1133
Outline
• Discuss pathogenesis and prevalence of heart failure
• Outline approach to diagnosis and evaluation of heart

failure patients
• Apply evidenced-based therapy to the population with

heart failure and reduced EF (HFrEF)
• Outline a management approach to heart failure with

preserved EF (HFpEF)
Pathophysiology of Heart Failure

Coronary Disease Cardiomyopathy Cardiac Overload
Left Ventricular Dysfunction
Neurohormonal
Vasoconstriction
Activation
↓ Peripheral Organ Bloodflow Cardiac Remodeling
↓Skeletal ↓RBF, Na LV LV
bloodflow retention Dilatation Hypertrophy
Arrhythmias
Symptoms, Fluid retention, Death
1134
Pathology of Heart Failure
HFpEF normal HFrEF

Concentric Remodeling Eccentric Remodeling
↑ Thickness ↔ Thickness
↔ Volume ↑ Volume
↓ Volume / Mass ↑ Volume / Mass
Images Courtesy of William Little and Marvin Konstam J Card Fail 9:1-3, 2003
Aurigemma, Zile, Gaasch Circulation 2006; 113; 296-304
HFpEF has Similar Outcomes as HFrEF

HF Admissions
• Approximately 50% of all HF

admissions are for HFpEF
• Pts w/ HFpEF are older, female,
HTN, CKD, Afib, ↓CAD
Cheng et al. Am Heart J 2014;168:721-30.e3
1135
Staging Heart Failure

ACC/AHA Classification
A. At risk patients without
structural heart disease
NYHA Classification
Progressive Disease
B. Structural heart disease I. Cardiac disease without

without symptoms functional limitation
Worsening QOL
C. Structural heart disease with II. Slight limitation of physical
prior or current symptoms activity
D. Refractory heart failure III. Marked limitation of physical

activity
IV. Inability to carry on physical

activity without discomfort
The Stage A Patient:

2013 ACC/AHA Recommendations
• Control hypertension w/ target < 130/80 mm Hg
– SPRINT trial: Intensive BP control reduces HF hospitalizations
• Treat lipid disorders in accordance with guidelines

• Control metabolic syndrome and diabetes
– EMPA-REG trial: Empagloflozin reduces incident HF
• Encourage smoking cessation and regular exercise

• ACE-I/ARB in appropriate patients (e.g. diabetes, vascular disease)
• Discourage excessive alcohol intake/illicit drug use
• Surveillance for LV dysfunction in high risk patients
– STOP-HF: Can use BNP > 50 pg/ml to refer to CV specialist to reduce incident HF
Yancy CW et al. CIR.0b013e31829e8776
1136
Goals of Therapy for Stage B HF

• Identify and treat reversible causes of LV dysfunction
• Prevent progressive LV remodeling and onset of
symptoms
– BP control in asymptomatic LVH
• Thiazide, CCB, or ACE-I
– Neurohormonal blockade in asymptomatic LV
systolic dysfunction
• ACE-I and Beta-blockers
• Aldosterone antagonist in post-MI LV dysfunction + DM
Goals of Therapy for Symptomatic HF:

Stage C HF
• Address precipitating • Identify and treat the
factors causative/inciting factor
• Initiate Rx to prevent dz • Neurohormonal blockade
progression and mortality • Manage related risks
(sudden cardiac death)
• Improve sxs and end-organ • Lower PCWP
perfusion • Increase CO
• Reduce LOS and re- • Pt education
hospitalization • Longitudinal dz
management programs
1137
Outcome Trials of
ACE Inhibitors in Heart Failure
NYHA Placebo
Patients Class Mortality Hazard ratio
V-HeFT II 804 I-III 25% 0.72

(Hyd/Iso)
CONSENSUS I 253 IV 44% 0.66
SOLVD Tx 2569 II-III 40% 0.84
SOLVD Px 4228 I 16% 0.91
SAVE 2231 Post MI 25% 0.81

EF<40%
ISIS-4 58,050 24h post MI 7.7% 0.93
ARB Trials in Heart Failure

ELITE I/II OPTIMAAL CHARM VALIANT ValHEFT
Patients NYHA II-IV Acute MI/CHF NYHA II-IV Acute MI/CHF NYHA II-IV
(n)
722/3152 5477 2548 14,808 5010
Study Losartan Losartan Candesartan Valsartan, Valsartan

Design or or and Captopril, or and
Captopril Captopril ACEI both ACEI
β-blocker
16% / 23% 79 % 55 % 70 % 35 %
Mortality No Captopril No No No difference

difference better difference differences
HF Hosp No Capt better Both better Both better Both better

difference
Other Losartan Losartan ↓ Mort. w/ ↓ BP w/ both ↑ Mort. w/
better better β-blker β-blker
tolerated tolerated
1138
β-Blocker Trials in Symptomatic HF

Annual Mortality
Trial Target Dose Mean Dose Control β-blocker RRR

(mg/d) (mg/d)) (%)
Bisoprolol
CIBIS I 5 3.8 11.0 8.7 NS
CIBIS II 10 7.5 13.2 8.8 34
Bucindolol
BEST 100-200 76 17 15 NS
Metoprolol
MDC 100-150 108 11.1 11.9 NS
MERIT-HF 200 159 11.0 7.2 34
Carvedilol
US Carvedilol 12.5-100 45 14.4 5.9 65
COPERNICUS 50 37 18.5 11.4 38
Aldosterone Antagonists in HF
Trial N LVEF NYHA End-pt HR
RALES1 1663 ≤ 35% III-IV All cause 0.7,

mortality p<0.001
EPHESUS2 6632 Post-MI EF II or All cause 0.85,
< 40% I w/ DM mortality P=0.008
EMPHASIS- 2737 EF < 30% II CV death 0.63,
HF3 or or HF p<0.0001
EF 30-35% hosp.
w/ QRS >
130
1Pitt, B et al. NEJM 1999;341:709-17; 2Pitt B et al. NEJM 2003;348:1309-21;

3Zennad F et al. NEJM 2011;364:11-21
1139
Sacubitril/Valsartan (LCZ696)
Mechanism of Action
Vardeny O et al. JACC: Heart Failure 2014;2:663-70.
PARADIGM-HF
Death from CV Causes or HF Hosp.
• N=8,442
• RCT:
– Enalapril 10mg bid vs. LCZ696
NNT=21 @ 27 mths
200mg bid
• Inclusion Criteria:
– EF ≤ 40% → 35%
– NYHA II-IV
– BNP ≥ 150, NT-BNP ≥ 600
– BNP ≥ 100 if hosp w/in 12 mths
– On optimal Rx
– SBP ≥ 95
* Increased hypotension, less renal
– eGFR > 30 ml/min dysfunction, no increase in
– K < 5.4 hyperkalemia, angioedema, or cough.
McMurray et al. NEJM 2014; 371:993-1004.
1140
Guideline Update
COR LOE Recommendations
I B-R ACEi OR ARB OR ARNI in conjunction with beta-blockers + MRA (where appropriate) is
recommended for patients with chronic HFrEF to reduce morbidity and mortality.
I B-R In patients with chronic, symptomatic HFrEF NYHA class II or III who tolerate and ACE
inhibitor or ARB, replacement by an ARNI is recommended to further reduce morbidity
and mortality
III B-R ARNI should NOT be administered concomitantly with ACEi or within 36 hours of last
ACEi dose
III C=EO ARNI should NOT be administered to patients with a history of angioedema
Population Initial Dose

Enalapril > 10 mg/d or 49/51 mg twice
Valsartan > 160 mg/d daily
Assess tolerability
Low dose ACE-I/ARB
Ensure 36 hrs off ACEi Up-titrate in step-wise
ACE-I/ARB naïve
Adequate BP fashion to 97/103 mg bid
eGFR<=30 mL/min/m2
eGFR ≥ 30 ml/min/1.73 m2 Re-assess BP, K and Cr
24/26 mg twice
Moderate Hepatic after each dose increase
daily
Impairment
(Child-Pugh Class B)
Elderly
Yancy et al. Circulation 2016; Yancy et al. JACC 2018;71(2):201-30.
Effect of Hydralazine/Isordil in
Symptomatic HF
Pts who are unable to take ACE-I/ARB should be placed

on hydralazine and isordil to reduce mortality and
improve symptoms
RR at 2 years: V-HeFT I 34% (p=0.028) V-HeFT II 28% (p=0.016)

Cohn et al. NEJM 1986;314:1547-52; Cohn et al. NEJM 1991;325:303-10.
1141
Alternative Vasodilator Strategies:

The A-HeFT Trial (Hydralazine/Isordil)
• 1050 NYHA III/IV AA pts
• Composite endpt (death, HF hosp,
QOL)
• Bidil (Hydralazine 37.5 mg + Isordil
20 mg) 2 tablets tid
– 68% at target
– Mean dose 3.8 tablets
• Contemporary background Rx
– ACEI/ARB 87 %
– Beta blkers 75 %
– Spironolactone 40 %
• Adverse events common
– HA 44% - Dizziness 29%
Taylor et al. NEJM 2004; 351:2049-57
Digoxin Reduces HF Hospitalization

But Not Mortality
30 50
Placebo n=93
DIGOXIN OVERALL MORTALITY
Withdrawal 40
20
No incremental benefit30
(and potential harm) at
p = 0.001 Placebo
10 Levels > 20
1.0 ng/mL
n=3403 p = 0.8
DIGOXIN n=85 10 DIGOXIN

0 n=3397
0
0 20 40 60 80 0 12 24 36 48
RADIANCE DIG Trial
N Engl J Med 1993;329:1 N Engl J Med 1997;336:525
1142
Ivabradine: A selective If Inhibitor

closed open
If
RR
Channel
Pure
0 mV heart rate
reduction
-40 mV
-70 mV
Ivabradine
If inhibition reduces the diastolic depolarization slope, thereby lowering heart rate
No effect on myocardial contractility or relaxation
Use-dependent block = low risk of bradycardia
Thollon et al. Br J Pharmacol. 1994;112:37-42.
SHIFT
Ivabradine (If inhibitor in SA node)
• N=6,558
• EF ≤ 35%, NYHA II-IV
• Resting HR ≥ 70 bpm
• On optimal med Rx
– ACE-I (91%)
– B-blocker (89%)
• Ivabradine: 5 bid → 7.5 bid
• Average HR: 64 vs 75 bpm @1 yr
• Greater the reduction in HR, greater
the benefit
• Side effects
– Symptomatic bradycardia: 5 vs 1%
– Phosphenes: 3 vs 1%
Swedberg et al. Lancet 2010;376:875-85.
1143
Guideline Update
COR LOR
IIa B-R Ivabradine may be beneficial to reduce HF
Moderate
hospitalization for patients with symptomatic
stable chronic HFrEF who are receiving GDMT,
including a beta blocker at maximum
tolerated dose, and who are in sinus rhythm
with a heart rate of ≥ 70 bpm at rest.
Age ≥ 75 Ivabradine HR < 50 Reduce to 2.5 mg

Re-assess whether b- 2.5 mg bid bid or stop
blockers maximized HR 50-60 Continue 5 mg bid
Assess eligibility for Age ≤ 75 Ivabradine 5
ivabradine mg bid HR > 60 Increase to 7.5 mg
bid
Yancy et al. Circulation 2016; Yancy et al. JACC 2018;71(2):201-30.
Iron Repletion in HF
• 50% HF patients have iron deficiency, with or without anemia
• Iron deficiency in HF is associated with ↑ mortality, independent of anemia
• No improvement in all-cause mortality and HF hospitalization with darbopoeitin
• No improvement in functional capacity or QOL with oral iron
Ponikowski et al. Eur Heart J 2015;36(11):657-68.
1144
2017 Guideline Update for Iron

Deficiency in HF
Yancy et al. Circulation 2017. DOI:10.1161/CIR0000000000000509
Heart Failure Management:

More Than Just Drugs
• Dietary counseling
• Patient education
• Medication compliance
• Nonpharmacologic Therapies
– CRT
– Sleep Disordered Breathing
• Management of Related Risks
– Sudden Death (ICD implantation)
– Thromboembolism/Stroke
1145
Cardiac Synchronization Therapy in

HF
• In pts w/ EF < 35%, NSR, QRS > 120 ms, and on
optimal medical therapy, CRT:
• Promotes reverse remodeling (even in NYHA I)
• Reduces HF hospitalizations (even in NYHA I)
• Improves symptoms
• Improves survival
• Predictors of benefit:
• LBBB morphology
• QRS duration ≥ 150 msec
CRT Guideline Update

• Class I: EF ≤ 35%, NYHA II-IV, NSR, LBBB w/ QRS ≥ 150 msec,
optimal med Rx
• Class IIa: EF ≤ 35%, NYHA III-IV, NSR, LBBB w/ QRS 120-150
msec, optimal med Rx
• Class IIa: EF ≤ 35%, NYHA III-IV, NSR, non-LBBB w/ QRS ≥
150 msec, optimal med Rx
• Class IIb: EF ≤ 30%, CAD, NYHA I, NSR, LBBB w/ QRS ≥ 150
msec
• *Not indicated in NYHA I-II, non-LBBB w/ QRS < 150 msec.
Circulation 2012; 126: 1784-1800
1146
Indications for ICD Therapy in HF

• Cardiac Arrest
• Sustained VT
• EF<40%, CAD, NSVT, inducible VT
• EF<30%, > 40d post-MI or 3mths post-
revascularization, NYHA I-III
• EF<35%, Non-ischemic CMP, NYHA II-III
• Contraindicated in NYHA IV, unless bridge to
advanced therapies
Anticoagulation in Patients with Heart

Failure and Sinus Rhythm (WARCEF)
N=2305;
HR=0.93, p=0.40 ASA 325 mg daily vs.
Warfarin (INR 2-3.5)
Reduced risk of
ischemic stroke
with warfarin offset
by increase in major
hemorrhage
Homma S, et al. N Engl J Med 2012;366: 1859-69.
1147
Symptomatic HF is a Clinical
Diagnosis
Nohria et al. JACC 2003;41:1797-1804.
BNP to Assist Diagnosis of HF

Pts presenting to EW with dyspnea
Maisel AS, et al. NEJM 2002;347:161

Januzzi J et al. Am Heart J 2005;149:744.
1148
Treatment of
Decompensated HF
DRY WET
WARM A Diuretics B
Vasodilators
Nitroprusside
Nitroglycerin
or
COLD L C Nesiritide
Low/Marginal BP Adequate BP
Inotropic Drugs
Dopamine
Dobutamine
Milrinone
Stevenson LW. Eur J Heart Failure 1999
DOSE Trial
Low High
• N=308 pts with ADHF, < 24 hrs admission
Dose Dose
HIGH vs. LOW DOSE Diuretics Q12 1X oral 2.5X oral

• ↑ improvement in dyspnea @ 72 hrs Bolus
• ↑ net diuresis and weight loss @ 72 hrs 1X oral 2.5X oral
Continuous
• ↑ proportion w/ WRF (↑Cr > 0.3 mg/dL)
• No diff in death, re-hospitalization, or ED visits @ 60d
BOLUS vs. CONTINUOUS Diuretic Infusion

• No difference in any outcomes
Felker et al. NEJM 2011;364:797-805.
1149
Inotropes Increase Mortality in ADHF

• ESCAPE trial
• 433 pts w/ ADHF, EF < 30%, SBP ≤ 125 mm Hg, 1 sign and
symptom of HF, HF hosp. w/in previous yr
• Inotropes↑ myocardial oxygen demand, arrhythmias, neurohormonal activation
Elkayam et al. Am Heart J 2007;153:98-104.
Who Should be Referred for

Advanced Therapies?
• Escalating diuretic dose requirements
• Progressive renal dysfunction
• Increasing frequency of HF hospitalization
• Increasing burden of ventricular arrhythmias
• Intolerance of standard medical therapy
• Refractory HF symptoms
• Need for inotropic support
• > 5% non-fluid related weight loss (cachexia)
• Peak oxygen consumption ≤ 10 ml/kg/min w/ RER >1
1150
HF-PEF: A Heterogeneous Clinical

Syndrome
• Must Exclude
• Primary Infiltrative, restrictive, or hypertrophic heart
disease
• Pericardial Disease
• Critical coronary artery obstruction
• Hemodynamically significant valvular disease
• Advanced renal (renovascular) disease
• Hypertensive Emergency
• Uncontrolled atrial arrhythmias
• Primary pulmonary hypertension
2017 Guideline Update for HFpEF
Yancy et al. Circulation 2017. DOI:10.1161/CIR0000000000000509
1151
Congestive Heart Failure: Summary

• Heart failure is a clinical diagnosis
• BNP can be helpful when diagnosis is uncertain, but should
not replace clinical assessment
• ACEi and beta-blockers are cornerstones of HF therapy and
should be titrated to target doses if tolerated
• ARBs should be used in ACEi intolerant patients
• Substitution w/ ARNI should be considered in pts on ACEi or
ARB to reduce HF mortality and hospitalization
• Beta blockers should not be started in acutely
decompensated patients
Congestive Heart Failure: Summary

• Aldosterone antagonists are increasingly the favored
‘second-line’ after ACEi/ARB and beta-blocker
• Hydralazine/Isordil is an alternative for the ACEi/ARB
intolerant and may be added for those still symptomatic on
ACEi/Beta-blocker/aldosterone antagonist
• Digoxin and ivabradine can be considered to reduce HF
hospitalization
• Device Therapy (ICD +/- CRT) is appropriate for many HF
patients with LVEF ≤ 35%
• Heart failure with preserved EF remains a poorly
understood, heterogeneous disorder with limited
therapeutic options
1152
Disclosures
• Amgen: research funding
• Takeda Oncology: consultant
References
• Yancy CW et al. 2013 ACCF/AHA guideline for the management of
heart failure. J Am Coll Cardiol. 2013;62(16):e147-239.
• Hunt S et al. HFSA 2010 comprehensive heart failure practice
guideline. J Cardiac Fail. 2010;16:e1-e194.
• McMurray JJV et al. Angiotensin-neprilysin inhibition versus
enalapril in heart failure. N Engl J Med. 2014;371:993-1004.
• Swedberg K et al. Ivabradine and outcomes in chronic heart
failure: a randomized placebo-controlled study. Lancet
2010;376:875-885.
• Abraham WT et al. Wireless pulmonary artery hemodynamic
monitoring in chronic heart failure: a randomised clinical trial.
Lancet 2011;377:658-666.
1153
Question 1
• A 45 yo woman with non-ischemic CMP (EF 30%) presents for a
routine clinic visit. She reports dyspnea after climbing 1 flight of stairs
but is otherwise asymptomatic.
• Medications include lisinopril 20 mg daily, carvedilol 12.5 mg bid,
spironolactone 25 mg daily, and furosemide 40 mg bid.
• Exam reveals HR 70 bpm BP 120/80. She has no JVD, clear lungs, RRR,
Nl S1, S2, soft systolic murmur @ the apex, no hepatosplenomegaly
and no edema
• Labs are notable for Na 136, K 4.8, BUN/Cr 20/1.2
• EKG shows NSR @ 70 bpm, LBBB with QRS duration 130 msec.
Question 1 contd.
• What would be the best next step in the
A) Placement of a biventricular pacemaker –
defibrillator
B) Up-titration of lisinopril
C) Up-titration of carvedilol
D) Stop lisinopril and start valsartan/sacubitril
1154
Rationale
• All the options presented are appropriate,
however, the intervention that is likely to give
her the greatest morbidity and mortality
benefit would be to stop her Lisinopril and
start sacubitril/valsartan. Since she is
tolerating Lisinopril 20 mg daily, we would
start her on 49/51 mg bid and then up-titrate
to 97/103 mg bid if tolerated by BP, K, and Cr.
Question 2
• A 60 yo man with known ischemic CMP (EF 35%) presents with new
onset atrial fibrillation and rapid ventricular response.
• His medications include losartan 50 mg daily, metoprolol succinate
200 mg daily, torsemide 20 mg daily, aspirin 81 mg daily, and
atorvastatin 80 mg daily.
• His exam is notable for a HR 110 bpm, BP 90/60, JVP 12 cm of water
sitting upright, bibasilar crackles, Irreg, irreg Nl S1, S2, no
hepatosplenomegaly and no edema.
• Labs with Na 137, K 4.8, BUN/Cr 25/1.4
• EKG with atrial fibrillation and VR 110 bpm. Old AMI. Non-specific ST-
T abnormalities.
1155
Question 2 contd.
• What would be the next best step in the
A) Add digoxin
B) Add ivabradine
C) Change to carvedilol
D) Emergent electrical cardioversion
Rationale
• He is hemodynamically stable and therefore
does not require urgent cardioversion. He is
on maximal dose metoprolol succinate with
marginal BP and therefore changing to
carvedilol is unlikely to help with rate control
and may cause hypotension. Ivabradine is not
indicated since the pt is in Afib. Digoxin is the
best option since it may help with rate control
without compromising BP.
1156
Adult Congenital Heart Disease

Anne Marie Valente, MD
Boston Adult Congenital Heart Disease and Pulmonary

Hypertension Program
Division of Cardiology
Brigham and Women’s Hospital, Boston Children’s Hospital
Disclosures
• No disclosures
1157
Outline
• To recognize the increasing prevalence of adults
living with congenital heart disease
• To emphasize key points about common ACHD
conditions
• To focus on the hemodynamic changes in pregnancy
and the risk factors for women with heart disease
CHD Patients Reaching Adulthood

2,600,000 –
– 2,300,000
20,000 new patients/yr
2,200,000 –
5% increase/yr
–
U.S. 1,800,000 –
Adult –
CHD 1,400,000 –
Patients – 1,400,000
1,000,000 –
– 1,000,000
600,000 –
750,000
– 500,000 Hoffman 1978 Kaiser
200,000 – 325,000 Fyler 1980 New England
2-0 – Ferencz 1985 Baltimore-DC
Gilboa 2016 Quebec
1970 1980 1990 2000 2010 2020
1158
Breakdown of Severity of CHD in Adults

Heterotaxy
Complex Single Ventricle
Transposition
Conduits
Cyanotic
Eisenmenger
15%
47%
38%
Simple Simple ASD

Simple Aortic Disease Tetralogy of Fallot
Simple Mitral Disease
Simple PDA
Moderate Coarctation
AV Canal Defects
Ebstein
Warnes C et al. J Am Coll Cardiol 2001

Marelli A et al. Am Heart J 2009
ACHD: Multisystem Disorder

Neurologic: Increased incidence of occult or clinically evident strokes
Decreased level of executive functioning skills
Anxiety, post-traumatic stress disorder, depression
Psychosocial disorders
Lungs: Restrictive lung disease
Pulmonary vascular disease
Renal: Decreased perfusion
Hepatic: Liver fibrosis
Peripheral Vasculature: Increased chronic venous insufficiency
Orthopedic: Scoliosis
Kyphosis
Hematologic: Anemia
Coagulopathies
1159
ACHD: Causes of Death
n = 6933 subjects CONCOR registry

n = 197 deaths; median age 48 yrs
Verheugt CL et al. Eur Heart J 2010
Genetic Considerations
Syndrome Common CHD Genetic Abnormality
DiGeorge syndrome Aortic arch anomalies, TOF, 22q11.2 deletion
Truncus arteriosus
Down syndrome ASD, VSD, AVC, TOF Trisomy 21
Holt-Oram syndrome ASD, VSD, MV disease TBX5
Noonan syndrome PS, ASD, HCM PTPN11, KRAS, SOS1, RAF1,

NRAS, BRAF, MAP2K1
Turner syndrome Coarctation, BAV, 45X
Aortopathy
Williams syndrome Supravalvar AS, 7q11.23 deletion

Arteriopathy
1160
Patent Foramen Ovale (PFO)
• Patency of the flap valve

of the fossa ovalis
• Present in 25% of adults
• Not associated with R
heart dilation
Echocardiography in Pediatric and Congenital Heart Disease, ed. Geva T . Wiley, 2016
PFO and Cryptogenic Stroke

CLOSE REDUCE
<60 years age, cryptogenic stroke PFO, large shunt or aneurysm, no cerebrovascular
disease
At 5.3 years, PFO closure had a lower risk • At 3.2 years, PFO closure had a
of recurrent stroke than those lower risk of recurrent stroke than
maintained on antiplatelet therapy (0% antiplatelet therapy (1.4% vs.
vs. 6%; HR, 0.03) 5.4%; HR, 0.23).
N Engl J Med 2017: 377:1011–1021 N Engl J Med 2017: 377:1033–1042
1161
PFO Management
Mojadidi MK et al. J Am Coll Cardiol 2018
Atrial Septal Defect (ASD)
• Left-to-right shunt causing pulmonary

overcirculation and R heart dilation
• Palpitations, dyspnea, exercise
intolerance
• Exam findings: Fixed, split S2
• EKG: RBBB, RAD*
*for secundum ASDs (most common)

If LAD -> think primum ASD
Harrison’s Textbook of Internal Medicine, ed. Loscalzo J. McGraw-Hill, 2018
1162
Types of ASD
• Secundum ASD: most common

• Primum ASD: on the spectrum of
AVC defects; associated with a
cleft mitral valve
• Sinus venosus defect*: associated
with partial anomalous
pulmonary venous return
* Not in the atrial septum
Echocardiography in Pediatric and Congenital Heart Disease, ed. Geva T. Wiley, 2016
Partial Anomalous Pulmonary Venous Return
• Left-to-right shunt often discovered

incidentally
• Results in mild R heart dilation
• Often asymptomatic or presents
with symptoms similar to ASD
1163
Ventricular Septal Defect

• Left-to-right shunt causing left
heart dilation
• Large VSDs cause symptoms of
heart failure and poor growth in
children
• Many VSDs found in adults are
pressure-and flow-restrictive and
do not cause LV dilation or
symptoms
• If not restrictive -> Eisenmenger
syndrome
Types of VSD
• Muscular: often pressure- and

flow-restrictive
• Membranous: “outlet”
• AV canal type: associated with
abnormalities of the AV valves
• Subpulmonary: “conal septal”
associated with R coronary cusp
prolapse and aortic insufficiency
Echocardiography in Pediatric and Congenital Heart Disease, ed. Geva T . Wiley, 2016
1164
Pressure-Restrictive VSD
The key is to have a HIGH

velocity on Doppler
interrogation of the VSD flow
4v2
~5 m/s = 4(25) = 100 mmHg
gradient between the RV and
LV
Essential Atlas of Cardiovascular Disease, ed Libby P. Springer, 2009
Patent Ductus Arteriosus
• Exam: continuous murmur

• Large PDAs cause left heart
dilation and may lead to
Eisenmenger syndrome
• Transcatheter closure preferred
if no evidence of pulmonary
hypertension
1165
Expected Chamber Enlargement with Cardiac Shunts
Shunt RA RV PA LA LV Aorta
ASD + + +
VSD +/- + + +
PDA + + + +
Eisenmenger Syndrome
ASD, VSD, or complex Over time, PVR PVR ↑’s: shunt reverses:
defect ↑ resulting in R-to-L → Eisenmenger
↑ Qp and/or PAp, with L-to- bi-directional flow syndrome: ↑ cyanotic
R shunting
1166
Eisenmenger Syndrome: Complications

• Hyperviscosity symptoms
• Bleeding
• Thrombosis, including stroke
• Arrhythmias
• Heart failure
• Gout
• Gallstones, cholecystitis
• Renal dysfunction
• Hypertrophic osteoarthropathy
• Sudden death
Ebstein Anomaly
• Failure of delamination of the
septal leaflet of the TV
• Results in “atrialized” portion of
the RV
• Symptoms depend on severity
of TR and associated lesions
– Signs of R heart failure
– Cyanosis (if ASD/PFO)
• Exam: Widely split S1 “sail sign”
• 20% of patients have WPW
1167
Ebstein Anomaly
Essential Atlas of Cardiovascular Disease, ed Libby P. Springer, 2009
Tetralogy of Fallot (TOF)

• The most common form of
cyanotic CHD
• Spectrum of severity
• Surgical repairs have changed
over time
– Palliative shunts
– Transannular patch
– RV-PA conduit
• Many adults undergo PVR
later in life
1168
Repaired TOF: Sequelae in Adulthood

• RA/RV dilation
• RV dysfunction
• Pulmonary regurgitation
• Tricuspid regurgitation
• Branch PA stenosis
• Residual VSD
• LV dysfunction
• Aortic root dilation
• Arrhythmias
• Sudden death
Transposition of the Great Arteries (TGA)
Complete TGA Congenitally Corrected TGA

D-loop TGA L-loop TGA
1169
TGA s/p Atrial Switch
• Senning Procedure (1957)

• Mustard Procedure (1963)
• Redirects blood flow to allow
systemic venous return to get
to the lungs
• Long-term complications:
– Systemic RV dysfunction
– Tricuspid regurgitation
– Atrial baffle complications
– Atrial arrhythmias
TGA s/p Arterial Switch
• Jatene procedure (1975)

• The great arteries are
transected and switched – the
coronaries are re-implanted
• Long-term complications:
– Branch PA stenosis
– Neo-aortic root dilation
– Neo-aortic regurgitation
– Coronary artery stenosis
1170
Congenitally Corrected TGA
• AV and VA discordance
• Symptoms depend on associated
lesions:
– ASD
– Tricuspid valve dysplasia ± TR
– Pulmonary stenosis
• 1% incidence of complete heart
block per year in adulthood
• May be diagnosed in adulthood
Coarctation of the Aorta

• Presents with hypertension
• Exam: Brachial-femoral delay
and diminished LE pulses
• Associations:
– Bicuspid aortic valve
– Ascending aortic dilation
– Aneurysms
– LVH
– Coronary artery disease
– Cerebral aneurysm
1171
Pregnancy Hemodynamics
50 Plasma volume
Stroke volume
% change from prepregnancy value
Heart rate
40 Cardiac output
SVR
30
20
10
-20
-40
4 8 12 16 20 24 28 32 36 Post-partum
Duration of pregnancy (weeks)
Risk Score for Pregnant Women with HD

PREDICTOR POINTS
Prior cardiac events or arrhythmias 3

Baseline NYHA III-IV or cyanosis 3
Mechanical valve 3
Ventricular dysfunction 2
High risk left-sided valve disease / left ventricular 2
outflow tract obstruction
Pulmonary hypertension 2
Coronary artery disease 2
High risk aortopathy 2
No prior cardiac intervention 1
Late pregnancy assessment 1
Silversides C et al. J Am Coll Cardiol 2018
1172
ACHD Question #1
A 30-year-old man is seen for systemic hypertension,
not controlled on two medications. His blood pressure
is 190/90 in the right arm. He has diminished femoral
pulses. Which of the following is not associated with
his condition?
a) Bicuspid aortic valve
b) Differential cyanosis
c) Risk of premature coronary artery disease
d) Intracranial aneurysm
ACHD Answer #1
A 30-year-old man is seen for systemic hypertension,
not controlled on two medications. His blood pressure
is 190/90 in the right arm. He has diminished femoral
pulses. Which of the following is not associated with
his condition?
a) Bicuspid aortic valve
b) Differential cyanosis
c) Risk of premature coronary artery disease
d) Intracranial aneurysm
1173
ACHD Answer #1
• Differential cyanosis
(cyanosis of the toes but not
the fingers)
• Occurs with a PDA and
Eisenmenger syndrome
• Right-to-left shunt bypasses
the upper limb vessels and
flows directly into the
descending aorta
• Does not occur with CoA
ACHD Question #2
A 28-year-old woman presents with a history of
childhood heart surgery. She is 22 weeks pregnant.
Which condition places her at highest risk for a
maternal cardiac event during pregnancy?
a) Unrepaired atrial septal defect with normal PA

pressure
b) Mild pulmonary stenosis, unrepaired
c) Repaired tetralogy of Fallot
d) Congenital mitral stenosis, s/p mechanical valve
1174
ACHD Answer #2
A 28-year-old woman presents with a history of
childhood heart surgery. She is 22 weeks pregnant.
Which condition places her at highest risk for a
maternal cardiac event during pregnancy?
a) Unrepaired atrial septal defect with normal PA

pressure
b) Mild pulmonary stenosis, unrepaired
c) Repaired tetralogy of Fallot
d) Congenital mitral stenosis, s/p mechanical valve
ACHD Answer #2
• Women with heart disease have a 15% incidence of
maternal cardiac complications during pregnancy
• Mechanical heart valves are included in the CARPREG
II risk score
• Complications include: valve thrombosis, valve
failure/dysfunction, endocarditis, cerebral vascular
accident, hemolysis, bleeding, ventricular
dysfunction, heart failure and arrhythmias
• Anticoagulation strategies must be carefully
individualized with meticulous monitoring during
pregnancy
1175
Summary
• The number of adults living with congenital heart

disease is growing
• Surgical strategies have evolved over time and long-
term complications depend on associated lesions
and surgical era of repair
• Many women with CHD tolerate the hemodynamic
changes of pregnancy. However, morbidity is
common, particularly with high-risk conditions
Resources
• Stout K et al. 2017 ACC/AHA Guideline for the Management of
Adults With Congenital Heart Disease. Soon to be published… 2018
• Valente AM, Landzberg MJ. Adult Congenital Heart Disease. Chapter

264. Harrison’s Textbook of Internal Medicine, ed. Loscalzo J.
McGraw-Hill, 2018.
• Regitz-Zagrosek V et al. ESC Guidelines on the management of

cardiovascular diseases during pregnancy The Task Force on the
Management of Cardiovascular Diseases during Pregnancy of the
European Society of Cardiology (ESC). European Heart Journal,
2011. 32(24), 3147-3197.
1176
Thank You!
Boston Adult Congenital Heart & Pulmonary Hypertension Program
Amvalente@partners.org
1177
Dale S Adler, MD
Executive Vice Chair
No Disclosures
All 15 cases are real

Nothing unusual
Can be figured out with a history, good cardiac examination & EKG
Think about epidemiology and physiology
Coronary, valvular, myocardial, pericardial and vascular

conditions
1178
Usually
occurs at
night as she
Case #1:
lies down
in bed
No SOB
It happened once
when I was walking
up the stairs
carrying my
briefcase
Rxxx59744
Case #1:
Medical Chronic left rotator cuff
difficulties.
History
Strong family history of
premature CAD.
BMI 32
Hypertension,
vigorously treated, and
controlled.
Dyslipidemia treated
with statin, with TC185
Rxxx59744 HDL50 LDL98 TG 211.
1179
Case #1: Medications
Aspirin Atenolol Lisinopril Furosemide Pravastatin Metformin
Rxxx59744
Basal insulin
Case #1: Exam

150/80 mmHg HR 100 bpm RR 14
JVP not elevated
Carotid upstrokes and volumes normal
Clear lungs
PMI non-displaced
S1 normal S2 Ø
2/6 systolic murmur, LSB, early peaking, decreases with Valsalva
Left arm hurts with rotation
Has neck sensation during exam

Rxxx59744
1180
What are the Appropriate Next

Steps?
Case #1: EKG
Rxxx59744
1181
Case #1: EKG
Rxxx59744
Rxxx59744
Multifactorial
Intervention
Gaede P, Lund-Anderson H, Parving HH, Pedersen O. Effect of a multifactorial intervention on mortality in type 2 diabetes. NEJM 2008; 358:580-91.
1182
Anatomy
Normal left main
95% LAD stenosis

after first
diagonal
Non dominant
LCX without
irregularities
80% RCA stenosis

after A.M. 1 60%
R-PDA stenosis
Rxxx59744
Revascularization
for ACS is
appropriate.
Stents or surgery
associated with equal
survival in non DM pts
with multi-vessel
disease and good LV
function.
For multi-vessel
disease with non
complex lesions,
stents or surgery
equal in DM pts.
1183
More complex anatomy,

greater benefit to CABG
32.4
20.3
14.2
24.3 6.1
10.5
4.8 2.2
0.004 0.001 13.5 0.04
12.2
5.4 0.001 4.1
Non DM
0.003 0.004
DM
CABG PES p CABG PES p CABG PES p
Composite MACE Cardiac Death Repeat Revasc
13
FREEDOM Trial
Future REvascularization Evaluation in Patients with Diabetes Mellitus: Optimal Management of
Multivessel Disease
Farkouh, ME et al
Freedom Trial, NEJM 2012; 367:2375-84
1184
Adjusted annualized rates of cardiovascular death and heart failure admission among patients referred for
coronary angiography by coronary flow reserve (CFR) and early revascularization (Revasc) strategy
(coronary artery bypass grafting [CABG], percutaneous coronary intervention [PCI], or neither).
Lower reserve needs more extensive/reliable

revascularization
Taqueti V R et al. Circulation. 2015;131:19-27
Crohn’s
Disease
Family History Stable
Father & paternal
grandfather had
MI’s in 6th decade
Impaired Glucose
Tolerance
A1c 6.3%
Treated with metformin
Angina
>1 year Smoking
quit in 5th decade
Cholesterol Hypertension
TC 180 Treated with Beta-blocker
HDL 70 ACE Inhibitor
LDL 92
TG 91
Atorvastatin 40mg
Case Study: MXXR - A 75 Year Old Woman with Easily Precipitated

Exertional…..
1185
Exercise Study CTA

(outside institution)
• 7 minutes, 30 seconds
(outside institution)
• Standard Bruce protocol
• Stops due to chest pain & SOB • 40-50% proximal LAD and LCx
• HR 118 stenosis
• BP 164/70 mmHg • 30% mid RCA stenosis
• 1.5mm horizontal ST segment
depression (resolves after 3
minutes of recovery)
• Perfusion images normal
• EF 77%
Case Study: MXXR
Exam
• 127 pounds (trim)
• BP 140/70 mmHg (both arms)
• HR 58
• RR 12
• JVP not elevated (<8)
• Carotid upstrokes & volumes normal
• Clear lungs
• PMI not displaced
• Single S1, physiologically split S2 with
mid systolic click at apex that moves
earlier in cardiac cycle with Valsalva
Case Study: MXXR
1186
The story & studies are The story & studies are
consistent with important consistent with
epicardial coronary microvascular angina Which of the
disease, and if symptoms with an outstanding
cannot be managed, prognosis and her statements
coronary angiography is medical regimen can be
indicated. reduced. are true?
The story is consistent The story is consistent

with mitral valve with the non-GI effects
prolapse. of Crohn’s Disease.
Case Study: MXXR
Cath
• Dominant RCA with
narrow right PDA and
PLV
• 30% LAD non-calcified
plaque
• FFR across LAD 0.96
Case Study: MXXR
1187
Sex Differences in CAD Outcomes
481 Men
72% had >50% stenosis
p>0.0001 p>0.0001
LJ Shaw, et al
CIRC Cardiovasc Imaging 2010 3:473-481
Sex Differences in CAD Outcomes

Non-obstructive CAD warrants attention in all, and especially in women.
LJ Shaw, et al
CIRC Cardiovasc Imaging 2010 3:473-481
1188
Extent Of Epicardial CAD, In This Population Referred For PET Exercise

Testing Then Angiography, Did Not Predict Global CFR.
Figure 1.
Taqueti V R et al. Circulation. 2015;131:19-27
Freedom From Cardiovascular Death Or Heart Failure Admission According

To Coronary Flow Reserve (CFR) And Angiographic Score (Coronary Artery Disease
Prognostic Index [CADPI]).
Taqueti V R et al.
Circulation. 2015;131:19-27
1189
Case Study:
61 year old man OX-500
Sudden onset SOB three
days post left total knee Anxious & diaphoretic
BP 108/60 mmHg
replacement
HR 98
RR 20
History Pulse Ox 79%
Hypertension
Dyslipidemia
Previous radiacal
prostatectomy JVP not elevated
Traumatic splenectomy Carotid upstrokes & volumes normal
Crackles at left lung base
PMI not displaced
Troponin-I 0.75 No sternal lift
CK 105 Normal S1, physiologically split S2, P2
MB 3.7 is not increased
Left leg swollen, above & below knee
Case Study: OX-500 - EKG
1190
This man, with multiple CAD risk factors, is most likely

having an acute coronary syndrome.
He should be heparinized and he should have coronary
angiography.
This man, s/p orthopedic surgery, is most likely

struggling with a pulmonary embolism.
He should be heparinized and have an echocardiogram.
This man should receive lytic therapy

immediately which will be helpful in either
circumstance
Case Study: OX-500
Case Study: OX500 - Echo
Dilated RV with paradoxic septum
1191
Case Study: OX500 - CT
Case Study: OX500

What are the logical next steps?
Lytic agents, given size of PE
IVC filter and lytic agents
IVC filter and ongoing heparinization
IVC filter and catheter or surgical embolectomy and

ongoing heparinization
1192
Case Study: Ox500 - Outcomes
Before Procedure After

• HR: 115
• BP: 100/70 Suction • HR : 87
• O2 Sat: 94% 100% embolectomy on • BP: 130/80
non-rebreather. right side; then • O2 Sat: 98% on
• PA: 50/20 placement of 40% face mask.
• Angiogram: Like CT. retrievable IVC filter. • PA: 40/
ECG & Pulmonary Embolism Prognosis
Vanni, S. et al.
A JMed 2009;122: 257-64.
1193
Pictorial View of PEITHO Results
Meyer G et al
N Engl J Med 2014;370:1402-1411
Seattle II Study
150
Patients
Age 59
RV/LV 1.55
PA 51
mmHg
1194
Case Study: JD47 Age 40

episode of chest pain and
shortness of breath. No further
treatment.
Age 43
47 y.o. man for progressive shortness of breath, had
CT-PE, and told of large clot in lungs →
with several Anticoagulated
weeks of
increasing
dyspnea Reported HTN,
Medications
Diltiazem
dyslipidemia, family
Furosemide history of “clots”
Atorvastatin
Warfarin
Case Study – JD47

Vitals: 120/82 mmHg HR 72 RR 14 94%- RA
Carotids: JVP 8-9 cm, prominent “a” wave
Lungs: Clear
Heart Sounds:
Left parasternal lift. PMI displaced laterally.
Normal sounding S1, physiologically split S2,
with P2 heard at apex, as well as in pulmonic
and left lower sternal border regions
1195
Case Study: JUD47 - EKG
06-17-11
37
Case Study – JD47

LABS
EKG
ED Reports
1196
Case Study: JD47 - CT

06-17-11
39
Case Study: JD47
Lytic agents for acute large PE, with EKG,

RV changes and risk of early
decompensation.
Heparinization and change to LMWH for

small PE atop chronic thromboembolic
pulmonary HT.
Echocardiogram, and if significant

pulmonary HT, TR confirmed, elective
surgical RX for CTEPH.
40
1197
Case Study: JD47 - Echo
06-17-11
41
Case Study: JD47 - Echo

06-17-11
42
1198
Race and Epidemiology of Venous

Thromboembolism
• Incidence of VTE is 30-60% higher in blacks than
whites.
• Incidence of pulmonary embolism is higher in
blacks, and percentage of black VTE patients who
have PE is higher.
• Incidence of fatal PE is higher in blacks, 3.73 vs. 1.15
deaths/100,000 people per year.
• Idiopathic PE is seen in 18% of blacks, vs. 10% of
whites. Sickle cell trait, factor VIII, VWF ↓ protein C
may play roles.
Tyler W. Buckner, MD
Nigel S. Key, MD
CIRC 2012;125:837-839
Case Study: LX
Impaired glucose
tolerance
ESRD secondary to
Dyslipidemia
prior lithium toxicity
58 yo woman Catheterization 15
brought from months prior for chest
Bipolar disorder and in from dialysis pain and reported
problematic marriage center with left NSTEMI: PA 45/10
with alcohol arm and chest mmHg, No gradient
dependent husband discomfort and across outflow tract or
“not feeling aorta. EF 65%. 30% LAD
and LCx stenoses.
well.”
1199
EKG - End of dialysis
1200
The Echo
Which Of Following
Technician is Statements Are True:
on the way!
Echo: Cath: V-gram:

Extensive anteroapical,
No coronary artery
inferoapical, apicolateral Like echo
akinetic region irregularities
Vigorous contraction of LV
outflow tract region
Mitral regurgitation
1201
Takotsubo.
Extensive mid anterior apical and infero apical akinesis.
EKG – 48 hours after admission
1202
Diagnosis:
Takotsubos or Stress Induced Cardiomyopathy
Seen in association with:
• Emotional or physiologic stress, including sepsis, cerebral events,

pheochromocytoma.
• Characterized by sympathetic stimulation
• Can have full range of ST-T wave abnormalities.
• Can be any region of myocardium.
• Can be associated with transient outflow tract obstruction and MR.
• Rare cases of VF or rupture.
• Usually, LV gets entirely better, with variable time course.
• Can recur in 10 – 15% of patients.
Takotsubos Frequency
2001 Enrollment 2013

Period
4325 Consecutive
ACS Patients
9/90 90 (2.1%) Confirmed

Arrhythmia Takotsubo’s
Ventricular
Potential?
Arrhythmia
Full recovery of
NSVT:VT Always within WMA
3:1 1st 48 Hours
No coronary lesion
≥50%
Auzel, O et al
AmJCardiol 2016;117:1242-1247
1203
Takotsubo.
Does not have to be apical.
Templin C et al
NEJM 2015;373:929-38
Takotsubo’s is NOT benign
Though most get better, and recurrence rate is ~ 15%,

Templin C et al there can be stroke, arrhythmia, death…over 30 days.
NEJM 2015;373:929-38
1204
Case Study: RP53 - Background
Case Study: RP53 - History

Works everyday as a hands-on
Quit Smoking in 3rd Decade
manager in a family business.
Received TPA, then

1988 Evolving Anterior MI under went LIMA-OMB,
SVG-AM, sequential
SVG-D1-LAD.
Patent LIMA-OMB, SVG-AM
occluded, Sequential SVG- 1999 Accelerating Angina
D1-LAD with 99% stenosis.
Received SVG-A.M, SVG-LAD
1205
Case Study: RP53 - Exam
Case Study: RP53
1206
Most likely reason (s) for this patient’s easily

precipitated angina (worse post prandial)
Case Study: RP53
Hiatal hernia + Para esophageal hernia without erosive

esophagitis.
Aortic stenosis combined with or without native or graft
coronary disease.
Mitral regurgitation and hypertensive/diabetic
microvascular impairment.
Worsening anemia and outflow tract obstruction.
Left subclavian stenosis jeopardizing flow to LIMA.
Case Study: RP53 - Echo
EDD 5.6
ESD 4.1
Wall thickness 1.4cm
EF 50%
No wall motion abnormalities.
Heavily calcified aortic valve.
Mean gradient 44
VMAX 4.4 m/sec
TVI below the valve 23, above
the valve 119
AVA 0.7cm²
1207
Case Study: RP53 - Cath

• Patent grafts.
• RCA occluded after acute marginal.
– Good L→R collaterals.
– Acute marginal mid 95% stenosis.
• Occluded left main.
• Far distal LAD 80% stenosis.
• Fully patent, large ileofemoral systems.
Case Study: RP53 – Surgery?

Patient States He Is Willing To Abide By Recommendation,
Convene Surgeons And Interventionalists:
CABG and SAVR

PCI and TAVR
PCI and SAVR
TAVR alone
Medical management
All of the above
All except E, F.
1208
TAVR vs SAVR,
Well Established In High Risk Patients
Partners-Sapien balloon 2014 Core Valve-self expanding
expanded valve valve
• Equal mortality early and at • TAVR with overall lower

2 yrs in high risk pts. mortality and stroke rate
• Higher stroke and vascular • Perivalvular leak a concern.
complication rate with • LBBB and CHB a concern.
TAVR.
• Smaller catheter systems.
• Perivalvular leak a concern.
• But developed smaller
catheter systems, and in
2015: medium risk pts
equal.
Intermediate Risk also

reasonable for TAVR
Patients 2032
Prior CABG,
24%
Age 81 Frail, 44%
Cerebrovas
STS 5.8
Disease,
32%
≥
NYHD III/IV 77% Moderate
MR, 17%
Mean Gradient 45±13

Atrial
COPD, 32%
Fibrillation,
Ejection Fraction 56% 31%
Leon, MB et al
PARTNER 2 NEJM 2016;374:1609-20
1209
Freedom from Degeneration
DVIR, D
Euro PCR 2016
Case Study: S99

39 year old woman who feels well.
Occasional orthostatic lightheadedness.
Maternal Grandfather died at age 55.
No history of heart murmur.
Medications: estrogen/progesterone, zolpidem.
1210
Case Study: S99
Vitals Exam Cardiac

Height 68” Neck Veins – not elevated Loud S1
Carotids – Upstrokes brisk;

Volumes normal, not Physiologically split S2
Weight 120 lbs increased
III/VI systolic murmur
Lungs – Clear loudest just left of lower left
sternal border
BP 100/70 HR 62
Chest – Minimal pectus With Valsalva, murmur
excavatum becomes minimally louder
With handgrip, extra sound
BP 90/60 HR 70 PMI – 5th intercostal space;
heard after S1, murmur
Mid clavicular line; No thrill
moves later
Case Study: S99 - EKG
1211
Case Study: S99 - Diagnosis

Autonomic insufficiency, unclear
etiology.
Mitral stenosis.
Obstructive hypertrophic
cardiomyopathy.
Mitral valve prolapse and mild mitral

regurgitation. Can follow with yearly
exams.
Posterior mitral valve prolapse and

significant mitral regurgitation.
a and d.
Movement of MV Clicks
Devereux, R et al
CIRC 1976;54:3-14
1212
34 year old woman Medical History Exam

Abdominal Pain Paraplegia in aftermath BP 124/84 mmHg
of MVA
Nausea Abdominal distention
Colostomy
& Emesis for 9 hours
Suspect bowel obstruction
CIRC 2016;133:1132-34
Hibbs, J et al
Troponin T Negative
Echo
Ejection Fraction 65%
No Wall Motion Abnormalities
Chest CT
No Pericardial Effusion
No Mass
EKG
Hibbs, J et al
CIRC 2016;133:1132-34
1213
Discussion
Represents Giant J Waves (Osborne Waves)
Sometimes seen with hypothermia
ST elevations
Due to gastric distention
Key is prominent J Waves that worsen with normal

echo (not ischemia/myocarditis/pericarditis)
Hibbs, J et al
CIRC 2016;133:1132-34
CASE STUDY S17

51 Year Old
Woman
Abrupt onset pleuritic chest

discomfort – worse supine
Hodgkins Disease Stage IIA – 22 yrs previously – treated
with Mantle RT and MOPP following splenectomy
Treated hypothyroidism
Soleal DVT – 3 years previously
Contrast allergy
1214
CASE STUDY S17

Vitals Neck Veins
BP 110/80-10mmHg paradox Mid neck level seated upright
HR 110 beats per minute Collapse with inspiration
RR 20
Lungs Carotids
Clear Upstrokes brisk
No palpable PMI Volumes diminished
Heart Sounds No Peripheral Edema

Normal S1, single S2
II/VI early peaking
systolic murmur
along LLSB
Case Study S17
1215
Which of the Following are True?

Pleuritic discomfort against her background of
DVT suggests pulmonary embolism as
possible diagnosis
Radiation & symptoms and EKG suggest
pericardial processes that could include
effusive disease or effusive constrictive disease
Prior radiation & symptoms suggest chronic
constrictive pericarditis
Appropriate testing would include ventilation

perfusion study and surface echo-doppler
All except c
All except b
Case Study S17: ECHO

Large circumferential pericardial
effusion
No diastolic collapse of RV or RA
Transmitral early filling falls 35%

with inspiration
Transtricuspid early filling increases

75% with inspiration
1216
Case Study S17: Hemodynamics
All diastolic
pressures
between 18-
20 mmHg
Blunted “y”
descent in RA
Blunted early
filling in RV
Case Study S17: Hemodynamics
Pericardial Pressure =
A B C
18-20 5-10
Zero
mmHg mmHg
1217
EKG Changes in Acute Pericarditis

• Diffuse ST segment elevation with upright T-waves (lead aVR may have ↓ ST)
• PR segment depression, except in lead aVR, where there is no elevation
• Jpoint/T wave peak ration often > 25%
• NO “reciprocal changes” except in R
• Resolution
• Normalization of PR segments and ST segments, followed by T wave inversions
• Ultimately resolution of T wave inversions
• Time course highly variable, effusions/myocarditis alter QRS amplitude
• Tamponade (especially from a complex effusion)
• Accompanied by QRS electrical alternans
Case 234
1218
Imazio, et al
CIRC 2011;124:1270-75
Results of the
COlchicine for acute
PEricarditis (COPE) Trial
Sample Size 120 patients
85%
Idiopathic
Diagnosis Acute Pericarditis 15%
Autoimmune/post
Pericardiotomy
Group I Group 2
Randomization Conventional
Conventional Treatment &
Treatment & ASA Colchicine
1219
Colchicine for Pericarditis
Imazio, et al
CIRC 2005;112:2012-16
• 31 year old man

• Dyspnea
• Sense of vibration
• Patient and mother have extreme wariness
HXS:NXJ regarding testing and results as well as

medications
• Father had atrial fibrillation and mitral
regurgitation
• Cousin received a pacer for HCM
• No history of sudden death
1220
HXS:NJX
BP 130/80
HR 83
RR 12
No fall in BP with standing
JVP<7cm H2O: No HJR
Brisk carotid upstrokes and volumes – post Valsalva in 2 components
Hypertrophic precordium, normal S1, S2 physiologically split, P2 not increased
Non displaced PMI – apical thrill
IV/VI systolic murmur across the outflow tract, not quite to neck
Definite increment with Valsalva (Stage III)
Chirping posteriorly directed holo-systolic murmur that increments with Valsalva
HXS:NJX: June
2017
1221
HXS-NJX
2011 2017
• Septum 1.9 cm, nl 1.0 cm. • Septum 2.9-3.1 cm.
• Vmax outflow and Ao valve • Vmax outflow and Ao valve
1.6 m/sec, 11 mmHg, nl 1.0 3.3 m/sec, 45 mmHg.
and 0. • E’s 0.07.
• E’s 0.11m/sec, nl >0.8. • SAM, and important MR.
• No SAM. • Valsalva Vmax 6.3 m/sec,
• Valsalva not done. 120 mmHg.
1222
1223
Case Study 085

Cardiac Testing Patient Presentation
Holter
8-10 beat runs of • 55 year old woman
ventricular tachycardia,
rate 170,
• Symptoms
clear-cut AV – Exertional dyspnea
dissociation – Heart pounding
RBBB
Superior axis • Family History
configuration – SCD in 18 year old grand
daughter of father
Echo • No history of HTN
EF 65%
Septal thickness 2.3 cm
Posterior wall 1.3 cm
Case Study 085
1224
Case Study 085
Case Study 085
Which
Ventricular ectopy with this
EKG, good EF: can be managed of the This patient has an infiltrative
process and should undergo
with a Beta-blocker and EMB, looking for sarcoid or
reassurance.
following amyloid.
statements
are true?
This patient has an excellent The combination of verapamil

story for hypertrophic and Beta-blockers may be used
cardiomyopathy and an MRI to quiet the ectopy and she can
might be helpful. be followed conservatively.
1225
Stratification of Hypertrophic
Cardiomyopathy Patients
Maron, B
JAMA Cardiology
Published online 02MAR2016
56 year old woman

with sudden onset Case Study 33
exertional dyspnea
and pleuritic
discomfort
2 months of
intermittent chills
Fit runner and busy

teacher
No history of
hypertension,
diabetes, elevated
lipids
1226
Case Study 33
3 Months Prior Subsequently
• Fell while running • “Not feeling well”
– “ brief double vision” – episodic chills
– had a neck injury • Day of Admission
– Seen in local ED
– noted exertional dyspnea
– Multiple attempts to
– pleuritic discomfort when
place IV
supine.
– Then underwent head
CTA • Medical Regimen
• unremarkable – Levothyroxine 50
micrograms daily.
heard throughout precordium,

3/6 slightly
Case
and loudest at apex and JVP < 6 cm
posteriorly. Moves minimally
later with hand grip
late systolic
murmur
H20 Study 33
Loud S1,
Carotid
S2Ǿ and P2
volumes
not heard
normal
at LLSB
102° BP 130/60 HR 110 RR 18 96% room air
Systolic murmur
PMI not heard left of
displaced spine, near
scapula
Hyperdyna
mic No pectus
precordium
1227
Case
Study 33
Case Study 33
Pleuropericarditis, with fever, chills, and rub.
Pleuropericarditis in patient with myxomatous mitral

regurgitation (MVP), with an expected loud S1 and murmur that
moves later in cardiac cycle with handgrip.
Subacute bacterial endocarditis atop myxomatous mitral valve

disease and suspect damage to the anterior mitral valve leaflet.
Perhaps an earlier embolic event, musculoskeletal and immune
symptoms.
Acute myocardial infarction 2 months previously, with

subsequent Dresslers syndrome and posteromedial papillary
muscle head rupture.
1228
Echo: Case
Nearly flail AMVL with redundancy
8-10mm vegetation
Study 33
Severe MR
Blood cultures
EF 65%
Strep mitis 4/4
Mild left atrial dilation
CASE 33: Next Steps
1. Antibiotics for 4-6 weeks.

Surgery for heart failure, embolic, recurrent
fevers.
2. Antibiotics, early mitral valve replacement
for destroyed valve and vegetation.
3. Mitral e-clip early, with antibiotics.
4. Early surgery if valve seems like it can be
repaired. Otherwise, follow conventional
indications for surgery.
1229
Early surgery vs. conventional treatment for infective

endocarditis. (EASE)
Conventional approach:
Operate for persistent fever, embolic events while on Rx, hemodynamic
compromise. Special considerations for STAPH and fungi.
“EASE”:
18-80 y.o. (mean 48), 76 patients definite endocarditis (largely viridans,
few staph, enterococci.
Severe AI or MR
Vegetation > 10mm
Surgery within 48 hours (37 pts) Surgery for conventional indications (39 pts)
Excluded major strokes, with risk of hemorrhagic transformation, prosthetic valves, right
sided vegetations
Kang, D et al
NEJM2012;366:2466-73
Large difference in embolic events 8 late vs 0 early 105
Guidelines – “Expert Opinion”

Antibiotic prophylaxis for heart conditions was considered excessive.
Without data, 2007 suggestion:

prophylaxis only for prosthetic heart valves, shunts, or people with prior SBE.
1 case of SBE for every 277

non-Rx’s pts in the UK. 35 new
cases/mo. above expected.
Drayer, MJ., et al. Lancet 2015;385: 1219-28
1230
Case Study JD-61
Symptoms Exam
• Squeezing, left-sided chest • BP 90/60 mmHg
pain • HR 85
• Lightheadedness • RR 12
• JVP 8 cm H20
• Diaphoresis
• Carotid upstrokes normal,
volumes diminished
• Clear lungs
• Left parasternal lift
• Muffled S1
• Physiologically split S2
Namana V, et al
NEJM 2016;374:872
Case Study JD-61
Namana V, et al
NEJM 2016;374:872
1231
Case Study JD-61

This patient is having an

The EKG is consistent V2, V3, ST segment
MI related to a
with acute pericarditis depression has to
dominant circumflex
and the story raises represent anterior
and leads V7,8,9 would
question of tamponade. ischemia, usually LAD.
be helpful.
This patient is having an RV involvement cannot

IMI with RV be ascertained without
involvement. obtaining a lead V4R.
Namana V, et al
NEJM 2016;374:872
Case Study JD-61
Namana V, et al
NEJM 2016;374:872
1232
CASE STUDY 82
64 year old man
Awoke with right arm numbness and back pain.
The back pain resolved, and shortly, the arm
numbness resolved.
However, he noticed that his heart rate was 40
5 years prior
LIMA-LAD, SVG- Diagonal
SVG-OMB
Increased weight
(BMI 39)
obstructive sleep apnea

Hyperlipidemia
CASE Study 82
Home Exam Labs

medications • 170/60 both arms
• HR 78, RR 18, Pulse Ox • Cr 1.4
• ASA 93% on 3 liters 0² • HCT 40
• Metropolol • JVP not elevated • WBC 9.5
• Symmetric carotid brisk • TR-T 0.02
• Clonidine upstrokes and normal
• Furosemide volumes • Lactate 1.6
• Spironolactone • Clear lungs
• Lovastatin • S1 S² physiologically split
• Non-tender, protuberant
abdomen
• Normal distal pulses
• No edema
1233
CASE STUDY 82
CASE STUDY 82
Differential diagnosis includes which of the following:
Acute ST segment
Massive acute
elevation
pulmonary Aortic dissection
myocardial
embolism
infarction
Pericardial
Esophageal spasm
tamponade
1234
CASE STUDY 82
Clinical presentations and signs of type A dissection

No previous cardiac surgery Previous cardiac surgery
Chest pain or
back pain 88% 68% p <0.05
Abrupt onset
pain 92% 84% p <0.05
Any pulse
deficit 28% 30% NS
Pericardial
effusion 48% 26% p <0.05
Tamponade 16% 3% NS
*Widest diameter
of ascending Ao 5.28 (1.34) 5.40 (1.57) NS
Collins, JS et al IRAD
CIRC 2004;110:II-237-242
Klodell, CT et al
Ann Thorac Surgery 2012;93:1206-14
1235
Case 234
Visits because his 35
year old brother died
suddenly 3 weeks
ago.
Participated in
36 year old man • Post mortem showed
multiple triathlons
rupture of non-coronary
sinus of valsalva aneurysm
into the pericardium, and
a forme fruste of a
bicuspid valve.
Case 234
1236
Case 234
Bicuspid Aortic Valve and Aortic Dilation (Bicuspid Aortopathy)

BAV Incidence 1.3%.
1/3 will have attention to valve.
? 1/2 to Aorta
Three common types:

1. Anterior-posterior or “horizontal” (R-L fusion);
dilation of right side of aorta. Aortic issues (> 4.5-
5.0cm) usually with age >50, and almost always
with some amount of aortic stenosis.
2. Vertical orientation (R-non fusion), with
ascending Aorta and Arch dilation.
3. Aortic root or sinus dilation. Age <40, with or
without valve; more often genetic.
1237
Case Study 322

Patient History Exam
• 21 year old man • BP 127/70 mmHg
• 3 days of intermittent flu-like • HR 88
symptoms
• “Lung burning” – worse supine, • RR 12
non-pleuritic • Pain free
• MVP • JVP not elevated
• Father 7th decade likely vascular
disease • Carotids normal
• Clear lungs
• Pectus excavatum
• Normal S1, click not heard
• Physiologically split S2
• TrT 1.41 -1.79 mg/dl
• CK 1570-900
1238
Case Study 322, 3 years prior

2 0 1 1
E K G
Case Study 322

2 0 1 6
E K G
1239
Case Study 322
Story is consistent with acute MI, coronary dissection,

coronary embolism, vasospasm
Suggestive of pericarditis
Suggestive of myocarditis, perhaps subtle pericarditis
Next step would include coronary angiography, emergently
Case Study 322

2 0 1 6
E c h o
1240
Case Study 322

2 0 1 6
M R I
XXX424
Heart Transplant Free Survival
Anzini M.
Circulation 2013;128:2384-94
1241
81 Year Old Man XXX675

with 3 Days of
Chest Discomfort.
Pain radiates to left jaw
GERD & esophageal strictures,

and has had multiple
dilatations.
DM
HT
Longstanding LBBB
BP 147/80
HR 114
Crackles and LVS3,
Paradoxically split S2
XXX675
1242
XXX675
EKG & History Suggest?

Ischemia based on history; cannot interpret “more”
on EKG secondary to LBBB.
Ischemia based on history and marked, global ST

segment changes that are significant even with a
LBBB.
Ischemia based on history and leads V3 and V4

concordant changes.
This patient needs an echo to decide next steps, for

he may simply have GERD symptoms and EKG
changes consistent with LBBB and tachycardia.
XXX675
Cath: Severe ramus stenosis

Stented
1243
PM631 Case Study
Premature Told of
Vascular Chest Pain –
Disease
LBBB following
mechanical
Right fall related
Cerebral Dyslipidemia left-hip
Event – Hypertension fracture and
soon after open reduction
initiating and internal
estrogen fixation
PM631
EKG Comparison
1244
PM631
Outcome
Underwent Emergent Catheterization
Occluded left
circumflex: stented
Occluded LAD:
collateralized
1245
Atrial Fibrillation and Common Supraventricular

Tachycardias
Sunil Kapur MD
Cardiac Electrophysiology
Instructor, Harvard Medical School
No disclosures
1246
Cardiac Conduction:
SVT = down to (and including) the AVN
Outline
• Atrial fibrillation
– Basics
– Atrial Flutter
• Regular Paroxysmal SVTs
– Atrial tachycardia
– AV Node Reentrant Tachycardia
– AV Reentrant Tachycaria (Accessory pathway
mediated)
• Questions
1247
Basics
• Atrial Fibrillation (AF) is the most common clinical arrhythmia
Normal Sinus Rhythm AF
• In AF, the normal regular electrical impulses of the atria are overwhelmed
by disorganized electrical impulses
JHeuser 06:08, 28 November 2005
1248
• AF is dramatically increasing in prevalence
Rahman. Nat. Rev. Cardiol. 2014
“AF–omics”
Is all atrial fibrillation the same?

Are there subtypes with different
genetic causes?
J Am Coll Cardiol. 2008 Jul 8; 52(2): 117–123.
1249
Clinical Risk Factors for the Development of Atrial Fibrillation

Non-Modifiable Modifiable Behavioral
Age Valvular heart disease Alcohol use
Gender Cardiac and Non-Cardiac Surgery Caffeine Use
Race Hypertension Medications
Familial/Genetic Dyslipidemia and Coronary Artery Physical Activity
Disease
Birth Weight Obesity, Diabetes Mellitus, and CLINICAL BOTTOM LINE
Metabolic Syndrome Initial assessment should
Pericardial Fat Heart Failure include laboratory tests
Obstructive Sleep Apnea (electrolytes, thyroid-
Chronic Kidney Disease stimulating hormone, and
Thyroid disease renal and hepatic function)
Pulmonary / Pulmonary Vascular to rule out underlying
Disease disorders and
Pericarditis/Inflammation echocardiogram to look for
Congenital Heart Disease structural heart disease.
Psychiatric Conditions
J Am Coll Cardiol 2014;63:2335–45
1250
• The macro-electro-pathophysiology of AF remains unclear
Nishida. JACC. 2014, 823 - 831
Definitions of Atrial Fibrillation: A Simplified Scheme1

Paroxysmal • AF that terminates (spontaneously or with intervention) within 7 days
of onset.
• Episodes may recur with variable frequency.
Persistent • Continuous AF that is sustained >7 days.
Long-standing persistent • Continuous AF >12 months in duration.
Permanent • When the patient and clinician make a joint decision to stop further
attempts to restore and/or maintain sinus rhythm.
• Acceptance of AF represents a therapeutic attitude on the part of the
patient and clinician rather than an inherent pathophysiological
attribute of AF.
• Acceptance of AF may change as symptoms, efficacy of therapeutic
interventions, and patient and clinician preferences evolve.
CLINICAL BOTTOM LINE
If the diagnosis is suspected and ECG is normal, longer-term monitoring
with a Holter monitor or loop recorder can be helpful.
1251
• The macro-electro-pathophysiology of AF remains unclear
Nishida. JACC. 2014, 823 - 831
• AF is associated with significant morbidity and mortality
Go AS. N Engl J Med 2009;360:2127-2129.

Eur Heart J. 2013 Apr;34(14):1061-7.
1252
Clinical Management
Priority– Risk Factor management
Clinical Risk Factors for the Development of Atrial Fibrillation

Non-Modifiable Modifiable Behavioral
Age Valvular heart disease Alcohol use
Gender Cardiac and Non-Cardiac Surgery Caffeine Use
Race Hypertension Medications
Familial/Genetic Dyslipidemia and Coronary Artery Physical Activity
Disease
Birth Weight Obesity, Diabetes Mellitus, and
Metabolic Syndrome
Pericardial Fat Heart Failure
Obstructive Sleep Apnea
Chronic Kidney Disease
Thyroid disease
Pulmonary / Pulmonary Vascular
Disease
Pericarditis/Inflammation
Congenital Heart Disease
Psychiatric Conditions
Clinical Management
Priority #2 – Cardioembolic stroke prevention
1253
• The evidence does not support the use of aspirin as

monotherapy for the prevention of thromboembolic events in
patients with AF.
• The issue of whether aspirin could be a reasonable antithrombotic

monotherapy in very low-risk patients (CHADS2 = 0) has not been well
addressed, as the individual trials enrolled very few such patients.
• A 2007 meta-analysis found that aspirin, compared to placebo or no
therapy, reduced the risk of stroke by about 20 percent, although this
effect was not statistically significant (relative risk reduction 19 percent;
95% CI -1.0 to 35.0).
• Further, aspirin had little effect on reducing the risk of disabling stroke.
1254
Priority #2 – Cardioembolic stroke prevention
Priority #3 – Electrical Management
• Rate Control-A rate-control strategy uses drugs that block (slow conduction through) the
atrioventricular (AV) node such as beta blockers, rate-slowing calcium channel blockers, or
digoxin. AV nodal ablation plus ventricular pacing to control symptoms is also considered
when pharmacologic therapy is ineffective.
• Rhythm Control-A rhythm-control strategy uses antiarrhythmic drug therapy,

radiofrequency catheter ablation, and/or a surgical procedure performed at the time of
open heart surgery to maintain sinus rhythm (SR).
1255
Atrial Fibrillation - no benefit of antiarrhythmic drug

therapy to maintain sinus rhythm?
Rate
Control Antiarrhythmic
drugs
AFFIRM poor efficacy
poor tolerance
PIAF toxicity
RACE
STAF
Rhythm- and rate-control strategies are associated with similar rates
of mortality and serious morbidity, such as embolic risk, which is best
addressed using anticoagulation based on the CHADS2 or
CHA2DS2-VASc criteria.
• So who gets rhythm control:
– Failure of rate control
– Symptomatic Afib
– Increasing indications ?
1256
Mixed effects of antiarrhythmic drugs
IA: quinidine procainamide disopyramide
III
sotalol
IC 1 ibutilide**Ikr + plateau Na
Ito ICa
Flecainide 2 dofetilide
Propafenone amiodarone*
Moricizine azimilide
0 Ikr
INa
IB 3 Iks
Lidocaine
Mexiletine
Tocainide
phase 4
IK1
IKACh
QRS T
Clinical Management: Priority #3 – Electrical Management
Wavelength (ƛ) =
Refractory Period (RP) x
Conduction Velocity (CV)
FibNAF = L / ƛ
Iwasaki et al. Circulation. 2011; 124: 2264-2274
1257
Amiodarone Vs Sotalol vs Placebo for Persistent

Atrial Fibrillation
Singh, B. N. et al. N Engl J Med 2005;352:1861
Persistent AF on warfarin
Patients 665
Age 67 yrs
Duration of AF < 1 yr 77%
AF symptoms 62%
Ischemic heart disease 26%
Time to Recurrence of AF among Patients in Whom

Sinus Rhythm Was Restored on Day 28
Rate Versus Rhythm Control
Rate and possibly Rhythm control
• So who gets rhythm control:
– Failure of rate control
– Symptomatic Afib
– heart failure ?
– Increasing indications ?
N Engl J Med 2018; 378:417-427
1258
Clinical Management: Priority #2 – Electrical Management
Pulmonary Vein Isolation:

60 – 70% efficacy for paroxysmal AF
Poor efficacy for persistent / permanent AF
Oral et al Circulation 2002;105:1077
Freedom from any AF >90% reduction in AF

with no drug therapy with or without drugs
mean follow-up: 150 days
1259
Outline
– Basics
– Atrial Flutter
mediated)
• Questions
Atrial Flutter and Atrial Fibrillation: Frequently Associated, but Not the
Same Arrhythmia
• TYPICAL Atrial flutter vs ATYPICAL ATRIAL FLUTTER
1260
Typical CTI dependent Isthmus Dependent

Atrial Flutter (counterclockwise)
P-waves:
II, III, F = negative
V1 = positive
Outline
– Basics
– Atrial Flutter
mediated)
• Questions
1261
Regular PSVT
Atrial tachycardia
Distinction from atrial flutter:
-Focal (“Focal” is Not a Mechanism)
–AT Mechanisms:
–Triggered
–Automatic
–Reentrant (Micro)
-Sinus tachycardia
-Multifocal atrial tachycardia
-Spectrum to atrial fibrillation
1262
AVNRT
-Typical and Atypical
-”Dual AVN
physiology”
-Influence AVN
physiology to alter
the arrhythmia
-Hidden retrograde
P waves
-Management
AVRT
Atrioventricular Reentrant Tachycardia =
utilization of an accessory pathway
-Orthodromic versus antidromic
-Manifest versus Concealed
-Wolf Parkinson White Pattern versus

Syndrome
-Management
1263
Summary
• Atrial fibrillation is the most common
arrhythmia and associated with morbidity and
mortality
– Management include decisions regarding (1) risk
factor management (2) anticoagulation (3) rhythm
management
• Paroxysmal SVTs including AVNRT, AT and
AVRT are often symptomatic yet less
commonly associated with mortality
Question #1
A 70-year-old woman with type 2 diabetes mellitus and rheumatic mitral stenosis is
evaluated for dyspnea and fatigue. She has a history of atrial fibrillation that has
resulted in these symptoms in the past. She has had successful cardioversions, most
recently about 2 years ago. She has hypertension controlled with medication. She also
has mild left-ventricular dysfunction related to coronary artery disease and history of
myocardial infarction. Her current medications include atenolol, lisinopril, aspirin,
atorvastatin, and insulin. Physical examination demonstrates an irregularly irregular
rhythm with a heart rate of 78 beats per minute. Blood pressure is 130/80 mm Hg. The
cardiovascular and pulmonary examinations are otherwise unremarkable.
What medication should this patient receive for at least 3-4 weeks before
cardioversion?
A. Warfarin
B. Clopidogrel
C. Rivoraxaban
D. No additional medication is needed
1264
Answer #1
A. Warfarin
B. Clopidogrel
C. Rivoraxaban
D. No additional medication is needed
Prior to cardioversion, anticoagulation prevents cardioembolic

risk. With rheumatic heart disease warfarin is the preferable
choice. Dual antiplatelet therapy is inferior to warfarin for
anticoagulation in atrial fibrillation.
Question #2
Which one of the following statements about atrial fibrillation is
correct?
A. Lone atrial fibrillation is a common cause of atrial fibrillation.
B. Atrial fibrillation is more common in younger women than in
older men.
C. Anticoagulation is not indicated in patients who have
nonrheumatic heart disease and atrial fibrillation.
D. Many patients who have atrial fibrillation do not require
antiarrhythmic therapy.
E. Atrial fibrillation is a serious and common problem in patients
with AVNRT.
1265
Answer #2
A. Lone atrial fibrillation is a common cause of atrial fibrillation.
Most atrial fibrillation occurs in the context of comorbidities
B. Atrial fibrillation is more common in younger women than in older men.

Atrial fibrillation is more common in elderly and more common in men at all age groups
C. Anticoagulation is not indicated in patients who have nonrheumatic heart

disease and atrial fibrillation.
Atrial fibrillation anticoagulation is indicated in nonrheumatic heart disease based on cardioembolic risk. The type
of anticoagulant is influenced by the rheumatic diagnosis
D. Many patients who have atrial fibrillation do not require antiarrhythmic

therapy.
Rate control is a common and acceptable strategy
E. Atrial fibrillation is a serious and common problem in patients with AVNRT

AVNRT is seen in many healthy patients both with and without atrial fibrillation. In WPW, atrial fibrillation can be
serious and more common, however in AVNRT there is no specific enrichment or alternative concern.
Supplemental Reference Slide

• Pritchett EL. Management of atrial fibrillation. N Engl J Med
1992; 326:1264.
• Atrial fibrillation: current understandings and research
imperatives. The National Heart, Lung, and Blood Institute
Working Group on Atrial Fibrillation. J Am Coll Cardiol 1993;
22:1830.
• Lip GY, Metcalfe MJ, Rae AP. Management of paroxysmal atrial
fibrillation. Q J Med 1993; 86:467.
• Ganz LI, Friedman PL. Supraventricular tachycardia. N Engl J
Med 1995; 332:162.
1266
Bradycardia and Sudden Death Prevention

Usha B. Tedrow, MD, MSc
Director, Clinical Cardiac Electrophysiology Program
Disclosures
• St Jude Medical, Faculty, fellows’ course,

Catheter ablation, arrhythmia
• Boston Scientific, Faculty, fellows’ course,
Catheter ablation, ventricular tachycardia
• Biosense Webster, Funded Research,
Catheter ablation, arrhythmia
1267
Bradycardia Examples
Sinus Bradycardia Mobitz I Block
Mobitz II Block
•Indicative of conduction
disease below the AV node
•Needs urgent temporary
Complete Heart Block (and then permanent)
pacing
Indications for Pacing
Symptomatic bradycardia
SA node disease AV node disease

(or distal conduction disease)
(spontaneous or drug-induced)
1268
What do pacemakers do?
What Pacemakers Do
• Electronic pacemakers deliver electrical
impulses that depolarize the myocardial cells
near the lead tip, such that the signal
propagates into the contiguous myocardium
• Pulses can be delivered in many ways,
depending on how the pacemaker is
programmed
1269
Types of Pacemakers
• Lead in the right atrium
• Lead in the right ventricle
• Leads in both RA and RV
• Leads pacing RV, LV = biventricular pacer
A single chamber ventricular

pacemaker is a clock
VVI at 60 ppm
1 second
1270
A VVI Pacemaker Is A Clock

(that resets)
0.7 seconds
Clock reset 1 second
A DDD Pacemaker is 2 Clocks

DDD at 60 ppm = rate clock
AV delay 200ms = PR interval clock
200 ms 140ms
0.7 seconds
1271
AS VS AS VP
AP VS AP VP
1272
What is mode switching?
Leadless pacing: Micra Transcatheter Pacing System

Positioned in the Right Ventricle.
Reynolds D et al. N Engl J Med 2016;374:533-541.
1273
His Bundle Pacing: Anatomy
1274
Main Consequences of LBBB

• Widening of QRS complex (>120
msec)
• Increased time to complete
ventricular contraction
• Septal activation much before
free wall of ventricle, leading to
discoordinated contraction and
wasted energy
• Mitral valve may leak as a result
of sequential activation of
papillary muscles
Deleterious Effects of Ventricular

Dyssynchrony on Cardiac Function
Reduced diastolic
filling time 1
+ Weakened
contractility 2
+ Protracted mitral
regurgitation 2
+ Post systolic regional
contraction 3
= Diminished stroke
1. Grines CL, et al Circulation 1989;79: 845-853
volume 2. Xiao HB, et al Br Heart J 1991;66: 443-447
3. Søgaard P, et al. J Am Coll Cardiol 2002;40:723–730
1275
Achieving Cardiac
Resynchronization
Goal: Pace Right and Left Ventricles
• Epicardial Approach
• Requires thoracotomy
• Transvenous Approach
• Requires access to the
coronary sinus
• Requires leads developed
for LV application
1. Bakker et al. J of Cardiac Failure 1998; 4[3]:1-35

2. Saxon et al. PACE 1998; 21 Part II: 914
3. Daubert et al. PACE 1997; 20[II]
4. Gras et al. PACE 1998; 21[II]:824
Surgical Left Ventricular Lead
1276
Pre-op EKG: QRS 216 msec
Post-op EKG: QRS 152 msec
1277
CRT Indications
• Class I
– LVEF less than or equal to 35%, sinus rhythm
– LBBB with a QRS duration greater than or equal to 150 ms, and NYHA
class II, III, or ambulatory IV symptoms on optimal medical therapy
• Class IIa
– LVEF less than or equal to 35%, sinus rhythm, LBBB with a QRS
duration 120 to 149 ms, and NYHA class II, III, or ambulatory IV
symptoms
– LVEF less than or equal to 35%, sinus rhythm, a non-LBBB pattern
with a QRS duration greater than or equal to 150 ms, and NYHA class
III/ambulatory class IV symptoms
Tracy CM et al. Heart Rhythm. 2012 Oct;9(10):1737-53
CRT Indications
• Class IIa
– Atrial fibrillation and LVEF less than or equal to 35% on
GDMT if a) the patient requires ventricular pacing or
otherwise meets CRT criteria and b) AV nodal ablation or
pharmacologic rate control will allow near 100%
ventricular pacing with CRT
– LVEF less than or equal to 35% and are undergoing new or
replacement device placement with anticipated
requirement for significant (40%) ventricular pacing
1278
CRT Indications
• Class IIb
– LVEF less than or equal to 30%, ischemic etiology of heart failure, sinus
rhythm, LBBB with a QRS duration of greater than or equal to 150 ms,
and NYHA class I symptoms
– LVEF less than or equal to 35%, sinus rhythm, a non-LBBB pattern with
QRS duration 120 to 149 ms, and NYHA class II, III/ambulatory class IV
• Class III: No Benefit
– NYHA class I or II symptoms and non-LBBB pattern with QRS duration
less than 150 ms
– CRT is not indicated for patients whose co-morbidities and/or frailty
limit survival with good functional capacity to <1 year
Sudden Cardiac Arrest

• >400,000 out-of-hospital cardiac arrests per year in
U.S.
• ~50% of these arrests are in patients having a
myocardial infarction
• 95% out-of-hospital mortality
• Goals:
– Prevention
– Recognition of high risk populations
1279
Survival in Cardiac Arrest

5% estimated out-of-hospital survival2,3 even
in the best ambulance/EMS programs
Many events are not witnessed
There is difficulty reaching victims within 6-8
minutes.
Early availability of defibrillation is very
important!
1 Swagemakers V. J Am Cardiol. 1997;30:1500-1505

2 Ginsburg W. Am J Emer Med. 1998;16:315-319.
3 Cobb LA. Circ. 1992;85:I98-102.
AEDs Improve Survival

60%
50%
53%
45% 49%
40%
35%
30%
29%
25%
20% 24%
15%
10%
5%
5%
0%
National Average Boston,MA Seattle,WA Rochester,MN Casino Study
White RD. Ann Emer Med. 96;28:480-485. Cobb LA. Circ. 92;85:I98-102.
Smith SC. Circ. 97;13:1321-1324. Valenzuela TD. N Engl J Med. 2000;343:1206-1209.
1280
Patients at risk for sudden cardiac death

General population
CAD risk factors
Prior coronary event
EF < 35% and CHF
Prior out-of-hospital
cardiac arrest
Prior MI, low EF, VT
Huikiri et al, NEJM 2001
How can we prevent morbidity and

mortality from Sudden Cardiac Death?
• Primary prevention of coronary disease
• Early identification of structural heart disease
• Identification and avoidance of medications that
increase risk
• Community resuscitation programs (CPR, emergency
response systems)
• Community-based automated defibrillators (AEDs)
• Implantable cardiac defibrillators (ICD)
1281
Evaluation after Arrest

• Evaluate for acute causes
– Myocardial ischemia/infarction
– Electrolytes
– Drugs
• characterize underlying heart disease
– echocardiogram
• LV or RV dysfunction, areas of infarct or scar
– coronary angiography / exercise testing
– Consider cardiac MRI
– Consider EPS
+ ICD
SVC coil
Shock
vector
_
RV coil
1282
How does it know what to shock?
Subcutaneous ICD
1283
CE Mark Approved.
Caution: S-ICD is an investigational device limited
Burke, S-ICD, HRS 2012, Boston, MA to investigational use only under US federal law. Not for sale.
1284
ICD guidelines summary

• Class I
– LVEF ≤ 35% due to prior MI at least 40 days post-MI and
are in NYHA Functional Class II or III
– LV dysfunction due to prior MI, at least 40 days post-MI,
with LVEF ≤ 30%, and are in NYHA Functional Class I
– survivors of cardiac arrest due to VF or hemodynamically
unstable sustained VT after evaluation to define the cause
of the event excludes any completely reversible causes
Epstein AE et al.J Am Coll Cardiol. May 27, 2008;51(21)

• Class I
– Nonischemic DCM who have an LVEF ≤ 35% and NYHA
Functional Class II or III
– With nonsustained VT due to prior MI, LVEF < 40%, and
inducible VF or sustained VT at electrophysiological study
– Structural heart disease and spontaneous sustained VT,
whether hemodynamically stable or unstable
– Syncope of undetermined origin with clinically relevant,
hemodynamically significant sustained VT or VF induced at
electrophysiological study
1285

• Class IIa
– Long QT syndrome with syncope or ventriuclar arrhythmia on beta
blocker
– unexplained syncope, significant LV dysfunction, and nonischemic
DCM
– Sustained VT and normal or near-normal ventricular function
– • With catecholaminergic polymorphic VT who have syncope and/or
documented sustained VT while receiving beta blockers
– • For the prevention of SCD in patients with HCM, Brugada syndrome
ARVD/C who have one or more risk factors for SCD
– Cardiac sarcoidosis, giant cell myocarditis, or Chagas disease
– Nonhospitalized patients awaiting transplantation
Sudden Death before the age of 35 Yrs

Corrado et al NEJM 339:364, 1998
Total - 0.8 per 100,000 pt yrs 269

Atherosclerotic CAD 17 %
Myocarditis / Cardiomyopathy 12 %
Arrhythmogenic RV Dysplasia 11 %
Mitral Valve Prolapse 10 %
Conduction System Disease 9%
Hypertrophic Myopathy 6%
Aortic Dissection 5%
Anomalous Coronary 3%
1286
Familial syndromes associated with syncope

and sudden death:
• 1. Hypertrophic cardiomyopathy
• 2. Congenital long QT syndrome
• 3. Arrhythmic right ventricular dysplasia
• 4. Brugada syndrome
• 5. Others:
- familial dilated cardiomyopathy
- congenital heart block
- catecholaminergic polymorphic VT (CPVT)
• 1. The ECG suggests which of the following:

• A. Hypertrophic cardiomyopathy
• B. Arrhythmogenic right ventricular dysplasia
• C. Brugada syndrome
• D. Congenital long QT syndrome
• E. Familial Dilated Cardiomyopathy
1287
Hypertrophic Cardiomyopathy
• Prevalence 1 in 500
• LVH or repolarization abnormalities in 85% of
patients
• Palpitations due to atrial fibrillation
• Sudden death risk 1 – 3% per year
4. The ECG suggests which of the following:

A. Hypertrophic cardiomyopathy
B. Arrhythmogenic right ventricular dysplasia
C. Brugada syndrome
D. Congenital long QT syndrome
E. Familial dilated cardiomyopathy
1288

C. Brugada syndrome
Arrhythmogenic right ventricular

dysplasia (cardiomyopathy)
• Prevalence: 1/5000
• T-wave inversions in precordial leads in 85%
• fibrofatty infiltration of RV / LV
• VT with LBBB morphology – often exercise provoked
• Estimated mortality risk 3% per year
• Autosomal dominant and recessive forms
• at least 8 causative genes:
Cell adhesion proteins: plakophilin (27%), plakoglobin
ryanodine receptor, TGF-beta
Hulot et al. Natural history and risk stratification of ARVD. Circulation. 2004;110:1879.
Sen-Chowdhry et al. ARVC: clinical presentation, diagnosis, and mgmt. Am J Med
2004;117:685. Gerull, B.et al. Mutations in the desmosomal protein plakophilin-2 are
common in ARVC. Nat Genet 36(11): 1162-4.
1289

C. Brugada syndrome
Brugada syndrome
• Sudden death due to PMVT – VF

typically during sleep, fever
Average age at first event: 41 yrs (range 2 - 77 yrs)
• atrial arrhythmias and AV block also occur
• Approx 20% have a sodium channel (SCN5A) mutation
• Male and Asian predilection
• Risk of cardiac arrest approximately 10% per year - (may
be substantially less if no arrhythmia symptoms at time of
diagnosis)
• ICD is protective
Brugada Syndrome 2nd Consensus Conference Antzelevitch et al Circulation 2004

Eckardt L, et al. Long-term prognosis …. Circulation. 2005;111:257-63.
1290

• A. Hypertrophic cardiomyopathy
• B. Arrhythmogenic right ventricular dysplasia
• C. Brugada syndrome
• D. Congenital long QT syndrome
• E. Familial dilated cardiomyopathy
Congenital Long QT
syndrome
• mutations in genes coding for cardiac potassium or sodium
channels
• autosomal dominant and recessive forms, variable
penetrance.
• Presenting symptoms: syncope, sudden death
• ECG: QTc usually > 0.46s
Torsade de pointes
1291
References
• Epstein AE et al.J Am Coll Cardiol. May 27, 2008;51(21)
• Bardy GH. N Engl J Med. 2005;352:225-237.
• Tracy CM et al. Heart Rhythm. 2012 Oct;9(10):1737-53
• Moss AJ, et al. N Engl J Med. 2009;361:1329–1338
• Linde C et al. J Am Coll Cardiol. 2008;52:1834–1843
1292
Inflammation and Cardiovascular Disease
Paul M Ridker, MD, MPH

Director, Center for Cardiovascular Disease Prevention
Divisions of Cardiovascular Medicine and Preventive Medicine
Eugene Braunwald Professor of Medicine
Conflicts of Interest Paul M Ridker, MD, MPH
Dr Ridker reports having received research funding support from multiple not-
for-profit entities including the National Heart, Lung, and Blood Institute, the
National Cancer Institute, the American Heart Association, the Doris Duke
Charitable Foundation, the Leducq Foundation, the Donald W Reynolds
Foundation, and the James and Polly Annenberg La Vea Charitable Trusts. Dr
Ridker also reports having received investigator-initiated research support
from Astra-Zeneca, Novartis, Pfizer, and Kowa, as well as non-financial
research support from Amgen. Dr Ridker is listed as a co-inventor on patents
held by the Brigham and Women's Hospital that relate to the use of
inflammatory biomarkers in cardiovascular disease that have been licensed to
Siemens and AstraZeneca, and has served during the past year as a
research consultant to Quintiles, Novartis, Corvidia, Inflazome, Easai, Sanofi,
and Jansen. Neither Dr. Ridker nor the BWH receives any royalties
attributable to sales of the hsCRP test used in connection with the CIRT or
CANTOS trials.
1293
Inflammation and Cardiovascular Disease : Summary
1. Atherosclerosis is a disorder driven by lipid accumulation and inflammation.
2. hsCRP, a clinical biomarker of inflammation, is as powerful a risk marker for heart

attack and stroke as is LDL cholesterol, HDL cholesterol, or blood pressure, and has
similar variability over time. Diet, exercise, and smoking cessation all lower hsCRP
and all lower cardiovascular risk.
3. In primary prevention, the JUPITER trial has proven that patients with hsCRP
>2mg/L greatly benefit from statin therapy even if lipid levels are low.
4. In secondary prevention, the CANTOS trial has proven that lowering hsCRP, at least
with canakinumab, significantly reduces cardiovascular events.
5. Quality cardiovascular care requires us to recognize the distinction between

“residual cholesterol risk” and “residual inflammatory risk” as these patient groups
have different reasons for recurrent events.
Residual Inflammatory Risk:

Addressing the Obverse Side of the Atherosclerosis Prevention Coin
Ridker PM. Eur Heart J 2016;37:1720-22
Known Cardiovascular Disease

LDL 150 mg/dL (3.8 mmol/L)
hsCRP 4.5mg/L
High Intensity Statin
“Residual Cholesterol Risk” “Residual Inflammatory Risk”

LDL 110 mg/dL (2.8 mmol/L) LDL 70 mg/dL (1.8 mmol/L)
hsCRP 1.8 mg/L hsCRP 3.8 mg/L
Additional Additional
LDL Reduction Inflammation Reduction
IMPROVE-IT : Ezetimibe 6% RRR No Prior Proof of Concept

FOURIER/SPIRE: PCSK9 Inhibition q2 weeks 15% RRR
1294
Sabatine et al, NEJM 2017;376:1713-1722

Ridker PM. Eur Heart J 2016;37:1720-22

LDL 150 mg/dL
hsCRP 4.5mg/L

LDL 110 mg/dL LDL 80 mg/dL
IMPROVE-IT : Ezetimibe 6% RRR CANTOS

FOURIER/SPIRE: PCSK9 Inhibition q2 weeks 15% RRR Canakinumab 150mg SC q 3 months 15%RRR
1295
Göran K. Hansson. NEJM 2005; 352:1685-95.
Inflammation in atherosclerosis: from pathophysiology to practice
Libby P et al JACC 2009;54:2129-38
1296
Low Grade Systemic Inflammation Precedes By Many Years the Onset of Vascular Events
Ridker et al NEJM 1997; 336:973-9
IL-6 and Risk of Future MI in Apparently Healthy Men
P Trend = 0.001
3
P=0.01
P=0.003
Relative Risk of MI
2
P=0.3
0
1 2 3 4
≤1.04 1.04-1.46 1.47-2.28 ≥2.28
Quartile of IL-6 (range, pg/dL)
Ridker et al Circulation 2000;101:1767-1772
1297
Event-Free Survival According to Baseline Quintiles of

hs-CRP and LDL Cholesterol
Quintiles of hsCRP Quintiles of LDL
1.00
1.00
CVD Event-Free Survival Probability
0.99
0.99
1
1
2
2
0.98
0.98
3
sICAM1 3
VCAM
4
P-selectin
4
0.97
0.97
Eselectin
IL-6, IL-18
IL1ra 5
5
TNF / YKL-40 0.96
0.96
0 2 4 6 8 0 2 4 6 8
Years of Follow-Up Years of Follow-Up
Ridker et al N Engl J Med. 2002;347:1157-1165.
The magnitude of independent risk associated with inflammation is

at least as large, if not larger, than that of BP and cholesterol
Risk Ratio (95%CI)
hsCRP 1.37 (1.27-1.48)
Systolic BP 1.35 (1.25-1.45)
Total cholesterol 1.16 (1.06-1.28)
Non-HDLC 1.28 (1.16-1.40)
0.5 1.0 1.2 1.4 1.8
Risk Ratio (95%CI) per 1-SD higher usual values
Adjusted for age, gender, smoking, diabetes, BMI, triglycerides, alcohol, lipid levels, and hsCRP
Emerging Risk Factor Collaborators, Lancet January 2010 CR-12
1298
High Sensitivity C-Reactive Protein (hsCRP) : A Test In Context

hsCRP 1 mg/L 3 mg/L 10 mg/L
Lower Risk Moderate Risk Higher Risk Possible Acute Phase Response
Repeat in 2 to 3 weeks
Relative Risk of Future CV Events
hsCRP (mg/L)
Ridker PM. JACC 2016;16:67:712-23
Variability, Tracking Over Time, and Additive Clinical Utility in Risk Prediction
for hsCRP is Almost Identical to That of Cholesterol
hsCRP
hsCRP(mg/L)
mg/L
Variable Intra-Class 95 % CI
15
Correlation
10
hsCRP 0.54 0.53-0.55

5
LDL-C 0.57 0.56-0.58

0
12 Month 24 Month 36 Month 48 Month
LDLC (mmol/L)
LDL Cholesterol mmol/L
4.5
.004 .005 .004

3.0
1.5
Non-lipid risk factors

plus TC
0.0
plus TC plus HDLC

HDLC (mmol/L)
HDL Cholesterol mmol/L
plus TC plus HDLC plus hsCRP
2.5
2.0
1.5
0.0 0.01 0.02

1.0
Change in C-statistic
0.5
(as compared with non-lipid-based model)

Glynn R et al, Clin Chem 2009;55:305-312 Emerging Risk Factor Collaborators, NEJM 2012;367:1310-1320
1299
Inflammation, Statin Therapy, and hsCRP: Initial Observations
P Trend = 0.005 -21.6% (P=0.004)

3
0.25
Median hs-CRP (mg/dL)

0.24 Placebo
Relative Risk
2 0.23
0.22
0.21
1 Pravastatin
0.20
0.19
0 0.18
Pravastatin Placebo Pravastatin Placebo Baseline 5 Years
Inflammation Absent Inflammation Present
Ridker et al Circulation. 1998;98:839–844. Ridker et al Circulation. 1999;100:230-235.

15
Minimal Relationship Between Achieved LDL and

Achieved CRP After Initiation of Statin Therapy
r = 0.18
Variance = 3 percent
100
Achieved CRP (mg/L)
10
.1
30 80 130 180
Achieved LDLC (mg/dL)
Ridker et al NEJM 2005;352:20-28. PROVE IT – TIMI 22
1300
Achieving Low Levels of BOTH Cholesterol and Inflammation

is Crucial for Best Clinical Outcomes: the Concept of “Dual Goals”
0.10
0.40
Recurrent Vascular Events (%)
Recurrent Vascular Events (%)

0.075
0.30
0.05
0.20
0.025
0.10
0.00
0.00
0 0.5 1.0 1.5 2.0 2.5 00 11 22 33 4 4 5 5 6 6 7
Years
Follow-Up (Years)
PROVE-IT IMPROVE-IT
Ridker et al NEJM 2005;352:20-8 Bohula et al, Circulation 2015;132:1224-33
LDL >70 mg/dL LDL <70 mg/dL LDL > 70 mg/dL LDL <70 mg/dL
hsCRP > 2mg/L hsCRP > 2mg/L hsCRP < 2mg/L hsCRP < 2mg/L
Neither Goal LDL Goal hsCRP Goal Dual Goals

Achieved Achieved Achieved Achieved
JUPITER Ridker et al NEJM 2008;359:2195-2207

Trial Design
JUPITER
Multi-National Randomized Double Blind Placebo Controlled Trial of
Rosuvastatin in the Prevention of Cardiovascular Events
Among Individuals With Low LDL and Elevated hsCRP
MI
Rosuvastatin 20 mg (N=8901) Stroke
No Prior CVD or DM
Men >50, Women >60 Unstable
LDL <130 mg/dL Angina
4-week Placebo (N=8901)
CVD Death
hsCRP >2 mg/L run-in CABG/PTCA
Argentina, Belgium, Brazil, Bulgaria, Canada, Chile, Colombia, Costa Rica,

Denmark, El Salvador, Estonia, Germany, Israel, Mexico, Netherlands,
Norway, Panama, Poland, Romania, Russia, South Africa, Switzerland,
United Kingdom, Uruguay, United States, Venezuela
Mean LDLC 104 mg/dL, Mean HDLC 50 mg/dL, hsCRP 4 mg/L

18
1301
JUPITER Ridker et al NEJM 2008;359:2195-2207
Primary Trial Endpoint : MI, Stroke, UA/Revascularization, CV Death
HR 0.56, 95% CI 0.46-0.69 Placebo 251 / 8901

0.08
P < 0.00001
- 44 %
0.06
Cumulative Incidence
0.04
Rosuvastatin 142 / 8901

0.02
0.00
0 1 2 3 4
Number at Risk Follow-up (years)

Rosuvastatin 8,901 8,631 8,412 6,540 3,893 1,958 1,353 983 544 157
Placebo 8,901 8,621 8,353 6,508 3,872 1,963 1,333 955 534 174
JUPITER Glynn et al, NEJM 2009;360:1851-61

Total Venous Thromboembolism
HR 0.57, 95%CI 0.37-0.86
0.025
P= 0.007
0.020
Placebo 60 / 8901
0.015
- 43 %
0.010
0.005
Rosuvastatin 34 / 8901
0.000
0 1 2 3 4
Follow-up (years)
Number at Risk
Rosuvastatin 8,901 8,648 8,447 6,575 3,927 1,986 1,376 1,003 548 161
Placebo 8,901 8,652 8,417 6,574 3,943 2,012 1,381 993 556 182
1302
Can Inflammation Reduction, in the Absence of Lipid

Lowering, Reduce Cardiovascular Event Rates?
From CRP to IL-6 to IL-1: Moving Upstream to Identify novel Targets for Atheroprotection
Sarilumab
Ridker PM. Circ Res 2016;118:145-156.
1303
NLRP3 Inflammasome, Caspase-1, and IL-1β Maturation

Role of Cholesterol Crystals
Canakinumab Anti-inflammatory Thrombosis Outcomes Study (CANTOS)
Stable CAD (post MI) N = 10,061

Residual Inflammatory Risk 39 Countries
(hsCRP > 2 mg/L) April 2011 - June 2017
1490 Primary Events
Randomized Randomized Randomized Randomized

Canakinumab 50 mg Canakinumab 150 mg Canakinumab 300 mg Placebo
SC q 3 months SC q 3 months SC q 3 months SC q 3 months
Primary Endpoint: Nonfatal MI, Nonfatal Stroke, Cardiovascular Death (MACE)
Secondary Endpoint: MACE plus Unstable Angina Requiring Urgent Revascularization (MACE+)
Additional Adjudicated Endpoints: Cancer, Infection
Ridker et al N Engl J Med. 2017;377:1119-31
1304
Canakinumab (Novartis)
• high-affinity human monoclonal anti-human
interleukin-1β (IL-1β) antibody currently
indicated for the treatment of IL-1β driven
inflammatory diseases (Cryopyrin-Associated
Period Syndrome [CAPS], Muckle-Wells
Syndrome)
• designed to bind to human IL-1β and
functionally neutralize the bioactivity of this
pro-inflammatory cytokine
• long half-life (4-8 weeks) with CRP and IL-6
reduction for up to 3 months
25
Interleukin-1 Beta as a Target for Atherosclerosis: Biologic Basis for

CANTOS and Beyond
Libby P. JACC 2017;70:2278-89
1305
CANTOS: Dose-Dependent Effects on Inflammatory Biomarkers and Lipids (48 Months)
Placebo SC q 3 mth
hsCRP
Percent Change from Baseline (median)
Canakinumab 50mg SC q 3 mth

LDLC
HDLC
TG
Months
Placebo Canakinumab 50 Canakinumab 150 Canakinumab 300
CANTOS: Primary Cardiovascular Endpoints

Placebo SC q 3 months
Canakinumab 150/300 mg SC q 3 months
MACE MACE - Plus
HR 0.85 HR 0.83
Cumulative Incidence (%)
95%CI 0.76-0.96 95%CI 0.74-0.92

P = 0.007 P = 0.0006
0 1 2 3 4 5
Follow-up Years Follow-up Years
35 - 40% reductions in hsCRP and IL-6

No change in LDLC
1306
CANTOS : Consistency of Effect Across All patient Groups

Defined By Baseline Clinical Characteristics
Group
MACE MACE Plus
Women
Men
Age < 60 yrs

Age ≥ 60 yrs
Diabetes
No diabetes
Non Smoker
Smoker
BMI < 30 kg/m2

BMI ≥ 30 kg/m2
LDLC < 80 mg/dL

LDLC ≥ 80 mg/dL
hsCRP < 4 mg/L

hsCRP ≥ 4 mg/L
HDLC > 45 mg/dL

HDLC ≤ 45 mg/dL
TG < 150 mg/dL

TG ≥ 150 mg/dL
Overall
0.5 1.0 0.5 1.0

Canakinumab Canakinumab Canakinumab Canakinumab
Superior Inferior Superior Inferior
Ridker et al Lancet 2018;391:319-328
CANTOS: Greater Risk Reduction Among Those

With Greater hsCRP Reduction (MACE)
HR (95% CI) P
Placebo 1.0 (ref) (ref)
On-treatment hsCRP: ≥ 2.0 mg/L 0.95 (0.81, 1.09) 0.48
On-treatment hsCRP: < 2.0 mg/L 0.75 (0.66, 0.85) <0.0001
Placebo
On-treatment hsCRP ≥ 2mg/L
On-treatment hsCRP < 2mg/L
MACE
25% reduction in risk for those achieving hsCRP < 2 mg/L
5 % reduction in risk for those achieving hsCRP ≥ 2 mg/L
(No change in LDL cholesterol)
Ridker et al Lancet 2018;391:319-328
1307
CANTOS : 31% Reduction in Cardiovascular Mortality and All-Cause Mortality

Among Participants with Robust Inhibition of the Inflammatory Response
CANTOS - Cardiovascular Mortality CANTOS - All Cause Mortality

0.20
0.20
Placebo 1.0 (referent) (referent) Placebo 1.0 (referent) (referent)
Canakinumab, hsCRP ≥2mg/L 0.99 (0.82-1.21) 0.95 Canakinumab, hsCRP ≥2mg/L 1.05 (0.90-1.22) 0.56
Canakinumab, hsCRP <2mg/L 0.69 (0.56-0.85) 0.0004 Canakinumab, hsCRP <2mg/L 0.69 (0.58-0.81) <0.0001
0.15
0.15
0.10
0.10
0.05
0.05
0.00
0 1 2 3 4 5 0.00 0 1 2 3 4 5
Years Years
35 - 40% reductions in hsCRP and IL-6

No change in LDLC
Ridker et al Circulation 2018;137:1763-1766
Lisa Coussens LM, Zena Werb.

Nature. 2002 420(6917):860-7.
“Inflammation is a critical component of

tumour progression (and) it is now becoming
clear that the tumour microenvironment,
which is largely orchestrated by inflammatory
cells, is an indispensable participant in the
neoplastic process, fostering
proliferation, survival, and migration”.
1308
CANTOS: Additional Non-Cardiovascular Clinical Benefits

Incident Lung Cancer
3.0
HR (95%CI) P
Placebo 1.0 (referent) (referent)
Canakinumab 50 mg 0.77 (0.49-1.20) 0.25
Canakinumab 150 mg 0.61 (0.39-0.97) 0.034
Canakinumab 300 mg 0.33 (0.18-0.59) 0.00008
P-trend across groups = 0.0003

2.0
1.0
Canakinumab 300 mg
67% reduction
in incident lung cancer
0.0
P=0.00008
0 1 2 3 4 5
Follow-up Years
Lancet. 2017;390:1833-1842
CANTOS: Increased Incidence Rates of MACE, Cardiovascular Death,

and All-Cause Mortality Among Patients with Moderate CKD as
Compared to Those with Normal Renal Function.
P < 0.0001
Incidence Rate / 100 person-years
P < 0.0001
P < 0.0001
Moderate CKD Normal Renal Function
1309
CANTOS : Effects of Canakinumab on Major Vascular Events Among

Those With and Without Moderate CKD at Study Entry
eGFR < 60 mL/min/1.73m2 eGFR > 60 mL/min/1.73m2

Confirmed MACE+Urgent Revascularization Confirmed MACE+Urgent Revascularization
Among Subjects whose baseline eGFR <60 Among Subjects whose baseline eGFR >=60
0.4
0.4
HR (95% CI) P
_______________________________________________ HR (95% CI) P
_______________________________________________
Placebo 1.0 (ref) (ref) Placebo 1.0 (ref) (ref)
Active Canakinumab 0.82 (0.68,1.00) 0.054 Active Canakinumab 0.86 (0.77,0.97) 0.012
HR 0.82 HR 0.86
0.3
0.3
95%CI 0.68-1.00 95%CI 0.77-0.97

P = 0.05 P = 0.01
0.2
0.2
0.1
0.1
0.0
0.0
0 1 2 3 4 5 0 1 2 3 4 5
No. at risk: Follow-up (years) No. at risk: Follow-up (years)
Placebo 626 561 499 Years423 182 27
Placebo 2717 2546 2422 Years
2155 1056 179
Canakinumab 1249 1139 1047 894 410 58
Canakinumab 5467 5177 4940 4410 2155 382
Moderate CKD Normal Renal Function

(N = 1875) (N = 8184)

Eur Heart J 2016;37:1720-22

LDL 150 mg/dL
hsCRP 4.5mg/L

LDL 110 mg/dL LDL 80 mg/dL
IMPROVE-IT : Ezetimibe 6% RRR CANTOS

FOURIER/SPIRE: PCSK9 Inhibition q2 weeks 15% RRR Canakinumab 150mg SC q 3 months 15%RRR
1310
CANTOS : Adding a New Axis to the Oxford LDL Lowering Line
60
50
JUPITER
Relative Risk Reduction (%)
40
30
20
10
0 10 20 30 40 50 60
% Reduction in LDL-C
Ridker ACC 2018
How Common is Residual Inflammatory Risk?

Following Following
High-Intensity Statins High-Intensity Statins
Plus Ezetimibe
Residual Inflammatory Risk Residual Cholesterol Risk Both Neither

hsCRP ≥ 2 mg/L hsCRP < 2 mg/L hsCRP ≥ 2 mg/L hsCRP < 2 mg/L
LDLC < 70 mg/dL LDLC ≥ 70 mg/dL LDLC ≥ 70 mg/dL LDLC < 70 mg/dL
Circulation Res 2017;120:617-9.
1311
Relationships of hsCRP Levels With Future Cardiovascular Events

Among High-Risk Patients Treated with Both Statins and PCSK9 Inhibitors
FOURIER SPIRE 1/2
Incidence rate / 100 person years

Incidence rate / 3 years
hsCRP hsCRP
Bohula et al, Circulation 2018 Pradhan et al, Circulation 2018
How Common is Residual Inflammatory Risk?

Following Following Following
High-Intensity Statins High-Intensity Statins High-Intensity Statins
Plus Ezetimibe Plus PCSK9 Inhibition
Residual Inflammatory Risk Residual Cholesterol Risk Both Neither

hsCRP ≥ 2 mg/L hsCRP < 2 mg/L hsCRP ≥ 2 mg/L hsCRP < 2 mg/L
LDLC < 70 mg/dL LDLC ≥ 70 mg/dL LDLC ≥ 70 mg/dL LDLC < 70 mg/dL
Circulation Res 2017;120:617-9.

Pradhan et al Circulation 2018 (on line).
1312
FOURIER: Residual Inflammatory Risk is Present

Irrespective of On-Treatment LDL-C
18.2%
16.4%
14.7% 15.4%
13.1%
20% 14.9%
Incidence Rate at 3 Years
12.6% 13.2%
10.8% 12.0%
15% 12.3%
10.4% 10.9%
9.0% 9.8%
10%
>3
5%
1-3
<1 hsCRP
0% (mg/L)
<20 20-49 50-69 70-99 ≥100
LDL-C at 1 month (mg/dL)
Bohula E. Circulation 2018. DOI: 10.1161/CirculationAHA. 118.034032
Inflammation and Atherothrombosis :

Clinical Approaches
Intervention Reduces Reduces Event Rates?

Inflammation?
Smoking Cessation Yes Yes
Exercise Yes Yes
Diet Yes Yes
Weight Loss Yes Yes
Statins Yes Yes
IL-1β inhibition Yes Yes
1313
Sustained Weight Loss Reduces hsCRP Irrespective of Diet : NIH Pounds Lost Trial
Median Percent Change 6 months 24 months
Nicklas JM, et al; Obesity 2013;21(4):681-9.
Cardiovascular Inflammation Reduction Trial (CIRT)

Primary Aims (NHLBI - Ridker PI)
Stable CAD • To directly test the

On Statin, ACE/ARB, BB, ASA inflammatory hypothesis of
atherothrombosis
• To evaluate in a randomized,
Persistent Evidence of Inflammation double-blind, placebo-
Diabetes or Metabolic Syndrome controlled trial whether MTX
given at a target dose of 20
mg po weekly over a three
year period will reduce rates
MTX 15-20 mg Placebo of recurrent myocardial
Weekly infarction, stroke, or
cardiovascular death among
patients with a prior history of
atherosclerosis and either
Nonfatal MI, Nonfatal Stroke, type 2 diabetes or metabolic
Cardiovascular Death syndrome.
N = 5,500 NHLBI-Sponsored
350 US and Canadian Sites
1314
Ongoing Trials
LoDoCo2
Colcot
Nidorf, SM, et al; JACC 2013; 61:404-10.
Conclusions:
The Canakinumab Anti-Inflammatory Thrombosis Outcomes Study (CANTOS)
1. CANTOS demonstrates that targeting the IL-1b to IL-6 pathway of innate

immunity with canakinumab reduces cardiovascular event rates and
potentially reduces rates of incident lung cancer and lung cancer mortality.
2. CANTOS thus provides critical proof-of-concept that inflammation

inhibition, in the absence of lipid lowering, can improve atherothrombotic
outcomes. This is the first hard evidence in 40 years of an effective therapy
for atherosclerosis not directly related to cholesterol reduction.
3. The magnitude of hsCRP reduction following a single dose of canakinumab

may provide a simple clinical method to identify individuals most likely to
accrue the largest cardiovascular and cancer benefits from continued
treatment, including 31% reductions in cardiovascular as well as all-cause
mortality.
1315
Biologic Residual Residual Residual Residual Residual

Issue Cholesterol Risk Inflammatory Risk Thrombotic Risk Triglyceride Risk Lp(a) Risk
Critical
Biomarker
LDL-C >100mg/dL hsCRP >2mg/L No simple TG >200mg/dL Lp(a) >50mg/dL
biomarker HDL <40mg/dL
Potential Targeted Targeted Targeted Targeted Targeted

Intervention LDL / Apo B Inflammation Antithrombotic Triglyceride Lp(a)
Reduction Reduction Reduction Reduction Reduction
Randomized IMPROVE-IT CANTOS COMPASS Ongoing Planned

Trial FOURIER, SPIRE
Evidence ODDYSEY
Inflammation and Cardiovascular Disease : Summary
1. Atherosclerosis is a disorder driven by lipid accumulation and inflammation.
2. hsCRP, a clinical biomarker of inflammation, is as powerful a risk marker for heart

attack and stroke as is LDL cholesterol, HDL cholesterol, or blood pressure, and has
similar variability over time. Diet, exercise, and smoking cessation all lower hsCRP
and all lower cardiovascular risk.
3. In primary prevention, the JUPITER trial has proven that patients with hsCRP
>2mg/L greatly benefit from statin therapy even if lipid levels are low.
4. In secondary prevention, the CANTOS trial has proven that lowering hsCRP, at least
with canakinumab, significantly reduces cardiovascular events.
5. Quality cardiovascular care requires us to recognize the distinction between

“residual cholesterol risk” and “residual inflammatory risk” as these patient groups
have different reasons for recurrent events.
1316
Inflammation, Atherothrombosis, and Vascular Prevention:

Three Translational Questions
Is there evidence that individuals with elevated levels of

inflammatory biomarkers are at high vascular risk even when
other risk factors are acceptable? Yes (hsCRP, 1997)
Is there evidence that individuals identified at increased risk
due to inflammation benefit from a therapy they otherwise
would not have received? Yes (statins, JUPITER 2008)
Is there evidence that reducing inflammation per se will
reduce vascular events? Yes (CANTOS, 2017)
“Lower is better” appears to be true for both LDLC and
hsCRP in both primary and secondary prevention
49
1317
Take Home Messages in

Cardiology
Akshay Desai, MD
PREVENTION
1318
Core Principles
• Lifestyle interventions are appropriate for

everyone
• Assess long term cardiovascular risk in all
• Match intensity of preventive interventions to

baseline cardiovascular risk
Fundamentals of Prevention
1. ≥150 minutes moderate activity /week

or ≥75 minutes vigorous activity/week
2. Eat a healthy diet (4-5 components of
healthy diet score*)
3. Have a normal body weight (BMI < 25)
4. Never smoked or quit >1 year ago
5. Total cholesterol <200 mg/dL
6. Blood pressure <120/80 mm Hg
7. Fasting blood glucose <100 mg/dL
* 1) 4.5 cups or more of fruits and vegetables per
day 2) two or more 3.5-oz servings of fish per
week 3) three servings per day of whole grains 4)
less than 1500 mg of sodium per day 5) 36 ounces or
less of sugar-sweetened beverages per week
Lloyd-Jones et al. Circulation 2010; 121:586-613
1319
4 Statin Benefit Groups

( 1-3) High Risk:
1. Clinical ASCVD*
2. LDL–c >190 mg/dL, Age >21 years
3. Primary prevention – Diabetes:
Age 40-75 years, LDL–c 70-189 mg/dL
(4) Primary prevention†
4. No Diabetes:
≥7.5% 10-year risk, Age 40-75 years, LDL–c 70-189
mg/dL
Generally use high-intensity statin (e.g. atorvastatin 40-80 mg or
rosuvastatin 20 mg) to achieve LDL reduction >= 50% from baseline
Stone et al JACC 2014;63:2889-934

Category Systolic Pressure Diastolic Pressure
(mmHg) (mmHg)
Normal < 120 and <80
Elevated 120-129 and <80
Stage 1 Hypertension 130-139 or 80-89
Stage 2 Hypertension ≥140 or ≥90
Class I recommendation in primary prevention:

Initiate BP-lowering meds for:
• SBP ≥140 mm Hg or DBP ≥90 mm Hg
• SBP ≥130 mm Hg or DBP ≥80, if 10-year ASCVD risk ≥10%
On-therapy BP target: < 130/80

Whelton PK, et al. 2017 Guideline for the prevention, detection, evaluation, and
management of high blood pressure in adults. J Am Coll Cardiol 2018; 71:2199.
1320
Lifestyle Modifications for BP Control
Modification Recommendation Approximate SBP

Reduction Range
Weight Maintain normal body weight 5-20 mmHg/10 kg

reduction (BMI=18.5-25) weight lost
DASH eating Diet rich in fruits, vegetables, 8-14 mmHg

plan low fat dairy and reduced in fat
Restrict <2.4 grams of sodium per day 2-8 mmHg

sodium intake
Physical Regular aerobic exercise for at 4-10 mmHg

activity least 30 minutes at least 5 days
of the week
Moderate <2 drinks/day for men and <1 2-4 mmHg
alcohol drink/day for women
Chobanian AV et al. JAMA 2003;289:2560-2572
Summary
1. First step in prevention is to assess ASCVD risk

(risk factors, global risk score)
2. Lifestyle improvement is the most important component of ASCVD
prevention and risk factor treatment (Life’s Simple 7)
3. Statins added to lifestyle to reduce risk of ASCVD in higher risk
individuals (4 statin benefit groups); PCSK9i in the very highest
risk patients
4. Blood pressure control: Target BP for most patients <130/80
mmHg; risk-based assessment
5. Aspirin (81-162 mg/d) in higher risk individuals if benefit outweighs
risk of bleeding (avoid in low risk individuals and elderly)
1321
VASCULAR MEDICINE
11
1322
• Lifestyle modifications
– Weight maintenance/reduction
• Smoking
– Complete cessation
– HbA1c goal, target specific agents
• Dyslipidemia
– High intensity statin + other agents (lower is better)
• Hypertension
– Therapies to achieve target, ACE inhibitors (HOPE Trial)
• Antithrombotic therapy
– Aspirin or Clopidogrel for symptomatic PAD
* Supervised Exercise program may improve

walking distance and relieve symptoms, consider
prior to revascularization
AAA: Summary Points
• Screen for AAA (exam + U/S) in

• Men > 60 who are siblings or offspring of
patients with AAA
• Men 65-75 who have ever smoked
• Intervene for symptomatic patients or

according to maximal diameter
• ≥ 5.5 cm Repair
• 4.0-5.5 cm Surveillance q 6-12 mos
• < 4.0 cm Surveillance q 2-3 years
13
1323
Thoracic Aortic Disease
When to Intervene?
• Generally 5.5 cm, or growth > 0.5 cm/y

including bicuspid AoV (unless RF for
dissection such as FH)
• For genetic syndrome (MFS, LDS, EDS,

familial syndrome) may undergo at smaller
diameters (4.0-5.0) – for MFS contemplating
pregnancy > 4.0 cm
2010 ACCF/AHA/AATS/ACR/ASA/
SCA/SCAI/SIR/STS/SVM Guidelines for the Diagnosis and Management of Patients with Thoracic Aortic Disease
Indications for Carotid Revascularization

ACC/AHA Guidelines
I IIa IIb III
• Patients at average or low surgical risk who
experience nondisabling ischemic stroke or TIA within
6 months should undergo CEA if the ipsilateral ICA
stenosis is >70%.
I IIa IIb III
• Carotid stenting is indicated as an alternative to CEA
for symptomatic patients at average or low risk of
complications.
Asymptomatic Carotid Stenosis is still an area of controversy,

routine revascularization likely not indicated
Brott et a. JACC. 2011;57:1002-44
1324
ACUTE CORONARY
SYNDROMES
ST-Elevation MI (STEMI)
• Consider immediate reperfusion therapy
• In whom?
– Within 12 hrs of sx onset, or
– 12-24 hrs after sx onset if clinical or ECG evidence of
ongoing ischemia
• How?
– Primary PCI (including transfer to PCI-capable hosp
if door-in to door-out time will be <30 min &
1st med contact to PCI anticipated <120 min)
– Fibrinolytic (barring contraindications*)
*Absolute: prior ICH; intracranial neoplasm, aneurysm, or AVM; stroke or head trauma w/in 3 mos; active
internal bleeding or diathesis; suspected AoD
*Relative: severe HTN; stroke; prolonged CPR; recent bleed, surgery or trauma; noncompressible vasc
puncture; pregnancy; current use of anticoagulants
1325
Management Strategy in NSTEACS

INVASIVE
ASA 162-325 mg
(ie, angiography for all in ~48 hrs)
P2Y12 inhibitor
NSTEACS PCI / CABG
Anticoagulant
anatomy
Long-term
Initial Med Rx
Med Rx
high-risk low-risk
recurrent
angina
Cont’d
Med Rx
INVASIVE APPROACH
PREFERRED IN MOST
PATIENTS CONSERVATIVE
(ie, selective angiography)
Discharge Checklist
Risk Factor Modification Medical Therapy

1. Low chol (<200 mg/d) and low 1. Aspirin 81 mg/d for life
fat (<7% saturated) diet 2. P2Y12 Inhibitor for 12 mos
2. LDL goal <70 mg/dl 3. β-Blocker
3. ? HDL >40 md/dl 4. Statin high-intensity lipid-lowering
4. BP <140/90, <130/80 if DM or (eg, atorva 80 mg qd)
CKD 5. ACEI (or ARB if ACEI intol) if CHF,
5. Smoking cessation EF<0.40, HTN, DM; ? in all CAD
6. If DM, HbA1c cntl 6. Aldo antag if EF <40% & CHF or
(? avoid TZDs) DM
7. Exercise (≥30 min 3-4 x per 7. Nitrates standing if sx, prn for all
wk)
8. BMI goal 18.5-24.9 kg/m2
1326
ST Which ST-T PR
Coving Leads? Evolution Segment
Pericarditis Diffuse Days- ↓

weeks
(STE < 5 mm)
Acute Localized Hours Normal

STEMI
1327
Management of Idiopathic (post-viral)

Acute Pericarditis
• Aspirin (e.g., 650 mg q 4-6 h)

• NSAIAs (e.g., ibuprofen 400-800 mg q 6-8 h)
• Colchicine (off-label; Class IIb: evidence favors efficacy)
CORP. Ann Int Med 2011;155:409.
COPE. Circulation 2005;112:2012.
CORE. Arch Intern Med 2005;165:1987.
• Prednisone 0.25-0.5 mg/kg/d (last resort)
• Sinus tach • Low voltage • Electrical alternans
1328
Cardiac Tamponade
(Beck’s Triad)
• Jugular venous distention

• Hypotension with pulsus paradoxus
• “Small, quiet heart”
HEART FAILURE
1329
Guideline-Directed Medical
Management of HF: 2018
Relief of EF≤40% NYHA II-IV Still

Congestive NYHA I-IV Symptomatic?
Symptoms
Consider
additional
therapies
MRA
ACEi/ARB/ Beta-Blocker
ARNI Ivabradine
Spironolactone Hydral/ISDN
Diuretics Lisinopril, etc. Carvedilol Digoxin
Eplerenone
Loop Valsartan, etc. Metoprolol
(thiazide) Sacubitril/Val Bisoprolol
Yancy C, et al. Circulation. 2013;128:e240-e327

McMurray JJV, et al. Eur Heart J. 2012;33:1787-1747
Yancy C, et al. Circulation 2017

Yancy, et al. J Am Coll Cardiol 2017
1330
Device Therapy
• ICD
– Prior Cardiac Arrest, Sustained VT
– Symptomatic HF, EF≤35%
– Asymptomatic, LVEF<30%, CAD
– High risk groups (HCM, Long QT, Brugada)
• CRT (Biventricular Pacing)

– EF≤35%, symptomatic HF, QRS>130 ms, LBBB
VENOUS THROMBOEMBOLISM
1331
DEFINITIONS OF PE:
AHA PE Guidelines 2011
• Massive PE (5-10%): sustained
hypotension, pulselessness, or
persistent bradycardia
• Submassive PE (20-25%): RV
dysfunction or myocardial necrosis,
without hypotension
• Low Risk PE (70%): no markers of
adverse prognosis
(Circulation 2011; 123: 1788-1830)
RISKS FOR POOR PROGNOSIS

1. Elevated biomarkers (troponin)
(European Heart J 2010; 31: 1836)
2. RV enlargement/ hypokinesis: ECG
RV/ LV ratio > 0.9
CT—(JACC Cardiovasc Imaging
2011; 4: 841-849)
ECHO—(Circulation 2010;122: 1124)
1332
RISK STRATIFY TO GUIDE

MANAGEMENT STRATEGY
5% 10% 15% 70%
High Risk Submassive Submassive Low Risk
High: RVD+Tn Low: RVD or Tn
Reperfuse: Reperfuse, Hospitalize, ? Early
Lysis/ Or Watch Anticoa- Discharge;
Embo- And gulate Anticoa-
lectomy Wait gulate
(ESC Guidelines. European Heart J 2014;
35: 3033-3080)
ACUTE VTE TREATMENT:

NOAC EFFICACY
• All 4 NOACs are noninferior to
LMWH/ warfarin for efficacy,
regardless of weight, PE vs. DVT,
CKD, and cancer.
• Edoxaban: prespecified submassive
PE subgroup showed superiority.
(van Es N, et al. Blood 2014; 124: 1968-1975)
1333
2014 ESC GUIDELINES

Recommendation Class Level
Extended oral IIa B

anticoagulation should
be considered for
patients with a first
episode of unprovoked
PE and low bleeding
risk.
(Konstantinides SV, et al. Eur Heart J 2014 Aug 29)
ECG / ARRHYTHMIAS
1334
1335
18 year old male with palpitations
1336
Management of Atrial Fibrillation
• Treat predisposing factors

• Prevent thromboembolism / stroke
• Rate control (target HR<110 bpm)
• Restore/maintain sinus rhythm?
CHADS2 – VASc Score for Stroke Risk in AF
Risk Factors Score Implications of the Score
Congestive HF 1 0 = stroke risk 1.2%/yr

- Rx: no oral
Hypertension 1 anticoagulation or asa
Age > 75 yrs 2
1 = stroke risk 2.2%/yr
Diabetes mellitus 1
- Rx oral antiicoagulant
or asa
Prior stroke or TIA 2
2 or more =
Vascular Disease 1 stroke risk >3% / yr
- Rx oral anticoagulant
Age 65 – 75 1
Sex category = AF guidelines of the European Society of

1
female Cardiology. European Heart J (2010) 31, 2369
1337
Anticoagulation - Platelet inhibitors
• Aspirin is inferior to warfarin
• Aspirin + clopidogrel is superior to asa

alone but with increased bleeding risk
• Aspirin + clopidogrel is inferior to warfarin
Direct Oral Anticoagulants
• All are non-inferior to warfarin in “non-valvular” AF*

Apixaban was superior for stroke prevension in one trial
* Should not be used in mitral stenosis (not evaluated) or

mechanical valves (dabigatran is inadequate, others
have not been evaluated)
• Lower risk of intracranial bleeding than warfarin

• Rapid onset of action, reliable pharmacokinetics, and
fewer drug interactions than warfarin
– Bridging with parenteral heparin is not needed for initiating
therapy
1338
VALVULAR HEART DISEASE
Natural History of Aortic Stenosis

Onset severe
Angina
symptoms
100 Syncope
Failure
80 period
Latent period,
(increasing
increasing obstruction,
60 myocardial overload) 0 2 4 6
hypertrophy
Avg
Yrs survival (yr)
after onset
40
Average death
20
age ( )
0
0 40 50 60 70 80
Age (yr)
Ross J Jr. and Braunwald E: Circ 38(Suppl 5):61, 1968
CP1061785-6
1339
Aortic Stenosis
Jet Velocity (m/s) < 3.0 3.0 - 4.0 > 4.0
Mean Gradient (mmHg) < 25 25-40 > 40
Valve Area (cm2) > 1.5 1.0-1.5 < 1.0
Valve Are Index (cm2/m2) < 0.6
Zoghbi W et al. J Am Soc Echocardiogr 2003; 16:777.
Severe Aortic Stenosis

Indication ACC/AHA1 ESC2

2006 2012
Symptoms I(B) I(B)

Need for CABG/Ao Surgery I(C) I(C)
LVEF < 0.50 I(C) I(C)
Abnormal ETT IIb(C) IIa or IIb(C)

Rapid Progression/Delay IIb(C) IIa(C)
Very severe AS IIb(C) IIa(C)
Severe LVH (>15mm) ----- IIb(C)*
1. Bonow R et al. J Am Coll Cardiol 2006
2. Vahanian A et al. European Heart Journal 2012
1340
BAV Aortopathy
Chronic MR
Medical Therapy
• ABx prophylaxis
No role when and if indicated
for vasodilator therapy
in
asymptomatic, normotensive patients
• Management of AF
with chronic severe
• Management of CAD MR and normal LV
function
• ACE-I or ARB for HTN, reduced EF
1341
Endocarditis Prophylaxis Recommend- Level of
ation Evidence
Prosthetic cardiac valve or prosthetic material IIa C-LD
for valve repair (including TAVR)
Previous infective endocarditis IIa C-LD
Unrepaired cyanotic congenital heart disease IIa C-LD
(CHD)
Repaired CHD with prosthetic material, first 6 IIa C-LD
months
Repaired CHD with residual defects at site of IIa C-LD
patch or device
Cardiac transplant with valve regurgitation IIa C-LD
due to structurally abnormal valve
For dental procedures that involve manipulation of either gingival tissue or the
periapical region of teeth or perforation of the oral mucosa.

• Types: secundum, primum , sinus venosus,
coronary sinus
• Exam: Grade 2 MSM, fixed splitting S2
• ECG: IRBB. LAD = primum.
• ECHO: RV volume overload, shunt flow,

associated findings (MVP, cleft MV, APVD)
1342
PATENT FORAMEN OVALE

• Present in 25-30% of population
• Sometimes associated with interatrial
septal aneurysm
• Implied role in
– Cryptogenic stroke
– Migraine
– Platypnea-orthodeoxia
– Decompression sickness
GOOD LUCK!
1343
Board Review in
Cardiology
Psychiatry Overview
Garrick C. Stewart, MD, MPH
Associate Physician, Center for Advanced Heart Disease
Division of Cardiovascular Medicine
Disclosures of Conflicts of Interest
•No disclosure
1344
Question #1
A 78-year old man with bioprosthetic mitral valve replacement and
10 year history of diabetes mellitus presents with new onset atrial
fibrillation with heart rate of 82 beats/minute and blood pressure of
156/96 mm Hg. Echocardiogram reveals LVEF 56%. Which of the
following is a true statement?
A. Restoration of sinus rhythm reduces risk of stroke compared with rate control
and anticoagulation
B. Patient can be treated with rivaroxaban instead of warfarin
C. Warfarin should be started to reduce risk of stroke
D. The combination of aspirin and clopidogrel is equivalent to warfarin
E. Patient can be cardioverted now and complete 4 weeks of dabigatran
Answer #1
A 78-year old man with bioprosthetic mitral valve replacement and
10 year history of diabetes mellitus presents with new onset atrial
fibrillation with heart rate of 82 beats/minute and blood pressure of
156/96 mm Hg. Echocardiogram reveals LVEF 56%. Which of the
following is a true statement?
A. Restoration of sinus rhythm reduces risk of stroke compared with rate control
and anticoagulation
B. Patient can be treated with rivaroxaban instead of warfarin
C. Warfarin should be started to reduce risk of stroke
D. The combination of aspirin and clopidogrel is equivalent to warfarin
E. Patient can be cardioverted now and complete 4 weeks of dabigatran
1345
Anticoagulation Indicated if Score ≥2

(Consider Anticoagulation if Score 1)
Chua SK et al. J Thorac Cardiovasc Surg. 2013 Apr 26

http://clincalc.com/Cardiology/Stroke/CHADSVASC.aspx
Novel Oral Anticoagulants
Nonvalvular Atrial Fibrillation: AF in the absence of rheumatic mitral

stenosis, a mechanical or bioprosthetic heart valve, or mitral valve repair.
Novel/Direct Oral Anticoagulants have only been studied in nonvalvular AF.
Fontana et al. Eur Heart J 2014; doi:10.1093/eurheartj/ehu027
1346
Question #2
A 42 year old man presents with several days of sharp substernal
chest pain that is relieved by sitting forward. He had a similar
presentation two years ago. Physical exam reveals flat neck veins,
regular rhythm, friction rub and clear lung fields. A 12-lead ECG is
obtained:
© 2015 ABIM
Question #2
Randomized, placebo-controlled trials have
shown which of the following agents to be
beneficial in the treatment of this condition?
A. Aspirin
B. Colchicine
C. Corticosteroids
D. Cyclophosphamide
E. Ibuprofen
1347
Question #2
Randomized, placebo-controlled trials have
shown which of the following agents to be
beneficial in the treatment of this condition?
A. Aspirin
B. Colchicine
C. Corticosteroids
D. Cyclophosphamide
E. Ibuprofen
Survival Free of Incessant or

Recurrent Pericarditis
Imazio M et al. N Engl J Med 2013;369:1522-1528.
1348
Question #3
A 45-year-old man is admitted with heart failure. He has noted orthopnea
and progressive severe fatigue over the past 6 months. He had been
previously healthy and takes no medications. On exam, he appears chronically
ill. His blood pressure is 90/75 mm Hg; heart rate is 100 bpm.
Numerous ecchymoses are scattered over his extremities. Jugular venous

pressures are elevated to the angle of the jaw in the seated position. Carotid
upstrokes are low volume. Both lung bases are dull. There is a soft
holosystolic murmur. Summation gallop is present with prominent P2. Ascites
and hepatomegaly are present. 2+ edema and cold extremities are noted.
ECG shows diffusely low QRS voltages. Echocardiogram shows left ventricular
ejection fraction (LVEF) 50% and septal and posterior wall 2 cm. N-terminal
pro–B-type natriuretic peptide is 5000.
Question #3
Which of the following is the most likely cause of his heart
failure?
A. Coronary artery disease
B. Cardiac amyloid
C. Thiamine deficiency
D. Constrictive pericarditis
E. Aortic stenosis
1349
Answer #3
Which of the following is the most likely cause of his heart
failure?
A. Coronary artery disease
B. Cardiac amyloid
C. Thiamine deficiency
D. Constrictive pericarditis
E. Aortic stenosis
Cardiac Amyloidosis
Normal Amyloid
Quarta et al. Circulation 2012; 126: e178-82.
1350
Question #4
Cardiac troponin are frequently used in medicine. Each
of the following statements regarding troponin elevation
is true EXCEPT:
A. Cardiac troponin T 0.09 (ULN 0.03) is associated with worse
outcomes in an acute coronary syndrome
B. Troponin is commonly elevated in asymptomatic patients
with chronic kidney disease
C. Non-ischemic cardiomyopathy patients admitted with mild
troponin elevations in the setting of decompensated heart
failure have a worse prognosis than patients with normal
troponins
D. Troponin does not increase with acute pulmonary embolism
E. Troponin elevation is a predictor of mortality in setting of
sepsis
Answer #4
Cardiac troponin are frequently used in medicine. Each
of the following statements regarding troponin elevation
is true EXCEPT:
A. Cardiac troponin T 0.09 (ULN 0.03) is associated with worse
outcomes in an acute coronary syndrome
B. Troponin is commonly elevated in asymptomatic patients
with chronic kidney disease
C. Non-ischemic cardiomyopathy patients admitted with mild
troponin elevations in the setting of decompensated heart
failure have a worse prognosis than patients with normal
troponins
D. Troponin does not increase with acute pulmonary
embolism
E. Troponin elevation is a predictor of mortality in setting of
sepsis
1351
Acute Right Ventricular Strain Can Lead to

Troponin Elevation in PE
Akram et al. QJM 2009; 102: 407-414
Meta-Analysis of Sepsis and

Troponin Elevation
Bessiere et al. Intensive Care Med 2013;39:1181-89
1352
Question #5
A 64 year old woman with chronic systolic heart failure, EF
25%, in NYHA Class 2 and 3 prior HF hospitalizations
presents for a routine visit. She is euvolemic with heart
rate is 60bpm in sinus rhythm, BP 110/62. She is on
carvedilol 25mg bid, enalapril 5mg bid and eplerenone
25mg daily. Creatinine is 1.2mg/dL, potassium 4.1. What
is the most appropriate step to reduce cardiovascular
death and HF hospitalization?
A. Transition from eplerenone to spironolactone 25mg daily
B. Start digoxin 0.125mg every other day
C. Initiate ivabridine 5mg bid
D. Stop enalapril and start sacubitril-valsartan 24-26mg bid no earlier
than 36 hours after stopping enalapril
E. Add losartan 25mg daily
Answer #5
A 64 year old woman with chronic systolic heart failure, EF
25%, in NYHA Class 2 and 3 prior HF hospitalizations
presents for a routine visit. She is euvolemic with heart
rate is 60bpm in sinus rhythm, BP 110/62. She is on
carvedilol 25mg bid, enalapril 5mg bid and eplerenone
25mg daily. Creatinine is 1.2mg/dL, potassium 4.1. What
is the most appropriate step to reduce cardiovascular
death and HF hospitalization?
A. Transition from eplerenone to spironolactone 25mg daily
B. Start digoxin 0.125mg every other day
C. Initiate ivabridine 5mg bid
D. Stop enalapril and start sacubitril-valsartan 24-26mg bid no
earlier than 36 hours after stopping enalapril
E. Add losartan 25mg daily
1353
PARADIGM-HF: CV Death or HF
Hospitalization (Primary Endpoint)
McMurray JJ et al. N Engl J Med. 2014;371:993-1004.
2016 HF Guideline Update

COR LOE Recommendation
I B-R ACEI or ARB or ARNI in conjunction with β blockers + MRA (where
appropriate) is recommended for patients with chronic HFrEF to
reduce morbidity and mortality
I B-R In patients with chronic, symptomatic HFrEF NYHA class II or III who
tolerate and ACEI or ARB, replacement by an ARNI is recommended to
further reduce morbidity and mortality
III B-R ARNI should NOT be administered concomitantly with ACEI or within
36 hours of last ACEI dose
III C-EO ARNI should NOT be administered to patients with a history of
angioedema
1. Yancy CW et al. J Am Coll Cardiol. 2016;68:1476-1488.
1354
Question #6
A previously healthy 38 year-old woman presents to the
emergency room with lightheadedness, palpitations and
generalized fatigue. She just returned from a 2-week
vacation to Martha’s Vineyard and noticed a rash on her left
thigh. ECG is performed:
Question #6 (cont)
Each of the following statements regarding this patient’s
condition is true EXCEPT:
A. This is a common cause of cardiomyopathy

B. Steroids may improve symptoms
C. AV block often requires temporary cardiac pacing
D. Pericarditis is common and responds to indomethicin
E. Myocarditis may occur in 10% of patients
1355
Answer #6
Each of the following statements regarding this patient’s
condition is true EXCEPT:
A. This is a common cause of cardiomyopathy

B. Steroids may improve symptoms
C. AV block often requires temporary cardiac pacing
D. Pericarditis is common and responds to indomethicin
E. Myocarditis may occur in 10% of patients
Lyme and the Heart
Krause PJ et al. Circulation 2013;127:e451
1356
Question #7
A 33-year old female presents to the emergency room at 25-
weeks gestation with progressive dyspnea (now at rest),
orthopnea, and fatigue. She has no prior medical problems.
Physical exam is notable for opening snap after S2 with a I/IV
diastolic murmur heard best in left lateral decubitus position.
HR is 108 beats/min and BP is 130/84 mm Hg. She receives
oxygen, IV furosemide, and diltiazem. Echocardiogram
demonstrates mitral valve area of 0.5 cm2 and normal left
ventricular ejection fraction. Which is the best approach for
management?
A. Start carvedilol
B. Start lisinopril
C. Balloon valvuloplasty
D. Immediate Cesarean section
E. Start digoxin
Answer #7
A 33-year old female presents to the emergency room at 25-
weeks gestation with progressive dyspnea (now at rest),
orthopnea, and fatigue. She has no prior medical problems.
Physical exam is notable for opening snap after S2 with a I/IV
diastolic murmur heard best in left lateral decubitus position.
HR is 108 beats/min and BP is 130/84 mm Hg. She receives
oxygen, IV furosemide, and diltiazem. Echocardiogram
demonstrates mitral valve area of 0.5 cm2 and normal left
ventricular ejection fraction. Which is the best approach for
management?
A. Start carvedilol
B. Start lisinopril
C. Balloon valvuloplasty
D. Immediate Cesarean section
E. Start digoxin
1357
Mitral stenosis
Left-sided symptoms
Hemoptysis, right-heart failure, hoarseness
10-20 years post-rheumatic fever
Echocardiogram useful to determine therapies
Exclude atrial myxoma
Mitral stenosis in pregnancy

• NYHA Class III and IV—Treat with
percutaneous valvotomy before delivery
• Judicious use of diuretics and beta-
blockers for milder forms of MS
• Propranolol (classic) vs. cardio-selective
(e.g., atenolol, metoprolol)
• Beware of bradycardia and hypoglycemia
in newborn
• Avoid ACE-inhibitors
Maisano F. Eur Heart J 2014; 35: 1575-7.
1358
Question #8
A 48-year old man with history of hypertension presents to
emergency room with acute chest pain radiating to back with
hypotension and a new, large left effusion on chest x-ray.
Systolic blood pressure differs in both arms by 22 mm Hg.
Appropriate steps in management include:
A. Treat with sodium nitroprusside alone

B. Start a loop diuretic alone
C. Refer for urgent transthoracic echocardiogram
D. Refer for urgent surgical repair for proximal dissection
E. Narcotics for pain relief alone
Answer #8
A 48-year old man with history of hypertension presents to
emergency room with acute chest pain radiating to back with
hypotension and a new, large left effusion on chest x-ray.
Systolic blood pressure differs in both arms by 22 mm Hg.
Appropriate steps in management include:
A. Treat with sodium nitroprusside alone
B. Start a loop diuretic alone
C. Refer for urgent transthoracic echocardiogram
D. Refer for urgent surgical repair for proximal dissection
E. Narcotics for pain relief alone
1359
Aortic Dissection
European Heart Journal 2014; 35:2873-2926
Acute Management of Aortic Dissection

• Stabilization and pain relief
• Combination of sodium nitroprusside and beta-
blocker to reduce BP and wall stress
• Immediate surgery for life threatening
complications
• Urgent confirmation of dissection
• Distal dissections are often in older patients and
associated with CAD
1360
Question #9
A 58 year old African-American man presents to primary care
office for routine physical examination. He expressed
concern about his cardiovascular risk due to his strong family
history of coronary artery disease. He has no medical
problems, exercises once weekly, and review of systems is
negative for any symptoms. BP is 142/78, HR 75, BMI 25.8.
Exam unremarkable. Lipid profile: Cholesterol 211, HDL 49,
LDL 122, Triglycerides 144. He denies smoking or illicit drug
use. Which is the incorrect statement?
A. Cardiovascular death rates increase as the patient ages
B. Cardiovascular death rates have decreased recently
C. Routine aerobic exercise may reduce his risk for MI
D. Death from cardiovascular disease peaked in the 1970s
E. Black race is not associated with increased stroke risk
Answer #9
A 58 year old African-American man presents to primary care
office for routine physical examination. He expressed
concern about his cardiovascular risk due to his strong family
history of coronary artery disease. He has no medical
problems, exercises once weekly, and review of systems is
negative for any symptoms. BP is 142/78, HR 75, BMI 25.8.
Exam unremarkable. Lipid profile: Cholesterol 211, HDL 49,
LDL 122, Triglycerides 144. He denies smoking or illicit drug
use. Which is the incorrect statement?
A. Cardiovascular death rates increase as the patient ages
B. Cardiovascular death rates have decreased recently
C. Routine aerobic exercise may reduce his risk for MI
D. Death from cardiovascular disease peaked in the 1970s
E. Black race is not associated with increased stroke risk
1361
Answer #9
• Plateau of cardiovascular death in
1970s CVD=CHD, HF, stroke, HTN
100
• CVD deaths decreased over past 90
decade 80
70
% of population
60
• HTN affects ~74 million in US
50
40
• MI or Fatal coronary heart disease 30
(CHD) affects 30,000 men and 20
10,000 women between ages 35-44 10
(0.8% of population) 0
20-39 40-59 60-79 80+
Age (years)
• Stroke hospitalization highest
Men Women
among blacks (4.0% vs 2.4% whites)
and 2-fold risk of 1st stroke
AHA 2013 Statistics
Question #10
A 21 year old male with a history of bicuspid aortic valve
presents to office with significant hypertension (192/102).
ECG demonstrates LVH. Brachial-femoral delay in noted
on pulse exam. In addition to blood pressure assessments
in arms and legs, what diagnostic tools should be
considered as routine parts of the evaluation?
A. Chest x-ray
B. Echocardiogram
C. MRI/MRA
D. All of the above
E. None of the above
1362
Answer #10
A 21 year old male with a history of bicuspid aortic valve
presents to office with significant hypertension (192/102).
ECG demonstrates LVH. Brachial-femoral delay in noted
on pulse exam. In addition to blood pressure assessments
in arms and legs, what diagnostic tools should be
considered as routine parts of the evaluation?
A. Chest x-ray
B. Echocardiogram
C. MRI/MRA
D. All of the above
Coarctation of Aorta
Brickner ME et al. N Engl J Med 2000;342:256-263.
1363
Coarctation of Aorta
– Associated with BAV, subaortic stenosis, circle of Willis aneursym, and
VSD
– Recognized risk in hypertension for young patients
– HTN in upper arms (especially right) compared with legs
– Death related to CHF, aortic rupture, endocarditis, MI, IC bleed
Warnes et al. Circulation 2008;118;e714-e833
Question #11
A 49 year old female with heart failure and ventricular
tachycardia presents with a new pericardial friction rub
and anti-histone antibodies. Which drug is most
associated with drug-induced lupus?
A. Verapamil
B. Hydralazine
C. Amiodarone
D. Lidocaine
1364
Answer #11
A 49 year old female with heart failure and ventricular
tachycardia presents with a new pericardial friction rub
and anti-histone antibodies. Which drug is most
associated with drug-induced lupus?
A. Verapamil
B. Hydralazine
C. Amiodarone
D. Lidocaine
Side Effect Profiles

Verapamil Hydralazine
-Constipation -Drug-induced SLE
-Skin reaction -Dizziness
-Gingival hyperplasia
Lidocaine
Perioral numbness
Diplopia Amiodarone
Seizures -Photosensitivity
Cholestatic jaundice -Lung toxicity
Hyperacusis -Hepatitis
Slurred speech -Thyroid abnormalities
1365
Question #12
A 69-year old man returns for a follow-up visit after an anterior
myocardial infarction 2 months ago complicated by heart
failure. On maximal medical therapy, he currently has no
symptoms of heart failure. A follow-up echocardiogram reveals
an improved left ventricular ejection fraction from 20% at the
time of MI to 33% today. What would you do next?
A. Consider ICD only if he becomes symptomatic (NYHA 2 or 3)
B. Refer for an implantable cardioverter-defibrillator (ICD)
C. Repeat echocardiogram in another month to see if LVEF improves
prior to implanting ICD
D. Consider cardiac MRI to assess LVEF
E. Educate patient about the contraindication of ICD due to his age
Answer #12
A 69-year old man returns for a follow-up visit after an anterior
myocardial infarction 2 months ago complicated by heart
failure. On maximal medical therapy, he currently has no
symptoms of heart failure. A follow-up echocardiogram reveals
an improved left ventricular ejection fraction from 20% at the
time of MI to 33% today. What would you do next?
A. Consider ICD only if he becomes symptomatic (NYHA 2 or 3)
B. Refer for an implantable cardioverter-defibrillator (ICD)
C. Repeat echocardiogram in another month to see if LVEF improves
prior to implanting ICD
D. Consider cardiac MRI to assess LVEF
E. Educate patient about the contraindication of ICD due to his age
1366
Epstein et al. Circulation 2008:117:2820-40
Question #13
A 63-year old man has recurrent non-sustained ventricular
tachycardia (up to 9-beats) in the setting of an acute
myocardial infarction. Mild signs of heart failure are present
and successful stent is placed in left anterior descending
artery. Ejection fraction is 25%. Which statement is true?
A. ACE-inhibitors do not improve outcomes in this population
B. Implantable defibrillator should be performed prior to discharge
C. Lidocaine should be started at this time
D. Beta blockers may improve survival and should be started once
congestion is resolved and prior to discharge
E. Eplerenone is not associated with improved survival
1367
Answer #13
A 63-year old man has recurrent non-sustained ventricular
tachycardia (up to 9-beats) in the setting of an acute
myocardial infarction. Mild signs of heart failure are present
and successful stent is placed in left anterior descending
artery. Ejection fraction is 25%. Which statement is true?
A. ACE-inhibitors do not improve outcomes in this population
B. Implantable defibrillator should be performed prior to discharge
C. Lidocaine should be started at this time
D. Beta blockers may improve survival and should be started
once congestion is resolved and prior to discharge
E. Eplerenone is not associated with improved survival
CAPRICORN
Carvedilol on outcome after myocardial infarction in patients
with LVEF<40% (n=1959)
Death from all causes

23 % risk reduction, p = 0.031
Post-MI Management
• ACE inhibitors improve outcomes
(SAVE, AIRE, TRACE)
• EPHESUS: 30% risk reduction in

mortality with eplerenone
• ICD should not be used within 40 days

post MI +/- revascularization
• Excess risk with type 1 anti-arrhythmic

agents
Lancet 2001;357:1385-1390
1368
Question #14
An 35-year old woman presents to the emergency room
following a motor vehicle accident in which she was wearing a
seatbelt. She noted mild dizziness while driving and awakens
finding herself on the side of the road. Past medical history is
notable for heart failure secondary to sarcoidosis. She takes
lisinopril 5 mg daily, metoprolol succinate 25 mg daily, and
prednisone 5 mg daily. Physical exam is remarkable for mild
facial lacerations. What is the most likely cause of this event?
A. Hysterical fainting
B. Epilepsy
C. Sinus bradycardia
D. Neurocardiogenic syncope
E. Ventricular tachycardia
Answer #14
An 35-year old woman presents to the emergency room
following a motor vehicle accident in which she was wearing a
seatbelt. She noted mild dizziness while driving and awakens
finding herself on the side of the road. Past medical history is
notable for heart failure secondary to sarcoidosis. She takes
lisinopril 5 mg daily, metoprolol succinate 25 mg daily, and
prednisone 5 mg daily. Physical exam is remarkable for mild
facial lacerations. What is the most likely cause of this event?
A. Hysterical fainting
B. Epilepsy
C. Sinus bradycardia
D. Neurocardiogenic syncope
E. Ventricular tachycardia
1369
History is the key for syncope

Event Classic scenario
Cardiac syncope - Rapid onset without aura; clear sensorium

- History of CAD, LV dysfunction
Bradyarrhythmias - History of conduction disease, heart transplant
Neurological syncope - Preceded by aura; clouded sensorium

- Incontinence, tongue biting, seizure activity
Hysterical fainting - Not accompanied by change in pulse, blood

pressure, or skin color
- Paresthesias of hands/face, hyperventilation
- Dyspnea, signs of anxiety
Event Classic scenario
Neurocardiogenic - 50% of syncopal episodes

- Precipitants: emotional distress, pain,
fatigue, fear, decreased venous return
Catecholamine state
Sympathetic stimulation of heart
Stimulates cardiac mechanoreceptors

(vagal afferent C fibers)
Vasodilatation and bradycardia
1370
Question #15
Which of the following is FALSE related to patients
undergoing percutaneous coronary intervention?
A. In patients with CKD (creatinine clearance<60 mL/min), the

volume of contrast media should be minimized
B. Administration of N-acetyl-L-cysteine is useful to prevent
contrast-induced acute kidney injury
C. Patients with prior reaction to contrast can proceed with
catheterization with appropriate prophylaxis
D. Administration of high-dose statin is reasonable before PCI
to reduce risk of peri-procedural MI
E. Patients not on aspirin should be given non-enteric aspirin
325 mg before PCI
Answer #15
Which of the following is FALSE related to patients
undergoing percutaneous coronary intervention?
A. In patients with CKD (creatinine clearance<60 mL/min), the

volume of contrast media should be minimized
B. Administration of N-acetyl-L-cysteine is useful to prevent
contrast-induced acute kidney injury
C. Patients with prior reaction to contrast can proceed with
catheterization with appropriate prophylaxis
D. Administration of high-dose statin is reasonable before PCI
to reduce risk of peri-procedural MI
E. Patients not on aspirin should be given non-enteric aspirin
325 mg before PCI
1371
-N=2308
-2 doses before and after
procedure
-Contrast-induced AKI (13.8% vs.
14.7% control, p=0.64)
Question #16
A 39 year old woman who is 30-weeks pregnant and
presents to emergency room with mild dyspnea on exertion.
Examination reveals BP 110/70 mm Hg, HR 95 beats/minute,
clear chest, jugular venous pressure 7 cm water, and III/VI
holosystolic murmur at apex. Echocardiography confirms
moderate mitral regurgitation. Estimated PA pressure is 30+
right atrial pressure. Management option includes which of
the following?
A. Start low-dose furosemide
B. Arrange for emergent delivery of fetus
C. Plan mitral valve repair prior to delivery
D. Left and right heart catheterization
E. Proceed with pregnancy with close follow-up
1372
Answer #16
the following?
Valvular Heart Lesions Associated With High

Maternal and/or Fetal Risk During Pregnancy
1. Severe AS with or without symptoms

2. AI with NYHA functional Class III–IV symptoms
3. MS with NYHA functional Class II–IV symptoms
4. MR with NYHA functional Class III–IV symptoms
5. Aortic and/or mitral valve disease resulting in severe pulmonary
hypertension (pulmonary pressure >75% of systemic
pressures)
6. Aortic and/or mitral valve disease with severe LV dysfunction
(EF<40%)
7. Mechanical prosthetic valve requiring anticoagulation
8. AI in Marfan’s syndrome
Nishimura et al. J Am Coll Cardiol. 2014;63(22):e57-e185
1373
Question #17
A 39-year old woman presents to the office with newly
diagnosed hypertension (BP 151/92). Lifestyle
modifications, as recommended by the JNC VII
guidelines, can produce blood pressure reductions
which are equivalent to:
A. One antihypertensive agent

B. Two antihypertensive agents
C. Three antihypertensive agents
Answer #17
A 39-year old woman presents to the office with newly
diagnosed hypertension (BP 151/92). Lifestyle
modifications, as recommended by the JNC VII
guidelines, can produce blood pressure reductions
which are equivalent to:
A. One antihypertensive agent

B. Two antihypertensive agents
C. Three antihypertensive agents
1374
Adapted from Chobanian et al. JAMA 2003;289: 2560-2572 and JNC 7
JAMA. 2014;311(5):507-520.
1375
Question #18
A 38-year-old female attorney has experienced palpitations over
past 2 years. The episodes are not associated with dizziness,
syncope, or diaphoresis. She is otherwise healthy and
examination is completely normal with an exception of heart rate
of 108 beats/minute which increases to 128 beats/minute with
standing and when she presents to an audience. An
electrocardiogram reveals sinus tachycardia and is otherwise
normal. Stress reduction and caffeine reduction did not change
symptom burden. What is the best treatment for her
palpitations?
A. Dofetilide
B. Nadolol
C. Radiofrequency Ablation
D. Amiodarone
E. Nifedipine
Answer #18
A 38-year-old female attorney has experienced palpitations over
past 2 years. The episodes are not associated with dizziness,
syncope, or diaphoresis. She is otherwise healthy and
examination is completely normal with an exception of heart rate
of 108 beats/minute which increases to 128 beats/minute with
standing and when she presents to an audience. An
electrocardiogram reveals sinus tachycardia and is otherwise
normal. Stress reduction and caffeine reduction did not change
symptom burden. What is the best treatment for her
palpitations?
A. Dofetilide
B. Nadolol
C. Radiofrequency Ablation
D. Amiodarone
E. Nifedipine
1376
Interventions and Indications

Amiodarone Dofetilide
-Paroxysmal atrial fib/flutter -Blockade of the cardiac ion

channel carrying the rapid
-PSVT component of the delayed
-Sustained VT rectifier potassium currents
-Atrial fib/flutter
Beta-adrenergic blocker Radiofrequency Ablation

-Sinus tachycardia -Treatment for atrial fib/flutter
-Palpitations -Pulmonary vein isolation
-Various CV conditions -Atrial tachycardia
Question #19
A 72-year old man with a history of severe mitral regurgitation
from anterior leaflet prolapse with a LVEF of 50% with LVEDD
59 mm presents for a second opinion. Dyspnea occurs when
walking up one flight of stairs and is otherwise healthy. Which
is the best option for management?
A. Refer for mitral valve surgery
B. Refer for percutaneous MitraClip
C. Follow serial echocardiograms and plan surgery when LVEF
decreases below 35%
D. Start ACE-inhibitor to attenuate the progression of LV dilatation
E. Refer for cardiac resynchronization to reduce mitral regurgitation
1377
Answer #19
A 72-year old man with a history of severe mitral regurgitation
from anterior leaflet prolapse with a LVEF of 50% with LVEDD
59 mm presents for a second opinion. Dyspnea occurs when
walking up one flight of stairs and is otherwise healthy. Which
is the best option for management?
A. Refer for mitral valve surgery
B. Refer for percutaneous MitraClip
C. Follow serial echocardiograms and plan surgery when LVEF
decreases below 35%
D. Start ACE-inhibitor to attenuate the progression of LV dilatation
E. Refer for cardiac resynchronization to reduce mitral regurgitation
Recommendations for Mitral Valve Surgery in

Severe Primary Mitral Regurgitation
J Am Coll Cardiol. 2014;63(22):e57-e185
1378
Question #20
Please review the following ECG:
Question #20
Each of the following statements about this ECG finding
is true EXCEPT:
A. Exercise stress testing should include imaging

B. This can represent end-organ damage from
systemic hypertension
C. Repolarization will normalize with exercise
D. Can be seen with both eccentric and concentric
ventricular remodeling
E. This ECG is diagnostic for left ventricular
hypertrophy
1379
Answer #20
Each of the following statements about this ECG finding
is true EXCEPT:
A. Exercise stress testing should include imaging

B. This can represent end-organ damage from
systemic hypertension
C. Repolarization will normalize with exercise
D. Can be seen with both eccentric and concentric
ventricular remodeling
E. This ECG is diagnostic for left ventricular
hypertrophy
Question #21
A 53-year old woman who has not seen a doctor in 10 years
presents to clinic for a routine visit given vague chest pain and
fatigue. She takes no medicines and denies allergies or past
medical history. She noticed her BP was 170/100 at a drug store 4
weeks ago prompting the visit. She has tried decreasing salt
intake. Exam demonstrates BP 166/106, HR 76, AV nicking and
loud S2. JVP is 7 (normal). Routine labs and ECG are normal.
She has uncontrolled diabetes, proteinuria, and LVEF is 40%.
While arranging for catheterization, which is the best next option?
A. Start enalapril
B. Further lifestyle change and recheck BP in 4-6
weeks
C. Start hydrochlorothiazide
D. Refer for implantable defibrillator
E. Start diltiazem
1380
Answer #21
A 53-year old woman who has not seen a doctor in 10 years
presents to clinic for a routine visit given vague chest pain and
fatigue. She takes no medicines and denies allergies or past
medical history. She noticed her BP was 170/100 at a drug store 4
weeks ago prompting the visit. She has tried decreasing salt
intake. Exam demonstrates BP 166/106, HR 76, AV nicking and
loud S2. JVP is 7 (normal). Routine labs and ECG are normal.
She has uncontrolled diabetes, proteinuria, and LVEF is 40%.
While arranging for catheterization, which is the best next option?
A. Start enalapril
B. Further lifestyle change and recheck BP in 4-6
weeks
C. Start hydrochlorothiazide
D. Refer for implantable defibrillator
E. Start diltiazem
Hypertension Treatment
• First line therapy is often a diuretic
• Tailor choice of drug to patient population
ACE-inhibitor: Diabetes, CHF, MI, proteinuria, and low LVEF
Beta-blockers: CAD
Long acting drugs and combination drugs for non-compliant patients
• Multiple drugs are often required

• Screen for secondary causes of hypertension
1381
Question #22
A 69-year old woman with history of cardiac transplantation
and normal appearing heart on recent echocardiogram
presents for routine office visit. She is asymptomatic and
has a past medical history of controlled hypertension,
diabetes, and dyslipidemia without history of endocarditis.
She is scheduled for a dental extraction next week. What
is the best recommendation for SBE prophylaxis?
A. Amoxicillin 2 grams orally 1 hour before procedure

B. Clindamycin 600 mg orally 1 hour before procedure
C. Ampicillin 2 grams IV 30 minutes before procedure
D. All are acceptable options
Answer #22
A 69-year old woman with history of cardiac transplantation
and normal appearing heart on recent echocardiogram
presents for routine office visit. She is asymptomatic and
has a past medical history of controlled hypertension,
diabetes, and dyslipidemia without history of endocarditis.
She is scheduled for a dental extraction next week. What
is the best recommendation for SBE prophylaxis?
A. Amoxicillin 2 grams orally 1 hour before procedure
B. Clindamycin 600 mg orally 1 hour before procedure
C. Ampicillin 2 grams IV 30 minutes before procedure
D. All are acceptable options
1382
Endocarditis Prophylaxis No longer recommended:
Class IIa – Acquired valvular dysfunction (RHD)
– Prosthetic cardiac valves – Hypertrophic cardiomyopathy
– Previous bacterial endocarditis – MVP with valvular
– Unrepaired cyanotic congenital heart regurgitation/thickened leaflets
disease
– Completely repaired cyanotic
congenital heart disease using
prosthetic material or within 6 months
of catheter intervention
– Repaired CHD with residual defect or
adjacent to site of a prosthetic patch
– Cardiac transplantation with valve
regurgitation due to structurally
abnormal valve
Nishimura et al. ACC/AHA Guidelines Circulation 118:887 (2008)
Question #23
A 56 year old male presents for a new visit for
management of his chronic heart failure with LVEF of 30%
and NYHA Class III functional class. Medications include
lisinopril 40mg once daily, carvedilol 25 mg twice daily, and
furosemide 40 mg daily. Which of the following statements
regarding therapy to improve survival is correct?
A. Hydralazine plus isosorbide dinitrate improves survival in self-described African-
American heart failure patients who are taking ACE-inhibitors and beta-blockers
B. Aldosterone-receptor antagonist reduces all-cause mortality in patients with NYHA
Class III or IV heart failure, MI patients with heart failure, and older patients with
milder forms of heart failure following hospitalization
C. Cardiac resynchronization therapy improves survival in patients with mild heart
failure patients (NYHA Class I/II) with left bundle branch block and QRS of 160
milliseconds
D. Angiotensin II receptor blockers in addition to ACE-inhibitors is associated with an
improvement in cardiovascular survival
E. All of the above are correct
1383
Answer #23
A 56 year old male presents for a new visit for
management of his chronic heart failure with LVEF of 30%
and NYHA Class III functional class. Medications include
lisinopril 40mg once daily, carvedilol 25 mg twice daily, and
furosemide 40 mg daily. Which of the following statements
regarding therapy to improve survival is correct?
A. Hydralazine plus isosorbide dinitrate improves survival in self-described African-
American heart failure patients who are taking ACE-inhibitors and beta-blockers
B. Aldosterone-receptor antagonist reduces all-cause mortality in patients with NYHA
Class III or IV heart failure, MI patients with heart failure, and older patients with
milder forms of heart failure following hospitalization
C. Cardiac resynchronization therapy improves survival in patients with mild heart
failure patients (NYHA Class I/II) with left bundle branch block and QRS of 160
milliseconds
D. Angiotensin II receptor blockers in addition to ACE-inhibitors is associated with an
improvement in cardiovascular survival
E. All of the above are correct
A-HeFT: Overall Survival

100
43% Decrease in Mortality
Fixed-dose HYD/ISDN
Survival (%)
95
90
Placebo
Hazard ratio=0.57
P=.01
85
0 100 200 300 400 500 600
Days Since Baseline Visit Date
HYD/ISDN 518 463 407 359 313 251 13
Placebo 532 466 401 340 285 232 24
Adapted from Taylor AL, et al. N Engl J Med. 2004;351:2052.
1384
EMPHASIS-HF in “Mild HF”

Event Eplerenone (%) Placebo(%) Adjusted HR p-value
CV Death/HF Hospitalization 18.3 25.9 0.63 (0.54-0.74) <0.001
CV Death 10.8 13.5 0.76 (0.61-0.94) 0.01
HF Hospitalization 12.0 18.4 0.58 (0.47-0.70) <0.001
Hyperkalemia Hospitalization 0.3 0.2 1.15 (0.25-5.31) 0.85
N Engl J Med. 2010 Nov 14.
CHARM-Alternative: Primary outcome CV death or

CHF hospitalization
%
50
406 (40.0%)
Placebo
40
334 (33.0%)
30
Candesartan
20
10 HR 0.77 (95% CI 0.67-0.89), p=0.0004

Adjusted HR 0.70, p<0.0001
0
Number at risk
0 1 2 3 3.5 years
Candesartan 1013 929 831 434 122
Placebo 1015 887 798 427 126
1385
Question #24
You are asked to see a 34-year-old woman with history of dental
abscess and IV drug use who has been admitted to the hospital
with fevers, chills, and dyspnea for 5 days. Temperature is 102.3.
Heart rate is 120 beats/minute, and blood pressure is 89/72 mm
Hg. Jugular venous pressure is 14 cm. Rales are heard
bilaterally. Cardiac examination reveals a soft S1 and a grade
II/IV early diastolic decrescendo murmur that is loudest at the
upper left sternal border; the apical impulse is normal and
extremities are cool. Echocardiogram reveals severe aortic
insufficiency with evidence of vegetation. Blood cultures are
pending.
Question #24
Which of the following is the best next step for this
patient?
A. Attempt to stabilize the patient with intra-aortic balloon counterpulsation
B. Perform emergency cardiac catheterization, and then refer for emergency
aortic valve replacement
C. Start IV dobutamine, IV furosemide, and IV antibiotics, and refer for
emergency aortic valve replacement
D. Start IV dobutamine, IV furosemide, and IV antibiotics and consider aortic
valve replacement if blood cultures do not clear with antibiotics in 2 weeks
E. Perform transesophageal echocardiogram to determine if surgery is
required
1386
Answer #24
Which of the following is the best next step for this
patient?
A. Attempt to stabilize the patient with intra-aortic balloon counterpulsation
B. Perform emergency cardiac catheterization, and then refer for emergency
aortic valve replacement
C. Start IV dobutamine, IV furosemide, and IV antibiotics, and refer for
emergency aortic valve replacement
D. Start IV dobutamine, IV furosemide, and IV antibiotics and consider aortic
valve replacement if blood cultures do not clear with antibiotics in 2 weeks
E. Perform transesophageal echocardiogram to determine if surgery is
required
Baddour et al. Circulation 2005;111:e394-434.
1387
Definition of Infective Endocarditis “Modified Duke Criteria”
Question #25
A 52-year old male presents to clinic for perioperative
evaluation prior to elective cholecystectomy. He works full
time in construction and exercises by walking ~40 minutes
several times per week. His past medical history is notable for
hypertension, hypercholesterolemia, and a myocardial
infarction 3 years ago. What is the best management?
A. Coronary angiography prior to surgery

B. Perform cholecystectomy only if emergency
C. Stress test with MIBI or echocardiogram
D. Proceed with surgery and ensure beta-blocker use
E. Stress test without imaging
1388
Answer #25
infarction 3 years ago. What is the best management?
A. Coronary angiography prior to surgery

B. Perform cholecystectomy only if emergency
C. Stress test with MIBI or echocardiogram
D. Proceed with surgery and ensure beta-blocker use
E. Stress test without imaging
Goldman Criteria
Estimates of Metabolic equivalents (METs)
Can take care of self, such as eat, dress, or use the
toilet (1 MET).
Can walk up a flight of steps or a hill (4 METs).
Can do heavy work around the house such as

scrubbing floors or lifting or moving heavy furniture
(between 4 and 10 METs).
Can participate in strenuous sports such as

swimming, singles tennis, football, basketball, and
skiing (>10 METs).
≥4 METs Very Reassuring for

Low Perioperative CAD Risk
Goldman L et al. NEJM 1977
1389
AHA/ACC Guidelines 2014

Major predictors requiring intensive management and may lead to
delay/cancellation of surgery
• Unstable coronary syndromes including unstable or severe angina or recent MI
• Decompensated HF including NYHA functional class IV or worsening or new-onset HF
• Significant arrhythmias including high grade AV block, symptomatic ventricular

arrhythmias, supraventricular arrhythmias with ventricular rate >100 bpm at rest, symptomatic
bradycardia, and newly recognized ventricular tachycardia
• Severe heart valve disease including severe aortic stenosis or symptomatic mitral stenosis
Other clinical predictors that warrant careful assessment of current status
• History of ischemic heart disease
• History of cerebrovascular disease
• History of compensated heart failure or prior heart failure
• Renal insufficiency
Fleisher et al. JACC 2014; 62:e77-e137.
Question #26
A 31-year old woman with history of mechanical mitral
valve replacement, on warfarin 7.5mg daily, who is 10
weeks pregnant presents to your office for consultation
regarding management of her anticoagulation. Which
situation may be considered for the use of low
molecular weight heparin?
A. When administered concomitantly with aspirin or dipyridamole
B. When administered twice daily at a dose adjusted for anti-Xa levels
C. When administered daily at a dose adjusted for activated partial
thromboplastin time
D. When unfractionated heparin has caused heparin-induced thrombocytopenia
1390
Answer #26
A 31-year old woman with history of mechanical mitral
valve replacement, on warfarin 7.5mg daily, who is 10
weeks pregnant presents to your office for consultation
regarding management of her anticoagulation. Which
situation may be considered for the use of low
molecular weight heparin?
A. When administered concomitantly with aspirin or dipyridamole
B. When administered twice daily at a dose adjusted for anti-Xa levels
C. When administered daily at a dose adjusted for activated partial
thromboplastin time
D. When unfractionated heparin has caused heparin-induced thrombocytopenia
Anticoagulation for Mechanical Valves During

Pregnancy
1391
Question #27
A 46 year old man from Vermont presents to the hospital with
an aborted cardiac arrest due to ventricular tachycardia. He
has a history of pacemaker placed at age 40 for complete
heart block. Echocardiogram revealed EF of 45% with
inferoseptal hypokinesis. There are normal epicardial
coronary arteries on angiography. Cardiac PET scan reveals
metabolic uptake in the septum and inferior wall with perfusion
defect. What is the most likely diagnosis?
A. Arrhythmogenic right ventricular cardiomyopathy
B. Cardiac sarcoidosis
C. Lyme disease
D. Coronary vasospasm
E. Chagas disease
Answer #27
A 46 year old man from Vermont presents to the hospital with
an aborted cardiac arrest due to ventricular tachycardia. He
has a history of pacemaker placed at age 40 for complete
heart block. Echocardiogram revealed EF of 45% with
inferoseptal hypokinesis. There are normal epicardial
coronary arteries on angiography. Cardiac PET scan reveals
metabolic uptake in the septum and inferior wall with perfusion
defect. What is the most likely diagnosis?
A. Arrhythmogenic right ventricular cardiomyopathy
B. Cardiac sarcoidosis
C. Lyme disease
D. Coronary vasospasm
E. Chagas disease
1392
Cardiac Sarcoidosis
Noncaseating Granuloma
Major Cardiac Sequelae

1. AV Block
2. Ventricular Arrhythmias
3. Heart Failure
Tadamura F et al. Circulation 2006; 113:e771-3.
Question #28
A 73-year old man with a 25 pack year history of smoking
(stopped 6 years ago), hypertension, and diabetes mellitus
presents to your office for an initial visit. Fasting lipid profile
reveals total cholesterol 233 mg/dL, HDL 51 mg/dL, LDL131
mg/dL, and triglycerides 140 mg/dL. In addition to diet
modifications, routine exercise, and blood pressure control,
what would you do to manage this patient?
A. Refer for exercise test and start statin if positive
B. Start atorvastatin 20mg nightly
C. Reassure her that she is at target cholesterol goals
D. Start ezetimibe 10mg daily
E. Start niacin 1 gram daily with aspirin
1393
Answer #28
A 73-year old man with a 25 pack year history of smoking
(stopped 6 years ago), hypertension, and diabetes mellitus
presents to your office for an initial visit. Fasting lipid profile
reveals total cholesterol 233 mg/dL, HDL 51 mg/dL, LDL131
mg/dL, and triglycerides 140 mg/dL. In addition to diet
modifications, routine exercise, and blood pressure control,
what would you do to manage this patient?
A. Refer for exercise test and start statin if positive
B. Start atorvastatin 20mg nightly
C. Reassure her that she is at target cholesterol goals
D. Start ezetimibe 10mg daily
E. Start niacin 1 gram daily with aspirin
4 Major Statin Benefit Groups:

1) With clinical ASCVD*
2) Primary elevations of LDL–C >190
mg/dL,
3) Diabetes aged 40 to 75 years with
LDL– C 70 to189 mg/dL and without
clinical ASCVD
4) Without clinical ASCVD or diabetes
with LDL–C 70 to189 mg/dL and
estimated 10-year ASCVD risk >7.5%
*ASCVD= Atherosclerotic
Cardiovascular Disease
1394
Question #29
the following?
1395
Answer #29
the following?
Valvular Heart Lesions Associated With High

Maternal and/or Fetal Risk During Pregnancy
1. Severe AS with or without symptoms

2. AI with NYHA functional Class III–IV symptoms
3. MS with NYHA functional Class II–IV symptoms
4. MR with NYHA functional Class III–IV symptoms
5. Aortic and/or mitral valve disease resulting in severe pulmonary
hypertension (pulmonary pressure >75% of systemic
pressures)
6. Aortic and/or mitral valve disease with severe LV dysfunction
(EF<40%)
7. Mechanical prosthetic valve requiring anticoagulation
8. AI in Marfan’s syndrome
1396
Question #30
A 67-year old man with known diabetes and coronary artery
disease presents with acute chest pain, dyspnea, and mild
hypotension with electrocardiogram demonstrating 2.4 mm
ST elevations in leads V1-V4 and I and avL. He had a
percutaneous coronary angioplasty with placement of a drug
eluting stent in the proximal left anterior descending artery 25
days ago after a positive stress test. Which is not a common
causes of in-stent thrombosis?
A. Multiple, consecutive long stents in the artery
B. Use of clopidogrel instead of prasugrel
C. Diseased coronary vessel with poor distal run-off
D. Inadequate expansion of the stent
E. Non-adherence to clopidogrel and aspirin
Answer #30
A 67-year old man with known diabetes and coronary artery
disease presents with acute chest pain, dyspnea, and mild
hypotension with electrocardiogram demonstrating 2.4 mm
ST elevations in leads V1-V4 and I and avL. He had a
percutaneous coronary angioplasty with placement of a drug
eluting stent in the proximal left anterior descending artery 25
days ago after a positive stress test. Which is not a common
causes of in-stent thrombosis?
A. Multiple, consecutive long stents in the artery
B. Use of clopidogrel instead of prasugrel
C. Diseased coronary vessel with poor distal run-off
D. Inadequate expansion of the stent
E. Non-adherence to clopidogrel and aspirin
1397
https://www.nhlbi.nih.gov/health/health-topics/topics/stents/risks
Porto et. al. The American Journal of Cardiology, Volume 105,

Issue 12, 15 June 2010, Pages 1710–1715
Question #31
81-year old woman presents for a routine clinical visit for a
physical and her exam is notable for splitting of the second
heart sound. Which statement regarding splitting of the
second heart sounds is NOT true?
A. Paradoxical splitting of S2 is expected in patients with a RV paced rhythm

B. Delayed closure of the pulmonic valve with inspiration contributes to
physiologic splitting
C. Fixed splitting of S2 is present with an ostium secundum atrial septal
defect
D. Severe pulmonary hypertension is associated with an accentuated P2
E. Right bundle branch block is associated with paradoxical splitting of S2
1398
Answer #31
81-year old woman presents for a routine clinical visit for a
physical and her exam is notable for splitting of the second
heart sound. Which statement regarding splitting of the
second heart sounds is NOT true?
A. Paradoxical splitting of S2 is expected in patients with a RV paced rhythm

B. Delayed closure of the pulmonic valve with inspiration contributes to
physiologic splitting
C. Fixed splitting of S2 is present with an ostium secundum atrial septal
defect
D. Severe pulmonary hypertension is associated with an accentuated P2
E. Right bundle branch block is a/w with paradoxical splitting of S2
Answer (Continued)
• Increased filling during inspiration delays the closure of the P2
Soft S2: Valvular stenosis

Fixed splitting: Atrial septal defect
Widened splitting: RBBB
Paradoxical splitting: LBBB, RV pacing
Joseph D. Sapira The Art and Science of Bedside Diagnosis. Williams and Wilkins 1990
1399
Question #32
An 45-year old man presents to the emergency room with
dyspnea. His blood pressure was 228/110 mm Hg and the
remainder of the physical examination was only notable for
faint crackles. Which of the following findings are
characteristics of a hypertensive crisis?
A. Retinal hemorrhages
B. Microangiopathic hemolytic anemia
C. Azotemia and proteinuria
D. Pulmonary edema and jugular venous distension
E. All are characteristics of hypertensive crisis
Answer #32
An 45-year old man presents to the emergency room with
dyspnea. His blood pressure was 228/110 mm Hg and the
remainder of the physical examination was only notable for
faint crackles. Which of the following findings are
characteristics of a hypertensive crisis?
A. Retinal hemorrhages
B. Microangiopathic hemolytic anemia
C. Azotemia and proteinuria
D. Pulmonary edema and jugular venous distension
E. All are characteristics of hypertensive crisis
1400
Features of Hypertensive Crisis
- Renal insufficiency with proteinurea

- Hematuria
- Azotemia
- Microangiopathic hemolytic anemia
- Heart failure
- Nausea and vomiting
Hypertensive encephalopathy
- Confusion, irritability, headaches, stupor, neurologic deficits,
seizures, coma
- Sudden rise in blood pressure causes acute damage to blood
vessels
- Not always present with malignant hypertension
- Failure of cerebral autoregulation causing excess cerebral blood
flow and damage to the wall leading to increased vascular
permeability
1401
Question #33
infarction 3 years ago. Risk factors associated with cardiac
complications after major non-cardiac surgery include all of
the following EXCEPT:
A. Severe mitral stenosis
B. Stable class II angina
C. Acute myocardial infarction 2 months ago
D. More than 5 premature ventricular contractions
(PVC)/minute on a pre-operative ECG
E. Presence of a S3
Answer #33
infarction 3 years ago. Risk factors associated with cardiac
complications after major non-cardiac surgery include all of
the following EXCEPT:
A. Severe mitral stenosis
B. Stable class II angina
C. Acute myocardial infarction 2 months ago
D. More than 5 premature ventricular contractions
(PVC)/minute on a pre-operative ECG
E. Presence of a S3
1402
Goldman Criteria
Goldman L et al. NEJM 1977
Thank you!
1403
INFECTION IN THE IMMUNOCOMPROMISED HOST
Sarah P Hammond, MD
Associate Physician
Division of Infectious Diseases, Department of Medicine
Assistant Professor
Disclosures
• I have research funding from Merck
1404
Overview
• Introduction and Basic Principles
• Drug-induced Immunodeficiency
– Corticosteroids
– TNF-α inhibitors
– Anti CD-20 therapy
• Asplenia
• Transplant
Introduction and Basic Principles
1405
Infection in Compromised Host

• The immunocompromised host (ICH) is
susceptible to opportunistic infections and
community-acquired infections
– Infection can result from exposure to a lower number
of organisms
• The inflammatory response to infection is
suppressed in ICH
– Attenuated signs and symptoms of infection
• ICH with infection typically has high burden of
organisms once infection established
Rubin, RH. N Engl J Med. 1987;317:1151-3.
Basic Principles
• Net state of immunosuppression
– Dose and duration of suppressive medications
– Mechanical factors
– Infections contributing to compromise
• Important epidemiologic exposures

– New exposures
– Remote exposures with possibility of reactivation
Fishman JA, Rubin, RH. N Engl J Med. 1998;338:1741-51.

Fishman JA. N Engl J Med. 2007;357:2601-14.
1406
Drug-Induced
Immunosuppression
Mechanism, Indication, Dose & Duration

• In last 2 decades the number of immunosuppressants
approved to treat malignant and auto-immune
disorders has expanded!
• Mechanism of an immunosuppressive agent is key to
predicting host susceptibility to infection
– Particularly true of biologic and targeted agents
• Indication for which an agent is given is important
when considering impact on host defenses
• Dose and duration over which the agent is given
impacts vulnerability
– Effect of some biologic agents last for 6 months or more
1407
Immunosuppressive Drugs
• Corticosteroids • Monoclonal antibodies
• Antimetabolites – Tumor necrosis factor-α (TNF-
– Methotrexate α) inhibitors
– Azathioprine, 6-mercatopurine • Infliximab
• (Etanercept)
– Mycophenolate
• Adalimumab
• T lymphocyte agents • Certolizumab pegol
– Tacrolimus, Cyclosporine • Golimumab
– Sirolimus – CD-20 antibodies
• ‘Targeted’ agents • Rituximab
• Ofatumumab, Obinutuzumab
– Janus kinase inhibitors • Ocrelizumab
• Ruxolitinib
• Tofacitinib
– IL12/23 antibody: Ustekinumab
• (Baricitinib) – CD 52 antibody: Alemtuzumab
– Proteosome inhibitors • Biologic agents
• Bortezomib – IL1 inhibitor: Anakinra
– PI3 kinase inhibitors – T cell costimulation inhibitor
• Idelalisib • Abatacept, Belatacept
Corticosteroids
• Acute effect of corticosteroids on host
defenses includes
– Neutrophil demargination and reduced
chemotaxis
– Lymphopenia and depletion of T lymphocytes
• Long term effect of corticosteroids on host
defenses includes
– Skin weakening and poor wound healing
Klein NC, et al. Infect Dis Clin North Am 2001;15:423-32.
1408
Corticosteroids and infection

• In general, steroids increase risk of infection
– In study of rheumatoid arthritis (RA), patients on
steroids vs. non-immunosuppressive therapy
• Rate ratio of mild infection: 1.15 (95% CI 1.11, 1.19)
• Rate ratio of severe infection: 1.9 (95% CI 1.75, 2.05)
– In metanalysis of 71 controlled trials of steroid vs.
non-steroid therapy, steroid recipients had
significantly higher rate of infection (12.7% vs.
8.0%) and lethal infection (1.2% vs. 0.5%)
• Included studies of GI, pulmonary, renal, neurologic
and rheumatic conditions
Lacaille D, et al Arthritis Rheum 2008;59:1074-81.
Stuck AE, et al. Rev Infect Dis 1989; 11:954-62.
Corticosteroids: dose and duration

• In metanalysis by Stuck, et
al., dose and duration of
steroids impacted infection
risk
• In large database study of
RA, IBD and psoriasis,
prednisone doses of <5, 5-
10, and >10 mg resulted in
a sequential increase in risk
of serious infection in RA
and psoriasis
• Dose-dependent risk of <10
mg of prednisone per day
has been shown in other
observational studies Stuck AE, et al. Rev Infect Dis 1989; 11:954-62.
Grijalva CJ, et al. JAMA 2011;306:2331-9.
Youssef J, et al. Rheum Dis Clin North Am 2016;42:157-76.
1409
Corticosteroids & specific infections

• Specific types of infection associated with
steroids
– Opportunistic pathogens
• Bacterial (eg. Listeria)
• Fungal (eg. Aspergillus)
• Viral (eg. zoster)
• Reactivation of latent tuberculosis
• Strongyloides hyperinfection syndrome
• Pneumocystis jiroveci pneumonia (PCP)
Corticosteroids and PCP

• Steroids are a major risk factor for PCP www.dpd.cdc.gov/dpdx/HTML/Pneumocystis.htm
– In a study of 116 non-HIV patients, 105

(91%) were on steroids
– Similarly, in a study of 134 non-HIV cancer
patients with PCP, 116 (87%) were on
steroids
• While PCP in non-HIV patients is a rare event, it is
associated with significant mortality
– Mortality rate among 114 non-HIV cancer patients
was 49% in one study
– Among 223 patient with connective tissue disease
with PCP the in-hospital mortality was 45.7%
Yale SH, Limper AH. Mayo Clin Proc 1996;71:5-13.
Sepkowitz KA, et al. JAMA 1992;267:832-7.
Ward MM, Donald F. Arthritis and Rheum 1999;42:780-9.
1410
Corticosteroids and PCP

• PCP risk depends on steroid dose and duration
– Among 105 non-HIV patients with PCP on steroids
• Median dose: 30 mg prednisone per day (25% on 16 mg/day or less)
• Median duration: 12 weeks (25% on for 8 weeks or less)
• PCP risk may not be uniform among patient types
– In general, risk in lupus, temporal arteritis and rheumatologic
disease all linked to ‘high dose’ steroids (30-50 mg/day)
– Risk may be especially high in patients with metastatic cancer
on steroids
– PCP risk is elevated, but occurs infrequently in IBD
• At what steroid dose/duration should prophylaxis start?
– There are no studies directly assessing this
– Extrapolating from available data many clinicians start
prophylaxis after 3-4 weeks of 20-30 mg prednisone per day
Yale SH, Limper AH. Mayo Clin Proc 1996;71:5-13. Chew LC, et al. J Clin Rheumatol 2015;21: 72–75
Sepkowitz KA, et al. JAMA 1992;267:832-7. Cotter TG, et al. Clin Gastroenterol Hepatol 2017;15:850-6.
Youssef J, et al. Rheum Dis Clin North Am 2016;42:157-76. Schoovaerts K, et al. Acta Clin Belg. 2017;27:1-4.
Case Presentation #1
• 65 year old woman with rheumatoid arthritis (RA)
presents with 3 days of productive cough and
progressive dyspnea
– She has had fever as high as 100.9 for last 2 days
• Past Medical History
– RA diagnosed 25 years ago
• Treated with infliximab and methotrexate for the last 15
years
– Hypertension
– Up-to-date on vaccines and cancer screening
• Vaccinated with influenza and conjugate pneumococcal
vaccine at her last PCP visit 4 month ago
1411
Case Presentation #1 (con’t)

• Social history
– She lives in CT with 2 indoor/outdoor cats
– No recent travel; she takes care of a 4 year old grandchild 2
days a week
• Exam
– T 100.7 F, P 112, R 21, O2 sat 93% 4L nasal canula
– Somewhat chronically ill-appearing women; tachycardic;
chest has coarse crackles in both lungs; the abdomen is
non-tender
• Labs: WBC 15.3 with 79% neutrophils, 7% bands
• Radiology: Chest x-ray shows dense infiltrates in right
upper and left lower lobes
Chest CT Scan
1412
Which is the most likely cause of

pneumonia?
A. Legionella pneumophilia
B. Cryptogenic organizing pneumonia
C. Aspergillus fumigatus
D. Influenza
E. Mycobacterium tuberculosis
TNF-α inhibitors
• TNF-α is an inflammatory cytokine produced by
macrophages
– Important for control of infection with intracellular organisms
and for granuloma formation
• There are 5 FDA-approved drugs that inhibit TNF-α
– Monoclonal antibodies that bind TNF-α
• Infliximab (1998), Adalimumab (2002), Golimumab (2009)
– Pegylated portion of a monoclonal antibody that binds TNF-α
• Certolizumab pegol (2008)
– Soluble TNF-α receptor that binds soluble TNF-α
• Etanercept (1998)
• ‘Biosimilars’ are biological products that are very similar to
approved agents– improved cost/availability
– Between 2016-2018 FDA has approved multiple biosimilars for
infliximab, etanercept and adalimumab
https://www.fda.gov/Drugs/DevelopmentApprovalProcess/HowDrugsareDevelopedandApproved/
ApprovalApplications/TherapeuticBiologicApplications/Biosimilars/ucm580432.htm, accessed 3/17/18
1413
TNF-α inhibitors and infection

• Several studies and registries have assessed if
TNF-α inhibitors increase overall risk of infection
– Many studies have assessed risk for bacterial
infection; results have been mixed
– Metanalysis including 9 trials assessed infection risk in
RA patients treated with infliximab or adalimumab vs.
non-TNF-α therapy
• Pooled odds ratio for serious infection: 2.0 (95% confidence
interval 1.3, 3.1)
• Most infections in this study were bacterial (114 of 126)
• Limited by control comparison: All controls got placebo (+/-
methotrexate, at same dose as TNF- α recipients)
Bongartz T, et al. JAMA. 2006;295:2275-85.
Curtis JR, et al. Arthritis Rheum. 2007;56:1125-33.
Schneeweiss S, et al. Arthritis Rheum. 2007;56:1754-64.
TNF-α inhibitors and infection

• Grijalva, et al. assessed infection requiring hospitalization in
autoimmune disorder patients treated with infliximab,
etanercept or adalimumab vs. comparators
– Large propensity score analysis study that included 16,022
patients; more than half had RA
• No difference in serious infection between those treated
with TNF-α inhibitor and comparators for patients with RA,
IBD, or psoriasis/spondyloarthropathy
• Among the 10,484 patients
with RA, those treated with
infliximab had higher risk for
serious infection than those
treated with non-biologics or
other TNF-α agent
Grijalva CJ, et al. JAMA 2011;306:2331-9.
1414
TNF-α inhibitors & Opportunistic Infection

• TNF-α inhibitors have been associated with several
opportunistic infections (OIs)
– Mycobacteria: Tuberculosis (TB), Non-tuberculous mycobacteria
– Bacteria: Listeria, Legionella, Nocardia
– Fungi: Pneumocystis, Cryptococcosis, Endemic mycoses
• TB is the most common OI
internationally
• In a recent large US
database study that
included 33,324 new TNF-α
users, Pneumocystis was
the most common OI
Winthrop KL, et al. Ann Rheum Dis. 2013;72:37-42..
Slifman NR, et al. Arthritis Rheum. 2003;48:319-24.
Perez-Alvarez R, et al. Medicine. 2011;90:359-71.
Salmon-Ceron D, et al. Ann Rheum Dis. 2011;70:616-23.
Baddley JW, et al. Ann Rheum Dis. 2014;73:1942-8.
TNF-α inhibitors & Opportunistic Infection

• In French registry study of infliximab, adalimumab
and etanercept incidence of OI was low (152 OIs per
100,000 patient-years)
– Severity of illness was high
– Median time to OI was 16.2 months (range 6-26)
– OI risk significantly higher in patients treated with
infliximab compared to etanercept
• In US database study of same TNF-α inhibitors,
incidence of non-viral OIs was also low (2.7 OIs per
1000 patient-years), but was significantly higher
than patients treated with non-biologic therapy
• In both studies OI risk significantly higher in those on
current steroids (>10 mg prednisone/day)
Winthrop KL, et al. Ann Rheum Dis. 2013;72:37-42.. Perez-Alvarez R, et al. Medicine. 2011;90:359-71.
Slifman NR, et al. Arthritis Rheum. 2003;48:319-24. Salmon-Ceron D, et al. Ann Rheum Dis. 2011;70:616-23.
Baddley JW, et al. Ann Rheum Dis. 2014;73:1942-8.
1415
TNF-α inhibitors and TB

• Keane, et al. analyzed all cases of TB associated with infliximab
reported to FDA 1998-2001
– 40/70 (57%) had extrapulmonary TB
– Median time to TB: 12 weeks
• Increased risk was again demonstrated in more recent large
database studies from Europe and US
– These studies have demonstrated differences in TB risk after
monoclonal antibodies vs. etanercept
• TB risk after infliximab is comparable to adalimumab but both are higher than
after etanercept
• TB develops earlier after infliximab than etanercept (~3 vs 12 months)
• When TNF-α therapy is planned, patients should be screened with
PPD (≥ 5mm is reactive) or interferon gamma release assay (IGRA)
– Those with reactive PPD and/or positive IGRA should be assessed for
active vs. latent TB and treated
Keane J, et al. N Engl J Med. 2001;345:1098-104.
Winthrop KL, et al. Arthritis Rheum. 2005;52:2968-74.
Winthrop, KL. Nat Clin Pract Rheumatol. 2006;2:602-610.
Salmon-Ceron D, et al. Ann Rheum Dis. 2011;70:616-23.
Winthrop KL, et al. Ann Rheum Dis. 2013;72:37-42.
Clinical Case #2
• A 58-year-old woman is diagnosed with diffuse
large B cell lymphoma (DLBCL) after she presents
with several weeks of fevers, night sweats, weight
loss and left neck swelling
• Past medical history
– Hypercholesterolemia
– An episode of ‘hepatitis’ requiring a brief hospital stay
after she was stuck by a needle when she was training
to be a phlebotomist 35 years ago
• Plans are made to initiate chemotherapy with
rituximab, cyclophosphamide, doxorubicin,
vincristine, and prednisone (R-CHOP)
1416
Clinical Case #2
• Physical exam is notable for a thin woman with
marked left neck lymphadenopathy
• Labs are notable for normal BUN, Cr, AST, ALT, and
bilirubin
– Hepatitis B surface antibody (HBsAb)– 27 IU/L
– Hepatitis B core IgG (HBcAb) – positive
– Hepatitis B surface antigen (HBsAg) – negative
– Hepatitis B virus PCR – negative
– Hepatitis C virus antibody – positive
– Hepatitis C virus PCR – negative
– HIV screening - negative
What is the best management for her

previous hepatitis exposures?
A. Monitor hepatitis C PCR and HBsAb every 2-4
weeks while she is on chemotherapy
B. Start prophylactic low dose ribavirin and
lamivudine to continue for 1 year
C. Start prophylactic entecavir to continue until
12 months after chemotherapy
D. No special care is indicated since both
hepatitis B and C are old infections that have
resolved
1417
CD-20 Antibodies
• Rituximab is a monoclonal antibody directed at CD-20, a
B lymphocyte marker
– Immunologic effect is depletion of B lymphocytes
– Functionally this leads to inability to mount antibody
response to new and recall antigens
• FDA approved for treatment of some lymphomas,
chronic lymphoid leukemia (CLL), and RA
– Used off-label to treat immune-mediated anemia and
thrombocytopenia, lupus, and pemphigus
• Ofatumumab and Obinutuzumab
– Newer CD-20 antibodies used in hematologic malignancy
only; thought to have same infection risks as rituximab
• Ocrelizumab
– The newest CD-20 antibody approved for multiple sclerosis
(MS) in early 2017-- likely has same side effects
Gelinck LBS, et al. Ann Rheum Dis. 2007;66:1402-3.
Van der Kolk LE, et al. Blood. 2002;100:2257-9.
Rituximab and Infection

• Pre-marketing trials showed no increase in infection in RA
or cancer patients on rituximab vs. non-rituximab regimens
– Similarly, ocrelizumab trials show no increase in infection in MS
• With clinical use, there have been several case reports of
various opportunistic infections
– PCP and Progressive multifocal leukoencephalopathy due to JC
virus are most commonly cited in case reports/series
– Others include CMV reactivation, pure red cell aplasia due to
parvovirus, and enterovirus encephalitis
– Interpretation of case reports is difficult since patients often on
multiple immunosuppressants
• Rituximab is definitively associated with
– Hepatitis B virus (HBV) reactivation
– Increased severity of babesiosis (in exposed patients)
Coiffier B, et al. N Engl J Med. 2002;346:235-42. Suzan F, et al. N Engl J Med. 2001;345:1000.
Edwards JCW, et al. N Engl J Med. 2004;350:2572-81. Sharma VR, et al. Blood. 2000;96:1184-6.
Montalban X, et al. N Engl J Med 2017;376:209-20. Padate BP, Keidan J. Clin Lab Haem. 2006;28:69-71.
Hauser SL, et al. N Engl J Med 2017;376:221-34. Perez-Alvarez R, et al. Medicine. 2011;90:359-71.
1418
HBV reactivation
Resolved HBV Reactivated HBV
Exposure
• Perinatal infection infection
RITUXIMAB
• Percutaneous • HBsAg+ HBsAb+ • HBsAg+
• Sexual • usually HBeAg+
• HBV DNA-
• HBV DNA high
• HBcAb+
• Abnormal LFTs
RITUXIMAB
Acute HBV
Infection
• HBsAg+
• HBV DNA+ Inactive Carrier
• HBsAg+
• usually HBeAb+
• HBV DNA low (or -)
Chronic HBV
• normal LFTs
infection
• HBsAg+ >6 months
• HBV DNA+
• HBcAb+
Chronic active
infection
• HBsAg+
• HBV DNA+
Rituximab and HBV Reactivation

• Fulminant hepatic failure and death have been reported
with reactivation
• Risk of reactivation is higher in chronic carriers (HBsAg+)
than in patients with resolved HBV
• Prevention
– All patients in whom rituximab, TNF-α inhibitor, or high-dose
steroid therapy is being considered should be screened
– Antiviral prophylaxis typically given to inactive carriers
• Agents with high barrier to resistance recommended
– Management of HBcAb+ patients varies
• Guidelines advocate for prophylaxis, but a few recent studies have
shown that careful monitoring with preemptive therapy is effective
• Note: risk in this population with TNF-α inhibitor appears to be very
low– prophylaxis not typically necessary
Terrault NA, et al. Hepatology. 2018;67:1560-99.
Perez-Alvarez R, et al. Medicine. 2011;90:359-71.
Kusumoto S, et al. Clin Infect Dis 2015;61:719-29.
KR Reddy, et al. Gastroenterol. 2015;148:215–219.
1419
Rituximab and Babesiosis

• A tick-borne malaria-like parasitic infection
– Northeastern US, Wisconsin and Minnesota
– Causes fevers, malaise, anemia (due to
Courtesy of Francisco Marty
– hemolysis) and thrombocytopenia
• Patients treated with rituximab who acquire babesiosis
shortly before or after treatment have worse illness
• In case-control study of persistent babesiosis vs.
uncomplicated infection, over half cases had received
rituximab
• Rituximab-treated patients with babesiosis:
– Often have a higher parasite burden (median 8% vs. 2.5%)
– More likely to develop severe complications including ARDS
– More likely to have relapse requiring repeat or prolonged
treatment courses (typically ~6 weeks)
Krause PJ, et al. Clin Infect Dis. 2008;46:370-6.
Vannier E and Krause PJ. N Engl J Med 2012;366:2397-407.
Wormser GP, et al. Clin Infect Dis. 2010;50:381-6.
Asplenia
1420
Asplenia
• Immunolgically the spleen plays an important role in
filtering blood
– Important for clearance of extracellular bacteria and
intracellular parasites (eg. babesia)
• Many important medical reasons for surgical
splenectomy including trauma, malignancy, and
refractory hematologic disorders (eg. ITP)
• Other conditions result in asplenia or ‘hyposplenism’
– Asplenia: Congenital absence, autoinfarction (eg. In sickle
cell disease)
– Hyposplenism: Advanced HIV, chronic graft-versus-host
disease
LG Rubin,W Schaffner. NEJM 2014;371:349-56
Asplenia and bacterial infection

• Asplenic patients are at risk for overwhelming bacterial infection
due to encapsulated organisms
– Streptococcus pneumoniae
– Haemophilus influenzae
– Neisseria meningitidis
• In recent study of severe sepsis in asplenic patients, S. pneumoniae
caused 42% of infections (most invasive infection), more than any
other pathogen
– No cases of H. influenzae or N. meningitidis observed
• Progression of infection can be rapid and mortality approaches 50%
in some studies
• Risk may vary by reason for and time since splenectomy
• Understanding of risk for bacterial infection impacts risk
– In one study rate of overwhelming infection was 16.9% among 79
asplenic patients with poor knowledge vs. <2% among 142 patients
with good knowledge
LG Rubin,W Schaffner. NEJM 2014;371:349-56
MS El-Alfy, MH El-Sayed. Hematol Journal 2004;5:77–80
Theilacker C, et al. Clin Infect Dis. 2016;62:871–8
1421
Vaccination of Asplenic Patients

• Vaccination for S. pneumoniae, H. influenzae, and N.
meningitidis crucial to prevent infection
• Timing with splenectomy
– Vaccinate at least 2 week pre-splenectomy in planned cases and
1-2 weeks after (or before hospital discharge) in unplanned
cases
• Vaccination algorithms
– S. pneumoniae: two vaccines recommended for use in asplenic
patients
• 23 valent polysaccharide vaccine (PPSV23, 1983)
• 13 valent protein conjugate vaccine (PCV13, 2011)
– Contains 12 serotypes in the PPSV23 vaccine
– N. meningitidis: the two vaccines types now also recommended
include conjugate meningococcal ACWY and (new)
meningococcus type B
Davidson RN, Wall RA. Clin Microbiol Infect 2001;7:657-60.
LG Rubin, W Schaffner. NEJM 2014;371:349-56
Bennett NM, et al. MMWR 2012;61:816-9.
Management of fever
• Asplenic patients
should be educated
about risk of severe
bacterial infection
– Survey studies show
5-25 % of asplenic
patients have poor
knowledge of
infection risk
• “Pill in pocket”
approach
Rubin LG , Schaffner W. N Engl J Med. 2014;371:349-56

MS El-Alfy, MH El-Sayed. Hematol Journal 2004;5:77–80
Wilkes A, et al. ANZ J Surg. 2008;78:867-70
1422
Asplenia and other infections

• Capnocytophaga canimorsus
– Gram-negative bacterial colonizer of canine mouth
– Cause of severe infection/sepsis in asplenic patients
– Usually susceptible to beta-lactam/beta-lactamases
– Asplenic patients should be educated about careful
cleaning after animal bite (especially dog) and medical
evaluation
• Babesiosis
– Severity of babesiosis is increased and parasite burden
higher in asplenic patients
– May require prolonged or repeated courses of
treatment
Stiegler D, et al. Am J Forensic Med Pathol. 2010;31:198-9.
Davidson RN, Wall RA. Clin Microbiol Infect. 2001;7:657-60.
Krause PJ, et al. Clin Infect Dis. 2008;46:370-6.
Transplantation
1423
Case Presentation #3
• A 39-year-old woman who underwent a renal
transplant 7 years ago presents with presents with 3
days of diarrhea and fever to 101.2° F
– Generally feels unwell with fevers and frequent diarrhea
but no SOB, cough, nausea, or vomiting
• Past medical history: HTN, history of IgA nephropathy
s/p renal transplant 7 years ago (baseline Cr 1.1)
– Donor CMV-/recipient CMV+; never had CMV post-
transplant
– Never had rejection since transplant
• Medications: Tacrolimus, Mycophenolate mofetil,
Lisinopril
Case Presentation #3 (con’t)

• Social History
– Accountant
– Married and lives with wife and 7-year-old son
who has a pet hedgehog at home
– Likes to garden
• Vital signs: T 100.9 P 110 BP 119/73
• Exam: Soft abdomen with mild diffuse
tenderness without rebound or guarding
1424
The most likely cause of her illness is:

A. Salmonellosis
B. CMV colitis
C. Cryptosporidium
D. Norovirus
E. Mycophenolate toxicity
Timing of Infection after Transplant

Time after 0-1 Month 1-6 Months* >6 Months
transplant
Type of Nosocomial Opportunistic Community-
infection MOSTLY BACTERIA OR VIRAL acquired
CANDIDA CMV VIRAL
Cather-related UTI VZV Influenza
Line infection BK HPV
Pneumonia BACTERIAL Norovirus
Nocardia HBV reactivation
Procedure- Listeria BACTERIAL
related FUNGAL S. pneumoniae
Wound infection PCP Listeria
Fever+ neutropenia Aspergillus Legionella
Donor-derived PARASITIC FUNGAL
Strongyloides Cryptococcus
RARE
Toxoplasma Endemic fungi
* Patients treated for rejection or graft-versus-host disease Fishman JA, Rubin RH. N Engl J Med. 1998:338;1741-51.
after 6 months are also at risk for these infections Fishman JA. N Engl J Med. 2007;357:2601-14.
1425
Summary
• ICH with infection often presents with attenuated signs
and symptoms of infection
• When treating an ICH with infection consider:
– Net state of immunosuppression
• Includes mechanism, indication, dose/duration for patients on
suppressive medications
– Epidemiologic exposures
• Asplenia increases risk for overwhelming bacterial
infection vaccinate and educate about fever
• Transplant recipients are susceptible to a wide range of
infections
– Risk depends on: 1) when the transplant occurred. 2)
whether significant rejection has been treated recently
Selected References
• Fishman JA, Rubin RH. N Engl J Med.
1998:338;1741-51.
• Stuck AE, et al. Rev Infect Dis 1989; 11:954-62.
• Youssef J, et al. Rheum Dis Clin North Am
2016;42:157-76.
• Rubin LG , Schaffner W. N Engl J Med.
2014;371:349-56.
1426
Disclosures
• I have research funding from Merck
1427
Tropical Medicine and Parasitology

Senior Physician
Division of infectious Disease and Department of Medicine
Disclosures
Bayer: Chagas disease advisory committee
1428
Outline
• Febrile illnesses
• Diarrhea
• Important infections of immigrants and
returning long-term expatriates
• Skin lesions
40 year old man with fever

and mental status changes
• 3 week stay in Nigeria 10 days earlier
• x1 week: malaise, feverishness
• Unusual behavior at home after work
• ER next morning:
– Temp 102o F
– Agitated, unable to follow commands
• Hct 32, WBC 6000, platelets 110,000,
creatinine 2.2
Differential diagnosis?
1429
Fever in returned US travelers

• 9624 visits 2000-2012 (Geosentinel clinics)
• 18.2% with fever
Malaria (27.4%)
Viral syndrome (18.5%)
Dengue (12%)
Mononucleosis syndrome (8.7%)
Rickettsial disease (4.7%)
Enteric fever (6.1%)
Fam Pract 31:678, 2014
• Also; fever with diarrhea or respiratory

infection, acute hepatitis, acute HIV
Further history:
- Immigrated from Nigeria 6 years earlier
- Prior to travel: no antimalarial
chemoprophylaxis, no vaccinations.
- Visited family
Further studies?
Plasmodium falciparum Rapid blood test for

malaria (dipstick) was
(8% of RBCs infected) also positive
1430
1485 reported cases of imported malaria in 2015
11 deaths in 2015
Purpose of travel: Visiting

friends and relatives 70%
MMWR Morb Mortal Wkly Rep. 2018;67(1-28)
Plasmodium falciparum: life-threatening

– High parasitemia
– Only rings on smears:
RBCs infected with later
stages adhere to
endothelium of small
blood vessels
– Pathophysiology
• Severe anemia
• Blockage of blood flow
• Systemic and local
cytokine production
1431
Plasmodium falciparum: life-threatening

– High parasitemia
– Only rings on smears:
RBCs infected with later
Falciparum
stages adheremalaria
to
Progressesofrapidly
endothelium small
blood vessels
Life threatening (especially non-immune)
– Pathophysiology
Mimics other infections
• Severe anemia
• Blockage of blood flow
• Systemic and local
cytokine production
Falciparum malaria: complications

• Cerebral malaria, hypoglycemia
• Pulmonary edema
• Renal failure, blackwater fever
• Jaundice, tender
hepatomegaly
• Diarrhea, dysentery
• Lactic acidosis
• Severe anemia
• Placental dysfunction
1432
40 year old man with fever:

• ICU: Intravenous quinidine
• CDC: artesunate (770-488-7788; -7100 after
hours)
• Artesunate 2.4 mg/kg i.v. at 0, 12, 24; 48 hr
• 24 hr: alert, oriented; parasitemia <1%
• 72 hours: parasitemia cleared
• Atovaquone 250 mg, proguanil 100 mg:
4 tablets daily x4
• Full recovery
Treatment of falciparum malaria

• Oral therapy
– Artemether-lumefantrine
– Alternatives:
• Chloroquine (sensitive strains)
• Quinine + doxycycline or
clindamycin
• Atovaquone-proguanil
• Severe falciparum malaria
– IV artesunate (CDC)
– Alt: IV quinidine gluconate +
doxycycline or clindamycin
1433
Treatment of falciparum malaria

• Oral therapy
– Artemether-lumefantrine
Artemether-lumefantrine
– Alternatives:
• Chloroquine (sensitive strains)
• Quinine + doxycycline or
clindamycin
• Atovaquone-proguanil
• Severe falciparum malaria
IVIV
– artesunate
artesunate (CDC)
(CDC)
– Alt: IV quinidine gluconate +
doxycycline or clindamycin
Artemisinin combination therapy

• Artemisinins: most rapidly acting antimalarials
• Active against resistant P. falciparum
• Improved survival compared with quinine
• Given in combination with second
drug (mefloquine, atovaquone-
proguanil, lumefantrine, others)
• Resistance spreading in SE Asia
Drugs of choice for treatment

of falciparum malaria
Cochrane Database Syst Rev. 2007 Oct 17;(4):CD005967; WHO Global malaria Program 2017
1434
Plasmodium vivax, ovale

• Infect only young cells
• No vascular sequestration
• Death unusual
Plasmodium vivax
• Relapses (4+ yrs)
• Treatment:
– Chloroquine* and
– Primaquine (prevent
relapses)
Plasmodium ovale
• 30 mg/day x 2 weeks
• G-6-PD screen
*Chloroquine-sensitive areas only
What prophylaxis do you recommend

for 59-year-old who will spend 10 days
traveling to Hanoi, Bangkok, and
Singapore for business?
• Weekly choloroquine
• Daily doxycycline
• Weekly mefloquine
• Daily atovaquone-proguanil (MalaroneR)
• Daily primaquine
• None of the above
1435
Malaria: chemoprophylaxis
• No chloroquine resistance:
weekly chloroquine
• Chloroquine-resistance:
– Doxycycline
– Atovaquone-proguanil
– Mefloquine (not border
areas in SE Asia)
• No chloroquine resistance
(predominantly P. vivax):
primaquine Mefloquine resistance
59-year-old will spend 10 days traveling

to Hanoi, Bangkok, and Singapore for
business
What do you recommend?
• Weekly choloroquine
• Daily doxycycline
• Weekly mefloquine
• Daily atovaquone-
proguanil (MalaroneR)
• Daily primaquine
• None of the above
Mefloquine resistance
1436
http://cdc.gov/malaria/map/
Province Prophylaxis for this State/Province/

Malaria in Province
Name District
None in the Red River
Hanoi delta and none in the Not applicable
city of Hanoi.
23-year old woman with fever and rash 3

days after returning from vacation in
Bahia, Brazil
• Abrupt onset: fever, chills, headache,
myalgia, arthralgia
• Temperature 102o F, diffuse
rash, lymphadenopathy
• WBC 3400 with normal
differential, platelets
120,000
Differential diagnosis?
1437
Diagnosis?
• Dengue • Enteroviruses
• Chikungunya • Rickettsial infection
• Zika • Gr A streptococcus
• Acute HIV • Syphilis
• EBV • Typhoid
• Measles • Leptospirosis
• Rubella • Drug reaction
• Parvovirus • Other
23 year old woman with fever and rash

• Clinical diagnosis: dengue
• Confirmed retrospectively with serology
(IgG, IgM)
• Afebrile on 7th day; prolonged fatigue for
several weeks
1438
Classic dengue
• Incubation period 1-7 days, up to 14+ days
• 5-7 days of fever; often biphasic
• Rash in ~50%: flushlike, later macular or
morbilliform
• Serologic tests negative during first 5-7 day
– CDC: symptoms < 5 days: PCR
– CDC: symptoms > 5 days: IgM antibody
test
• Dengue shock syndrome/dengue
hemorrhagic fever after second infections:
rare in travelers
Chikungunya Zika
• ‘That which bends up’ • Like dengue + joint
in the Kimakonde swelling, conjunctivitis
language of
Mozambique’ • Infection during
• Dengue-like illness pregnancy:
except >1/3 patients microcephaly, fetal brain
have incapacitating defects
arthralgia/arthritis
lasting months or years • Increase in Guillain-
Barre syndrome
• Sexual transmission
Clinical differentiation of dengue, zika,

and chikungunya, difficult: avoid NSAIDs
1439
Dengue 2018
Geographical limits
for year-around
survival of the
principle vector,
Aedes aegypti
Countries and territories Countries and territories

where chikungunya cases where Zika cases have
have been reported been reported
Areas with risk of Zika
CDC.gov Zika: Americas 2015-17 (www.paho.org)
1440
Approximate ranges of Aedes aegypti and A. albopictus

in the United States, 2017 (CDC)
N Engl J Med 2016. DOI: 10.1056/;CDC.gov; CDC and Denguevirusnet.com
1441
42 year old man with diarrhea after

travel to Thailand
• Chills, cramps, watery diarrhea on return
flight
• Self-treated with levofloxacin
• Markedly improved after 7 days; one loose
stool/day
• 24 hours after stopping levofloxacin: chills,
diarrhea, crampy abdominal pain
42 year old man with recurrent diarrhea

after travel to Thailand
Most likely diagnosis?
• Treatment failure
• Amebic dysentery
• Clostridium difficile colitis
• Falciparum malaria
1442
42 year old man with recurrent diarrhea

after travel to Thailand
• Fecal leukocytes: few/hpf
• Stool for ova and parasites: negative
• Assay for Clostridium difficile toxin: negative
• Stool culture: Campylobacter resistant to
quinolones
Treatment: azithromycin 1 gm po
Acute illness subsides, but 6 months later
he still has frequent loose stools, cramps
Persistent travelers’ diarrhea

• Diarrhea lasting > 2-3 weeks
• Six months following bout of diarrhea, 18%
experience chronic GI symptoms
• Three major categories:
– Infections
– Chronic gastrointestinal disease unmasked by
enteric infection (e.g., inflammatory bowel disease,
celiac sprue)
– Post-infectious processes
(Amer J Gastroenterol 2004;99:1774-8; Trop Dis Travel Med Vaccines 2017; 3:9)
1443
Persistent travelers’ diarrhea:

infectious causes
• Protozoan infections most common (Giardia,
Cryptosporidium, Cyclospora, Cystoisospora,
Entamoeba histolytica)
• Helminths less common: Strongyloides,
Schistosoma
• Bacteria: C. difficile,
Enteroadherent E. coli;
tropical sprue
• Multi-pathogen molecular
assays available CDC-DPDx
Persistent travelers’ diarrhea: post-

infectious causes
• Post-infectious malabsorption
– Lactase deficiency
– Bacterial overgrowth
• Post-infectious irritable bowel syndrome
Our patient: probable irritable bowel syndrome
1444
Diarrhea: strategies for travelers

Prevention Empirical treatment
• Food & beverages • Fluids
– “Boil it, cook it, peel it or • Loperamide 4 mg x1, then 2
forget it!” mg for each loose stool up
– Easier said than done to 16 mg/day; not in
• Hand hygiene dysentery)
• Chemoprophylaxis (high • Bismuth subsalicylate
risk travelers) +/-
– Bismuth subsalicylate • Antibiotics (severe cases)
(65% protection) – Azithromycin 1gm x1;
– Rifaximin (70-80% 500 mg x 1 + loperamide;
protection) 500 mg x 3days
– Fluoroquinolones – Nondysenteric cases
(effective, not Rifaximin 200 mg TID x3
recommended) days (max); fluoro-
– ETEC vaccines quinolones x1 or x3d
J Travel Med 2017; 24:s57, Am J Gastroenterol 2016, 111:602
In South Asia, 80% of travelers who

received antibiotics for treatment of
travelers’ diarrhea became colonized
with ESBL-producing bacteria
Clin Infect Dis 2015; 60:837
1445
Subclinical chronic infections of

immigrants and returning long-term
expatriates
• Tuberculosis
• HIV
• Hepatitis B
• Chagas’ disease
• Strongyloidiasis
• Schistosomiasis
• Cysticercosis
Case history
Recent immigrant from rural
El Salvador receives a letter
after donating blood at his
local blood bank. His blood
tested positive for infection with
Trypanosoma cruzi.
He has no symptoms. Physical examination

is negative. CBC, diff, LFTs are all normal
Does he have Chagas disease?
Does he need further evaluation or treatment?
1446
Chagas disease (American trypanosomiasis)

• ~250,000 immigrants with
T. cruzi infection in US
• Most unaware of infection
• Most US blood banks
screening blood donors
• Diagnosis Triatomine bug
– History of exposure: Latin
America, not Caribbean;
poor housing; history of
blood transfusion; infected
mother or sibling
– Serology: 2 or more tests
(IFA, ELISA, Western blot,
etc.)
Chronic Chagas disease

– 70-80%: subclinical
– 20-30%: decades later
• Chronic cardiomyopathy:
CHF, arrhythmias (sudden
death), heart block,
thromboembolism; RBBB
• Mega-esophagus, -colon
• Reactivation in HIV-
infected, other immune
suppressed: CNS lesions
mimic toxoplasmosis, acute
myocarditis
– Congenital transmission
– Treatment: nifurtimox (CDC),
benznidazole (FDA-approved) Megaesophagus
1447
32 y.o. man from Ecuador with renal failure

• Living in US for 8 years
• Evaluation for kidney transplant
– Epigastric pain-? gastritis
– WBC 7900, 9% eosinophils
• 6 weeks after renal allograft:
– Temp 102.5o
– Abdominal pain
– Diarrhea (heme +)
– Blood cultures+ for E. coli
– Broad spectrum antibiotics
- Progressive respiratory failure
32 y.o. man from Ecuador with renal failure

• Living in US for 8 years
• Evaluation for kidney transplant
Diagnosis?
– Epigastric pain
– WBC 7900, 9% eosinophils
• 6 weeks after renal allograft:
– Temp 102.5o
– Abdominal pain
– Diarrhea (heme +)
– Blood cultures+ for E. coli
– Broad spectrum antibiotics
- Progressive respiratory failure
1448
Bronchoscopy
• Filariform larvae of
Strongyloides
stercoralis
• Immunosuppression
held
• Daily ivermectin per
N-G tube
• E.coli meningitis
• Post-mortem: larvae
throughout gut,
lungs, brain, heart
Strongyloides stercoralis
• Able to complete life cycle in host
without exogenous reinfection
– Infection life-long
– Eosinophilia in >75%
– Potential for life threatening
hyperinfection/dissemination
(corticosteroids, HTLV-1>>>HIV,
malnutrition)
• Diagnosis: microscopic examination
(stool, secretions, CSF), serology
• Treatment: ivermectin
1449
25 year old woman with seizure

• Spent a semester in Ghana
• Avoided swimming in fresh water
• 4 years later: seizure
• MR of brain: suspicious for tumor
• Craniotomy
• After diagnosis made
recalled walking barefoot
along the side of a river
one afternoon
Schistosoma mansoni
Schistosomiasis
• Contact with fresh water infested
with snail intermediate host
• Chronic disease: response to eggs
in tissue: acute inflammation, Schistosoma mansoni
granulomas, fibrosis
• Multiple complications including
ectopic egg deposition with
disastrous complications (spinal
cord, central nervous system)
• Diagnosis:
– Eggs in stool/urine
– Serology
• Treatment: praziquantel
1450
Cysticercosis (Taenia solium)

– Ingestion of pork tapeworm
eggs (not pork)
– Most common presentation:
seizures several years after
infection due to inflammation
around degenerating cysts
Cysticercosis (Taenia solium)

• Diagnosis:
– CT or MR pathognomonic if
scolex visualized
– ELISA and immunoblot (CDC)
• Treatment (when indicated):
– High dose albendazole or praziquantel
– Funduscopic examination
– Corticosteroids, anticonvulsants
– Surgery, shunts
• Search for tapeworm carrier in household
1451
Skin lesions in returning travelers

• Teenager with an itchy rash
• Developed after 10-day vacation in Trinidad
• Worsened despite 7-days of amoxicillin
Diagnosis?
1452
Cutaneous larva migrans (creeping eruption)
Cutaneous larva migrans

(creeping eruption)
• Infection with dog or cat hookworms
(Ancylostoma braziliensis, others)
• Contact of bare skin with contaminated,
usually sandy, soil
• Diagnosis: clinical
• Treatment
– ivermectin 200 mcg/kg PO QD x1-2 days
– albendazole 400 mg PO QD x3 days
1453
Cutaneous lesions in returning travelers

• Cutaneous larva migrans — 25 percent
• Pyoderma — 18 percent
• Arthropod-reactive dermatitis —10 percent
• Myiasis — 9 percent
• Tungiasis — 6 percent
• Urticaria — 5 percent
• Fever and rash — 4 percent
• Cutaneous leishmaniasis – 3 percent
Clin Infect Dis. 1995;20(3):542
Healthy 47-year-old man with skin lesions.

• One week earlier he left West Africa
• 5 days in five-star hotel, ate only hotel food,
slept in an air-conditioned room with the
windows closed
• He walked on the beach outside the hotel,
swam in the chlorinated hotel pool, and
lounged on wooden cots near the pool
• No history of insect bites, but sensation of
bites and small red bumps on his buttocks
and thighs
1454
• On flight to US: numerous

boils several centimeters
in diameter; unable to sit
because of pain
• Back in US, the lesions
increasing in size in front
of his eyes
• In EW reports things
moving inside, blowing
bubbles in bath tub
Diagnosis?
Furuncular myiasis
(infestation with maggots--fly larvae)
• Tumbu fly: (Cordylobia

anthrophaga): sub-Saharan Africa
– Eggs deposited on sandy soil
or clothes contaminated with urine or sweat
– Larvae hatch, penetrate skin to subcutaneous
tissue where they feed and grow
– Larval chamber becomes boil-like and inflamed
– 10-14 days later mature larvae falls out of lesion,
pupates on ground
• Human botfly (Dermatobia hominis): Latin America
• Treatment: extraction (squeezing, suffocation;
excision)
1455
60-year old biologist: painless, slowly

expanding ulcer for 2 months after
returning from forest in Peru
Cutaneous leishmaniasis
(vector: sand flies)
1456
Leishmaniasis (Leishmania braziliensis)

• Diagnosis: biopsy,
scrapings, aspirate for
intracellular organisms
• Treatment: lipid-
associated amphotericin
compounds, parenteral
pentavalent antimony,
miltefosine
• Complication: mucosal
leishmaniasis
Take home points

• Include travel-related infections when formulating
differential diagnoses
• Falciparum malaria can be rapidly fatal and should be
ruled out in all febrile patients returning from malaria-
endemic areas regardless of clinical presentation
• Infectious diseases among immigrants and short-term
travelers often differ; important infections of
immigrants are often subclinical at the time of entry
• Most travel-associated infectious diseases can be
prevented by inquiring about patients’ travel plans
frequently and providing advice, vaccines and
prophylactic medication
1457
A young man returns from Haiti with fever and

headache. His temperature is 103o F but he
appears well. Laboratory studies show mild
anemia, thrombocytopenia, and normal renal
function . A blood smear shows a few rings
of Plasmodium falciparum.
Treatment of choice: a. Chloroquine

b. Mefloquine
c. Quinine + doxycycline
d. Quinidine +clindamycin
e. Artemether /lumefantrine
Treatment of choice: a. Chloroquine

b. Mefloquine
c. Quinine + doxycycline
d. Quinidine +clindamycin
e. Artemether /lumefantrine
*
Artemisinin combination therapy is the
treatment of choice for all cases of falciparum
malaria because of more rapid action and
increased survival compared to other agents.
1458
Failure to treat which of the following can lead

to death from overwhelming infection in a
person receiving high doses of corticosteroids?
a. Falciparum malaria
b. Babesiosis
c. Giardiasis
d. Strongyloidiasis
e. Schistosomiasis
Failure to treat which of the following can lead

to death from overwhelming infection in a
person receiving high doses of corticosteroids?
a. Falciparum malaria
b. Babesiosis
c. Giardiasis
d. Strongyloidiasis *
e. Schistosomiasis
Splenectomy (not steroid therapy is associated
with overwhelming malaria and babesiosis;
steroids accelerate strongyloides replication;
schistosomes do not replicate in the host.
1459
References
• CDC: Travelers’ Health
– www.cdc.gov/travel
– CDC “Yellow Book”
• World Health Organization
– www.who.int/int
– WHO “Green Book”
• Ashley EA et al. Malaria. Lancet 2018;391:1608-21.
• Paixão ES, et al Zika, chikungunya and dengue: the
causes and threats if new and re-emerging arboviral
diseases. BMJ Glob Health 2018;3:suppl 1.
• Riddle MS, et al. Guidelines for the prevention and
treatment of travelers’ diarrhea: a graded expert panel
report. J Travel Med 2017; 24:s63-80.
• Thwaites GE, Day NPJ. Approach to fever in the
returning travelers. N Engl J Med 2017; 376:548-60.
1460
Tuberculosis for the Non-ID Specialist

Gustavo E. Velásquez, MD, MPH
Associate Physician
Division of Infectious Diseases, Department of Medicine
Instructor in Medicine
Research Associate in Global Health and Social Medicine
No financial disclosures
1461
Objectives
• Review diagnostic approaches for latent
tuberculosis infection (LTBI)
• Review treatment of LTBI
• Approved regimens
• Side effects, monitoring, contraindications
• Prevention/management of complications
• Review new approaches to the diagnosis and
management of active tuberculosis
Tuberculosis burden
• 1/3 of the world’s population is infected
• ~10.4 million new cases each year
• ~1.6 million deaths last year
• The 9th leading cause of death worldwide
• The leading cause of death from a single
infectious agent (ranking above HIV/AIDS)
• The leading cause of death among PLHIV
WHO/HTM/TB/2017.23
1462
WHO/HTM/TB/2017.23
Tuberculosis progress
1463
Clinical scenarios
• Latent TB
• Suspected active TB
• Active TB
• Special scenarios
Diagnosis and treatment of

latent tuberculosis
1464
What is latent TB?
Latent Active
Sterile Quiescent Subclinical Percolator Chronic Pulmonary Fulminant
Pathologic
Protective
Pathologic
Skin testing for TB (TST)

• PPD (purified protein derivative) contains multiple
antigens
• Sensitized inflammatory cells migrate to the site
causing a delayed-type hypersensitivity reaction
• Sensitivity and specificity impossible to determine
• A positive reaction is usually indicative of current
infection
• Sometimes negative even in active disease;
therefore, not a good diagnostic aid
1465
Who should receive TST testing?

• High-risk individuals
• Close contacts of active TB patients
• Immigrants
• HIV or other immunosuppression
• IV drug use
• Abnormal CXR
• Healthcare workers
What is a positive TST?

• 5 mm
• HIV, close contacts of TB cases
• 10 mm
• Other high-risk individuals
• 15 mm
• Everyone else
• (0 mm)
• Immunocompromised high-risk close contacts
1466
Lewinsohn et al. Clin Infect Dis 2017;

64(2):e1–e33
BCG and TST

• BCG administration can lead to positive TST
• The risk of positive TST resulting from BCG
varies with administration schedule
• Infancy vs. adolescence
• However, the rate is low and most positive
TSTs represent TB infection even in
vaccinated individuals
1467
Interferon γ release assays

(IGRAs)
• Measure memory response to TB and M.
avium antigens using stimulation of
lymphocytes to produce interferon
• Only sensitized (i.e., immune individuals)
produce interferon
• Two formats
• ELISPOT (T-SPOT.TB)
• ELISA (QuantiFERON-TB Gold)
Sensitivity/specificity of IGRAs
• Current generation of tests (Quantiferon-TB
Gold, T-SPOT.TB) utilize antigens found in M.
tuberculosis but not M. bovis BCG
• Assays have similar sensitivity/specificity to
TST for diagnosis of LTBI
1468
Interferon γ release assays

(IGRAs)
• Advantages (over TST)
• Testing can be completed in a single visit
• Not subjective
• No interference from previous BCG vaccination
• Disadvantages
• Cost
• Availability
• Logistics
• Current CDC recommendation is that IGRA can be
used in all settings where TST is currently used
When to perform IGRA over TST?

• 5 years or older
• Are likely to be infected with Mtb
• Low or intermediate risk of disease progression
• Testing for LTBI is warranted
• Either have
• A history of BCG vaccination OR
• Are unlikely to return to have their TST read
(TST acceptable if IGRA not available, too costly, or
too burdensome)
Lewinsohn et al. Clin Infect Dis 2017;64(2):e1–e33
1469
Treatment options for LTBI

• 9H: INH x 9 months (with B6)
• 6H: INH x 6 months (with B6)
• 4R: Rifampin x 4 months
• 2RZ: Rifampin + Pyrazinamide x 2 months (*high
risk of hepatotoxicity*)
• 3HP: INH + Rifapentine x 3 months (with B6)
• No age cutoff (except for 3HP if aged <2 years)

• Must be evaluated for active TB
• Generally no need to retreat if previously treated
INH + Rifapentine (3HP)

• Supervised regimen of INH + RPT + B6, one
weekly dose for 12 weeks
• Equivalent efficacy to INH alone (6H or 9H)
• Currently recommended by CDC as an
alternative to INH or RIF monotherapy
• Cannot be used in pregnancy or age <2 years
• Now recommended with DOT or self-
administered therapy (SAT)!
• Belknap et al. Ann Intern Med 2017;
167(10):689–97
1470
Hot new CDC guidelines

• 3HP recommended for LTBI in 2011
• Additional indications in 2018
– In persons with LTBI aged 2-17 years
– In persons with LTBI with HIV infection
including AIDS, and taking ARVs with acceptable
drug-drug interactions with RPT
– By DOT or self-administered therapy (SAT) in
persons aged ≥ 2 years
Borisov AS et al. Morb Mortal Wkly Rep. 2018;67(25):723–6
When to perform baseline LFTs?

• Underlying liver disease (HBV, HCV, EtOH,
cirrhosis)
• Pregnant and within 3 months postpartum
• Regular EtOH use
• Concomitant medications with potential
hepatotoxicity
1471
Stopping rules based on LFTs

• Symptomatic and transaminases >3x ULN
• Asymptomatic and transaminases >5x ULN
• If any of the above, do not rechallenge!
Diagnosis and treatment of

suspected active TB
1472
AFB smear
• Rapid, first bacteriologic evidence of
mycobacterial disease
• Quickly identifies infectious “spreaders” of
TB
• Stained smears may be used as a rapid
monitor of patient response to treatment
Drawbacks of AFB smear

diagnosis
• Least sensitive detection method. Detects
10,000 AFB per mL of sputum while culture
detects 10-100 AFB per mL
• Is not specific for M. tuberculosis. Other
organisms such as Nocardia spp. may also
be acid-fast
1473
Mycobacterial culture
• More sensitive and specific for TB diagnosis
than AFB smear
• True sensitivity and specificity is difficult to
calculate due to culture negative TB:
– 80 - 90% of cases reported in the US are
culture proven
– Specificity = 98% (false-positives due to
contamination)
• Major limitation - Slow
“Rapid” culture of TB
• Liquid culture methods (e.g., BACTEC,
MGIT) - 7-12 days
• Diagnosis in fluids other than sputum
remains problematic
1474
ATS/IDSA/CDC guidelines
• If suspect pulmonary TB
• AFB smear should be performed
• 3 specimens strongly recommended and
improve sensitivity
• At least 3mL sputum volume, optimally 5-10mL
• Concentrated specimens and fluorescence
microscopy preferred
• Both solid and liquid AFB cultures for every
specimen
• NAAT should be done on the initial respiratory
specimen
Lewinsohn et al. Clin Infect Dis 2017;64(2):e1–e33
Alternative diagnostics
• Several groups are trying to develop rapid
diagnostics based on detecting bacterial
components
– Lipoarabinomannan (LAM)
– Volatile lipids
– Nucleic acid amplification
1475
Urinary lipoarabinomannan
• LAM is an abundant cell wall glycolipid
• LAM is shed in the urine of many infected
patients
• Can be detected using a urine dipstick
• Early results suggest good specificity,
relatively high sensitivity even in HIV
patients
Volatile lipids
• Metabolism in M. tuberculosis produces
distinctive lipid molecules some of which
are volatile
• These can be detected in exhaled breath
by:
– Mass spectrometry
– “Electronic nose”
– Giant rats
1476
GeneXpert MTB/RIF Performance

• Very high specificity for TB
• Very high sensitivity for smear-positive
disease
• Sensitivity 50-60% for smear-negative
disease but improves with repeated
samples
• Excellent rates of detection for rifampin
resistance
1477
Guidelines for treatment of

smear-negative suspected TB
• Start treatment while awaiting results of
culture
• When culture results become available
– Continue if culture positive
– Continue if response to treatment or high
suspicion
– Discontinue if no response and low suspicion
Treatment of active TB
1478
TB pneumonia treatment
• Current CDC recommendation:
– INH x 6 months (add pyridoxine)
– Rifampin x 6 months
– Ethambutol x 2 months
– Pyrazinamide x 2 months
Nahid P et al. Clin Infect Dis. 2016 Oct 1;63(7):e147–95
Continuation phase
• INH + Rifampin for 4 months
• Intermittent dosing (2-3 doses/week) with
DOT is possible, generally avoid if:
– HIV co-infection
– Smear positive
– Cavitary disease
• Major consideration is adherence
Nahid P et al. Clin Infect Dis. 2016 Oct 1;63(7):e147–95
1479
Why so many drugs?

• Drug resistance occurs at a rate of 1/105 -
1/109
• Cavitary lesions contain from 109 - 1011
organisms per gram of tissue
• Drug resistance can either be primary or
arise de novo during treatment
Treatment modifications
• INH intolerance
– Add PZA for the duration of treatment
• PZA intolerance
– Continue therapy for 9 months
• RIF or multiple drug intolerance
– Expert consultation
• HIV
– No change, but beware of interactions
between rifamycins and antiretrovirals
(and rifabutin is less effective than rifampin)
1480
Directly observed therapy

• Standard in most of the world
• Local standards vary throughout US
• Massachusetts takes a graded approach
ranging from unsupervised drug
administration to institutionalization
Practical treatment options

• Write prescriptions
• Refer to public health clinic
• Refer for inpatient therapy
1481
Public health considerations

• Only active disease is transmissible
• The frequency of transmission is roughly
proportional to the burden of organisms in
expectorated sputum
• Transmission is largely restricted to
contacts of smear positive patients
• All cases should be reported for contact
tracing
Should patients be isolated

(Massachusetts)?
• Adherent patients can go home
• Contacts should be screened
• Patients with positive smears are
considered infectious
• Most smear positive patients will convert
to smear negative after 2 weeks of
treatment
1482
Special scenarios
• High risk groups
• Drug-resistant tuberculosis
Who is at risk for developing

disease?
• Increased exposure
• Decreased cell-mediated immunity
– Congenital immune suppression
– Cancer, chemotherapy
– Pregnancy
– HIV - mechanism unknown but striking
increase in susceptibility
1483
Clinical presentation of TB in HIV

CD4 Disease
• PLHIV are more High Lung
susceptible to both
primary disease and
reactivation at all CD4
levels
• Patients with AIDS are
much more likely to
develop
extrapulmonary
disease
Low Other
TB therapy in HIV
• Rifampin has significant interactions with many
drugs, particularly protease inhibitors
• Can consider rifabutin, but less favorable
pharmacokinetics
• Timing of therapy remains poorly defined
• Regimens that do not contain rifamycins could
help considerably
1484
TNF and tuberculosis

• Mice with mutations in TNF or its receptor
are very susceptible to TB
• Patients receiving TNF blocking agents
develop reactivation TB at very high rates
– Infliximab (Remicade) seems to produce a
higher risk than Etanercept (Enbrel)
Vaccination against TB
• BCG vaccine derived from Mycobacterium
bovis by years of serial passage
• In use in much of the world since the
1930’s
• Studies of efficacy show variable results;
however, not very effective against adult
TB
1485
Multidrug resistance
• Defined as resistance to INH and Rifampin
• Treatment requires expert consultation
New antibiotics
Bedaquiline
Delamanid Pretomanid
1486
New drugs in MDR-TB

• Both delamanid and bedaquiline have been
tested in MDR-TB
• Both randomized controlled trials of best
regimen vs. best regimen plus new agent
Delamanid Bedaquiline
Delamanid and Bedaquiline
1487
But a big red flag
Bedaquiline black box warning
1488
Attempts to shorten therapy
Nimmo C et al. Lancet Infect Dis. 2015 Feb;15(2):141–3
Summary
• New diagnostics and treatment options are
now available for latent TB
• New diagnostics for active TB will likely
soon be available
• While promising, new treatment options
for active TB are several years away
1489
Question 1
• Which of the following are acceptable
treatments for latent tuberculosis infection
a. Isoniazid and B6 daily for 5 months
b. Rifampin daily for 4 months
c. Isoniazid and Rifapentine and B6 daily for 12 weeks
d. All of the above
e. None of the above
Question 1
• Which of the following are acceptable
treatments for latent tuberculosis infection
a. Isoniazid and B6 daily for 9 months
b. Rifampin daily for 4 months
c. Isoniazid and Rifapentine and B6 weekly for 12 weeks
d. All of the above
e. None of the above
1490
Question 2
• Which of the following is true of treatment for
active tuberculosis
a. Treatment should be initiated after the results of
antibiotic sensitivity tests are available
b. Pregnant women should not receive isoniazid
c. Antibiotic choice or duration should be altered in the
presence of drug resistance
d. Antibiotic resistance is found only in those previously
treated with drugs
e. All of the above
Question 2
• Which of the following is true of treatment for
active tuberculosis
a. Treatment should be initiated before the results of
antibiotic sensitivity tests are available
b. Pregnant women may receive isoniazid
c. Antibiotic choice or duration should be altered in the
presence of drug resistance
d. Antibiotic resistance is found not only in those
previously treated with drugs
e. All of the above
1491
References
• World Health Organization. Global Tuberculosis Report 2016. Geneva, Switzerland: World
Health Organization; 2017. Report No.: WHO/HTM/TB/2017.23. Available at:
http://www.who.int/tb/publications/global_report/en/
• Lewinsohn DM, Leonard MK, LoBue PA, Cohn DL, Daley CL, Desmond E, et al. Official
American Thoracic Society/Infectious Diseases Society of America/Centers for Disease
Control and Prevention Clinical Practice Guidelines: Diagnosis of Tuberculosis in Adults and
Children. Clin Infect Dis. 2017 Jan 15;64(2):e1–e33. Available at:
https://academic.oup.com/cid/article-pdf/64/2/e1/13132770/ciw694.pdf
• Nahid P, Dorman SE, Alipanah N, Barry PM, Brozek JL, Cattamanchi A, et al. Official
American Thoracic Society/Centers for Disease Control and Prevention/Infectious Diseases
Society of America Clinical Practice Guidelines: Treatment of Drug-Susceptible
Tuberculosis. Clin Infect Dis. 2016 Oct 1;63(7):e147–95. Available at:
https://academic.oup.com/cid/pdf-lookup/63/7/e147
• Borisov AS, Bamrah Morris S, Njie GJ, Winston CA, Burton D, Goldberg S, et al. Update of
Recommendations for Use of Once-Weekly Isoniazid-Rifapentine Regimen to Treat Latent
Mycobacterium tuberculosis Infection. Morb Mortal Wkly Rep. 2018;67(25):723–6. Available
at: https://www.cdc.gov/mmwr/volumes/67/wr/mm6725a5.htm
1492
Update on Adult Immunizations

2018
Lindsey R. Baden, MD
Division of Infectious Diseases
Disclosures
• None
1493
Greatest Medical Triumph of

the 20th Century
Annual 20thCentury 1998 Morbidity % Decreased
Morbidity
Smallpox 48164 0 100
Diphtheria 175885 1 100
Pertusis 147271 7405 95
Tetanus 1314 41 97
Paralytic Polio 16316 1 100
Measles 503282 100 100
Mumps 152209 666 >99
Rubella 47745 364 >99
HiB 20000 61 >99
Total 1112186 8639 >99
AAP, Red Book: 2000, 2012
Types of Vaccines
Live Attenuated Killed Whole Purified Protein or Genetically
Organism Polysaccharide Engineered
Smallpox, 1798
Rabies, 1885 Typhoid, 1896

Cholera, 1896
Plague, 1897
BCG, 1927 Pertussis, 1926 Diphtheria, 1923

Yellow fever, 1935 Influenza, 1936 Tetanus, 1927
Rickettsia, 1938
After World War II (advent of cell culture)
Polio Polio Pneumococcus Hepatitis B
Measles Rabies Meningococcus Pertussis
Mumps Japanese enceph HiB
Rubella Hepatitis A Hepatitis B
Adenovirus Tick-borne enceph
Ty21a Typhoid (Vi)
Varicella Pertussis
Rotavirus
Plotkin and Ornstein, Vaccine: 1999, 2012
1494
Recommended Adult Immunization Schedule

by vaccine and age group
MMWR 2018
Recommended Vaccinations Indicated for Adults

based on medical and other indications
MMWR 2018
1495
Spacing the Administration of

Killed and Live Antigens
• > 2 Killed antigens
– May be given at any interval between doses
• Killed and live antigens
– May be given at any interval between doses
– Exception: cholera and yellow fever
• > 2 Live antigens
– 4 weeks if not given simultaneously
– Exception: OPV in relation to MMR or Ty21a
MMWR 2011;60(RR-2):1-64
Mitigating Factors to Response

• Preformed antibodies
– IVIg, blood, plasma, and platelet products
• MIG, TIG, VZIG, RIG, HBIG, RSV-Ig, anti-Rh(D)
– Impairs live viral replication
• Varicella, measles >rubella, mumps >>yellow fever (YF),
typhoid
– Recommendations
• Ig and killed antigen: no time
• Ig and live vaccines (depends on dose of IG)
– Ig live: none-OPV, YF, Ty21a; 3m–mumps, RA27/3; 5m–
measles,VZV
– Live Ig: 2wk – MMR; 3wk VZV
– Consider follow-up serologic testing
• Antibiotic use
– Live bacterial vaccines (e.g., Ty21a)
1496
Contraindications
• Bleeding risks (e.g., IM injections)
– Hemophilia, anti-coagulation
• Immunosuppressed
– Medications, pregnancy, HIV, transplantation
• Infection, rejection, diminished responsiveness
• Live antigens: MMR, YF, OPV, VZV
• Fetal risk: rubella, VZV (registry: 800-986-8999)
• Household contacts: OPV, ??VZV
• Prednisone (>20mg qd for >14 days, wait 1m post discontinuation)
• Hypersensitivity
– Egg: influenza, YF, measles, mumps
– Gelatin: MMR, YF, VZV
– Abx: neomycin, streptomycin, or polymyxin B
– Thimerosal: DTP, HBV, influenza, Japanese encephalitis
• Current moderate/severe illness
Specific Vaccines
• dT, Tdap
• MMR
• Influenza
• Pneumoccocus, Menningococcus, HiB
• Varicella and Zoster
• HAV, HBV
• HPV
1497
dT Tdap
• Dosing
• Boost every 10 years
• 5 years if high risk behaviors anticipated
• Who: all adults
• 45-65 cases tetanus annually in US w/ 60% in adults
• Serologic studies show that >40% and 40-80% of 60+yo and
11% and 62% of 18-39yo w/o neutralizing antibody to tetanus
and diphtheria respectively
• PEP: Wound management
• History of <3 doses adsorbed tetanus toxoid
– Clean, minor wounds: dT
– Other wounds: TIG (250 U IM) and dT
• History of >3 doses
– Clean, minor wounds: boost if >10 years since last dT
– Other wounds: boost if >5 years
MMWR:Vol 55 RR-17; Dec 15, 2006
1498
Pertussis
N=2781, 1:1 randomization
Acellular pertussis vaccine
Median 22 months follow-up
0.7 to 5.7% of illness due to
pertussis
Incidence of pertussis 370-450
per 100,000 pt-years
Vaccine 92% effective
Ward et al. NEJM 2005;353:1555
Tdap
• 2005 two formulations approved in US
– ADACEL (sanofi pasteur); licensed 7/10/05; single booster; 11-64 year
olds. 0.5 mL IM
– BOOSTRIX (GSK); single booster; 10-18 year olds
• Recs
– 19-64 yr olds -- use as next tetanus booster
• Can be given as close as 2 years from last boost
• Priority to boost following groups
– Close contacts of infants/elderly and health care workers
– Not licensed for decennial re-booster
– Contraindications
• Allergy to prior tetanus vaccination;
• Adults with history of unexplained encephalopathy w/in 7 days of a vaccine
with a pertussis component;
• ?GBS w/in 6 weeks of prior tetanus vaccination;
• ?Ongoing/evolving neurologic condition
MMWR:Vol 55 RR-17; Dec 15, 2006
1499
Patients with Measles According to the Day of Onset of Rash, Indiana, May to June 2005
Parker A N Engl J Med 2006;355:447-455
Estimated Direct Costs of Containing Measles during the Outbreak in Indiana
Parker A. N Engl J Med 2006;355:447-455
1500
Fluctuation in the Number of Persons Susceptible to Measles in a Community Where

Measles Virus Is Circulating
Mulholland E. N Engl J Med 2006;355:440-443
MMR I
• General
• Contains neomycin and gelatin, made from chick-embryo cell
culture, live attenuated
• Mumps (Jeryl Lynn strain)
• ~78% w/ Ab after 1 dose; ~88% (range 66-95%) after 2 doses
• AEs: rarely orchitis, parotitis
• Before vaccination, in 1967, about 186,000 cases/yr
– In 2012 - 229 cases
– As of June 6, 2016- 1,272 cases in 33 states (>100 in MA)
• Rubella (RA 27/3)
• >95% w/Ab after 1 dose
• About 10% of young adults are not immune
• AEs: Fever (5-15%), rash (5%), joint pain (up to 25% of young
women 7-21d post vaccination)
• Avoid in pregnancy
1501
MMR II
• Measles
– 95-98% w/ Ab after 1st dose, >99% post 2nd dose
• 1963-7 inactivated vaccine – atypical measles
– Recent IgG use interferes w/ immunogenicity
– AEs: 5-15% w/ T>103 5-12d post vaccination, CNS
<1/million doses, decreased plat seen 2-3 wks post
vaccination, may decrease ppd reactivity for 4-6 weeks
– Who
• Everyone born after 1956, colleges typically require
documentation of 2 dose
• Recommended for HIV+ patients if not severely
immunosuppressed
– PEP: Can vaccinate w/in 72h of exposure, also
consider Ig (0.25 – 0.5 mL/kg, max 15 mL) w/in 6d
Influenza: 3 vs 4 valent
• Inactivated, multivalent (tri: 2 A’s and 1 B and now quad:
2 A’s and 2 B’s) adapted periodically to the strains
expected to circulate in the winter (A/H1N1, A/H3N2, B-Victoria
+/-Yamagata)
– 1 dose annually in autumn
– Efficacy: 56% resp illness, 50% pneumonia hosp, 68% death
• Who -ALL
– Age>50, CRF, DM, cardiac dz, pulm dz, HIV,
immunosuppressed, nursing home residents
– Health care workers, household contacts of at risk patients
• AEs: local reaction 10%
– Caution in the setting of egg allergy
• PEP: consider chemoprophylaxis (rimant/amant, oseltamivir/zanamivir)
MMWR 62 (RR-07):1-
43;2013
1502
FluMist
Not recommended for 2017-18 season
• Cold adapted, live attenuated, intranasal, 2.5ml/nares

• Decrease febrile URI 24%, HCW visit 18-37%, Abx use
41-45%
• FDA approved (6/03) for healthy people, age 5-49
• AE: runny nose (45%), sore throat (28%), tiredness
(26%), cough (14%), chills (9%)
• Contraindications: >50yo, pregnancy, egg allergy, h/o
GBS, immunocompromised, recent resp illness (72h), or
those w/cardiac, pulmonary, metabolic, or renal dz
• Possible transmission of vaccine strain thus avoid in
those who are in contact w/ immunosuppressed patients
• Avoid antiviral therapy for 2 weeks
• Expensive
MMWR 62 (RR-07):1-43;2013
Pneumococcus
• Pneumovax
– 23 valent polysaccharide vaccine
• 88% of strains causing bacteremia/menningitis
– 0.5mL IM (25ug of each polysaccharide)
– About 70-81% effective, bacteremia
– Consider boost in 5yrs
• Prevnar
– 13+ valent protein conjugated vaccine, rec for children
• Who?
– Lung disease, CHF, age>65, immunosuppressed, DM, cirrhosis,
corticosteroid use, transplantation, asplenic, nephrotic
syndrome, renal failure, HIV, CSF leaks
– About 1/3 of 50-64yo have an indication
MMWR 46(RR-8):1-24;1997 and 49(RR09):1-38;2000
1503
Ada NEJM 2001;345:1045
Menningococcus and HiB

• Menningococcus
– Serogroups A, C, Y, and W-135 (50ug of each)
– ?Boost in 5 years
– Who: asplenic, hypocomplementemia, properidin
deficiency, travelers, college students
– Consider in setting of serogroup A/C outbreak
– Types of vaccine
• Polysaccharide
• Conjugate (preferred in adults <55 years old)
– MenB
• HiB
– Part of the childhood vaccination schedule
– Various conjugate formulations: HbOC, PRP-OMP,
PRP-T, PRP-D
– Who: consider in asplenic patients
1504
Meningococcal B Vaccines
• Oct 2014 -MenB-FHbp (Trumenba)
– 3 dose series (0, 2, 6 months)
• Jan 2015 – MenB-4C (Bexsero)
– 2 dose series (0, 1-6 months)
• Approved for
– 10-25 year olds
• Those at increased risk
– Complement deficiency, receive eculizumab, asplenia
– Microbiologists, persons associated with a MenB
outbreak
MMWR Vol 64 No. 22 -- June 12, 2015
Varicella Vaccine
• Oka strain, ~1350 pfu/dose
• Given SC, 0.5 mL
• Varivax (Merck) licensed 1995
• ProQuad (MMR-Varicella) licensed 2005
• Store frozen
1505
Burden of Varicella over Time
MMWR:Vol 56 RR-4; June 22, 2007
VZV: Varicella Vaccine

• Live attenuated, Oka strain, licensed 3/95
• 0.5mL SQ/IM, 2 doses 4-8 weeks apart
• Seroconversion
– 78-82% after 1 dose
– >99% after 2nd dose
• Issues
– Mild varicella syndrome in 1-4%, 5-26 days post vaccination
• Who
– All children, occupation exposure, non-pregnant women of
childbearing age, travelers
– ?Immunocompromised patients and household contacts
– 70-90% of individuals w/o h/o infection are seropositive
1506
Varicella Vaccine Recs

• 2 doses in children (12-15 m and 4-6 yrs of age)
• Catch-up for those who received 1 dose
• > 13 years old w/o evidence for varicella immunity
• HIV infected individuals (CD4>200)
– 2nd dose at 3 months
• Outbreak control
• PEP (within 3-5 days of exposure)
• Postpartum women
• School requirements
Zoster (HZ)
• Oxman et al NEJM 2005;352:2271-84
– N= 38,546
– Used Oka/Merck strain
• Decreased incidence of zoster by 51.3%
• Decreased postherpetic neuralgia by 66.5%
1507
NEJM 2005;352:2271-84
HZ Vaccine Recs
• Who
– Persons > 60 years old with a history of
varicella
• Contraindications
– Significant immunosuppression
1508
HZ/su- VZV glycoprotein E/ASO1E
Lal et al. NEJM May 2015
HAV
• Vaccines
– Havrix (1440 ELU) and Vaqta (50U):
• 2 doses 1mL IM at 0 and 6-12m
• Seroconversion at 15d 88-93% and 28d 95-99%
• AEs: local discomfort
• Who
– Travelers, individuals under custodial care, persons
with hepatitis B+C infection, chronic liver disease,
high-risk behaviors (IVDU, MSM), or receive clotting
factors
• PEP
– Ig w/in 14d of exposure (85% effective, 0.02 mL/kg)
– Vaccination
1509
HBV I
• Recombinant vaccine to HBsAg
– Recombivax and Engerix-B
• 10-20 ug/mL of antigen w/ aluminum hydroxide
• 40 ug/mL formulation for dialysis and immunosuppressed
patients
• Series: 3 doses at 0, 1, and 6 months
– Donot vaccinate in buttock (diminished
immunogenicity)
• Obtain f/u serology in persons at risk thus PEP
affected (e.g., IVDU, MSM, STDs, health care
workers)
– If seronegative then revaccinate up to 3 more times
– Boost in hemodialysis pts when titer <10 mIU/mL
HBV II
• Who
– Children, travel, hepatitis C infection, liver disease,
household contacts of HBV infected persons, health
care workers, high-risk behaviors (e.g., IVDU, MSM)
• PEP
– Unimmunized or immunized nonresponder: HBIG
(0.06 mL/kg) w/in 14d and vaccinate
– Immunized and known responder: nothing
– Immunized and unknown response: check titer if
negative then Rx as nonresponder
• First vaccine preventable cancer: hepatoma
1510
HPV Associated Disease

• Estimated in US in
2007
– 6.2 million new HPV
infections
– 11,000 new cases
of cervical cancer
– 3,700 cervical
cancer deaths
MMWR:Vol 56 RR-2; Mar 2007
Age-Standardized Rates of New Cases of Cervical Cancer per 100,000 Women, 2002
Agosti J and Goldie S. N Engl J Med 2007;356:1908-1910
1511
HPV Vaccine(s)
• Gardasil (Merck)
– Licensed 8/18/06
– Quadravalent HPV L1 protein (major capsid protein)
adjuvanted with alum
– Serotypes 6, 11, 16, 18
– Given 0.5 mL, IM at 0, 2, 6 months
– 9-valent
• Serotypes 31, 33, 45, 52, and 58. Joura et al NEJM 2015; 372:711-23
• Cervarix (GSK)
– Bivalent HPV L1 protein adjuvanted with AS04
– Serotypes 16, 18
– Given 0, 1, 6 months
1512
Times to End-Point Events in the Intention-to-Treat Population
Garland S N Engl J Med 2007;356:1928-1943
Some HPV Vaccine Unknowns

• Efficacy appears to be linked to vaccination prior
to serotype exposure
– Age of vaccination
• Duration of protection
• Role of vaccinating males
• Serotype replacement
• Impact on non-cervical HPV associated
malignancies
• Impact on cervical cancer screening
1513
Contraindications to Vaccines
MMWR 2018
Recommended Adult Immunization Schedule

by vaccine and age group
MMWR 2018
1514
Recommended Vaccinations Indicated for Adults

based on medical and other indications
MMWR 2018
Q1) Which vaccine is not live

attenuated?
A) MMR
B) Hepatitis B virus
C) Zoster Vaccine
D) Yellow Fever
E) Oral Polio Virus
1515
Q1) Which vaccine is not live

attenuated?
A) MMR
B) Hepatitis B virus
C) Zoster Vaccine
D) Yellow Fever
E) Oral Polio Virus
Correct is B-hepatitis B virus
Q2) The shingles vaccine is indicated for

which patient group?
A) Those who have had zoster in the past

B) Those who are immunosuppressed
C) Anyone older than 50 years
D) Anyone older than 60 years
E) Anyone older than 50 or 60 years
1516
Q2) The shingles vaccine is indicated for

which patient group?
A) Those who have had zoster in the past

B) Those who are immunosuppressed
C) Anyone older than 50 years
D) Anyone older than 60 years
E) Anyone older than 50 or 60 years
Correct is E –anyone over 50 or 60 years
References
1) 2012 Red Book, Report of the Committee on
Infectious Diseases, 29th Edition, AAP
2) Guide for Adult Immunization by the ACP
3) MMWR at www.cdc.gov/mmwr
– 2018 Adult Vaccine Recommendations
– Dec 2006;55(No.RR-15) Pg1-48 General
Recommendations on Immunization (ACIP and
AAFP)
4) Vaccines by Plotkin and Orenstein. 6th Edition,
Elsecvier 2012
5) Vaccines and Vaccinations, G Ada, NEJM
2001;345:1042-50
1517
HIV DISEASE: AN OVERVIEW

Jennifer A. Johnson, MD

Division of Infectious Disease
1518
Estimated HIV Incidence among Persons Aged ≥13 Years, by Transmission Category,
2010–2015—United States
Note. Estimates were derived from a CD4 depletion model using HIV surveillance data. Data have been statistically adjusted to account for missing
transmission category. Heterosexual contact is with a person known to have, or to be at high risk for, HIV infection.
* Difference from the 2010 estimate was deemed statistically significant (P < .05).
Diagnoses of HIV Infection among Men Who Have Sex with Men,
by Age at Diagnosis, 2010–2015—United States and 6 Dependent Areas
Note: Data have been statistically adjusted to account for missing transmission category. Data on men who have sex with men do not include
men with HIV infection attributed to male-to-male sexual contact and injection drug use.
1519
Estimated HIV Incidence among Persons Aged ≥13 Years, by Area of Residence,
2015—United States
Total = 38,500
Note. Estimates were derived from a CD4 depletion model using HIV surveillance data. Estimates rounded to the nearest 100 for estimates >1,000 and to
the nearest 10 for estimates ≤1,000 to reflect model uncertainty.
Estimated HIV Prevalence among Persons Aged ≥13 years, by Area of Residence,
2015—United States
Total = 1,122,900
Note. Estimates were derived from a CD4 depletion model using HIV surveillance data. Estimates rounded to the nearest 100 for estimates >1,000 and
to the nearest 10 for estimates ≤1,000 to reflect model uncertainty.
1520
Diagnosed Infection among Persons Aged ≥13 Years Living with Diagnosed or
Undiagnosed HIV Infection, 2010–2015—United States
Note. Estimates were derived from a CD4 depletion model using HIV surveillance data.
*Difference from the 2010 estimate was deemed statistically significant (P < .05).
HIV Diagnosis
CDC Laboratory Testing for the Diagnosis of HIV Infection:

Updated recommendations, 2014
1521
HIV prognosis
Prognosis is EXCELLENT!
Life expectancy of HIV-positive patients on
antiretroviral therapy (ART) with undetectable viral
load who maintain or recover CD4 count to ≥ 500
have NO INCREASED MORTALITY above the
general population
SMART and ESPRIT studies – analysis of non-IDU
participants in continuous ART control arms, includes
2380 participants over 12,357 person-years of follow-
up
Rodger AJ. AIDS 2013.
Not quite there yet, but closing the gap
1522
Case 1
26yo man with depression, MSM, presents for discussion new HIV
diagnosis. Presented 2 weeks ago for STI testing for rectal
discharge, + for rectal gonorrhea by NAAT on rectal swab, and HIV
screening same day was positive. Received IM ceftriaxone and oral
azithromycin last week, and had additional testing sent at that time:
CD4 470, HIV-1 VL 12,743, no resistance mutations. Syphilis
serology, HCV Ab and HBSAg all negative. Which of the following
would be appropriate for today’s visit?
A) Initiate antiretroviral therapy with

tenofovir/emtricitabine/cobicistat/elvitegravir
B) Initiate sulfamethoxazole/trimethoprim daily for prophylaxis and
to ensure medication adherence, return in 6 months to discuss ART
C) Initiate post-exposure prophylaxis with
tenofovir/emtricitabine/raltegravir for 28 day course
D) No medications, follow-up in 12 months for repeat bloodwork
Case 1
26yo man with depression, MSM, presents for discussion new HIV
diagnosis. Presented 2 weeks ago for STI testing for rectal
discharge, + for rectal gonorrhea by NAAT on rectal swab, and HIV
screening same day was positive. Received IM ceftriaxone and oral
azithromycin last week, and had additional testing sent at that time:
CD4 470, HIV-1 VL 12,743, no resistance mutations. Syphilis
serology, HCV Ab and HBSAg all negative. Which of the following
would be appropriate for today’s visit?

B) Initiate sulfamethoxazole/trimethoprim daily for prophylaxis and
to ensure medication adherence, return in 6 months to discuss ART
C) Initiate post-exposure prophylaxis with
tenofovir/emtricitabine/raltegravir for 28 day course
1523
Case 1
All HIV-positive patients should be offered ART. In this case his CD4 cell count is
> 350 so not immediate risk of opportunistic infections, but evidence supports
benefits of initiation of ART even at high CD4 cell count, and risks of drug
resistance and ART-toxicities are low with current treatments. From public health
perspective this also decreases his risk of transmission to others which could be
significant given recent new rectal gonorrhea.
B) Initiate sulfamethoxazole/trimethoprim daily for prophylaxis and to ensure
medication adherence, return in 6 months to discuss ART
SMX/TMP prophylaxis for PCP not necessary or of benefit at CD4 count > 200, and
there is no evidence to support test of adherence prior to initiation of ART
C) Initiate post-exposure prophylaxis with tenofovir/emtricitabine/raltegravir
for 28 day course
Patient already has documented HIV infection, too late for PEP
12 months is too long to wait for follow-up, even for patient who elects not to start ART
immediately.
Who should be treated with ART?
ALL HIV-POSITIVE PERSONS
1524
How urgently should ART be initiated?
Urgently There’s time to breath

For those with risk of AIDS- CD4 > 500, asymptomatic,
related complications not pregnant
CD4 < 200-350
Current opportunistic infection
(OI) – start within 2 weeks Patients starting ART should
For pregnant women or others at ideally be willing and able to
high risk of transmission commit to lifelong treatment;
in stable patients clinicians
(Acute HIV) may postpone therapy if
Hep B or hep C coinfection needed to manage problems
If any HIV-related complications that may interfere with
HIV Associated Neurocognitive medication adherence (eg.
Disorder (HAND) Psychiatric, substance
HIV Associated Nephropathy abuse…).
(HIVAN)
What ART to start?

Currently > 25 antiretroviral formulations available
(including co-formulations)
First-line regimens = 3 drugs from 2 classes:

2 nucleos(t)ide reverse transcriptase inhibitors (NRTIs) +
1 non-nucleoside reverse transcriptase inhibitor (NNRTI), or
1 integrase inhibitor (INSTI), or
1boosted protease inhibitor (PI)
1525
Single Tablet Regimens
Antiretroviral agents – not STRs
1526
A few selected antiretroviral toxicities
Tenofovir disproxil fumarate – nephrotoxicity (rare),

osteopenia (cumulative exposure)
Tenofovir alafenamide – lower risk of
nephrotoxicity and osteopenia than with TDF
Abacavir – hypersensitivity syndrome (possible if
HLA B5701 positive)
Efavirenz – neuropsychiatric side effects
(depression, poor sleep, vivid dreams)
Ritonavir – diarrhea, GI upset
A few selected drug/food interactions
Rilpivirine – requires fatty meal for optimal

absorption, not absorbed well in presence of any
antacids (H2B, PPI, etc)
Atazanavir – not absorbed well in presence of any
antacids (H2B, PPI, etc)
Ritonavir and cobicistat –

potent CYP 450 inhibitors,
interact with MANY
medications
1527
HIV as a chronic disease
http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(13)61809-7/abstract
Treatment failure
Assess adherence (discuss with patient, call
pharmacy, review viral load trend)
Assess drug-drug interactions
Drug resistance testing:
HIV genotype
HIV Integrase Resistance genotype
New regimen should include ideally 3 active agents
1528
Complications of HIV
On ART and Off ART Off ART
Cardiovascular disease Opportunistic infections

Malignancies (lung, (PCP, MAI, cryptococcal
meningitis, toxoplasmosis)
anal, oropharyngeal,
liver, skin) Malignancies (Kaposi’s
sarcoma, non-Hodgkin
Toxicities of ART: bone lymphoma)
demineralization (TDF),
HIV-associated dementia
renal toxicity (TDF),
(HAD)
metabolic syndrome
CD4 count Opportunistic Infections

Any CD4 TB, bacterial pneumonia, other
STIs
< 200 Pneumocystis pneumonia,
candidal infections
< 100 Toxoplasma encephalitis
< 50 CMV infections, disseminated

MAI, cryptococcal meningitis
1529
Case 2
22yo man, generally healthy, MSM, presents for evaluation of rash and
fever. Found to have secondary syphilis with RPR 1:128. Treated with
IM penicillin. In discussion reports > 6 sex partners in last 6 months,
50% condom use. Interested in HIV risk reduction, including PrEP. The
next best steps are:
A) Initiate tenofovir/emtricitabine today, return in 3 mo for next HIV test

B) HIV Ag/Ab test today, initiate tenofovir/emtricitabine/raltegravir x
28 days for PEP then transition to tenofovir/emtricitabine for PrEP
C) HIV Ag/Ab test today, initiate tenofovir/emtricitabine if HIV-negative,
return in 3 months for repeat HIV test
D) HIV Ag/Ab test today, risk reduction counseling and condoms for now,
return in 3 months to start PrEP if still interested
Case 2
22yo man, generally healthy, MSM, presents for evaluation of rash and
fever. Found to have secondary syphilis with RPR 1:128. Treated with
IM penicillin. In discussion reports > 6 sex partners in last 6 months,
50% condom use. Interested in HIV risk reduction, including PrEP. The
next best steps are:
A) Initiate tenofovir/emtricitabine today, return in 3 mo for next HIV test

B) HIV Ag/Ab test today, initiate tenofovir/emtricitabine/raltegravir x
28 days for PEP then transition to tenofovir/emtricitabine for PrEP
C) HIV Ag/Ab test today, initiate tenofovir/emtricitabine if HIV-
negative, return in 3 months for repeat HIV test
D) HIV Ag/Ab test today, risk reduction counseling and condoms for now,
return in 3 months to start PrEP if still interested
1530
Case 2
A) Initiate tenofovir/emtricitabine today, return in 3 mo for next HIV
test
Do not initiate PrEP before confirming that patient is HIV-negative
B) HIV Ag/Ab test today, initiate tenofovir/emtricitabine/raltegravir
x 28 days for PEP then transition to tenofovir/emtricitabine for PrEP
Unclear date of last exposure, no indication for PEP, should start PrEP once
confirmed HIV-negative
C) HIV Ag/Ab test today, initiate tenofovir/emtricitabine if HIV-
negative, return in 3 months for repeat HIV test
Baseline HIV test is critical to confirm patients starting PrEP are not already
infected with HIV. Other routine baseline bloodwork and STI screening is
also important. Once these are reviewed and HIV-negative confirmed, no
reason to delay PrEP for this high-risk individual, should start right away.
Needs HIV testing every 3 months while on PrEP and other STI testing at least
every 6 months.
D) HIV Ag/Ab test today, risk reduction counseling and condoms for
now, return in 3 months to start PrEP if still interested
No reason to delay PrEP if HIV-negative and interested.
HIV Prevention
Risk reduction counseling

Needle exchange programs
Barrier protection (condoms)
Pre-exposure prophylaxis (PrEP) http://www.cdc.gov/actagainstaids/pdf/campaigns/starttalk
ing/stsh-prep-infographic-basics.pdf
Post-exposure prophylaxis (PEP)
Prevention of mother-to-child transmission (PMTCT)
Treatment as prevention (TASP)
Male circumcision
(HIV vaccines? Someday…)
1531
Treatment as prevention
730 serodiscordant couples

60% heterosexual
HIV+ partner on ART, VL < 200
> 44,000 condomless sex acts
ZERO HIV transmissions
U=U: Undetectable = Untransmittable
https://www.preventionaccess.org/undetectable
1532
PrEP
https://wwwn.cdc.gov/hivrisk/
http://www.cdc.gov/vitalsigns/pdf/2015-11-24-vitalsigns.pdf
Pre-exposure prophylaxis (PrEP)

Indicated for MSM, heterosexual men and women,
and IDU with “substantial risk of acquiring HIV”
Screen for HIV, hep C and hep B, basic labs
Tenofovir/emtricitabine once daily (≤ 3 month
supply at a time)
Clinic visits q3 months: counseling, HIV screening,
other STI screening renal function monitoring,
pregnancy testing if indicated
US Public Health Service PrEP Clinical Practice Guideline, 2014
1533
PrEP
540 HIV- ppt at 13 STI clinics in England

Randomized immediate TDF/FTC or defer 1 yr
3 vs. 20 HIV infections relative risk reduction 86%
No difference in other STIs
PrEP works in a real world setting
On-demand PrEP?
1534
PEP
If potential exposure, evaluate and offer PEP within
72 hours
In most cases PEP = tenofovir/emtricitabine +
raltegravir or dolutegravir x 28 days
Kuhar DT, Infect Control Hosp Epidemiol 2013.
https://www.aids.gov/hiv-aids-basics/prevention/reduce-your-risk/post-exposure-prophylaxis/
Despite the progress…
1535
Still a long way to go
Take home points

HIV incidence is decreasing in US but still > 35,000
annually, and risk is quite high for MSM
Prognosis with HIV is excellent on ART
All HIV-positive patients should be offered ART
Many antiretroviral drugs available, including
several single-tablet once-daily regimens
Fewer AIDS diagnoses and opportunistic infections
as more patients take effective ART
There are many strategies for HIV prevention –
PrEP should be discussed with high-risk patients
1536
References
CDC, Division of HIV/AIDS Prevention. “Epidemiology of HIV Infection through
2014” slide set. http://www.cdc.gov/hiv/library/slideSets/
Centers for Disease Control and Prevention and Association of Public Health
Laboratories. Laboratory Testing for the Diagnosis of HIV Infection: Updated
Recommendations. Available at http://dx.doi.org/10.15620/cdc.23447 .
Published June 27, 2014.
Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the
use of antiretroviral agents in HIV-1-infected adults and adolescents. Department
of Health and Human Services. Available
at http://aidsinfo.nih.gov/contentfiles/lvguidelines/AdultandAdolescentGL.pdf.
Kuhar DT, Henderson DK, Struble KA, et al. Updated US Public Health Service
guidelines for the management of occupational exposures to human
immunodeficiency virus and recommendations for postexposure prophylaxis. Infect
Control Hosp Epidemiol 2013;34(9):875-92. doi: 10.1086/672271.
US Public Health Service. Preexposure prophylaxis for the prevention of HIV
infection in the United States – 2014 Clinical Practice Guideline. Updated May
2014. Available at: http://www.cdc.gov/hiv/pdf/PrEPguidelines2014.pdf
1537
Thank you!
1538
Pneumonia in Hospitalized Patients
41st Intensive Review of Internal Medicine

July 25, 2018
Michael Klompas MD, MPH, FIDSA, FSHEA

Hospital Epidemiologist, Brigham and Women’s Hospital
Professor, Harvard Medical School & Harvard Pilgrim Health Care Institute
Disclosures
o Grant funding from CDC
1539
Outline
o How accurate are clinical signs for pneumonia?

o What kind of imaging should we get?
o Is there a role for procalcitonin?
o What pathogens cause pneumonia?
o Do we need to get cultures?
o Do we need to include atypical coverage?
o Should we add steroids?
o How long should we treat?
Case Study
o A 68 year old woman with a history of congestive heart
failure and mild dementia is admitted to hospital from a
nursing home with confusion. She appears a little bit
tachypneic but denies shortness of breath. She has an
intermittent non-productive cough but it’s not clear
whether this is different from baseline.
o On exam, she is lethargic but easily arousable.
Temperature is 100.0, HR 110, BP 108/64, RR 24, SaO2
90% RA. JVP difficult to visualize. Possible crackles in
the bases. Mild lower extremity edema.
o Labs are notable for WBC count of 10.2, hct 32, plt 240,
Na 130, creatinine 1.4, LFTs normal.
o Urinalysis with 4-6 WBC/hpf
o Portable chest x-ray with edema +/- LLL infiltrate
1540
Does this patient have pneumonia?
1541
Would you start antibiotics?
Why is Pneumonia So Difficult to Diagnose?
o Many medical conditions in hospitalized patients

present with the same clinical signs as
pneumonia
o Radiographic opacities
o Fever
o Abnormal white blood cell count
o Impaired oxygenation
o Increased pulmonary secretions
1542
Accuracy of clinical signs for VAP

Relative to autopsy, systematic review, 14 studies, 655 pts
0.1 0.2 0.5 1 2 5 10
Fever
Abnormal WBC
Purulent sputum
Crepitations
Hypoxemia
New infiltrate
Negative Positive
Likelihood Ratio Likelihood Ratio
JAMA 2007; 297:1583
Accuracy of Clinical Diagnosis of VAP

Relative to 253 autopsies
100% Loose definition:

Positive Predictive Value
Infiltrate and 2 of
80% temp / wbc / purulence
Sensitivity /
60% Strict definition:

Infiltrate and 3 of
40% temp / wbc / purulence
20%
0%
Sensitivity Positive
Predictive
Value
Tejerina et al., J Critical Care 2010;25:62
1543
Would further imaging help?
Chest X-Ray vs CT Scan

319 patients with clinically suspected pneumonia
Initial pneumonia classification following chest x-ray
150
120
No. of Patients
90
60
30
0
Definite Probable Possible
Pneumonia Pneumonia Pneumonia
AJRCCM 2015;192:974-982
1544

Revised pneumonia classification following CT chest
Excluded Possible Probable Definite

150
120
No. of Patients
90
60
30
0
Definite Probable Possible
Pneumonia Pneumonia Pneumonia
AJRCCM 2015;192:974-982

Final Pneumonia Probable

Classification:
Possible
Definite
Excluded
AJRCCM 2015;192:974-982
1545
Intensive Care Med 2016;42:1159-63
Is this pneumonia more likely

bacterial or viral?
1546
Etiology of Community-Acquired Pneumonia

2,259 adults admitted to 5 hospitals in Chicago and Nashville
Viruses
23%
No
pathogen
isolated
62%
Bacteria
11%
Bacteria + Virus 3%
Fungus or AFB 1%
N Engl J Med 2015;373:415-427
Prevalence of Viruses in CAP
Pooled Prevalence
24%
Eur Respir Rev 2016;25:178-88
1547
Could procalcitonin help?
Procalcitonin and Pneumonia Etiology

1,735 adults admitted to 5 U.S. hospitals with pneumonia
100%
No pathogen
isolated
75%
50%
Bacteria
25%
Virus
0%
<0.1 0.1-0.24 0.25-0.49 ≥0.5
Procalcitonin Level
Clin Infect Dis 2017;65:183-90
1548
o Population: 1,656 patients with suspected lower

respiratory tract infection and in whom clinicians
were unsure whether to start antibiotics or not
o Intervention: randomized to procalcitonin &

guidelines on interpretation versus usual care
N Engl J Med 2018;ePub ahead of print
Procalcitonin for ?Pneumonia

1656 patients with possible pneumonia randomized to PCT vs routine care
Antibiotic Starts in the ED Duration of Antibiotics

8
40% NS
6
30%
Days of Antibiotics
Percent of Patients
NS
4
20%
2
10%
0
0%
Usual Care Procalcitonin
N Engl J Med 2018;ePub ahead of print
1549
Should we culture for bacteria

and test for viruses?
Positive cultures will allow you to tailor therapy.
Negative cultures may help facilitate stopping abx early.
Cultures essential to help us track pathogen frequency and

resistance rates.
1550
Rapid Viral PCR Panels
o 720 patients with acute respiratory illness, fever

>37.5C, or both presenting to the emergency
department in the winter
o Randomized to rapid respiratory virus PCR

panel vs usual care
Lancet Repir Med 2017;5:401-11
Rapid Viral PCR Panels

720 patients randomized to rapid viral PCR panels vs usual care
o No difference in antibiotic starts

o No difference in mean duration of antibiotics
But…
o More patients in the viral PCR group received very brief

(<48h) courses of antibiotics (17% vs 9%)
o Length-of-stay shorter in the PCR group
(mean 5.7 vs 6.8 days)
o Appropriate antiviral treatment for flu more common in
the PCR group (91% vs 65%)
Lancet Repir Med 2017;5:401-11
1551
This patient is from a nursing home.

Should we include coverage for
MRSA and Pseudomonas?
Trends in Antimicrobial Use

128 VA Medical Centers, 2006-2010
40%
Percent of Hospitalized Patients
30%
20%
10%
0%
2006 2007 2008 2009 2010
1552
Pathogen Prevalence
128 VA Medical Centers, 2006-2010
5.0%
% of Patients with Positive Cultures
Treatment:
4.0%
Prevalence Ratio
(Blood, Sputum, Lung)
3.0%
50:1
2.0%
1.0%
0.0%
MRSA Pseudomonas Acinetobacter
Would a nasal swab for MRSA help?
1553
Nasal MRSA Culture/PCR
o Can a nasal swab screen MRSA predict the

presence or absence of MRSA pneumonia?
o Meta-analysis of 22 studies, 5163 patients
Sensitivity 85%
Positive predictive value 57%
Negative predictive value 98%
Clinical Infectious Disease 2018;ePub ahead of print
Do we need to include coverage for

atypicals?
1554
βlactam vs βlactam+macrolide vs βlactam+quinolone

Cluster randomized trial of 2,283 non-ICU patients with CAP in the Netherlands
12.0%
NS
NS NS
90-day Mortality
8.0%
4.0%
0.0%
Beta lactam Beta lactam + Beta lactam +
macrolide quinolone
N Engl J Med 2015372:1312-23;
βlactam vs βlactam+macrolide vs βlactam+quinolone

Cluster randomized trial of 2,283 non-ICU patients with CAP in the Netherlands
8.0
Median Hospital Length of Stay
6.0
4.0
2.0
0.0
Beta lactam Beta lactam + Beta lactam +
macrolide quinolone
N Engl J Med 2015372:1312-23;
1555
βlactam alone vs βlactam+macrolide

Randomized controlled trial of 580 patients with CAP in Switzerland
Mild Illness Moderate-Severe Illness
βlactam βlactam + macrolide
JAMA Internal Med 2014;174:1894-1901
Should we add steroids?
1556
Steroids and Mortality

Severe pneumonia
Less severe pneumonia
Combined
Ann Intern Med 2015;163:519-522
1557
Need for Mechanical Ventilation
Risk for ARDS
Ann Intern Med 2015;163:519-522
Length of Stay
Low Risk of Bias
-1.0 days (-1.8 to -0.2)

High Risk of Bias
Ann Intern Med 2015;163:519-522
1558
Hyperglycemia
RR 1.5 (95% CI 1.0-2.2)
Ann Intern Med 2015;163:519-522
How long should we treat for?
1559
8 vs 15 Days Rx for VAP

Double-Blind, Randomized Trial in 51 French ICUs, N=401
8 Days 15 Days
35
Mortality % or No. of Days
NS
30
25
NS
20
15
NS NS
10
0
All Cause Ventilator-Free Organ Failure- ICU Length-of-
Mortality Days Free Days Stay
JAMA 2003;290:2588
Clinical Outcomes in Patients with

Non-Fermenting Gram Negative Bacilli
8 Days 15 Days
35
Mortality % or No. of Days
30
25
20
15
10
0
All Cause Ventilator-Free Organ Failure- ICU Length-of-
Mortality Days Free Days Stay
JAMA 2003;290:2588
1560
Is less than 8 days feasible?
o Randomized controlled trial in 4 hospitals in Spain

o 312 patients with CAP randomized to stopping antibiotics on
day 5 vs usual care (median 10 days)
o Antibiotics stopped if temperature ≤37.8°C for ≥48hrs and ≤1
sign of clinical instability
o SBP<90mm Hg, HR >100/min, RR>24/min, SaO2≤90%, PaO2≤60mm Hg
JAMA Internal Medicine 2016;176:1257-65
1561
5 vs 10 Days for Community Acquired Pneumonia

Randomized controlled trial, 312 patients, 4 hospitals in Spain
5-Day Rx (N=150) 10-Day Rx (N=162)

100%
Percent of Patients
75%
50%
25%
0%
Clinical Success (Day 10) Clinical Success (Day 30)
JAMA Internal Medicine 2016;ePub ahead of print
Is less than 5 days feasible?

Image: www.she.stir.ac.uk/env-carbon-management/challenge.php
WE
1562
o Randomised controlled trial amongst patients admitted to 9 hospitals in

the Netherlands with community acquired pneumonia
o Excluded if immunocompromised, recent hospital or nursing home
admission, recent exposure to systemic antibiotics, PaO2 < 50mm Hg, ICU
admission, empyema, isolation of Staph aureus, Klebsiella sp., or an
atypical organism
3 Days vs 8 Days of Amoxicillin for Patients

Hospitalized with Pneumonia
3-Day Rx (N=56) 8-Day Rx (N=63)

100%
Percent of Patients
75%
50%
25%
0%
Clinical Cure Bacteriological Radiologic
success Success
BMJ 2006;332:1355
1563
Could procalcitonin help?
Procalcitonin Surveillance: SAPS

1575 critically ill patients, open label RCT, 15 ICUs, Netherlands
Procalcitonin (n=761) Control (n=785)

25
20 VAP Subgroup (N=102)

Median Duration of Treatment
15
Procalcitonin Arm: 4.0 days (IQR: 2-7)
Control Arm: 7.0 days (IQR: 4-11)
10
***
5
0
Median Duration ICU of Stay
ICU Length Mortality
Mortality (28-day)
Antibiotics Length-of-Stay (28-day)
Lancet Infect Dis 2016;16:819-827
1564
Summary
o Diagnosing pneumonia is challenging. We’re often wrong.
CT and procalcitonin may help.
o Many (?most) pneumonias are caused by viruses. Test for

them.
o Know your antibiogram. Vancomycin not necessary for most

patients. If you start it, stop at 48hrs if MRSA not isolated.
Routine coverage for atypicals probably not necessary for
most immunocompetent patients with non-severe disease.
o Steroids may confer a mortality benefit in patients with

severe disease
o Short course regimens (3-5 days) usually adequate. Serial

procalcitonin measurements may facilitate short courses.
Question 1
A 54 year old woman is admitted to the ICU with an episode of
pancreatitis. 7 days after admission she develops a new fever, has
increased respiratory secretions, and requires increased ventilator
support. You start empiric treatment with vancomycin and cefepime. An
endotracheal aspirate is culture positive for Pseudomonas aeruginosa.
How long will you treat her?
A. 3 days
B. 7 days
C. 15 days
D. 21 days
1565
Answer 1
A 54 year old woman is admitted to the ICU with an episode of
pancreatitis. 7 days after admission she develops a new fever, has
increased respiratory secretions, and requires increased ventilator
support. You start empiric treatment with vancomycin and cefepime. An
endotracheal aspirate is culture positive for Pseudomonas aeruginosa.
How long will you treat her?
RCT data suggests that while microbiologic

A. 3 days
persistence / recurrence is higher with short
B. 7 days course vs long course therapy, clinical
C. 15 days outcomes are identical. Short course therapy
is therefore preferred even for patients with
D. 21 days
Pseudomonas.
Question 2
64 year old gent with diabetes, rheumatoid arthritis (on prednisone 5mg
po qd), and a remote history of stroke is admitted from an assisted living
facility with fever, cough, and shortness of breath. Temp 37.8, BP 100/64,
HR 90, RR 22, SaO2 90% RA. Chest x-ray is clear. WBC count 10.8.
What tests would you obtain?
A. CT scan chest, procalcitonin, sputum Gram stain & culture

B. Procalcitonin, sputum stain & culture, NP swab for viruses
C. CT scan chest, sputum stain & culture, NP swab for viruses
D. CT chest alone
E. Procalcitonin alone
F. None of the above
1566
Question 2
64 year old gent with diabetes, rheumatoid arthritis (on prednisone 5mg
po qd), and a remote history of stroke is admitted from an assisted living
facility with fever, cough, and shortness of breath. Temp 37.8, BP 100/64,
HR 90, RR 22, SaO2 90% RA. Chest x-ray is clear. WBC count 10.8.
What tests would you obtain?
A. CT scan chest, procalcitonin, sputum Gram stain & culture

B. Procalcitonin, sputum stain & culture, NP swab for viruses
C. CT scan chest, sputum stain & culture, NP swab for viruses
D. CT chest alone
E. Procalcitonin alone 1. CT can both rule in and rule out
pneumonias not seen on CXR
F. None of the above
2. Procalcitonin not helpful for diagnosis in
intermediate probability cases. More useful
for informing duration of therapy
3. Bacteria and viruses are equally common
in CAP – test for them!
Disclosures
o Grant funding from CDC
1567
Thank You!
mklompas@partners.org
1568
Infectious Diseases: Take-Home

Messages and Clinical Pearls
Senior Physician
Division of infectious Disease and Department of Medicine
Disclosures
Bayer: Chagas disease advisory committee
1569
Infections and immunodeficiency

Organism Humoral Complement Phagocyte Cellular
Bacteria Pneumococcus, Meningococcus S. aureus, Salmonella,

meningococcus, (terminal enterics, P. Listeria.
H. influenzae components) aeruginosa, Legionella
Viruses Enterovirus - - Herpesviruses
Hepatitis B,C
Fungi - - Candida, Cryptococcus,
Aspergillus, endemic fungi,
Mucor Candida,
Pneumocystis
Mycobacteria - - - TB, atypicals
Protozoa Giardia - - Toxoplasma,
Cryptosporidium,
T. cruzi,
Leishmania
Helminths - - - Strongyloides
Opportunistic infections in HIV

• Previously undiagnosed HIV, not taking
antiretroviral therapy (ART) for financial,
psychosocial or medical reasons
• Recently started on (effective) ART
(immune reconstitution inflammatory
syndrome (IRIS)
• Exceedingly rare in longstanding well-
controlled HIV infection
1570
Fever in HIV
• Unrelated to HIV; drug fever
• Acute HIV
• CD4 200-500: pneumococcal infection,
other respiratory infections, tuberculosis,
lymphoma (“ARC”-zoster, thrush)
• CD4 <200: PCP, toxoplasmosis, endemic
fungi, cryptocococcosis
• CD4 <50: M. avium complex, CMV
• IRIS
Immune reconstitution
inflammatory syndrome (IRIS)
• Recommend initiation of ART within 2
weeks of diagnosis of opportunistic
infection (exception=CNS infections)
• IRIS: paradoxical worsening of infection or
disease process following initiation of
effective ART and restoration of immune
response
• Most common with mycobacterial, viral
and fungal infections; incidence 10-20%
1571
Immune reconstitution
inflammatory syndrome (IRIS)
• Fever, adenopathy common; localized
symptoms and signs
• Usually occurs within a week to a few
months after starting ART
• Continue ART and directed therapy for
opportunistic infection in most cases
• NSAIDS, steroids
http://aidsinfo.nih.gov/contentfiles/lvguidelines/adult_oi.pdf (2018)
Expert Rev Anti Infect Therapy 2015,13:751
Infections and immunodeficiency

• Neutrophils
– Decreased numbers
– Impaired function
• Neutropenia
– Cytotoxic chemotherapy, drug
hypersensitivity, marrow disorders, other
– Severe: ANC <500; profound <100
– Signs of infection often masked
– Infections can progress rapidly, life-
threatening
1572
Neutropenia and infections

• Common pathogens
– Gram-negative enterics (E. coli, Klebsiella,
Enterobacter) > Pseudomonas aeruginosa
– Gram-positive organisms (intravascular
catheters): S. aureus, coagulase-negative
staphylococci, enterococci
– Fungi (prolonged neutropenia, antibiotics):
Candida spp., Aspergillus, Zygomycetes
Neutropenia and infections

• High risk patients-empirical therapy:
– Antipseudomonal β-lactam (cefepime, others)
– Vancomycin – only when indicated
– Prolonged fever : echinocandin (e,g.,
micafungin)
• Low risk: oral therapy (e.g., amoxicllin-
clavulanate/ciprofloxacin; moxifloxacin)
Clin Infect Dis. 2011;52(4):e56.
1573
Impaired neutrophil function

• Genetic: Chronic granulomatous disease,
hyper-IgE (Job) syndrome, others
• Acquired: steroids, diabetes
• Infections in diabetics
– Impaired phagocytes
– Vascular insufficiency
– Neuropathy
– Colonization (S. aureus, Candida)
(Impaired cellular immunity (TB, Coccidioides))
Infections in diabetics
• S. aureus-skin and soft tissue, pneumonia,
bacteremia
• Pseudomonas aeruginosa: malignant otitis
externa
• Rhinocerebral mucormycosis (acidosis)
• Candidiasis: cutaneous, mucosal, urinary
• Enteric organisms: UTIs, emphysematous
cystitis/pyelonephritis, papillary necrosis
• Diabetic foot infections
• Necrotizing soft tissue infections
1574
Skin and soft tissue infections

• Erysipelas (superficial): β-hemolytic
streptococci>Staphylococcus aureus
• Cellulitis: β-streptococci, S. aureus
• Necrosis, purulence, abscess: S. aureus,
especially MRSA
• Recurrent cellulitis (β-streptococci)
• Lymphedema
• Strategy: edema control, antifungals,
foot care, prophylactic penicillin
Skin and soft tissue infections:

special cases
Dog/cat bites Pasteurella multocida,

Capnocytophaga canimorsus
Saltwater Vibrio vulnificus
Freshwater Aeromonas, Pseudomonas
Hot tubs Pseudomonas
Human bites Skin and mouth flora
Fish, raw meat,
poultry Erysipelothrix rhusiopathiae
1575
Treatment of MRSA skin and soft

tissue infections
• Incision and drainage
• Oral antibiotics
– TMP-SMX
– Doxycycline }
Not uniformly active
against streptococci
– Clindamycin if susceptible
– Linezolid
• Intravenous antibiotics: vancomycin,
daptomycin, ceftaroline, linezolid
• Attempt decolonization for recurrences
Necrotizing soft tissue infections

• Necrotizing fasciitis
– Group A β-hemolytic streptococci
– Polymicrobial including anaerobes
– Marine Vibrios, Aeromonas, rare MRSA
• Clostridium perfringens necrotizing
cellulitis, myonecrosis
• Pain → erythema, edema → necrosis
• Treatment: antibiotics, surgical
debridement, supportive therapy
1576
Toxic shock syndromes

• S. aureus: menstrual, non-menstrual
• Group A streptococci: skin, soft tissue
infections, other
• Exotoxin, super-antigen
• Hypotension, diffuse erythematous rash, end
organ failure
• Treatment
• Clindamycin plus beta-lactam antibiotic or
vancomycin +/-IVIG
• Source control: remove foreign body, surgery
• Supportive care
Respiratory infections
• 22 year old: 6 day history sore throat,
difficulty swallowing admitted to ICU with
fever, shortness of breath, hypotension,
leukocytosis with left shift , ↑creatinine
• CXR/CT of chest: nodular opacities, effusion
• CT of neck: paratonsillar abscess,
thrombosis of right internal jugular vein
• Cultures: Fusobacterium necrophorum
• Diagnosis: Lemierre syndrome
• Pressors, surgery, antibiotics, anticoagulation
1577
Ann Int Med 2015;162:2412
• Young adults with pharyngitis

– 21% Fusobacterium necrophorum
– 10% group A streptococcus
• Fusobacterium is resistant to macrolides
• Recommend: treat severe sore throat (3 or
4 of following: fever, no cough, tender
anterior nodes, tonsillar exudate) with
penicillin not azithromycin
Extrapulmonic tuberculosis
• Seen in 50% or more of patients with HIV/TB
coinfection but also in not HIV-infected
• Clues
– Sterile pyuria
– Chronic lymphadenopathy (especially cervical)
– Monarthritis, spinal osteomyelitis (esp thoracic)
– Lymphocytic predominant ascites
– Chronic lymphocytic meningitis
– Exudative pleural effusion
– Pericarditis
1578
Nontuberculous mycobacterial infection

• Acquired from environment
• Immune compromised; immune competent
often with risk factor (lung disease, trauma,
surgery)
• Sensitivity testing helpful, but not always
predictive of response
• Treatment: combination therapy, prolonged,
may require surgery
Nontuberculous mycobacterial infection

Disseminated (esp. M. avium-intracellulare (MAC)
HIV) M. kansasii
Pulmonary MAC
M. kansasii
M. abscessus
Skin and soft tissue M. marinum
M. abscessus, fortuitum, chelonae
Catheter-associated M. abscessus, fortuitum, chelonae
Cervical lymphadenitis MAC, M. scrofulaceum
Leprosy M. leprae
Buruli ulcer M. ulcerans
1579
Fungal infections of the lungs

• “Endemic” mycoses (dimorphic fungi)
– Histoplasmosis: river valleys, guano in soil
– Coccidioidomycosis: SW USA, Latin America
– Blastomycosis: USA (south, south central)
– South American blastomycosis (CA, SA)
– Sporotrichosis (sphagnum moss, thorns)
– Penicilliosis [talaromycosis] (China, SE Asia)
• Cryptococcosis (soil contaminated with bird
droppings)
Tick-borne infections in the USA

Bacteria • Relapsing fever
• Borrelia burgdorferi Borrelia
• Anaplasma • Borrelia miyamotoi
phagocytophilum Viruses
• Ehrlichia chafeensis • Colorado Tick Fever
• Rickettsia rickettsii • Powassan virus
• Rickettsia 364D, • Heartland virus
others • Bourbon virus
• STARI Protozoa
• Francisella tularensis • Babesia spp
1580
Lyme disease CDC
• Suspect in persons with possible exposure

• Most do not report tick bite
• Early Lyme disease
– Diagnose clinically (serology often negative)
– Erythema chronicum migrans
– Fever, myalgia, Bell’s palsy, meningitis,
heart block, arthralgia
• Late Lyme disease: arthritis, neurological
(encephalitis, neuropathy, radiculitis)
Lyme disease
• Diagnosis: screening ELISA, confirmatory
Western blot
• Treatment
– Oral doxycycline, amoxicillin or cefuroxime
– Intravenous ceftriaxone: certain syndromes
– Treatment > 28 days not indicated for
chronic Lyme
– No antibiotics for post-Lyme syndrome
• Prophylaxis for attached tick in Lyme-
endemic area: doxycycline 200 mg PO x1
1581
Ticks may carry and transmit transmit multiple

pathogens to same host (e.g., Ixodes scapularis
(Lyme, anaplasmosis, babesiosis, Powassan
virus, Borrelia miyamotoi)
Distribution of tick-borne infections (CDC)
Clinical approach to tick-borne infections

• Tick-borne infections can be rapidly fatal
(e.g., Rocky Mountain Spotted Fever)
• Unexplained fever, chills, headache, fatigue,
myalgia, arthralgia, rash, neurologic
symptoms
• Consider place, season,
activities, pets
• Rapid diagnostic testing
often not available
• Early, empirical treatment CDC.gov
can be life-saving (doxycycline)
1582
Salmonella bacteremia
• Typhoid and other enteric fevers
• Transient bacteremia with gastroenteritis
• Endovascular infections
– Atherosclerosis-aneurysms
– Heart valves, especially prosthetic
– Schistosomiasis
• Persistent infection, localized infections:
immune deficiency: AIDS, transplant, etc
• Usually do not treat salmonella gastroenteritis
unless at risk of localized or persistent
infection
Typhoid
• Risk in South Asia 6 to 30 times higher than
East and Southeast Asia, Africa, the
Caribbean, and Central and South America
• Increasing antibiotic resistance
• Oral live attenuated Ty21a vaccine: 1
capsule orally q 48 hrs x4; boost every 5
years
• Vi capsular polysaccharide vaccine:
intramuscular injection every 2 years
• Protection: 50-80%; not paratyphoid fever
1583
Vaccinations for travel

Routine adult immunization, plus:
Cholera Plague
Hepatitis A Meningococcal
Hepatitis B Rabies
Inactivated polio Typhoid
Japanese Yellow Fever
encephalitis Tick-borne
Influenza encephalitis
Yellow fever vaccine

• Travel to endemic areas or requiring proof of
vaccination for entry to country
• Contraindications: hypersensitivity to egg or
chicken proteins, immune suppression, age
under 9 months
• Precautions (weigh risks and benefits): age >
60 years, asymptomatic HIV infection,
pregnancy, breastfeeding
• Vaccinate at least 10 days before travel; WHO:
no need to revaccinate after 2016: but every
10 years, if required for entry, special cases
1584
Areas with Risk of

Yellow Fever Virus
Transmission
CDC.gov
Yellow Fever Vaccine Outbreak of Yellow Fever

in Brazil
shortage mid-2017 to 2016 – present
mid- 2018: consult CDC
(cdc.gov/travel/page/search-for-
stamaril-clinics)
CDC.gov
1585
Wild poliovirus & cVDPV cases, 2018

01 January – 22 June
Inactivated poliomyelitis
vaccine:
All travelers to endemic or
epidemic areas, including
Wild poliovirus type 1 (N=11)
those with recent wild virus
cVDPV1 (N=14)
Reintroduction of wild type

circulation and neighboring
virus in Venezuela not
confirmed
countries
• Booster if received
primary series
http://www.polioeradication.org/Dataand monitoring.aspx
1586
Sexually Transmitted Diseases

Update 2018
Todd B Ellerin, MD
Director of Infectious Diseases
South Shore Hospital
tellerin@southshorehealth.org
Disclosure
None
1587
What’s New
More than 2 million cases of chlamydia,
gonorrhea, and syphilis were reported in the US
in 2016, the highest number ever
Majority of these (1.6 million) were Chlamydia
470,000 cases of GC and 28,000 cases of
primary and secondary syphilis
CDC. Sexually Transmitted Disease Surveillance 20016
Case 1
24 yo black male HIV+ diagnosed in 2000, last

CD4 count 380 cells/mm3 and VL of 50K
copies/ml. Lost to follow up for 5 years. No ARV
therapy.
H/o gonorrhea and genital herpes-type 2
(treated episodically approx 2 outbreaks/yr).
Presents with dysuria, painful ulcers surrounding
his edematous penile foreskin, and blood at the
tip of his urethral meatus.
1588
Case 1
Previous herpetic outbreaks had been unilateral,

small vesicles on the foreskin which crusted
over in days.
Last herpetic outbreak several years ago.
HIV acquired through unprotected heterosexual
intercourse.
Last protected sexual intercourse was 4 days
prior with his girlfriend.
No recent unprotected intercourse.
1589
What’s the most likely cause of

these painful ulcers?
A) Syphilis with bacterial superinfection
B) Chancroid
C) Genital herpes in the setting of declining cell-
mediated immunity
D) Lymphogranuloma venereum (LGV)
E) Gonorrhea
Viral culture + HSV-2

CD4 count 100 cells/mm3
1590
STD Treatment Guidelines 2015
https://www.cdc.gov/std/tg2015/tg-2015-print.pdf
Genital HSV - Epidemiology

At least 50 million persons, 12 and older, in the US are
infected with HSV-2
HSV-2 is more common in women (~25%) than men
Most (as many as 90%) of HSV-2-infected individuals are
undiagnosed and unaware of their infection; those
periodically shed virus in their genital tract (2-28% of
days)
Most transmission is from asymptomatic carriers
5-50% of clinical genital HSV is caused by HSV-1;
Recurrence and asymptomatic shedding are more
common with genital HSV-2
1591
Type-Specific HSV-2 serology
Testing for antibodies directed against HSV type-

specific glycoproteins (GP-G1 & G2 for HSV 1 or 2)
Sensitivity 80-98%, Specificity > 96%
Point-of-care tests are available
Evolving role in clinical practice: assessment of
partners, diagnosis of culture-negative ulcers, STD
screen, identification of asymptomatic carriers,
vaccine candidates
Limitations: lag after initial exposure, a positive test
only indicates previous exposure
Genital HSV Prevention
1592
Antiviral Therapy for Prevention of HSV-2

Transmission
Prospective placebo-controlled study of heterosexual HSV-

2 sero-discordant couples
HSV-2 positive partner given valacyclovir 500 mg daily or
placebo
HSV-2 susceptible partners assessed monthly
Condoms and safe sex counseling provided at all visits
After 8 months of therapy Symptomatic HSV-2 transmission
was reduced by 77%, and asymptomatic acquisition by
50%
Valacyclovir is now FDA approved for this indication
Characteristics of common ulcerative

diseases
HSV Syphilis Chancroid
Ulcer Painful, often Painless Painful,

many, papules purulent,
irregular, deep
LN Rare except Small 1-2 weeks later
primary infxn
Comments COMMON Must test for Unusual in US

and treat
1593
Characteristics of less common ulcerative

diseases
LGV Donovanosis
Ulcer Small, painless, Large,

heal before LAD irregular,
bleeding
LN Large, draining None,
nodes hypertrophied
tissue
Comments Rare in US, Rare in US

except MSM
Evaluation of the Patient with Genital Ulcer

A diagnosis based on history/physical is often inaccurate
Obtain a serologic test for syphilis
If serology negative, repeat at 1 & 3 months
Culture (or antigen test) for herpes simplex
HSV PCR more sensitive than culture
In endemic areas or during outbreak: GS/Culture of edge
of ulcer for H. ducreyi (53-88% sensitive)
MSM and endemic areas: serology for LGV and
Chlamydia PCR / NAAT
Consider empiric therapy based on most likely
diagnosis
1594
Case 3: Penile Funk
1595
1596
Syphilis Fast Facts

Painless ulcer, think syphilis, test and treat empirically
Rash involves palms and soles, think syphilis, test,
and treat empirically
Early syphilis (primary/secondary) treat all sex
partners with past 90 days and sex partners after 90
days can be tested
Follow pts to make sure RPR has fallen at least 4 fold
Screening withy RPRs leads to false +’s so +RPRs
need to be confirmed by treponemal test
Screening with specific Treponemal test avoids false + RPR
but introduces scenario +Treponemal test with negative RPR
1597
Syphilis Serology Sensitivities
Test Stage
0
1 20 30
VDRL 70% 99% 56%

RPR 80% 99% 56%
FTA-abs 85% 100% 98%

MHA-TP/TPHA 65% 100% 95%
TPI 50% 97% 95%
Syphilitis Condylomata Lata, female
1598
The Prozone reaction

False Negative Syphilis Screening Tests
The RPR testing methodology uses charcoal particles,
added to a cardiolipin Ag suspension
A test is positive when an optimal Ab:Ag ratio creates a
precipitate (lattice, also referred to as the zone of
equivalence). Charcoal is trapped in this lattice and
allows the reaction to be visible macroscopically
Antibody excess (prozone) or antigen excess
(postzone) will yield false negative test results because
they do not form the lattice needed to trap the charcoal
particles
Neurosyphilis
May occur during any stage Indication for CSF Analysis
Symptoms: asymptomatic, Neurologic or ophthalmic/otic
meningitis, cranial nerve signs/sx
palsies, general paresis, tabes Active tertiary disease
dorsalis, meningovascualr
disease, auditory symptoms, Treatment failure
optic neuritis, cognitive Controversial: HIV infection
dysfunction,
CSF-VDRL is specific but Controversial: nontreponemal
insensitive titer of >1:32
Elevated CSF protein and ‘CSF should be followed after
WBC (>4/mL) is supportive but treatment until normal (6m, 2y)
non-specific; When in doubt consider
>20cells/mL may be more empiric therapy
specific in HIV-infected
1599
Syphilis
Follow Response to Treatment
Re-examine clinically and follow non-treponemal test

titer (RPR, VDRL)
Goal: sustained ≥ 4-fold decrease in titer and
symptom resolution
Testing intervals:
Primary/secondary syphilis: 6 and 12 months
Late syphilis: 6, 12, 18, and 24 months
HIV-infection: 3,6,9,12, and 24 months (most
respond to therapy)
Syphilis
Treatment Failure
Definition of treatment failure:
Signs/symptoms persist
Failed to achieve 4-fold decrease in titer within 6-12
months
Sustained 4-fold increase in titer (e.g. 1:8 1:32; repeat
1:32)
Management of treatment failure:
HIV test (should have been done at diagnosis)
CSF analysis
If CSF normal administer benzathine pcn weekly x 3 wks
If titers don’t decline after repeat therapy (re-infection not
suspected and the CSF examination is normal) no
additional therapy indicated
1600
Case 4: 34 y.o. male with fever, rash,

headache
Well until 7 days prior, when he developed sore

throat, anorexia, diarrhea; + non-pruritic rash
PE: Ill-appearing. T = 103.4. Oroph with ulcer left
tonsil. Mild generalized lymphadenopathy. Diffuse
maculopapular exanthem over body, greatest on
neck, back, trunk, and arms.
LAB: WBC 5.1 (53 P, 11 B, 28 L, 8 M, 0 Atyp), PLT =
125; ALT 88, remainder of labs normal
1601
34-y.o. male with fever, rash:

Evaluation
Throat culture no beta strep; blood
cultures heterophile, RPR neg;
CMV IgG pos, IgM neg; hep A, B:
no evidence acute infection.
HIV antigen/antibody negative
1602
What’s the most likely diagnosis?

A) Syphilis
B) Epstein-Barr Virus
C) Acute HIV
D) Primary HSV gingivostomatitis
HIV Viral Load >750,000 copies/ml
1603
27 yo male with tender swelling in left groin,

multiple sex partners
Lymphogranuloma Venereum
Primary lesions (3-30d incubation): papule of small ulcer,
Indistinct from HSV or syphilis, often painless
Secondary stage (2-6w)
Anogenitorectal: proctitis (purulent, mucous, bloody)
Inguinal: buboes, cellulitis, periadnitis, dissemination
Long-term complications: chronic ulceration, fistulae,
strictures, genital elephantiasis
Diagnosis
Culture: positive in <30% of cases
Nucleic acid testing: may be positive in early stages,
not FDA approved, and requires lab validation
Serology: complement fixation (CF ≥ 1:64) or
microimmunofluorescence (MIF ≥1:128)
1604
Clinical Manifestations of LGV
Weir. CMAJ 2005;

172:185
Primary Lesion
LGV
Complications
Anal Stricture
Williams et al. BMJ, 2006; 332:99-100
1605
LGV Therapy
Treat suspected cases, as diagnosis is challenging

Treatment:
doxycycline, 100 mg BID x21 days
alternative: azithromycin 1g/week x 3 weeks
Asymptomatic sex partners:
doxycycline 100 mg bid x 7 days
azithromycin 1g x1
Non-Ulcerative Sexually Transmitted

Diseases
1606
Clinical Manifestations of Gonorrhea
• Urethritis (men or women)

• Epididymitis
• Cervicitis
• PID
• Proctitis
• Pharyngitis
• Disseminated infection (DGI) (complement
deficiency, women> men, tenosynovitis, dermatitis)
• Conjunctivitis
• Rare: meningitis, hepatitis, endocarditis
Images: CDC
Diagnosing Gonorrhea
• Gram stains: 95-100% sensitive 98%
specific in male urethritis; o/w low
sensitivity
• Culture: for sites not approved for NAAT
(rectal, pharyngeal) or if susceptibility
testing required). 35-370c, 3-5% co2,
Thayer-Martin
• Nucleic acid amplification tests (NAATs)
approved for vaginal, endocervical,
urethral, & urine specimen; 97-99%
sensitive and 99% specific for cervical &
urethral swabs. Some labs validated for
oral and rectal; not FDA cleared
1607
Use of FQ is NOT
recommended unless
susceptibility results available
Antimicrobial susceptibility
results only available with
culture tests
Perform culture & susceptibility if
GC infection persists or recurs
Most common cause is re-
infection
True Rx failures or resistant GC
isolates should be reported
Treatment of Gonorrhea
IM ceftriaxone (250 mg) plus either doxy 100 mg po bid x 7d or azithromycin 1g po x1
is the treatment of choice
PO cefixime 400 mg is alternative if Ceftriaxone not available plus add doxy x 7d or
azithro 1g po x1 plus test of cure in 1 week; cefuroxime not adequate
True beta-lactam allergy:
Azithromycin 2 g po x1 dose (some resistance reported), testof cure in 1 week
Gemifloxacin 320 mg po x1 plus azithro 2g po x1 (2014 draft guidelines)
Gentamicin 240 mg IM x1 plus azithromycin 2 g po x1 (2014 draft guidelines)
Recent shift towards higher ceftriaxone MICs hence 250mg dose
Higher dose for DGI
Rescreen at 3m or within 12m (NOT A TEST OF CURE)
MMWR August 10, 2012 / 61(31);590-594
1608
Epidemiology of Chlamydia
trachomatis (serotypes D-K)
Most frequently reported infectious disease in

the US
At least 75% of women and 50% of men have
no symptoms
Rapid diagnostic tests allow for easier office
testing
Screening for Chlamydia

trachomatis
Up to 40% of women with untreated chlamydia will
develop PID. Of those with PID:
20% will become infertile
18% will experience chronic pelvic pain
9% will have a tubal pregnancy
Two CDC asymptomatic screening studies have resulted
in decline in overall infection rates
Chlamydia screening followed by treatment not only
reduced the prevalence of lower genital tract infection,
but also complication rates and cost
1609
Screening for Chlamydia trachomatis

Screening for Women:
<25 yrs screen annually
>24 screen at least once a year if at risk:
inconsistent use of barrier method
new or more than one partner in last 3 months
other STD
Screening for Men: no routine screening. May be
considered in high risk setting (adolescent and STD
clinics, correctional facilities)
Chlamydia
Rescreening and test-of-cure
CDC guidelines: rescreen all women with
Chlamydia infection 3-4 months after
treatment or when they next present for care
Rescreening is distinct from early retesting to
detect therapeutic failure (test-of-cure)
Except in pregnant women, test-of-cure is not
recommended unless therapeutic compliance
is in question
1610
Screening Guidelines for MSM*
HIV test if not done in the past year

Syphilis serology with confirmatory testing
Urethral or urinary GC and Chlamydia (if insertive)
Rectal GC and Chlamydia (NAAT preferred, if
receptive)
Pharyngeal GC (NAAT preferred, if receptive oral)
Consider serologic evaluation for HSV-2
HBsAg
HCV if also using drugs (receptive anal? not in
guidelines)
Vaccines for HAV and HBV
Screen q3-6m if multiple anonymous partners
*sexually active
What’s New with 2015 STD Guidelines

Mycoplasma genitalium causes 15-20% of male
NGU and 30% of recurrent persistent urethritis
Pathogenic role in females less clear given
majority asymptomatic but seen in 10-30% of
female clinical cervicitis
Use Azithromycin. Doxy ineffective.
Moxifloxacin 400 mg po daily x 7-14d
Trichomonas vaginalis + test in female rescreen
after 3 months. NAAT testing more sensitive than
wet mount
1611
What’s New with 2015 STD Guidelines

Annual HCV testing for HIV+ patients
Pts diagnosed and treated for urethritis
should abstain from sex for 7d after treatment
(of patient and partner) and be retested at 3
months to detect repeat infection
HPV9 vaccine recommended for girls ages 9-
26 (ideally given age 11-12) and boys 9-21
(ideal 11-12) and up to 26 years in MSM and
immunocompromised men
Question 1
A pregnant woman is referred for a lab finding
of an RPR titer of 1:8 and a positive FTA
during her first prenatal visit. She reports no
h/o syphilis, and is asymptomatic. She reports
an allergy to beta-lactam antibiotics (hives
during a course each of of amoxicillin and
cephalexin). What is the most appropriate
treatment?
1612
What is the most appropriate treatment?
a. This is a false positive test due to pregnancy,

no treatment recommended
b. Doxycycline 100 mg orally bid, for 14 days
c. Doxycylcine 100 mg orally bid, for 28 days
d. Azithromycin 2g in a single dose
e. Desensitization, and treatment with penicillin
a. This is a false positive test due to pregnancy,

no treatment recommended
b. Doxycycline 100 mg orally bid, for 14 days
c. Doxycylcine 100 mg orally bid, for 28 days
d. Azithromycin 2g in a single dose
e. Desensitization, and treatment with penicillin
1613
Syphilis in Pregnancy
Screen in first prenatal visit
Screen high risk mothers again around 28 weeks
and at delivery
Treat for appropriate stage of syphilis (although
some expert endorse additional doses for early
syphilis)
Treat with penicillin, even if desensitization
required
Repeat RPR titer at 3 months
Question 2
A 57 y/o MSM with allergies to beta-lactams and

azithromycin is seen for a penile discharge and
dysuria. NAAT is positive for both GC and
Chlamydia. He receives a dose of ciprofloxacin
(500mg) and a one week treatment course of
doxycyline. He returns to urgent care at the end of
the treatment course reporting no improvement. A
probe is repeated and is again positive for both
organisms.
Which of the following statements is incorrect?
1614
Question 2
Which of these statements is incorrect?
a. Re-infection is a common cause of relapsed

symptoms
b. One week is too early for a test of cure (repeat
probes)
c. FQ-resistant gonorrhea should be suspected and
culture and sensitivities are recommended
d. FQ-resistant Chlamydia should be suspected, culture
is recommended, and azithromycin should be
prescribed
Question 2
Which of these statements is incorrect?
Correct answer (incorrect statement) is d
a. Re-infection is a common cause of relapsed

symptoms
b. One week is too early for a test of cure (repeat
probes)
c. FQ-resistant gonorrhea should be suspected and
culture and sensitivities are recommended
d. FQ-resistant Chlamydia should be suspected,
azithromycin should be prescribed
1615
References
CDC. Sexually transmitted diseases treatment
guidelines, 2015. MMWR 2015;64 No.3
Up to Date in Medicine: Screening for STD’s (last
update May 2017)
1616
Infectious Diseases Board

Review
Todd Ellerin, MD
Infectious Diseases
South Shore Hospital
todd_ellerin_md@sshosp.org
Disclosures
• NONE
1617
HSV-1 encephalitis; Treatment with high dose IV

acyclovir
50 yo female with 5 days of fevers, increasing confusion, and

personality changes. LP with 350 WBCs (90% lymphocytes),
glucose normal, CSF gram stain and cultures negative
Fish tank granuloma with nodular lymphangitis d/t

Mycobacterium marinum
55 yo male no sig PMHx slammed his hand in a drawer and

developed this nodular rash a couple of weeks later. Not a
gardener. Has 2 pets named sushi and bubbles. What’s the dx?
1,2
1618
Unexplained seizure
• 36 yo male from Brazil lives near Boston
h/o 1 seizure 20 years before had a 2nd
witnessed seizure.
• Felt well before seizure
• No additional medical hx, no ETOH, no
illicit meds, HIV negative
• Labs normal
1619
What’s most likely dx

• A) Tuberculous meningitis
• B) Calcified meningioma
• C) Neuroschistosomiasis
• D) Cryptococcoma in immunocompetent pt
• E) Neurocysticercosis
1620
• A) Tuberculous meningitis
• B) Calcified meningioma
• C) Neuroschistosomiasis
• D) Cryptococcoma in immunocompetent pt
• E) Neurocysticercosis
1621
1622
Crusted (Norwegian) Scabies
What’s the diagnosis and the fastest

way to make the diagnosis? What’s the
treatment?
1623
Crusted (Norwegian) Scabies

• Skin scraping looking for mites/eggs
• Given high burden of mite infestation hundreds
to thousands of mites as opped to 5-15 in
typical cases, treatment:
– ●Topical 5% permethrin or topical 5% benzoyl
benzoate applied daily for seven days, then twice
weekly until cure
• AND
– ●Oral ivermectin (200 mcg/kg/dose) given on days
1, 2, 8, 9, and 15
1624
Name 3 first line therapies for

cystitis in a woman of child
bearing age
• A) Amoxicillin
• B) Levofloxacin
• C) Nitrofurantoin
• D) Fosfomycin
• E) Trimethoprim/Sulfamethoxazole
1625
• A) Amoxicillin
• B) Levofloxacin
• C) Nitrofurantoin 100 mg po bid x 5d
• D) Fosfomycin 3g mixed in 4 oz water po
x1
• E) Trimethoprim/Sulfamethoxazole DS
po bid (as long as community sulfa-
resistant E coli <20%)
Enterovirus (Aseptic) meningitis
•34 yo school teacher develops 3-4 days of worsening

HA, stiff neck, and mild photophobia after only being
back to school for 2 weeks after summer break.
No confusion
•No PMHx
•LP reveals 120 WBCs, 90% lymphocytes,
protein 60 mg/dl, glucose normal
What’s the most likely dx?
1626
Hand Foot and Mouth Disease
•What illness is spreading around the school?
CMV infectious mononucleosis; 10% atypical

lymphocytes
40 yo male develops 3 weeks of unexplained fevers,

sweats, and 10 pound weight loss. Mild pharyngitis early
on that he forgot about. Exam nl x spleen tip.
WBC count 3K with 50% polys and 40% lymphocytes
on diff. HCT nl. PLTs 120K. LFTs elevated
AST 260, ALT 400, TB 2.5, and AP 290.
Monospot negative. What’s the most likely dx?
1627
1628
Sporotrichosis and either oral Itraconazole solution or

Fluconazole
51 yo female gardener who was making wreaths from boxwood

prior to Christmas and also works with sphagnum moss
Likely injured fingers but doesn’t recall specific trauma
Biopsy of finger revealed acute and chronic inflammation, loosely
formed granulomas, and numerous oval shaped yeast forms
What’s the likely dx and what’s the treatment
1629
1630
Ferritin 6K; Adult-onset Still’s disease; Important ID

principle the longer a patient has bonafide fevers without
a diagnosis, the less likely the dx is infectious (e.g fevers
beyond 6 months rarely infectious!)
55 yo male architect designs marinas reports 9 months
of periodic fevers ranging from 100-103F. Fevers and
polyarthralgias every few weeks. Duration several
days. Intermittent truncal rash and periodic pharyngitis.
Ankles swelled recently. No oral/genital ulcers
No diarrhea or red eye. WBC count 18K (90% polys)
ESR 100. Blood and pharyngeal cxs off abxs all
negative. HIV negative, blood smear for parasites,
ANA, RF, ANCA all negative. What is a key test to
help with diagnosis?
• 45 yo female from Wisconsin notes 10 days of

worsening HA and mild neck stiffness w/o photophobia
• No fevers and no sick contacts
• USOH until 4 weeks ago when she had a left
popliteal fossa cellulitis treated with cephalexin which
led to resolution in less than 1 week
achier than usual but attributes it to workouts
1631
Lyme meningitis; Ceftriaxone 2g IV q24h x 2-4 weeks
CSF Results
• 100 WBCs (80% lymphs)

• Protein=60 mg/dl
• Glucose= normal
• CSF gram stain negative
• CSF culture negative
• What’s the diagnosis and treatment?
1632
Parvovirus B19; adults get the lacy rash more than

slapped cheek; usually self-limited polyarthritis of small
joints. Need to make sure she is not pregnant given
potential pregnancy complications; +Lyme IgM false +
28 yo school teacher
develops febrile illness a/w HA and mild diarrhea
and after 8 days develops a rash on her lower extremities.
Her rash fades but she develops swelling in both hands
which persists after 5 weeks.
Her Lyme screen is reactive and her IgM western blot is +
What is the most like dx and what are complications?
Plasmodium falciparum malaria; coArtem (artemether

20mg/lumefantrine 120 mg) time 0, 8 hrs later, then bid x 2d (6
doses total) or malarone (atovaquone 250 mg/proguanil 100 mg) 4
tabs po daily x 3d (assuming no malarone prophylaxis)
40 yo male from Kenya living in Boston returns to Kenya

for 1 month visiting friend and family. He spends a lot of
time outdoors. 2 weeks after returning home he develops
fevers, chills, aches and malaise. No abdominal pain
or diarrhea. No rash. Exam shows moderately ill
appearing male with normal physical exam. Labs
notable for thrombocytopenia (70K) and mild elevation in
transaminases (AST 80, ALT 90). If you only had
1 diagnostic test what would you send and what’s
treatment of choice?
1633
TMP-SMX is the only antibiotic that lacks anaerobic

activity
Which antibiotic does not belong?
Clindamycin
Imipenem
Trimethoprim/Sulfamethoxazole
Piperacillin/Tazobactam
Cefoxitin
1634
•20 yo male previously healthy p/w 2 wks fevers, HA, increasing

neck stiffness, and double vision. Immigrated from India 9
months ago, lives in Austin,TX visiting family in Massachusetts.
Given BCG as child
•No sick contacts, exposure to animals/birds, recent travel,
monogamous with wife, business consultant
•Exam reveals temps (99-101F) and b/l CN 6th palsies
•Labs normal except Na 127
•Head CT w/o contrast normal

•Lumbar puncture:
– 775 WBCs/mm3 (56% lymphocytes, 37% polys)
– Protein 169 mg/dl
– Glucose 19 mg/dl
– OP elevated 280 mm water (nl<200)
1635
1636
Results
• Bacterial cultures negative
• CSF cryptococcal antigen negative
• CSF fungal cultures negative
• CSF VDRL negative
• CSF HSV PCR
• CSF Tb PCR negative
• CSF AFB cultures negative x 4 wks
• CSF cytology normal
• HIV antibody negative
1637
Results
• Bronchoscopy revealed negative AFB
smears and fungal cultures
• Mediastinoscopy revealed non-necrotizing
granulomas and fibrosis with special stains
negative for AFB and fungi. No malignancy
• TB PCR on lymph node negative
TB meningitis; TB PCR of CSF low sensitivity and CSF

AFB culture may take 6 weeks to grow
1638
1639
What’s the dx and cause?
Oral Hairy Leukoplakia

EBV
What’s more important than that?
HIV+
1640
Rash and periorbital HA after

travel?
• 30 yo female traveled to Brazil 3 mos
before
• Traveled to St. John island 10d before and
spent 5d there and felt well
• 2d after returning home developed HA at
her eyes, mild sore throat, itchy rash starting
on her face and spreading down her chest
and abdomen. No aches. No red eye
• Labs normal x WBC count 4K
1641
1642

• A) Measles
• B) Dengue
• C) Chikungunya
• D) Zika
1643
• A) Measles
• B) Dengue
• C) Chikungunya
• D) Zika
1644
Stage 1 Lyme disease and Babesiosis; Send either blood smear for
parasites or babesia or whole blood DNA testing and consider
Anaplasma whole blood PCR testing; Treat with 10-20 days of
doxycycline and 7-10 days of atovaquone 750 mg suspension bid
and azithromycin 500 mg po d#1 then 250 mg for remainder
40 yo male presents 2 wks after camping in NE in July with

expanding, red, painless circular rash on trunk. He has noted
fevers and HA for about 5 days and rigors over
past 48 h. Labs show normal WBC count
with left shift, PLT count 90K, and
LFTs 2-3x normal with bilirubin of 2.
Hematocrit shows new anemia (30%).
What’s the diagnosis, what diagnostics would
you send, and what’s the tx?
1645
Blood culture + for gram + cocci in chains=Subacute

bacterial endocarditis. Blood cultures much more
sensitive than TTE for dx!
60 yo male presents with 3 weeks of fevers and

drenching night sweats. Exam normal except resting
tachycardia around 100 bpm. CBC normal x WBC
count 12.5K. CMP normal. UA and CXR both normal.
Referred for TTE which was normal. If you could only
order 1 test what would it be?
1646
Contraception: An Update
Kari P. Braaten, MD, MPH
Associate Gynecologist, Fish Center for Women’s Health
Director of Quality Assurance, BWH Family Planning
Department of Obstetrics and Gynecology
Instructor in Obstetrics, Gynecology and Reproductive Medicine

I have no financial disclosures
1647
Why we need a fresh look at contraception
• Most Americans want two children.
• Women spend about 5 years pregnant, postpartum or trying to

get pregnant and about 30 years trying to avoid pregnancy.
• About half (49%) of pregnancies in the U.S are unintended

(3.1 million per year).
• The U.S. has one of the highest unintended pregnancy rates in

the developed world
• U.S. women are less likely to use highly effective reversible

contraceptive methods than women in other developed
countries.
Objectives
• Understand differences in real-life effectiveness of
various contraceptive methods
• Understand the benefits and risks of long-acting

reversible contraceptive methods (LARC)
• Reduce barriers and increase access to highly effective
methods
• Utilize CDC contraceptive guidelines

• Medical Eligibility (MEC) and Practice Management (SPR)
1648
Contraceptive Effectiveness
% experiencing unintended preg. in 1st yr
Tier Method Typical Use Perfect Use
No method 85 85
Diaphragm 12 6
III
Condom (male) 18 2
Combined pill and minipill 9 0.3
Combined patch (Evra) 9 0.3
II
Combined ring (NuvaRing) 9 0.3
DMPA (Depo-Provera) 6 0.2
IUD
Copper T (Paragard) 0.8 0.6
I
Lng-IUS (Mirena) 0.2 0.2
Etonogestrel implant (Nexplanon) .05 .05
Female Sterilization 0.5 0.5
Male Sterilization 0.15 0.10
Trussell J. Contraceptive Efficacy. In: Hatcher et.al. Contraceptive Technology 20th edition, 2009
1649
Contraceptive Use and

Unintended Pregnancy
• 46% of unintended pregnancies occur in
contraceptive users1
• The majority contraceptive failures come from

inconsistent or incorrect use
• Only 5% of unintended pregnancies are
related to true method failure1
The Alan Guttmacher Institute. Fact Sheet: Contraceptive Use in the United States, 2016
Each year, one third of U.S. women at risk of

unintended pregnancy are not fully protected
14%
18%
68%
The Alan Guttmacher Institute. Fact Sheet: Contraceptive Use in the United States, 2016
1650
Continuation rates
Method % Continuation at 1 year
Fertility awareness methods 47
Diaphragm 57
Condom (male) 43
Combined pill and minipill 67
Combined patch (Evra) 67
Combined ring (NuvaRing) 67
DMPA (Depo-Provera) 56
IUD
Copper (ParaGard) 78
LNG-IUS (Mirena) 80
Etonogestrel implant (Nexplanon) 84
Female Sterilization 100
Male Sterilization 100
The Case for Long-Acting

Reversible Contraception (LARC)
• Need for effective contraceptive methods
that are “forgettable,” user-independent
• Traditionally, sterilization has been very

popular in the U.S. (approximately 1/3 of
U.S. contraceptive users)
• 20% of women selecting sterilization at

age < 30 years later express regret
Hillis et al. Obstet Gynecol 1999
Stanwood, NL. Obstet Gynecol 2002
Spinelli et al. Am J Public Health 2000;90:1403
Abma et al. Vital Health Stat 23 1997;19:1
1651
Characteristics of IUDs and Implants

• Highly effective
• Safe
• Long-term protection
• Single motivational act for insertion (‘forgettable’)
• Not related to coitus
• Immediately effective
• Rapid return to fertility upon removal
• Highest satisfaction among methods (IUDs)
• Appropriate for women with a variety of medical
problems Belhadj H, et al. Contraception. 1986
Skjeldestad F, Bratt H. Advances in Contraception. 1988
Arumugam K, et al. Med Sci Res. 1991
US use of LARC is increasing
1652
LARC: Effectiveness
Winner B., NEJM 2012
Intrauterine Contraception
• What’s available in the U.S?

• Benefits?
• Side Effects and Risks?
1653
The IUDs you already know…
CuT380A (Paragard®) Lng-IUS 52 (Mirena®)
TCu380A (Paragard®)
• Contains 380mm2 of copper
• Mechanism of action:
• Foreign body effect – sterile inflammatory response
which is toxic to sperm/ova and impairs implantation
• Copper ions enhance this response
• Efficacy:
• 0.5-0.8% pregnancy rate in first year
• 1.6% cumulative rate at 7, and 2.2% at
8 and 12 years
• Approved for 10 years of use
• Evidence based used for 12 years
1. Trussell J. ContraceptiveEfficacy. In: Hatcher et.al. Contraceptive Technology 20th edition
2. Sivin I, Fertil Steril 1994
3. Rowe P. Contraception 2016
1654
Levorgestrel-IUS20 (Mirena®)
• Contains 52 mg of levonorgestrel
• Releases 20 mcg daily
• Mechanism of action:
• Foreign body effect
• Endometrial thinning/decidualization
• Cervical mucous thickening
• Efficacy
• 0.1-0.2% pregnancy in first year
• 0.5-1% cumulative pregnancy rate
at 7 years
• Evidence-based use for 6-7 years
The IUDs you maybe don’t know…
Three newer levonorgestrel (progestin)

IUDs
• Skyla – approved Feb 2013
• Liletta – approved Feb 2015
• Kyleena – approved Sept 2016
1655
Skyla
• Lower dose of levonorgestrel (14mcg /day)

• IUD & inserter smaller than Mirena™(28x32 mm)
• Less amenorrhea than Mirena™
• Possibly less pain with insertion, lower expulsion
• Efficacy:
• First year failure rate 0.3 per 100 women1
• Three year cumulative failure rate 0.9 per 100
women1
1. Nelson A et al. Obstet Gynecol 2013
Liletta
• SAME size and dose of levonorgestrel as Mirena™,
different inserter
• Developed by non-profit pharmaceutical company
• CHEAPER*
The Liletta IUD is the progestin-
• Currently approved for 4 years
containing
• Under FDA review IUDforof choice of the
5 years
• Efficacy, bleeding profile, side effects appear identical
BWH Family
in clinical trials Planning Division
• Efficacy:
• First-year failure rate: 0.15 per 100 women1
• 3-year failure rate 0.55 per 100 women1
1. Eisenberg D et al, Contraception 2015
1656
Kyleena
• Dose of levonorgestrel between Mirena/Liletta
and Skyla (19.5 mg)
• Rates of amenorrhea higher than Skyla, lower
than Mirena/Liletta
• Same size as Skyla (30 x 28 mm)
• Approved for five years of use
• Efficacy:
• First year failure rate 0.16 per 100 women
• Cum. 5-year failure rate 1.45 per 100 women*
• Kyleena will likely take the place of Skyla
LNG IUS: Side Effects

• Disrupted bleeding patterns
• Extra bleeding and spotting for first 3-6 months
• Mirena/Liletta:
• After 8 months ~50% of women have no menstrual bleeding, just occasional
spotting
• 20% of women have amenorrhea (no periods) at the end of the first year,
increases to ~40% at 3 years
• Overall decrease in bleeding by ~80-90%
• Skyla:
• Initial increase in bleeding/spotting also decreases, but amenorrhea less
common (6% at 1 year)
• Kyleena
• Bleeding decreases over time, amenorrhea ~13% at the end of year 1, 20%
at year 3 and 23% at year 5.
• Overall bleeding > Mirena but < Skyla
Lahteenmaki et.al., Steroids 2000
Eisenberg et al Contraception 2015
Gemzell-Danielsson K. Fertil Steril 2012
1657
LNG IUS: Side Effects

• Lower abdominal pain
• Possible hormonal side effects (~10% of women)
• Mood changes
• Acne
• Headache
• Persistent ovarian follicles ( 52 mg IUS)
• Breast tenderness (uncommon)
• Nausea (uncommon)
• Most hormonal side effects decrease after 3 months of use
• No reported weight gain
Lahteenmaki et.al., Steroids 2000; 65:693
Cu T380-A (Paragard®)
• Side effects
• No hormonal side effects (no hormones)
• Heavier menstrual bleeding
• Most women experience increased blood loss
• Approximately 50% increase in blood loss
• Especially heavy in first few months post insertion
• More cramping and/or pain
• Menstrual pain, discomfort with intercourse, backache
• Anemia
1658
Potential IUD (device) complications

• Expulsion (1st year)
• Cu-T380A 3-10%
• LNG-IUS 3-6%
• Perforation (~1/1000)
• Malposition within the uterus
• Embedded in uterine muscle, rotated, too low
• Infection in uterus (pelvic inflammatory disease)
• Risk only increased in first 20 days after insertion
(1-10 / 1000 women)
• After that PID risk only related to risk of acquiring
an STI and rare (1.4 / 1000)
Dean and Goldberg, Up to Date 2013
Contraceptive Implant
• What’s available in the U.S?

• Benefits?
• Side Effects and Risks?
1659
Implantable Contraceptive Device

Available in the United States
• Etonogestrel Implant
(Nexplanon™)
• Replaced Implanon ™
• Approved for 3 years
use, evidence based
use for 4-5 years
• Differences:
• Radio-opaque
• New easier inserter
Etonogestrel Implant
(NEXPLANON)
• Inserted subdermally in the groove between the
biceps and triceps muscles
• Can only be inserted and removed by clinicians
completing FDA mandated training
• Highly effective, 0.38 pregnancies/100 woman-

years
• Very few absolute contraindications to use.

• Only women with current breast cancer can’t use
• OK with any other medical problems or risk factors
Darney P et. al, Fertil Steril May 2009
1660
Side effects with Nexplanon

Irregular bleeding is expected.
Patterns are unpredictable. Usually not heavy.
Most discontinuation for irregular bleeding.
10-14% of users:
• Acne
• Headache
• Weight increase
<10% of users:
• Breast Pain
• Emotional changes
• Abdominal Pain
• Decreased Libido
• Nausea
Contraception 1998; 58: 99S-115S
Potential device complications
• Deep insertion / difficult removal

• Nexplanon™ is second generation product
• Easier to use inserter, makes insertion fool-proof
• Visible on X-ray
• Infection at insertion site

• Expulsion (very rare)
1661
Extended use of LARC

• Strong data for extended use of etonogestrel implant,
copper IUD and 52 mg levonorgestrel IUDs beyond
their FDA approval durations
• Etonogestrel implant: no pregnancies reported up to 5
years of use in 550 women1,2
• Recommended by BWH/PPFA for 4-5 years
• Lng-IUS 52 (Mirena and Liletta): 0.53% cumulative

pregnancy rate at 7 years3
• Recommended by BWH/PPFA 6-7 years
• Copper IUD: 12 years: 2.2% cumulative pregnancy rate

at 12 years, with no pregnancies in years 10 or higher4
• Recommended by BWH/PPFA 12 years
1. Ali et al. Hum Reprod 2016
2. McNicholas et al. Am J Obestet Gynecol 2017
3. Rowe P. Contraception 2016
4. United Nations Development Programme, Contraception 1997
Extended use of LARC

Women do not need to rush to replace!
• Decisions should be individualized with patients

• Consider age, baseline fertility, time to menopause
• Important to consider whether they will replace with

another highly effective method
• Non-LARC methods still less effective
32
1662
Contraceptive Eligibility
Who is eligible (which patients) for each method?
CDC guidelines:
Medical Eligibility for Contraceptive Use
Updated 2016
1663
CDC MECs
• Available as free iPhone application
• Can search by medical condition or
contraceptive method
WHO & CDC

Medical Eligibility Criteria (MEC)
• Recommendation Grading System
• Category 1: No restrictions
• Category 2: Generally use (Benefits usually outweigh risks)
• Category 3: Not recommended, unless other

methods not available or
appropriate. (Risks usually outweigh benefits-
use requires careful clinical judgment and access to
clinical services)
• Category 4: Absolute contraindication
1664
Examples from CDC MEC

COC,
patch, TCu-380A LNG-IUS
ring CDC Risk CDC Risk
Medical Conditions
CDC Risk Category Category
Category
Hypertension
Adequately controlled HTN 3 1 1
Elevated blood pressure levels 3 1 1
SBP 140-159 or DBP 90-99
SBP ≥ 160 or DBP ≥ 100 4 1 2
Headaches
Non-migraine 1 1 1
Migraine
2 1 1
Without aura
With aura
4 1 1
MMWR, July 2016
CDC Selected Practice

Recommendations (SPR) for
Contraceptive Use, 2016
How to initiate and manage each method?
1665
Examples from CDC SPR, 2016

• Initiating contraception
• How to be reasonably
certain a woman is not
pregnant?
• Switching from one
method to another
• When back-up method
needed?
• Examinations and
tests before starting
• i.e. blood pressure
measurement before
starting an estrogen-
containing method
1666
Examples from
CDC SPR, 2016
Reducing barriers
Expanding access to LARC
1667
Removing barriers and expanding access
• Removing restrictions on who is eligible

• Removing requirements for screening tests
• What screening is truly necessary before insertion?
• Provision at point of care

• At time of current office visit (no need to return or
reschedule)
• At the time of abortion
• At the time of delivery
Who can get an IUD? Eligibility

• Nearly all reproductive age women
• OK regardless of age
• OK if nulliparous (or never been pregnant, or never
had sex!)
• OK with nearly all medical conditions
• OK if had a sexually transmitted infection in the past
1668
Who should not get an IUD?

(Contraindications)
• Women who are currently pregnant
• Women with a current uterine infection (PID)
• Women with current untreated gonorrhea or
chlamydia
• Women with current cervical cancer (pre-
treatment)
• Women with current breast cancer
• OK for Copper IUD, non-hormonal
• Women with uterine anomalies (i.e. bicornuate

uterus)
When can an IUD be inserted?

• IUD can be inserted anytime in the cycle if1
• Patient is consistently using reliable method
• Patient has been abstinent since last period
• Within 5 days of a single act of unprotected IC
• Copper T380A only (as emergency contraception)
• IUDs can be inserted immediately after1

• Abortion or miscarriage
• At the time of procedure if having uterine evacuation
• Once pregnancy has passed (if medical tx or spontaneous)
• Delivery
• Right after the placenta, at vaginal birth or c-section.
1. Carusi and Goldberg, Up To Date, 2010
1669
Impact of post-abortion
IUD insertions
• Increased utilization at 6 months
• Reduced repeat unintended pregnancy
Bednarek et.al., NEJM 2011 Goodman et.al., Contraception 2008

Hohmann et.al., Contraception 2012 Roberts et.al., Contraception 2010
Cremer et.al., Contaception 2011
Professional Organization Statements
• ACOG 2012: LARC methods are safe and

appropriate for most women including nulliparous
women and adolescents. Adolescents should be
encouraged to consider LARC1
• AAP 2014: LARC methods should be considered

first-line for adolescents2
1. ACOG Committee opinion no. 539. Obstet Gynecol 2012

2. Contraception for adolescence. Pediatrics 2014
1670
Impact of LARC:
Contraceptive CHOICE Project
• 9,256 adolescents and women in the St Louis area offered
all contraceptive methods at no cost, 2007-2011
• Counseling focused on efficacy
• 75% of women chose LARC, including 2/3 of adolescents
• 12-month continuation rates >80%, high rates of
satisfaction1
• LARC users were 22 times LESS likely to have an
unintended pregnancy than non-LARC users2
• Abortion rates in the cohort <50% that of regional and
national rates.3
• Significant reduction in the percentage of abortions
that were repeat abortions.3 1. Rosenstock JR et al. Obstet Gynecol 2012
2. McNicholas et. al. Clin Obstet Gynecol 2014
3. Peipert JF et al, Obstet Gynecol 2012
Greater use of long-acting

reversible contraception holds
great promise as a means to
reduce unintended pregnancy in
the United States.
1671
Take-home points
• Challenges with correct use, adherence and
continuation of short-acting contraceptive methods are
leading contributors to undesired pregnancy rates in
the US
• Guidelines are available to help clinicians determine,
who, when and how contraceptive methods can be
used.
• Increased use of LARC methods holds significant
promise in reducing unintended pregnancy rates
• Women want to use LARC, and we must work to
reduce barriers restriction women’s use of these
methods
Question 1
Which of the following LARC methods does not have
evidence to support extended use?
A. Lng IUS 52 (Mirena)
B. Lng IUS 13.5 (Skyla)
C. CuT380A (Paragard)
D. Etonogesterel contraceptive implant (Nexplanon)
1672
Question 1
Lng IUS 13.5 (Skyla) does not have evidence that it

protects from pregnancy at greater than 3 years.
Exchange should be encouraged at the three year
mark.
Question 2
Which patient is NOT eligible for a LNG IUD?
a) 19 y.o, G0, monogamous woman
b) 40 y.o. G2P2, with recent new partner. History of

chlamydia as a teen.
c) 21 y.o, G4P2, diagnosed with chlamydia a few weeks

ago, but never took the antibiotics.
d) 35 y.o. G3P3, monogamous woman with fibroids
1673
Question 2
Untreated genital tract infection is a contraindication to IUD
insertion.
This patient may be eligible for insertion after completion of
treatment.
Adolescence, nulliparity, previous STI, fibroids are not
contra-indications.
References
• Bednarek et.al., NEJM 2011
• Hohmann et.al., Contraception 2012
• Peipert et.al., Obstet Gynecol 2012
• Goodman et.al., Contraception 2008
• Roberts et.al., Contraception 2010
1674
I have no financial disclosures
Thank you
Questions?
1675
Medical Complications of Pregnancy
Ellen W. Seely, M.D

Director of Clinical Research
Endocrinology, Diabetes & Hypertension Division
Potential Conflicts:
None
1676
Objectives
•To understand the implications of common
medical conditions on pregnancy
•To be able to appropriately change medical
management of patients prior to pregnancy
•To understand difference in disease
management goals in pregnancy
Common Complicating Medical Conditions

that Precede Pregnancy
Hypertension ~5-10%
Diabetes Mellitus ~1-2%
Hypothyroidism~2-3%
Leading causes of hospitalization in pregnancy:
■ Preterm labor
■ Hypertension
■ Diabetes Mellitus
■ Bleeding
1677
Why Is it Important for Medical Caregivers

to Know about these?
Prepregnancy Planning and Counseling

Key to Successful Pregnancy Outcome
Most pregnancies are unplanned
Hypertensive Disorders in Pregnancy

Chronic Hypertension:
Hypertension before 20 weeks gestation
Preeclampsia:
Hypertension with proteinuria or other end organ manifestations
after 20 weeks gestation
Gestational Hypertension:
Hypertension after 20 weeks gestation , without signs of
preeclampsia
Superimposed Preeclampsia:
Preeclampsia in woman with pre-existing hypertension
ACOG Hypertension in Pregnancy, 2013 Ob Gyn
1678
Risks of Hypertension in Pregnancy
Fetus/Neonate
Intrauterine growth restriction-Small for gestational
age infant
Prematurity (induced)
Mother
Exacerbation of hypertension and risk of stroke, MI,
renal failure
Superimposed preeclampsia
Chronic Hypertension and

Preeclampsia Rates
General population 4-5%

Preexisting hypertension 25 %
< 4 y duration 22%
> 4 y duration 31%
DBP <100 mm Hg 24%
DBP 100-110 mm Hg 42%
Based on BP at visit regardless of antihypertensive Rx
Adapted from Sibai Am Obstet Gyn 2002;100:369
1679
Preexisting Hypertension in Pregnancy
Pregnancies do well unless superimposed

preeclampsia develops
Goal SBP 120-160; DBP 80-105 mm Hg *
Antihypertensives generally can be tapered

during pregnancy to lower fetal exposure
* ACOG Hypertension in Pregnancy 2013, Ob Gyn
Control of Hypertension in Pregnancy Study

CHIPS Results
987 women; 74.6% had preexisting hypertension
Tight control DBP goal 85 mmHg (vs less tight DBP
100 mmHg) did not affect rates
Primary outcome: pregnancy loss/high-level
neonatal care >48 hours 31.4% and 30.7%, respectively;
adjusted odds ratio, 1.02; 95% confidence interval [CI], 0.77 to 1.35
Secondary outcomes: serious maternal
complications 3.7% and 2.0%, respectively; adjusted odds ratio,
1.74; 95% CI, 0.79 to 3.84
DID lower rates of severe hypertension (≥160/110 mm Hg) (40.6% less-tight,
27.5% of tight)
NEJM 2015
1680
Pharmacologic Treatment of Preexisting

Hypertension in Pregnancy
CEIs and ARBs prior to conception

fetal anuria and oligohydramnios (2nd & 3rd trimester)
neonatal renal failure (2nd & 3rd trimester)
birth defects? (1 trimester Cooper et al. N Engl J Med, 354: 2443-51
st
2006 versus Li DK et al. BMJ. 2011 Oct 18;343:d5931; Bateman et al, Am J Ob

Gyn 2015)
Antihypertensive Options
Methydopa
used since 1960s
infant F/U up to 7.5 yrs (Cockburn J et al. Lancet 1982;1(8273):647)
First line option
Alpha-Beta blocker
labetolol alternative first line (ACOG/Canadian)
Beta blockers
Concern with growth restriction with atenolol
Calcium channel blockers
Only long acting ones
Diuretics (concern of dehydration expressed by ACOG)
1681
Summary: Chronic Hypertension and

Pregnancy
Importance of family planning with all
women with hypertension
Awareness re need to switch from certain
antihypertensives (ACEIs, ARBs)
Knowledge that BP goals differ during
pregnancy
Awareness of hypertensive complications
of pregnancy
Diabetes Mellitus
Birth defect risk rises related to level of

HbA1C at conception- as high as 20%
Preconception glucose control can reduce

birth defects to ~1% over general
population
1682
Risks of Diabetes Mellitus in Pregnancy
Fetus/Neonate
Birth defects
Macrosomia
Prematurity (induced)
Birth Trauma
Neonatal Hypoglycemia
Mother
Progression of diabetic complications: retinopathy, nephropathy
Preeclampsia
Increased chance for C-section
Prepregnancy Planning for Women with

Diabetes
Discuss family planning at least yearly and stress the
importance of prepregnancy glucose control
If HbA1C not in normal range, plan with patient 6 months

to achieve glucose control prior to conception
Counseling re risks
Prepregnancy determination of retinopathy, nephropathy

and other complications (i.e. gastroparesis)
Adjustment of diabetes medications (including BP meds)
1683
Optimal Diabetes Control for Conception
American Diabetes Association control goal:

HbA1C < 6.5 %
Diabetes Care 2018
1684
Management of Diabetes Mellitus

Preconception and During Pregnancy
Diet and home glucose monitoring are the mainstay
of management
For Type 2 DM, if on other agents, change to
insulin- insulin remains the gold standard for
treatment of diabetes during pregnancy.
“Insulin is the preferred medication ; Noninsulin
medications lack long-term safety data” ADA. Standards
of medical care in diabetes-2015.
Diabetes Care 2015;38 (suppl 1):S1-S93
Oral agents for Type 2 DM - the jury is out.
Insulin in Management of Diabetes Mellitus

Preconception and During Pregnancy
Only human insulin should be used
Long experience with NPH and regular
Shorter acting i.e. lispro and aspart are commonly
used
Longer acting:
Levemir
Glargine insulin controversial (Category C) increased IGF-1-
receptor affinity and mitogenic potency in human
osteosarcoma cell-culture model
Pumps can be used
1685
Insulin resistance during pregnancy
Insulin resistance increases as pregnancy

progresses
Insulin requirements typically increases in
pregnancy but may decrease just before
delivery therefore doses needed to be
adjusted throughout pregnancy
Glucose goals during pregnancy
FBS <95 mg/dl

Post meals
1 hr <140 mg/dl
2 hr <120 mg/dl
HbA1C <6% (if achievable without too
much hypoglycemia)
ADA and ACOG
1686
Gestational Diabetes Mellitus and the

Primary Care Physician
GDM: Diabetes first diagnosed in pregnancy

after the 1st trimester, resolves with delivery
Risk of future Type 2 DM as high as 60-70%
ADA recommends regular screening of all

women with a hx of GDM for Type 2 DM (yearly
and if normal can move to q 3 yrs)
Gestational diabetes and the incidence of type 2 diabetes
80
Cumulative incidence of type 2 diabetes (%)
70
60
50
40
30 Latin American
Mixed or other
20 Boston cohort
Zuni
10 Navajo
0
0 5 10 15 20 25 30
Length of follow up after delivery (years)
Adapted from Kim C et al. Diabetes Care. 2002 Oct;25(10):1862-8.
1687
Summary: DM and Pregnancy

Need for pregnancy planning to normalize
HbA1c
May need to switch medications (both
glycemic and antihypertensive meds) before
conception
Insulin doses require adjustment throughout
pregnancy
Women with a history of GDM should
receive regular screening for Type 2 DM
Hypothyroidism
1688
Thyroid Changes in Pregnancy
Diagnosis often complicated by the changes in thyroid

function that take place in normal pregnancy.
Early pregnancy, rise in HCG (has thyroid stimulatory

activity), leads to compensatory fall in TSH.
TSH concentration is usually within the normal range;

in some women falls into the suppressed range.
Relationship between TSH and hCG

1.5— —50
TSH
TSH (uIU/mL)
—40
hCG (IU/L x 103)
1.0—
—30
—20
0.5—
hCG
—10
—0
0 10 20 30 40
Weeks of Gestation
Adapted from Glinoer et al. JCEM 1990; 71(2):282
1689
Serum TSH in Pregnancy: Mean and 95% CI

4.5
3.5
TSH (mIU/mL)
2.5
1.5
0.5
0.03
1st trimester 2nd trimester 3rd trimester

10 20 30 40
Weeks Gestation
Adapted from Panesar et al. Ann Clin Biochem 2001; 38: 329
TSH normal range in pregnancy

■ Use pregnancy specific normal range of
your lab
■ If trimester-specific reference ranges for
TSH are not available in the laboratory, the
following reference ranges are
recommended:
■ First trimester, 0.1-2.5 mIU/L
■ Second trimester, 0.2-3.0 mIU/L
■ Third trimester, 0.3-3.0 mIU/L.
Guidelines of the American Thyroid Association for the Diagnosis and Management of Thyroid
Disease During Pregnancy and Postpartum
1690
Hypothyroidism: Diagnosis In
Pregnancy
2-10% of pregnancies
Universal screening not recommended by ACOG,
the Endocrine Society, or American Association of
Clinical Endocrinologists
Diagnosis made by elevated TSH
Symptoms:
weight gain
constipation (typical of normal pregnancy)
cold intolerance (not typical of pregnancy)
Clinical Hypothyroidism: Risks to

Pregnancy
Fetal/Infant
Poor growth
Premature Birth
Pregnancy loss
decrease in IQ
Maternal
Increases risk for preeclampsia, placental
abruption (preterm delivery)
1691
Subclinical Hypothyroidism: Risks to

Pregnancy
Fetal/Infant
Poor growth
Premature Birth conflicting data
Early Pregnancy loss +
decrease in IQ controversial
Maternal
Increases risk for preeclampsia, placental
abruption (preterm delivery)
Hypothyroidism: Treatment Prior to and

During Pregnancy
Aim for TSH <2.5 at conception
Check TSH as soon as pregnancy test positive
Requirement for thyroid hormone characteristically

increases in pregnancy and returns to prepregnancy
requirement postpartum
Titrate thyroid hormone dose to maintain TSH <2.5 1st and

2nd trimesters, <3.5 3rd trimester
Reduce thyroid hormone dose to prepregnancy dose at

delivery and check TSH at 6 wk pp visit
1692
Summary Hypothyroidism and Pregnancy
TSH values vary through pregnancy and may be

suppressed in first trimester due to rise in HCG
TSH levels run lower in pregnancy so aim for T4

replacement is a lower TSH.
Overall Summary
Women with medical problems should receive

regular family planning counseling
Adjustment of medications is often necessary prior

and during to pregnancy
Goals for treatment of medical problems may differ

during pregnancy
1693
Potential Conflicts:
None
Question 1
You see a 34 yo women with Type 2 diabetes and
hypertension who has recently stopped using
contraception. She is taking glyburide and lisinopril. Her
last HbA1c was 9%.
Your recommendations include all of the following except:

a) Aim for HbA1c <6.5%.
b) D/C lisinopril and substitute labetolol before she tries to become

pregnant
c) D/C lisinopril and substitute an angiotensin 2 receptor blocker (ARB)

to help protect her kidneys during pregnancy
d) Eye exam for retinopathy assessment
1694
Question 1-Answer
Your recommendations include all of the following except: Answer C
a) Aim for HbA1c<6.5%. This is a correct goal for conception per ADA.
b) D/C lisinopril and substitute labetolol before she tries to become

pregnant. Lisinopril is contraindicated in pregnancy and labetolol is a
1st line medication.
c) D/C lisinopril and substitute an angiotensin 2 receptor blocker (ARB)

to help protect her kidneys during pregnancy. Both ACEIs and ARBs
cause fetal renal damage.
d) Eye exam for retinopathy assessment. An eye exam should be

performed prior to pregnancy in women with diabetes.
Question 2
A 24 yo women reports a home positive pregnancy test

and having missed her period. Because of fatigue, another
clinician ordered a TSH to rule out hypothyroidism and
which returned at 5.0 mIU/L. She has no symptoms.
You:
a) Recommend recheck of TSH in 4 wks.
b) Explain that TSH values may increase over the course of

normal pregnancy due to the rise in HCG.
c) Start T4 with a goal TSH < 2.5.
d) Start T4 with a goal TSH < 4.5.
1695
Question 2 Answer
You: Answer D
a) Recommend recheck of TSH in 4 wks. Incorrect:T4
requirement rises over the course of pregnancy.
b) Explain that TSH values usually increase in 1st trimester of

normal pregnancy due to rise in HCG. Incorrect:TSH levels
typically fall in the 1st trimester due to rise in HCG.
c) Start T4 with a goal TSH < 4.5. Incorrect: TSH goals are
lower in pregnancy. Do not use non pregnant nl range.
d) Start T4 with a goal TSH < 2.5. Correct: TSH goals are
lower in pregnancy.
References
Seely EW, Ecker JL. Medical complications in pregnancy. In:
Singh AK, editor. Scientific American medicine [online].
Hamilton (ON): Decker Intellectual Properties; June 2016.
DOI: 10.2310/7900.1041. Available at:
http://www.sciammedicine.com (accessed June 4, 2018).
Seely EW, Ecker J. Chronic hypertension in pregnancy.
Circulation. 2014;129(11):1254-61.
Executive summary: hypertension in pregnancy. ACOG.
Obstet Gynecol 2013;122: 1122.
Standards of Medical Care in Diabetes 2018. Diabetes Care.
2018 Jan; 41(Supplement 1): S137-S143.
Alexander EK, Pearce EN, Brent GA, et al. 2017 Guidelines of
the American Thyroid Association for the Diagnosis and
Management of Thyroid Disease During Pregnancy and the
Postpartum. Thyroid. 2017; 27(3):315.
1696
Global Burden Of HPV-Related Disease

The Challenges of HPV Vaccine
Implementation
Annekathryn Goodman, MD, MPH
Disclosures
• none
1697
OUTLINE
• Background
– cervical cancer stats
– Human Papillomavirus Infection (HPV)
• Vaccination
• Screening
• Management of abnormal screening tests
• Management of abnormal cervical biopsies
Cervical Cancer
• Cervical cancer is the most common HPV-
associated cancer among women
– 500,000+ new cases and 275,000 attributable deaths
world-wide in 2012
– 13,240 new cases and 4,170 attributable deaths in
estimated for 2018 in the U.S.
– 25.9% cervical cancers occur in women who are
between the ages of 35 and 44
– 14% between 20 and 34
– 23.9% between 45 and 54
1698
Cervical Cancer
HPV-associated Disease
• Types 16, 18: US ETIOLOGY
– ~62% of HPV-associated cancers
• Human Papillomavirus
– ~50% of ≥ CIN*2
• Types 31, 33, 45, 52, 58
Infection (HPV)
– Worldwide: ~20% of invasive cervical • Persistence of HPV
cancer
– US • Lack of treatment of
~14% of HPV-related cancers in
women pre-invasive disease
• ~15% of invasive
cervical cancer
• ~25% of ≥ CIN2
~5% in men
• Types 6, 11
– 90% of anogenital warts
*CIN = cervical intraepithelial neoplasia 5

Serrano B, et al. Infect Agent Cancer. 2012;7:38.
HPV Transmission
• 80% of people will be infected with HPV in their

lifetime.a
– The most common route of transmission is sexual
intercourse: genital-genital, anal-genital, oral-genital,
manual-genital.
• Nearly 50% of high school students have engaged
in sexual (vaginal-penile) intercourse.b
– 1/3 of 9th graders and 2/3 of 12th graders have
engaged in sexual intercourse.b
– 24% of high school seniors have had sexual intercourse
with 4 or more partners.b
a. Dunne EF, et al. JAMA. 2007;297:813-819. 6

b. Jemal A, et al. J Natl Cancer Inst. 2013;105:175-201.
1699
HPV (High Risk): Natural History
• 3-8 month incubation period
• 80% cleared in 12 months
• 95% cleared by three years
• Less than 1% of all HPV High

Risk infections lead to
invasive cancer
HPV Types Differ in Their

Disease Associations
Mucosal Cutaneous
~40 Types Sites of infection Sites of infection ~ 80 Types
High risk (oncogenic)

HPV 16, 18, 31, 33, 45, 52, 58 Low risk (non-oncogenic)
HPV 6, 11
Cervical Cancer
Anogenital Cancers Genital Warts “Common”
Oropharyngeal Cancer Laryngeal Papillomas Hand and Foot
Cancer Precursors Low Grade Cervical Disease Warts
Low Grade Cervical Disease
1700
New Cancers Probably Caused by HPV,

United States, 2006-2010
Oropharynx Vagina Vulva Anus Cervix Penis
n=
n = 2200 n = 700
600 13% n = 2600 8%
3% 15%
nn == 1800
1800
10%
10%
n = 10,400
59% n = 7200
77%
Women (n = 17,600) Men (n = 9300)
9
CDC. http://www.cdc.gov/vaccines/who/teens/for-hcp/hpv-resources.html.
HPV Vaccines
• Safe, well tolerated, and effective HPV

vaccines are available that could prevent
most HPV-related cancers.
• There are clear recommendations from
ACIPa,b and AAPc for use of HPV vaccines in
11 through 12-year-old girls and boys.
a. Markowitz LE, et al. MMWR Recomm Rep. 2014;63:1-30.

b. Petrovsky E, et al. MMWR Morb Mortal Wkly Rep. 2015;64:300-304. 10
c. AAP. Red Book. 2015.
1701
Available HPV Vaccines
Bivalent Quadravalent 9-valent

(Ceravix®) (Gardasil®) (Gardasil®9)
Manufacturer GlaxoSmithKline Merck Merck
6,11,16,18
L1 VLP types 16,18 6,11,16,18
31,33,45,52,58
Trichoplusia ni insect cell line Saccharomyces Saccharomyces

Manufacturing infected with L1 encoding cerevisiae (Baker’s cerevisiae (Baker’s
recombinant baculovirus yeast) – expressing L1 yeast) – expressing L1
Females 9-26 y Females 9-26 y

Licensed Females 9-25 y
Males 9-26 y Males 9-15 y
11
Petrovsky E, et al. MMWR Morb Mortal Wkly Rep. 2015;64:300-304.
HPV Vaccine Efficacy

Results of Selected Clinical Trials
Outcome Vaccine Sex Efficacy, %
Bivalent and
Cervical precancer Females > 93
quadrivalent
Vaginal/vulvar
Quadrivalent Females 100
precancer
Anal precancer Quadrivalent Males 75
Females 99
Anogenital warts Quadrivalent
Males 98
12
Dunne EF, et al. MMWR Morb Mortal Wkly Rep. 2014;63:1-84.
1702
ACIP/AAP Recommendations for Use of

HPV Vaccines
• Routine vaccination at age 11 or 12 years
– Can start at age 9 years
• Vaccination for females age 13 through 26 years and males

age 13 through 21 years* who have not completed the
series
• Males age 22 through 26 years* may be vaccinated
• Males age 22 through 26 years who are
immunocompromised and MSM should be vaccinated
*Recommendation for males ≥ 16 years is off label for the
9vHPV vaccine.
Markowitz LE, et al. MMWR Recomm Rep. 2014;63:1-30.; Petrovsky E, et al. 13
MMWR Morb Mortal Wkly Rep. 2015;64:300-304.; AAP. Red Book 2015.
ACIP/AAP Recommendations for Use of

HPV Vaccines
• Females: 2vHPV, 4vHPV (as long as available), or

9vHPV vaccine can be used
• Males: 4vHPV (as long as available) or 9vHPV
vaccine can be used
• 3-dose schedule
– 2nd at least 1 month after 1st, 3rd at least 6 months after
1st
• Complete series with same HPV product when

possible
– 9vHPV vaccine can be used to complete the 4vHPV 14
vaccine series
1703
Guidance on ACIP Website:

Additional HPV 9 Vaccine Doses
Completing HPV vaccination
http://www.cdc.gov/vaccines/who/teens/downloads/9vHPV-guidance.pdf
• There is NO ACIP recommendation for
routine additional 9vHPV vaccination for
anyone that’s already completed 4vHPV or
2vHPV vaccination series.
• No serious safety concerns giving 9vHPV
after 3 dose 4vHPV series (but more injection
site reactions)
• Additional HPV 9v protection: mostly limited
to females (cervical cancers & pre-cancers)
HPV Vaccine in
Immunocompromised Host
• Transplant recipient & HIV infection with <200
CD4 counts higher risk of HPV-related disease
• Vaccine safe and immunogenic
• ACIP recommends Vaccination through age 26
years
16
1704
HPV Vaccine and Adult Women

• Placebo-controlled randomized trial of HPV4 underway
– 38,000 women (ages 24-34, 35-45)
– Excluded women with h/o LEEP, biopsy-proven cervical
HPV, vulva/ vaginal pre-cancers, h/o genital warts
– At enrollment, 1/3 positive for exposure to >1 vaccine
type
– So far (>3 yrs): good vaccine efficacy (overall 89%)
against persistent infection, dysplasia, and genital warts
– Efficacy better in younger women
– Cost effectiveness of vaccine decreases as age
increases
– Still considered “off label for women > 26 years
LEEP- Loop Electrosurgical Excision Procedures
Data – presented to ACIP 2/10
HPV Vaccine and Adult Women

Lancet Infectious Dis 2016
• Double blind vaccine (2vHPV) vs placebo

• Women > 25 years; 5747 participants
• HPV 16/18 vaccine continues to protect against
infections, cytological abnormalities, and lesions
associated with HPV 16/18 and CIN1+ irrespective
of HPV type, and infection with non-vaccine
types HPV 31 and HPV 45 over 7 years of follow-
up.
18
1705
HPV Vaccine FAQ

Can you get HPV infection from getting the
vaccine?
No, the vaccine does not contain any viral DNA so
there is no way to become infected with the virus
by getting the vaccine.
Do you have to do pregnancy test before
giving vaccine?
No, but neither vaccine should be given to women
who are pregnant or are planning to get pregnant
soon.
HPV Vaccine FAQ

Can you get HPV vaccine while nursing?
Yes, ACIP says lactating women can receive HPV
vaccine.
Can the HPV vaccine be used to treat
abnormal pap smear?
NO. They are not meant to be a treatment for HPV
infection or HPV related disease.
1706
HPV vaccine FAQ

• Do you still have to get cervical cancer
screening if you get HPV vaccine?
– Yes. HPV Vaccines are prophylactic vaccines. They
work best if given before exposure to HPV virus.
They are not meant to be a treatment for HPV
infection or HPV related disease. Women must still
get regular cervical cancer screening. (Begin at age 21)
HPV Vaccine
Adverse Events
• Local
– Injection site swelling (29.1-40.3%)
– Injection site erythema (25.8-34%)
• Systemic
– Pyrexia (10.1% vaccine vs 8.4% placebo)
– Headache, dizziness, myalgia, arthralgia, GI (0.5%
difference between vaccine & placebo)
1707
HPV Vaccine
Severe Adverse Effects
• No SAE
• No relationship between exposure to HPV
vaccination and autoimmune outcomes, Multiple
sclerosis, demyelinating conditions, venous
thromboembolism
• No deaths considered vaccine related
• No increase SAE with combo with other vaccines
International uptake
of 3 doses HPV vaccine
Australia UK Canada Netherlands USA
Brotherton, Lancet 2011; Cuzick BJC 2010; Ogilvie et al., 2010; Marc et al., 2010, NIS-Teen 2011
1708
HPV Vaccine Impact:

High HPV Vaccine Coverage in Australia
• 80% of school-age girls in Australia are fully
vaccinated
• High-grade cervical lesions have declined in women
less than 18 years of age
• For vaccine-eligible females, the proportion of genital
warts cases declined dramatically by 93%
• Genital warts have declined by 82% among males of
the same age, indicating herd immunity
Garland et al, Prev Med 2011

Ali et al, BMJ 2013
Summary
• HPV is the most common STI in adolescents and is
directly linked to anogenital warts and cervical cancer
• To date, HPV vaccine is safe and highly efficacious in
preventing precursors to cervical cancer
• Routine vaccination of 11-12 year-old girls is supported
by the CDC, ACIP and AAP, with catch-up for women
through age 26
• Males can now be offered vaccination with Gardasil
• Parents are generally accepting of this vaccine,
especially if counseled correctly
1709
Why does Cervical Cancer Happen?

• Social Ecology
• Risk Factors High Income Countries
– Poverty
– Access to health care
– Lack of medical insurance
• Risk Factors LMIC
– Poverty
– Lack of screening
Social Ecology of Cervical Cancer
1710
Social Ecology Levels

• Intrapersonal
• Interpersonal
• Organizational
• Community
• Society
Challenges to Cervical Cancer

Screening
General Influences INTRAPERSONAL LEVEL
Barriers to Screening
Personality Depression, anxiety
Comprehension Ability to navigate healthcare system
Genetics Less common high risk subtype
Family Family history of cervical cancer
Home environment Shame, role of family decision maker
1711

Screening
General Influences Barriers to Screening
INTERPERSONAL LEVEL
Culture Fatalistic beliefs
Social Mores Smoking
Employment Unemployed

Screening
General Influences ORGANIZATIONAL LEVEL
Barriers to Screening
School Lack of healthcare awareness
Health Insurance Lack of healthcare coverage
Race, Ethnicity Minority status, discrimination, trust
1712

Screening
COMMUNITY LEVEL
Socio-economic status Low socio-economic status
Public resources Citizenship status
Healthcare facilities Delay of services
Economics Poverty

Screening
LEVEL
Educational system Utilization of healthcare
Governmental policy Lack of financial support
1713
Cervical Cancer Prevention

• Primary: HPV Vaccination
• Secondary: Screening
– Pap , colposcopy, biopsies, treatment
– Visual Inspection with Acetic Acid (VIA), colpo, RX
– VIA, treatment
– HPV testing, colpo, treatment
– VIA & HPV testing, treatment
Guidelines
• www.asccp.org/Portals/9/docs/AS
• Guidelines are only for women at CCP%20Management%20Guideli
nes_August%202014.pdf
average risk for cervical cancer.
• App available for iPad, iPhone and
Android
• Guidelines should never
• These guideline do not apply to replace clinical judgment.
women with:
– History of cervical cancer
– In Utero exposure to DES
– Immuno-compromised
– HIV positive
1714
The Dangers of Guidelines

• 67 year old nurse with h/o DES exposure
• s/p cryotherapy and LEEP in her 20’s
• Last pap 2014 normal
• Medicare denied approval of repeat pap in 2017
• 2018 presented with enlarged left inguinal node.
Biopsy squamous cell ca
• Exam exophytic 10 cm cervical mass with
extension to sidewall
When To Perform A Pap Smear
• Screening should start at age 21.
• Screening guidelines are age dependent.
• Annual Pap Smears in women without a history of

premalignant or malignant lower genital disease are no
longer recommended.
• Recommended screening practices should not change

on the basis of HPV vaccination status.
1715
When to perform a Pap Smear

• Guidelines for management of abnormal
Pap smears are different by the following
age categories:
– Ages 21- 24
– Ages over 30

pap smears are different for the pregnant
woman.
Cervical Cancer:
Screening Guidelines
• Ages 21- 29 years: PAP SMEAR screening

every three years:
– No screening HPV testing.
– HPV testing only for evaluation of atypical

squamous cells of uncertain significance (ASCUS).
1716
Cervical Cancer:
Screening Guidelines
• Ages 30 – 65 years:
– Screening with both PAP SMEAR and HPV
testing every five years (preferred).
– Or PAP SMEAR testing every three years

(accepted).
– Or HPV testing alone with Cobas HPV test

every three years for women over 25.
Cervical Cancer: Screening

Guidelines
pap smears are different by the following
age categories:
– Ages 21- 24
– Ages over 30

pap smears are different for the pregnant
woman.
1717
When To Stop?
• Age 65 and not at high risk for cervical cancer (USPSTF,
ACOG, ASCCP).
• Discontinuation of screening assumes adequate prior
negative screening.
• Three consecutive negative cytology results or 2
negative cytology results with (-) co-testing within the
prior 10 yrs with one within 5 yrs.
• No prior hx of cervical cancer, CIN2/3.
• If any present, continue screening for 20 yrs.
When to stop?
• After hysterectomy (with cervix removal) if no

CIN 2/3 or cervical
cancer.
• If CIN 2+, and cervix removed, continue screening
of vaginal cuff for
20 years, even if > 65 years old.
• If hysterectomy and cervix not removed, continue
screening as
recommended for age.
1718
Essential Changes From Prior Management

Guidelines
• Genotyping triages HR HPV positive women to
colposcopy earlier after negative cytology
– Colposcopy indicated for ASCUS +HPV regardless of
genotyping
• HPV negative ASCUS

– Follow up at 3 years with co-testing
– Not sufficient for exiting women from screening at age
65
Essential Changes From Prior

Management Guidelines
• Cytology reported as negative, but lacking
endocervical cells can be managed without early
repeat.
• Cytology reported as unsatisfactory requires

repeat even if HPV negative.
• Genotyping triages HPV (+) women with 16 or 18

to earlier colposcopy.
1719
Essential Changes From Prior

Management Guidelines
• HPV negative ASCUS
– Follow up at 3 years with co-testing
– Not sufficient for exiting women from screening at age 65
• Women aged 21 – 24 are managed conservatively
• CIN 2+ follow up is more clearly defined with

incorporation of co-testing.
• Incorporate co-testing post colposcopy.
The Consequences of Over-Screening:

Long Term Changes
• LEEP Procedure and Preterm Birth • 80 percent of low
– one LEEP: 7.2% preterm grade lesions will
deliveries (between 28 and 37
weeks) spontaneously
regress.
– No LEEP: 4.6%
– Two LEEPs: preterm risk • 63 percent of CIN 2

increases 3x lesions regress by
three years.
Obstet Gynecol vol121:1063-1067, 2013
1720
Case 1
• 58 year old G2P2

• Menopause at age 52
• No history of abnormal Pap testing
• Pap test with physical shows:
– Insufficient cellularity. HPV co-testing is negative.
• Now what?
Unsatisfactory Cytology
• 1% or less across all preparations.
• Decreased with use of liquid based pap.
• Most cases now due to insufficient squamous

cells.
1721
Case 2
• 58 year old G2P2

• Menopause at age 52
• No history of abnormal Pap testing
• Now pap test shows normal results, but no
EC/TZ
• HPV remains negative
• Now what?
Cytology Normal
EC/TZ Absent/Insufficient
• Suggests squamo-columnar junction may not have
been adequately sampled.
• Reported rates 10-20%.
• More prevalent in older women and adolescents.
• HPV testing is independent of TZ sampling

– Adds margin of safety when co-testing is performed.
1722
Management
• Age 21-29: routine screening.
• Age 30-64
– HPV negative: Routine screening
– HPV unknown: Test for HPV or repeat cytology in 3
years
– HPV positive:
• Cytology and HPV testing in 1 year or
• HPV genotyping (HPV 16 and 18)
Management
Negative Cytology, HPV positive
• Due to increased risk for CIN 3+ if hrHPV positive

guidelines balance risk of observation vs.
intervention.
• Two options:
1. Cytology and HPV co-testing at 12 months.
2. HPV genotyping
• Positive HPV 16/18: Colposcopy and ECC.
• Negative HPV 16/18: Repeat cytology and HPV co-testing in
one year.
1723
Risk of HSIL with + HPV HR

• 2% (52 of 2562 over 10 years) Khan 2005
• 3% (88 of 2941 over 10 years) Castle 2002
• 1.2% (30 or 2562 over 10 years) Miller 2002
Atypical Squamous Cells: Pap Smear Diagnosis

• ASC-US
– 50% will be positive for high risk HPV
– 5-7% presence of CIN 2-3
• ASC-H
– 24-94% presence of CIN 2-3
1724
ASC-US in Pregnancy
• Pregnant women
– Identical to non-pregnant women.
– Acceptable to defer colposcopy until 6 weeks

postpartum.
– ECC is unacceptable.
– If no suspected CIN 2+ at initial colposcopy, follow up

postpartum.
Case 3
• 22 year old G0.

• No previous Pap smear.
• Asymptomatic.
• Seen for routine Gyn exam.
• Pap test shows LSIL.
• What next?
1725
Women Ages 21-24

• No screening before age 21.
• Routine screening with initial normal pap test is every 3

years:
– Cervical CA risk is low through age 25
– HPV is common
– Most lesions will regress
• Less intensive management.
• Encourage HPV vaccination, smoking cessation.
Women Ages 21-24
• ASCUS/LSIL:
– Cytology every 12 months preferred
– HPV reflex is acceptable

• Follow up is repeat cytology if positive
• Routine screening if negative
• Colposcopy only if ASC-H, AGC, HSIL at follow

up.
1726
Low-grade Squamous
Intraepithelial Lesions (LSIL)
• ALTS Trial showed natural history to be similar
to ASC-US HPV+.
• Women 21-24 have lower risk CIN 3+.
• Estimated 77% of LSIL are HPV positive.
LSIL Management
• Colposcopy (recommended):
– Manage based on colposcopic findings
• If co-test is negative, repeat co-test in 1 year

– If cytology negative and HPV negative
• Repeat co-testing in 3 years
– If >ASC or HPV positive

• Colposcopy
1727
ASC-H Management
• Colposcopy for all women.
• High rate of HPV + makes reflex testing

unsuitable.
• 5 year cancer risk among ASC-H, HPV negative

is 2%.
High-Grade Squamous
Intraepithelial Lesion (HSIL)
• CIN 2+ identified in 60% of women at
colposcopy.
• Consider immediate excision of
transformation zone.
• Cervical cancer found in 2% at colposcopy
– Risk rises with age
– Risk modifies with HPV result
• HPV result from co-test may help inform
choice.
1728
Management HSIL
• Immediate LEEP
• Colposcopy
– Diagnostic excisional procedure recommneded for
inadequate colposcopy
• Except if pregnant
HSIL in Young Women
• Colposcopy
– If no CIN 2+ observe with colposcopy and cytology

at 6 month intervals for 24 months.
– If CIN 2/3 present manage with colposcopy and

biopsy or treat
1729
Endometrial Cells with Cervical cytology

• No further evaluation in asymptomatic
premenopausal women.
• If postmenopausal, endometrial assessment is

recommended regardless of symptoms.
• No further evaluation with benign glandular cells

following hysterectomy
Ages 21-24: Biopsy CIN I
• Treatment not recommended.
• After ASC-US or LSIL pap: Repeat pap smear.
• After ASC-H or HSIL pap: Repeat pap smear and

colposcopy every six months for one year.
– If colposcopy is inadequate: Excisional
procedure.
1730
Biopsy: CIN 2-3:

Recommend excisional
procedure
Biopsy: AIS
-Excisional procedure
-Hysterectomy is preferred treatment
1731
Special Screening Situations:
Pregnancy
• Pap smear is performed at first prenatal visit

and at the six week post partum visit.
• Abnormal Pap smears are evaluated in a

similar manner to non-pregnant women.
CIN in Pregnant Patient

• Colposcopy should have exclusion of invasive cancer as its primary
goal.
• Unless cancer is identified or suspected, treatment of CIN in

pregnancy is contraindicated.
• A diagnostic excisional procedure is recommended only if invasion

is suspected.
• Initial evaluation of AGC is the same except NO ECC or endometrial

biopsy.
• Reassess with cytology and colposcopy no sooner than 6 weeks
postpartum.
1732
FINAL THOUGHTS
for the over 65 crowd
• 25 % of cervical cancers occur in women over
age 65
• 40 % of cervical cancer deaths occur in
women over age 65
• Cervical cancer statistics artificially lower in
over 65 age because because statistics include
women who have had hysterectomies
• Stay tuned for possible guideline changes
• Maintain high clinical level of suspicion
1733
A practical approach to the

patient with menopausal
symptoms
Kathryn A Martin, MD
Reproductive Endocrine Unit, Department of
Medicine
Senior Deputy Editor, Endocrinology and Patient
Education, UpToDate
Conflict of Interest Disclosure
Kathryn A Martin, MD
Senior Deputy Editor, UpToDate
1734
Menopausal hormone therapy (MHT):

Major messages
• Indicated for treatment of moderate to

severe symptoms (hot flashes) in younger
menopausal women (50s or <10 years
postmenopause- if no contraindications)
• Safety in this group is well
established
• Under prescribed
• Difficult for women to get treated
• Untreated hot flashes have important
consequences
Major messages
• Hot flashes last a LONG time

• Duration of therapy should be
individualized
• Vulvovaginal atrophy a common symptom

• Low dose vaginal estrogen
• WHI 2017 safety data
1735
Trends in oral MHT use
WHI
Sprague et al
Obstet Gynecol 2012
Why are prescription rates so low?
• Lack of awareness of most current MHT

evidence
• Difference in guideline recommendations
• Current generation of new trainees have no
experience (Manson NEJM 2016; Santen et
al 2014)
• 10-12 million women in US are candidates;

not receiving MHT
1736
Consequences of not treating PMW
Untreated hot flashes:

• Quality of life
• Sleep disturbances
• Economic impact (Sarrel Menopause 2015)
– Lost productivity
– Increased healthcare costs
• Increase in osteoporosis-related fractures
Consequences of not treating PMW

• Increase in use of compounded “bioidentical
hormones” (as many women on BHT as MHT)
–Perceived to be safer
–A high percentage of women believe they are
FDA-approved products (Pinkerton and
Santoro, Menopause 2015)
–Concerns re: standardization and purity;
expensive
–Endocrine Society Scientific Statement
1737
Women’s Health Initiative: Program Design

Effect of MHT on prevention of chronic disease (CHD, OP)
Hysterectomy
YES NO
N=10,739 N=16,608
CEE CEE 0.625 Placebo

Placebo mg/d + MPA
0.625
mg/d 2.5 mg/d
Trial stopped in 2002: breast

Trial stopped in 2004:
No CHD or breast ca; cancer risk and apparent
stroke concern. *Role of MPA CV risks. (HR vs AR)
Current thinking
• Age is important (WHI mean age 63)
Timing of exposure: Probable underlying
atherosclerosis and vulnerable plaque older
but not younger PMW
Don’t initiate MHT in older women!
• Safety in younger postmenopausal women
well established (ages 50-59, < 10 years
postmenopause)
• WHI follow-up analyses, coronary
calcification, 2 RCTs (KEEPS, ELITE),
Cochrane, WHI mortality data 2017
1738
Current thinking
Younger PMW – prevention of CHD is NOT
established
• No evidence for increased risk CHD, but
data in the two RCTs are inconsistent
(KEEPS and ELITE using E2 and P)
• Use for symptom management only
• WHI – with less favorable regimen:
• Additional 2.5 cases/1000 women/5
years of use; 5.5 fewer cases for E only
KEEPS: KRONOS Early Estrogen Prevention Study
• 726 women ages 42-58

• Oral CE 0.45 mg, transdermal E2 50 mcg,
placebo; Micronized P 200 mg x 12 (4 yrs)
• Endpoints: carotid IMT, coronary artery calcium
scores
• E improved markers of CVD risk
• Carotid IMT no different oral or transdermal
estrogen, vs placebo Harman Ann Intern Med 2014
• No rebound increase thickness 3 years after
stopping E (Menopause 2018)
1739
ELITE Trial
• Early Versus Late Intervention Trial With Estradiol

• 643 postmenopausal women
• < 6 yrs or ≥ 10 yrs from menopause (mean age 55
or 65)
• Oral E2 1 mg vs placebo for 6 years (vaginal P 12
days if uterus)
• Carotid IMT: (data support timing hypothesis)
• ≥10 yrs from menopause no diff from placebo
• < 6 yrs slower progression of atherosclerosis
Hodis N Engl J Med 2016; 374:1221
Early vs Late Initiation of Hormone Therapy

and Carotid Intima Media Thickness
Hodis et al,
NEJM, 2016
1740
Mortality all ages: 18 years of follow-up
Manson
JAMA
2017
Overall risk vs benefit: WHI data (women 50-59)

Number of events per 1000 women per 5 years use
1741
Endocrine Society Clinical Practice Guideline 2015

• Individualize therapy based upon clinical factors
and patient preference
• Medical history – contraindications: breast ca,
CHD, stroke, VTE, active liver disease, high risk
endometrial ca, TIA, undiagnosed vaginal
bleeding
• Before initiating MHT, estimate patient’s:
• 10-year cardiovascular risk
• 5-year breast cancer risk
Stuenkel et al JCEM 2015
Choosing Candidates: Evaluate CVD risk
10-year CVD risk MHT recommendation if <10

years since menopause
Low (<5%) MHT ok
Moderate (5-10%) MHT ok, but use transdermal
High (>10%) Avoid MHT
Calculated using ACC/AHA risk calculator Stuenkel et al, JCEM 2015;

Adapted from Manson, Fertil Steril 2014
1742
Breast Cancer Risk Cutoffs for MHT

Risk category 5-y NCI or IBIS Suggested
Breast cancer risk approach
assessment, %
Low <1.67 MHT ok
Intermediate 1.67-3 Caution
High >3 Avoid
Stuenkel et al, JCEM 2015
Menopausal symptoms
Hot flashes
• Peak in late menopausal transition/ early
postmenopause (longitudinal cohort studies about
85%)
• Varies by ethnicity
• Risk factors: obesity, PMS, genetic variants tachykinin
receptor 3 (TACR3)
Duration
• For many/most women: 7 to 10 years
• Long duration of symptoms has important implications
for duration of therapy
• Patterns/trajectories
1743
Trajectories – hot flashes
26%
18% 29%
27%
Case 1
• A 51 year old woman with 4 months of amenorrhea
• She is awakened at least six to seven times a night

and has frequent episodes during the day that are
interfering with her ability to function at work
• No history VTE, stroke. Calculated 10-year risk CVD

5%, breast cancer risk 1.2% in 5 years
• What would you recommend?
1744
Case 1
• A. Black cohosh
• B. Conjugated estrogen with continuous

medroxyprogesterone
• C. 17-B estradiol (oral or transdermal) with cyclic

micronized progesterone
• D. Bazedoxifene/Conjugated estrogen
Case 1
• A. Black cohosh – is ineffective in trials and meta-analyses,
and this patient has significant symptoms.
• B. Conjugated estrogen with continuous

medroxyprogesterone – this could be used, but a continuous
progestin will result in breakthrough bleeding (patient still has
ovarian function. A cyclic progestin regimen is preferred
initially
• C. 17-B estradiol (oral or transdermal) with cyclic micronized

progesterone- this would be my first choice: a cyclic progestin
to minimize BTB and 17-B estradiol, the same estrogen made
by the ovary
• D. Bazedoxifene/Conjugated estrogen – this is not a first line

therapy for MHT, but it can be helpful for women who are
unable to tolerate progestins
1745
Other menopausal symptoms

• Mood disorders (perimenopausal)
• Sleep disturbances
– 40% even in the absence of HF: contributors are
primary sleep disorders, depression and
anxiety.
• Joint pain – similar to the MS side effects of
aromatase inhibitors (AIs), improves with estrogen
• Vulvovaginal atrophy (VVA) - Genitourinary
syndrome of menopause (GSM)--tends to develop
in the years or decades after menopause
• Long-term consequences: bone loss, CVD
Perimenopausal mood disorders

• Depression/mood disorders (35-40% in menopausal
transition)
• More common in women with hot flashes
• Particularly nighttime HF associated with mood
symptoms (not just sleep deprivation)
• Other risk factors: personal or family history of
mood disorders, PMS Freeman EW Arch Gen Psych 2006
• Choose initial therapy based upon predominant

symptom (depression vs VMS) – often need both E and
SSRI (citalopram, escitalopram, duloxetine)
• Usually progestin intolerant
1746
Estrogen for vasomotor symptoms
• 80-95% decrease in VMS (dose)

• Which estrogen? - 17-B estradiol
• Dose – start low unless sx are severe.
• Lower doses effective in many women
• Lower risk of VTE and stroke
Route: transdermal vs oral

Transdermal estrogens have less effect on:
•Clotting factors, triglycerides, C-reactive protein
•SHBG
Lower risk of:
• VTE (Canonico Circ 07, BMJ 08)
• Stroke (if dose < 50 mcg) Renoux BMJ 2010)
• Increase in mammographic density
Most important for women with high TG,
gallbladder disease, and risks for CVD or
VTE
1747
Which progestin?
Advantages of micronized progesterone
• Bioidentical, physiologic
• Neutral metabolic effect. (eg does not negate
benefits of oral E)
• Vascular –Unlike MPA, P does not negate
vasodilatory effect of E (primate data). Differential
effects on endothelial function
• Ischemic stroke risk (Canonico Stroke 2016) MP
better than MPA
• Breast cancer - ? lowest risk with micronized P ;
(European observational studies; Endo Society metaanalysis JCEM 2015)
My approach
Late transition/early postmenopause
• Transdermal E2 0.025 mg (25 mcg) + cyclic MP 200 mg
days 1-12 (**higher dose 50 mcg for severe symptoms)
Postmenopausal (≥ 2 years)
• Transdermal E2 0.025 mg (25 mcg) + continuous MP
100 mg (higher dose E2 for severe symptoms)
• Oral E2 ok for healthy women without DVT risks who

prefer oral preps (0.5-1 mg)
• Consider low dose OC in some women in 40s with
heavy bleeding who desire contraception
• POI/POF
1748
Women who cannot tolerate oral progestins
• 20% side effects: BTB and mood issues

• Vaginal progesterone (45 mg daily x 10 days/month)
• Progestin IUD (levonorgestrel) – off-label use in US.
Breast cancer concerns
• Quarterly progestin regimens: safety not established
• Tissue selective estrogen complex (TSEC)
–Oral conjugated estrogen 0.45 mg with bazedoxifene
20 mg
–SERM antagonizes E effect on endometrium, so no P
needed
Duration of therapy and stopping

• Extended use: ACOG, NAMS statements
–Extended use (beyond age 60 [or 65]) may be
appropriate for women with severe vasomotor
symptoms and low risk for cardiovascular
disease/breast cancer
–Periodic weaning to assess need (anticipate recurrent

VMS, use nonhormonal agents while weaning)
–Tapering vs not tapering
Obstet Gynecol 2014 123:202; Menopause 2015; 22:693)
1749
Case 2
• A 53 year old woman with breast cancer. She
has undergone surgery, chemotherapy, RT,
and is now on tamoxifen
• Since starting tamoxifen she has had severe

hot flashes, They are most bothersome at
night
• She is having trouble functioning at work
• What would you suggest?
Case 2
A. Black cohosh
B. Gabapentin
C. Acupuncture
D. Paroxetine
1750
Case 2
A. Black cohosh – ineffective for hot flashes; binds to
estrogen receptors (although there is no evidence
that it increases recurrence risk)
B. Gabapentin – this would be my first choice.

Gabapentin is better than placebo in trials, although
not as effective as estrogen. A single bedtime dose is
often helpful and avoids daytime sleepiness
C. Acupuncture – the best clinical trial evidence

suggests that acupuncture is ineffective for HF
D. Paroxetine – avoid in women on tamoxifen; it inhibits

CYP2D6, the enzyme the converts TAM to endoxifen
Nonhormonal alternatives
Phytoestrogens, soy, red clover
• Inconsistent data
• Large effects unlikely
Black cohosh (Cimicifuga): widely used
• HALT trial - Black cohosh alone no more effective than
placebo. CEE effective as expected. (Newton, Ann Intern
Med 2006)
• Cochrane 2012 – no evidence that better than placebo but
heterogeneity
Concerns about estrogen agonist effects
Acupuncture – both acupuncture and sham acupuncture
work
1751
Nonhormonal therapies: Pharmacologic

SSRIs
• Citalopram 20 mg
• Escitalopram 10 to 20 mg
• Paroxetine 7.5 mg (Brisdelle- low dose mesylate salt; FDA
approved) or paroxetine HCl 20 mg, CR 12.5-25 mg
• Sertraline and fluoxetine are less effective
• Women on tamoxifen: Avoid paroxetine! (CYP2D6
inhibitor); escitalopram weakest inhibitor
SNRIs
• Venlafaxine 75 mg; Desvenlafaxine 50 mg
Nonhormonal therapies: Pharmacologic

• Gabapentin 100 to 1200 mg one hour before bedtime.
Titrate dose up. (good choice for night time symptoms)
• Clonidine – use limited by side effects
• Range of effect all drugs: only a 40 to 50% reduction (e.g.
only 20% better than placebo (25-30%) Loprinzi et al J Clin Oncol
2009
• Response not explained by mood effect
• Promising new approach: NK3R antagonist

administration- 80% decrease frequency vs 30 % for
placebo Prague et al Lancet 2017; 389 epub
1752
Vulvovaginal atrophy:Low-dose vaginal estrogen

Do not need systemic dosing for vulvovaginal sx
• E2 or CEE creams: difficult to administer low
doses
• E2 tablets: 10 µg twice weekly (serum
E2<10pg/ml; 37 pmol/L)
• Vaginal ring 8 ug/day (serum E2 = 7 pg/mL; 26
pmol/L)
• Improved sexual QOL (Setty, Menopause August
2015), no endometrial thickening
Vulvovaginal atrophy:Low-dose vaginal estrogen
• *Breast cancer patients (discuss with

oncologist, no vaginal E if taking an
aromatase inhibitor)
• **WHI 2017: no increase endometrial or
breast cancer, stroke or VTE
• Ospemifene, DHEA
1753
Key points
• For many/most symptomatic women <age 60 or <10
years postmenopause, the benefits of MHT outweigh the
risks
• Women with moderate to severe menopausal symptoms
are currently undertreated
• Reluctance to prescribe coincides with an increase in
use of bioidentical hormone therapy
• Individualized approach: assess baseline CVD and
breast cancer risks
• Start with low dose E and titrate up, unless severe
symptoms
• Preferred regimen: E2 and MP
Key points
• Hot flashes last a long time – has implications for
duration of therapy
• Extended use (beyond age 60) may be
appropriate for women with severe vasomotor
symptoms and low risk cardiovascular
complications
• After stopping, if recurrent VMS, try SSRIs/SNRIs
or gabapentin
• Vaginal estrogen should be discussed with ALL
women, particularly when systemic estrogen is
stopped
1754
References
• Stuenkel et al. Treatment of symptoms of the Menopause: An
Endocrine Society Clinical Practice Guideline. J Clin Endocrinol
Metab 2015l 100:3975
• Moyer VA U.S. Preventive Services Task Force. Menopausal
hormone therapy for the primary prevention of chronic conditions:
U.S. Preventive Services Task Force recommendation statement.
Ann Intern Med. 2013;158(1):47.
• Manson JE, Chlebowski RT. Menopausal hormone therapy and
health outcomes during the intervention and extended
poststopping phases of the Women's Health Initiative randomized
trials. JAMA. 2013;310(13):1353.
• Hodis HN, Mack WJ. Vascular Effects of Early versus Late
Postmenopausal Treatment with Estradiol. N Engl J Med.
2016;374(13):1221
• Boardman HM, Hartley L et al. Hormone therapy for preventing
cardiovascular disease in post-menopausal women. Cochrane
Database Syst Rev. 2015 CD002229
1755
Evaluation of the Patient

with Menstrual Irregularities
Associate Program Director, Internal Medicine Residency

I have no conflicts of interest to report.
1756
Female Hypothalamic-Pituitary-Gonadal Axis
Hypothalamus
GnRH
Pituitary
LH E2,
FSH Progesterone,
Inhibin A & B
Ovary
150
Hormone Secretion in the
40
Normal Menstrual Cycle
LH (IU/L)
FSH (IU/L)
100
20
50
Length 25-35 days
Luteal phase 12-14 days
0 0 Follicular phase variable
300 20
P4 (ng/mL)
E2 (pg/mL)
200
10
100
0 0
-20 Menses -10 -5 0 5 10
Days Centered to Ovulation Welt et al, JCEM 1999
1757
Case #1: History

• 19 year old woman presents to your clinic for
evaluation because she has had no menses
for 8 months.
• Her menarche was at age 13, and she had

regular menses until 8 months ago.
• About one year ago, she increased her

aerobic exercise with a 20 lb weight loss.
Case #1: History

• She has not had any headaches, vision
changes, hot flushes, or night sweats.
• She has no history of an eating

disorder.
• Her thyroid review of systems are

negative.
1758
Case #1: Physical Exam

• BMI 18 BP 100/60 P60
• Skin with no hirsutism, acne, or alopecia.
• Visual fields full.
• Thyroid size is normal. No nodules.
• No galactorrhea.
• Pelvic exam normal.
What is her diagnosis and

what labs would you order?
Amenorrhea
• Primary Amenorrhea
– Absence of menses by age 16
• Secondary Amenorrhea
– Absence of menses for 3 months
Pathophysiologic considerations are the

same for both.
Incidence of genetic & anatomic

abnormalities higher with primary
amenorrhea.
1759
Etiologies
• Pregnancy
• Uterine or Outflow Tract Disorders
• Ovulatory Disorders
Causes of Primary Amenorrhea
Hypothalamus – Hypothalamus 27%
– Pituitary 2%
– PCOS 7%
Pituitary
LH – Ovary 43%
E2
FSH Inhibin A &
B – Uterus/Outflow Tract 19%
Ovary
1760
Causes of Secondary Amenorrhea
Hypothalamus – Hypothalamus 36%
– Pituitary 15%
Pituitary – PCOS 30%

LH E2
FSH Inhibin A & B – Ovary 12%
Ovary – Uterus/Outflow Tract 7%
Diagnostic Lab Evaluation
• βhCG (rule out pregnancy!)

• FSH (test for ovarian insufficiency)
• Prolactin
• TSH
1761
Case #1: Labs

• FSH 3.2 IU/L
• Prolactin 6.3 ng/mL
• TSH 2.6 µU/mL
• βhCG neg
• Provera challenge was negative for a

withdrawal bleed.
What is her diagnosis?
Hypothalamus
Pituitary
LH E2,
FSH Progesterone,
Inhibin A & B
Ovary
1762
Hypothalamic & Pituitary Etiologies

• Hypothalamic Amenorrhea (HA)
• Hyperprolactinemia
• Tumors and Destructive/Infiltrative Lesions
• Genetic: IHH, Kallmann syndrome
• Cranial Irradiation
• Others: hypo- or hyperthyroidism, excess
cortisol
• Pituitary tumor (mass effect)
• Lymphocytic hypophysitis
• Pituitary infarction
• Empty-sella syndrome
Hypothalamic Amenorrhea
• Etiology
–Energy Output > Energy Input
• Weight loss
• Eating Disorders
• Excessive exercise
–Stress
• Psychological
• Physical
1763
• Leptin
Peripheral signal indicating sufficient
energy stores for reproduction.
Baseline After 2 Weeks r-metHuLeptin
8
* *
* 30
Leptin (ng/mL)
LH (mIU/mL)
6
* *
* 20
4 *
2 10
0 0
0 1 2 3 4 5 6 7 8 9 101112 0 1 2 3 4 5 6 7 8 9 101112
7PM Time (hr) 7AM 7PM Time (hr) 7AM
Welt et al., 2004
Management Questions
• Does this patient need a MRI?
– Headaches or neurological symptoms
– Elevated prolactin
– History unclear
– Primary amenorrhea
• How about a Bone Mineral Density Scan?

– amenorrhea >6 months
1764
Hypothalamic Amenorrhea: Recovery
Percentage Recovered
100
80
60
40
20
0
Eating Idiopathic Stress/
Disorder n=9 Weight Loss
n=15 n=6 (Perkins et al., 2001)
Hypothalamic Amenorrhea:
Treatment
• Weight gain, decrease exercise
• Oral contraceptives or
hormone replacement therapy
• Calcium and Vitamin D
1765
Case #2
• 27 yo with 3 months amenorrhea

• Moderate exercise, no eating disorders
• Insomnia
• No hirsutism, mild acne
• History of hypothyroidism on thyroid
hormone replacement
Case #2
• Family history of early menopause

• Physical exam unremarkable
• Labs:
–FSH 56 IU/L, TSH 3.7 µU/mL, neg
βhCG, prl 10.8 ng/mL
• Diagnosis?
• Further workup?
1766
Hypothalamus
Pituitary
LH E2,
FSH Progesterone,
Inhibin A & B
Ovary
Primary Ovarian Insufficiency

• Elevated FSH, age < 40 yrs
• Repeat testing important: follicular phase
• Causes:
– Turner’s syndrome
– X chromosome deletions, translocations
– Fragile X premutations
– Autoimmune
– Chemotherapy or radiation therapy
– Galactosemia, FSH/LH receptor mutations,
blepharophimosis, BMP 15 mutations
1767
Primary Ovarian Insufficiency:

Diagnostic Tests
• Karyotype
– Age <30 yrs, familial cases, ?everyone
– Turner’s features
• Fragile X Premutation screen
• Anti-thyroid and anti-adrenal antibodies
• Anti-ovarian antibodies poor test

• Ovarian biopsy is not helpful
Primary Ovarian Insufficiency:

Treatment
• Oral contraceptive pills or hormone
replacement therapy
• Calcium and vitamin D
1768
Case #3: History

• 28 year old woman presents to your clinic for
evaluation of irregular menses
• She describes irregular menses since age of

menarche which was at 14 years of age
• She has also had problems with increased

hair growth on her upper lip and chin
Case #3: History

• She does not have hot flashes, night sweats,
galactorrhea, or positive thyroid review of
systems
• She is on no meds currently and has a family

history of type 2 diabetes.
1769
Case #3: Physical Exam

• BMI of 29
• Skin with hirsutism of the upper lip, chin, and
sides of her face. No acanthosis.
• No clitoromegaly.
What labs/studies would you order?
Case #3: Labs

• Laboratory testing reveals normal
– TSH
– Prolactin
– FSH
– Androgen levels (total testosterone)
1770
Polycystic Ovarian Syndrome
Hypothalamus
Adipose
Tissue
Pituitary
Muscle
Ovary
PCOS: Epidemiology
• 4.7-6.8% of women have PCOS as defined
by the NIH criteria
(Knockenhauer et al., JCEM 1998; Diamanti-Kandarakis,
JCEM, 1999; Asuncion, JCEM 2001)
• Most common cause of female infertility (50-

60%)
• May be the most endocrinopathy in young

women
1771
PCOS: NIH Definition

• Menstrual dysfunction
– < 9 menses per year
• Hyperandrogenism
– Hirsutism, acne, alopecia and/or
– Elevated serum androgens
• Exclusion of other diseases (e.g.

hyperprolactinemia, androgen secreting
tumors, CAH)
(NIH Conference, 1990)
PCOS: Rotterdam Definition

• 2 out of 3 of the following must be true:
– Oligo- or anovulation
– Clinical and/or biodchemical signs of
hyperandrogenism
– Polycystic Ovaries
Exclusion of other etiologies (e.g.

hyperprolactinemia, CAH, androgen
secreting tumors)
(ESHRE/ASRM sponsored PCOS Consensus Workshop Group,Fert and Ster, 2004)
1772
Polycystic ovary (PCO):

multiple small (2 – 9
mm) follicles
peripheral distribution
increased stromal
volume
ovaries usually
enlarged
(Adams et al, 1985,
Fert and Ster, 2004)
Normal ovary:
fewer follicles
random distribution
no increased stroma
( images courtesy of Judy Adams)
Polycystic Ovarian
Morphology (PCOM)
• 100% of women with PCOS have PCOM
(Taylor et al JCEM 1997)
• 23% of normally cycling women will have PCOM

(Polson et al, Lancet, 1988)
• Present in other ovulatory disorders

(hyperprolactinemia, late onset CAH, adolescence
(Azziz R. JCEM 2006)
1773
Clinical Manifestations
• Oligo- or anovulation
• Hyperandrogenism
• Infertility
• Insulin Resistance
Treatment of PCOS
Hyperandrogenism
• Weight loss
• Cosmetic measures
• Hormonal therapy
1774
Treatment of PCOS
Hyperandrogenism Oligo-amenorhea
• Weight loss • Weight Loss
• Cosmetic measures • Hormonal therapy
• Hormonal therapy • Metformin
Treatment of PCOS
Infertility
• Weight Loss
• Metformin
• Ovulation Induction/IVF
1775
Treatment of PCOS
Infertility Insulin Resistance

• Weight Loss • Weight Loss/ Exercise
• Metformin • Metformin
• Ovulation Induction/IVF • Monitor BPs, lipids
Treatment of PCOS
Infertility Insulin Resistance

• Weight Loss • Weight Loss/ Exercise
• Metformin • Metformin
•Ovulation Induction/IVF • Monitor BPs, lipids
1776
Summary
• Hypothalamic Amenorrhea
– Diagnosis
– Management (MRI, BMD)
– Treatment (weight gain, OCPs, HRT)
• Primary Ovarian Insufficiency

– Definition
– Diagnostic evaluation (karyotype, Fragile X)
– Treatment options (OCPs, HRT)
Summary
• PCOS
– Epidemiology
– Diagnosis (NIH versus Rotterdam criteria)
– Clinical Manifestations (anovulation,
hyperandrogenism, fertility, insulin
resistance)
– Treatment options (weight loss, OCPs,
spironolactone, metformin)
1777
Question #1
24 year old woman with a 6 month history of
amenorrhea comes in for evaluation. Her
thyroid review of systems are negative. She
does not have hot flushes, night sweats, or
galactorrhea. She is on no medications.
Physical exam is unremarkable. hCG
negative. FSH and TSH normal. Prolactin is
slightly elevated at 30 ng/mL (<18 ng/mL) and
confirmed on repeat evaluation.
Question #1
What is the next best step?
A) Treat with bromocriptine/cabergoline
B) Treat with an oral contraceptive pill
C) Give a progesterone challenge
D) Obtain a pituitary MRI
E) Repeat the prolactin in 3 months. No treatment for

now.
1778
Question #1
What is the next best step?
A) Treat with bromocriptine/cabergoline
B) Treat with an oral contraceptive pill
C) Give a progesterone challenge
D) Obtain a pituitary MRI
E) Repeat the prolactin in 3 months. No treatment for

now.
Question #2
34 year old woman with a 4 month history of
amenorrhea comes to see you for evaluation.
Her menses had occurred every 2 months
before they stopped. Her exercise routine is
unchanged; she runs about 25 miles per
week. She has had no hot flushes or night
sweats. Her thyroid review of systems are
negative. Physical exam reveals some
terminal hair growth of her face. TSH, FSH,
and prolactin are normal. hCG negative.
1779
Question #2
What would you do next?
A) Medroxyprogesterone challenge
B) Treat with OCPs
C) Treat with metformin
D) MRI of the pituitary gland
E) Pelvic ultrasound
Question #2
A) Medroxyprogesterone challenge
B) Treat with OCPs
C) Treat with metformin
D) MRI of the pituitary gland
E) Pelvic ultrasound
1780
References
• Gordon CM, et al. 2017 Functional hypothalamic amenorrhea:

An Endocrine Society Clinical Practice Guideline. JCEM
102:1413.
• Legro RS, et al. 2013 Diagnosis and Treatement of Polycystic

Ovarian Syndrome: An Endocrine Society Clinical Practice
Guideline. JCEM 98:4565.
• Nelson LM. 2009 Clinical practice. Primary ovarian insufficiency.

NEJM 360:606.
I have no conflicts of interest to report.
1781
Osteoporosis and Metabolic

Bone Diseases
Carolyn Becker MD
Master Clinician Educator
Division of Endocrinology, Diabetes and Hypertension
Disclosures
• Royalties from UpToDate for 2 chapters on
Premenopausal Osteoporosis ($1800/yr)
1782
What Does the Primary Care Clinician

Need to Know About Bone in 2018?
• Calcium and vitamin D: anything new?
• Fracture risk factors to watch out for: falls,
meds, mental health, hyponatremia
• 2017 ACP Guidelines: the good and the bad
• Update on denosumab: the good, the bad,
and the ugly
• Managing osteoporosis over the long-term:
have we learned anything?

and the ugly
1783
Calcium and Vitamin D: A Summary

• Ca + D supplementation leads to a modest
reduction in fracture risk; Ca alone is not effective
• Vitamin D supplementation may reduce falls
• Population-level intervention with Ca + D has not
proven to be an effective public health strategy
• Side effects of Ca supplementation include kidney
stones and GI upset
• Increased CVD risk from Ca supplementation is not
convincingly supported by current evidence
Harvey NC et al. 2017 Osteoporos Int 28(2):447
Who Should Receive Calcium and

Vitamin D Supplementation?
• Those at high risk for calcium and/or vitamin
D insufficiency (frail elderly, institutionalized,
lack of sunlight exposure, malabsorption,
malnutrition, obese, teenage girls, etc)
• Those receiving treatment for osteoporosis
CHECK 25OHD LEVELS IN ALL OF THESE
GROUPS AND REPLETE TO ~30 ng/mL
Harvey NC et al. 2017 Osteoporos Int 28(2):447
1784
Checking Vitamin D Levels…

• For elderly without osteoporosis or high
fracture risk, can simply follow Institute of
Medicine (IOM) recommendations and give
800 IU cholecalciferol (vitamin D3) daily
Repleting Vitamin D
• Vitamin D3 (cholecalciferol) is preferred for
chronic therapy; can use D2 (ergocalciferol)
for “loading dose” in severe deficiency
• 800 - 1000 IU D3 daily will increase 25OHD by
~ 10 - 16 ng/ml
• Higher doses needed for obese, those with
malabsorption, or those with increased
metabolism (eg. anticonvulsants)
1785

and the ugly
Current Guidelines for Ordering

Screening DXA
• Women age 65 yrs
and older
• Men age 70 and older
• Postmenopausal
women and men age
50-69 with risk
factors
• Post-fragility fracture
National Osteoporosis Foundation 2013 Clinicians Guide to Prevention and Treatment

of Osteoporosis
1786
Standard Clinical Risk Factors for

Osteoporosis Screening
• Caucasian/Asian • Rheumatoid arthritis
• Older age • Hypogonadism (no rx)
• Previous adult fracture • Inflammatory bowel
• Female gender disease; malabsorption
• Low body weight • Prolonged immobility
• Parental hip fracture • Organ transplantation
• Smoking • Hyperthyroidism
• Alcohol (3 or more/d) • COPD
• Glucocorticoids (5 mg pred • Diabetes (Type 1)
or > x 3 mos or more)
Kanis JA et al 2013 Osteoporos Int 24:23
Standard Clinical Risk Factors for

Osteoporosis Screening
• Caucasian/Asian • Rheumatoid arthritis
• Older age • Hypogonadism (no rx)
• Previous adult fracture • Inflammatory bowel
• Female gender disease; malabsorption
•
ARE WE
Low body weight
MISSING SOME IMPORTANT
• Prolonged immobility
• Parental CLINICAL
hip fracture RISK FACTORS?
• Organ transplantation
• Smoking • Hyperthyroidism
• Alcohol (3 or more/d) • COPD
• Glucocorticoids (5 mg pred • Diabetes (Type 1)
or > x 3 mos or more)
Kanis JA et al 2013 Osteoporos Int 24:23
1787
Osteoporotic Fractures in the US
>50% OF OSTEOPOROTIC
FRACTURES
OCCUR DUE TO A FALL!
Shuler FD et al. 2012 Orthopedics 35(9):798
To Reduce Fractures, We Need to Reduce

Falls, Increase Bone Strength, or Both
1788
We Have Under-Emphasized
Identifying Risk Factors for Falls
• Dementia
• Frailty
• Poor visual acuity
• Gait instability
• Postural hypotension
• Peripheral neuropathy
• Neurodegenerative disorders
• Osteoarthritis of hips, knees
• Diabetes
Strongest Predictor = Previous Fall!
• Vitamin D deficiency
• Medications
Screening for Falls During the Annual

Physical Exam
• Any falls in the past year?
• If yes, how many, where did they occur, and
any injuries?
• Any unsteadiness while standing or walking?
• Any fears or worries about falling?
1789
Screening for Falls

• Medication review
• Cognitive screen
• Feet and footwear
• Use of assistive device
• Visual acuity assessment
Moncada LVV, Mire LG. 2017 Am Fam Physician 96(4):240
Fall-Focused Physical Exam

• Vital signs: including orthostatic BP
• Gait, strength, and balance testing (go to
“YouTube” for demonstrations).
– Timed Up and Go test
– 4-Stage Balance Test
– 30-Second Chair Stand
1790
• > 68,000 patients with mental disorders or on

psych meds underwent baseline DXA and
FRAX® calculations and were followed x 7
years
• Observed hip fracture rates were much
higher than FRAX-predicted hip fracture rates
for this population
Bolton JM et al. 2017 JAMA Psychiatry 74(6):641
1791
FRAX MAY UNDERESTIMATE ACTUAL

HIP FRACTURE RATE BY 50% FOR THOSE
WITH DEPRESSION OR SSRI USE
N = 447,169
• SSRIs
• Benzodiazepines THESE MEDICATIONS
WERE
• Anticonvulsants
HIGHLY ASSOCIATED
• Hypnotics WITH FALLS
• Antipsychotics
1792
Limitations of DXA and FRAX®

DXA FRAX®
• Does not predict • Does not include falls
falls • Underestimates
fracture risk (eg. in DM
• Does not measure
and mental illness)
bone quality
• Assumes glucocorticoid
• Underestimates dose 2.5 – 7.5 mg/d
fracture risk (eg. in • Does not account for
those with diabetes) other high-risk meds
• Low sensitivity (AIs, SSRIs, PPIs, etc)
Can We Tweak FRAX® to Make it A

Better Predictor?
• For fallers, multiply FRAX® score by 1.3
• For mental disorder or use of psychotropic
drugs, multiply FRAX® score by 1.5
• For glucocorticoid dose > 7.5 mg/d, multiply
FRAX® by 1.15 at spine and 1.2 at hip
• For those with diabetes add 10 years to age
then recalculate FRAX® or, check off box for
“Rheumatoid Arthritis” and recalculate
Kanis JA et al. 2011 Osteoporos Int 22:2395
McCloskey EV et al. 2016 Curr Opin Rheumatol 28:433
1793
• Matched case control study from a large

US healthcare system with over 2.9
million lives
• Multiple variables were compared
including presence of hyponatremia
(Na < 135 mEq/L)
Slide from Verbalis JG, Clinical Endocrine Update 2017, Chicago
1794
Slide from Verbalis JG, Clinical Endocrine Update 2017, Chicago
Loss of osmolytes, Hyponatremia stimulates

eg. glutamate, a osteoclasts to mobilize
neurotransmitter sodium from bone;
associated with gait AVP may also play a role
Negri AL, Ayus JC. 2017 Rev Endocr Metab Disord 18:67
1795
Implications for the Clinician

• All patients with osteoporosis, fractures, or
unsteady gait should be screened for
hyponatremia
• If Na < 135 is found, an effort should be
made to stop the offending agent (eg.
thiazide or SSRI) or find another underlying
cause
• Look for osteoporosis in outpatients with
hyponatremia
Negri AL, Ayus JC. 2017 Rev Endocr Metab Disord 18:67

and the ugly
1796
• In postmenopausal women with osteoporosis,

– Use alendronate, risedronate, zoledronate, or
denosumab to reduce risk of hip or vertebral
fractures
– Menopausal estrogen, estrogen + progestin, or
raloxifene are not recommended
• Treat osteoporotic women with pharmacologic
therapy for 5 years
• BMD monitoring during the 5-year

pharmacologic treatment period is not
recommended
• For men with osteoporosis, offer
bisphosphonates to reduce risk of vertebral
fractures
1797
• ACP guidelines over-simplify the process

• They exclude anabolic therapy and SERMs
(raloxifene) for postmenopausal osteoporosis
• For men, they exclude denosumab and teriparatide
• By recommending therapy for 5 years, they fail to
promote an individualized, patient-centered
approach
• Treating to a target (eg. T-score > -2.5 at total hip) is

better than a strict “end-date”
• Lack of DXA monitoring during 5 years of treatment
is problematic and will miss noncompliance, non-
response to therapy, etc.
• They don’t address concerns about stopping
denosumab (to follow)
1798
Case
• A 75 year old woman comes for follow-up.
Recently, she fell and fractured her wrist and
humerus. Everything healed well.
• Screening DXA at age 65 showed
osteoporosis. She started alendronate but
stopped after 2 pills and refused follow-up
BMD. She doesn’t like medications.
• PMH: HTN
• SH: non-exerciser; no bad habits
• Meds: lisinopril 5 mg daily
Case 2 (cont)
• On exam, BP 128/80. Wt 110 lbs, BMI 22. She
has poor tandem gait and is unable to stand
on 1 foot. Rest of exam: Negative
• Current DXA shows T-score -3.0 at spine, -3.2
at the femoral neck and -2.4 at the total hip.
WHAT WOULD BE YOUR APPROACH
TO THIS PATIENT TO REDUCE HER RISK
OF FUTURE FRACTURES?
1799
Rule Out Secondary Causes of Low

Bone Mineral Density
• CBC • 24-hour urine calcium
• Complete chemistry • Intact-PTH
screen • SPEP, ESR, CRP
• Celiac antibodies
– lytes, Ca, phos, • 24-hr urine free cortisol
creat, alk phos, • Fe/TIBC, ferritin
albumin • Tryptase
• 25(OH)Vitamin D • Homocysteine
• Connective tissue screen
• Testosterone (men) • Bone biopsy
• TSH (when indicated)
Results
• Labs:
– 25(OH)-vitamin D 15 ng/mL (30 – 50
ng/mL)
– Everything else, including SPEP, is normal
• You begin cholecalciferol 2000 IU daily and
will recheck levels in 12 weeks
1800
Next: Reduce Her Risk for Falls

• Correct vitamin D deficiency
• Take a good fall history, visual assessment
and home evaluation
• Prescribe physical therapy for gait, balance,
and strength training and tai chi
1801
Compared to Usual Care,

Injurious Falls Can Be Reduced With…
• Exercise (particularly strengthening and
balance, gait training); consider PT
• Vision assessment and treatment
• Environmental assessment and modification
• Calcium and vitamin D supplementation
RECOMMENDATIONS MUST BE TAILORED

TO THE INDIVIDUAL
Next: Increase Bone Strength

• You recommend restarting alendronate but
she worries about side effects from BPs
1802
Counseling Patients About

Osteonecrosis of the Jaw
• Dental check-up before initiation: if major
surgery required (implant or extraction),
delay start of bisphosphonate.
• If dental surgery needed during BP therapy,
stop the drug only if the dentist insists (data
do not show that this makes a difference)
Adler RA et al. 2016 J Bone Miner Res 31(1):16
Counseling Patients About

Bisphosphonates and AFFs
• 70% of patients get aching pain in femur or
groin prior to complete fracture
• In general, risk for AFF is exceedingly low
(< 0.1%) when BP is used according to
guidelines in suitable candidates (duration ≤
5 years)
• Stress fractures of femur can be picked up
ahead of time by bone scan, MRI, radiograph,
or DXA in symptomatic or worried patients
Adler RA et al. 2016 J Bone Miner Res 31(1):16-35
1803
85 yo F on Risedronate x 6 Years
with Right Anterior Thigh Pain
Bush and Chew 2009; Radiol Case Rep 4(1)
Bisphosphonates: Monitoring and

• Annual clinical assessment
• Treat with oral bisphosphonate x 5 years
• Treat with IV bisphosphonate x 3 years
• Repeat DXA 1-2 years after starting oral BP
and at completion (for oral and IV)
1804
Bisphosphonates: Monitoring and

• Annual clinical assessment
• Treat with oral bisphosphonate x 5 years
• Treat with IV bisphosphonate x 3 years
• Repeat DXA 1-2 years after starting oral BP
THEN REASSESS!
and at completion (for oral and IV)
Returning to the Patient….

• She increases dietary calcium to avoid taking
Ca supplements
• She takes 2000 IU cholecalciferol daily and
after 12 weeks, raises her 25OHD to 32
ng/mL; you reduce her dose to 1000 IU daily
• She refuses all bisphosphonates (both oral
and intravenous), refuses to give herself daily
injections (teriparatide), but agrees to take
denosumab 60 mg SQ q 6 months.
1805
Five Years Later…Success!

• At age 80, after 5 years of therapy, she asks if
she can stop denosumab. She has had no
additional fractures and her BMD has
improved significantly
• T-scores are now -2.3, -2.8, and -2.0 at the
spine, femoral neck, and total hip,
respectively.
Five Years Later…Success!

• At age 80, after 5 years of therapy, she asks if
she can stop denosumab. She has had no
additional fractures and her BMD has
improved
CAN SHEsignificantly
STOP DENOSUMAB AND
GO ON
• T-scores A “DRUG
are now HOLIDAY?”
-2.3, -2.8, and -2.0 at the
spine, femoral neck, and total hip,
respectively.
1806
Assessing for “Drug Holiday” After

Anti-Resorptive Therapy
1. Does the patient have a history of multiple
major fractures, a hip fracture, or a
vertebral fracture before or during
therapy?
2. Does the patient have a high risk for bone
loss, falls, or fractures in the future (eg.
frailty, frequent falls, glucocorticoids, other
high risk medications or co-morbidities)?
3. Is BMD at the hip ≤ -2.5?
Assessing for “Drug Holiday” After

Bisphosphonate Therapy
1. Does the patient have a history of multiple
major fractures, a hip fracture, or a
vertebral
IF fracture before
THE ANSWER TO ANY or during BP
OF THESE
therapy?
QUESTIONS IS “YES,” THEN
2.
DRUGDoesHOLIDAY
the patientIShave
NOTa RECOMMENDED
high risk for bone
loss, falls, or fractures in the future (eg.
frailty, frequent falls, glucocorticoids, other
high risk medications, co-morbidities)?
3. Is BMD at the hip ≤ -2.5?
1807

and the ugly
Denosumab Update
1808
• Hip and spine BMD continued to increase

throughout 10 years
• Fracture rates in long-term DMAB cohort
remained similar to 1st 3-year rates but there
was no true placebo group for comparison
• Analyzed BMD results of 12 women from

FREEDOM trial who stopped DMAB after 7-
10 consecutive years of taking it
• BMD was measured 18 months after last
dose (12 months after DMAB effect wears
off)
1809
BMD Changes at Lumbar Spine
↓15%
Popp AW et al. 2018 Calcif Tissue Int [epub]
1810
• Case series of 9 patients who sustained 50

spontaneous vertebral fractures after
stopping denosumab (within 10 mos after
last injection wore off)
• Associated with marked increase in bone
resorption and rapid loss of BMD
1811
• Describe 24 postmenopausal women who

experienced 112 vertebral fracture(s) after
stopping denosumab
• Mean # of fractures per person = 4.7 (range
1 – 9); 92% had more than 1 fracture
• All fractures occurred within 2-10 months
after the next injection was due
Spinal CT Scan Several Months Before

(a) and After (b) Vertebral Fractures
Tripto-Shkolnik L et al. 2018 Calcif Tissue Int [epub]
1812
What To Do?
• After 5 years of DMAB, reassess fracture risk
• If fracture risk remains high, based on BMD,
multiple vertebral fractures, or high FRAX®
score, consider continuing DMAB for 10 years
or switch to different agent
• If and when DMAB is to be stopped, consider
infusion of zoledronate or 1-2 years of oral
bisphosphonate to prevent rapid loss of BMD
Tsourdi E et al. 2017 Bone 105:11-17

and the ugly
1813
Long-Term Management of
Postmenopausal Osteoporosis
ABALO
Meier C et al. 2017 Swiss Med Wkly147:w14484
Long-Term Management of
Postmenopausal Osteoporosis
ABALO
WHAT TO DO WITH THOSE FOR WHOM

BISPHOSPHONATES
ARE CONTRAINDICATED OR NOT TOLERATED?
Meier C et al. 2017 Swiss Med Wkly147:w14484
1814
Take-Home Messages
Osteoporosis
101
Take-Home Messages
1. Prescribe Ca + D for those at high risk for
deficiencies and for those with osteoporosis
2. Reduce fractures with a two-pronged approach:
reduce falls and improve bone strength.
3. Falls are independent risk factors for fracture and
major causes of morbidity and mortality. Do
careful fall assessments by history, medication
review, and physical exam
4. In addition, keep mental health issues,
psychotropic meds, and hyponatremia on your
radar when assessing fracture risk; potentially
reversible!
1815
Take-Home Messages (cont)

5. Understand the limitations of the new ACP
osteoporosis guidelines
6. Use bisphosphonates as 1st line therapy but
consider denosumab and anabolic therapy
as alternatives
7. Do NOT give a “holiday” from denosumab!
When in Doubt, Stop Worrying and

Get an Endocrine Consult!
1816
"We come into the world under the

brim of the pelvis and go out through the
neck of the femur"
Sir John Charnley (1911-1982)
THANK YOU!!!!
1817
Women’s Health:
Take Home Messages
Caren Solomon, MD
Associate Physician, BWH
Associate Professor of Medicine, HMS
Deputy Editor, NEJM
• No disclosures
1818
Contraception
• Rates of unintended pregnancy with typical use:
– NO method- 85%
– Diaphragm 12%
– Condom 18%
– Pill/patch/ring 9%
– DepoProvera 6%
– IUD- Copper T 0.8%, LNG-IUS 0.2%
– Etonorgestrel Implant 0.05%
1819
Long-Acting Reversible Contraception:

IUDs and Implants
• Highly effective (immediately); “forgettable”
• IUDs
– Pregnancy rare (but ectopic pregnancy common if
pregnancy occurs)
– Safe; Most women eligible (including nulliparous, prior h/o
STD)
– Potential complications: expulsion, perforation (rare),
malposition in uterus, PID (risk higher first 20 d after
insertion 1-10/1000 women but after that, rare).
– Types
• Levonorgestrel (Mirena, Skyla, Liletta, Kyleena)
– Overall less bleeding ; often used in women with menorrhagia or
dysmenorrhea; may have hormonal side effects
• Copper IUD (Paragard)
– increased bleeding (espec in first few months after insertion);
more cramping/pain
– Can be inserted within 5 d after single act of unprotected
intercourse as emergency contraception
Long-acting reversible contraception

• Implantable contraception (Etonogestrel (Nexplanon); progestin
subdermal implant )
– Highly effective, use up to 3 years approved (but effective longer)
– Must be inserted by trained provider
– Irregular bleeding common
– Contraindication: current breast cancer
– Potential complications: deep insertion /difficult removal (but
inserter easy to use, infection at insertion site, expulsion (rare)
1820
Medical Disorders
Complicating Pregnancy
Pre-Existing Hypertension
• Generally good pregnancy outcomes unless
superimposed preeclampsia develops
• Antihypertensive therapy
– generally can be tapered during pregnancy
– Goal SBP 120-160 mm Hg; DBP 80-105 mm Hg
– Stop ACEIs and ARBs prior to conception
– Methyldopa recommended 1st line (long term
outcomes data); or labetolol
1821
Pre-existing diabetes mellitus

• Birth defect risk directly related to HbA1c at conception
• Other risks: macrosomia, iatrogenic prematurity, birth trauma,
neonatal hypoglycemia; maternal: progression of DM
complications, preeclampsia, increased risk of C-section
• ADA recommends goal of HbA1c < 6.5% at conception
• Goals during pregnancy: fasting blood sugar < 95 mg/dl; 1 h post
prandial < 140 mg/dl; 2 h pp < 120 mg/dl: HbA1c < 6 % (if can be
achieved without a lot of hypoglycemia)
• Treatment
– Human insulin recommended; most experience with NPH and
regular (Category B); Lispro and Aspart also used
– Pump ok
– Insulin requirements typically increase in pregnancy but may
decrease just before delivery
Gestational diabetes mellitus

• DM first diagnosed in pregnancy
• High risk of subsequent Type 2 DM
• Women with history of GDM should be
screened for Type 2 DM
1822
Hypothyroidism
• Diagnosis made by elevated TSH

• Possible risks: poor fetal growth; premature birth;
pregnancy loss; possible effects on IQ; increased risk
for preeclampsia and placental abruption in mother
• Requirement for thyroid hormone increases in
pregnancy and returns to pre-pregnancy requirement
postpartum
• Titrate thyroid hormone dose to maintain TSH <2.5 at
conception and first 2 trimesters; < 3.5 third trimester
HPV-Related Disease and Vaccination
1823
HPV
• 80% of people infected over lifetime
• Natural history: 80% clear infection in
12 months
• High risk types: HPV 16, 18, 31, 33, 45,
52, 58
HPV Vaccination
• Recommended starting age 11 or 12
(and through age 26, possibly older but
“off label”.)
• Bivalent (16 and 18), quadrivalent, and
9 v vaccines can be used
• 3 doses
• STILL NEED cervical cancer screening
1824
Cervical Cancer Screening

• Initiate screening at age 21
• Age 21-29: Pap q 3 years (no HPV screening)

• Age 30-65 (and NOT high risk), may do:
– Combined Pap/HPV q 5 years if both tests
negative
– Paps q 3 years
– HPV alone (Cobras HPV test) q 3 years over age
25
• More frequent screening needed in high risk women

(HIV infection, immunosuppressed, h/o DES
exposure, previously treated CIN2 or 3 or
adenoCA in situ or CA )
Follow-Up of Various Pap Findings

– Absent Endocervical Cells
• Ages 21-29: Routine screening
• Age 30+ : HPV testing
– ASCUS
• If HPV negative, repeat co-testing in 3 years
• If HPV positive- colposcopy
(except ages 21-24, where would repeat PAP in 1 y)
– ASC-H (ie cannot exclude high grade SIL)
• Colposcopy needed
– Endometrial cells
• No further evaluation in asymptomatic premenopausal
women
• If postmenopuasal, need endometrial assessment
1825
Menopause
Postmenopausal hormone
therapy
• Improves vasomotor symptoms (and this remains
indication for use)
• WHI data
HRT: Increased risks of CHD, stroke, invasive breast
cancer, DVT/PE, urinary incontinence; Reduced risks
of fracture, colorectal cancer
ERT: Increased risk of stroke, reduced risk of fx
Both increased risk of dementia among women 65+
1826
Postmenopausal hormone therapy:

Endocrine Society Prescribing
Recommendations
• Individualize therapy based on clinical features and
patient preference
• Contraindications: h/o DVT/PE, breast CA, CVD, high
risk endometrial cancer/unexplained vaginal
bleeding, liver disease
• Assess CVD risk (10y) and breast cancer risk (5 y)
before initiate; avoid where risk high (> 10% and >
3% , respectively)
Management of symptoms
• Vasomotor
– ERT/HRT- at lowest effective doses/generally not
more than 5 years (though longer may be OK in
low risk highly symptomatic women)
– Lifestyle- keep cool, weight control, exercise, don’t
smoke, avoid excessive alcohol..
– Phytoestrogens- not generally effective in RCTs
and potential concerns re estrogen agonist effects
– Other medications –
• SSRIs, SNRIs (only paroxetine FDA approved for
vasomotor symptoms; recommended that paroxetine be
avoided in women taking tamoxifen)
• Gabapentin
• Clonidine (but use limited by side effects)
1827
Management of symptoms
• GU (vulvovaginal atrophy)
– Local estrogen (creams, E2 tablets, vaginal ring)
– Lubricants
– Ospemifene: SERM approved for treatment of
dypareunia in postmenopausal women (potential
adverse effects: hot flashes, DVT/PE..)
Menstrual Irregularities
1828
Amenorrhea
• Types
– Primary (Absence of menses by age 16)
– Secondary (Absence of menses for 3
months)
• Causes
– Pregnancy, Uterine or Outflow Tract
Disorders,Ovulatory Disorders
– genetic and anatomic abnormalities more
likely with primary amenorrhea
• Eval
– βHCG, FSH, PRL, TSH
• Causes
– Energy Output > Energy Input
• Wt loss, eating disorders, excessive exercise
– Stress
• Psychological, Physical
• Eval: r/o other cause, MRI, BMD
• Treatment
– Weight gain, decrease exercise
– Oral contraceptives/HRT (?)
– Adequate calcium, vitamin D
1829
Premature Ovarian Insuffiency

• Elevated FSH, age < 40 yrs
• Causes
–Turner’s syndrome ; X chromosome deletions,
translocations; Fragile X premutations
– Autoimmune, Chemotherapy or radiation therapy, other
• Evaluation
•Karyotype, Fragile X premutation screen, anti-thyroid and anti-adrenal
antibodies
•Treatment
–OCPs/HRT; calcium/vit D
PCOS
• Rotterdam definition
– 2 out of 3 of the following:
– Oligo- or anovulation
– Clinical and/or biochemical signs of
hyperandrogenism
– Polycystic Ovaries
Exclusion of other causes (e.g. hyperprolactinemia,
CAH, androgen secreting tumors)
• Other common features:
– obesity; insulin resistance; infertility
1830
PCOS Management
• Weight loss /exercise
• OCP
• Metformin
• Ovulation induction/IVF
• Hair removal/spironolactone
• Follow up of glucose, lipids, bp
Osteoporosis and
Metabolic Bone Disease
1831
Calcium and vitamin D

• Supplementation with both may modestly reduce
fracture risk
• Adverse effects (calcium) :GI upset, kidney stones;
not strong evidence to support increased CVD risk
• Supplementation recommended in those with high
risk for deficiency( frail elderly, malabsorption…) and
those receiving osteoporosis treatment
• 25OH vit D levels do not need to be checked in
elderly persons without osteoporosis or high fracture
risk: vit D3 800 IU daily recommended
Bone density
• T-score
BMD compared with “young normal” adults; ( number
of standard deviations (SD) above or below the
mean); Used to dx osteopenia (-1 to -2.5)
osteoporosis (below -2.5)
• Z-score
BMD compared with persons of same sex and age.
A low Z-score indicates possible secondary cause of
osteoporosis.
, BMD recommended in women age 65+ , and men age

70+ without risk factors; earlier with risk factor or
history of fracture
1832
Risk Factors for Osteoporosis in Women

• Caucasian/Asian ALSO:
• Older age H/o falls (or risk factors for falls)
• Prior fx Mental illness or psychotropic meds
• Low weight Chronic hyponatremia
• Fam hx of fx
• Smoking
• Excess alcohol
• Glucocorticoids
• RA
• Hypogonadism
• IBD/malabsorption
• Organ tx
• Hyperthyroidism
• COPD
• Type 1 DM
Overall management strategy
• Minimize falls
– Exercise (strength and balance, gait
training), vision assessment/treatment,
environmental assessment/management,
calcium/vit D recommended
• Increase bone strength
1833
Treatment of Postmenopausal
Osteoporosis
• ACP recommends:
– use bisphosphonate or denosumab (and NOT to
use estrogen +/- progestin or raloxifene)
– treat for 5 years (without BMD monitoring)
– BUT there is controversy

• ? better to treat to target (T score > -2.5) /Others
recommend assessment to determine if bisphosphonate
holiday appropriate
• DXA may indicate lack of response or ?noncompliance
• Stopping denosumab at 5 y associated with rapid bone
loss , rebound associated fxs reported
1834
Women’s Health Board Review
Kathryn M. Rexrode, MD, MPH

Chief, Division of Women’s Health

Disclosure: None
1835
Question 1
A 32-year-old woman, G1P1, comes in for a visit 6
months postpartum.
• She is fatigued and has lost few of the 30 lbs she gained
during pregnancy.
• She takes a multivitamin, no other medications.
• On physical examination:
– Weight is 150 lb, height is 5’2”.
– The thyroid feels slightly enlarged, without nodules, and is
nontender.
• CBC is normal.
• TSH is 24 mIU/L.
Question 1
Which of the following is TRUE?
A. Subacute thyroiditis is the most likely diagnosis.
B. This condition is likely to recur in subsequent
pregnancies.
C. TPO antibodies are likely to be negative.
D. You should wait for spontaneous resolution
rather than treating with thyroxine.
E. She should have a thyroid ultrasound.
1836
Question 1: Answer
A. Subacute thyroiditis is the most likely diagnosis.
B. This condition is likely to recur in subsequent
pregnancies.
C. TPO antibodies are likely to be negative.
D. You should wait for spontaneous resolution
rather than treating with thyroxine.
E. She should have a thyroid ultrasound.
Question 1: Discussion
• This patient has postpartum thyroiditis, a variant of autoimmune thyroiditis,
which is characterized by 3 phases:
– An initial hyperthyroid phase (within 6 months postpartum, lasting up to 2
months) due to leakage of thyroid hormone from an inflamed thyroid gland
– Followed by a hypothyroid phase (typically occurring up to 10 months
postpartum, and lasting 3–6 months), and then, in most cases,
– Return to euthyroidism.
• TPO antibodies are characteristically positive, and recurrence is common
following subsequent pregnancies.
• Symptomatic hypothyroidism should be treated with thyroxine, which should
not be required for more than 6 months unless the patient has developed
permanent hypothyroidism.
• Thyroid ultrasound may be useful in the evaluation of a thyroid nodule but is
not indicated in the evaluation of thyroiditis.
• Subacute thyroiditis is a painful inflammation of the thyroid that often is
described following upper respiratory infection.
1837
Question 2
A 28-year-old woman comes to establish care.
• She has a long history of oligomenorrhea and hirsutism and was
diagnosed with PCOS.
• Last menstrual period was 4 months ago, which is not unusual
for her. She takes no medications.
• Physical exam: weight is 160 lb, height 5’3”. Blood pressure is
normal.
– Slight terminal hair growth on moustache and sideburns
above her umbilicus, and around her nipples.
– Pelvic exam is limited by body habitus but appears to be
within normal limits.
• Records indicate normal prolactin and TSH levels, normal level
of fasting 17-OH progesterone, and slightly elevated total
testosterone level.
Question 2
All of the following are true EXCEPT:
A. This condition is associated with increased risk for
glucose intolerance or diabetes.
B. Risk for endometrial hyperplasia or cancer is
increased.
C. The finding of polycystic ovaries on pelvic ultrasound
is highly sensitive and specific for the diagnosis.
D. Luteinizing hormone (LH) levels are not required to
make the diagnosis.
E. Spironolactone may be useful in treatment of
associated hirsutism.
1838
Question 2: Answer
All of the following are true EXCEPT:
A. This condition is associated with increased risk for
glucose intolerance or diabetes.
B. Risk for endometrial hyperplasia or cancer is increased.
C. The finding of polycystic ovaries on pelvic
ultrasound is highly sensitive and specific for the
diagnosis.
D. Luteinizing hormone (LH) levels are not required to make
the diagnosis.
E. Spironolactone may be useful in treatment of associated
hirsutism.
• PCOS is a diagnosis of exclusion and is clinically diagnosed by the
combination of chronic anovulation and androgen excess not explained by
another endocrine disorder (such as late-onset congenital adrenal
hyperplasia, hyperprolactinemia, androgen-secreting tumor.)
• Although a polycystic appearance of the ovaries is generally present, this has
also been identified in 25% of women without other features of PCOS, and
this finding is considered neither sufficient nor necessary for the diagnosis.
• LH levels are typically elevated (with increased LH/FSH ratio), but this is not
necessary for the diagnosis and need not be routinely measured.
• A clear association has been observed between PCOS and insulin resistance,
and studies have documented an increased prevalence of glucose intolerance
and diabetes in affected women, even independent of associated obesity,
which is common but not always present in affected women.
• Women with PCOS also have increased risk for endometrial hyperplasia and
cancer.
1839
Question 3
A 48-year-old woman reports irregular menstrual
cycles for the past year.
• Last menstrual period 9 weeks ago
• Hot flashes for past 2 years, affecting sleep
• No significant past medical history
• No family history of blood clots or breast cancer
• No current medications.
• Physical exam is unremarkable:
– Blood pressure normal
– Normal pelvic exam and breast exam
Question 3
Which of the following statements is FALSE?
A. A follicle-stimulating hormone (FSH) level should be

checked to confirm menopause.
B. Low-dose hormone therapy could be considered.
C. A history of deep venous thrombosis would be a
contraindication to the use of postmenopausal hormone
therapy.
D. Combined therapy with low dose estrogen and progestin
would be preferable to an estrogen only regimen.
1840
Question 3: Answer
A. A follicle-stimulating hormone (FSH) level should be

checked to confirm menopause.
B. Low-dose hormone therapy could be considered.
C. A history of deep venous thrombosis would be a
contraindication to the use of postmenopausal hormone
therapy.
D. Combined therapy with low dose estrogen and progestin
would be preferable to an estrogen only regimen.
• Menopause is strictly defined as cessation of menses for ≥12 months,
but menopausal symptoms and changes in menstrual cycle pattern often
begin well before menses cease.
• A high FSH is characteristic of menopause, but checking FSH levels is not
indicated routinely, as an FSH level is an unreliable indicator of
impending menopause in perimenopausal women.
• Postmenopausal hormone therapy is very useful for managing hot
flushes. In a woman with an intact uterus, estrogen therapy should be
accompanied by progestin therapy to prevent development of
endometrial hyperplasia.
• When postmenopausal hormone therapy is used, short-term use is
recommended, rather than indefinite use.
• Contraindications to hormone therapy include venous
thromboembolism, history of breast cancer, coronary heart disease,
unexplained vaginal bleeding, and active liver disease.
1841
Question 4
This patient decides at first to take nothing for her
symptoms but returns a year later:
• She has persistent hot flashes and no menses for
the past 6 months.
• She is interested in postmenopausal hormone
therapy.
• Physical exam is normal.
• Mammogram is negative.
Question 4
A. Hormone therapy is associated with increased risk
for gallstones.
B. Hormone therapy increases the risk for deep venous
thrombosis/pulmonary embolism.
C. Progestins may have negative effects on mood.
D. Vaginal bleeding is rare after the first 3 months on
combined hormone replacement.
E. Hormone therapy increases the risk for stroke.
1842
Question: Answer
A. Hormone therapy is associated with increased risk
for gallstones.
B. Hormone therapy increases the risk for deep venous
thrombosis/pulmonary embolism.
C. Progestins may have negative effects on mood.
D. Vaginal bleeding is rare after the first 3 months
on combined hormone replacement.
E. Hormone therapy increases the risk for stroke.
• Patients should be educated regarding potential adverse effects of hormone
therapy. Side effects of estrogen include nausea, headache, and heavy
bleeding, whereas progestins may have adverse effects on mood and may
cause breast tenderness.
• Bleeding is common on combined estrogen/progestin therapy. Bleeding is
usually predictable on cyclical regimens, whereas unpredictable intermittent
bleeding is common the first several months on daily combined regimens.
• CEE/medroxyprogesterone increases risks for DVT/PE, stroke, breast cancer,
gallstones, and dementia (in women 65 years or older).
• Coronary events were increased early after initiation of
CEE/medroxyprogesterone in randomized trials of secondary prevention and
among women generally without history of heart disease.
• Postmenopausal hormone therapy is not indicated for the prevention of
cardiovascular disease.
1843
Question 5
A 24-year-old woman complains of irregular
menstrual cycles.
• She reports a 30-lb weight gain over the past 3
years, which she has attributed to a sedentary job.
• She takes no medications.
• Physical exam: weight 180 lb, height 5’6”.
– Mild hirsutism and acne on the face and back.
– Abdomen is obese, with pale striae.
Question 5
Which of the following conditions is
inconsistent with this presentation?
A. Late-onset congenital adrenal hyperplasia
B. Polycystic ovary syndrome
C. Cushing’s syndrome
D. Turner syndrome
E. Androgen-secreting tumor
1844
Question 5: Answer
Which of the following conditions is
inconsistent with this presentation?
A. Late-onset congenital adrenal hyperplasia
B. Polycystic ovary syndrome
C. Cushing’s syndrome
D. Turner syndrome
E. Androgen-secreting tumor
• This patient is demonstrating symptoms and signs consistent with
androgen excess, including irregular menstrual cycles, acne, and
hirsutism.
• Possible causes of androgen excess include polycystic ovary syndrome,
late-onset congenital hyperplasia, Cushing’s syndrome, and an
androgen secreting tumor.
• Turner syndrome (XO karyotype) is a cause of primary amenorrhea
and is associated with other characteristic features, including short
stature, failure to develop secondary sexual characteristics, and
somatic abnormalities (e.g., webbed neck, shield-like chest); androgen
excess is not a feature of Turner syndrome.
1845
Question 6
A 62-year-old woman comes to establish primary care.
• Completed menopause at age 52
• No prior hormone therapy.
• History of right tibia fracture while skiing 10 years ago and
hypertension.
• Current medication: hydrochlorothiazide 25 mg daily.
• Smokes cigarettes, ½ pack/day. She does not drink alcohol. She
swims regularly for exercise.
• No family history of hip fracture.
• Physical examination: weight 114 lb, height 5’4”.
– Blood pressure is 128/80 mm Hg.
– Rest of the exam unremarkable.
Question 6
Which of the following is NOT a risk factor for
osteoporosis in this woman?
A. Postmenopausal status
B. Cigarette smoking
C. Her weight
D. Her prior fracture
E. Use of hydrochlorothiazide
1846
Question 6: Answer
Which of the following is NOT a risk factor for
osteoporosis in this woman?
A. Postmenopausal status
B. Cigarette smoking
C. Her weight
D. Her prior fracture
E. Use of hydrochlorothiazide
• Risk factors for osteoporosis include age, estrogen
deficiency, cigarette smoking, lean body habitus, personal
history of fracture, family history of osteoporosis in a first-
degree relative, excessive alcohol intake, physical inactivity,
Caucasian race, and inadequate intake of calcium.
• A history of dementia, falls, or frailty also increases fracture
risk.
• Although some medications (e.g., glucocorticoids,
aromatase inhibitors) increase the risk for osteoporosis,
hydrochlorothiazide reduces urinary calcium excretion and
has been associated with reduced fracture risk.
1847
Question 7
All of the following statements are true for the
A. She should consume 1200 mg calcium daily.
B. Drinking 2 cups of milk daily will give her adequate
vitamin D.
C. Weight-bearing exercise is recommended.
D. Calcium carbonate supplements should be taken with
meals.
E. Swimming would not be expected to increase her
bone density.
Question 7: Answer
All of the following statements are true for the
A. She should consume 1200 mg calcium daily.
B. Drinking 2 cups of milk daily will give her
adequate vitamin D.
C. Weight-bearing exercise is recommended.
D. Calcium carbonate supplements should be taken with
meals.
E. Swimming would not be expected to increase her
bone density.
1848
• Approaches recommended to optimize bone health include adequate
intake of calcium (1200 mg recommended daily in a postmenopausal
woman), and vitamin D (≥ 400-800 IU daily).
• Calcium carbonate (e.g., in Tums, Os-Cal, Caltrate) is reportedly better
absorbed with meals.
• In contrast, calcium citrate (e.g., Citracal) can be taken at any time; the
latter is recommended in patients taking proton pump inhibitors and is
better tolerated by some women but is also more expensive.
• Vitamin D is added to milk, but only 100 IU per 8-oz serving. A
standard multivitamin will provide 400 IU vitamin D daily.
• Weight-bearing exercise is recommended. Swimming is not associated
with an increase in bone density.
Question 8
Bone density of the spine shows T-score –2.6 and
Z-score –1.1.
A. She has osteoporosis.

B. Osteoarthritis of spine could falsely increase her
bone density.
C. Her Z-score compares her to young normal women.
D. Bone mineral density (BMD) is the single best
predictor of fracture.
E. This Z-score would not suggest the need for a
workup for secondary causes of osteoporosis.
1849
Question 8: Answer
Bone density of the spine shows T-score –2.6 and
Z-score –1.1.
A. She has osteoporosis.

B. Osteoarthritis of spine could falsely increase her bone
density.
C. Her Z-score compares her to young normal women.
D. Bone mineral density (BMD) is the single best predictor of
fracture.
E. This Z-score would not suggest the need for a workup for
secondary causes of osteoporosis.
• The T-score in a bone density report represents a comparison with
“peak” bone density of young normal women
• The Z-score represents a comparison with age-matched women.
• The T-score is used to make the diagnoses of osteopenia or
osteoporosis:
– Osteopenia = T-score between –1 and –2.5 standard deviations below
peak
– Osteoporosis = T-score < –2.5 standard deviations below peak.
• A Z-score below –2 suggests bone loss out of proportion for age
– May be used to identify women more likely to have secondary causes
of osteoporosis.
• Osteophytes or a compression fracture may falsely elevate bone
density readings, and such affected areas should be deleted from
bone density analysis.
1850
Question 9
Which of the following statements is TRUE regarding
anti-resorptive therapy?
A. Raloxifene therapy would be expected both to improve
bone density and to reduce hot flashes.
B. Estrogen therapy is considered first line treatment for
osteoporosis.
C. Neither alendronate nor risedronate may be taken with
food.
D. Raloxifene does not increase risk for blood clots.
E. Routine dental work should be deferred in patients taking
bisphosphonates.
Question 9: Answer
Which of the following statements is TRUE
regarding anti-resorptive therapy?
A. Raloxifene therapy would be expected both to improve
bone density and to reduce hot flashes.
B. Estrogen therapy is considered first line treatment for
osteoporosis.
C. Neither alendronate nor risedronate may be taken
with food.
D. Raloxifene does not increase risk for blood clots.
E. Routine dental work should be deferred in patients taking
bisphosphonates.
1851
• Postmenopausal estrogen therapy reduces the risk of fracture, but due to risks
associated with long-term use, is not recommended as a standard therapy for
osteoporosis.
• Raloxifene (a SERM) reduces the risk of vertebral fractures but not hip
fractures. It may worsen hot flashes and increases risk for DVT/PE.
• Oral bisphosphonates should be taken on an empty stomach, first thing in the
morning, 30 minutes prior to eating, to facilitate absorption (and one should
remain upright after taking ).
• Osteonecrosis of the jaw has been reported among patients taking
bisphosphonates.
– Most reports are in patients using high doses intravenously for metastatic
bone disease, although they are reported in osteoporosis patients.
• Routine dental care should not be withheld in patients taking bisphosphonates.
• Atypical femur fractures have also been associated with bisphosphonate use,
although rare, and fractures overall are reduced with bisphosphonate use.
Question 10
A 48-year-old woman who has been your patient for
several years complains of constipation and abdominal
pain.
• She has seen 2 outside gastroenterologists in the past year.
• Colonoscopy, barium enema, endoscopy, and abdominal CT scan were
all negative.
• Otherwise healthy except for a fracture of the radius from a fall down the
stairs the preceding year.
• Married, without children.
• Physical exam remarkable only for ecchymoses on the back and right
arm.
1852
Question 10
The most appropriate next step would be to:
A. Repeat a colonoscopy at your institution.

B. Ask her whether she has ever been hurt or
threatened in her relationship.
C. Ask her generally about how she is doing, but avoid
asking directly about domestic violence.
D. Call her husband and discuss the situation with him.
Question 10: Answer

The most appropriate next step would be to:
A. Repeat a colonoscopy at your institution.

B. Ask her whether she has ever been hurt or
threatened in her relationship.
C. Ask her generally about how she is doing, but avoid
asking directly about domestic violence.
D. Call her husband and discuss the situation with him.
1853

• The possibility of domestic violence should be considered
in all women, regardless of background.
• Gastrointestinal complaints are common in women who
have experienced domestic violence.
• Unexplained fractures or bruising are more obvious clues,
but there are often no outward signs, and abuse may be
psychological rather than physical.
• It is recommended that all women be screened with a
straightforward question asking about any history of
being hurt or threatened.
Question 11
A 37-year-old woman comes for evaluation of a lump she
discovered in the left breast 1 month earlier.
• G1P1, menarche at 14 years. Regular menses.
• Last menstrual period occurred 1 week ago.
• She drinks 4 cups of coffee daily.
• Family history is negative for breast cancer. Her mother
has fibrocystic breast disease.
• Physical examination: well appearing.
– 1.5-cm mass palpable in the upper outer quadrant of the
left breast, slightly tender to palpation.
– No axillary adenopathy.
• Mammogram is negative.
1854
Question 11
A. Reassure her. No intervention is indicated.
B. Schedule repeat mammogram in 4–6 months.
C. Tell her to stop coffee and other caffeine intake and
return in 4–6 months for reexamination.
D. Order an ultrasound; if this is negative, no further workup
is required.
E. Order an ultrasound; referral should be made for biopsy
unless the lump is consistent with a simple cyst.
Question 11: Answer

A. Reassure her. No intervention is indicated.

B. Schedule repeat mammogram in 4–6 months.
C. Tell her to stop coffee and other caffeine intake and
return in 4–6 months for reexamination.
D. Order an ultrasound; if this is negative, no further workup
is required.
E. Order an ultrasound; referral should be made for
biopsy unless the lump is consistent with a simple
cyst.
1855
Question 11:Discussion
• A palpable breast mass requires further evaluation
regardless of patient age or mammogram results.
• Although coffee has been associated with fibrocystic
breast disease, a palpable discrete mass should not
be attributed to this or other benign etiologies
without appropriate workup.
• Ultrasound would be the next step; biopsy would be
indicated for findings other than a simple cyst in this
woman.
Question 12
A 30-year-old G0P0 with a 10-year history of Type 1
DM is interested in becoming pregnant.
• History of nonproliferative retinopathy: last eye exam 2
years ago.
• Checks blood sugars once daily.
• Current Medications: NPH 15 units twice daily, lispro 10
units with meals, and prenatal vitamin.
• Her blood pressure is 124/80 mm Hg; the rest of the
examination is unremarkable.
• Labs: HbA1c 9.0, creatinine 1.3 mg/dL. There is trace
protein on urine dipstick.
1856
Question 12
All of the following would be recommended prior to
conception EXCEPT:
A. An angiotensin-converting enzyme inhibitor should be

started to minimize progression of renal disease in
pregnancy.
B. She should increase her frequency of blood sugar
monitoring.
C. She should be referred to ophthalmology.
D. Blood sugar control should be tightened to achieve a
normal hemoglobin A1c.
E. She should have a prescription for glucagon.
Question 12: Answer

All of the following would be recommended prior to
conception EXCEPT:
A. An angiotensin-converting enzyme inhibitor should

be started to minimize progression of renal disease
in pregnancy.
B. She should increase her frequency of blood sugar
monitoring.
C. She should be referred to ophthalmology.
D. Blood sugar control should be tightened to achieve a
normal hemoglobin A1c.
E. She should have a prescription for glucagon.
1857

• Tight glycemic control is recommended prior to conception in women with
diabetes; risk of congenital anomalies increases with increasing first-
trimester hemoglobin A1c levels.
• Target hemoglobin A1c entering pregnancy should be near 6%.
• Eyes should be checked prior to pregnancy, as proliferative retinopathy
may progress during pregnancy.
• Hypoglycemia is common in the first trimester; women should be aware of
symptoms and treatment of hypoglycemia and have glucagon available.
• Angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor
blockers are contraindicated in pregnancy.
– Use in 1st trimester has been associated with major congenital anomalies,
including cardiac and central nervous system defects.
– Use in 2nd and 3rd trimesters is associated with oligohydramnios,
intrauterine growth retardation, anuria, renal failure, and death.
Question 13
A routine Pap smear in a 42-year-old woman shows atypical
cells. She is in a monogamous relationship and has had
normal Pap smears in previous years.
Which of the following would be MOST appropriate?
A. Treat empirically with doxycycline and repeat Pap in 3 months.

B. This is a normal finding in a perimenopausal woman and does not
require follow-up.
C. Endometrial sampling should be done to exclude endometrial
cancer.
D. Perform human papilloma virus (HPV) testing for high-risk subtypes.
1858
Question 13: Answer

A routine Pap smear in a 42-year-old woman shows atypical
cells. She is in a monogamous relationship and has had
normal Pap smears in previous years.
Which of the following would be MOST appropriate?
A. Treat empirically with doxycycline and repeat Pap in 3 months.

B. This is a normal finding in a perimenopausal woman and does not
require follow-up.
C. Endometrial sampling should be done to exclude endometrial
cancer.
D. Perform human papilloma virus (HPV) testing for high-risk
subtypes.

• Atypical cells are a common finding on Pap smears.
• Bacterial infection is sometimes an underlying cause
of atypical cells and should be treated if there is good
reason to suspect this, but not in asymptomatic low-
risk women.
• HPV screening for high-risk subtypes is indicated when
atypical cells are found; when positive, colposcopy is
indicated.
1859
Question 14
A 32-year-old woman, G1P0, is 16 weeks pregnant.
• Current symptoms include palpitations and weight loss.
• Physical exam is notable for pulse 110.
– She has lid lag but no appreciable exophthalmos.
– The thyroid gland is symmetrically enlarged to about
1½ times normal size.
• TSH is <0.05 mIU/L, T4 is 22.
Question 14
Which of the following is incorrect?
A. PTU can be used in the first trimester of pregnancy.

B. A thyroid uptake should be performed to confirm the
diagnosis.
C. A beta blocker could be used for symptoms.
D. Thyroid-stimulating immunoglobulin (TSI) would
likely be elevated.
E. This condition is likely to improve with treatment over
the course of pregnancy.
1860
Question 14: Answer

Which of the following is incorrect?
A. PTU can be used in the first trimester of pregnancy.

B. A thyroid uptake should be performed to confirm
the diagnosis.
C. A beta blocker could be used for symptoms.
D. Thyroid-stimulating immunoglobulin (TSI) would
likely be elevated.
E. This condition is likely to improve with treatment over
the course of pregnancy.

• The presentation is most consistent with Graves’ disease, which may
present early in pregnancy.
• Thyroid-stimulating immunoglobulins (TSI) are typically detectable but
need not be checked clinically.
• If antithyroid drug therapy is needed in the 1st trimester, PTU is considered
the preferred drug, as methimazole is associated with a rare scalp defect,
aplasia cutis.
• Outside of the 1st trimester, methimazole is the preferred drug, given
reports of liver toxicity and liver failure associated with PTU.
– The minimal dose necessary to keep T4 levels upper normal or slightly above
the normal range is recommended to minimize drug exposure of the fetus (as
this crosses the placenta).
• Beta blockers can be used for symptom control in pregnancy.
• Thyroid uptake testing or treatment with radioactive iodine is strictly
contraindicated in pregnancy.
• The disease tends to remit with treatment over pregnancy, and thyroid
function should be followed closely to avoid overtreatment.
1861
Question 15
A 22-year-old woman comes for contraceptive counseling. All
of the following are true EXCEPT:
A. The risks associated with use of oral contraceptive pills (OCPs)
outweigh the benefits for women with a history of coronary
heart disease or stroke.
B. OCP use is associated with a reduced risk for ovarian cancer.
C. Women who are at average risk of STDs (without current
cervicitis) are considered appropriate candidates for current
IUDs.
D. Currently used OCPs are associated with a three-fold increase
in breast cancer risk.
Question 15: Answer

A 22-year-old woman comes for contraceptive
counseling. All of the following are true EXCEPT:
A. The risks associated with use of oral contraceptive pills (OCPs)
outweigh the benefits for women with a history of coronary
heart disease or stroke.
B. OCP use is associated with a reduced risk for ovarian cancer.
C. Women who are at average risk of STDs (without current
cervicitis) are considered appropriate candidates for current
IUDs.
D. Currently used OCPs are associated with a three-fold
increase in breast cancer risk.
1862

• Risks of OCPs include DVT/PE, even with low-dose preparations; the
risk is reported to be higher with OCPs containing desogestrel versus
progestins such as levonorgestrel.
• Myocardial infarction and stroke are rare risks; the risk is higher in
women who smoke (especially older women) or who have
uncontrolled hypertension.
– A history of cardiovascular disease is a contraindication to use of OCPs.
• OCP users have been reported to have lower risk of ovarian cancer.
• Current OCPs have been associated with a small (about 20%)
increase in breast cancer risk.
• Long acting reversible contraceptives are highly effective ; their use
is associated with reduced risk of unintended pregnancy in sexually
active young women (versus short acting methods). Most women are
eligible for IUDs, except for those with cervicitis at time of insertion.
Question 16
You are paged by a 32-year-old woman who is worried
about pregnancy after having had unprotected
intercourse 36 hours prior. Her LMP was 16 days ago.

A. Loestrin (20 µg EE), 2 now and 2 more in 12 hours, is
appropriate for use as emergency contraception.
B. Levonorgestrel, 1.5 mg as a single dose, is appropriate
for use as emergency contraception.
C. It is too late to use emergency contraception.
D. Emergency contraception is not warranted at this time in
the cycle.
1863
Question 16: Answer

You are paged by a 32-year-old woman who is worried about
pregnancy after having had unprotected intercourse 36
hours prior. Her LMP was 16 days ago.
A. Loestrin (20 µg EE), 2 now and 2 more in 12 hours, is
B. Levonorgestrel, 1.5 mg as a single dose, is
C. It is too late to use emergency contraception.
D. Emergency contraception is not warranted at this time in
the cycle.

• Emergency contraception reduces rate of pregnancy when given within 72
to 120 hours of unprotected intercourse.
• Effective emergency contraception therapies include:
– Plan B: levonorgestrel 1.5 mg single dose
– Ulipristal acetate 30 mg.
– The Yuzpe regimen, which is combination OCP to provide 100 µg ethinyl
estradiol initially and then again at 12 hours: e.g., 2 Ovral (50 µg ethinyl
estradiol each), 2 doses 12 hours apart (now uncommonly used)
• Levonorgestrel is usually the preferred method of emergency contraception,
as it is available without a prescription (and is associated with a better side
effect profile than the Yuzpe regimen). A prescription is required for
ulipristal acetate.
• Intercourse during the luteal phase (based on LMP) does not rule out
possible pregnancy; emergency contraception is still appropriate in this
setting.
• Although the efficacy of emergency contraception falls with increasing time
after intercourse, it is still reasonable to use within 5 days of unprotected
intercourse.
1864
Question 17
Which of the following strategies is consistent with
current guidelines for cervical cancer screening:
A. Pap testing alone every 3 years (if testing normal) in

woman in her 40s.
B. Combined Pap and HPV testing every 5 years (following
normal test) starting at age 21.
C. Pap testing annually starting at age 18 in sexually active
woman.
D. No screening in women who have had HPV vaccination.
Question 17: Answer

Which of the following strategies is consistent with
current guidelines for cervical cancer screening:
A. Pap testing alone every 3 years (if testing normal) in

woman in her 40s.
B. Combined Pap and HPV testing every 5 years (following
normal test) starting at age 21.
C. Pap testing annually starting at age 18 in sexually active
woman.
D. No screening in women who have had HPV vaccination.
1865

• Pap smears are recommended starting at age 21 (not before).
For average risk women:

• Ages 21-29: Pap smears recommended q3 years (if normal) ;
no HPV testing for screening purposes.
• Age 30-65: can screen with PAP and HPV q 5 years (preferred)
or PAP smear q 3 years (accepted) if normal
• Age > 65: no further Pap smears if > 3 consecutive normal Pap
tests , or > 2 consecutive negative Pap/HPV tests past 10 years
(latter in past 5 y; ) or hysterectomy for benign disease.
• These do not apply to high risk women.

• Screening recommendations not altered by HPV vaccination.
Question 18
A 35-year-old woman presents for her initial
primary care visit.
• Past medical history only notable for gestational diabetes
during her pregnancy 3 years ago.
• At her 6-week postpartum visit, she completed an oral
glucose tolerance test (OGTT) and was told that her
diabetes in pregnancy had completely resolved.
• She has not seen another physician since her delivery 3
years ago.
1866
Question 18
A. Gestational diabetes is unlikely to recur in a subsequent

pregnancy.
B. Since she had a normal postpartum OGTT, her risk for
developing diabetes in the future is no higher than that of a
woman whose pregnancy was not complicated by GDM.
C. She is at increased risk for developing Type 2 diabetes,
compared with the general population.
D. Sulfonylureas are recommended to reduce future risk of
diabetes.
Question 18: Answer

A. Gestational diabetes is unlikely to recur in a subsequent

pregnancy.
B. Since she had a normal postpartum OGTT, her risk for
developing diabetes in the future is no higher than that of a
woman whose pregnancy was not complicated by GDM.
C. She is at increased risk for developing Type 2 diabetes,
compared with the general population.
D. Sulfonylureas are recommended to reduce future risk of
diabetes.
1867

• Women with gestational diabetes (based on ≥ 2 abnormal values on OGTT
performed at 24-28 weeks gestation) often have normal glucose levels
after delivery.
• Women should complete a 75-gram OGTT 6-12 weeks postpartum to
assess for persistent glucose abnormalities, such as impaired fasting
glucose, impaired glucose tolerance or overt diabetes.
• Even with normal postpartum OGTT results, women have increased risk for
progressing to pre-diabetes or overt diabetes
• Glycemic status should be monitored long-term in these women by
periodic assessment of fasting blood sugar, HbA1c, or 75 g OGTT:
– At a minimum, monitoring every 3 years is recommended
– Annual screening recommended in women with impaired fasting glucose or
impaired glucose tolerance.
• Based on data from the Diabetes Prevention Program, lifestyle modification
and metformin are effective in preventing progression to diabetes in the
future; sulfonylureas are not used for diabetes prevention.
1868
BOARD REVIEW PRACTICE #2
David D. Berg, MD
Fellow in Cardiovascular Medicine
No Disclosures
1869
Case 1
A 23 year-old gentleman with a history of mild asthma presents for evaluation of
intermittent dysphagia for solid foods. He denies heartburn. He has not lost
weight. He reports that one year ago he underwent an upper endoscopy for
removal of pieces of steak. He has taken omeprazole 40 mg BID for the last
month but his symptoms have persisted.
His physical examination is unremarkable. An upper endoscopy reveals circular

rings in the mid esophagus. A biopsy shows a dense eosinophilic infiltrate.
Which of the following is the most appropriate first line therapy?

A. Increase the omeprazole to 80 mg twice daily
B. Esophageal Dilation
C. Topical swallowed fluticasone
D. Oral nifedipine
E. Botulinum toxin injection into the lower esophageal sphincter
Case 1 – The correct answer is C

Eosinophilic esophagitis
• Diagnostic criteria:
– Symptoms of esophageal dysfunction
(dysphagia, food impaction)
– Biopsy: >15 eosinophils/HPF
– Poor response to high dose PPI or
Normal pH in distal esophagus
Endoscopic View of Eosinophilic Esophagitis
UpToDate.com, courtesy of Dr. Eric Libby
• Diagnosis more common in men > women

• First line therapy: topical corticosteroids, 4–6 weeks
• Fluticasone, Budesonide
• Other therapies: elimination diets, leukotriene antagonists
• Dilation reserved for fixed strictures failing medical therapy
Gastroenterology 2007; 133:1342-1363
1870
Case 2
A 22 year old woman sustained a compound tibial fracture during a motor
vehicle accident requiring surgery. Her hospital course was complicated by a
lower extremity deep venous thrombosis. She has no personal or family
history of PE/DVT and a hypercoaguable work up is negative. She is not
taking any medication.
She is started on rivaroxaban 15 mg BID for 21 days followed by 20 mg once

daily.
How long should she be anticoagulated?

A. 1 months
B. 3 months
C. 12 months
D. Lifelong anticoagulation
Case 2 – The correct answer is B
Anticoagulation duration for VTE:

• Provoked:
– OCP use, surgery / prolonged
immobilization, trauma, pregnancy
– 3 months
• Unprovoked or recurrent:
– Extended or lifelong therapy Ann Intern Med. 2007;146(3):211-222
– Duration depends on patient history and Phlegmasia

preference cerulea dolens
Thrombolytics +/-
Chest. 2016;149:315-352. thrombectomy
1871
Case 3
A 64 year old woman presents for new primary care visit with complaints
of increasing dyspnea on exertion and fatigue.
On physical examination, the patient appears pale. She has no jugular

venous distention or heart murmurs. Her lungs are clear. Liver and spleen
are not palpable and she has no lower extremity edema.
Laboratories include WBC count 10,000/ml, Hct 23%, MCV 65 fL, RDW
20%, Plts 1,006,000/ml, LDH 158, ESR 24.
What is the most likely cause of the thrombocytosis?
A. Iron deficiency
B. Subacute bacterial endocarditis
C. Acute myocardial infarction
D. Autoimmune hemolytic anemia
E. Essential thrombocythemia
Case 3 – Correct Answer is A

Thrombocytosis
Primary Secondary
Clonal Reactive
Platelet count
Acute inflammation, does not
Bone Marrow Disorder infection, chronic illness,
post-splenectomy determine
primary vs
secondary cause
OFTEN associated with RARELY associated with
vasomotor, thrombotic, vasomotor, thrombotic,
bleeding complications; bleeding complications;
Splenomegaly No organomegaly
Iron deficiency causes

Am J Med 1994;96:247-53
thrombocytosis due to stimulation
NEJM 2004;350:1211-19 of platelet precursors by EPO
1872
Case 4
A 42 year-old gentleman with HIV infection (CD4 cell count
188/ul) presents with new headaches.
CT scan of the head reveals two ring enhancing lesions with mass
effect.
Which of the following is LEAST likely to be the etiology of this

finding?
A. Toxoplasmosis
B. Primary central nervous system lymphoma
C. Progressive multifocal leukoencephalopathy
D. Tuberculosis
E. Staphylococcus

CNS Lesions in Patients with HIV Infection
CNS lesions WITH Toxoplasmosis

mass effect CNS lymphoma
(ring enhancing) Tuberculosis
CD4 < 200

CNS lesions PML
WITHOUT mass effect HIV Encephalopathy
(non-enhancing) CMV Encephalitis
Brain tumors
CD4 > 500 Metastases
Clin Infect Dis 2002; 34:103

Mandell 2005: 1583-1601
1873
Case 5
A 55 year-old gentleman with HCV cirrhosis presents for follow up
after an upper endoscopy reveals medium-sized esophageal varices.
He has no history of GI bleeding.
On examination, his blood pressure is 110/55 with a pulse of 85

bpm. His abdominal examination reveals splenomegaly. No shifting
dullness or fluid wave is present.
Which of the following is indicated for primary prophylaxis?

A. Norfloxacin
B. Nadolol
C. Transjugular intrahepatic portosystemic shunt (TIPS)
D. Nadolol and variceal banding
E. Isosorbide mononitrate

Primary variceal bleeding prophylaxis
Patients Screening SBP Norfloxacin

with Endoscopy
cirrhosis
Medium
or Large Non-
Varices selective BB
Non-
selective BB
+ With Without OR
Bleed Bleed
Variceal
Ligation Variceal
TIPS Ligation
Hepatology 2007; 46:922-938
1874
Case 6
A 50 year-old woman with Marfan syndrome presents with substernal
CP radiating to her back. Physical exam reveals a II/VI early diastolic
murmur. An ECG is obtained:
Case 6
What diagnostic study would you obtain first?
A. Transthoracic echocardiogram
B. Computed tomography angiography of the chest
C. Cardiac catheterization
D. Lung ventilation-perfusion (V/Q) scan
E. Vasodilator SPECT
1875

Imaging of Acute Aortic Dissection
• Aortic dissection • Dissection can cause STEMI due
– Substernal chest pain, to extension of the dissection
radiating to back flap into the coronary arteries
– New diastolic murmur (R > L)
• Risk factors • Diagnostic tests

– Connective tissue disease – CTA chest / aorta
– Hypertension – Trans-esophageal
echocardiogram (TEE)
– Smoking
– [MRA]
– Atherosclerosis
– Pregnancy • Vasodilator SPECT evaluates
– Trauma myocardial ischemia, not
dissection
– Preexisting aortic aneurysm
Circulation 2003; 108:628-35; 772-8
Case 7
A 58 year-old woman with HTN on HCTZ and atenolol presents
with RLQ abdominal pain. Abdominal CT reveals a low-
attenuation, homogenous adrenal mass (2.7 cm).
Her abdominal pain resolves without intervention after several

hours and she has no further complaints.
What should be the first step in your evaluation?

A. Fine needle biopsy
B. Magnetic resonance imaging (MRI)
C. Repeat CT scan
D. Plasma and urine hormone evaluation
E. Surgical exploration and resection
1876
Case 7 – The correct answer is D

Adrenal Incidentaloma
Adrenal Incidentaloma Evaluation

• Adrenal mass >1cm •First step: hormonal testing
• Incidence 4-6% •If hormonal testing is negative,
• Most are nonfunctional, FNA can be performed to
benign adenomas evaluate for metastatic disease
• But rarely can be: •Never biopsy or resect without
– Cortisol-secreting adenoma ruling out a hormonally active
– Aldosteronoma tumor
– Pheochromocytoma
•MRI gives clues regarding
– Adrenocortical carcinoma etiology, but does NOT rule out a
– Metastastic lesion functioning tumor
NEJM 2007; 356: 601
Case 8
A 54 year-old woman presents to her PCP with new-onset
headache. The pain is retro-orbital, unilateral (right side only), and
has been progressive over the course of three weeks with
intermittent responsiveness to acetaminophen. She denies visual
changes, fevers, chills, jaw claudication, or weakness. Her exam is
normal, including thorough neurological exam.
A. Oxycodone
B. Head MRI/MRA
C. Amitriptyline
D. Sumatriptan
E. Referral to physical therapy
1877

Brain Imaging for Headaches
• Headache warning signs
– ‘First or worst’
– Increased frequency, increased severity
– New-onset headache after age 50
– New-onset with history of cancer / immunodeficiency
– Mental status changes
– Fever, neck stiffness, and meningeal signs
– Focal neurologic deficits (if not migraine with aura)
• Treatment for migraines:
– Abortive therapies: NSAIDs, triptans, anti-emetics
– Prophylaxis: amitriptyline, beta blockers, antiepileptics
• Less effective: opioids & physical therapy
Martin, et al., National Headache Foundation 2004

L.S. Medina et al / Neuroimag Clin N Am 13 (2003) 225–235
Case 9
A 31 year-old monogamous woman with no past medical
history presents for routine Pap smear. The cytological result is
negative for intraepithelial lesion or malignancy. Reflex DNA
testing for high-risk human papillomavirus (HPV) is performed
and is negative. She has no history of abnormal Pap Smears.
What is the next step in management?

A. Repeat cytology with HPV co-testing in 6 months
B. Repeat cytology with HPV co-testing in one year
C. Repeat cytology with HPV co-testing in two years
D. Repeat cytology with HPV co-testing in three years
E. Repeat cytology with HPV co-testing in five years
1878
Case 9 – The correct answer is E

Cervical Cancer Screening Guidelines (USPSTF)
• Women age ≥ 30 years

– Cytology (Pap smear) every three years
OR
– Cytology AND HPV co-testing every five years
• Women age 21-29 years

– Cytology (Pap smear) every three years
– Screening with HPV co-testing has limited utility in
this population (should be avoided)
Annals of Internal Medicine, 2012 June;156(12):880-891
Case 10
A 56 year-old male from Western Massachusetts presents to
his primary care physician with a fever and rash x 2 weeks. He
has no other symptoms. His Lyme ELISA and Western Blot tests
are positive.
What is your next BEST step in

management?
A. Doxycycline 200mg x1
B. Ceftriaxone 2g IV daily x3wks
C. Amoxicillin 500mg TID x2wks
D. Doxycycline 100mg BID x2wks
E. Azithromycin 500mg x1d,
F. then 250 mg x4d
1879

Treatment of Early Lyme Disease
• Erythema Migrans
– Within 7-14 days after tick detaches
– Most have 1 lesion; 25% have multiple
• Serologic testing
– Only 40% sensitive
– Not required if classic erythema migrans rash
• Treatment of choice: Doxycycline (10-21 days)
– Also treats anaplasmosis; MISSES babesiosis
– In pregnancy & pediatrics: Penicillin or Amoxicillin
• Treatment for advanced disease: 3rd generation
cephalosporin
– Includes advanced heart block, meningitis, neuritis
NEJM 2006;354: 2794-801.

NEJM 2001; 345: 115-125. NEJM 2001; 345: 79-84.
Case 11
A 68 year-old woman with asthma presents to her PCP with right foot
paresthesias, progressive right foot drop, and erythematous rash over
both lower extremities. Five months prior, she had a productive cough
and was found to have patchy infiltrates on CXR, prompting treatment
with antibiotics. Her labs are notable for WBC count 9,600/ml (58%
neutrophils, 9% lymphocytes, and 31% eosinophils), Hct 36.2, plts 271
K/ml.
Which of the following diseases is most likely to be the cause of the

patient’s presentation?
A. Granulomatosis with polyangitis (formerly Wegener’s)

B. Temporal arteritis
C. Schistosomiasis
D. EGPA (formerly Churg-Strauss)
E. Hodgkin’s disease
1880

Eosinophilic Granulomatosis with Polyangiitis
(formerly Churg-Strauss)
• Classic Triad = Asthma, sinus disease, peripheral eosinophilia
• Diagnosis:
- Asthma (particularly late onset)
- Mononeuropathy (multiplex) or polyneuropathy
- Rash: variable pattern (present in ~60%)
- Paranasal sinus abnormalities
- Allergic rhinitis, recurrent sinusitis, nasal polyposis
- Eosinophilia: >10% or > 1500 eosinophils/ml
- Migratory or transient pulmonary opacities on CXR
• Diagnosis supported by p-ANCA or anti-MPO antibodies
• Biopsy may show extravascular accumulation of eosinophils / granulomas,
eosinophilic pneumonia, small-vessel vasculitis
Semin Arthritis Rheum. 2003;33:106-14

Semin Respir Crit Care Med. 2006;27:148-57
Case 12
A 19 year-old woman presents with 3 days of vaginal discharge. She is
sexually active with one partner. Her LMP was 4 days ago. Exam
shows temp 99, BP 100/60 and HR 90. Her pelvic exam shows copious
mucopurulent discharge from a red, inflamed cervix. She has
tenderness on palpation of the cervix but no adnexal or uterine
tenderness. A GC/chlamydia nucleic acid amplification probe returns
positive for N. gonorrhoeae.
What is the next management step?
A. Ceftriaxone 125 mg IM x1
B. Ceftriaxone 250 mg IM x1
C. Ceftriaxone 125 mg IM x1 + Azithromycin 1 gram PO x1
D. Ceftriaxone 250 mg IM x1 + Azithromycin 1 gram PO x1
E. Doxycycline 100 mg PO BID x 7 days
1881
Case 12 – The Answer is D

Treatment of Gonococcal Infections
• CDC treatment guidelines 2015 recommend:

– Ceftriaxone 250 mg IM (increased from 125 mg in 2011 guidelines)
– AND Azithromycin or doxycycline (dual therapy regardless of chlamydial
coinfection)
• Rationale for increased CTX dose and dual therapy:

– Reports of clinical treatment failures
– Some isolates had decreased susceptibility to cephalosporins
• Increased minimal inhibitory concentration (MIC)
• Cephalosporin-resistant strains are likely tetracycline-resistant as well
2015 STD Treatment Guidelines, www.CDC.gov

J Antimicrob Chemother. 2010;65(10):2141
Case 13
A 34 year-old woman is seen in the ED with confusion, malaise, nausea.
Past medical history is notable for allergic rhinitis. Medications include
loratadine and flonase. On exam, the patient is alert and oriented to self
only. She is noted to have jaundice and bilateral lower extremity
petechiae.
Labs are notable for hematocrit 21, platelets 45,000/ml, reticulocyte

count 15%, and LDH 1,500 U/L. Coagulation studies are normal.
Peripheral smear shows:
1882
Case 13
Which of the following is the BEST next step?
A. Perform direct antiglobulin (Coombs) test

B. Check ANA
C. Obtain transthoracic echocardiogram
D. Give Intravenous immune globulin
E. Initiate plasma exchange
Case 13 – The Correct Answer is E

Management of primary TMA syndromes
Smear: microangiopathy (schistocytes >5/hpf), rare platelets
• Primary TMA syndromes include TTP,
HUS, and others
• Clinical features:
• MAHA
• Neurologic abnormalities
• GI symptoms
Peripheral blood smear with schistocytes (arrows)
• AKI (less common with TTP)
• Low ADAMST13 activity (<10%) is hallmark of TTP
• Early empiric initiation of plasma exchange to treat
presumptive TTP is critical to decrease morbidity and mortality
NEJM 2006: 354(18): 1927
1883
Case 14
A 45 year-old man with a history of dyspepsia presents to the office
with new dysphagia. He initially developed dyspepsia with occasional
heartburn several years ago and these symptoms responded to
omeprazole 20 mg daily. Two years ago, his symptoms recurred so his
omeprazole dose was increased to 40 mg daily, which again helped his
symptoms. He now presents with difficulty swallowing solid foods.
Which of the following is the next best step?
A. Change the proton pump inhibitor to twice per day

B. Add a night-time dose of a H2 blocker
C. Refer for a barium swallow study
D. Refer for an upper endoscopy
E. Treat the patient for Helicobacter pylori infection

Endoscopy for Dyspepsia
• Dyspepsia: chronic / recurrent upper abdominal pain
• Alarm symptoms need early endoscopy
– New onset at > 55 years old
– Family history of upper GI cancer
– Weight loss
– GI bleeding or unexplained iron-deficiency anemia
– Progressive dysphagia or odynophagia
– Persistent vomiting
– Palpable mass or lymphadenopathy
• If younger than 55 years and no alarm features:

– H. pylori test and treat, PPI therapy if still symptomatic
• If alarm features:
– Early endoscopy with biopsy for H. pylori
– Low positive predictive value, high negative predictive value for cancer
Gastroenterology. 2005;129:1756-80
1884
Case 15
A 24 year-old man presents for an annual physical. On exam,
he is noted to have a harsh III/VI systolic crescendo-
decrescendo murmur best appreciated at the LLSB. The
murmur does not radiate to the carotids and is increased
with Valsalva maneuver. A prominent S4 is heard. What is the
most likely underlying pathology?
A. Congenital aortic stenosis
B. Marfan syndrome
C. Hypertrophic cardiomyopathy
D. Early-onset hypertension
E. Rheumatic heart disease

Differentiating systolic murmurs on exam
• Hypertrophic cardiomyopathy
– Systolic crescendo-decrescendo murmur
related to LVOT obstruction and mitral
regurgitation from SAM
– Generally does not radiate to carotids, and
is increased with Valsalva
– HCM is an autosomal dominant disorder of
the cardiac sarcomere with variable
penetrance
– Increased risk of sudden cardiac death
• Aortic Stenosis
– Systolic crescendo-decrescendo murmur,
radiates to carotids, decreased with
Valsalva
– Can be related to bicuspid, calcific, or Hypertrophic cardiomyopathy
rheumatic heart disease
Circulation 2006; 113: e858-862

JACC 2000; 36:2212
N Engl M Med 2004;350:1320-7.
1885
Case 16
A 22 year-old male college football player with no PMH
presents to the emergency room for evaluation of a small
abscess on his neck. The collection is incised and drained,
and gram stain demonstrates gram positive cocci in clusters.
What treatment would you prescribe?
A. Oral vancomycin
B. Dicloxacillin
C. Oral trimethoprim-sulfamethoxazole
D. Oral penicillin
E. Intravenous nafcillin

Treatment of community acquired MRSA
• Community acquired MRSA (CA MRSA)
– Most common organism in skin and soft tissue infections in ED
– Outbreaks reported in athletes, military, IVDU, MSM
– Should be considered in anyone
• CA MRSA is NOT susceptible to penicillins

– Cannot use penicillin, dicloxacillin, or nafcillin
• CA MRSA in stable patients can be treated with:

– Clindamycin, trimethoprim-sulfamethoxazole, long-acting tetracycline
(minocycline or doxycycline), linezolid
• Severe infections with CA MRSA (parenteral agents):

– IV vancomycin, daptomycin, ceftaroline, linezolid
– No role for oral vancomycin besides C. difficile infections
NEJM 2006;355:666-674
1886
Case 17
A 56 year-old man with heart failure with reduced ejection fraction
is admitted with cough, fever, and a RLL infiltrate on CXR. He is
diagnosed with community acquired pneumonia and started on
levofloxacin. On hospital day 2, the following rhythm is seen on
telemetry and the patient is unresponsive.
JAMA 1990; 264: 2788
Case 17
What is the next best step in management?
A. Defibrillation
B. Synchronized cardioversion
C. Intravenous magnesium
D. Amiodarone
E. Isoproterenol
JAMA 1990; 264: 2788
1887
Case 17 – The correct answer is A

Management of Torsades de Pointes (TdP)
• TdP: Polymorphic VT in setting of prolonged QT
– Congenital (LQTS genetic variants)
– Acquired
• Drugs (e.g. fluoroquinolones, macrolides, antipsychotics)
• Electrolyte abnormalities (e.g. hypokalemia, hypomagnesemia)
• Bradyarrhythmias (long-short sequences)
• Treatment for unstable VT/VF: Immediate defibrillation
• Intravenous magnesium
– Treats and prevents recurrent TdP
– Not useful for terminating hemodynamically unstable TdP
• Isoproterenol and RV pacing
– Prevents bradycardia, QT dispersion, EADs that predispose to TdP
– Not useful for terminating hemodynamically unstable TdP
JAMA 2003; 289: 2041

Am Heart J 2007;153:89129
Case 18
A 42 year-old alcoholic man with no other PMH is admitted with
nausea and vomiting after a recent drinking binge.
Lab studies reveal an anion gap metabolic acidosis and urine

ketones. Blood glucose is 100 mg/dl.
What is the appropriate first step in management?

A. Intravenous insulin
B. Intravenous steroids
C. Intravenous dextrose
D. Intravenous normal saline
E. Intravenous folate
1888

Alcoholic ketoacidosis
• AKA is caused by:
– Decreased carbohydrate intake
– Alcohol-induced inhibition of gluconeogenesis
– Alcohol-induced stimulation of lipolysis
• Presents as AGMA with ketonemia/ketonuria in an alcoholic

without diabetes
• Initial treatment is IV fluid resuscitation

– Insulin not given because glucose not elevated
– Dextrose given only after thiamine administration to avoid
Wernicke’s encephalopathy
– Folate repletion is important for malnourished or alcoholic
patients, but not for acute treatment of AKA
Emerg Med J. 2006;6:416
Am J Med 1991; 91:119
Case 19
A 52 year-old man is seen in urgent care after he was found to have
2+ blood on a urinalysis performed as part of a life insurance
evaluation. He is a former smoker but otherwise has no PMH, no
prior chemical exposures, and no family history of cancer. You repeat
a urinalysis and examine his urine sediment under a microscope. He
has 6 RBCs per high-powered field, which are normal-appearing.
What is the most appropriate evaluation?
A. Check IgA level
B. Obtain CT urogram
C. Refer to nephrology for a renal biopsy
D. Refer to urology for cystoscopy
E. Obtain CT urogram AND refer for cystoscopy
1889

Evaluation of microscopic hematuria
• Microscopic hematuria: ≥3 RBCs / HPF
• If dysmorphic RBCs or RBC casts are present:

–Suspect glomerular source
–Consider renal biopsy
• If RBCs are normal-appearing:

–Suspect non-glomerular source
• Ureteral bleeding (nephrolithiasis)
• Bladder bleeding (bladder cancer or cystitis)
–Initial evaluation should include CT urogram
–Obtain CTU and cystoscopy if age > 35 or at risk for bladder cancer
NEJM 2003; 348: 2330-8
Case 20
A 50 year-old woman presents to the ED complaining of a sore throat
and concern that a fish bone is stuck in her throat. She had a URI three
weeks prior but is now feeling well. Her vitals signs are stable with a
heart rate of 80 and blood pressure 126/76. Her anterior neck is tender
on exam. Direct laryngoscopy is normal.
Labs are notable for a TSH 0.03 mIU/L and ESR 80 mm/hr.
A. Propylthiouracil 150 mg BID

B. Atenolol 50 mg daily
C. No treatment, recheck TSH in 4-6 weeks
D. 131I ablative therapy
E. Methimazole 10 mg TID
1890

Management of subacute thyroiditis
• Pain or tenderness of the thyroid on exam helps distinguish
different forms of thyroiditis
• Painless thyroiditis is an autoimmune process

– Includes Hashimoto’s, postpartum, drug-induced thyroiditis
– Often results in a chronically hypothyroid state
• Painful subacute thyroiditis often follows a URI

– Beta blockers are useful only for symptoms or tachycardia
• 131I
ablative therapy is reserved for Graves disease, toxic
multinodular goiter, or thyroid cancer
NEJM 2003; 348: 2646-55

BMJ 2006; 332: 1369-73
Case 21
A 35 year-old male presents to urgent care with a two-week history of
purulent rhinorrhea and right-sided maxillary sinus pain. His symptoms
have persisted despite acetaminophen, fluticasone nasal spray, and
saline irrigation. He takes HCTZ 25 mg daily and amlodipine 5 mg daily
for hypertension, and has no known drug allergies. Exam is notable for
a temperature of 101.5ºF, copious rhinorrhea, and tenderness with
percussion over the maxillary sinuses. Cardiac and pulmonary exams
are unremarkable.
A. Amoxicillin 500mg TID x5-7 days

B. Amoxicillin/Clavulanate 875/125mg BID x5-7 days
C. Amoxicillin/Clavulanate 2g/125mg BID x10 days
D. Doxycycline 200mg QD x5-7 days
E. Levofloxacin 500mg daily x5-7 days
1891

Acute Bacterial Rhinosinusitis
• Clinical Presentation
– Persistent symptoms (≥ 7-10 days)
– Severe symptoms
• Fever ≥102ºF
• Purulent nasal discharge
• Facial pain lasting ≥ 3 days
– Initial improvement, then worsening of symptoms
• Treatment: amoxicillin-clavulanate is first-line (IDSA 2012)
– High-dose amoxicillin-clavulanate for patients with risk factors such as:
• Age >65yrs
• Immunocompromised
• Recent antibiotic use
• Recent hospitalization
• High prevalence of resistant S. pneumoniae
– Doxycycline and levofloxacin for patients with penicillin allergy
Clin Infect Dis. 2012;54(8):e72-112
Case 22
A 30 year-old female presents to clinic complaining of bilateral breast
pain. She states that the pain is worse toward the end of her cycles and
also in the evening. She has had the pain for 3 months and describes it as
an aching, diffuse pain. Her exam is notable for a BMI of 28, and
pendulous breasts without erythema, masses or discharge. She has no
lymphadenopathy or skin changes. She is concerned she may have cancer
and tells you that her maternal grandmother had breast cancer at age 76.
What is the best next step in management?
A. Bilateral mammography
B. Bilateral breast MRI
C. Bilateral breast ultrasound
D. BRCA testing
E. Reassurance and recommendation for a more supportive bra
1892

Cystic Mastalgia
• Cyclic mastalgia
– Thought to be related to pain in Cooper’s ligament from
inadequate support of pendulous breasts
• Further testing with imaging and/or BRCA testing would

be overly aggressive
Journal of Reproductive Medicine 2005 Dec;50(12):933-9
Case 23
A 35 year-old man presents to his PCP for a routine physical
exam. His only PMH includes seasonal allergies for which he
uses fluticasone nasal spray. He does not smoke cigarettes or
drink alcohol. There is no family history of colorectal cancer
although his mother did have two adenomatous polyps at
age 55.
When should he undergo his first screening colonoscopy?
A. Now
B. Age 40 years
C. Age 45 years
D. Age 50 years
1893

Colorectal cancer screening
• For average risk patients:
– Colonoscopy beginning at age 50
• If history of adenomatous polyps in a 1st degree relative:

• Screening colonoscopy beginning at age 40*
OR
• Screening colonoscopy 10 years before the diagnosis of
adenomatous polyps in the relative*
(*whichever comes first)
Gastroenterology 2008: 134 1570-1595
1894
Pulmonary Disease Overview:

Selected Topics
Christopher H. Fanta, M.D.
Pulmonary and Critical Care Medicine

Partners Asthma Center
Financial Conflicts of Interest
None.
1895
Selected Topics
• Hemoptysis
• Bronchiectasis and bronchiolitis
• Solitary pulmonary nodule
Hemoptysis: Case Example
• 56-year-old man presents for evaluation of a

lingering chest cold.
• He had the onset of cough and chest

congestion 8 weeks ago. He expectorated
discolored phlegm with blood streaks for
several days. His cough persists, productive of
small amounts of blood mixed with white
phlegm.
1896
Hemoptysis: Case Example (cont.)
• He smokes one pack of cigarettes per day and

takes one aspirin daily.
• His chest exam reveals a few scattered rhonchi.
Hemoptysis: Case Example (cont.)
• His chest X-ray is normal.
1897
Hemoptysis: Initial Work-Up
• Chest radiograph
• Sputum analysis
In massive hemoptysis
• Adequacy of oxygenation/ventilation
• Coagulation studies
• Hemoglobin/hematocrit
Hemoptysis: Differential Diagnosis
• Neoplastic: primary lung cancer, metastases

• Infectious: TB, abscess, bronchiectasis,
necrotizing pneumonia
• Immunologic: vasculitis, capillaritis
• Cardiovascular: PE, AVM, mitral stenosis
• Inflammatory: chronic bronchitis, trauma
1898
Chest X-rays in Hemoptysis:

Case Histories
Case 1: Four weeks of cough with discolored

phlegm intermittently mixed with
blood; fevers, night sweats, and
significant weight loss.
1899
Case 1: Further Work-Up/Treatment
Dx: Isolation room; face mask (outpatient)

Sputum for AFB smear and culture
Rx: Anti-tuberculosis therapy with 3-4 drugs

Case Histories
Case 2: Several days of hemoptysis with

progressive shortness of breath; dark-
colored urine and creatinine of
2.5 mg%.
1900
Case 2. Further Work-Up/Treatment
Dx: Serologies (ANCA, anti-GBM antibody, ANA)

Bronchoscopy with BAL
Biopsy of kidney or lung
Rx: High-dose systemic corticosteroids +

immunosuppressives
Plasmapheresis
1901

Case Histories
Case 3: Expectoration of blood-streaked

sputum preceded by chronic a.m.
cough in a heavy cigarette smoker.
Exam is notable for clubbing and
obvious weight loss.
1902
Dx: Sputum cytology

Fiberoptic bronchoscopy
Rx: Radiation therapy, chemotherapy

(Possible brachytherapy or endobronchial
laser therapy)

Case Histories
Case 4: Hemoptysis and pleuritic chest pain on

the third post-operative day.
1903
1904
Dx: Chest CT angiogram

Ventilation-perfusion lung scan
(Conventional pulmonary angiogram)
Rx: Anticoagulation
Which of the Following Is the Most

Common Cause of Recurrent/Persistent
Hemoptysis in a Cigarette Smoker with
a Normal CXR?
A. Lung cancer
B. Chronic bronchitis
C. Tuberculosis
D. Aspiration
E. Pulmonary embolism
1905
Which of the Following Is the Most

Common Cause of Recurrent/Persistent
Hemoptysis in a Cigarette Smoker with
a Normal CXR?
A. Lung cancer
B. Chronic bronchitis
C. Tuberculosis
D. Aspiration
E. Pulmonary embolism
Hemoptysis with a Negative Chest X-ray:

Incidence of Lung Cancer
Authors No. of Pts No. (%) with Lung Cancer
Rath et al. 17 1 (6)
Zavala 55 9 (16)
Weaver et al. 15 0 (0)
Kalenbach et al. 32 7 (22)
Gong et al. 42 3 (7)
Dreisin et al. 19 2 (11)
Donlan et al. 72 0 (0)
Peters et al. 26 0 (0)
Poe et al. 196 12 (6)
Lederle et al. 106 6 (6)
O’Neil et al. 119 6 (5)
TOTAL 699 46 (7)
1906
Hemoptysis With a Normal CXR:

Risk Factors for Lung Cancer
• Past or present cigarette smoker
• Age >40 years
• Hemoptysis that continues beyond 1 week
Hemoptysis with a Normal CXR:

Pursuing Further Evaluation
• Chest CT scan
• Fiberoptic bronchoscopy
• (Serial chest radiographs)
1907
Hemoptysis with a Normal Chest X-ray:

Complementary Roles of Bronchoscopy
and Chest CT Scanning
Among 50 patients with hemoptysis and

a normal or non-localizing chest X-ray,
a definitive diagnosis was established
in 17 (34%) patients:
- CT made Dx in 15 (30%)
- FB made diagnosis in 5 (10%)
Tak S, et al. Australas Radiol 1999; 43:451.
Massive Hemoptysis
Definition: 600 ml of blood/24 hr
500 cc
125 cc
1908
Causes of Massive Hemoptysis
• Cancer of the lung

• Tuberculosis (active and inactive)
• Bronchiectasis
• Lung abscess
• Mycetoma
• Pulmonary vasculitis
1909
Non-Specific Treatments of
Massive Hemoptysis
• Provide adequate oxygenation and ventilation
• Position with bleeding lung dependent
• Interventional pulmonology:
• Balloon-tipped catheter placement for tamponade
• Laser or argon plasma photocoagulation
• Interventional radiology:
• Bronchial artery embolization
• Potential complication: spinal artery infarction
• Thoracic surgery: Surgical resection
Obstructive Lung Diseases
• Asthma
• Chronic Bronchitis and Emphysema
• Bronchiectasis (including cystic fibrosis)
• Bronchiolitis
• Upper airway obstruction
1910
Case History
• 66-year-old woman was referred for evaluation of

her “asthma.“
• She had a 10-year history of intermittent wheeze,
cough and exertional dyspnea, made worse by
respiratory tract infections, cold air and exercise.
Her medications were theophylline and inhaled
albuterol.
Case History (cont.)
• Chest exam was notable for inspiratory

rhonchi at the right base. Spirometry revealed
a mild restrictive pattern.
• Sputum culture on several occasions grew H.
influenzae.
1911
1912
Clinical Presentations of Bronchiectasis:

Historical Features
• Chronic productive cough

• Recurrent hemoptysis
• Recurrent bronchitis/pneumonia
• Persistent radiographic “pneumonia”
• Associations: sinusitis, infertility
Clinical Presentations of Bronchiectasis:

• Focal inspiratory crackles

• Low-pitched wheezing (“rhonchi”)
• Clubbing
1913
Microbiology of Bronchiectasis
• Bacterial
• Staphylococcus
• Hemophilus
• Pseudomonas
• Mycobacterial (MAI)
• Fungal (Aspergillus)
1914
Chest CT Appearance in
Bronchiectasis
• Lack of bronchial tapering

• Bronchial dilatation (internal diameter >1.5 x
diameter of accompany vessel)
• Visualization of bronchi in lung periphery
(within 1 cm of pleura)
• Bronchial wall thickening may be present
1915
Bronchiectasis with
mucoid impaction
1916
Etiologies of Bronchiectasis
• Localized
• Residuum of pneumonia
• Distal to a focal airway obstruction
• Widespread
• Cystic fibrosis
• Primary ciliary dyskinesia
• Hypogammaglobulinemia
• Alpha-1 antitrypsin deficiency
Etiologies of Bronchiectasis:
Other Observations
• AIDS
• Rheumatoid arthritis
• Bronchiolitis
• Non-tuberculous mycobacterial infection
• Allergic bronchopulmonary aspergillosis
1917
Non-Tuberculous Mycobacterial
(NTM) Pulmonary Infection
• In non-immunocompromised host:
• Bronchiectasis and tree-in-bud nodules
• Predominantly middle and lower lobes
• Predilection for middle-aged and older thin
women (“Lady Windermere’s syndrome”)
• Dx: positive culture from sputum x2 or BAL
• Rx: macrolide, ethambutol, rifampin (>1 year)
1918
Allergic Bronchopulmonary
Aspergillosis (ABPA)
• Susceptible hosts: asthma and cystic fibrosis
• Aspergillus colonization of airways with
intense allergic response
• Central bronchiectasis
• Very high serum IgE and positive specific IgE
and IgG to aspergillus; eosinophilia
• Rx: steroids plus antifungal therapy (azoles)
1919
Etiologies:
Special Syndromes
Congenital anatomic defects

Munier-Kuhn syndrome (tracheobronchomegaly)
Yellow nails syndrome (lymphatic hypoplasia)
Young’s syndrome (bronchiectasis and
azospermia)
Williams-Campbell syndrome (bronchial cartilage
deficiency)
Therapeutic Options in
Bronchiectasis
• Antibiotics
• Clearance of secretions
• Bronchodilators
• Mucolytics
• Mechanical vibration techniques
• Other: azithromycin, corticosteroids
1920
Randomized Trial of Suppressive

Antibiotics (in Cystic Fibrosis)
• 520 patients with cystic fibrosis randomized to

inhaled tobramycin 300 mg BID vs. placebo
every other month for 6 months.
Outcomes: Lung function (FEV1)

Density of Ps. aeruginosa in
sputum
Need for hospitalization/intravenous
antibiotics
Ramsey BW, et al., N Engl J Med 1999; 340:23-30
Randomized Trial of Nebulized

Tobramycin (in Cystic Fibrosis)
Change in Lung Function
Ramsey BW, et al., N Engl J Med 1999; 340:23-30
1921
Other Therapeutic Options in

Bronchiectasis
• Bronchodilators
• Clearance of secretions
• Chest physiotherapy and postural drainage
• Vibratory PEP device
• External electric vibrator
• Pneumatic vest
• Exercise
Cough Assist Devices
Flutter Acapella
Aerobika
1922
Azithromycin in Bronchiectasis
Azithromycin 500 mg
(or placebo) 3 days/week
Lancet 2012; 380:660-7.
Azithromycin in Bronchiectasis
Azithromycin 500 mg
(or placebo) 3 days/week
Lancet 2012; 380:660-7.
1923
Complications of Bronchiectasis
• Hemoptysis
• Infection with resistant organisms
• Respiratory failure
• Other: weight loss, mycetoma
Bronchiolitis: Definition
Acute or chronic cellular inflammation

of the bronchiolar walls.
Acute: Viral (e.g., RSV), mycoplasma
Chronic: Follicular bronchiolitis

Mineral dust bronchiolitis
Cigarette smoke respiratory bronchiolitis
Diffuse panbronchiolitis (Japan)
Bronchiolitis obliterans
1924
1925
Bronchiolitis Obliterans: Etiologies

• Toxic fume inhalation (e.g., nitrogen oxides in
silo filler’s lung disease; diacetyl in workers
exposed to artificial butter flavoring for popcorn)
• Post-infectious (e.g., viral, mycoplasma)
• Immune-mediated
• Ulcerative colitis
• S/P transplantation (e.g., bone marrow, lung)
Bronchiolitis: Clinical Features
• Hx: dyspnea, non-productive cough

• P.E.: inspiratory crackles; mid-inspiratory
squeak; expiratory wheezes
• CXR: hyperinflation; +small patchy
parenchymal infiltrates
• CT: areas of relative oligemia (“mosaic
oligemia”); “tree-in-bud” appearance
1926
1927
Bronchiolitis: Treatment
• Corticosteroids (systemic/inhaled)
• Bronchodilators
• (Post-transplant: extracorporeal
photopheresis; etanercept; montelukast)
• Supplemental oxygen as needed
Bronchiolitis obliterans is often refractory to
therapy.
1928
Evaluation of SPN
In a 50-year-old cigarette smoker, the

next step in the evaluation of this
pulmonary nodule should be
percutaneous needle biopsy:
A. True
B. False
1929
Evaluation of SPN
In a 50 year-old cigarette smoker, the

next step in the evaluation of this
pulmonary nodule should be
percutaneous needle biopsy:
A. True
B. False
Solitary Pulmonary Nodule:

Etiologies
• Benign
• Malignant
1930

Aphorism
“When in doubt, cut it out.”

Radiographic Features Definitive for
Benign Disease
• Calcification (exception: small eccentric

focus of calcium within nodule)
• Absence of increase in size over 2 years*
*exception: ground-glass (“sub-solid”)

nodule
1931
(Bronchoalveolar Cell Carcinoma)

Adenocarcinoma In Situ or
Minimally Invasive Adenocarcinoma

Clinical Features Favoring
Benign Disease
• Age <40 yrs

• Non-smoker
• Residence in area endemic for fungal
infections
1932

Radiographic Features Favoring
Benign Disease
• Smooth margin
• Round edge
• Presence of satellite lesions
• Small size (<6 mm on chest CT scan)

Use of Biopsy Techniques to Identify
Benign Disease
• Percutaneous needle aspiration (or

navigational bronchoscopy) is the preferred
technique, but yield for a specific benign
etiology is low, and a non-specific benign
result is unreliable in excluding malignancy
(false negatives >20%).
1933
Video-Assisted Thoracoscopic
Surgery (VATS)
• Three one-inch chest incisions, plus

chest tube drainage
• Average length of hospital stay:
2-3 days
• Pre-resection mediastinoscopy is routine
at many centers

Novel Techniques to Identify Benign
Disease
• Positron emission tomography (PET)

scanning with fluorodeoxyglucose
• Contrast-enhanced CT scan
• Radiolabeled peptide analogs of somatostatin
(depreotide)
1934
PET Scanning
for Solitary Pulmonary Nodules
Rationale:
• Malignant tumors have increased metabolic activity
• 18F-2-fluoro-2-deoxyglucose (FDG) is a radiotracer
taken up by malignant tumors but not by
metabolically inactive tissue.
• Intensity of FDG uptake in a lung nodule is
compared with background activity.
1935
1936
PET Scanning
For Solitary Pulmonary Nodules
Results:
for nodules >8 mm in diameter
• Sensitivity: ~95%
• Specificity: ~85%
• Negative predictive value: ~95%
• False negatives: Bronchoalveolar carcinoma
Pre-Operative Assessment
• Exclude distant metastases

• Brain, bone, liver, adrenals
• Exclude extrathoracic primary malignancy

• Breast, thyroid, and rectal exams; urinalysis
• Assess adequacy of cardiopulmonary reserve

• PFTs; possible ABGs; ETT if indicated
1937
PET Scanning
For Assessing Distant Metastases
Comparison of conventional staging work-up vs.

conventional work-up plus PET-CT scan in NSCLC:
• Significant reduction in futile thoracotomies;
• No difference in justifiable thoracotomies;
• No difference in mortality.
Fischer B, et al., NEJM 2009; 361:32-9.
Prospective Monitoring of Solitary

Pulmonary Nodule in Low-Risk Patients
• Serial chest X-rays or CT scans

• Surgical resection of enlarging nodule
• Compulsive follow-up!
1938
Screening for Lung Cancer:

Early Lung Cancer Action Project (ELCAP)
• 1000 cigarette smokers (> 10 pack-years),

> age 60, and fit to undergo thoracic surgery
• Screened with helical low-dose chest CT scans
• 233 persons (23%) had noncalcified nodule(s)

detected on CT scan (vs. 68 persons [7%] on CXR)
Henschke Cl et al., Lancet 1999; 354:99-105.

Early Lung Cancer Action Project (ELCAP)
• 27 of the 233 persons with nodules had

malignancy (12% of those with nodules,
3% of the total screened population)
• 23/27 (85%) of the malignant tumors were

Stage 1
Henschke Cl, et al., Lancet 1999; 354:99-105.
1939
Prognosis for Stage I Lung Cancers

Detected by CT Screening
IELCAP
investigators.
NEJM 2006;
355:1763-71.

National Lung Screening Trial
• 50,000 current and former smokers enrolled
between 9/02 and 2/04.
• Randomized to low-dose screening chest CT
scans vs. routine CXRs annually for 3 years.
• Annual follow-up through 2009.
• Primary outcome: Is there a > 20% decrease
in lung cancer mortality with CT screening?
-- www.nci.nih.gov/nlst
1940
NLST: Preliminary Results
Arm Person years Lung Lung cancer Reduction in Value of Efficacy

(py) cancer mortality per lung cancer test boundary
deaths 100,000 py mortality (%) statistic
CT 144,097.6 354 245.7 20.3 –3.21 –2.02
CXR 143,363.5 442 308.3
Deficit of lung cancer deaths in CT arm exceeds that expected by chance
NEJM 2011; 10.1056/NEJMoa1102873
NLST: Results
National Lung Screening Trial Research Team.

NEJM 2011; 365:395-409.
1941
Who Should Be Screened?

(Yearly Low-Dose Chest CT Scans Until Age 77)
• Age 55-80 years;

• Current or former (within 15 years) cigarette
smoker of at least 30 pack-years;
• Absence of life-threatening co-morbidity;
• With proper pre-screening counseling, including
smoking cessation counseling, and follow-up of
detected nodules by experienced team.
-- recommendations of ALA, ACS, and CMS.
Radiographic Follow-Up of SPN:

Fleischner Society 2017 Guidelines
Does not
apply to:
• Patients
who have a
known
cancer.
• Immuno-
suppressed
patients.
• Lung cancer
screening
MacMahon H, et al. Radiology 2017 Feb 23:161659.

doi: 10.1148/radiol.2017161659. [Epub ahead of print].
1942
Risk Factors for

Lung Cancer:
MacMahon • Tobacco use
H, et al. • Family history of
Radiology lung cancer
2017 Feb • Upper pulmonary
23:161659. lobe location of
nodule
• Presence of
doi: emphysema or
10.1148/ pulmonary fibrosis
radiol. • Older Age
2017161659 • Female gender
[Epub ahead
of print].
Summary Recommendations
Conclusions:
“In general, all SPNs should be considered
malignant until proven otherwise.
Resection is the treatment of choice for all
patients who are surgical candidates after
approriate preoperative evaluation,
including those with indeterminate
nodules.” ACCP Evidence-Based Guidelines:
Diagnosis and Management of Lung Cancer.
Chest 2003; 123 (suppl):1S-337S.
1943
References
Hemoptysis:
• Dudha M, Lehrman S, Aronow WS, et al. Hemoptysis: diagnosis
and treatment. Compr Ther 2009; 35:139-49.
Bronchiectasis:
• Barker AF. Bronchiectasis. N Engl J Med 2002; 346:1383-93.
Bronchiolitis:
• Barker AF, et al. Obliterative bronchiolitis. N Engl J Med 2014;
370:1820-8.
• Fischer B, Lassen U, Mortensen J, et al. Preoperative staging of lung
cancer with combined PET-CT. N Engl J Med 2009; 361:32-9.
• National Lung Screening Trial Research Team. Reduced lung-
cancer mortality with low-dose computed tomographic screening.
N Engl J Med 2011; 365:395-409.
None.
1944
BRIGHAM AND Harvard

WOMEN’S HOSPITAL
Medical School
Interstitial Lung Disease
Hilary J. Goldberg, MD, MPH

Division of Pulmonary and Critical Care Medicine
Clinical Coordinating Center Member for multicenter

trial of pirfenidone in RA-ILD
– Genentech, Inc.
1945
Overview
Presentation and Evaluation

Idiopathic Interstitial Pneumonias
– IPF
– CPFE
Autoimmune Lung Disease
Granulomatous Lung Disease:
– Sarcoidosis
– Hypersensitivity Pneumonitis
Presentation
Presenting symptoms
SOB
Cough
Chest pain
Duration of symptoms
Presenting physical signs

Hypoxia
Tachypnea
Inspiratory crackles
Clubbing
Cor pulmonale
1946
Imaging
Radiographic features:
Pattern:
Reticular
Nodular
Combined: Reticulonodular
Location:
Upper lobe
Lower lobe
Homogenous vs. heterogenous
CT features
1947
CT features
Pulmonary function testing

Restrictive ventilatory
defect:
Symmetric decrease
in FEV1 and FVC
Decrease in TLC
Decreased diffusion
capacity
Mixed restriction and

obstruction
1948
Further evaluation
Bronchoscopy: Patients with atypical

– Rule out infection features (age <45,
– Cell counts extensive ground glass,
– Transbronchial sparing of bases, nodular
biopsies: pattern, absence of
Rule out other causes honeycombing, atypical
Granulomatous PFT findings) should be
disease considered for biopsy if
feasible
Surgical lung biopsy
Neither
Diagnosis
AJRCCM 2011; 183: 788
1949
The Idiopathic Interstitial Pneumonias
ATS/ERS Joint Statement, AJRCCM 2002; 165: 277
Am J Resp Crit Care Med 2013; 188: 733
1950
CRP Diagnosis Histology

Idiopathic pulmonary Usual interstitial Pneumonia
fibrosis
Nonspecific interstitial Nonspecific interstitial
pneumonitis pneumonitis
Acute interstitial Diffuse alveolar damage
pneumonia
Desquamative Desquamative interstitial
interstitial pneumonitis pneumonitis
Respiratory bronchiolitis Respiratory Bronchiolitis
– interstitial lung
disease
1951
Pathophysiology of Idiopathic
Pulmonary Fibrosis
Annals of Internal Medicine, vol 134, 2001
Idiopathic Pulmonary Fibrosis –

Potential Risk Factors
Cigarette smoking
Environmental
Microbial agents
GERD
Genetic factors
ATS/ERS/JRS/ALAT Statement;
AJRCCM 2011; 183: 788
Respirology 2015; 20: 1010
1952
ATS/ERS criteria for diagnosis
Exclusion of other known causes of ILD

Presence of UIP pattern on HRCT in patients not
subjected to surgical lung biopsy
Specific combinations of HRCT and surgical lung biopsy
pattern in patients subjected to surgical lung biopsy
ATS/ERS/JRS/ALAT Statement; AJRCCM 2011; 183: 788-824
Differential diagnosis of Idiopathic

Pulmonary Fibrosis
Other idiopathic interstitial pneumonias
Hypersensitivity pneumonitis
Sarcoidosis
Cryptogenic Organizing Pneumonia
Eosinophilic pneumonia
Malignancy
Infection
1953
Radiologic features
Usual Interstitial Pneumonitis Alternate Diagnosis

Subpleural, basilar Upper or mid-lung
predominance predominance
Reticular pattern Peribronchovascular
Honeycombing with or distribution
without traction Ground glass,
bronchiectasis micronodules, cysts
Mosaicism
HRCT features of Idiopathic Pulmonary

Fibrosis
1954
Histologic features
Usual Interstitial Pneumonitis Alternate Diagnosis

Subpleural, paraseptal Hyaline membranes
distribution Granuolmas
Fibrosis, architectural Organizing pneumonia
distortion, honeycombing Inflammatory infiltrate
Temporal and spatial Airway centered changes
heterogeneity
Fibroblastic foci
Histologic features of Usual Interstitial

Pneumonia
1955
Histologic features of Usual interstitial

Pneumonia
Acute exacerbation of interstitial lung

disease
1956

disease

disease
Chest 2008; 134: 1265

Chest 2008; 134: 844
1957
Acute exacerbation Idiopathic

Pulmonary Fibrosis
Am J Respir Crit Care Med 2007; 176: 636
Idiopathic Pulmonary Fibrosis -

Therapy
Recommendation against the following:
– Corticosteroid monotherapy
– Colchicine
– CSA
– Combined corticosteroid and immune-modulator
therapy
– INF alpha
– Bosentan
– Etanercept
1958

therapy
No medical therapies proven to prolong survival
The only therapy demonstrated to prolong survival is
lung transplantation
– Endothelin receptor antagonists
– Anticoagulation
– N-Acetyl-Cysteine
– IL-13 modulation
– Other
Recently published results demonstrate effects on lung
function, composite end points (and mortality)
Newly FDA Approved Medications
– Pirfenidone
– TK inhibitors - nintedanib NEJM 2005; 353(21): 2229-2242
N-Acetyl-Cysteine
Precursor of antioxidant
glutathione
Randomized, placebo
controlled trial of NAC in
addition to “standard
therapy”
NEJM 2005; 353: 2229 - 42
1959
PANTHER
Triple therapy vs.
placebo
Triple therapy arm
closed early:
Increased
mortality (11% vs
1%)
Increased
hospitalization
(29% vs 8%)
More SAE’s (31%
vs. 9%)
Eur Respir J 2012; 39: 805–806
NEJM 2012; 366: 1968
PANTHER
N Eng J Med 2014; 370: 2093
1960
Pirfenidone
Anti-inflammatory
and antifibrotic
Inhibits production
and activity of TGF-
beta
Animal studies:
Inhibits TGF-beta
and pro-
collagen/collagen
gene and mRNA
expression
Inhibits fibroblast
mitogenesis
Expert Opin Investig Drugs. 2010

Feb; 19(2): 275–283
N Eng J Med 2014; 370: 2083
Impact of pirfenidone in setting of

declining FVC
Thorax 2016; 71: 429
1961
Impact of pirfenidone in setting of

declining FVC
Thorax 2016; 71: 429
Nintedanib
Competitive
inhibitor of FGFR-1,
VEGFR-2, PDGFR
alpha and beta
Reduced
proliferation,
migration and
survival of
fibroblasts
Potentially also
attenuates
angiogenesis
Eur Resp J 2015; 45: 1434

N Eng J Med 2014; 370: 2071
1962
Nintedanib
N Eng J Med 2014; 370: 2071

prognosis
Prognosis
3 year 50% mortality
only 10-25% of patients respond to therapy
ATS/ERS Joint Statement, AJRCCM 2002; 165: 277
1963
Idiopathic Pulmonary Fibrosis – natural

history
Combined Emphysema and Pulmonary Fibrosis
Chest 2009; 136: 10
1964
Autoimmune ILD
Lancet 2012; 380: 689
Sarcoidosis pathophysiology
AJRCCM 1999; 160: 736

Am J Resp Crit Care Med 2011; 183:573
1965
Sarcoidosis – Systemic Disease
Organ involvement:
Lung (90%)
Skin (dermatitis, EN, LP)
Eyes (ant/post uveitis)
RES (liver, spleen)
Cardiac (Arrhythmias; cardiomyopathy)
Upper airways (Chronic sinusitis)
Hypercalcemia
Renal (stones, granulomas)
Neurologic (Psych/Thalamic pain)
Sarcoidosis – Pulmonary Staging
CXR Abnormalities:
stage I - hilar adenopathy (80% remit)
stage II - adenopathy + interstitial (60%)
stage III - interstitial (30%)
stage IV - end stage upper lobe fibrosis
More acute presentation = better prognosis
1966
Sarcoidosis – Stage I
Sarcoidosis – Stage II
1967
Sarcoidosis - Pathology
Sarcoidosis -
Syndromes
Specific Syndromes
Lofgrens
syndrome - E.
nodosum, fever,
hilar adenopathy.
Heerfordt’s
syndrome -
uveitis, parotitis,
fever
N Eng J Med 2013; 369: 458
1968
Diagnosis
Sarcoidosis – Indications for Treatment
Indications for treatment

Symptomatic pulmonary disease
DOE
Cough
Airway sarcoid
Worsening PFTs (DLco)
Cardiac involvement
Renal disease
Posterior uveitis
Neurologic involvement
Lupus pernio
Hypercalcemia
1969
Sarcoidosis - Treatment
Hypersensitivity Pneumonitis
Can result from various antigen exposures

Leads to variable presentations
Lack of consensus on diagnostic criteria
Arch Pathol Lab Med 2008; 132: 195 – 198

AJRCCM 2005; 171: 792-798
1970
Hypersensitivity Pneumonitis -
Allergens
Hypersensitivity pneumonitis– Clinical

Presentation
Dyspnea
Cough
Crackles
Acute, subacute, or chronic
Allergen may be difficult to identify
1971
Hypersensitivity Pneumonitis -
Evaluation
Detailed history
(Serum precipitans)
Pulmonary function tests
High resolution CT scan
Bronchoscopy
Surgical lung biopsy
Hypersensitivity pneumonitis -
Imaging
Upper lobe predominant
Interstitial prominence
Can present in fibrotic phase
1972
Hypersensitivity pneumonitis -
Imaging
Hypersensitivity
pneumonitis -
Pathology
Interstitial pneumonitis
Cellular bronchiolitis
Non-necrotizing
granulomas
Arch Pathol Lab Med 2008; 132: 199-203
1973
Hypersensitivity pneumonitis –
Management
Identification and elimination of offending allergen
Minimization of exposure
Systemic corticosteroids
Approach to Interstitial lung disease
Confirm diagnosis of ILD

CXR, HRCT scan, Bronchoscopy, OLBx, “clinical
picture”
Assess function
PFTs, exercise oximetry testing, QOL tool (SF-36)
Treatment plan
disease specific plus vaccines, exercise, nutrition,
etc.
1974
Question 1
A 38 yo Caucasian woman reports to your office with joint
discomfort as well as a painful, red rash on her legs for the past 2
weeks. She denies fevers, chills, and weight loss but states that
she has had some sweats. A lung exam reveals no adventitous
sounds. Pulmonary function tests are normal and a chest x-ray
displays bilateral lymphadenopathy without pulmonary
parenchymal abnormalities. The most appropriate course of
action at the present time is which of the following:
A) Refer for lung biopsy as these findings represent an atypical
presentation of an interstitial lung disease
B) Start 40mg of prednisone per day
C) After alternative diagnoses such as heart failure and indolent
infection are ruled out, consideration for lung transplant referral
should be made
D) Schedule follow-up in 4-6 weeks for –reassessment
Question 1
A 38 yo Caucasian woman reports to your office with joint
discomfort as well as a painful, red rash on her legs for the past 2
weeks. She denies fevers, chills, and weight loss but states that
she has had some. A lung exam reveals no adventitous sounds.
Pulmonary function tests are normal and a chest x-ray displays
bilateral lymphadenopathy without pulmonary parenchymal
abnormalities. The most appropriate course of action at the
present time is which of the following:
B) Start 40mg of prednisone per day
infection are ruled out, consideration for lung transplant referral
should be made
D) Schedule follow-up in 4-6 weeks for –reassessment
1975
Question 2
A 61 yo man with a 40 pack year smoking history as well as
hyperlipidemia presents to his primary care physician with
reports of progressive dyspnea on exertion and a dry cough
for the past 2 years. Once an active man, able to walk an
infinite distance on a flat surface, he now notes feeling short
of breath with 3 flights of stairs and while playing with his
grandchildren. His cough is non-productive and is not
associated with various environmental exposures. He is a
former banker. On exam, he is noted to have an oxygen
saturation of 98% on room air and 97% after walking 200
yards. He has fine crackles at the bases of his lungs and no
clinical evidence of volume overload. His basic lab values are
normal. Pulmonary function tests show a reduced total lung
capacity. A CT scan of the chest shows bibasilar, subpleural
reticular findings without infiltrate or lymphadenopathy.
Question 2
The most appropriate course of action at the present time is which

of the following:
B) Start 40mg of prednisone a day
infection are ruled out, consider for lung transplant referral
D) Refer the patient for pulmonary rehabilitation
1976
Question 2
The most appropriate course of action at the present time is which
of the following:
B) Start 40mg of prednisone a day
infection are ruled out, consider for lung transplant referral
D) Refer the patient for pulmonary rehabilitation
Consider appropriateness for pirfenidone/nintedanib and/or

referral for lung transplant
Summary
Interstitial lung disease has a variety of causes

A detailed history and targeted evaluation is warranted
IPF is the most common IIP and carries a poor prognosis
New therapies are emerging to slow disease
progression
Other IIPs may be more responsive to immune
suppressive agents
1977
References
Travis, WD et al, 2013, “An Official American Thoracic Society/European

Respiratory Society Statement: Update of the International
Multidisciplinary Classification of the Idiopathic Interstitial Pneumonias,”
Am J Respir Crit Care Med Vol 188, Iss. 6, pp 733–748
Collard, HR, et al, “Acute Exacerbation of Idiopathic Pulmonary Fibrosis:

An International Working Group Report,” Am J Respir Crit Care Med Vol
194, Iss. 3, pp 265–275
Freemer, M. & King, T.E., Jr. 2001, "The ACCESS Study. Characterization of
Sarcoidosis in the United States", American Journal of Respiratory and
Critical Care Medicine, vol. 164, no. 10, pp. 1754-1755.
Valeyre, D., Prasse, A., Nunes, H., et al, “Sarcoidosis,” Lancet, Vol 383,
Iss. 9923, pp 1155-1167
Madison, JM, 2008, “Hypersensitivity Pneumonitis: Clinical Perspectives,”

Archives of Pathologic and Laboratory Medicine, vol 132, pp. 195-198
Financial Disclosures
Site PI for multi-center clinical trials sponsored by:

– Gilead, Inc.
– Biogen Idec, Inc.
Clinical Coordinating Center Member for multicenter

trial of pirfenidone in ILD
– Genentech, Inc.
1978
Craig P. Hersh, MD, MPH

Associate Physician, Channing Division of Network Medicine and
Division of Pulmonary and Critical Care Medicine,
Associate Professor of Medicine, Harvard Medical School
BRIGHAM AND
WOMEN’S HOSPITAL
HARVARD
MEDICAL SCHOOL
Consultant:
◦ 23andMe
Grant support:
◦ Boehringer-Ingelheim
◦ Novartis
1979
COPD: Definition and pathophysiology

Assessment of COPD Patients
Treatment of stable COPD
Exacerbations
Summary and Review Questions

Exacerbations
1980
COPD is a common, preventable and treatable

disease that is characterized by persistent
respiratory symptoms and airflow limitation
that is due to airway and/or alveolar
abnormalities usually caused by significant
exposure to noxious particles or gases.
Global Initiative for Chronic Obstructive Lung Disease 2017

www.goldcopd.org


www.goldcopd.org
1981
NHANES 3 Mannino, MMWR Aug 2002

◦ 12 million diagnosed with COPD
◦ Additional 12 million with undiagnosed airflow
obstruction
State-by-state:
◦ BRFSS 2011
www.cdc.gov/brfss/


www.goldcopd.org
1982
Normal spirometry
Airflow obstruction
www.nhlbi.nih.gov
http://www.swiss-exped.ch/content/ge/research_reports/pneumologie/pneumologie_en.html
1983


www.goldcopd.org
Normal
Kim V, Proc Am Thorac Soc 2008;5:478 Courtesy of histology-world.com
1984
Kim V, Proc Am Thorac Soc 2008;5:478
Normal
Kim V, Proc Am Thorac Soc 2008;5:478 Courtesy of histology-world.com
1985
Crapo J, ed. Atlas of COPD, 2009
Crapo J, ed. Atlas of

COPD, 2009
1986


www.goldcopd.org
1987
Global Strategy for Diagnosis, Management and Prevention of COPD
Risk Factors for COPD
Genes
Infections
Socio-economic
status
Aging Populations
© 2014 Global Initiative for Chronic Obstructive Lung Disease
1988
Lange P, NEJM 2015;373:111


www.goldcopd.org
1989

Exacerbations
Assessment of COPD
Assess symptoms
Assess degree of airflow
limitation using spirometry
Assess risk of exacerbations
Assess comorbidities
1990
Symptoms Physical Exam

Cough Tripod posture
Sputum Skin: cyanosis
Dyspnea Breathing: tachypnea, pursed
Wheeze lip, prolonged expiration,
Chest tightness accessory muscle use
Weight loss Barrel Chest
Muscle weakness Breath Sounds: distant,
wheezes
Edema
Cardiac: distant, increased
Depression P2, JVD, edema
Cachexia
http://www.catestonline.org/
1991
Mahler DA, Chest 1988;93:580
Classification of Severity of Airflow

Limitation in COPD*
In patients with FEV1/FVC < 0.70:
GOLD 1: Mild FEV1 > 80% predicted
GOLD 2: Moderate 50% < FEV1 < 80% predicted
GOLD 3: Severe 30% < FEV1 < 50% predicted
GOLD 4: Very Severe FEV1 < 30% predicted
*Based on Post-Bronchodilator FEV1

1992
Hurst JR, NEJM 2010;

363:1128.
www.goldcopd.org
1993
COPD Tuberculosis
Asthma ◦ CXR with infiltrate
◦ Earlier onset Obliterative Bronchiolitis
◦ Atopic history ◦ Young, non-smokers
CHF ◦ Occupational, CVD
◦ Crackles, edema ◦ Air trapping on CT
◦ Restriction on PFTs Diffuse Panbronchiolitis
◦ Male, nonsmokers
Bronchiectasis
◦ Sinusitis
◦ Sputum
◦ Centrilobular nodules
◦ Abnormal X-ray/CT
Lung volumes, diffusing capacity

◦ hyperinflation
Arterial Blood Gas
◦ Recommended in severe COPD
◦ O2 sat gives no information about pCO2
6-minute walk test
◦ Evaluate disability, rehab assessment
Testing for α1-antitrypsin deficiency
◦ Serum levels
◦ Genotyping or protein phenotyping
1994
Flattened diaphragms
Reduced lung markings
Narrow cardiac
silhouette
Cachexia
Low sensitivity and

specificity
Alternative diagnoses
Muller, Thorax 2002;57:982
Age 47, FEV1 20% predicted
Age 42,
Age 42,FEV
FEV1 38% predicted
1 38% predicted Age 47, FEV1 20% predicted
Hersh CP, COPD 2007;4:331-7
1995
Crapo J, ed.,
Atlas of COPD, 2009
Pulmonary hypertension
◦ Echocardiogram if signs of right heart failure
Coronary artery disease
◦ Low threshold for evaluation
Lung cancer
◦ CT screening may reduce mortality
Osteoporosis, Depression, GERD, Anemia,
etc.
◦ Usual clinical assessments
National Lung Screening Trial, NEJM 2011;365:395

Vanfleteren LE, Lancet Respir Med 2016
1996

Exacerbations
Manage Stable COPD: Goals of Therapy
Relieve symptoms
Improve exercise tolerance Reduce
symptoms
Improve health status
Prevent disease progression

Reduce
Prevent and treat exacerbations risk
Reduce mortality
1997
Smoking Cessation
Smoking Cessation
Smoking Cessation
Supplemental oxygen
Vaccination
◦ Influenza
◦ Pneumococcal polysaccharide-23
◦ Pneumococcal conjugate-13 in adults ≥65
Pulmonary Rehabilitation
Poole PJ, Cochrane Database Syst Rev 2006

Dransfield MT, AJRCCM 2009;180:499
1. ASK: every patient at every visit

2. ADVISE: clear, strong, personalized
3. ASSESS: willingness to quit
4. ASSIST: plan, support, pharmacotherapy
5. ARRANGE: follow-up contact
JAMA 2000;283:3244
1998
Nicotine replacement therapy

◦ OTC: Patch, Gum, Lozenge
◦ Rx: Inhaler, Nasal spray
Bupropion SR
Varenicline
Combination therapy
◦ Short acting NRT + patch
◦ Bupropion + NRT
◦ Varenicline + NRT
Second-line (off-label)
◦ nortriptyline, clonidine
E-cigarettes???
Patnode CD, Ann Intern Med 2015;163:608
Rigotti N, Lancet Respir Med 2013;1:241
Hartman-Boyce, Cochrane Database Syst Rev 2016
1999
PaO2 ≤55mmHg or SaO2 ≤88%, or

PaO2 ≤60mmHg or SaO2 ≤89%,
◦ with cor pulmonale, right heart failure or
polycythemia
Benefits for exercise-induced desaturation
are unclear LOTT, NEJM 2016;375:1617
Shortness of
breath
Decreased exercise Reduced

capacity Activity
2000
Pulmonary rehab
◦ Stable lung disease
◦ Symptomatic dyspnea
Multidisciplinary
6-12 week program, 2-3 times/week
Exercise
◦ Lower body exercise
◦ Upper body exercise
◦ Respiratory Muscle Training
Education
Psychosocial Support
Spruit MA, AJRCCM 2013;188:e13
Reduction in dyspnea
Improved exercise performance
Reduced ER visits and hospitalizations
Improved quality of life
Psychological benefits
Pulmonary rehab is cost-effective
Pulmonary rehab is covered by Medicare
and most private insurers
2001
Beta2-agonists
Short-acting beta2-agonists
Long-acting beta2-agonists
Anticholinergics
Short-acting anticholinergics
Long-acting anticholinergics
Combination short-acting beta2-agonists + anticholinergic in one inhaler
Combination long-acting beta2-agonist + anticholinergic in one inhaler
Methylxanthines
Inhaled corticosteroids
Combination long-acting beta2-agonists + corticosteroids in one inhaler
Phosphodiesterase-4 inhibitors
Bronchodilators are first-line therapy

◦ Strong recommendation for FEV1<60%
Long-acting bronchodilators
◦ LABA or LAMA
Dual bronchodilators: LAMA/LABA
◦ Reduces symptoms and exacerbations compared to
monotherpy
Short-acting bronchodilators in all patients
Qaseem, Ann Intern Med 2011;155:179

Tashkin DP, NEJM 2008;359:1543
Rodrigo GJ, Int J COPD 2017;12:907
2002
Bronchodilators are first-line therapy

ICS monotherapy is never appropriate
ICS may reduce exacerbation risk in severe
COPD
Triple therapy
ICS are associated with increased risk of
pneumonia
Chronic systemic steroids should be avoided
Calverley PMA, NEJM 2007:356:775

Ernst P, AJRCCM 2007;176:162
Magnussen H, NEJM 2014;371:1285
2003
www.copdfoundation.org
Calverley, AJRCCM 2007;176:154

Martinez, Lancet 2015;385:857
2004
MACRO trial
N=1142 HR 0.73 (p<0.001)
1 year
More effective
◦ >65 years old
◦ Ex-smoker
◦ Milder COPD
Albert, NEJM 2011;365:689

Han, AJRCCM 2014;189:1503
Lung volume reduction surgery

◦ Upper lobe predominant
◦ Low exercise capacity
Bronchoscopic lung volume reduction
Lung transplantation
NETT, NEJM 2003;348:2059

*Klooster K, NEJM 2015;373:2325
Davey C, Lancet 2015;386:1066
Yusen R, J Heart Lung Transplant 2015;34:1264
2005

Exacerbations
Symptoms
◦ dyspnea, sputum volume, purulence
Arterial blood gas
Chest X-ray
ECG
CBC
Blood chemistries
Spirometry: not recommended
www.goldcopd.org
2006
Supplemental oxygen
Bronchodilators
Consider antibiotics
Non-invasive mechanical ventilation
◦ pH≤7.35 and/or PaCO2≥45 mmHg
Fluid status and nutrition
DVT prophylaxis
Co-existing conditions
www.goldcopd.org
Brochard L, NEJM 1995;333:817
Criner GJ, Chest 2015;147:883-893, 894-942
2007

Exacerbations
COPD includes emphysema, large and

small airway disease
Spirometry is essential for diagnosis
Multidimensional assessment
◦ Symptoms
◦ Airflow limitation
◦ Exacerbation risk
◦ Comorbidities
2008
Tried and true treatments

◦ Smoking cessation
◦ Supplemental oxygen
◦ Pulmonary rehab
Pharmacotherapy
◦ Bronchodilators are first line
◦ LABA and/or LAMA
◦ ICS: add-on/combination
◦ Roflumilast for frequent exacerbations
a) COPD
b) Asthma
c) Pulmonary fibrosis
d) Congestive heart failure
e) All of the above
2009
a) COPD
b) Asthma
e) All of the above
COPD is not the only cause of
dyspnea in a smoker
a) COPD
Spirometry is essential for diagnosis.
b) Asthma
Possible, hx of atopy. Spirometry post-BD.
Restricted PFTs. Abnormal chest x-ray, CT scan.
Hx of CAD. Exam, chest x-ray, echocardiogram.
e) All of the above
2010
a) LAMA
b) ICS-LABA combination
c) Nicotine replacement therapy
d) All of the above
e) (a) and (c) only
a) LAMA
b) ICS-LABA combination
c) Nicotine replacement therapy
d) All of the above
e) (a) and (c) only
2011
FEV1 55%
Bronchodilators first-line
◦ LAMA or LABA
◦ LAMA-LABA combination
ICS for frequent exacerbations (Group D)

Smoking cessation for all current smokers
Assessment of comorbidities
2012
Global Initiative for Chronic Obstructive Lung Disease, Global

Strategy for the Diagnosis, Management and Prevention of
Chronic Obstructive Pulmonary Disease (updated 2018),
available at www.goldcopd.org
COPD Foundation, www.copdfoundation.org
Criner GJ et al., Prevention of acute exacerbations of COPD.
Chest 2015;174:894-942.
Qaseem A, et al., Diagnosis and Management of Stable
Chronic Obstructive Pulmonary Disease. Ann Intern Med
2011;155:179-191.
2013
Sleep Apnea:
Diagnosis & Treatment
Lawrence J. Epstein, MD
Assisiant Clinic Director
Division of Sleep and Circadian Disorders,
Disclosure
Consultant
American Academy of Sleep Medicine
CareCore National
AIM Specialty Health
2014
Sleep Apnea
Sleep Apnea is
Common
Dangerous
Easily recognized
Treatable
2015
Types of Sleep Disordered

Breathing
Apnea
Cessation of airflow > 10 seconds
Hypopnea
Decreased airflow > 10 seconds
associated with either :
Arousal
Oxyhemoglobin desaturation
Apnea Patterns
Obstructive Mixed Central
Airflow
Respiratory
effort
2016
Central Sleep Apnea

Central Alveolar Hypoventilation
High-Altitude Periodic Breathing
Cheyne-Stokes Ventilation
Congestive Heart Failure (CHF)
40% of those with LVEF < 40%
Causes sleep fragmentation and hypoxemia
Treatment: CHF tx, oxygen, theophylline,
acetazolamide, Positive Airway Pressure
Obstructive Sleep Apnea is

A disorder of sleep and breathing due to
repetitive collapse of the upper airway
Causes
Awake symptoms
Impaired performance
Cardiovascular complications
2017
Prevalence of Obstructive Sleep

Apnea
30-60 year olds
25
20
Percent of
Population 15
Male
Female
10 U.S. Pop
0
AHI > 5 SAS Asthma
Adapted from Young T et al. N Engl J Med 1993;328.
Obesity Trends* Among U.S. Adults

BRFSS, 1990, 1999, 2009
(*BMI ≥30, or about 30 lbs. overweight for 5’4” person)
1990 1999
2009
No Data <10% 10%–14% 15%–19% 20%–24% 25%–29% ≥30%
Source: Behavioral Risk Factor Surveillance System, CDC
2018
Pathophysiology of Apnea
Pathophysiology of Sleep Apnea

Awake: Small airway + neuromuscular compensation
Loss of neuromuscular Sleep Onset Hyperventilate:

compensation correct hypoxia
+ & hypercapnia
Decreased pharyngeal
muscle activity Airway opens
Airway collapses
Pharyngeal muscle
activity restored
Apnea
Arousal from
Hypoxia & Increased sleep
Hypercapnia ventilatory
effort
2019
Clinical Consequences
Sleep Apnea
Sleep fragmentation,
Hypoxia/Hypercapnia
Excessive daytime Cardiovascular

sleepiness Complications
Morbidity
Mortality
Consequences
Excessive Daytime Sleepiness Cardiovascular
Increased motor vehicle Systemic hypertension
crashes
Cardiac arrhythmias
Increased work-related
accidents Myocardial ischemia
Poor job performance
Cerebrovascular disease
Decreased quality of life
Pulmonary Hypertension/
cor pulmonale
2020
Consequences: Mortality
18 Year Follow-up: All Cause Mortality
No CPAP Treatment
N = 1396
Adjusted for age,

BMI, Htn, CV
disease
Young et al. Sleep

2008;31:1071
Consequences:
Hypertension
Shepard JW Jr. Med Clin North Am 1985;69
2021
Cardiovascular Consequences:
Hypertension
Prospective Study of Association
Between OSA and Hypertension
3 Adjusted for
2.5 age, sex
BMI, neck
2
Odds circ., cigs.,
Ratio 1.5 ETOH,
1 baseline Htn
0.5
0
0 0.1 - 4.9 5 - 14.9 > 15
Apnea-Hypopnea Index (AHI)
Adapted from Peppard PE et al. N Engl J Med 2000;342.
Sleep Apnea Risk Factors

Obesity
Increasing age
Male gender
Anatomic abnormalities of upper airway
Family history
Alcohol or sedative use
Smoking
Associated conditions
2022
Risk Factor: Obesity

80
>4% Arterial saturation dipa h-1
70
60
50
40
30
20
10
0
70 80 90 100 110 120 130 140
% Predicted normal neck circumference
Adapted from Davies RJ et al. Eur Respir J 1990;3
Risk Factor: Age & Gender
35
30
25
% with 20
AHI > 5 Female
15 Male
10
0
30-39 Yrs 40-49 Yrs 50-60 Yrs
Adapted from Young T et al. N Engl J Med 1993;328.
2023
Risk Factor: Menopause

Odds Ratios:
AHI > 5/hr
Peri: 1.2 (0.7, 2.2)
Post: 2.6 (1.4, 4.8)
AHI > 15/hr
Peri: 1.1 (0.5, 2.2)
Post: 3.5 (1.4, 8.8)
Young T, et al, Am J Respir Crit Care Med 2003; 167:1183
Evaluation for OSA

Routine Health Pt Complains of High Risk
Maintenance Exam (PCP) Symptoms (PCP/SS) Screenings (PCP)
Sleep Disorders
Symptoms?
Yes
Sleep Evaluation
(PCP/SS)
No Yes
Evaluate for Other OSA
Symptoms? Sleep Study
Sleep Disorders
Adapted from Epstein et al. J Clin Sleep Med 2009;5(3):263-276
2024
Routine Health Maintenance

Evaluations
Screening questions about OSA
Is the patient obese?
Is the patient retrognathic?
Does the patient complain of daytime
sleepiness?
Does the patient snore?
Does the patient have hypertension?
A positive response to any of these questions
should trigger a comprehensive sleep evaluation
Epstein et al. J Clin Sleep Med 2009;5(3):263-276
Diagnosis: History
Snoring (loud, chronic)
Nocturnal gasping and choking
Ask bed partner (witnessed apneas)
Automobile or work related accidents
Personality changes or cognitive problems
Risk factors
Excessive daytime sleepiness
Sleep Apnea: Is Your Patient at Risk? NIH Publication, No 95-3803
2025
Diagnosis: Assessing Daytime

Sleepiness
Often unrecognized by patient
Ask family members
Must ask specific questions
Fatigue vs. sleepiness
Auto crashes or near misses
Sleep in inappropriate settings
- Work
- Social situations
Diagnosis: Physical Examination

Upper body obesity / thick neck
> 17” males
> 16” females
Hypertension
Obvious airway abnormality
2026
http://www.ispub.com/ispub/ija/volume_13_number_1_fig2.jpg
Guilleminault C et al. Sleep Apnea
Syndromes. New York: Alan R. Liss, 1978
Case History: MVA victim

History
“Passed out” while driving
Doesn’t remember what happened in car but
was sleepy on drive prior to accident
Falls asleep frequently at work & movies
Wife won’t sleep in same room due to snoring
Exam
BP 160/95, 5’10”, 270 lbs, BMI = 38.7,
18”neck circumference
Crowded oropharynx
What should be done next?
2027
MVA Victim: Next step?

a. Electrophysiologic study
b. Sleep deprived EEG
c. Overnight sleep study
d. 24 hour Holter monitor
e. Brain MRI
Answer: Overnight Sleep Study

Most likely etiology
Documents presence and severity of OSA
Signs and symptoms poorly predict
disease severity
Appropriate therapy dependent on
severity
Other causes of daytime sleepiness
2028
Testing Options
In-laboratory full night polysomnography
Split night studies
Home diagnostic systems
Oximetry to full polysomnography
In-Lab Polysomnogram
2029
Home-based Test
Redline S et al. Chest 1991;100
Home-Based,
Limited Channel Tests
Advantages
Don’t require stay in sleep laboratory
Accurate for moderate to severe OSA
May cost less
Disadvantages
Reliability unknown in patients with other
medical comorbidities
Can’t detect other sleep disorders
Higher failure rate
Don’t know who takes test with most devices
2030
Therapeutic Approach
Behavioral
Medical
Surgical
Behavioral Interventions
Encourage patients to:
Lose weight
Avoid alcohol and sedatives
Avoid sleep deprivation
Avoid supine sleep position
Stop smoking
2031
Weight Loss and Sleep Apnea

6
5
4
3
2
1
0
-1
-2
-3
-4
-20 to -10 to -5% to +5 to +10%
Adapted from <-10% <-5% <+5 +10% to +20
Peppard PE et al.
JAMA 2000;284. Change in Body Weight
Medical Interventions
Positive airway pressure
Continuous (CPAP)
Bilevel PAP
Automatic titrating PAP (AutoPAP)
Oral appliances
Expiratory resistance valves
Other (limited role)
Medications
Oxygen
2032
Positive Airway Pressure
CPAP Benefits: Blood Pressure

Effect of Therapuetic vs. Subtherapeutic
CPAP on BP
Becker et al., Circulation 2003;107:68-73
2033
Benefits of CPAP: Mortality

Observational Trial of Long-term Cardiovascular Outcomes from OSA
Marin et al Lancet 2005; 365: 1046–53
Benefits of CPAP: Performance

35
30
25
20
15
10
0
Before CPAP After CPAP No Apnea
(n=6) (n=6) (n=12)
Adapted from Findley L et al. Clin Chest Med 1992;13.
2034
CPAP Compliance
Patient report: 75%
Objectively measured use
> 4 hrs for > 5 nights/week: 46%
Maintenance programs improve compliance
Intensive compliance programs: 65-80%
CPAP Compliance
CMS and most payers require demonstration of
compliance for reimbursement
By 3 months patient must
Show objective evidence of compliance
> 4 hrs/night for 70% of nights
Show subjective improvement
Eval by MD between 31-90 days from start
Ongoing compliance required for supplies
Compliance monitoring and management needs to
be part of any OSA treatment program
2035
Oral Appliances
Indications
Snoring and apnea (not severe)
Efficacy
Variable
Side effects
TMJ discomfort, dental misalignment,
and salivation
Oral Appliance: Mechanics
2036
Expiratory Resistance Valves

Mild-moderate OSA
Variable efficacy
Surgical Alternatives
Bypass upper airway
Tracheostomy
Reconstruct upper airway
2037
Surgical Alternatives
Reconstruct upper airway
Nasal operation
Tonsillectomy
Uvulopalatopharyngoplasty (UPPP)
Laser-assisted
uvulopalatopharyngoplasty (LAUP)
Radiofrequency tissue volume reduction
Palatal implants
Genioglossal advancement
Maxillomandibular advancement
Uvulopalatopharyngoplasty
(UPPP)
2038
Staged Surgical Procedures
Electrical Nerve Stimulation
Strollo PJ et al.
N Engl J Med
2014;370:139-49.
2039
Electrical Nerve Stimulation

Prospective, multicenter,
single group cohort study
N = 126 with moderate
– severe OSA
Results
66% responders
29% with AHI < 5
Symptom improvement
Adverse events
21% Serious
57% procedure-related
67% device-related
Role ? (BMI <32, AHI 20-50) Strollo PJ et al. N Engl J Med 2014;370:139-49.
Case: Persistent Sleepiness

47 yo male diagnosed with moderate OSA
and treated with CPAP
After 3 months on CPAP c/o continued
daytime sleepiness
Reports sleeping 8 hrs/night
No change in weight
Still sleepy while driving
What should you do next?
2040
Case: Persistent Sleepiness

Send for surgical evaluation
Send for oral appliance
Send for bariatric surgery
Check CPAP compliance
Start on modafinil (Provigil)
Answer: Check CPAP Compliance

Reasons for lack of improvement
Noncompliance – most common
Poor sleep habits
Alcohol and sedative use
Depression
Weight gain
Nonapneic sleep disorder
Persistent or recurrent symptoms
Consider referral to sleep specialist
2041
PAP Compliance Monitoring

Monitor objective adherence – Tracking Systems
Sleep Apnea
Dangerous
Common
Easily recognized
Treatable
2042
Sleep Apnea
Disclosure
Consultant
American Academy of Sleep Medicine
CareCore National
AIM Specialty Health
2043
References
Epstein L et al. Clinical guideline for the evaluation,
management and long-term care of obstructive sleep apnea in
adults. J Clin Sleep Med 2009;5:263-76.
Collop et al. Clinical guideline for the use of unattended
portable monitors in the diagnosis of obstructive sleep apnea in
adult patients. J Clin Sleep Med 2007;3:737-47.
White DP. Pathogenesis of obstructive and central sleep apnea.
Am J Respir Crit Care Med. 2005;172:1363-70.
Young T et al. The occurrence of sleep-disordered breathing
among middle-aged adults. N Engl J Med 1993;328:1230–35
Marin et al Long-term cardiovascular outcomes in men with
obstructive sleep apnoea-hypopnoea with or without treatment
with continuous positive airway pressure: an observational study.
Lancet 2005; 365: 1046–53
2044
Asthma
Elliot Israel, M.D.
Director of Clinical Research
Pulmonary & Critical Care Division
Division of Allergy and Immunology
I disclose the following relationships in the past year:
• AstraZeneca Consultant
• Entrinsic Health Solutions Consultant
• Genentech Clinical Research Grant
• GlaxoSmithKline Consultant
• Merck Consultant
• Novartis Consultant & Clinical
Research Grant
• 4D Pharma Consultant
• Pneuma Respiratory Consultant
• Regeneron Pharmaceuticals Consultant
• Sanofi Consultant & Clinical
Research Grant
• Vorso Corp Consultant
2045
Asthma
• Effect of Asthma
• Pathobiology and classification of severity
• Therapy including new rx and controversies
• Subcategories eg Exercise, Aspirin-induced
• Difficult to control asthma
• Asthma Exacerbations
GOALS
• Understand who needs controller therapy or
intensification of therapy
• Understand how to move up therapy
• Recognize when referral is necessary and
understand differential and aggravating
factors
• Understand high risk asthma characteristics
2046
Definition of Asthma
Chronic inflammatory disorder of the airways
Characterized by:
— Airflow limitation,
• reversible either spontaneously or with treatment
— Airway inflammation
— Increased responsiveness to a variety of stimuli
One Year in the USA with

Asthma
• Over 30 million people had a diagnosis of asthma
• 20 million people said they currently had asthma
• 60% of them had an asthma attack in a year
• In one year almost 2 million had to be cared for an
emergency room
• Half a million required hospitalization
• Almost 4,000 died from their asthma
• The 2015 the estimated economic cost was 82 billion
dollars
2047
Asthma
• Reversible airway obstruction

• Airway hyperreactivity
• Airway inflammation
Inflammatory Changes in
Chronic Asthma
• Mucus secretion
• Inflammatory cell
infiltration
• Edema INFLAMED
• Smooth muscle
constriction &
NORMAL
hypertrophy
• BM thickening and
subepithelial
collagen
2048
Inflammation in Asthma
Desquamation
BM
Eosinophils
Normal Asthma
Diagnosis
• Compatible history of wheezing,
shortness of breath, or cough
– Reversible airway obstruction
• FEV1 improved at least 12% post-bronchdilator
OR
– Airway reactivity – methacholine, mannitol,
exercise, hypertonic saline
• Exclusion of other causes of symptoms
2049
Goal of Asthma Therapy:

Achieve Control
Reduce Impairment
• Prevent chronic and troublesome symptoms
• Require infrequent use of inhaled SABA (≤2 days/week)
• Maintain (near) “normal” pulmonary function
• Maintain normal activity levels
• Meet patients’ expectations of, and satisfaction with, asthma care
Reduce Risk
• Prevent recurrent exacerbations
• Minimize need for emergency department visits or hospitalizations
• Prevent progressive loss of lung function
• Provide optimal pharmacotherapy, with minimal or no adverse effects
NHLBI. National Asthma Education and Prevention Program. Expert Panel Report 3. Available at:
http://www.nhlbi.nih.gov/guidelines/index.htm. Accessed 2.8.07.
Classifying Asthma Severity & Initiating

Treatment in Youths >12 Years & Adults
Classification of Asthma Severity
(Youths >12 years of age & adults)
Components of Severity
Persistent
Intermittent
Mild Moderate Severe
>2 days/week
Symptoms <2 days/week Daily Throughout the day
but not daily
Often
Nighttime awakenings <2/month 3-4/month >1/week but not nightly
7/week
Short-acting beta2-agonist
>2 days/week
use for symptom control <2 days/week Daily Several times per day
but not >1/day
(not prevention of EIB)
Impairment Interference with
None Minor limitation Some limitation Extremely limited
normal activity
• Normal FEV1
between • FEV1 <60%
exacerbations • FEV1 <80% pred • FEV1 >60-80% but <80%
predicted
Lung function • FEV1/FVC pred
• FEV1 >80% • FEV1/FVC reduced
predicted normal • FEV1/FVC reduced 5%
>5%
• FEV1/FVC normal
Exacerbations 0-2/year >2 in 1 year

Risk (consider frequency and Frequency and severity may fluctuate over time for patients in severity category
severity) Relative annual risk of exacerbations may be related to FEV1
Step 1 Step 2 Step 3 Step 4 or 5
Recommended Step for Initiating and consider short course of

systemic oral corticosteroids
Therapy
In 2-6 weeks, evaluate level of asthma control that is achieved, and adjust therapy accordingly.
NHLBI. National Asthma Education and Prevention Program. Expert Panel Report 3. Available at:
2050
Rule of 2’s for Severity and Control
• Mild Persistent or Lack of Control

— Nighttime awakenings >2/mo
— SABA use for sxs (not pre-exercise) >2/wk
— Sx >2 wk
— ACT / ACQ <20 / >1.5
— Lung function Reduced by >20%
— Exacerbations >2/yr
• Moderate
— Daily or weekly as appropriate
— FEV1 >40% reduction
Stepwise Approach for Managing Asthma

in Patients > 12 Years of Age
Persistent Asthma: Daily Medication
Intermittent
Consult with asthma specialist if step 4 care or higher is required.
Asthma
Consider consultation at step 3.
STEP 6
STEP 5 PREFERRED •Step up if
STEP 4 needed
PREFERRED (first, check
PREFERRED High-dose ICS
STEP 3 adherence,
+ LABA + oral environmental
Medium-dose High-dose ICS
ICS + LABA corticosteroid control and
PREFERRED + LABA
STEP 2 comorbid
Medium-dose AND conditions)
ALTERNATIVE AND
ICS
PREFERRED OR
STEP 1 Low-dose ICS Low-dose ICS Medium-dose Consider ASSESS
+ LABA ICS + either Consider CONTROL
Omalizumab
PREFERRED ALTERNATIVE LTRA, Omalizumab
ALTENATIVE
Theophylline for patients
for patients •Step down
Low-dose ICS or Zileuton who have
who have
SABA PRN Cromolyn, + either LTRA,
allergies
allergies if possible
Nedocromil, Theophylline or
LTRA or Zileuton (and asthma is
Theophylline well-controlled
at least 3
months)
Patient Education and Environmental Control at Each Step
• Quick-Relief Medication for All Patients:
• SABA as needed for symptoms. Intensity of treatment depends on severity of symptoms: up to 3 treatments at
20-minute intervals as needed. Short course of systemic oral corticosteroids may be needed.
• Caution: Increasing of β-agonist or use >2x/week for symptoms control indicates inadequate control and the
need to step up treatment.
NHLBI. National Asthma Education and Prevention Program. Expert Panel Report 3: page 517. Available at:
2051
Asthma Control Test™ (ACT)

1. In the past 4 weeks, how much of the time did your asthma keep you Score
from getting as much done at work, school or at home?
2. During the past 4 weeks, how often have you had shortness
of breath?
3. During the past 4 weeks, how often did your asthma symptoms
(wheezing, coughing, shortness of breath, chest tightness or pain) wake
you up at night, or earlier than usual in the morning?
4. During the past 4 weeks, how often have you used your rescue
inhaler or nebulizer medication (such as albuterol)?
5. How would you rate your asthma control during the past
4 weeks?
Asthma Control Test is a trademark of QualityMetric Incorporated.

Copyright 2002, QualityMetric Incorporated. Patient Total Score
Control on ACT or ACQ
• ACT
— 20 or more
• ACQ
— <1.0
— A 0.5 change is felt to be enough to make IS1
a
change in therapy
• Therefore 1.5 is inadequately controlled
2052
Slide 19
IS1 Partners Information Systems, 4/24/2011
2053
MEDICATIONS
Short-Acting Beta2-Agonists
Most effective medication for relief of acute

bronchospasm
More than 2 times a week (other than pre-exercise)
suggests inadequate asthma control
Regularly scheduled use is not generally
recommended
May lower effectiveness
May increase airway hyperresponsiveness
May be particulary problematic for those who
are Arg/Arg at the 16th amino-acid position
2054
Albuterol-HFA
MDI inhalers contain propellants,

traditionally CFCs.
Environmentally-friendly propellants (HFAs)
have replaced CFCs.
For albuterol, these are:
ProAir-HFA, Proventil-HFA, and Ventolin-HFA (as
of yet, no generic albuterol-HFA)
Three Things to Know about

Albuterol-HFA Inhalers
1. They are equally effective as albuterol-

CFC.
2. They have a different feel; a less
forceful, less cold “plume” of
medication.
3. The plastic holder needs to be cleaned
weekly to prevent plugging of
medication.
2055
Long-Acting Beta2-Agonists
Not a substitute for anti-inflammatory therapy

Not appropriate for monotherapy
Not for acute symptoms or exacerbations
May be beneficial when added to inhaled corticosteroids to
allow lower ICS dose
BLACK BOX WARNING based on data that suggest that their
use (particularly without ICS, but possibly even with them) can
increase the risk of severe asthma exacerbations and deaths
especially in Blacks.
Due to the above, the FDA has suggested that patients
controlled on combination therapy undergo an attempt to have
their LABA eliminated after they achieve control
ICS
• Most effective controller medications

• Use with a spacer reduces local side-effects such as
thrush and dsyphonia
• Long-term high doses are associated with small
increases in
— Osteoporosis -Glaucoma
— Cataracts -Dermal thinning esp elderly
• Prn use with symptoms has been shown to be as
effective as regular use in patients with mild-
persistent asthma in adults and children
• Prn use in combination with LABA, when combined
with regular bid use, appears to produce good
symptom control but is NOT APPROVED IN THE
USA and actively discouraged by the FDA.
2056
Exacerbation Rates
(symptoms triggering course of inhaled or oral cs)
Boushey & ACRN, NEJM, 2005
GENERAL RULE
Hi DOSE TREATMENT
4 PUFFS A DAY OF HIGHEST

FORMULATION
2057
ICS/LABA
Currently Approved
• salmeterol/fluticasone (Advair)
• formoterol/budesonide (Symbicort)
• formoterol/mometasone (Dulera)
• formoterol/fluticasone (AirDuo)
• Formoterol/fluticasone (Generic)
Super long-acting beta-agonist

combinations
• Fluticasone furoate 100/vilanterol 25
• Fluticasone furoate 200/vilanterol 25
— Combined long-acting ICS and super-long
acting (LA)BA.
• Only approved in 18 yo and above
• Dose equivalency
— 1 puff 100/25 qd = 1 puff bid FP250/Salm 50
BID
— 1 puff 200/25 qd = 1 puff bid FP500/Salm50
BID
• Not yet approved in asthma
ICS/LAMA/LABA once a day for COPD
2058
Leukotriene Modifiers
Indications
- Aspirin-exacerbated respiratory disease
- Exercise-induced asthma
Equal or better long term protection than long acting
beta-agonists
Alternative in guidelines to additional ICS or
LABA
Add-on therapy in severe asthma
• Caveats
— Watch for CSS with steroid tapers
Tiotropium as Add on Therapy
Peters & ACRN, NEJM, 2010
2059
Anti-IgE
• For poor control on high dose ICS/LABA or

equivalent Step 5 therapy
• Qualifications – IgE 30 to 700 and a positive
skin test or RAST to perennial allergen
• Efficacy – reduces exacerbations by ¼ to ½
— FEV1 increases 4%
— Not all patients respond
• Toxicity – rare anaphylaxis
— Questionable increases in cancers
Type 2 & Non-Type 2

Inflammation
Israel & Reddel, NEJM, 2017
2060
Anti-IL5 Antibody Therapy

• Block IL5 which is responsible for the
development and migration of eosinophils
• Mepolizumab and reslizumab attach to the
IL5 cytokine and block its ability to stimulate
the IL5 receptor
• Benralizumab attaches to the IL5 receptor
and blocks signaling but also is cytotoxic to
cells bearing the IL5 receptor
Anti-IL5
(Mepolizumab, Reslizumab,
Benralizumab)
• Reduce eosinophils
• Reduce exacerbations by >50% in patients
with >2 exacerbations/year and h/o blood
eosinophils
• Mepolizumab and reslizumab have been
shown to reduce OCS
• Variable and less effect on FEV1 and
symptoms
• Use in patients with persistent exacerbations
despite compliance with high dose
ICS/LABA and blood eosinophils >300
2061
Modeling Suggests that Mepo’s Greatest

Effect is on Patients with 3 or more
Exacerbations or Very High Eosinophils
Pavord, Lancet, 2012
ADMINISTRATION
• Mepolizumab
– Age 12 or older
– 100 mg SC q 4 weeks
– Solution must be used within 8 hours
– Package insert does not assert improvement in
FEV1
• Reslizumab
– Age 18 and above
– 3 mg/kg IV infusion over 20-45 min
– Package insert warns about anaphylaxis (0.3%)
– Labeling consistent with improvement in FEV1
• Benralizumab
– 30 mg SC Q4 weeks for first 3 doses and then q8
weeks
2062
Bronchial Thermoplasty
— Reduces symptoms and reduces

asthma exacerbations counted after
bronchoscopy
— Significant up front morbidity
— Severe asthma task force
recommends it only be performed in
the context of a clinical trial or registry
Use of Exhaled Nitric Oxide
• Level of >30 ppb is consistent with

persistent eosinophilic inflammation
• Markedly reduced by use of ICS
• Persistently high FeNO despite therapy is
c/w non-compliance or pathobiology
resistant to therapy
• May be a good predictor of response to
therapy for patients considered for biologic
aimed at Type 2 process (Anti-
IgE/IL5/IL4/IL13
2063
Therapies Not Yet Approved

• Anti-IL4/13 (Dupilumab)
— Improves lung function
— Reduces exacerbations
— Reduces OCS dose
— Very effective to treat atopic dermatitis
— Eosinophils may not be a requirement but may
be exacerbations and reversibility despite
compliance with high dose ICS/LABA
Patients with Greater T2 Markers

Had Reduced Asthma
Exacerbations w/ Dupilumab
•Castro et al , NEJM, 2018
2064
Recommendations Regarding Allergen

Immunotherapy
Consider allergen immunotherapy

for asthma patients when:
Clear relationship exists between symptoms
and unavoidable exposure
Symptoms are seasonal
Strong rhinitis component
Stepwise Approach for Managing Asthma

in Patients > 12 Years of Age
Persistent Asthma: Daily Medication
Intermittent
Consult with asthma specialist if step 4 care or higher is required.
Asthma
Consider consultation at step 3.
STEP 6
STEP 5 PREFERRED •Step up if
STEP 4 needed
PREFERRED (first, check
PREFERRED High-dose ICS
STEP 3 adherence,
+ LABA + oral environmental
Medium-dose High-dose ICS
ICS + LABA corticosteroid control and
PREFERRED + LABA
STEP 2 comorbid
Medium-dose AND conditions)
ALTERNATIVE AND
ICS
PREFERRED OR
STEP 1 Low-dose ICS Low-dose ICS Medium-dose Consider ASSESS
+ LABA ICS + either Consider CONTROL
Omalizumab
PREFERRED ALTERNATIVE LTRA, Omalizumab
ALTENATIVE
Theophylline or Anti-IL5 in
Low-dose ICS or Zileuton
or Anti-IL5 in appropriate •Step down
SABA PRN Cromolyn, + either LTRA, appropriate patients if possible
Nedocromil, Theophylline or patients
LTRA or Zileuton (and asthma is
Theophylline well-controlled
at least 3
months)
Patient Education and Environmental Control at Each Step
• Quick-Relief Medication for All Patients:
• SABA as needed for symptoms. Intensity of treatment depends on severity of symptoms: up to 3 treatments at
20-minute intervals as needed. Short course of systemic oral corticosteroids may be needed.
• Caution: Increasing of β-agonist or use >2x/week for symptoms control indicates inadequate control and the
need to step up treatment.
NHLBI. National Asthma Education and Prevention Program. Expert Panel Report 3: page 517. Available at:
2065
Specific Sub-Types
Managing Exercise-Induced
Bronchospasm (EIB)
Management Strategies
— Short-acting inhaled beta2-agonists used shortly
before exercise last 2 to 3 hours
— Salmeterol may prevent EIB for 10 to 12 hours
• 50% or greater tachyphylaxis occurs if used regularly
— LT modifiers provide long acting inhibition
— Cromolyn and nedcromil are also acceptable
— A lengthy warmup period before exercise may
preclude medications for patients who can
tolerate it
— Long-term-control therapy, if appropriate
2066
Aspirin-Exacerbated Respiratory
Disease (AERD)
• Characterized by leukotriene overproduction

in response drugs that block cox-1
–Appears to be related to downregulation of
PGE2 which “brakes” leukotriene production
• Most common in patients with rhinosinusitis
–-Usually occurs in adulthood
• Prevalence 5-25% with increased prevalence
in those with more severe asthma
0498
AERD (Rx)
• Use LT modifiers as part of treatment regimen
since they affect leukotriene mediated effects
• Treat rhinosinusitis aggressively
• Specific Cox-2 inhibitors are generally safe in
moderate doses
• Acetaminophen safe in most patients
although some may have reactions to high
doses
• Aspirin desensitization if poor control
• Anti-IL5 may work
0498
2067
Asthma-COPD Overlap (ACO)

• Evolving terminology for patients who
have a h/o asthma and also smoked
(some would also define it as asthma
patients with limited reversibility)
• May respond better to anti-cholinergics
• May not be able to restore their lung
function
Neutrophilic or Non-Type 2
Asthma
• More than half of asthma patients have
asthma that involves inflammation
mediated by Type 2 cytokines (IL4,5,
and 13) ≽ IgE/Eosinophils
• A significant minority may have
neutrophilic or paucigranulocytic
inflammation
– May be less responsive to steroids
2068
Examining Factors
Contributing to Asthma Severity
– Poor adherence/technique
– Rhinitis/sinusitis
– Gastroesophageal reflux (only in
those that have symptomatic reflux)
– Drugs (NSAIDs, beta-blockers)
– Environmental allergens
– Occupational exposures
– Sulfite sensitivity
Differential Dx of Persistent
Wheezing Poorly Responsive to
Therapy
• VCD
– Flattening of the FV loop
– Chinking of the vocal cords on fiberoptic exam
– Frequently in depressed patients
– Almost always in setting of some degree of
airway hyperresponsiveness
• Central airway obstruction
– Mass
– Collapsible airways
2069
Differential Dx of Persistent
Wheezing Poorly Responsive to
Therapy
• Aspirated foreign body

• Constrictive bronchiolitis
– Rheumatoid Arthritis, Ulcerative Colitis
• Bronchiectasis
• CHF
EXACERBATIONS
2070
Treatment
• Increased beta-agonists up to every 20
minutes
• 40-60 mg of prednisone for 5-10 days
Emergency Dept Referral
• Beta-agonist effects not lasting more

than an hour
• Unable to complete sentences
• Lower threshold for high-risk patients
2071
Definition of “High-Risk”
• Newly diagnosed asthma

• On daily prednisone prior to admission
• >2 E.D. visits in last 6 months
• >1 prior hosp’ns in last 12 months
• Ever intubated for asthma
• Severe psychosocial problems
• Drug addiction
• Lower socio-economic status
Antibiotics for Acute,

Severe Asthma
• Purulent-appearing sputum often
contains eosinophils rather than
neutrophils
• During attacks, transtracheal aspirates
reveal no greater prevalence of bacterial
pathogens than among controls without
respiratory disease
• Empiric antibiotics of no proven benefit
in hospitalized patients with acute
attacks
2072
Achieving Asthma Control
The Five-Point Plan:

A. Making the correct diagnosis
B. Modifying environmental inciters
C. Medications to control asthma
D. Plan for dealing with asthmatic attacks
E. Specialist consultation
Indications for Specialist

Consultation
• Uncertainty regarding diagnosis;

• Failure to achieve good asthma control;
• Frequent need for systemic steroids;
• Frequent ED visits or hospitalizations;
• Unacceptable medication side-effects.
2073
Points to Remember
• Rules of two’s for initiation of controller and for step up
• Escalation pattern
– (2) ICS (or LTRA) → (3) ↑ ICS or ICS/LABA → (4) Mod Dose
ICS/LABA → (5) Hi Dose ICS/LABA
• Referral if require Hi Dose ICS/LABA for control or preventing
exacerbation
– Aggravating factors
– Differential Diagnosis
• EIB
– LTRA or intermittent salmeterol
– Warm-up
– Treat underlying severity
• AERD – LTRA and referral if poor control
• IgE >30 or Eos >300 may be candidates for biologics especially
with 2 or more exacerbations per year
• High risk patients
Question #1
Which of the following is NOT indicative of
poor asthma control?
A. As needed reliever medication 3x/wk

B. Reliever medication use pre-exercise
4x/week
C. Night-time awakening 3x/mo
D. Three exacerbations/yr
2074
Answer Question #1
• B – use of bronchodilators pre-exercise
is not considered a index of poor control
• All the others exceed the thresholds for

control which in each case is no more
than 2 times
Question #2
Which of the following is NOT required for
consideration for anti-IgE therapy?
A. IgE > 30
B. Allergic rhinitis
C. A positive skin test or RAST
D. Poor response to level 5 therapy
2075
Answer Question #2
• B – patients do not need to have allergic
rhinitis
• They do need to have an IgE>30, a

positive skin test or RAST to a perennial
aeroallergen
• In order to consider this therapy they
should have failed high dose ICS and a
LABA
Severe Asthma Program
State of the Art Multidisciplinary

Evaluation and Treatment of
Patients with Severe Asthma
•Pulmonary •GI
•Allergy •Psychiatry
•ENT •Alternative Medicine
2076
Short List of References

• -National Institutes of Health. Expert Panel Report 3
(EPR3): Guidelines for the diagnosis and
management of asthma. Bethesda, Maryland:
National Institutes of Health National Heart Lung and
Blood Institute. Publication Number 08-4051.
Accessed: May 2010, 2007 July. Report No.:
Publication Number 08-4051 Contract No.:
Publication Number 08-4051.
• -Kerstjens HA, Engel M, Dahl R, et al. Tiotropium in
asthma poorly controlled with standard combination
therapy. N Engl J Med 2012;367:1198-207.
• -Pavord ID, Korn S, Howarth P, et al. Mepolizumab
for severe eosinophilic asthma (DREAM): a
multicentre, double-blind, placebo-controlled trial.
The Lancet 2012;380:651-9.
I disclose the following relationships in the past year:
• AstraZeneca Consultant
• Entrinsic Health Solutions Consultant
• Genentech Clinical Research Grant
• GlaxoSmithKline Consultant
• Merck Consultant
• Novartis Consultant & Clinical
Research Grant
• 4D Pharma Consultant
• Pneuma Respiratory Consultant
• Regeneron Pharmaceuticals Consultant
• Sanofi Consultant & Clinical
Research Grant
• Vorso Corp Consultant
2077
06/20/17 additions
• 4 puffs a day high dose
• Air duo and generic slide 30
• FeNO update on >20. Slide 37
• Fixed type on LABA on IL4/13 slide 38
• Correction to anti-ige #2 perennial allergen
• Fixed up points to remember
• Fixed FeNO
• Inserted Type 2
• Inserted ACO
• Added il5 to naepp diagram
• Updated cost
06/18 Addition
• T2 and non –T2 diagram

• Dupilumab forest plot
• 2105 costs
2078
Pleural Effusions: a case-

based review
Scott Schissel, MD, PhD
Chief, Department of Medicine
Brigham and Women’s Faulkner Hospital

Disclosure
• None
2079
Outline
• Normal pleural anatomy and function
• Mechanisms of pleural fluid accumulation
– Transudates vs. Exudates
• Evaluating pleural effusions
– Imaging
– Thoracentesis
– Pleural fluid analysis
• Diagnosis and management of common exudative
effusions
• Evaluating the exudative effusion of unknown
etiology
Normal Pleural Anatomy

Parietal Pleura
Visceral Pleura • Basal pleural fluid
volume: ~2.0 ml/hr
Pleural Space – Daily production:
~25 ml/day
• Drainage capacity:
~15 ml/hour
– Daily absorption
~350 ml/day
2080
First Case
• 67 year old man with
dyspnea and cough x 2
months
• Exam: poor chest excursion
on the R with absent BS
• US of the R chest: small
pleural effusion
• Pleural Fluid Analysis:
– PF protein 3.9 (serum 7.9)
– LDH 200 (serum 250)
– Glucose 98
– pH 7.48
– GS, Cultures AFB smear NEG
– Cytology NEG
First Case
The next step in managing this patient is:

A. Perform a large volume thoracentesis
B. Place an indwelling pleural catheter
C. Thoracoscopy with pleural biopsy
D. Perform a bronchoscopy
E. B and D
2081
Pleural Effusions from “trapped lung”
Pleural
effusion
Mass
7
7
Pleural Fluid Origins: Trapped Lung
Parietal Visceral
Pleural
Space
NL
Phydrostatic Serous
Fluid
Ppleura=
-25 cmH20
NL Phydrostatic
2082
Entrapped v. Trapped Lung
Causes of TRANSUDATIVE Pleural

Effusions
• Congestive Heart Failure (40%)
• Cirrhosis
• Nephrotic Syndrome
• Trapped Lung (also can be exudative)
• Pulmonary Embolism (also can be exudative)
• Myxedema
• Urinothorax
• CSF leak
10
2083
Causes of EXUDATIVE Pleural Effusions
• Parapneumonic / • Uremia
empyema (25%) • Post-cardiac injury /
• Malignancy (12%) surgery
• PE (10%) • Asbestos
• Tuberculosis • Chylothorax
• Pancreatitis • Intra-abdominal
• RA, SLE Abscess
• Meig’s Syndrome
11
A Quick Interesting Case…

• 57 year old woman with a h/o HTN, HFpEF, HLD and
nephrolithiasis present with dyspnea x 3 weeks
• CXR revealed a large RIGHT pleural effusion only
• Pleural Fluid Analysis:
– PF protein 2.0 (serum 7.9)
– LDH 90 (serum 250)
– Glucose 92
– pH 6.9
– GS, Cultures AFB smear NEG
– Cytology NEG
The cause of this effusion is…?

A URINOTHORAX, secondary to renal
fornix rupture
2084
Diagnostic Evaluation of Pleural Effusions

• Identifying the etiology of a pleural effusion
requires:
• CLINICAL information
– To suggest an underlying diagnosis
• Radiographic findings
– Infiltrate, mass, lymphadenopathy
• Pleural fluid analysis
– Transudate v. Exudate ->
• Cell count and differential, cytology, culture, etc….
13
Pleural Effusions: When to Tap

Pleural effusion
Substantial fluid?
(>10 mm thick on lateral decubitus CXR)
No Yes
Observation CHF?
No Yes
Thoracentesis Asymmetry, chest pain, fever?
Yes -> No
Thoracentesis
Diuresis,
Observation
Effusion >
3 days ->
Thoracentesis
2085
The Value of the Lateral Film

AP film Lateral film
Effusion!
Up to 500 ml can be “hidden” on an AP film
15
Value of the Lateral Decubitus CXR

AP film Lat Decubitus film
Thickness of effusion <10 mm likely too small to tap
16
2086
Imaging Pleural Effusions

Chest Ultrasound
Effusion
Lung
Gastric air
17
Large Volume Thoracentesis:

OK to remove > 1 liter ??
185 pts with 1L -> 3.5L removed
• 1 pt (0.5%) had symptomatic re-expansion
pulmonary edema (RPE) [1.4L removed]
• 4 pts (2.2%) had radiographic RPE only
• RPE did not correlate with pleural fluid volume, end-
expiratory pleural pressure, or symptoms during the
procedure
• No clear guidelines, but RPE is rare and strict
adherence to limiting thoracenteses to 1L is not
supported by data
Feller-Kopman et al 2007 Ann Thoracic Surg:
18
2087
Transudate or Exudate?:
Light’s criteria
• Distinguish transudate from exudate
• One or more of the following defines an

exudate:
– Pleural fluid (PF) protein : Serum protein>0.5
– PF LDH : Serum LDH>0.6
– PF LDH > 2/3 upper limit normal serum LDH
19
Transudate or Exudate?
• If you truly suspect a transudate (e.g. a
“diuresed” CHF-related effusion), check…
– Serum - PF protein >3.1 gm/dL

– Serum– PF albumin gradient > 1.2 gm/dL
– Then = TRANSUDATE
*Light,
20 RW. Clin Chest Med 2013; 34: 21-26
2088
Transudate or Exudate*?
Test Sensitivity* Specificity*
PF:serum protein>0.5 98% 83%
PF:serum LDH>0.6 86% 84%
PF LDH>2/3 nl serum 90% 82%
Serum-PF alb < 1.2 87% 92%
21
Next Case!
• 37 year old woman with 2 months of dry
cough and dyspnea on exertion with mild R
anterior pleuritic chest pain
• Past Medical History

– Migraines
– HTN
– Anemia
– Metromenorragia
– Ectopic thyroid, hypothyroidism
22
2089
Chest X-ray
23
Pleural Fluid Analysis

Pleural Fluid:
LDH: 459
pH: 7.37
glucose: 72
WBC: 900 Diff: 27N 28M 40L 5 mesothelial cells
RBC: too numerous to count

Fluid hematocrit: 22%
24
2090
Grossly Bloody Pleural Fluid

Fluid Hematocrit Cause
<1% Not significant
1-20% Cancer>>
(hemorrhagic process) PE>Trauma>empyema
20 – 50% Hemorrhagic process
v. Hemothorax
>50% circulating HCT Hemothorax
25
Spontaneous Bloody Effusions and Hemothorax

BLOODY Pleural effusion
No Trauma
No Procedures
Pleural Fluid HCT < 50% Pleural Fluid HCT > 50%
of peripheral blood HCT of peripheral blood HCT
(frank hemothorax)
Etiologies CT Angiogram
Lung Ca or MRA
PE - pulmonary infarction
Tuberculosis
Hemorrhagic Empyema Vascular NON-vascular

Uremia Anomalies
Coagulopathy
Mesothelioma
AVM's Endometriosis Chest wall

Neurofibromatosis Pleural Metastases Bony anomaly
Aneurysms Angiosarcomas "Exostoses"
26
(intercostal, IMA) Thymoma / Thymic cysts
2091

No Trauma
No Procedures
(frank hemothorax)
Lung Ca or MRA
Tuberculosis

Uremia Anomalies
Coagulopathy
Mesothelioma


No Trauma
No Procedures
(frank hemothorax)
Lung Ca or MRA
Tuberculosis

Uremia Anomalies
Coagulopathy
Mesothelioma

2092
Back to the case…
• R VATS with pleural

biopsy and wedge
resection
– hemothorax > 1 L
– Endometrial tissue
– lung
29
Thoracic Endometriosis Syndrome (TES):

Clinical Manifestations
• Major manifestations of TES -
– Pneumothorax ~ 80%
– Hemothorax / hemopneumothorax ~ 14%
– Hemoptysis ~ 7%
– Lung nodules ~ 6%
• Other rare manifestations of TES

– Isolated, catamenial chest pain
– Catamenial pneumomediastinum
– Pulmonary vascular invasion
– Pleural-based mass
• Interesting aside –
– Pelvic endometriosis is NOT found in up to 15 – 30% (depending on case
series) of TES patients
30
2093
TES: treatment and outcome

• Medical therapy – goals are to suppress growth and
maintenance of the endometrium
– Oral contraceptives
– Danazol
– Progestational agents
– GnRH analogs
• Most successful for long-term suppression of catamenial pneumothorax
and hemoptysis
– Medical therapy ALONE often leads to recurrent thoracic
disease
• Catamenial pneumonthorax recurs in 60% of patients on hormonal
therapy at 12 months
• Pleuroscopic surgery / pleurodesis, beneficial adjunct treatment
31
Another Case!
• 72 year old man with 2 days of

– Intense R sided chest pain, dry
cough, chills and dyspnea
• Exam
– T 100.9, Decreased BS right base
• Labs
– Serum WBC 15K (80 poly’s, 10%
bands)
• Lateral Decubitus CXR revealed
a flowing moderate-sized
effusion
• Blood cultures were obtained
and Antibiotics started
32
2094
Quick Quiz
The most likely infection in this
• Thoracentesis -> case is:
• Pleural Fluid Analysis
– Sero-sanguinous A. S. pneumoniae
– PF protein 3 (serum 4) B. S. milleri
– PF LDH 800 (serum 300) C. H. influenza
– PF pH 7.18 D. S. aureus
– Gram stain and cultures NEG E. A or C
33
Microbiology of COMMUNITY-Acquired
Pleural Infections
S. Pneumoniae Strep Milleri

13% 32%
Staphylococci
11%
Other 18%
Anaerobes H. Flu 3%
16%
Enterobacter
7%
34
2095
Quick Quiz
The next step in managing this
• Thoracentesis -> effusion is:
• Pleural Fluid Analysis A. Antibiotics and close
– Sero-sanguinous observation, including daily
– PF protein 3 (serum 4) CXRs
– PF LDH 800 (serum 300) B. Thoracentesis to drain the
– PF pH 7.18 pleural space
– Gram stain and cultures NEG C. VATS decortication
D. Chest tube drainage +/-
fibrinolytics to the pleural
space
E. A or D
35
COMPLICATIONS of Parapneumonic Effusions:

why drain?
• Chronic Pleural Infection
• Secondary Lung Abscess
• Bronchopleural Fistula
• Empyema Necessitans
– Pleuro-cutaneous fistula
• Pleural Fibrosis
– Lung entrapment
– Impaired lung function
– Surgical decortication
36
2096
Who to Drain ?
Pleural Fluid Fluid pH Risk of Drain?
Anatomy Micro Poor
outcome
<10 mm on N/A N/A LOW No
Lat decub
CXR
<½ GS and pH > 7.20 LOW No, BUT
hemithorax Cx NEG need to
AND -> AND -> follow
>½ GS or pH < 7.20 Moderate / YES
hemithorax, Cx + High
loculated, Or ->
thick pleura
Or ->
37
Treating Complex Parapneumonic Effusions / Empyema
• Definitive Pleural Drainage

– Commonly via chest tube
– Serial thoracenteses an alternative, but not well-studied
• Pleural Catheter + Fibrinolytics

– Variably used and STILL requires individual assessment
– Multicenter Intrapleural Sepsis Trial (MIST-1)
• Pleural saline v. streptokinase
• Streptokinase did NOT improve survival, need for surgical intervention,
Chest CT appearance, or lung function
– N Engl J Med 2011 365: 516
• Additional fibrinolytic trial (s)….
38
2097
Small Drainage Catheters + Fibrinolytic + DNA’se

Treatment of Empyema
• N Engl J Med 2011 365: 516
– Pleural saline v. tPA v. DNAse v. tPA + DNAse x 3
days
– tPA + DNAse group had decreased need for:
• Surgical intervention (4% compared to 39% for placebo); and…
• An improved CXR by day 7 and 30
Important considerations with intra – pleural tPA

~1.8% risk of pleural hemorrhage
Markedly simulates pleural fluid production (up to 6-fold)
Contraindicated in presence of broncho-pleural fistula
39
Treating Complex Parapneumonic Effusions / Empyema

• Surgical Decortication
– Indicated if little clinical or radiographic improvement after 1
week of antibiotics and chest tube drainage +/- pleural lytics
– Required in ~30% of cases
– VATS adequate in 60% of these cases
• Appropriate Antibiotics
– Duration uncertain: 2 weeks minimum, but as long as
necessary for drains to be removed
– Sometimes longer courses required for atypical pathogens

(e.g. actinomyces) or in cases of prolonged pleural drainage
40
2098
A Surprise Case…
• 53 year old man with 2 months of acute on chronic
exertional dyspnea
• 3+ ankle edema
• Orthopnea & paroxysmal nocturnal dyspnea, worse
than baseline
41
Past Medical History
– HFpEF: LV EF 55% – CKD: stage III

– Atrial Fibrillation – Diabetes (type II)
– HTN
– Dyslipidemia
– Peripheral Vascular
Disease
– Obesity: BMI 50
42
2099
Case CXR
43
Removed: 1200 cc
Thoracentesis
WBC 1650 (P14 L83 M2)
pH 7.57
Glucose 262
Total Protein 3.9
Albumin 2.3
LDH 159
Gram stain/culture negative

Cytology negative
Cholesterol 77
Triglycerides 1,276
44
2100
Chylothorax?
Pleural Fluid Triglyceride level (mg/dl)
>110 50-110 <50

Chylothorax Lipoprotein PSEUDO-
analysis Chylothorax
(likely chronic exudate)
+ Chylomicrons ->
CHYLOTHORAX
Traumatic Non Traumatic

Chest trauma Lymphoma, solid tumors, chest XRT
Thoracic surgery Histoplasmosis, MTB, Sarcoid
Chylous ascites
LAM, yellow nail syndrome, Amyloid
L subclavian DVT
Filariasis
45
Pseudo - Chylothorax
• Pseudo - Chylothorax: Cholesterol, phospholipid Complexes = from:
Cell degradation, chronic exudate, empyema
Cholesterol > 250 mg/dL

+ cholesterol crystals (rhomboid)
TGfluid LOW
• Chylothorax:
TG fluid > 110mg/dL
TG fluid > TG serum
Cholesterol fluid < 200 mg/dL
+ chylomicrons
46
2101
Location of Duct Disruption

Determines Side of Chylothorax
47
Chyle Loss Increases Mortality
Fat
Malnutrition
Vitamins 17-35% mortality
A, D, E, K (limited data)
Proteins 4.5-fold ↑ risk

Immunosuppression of death in
Immunoglobulins
surgical patients
Lymphocytes
Paul et al. J Thorac Cardiovasc Surg. 1985 Feb;89(2):221-7.

48 Shah et al. Ann Thorac Surg. 2012 Mar;93(3):897-903.
2102
Management
Remove Chyle
↓ Chyle Flow Thoracentesis
No short- or long-chain TG intake Tube Thoracostomy
Octreotide or Somatostatin Pleuroperitoneal Shunt
Pleurovenous Shunt
Close Chyle Leak

Maintain Nutrition Pleurodesis
Duct Embolization
Medium-chain TGs Surgical Duct Ligation
enter portal circulation directly
Total parental nutrition (TPN)
49
Exudative Effusion of Unclear Etiology

• 46 year old man with a h/o myelodysplastic
syndrome, s/p an unrelated allo-stem cell transplant:
complicated by cutaneous and GI graft-versus host
disease
• NOW with dyspnea and progressive right-sided

pleuritic chest pain x 2-3 weeks
• No fevers/chills, known sick contacts, or recent travel

• Medications: prednisone 20 mg daily, tacrolimus,
atovaquone, valganciclovir
50
2103
Chest X ray
51
Thoracentesis
• Labs:
– Serum: LDH 229, Total Protein 6.5, Albumin 3.7
– Fluid: LDH 226, Total Protein 4.1, Albumin 2.7
– Fluid: pH 7.6, Glucose 208, Amylase 12
– Fluid: ADA 3.1 (usually > 40 U/L in tuberculous pleural
effusions)
• Cultures: AFB, Fungal, Aerobic/Anaerobic,

Actinomyces, Nocardia, PCP all negative
• Cytology + flow cytometry negative for malignancy
52
2104
Exudative Effusion of Unclear Etiology

• Up to 20% of exudative pleural effusions have no clear
etiology, even after:
– Pleural fluid analysis from thoracentesis and
– Thoracoscopy and pleural biopsy
• Most undiagnosed exudates are from:
– Malignancy (including mesothelioma)
– Chronic empyema (including atypical organisms)
– Tuberculosis
– Rheumatoid Arthritis / inflammatory
– Pulmonary Embolus
– “Diuresed” CHF
53
Exudative Pleural Effusion
"Borderline" Exudate All Other Exudates
Serum:PF Albumin > 1.2 g/dL NEGATIVE

Pleural Fluid NT-proBNP > 2000 pg/mL History
Consider CHF, nephrosis, cirrhosis Microbiology
Cytology
Consider PE (DDIMER, PE-CT)

Consider TB
ADA > 40 U/L or
IFN-gamma > 140 pg/mL
NEGATIVE
Thoracoscopy and
Pleural Biopsy
54
2105
Pleural Fluid Biomarkers:

new diagnostic tools for idiopathic exudates
Porcel JM. Clin Chest Med 2013; 34: 27–37
55
Back to the case… evaluation for Infection

• Blood cultures negative
• 1,3 Beta D-glucan <31
• Galactomannan 0.15 (negative)
• S pneumo and Legionella Urine Ag negative
• Histoplasma and Blastomyces Urine Ag negative
• Cryptococcal Ag negative
• CMV PCR (blood) negative
• PCP (sputum) negative
56
2106
Bronchoscopy, Pleuroscopy and

Pleural Biopsy
Methenamine Silver Stain (MSS) 100x Modified AFB Stain 100x
57
Our Case:
after 6 months of antibiotic therapy
58
2107
Quick FINAL Case!
• 55 yo man with subacute

dyspnea
– History: EtOH
– Exam: Decreased BS R chest,
+ Ascites
– Pleural fluid analysis:
• PF protein 1.0 (serum 3.0)
• PF LDH 100 (serum 300)
• What is the etiology of

the patient’s R-sided
pleural effusion?
Quick FINAL Case: Answer

• Hepatic Hydrothorax
– Occurs in ~7% of pts with ascites
– Usually large R effusion (80% on R)
– Forms due to rifts in the diaphragm
– Can accumulate rapidly
– 20% of HH can form withOUT ascites
– Tap pleural + peritoneal fluid (to r/o infection
– “SBP” - and alleviate symptoms)
– Treat underlying ascites and cirrhosis -> often
difficult…
– TIPS can be affective for refractory HH
2108
Hepatic Hydrothorax: follow-up

• Spironolactone,
furosemide, IV Albumin,
and octreotide minimally
effective –
• TIPS performed and

discharged on diuretic
regimen
• CXR 3 months later!
Further Reading
1. Light, RW. Pleural Effusion. N Engl J Med 2002; 346:
1971
2. Light, RW. The Light Criteria The Beginning and
Why they are Useful 40 Years Later. Clin Chest Med
2013; 34: 21-26
3. Heffner, JE. Discriminating Between Transudates
and Exudates. Clin Chest Med 2006; 27: 241
4. McGrath EE and Anderson PB. Diagnosis of Pleural
Effusion: A systematic approach. Am J Critical Care
2011; 20: 119
5. Porcel Jose M. Pearls and myths in pleural fluid
analysis. Respirology 2011; 16: 44
62
2109
Thanks!
63
2110
Chest X-ray Refresher
Pulmonary and Critical Care Division

None.
2111
Chest X-ray Refresher:

Three Themes
I. Chronic interstitial pneumonitis
II. Obstructive lung diseases
III. Pulmonary infiltrates in the
immunocompromised host
Note: the order of the chest X-rays does not

match the order of the case histories.
LINEAR
NODULAR
LINEAR
AND
NODULAR
HONEY-
COMBING
2112
2113
2114
I. Chronic Interstitial Lung

Disease
The patient presents to you with

progressive dyspnea on exertion of
more than 6 weeks' duration and a
non-productive cough. On chest
examination, you auscultate bilateral
posterior inspiratory crackles. On
further questioning, you obtain the
additional history of:
I. Chronic Interstitial Lung

Disease – Case Histories
A. Work cleaning and insulating boilers

for 30 years.
B. Work as a stone-cutter in a quarry.
for 20 years, now retired for 10 years.
C. Prior episodes of erythema nodosum
and uveitis.
D. Inoperable gastric cancer.
2115
C. Sarcoidosis
2116
2117
Bilateral Hilar Adenopathy:

Differential Dx
• Sarcoidosis
• Berylliosis
• Lymphoma
• Granulomatous disease (e.g., TB)
• Metastatic cancer
Sarcoidosis:
Radiographic stages
• Stage 1: Hilar/mediastinal adenopathy
alone
• Stage 2: Hilar/mediastinal adenopathy
with pulmonary infiltrates
• Stage 3: Pulmonary infiltrates without
hilar/mediastinal adenopathy
2118
Sarcoidosis: Radiographic
Features
• Myriad radiographic patterns:

linear, tree-in-bud nodularity,
larger nodules, miliary, etc.
• Often upper lobe predominant
• Active disease is PET-positive
2119
2120
2121
A. Asbestosis
A. Asbestosis
2122
A. Asbestosis
2123
B. Silicosis with progressive

massive fibrosis
2124
2125
2126
2127
D. Lymphangitic carcinomatosis
D. Lymphangitic carcinomatosis
2128
Lymphangitic Carcinomatosis
Histologic type: almost always adeno-

carcinoma. Usual primary sites include:
• Breast
• Lung
• Stomach
• Pancreas
• Thyroid
Three Themes

2129
Common Obstructive Diseases
• Asthma
• Chronic bronchitis and emphysema
(COPD)
• Bronchiectasis
• Bronchiolitis
• Upper airway obstruction
Other Diseases Manifesting

with Airflow Obstruction
• Sarcoidosis
• Congestive heart failure
• Lymphangioleiomyomatosis (LAM)
2130
II. Obstructive Lung Diseases
This patient complains of long-

standing shortness of breath, especially
on exercise, and a daily cough. By
reviewing the patient's history, you
learn that:

– Case Histories
A. The patient's father and older brother
died in their 40's of emphysema.
B. The patient has had a chronic
productive cough and recurrent
sinusitis since childhood and now
presents for evaluation of infertility.
2131

– Case Histories (cont.)
C. The patient, a non-smoker, had
recurrent pneumothoraces in the
past and a pleural effusion that was
said to look "milky" when drained.
D. The patient complains of weight loss,
chronic diarrhea, and sinusitis.
Mucoid pseudomonas has been
grown from the sputum.
2132
A. Emphysema with alpha-1

antitrypsin deficiency
2133
2134
2135
C. Lymphangioleiomyomatosis
2136
B. Primary ciliary dyskinesia
Primary Ciliary Dyskinesia

(Immotile Cilia Syndrome)
(Kartagener’s Syndrome)
• Bronchiectasis
• Sinusitis
• Situs inversus (50%)
• Immotile sperm
- Ultrastructural and/or functional

abnormality of cilia
2137
Normal
Immotile cilia syndrome
Primary Ciliary Dyskinesia: Dx
• Electron microscopy (nasal or bronchial

mucosal biopsy); sperm analysis
• Low nasal nitric oxide level
• Ciliary immunofluorescence
• Genetic testing (“bronchiectasis panel”)
2138
D. Cystic fibrosis
2139
D. Cystic fibrosis
Molecular Basis of Cystic Fibrosis
• Deletion of 3 base pairs at codon 508

causes most cases (∆F 508 mutation).
• Gene product: CF transmembrane

conductance regulator (CFTR); functions
as chloride channel in apical cell membrane.
• Impaired chloride ion flux across

respiratory epithelium leads to viscous
airway mucus.
2140
Three Themes

III. Fever and Pulmonary Infiltrates

in Immunocompromised Hosts
-- Case Histories
A. This patient received a cadaveric renal
transplant two months ago and now
presents with rapidly progressive dyspnea,
tachypnea, and hypoxemia.
B. This patient with acute myelogenous
leukemia received combination chemo-
therapy, including adriamycin to a total
dose of 450 mg. He/she complains of
gradually worsening shortness of breath and
a non-productive cough.
2141
III. Fever and Pulmonary Infiltrates

in Immunocompromised Hosts
-- Case Histories
C. This patient with Hodgkin's Disease is
eight weeks status post radiation treatment
to a mantle port and to the spleen.
D. This neutropenic patient with acute
leukemia has received broad-spectrum
antibiotics for seven days because of fever
without identifiable source. Now he/she
develops cough, a new fever spike, and an
episode of hemoptysis.
Fever and Pulmonary Infiltrates:

Clinical and Radiographic
Considerations
• Diffuse vs. (multi-)focal infiltrates

• e.g., PCP/viral vs. gram-negative bacterial
• Nature of immunocompromise
• e.g., splenectomy vs. neutropenia
• Time of onset and tempo of illness
• e.g., timing after RTx or BMT;
• e.g., tempo of bacterial vs. mycobacterial
infection.
2142
Non-infectious Causes of Pulmonary

Infiltrates in Immunocompromised Hosts
• Radiation-induced pneumonitis and fibrosis

• Drug-induced pulmonary infiltrates
• Localized bleeding/diffuse alveolar
hemorrhage
• Pulmonary spread of malignancy
• Cryptogenic organizing pneumonia
(Bronchiolitis obliterans organizing
pneumonia)
• Non-specific interstitial inflammation/fibrosis
2143
D. Invasive aspergillosis
2144
C. Radiation pneumonitis
2145
C. Radiation pneumonitis
Radiation Pneumonitis:
Radiographic Features
• Onset 2-6 months following

completion of radiation therapy
• Defies normal anatomic boundaries
• Matches radiation fields in
distribution
2146
2147
B. Interstitial pulmonary edema
Pulmonary Venous Hypertension:

Radiographic Features
• Upper zone vessel dilatation

• Interstitial edema
• Septal (Kerley) lines
• Peribronchial/perivascular edema
• Hilar haze
• Mottling of lung fields
• Alveolar edema
• Pleural effusions/thickening of
fissures
2148
A. Pneumocystis pneumonia (?)
2149
Diffuse Ground-Glass Opacities
A. Pneumocystis pneumonia (?)
Diffuse Airspace (Alveolar

Filling) Opacities
• Pneumocystis pneumonia
• Cytomegalovirus (CMV) pneumonia
• Diffuse alveolar hemorrhage
• Others: e.g., pulmonary alveolar
proteinosis; drug-induced
pneumonitis
2150
Mystery Film: 48 year-old

cigarette smoker with dyspnea.
Question #1:
Which of the following blood tests is most

likely to be helpful in assessment of this
patient?
A. Cystic fibrosis gene mutation
B. ANCA
C. Alpha-1 antitrypsin level
D. Angiotensin converting enzyme
E. Hypersensitivity pneumonitis
antibody panel
2151
Question #1:
Which of the following blood tests is most

likely to be helpful in assessment of this
patient?
A. Cystic fibrosis gene mutation
B. ANCA
C. Alpha-1 antitrypsin level
D. Angiotensin converting enzyme
E. Hypersensitivity pneumonitis
antibody panel
Question #2:
This patient has cough with thick, green

sputum on a daily basis. The
abnormality at the left lower lobe is most
likely?
A. Bronchoalveolar carcinoma
B. Bronchiectasis
C. Left lower lobe collapse
D. Aspergilloma
E. Loculated pleural effusion
2152
Mystery Film with Close-up
Question #2:
This patient has cough with thick, green

sputum on a daily basis. The
abnormality at the left lower lobe is most
likely?
A. Bronchoalveolar carcinoma
B. Bronchiectasis
C. Left lower lobe collapse
D. Aspergilloma
E. Loculated pleural effusion
2153
References
• Goodman LR. Felson’s Principles of Chest
Roentgenology: A Programmed Text (3rd ed.).
Philadelphia: Saunders Elsevier, 2007.
• McLoud TC, Boisell PM. Thoracic Radiology:
The Requisites (2nd ed.). Philadelphia: Mosby
Elsevier, 2010.
• Fraser RS, et al. Fraser and Pare’s Diagnosis of
Diseases of the Chest (4th ed. – 4 volume set).
Philadelphia: Saunders,1999.
None.
2154
Pulmonary Function Testing

Scott Schissel, MD, PhD
Chief, Department of Medicine
Brigham and Women’s Faulkner Hospital


NO FINANCIAL DISCLOSURES
Scott L. Schissel, M.D.,PhD
2155
The “Standard” PFTs

• Spirometry
– Measures air FLOW -> assess for airway
obstruction
– Good screening test for RESTRICTION
• Lung Volume Measurement
– ONLY test that proves RESTRICTION in lung
function – can also assess for gas trapping
• Gas Exchange = DLco
– Indirect assessment of parenchymal lung disease,
pulmonary vascular disease, and / or anemia
• Respiratory Muscle Strength Testing
– Maximum inspiratory and expiratory pressures =
“MIP” and “MEP”
3
Spirometry: the MANEUVER

“deep breath in”
inspiration
Tidal Breathing
expiration
“keep blowing out”
2156
Spirometry: what we measure

TLC
IRV Inspiratory Reserve Volume
FVC
VT Tidal Volume (VT)
Expiratory Reserve Volume (ERV)
ERV
RV Residual Volume
Spirometry: exhaled volume over time
NORMAL OBSTRUCTION
Volume (liters)
Volume (liters)
FVC
FEV1 FVC
FEV0.5
FEV1
Time (seconds) Time (seconds)
2157
Spirometry: continuous
FLOW versus VOLUME
Exhale
Inhale
Spirometry: the numbers should

be known before looking at them!
Exhale
1
Inhale
2158
Spirometry Example 1: what’s going on ??
Severe Obstruction
(FEV1 / FVC < 0.7)
What’s “normal”:
>80% of the mean or > 95% CI
2159
PFT’s: an aside to define “normal”

• Use the 95% confidence interval (CI) to
determine Normal v Abnormal but….
• Still use % predicted (% of the mean) to SCORE
severity of obstruction or restriction
• Why ?
95% CI 95% CI
Grading OBSTRUCTION on Spirometry

• First – is there obstruction?
– FEV1 / FVC ratio <0.70 YES = obstruction present
• Examine FEV1 to grade severity
– 70 – 100% predicted = MILD
– 60 - 69% = MODERATE
– 50 - 59% = MODERATELY SEVERE
– 35 – 49% = SEVERE
– < 35% = VERY SEVERE
• Bronchodilator Response
– 12% and 200 mL change in FEV1 or FVC
– Hold short-acting and long-acting bronchodilators 4 hours
and 12 hours, respectively, prior to testing
2160
Back to cases…
13
2161
Fixed Large Airway Obstruction:

Peak flow << FEV1 = RED FLAG
Spirometry Example 2:
severe upper airway stenosis
Sub glottic trachea

1
6
2162
QUIZ on PFT Patterns of Large Airway

Obstruction
A B C
Variable Variable
FIXED EXTRA-thoracic INTRA-thoracic
Spirometry Example 3: what’s going on ?
Obstructed? Restricted? BOTH??
2163
In Severe Obstruction FVC is LOW Due to

Trapped Gas at End-Exhalation
TLC
IRV Inspiratory Reserve Volume
VT Tidal Volume (VT) FVC

ERV
Expiratory Reserve Volume (ERV)
RV Residual Volume
So, when the FVC is LOW……

• We JUST need to know whether the RV (or
FRC), the gas left on end-exhalation, is HIGH
or LOW to define RESTRICTION versus pure
OBSTRUCTION
• And, this is the exact principle and utility of

LUNG VOLUME TESTING
20
2164
Techniques to Measure Lung Volumes:

RV and FRC in Particular!
• Helium Dilution
– Cheaper technology
• Body Plethysmography
– Most accurate
• Nitrogen washout
–Rarely used
21
Body Plethysmography: “body box”

• Patient in closed chamber
• Plethysmograph is vented to
outside
• Shutter closed at end expiration =
FRC
• Patient then pants against closed
shutter / manometer ->
compressing FRC volume ->
• Based on Boyle’s Law:

• P1 * V1 = P2 * V2…..
• Volume of FRC can be calculated
2165
Spirometry: obstructed, restricted, both??
Lung Volumes example 1
Note the HIGH RV, FRC and LOW IC
2166
Restrictive Mechanisms
• Parenchymal lung disease / pulm fibrosis
– Increased lung elastance – sets FRC and RV
LOWER since the lung recoils the chest wall
inward
• Neuromuscular disease
– Since FRC is passive, set point between lung
and chest wall recoil relatively UNCHANGED
• Chest wall disease (skeletal, soft tissue =
slceroderma / Pleural fibrosis)
– DEPENDS, but FRC and RV usually LOW
25
Lung Volumes example 2
Severe Restriction: note relatively preserved FRC, RV.

Dx = ALS, diaphragm weakness
2167
DLco / Gas Exchange Principles

• Oxygen is CONSUMED, thus its diffusion is nearly
impossible to measure
• CO is great since it is freely diffusible, metabolically
inert, binds HgB ~250 x more avidly than O2, our
PaCO should be zero, and it is easy to measure
Vco = DLco (Palv CO – Pcap CO)

Vco = AD (P1- P2) 0 mmHg
T
[DLco]
DLco = Vco / Pa CO ml/min/mmHg
DLco Example 1
Note Obstruction with a LOW DLco and DL/VA = emphysema
2168
DLco Example 2
1
Note Restriction with a LOW DLco and DL/VA = ILD
Factors and Conditions that Affect the DLco

May DECREASE the DLco May INCREASE the DLco
Poor inspiratory effort Muller maneuver
(inhaled volume should >85% of best (inspire forcefully against a closed airway
FVC) / opposite of valsalva)
Poor CO equilibration during testing Supine position
(breath hold < 10 seconds)
Prior valsalva maneuvers Polycythemia
Elevated carboxyhemoglobin level Left to Right Shunt
Emphysema Alveolar hemorrhage
Interstitial lung disease Asthma
Pulmonary vascular disease Obesity
Lung resection
Increase FiO2
(use of supplemental oxygen)
2169
Pulmonary Function Tests in OBESITY

Change from normal
Parameter BMI Comments
FVC, TLC, and RV DECREASED Modest, linear decrease by ~0.5% / unit
increase in BMI
Significant, exponential decrease by 3 – 5%
FRC and ERV DECREASED / unit increase in BMI
DLco UNCHANGED to
INCREASED
Jones, RL et al. 2006. Chest, 2006. 130 (3): 827-33
Exhaled Breath Analysis: nitric oxide in asthma

52 yo F with 5 years of intermittent cough and chest
tightness; spirometry is normal
Labs revealed:
Peripheral eosinophils of 6%, absolute count 550
The best next step(s) include:

A. Start empiric albuterol and high dose inhaled fluticasone
B. Perform a methacholine challenge
C. No action since spirometry is normal
D. Measure exhaled nitric oxide level
E. B or D
Answer: E exhaled NO = 75 ppb
2170
Exhaled Nitric Oxide in Asthma

• An exhaled NO level > 50 ppb has good specificity for
eosinophilic airway inflammation and corticosteroid-
responsive symptoms
Exhaled Nitric Oxide Level
NON
asthmatics
Stable
ASTHMA
“Cut Point” for

corticosteroid
response
Exhaled Nitric Oxide: bottom-line guidelines

• Interpretation of exhaled nitric oxide levels in DIAGNOSIS of
eosinophilic airways disease:
– < 25 ppb NEGATIVE
– 25 – 50 ppb equivocal
– > 50 ppb POSITIVE
• Interpretation of significant CHANGE in nitric oxide levels
– Baseline NO level > 50 ppb = 20% change
– Baseline NO level < 50 ppb = 10 ppb change
• USE of exhaled NO levels to GUIDE asthma therapy very

uncertain / controversial:
– Likely effective as a marker of medication compliance in eosinophilic
asthma
– No clear advantage over other markers of asthma control
– In pregnancy, use of exhaled NO levels may decrease asthma
exacerbations and use of oral corticosteroids
2171
PFTs: pulling it all

together in 3 cases….
35
Case 1
• 69 yo F with a 40 pack year h/o Tobacco
use with 3 years of progressive DOE
• No cough, sputum, wheeze, or chest pain
• No significant co-morbidities
• Otherwise – had been quite active….
36
2172
Case 1: spirometry
Case 1: full PFTs

1
2173
Case 1 Question
• Which of the following processes are
LEAST likely present in this patient?
A. Anemia
B. Interstitial lung disease
C. Asthma
D. Pulmonary vascular disease
39
Case 1: ANSWER (C. Asthma LEAST Likely)
The isolated reduced DLco suggests anemia, pulmonary vascular disease, or

BALANCED obstruction and restriction (emphysema and IPF); asthma does not affect
the DLco
2174
Case 1: ANSWER
Homogeneous EMPHYSEMA Subpleural ILD
The interstitial fibrosis decreases the hyperinflation of emphysema -> “normalizing”

spirometry and lung volumes BUT BOTH processes DECREASE the DLco and impair
gas exchange!
Case 2
• 44 yo M with a history of “asthma”
presents with 2 years of progressive DOE,
cough and intermittent wheeze
• No tobacco history
42
2175
Case 2: spirometry
Case 2: full PFTs
The FEV1 and FVC do NOT change after bronchodilator treatment
2176
Case 2 Question
• Which of the following diagnoses is most
consistent with these PFT data?
A. Emphysema
B. Idiopathic pulmonary arterial
hypertension
C. Asthma
D. Sarcoid
45
Case 2: ANSWER (D. Sarcoid)
COMBINED severe obstruction and restriction =

SARCOID
2177
Case 2: ANSWER
“Bronchocentric” Fibrosis
SARCOID -> airway and parenchymal fibrosis ->

obstruction AND restriction with a low DLco
Case 3
• 47 yo F presents with 2 years of episodic
shortness of breath and DOE
• No associated cough or wheeze
• No tobacco use history
• Usually active = plays tennis, but has
DYPNEA with each episode
48
2178
Case 3: SPIROMETRY
Mean 95% CI Actual % Pred
FVC 3.01 2.20 2.77 92
FEV1 2.52 1.88 1.78 70
FEV1/FVC 0.74 0.70 0.65 --
PEFR 5.81 -- 5.24 90
Case 3 Question
• Which of the following statements is
TRUE?
A. The spirometry data are consistent with a

restrictive ventilatory defect
B. The normal peak expiratory flow rate (PEFR)
excludes a diagnosis of asthma
C. Repeat spirometry with and without a
bronchodilator is indicated, since PEFR can be
normal in asthma
D. The reduced FEV1 and FEV1/FVC but normal PEFR
is most suggestive of COPD
2179
Case 3: ANSWER (C. Repeat testing +/- a bronchodilator )

Pre bronchodilator Post bronchodilator
Mean 95% CI Actual % Pred Actual % Pred % Change
FVC 3.01 2.20 2.77 92 3.00 99 8
FEV1 2.52 1.88 1.78 70 2.28 90 28
FEV1/FVC 0.74 0.70 0.65 -- 0.76 -- --
PEFR 5.81 -- 5.24 90 5.82 100 11
Pre bronchodilator
Post bronchodilator
Flow (L/sec)
Volume (L)
Case 3: ANSWER
Appreciate that PEAK FLOW can be
NORMAL in ASTHMA
2180
Selected References
• Miller, MR et al. ATS/ERS Task Force: standardization of lung
function testing. Eur Respir J. 2005. 26: p153-161
• Pellegrino, R et al. ATS/ERS Task Force: interpretative strategies for

lung function tests. Eur Respir J. 2005. 26: p948-968
• MacIntyre, N et al. ATS/ERS Task Force: standardization of the

single-breath determination of carbon monoxide uptake in the lung.
Eur Respir J. 2005. 26: p720-735
• Jones, RL et al. The effects of body mass index on lung volumes.

Chest. 2006. 130: p827 – 833
• Essat, M et al. Fractional exhaled nitric oxide for the management of

asthma in adults: a systematic review. Eur Respir J. 2016. epub
53
2181
Take Home Messages in

Pulmonary Medicine
None.
2182
Topics Covered This Morning

1. Hemoptysis
2. Bronchiectasis/bronchiolitis
3. Solitary Pulmonary Nodule
4. Interstitial Lung Disease
5. COPD
6. Sleep Apnea Syndrome
7. Asthma
8. Pleural Disease
“Brevity is the Soul of Wit”
The Reduced
Shakespeare
Company
All 37 plays in 97
minutes!
2183
1. Hemoptysis
P Evaluation should include a chest X-ray; further
work-up depends on the findings on the chest
X-ray.
P A normal chest X-ray does not exclude serious
pulmonary pathology (i.e., lung cancer found in
5-7% of high-risk patients).
P At risk: cigarette smokers; >age 40; persistent
hemoptysis for >1 week.
P Chest CT and bronchoscopy of complementary
value in hemoptysis with negative chest X-ray.
Massive Hemoptysis
P Definition: >600 ml/24 hr; lesser amounts can
also cause respiratory insufficiency.
P Think bronchiectasis, TB, cancer, mycetoma,
vasculitis.
P Conservative measures include oxygenation,
sometimes intubation, positioning with bleeding
side down.
P Management team: thoracic surgery;
interventional pulmonology; and interventional
radiology (bronchial artery embolization).
P Major complication of the latter: spinal infarct.
2184
2. Bronchiectasis
P Definition: irreversible focal/multifocal

dilation of bronchi, predisposing to
recurrent/persistent bronchial infection.
P Causes: necrotizing infection/inflammation.
P Multifocal bronchiectasis: think
hypogammaglobulinemia, cystic fibrosis,
primary ciliary dyskinesia. Many cases
remain idiopathic.
Bronchiectasis (cont.)
P Diagnosis: CT scan.
P Typical pathogens: staph, hemophilus,
pseudomonas.
P Treatment: bronchodilators, clearance of
secretions, and antibiotics, including the
option of inhaled antibiotics and macrolide.
P Choice of antibiotics guided by sputum
culture.
2185
Bronchiolitis obliterans
P Definition: chronic cellular inflammation of
bronchioles with characteristic intraluminal
polypoid tissue.
P Causes: viral infection; noxious gas
inhalation; rheumatoid arthritis; ulcerative
colitis; s/p transplant.
P Diagnosis: obstructive lung disease – not
asthma or COPD or bronchiectasis;
occasionally: tree-in-bud small nodules.
“Tree-in-bud” pattern
2186
Bronchiolitis obliterans (cont.)
P Treatment: bronchodilators,
steroids (inhaled and systemic),
immunosuppressants.
P Often poorly responsive to treatment.
3. Solitary Pulmonary Nodule
P Differential diagnosis: benign or malignant.

P Features of benign nodules: calcification;
lack of growth (over 2 years; exception:
ground-glass [sub-solid] nodules).
P Diagnostic test: PET scan for nodules >8
mm (negative scan indicates benign disease
with 95% certainty;
other 5%: bronchoalveolar Ca).
2187
Solitary Pulmonary Nodule (cont.)

P Other diagnostic tests: bronchoscopy and
transthoracic needle aspirate unreliable in
excluding malignancy in small peripheral nodules.
P For high-risk patients/larger nodules: surgical
excision.
P For low-risk patients/smaller nodules: serial chest
imaging over at least 2 years.
P Screening for lung cancers with chest CT scans:
20% reduction in lung cancer deaths; current and
former (<15 years) smokers (>30 pack-years)
screened annually from age 55–80 yrs.
4. Interstitial Lung Disease

(Dr. Hilary Goldberg)
P Consider chronic interstitial lung disease:
P Exertional dyspnea with non-productive
cough
P Inspiratory crackles
P Not heart failure
P Obtain additional history:
P environmental/occupational exposures
P collagen-vascular disease
2188
Interstitial Lung Disease (cont.)

P Confirm chronic interstitial lung disease:
P Reticulonodular infiltrates on CXR, CT scan
P Restriction on PFTs
P exceptions: some sarcoidosis, eosinophilic
granuloma, LAM
P Oxygen desaturation with exercise
Interstitial Lung Disease (cont.)

P Establish diagnosis of chronic interstitial lung
disease:
P Thoracoscopic lung biopsy (VATS)
P Bronchoscopy
P to Dx sarcoidosis, hypersensitivity pneumonitis,
or lymphangitic carcinomatosis
P to exclude infection, malignancy
2189
Idiopathic Pulmonary Fibrosis vs.

Sarcoidosis
IPF Sarcoidosis
Age of onset >Middle age 20-50 y.o.

Radiographic Bibasilar Lymphadenopathy;
appearance predominance upper lobe
predominance
CT appearance Characteristic Variable: ground-glass
subpleural opacities; peribronchial
honeycombing nodules

Sarcoidosis
Idiopathic
pulmonary fibrosis
2190

Sarcoidosis
Sarcoidosis

Sarcoidosis
IPF Sarcoidosis
Extra- None (except Myriad, including:

pulmonary clubbing) eyes, liver, skin,
involment calcium metabolism.
Pathology UIP: fibrosis Non-caseating
interspersed with granulomas
normal lung
2191

Sarcoidosis
IPF Sarcoidosis
Natural 50% mortality at 3 Progression in small

history years minority
Treatment Pirfenidone or Nothing needed;
nintedanib; prednisone;
supplemental oxygen; methotrexate or
lung transplantation infliximab (Remicade)
5. COPD (Dr. Craig Hersh)

P Definitions:
P Chronic bronchitis: daily cough and sputum
production for at least 3 months out of the
year for at least 2 consecutive years.
P Emphysema: abnormal dilation of airspaces
due to destruction of alveolar walls.
P COPD: some combination of chronic
bronchitis and emphysema, causing airflow
obstruction that is not fully reversible.
2192
Therapeutic Interventions:
Smoking Cessation
P Smoking cessation counseling

P Nicotine replacement therapy
P Patch, gum, lozenge, inhaler, nasal spray
P Bupropion (Wellbutrin, Zyban)
P Varenicline (Chantix) – a nicotinic acetylcholine
receptor antagonist (and partial agonist)
P (Financial incentives: NEJM 2018; May 23, 2018
DOI: 10.1056/NEJMsa1715757)
2193
Medical Therapies for COPD

P Bronchodilators (once- or twice-daily)
P Long-acting inhaled beta-agonists (LABA)
P Long-acting muscarinic antagonists (LAMA)
P Inhaled corticosteroids (ICS)

P Do not slow decline in lung function;
P Increase the risk of pneumonia
P Role: frequent exacerbations; eosinopilia
Medical Therapies for Severe COPD
P LABA/ICS (Advair, AirDuo, Breo, Dulera,

Sybicort)
P LABA/LAMA (Anoro, Bevespi, Stiolto, Utibron)
P LABA/LAMA/ICS (Trelegy)
2194
(My) Current Thinking

• Do not use ICS alone.
• LAMA or LABA/ICS similar as first choice.
• LABA/LAMA provides greater improvement
in lung function than LABA/ICS or LAMA alone.
• Triple therapy (ICS/LABA/LAMA) appropriate for
severe disease with frequent exacerbations,
eosinophilia.
Additional Therapies for COPD
P Supplemental oxygen for the hypoxemic patient

P Improves exercise capacity, reduces pulmonary
hypertension and secondary polycythemia, and
prolongs survival in COPD with resting SaO2 <88%.
P Long-Term Oxygen Treatment Trial (LOTT)

P No long-term benefit from chronic supplemental
oxygen in COPD with SaO2 89-93% and/or oxygen
desaturation (to SaO2 80-90%) with exercise.
(N Engl J Med 2016; 375:1617-27).
2195
Additional Therapies for COPD (cont.)
• Don’t forget about outpatient pulmonary

rehabilitation.
• Highly selected patients: lung volume reduction.
• Everyone: influenza and pneumococcal vaccines.
6. Sleep Apnea (Dr. Lawrence Epstein)
P Definitions:
P Apnea = cessation of airflow >10 seconds
P Obstructive apnea = apnea despite respiratory
effort
P Central apnea = apnea without respiratory effort
P Mixed apnea = central followed by obstructive
apnea
P Hypopnea = reduction in airflow by >30%
with arousal or O2 desaturation (>3%)
2196
Prevalence of Sleep Apnea Syndrome

Among working population aged 30-60 yrs:
Men: 4%
Women: 2%
Apnea-hypopnea index (AHI) = # of apneas
and hypopneas per hour of sleep.
AHI 5-15 = Mild OSA
AHI 15-30 = Moderate OSA
AHI >30 = Severe OSA
Consequences of Sleep Apnea

Sleep fragmentation +
recurrent hypoxemia/hypercapnia
Daytime Cardiovascular
hypersomnolence consequences
Decreased productivity Pulmonary HT
Automobile accidents Myocardial ischemia
Cardiac arrhythmias
Systemic HT
Cerebrovasc. disease
Increased morbidity and mortality
2197
When to Suspect Sleep Apnea

P Snoring (loud, chronic)
P Nocturnal gasping and choking
P Ask bed partner (witnessed apneas)
P Excessive daytime sleepiness
P Automobile- or work-related accidents
P Personality changes or cognitive problems
P Risk factors
Risk Factors for Sleep Apnea

P Obesity (neck size: >17” in men; > 16” in women)
P Increasing age
P Male gender; post-menopausal women
P Anatomic abnormalities of upper airway
P Family history
P Alcohol or sedative use
P Smoking
2198
Diagnosis of Sleep Apnea Syndrome

P Overnight polysomnogram
Treatment of Sleep Apnea Syndrome

P Behavioral
P Weight loss; avoid alcohol/sedatives; avoid sleeping on
back; quit smoking
P Medical
P CPAP/B-PAP
P Oral appliances
P Nasal expiratory resistance valves
P Surgery
P UP3; mandibular advancement; others
P Tracheostomy
2199
7. Asthma (Dr. Elliot Israel)

P Step-care approach to asthma treatment:
P Old approach: categorize severity of asthma
P New approach: assess asthma control
P Current impairment domain (within 2-4 weeks)
P Frequency of “rescue” bronchodilator use (goal: <2 days/wk)
P Frequency of nocturnal awakenings (goal: <2 days/mo)
P Lung function (goal: >80%)
P Future risk domain (within past year)
P Number of severe asthma attacks (goal: <1/yr)
Asthma (cont.)
P Stepping up therapy in poorly controlled asthma:
Specialized Rx:
Biologics (anti-IgE, anti-IL-5); BT
Three controllers
ICS+Anti-LT or ICS-LABA
ICS or Anti-LT
Rescue Inhaler Only
2200
Asthma Therapy
Inhaled corticosteroids:
P Reduce symptoms and prevent asthmatic
exacerbations
P Do not appear to alter the natural history of
asthma (that is, have not been shown to prevent the
development of irreversible airflow obstruction)
P Have dose-dependent systemic absorption,
impacting at high doses over prolonged period:
P Bone density, cataracts, intraocular pressure, and
skin bruising/thinning
P Can be used intermittently in mild, well-controlled
asthma
Inhaled Steroid Preparations

mcg/puff
• Budesonide DPI* Pulmicort 90, 180
• Mometasone MDI-HFA* Asmanex 100, 200
• Mometasone DPI* Asmanex Twisthaler 110, 220
• Beclomethasone DPI Qvar 40, 80
• Fluticasone MDI-HFA Flovent 44, 110, 220
• Fluticasone DPI Flovent Diskus/ArmonAir 50/55, 100/113, 250/232
• Fluticasone furoate DPI* Arnuity 100, 200
• Ciclesonide MDI-HFA* Alvesco 80, 160
• Flunisolide MDI-HFA Aerospan 80
* category B in pregnancy ; available by nebulization
* approved for once-daily dosing * small particle size; pro-drug formulation
2201
Dosing of Inhaled
Corticosteroids (mcg/day)
Low Medium High
<400 mcg 400 – 800 mcg >800 mcg
Combination ICS and LABA

Combination Brand name Dose per inhalation
Fluticasone propionate Advair DPI 100/50, 250/50, 500/50

+ salmeterol Advair HFA 44/21, 115/21, 230/21
AirDuo DPI 55/14, 113/14, 232/14
Budesonide + Symbicort HFA 80/4.5, 160/4.5
formoterol
Mometasone + Dulera HFA 100/5, 200/5

formoterol
Fluticasone furoate + Breo DPI 100/25, 200/25
vilanterol*
*Once-daily dosing
2202
Safety Concerns Regarding

Long-Acting Inhaled Beta-Agonists
• Black Box warning regarding salmeterol
and all other LABAs – now removed
WARNING: DATA FROM A LARGE PLACEBO-CONTROLLED US
STUDY THAT COMPARED THE SAFETY OF SALMETEROL
(SEREVENT® INHALATION AEROSOL) OR PLACEBO ADDED
TO USUAL ASTHMA THERAPY SHOWED A SMALL BUT
SIGNIFICANT INCREASE IN ASTHMA-RELATED DEATHS IN
PATIENTS RECEIVING SALMETEROL (13 DEATHS OUT OF
13,176 PATIENTS TREATED FOR 28 WEEKS) VERSUS THOSE ON
PLACEBO (3 OF 13,179) (SEE WARNINGS AND CLINICAL
TRIALS: ASTHMA: SALMETEROL MULTI-CENTER ASTHMA
RESEARCH TRIAL).
Fluticasone + Salmeterol vs.

Fluticasone alone
• Among 11,679 patients randomized to fluticasone (in 3
doses) vs. fluticasone (3 doses) plus salmeterol
• No deaths; only 2 intubations (both in fluticasone
alone group); overall no difference in “serious adverse
events”
• Fewer severe asthma exacerbations in group treated
with fluticasone + salmeterol.
Stempel DA, et al, NEJM 2016; 374:1822.
2203
Leukotriene Modifiers
Leukotriene Receptor Montelukast (Singulair)

Antagonists:
Zafirlukast (Accolate)
Lipoxygenase Inhibitor: Zileuton (Zyflo)
Arachidonic Acid Pathway

Phospholipase A2
Arachidonic Acid Zileuton
Cyclooxygenase 5-lipoxygenase
Prostaglandins Leukotrienes Montelukast
Thromboxanes C4, D4, E4 Zafirlukast
Cysteinyl leukotriene receptor
2204
Aspirin-Intolerant Asthma
Phospholipase A2
Aspirin
NSAIDs Arachidonic Acid
Cyclooxygenase 5-lipoxygenase
Prostaglandins Leukotrienes C4,
Thromboxanes
D4, E4
Cysteinyl leukotriene receptor
8. Pleural Effusions
(Dr. Scott Schissel)
P Mechanisms:
P Hydrostatic imbalance (transudates)
P Besides congestive heart failure:
P Nephrotic syndrome
P Trapped lung (also can be exudative)
P Pulmonary embolism (also can be exudative)
P Myxedema
2205
Exudates vs. Transudates
P Light’s criteria for an exudate (any one of the following

3 characteristics):
P Pleural fluid to serum total protein ratio >0.5
P Pleural fluid to serum LDH ratio >0.6
P Absolute pleural fluid LDH >2/3 upper limit of
normal of serum LDH
Exudates vs. Transudates (cont.)

P Additional criteria for transudate:
P Serum TP - pleural fluid TP >3.1 gm/dl
P Serum albumin - pleural fluid albumin >1.2 gm/dl
P Pleural fluid NT-proBNP >1500 pg/ml
P Other criterion for exudate:

P Pleural fluid cholesterol: >60 mg/dl
2206
Pleural Fluid Analysis

P Bloody effusion:
P In the absence of chest trauma, think:
cancer, pulmonary embolism, pneumonia.
P Chylous effusion:
P Chylomicrons present on lipoprotein analysis;
pleural fluid triglycerides >110 mg/dl).
P In the absence of thoracic duct trauma, think
obstruction due to: tumor, granulomatous disease,
LAM, radiation fibrosis, or yellow nails syndrome.
Chylous
effusion
2207
White Blood Cell Differential

Lymphocyte-predominant: think cancer, TB,
post-CABG (Dressler’s syndrome), collagen-
vascular disease
Neutrophil-predominant: think
parapneumonic, pulmonary embolism,
pancreatitis.
Eosinophilic: not helpful!!
Low Pleural Fluid pH
Seen in: complicated parapneumonic effusion

/ empyema; tuberculous pleuritis; rheumatoid
and lupus pleuritis; and long-standing
malignant pleural effusions.
Also seen with esophageal rupture;
hemothorax; systemic acidosis.
Most useful in management of
parapneumonic effusions.
2208
Pleural Fluid pH
in Parapneumonic Effusions
P Results from intense inflammation and anaerobic
glucose metabolism leading to production of
lactic acid and CO2.
Pleural Fluid Micro Fluid pH Risk of Drain?
Anatomy Poor
outcome
<½ GS and Cx NEG pH >7.20 LOW No, BUT need
hemithorax and to follow
>½ GS or Cx POS pH <7.20 Moderate YES
hemithorax, or / High
loculated
Unexplained Exudative Effusion

Special studies in certain cases: amylase,
D-DIMER, adenosine deaminase, interferon-
gamma, ANA, LE cells, RF, fibulin-3,
mesothelin, CEA, CA15-3.
Send cytology again.
Thoracoscopic pleural biopsy.
Rare indication for closed needle biopsy.
2209
None.
2210
Evaluation of the dyspneic

patient
David M Systrom, M.D.
Associate Physician
Pulmonary and Critical Care Medicine
Asst. Prof.
No disclosures
2211
Patient MF
21 yo male Harvard Crew
1.5 years SOB, especially w/ intense
training, competition
Patient and mom endorsed “noisy
breathing” during exacerbations
Rapid clearing of sx, EMT’s : “normal
exam”
Patient MF
“Doc make me better, we are going to the
Henley”
2212
Pt MF
Exam: normal
Spirometry:
Unexplained Dyspnea
2213
Vocal Cord Dysfunction

AKA laryngeal dyskinesia
Often young women w/ PTSD, many = conversion
reaction
Can be worsened by PNDr, GERD
Key to hx is inspiratory stridor, hoarseness
Often confused w/ asthma, methacholine
challenge may help, ABG’s should be normal
Spirometry: flattened inspiratory F-V loop
Confirmation w/ direct laryngoscopy: panting, full
exhalation: forced inspiration, exercise…
..inappropriate closure of glottis during inspiration
Treatment: voice training, SSRI
Pt WL
51 YO M, mildly obese
Previously 35 min Elliptical, 4 d /week, TM
4.4 mph, 4 deg, 15 min.
In 6/12 hanging an AC unit out a window,
leaning over a window sill, and had sudden R
anterior sharp CP, persistent R shoulder pain
and SOB since, immediate orthopnea
No persistent cough, wheeze, F, C, sweat, B
sx.
2214
Pt WL
SPIROMETRY (BTPS)
Predicted Pre-BD
Mean 95% CI Actual %Pred
FVC (Lts) 5.24 4.12 2.30 44
FEV1 (Lts) 4.14 3.30 1.70 41
FEV6 (Lts) 5.19 4.23 2.28 44
FEV1/FVC (%) 79 71 74 94
LUNG VOLUMES (PLETHYSMOGRAPHY)

TLC (Lts) 7.41 5.80 4.68 63
DIFFUSING CAPACITY
DLCO Unc (mL/min/mmHg) 32.71 22.69 25.85 79
DLCO Corr (Hb) (mL/min/mmHg) 32.71 22.69 25.85 79
VA@BTPS (Lts) 7.41 6.26 3.93 53
DL/VA (%) 4.43 3.50 6.58 149
RESPIRATORY MUSCLE STRENGTH

MIP 89 34 38
MEP 134 68 51
Pt WL
2215
Pt WL
Respiratory Muscle Weakness

Acute or chronic DOE, immediate orthopnea
Usually B diaphragmatic dysfxn, but unilateral plus other
can > SOB
Diagnosis:
Restrictive defect may be mild
VC upright > supine (10% fall), MIP
CT chest>r/o mass, LAD
Phrenic nerve conduction, diaphragmatic EMG
Treatment
Time, e.g., trauma, CABG
Weight loss
Elevate HOB
PSG: look for hypopneas>BiPAP
Inspiratory muscle training
IVIg, steroids
2216
Pt MR
•61 yo running Shoe Co Exec
•Two year decline in running splits 6>8
min miles due to SOB

•No immediate orthopnea, myalgias,
lightheadedness
•Exam routine labs normal
•Spirometry, TTE, CT chest, cardiac
stress normal
•Invasive CPET:
Invasive CPET
VO2max
CaO2
mPAP-PCWP
CvO2
2217
Invasive CPET Dx Algorithm

Impairment
VO2max < 80%
Pulmonary Mechanical O2 Flux

VEmax/MVV > 0.7 AT < 40%
Central Cardiac Mt Myopathy

Qtmax < 80% Ca-vO2 < [Hb]
Left Heart
PCWPmax > 20 mmHg
Right Heart
mPAPmax > 30 mmHg and
PVRmax >120 dynes .s.-5
Preload Failure
RAPmax < 9mm Hg
All else normal
Pt MR
2218

Impairment
VO2max < 80%


Left Heart
PCWPmax > 20 mmHg
Right Heart
Preload Failure
RAPmax < 9mm Hg
All else normal
EiPAH
2219
EiPAH
EiPAH
2220
eiPAH
•Presents w/ unexplained dyspnea
•aCPET: Intermediate exercise phenotype
between normal and resting PAH

•? Early disease vs stable variant
•Missed by TTE and resting RHC
•Ambrisentan responsive, ? Others
•Need clinical trials
Case ED
23 yo college student
In middle school, had DOE running in
field hockey.
Several years orthostatic
lightheadedness, occ. syncope, s/p tilt
table x 3, results equivocal > Rx'd w/
midodrine q 3h.
PMHx: mild asthma, migraines
ROS: pos. myalgias during and post
exercise x years.
Exam and spiro normal
2221
Pt ED
Case ED
PRE FLUIDS
Rest Heart Rate (bpm) 100
Max.Cardiac Output (L/min)) 8.56 (62%)
Max VO2 (mL/min) 856 (44%)
POST FLUIDS
Rest Heart Rate (bpm) 87
Max Cardiac Output (L/min) 11.67 (85%)
Max. VO2 (mL/min) 1004 (52%)
2222

Impairment
VO2max < 80%


Left Heart
PCWPmax > 20 mmHg
Right Heart
Preload Failure
RAPmax < 9mm Hg
All else normal
Case ED
Follow-up
In 3/13 started pyridostigmine 30 mg
po TID
BP's up off midodrine now used prn
fatigue, lightheaded approximately 1 x
week.
Currently, on good days, can move
around house comfortably, biking 6
min>20 min, limit is fatigue >> SOB
2223
Preload Failure
Young women, SOB, fatigue,
lightheadedness
Exacerbations after stress: viral, pregnancy
Overlap w/ POTS/OH, Mt myopathy, SFPN
Tilt Table may help, cort stim, consider
structurally impaired venous return, e.g.,
chronic DVT
Rx salt and H20 load, compression stockings,
aerobic exercise, Florinef, SSRI, midodrine,
Mestinon
Pt MP
28-year-old woman with increasing DOE x 5 mos.
A year ago she noted DOE climbing 6-7 stairs, now
on level ground w/ B leg fatigue.
Past medical history:

Childhood asthma
2003 mild aortic stenosis and insufficiency
1999 Raynaud's Disease
1999 Migraine headaches
S/p negative Tilt Table
ROS: No myalgias, arthralgias, cough, wheezing.
2224
Pt MP
Predicted Measured (% Pred)
Max VO2 (mL/min) 1820 1198 66%
Max VO2 (mL/kg/min) 20.3
VO2 (mL/min) at AT >40% 439 24%
Cardiac Output max (L/min) 13 13.5 104%
Case MP
==================================
= ADVANCED CARDIOPULMONARY GASES =
==================================
-----------------------------------------------------
Time CaO2 CvO2 Ca-vO2 PaO2 PaCO2 pH Lactate
-----------------------------------------------------
REST 18.7 11.8 6.9 106 43 7.39 0.5
-----------------------------------------------------
FW1 18.2 9.0 9.2 95 41 7.38 0.9
-----------------------------------------------------
1 17.2 9.4 7.8 110 36 7.41 0.9
2 17.8 9.7 8.1 105 40 7.41 0.9
3 18.5 9.6 8.9 110 39 7.40 1.1
4 17.9 9.4 8.5 104 39 7.39 2.1
5 17.4 9.2 8.2 116 38 7.38 3.5
-----------------------------------------------------
PEAK 18.0 9.1 8.9 125 36 7.37 5.5
2225

Impairment
VO2max < 80%


Left Heart
PCWPmax > 20 mmHg
Right Heart
Preload Failure
RAPmax < 9mm Hg
All else normal
Mitochondrial Myopathy
Present in adulthood w/ dyspnea > fatigue
Exacerbations after stress: e.g., viral, surgery
Often w/ longstanding, but sometimes
episodic exertional intolerance
w/u may include blood Mt mutation screen,
muscle bx, iCPET
Rx is Vitamin cocktail, including CoEnzyme
Q10
2226
Advanced CPET Diagnoses

(%, n=225)
7
HFpEF
13 30 eiPAH
rPAH
Mt myopathy
20 22 Normal/Detrained
Preload
Take-Home Messages
a. Unexplained dyspnea is defined as un or
underexplained sx after a thorough hx,
exam, routine labs, full PFT’s, TTE and
chest radiography when appropriate
b. Additional testing might include an ENT
eval, MTC, MIP’s
c. iCPET can rule in or out exercise-
induced PH, preload failure and suggest
a Mt myopathy
2227
Board Questions
23 yo F presents w/ 18 mos of DOE
following an apparent viral syndrome.
Her DDx includes:
a. eiPAH
b. Preload failure
c. Mt myopathy
d. All of the above
e. b&c
Board Questions
23 yo F presents w/ 18 mos of DOE and
episodic lightheadedness following an
apparent viral syndrome. Her DDx includes:
a. eiPAH
b. Preload failure
c. Mt myopathy
d. All of the above
e. b&c
2228
Case 1
Preload failure and Mt
myopathies often present
together and in the post-
infectious setting
An autoimmune
pathogenesis is suspected
Board Questions
18 yo F presents w/ two years of DOE and subjective
wheezing. Exam in office is normal. PEFR in the office
and field is repeatedly normal. SABA and ICS/LABA
have not helped. The next step should be:
a. Escalation of asthma controllers, e.g., tiotropium

b. CT chest
c. TTE
d. Cardiopulmonary exercise testing
e. Methacholine challenge
2229
Board Questions
18 yo F presents w/ two years of DOE and subjective
wheezing. Exam in office is normal. PEFR in the office
and field is repeatedly normal. SABA and ICS/LABA
have not helped. The next step should be:
a. Escalation of asthma controllers, e.g., tiotropium

b. CT chest
c. TTE
d. Cardiopulmonary exercise testing
e. Methacholine challenge
Case 2
Vocal cord dysfunction presents in a similar
fashion to asthma. Exacerbations can be
provoked by emotions and exercise, and
aggravate by post nasal drip and GERD.
Negative MTC essentially rules out asthma.
Clues are subjective and objective stridor, rapid
clearing, flattened inspiratory F-V loop. Dx
confirmed by direct laryngoscopy w/ maneuvers.
Rx = speech therapy.
2230
References
Morris MJ, et al. Vocal cord dysfunction: etiologies and treatment. Clin
Pulmonary Med. 2006; 13:73–86.
Oldham WM, Lewis GD, Opotowsky AR, Waxman AB, Systrom DM.
Unexplained exertional dyspnea caused by low ventricular filling
pressures: results from clinical invasive cardiopulmonary exercise testing.
Pulm Circ 2016; 6:1, 55-62
Taivassalo T, et al. The spectrum of exercise tolerance in mitochondrial
myopathies: a study of 40 patients. Brain 2003; 126:413-423.
Functional impact of exercise pulmonary hypertension in patients with
borderline resting pulmonary artery pressure. Oliveira RKF Faria Urbina
M, Maron BA, Santos M, Waxman AB, Systrom DM. Pulm Circ 2017.
DOI: 10.1177/2045893217709025
Segrera SA, Lawler L, Opotowsky AR, Systrom DM, Waxman AB. Open
label study of ambrisentan in patients with exercise pulmonary
hypertension. Pulm Circ 2017; 7(2) 1–8
W Huang, S Resch, RKF Oliveira, BA Cockrill, DM Systrom, AB
Waxman. Invasive cardiopulmonary exercise testing in the evaluation of
unexplained dyspnea: Insights from a multidisciplinary dyspnea center.
Eur J Prev Card 2017; 0(00) 1–10 DOI: 10.1177/2047487317709605
Maron BA, Cockrill BA, Waxman AB, Systrom DM. The invasive
cardiopulmonary exercise test. Circulation. 2013;127:1157-1164
2231
PULMONARY MEDICINE
BOARD REVIEW

None.
2232
Question #1:
A 75-year-old smoker (1 ppd for 40 years,

quitting 15 years ago) presents with
progressive exertional dyspnea over the last 6
months. He reports a non-productive cough,
worse in the mornings, without fever, chest
pain, or hemoptysis. He denies orthopnea,
PND, or swelling of his lower extremities.
Question #1 (Cont.):
He has retired from his work as a lawyer. He

has no unusual exposures at home, no arthritic
complaints or symptoms of Raynaud’s
disease.
His exam is notable for clubbing of the digits
and coarse inspiratory crackles in the lower
lung zones.
2233
His oxygen saturation is 95% at rest and falls
to 87% with walking.
Spirometry suggests moderate restriction.
Chest X-ray shows increased linear
markings, predominantly in the lower lung
zones. His chest CT scan shows basilar
honeycombing and traction bronchiectasis,
read as “suggestive of usual interstitial
pneumonitis.”
2234
Question #1
Which of the following actions would you take?
A. Refer to Pulmonary for transbronchial lung biopsy

B. Refer to Thoracic Surgery for thoracoscopic lung
biopsy
C. Begin anti-inflammatory therapy with high-dose
prednisone
D. Begin immunosuppressive therapy with prednisone
and azathioprine
E. Begin anti-fibrotic therapy with pirfenidone or
nintedanib.
Question #1
Which of the following actions would you take?
A. Refer to Pulmonary for transbronchial lung biopsy

B. Refer to Thoracic Surgery for thoracoscopic lung
biopsy
C. Begin anti-inflammatory therapy with high-dose
prednisone
D. Begin immunosuppressive therapy with prednisone
and azathioprine
E. Begin anti-fibrotic therapy with pirfenidone or
nintedanib.
2235
Question #2
Conditions commonly associated with cystic fibrosis
include each of the following except:
A. Bronchiectasis
B. Sinusitis
C. Airflow obstruction
D. Aspermia
E. Systemic Pseudomonas infections
Question #2
Conditions commonly associated with cystic fibrosis
include each of the following except:
A. Bronchiectasis
B. Sinusitis
C. Airflow obstruction
D. Aspermia
E. Systemic Pseudomonas infections
2236
Question #3
Typical manifestations of asbestos-related intrathoracic
disease include each of the following except:
A. Fibrocalcific parenchymal disease, predominantly

involving the upper zones of the lung
B. Pleural plaques
C. Malignant mesothelioma
D. Benign pleural effusions
E. Bronchogenic carcinoma
Question #3
Typical manifestations of asbestos-related intrathoracic
disease include each of the following except:
A. Fibrocalcific parenchymal disease, predominantly

involving the upper zones of the lung
B. Pleural plaques
C. Malignant mesothelioma
D. Benign pleural effusions
E. Bronchogenic carcinoma
2237
2238
2239
Question #4:
During December of last year, a 63-year-old

man with a 60 pack-year history of cigarette
smoking noticed an increase in the amount of
his usual sputum production. His sputum
became now yellow-green. Findings on
physical examination were normal. His
temperature was 37.8oC (100oF). A chest X-
ray was obtained and was normal.
A gram stain of sputum showed less than 10

squamous epithelial cells per low-power field
and many neutrophils per high-power field.
The predominant organisms on the gram-
stained smear were gram-negative cocci in
pairs.
2240
Question #4
You would initiate a course of antibiotic therapy
using which of the following?
A. Ampicillin, orally
B. Amoxicillin-clavulanic acid, orally
C. Procaine penicillin G, intramuscularly twice a day
D. Cefoxatime, intravenously
E. Cephalexin, orally
Question #4
You would initiate a course of antibiotic therapy
using which of the following?
A. Ampicillin, orally
B. Amoxicillin-clavulanic acid, orally
C. Procaine penicillin G, intramuscularly twice a day
D. Cefoxatime, intravenously
E. Cephalexin, orally
2241
Question #5
An intensive pulmonary rehabilitation program
in patients with chronic obstructive pulmonary
disease has been shown to improve
A. Survival
B. Cardiovascular function
C. Exercise tolerance
D. Expiratory flow rates
2242
Question #5
An intensive pulmonary rehabilitation program
in patients with chronic obstructive pulmonary
disease has been shown to improve
A. Survival
B. Cardiovascular function
C. Exercise tolerance
D. Expiratory flow rates
2243
Question #6 (cont.):
Her chest exam reveals only a transient
expiratory rhonchus.
Chest X-ray is read as showing a lingular
pneumonia.
Chest CT scan shows bronchiectasis with
tree-in-bud nodularity in the RML, lingula, and
RLL. The radiologic interpretation raises the
possibility of non-tuberculous mycobacterial
infection.
2244
Question #6
Based on these findings you recommend:
A. Levofloxacin for 2 week course

B. Initiation of therapy for M. avium-intracellulare with
azithromycin, ethambutol, and rifampin
C. Initiation of therapy for non-tuberculous
mycobacteria with INH, ethambutol, rifampin, and
pyrazinamide
D. Sputum for AFB culture and smear X 3
E. Blood for anti-nuclear cytoplasmic antibody (ANCA)
Question #6
Based on these findings you recommend:
A. Levofloxacin for 2 week course

B. Initiation of therapy for M. avium-intracellulare with
azithromycin, ethambutol, and rifampin
C. Initiation of therapy for non-tuberculous
mycobacteria with INH, ethambutol, rifampin, and
pyrazinamide
D. Sputum for AFB culture and smear X 3
E. Blood for alpha-1 antitrypsin level
2245
Question #7:
An arterial blood gas analysis shows a PO2

of 40 mm Hg, PCO2 of 80 mm Hg, and a pH of
7.10 in a patient breathing room air.
Question #7
These findings are most likely to be associated
with which of the following disorders?
A. Adult respiratory distress syndrome

B. Status asthmaticus
C. Severe bacterial pneumonia
D. End-stage chronic obstructive pulmonary disease
E. Sedative drug overdose
2246
pH Changes in Respiratory Acidosis
Acute: ∆ pH = ∆ PCO2 * 0.008
Chronic: ∆ pH = ∆ PCO2 * 0.003
Acute - on -
Chronic: ∆ pH = ∆ PCO2 * 0.005
Case Example
Acute: ∆ pH = 40 * 0.008 = 0.32

Predicted pH = 7.08
Chronic: ∆ pH = 40 * 0.003 = 0.12

Predicted pH = 7.28
Acute - on -
Chronic: ∆ pH = 40 * 0.005 = 0.20
Predicted pH = 7.20
2247
A-a Gradient for Oxygen
A -aDO2 = PAO2 - PaO2
PAO2 = (PB - 47) * FlO2 - PCO2/R
= (760 - 47) * 0.21 - PCO2/0.8
= 150 - PCO2/0.8
Case Example
PAO2 = (PB - 47) * FlO2 - PCO2/R
= 150 - 80/0.8
= 50
PAO2 - PaO2 = 50 - 40
A-aDO2 = 10 (Normal = 5 - 20)
2248
Question #7
These findings are most likely to be associated
with which of the following disorders?

B. Status asthmaticus
C. Severe bacterial pneumonia
D. End-stage chronic obstructive pulmonary disease
E. Sedative drug overdose
Question #8:
A 52-year-old school teacher presents for a

check-up. She has recently moved to the area
to assume a new teaching position. She has
never smoked cigarettes and has been found
healthy at previous annual check-ups.
2249
Her physical examination and routine

laboratory studies are normal. However, a
routine posteroanterior and lateral chest X-ray
shows a 1-cm x 1.8-cm smooth, well-
demarcated lesion in the right middle lobe.
Question #8
The appropriate initial step for the patient’s
internist would be:
A. Obtain a chest PET-CT scan

B. Order a transthoracic needle biopsy
C. Ask a pulmonologist to perform bronchoscopy
D. Obtain prior CXRs from her former physician
E. Order chest MRI
2250
Question #8
The appropriate initial step for the patient’s
internist would be:
A. Obtain a chest PET-CT scan

B. Order a transthoracic needle biopsy
C. Ask a pulmonologist to perform bronchoscopy
D. Obtain prior CXRs from her former physician
E. Order chest MRI
Question #9:
A 47-year-old woman presents with a six-week
history of nonproductive cough, moderate exertional
dyspnea, and temperature to 38.3oC (101oF). The
patient has been in good health in the past, although
she has smoked two packs of cigarettes per day for
the last 25 years. The patient has received
clarithromycin 500 mg orally four times a day for 10
days on two occasions without improvement in her
symptoms.
2251
There is no history of ocular inflammation, skin
rash, or arthritis.
The physical examination shows normal jugular
venous pressure and no peripheral
lymphadenopathy. The intensity of breath sounds is
normal except over the lower lobes bilaterally where
they are significantly reduced. There are also
bibasilar crackles, but no bronchial breathing or
egophony, and no wheezing.
Laboratory studies:
• Hematocrit 31%
• Leukocyte count, 11,100/uL with 18% lymphocytes,
64% polys, 7% band forms,
6% monocytes, and 5% eosinophils
• Serum creatinine 0.8 mg/dl
• Urinalysis is normal
• The chest X-ray shows airspace disease at both lung
bases.
2252
Question #9
A. Legionnaire’s disease
B. Wegener’s granulomatosis
C. Streptoccoccus pneumoniae pneumonia
D. Idiopathic pulmonary fibrosis
E. Cryptogenic organizing pneumonia (Bronchiolitis
obliterans organizing pneumonia)
2253
Question #9
A. Legionnaire’s disease
B. Wegener’s granulomatosis
C. Streptoccoccus pneumoniae pneumonia
D. Idiopathic pulmonary fibrosis
E. Cryptogenic organizing pneumonia (Bronchiolitis
obliterans organizing pneumonia)
Differentiating BOOP from

Bronchiolitis Obliterans
Cryptogenic Organizing Constrictive

Pneumonia (BOOP) Bronchiolitis (BO)
Presentation Pneumonia-like Emphysema-like
Chest X-ray Multifocal or diffuse Hyperinflation

pulmonary opacities
Physiology Restrictive Obstructive
Response to Good Poor

Steroid
Treatment
2254
Questions #10 - 14
10. A majority of cigarette smokers are affected
11. Reduced FEV1/FVC ratio
12. Decreased diffusing capacity (DLCO)
13. Most patients have a deficiency of alpha-1
antitrypsin
14. Montelukast (Singulair®) is useful in treatment
A. Emphysema
B. Asthma
C. Both
D. Neither
Questions #10 - 14
A. Emphysema
B. Asthma
C. Both
D. Neither
2255
Questions #10 - 14
A. Emphysema
B. Asthma
C. Both
D. Neither
Questions #10 - 14
A. Emphysema
B. Asthma
C. Both
D. Neither
2256
Questions #10 - 14
A. Emphysema
B. Asthma
C. Both
D. Neither
Questions #10 - 14
A. Emphysema
B. Asthma
C. Both
D. Neither
2257
Questions #10 - 14
A. Emphysema
B. Asthma
C. Both
D. Neither
Questions #10 - 14

antitrypsin
A. Emphysema
B. Asthma
C. Both
D. Neither
2258
Questions #10 - 14

antitrypsin
A. Emphysema
B. Asthma
C. Both
D. Neither
Questions #10 - 14
A. Emphysema
B. Asthma
C. Both
D. Neither
2259
Questions #10 - 14
A. Emphysema
B. Asthma
C. Both
D. Neither
Questions #15 - 18
15. May be characterized by severe and diffuse lung infiltrates
16. Most commonly caused by sepsis and gastric aspiration
17. Positive-pressure ventilation may be an important adjunct
treatment
18. Corticosteroid therapy has been shown to be beneficial when
initiated early

B. Severe cardiogenic pulmonary edema
C. Both
D. Neither
2260
Questions #15 - 18
15. May be characterized by severe and diffuse

lung infiltrates

C. Both
D. Neither
Questions #15 - 18
15. May be characterized by severe and diffuse

lung infiltrates

C. Both
D. Neither
2261
Questions #15 - 18
16. Most commonly caused by sepsis and gastric

aspiration

C. Both
D. Neither
Questions #15 - 18
16. Most commonly caused by sepsis and gastric

aspiration

C. Both
D. Neither
2262
Questions #15 - 18
17. Positive-pressure ventilation may be an

important adjunct treatment

C. Both
D. Neither
Questions #15 - 18
17. Positive-pressure ventilation may be an

important adjunct treatment

C. Both
D. Neither
2263
Questions #15 - 18
18. Corticosteroid therapy has been shown to be

beneficial when initiated early
C. Both
D. Neither
Questions #15 - 18
18. Corticosteroid therapy has been shown to be

beneficial when initiated early
C. Both
D. Neither
2264
Questions #19 - 22
19. Necrobiotic nodules
20. Occurrence in women only
21. Diabetes insipidus
22. Recurrent aspiration pneumonias
A. Rheumatoid arthritis
B. Scleroderma
C. Langerhans cell histiocytosis (histiocytosis X;
eosinophilic granuloma)
D. Lymphangioleiomyomatosis
E. Idiopathic pulmonary fibrosis
Questions #19 - 22
B. Scleroderma
2265
Questions #19 - 22
B. Scleroderma
Questions #19 - 22
B. Scleroderma
2266
Questions #19 - 22
B. Scleroderma
Questions #19 - 22
B. Scleroderma
2267
Questions #19 - 22
B. Scleroderma
Questions #19 - 22

B. Scleroderma
2268
Questions #19 - 22

B. Scleroderma
Questions #23 - 27
Detection and Treatment of
Asymptomatic (Latent) Tuberculous
Infection
• Tuberculosis germs in the lungs without any evidence
for active infection = latent tuberculous infection (LTBI).
• Most cases of active TB are due to reactivation of

LTBI.
• Treatment of LTBI can eradicate TB germs and prevent

reactivation, but carries risk of potentially serious side
effects (in an asymptomatic person).
2269
Questions #23 - 27
Indications for Treating Latent
Tuberculous Infection
• Household contact
• Recent convertor
• X-ray of inactive TB; never treated with TB drugs
• Special circumstances (e.g., diabetes, HIV, dialysis,
immunosuppressing drugs, major weight loss, silicosis,
recent immigration from an endemic area)
• (Under age 35 years)
Defining a Positive PPD Skin Test
• High risk pop’n: > 5 mm induration
• Moderate risk pop’n: > 10 mm induration
• Low risk pop’n: > 15 mm induration
2270

(cont’d)
• High risk:
• HIV disease or immunosuppression;
• Recent close contact; or
• Scarring on CXR c/w inactive disease

(cont’d)
• Moderate risk:
• Increased risk of exposure
• (e.g., from countries with high TB prevalence;
I.V. drug abusers; homeless; nursing home
residents; health care workers; children
exposed to high-risk adults)
2271

(cont’d)
• Moderate risk (cont’d):

• Increased risk of activation
• (e.g., diabetes; chronic renal failure; weight loss
>10% IBW; gastrectomy; lymphoma or
leukemia; lung or head/neck cancer; Rx with
tumor necrosis factor alpha inhibitors)
Influence of Prior Vaccination with

BCG
• It is recommended that a history of prior

vaccination with BCG should be ignored
when deciding about treatment of a positive
PPD skin test.
2272
Interferon Gamma Release Assays
• IGRAs and TSTs can be used interchangeably;

• BCG does not cause a positive IGRA result; and
• IGRAs are less likely to be positive due to cross-
reactivity with atypical mycobacteria.
Mazurek GH, et al. Updated guidelines for using
interferon gamma release assays to detect
Mycobacterium tuberculosis infection – United
States, 2010. MMWR 2010; 59:RR-5.
Questions # 23 - 27
Treatment of latent tuberculous infection (e.g.,
isoniazid 300 mg daily) should be given in
which of the following cases?
23. A 21-year-old healthcare worker with a TB skin test

reaction of 15 mm induration. Chest X-ray is normal.
The skin test was positive 5 years ago at 10 mm
induration.
A. Yes
B. No
2273
Questions # 23 - 27
23. A 21-year-old healthcare worker with a TB skin test

reaction of 15 mm induration. Chest X-ray is normal.
The skin test was positive 5 years ago at 10 mm
induration.
A. Yes
B. No
Questions # 23 - 27
24. A 74-year-old man with no known TB exposure has a

TB skin test of 5 mm induration discovered on routine
testing. A repeat skin test 1 week later shows a 15 mm
induration. A chest X-ray is obtained and is normal.
A. Yes
B. No
2274
Questions # 23 - 27
24. A 74-year-old man with no known TB exposure has a TB

skin test of 5 mm induration discovered on routine
testing. A repeat skin test 1 week later shows a 15 mm
induration. A chest X-ray is obtained and is normal.
A. Yes
B. No
Booster Phenomenon
Person previously exposed to TB who on

initial testing has a negative result but who, on
repeat testing one to a few weeks later, has a
positive test.
2275
Booster Phenomenon (Cont.)
The initial result is a “false negative” due to

waning cellular immunity; the latter is a true
positive due to “boosting” of the immune
response by the recent re-exposure to
tuberculin protein.
Booster Phenomenon (Cont.)
Booster phenomenon should be

distinguished from a recent conversion.
Screening (e.g., in nursing homes, hospitals)
often uses an initial two-step PPD testing
procedure, with repeat testing 1-3 weeks
after an initial negative result.
2276
Questions #23 - 27 (cont’d)

25. A 45-year-old former IV drug abuser who is HIV

positive has a clear chest X-ray. His TB test is 5 mm
in induration. Prior skin tests are reported as
“equivocal.”
A. Yes
B. No

25. A 45-year-old former IV drug abuser who is HIV

positive has a clear chest X-ray. His TB test is 5 mm
in induration. Prior skin tests are reported as
“equivocal.”
A. Yes
B. No
2277

26. A 53-year-old woman with no known medical illnesses

and a clear chest X-ray has a TB test reaction of 8 mm.
She has never had skin testing and is tested now
because her husband has just had active TB
diagnosed after a 6-mos illness.
A. Yes
B. No

26. A 53-year-old woman with no known medical illnesses

and a clear chest X-ray has a TB test reaction of 8 mm.
She has never had skin testing and is tested now
because her husband has just had active TB
diagnosed after a 6-mos illness.
A. Yes
B. No
2278

27. A 26-year-old homeless man has a TB skin test of

15 mm induration. He has no symptoms but his
chest X-ray shows a left upper lobe infiltrate.
A. Yes
B. No

27. A 26-year-old homeless man has a TB skin test of

15 mm induration. He has no symptoms but his
chest X-ray shows a left upper lobe infiltrate.
A. Yes
B. No
2279
Additional Recommendations for

Treatment of Latent Tuberculous
Infection
• INH for 9 months is preferred therapy. Alternatives:

• INH for 6 months;
• Rifampin for 4 months
• INH + rifapentine once weekly for 3 months
• Routine laboratory monitoring not indicated, with

certain exceptions: HIV infection; pregnancy;
chronic liver disease; or regular alcohol use.
None.
2280
Women’s Neurology
Mary Angela O’Neal, M.D.

Assistant Professor, Department of Neurology, Harvard Medical School
Director of the Women’s Neurology Program
Director of the Neurosciences clinic
Disclosures
2281
Objectives
Use Cases to:

• Discuss gender specific neurological concerns
• Review the pathophysiology of the neurologic

disorder as it relates to gender
• Describe treatment specific concerns for
women with neurologic disease
MS, Migraine, Stroke in pregnancy, Eclampsia &
Stroke Risk Factors in Women
Women’s Life Cycle
Menarche Pregnancy Menopause
Multiple Sclerosis
Migraine
Alzheimer's
Dementia
Stroke
2282
Women’s Life Cycle
Menarche Pregnancy Menopause
Eclampsia
Stroke
Issues to discuss when caring for Women in their

Reproductive years
Family planning
Discussion of medication risks in pregnancy
Effects of pregnancy on the underlying

disease
Effects of the underlying disease on

pregnancy
2283
FDA Pharmaceutical Pregnancy Categories
A Adequate and well controlled human studies have failed to demonstrate a risk to the
fetus in the first trimester of pregnancy ( and there is no risk in later trimesters).
B Animal reproduction studies have failed to demonstrate a risk to the fetus and there
are no adequate and well controlled studies in pregnant women OR Animal studies have
shown an adverse effect, but adequate and well-controlled studies in pregnant women
have failed to demonstrate a risk to the fetus in any trimester.
C Animal reproduction studies have shown an adverse effect on the fetus and there
are no adequate and well-controlled studies in humans, but potential benefits may
warrant use of the drug in pregnant women despite potential risks.
D There is positive evidence of human fetal risk based on adverse reaction data from
investigational or marketing experience or studies in humans, but potential benefits
may warrant use of the drug in pregnant women despite potential risks
X Studies in animals or humans have demonstrated fetal abnormalities and/or there
is positive evidence of human fetal risk based on adverse reaction data from
investigational or marketing experience, and the risks involved in use of the drug in
pregnant women clearly outweigh potential benefits
Reproductive Health and Pregnancy Concerns
• Multiple Sclerosis
• Migraine
2284
Case 1
A 28 year old women with

relapsing remitting MS
who has stable disease.
She is on interferon beta-
1b and an oral
contraceptive.
She wants to get pregnant.
Questions
• What should I do about my medication?
• How will pregnancy effect my MS?
• What if I have a relapse?
• Is it safe for me to breast feed?
2285
Immuno- FDA Drug Half Fetal and maternal risks Secretion in breast milk
modulating Class Life
agents
C 10 hours
Interferon β-1-b Spontaneous abortions in animals. not seen in
Minimal
and β-1-a humans
B 7 hours
Glatiramer acetate None reported Minimal
C 25 - 32
Intravenous
days Probably safe in pregnancy Unknown
immunoglobulin
Fingolimod C 6-9 days Teratogenicity seen in animals and humans. No Avoid in lactation
specific pattern observed.
Dimethyl Fumarate C 1 hour increased spontaneous abortion in animals. Not Avoid in lactation
reported in humans
Teriflunomide X 18-19 days Teratogenicity seen in animals; precursor leflunomide Avoid in lactation
is a known human teratogen. No malformations in
humans observed thus far.
Daclizumab C 20 days Embryofetal deaths observed in animals with early Avoid in lactation
exposure. No fetal malformations in humans observed
thus far.
Natalizumab C 7-15 days Yes (at supratherapeutic doses in primates). Transient Avoid in lactation
hematologic abnormalities in late pregnancy exposure
in humans.
Alemtuzumab C 12 days Animals. No human malformations seen, but thyroid Avoid in lactation
monitoring necessary for mother throughout
pregnancy. No evidence for spontaneous abortion or
birth defects.
Rituximab/ C 22 days/26 Animals. No human malformations seen; transient B- Avoid in lactation

days cell depletion in human neonates following pregnancy
Ocrelizumab
exposure
Immune System and Pregnancy
Low Estrogen
MS
Th1 IL-2
IFN
LT
Th
Th2 IL-4
High Estrogen
IL-5
IL-6
IL-10
2286
Multiple Sclerosis Relapse Rate

Annual RR P value
Year before pregnancy 0.7 --
First trimester 0.5 0.03
Second trimester 0.6 0.17
Third trimester 0.2 <0.001
1-3 months postpartum 1.2 <0.001
4-6 months postpartum 0.9 0.17
Breastfeeding
Who’s at risk?
Effects of breast feeding
Exclusive breastfeeding and the risk of postpartum relapses in women with multiple sclerosis.
Arch Neurol 2009 Aug;66(8):958-63.
Exclusive Breast feeding and the Effect on Postpartum Multiple Sclerosis Relapse. JAMA Neurol 2015 OCT:1132-1138
2287
Reproductive Health and Pregnancy Concerns
MS
Migraine
Case 2
A 23 year old women with migraine without aura

is now 8 weeks pregnant. Her migraines had been
well controlled with sumatriptan.
She’s now having her usual headaches with nausea

and vomiting 2-3 times a week.
2288
Treatment
A. Continue the sumatriptan
B. Have her take acetaminophen
C. Try caffeine and metoclopramide
D. Give her oxycodone
2289
Migraine during Pregnancy
60-70 % migraines undergo remission
Small percent of new onset migraine during

pregnancy
Increased risk of preeclampsia/ eclampsia
Migraine Treatment in Pregnancy
Planning
Symptomatic therapy
Other
2290
Symptomatic Therapies
Generic Name Level of Risk in Breastfeeding- Hale
Pregnancy Lactation Rating
Acetaminophen B L1
B (D in 3rd trimester) L1-L2

NSAIDS
Metoclopramide B L2
Prochlorperazine C L3
Dihydroergotamine X L4
Magnesium A (D) L1
Triptans C L3
Preventative Medications
Drug Class Generic Name Level of Risk in Breastfeeding
Pregnancy
Beta- blockers Atenolol D Caution

Propranolol C (D at term) Compatible
Gabapentin C Compatible
Antiepileptics Topiramate D Caution
Valproate X Caution
C Compatible
Tricyclics Amitriptyline
2291
Triptans and Pregnancy
Data from the Sumatriptan/Naratriptan Pregnancy

Registry
Data from Norwegian Mother and Child Cohort
Migraine and Lactation
Triptans considered safe
Several Preventative drugs also

safe
LactMed
2292
Pregnancy Related Disorders
Ischemic Stroke
Eclampsia
Case 3
A 28-year-old woman G2P1 at 30 weeks gestation

was last seen well at 10 am. She was found on the
ground not speaking or moving her right side at
10:50 am.
On initial exam at noon, she was mute with left
gaze deviation and dense right hemiplegia.
NIHSS* was 15.
2293
How should you treat this lady?
What imaging is most appropriate?
A. Head CT/ CTA Neck and Brain
B. Brain MRI, Vessel Imaging
Radiation Exposure
DETERMINISTIC EFFECTS
2294
Radiation Exposure
STOCHASIC EFFECTS
Imaging
Neuroimaging can be performed safely
MRI versus CT
Gadolinium is avoided
2295
2296
Use of IV t-PA in Pregnancy
Use of IA t-PA in Pregnancy
2297
Causes of Ischemic Stroke in Pregnancy
Cardiac emboli
Dissection
Pre-eclampsia/ Eclampsia
Coagulopathy
Cerebral Venous Thrombosis
Reversible Cerebral Vasoconstriction Syndrome
Other
Pregnancy Related Disorders
Ischemic Stroke
Eclampsia
2298
Case 4
A 35 year old woman G1 P0 at 31 and 5/7 weeks of

gestation was woke with a severe headache. She
began seeing visual spots, and a half hour later she
completely lost her vision.
Shortly thereafter, she developed the worst

headache of her life and blacked out. At the
outside hospital her blood pressure was 170/120.
She was transferred to our hospital.
Red Flags
• Change in headache character or pattern
• Headaches with characteristics of elevated ICP
• New headaches
• Associated with elevated BP
• Unusually severe headache
• Abnormal neurologic exam
• Headaches associated with systemic disorders
2299
Frequency and Headache Type by Trimester
Migraines
Idiopathic Intracranial Hypertension
Preeclampsia/Eclampsia
Post Dural Puncture Headache
Cerebral Venous Thrombosis
First Trimester Second Trimester Third Trimester Postpartum
Pre-eclampsia/Eclampsia Definition
Diagnosed when a pregnant woman develops

High blood pressure (two separate readings taken
at least six hours apart of 140 or more in systolic
blood pressure and/or 90 or more in diastolic
blood pressure)
300 mg of protein in a 24-hour urine sample
(proteinuria
Onset of seizures and change in mental status
defines eclampsia
2300
Pathogenesis of Eclampsia
Pre-eclampsia/ Eclampsia
PEE is associated with both significant maternal

and fetal morbidity and mortality
Maternal complications include abruption
placentae, disseminated coagulopathy, acute renal
failure, stroke, hemorrhage, death and long term
cardiovascular morbidity
Fetal complications include premature delivery,
low birth weight, hypoxic neurologic injury, and
death.
2301
Maladaptation to placental
implantation
Axial Flair MRI
2302
Treatment of Eclampsia
• Blood Pressure control

– Labetalol
• Magnesium Sulfate
– Prevention of progression from preeclampsia to
eclampsia and eclamptic seizures
Lucas et al. A comparison of magnesium sulfate and phenytoin for the prevention of eclampsia.
N Engl J Med 1995;333:201–5.
Postmenopausal Health
Stroke
2303
Case 5
A 76 year old woman with a PMH of DM has new

onset atrial fibrillation. She does not smoke and
drinks 1-2 alcoholic beverages a week. She has never
had a TIA or stroke. She is normotensive and not
overweight.
What gender specific questions should be asked?
What is her stroke risk?
Stroke in Women
Third leading cause

of death
Incidence
2304
Pregnancy complications and long term

stroke risk
Gestational diabetes
Preeclampsia/Eclampsia
Pregnancy induced hypertension
Preeclampsia and stroke risk in later life

Study date Total no. of Design OR - 95% CI
subjects
Lykke-2009 782,287 Retrospective cohort 1.36-1.66 (1.29-2.14)
Funai- 2005 37,061 Retrospective cohort 3.07 (2.18-4.33)
Kestenbaum- 2003 124,141 Case control study 2.53 (1.70-3.77)
Irgens- 2001 626,272 Retrospective cohort Preterm PE 5.0

(2.09-12.35)
2305
Atrial Fibrillation
Female sex is an independent predictor of stroke in

patients with AF
Higher risk in older women than men
2306
Women’s Issues in Neurology- expected take home points
Reproductive Health & Pregnancy MS, Migraine

Concerns
Pregnancy Ischemic Stroke, Eclampsia
Postmenopausal Stroke
Health
2307
Headache
Carolyn Bernstein M.D. FAHS
Asst. Professor of Neurology, Harvard Medical School
Associate Neurologist, Brigham and Women’s Hospital
Dr. Bernstein receives research

support from Palmer Chiropractic, and
consults for Amgen.
2308
Goals
• Understanding of diagnosis of common types
of headaches
• “red flag” recognition
• Work-up
• Treatment, medication and integrative
therapies
• Preparedness for board questions
According to article in The Telegraph ,

average attention of humans has fallen
to 8 seconds, less than a goldfish
2309
What is a headache?
• Full Definition of HEADACHE
• 1: pain in the head
• 2: a vexatious or baffling situation or
problem <meetings had become a
giant headache — Franklin Foer>
Primary vs. Secondary

• Idiopathic • “secondary” to
• Non-structural underlying disease
• Rule-out diagnosis • Tumor
• Aneursym
• Infection
• inflammatory
2310
Psychogenic headache
• Nice summary by Dr. Elizabeth Loder on HCNE
website
• Headache which is associated with psychiatric
origin
• Psychiatric disease may co-exist with other
primary and secondary headaches
Office evaluation of headache—

the essentials
• How long
• Where on head
• Quality of pain
• Positional
• Nausea, vomiting
• Photophobia/phonophobia
• Dizziness, vertigo
• Focal neurologic symptoms, especially visual
• Duration
• Degree of disability
• Family history
2311
Red Flags
“first or worst”
New and different
LOC
Focal signs
Increasingly worse
ecology
International Headache Society

Criteria
• Website at the end of talk
• Very specific organization
• Clearly defined criteria
• Useful to refer
• Lots of esoterica
2312
Focus on Primary
Location, location, location
2313
Migraine
• Unilateral
• Minimum four hours
• Throbbing pain
• Moderate to severe intensity
• Photo/phono
• Nausea or vomiting
• At least five events
Migraine with aura

• At least two attacks
• Fully reversible symptoms
• More than 5 and less than 60 minutes
• Speech, sensory or visual
2314
Cortical spreading depression—wave of depolarization
2315
Other migraine variants

• Menstrual
• “complicated”
• Hemiplegic
• Chronic
Tension Type Headache

“hatband headache”
• Ten episodes
• Bilateral
• Pressing/tightening
• Mild to moderate
• 30 min to 7 days
• Variants—infrequent/frequent/chronic
• No nausea or vomiting
• Sound or light sensitivity
2316
Chronic daily headache—

what is it?
TACs
• SUNCT
• SUNA
• Cluster
• Hemicrania
2317
SUNCT
• This syndrome is characterised by short-
lasting attacks of unilateral pain that are much
briefer than those seen in any other TAC and
very often accompanied by prominent
lacrimation and redness of the ipsilateral eye.
• 5 to 240 seconds, occuring multiple times/day
SUNA
• Attacks of unilateral orbital, supraorbital or
temporal stabbing or pulsating pain lasting
from 2 seconds to 10 minutes
2318
Cluster
Clint Eastwood Headache?
15-180 minutes
Unilateral pain, very severe, same distribution
Tearing/rhinorhea/injection/ipsi hydrosis
Meosis/ptosis
Cluster sufferers pace, migraine patients lie in

the dark with ice
hemicrania
• 2 to 30 minutes
• Indomethacin responsive
• Side-locked
2319
When to image and what to order

• Red flags
• Focal symptoms
• Age
• Positional
• Choosing Wisely article for patients
CT vs. MRI
CT Scan—blood, bone MRI
• Trauma • Acute neurologic changes
• ? SAH • ? Stroke
• Acute neurologic changes • Hydrocephalus, IIH
• ? Tumor
• ? Infection
• Imaging of posterior fossa
2320
Ask the clinical question

CALL THE RADIOLOGIST
CADASIL
• Cerebral autosomal dominant arteriopathy
with sub-cortical infarcts
• Inherited, notch 3 gene mutation
• Migraines and multiple strokes progressing to
dementia
• Cognitive deterioration, seizures, psychiatric
problems
• Genetic testing is available
2321
Syndrome
Call-Fleming Syndrome
• Can last for weeks
• Thunderclap headaches
• Focal neurologic signs
• Seizures
• Many potential triggers
2322
Labs, other tests

• Case specific—arteritis, lyme, infection
• EEG—change in LOC, odd aura
• Cardiac work-up—syncope with headache
2323
Treatment
Medication vs integrative
• Evidence-based • Evidence-based
• How to monitor • Safety
• Ecology • Cost
• Patient preference • Patient preference
2324
Guidelines--
• AAN 2012 Migraine is excellent
• Start low and titrate up for preventives
• “minimal effective dose”
• Review contraception if indicated
• Abortives--stratify
Migraine
• Antihypertensives
• Anticonvulsants
• Antidepressants
• antispasmodics
• Onabotulinum toxin
• CGRP monoclonal antibodies!!!

Newly approved, target molecule or receptor
2325
abortives
• Triptans--formulations
• Ergots—potential for side effects
• Anti-inflammatories
• Anti-nausea
• Little or no role for narcotics/barbiturates
hormonal
• ? Estrogen/progesterone formulations
• Role of HRT
2326
TTH
• All off-label
• Antidepressants
• Anticonvulsants
• Antispasmodics
• Anti-inflammatories
TACS
• Indomethacin—for hemicrania
• Triptans
• Calcium-channel blockers
• Steroids
• ?lithium
2327
procedures
• Nerve blocks
• Trigger point injections
• Onabotulinum toxin
• Transcranial magnetic stimulation
• ? Migraine surgery
Migraine headband—FDA approved
2328
Integrative therapies
• Yoga
• Mindfulness
• Tai Chi
• Herbs
• Vitamins/supplements
• Nutrition
• Acupuncture
• massage
Apps for tracking

• Iheadache
• My migraine
• migrainebuddy
2329
Case One
• Jane, age 24, grad student
• No medical problems besides headache
• Occurs several times/month
• Throbbing pain, usually behind her right eye
• Preceded by floating wedge shape that glows and
crosses from one side to the other
• Needs dark and quiet room when it happens
• Usually occurs one day before period and mid-
cycle
Diagnosis?
• Migraine with aura
• Menstrual migraine
• TIA
• Tension-type headache
2330
How would you treat?

• Continuous combined oral contraceptive
• Trial of topiramate
• Abortive plan: triptan plus NSAID
• OTC
Case Two
• Ashley, age 19, college student
• Throbbing pain over forehead and under eyes
• Worse with movement
• Light bothers her
• Slight nausea
• Runny nose, some tearing
• Very anxious about school, headaches, life
2331
Diagnosis?
• Sinus headache
• Migraine without aura
• Tension-type headache
Headache attributed to Rhinosinusitis

• Diagnostic criteria: Frontal headache accompanied by pain
in one or more regions of the face, ears or teeth and
fulfilling criteria C and D. Clinical, nasal endoscopic, CT
and/or MRI imaging and/or laboratory evidence of acute
or acute-on-chronic rhinosinusitis1;2Headache and facial
pain develop simultaneously with onset or acute
exacerbation of rhinosinusitis. Headache and/or facial
pain resolve within 7 days after remission or successful
treatment of acute or acute-on-chronic rhinosinusitis.
• Notes: Clinical evidence may include purulence in the
nasal cavity, nasal obstruction, hyposmia/anosmia and/or
fever. Chronic sinusitis is not validated as a cause of
headache or facial pain unless relapsing into an acute
stage.
2332
How would you treat?

• Preventive med
• Antibiotics
• Nasal spray
• Biobehavioral therapies
Case Three
• Tom, age 53, no headache history
• Wakes up at 4 a.m. at least half the month
with dull headache
• Pain lasts at least 15 minutes, some occasional
nausea associated
• NSAIDS are not helpful
• No autonomic symptoms
2333
Diagnosis
• Cluster
• Migraine
• Tumor
• Aneurysm
• Other
Treatment?
• Verapamil
• Lithium
• Amitryptilene
• coffee
2334
Case Four
• Christine, age 42
• Works in an office
• Frequent headache of minor to moderate
severity but annoying
• Band around her head, neck pain
• Mild phonophobia, no other symptoms
• Has been present for years
• Exam is normal other than paracervical trigger
points
Diagnosis?
• Migraine without aura
• Chronic Daily headache
• Episodic Tension-type headache
• Chronic Tension-type headache
2335
How to treat Christine

• Physical therapy
• Amitryptilene
• Muscle relaxants
• Exercise/yoga therapies
• psychotherapy
Case Five
• Anna, age 51
• Pain on top of head in very focal area, circular,
about 4 cm
• Present almost all the time
• Irritated by combing/brushing hair and
washing
• Mild to moderate severity
2336
Diagnosis
• Vasculitis
• Migraine
• Tumor
• Skin lesion
• Nummular headache
How to treat?
• Gabapentin
• Amitryptilene
• Topiramate
• clonazepam
2337
Case 6
• 47 yo woman with migraine with both visual
and sensory aura
• Never had previous complications
• Getting married
• Placed on birth control patch by her PCP for
contraception
• No FH
• Leg cramps first—”muscle spasm”

• Shortness of breath
• Right body weakness
2338
Poor outcome
• Migraine with aura
• Father had coagulopathy—Factor 5 Leiden
thrombophilia—had a number of strokes and
an MI before the age of 50
• ? Other types of birth control
• Maintained on warfarin—had persistent
increased intracranial pressure headache plus
migraines
2339
Case 7
• Hannah, college student, age 19, LH
• Occasional throbbing headache, has
scintillations followed by pain
• Studying animal science, goes to Zambia for a
semester
• Arrives on a hot day to rural village and goes
running
• Can’t see to the left

• Left arm and face tingling
• Unable to talk
• Throbbing excruciating headache 30 minutes
later
2340
TRANSFERRED TO LUSAKA
• Given some medication intravenously

• Process cleared
• Had a few headaches with scintillations after
• Came to see me about three months after

arriving home
2341
• Ecology—was on estrogen containing birth

control
• Really hot and had not been drinking much
water…
What happened?
What would you recommend?
2342
Websites
• http://www.headaches.org/pdf/MIDAS.pdf
• http://www.americanheadachesociety.org/
• http://www.headaches.org/
• http://www.achenet.org/
• http://itunes.apple.com/us/app/headache-
diary-lite/id309227463?mt=8
• http://www.ncbi.nlm.nih.gov/pubmed/22671
714
2343
Update is Ischemic Stroke
Director of the Division of Neurocritical Care
Psychiatry Overview
Department of Neurology
Assistant Professor of Neurology
I have no conflicts of interest
2344
Outline
Epidemiology
Definitions of TIA
Imaging (which type is best)
New time standard in catheter based treatment
Cardiac Echo
2345
Stroke in the US
• 795 000 people experience a new or
recurrent stroke.
– Approximately 610 000 of these are
first attacks, and 185 000 are recurrent
attacks.
• 137 000 stroke deaths annually in
the United States.
• Leading cause of serious, long-term
disability
• Third leading cause of death in the U.S.;
second leading cause worldwide
• Second-leading cause of hospital
admission among older adults
Stroke. 2011;42:849-877
Estimated Outcomes After

Ischemic Stroke
70%
Estimated %
60% Low
60%
Percentage With O utcom e
53% High
50%
40% 40% 40%

34%
30%
25% 24%
20%
10%
0%
5-yr stroke 5-yr stroke Functional Dementia at
disability (complete
recurrence mortality or partial 52 mo
dependence)
Estimated Outcomes
Adapted with permission from Sacco RL. Neurology. 1997;49(5 suppl 4):S39.
2346
Original Article
Five-Year Risk of Stroke after TIA or Minor
Ischemic Stroke
Pierre Amarenco, M.D., Philippa C. Lavallée, M.D., Linsay Monteiro Tavares, B.S.T.,
Julien Labreuche, B.S.T., Gregory W. Albers, M.D., Halim Abboud, M.D., Sabrina
Anticoli, M.D., Heinrich Audebert, M.D., Natan M. Bornstein, M.D., Louis R.
Caplan, M.D., Manuel Correia, M.D., Geoffrey A. Donnan, M.D., José M. Ferro, M.D.,
Fernando Gongora-Rivera, M.D., Wolfgang Heide, M.D., Michael G. Hennerici, M.D.,
Peter J. Kelly, M.D., Michal Král, M.D., Hsiu-Fen Lin, M.D., Carlos Molina, M.D., Jong
Moo Park, M.D., Francisco Purroy, M.D., Peter M. Rothwell, M.D., Tomas
Segura, M.D., David Školoudík, M.D., Ph.D., P. Gabriel Steg, M.D., Pierre-Jean
Touboul, M.D., Shinichiro Uchiyama, M.D., Éric Vicaut, M.D., Yongjun Wang, M.D.,
Lawrence K.S. Wong, M.D., for the TIAregistry.org Investigators
N Engl J Med
Volume 378(23):2182-2190
June 7, 2018
Study Overview/Conclusions
• In a follow-up to a 1-year
study involving patients who
had a TIA or minor stroke,
the rate of cardiovascular
events including stroke was
6.4% in the first year and
6.4% in the second through
fifth years.
2347
Prevalence of Ischemic Stroke

88%
of all strokes
are
ischemic
Ischemic Stroke
88% Intracerebral
Hemorrhage
9%
Subarachnoid
Hemorrhage
3%
American Heart Association. Heart Disease and Stroke Statistics—2005 Update. 2005.
Common Causes – Not a single

disease
•Atherothrombosis •Cardiac source
– Large-vessel – Atrial fibrillation
• Extracranial – Dilated cardiomyopathy
• Aortic
• Cervical ICA •Nonatherosclerotic
• Cervical CCA arteriopathies, eg:
• Intracranial – Vasculitis
• ICA – Migraine
• MCA
• Vertebral artery •Prothrombotic disorders
• Basilar artery
– Small vessel
• Lacunar
Helgason CM et al. Circulation. 1997;96:701-707.
2348
Risk Factors for Stroke

Modifiable Nonmodifiable
•Hypertension •Age
•Diabetes
•Cardiac disease •Gender
•Atrial fibrillation •Race/ethnicity
•TIA/prior stroke •Heredity
•Metabolic syndrome
•Dyslipidemia
•Cigarette smoking
•Alcohol abuse
•Obesity
•Physical inactivity
•Carotid stenosis
Goldstein L et al. Circulation. 2001;103:163-182.

Broderick J et al. Stroke. 1998;29:415-421.
Brown WV. Clin Cornerstone. 2004;6 Suppl 3:S30-S34.
2349
INTERSTROKE: Population-attributable
risk for common risk factors
Risk factor Population-attributable
risk, % (99% CI)
Hypertension 34.6 (30.4–39.1)

Smoking 18.9 (15.3–23.1)
Waist-to-hip ratio (tertile 2 vs tertile 1) 26.5 (18.8–36.0)
Dietary risk score (tertile 2 vs tertile 1) 18.8 (11.2–29.7)
Regular physical activity 28.5 (14.5–48.5)
Diabetes 5.0 (2.6–9.5)
Alcohol intake 3.8 (0.9–14.4)
Cardiac causes 6.7 (4.8–9.1)
Ratio of apolipoprotein B to A1 24.9 (15.7–37.1)
(tertile 2 vs tertile 1)
Psychological factors
•Stress 4.6 (2.1–9.6)
•Depression 5.2 (2.7–9.8)
*For the protective factor of physical activity, the population-attributable risks are provided for individuals who
do not participate in regular physical activity.
O'Donnell MJ et al. Lancet 2010; available at: http://www.thelancet.com.
Sleep Apnea
• OSA increased stroke rate 2-5x

• Prevalence of OSA in patient with
stroke/TIA up to 70%
• Screening
– Sleep questionnaire
– Nocturnal polysomnographic diagnostic testing
2350
Sleep Apnea
Epworth Sleepiness Scale
0=would never doze or sleep
1=Slight chance Chance of Dozing or Sleeping
2=Moderate chance Sitting and reading
3=High chance Watching TV
Sitting inactive in a public area
Being a passenger in a motor vehicle
for an hour or more
Sitting and talking to someone
Sitting quietly after lunch (no alcohol)
Stopped for a few minutes in traffic
while driving
Total score: up to “9” WNL
Prevalence of Stroke by Age

14
12
% of population
10 Men
8 Women
6
4
2
0
20–24 25–34 35–44 45–54 55–64 65–74 75+
Age range (years)
AHA. Heart Disease and Stroke Statistics—2015 Update.
2351
Total Number of Elderly by Age

Group: 1900 to 2050
Millions
80
60
40 65 or older
20 85 or older
0
1900 1950 2000 2050
Projected
Note: data for the years 2000 to 2050 are middle-series projections of the population.
Reference population: these data refer to the resident population.
US Census Bureau. Decennial Census Data and Population Projections, 2003.
Transient Ischemic Attacks

(TIAs)
Historic Definition
Temporary focal brain or retinal
deficits caused by vascular
disease that resolve within 24
hours
2352
New Definition of TIA
TIA is a brief episode of

neurologic dysfunction caused
by focal brain or retinal ischemia,
with clinical symptoms typically
lasting less than one hour, and
without evidence of acute
infarction
N Engl J Med, Vol. 337, Nov 21, 2002, 1713-1717.
Stroke, Vol 37, 2006, 577-617.
Stroke. 2009;40:2276.
Short-term Prognosis after

Emergency Department Diagnosis of TIA
30.0%
Inclusion criteria: TIA by ED physicians
25.1%
Outcome events Objective: Short-term risk of stroke
25.0% after ED diagnosis
Outcome
Measures: Risk of stroke and other
20.0% events during the 90
days
after index TIA
15.0% 12.7%
10.5% Johnston SC. et al. JAMA 2000;
10.0% 284: 2901-2906
5.0% 2.6% 2.6%
0.0%
Total Stroke Recurrent CV event Death
TIA
2353
ABCD2 of TIA
• Patients with TIA score points for each of the following factors:
• Age 60 years (1 point)
• Blood pressure 140/90 mm Hg on first evaluation (1 point)
• Clinical symptoms of focal weakness with the spell (2 points) or

speech impairment without weakness (1point)
• Duration 60 minutes (2 points) or 10 to 59 minutes (1 point)
• Diabetes (1 point).
• 2-day risk of stroke:

• 0% for scores of 0 -1
• 1.3% for 2 -3
• 3, 4.1% for 4-5
• 8.1% for 6-7 Stroke. 2009;40:2276.
Admit to the Hospital?
• Reasonable to hospitalize patients with TIA

if they present within 72 hours of the event
and any of the following criteria are
present:
–ABCD2 score of 3 or greater
–ABCD2 score of 0-2 and uncertainty that

diagnostic workup can be completed within
2 days as an outpatient
Stroke. 2009;40:2276.
2354
Working up TIA
• Neuroimaging evaluation within 24 hours of symptom

onset.
• MRI, including DWI, is the preferred brain
diagnostic imaging modality.
• Noninvasive imaging of the cervicocephalic vessels

should be performed routinely as part of the evaluation
• Noninvasive testing of the intracranial vasculature

reliably excludes the presence of intracranial stenosis
• Patients with suspected TIA should be evaluated as

soon as possible after an event
• ECG/ECHO/Holter Stroke. 2009;40:2276
Imaging approach to acute

stroke
• Four P’s
– Parenchyma
• Assess early signs of acute stroke
• Rule out haemorrhage
– Pipes
• Assess extracranial circulation (carotid & vertebral) and
intracranial circulation for evidence of intravascular thrombus
– Perfusion
• Assess Cerebral blood volume (CBV), Cerebral blood flow (CBF)
and Mean transit time (MTT)
– Penumbra
• Assess tissue at risk of dying if ischemia continues without
recanalization of intravascular thrombus
2355
Evaluation of Tissue Status:

Noncontrast Head CT
Advantages Disadvantages
• Almost universally •Often normal in

available hyperacute phase
• Rapid •Insensitive to lacunar

and posterior fossa
• High sensitivity for strokes
detection of
hemorrhage (100%
ICH, 90% SAH)
Evaluation of Tissue Status:

Multimodal MRI (including DWI)
Advantages •Disadvantages
– More sensitive to – Not universally
acute ischemia available
– More sensitive to – Longer scanning time

posterior fossa lesions
– Patient
– More sensitive to contraindications (e.g.
small vessel, lacunar pacemaker)
lesions
2356
MRI - Tissue Status: Ischemia
CT
DWI
Evaluation of Vessel Status

1. CT Angiography
2. MR Angiography
3. Ultrasound Techniques
4. Catheter Angiography
2357
CT Angiography
•Requires injection of intravenous contrast
agent
•New generation helical scanners allow rapid

evaluation of aortic arch, neck, and intracranial
vessels with 1 injection
•80-100% accuracy compared with catheter

angiography
•Disadvantages: iodinated contrast agent,

radiation exposure
CTA: Carotid Stenosis
2358
CTA: MCA Stenosis
MR Angiography
•Noninvasive means to evaluate neck and intracranial
vessels
•Time of flight technique may overestimate stenoses
•Not reliable in identifying distal or branch

intracranial occlusions
•Sensitivity and specificity 70-100% compared to

catheter angiography
•Power-injector, contrast-enhanced techniques –

increased sensitivity
•Subject to limitations of standard MRI
2359
MR Angiography
Neck MRA: Right Intracranial MRA:

Carotid Stenosis Left ICA Occlusion
Evidence-based guideline: The role of diffusion and

perfusion MRI for the diagnosis of acute ischemic stroke
• DWI should be considered superior to

noncontrast CT scan for the diagnosis of
acute ischemic stroke in patients
presenting within 12 hours of symptom onset
(Level A).
• There is insufficient evidence to support or
refute the value of PWI in diagnosing acute
ischemic stroke (Level U).
• Baseline DWI volume should be considered
useful in predicting baseline clinical
stroke severity and final lesion volume
in anterior-circulation stroke syndromes (Level
B).
NEUROLOGY 2010;75:177-185
2360
Role of CT in Acute stroke –

CT perfusion imaging
• MTT perfusion map is the most sensitive indicator of
stroke
• CBF and CBV more spicific in distinguishing ischemia from
infarction
MTT CBF CBV
2361
CT vs MRI in acute stroke

• CT is widely available and fast
–Noncontrast CT, CT angiography and CT
perfusion can be performed in under 15
minutes
–Superior to MRA in evaluating the vessels
• Less artefacts and better quantification of
lesions
• MRI stroke protocol takes longer
–Conventional MRI, DWI, MRA and PWI
–No radiation
–Can be performed without contrast
• Arterial spin labelling, time-of-flight
• The two modalities are equally useful for
evaluating acute stroke
–Equivalent depiction of the penumbra
Whics scan to order?

• Office practice MRI/MRA
• In ED and symptomatic CT/CTA
• In ED and asymptomatic MRI/MRA
• When there is a consideration of

thrombolysis IV/IA Either
• IV TPA < 4.5 hours CT is min.
2362
Acute Ischemic Stroke:

ASA/AAN/ACCP Guidelines
• Pharmacotherapies
– tPA (tissue plasminogen activator) within 3 hours of stroke
onset
– Aspirin for acute stroke (within 48 hours of symptom onset):

160 to 325 mg/day) (Grade 1A) to reduce stroke mortality and
decrease morbidity; ONLY if no contraindications or if patient
will not be given rtPA1
– Heparin and low molecular weight heparin (LMWH): not

indicated and may increase bleeding complications;
– LMWH and heparinoids may be considered for DVT

prophylaxis in at-risk patients1
• Early consultation by neurologist or stroke team critical2

1. Coull BM et al. Stroke. 2002;33:1934-1942.
2. Adams HP et al. Stroke. 2003;34:1056-1083.
IV tPA, the “Gold Standard”

• Systemic “Clot Buster”
• FDA Approved for the treatment of AIS in 1996
• Only 8% of ischemic stroke patients are eligible
for IV tPA
• Narrow time window
*Non FDA-Approved Therapies
• Risk of cerebral and systemic hemorrhage
• Achieves early reperfusion in only 13-50% of
large vessel occlusions
National Institute of Neurological Disorders and Stroke rt-PA Stroke Study Group. Tissue plasminogen activator for acute ischemic stroke. N Engl J Med.
1995;333:1581-1587. Kleindorfer DO, Broderick JP, et al. Emergency department arrival times after acute ischemic stroke during the 1990s. Neurocrit Care.
2007;7(1):31-5. del Zoppo GJ, Poeck K, Pessin MS, et al. Recombinant tissue plasminogen activator in acute thrombotic and embolic stroke. Ann Neurol
1992;32:78-86. 6. Bhatia R, Hill MD, Shobha N, et al. Low rates of acute recanalization with intravenous recombinant tissue plasminogen activator in ischemic
stroke: realworld experience and a call for action. Stroke 2010;41:2254-8.
2363
Meta-analysis Shows a Strong Correlation Between

Revascularization and Good Patient Outcomes
70%
60% 58.1%
50%
% of Patients
41.6%
40%
30% 24.8%
20% 14.4% 13.7% 12.5%

10%
0%
Good Outcome 90-Day Mortality SICH *
(mRS 0-2)
Revascularized Non-revascularized
*Differences in sICH were not statistically significant between the
revascularized and non-revascularized groups
Rha JH, Saver JL. The impact of recanalization on ischemic stroke outcome:
a meta-analysis. Stroke. 2007 Mar;38(3):967-73.
35-40% of Ischemic Strokes are Considered

“Large Vessel”
• This subset of ischemic stroke comprises blockages in the:
– Internal Carotid Artery (ICA)
– Middle Cerebral Artery (MCA)
– Vertebral / Basilar Artery
• Patient prognosis with these types of stroke is poor
Vessel Mortality Rate

ICA 53%1
MCA 27%2
Basilar Artery 89-90%3
1. Jansen O, et al.
2. Furlan A et al. PROACT II Trial
3. Brückmann H et al.
2364
Turning Point
The Era of Stent-Retrievers
Technological advances
• Stent-retriever technology for safe, reliable performance
• Significant improvement in revascularization and patient

outcomes vs older technology, proven in randomized
clinical trials*
*Non FDA-Approved Therapies
Trial Summary
mRS 0-2
Imaging Required TICI 2b/3
to Confirm Device(s) Used in Revascularization
Trial Intervention Control Odds Ratio
Occlusion Prior to Intervention Arm Rate in the
Randomization? Intervention Arm Arm Arm (95% CI)
IA Lytic (138), Merci 38% ICA

0.02
Retriever® (95), EKOS 44% M1 40.8% 38.7%
IMS III No (-0.06 to
(22), Penumbra (54), 44% M2 (N=415) (N=214)
0.09)
Solitaire FR (5) 23% multi M2
24% pen 21% pen 26% pen
Merci Retriever®,
(n=34) (n=34) (n=34)
MR RESCUE No EKOS, IA Lytic, NS
27% nonp 17% nonp 10% nonp
Penumbra
(n=30) (n=30) (n=20)
97% Stent
33% 19% 2.16
MR CLEAN Yes Retrievers, 2% other 58.7% (N=196)
(N=233) (N=267) (1.39-3.38)
Mechanical
72.4% 53.0% 29.3% 1.8

ESCAPE Yes 86% Stent Retriever
(n=156) (n=164) (n=147) (1.4-2.4)
88.0% 60.2% 35.5% 2.75
SWIFT PRIME Yes 100% Stent Retriever
(n=83) (n=98) (n=93) (1.53,4.95)
86.2% 71% 40% 4.2
EXTEND-IA Yes 100% Stent Retriever
(n=29) (n=35) (n=35) (1.3-13)
2365
Goal of Ischemic Stroke Treatment

Before Intervention
After Successful Intervention
2366
Original Article
Thrombectomy 6 to 24 Hours after Stroke with a
Mismatch between Deficit and Infarct
Raul G. Nogueira, M.D., Ashutosh P. Jadhav, M.D., Ph.D., Diogo C. Haussen, M.D.,
Alain Bonafe, M.D., Ronald F. Budzik, M.D., Parita Bhuva, M.D., Dileep R.
Yavagal, M.D., Marc Ribo, M.D., Christophe Cognard, M.D., Ricardo A. Hanel, M.D.,
Cathy A. Sila, M.D., Ameer E. Hassan, D.O., Monica Millan, M.D., Elad I. Levy, M.D.,
Peter Mitchell, M.D., Michael Chen, M.D., Joey D. English, M.D., Qaisar A.
Shah, M.D., Frank L. Silver, M.D., Vitor M. Pereira, M.D., Brijesh P. Mehta, M.D.,
Blaise W. Baxter, M.D., Michael G. Abraham, M.D., Pedro Cardona, M.D., Erol
Veznedaroglu, M.D., Frank R. Hellinger, M.D., Lei Feng, M.D., Jawad F.
Kirmani, M.D., Demetrius K. Lopes, M.D., Brian T. Jankowitz, M.D., Michael R.
Frankel, M.D., Vincent Costalat, M.D., Nirav A. Vora, M.D., Albert J. Yoo, M.D., Ph.D.,
Amer M. Malik, M.D., Anthony J. Furlan, M.D., Marta Rubiera, M.D., Amin
Aghaebrahim, M.D., Jean-Marc Olivot, M.D., Wondwossen G. Tekle, M.D., Ryan
Shields, M.Sc., Todd Graves, Ph.D., Roger J. Lewis, M.D., Ph.D., Wade S.
N Engl JM.D.,
Smith, M.D., Ph.D., David S. Liebeskind, Med Jeffrey L. Saver, M.D., Tudor G.
Jovin, M.D.,Volume 378(1):11-21
for the DAWN Trial Investigators
January 4, 2018
Study Overview
• Among patients with occlusion of a

large intracerebral vessel who had
a clinical deficit that was
disproportionately severe relative to
the infarct volume, 90-day
outcomes for disability were better
with late thrombectomy plus
standard care than with standard
care alone.
2367
Imaging Inclusion Criteria:

• < 1/3 MCA territory involved, as evidenced
by CT or MRI
• Occlusion of the intracranial ICA and/or
MCA-M1 as evidenced by MRA or CTA
• Clinical Imaging Mismatch (CIM) defined as
one of the following on MR-DWI or CTP-rCBF
maps:
– 0-<21 cc core infarct and NIHSS ≥ 10 (and age
≥ 80 years old)
– 0-<31 cc core infarct and NIHSS ≥ 10 (and age
< 80 years old)
– 31 cc to <51 cc core infarct and NIHSS ≥ 20
(and age < 80 years old)
Distribution of Scores on the Modified Rankin Scale at 90 Days.
Nogueira RG et al. N Engl J Med 2018;378:11-21
2368
Subgroup Analyses of the First Primary End Point.
Nogueira RG et al. N Engl J Med 2018;378:11-21
• For every 100 patients treated with

endovascular therapy, 49 will have a
less disabled outcome as a result of
treatment, including 36 who will be
functionally independent.
2369
Conclusions
• Among patients with acute stroke

who had last been known to be well
6 to 24 hours earlier and who had a
mismatch between clinical deficit
and infarct, outcomes for disability
at 90 days were better with
thrombectomy plus standard care
than with standard care alone.
PHANTOM-S: The Pre-Hospital Acute Neurological Therapy and

Optimization of Medical Care in Stroke Patients - Study "PHANTOM-S"
Lancet Neurol. 2012 May;11(5):397-404. doi: 10.1016/S1474-

4422(12)70057-1. Epub 2012 Apr 11.
2370
Telestroke
• AAN and ASA are supporters of
bipartisan legislation which was
recently introduced in Congress, the
Furthering Access to Stroke
Telemedicine (FAST) Act (H.R. 2799).
• This bipartisan bill expands access to

stroke telemedicine (also called
“telestroke”) treatment in
Medicare. Similar legislation (S.1465)
has been introduced in the Senate.
Lowering Blood Pressure
2371
ASA Treatment Guidelines: Ischemic Stroke Not

Eligible for Thrombolytic Therapy
BP Level
Treatment
(mm Hg)
SBP <220
OR No treatment unless end-organ involvement
DBP <120
SBP >220
OR Nicardipine or labetalol to 10% -15% ↓ in BP
DBP <121-140
DBP >140 Nitroprusside to 10% -15% ↓ in BP
ASA = American Stroke Association; IS = ischemic stroke; SBP = systolic blood pressure; DBP = diastolic blood pressure.
Adams HP, et al. Stroke. 2007;38:1655-1711.
ASA Treatment Guidelines: Ischemic Stroke

Eligible for Thrombolytic Therapy
BP Level (mm Hg) Treatment

Pretreatment Labetalol (may repeat once), nitropaste, or
SBP >185 or nicardipine
DBP >110 If BP not reduced and maintained,
do not administer rt-PA
During and after
rt-PA
SBP 180-230
OR Labetalol
DBP 105-120
SBP >230
Nicardipine or labetalol
OR
If BP not controlled, consider nitroprusside
DBP 121-140
rt-PA = recombinant tissue plasminogen activator.
Adams HP, et al. Stroke. 2007;38:1655-1711.
2372
Blood Pressure and Stroke

What to Conclude
• All studies support detection and aggressive treatment of
blood pressure for both primary and secondary
prevention
• Reduction of stroke by 35%-40% possible1
• Thiazide-type diuretic recommended as first therapeutic

agent1
• ACEI and ARBs are more effective in reducing
progression of renal disease and are recommended as
first-choice medications for patients with diabetes
1. Chobanian AV et al, and the National High Blood Pressure Education Program Coordinating Committee.
JAMA. 2003;289:2560-2572.
2. Stroke, Vol 37, 2006, 577-617.
3. Schrader J. Stroke. 2003;34:1199-1703.
Antiplatelets
2373
In patients with a history of noncardioembolic ischemic

stroke or TIA, we recommend long-term treatment with:
• Aspirin (75-100 mg once daily)

• Clopidogrel (75 mg once daily)
• Aspirin/extended-release dipyridamole (25 mg/200 mg
bid)
• Cilostazol (100 mg bid)
Over
• No antiplatelet therapy (Grade 1A)
• Oral anticoagulants (Grade 1B)
• Combination of clopidogrel plus aspirin (Grade 1B)
• Triflusal (Grade 2B)
CHEST. 2012;141(2_suppl):1S-1S. doi: 10.1378/chest.1412S1
Which antiplatelet is better?

• Of the recommended antiplatelet regimens, we
suggest clopidogrel or aspirin/extended
release dipyridamole over aspirin (Grade 2B)
or cilostazol (Grade 2C)
• Remarks: With long-term use (> 5 years), the

benefit of clopidogrel over aspirin in
preventing major vascular events may be
offset by a reduction in cancer-related
mortality with regimens that contain aspirin.
CHEST. 2012;141(2_suppl):1S-1S. doi: 10.1378/chest.1412S1
2374
Original Article
Clopidogrel with Aspirin in Acute Minor Stroke or
Transient Ischemic Attack
Yongjun Wang, M.D., Yilong Wang, M.D., Ph.D., Xingquan Zhao, M.D., Ph.D., Liping
Liu, M.D., Ph.D., David Wang, D.O., F.A.H.A., F.A.A.N., Chunxue Wang, M.D., Ph.D.,
Chen Wang, M.D., Hao Li, Ph.D., Xia Meng, M.D., Ph.D., Liying Cui, M.D., Ph.D.,
Jianping Jia, M.D., Ph.D., Qiang Dong, M.D., Ph.D., Anding Xu, M.D., Ph.D., Jinsheng
Zeng, M.D., Ph.D., Yansheng Li, M.D., Ph.D., Zhimin Wang, M.D., Haiqin Xia, M.D., S.
Claiborne Johnston, M.D., Ph.D., for the CHANCE Investigators
N Engl J Med
Volume 369(1):11-19
July 4, 2013
Primary objective of the CHANCE trial
• To assess the efficacy of a 3-month regimen of

clopidogrel-aspirin (300 mg load followed by
75 mg/day) vs. aspirin alone on reducing the 3-
month risk of new stroke (ischemic or
hemorrhagic) when initiated within 24 hours of
symptom onset in patients with high-risk TIA
or minor stroke.
N Engl J Med Volume 369(1):11-19 July 4, 2013
2375
CHANCE trial
• Age ≥ 40 years;
• Either:
Non-disabling ischemic
stroke(NIHSS≤3), or
TIA with moderate-to-high risk of
stroke recurrence (ABCD2 score ≥ 4).
• Study drug can be given within 24 h of

symptom onset.
2376
CHANCE Trial Summary

• TIA and minor ischemic stroke are a treatable
emergency
• Clopidogrel with a 300 mg load plus aspirin reduces

subsequent stroke risk compared to aspirin alone.
• Clopidogrel-aspirin is safe in this setting with no

increase in bleeding.
• Even more aggressive interventions after acute TIA

and minor stroke may be indicated but require clinical
trials.
2377
O r i g i na l A r t i c l e
Clopidogrel and Aspirin in Acute Ischemic Stroke and High-Risk

TIA
S. Claiborne Johnston, M.D., Ph.D., J. Donald Easton, M.D., Mary
Farrant, M.B.A., William Barsan, M.D., Robin A. Conwit, M.D.,
Jordan J. Elm, Ph.D.,
Anthony S. Kim, M.D., Anne S. Lindblad, Ph.D., and Yuko Y.
Palesch, Ph.D., for the Clinical Research Collaboration,
Neurological Emergencies Treatment Trials Network, and the
ABSTRPOINT
ACT Investigators
BACKGROUND
Combination antiplatelet therapy with clopidogrel and aspirin may reduce the rate of recurrent stroke during
the first 3 months after a minor ischemic stroke or transient ischemic attack (TIA). A trial of combination
antiplatelet therapy in a Chinese population has shown a reduction in the risk of recurrent stroke. We tested
this combination in an international population.
METHODS
In a randomized trial, we assigned patients with minor ischemic stroke or high-risk TIA to receive either
clopidogrel at a loading dose of 600 mg on day 1, followed by 75 mg per day, plus aspirin (at a dose of 50 to 325
mg per day) or the same range of doses of aspirin alone. The dose of aspirin in each group was selected by the
site investigator. The primary efficacy outcome in a time-to-event analysis was the risk of a composite of major
ischemic events, which was defined as ischemic stroke, myocardial infarction, or death from an ischemic
vascular event, at 90 days.
RESULTS
A total of 4881 patients were enrolled at 269 international sites. The trial was halted after 84% of the
anticipated number of patients had been enrolled because the data and safety monitoring board had
determined that the combination of clopidogrel and aspirin was associated with both a lower risk of major
ischemic events and a higher risk of major hemorrhage than aspirin alone at 90 days. Major ischemic events
occurred in 121 of 2432 patients (5.0%) receiving clopidogrel plus aspirin and in 160 of 2449 patients (6.5%)
receiving aspirin plus placebo (hazard ratio, 0.75; 95% confidence interval [CI], 0.59 to 0.95; P=0.02), with
most events occurring during the first week after the initial event. Major hemorrhage occurred in 23 patients
(0.9%) receiving clopidogrel plus aspirin and in 10 patients (0.4%) receiving aspirin plus placebo (hazard ratio,
2.32; 95% CI, 1.10 to 4.87; P= 0.02).
CONCLUSIONS
In patients with minor ischemic stroke or high-risk TIA, those who received a combination of clopidogrel and
aspirin had a lower risk of major ischemic events but a higher risk of major hemorrhage at 90
1
days than those
n e ngl j med nejm.org
who received aspirin alone. (Funded by the National Institute of Neurological Disorders and Stroke; POINT
ClinicalTrials.gov number, NCT00991029.)
A Primary Efficacy
Outcome
10
100
90 9
8
80
7 Aspirin
6.5
70
Patients with Event (%)
6
60 Clopidogrel plus aspirin 5.0
5
50 4
40 3
No. of Patients No. with Event
2 Aspirin 2449 160
30 Clopidogrel plus Aspirin 2432 121
1 Hazard ratio, 0.75 (95% CI, 0.59–
20 0.95) P=0.02
0
0 7 30 76 90
10
0
0 7 30 76 90
Days since Randomization
No. at Risk
Aspirin 24492269 2153 2105 1365
Clopidogrel plus aspirin 24322279 2178 2113 1445
BPrimary Safety Outcome: Major Hemorrhage

100 10
9
90
No. of Patients No. with Event
8 Aspirin 2449 10
80 Clopidogrel plus Aspirin 2432 23
7
Hazard ratio, 2.32 (95% CI, 1.10–
70 4.87) P=0.02
6
Patients with Event (%)
60 5
50 4
3
40
2
30 Aspirin Clopidogrel plus aspirin
1 0.9
20 0.4
0
0 7 30 76 90
10
0
0 7 30 76 90
Days since Randomization
No. at Risk
Aspirin 2449 2372 2271 2230 1448
Clopidogrel plus aspirin 2432 2336 2256 2192 1505
Figure 2. Primary Efficacy and Safety Outcomes.

Shown are the percentages of patients with the primary efficacy outcome (a composite of ischemic stroke, myocardial
infarction, or death from ischemic vascular causes) (Panel A) and the primary safety outcome of major hemorrhage (Panel
B). Inset graphs show the same data on an expanded y axis.
n e ngl j med nejm.org 7

The New England Journal of Medicine
Downloaded from nejm.org by GALEN HENDERSON on June 13, 2018. For personal use only. No other uses without permission.
Copyright © 2018 Massachusetts Medical Society. All rights reserved.
2378
Effect of statins on all strokes, fatal

stroke, and hemorrhagic stroke
Studies Relative risk

reduction
All stroke (total) 0.82 (0.77–0.87)
•All stroke (primary-prevention studies) 0.81 (0.75–0.87)
•All stroke (secondary prevention: SPARCL, HPS, LIPID, 0.88 (0.78-0.99)
and CARE)
Fatal stroke (total) 0.87 (0.73–1.03)
•Fatal stroke (primary-prevention studies) 0.90 (0.76–1.05)
•Fatal stroke (secondary prevention: SPARCL) 0.59 (0.36–0.97)
Hemorrhagic stroke (total) 1.03 (0.75–1.41)
•Hemorrhagic stroke (primary-prevention studies) 0.81 (0.60–1.08)
•Hemorrhagic stroke (secondary prevention: SPARCL 1.73 (1.19–2.50)
and HPS)
Amarenco P, Labreuche J. Lancet Neurol 2009; 8:453-463.
SPARCL
Effects of High-dose Atorvastatin After
Stroke or TIA
Placebo
Stroke or TIA (%)
Atorvastatin 80 mg qd
HR, 0.77 (95% CI, 0.67–0.88); P<0.001
Years Since Randomization

No. at Risk
Atorvastatin 2365 2148 2023 1933 1837 871 119
Placebo 2366 2132 1998 1871 1780 803 126
SPARCL=Stroke Prevention by Aggressive Reduction in Cholesterol Levels.

SPARCL Investigators. N Engl J Med. 2006;355:549-559.
2379
ACC/AHA Guidelines for the Treatment of Blood

Cholesterol in Primary Prevention
• Recommendations based on the 10

year risk for cardiovascular disease
• Shifts away from specific cholesterol
goals
• Estimated risk dictates intensity of
statin Rx: high risk mandates high
intensity statin Rx
• Atorvastatin 10 mg is moderate
intensity statin Rx and 40 t0 80 mg is
high intensity
• 10 year Risk calculator
Brain Attack Coalition

Types of Stroke Care Centers
• Primary Stroke Centers • Comprehensive Stroke
Center
– The primary stroke center
stabilizes and provides – The comprehensive stroke
emergency care to acute center provides complete
stroke patients. care to patients
experiencing the most
– Primary stroke centers complex strokes that
ultimately transfer patients require specialized testing
to a comprehensive stroke and other interventions.
center or admit patients for
further care, based on level – These centers typically
of need. include tertiary care
centers or hospitals with
appropriate infrastructure.
2380
Primary Stroke Center vs. Comprehensive

Stroke Center
Component Primary Stroke Center Comprehensive Stroke Center
Education Community, EMS, & 1 hr Nursing/Staff Education Increased Community, EMS Nursing/Staff Education; Referring hospital teaching
Performance Measures Ischemic Stroke focus of 10 quality measures Ischemic + Hemorrhagic Stroke measurement and reporting + 56 other elements of data
Patient Care Follow-up N/A Patient call within 7 days of discharge

Modified ranking scall for all intervention patients 90-days post discharge
Patient satisfaction data collection
Stroke Research N/A Patient centered stroke research w/ IRB approval

Participation from advanced practice nurse
Volume Requirements N/A 20 Aneurysm cases annually

15 endovascular procedures annually
25 tPA patients annually
Ultrasound, angiography, CT, Ultrasonography,

Advanced Imaging Access to Imaging MR/MRA, TCD, TEE/TTE
Stroke Director, Emergency MD, Neuro-

Stroke Director, Program Manager, access to Interventionalist, Neuroradiologist, CV
MD Staffing Neurology and Neurosurgery neurosurgeon, vascular surgeon
Doctorate-prepared NP with leadership,

Advances Practice Nursing N/A education, and research responsibilities
Dedicated Neuro-ICU, IR suite to accommodate

two complex stroke patients; EMS coordination
Other Assets/Resources N/A and documentation
Questions for the future

• Which out-of-hospital stroke scale to use for identifying large
artery occlusions?
• Would telemedicine directed by a remote stroke physician be

a better triage technique?
• Should primary stroke centers be bypassed to transport

patients to comprehensive centers, even if it means delaying
the start of intravenous tissue plasminogen activator (tPA)?
• How much delay in bypass is acceptable?
• Would a mobile stroke unit with computed tomographic
2381
Impact of PROTECT pilot phase on

Treatment Rates at Discharge
Pre PROTECT
100
90
P 80
e 70
r 60
c 50
e 40
n 30
t 20
10
0
Antithrombotic Statin ACEI/ARB Thiazide
--Ovbiagele et al, Stroke 2003
2382
Evidence of Better Outcomes in

Stroke Centers
• Stroke unit trialists’ collaboration meta-analysis
– OR death: 0.82 (0.69, 0.98)
– OR death/inst: 0.76 (0.64, 0.90)
– OR death/dep: 0.71 (0.61, 0.84)
• In-hospital death less frequent in facilities with

vascular neurologist; adjusted OR=0.49, P<0.0001
• Trend toward fewer deaths in facilities with dedicated

stroke team available by pager
• JCAHO credentialing of stroke centers ensures that

patients receive proper care
– www.jointcommission.org/
Indredavik B, et al. Stroke. 1999;30:917-923. Goldstein LB, et al. Neurology. 2003;61:792-796.
Indredavik B, et al. Stroke. 1997;28:1861-1866. Alberts MJ, et al. JAMA. 2000;283:3102-3109.
Indredavik B, et al. Stroke. 2000;31:2989-2994. Gillum LA, et al. Stroke. 2001;32:2137-2142.
Work-up of TIA and Ischemic Stroke

All Patients •Lipids
•Brain Imaging
•Neurovascular Selected Patients
imaging – Hepatic functions
•Blood glucose – Toxicology
•Serum electrolytes – Blood alcohol level
•CBC w/ Platelets – Pregnancy
•PT/PTT/INR – Hypercoagulable w/u
•12 lead EKG/ROMI – EEG
•Holter monitoring – LP
•TTE/TEE
•Supplemental O2
•Fever reduction
2383
Original Article
Atrial Fibrillation in Patients with Cryptogenic
Stroke
David J. Gladstone, M.D., Ph.D., Melanie Spring, M.D., Paul Dorian, M.D., Val
Panzov, M.D., Kevin E. Thorpe, M.Math., Judith Hall, M.Sc., Haris Vaid, B.Sc., Martin
O'Donnell, M.B., Ph.D., Andreas Laupacis, M.D., Robert Côté, M.D., Mukul
Sharma, M.D., John A. Blakely, M.D., Ashfaq Shuaib, M.D., Vladimir Hachinski, M.D.,
D.Sc., Shelagh B. Coutts, M.B., Ch.B., M.D., Demetrios J. Sahlas, M.D., Phil
Teal, M.D., Samuel Yip, M.D., J. David Spence, M.D., Brian Buck, M.D., Steve
Verreault, M.D., Leanne K. Casaubon, M.D., Andrew Penn, M.D., Daniel
Selchen, M.D., Albert Jin, M.D., David Howse, M.D., Manu Mehdiratta, M.D., Karl
Boyle, M.B., B.Ch., Richard Aviv, M.B., Ch.B., Moira K. Kapral, M.D., Muhammad
Mamdani, Pharm.D., M.P.H., for the EMBRACE Investigators and Coordinators
N Engl J Med
Volume 370(26):2467-2477
June 26, 2014
Study Overview
• In this study, patients with

cryptogenic stroke who were
randomly assigned to undergo
intensive ECG monitoring for 30
days had a higher incidence of
detected atrial fibrillation (16%)
than those assigned to receive
standard 24-hour monitoring (3%).
2384
Incremental Yield of Prolonged ECG Monitoring for the Detection of Atrial Fibrillation in
Patients with Cryptogenic Stroke or TIA.
Gladstone DJ et al. N Engl J Med 2014;370:2467-2477
Conclusions
• Among patients with a recent cryptogenic

stroke or TIA who were 55 years of age or
older, paroxysmal atrial fibrillation was
common.
• Noninvasive ambulatory ECG monitoring for

a target of 30 days significantly improved the
detection of atrial fibrillation by a factor of
more than five and nearly doubled the rate of
anticoagulant treatment, as compared with
the standard practice of short-duration ECG
monitoring.
2385
Discharged with:
•Blood pressure control
–Diabetics ACEI/ARBs
•Antiplatelets
•Statins
•Lifestyle changes
2386
Summary
Epidemiology
Definitions of TIA
Imaging (which type is best)
New time standard in catheter based treatment
Cardiac Echo
I have no conflicts of interest
2387
Question 1
Mr. Jones has 3 hours of sudden onset
dysarthria and arm/hand weakness
and then symptoms completely
resolve.
Is this a:
A. Stroke
B. TIA
C. RIND
D. Complicated migraine
Answer to Question 1
• Then answer is A.
• The definition of TIA is < 1 hour and

negative imaging
• Reversible ischemic neurologic deficit

is no longer a valid term
• Migraine symptoms are not sudden
2388
Question 2
What is the most practical cerebral
imaging study within 3 hours of
stroke signs and symptoms?
A. CT of brain
B. CT of brain/CT angiogram of head
and neck
C. MRI of brain
D. MRI of brain/MRA of head and neck
• The answer is B.
• CT/CTA scans seem to to be the most

practical cerebral imaging study in the
EDs, ICUs, and for other inpatients.
2389
Question 3
Mr. Jones 83 years old right handed
male has a NIHSS of 12, had a
witnessed onset of his stroke and is
within 2 hours with a neg. CT
A. Too old to consider to give TPA

B. Give ASA only
C. If there are no protocol exclusions,
give TPA
D. Give Clopidogrel only
• The answer is C.
• In giving IV TPA within 3 hours, there

is no age cutoff.
• ASA or Clopedigril should be given

ASAP only if the patient is not a TPA
candidate
2390
Question 4
Which is the most appropriate
antiplatelet therapy for
noncardioembolic stroke?
A. Aspririn
B. Clopidogrel
C. Asp/dyp combination
D. Asp/Clopidogrel
E. Any listed above
• The answer is E.
• Ischemic stroke is a very

heterogeneous disease and the
treatment regimen depends on the
etiology of the patient’s ischemic
event.
2391
Question 5
How do I workup the patient with the
diagnosis of TIA?
A.Cardiac Echo
B.EKG/Holter
C.Brain imaging (CT or MRI)
D.Vascular imaging (CTA or MRA)
E.All of these above
• The answer is E.
• Echo to r/o PFO and to evaluate

ejection fraction.
• EKG and Holter to r/o Afib.
• We always need brain imaging and

neurovascular imaging
2392
Thank you for your Attention
2393
Seizure Disorders
Tracey A. Milligan, MD, MS, FAAN

Distinguished Clinician
Psychiatry Overview
Vice Chair for Education
Edward B Bromfield Epilepsy Center
Department of Neurology
Assistant Professor of Neurology
No Disclosures
2394
Epilepsy is Common: 1 in 26
Diagnosis US Prevalence US New Cases/yr
Migraine 28 million
Alzheimer’s Dementia 5.4 million 454,000
Stroke 4.4 million 700,000
Epilepsy 3.4 million 300,000 / 200,000

Parkinson’s disease 500,000 50,000
Multiple sclerosis 400,000 10,000
https://www.cdc.gov/epilepsy/data/index.html
Definitions
• Seizure: the clinical

manifestation of an
abnormal and excessive
excitation of a population
of cortical neurons
• Epilepsy: a tendency
toward recurrent seizures
unprovoked by systemic or
neurologic insults
2395
Symptomatic Seizures
• Close temporal relationship to
acute brain injury
or
• Simultaneously due to metabolic,
toxic, infections, inflammatory
process
• Clinically and on EEG look like

epileptic seizures (typically GTC)
• Different pathogenesis, therapy,
prognosis
Organ Dysfunction
Cardiac
• focal seizures from cardioembolic stroke
• generalized tonic-clonic or nonconvulsive or
myoclonic seizures from global cerebral ischemia
after cardiac arrest
Renal
• Common in acute uremia
• 7-10 days after onset of renal failure
• Typically bilateral tonic-clonic, but can be focal
• Uncommon in chronic renal insufficiency
• Treat by correcting metabolic abnormalities and
blood pressure if hypertensive encephalopathy
• Increased risk with penicillin
Hepatic
• Uncommon in acute hepatic encephalopathy and
chronic liver disease
• Check for hypoglycemia as a cause
• Acute intermittent porphyria – frequently
associated with seizures and epilepsy
2396
• Alcohol dependence:
10.2% among excessive
drinkers (>8 drinks per
week in 30 days) and
10.5% among binge
drinkers (>4 drinks per
occasion
• 50% will experience
symptoms of
alcohol withdrawal
upon reduced
alcohol intake
• 2 million episodes of
ETOH withdrawal per year
in US
• 5-10% of
patients have a
seizure
• 8% of all patients
Alcohol Withdrawal admitted to the hospital
• 16-31% of patients in ICU
Seizures • Up to 31% of trauma
patients
Uusaro A, Parviainen I, Tenhunen JJ, et al. The proportion of intensive care unit admissions related to
alcohol use: a prospective cohort study. Acta Anaesthesiol Scand. 2005;49:1236-1240
The Alcohol Withdrawal Syndrome
Victor, M. & Adams, R.D. Res Publ Assn Nerv Ment Dis 32, 526-573 (1953).
2397
Alcohol Withdrawal
Seizures
Typically occur after years of drinking
and multiple episodes of withdrawal.
Onset 12-48 after last drink
Generalized tonic-clonic
Multiple, within 6 hours
Post-ictal drowsiness < 1 hour
Treat with benzodiazepine or
barbiturate (dosed by CIWA)
Victor and Brausch; Epilepsia 1967; 1-20
Antibiotics
• Unsubstituted penicillins
• 4th generation
cephalosporins
(cefepime)
• Imipenem
• Ciprofloxacin
• In combination with
renal dysfunction, brain
lesions and epilepsy
• Isoniazid (pyridoxine
deficiency – treat with
B6 and benzodiazepine)
2398
Bupropion
• Incidence is correlated with dose
o Incidence is 0.4% at doses of 300-450mg/day
but increases by 100 fold in doses > 600 mg/day
o Sustained release formulation has lower
incidence due to lower peak plasma
concentrations
o By comparison
-0.1% with SSRIs
- 0.4-2 % with TCAs
• Anorexia and bulimia further increase the risk
(a randomized trial in which bupropion was
given to 55 nondepressed presents induced a
GTC in 4 patients – 7 percent).
Davidson J J Clin Psyciatry 1989
Sodium
• Hyponatremia
• Symptoms relate to rate
of change rather than
absolute value
• Hypernatremia
Electrolyte • Seizure may occur during
rehydration
Abnormalities Calcium
• Hypocalcemia
• Focal seizures in 20% of
patients, accompanied by
altered mental status and
tetany
• Hypercalcemia
• Infrequently causes
seizures
Magnesium
• Hypomagnesemim (< 0.8
mEq/L)
• Multifocal and generalized
seizures
2399
Conceptual Definition of Epilepsy
Epilepsia, 46(4):470-472, 2005

Blackwell Publishing, Inc. © 2005 International League Against Epilepsy
Epileptic Seizures and Epilepsy: Definitions Proposed By the International

League Against Epilepsy (ILAE) and the International Bureau for Epilepsy
(IBE).
Fisher RS, van Emde Boas W, Blume W, Elger C, Genton P, Lee P, Engel J Jr.
Epilepsy is a disorder of the brain characterized by an enduring predisposition

to generate epileptic seizures, and by the neurobiologic, cognitive,
psychological, and social consequences of this condition. The definition of
epilepsy requires the occurrence of at least one epileptic seizure.
ILAE OFFICIAL
REPORT
Epilepsy is a disease of the brain defined by any of the following conditions
1. A least two unprovoked (or reflex) seizures occurring >24 h apart
2. One unprovoked (or reflex) seizure and a probability of further seizures similar to
the general recurrence risk (at least 60%) after two unprovoked seizures, occurring
over the next 10 years
3. Diagnosis of an epilepsy syndrome
Epilepsy is considered to be resolved for individuals who had an age-dependent epilepsy syndrome but
are now past the applicable age or those who have remained seizure-free for the last 10 years, with no
seizure medicines for the last 5 years. Can Dx and Tx for Epilepsy after
ONE seizure
2400
Classification System
• Designed to provide greater diagnostic specificity
for treatment and research
• Change in terminology used to describe seizure
type and to describe etiology
2401
Instruction manual for the ILAE 2017 operational classification of seizure types
Epilepsia
8 MAR 2017 DOI: 10.1111/epi.13671
http://onlinelibrary.wiley.com/doi/10.1111/epi.13671/full#epi13671-fig-0002
ILAE classification of the epilepsies: Position paper of the ILAE Commission for
Classification and Terminology
Epilepsia
8 MAR 2017 DOI: 10.1111/epi.13709
http://onlinelibrary.wiley.com/doi/10.1111/epi.13709/full#epi13709-fig-0001
2402
Case 1: Status Epilepticus
• 36 y.o. man with a PMH of a penetrating head injury 10 years

previously resulting in behavioral and cognitive deficits
• While having dinner with his mother he has a “fit” and has 2
seizures later that night
• He does not receive treatment and 3 months later has a severe
seizure
• He receives treatment, but he continues to have seizures and
dies 2 days later
Status Epilepticus
Treatment
Bloodletting
2403
The year is 1860

The patient is Phineas Gage
Status epilepticus
• 30 minutes of either:
– Continuous seizure activity
– Repetitive seizures without recovery in between
Epilepsy Foundation of America –
JAMA 1993
• 5 minutes or more of continuous clinical and/or electrographic

seizure activity or recurrent seizure activity without recovery
between seizures
Brophy, Gretchen M., et al. "Guidelines for the evaluation and management of
status epilepticus." Neurocritical care 17.1 (2012): 3-23.
2404
How do you treat Status Epilepticus?
Use algorithm
Lowenstein, DH, Alldredge, BK Status Epilepticus

N Engl J Med 1998 338: 970-976
2405
Status Epilepticus Pearls
• A seizure lasting 5 minutes is a medical emergency

• Treat while looking for cause
• Faster treatment is more effective treatment
• 1st line benzodiazepine
• 2nd line fosphenytoin
2406
Case 2: Epilepsy in the Elderly
A 75 year old woman is brought to the physician for episodes of

confusion. She has weekly episodes of feeling unwell and staring
into space for 30-60 seconds followed by mild confusion. She
has a history of hypertension, tobacco use and was recently
diagnosed with lung cancer. Her examination is normal. Which of
the following is the most likely diagnosis?
A. Generalized seizure disorder

B. Focal motor seizure
C. Dementia
D. Psychogenic non-epileptic seizure
E. Absence seizure
F. Focal seizure with impaired awareness
Classification System: 2 Seizure Categories
Focal Generalized
originate within originate at some
networks limited point within, and
rapidly engaging,
to one bilaterally distributed
hemisphere (may networks (can include
be discretely cortical and
localized or more subcortical structures,
but not necessarily
widely include the entire
distributed) cortex)
2407
Videos
Generalized Absence Seizures (=Petit Focal Impaired Awareness (=Complex
Mal) Partial)
• Children • Can occur at any age
• Easily controlled • 2/3 controlled
• EEG shows generalized spike wave • EEG shows focal discharges
discharges • MRI is required, may be abnormal
• MRI is normal • Variable prognosis
• Excellent prognosis
Focal impaired awareness evolving to bilateral convulsions
2408
Seizure Classification
Focal Generalized
Focal Aware Focal Impaired

Awareness
(simple partial)
(complex partial)
Evolve to bilateral convulsions
And others
Absence Tonic Clonic Myoclonic (clonic, tonic,
atonic)
International League Against Epilepsy (ILAE)

Idiopathic Genetic
Symptomatic
Structural/Metabolic
Cryptogenic
Generalized and Focal will not apply
to electroclinical syndrome
FOCAL = network limited to 1
hemisphere
GENERALIZED = bilaterally
distributed networks
2409
Practice Guidelines
• EEG - after a first seizure an EEG should be
considered as part of the routine
neurodiagnostic evaluation because it has
substantial yield and has value in determining
risk of seizure recurrence (Level B).
• Neuroimaging - brain imaging using CT or

MRI should be considered as part of the
neurodiagnostic evaluation of adults
presenting with an apparent unprovoked first
seizure (Level B).
AAN Practice Parameter 2007
Which of the following are true?
A. A normal EEG excludes the diagnosis of epilepsy

B. The EEG will show generalized seizure activity
C. Focal slowing on the EEG helps to localize the anatomic origin
of the seizures
D. A normal MRI excludes seizures as a diagnosis
2410
EEG
• Assess for epileptiform discharges (30%,

increases to 80-90% with 3 EEGs)
• Help diagnose presence, type, and location
of epilepsy
• Negative EEG does not rule out epilepsy
• Sleep deprived EEG more sensitive
(increase yield by 30%)
• EEG after spell or seizure is more sensitive
(51% vs 30%)
• Extended monitoring: video EEG or
ambulatory EEG
MRI in New-Onset Seizures

• 77% of 993 Consecutive patients in a 1st seizure
clinic (14-94 yoa) had an MRI
– 28% had potentially epileptogenic lesions (1/2 gliosis or
encephalomalacia) (1/2 developmental abnormalities,
vascular, tumors, MTS)
• Highest in those with focal seizures (53%) (p < 0.001)
– Gliosis or Encephalomalacia (49%)
– Tumors (15%)
– Cavernomas (9%)
– MTS (9%)
• Only 16% of those with potentially epileptogenic lesions
had epileptiform EEG abnormalities
Hakami T, et al. Neurology 2013
– 22% had other MRI abnormalities unrelated to seizures
2411
Late-onset epilepsy
Common Causes
Cerebrovascular disease >50%
Neurodegenerative disease 10-20%
Intracerebral tumors 10-30%
Traumatic brain injury 20%
Brodie et al, Lancet Neurol 2009; 8: 1019–30
Age and Etiology of Epilepsy
When etiology is known:

Older Adults (>60 years)
Adapted from Hauser WA. Epilepsia. 1992;33(suppl 4):S6-S14.
2412
Many Antiepileptic Drugs (AEDs)

Older Medications Newer Medications
(1st Generation) (2nd Generation)
Year Trade FDA Trade
Generic Name Generic Name
Introduced Name Approval Name
Bromides 1857 —
Felbamate 1993 Felbatol®
Gabapentin 1993 Neurontin®
Phenobarbital 1912 Luminal®
Lamotrigine 1994 Lamictal®
Phenytoin Sodium 1956 Dilantin® Topiramate 1996 Topamax®
Ethosuximide 1960 Zarontin® Tiagabine 1997 Gabitril®
Diazepam 1963 Valium® Levetiracetam 1999 Keppra®
Carbamazepine 1968 Tegretol®
Oxcarbazepine 2000 Trileptal®
Zonisamide 2000 Zonegran®
Lorazepam 1977 Ativan® Pregabalin 2005 Lyrica®
Valproic acid 1978 Depakene® Lacosamide 2008 Vimpat®
Divalproex 1983 Depakote® Rufinamide 2008 Banzel®
sodium
Ezogabine 2011 Potiga®
Carbamazepine 1986 Epitol®
Clobazam 2011 Onfi®
Diazepam 1997 Diastat®
Perampanel 2012 Fycompa®
Carbamazepine 1997 Carbatrol®
Eslicarbazepine 2014 Aptiom®
Phenytoin Sodium 1998 Phenytek® Brivaracetam 2016 Briviact®
Many Antiepileptic Drugs (AEDs)
Older Medications Newer Medications

(1st Generation) (2nd Generation)
Trade
Generic Name Generic Name FDA Approval
Name
Gabapentin 1993 Neurontin®

Phenobarbital
Lamotrigine 1994 Lamictal®
Phenytoin Sodium
Topiramate 1996 Topamax®
Carbamazepine Levetiracetam 1999 Keppra®
Oxcarbazepine 2000 Trileptal®

Divalproex sodium
Zonisamide 2000 Zonegran®
Pregabalin 2005 Lyrica®
Lacosamide 2008 Vimpat®
2413
Summary AEDs in the Elderly

• Lamotrigine most effective and tolerable
• Levetiracetam not studied in RCT but seems effective in
retrospective studies
• Oxcarbazepine and Carbamazepine not well tolerated
• General recommendation:
• Slow titration to Lamotrigine to 50mg BID or Levetiracetam to
500mg BID
• Elderly patients tend to achieve seizure control at lower AED
dosages and lower serum AED levels
Buchsbaum et al, Arch Neurol. 2010;67(4):408
A. J. Rowan et al. Neurology 2005;64:1868-1873
Epilepsy in the Elderly- Pearls
• Epilepsy most commonly occurs in the elderly

• New onset epilepsy is focal epilepsy
• EEG and MRI may be normal
• Monotherapy – low dose lamotrigine, levetiracetam,
gabapentin
• Newer AEDs have less side effects and fewer drug-drug
interactions
• Have a high index of suspicion for episodes of altered
awareness, confusion, falls, loss of consciousness
2414
Case 3 – First Seizure?
• Emily is brought to the ED after a witnessed GTC

• She was with a friend at a coffee shop the morning after a
concert
• At the concert, she drank ETOH
• She did not sleep that night
• Her friend noticed jerking movements and then Emily had a
GTC
• Emily feels tired and sore and doesn’t remember anything
• Her examination is normal
After 1 unprovoked seizure: 21%-45% risk of

another in 2 years (especially after the first year)
Lower Risk with AED

Higher Risk
• Decreases AR by 35%
• Prior brain lesion or insult
(2y)
(e.g., stroke or trauma)
• QOL (and risk of harm)
• Epileptiform EEG
may not be affected
• Significant brain-imaging
• Long term px not
abnormality
affected
• Nocturnal seizure
• ADE: 7-31% (usually
mild and reversible)
Treat after second seizure because of higher risk (57% by 1 year and 73% by 4 years)
2415
Syncope vs Seizure vs Psychogenic
2416
Clinical Feature Syncope Seizure
Syncope vs. Seizure

Loss of consciousness Typical Common
Episode duration Seconds Minutes
Involuntary movements Common Typical
Triggers Frequent Rare
nausea, blurred vision, feeling

Preceding Symptoms hot, tinnitus, palpitations sensory, motor, psychic auras
Amnesia for event, Amnesia for event plus confusion,

Post-Ictal somnolence, headache somnolence, headache
EEG Slow waves, flattening Focal or generalized spike-wave
2417
Psychogenic Nonepileptic Seizures
• 10-45% of refractory epilepsy

(referral centers); minority have both NES and ES
• Females>males
• Psychiatric mechanism —
dissociation, conversion, abuse
• Often requires video-EEG monitoring
49
Psychogenic Nonepileptic Seizures
Clinical Feature Psychogenic Nonepileptic Seizures Epilepsy
Trigger Frequent Rare
Onset Often gradual Usually sudden
May stop and stop, pelvic thrusting, back arching, erratic movements Usually synchronized
Movements
and absence of stereotypy and stereotyped
Eyes Closed Open
Lateral tongue bite Rare Common
Self-injury Rare Common
Incontinence Rare Common
Post-ictal confusion Rare Common
Duration lengthy (hours) 1-2 minutes
Serum prolactin usually normal usually elevated
2418
Pseudo-pseudoseizure
(Frontal Lobe Epilepsy)
• When it might be a seizure, but sounds bizarre, think frontal lobe
epilepsy
• Complex behaviors with motor agitation, strong emotional feelings,
repetitive motor activity involving pelvic thrusting, pedaling, thrashing
• Often accompanied by vocalizations or laughter/crying
• Often bizarre and misdiagnosed as psychogenic
• Tend to be frequent and brief, with less post-ictal confusion
• Clues: stereotyped semiology, occurrence during sleep, brief in
duration, abnormal MRI
2419
Self-Reported Symptoms
Less Frequent More Frequent
Syncope PNES Epilepsy

After: I feel drained or sleepy
I want to know what happens when I have blacked out
My attacks come on without any warning
During: I have no idea what is happening around me
After: I feel very upset
After: I feel very confused
In: I feel lightheaded, like I might pass out
After: my muscles ache
My attacks make me feel very low or empty
My attacks come over me
When I feel an attack coming on I try to fight it
In: sounds are distorted
In: my vision goes dim or dark
In: I feel hot or cold
After: I feel relieved
In: I am conscious but I can’t react to things
In: my mouth goes very dry
My attacks are associated with emotional stress
I am aware of a trigger for my attacks
During: my heart pounds and I feel shaky and sweaty
During: I feel very frightened
During: I can see or hear the people around me
My head spins in my attacks
During: I do not recognize my friends or family
In: everything seems to move away from me
Reuber, M et al. 2016. Neurology
1. Was it really a seizure?

(open ended questions, eye-witness, pre- & post-ictal clues)
2. Is it a provoked seizure?
(alcohol or drugs, etc.)
Key 3. Is it the first seizure?

Questions (myoclonus, prior auras, altered awareness, photosensitive)
Guiding 4. Localization/Type of seizure

the
History 5. Cause of seizure
6. Epilepsy syndrome?
2420
Epilepsy Syndromes
• Defined typical characteristics in addition to seizure
type
• Age, location, EEG, treatment, prognosis
• Examples include: Childhood absence epilepsy
(CAE), juvenile myoclonic epilepsy (JME), and
benign rolandic epilepsy (BRE)
• Spectrum of action (broad vs.

narrow)
• Parenteral
Anti-Epileptic administration/loading options
• Pharmacokinetics and drug
Drug (AED) interactions
• Inducers: carbamazepine,
Considerations phenytoin, phenobarbital
• Inhibitors: valproate,
felbamate
• Protein bound: valproate,
phenytoin
• Concomitant disease
• Birth control
Broad Spectrum – use when you don’t • Likely adverse effects

know the type or cause of seizure – • Efficacy
levetiracetam, lamotrigine, valproate, • Cost
topiramate, zonisamide
2421
Idiosyncratic: usually systemic/allergic
• Rashes
• Organ toxicity
AEDs: Dose-related: usually CNS
Adverse • Dizziness, drowsiness, ataxia

• Cognitive slowing, depression (may also be
Effects idiosyncratic)
Chronic: drug-induced diseases
• Osteoporosis
DO NOT START:
Carbamazepine
351% Oxcarbazepine
Phenytoin
increased risk
Lamotrigine
(Eslicarbazepine)
2422
Bone Health
Increased risk of fracture in
Decrease in bone density people with epilepsy
• Phenytoin
• Primidone
• Phenobarbital
• Carbamazepine
• Valproic acid
Significant bone loss in men too

Supplement with vitamin D and more frequent evaluation of bone
mineral density
Neurology 2003; 61: S2-17; Adnress DL et al,
Arch Neurol, 2002
Women With
Epilepsy
OCP’s less effective: phenytoin,
phenobarbital, carbamazepine,
oxcarbazepine, eslicarbazepine,
topiramate
OCP’s lower lamotrigine level and
can cause breakthrough seizures
• Folic acid 1 mg daily
• Check vitamin D level
• Increased risk of osteopenia with
phenytoin, phenobarbital,
carbamazepine, valproate
2423
Teratogenic Risk
Profiles of
Antiepleptic Drugs
Pennell PB. Neurotherapeutics 2016.
Driving
• Epilepsy may account for 0.02% to
0.04% of reported car crashes
• Required seizure-free intervals vary
greatly among jurisdictions (typically
3 to 12 months)
• Mandatory physician reporting:
CA, OR, PA, DE, NV, NJ
• State driver licensing laws available
at
http://www.epilepsyfoundation.org
• Discuss driving with patient and
document in medical record
2424
Start with possibility it was not a

seizure
Look for provoking causes
50% of patients with 1st seizure

1st Seizure have epilepsy
Pearls Family hx, neuro exam, MRI, EEG

are key for prognosis
Start AED in some cases
Counsel regarding safety and no

driving
• No seizure for >5 years

• Favorable factors
• control on one
Discontinuing drug at low dose
• no unsuccessful
AEDs attempts at
withdrawal
• Normal neurologic
exam, EEG,
“benign
syndrome”
• Consider risks/benefits
(e.g. driving,
Epilepsypredictiontools.info pregnancy, job issues)
• Always taper
Lamberink HJ et al. Lancet Neurology 2017; 16(7):523
2425
Other Treatment Options

Laser Ablation Vagus Nerve Stimulation
Responsive Neurostimulation
Cannabidiol
SUDEP: Sudden unexpected

death in epilepsy
• Morbidity and mortality:

• Falls, drowning, co-morbid
conditions
• SUDEP (1/500-1/1000 adults per
year; 1/4500 children per year)
• 27 X that in the general population
and the cause of death in 2-18% of
patients, but less than half of
epilepsy related deaths
• Patients randomized to placebo –
10X more likely to have SUDEP
2426
Depression and
Death
• More than 1 of every 3 people
with epilepsy have depression
• 3-4X risk of suicide
• newly diagnosed (5X),
• hx psychiatric illness (29X)
• Prior suicide attempt -> 5X risk of
subsequent epilepsy
• Substance abuse, psychosis,
bipolar disorder, schizophrenia,
depression independently
associated with new-onset
epilepsy
Leestma et al. Ann Neurol 1989;26(2):195-203 ;Fricker,
1998;Walczak et al. Neurology 2001;56(4):519-525;
Martin et al Epilepsia 2014; Fazel S et al. 2013. Lancet;
382:1646-54
Epilepsy is a common disease with different

causes and manifestations
Other disorders can mimic seizures, including

convulsive syncope and psychogenic seizures
History is key to accurate diagnosis

Summary
of Key Diagnostic studies for all patients: MRI, EEG
Points
There are many therapeutic options
Education and safety issues are important

considerations
2427
Exam question:
• A 36 year old man presents with seizures x 1 day. He has a

history of a penetrating head injury 10 years ago and resultant
behavioral and cognitive disorders. He had his first seizure 3
months ago. He did not receive any treatment. His current
seizure began last night and he has had several seizures
without regaining consciousness. Which of the following is the
best treatment?
A. Lorazepam IV
B. Lorazepam + phenytoin
C. Clonazepam
D. Clonazepam + fosphenytoin
Exam Question 2
• A 29-year-old woman with juvenile myclonic epilepsy comes to

the physician for prepregnancy counseling. Her last seizure
was 8 years ago. She takes levetiracetam 500 mg twice daily
and an oral contraceptive. Which of the following is correct
regarding her management?
• A. Use high estrogen OCP since efficacy is decreased with
levetiracetam
• B. Discontinue AED treatment
• C. Prescribe folate
• D. Advise consideration of adoption given risk of birth defect
2428
• No disclosures
References
• Brophy, Gretchen M., et al. "Guidelines for the evaluation and

management of status epilepticus." Neurocritical care 17.1 (2012):
3-23.
• Krumholz, A., et al. "Practice Parameter: Evaluating an apparent
unprovoked first seizure in adults (an evidence-based review) Report
of the Quality Standards Subcommittee of the American Academy of
Neurology and the American Epilepsy Society." Neurology 69.21
(2007): 1996-2007.
• Meador KJ. To Stop or Not to Stop the AED? Epilepsy Currents.
2008;8(4):90-91. doi:10.1111/j.1535-7511.2008.00250.
• Laxer, Kenneth D., et al. "The consequences of refractory epilepsy
and its treatment." Epilepsy & Behavior 37 (2014): 59-70.
• Pugh, Mary Jo, and Katharine K. McMillan. "Guidelines and Quality
Standards for Adults with Epilepsy." Neurologic clinics 34.2 (2016):
313-325.
2429
Board Review: Neurology

Mary A. O’Neal, MD
Clinical Director of the Neurosciences Center
Director of the Women’s Neurology Program, BWH
Assistant Professor of Neurology, Harvard Medical School
No disclosures
2430
Question 1:
A 47 year-old hiker has pain in the left buttock

that radiates to her left lateral foot. The pain is
not affected by position or movement.
Question 1 (cont’d):
She also says that her left foot tingles as do

parts of her right foot and thigh, left fingers, and
the left anterior part of her chest.
2431
One month ago, a physician treated her for a

right Bell palsy and arthritis.
Which of the following would be most helpful in
establishing a diagnosis?
A. Electromyography and nerve conduction velocity

measurements
B. Somatosensory evoked responses
C. Magnetic resonance imaging of the spine and spinal
cord
D. Lumbar puncture
E. Lumbar roentgenography
2432
Question 1:
The answer is D
Question 1 Answer
Which of the following would be most helpful in establishing a diagnosis?
A. Electromyography and nerve conduction velocity measurements
B. Somatosensory evoked responses
C. Magnetic resonance imaging of the spine and spinal cord
D. Lumbar puncture
E. Lumbar roentgenography
Lyme disease can present with cranial neuropathies (typically the facial nerve, may
be bilateral, occurs in 5-10% of untreated patients) and inflammatory radiculopathy
(may mimic a mechanical radiculopathy with pain and sensorimotor symptoms).
Lumbar puncture will rule out other inflammatory, infectious or neoplastic etiologies
and will be abnormal and diagnostic in Lyme disease. CSF will typically show a
lymphocytic pleocytosis. EMG/NCS and MRI may be abnormal, but would not
provide a definitive diagnosis. An X-ray of the lumbar spine (lumbar roetenography)
would not be helpful.
2433
Question 2:
A 78 year-old normotensive woman realizes

suddenly that she cannot see to her left and that
her left hand tingles.
Two years previous, she had a stroke which left

her right arm and right leg weak. The family
reports that during the past year she has
become unreliable in daily responsibilities, and
often forgets people’s names.
2434
Computed tomographic scan shows a recent,

well-circumscribed homogeneous right parietal-
temporal hemorrhage; an old, slit-like cavity in
the left medial frontal lobe under the cortex; and
moderate ventricular dilatation and cortical
sulcal widening.
A. Hemorrhage into a brain tumor

B. Cerebral amyloid angiopathy
C. Embolization of cardiac origin with hemorrhagic
infarction
D. Multiple cerebral aneurysms
E. Recurrent head trauma
2435
Question 2:
The answer is B
Question 2 answer

A. Hemorrhage into a brain tumor
B. Cerebral amyloid angiopathy

C. Embolization of cardiac origin with hemorrhagic infarction
D. Multiple cerebral aneurysms
E. Recurrent head trauma
Her acute symptoms of a left hemifield vision loss and left hand
somatosensory complaints are explained by the recent right parietal-
temporal hemorrhage. Her prior stroke resulted in right sided weakness and
is explained by the lesion in the left frontal lobe. A slit-like cavity is seen as a
residual finding after a hemorrhage. Therefore she has had at least 2
intracerbral hemorrhages and has a possible dementia (family’s report of
one year of being unreliable). ICH is the most recognized complication of
CAA.
2436
Question 3:
After skiing, a 27 year-old woman developed

pain in the left mastoid region that radiated to
the left occiput and neck.
The next day she became dizzy, staggered, and

felt pain in the left forehead and eye.
2437
Physical examination shows normal blood

pressure, but with abnormal neurologic findings
including:
decreased pin perception on the left side of the face and
the right limbs and trunk;
a left Horner syndrome;
rotatory nystagmus;
weakness of the left palate and pharynx;
clumsiness and uncoordination of the left limbs.
A. Embolization to the basilar artery with pontine infarction

B. Pontine hemorrhage
C. Dissection of the left vertebral artery
D. Dissection of the left internal carotid artery
E. Artherosclerotic occlusion of the internal carotid artery
2438
Question 3:
The answer is C
Question 3 answer
A. Embolization to the basilar artery with pontine infarction
B. Pontine hemorrhage
C. Dissection of the left vertebral artery

D. Dissection of the left internal carotid artery
E. Artherosclerotic occlusion of the internal carotid artery
Vertebral artery dissection can present with ipsilateral occipital or neck

pain. Her examination is consistent with a left lateral medullary
syndrome (Wallenburg syndrome). This area of the medulla is supplied
by the PICA (posterior inferior cerebellar artery), a branch of the
vertebral artery. The lateral meduallary syndrome consists of: crossed
sensory findings with ipsilateral loss of pain and temperature to the
face and cotralateral to the body, ipsilateral horner syndrome,
ipsilateral ataxia, weakness of the larynx and pharynx leading to
dysphagia, dysarthria, vertigo.
2439
Question 4:
A 64 year-old man has progressive spasticity of

gait, impotence, and urinary frequency. He has
occasional headaches at the vertex.
Physical examination shows increased tone in

the bilateral lower extremities, 3+ patella and
ankle reflexes and bilateral extensor plantar
reflexes.
Which of the following is the next best step in his
care?
A. Physical therapy
B. Magnetic resonance imaging of the neck
C. EMG and NCV
D. CT of the lumbar spine
E. Cerebral angiogram
2440
Question 4:
The answer is B
Question 4 answer:
Which of the following is the next best step in his care?
A. Physical therapy
B. MRI of the neck

C. EMG and NCV
D. CT of the lumbar spine
E. Cerebral angiogram
MRI of the neck is the test of choice to assess for cervical

myelopathy. Cervical cord compression can lead to progressive
spasticity in gait, sexual dysfunction, and spastic bladder (urinary
frequency). The most common etiology of spinal cord dysfunction
in the elderly is cervical spondylosis. Signs of cervical canal
narrowing can be seen on plain films, CT, MRI, and CT
myelogram. EMG/NCV are rarely helpful, but can be used when
assessing for peripheral nerve pathology.
2441
Question 5:
An 80 year-old woman with mitral valve disease

and chronic atrial fibrillation becomes suddenly
confused during a family dinner.
She is awake and alert, and her motor function

appears intact and symmetric. She speaks in
long sentences unconnected to the events of the
evening or the questions asked of her.
2442
She uses many word substitutions and

nonsense words. She appears unable to
understand questions put to her by family
members.
A. Complex partial seizure

B. Transient global amnesia
C. Dominant hemisphere stroke
D. Nondominant hemisphere stroke
E. Delirium
2443
Question 5:
The answer is C
Question 5 answer
A. Complex partial seizure
B. Transient global amnesia
C. Left (dominant) hemisphere stroke

D. Right (nondominant) hemisphere stroke
E. Delirium
She has risk factors for stroke (AF) and has sudden onset of deficits. She speaks
fluently but uses word substitutions (paraphasias) and nonsense words
(neologisms). She has impaired comprehension. This description is classical for
Wernicke’s type aphasia and localizes to the left hemisphere involving the posterior
temporal lobe (Wernicke’s area). There are often no motor deficits because the
motor pathways are spared. Sometimes there is a visual field cut on the right due
to involvement of the optic radiations. A lesion involving the optic radiations in the
temporal lobe will result in a superior quadrantonopsia. Over 95% of right handed
people and the majority of left handed people have language in the left hemisphere.
Therefore it is called the dominant hemisphere (short for dominant hemisphere for
language).
2444
Question 6:
A 48 year-old man comes to the physician

complaining of right leg pain and numbness for the
past 3 weeks. The pain is on the upper, lateral
thigh and is burning and stinging in quality. The
pain radiates to the groin and down to the knee.
He has a PMH of obesity and has not seen a
doctor for many years.
On examination, he is obese and otherwise well-
appearing. Strength is 5/5 bilaterally. There is decreased
sensation in the right lateral thigh to temperature and
pinprick. There is decreased sensation to pinprick,
temperature and vibration in a bilateral stocking distribution
to the mid-calves bilaterally. Reflexes are 1+ at the patella
and 0 at the Achilles and bilateral flexor plantar reflexes
bilaterally.
2445
Which of the following is the best diagnostic test to obtain at
this time?
A. Hemoglobin A1C
B. Vitamin B12
C. EMG
D. MRI of the lumbar spine
E. CT of the pelvis
Question 6:
The answer is A
2446
Question 6 answer:
Which of the following is the best diagnostic test to obtain at this time?
A. Hemoglobin A1C
B. Vitamin B12
C. EMG
D. MRI of the lumbar spine
E. CT of the pelvis
The patient is presenting with meralgia paresthetica, a

neuropathy of the lateral femoral cutaneous nerve. This nerve
can be compressed by tight fitting clothing, often in association
with weight gain. Weight loss can also lead to this condition,
presumably by decreasing the fat padding around this nerve. The
diagnosis is made clinically in the setting of characteristic sensory
changes with normal motor function. It is more common in
patients with diabetes mellitus. This patient has signs of a
peripheral neuropathy as well that may be due to undiagnosed
diabetes. A B12 deficiency causes a myelopathy as well as
neuropathy and would not present in this fashion.
Question 7:
Ten days ago, a 22 year-old man had an

inoculation of tetanus toxoid in his right arm after
removal of a splinter.
2447
He now has severe pain in the right shoulder

and arm and parasthesias in the right hand.
Physical examination shows severe weakness of

muscles around the right shoulder girdle and
absence of the right biceps reflex.
2448
Passive range of movement of the shoulder is

normal. Sensory examination is normal, and
other reflexes in the arms and legs are normal.
A. Brachial neuritis
B. Herniated C-7 disk
C. Epidural cervical spinal abscess
D. Cervical spinal cord tumor
E. Rotator cuff injury
2449
Question 7:
The answer is A
Question 7 answer:
A. Brachial neuritis
B. Herniated C-7 disk
C. Epidural cervical spinal abscess
D. Cervical spinal cord tumor
E. Rotator cuff injury
“Parsonage-Turner syndrome” is characterized by inflammation of the brachial

plexus. It typically presents with severe shoulder pain and then as the pain is
improving, there is weakness in the deltoid and periscapular muscles. It is often
idiopathic, but may be autoimmune and triggered by immunization. There is typically
good recovery and treatment is supportive with physical therapy and pain control.
There is no role for immunosuppression. A C7 disc herniation would lead to
weakness in the triceps and wrist extensors and the biceps reflex would not be
affected.
2450
Question 8:
A 60 year-old man with a long history of back

pain recently began feeling weakness and
tingling in his legs when he walks more than a
half a block. The symptoms disappear when he
sits.
He has no symptoms when doing bicycling-like

exercises supine on his bed even after 30
minutes.
2451
Except for an absent left ankle reflex, neurologic

examination is normal. Foot and femoral pulses
are normal.
A. Aortic atherosclerosis with claudication

B. Polyneuropathy
C. Herniated lumbar L-5 disk
D. Lumbar spinal stenosis
E. Cervical spondylitic myelopathy
2452
Question 8:
The answer is D
Question 8 answer:
A. Aortic atherosclerosis with claudication
B. Polyneuropathy
C. Herniated lumbar L-5 disk
D. Lumbar spinal stenosis

E. Cervical spondylitic myelopathy
“Neurogenic claudication”
Lumbar stenosis can be asymptomatic, associated with low back pain, cause
symptoms and signs of focal nerve root compression, or give rise to neurogenic
claudication Neurogenic claudication refers to pain and discomfort in the low back,
buttocks, and legs that occurs after walking and is relieved by sitting. Relief of
symptoms with flexion of the spine explains why it is often easier to walk up an
incline than on a level surface, and forms the basis of the bicycle test. A patient with
neurogenic claudication will be able to cycle (spine flexed), but will not be able to
walk erect (spine extended) for an equivalent time. A patient with vascular
claudication is expected to have the same tolerance for both activities.
2453
Question 9:
A 25 year-old previously healthy man is found

unconscious in his apartment. There is no
evidence of trauma.
On examination, he is responsive to voice and

painful stimulation. There is no evidence of
meningeal irritation. The pupils are 3 mm and
unreactive.
2454
There is no inducible eye movements by the

doll’s eye maneuver or irrigation of a tympanic
membrane with ice water.
The blood pressure is 90/70 mm Hg, and the

pulse rate is 54/min. Respiratory function is
depressed.
2455
A. Sedative drug overdose

B. Subarachnoid hemorrhage
C. Intracranial mass
D. Brain stem stroke
E. Narcotic overdose
Question 9:
The answer is E
2456
Question 9 answer
A. Sedative drug overdose
B. Subarachnoid hemorrhage
C. Intracranial mass
D. Brain stem stroke
E. Narcotic overdose
The clues to this diagnosis are that he has small pupils and
has depressed respiratory rate. This patient has impaired brain
stem function, which can occur temporarily with drug
overdose. Both sedative and narcotic drug overdose can lead
to absent oculovestibular reflexes, but pupils are not small with
a sedative drug overdose.
Question 10:
A 35 year-old woman, who had a renal

transplant 4 years ago for renal failure due to
membranous glomerulonephritis, is hospitalized
because of progressive left sided weakness and
dysarthria.
2457
She has been treated with prednisone and

cyclosporine. A test for the human
immunodeficiency virus is negative.
MRI of the brain shows, in the right frontal lobe,

a focal area of abnormal signal, that spared the
cortical gray matter.
2458
There is minimal mass effect and no contrast

enhancement. There are also similar smaller
lesions throughout the white matter.
A. Multiple sclerosis
B. Glioma
C. Embolic stroke
D. Progressive multifocal leukoencephalopathy
E. Primary central nervous system lymphoma
2459
Question 10:
The answer is D
Question 10 answer
A. Multiple sclerosis
B. Glioma
C. Embolic stroke
D. Progressive multifocal leukoencephalopathy

E. Primary central nervous system lymphoma
The patient is immunosuppressed leaving her vulnerable to reactivation of the JC

virus. This disease is usually associated with AIDS, but is also seen patients
immunocompromised due to other reasons. This virus causes destruction of the
CNS white matter by infecting the oligodendrocytes. With acute lesions of multiple
sclerosis, glioma and with lymphoma there is often enhancement due to break
down of the blood brain barrier. Additionally, MS requires 2 separate episodes of
demyelination in time and space. A stroke affects the gray matter as well as the
white matter.
2460
Question 11:
The diagnosis can be established by:
A. Measuring beta2-microglobulin in cerebrospinal fluid

B. Electroencephalography
C. Arteriography
D. Magnetic resonance imaging
E. Brain biopsy
Question 11:
The answer is E
2461
Question 11 answer:
The diagnosis can be established by:
A. Measuring beta2-microglobulin in cerebrospinal fluid
B. Electroencephalography
C. Arteriography
D. Magnetic resonance imaging
E. Brain biopsy
A diagnosis of PML can be made via CSF

with polymerase chain reaction (PCR) for
the JC virus or by brain biopsy. PCR of the
CSF has been shown to be highly specific
(92-99%) and sensitive (74-93%) for the
detection of JC virus in patients with PML.
Brain biopsy has a sensitivity of 74-92%
and a specificity of 92-100%.
Question 12:
A 60 year-old businessman suddenly becomes

confused at a meeting. He has no perceivable
motor impairment and recognizes his
colleagues.
2462
He continually asks the same questions about

the subject matter under consideration at the
meeting.
One week later, the patient is normal, but unable

to remember the events of the meeting.
2463
A. Hysterical fugue state

B. Pulmonary embolism
C. Stroke syndrome
D. Transient global amnesia
E. Complex partial seizure
Question 12:
The answer is D
2464
Question 12 answer
A. Hysterical fugue state
B. Pulmonary embolism
C. Stroke syndrome
D. Transient global amnesia

E. Complex partial seizure
TGA is characterized by <24 hours of inability to form new memories

(anterograde amnesia), which cannot be attributed to other causes such as stroke
or seizure, with normal level of consciousness and otherwise normal cognitive
functioning and neurologic examination. It most commonly affects the middle-
aged or elderly. The underlying cause of TGA is unclear, but there appears to be
reversible dysfunction of the hippocampus possibly due to ischemia or
excitotoxicity.
Question 13:
Four years after having lumpectomy and

radiation treatment for breast carcinoma, a 45
year-old woman develops pain and weakness of
the left leg that spreads over a period of 1 week
to involve the right leg.
2465
She also has local back pain in the midthorax

and a circumferential band-like sensation.
In the past day, she has become incontinent of

urine after brief urgency, and her genitalia are
numb.
2466
The patient weighs 160 kg (352 lbs). Reflexes

are 3+ with unsustained ankle and knee clonus;
toes are extensor and the legs occasionally jerk
into a flexed posture.
A. Intramedullary metastasis
B. Epidural metastasis
C. Carcinomatous meningitis
D. Metastasis to the sagittal sinus
E. Radiation necrosis of the spinal cord
2467
Question 13:
The answer is B
Question 13 answer
A. Intramedullary metastasis
B. Epidural metastasis
C. Carcinomatous meningitis
D. Metastasis to the sagittal sinus
E. Radiation necrosis of the spinal cord
Cord compression at the thoracic level

In a patient with bilateral leg weakness, it is crucial to check for a
sensory level, bowel and bladder dysfunction, and saddle
anesthesia. This presentation is a neurologic emergency. The most
common metastases leading to cord compression are prostate,
breast and lung cancer. Metastasis usually arises in the posterior
aspect of vertebral body with later invasion of epidural space. The
most common complaint is pain, and two thirds of patients will have
motor signs at time of diagnosis of spinal epidural metastasis.
2468
Question 14:
A 25 year-old woman had lost the vision in the

right eye for 6 weeks at age 18. The loss was
attributed to “nerves” when her father died.
Her visual acuity has been as bad as 20/400, but

is now 20/20 with 20/15 acuity in the left eye.
2469
She has been having recurrent 20- to 30-minute

episodes of dimming of vision related to exercise
and hot showers. She has no other neurologic
symptoms.
Which of the following statements about this
patient is (are) true?
A. She has a larger pupil on the right

B. She probably has a normal visually evoked potential
C. She has a right afferent pupillary defect
D. She has definite multiple sclerosis
E. She has an optic nerve tumor
2470
Question 14:
The answer is C
Question 14 answer
Which of the following statements about this patient is (are) true?
A. She has a larger pupil on the right
B. She probably has a normal visually evoked potential
C. She has a right afferent pupillary defect

D. She has definite multiple sclerosis
E. She has an optic nerve tumor
She has a right afferent pupillary defect. She had an initial

presentation consistent with R optic neuritis, which is associated with
ipsilateral afferent pupillary defect. 20-30% of the time optic neuritis is
the presenting sign of multiple sclerosis (MS). Up to 50% of patients
with MS will develop an episode of optic neuritis.
Uhthoff's phenomenon, episodic transient worsening of symptoms

with increased body temperature (due to exertion, hot weather, hot
showers), occurs in isolated optic neuritis and in MS.
2471
Six months later she returns after having an
episode of right leg weakness and numbness
that resolved. MRI of the brain at that time
showed an enhancing lesion of the left
periventricular white matter. She begins
treatment for MS, but develops fever, chills,
malaise, muscle aches and fatigue.
Which of the following is the most likely treatment
that was initiated?
A. Intravenous methylprednisolone
B. Rituximab
C. Glatiramer
D. Interferon beta
E. Natalizumab
2472
Question 14:
The answer is D
Question 14 answer
Which of the following is the most likely treatment
that was initiated?
A. Intravenous methylprednisolone
B. Rituximab – nausea, vomiting, dizziness, h/a, pruritus,
asthenia, shivering
C. Glatiramer – post-injection reactions (systemic & local)
D. Interferon beta
E. Natalizumab – depression, nausea/GI, PML
Interferon beta frequently causes flu-like side effects and this is the
most common side effect requiring intervention. These side effects
usually appear early in therapy, last about 1 day after injection and may
subside over time. NSAIDs and acethaminophen are used to manage
symptoms.
2473
Question 15:
A 60 year-old mechanic fractured his left tibia.

Two weeks later he develops a severe, constant
ache in his leg.
The leg becomes pale with some cyanotic

mottling, feels cold and sweaty, and movement
is limited. The toenails are brittle and short.
2474
A. Tarsal tunnel syndrome

B. Occlusion of the tibial artery
C. Psychophysiologic disorder
D. Complex regional pain syndrome
E. Dermatophyte infection
Question 15:
The answer is D
2475
Question 15 answer
A. Tarsal tunnel syndrome
B. Occlusion of the tibial artery
C. Psychophysiologic disorder
D. Complex regional pain syndrome
E. Dermatophyte infection
Reflex symptathetic dystrophy (RSD)/ Complex regional pain syndrome (CRPS). CRPS
is a chronic progressive disease characterized by severe pain, swelling and changes in
the skin. The cause of this syndrome is currently unknown. Precipitating factors include
injury and surgery, although there are documented cases that have no demonstrable
injury to the original site. The syndrome is diagnosed by: the presence of an initiating
noxious event or a cause of immobilization (type 1) or after nerve injury (type 2),
continuing pain, allodynia (perception of pain from a nonpainful stimulus), or hyperalgesia
disproportionate to the inciting event, evidence at some time of edema, changes in skin
blood flow, or abnormal sudomotor activity in the area of pain.
Question 16:
The diagnosis of brain death requires

documentation of each of the following except:
A. Isolectric electroencephalogram
B. Pupillary unreactivity
C. Absence of eye movements
D. Apnea
E. Lack of receptivity and responsivity
2476
Question 16:
The answer is A
Question 16 answer:
The diagnosis of brain death requires documentation of each of the
following except:
A. Isolectric electroencephalogram
B. Pupillary unreactivity
C. Absence of eye movements
D. Apnea
E. Lack of receptivity and responsivity
EEG is not necessary to diagnose brain death, although it can

be used as an augmentative tool in certain conditions.
2477
Question 17:
A 24 year old woman comes to the physician

complaining of headaches for the past 6 months.
The headaches are bilateral and pulsatile. They
last 3-10 hours and are associated with nausea
and photophobia. She has missed several days of
work this past month due to headaches. She has
a past medical history of asthma, depression and
insomnia. She takes lorazepam prn and an oral
contraceptive.
Question 17:
Her optic fundi are shown below. Her neurologic

examination is normal.
Non-contrast MRI of the brain was performed last

week when she was seen in the emergency
department for a headache and it was normal.
2478
Question 17:
Which of the following is the next best step in her

care? Order or prescribe:
A. Repeat MRI of the brain with gadolinium

B. Lumbar puncture
C. Sertraline
D. Amitriptyline
E. Propranolol
Question 17:
The answer is D
2479
Question 17 answer:
Which of the following is the next best step in her care? Order or prescribe:
A. Repeat MRI of the brain with gadolinium
B. Lumbar puncture
C. Sertraline
D. Amitriptyline
E. Propranolol
She meets criteria for migraine without aura, despite the bilateral
pain. She is having frequent enough headaches (>2/mo that are
disabling) to benefit from a prophylactic agent. Amitriptyline is
considered a first-line agent for this purpose and would be preferable
to propranolol given her history of depression, asthma and insomnia.
Sertraline is less efficacious. Fundoscopic photos are of normal
discs. There is no indication for MRI or LP.
Papilledema
2480
Questions 18 & 19:
For each numbered word, phrase or statement,

select the one lettered heading that is most
closely associated with it. Each lettered heading
may be selected once, more than once, or not at
all.
Question 18:
A. Recurrent vertigo attacks lasting 1. Gentamicin
seconds occurring most frequently ototoxicity
when turning in bed at night without 2. Benign
tinnitus and with normal hearing positional vertigo
B. Single vertigo episodes lasting weeks 3. Vestibular
without decrease in hearing neuritis
C. Recurrent vertigo attacks lasting hours 4. Wallenberg
with tinnitus, and unilateral hearing loss syndrome (lateral
medullary
D. Vertigo and dysequilibrium lasting
infarction)
years with bilateral hearing loss
5. Meniere’s
E. An attack of vertigo with hiccups, facial
disease
numbness, and Horner syndrome
followed by months of dizziness
2481
Question 18:
The answers are 1-D, 2-A, 3-B, 4-E, and 5-C
Question 18 answer:
A. Recurrent vertigo attacks lasting 1. Gentamicin
seconds occurring most frequently ototoxicity - D
when turning in bed at night without 2. Benign
tinnitus and with normal hearing - 2 positional vertigo
B. Single vertigo episodes lasting weeks -A
without decrease in hearing - 3 3. Vestibular
C. Recurrent vertigo attacks lasting hours neuritis - B
with tinnitus, and unilateral hearing loss 4. Wallenberg
5 syndrome (lateral
D. Vertigo and dysequilibrium lasting medullary
years with bilateral hearing loss - 1 infarction) - E
E. An attack of vertigo with hiccups, facial 5. Meniere’s
numbness, and Horner syndrome disease - C
followed by months of dizziness -4
2482
Question 19:
A. Guillain-Barre syndrome 1. Treated with

(acute inflammatory plasmapheresis or IVIG
polyneuritis)
2. Treated with
B. Chronic inflammatory
demyelinating corticosteroids
polyneuropathy (CIDP)
3. Complicated by
C. Both respiratory dysfunction
D. Neither
Question 19:
The answers are 1-C, 2-B, and 3-A
2483
Question 19 answers:
A. Guillain-Barre syndrome 1. Treated with

(acute inflammatory plasmapheresis or IVIG
polyneuritis)
Both
B. Chronic inflammatory
demyelinating 2. Treated with
polyneuropathy (CIDP) corticosteroids
CIDP only
C. Both
D. Neither 3. Complicated by
respiratory dysfunction
AIDP only
Question 20
A 28-year-old woman G2P1 at 30 weeks gestation
was last seen well at 10 am. She was found on
the ground not speaking or moving her right side at
10:50 am.
On initial exam at noon, she was mute with left
gaze deviation and dense right hemiplegia.
NIHSS* was 15.
2484
What is the next best step? Order or

Prescribe?
A. Brain MRI
B. Head CT with contrast
C. Head CT without contrast
D. IV tPA
Question 20:
The answer is C
2485
Question 20:
The treatment of stroke during pregnancy should be, in

most cases, the same as in the non-pregnant state. The
mother’s health is the most important factor in maintaining
the health of the fetus.
Computerized tomography (CT) imaging raises concern

about fetal exposure to ionizing radiation. The level of
radiation exposure from most diagnostic imaging is far
below that known to cause fetal anomalies. Therefore, if
needed for accurate diagnosis, CT is appropriate.
Good Luck!
2486
Update in Geriatrics
Suzanne E. Salamon, MD
Associate Chief Clinical Geriatrics
Division of Gerontology
Assistant Professor ,Harvard Medical School
No Disclosures
2487
Structure
• Title and Reference
• Background which led to study
• Study structure
• Results
• Conclusion
Topics
• Is the high dose flu shot really more effective?
• The new shingles vaccine
• Is vaginal estrogen safe?
• Methylphenidate (Ritalin) for Alzheimer’s
• Magnesium for leg cramps?
• What is effective for preventing falls?
• Can we prevent dementia?
• Thyroid-when to treat-or not
• Myths about getting older
2488
Vaccines Recommended for People > 65
• Flu (every year)

• Pneumonia (once each for most people)
PPSV 23
PVC or Prevnar 13
• TDaP once, then Td every 10 years
• Shingles
2489
Comparative effectiveness of high-dose vs

standard-dose influenza vaccination on numbers
of US nursing home residents admitted to
hospital: a cluster-randomised trial
Lancet Respir Med 2017 Jul 20
Gravenstein et al
Background
• The US Advisory Committee on Immunization
Practices recommends that all>6 mos old get flu
shot by October.
• Flu season usually starts in December or early
Jan., Average flu season lasts ≈13 weeks
• Flu vaccine available in US by end of
July,though most get flu shots starting in
September (peak shots in Oct.)
• Maximum vaccine effectiveness seen shortly after
vaccination (takes ≈ 14 days to mount protective
response) then declines in
effectiveness/antibodies of about 7% month
• On average, flu vaccine is 30% effective-this year
2490
Background
• 2 vaccines designed specifically for people 65 and older:
1-The high dose vaccine (IIV3-HD, Fluzone) -4 times the amount of antigen
as the regular flu shot.(IIV3-SD) stronger immune response (higher antibody
production).
-Clinical trial of >30,000 participants showed that adults >65 years who got
high dose vaccine had 24% fewer influenza infections than those who received the
standard dose flu vaccine. (NEJM 2014;371:635 Aug 14,2014.DiazGrados et al)
-Approved for use in the United States since 2009.
2 -The adjuvanted flu vaccine, Fluad designed to create a stronger immune

response to vaccination.
- Canadian observational study of 282 persons > 65 during the 2011-12
season, Fluad was 63% more effective in preventing illness than regular-dose
unadjuvanted flu shots.
- No randomized studies comparing Fluad with Fluzone High-Dose.
- Available for the first time in the US during the 2016-2017 season.
CDC does not recommend 1 flu shot over the other
High dose twice as expensive as standard dose ($ 30 vs $50)
The Study
• Done to compare high-dose trivalent influenza
vaccine (IIV3-HD) with a standard-dose
vaccine(IIV3-SD) in reducing hospital admissions of
nursing home residents in the USA.
• Randomized 823 US nursing homes (38,000 pts) to

standard vs high dose vaccine
2491
Results
• Incidence of respiratory-related hospital
admissions significantly lower in facilities
where residents received high-dose influenza
vaccines than in those that received standard-
dose influenza vaccines
• 3-4% over 6 months(HD) vs 3-9% over 6
months (SD)
• Statistically significant, though not
dramatic during flu season 2013-2014.
Conclusion
• When compared with standard-dose vaccine,

high-dose influenza vaccine can reduce risk of
respiratory-related hospital admissions from
nursing home residents aged 65 years and
older.
2492
Efficacy of the Herpes Zoster Subunit Vaccine in

Adults 70 Years of Age or Older
NEJM 2016;375: 1019-1032
Cunningham et al
Background
• Herpes zoster (shingles) results from reactivation of
latent varicella-zoster virus (VZV)/chickenpox,
presents as vesicular, painful dermatomal rash.
• In US, estimated 1 million cases of shingles a year
• One in three people will get shingles during their
lifetime.
• One in five people who have shingles will develop
post-herpetic neuralgia.
2493
Background
• Increased incidence with age
• T cell immunity decreases with age
• Postherpetic neurlagia (PHN) is most common
complication with chronic neuropathic pain
• 1st vaccine, Zostavax, is a live attenuated
vaccine (2006)
• Effectiveness is less in older adults:
70% in adults 50-59 41% in adults 70-79
64% in adults 60-69 18% in adults >80 YO
2494
Background, cont.
• CDC recommended zoster vaccine in 2006 for those
>60 yrs
• Now a new shingles vaccine was approved 10/2017
• Shingrix-nonlive, subunit (HZ/su) vaccine that
combines a protein found on the surface of the VZV
that causes shingles, with an adjuvant system, to
enhance the immune response to the antigen
• This study is 2nd to test safety and efficacy
The Study
• Randomized, placebo-controlled phase 3 trial
conducted in 18 countries
• Adults 70 years of age and older
• Participants received 2 doses of HZ/su or placebo
(1:1 ratio), I.M. 2-6 months apart.
• 6950 vaccine, 6950 placebo, mean age 75.6 YO
• Assessed vaccine efficacy against herpes zoster and
PHN
2495
Results
• Mean follow-up period 3.7 years
• Shingles occurred in 23 HZ/su recipients and 223
placebo recipients
• Vaccine efficacy ages 70-79: 90%
• Vaccine efficacy > 80 YO 89.1%
• Vaccine efficacy against PHN 88.8% (mostly because
of decreased incidence of shingles)
• Side effects of injection-site and systemic reactions
(fatigue) more common,( 79% vs 29 %), transient,
not considered serious
Risk of Development of Herpes Zoster after Vaccination.
Cunningham AL et al. N Engl J Med 2016;375:1019-1032
2496
Risk of Development of Postherpetic Neuralgia after Vaccination in the Pooled Population.
Cunningham AL et al. N Engl J Med 2016;375:1019-1032
Shingrix®: Adverse Reactions
Cunningham AL et al. N Engl J Med. 2016; 375:1019-1032
2497
Conclusion
• Adjuvanted subunit HZ/su vaccine reduced the risk of
herpes zoster and postherpetic neuralgia among adults
>70 Y.O. without substantial safety concerns
• Requires 2 injections, given 2-6 months apart
• Side effects, not dangerous, more common than
present vaccine
• October 2017, FDA approved Shingrix for adults
>50, (even those with prior shingles, previous
vaccination, no h/o chicken pox)
Addendum
• Immunocompromised persons. As with ZVL, the
ACIP recommends the use of RZV in persons taking
low-dose immunosuppressive therapy (e.g., <20
mg/day of prednisone or equivalent or using inhaled
or topical steroids) and persons anticipating
immunosuppression or who have recovered from an
immunocompromising illness
• Whereas RZV is licensed for all persons aged ≥50

years, immunocompromised persons and those on
moderate to high doses of immunosuppressive
therapy were excluded from the efficacy studies and
thus, ACIP has not made recommendations regarding
the use of RZV in these patients
2498
Breast cancer, endometrial cancer, and

cardiovascular events in participants who used
vaginal estrogen in the Women’s Health
Initiative Observational Study
Menopause:January 2018,
Vol 25,Issue 1,p.11-20
Crandall et al.
Background
• Vaginal atrophy after menopause -vaginal dryness, pain &
bleeding during sex, itching, irritation, burning, and discharge,
urinary symptoms, recurrent UTI
• Up to 45% of postmenopausal women ,but few seek help
• Due to decreased estrogen
• Underreported and undertreated.
• NAMS recommends non-hormonal vaginal
lubricants (Replens,K-Y,Astrogllide) and increased sexual
activity. OK for mild, but not moderate or severe sx.
• Systemic hormones OK for menopause symptoms, but long-
term therapy not recommended
2499
Background
• Increased risk for deep vein thrombosis, pulmonary embolism,
coronary heart disease, and endometrial and breast cancer.1
• Long-term systemic hormone therapy no longer recommended
if considered solely for the treatment of vaginal atrophy
• Local vaginal estrogen therapy –increased blood flow to
uterine lining,epithelial thickness,secreations,reverses
atrophy,decreases symptoms
• BUT-is it safe?
• This study done to determine association between vaginal
estrogen and risk of coronary heart disease (CHD), invasive
breast cancer, stroke, pulmonary embolism, hip fracture,
colorectal cancer, endometrial cancer, or death from any cause.
Vaginal Estrogen Formulations
• Vaginal ring-every 3 months. Slow,steady

release of estrogen
• Estrogen cream-1-2 times/week
• Estrogen tablets 1-2 times/week
2500
• Estradiol Vaginal Insert

• Dosage Form: vaginal insert
• WARNING: ENDOMETRIAL CANCER, CARDIOVASCULAR DISORDERS,
BREAST CANCER and PROBABLE DEMENTIA
• Estrogen-Alone Therapy
• -Endometrial CancerThere is an increased risk of endometrial cancer in a woman with a
uterus who uses unopposed estrogens. Cardiovascular Disorders and Probable Dementia
• -The Women’s Health Initiative (WHI) estrogen-alone substudy reported increased risks of
stroke and deep vein thrombosis (DVT) in postmenopausal women (50 to 79 years of age)
The WHI Memory Study (WHIMS) estrogen-alone ancillary study of WHI reported an
increased risk of developing probable dementia in postmenopausal women 65 years of age or
older during 5.2 years of treatment with daily CE (0.625 mg)-alone, relative to placebo In the
absence of comparable data, these risks should be assumed to be similar for other
doses of CE and other dosage forms of estrogens.
• Breast Cancer
• The WHI estrogen plus progestin substudy also demonstrated an increased risk of invasive
breast cancer [see Warnings and Precautions (5.3), and Clinical Studies (14.2)].
• In the absence of comparable data, these risks should be assumed to be similar for other
doses of CE and MPA, and other combinations and dosage forms of estrogens and
progestins.
• Estrogens with or without progestins should be prescribed at the lowest effective doses and
for the shortest duration consistent with treatment goals and risks for the individual woman.
•
•
The Study
• Prospective observational cohort study
• Data from participants of the Women's Health
Initiative Observational Study
• Recruited at 40 US clinical centers, aged 50 to 79
years at baseline
• Did not use systemic estrogen therapy during follow-
up (n = 45,663, median follow-up 7.2 years).
• Collected data regarding incident CHD, invasive
breast cancer, stroke, pulmonary embolism, hip
fracture, colorectal cancer, endometrial cancer, death,
and self-reported use of vaginal estrogen (cream,
tablet).
2501
Results
• Among women with an intact uterus, the risks of
stroke, invasive breast cancer, colorectal cancer,
endometrial cancer, and pulmonary
embolism/deep vein thrombosis were not
significantly different between vaginal estrogen
users and nonusers
• Risks of CHD, fracture, all-cause mortality, were
lower in users than in nonusers
• Among hysterectomized women, the risks were
not significantly different in users versus nonusers
of vaginal estrogen
Conclusion
• The risks of cardiovascular disease and cancer

were not elevated among postmenopausal
women using vaginal estrogens, providing
reassurance about the safety of treatment.
2502
Methylphenidate for Apathy in Community-

Dwelling Older Veterans With Mild Alzheimer’s
Disease: A Double-Blind, Randomized, Placebo-
Controlled Trial
The American Journal of Psychiatry

Published online Sept.15, 2017
Padala et al
2503
Background
• Methylphenidate (Ritalin) (MP)has been around since
1950’s-1960’s.
• Psychostimulant, similar to amphetamine
• Works by inhibiting uptake of dopamine and
norephinephrine, and some serotonin, increasing level
of dopamine leading to increased alertness
• Despite its availability and use in children with
ADHD for decades, it is rarely used in the older
population because of concerns of side effects and
DEA schedule II controlled substance classification
Clinical Applications
• DEPRESSION:
-Wallace et al studied 13 patients,mean age 72, with
major depression in double blind study using MP
BID (8 a.m & noon). Improved depression scores
within 8 days, no adverse effects.(Am J Psych:1995)
• Fast-acting, few side effects
• Can be used together with SSRI while SSRI is
reaching therapeutic levels
2504
Combined citalopram and methylphenidate

improved treatment response compared to either
drug alone in geriatric depression: a randomized
double-blind, placebo-controlled trial
Am J Psychiatry 2015 Jun 1; 172 (6):561-569
Lavretsky et al
• POSTSTROKE RECOVERY:
-Studies note improvements in mood, ADL’s and
motor functioning with MP following stroke
-Similar studies showed improvement in stroke

recovery with SSRI, separate from post-stroke
depression
2505
• IMPROVED MOTOR FUNCTION with MP in

Parkinson’s disease
-Several studies showed that a single dose of MP
improved gait speed, postural stability, freezing in older
people with PD (Shorer.J Gerontol A Biol Sci Med Sci.2013;29:15-17)
• PALLIATIVE CARE AND HOSPICE

- Decreased depression and fatigue (Hardy.Am J Geriatr
Pharmacother.2009;7:34-59). Doses 10-20 mg/day
-Main side effects: dry mouth, agitation, insomnia
Background
• Apathy is a common behavioral problem in
Alzheimer’s disease.
• Leads to functional impairment, higher service
utilization, higher caregiver burden, and increased
mortality.
• The authors’ objective was to study the effects of
methylphenidate on apathy in Alzheimer’s disease.
2506
The Study
• 12-week, prospective, double-blind, randomized,
placebo-controlled trial (methylphenidate versus
placebo) in community-dwelling veterans (N=60)
with mild Alzheimer’s disease.
• The primary outcome for apathy (Apathy
Evaluation Scale–Clinician) and secondary
outcomes for cognition (Mini-Mental State
Examination), functional status (activities of daily
living, instrumental activities of daily living)
• Improvement and severity measured at baseline
and at 4, 8, and 12 weeks.
Results
• Participants were all men (77 years old, SD=8).
• Methylphenidate group had significantly greater
improvement in apathy than the placebo group at
4 weeks, 8 weeks, and 12 weeks.
• At 12 weeks, there was also greater improvement
in cognition, functional status, caregiver burden,
CGI scores, and depression in the
methylphenidate group compared with the
placebo group.
2507
Conclusion
• Methylphenidate improved apathy in a group

of community-dwelling veterans with mild
Alzheimer’s disease.
• Methylphenidate also improved cognition,
functional status, caregiver burden, CGI
scores, and depression.
•
Effect of Magnesium Oxide Supplementation on

Nocturnal Leg Cramps
Jama Intern Med 2017:177(5) 617-623
Maor et al
2508
Background
• Nocturnal leg cramps (NLC) are painful contractions
of muscles occurring at rest, mostly at night
• Up to 60% adults report having NLC
• Although may be due to electrolyte imbalance,
hemodialsis, other conditions, most are idiopathic.
• Quinine is only treatment with moderate evidence in
reducing muscle cramps, but US FDA issued a
warning in 2010 against quinine due to risk of life-
threatening reactions
• Tonic water contains no more than 83 mg of quinine
per liter—a much lower concentration than the 500 to
1,000 mg in the therapeutic dose of quinine tablets.
2509
Background
• Magnesium commonly recommended for NLC, but
study of magnesium citrate did not decreased leg
cramps
• Magnesium oxide increased intracellular magnesium
levels more than mag citrate.
• This study was done to determine if Magnesium
oxide deceased leg cramps.
The Study
• 94 individuals, each with at least 4 NLC
during the screening 2 week period, mean age
65, randomly assigned to magnesium oxide or
placebo.
• Treated for 4 weeks
• Primary outcomes: difference in mean number
of NLC per week.
• Secondary outcomes: severity and duration of
NLC, quality of life, quality of sleep
2510
Results
• There was no difference between the severity
and duration of NLC, quality of life or quality
of sleep.
• Both groups had slightly lower number of

NLC (placebo effect)
Conclusion
• Oral magnesium oxide was not superior to placebo
for older adults with NLC.
• Decrease number of NLC in both groups is probably
a placebo effect that may explain the wide use of
magnesium for NLC
2511
Comparisons of Interventions for Preventing

Falls in Older Adults
Tricco,A. et al
JAMA 2017 Nov 7;318:1659
2512
Background
• 2010 National Institute of Aging data showed 2-year
prevalence of falls among those >65 YO was 36%
• Falls cause injury, death, anxiety, depression
• Difficult to determine effectiveness of fall prevention
programs
• This study was done to evaluate all available fall-
prevention interventions for older people to determine
which are most effective.
The Study
• 283 RCTs comparing falls interventions with
“usual” care to determine what works to
decrease incidence of falls
2513
Results
• (159,910 participants), mean age 78
• When compared with usual care,these interventions
were associated with reductions in injurious falls:
- exercise
-combined exercise and vision evaluation and
treatment
-combined, exercise, vision, and environmental
assessment modification
-Calcium + vitamin D
Conclusion
• Exercise alone and various combinations of
interventions were associated with lower risk
of injurious falls compared with usual care.
• Choice of fall preventions intervention

depends on patient and caregiver preferences.
2514
2515
Can We Prevent Dementia?
Annals of Internal Medicine
December 19, 2017
2516
Background
• 47 million people with Alzheimer disease and related dementias
(ADRD) worldwide
• Incidence in US is declining, prevalence increasing as population
ages
• Dementia-related costs exceed those of heart disease and cancer.
• Since we have no cure, preventing or delaying the onset of dementia
is a public health priority.
• Is there a “magic bullet” for preventing dementia?
• What is the evidence for preventing dementia by cognitive training

physical activity, O.T.C. supplements and prescription medication,?
• December 19, 2017 Annals of Internal Medicine published 4

evidence-based reviews of trials of preventive interventions of
adults without dementia to see if any interventions did indeed
prevent dementia.
Background
2517
Does Cognitive Training Prevent Cognitive

Decline?: A Systematic Review
Annals Internal Medicine

2 January 2018 Vol: 168, Issue 1
Butler et al
Background
• Fear of Alzheimer disease and related dementias
(ADRD) considered by many to be worse than death ,
driving a growing “brain-training” industry.
• Structured activities to stimulate brain, - cognitive
training exercises-marketed to otherwise healthy
adults and persons with recent diagnosis of mild
cognitive impairment (MCI)
• promoted to slow or prevent cognitive decline,
including dementia, but effectiveness is highly
debated.
• This study reviewed the evidence for cognitive
training on the occurrence of dementia
2518
The Study
• Looked at studies 2009-2017, found 34
randomized trials of cognitive training
interventions lasting from 2 weeks to 6
months, then followed them for up to 2 years.
• Most measured outcomes of test performance
(memory, processing speed)
Results
• Improvments in test performance of the domain
tested (eg memory)which improved in that area
rather than measuring progression to dementia
• Evidence was insufficient to determine whether

cognitive training exercises prevented mild cognitive
impairment or dementia
• Often plaques and tangles start to form many years

earlier, so these trainings were started late.
2519
Conclusion
• Cognitive training seemed to improve test

performance only in the domain trained
• Evidence was insufficient that training

prevented or delayed cognitive decline
Physical Activity Interventions in Preventing

Cognitive Decline and Alzheimer-Type
Dementia: A Systematic Review
Ann Intern Med Dec.19, 2017
Brasure, et al
2520
The Study
• Reviewed several electronic databases 2009-2017 that
lasted 6 months or longer, enrolled adults without
clinically diagnosed cognitive impairments and
compared dementia outcomes between physical
activity interventions and inactive controls
• Follow-up 6 months to 2 years
• Looked at studies of aerobic training, resistance

training, tai chi, diet
Results
• Insufficient evidence that physical activity
intervention is effective in preventing
cognitive decline.
2521
Conclusion
• Physical activity interventions begun after
decades of high-risk behavior likely are
insufficient to reduce dementia risk
• However regular physical activity may need to
begin earlier in life and be sustained as a
lifestyle.
• Physical activity may slow cognitive decline
by decreasing dementia due to vascular factors
Over-the-Counter Supplement Interventions to

Prevent Cognitive Decline, MCI, and Alzheimer-
Type Dementia: A Systematic Review

December 19, 2017
Brasure, et al
2522
Background
• Fear of dementia has lead to a growing industry of
OTC supplements intended to boost brain health and
prevent or slow cognitive decline.
• Alzheimer’s Research and Prevention Foundation

says “you should definitely take a high potency
multiple vitamin and mineral capsule” as well as:
coenzyme Q10,alpha lipoic acid, ginkgo biloba,
phosphatidylserine, Omega-3’s,acetyl-L-carnitine
vitamin C 2000 mg/day vitamin E
Background
• >60% older adults use OTC supplements
• 2015 Americans spent $37 billion on OTC
supplements, $91 million on ginkgo biloba
• Do they work?
• This review summarizes the evidence on
efficacy of OTC supplements in preventing or
delaying cognitive or Alzheimer-type dementia
2523
The Study
• On line search of studies 2009-2017 of people
with normal cognition.
• Followed people for a minimum of 6 months
• Measured neuropsych testing for dementia or
MCI (mild cognitive impairment)
Results
• 56 studies covering 13 categories of OTC treatments:
• -Omega Fatty Acids-up to 6 years: no better than placebo
• -Soy: No difference from placebo
• -Ginkgo biloba: No difference
• -B Vitamins (Folate,B6,B12)-no benefit
• -Vitamin D + Calcium-no benefit
• -Vitamin E-no difference in incidence of dementia at 10 years
• - Vitamin C(500 mg) or Beta Carotene: Vit C +/-
• -Multivitamins-no difference over 5 years
2524
Conclusion
• Small number of OTC supplements evaluated for
potential effects on dementia
• Most OTC interventions studied have no proven
benefit in preventing or delaying dementia in older
adults
• Supplements may work better in persons with low
levels of nutrient or vitamin (baseline deficiencies
reported only in B vitamins
• Evidence is insufficient for clinicians to recommend
any of the OTC supplements to patients with normal
cognition or MCI for preventing dementia
• Few trials are currently ongoing
Pharmacologic Interventions to Prevent

Cognitive Decline, MCI, and Alzheimer’s
Dementia

Dec. 19,2017
Fink, et al
2525
Background
• Several medications have been suggested to

possibly prevent or reduce the risk of
Alzheimer dementia
• This review was done to assess the most
current evidence about the efficacy and safety
of drug therapy in preventing or delaying
dementia
The Study
• The authors search Medline and other large
data bases 2009-2017 looking at prescription
drugs to see if any decrease risk of dementia
- dementia medications -blood pressure meds

- diabetes meds -lipid-lowering meds
- NSAID’s - hormone therapy
- Testosterone
2526
Results
• Cholinesterase inhibitors- in pts with 1 apolipoprotein
E4 allele, less progression to Alz.disease (not stat.sig)
• Antihypertensives-no difference from placebo
• Diabetes meds-insufficient evidence for prevention
• Lipid-lowering meds-no difference from placebo
• NSAID’s-no difference
• Estrogen only-none or slight increase dementia
• Estrogen + progesterone-increased risk stroke, CAD,
breast cancer, PD
• SERM’s-no risk reduction
• Testosterone-no decrease risk
Conclusion
• Evidence did not support use of

antihypertensives, statins, NSAID’s, aspirin,
diabetes drugs or cholinesterase inhibitors for
preventing Alzheimer’s dementia in adults
with normal cognition or mild cognitive
impairment
2527
Except in extreme cases:

• 1. Thyroid medication does not alleviate most
symptoms.
• 2. People with higher TSH live longer
• 3. Suppressed/low TSH (i.e. higher free

thyroid levels, from overactive thyroid or
meds) leads to increased incidence of
osteoporosis and fractures
2528
Thyroid Hormone Therapy for Older Adults with

Subclinical Hypothyroidism
N Engl J Med 2017; 376:2534-2544

Stott, et al
Background
• Subclinical hypothyroidism defined as high

TSH with normal free T4
• TSH, Normal T4
• Occurs in 8-18% adults >65 YO
• Most have no symptoms
• Should the elevated TSH be treated?
2529
The Study
• Double-blind, randomized, placebo-controlled trial
• 737 adults >65 YO with elevated TSH 4.6-19.99 with
normal free T4
• Half got levothyroxine of 50 µg daily (25 if weight
<50 kg or had CAD), half got placebo
• Primary outcome:
• -Changes in hypothyroid symptoms(feeling cold,
constipation, weight gain, slow movements, dry skin,
fatigue)
Results
• Mean age 74 years

• Mean TSH 6.4
• At 1 year, no difference in the 2 groups in
hypothyroid symptoms.
2530
Conclusion
• Levothyroxine provided no apparent benefits

in older persons with subclinical
hypothyroidism in 396 patient age 75
Association of Thyroid Function With Life

Expectancy With and Without Cardiovascular
Disease
JAMA Intern Med 2017 Sep 18

Bano et al
2531
Background
• Subclinical hypothyroidism characterized by
abnormal TSH and normal T4
• Both clinical and subclinical thyroid dysfunction

associated with increased heart disease and mortality
Background
• Overactivity of the thyroid gland is thought to have a
negative effect on overall health.
• Higher FT4 associated with an increased heart rate
• This study was done to investigate life expectancy

(LE) and cardiovascular disease (CVD) among
thyroid status categories ( ie, hypothyroidism,
euthyroidism, hyperthyroidism)
2532
The Study
• 7785 adults (mean age 65)without known
thyroid disease (TSH and FT4 within normal
reference ranges) divided into 3 groups
according to TSH and FT4 levels
• Followed for 8 years for fatal or nonfatal

adverse CVD events
Results
• During median follow-up of 8 years, adverse CVD
events occurred in 10% of patients and 17% died
overall.
• Group with highest Free T4 (FT4) had 32% higher
risk for CVD and 50% more likely to die than people
in lowest group
• People in group with lowest FT4 lived 3 years longer
than people in highest FT4 group
• Group with highest TSH 20% less likely to die than
other groups
2533
Higher thyrotropin (TSH) and lower free thyroxine (Free T4) =longer life
expectancy
Conclusion
• People with higher TSH and low-normal FT4 five up
to 3.5 years longer than those with high normal FT4.
• Helpful in knowing how to treat patient who believe

that higher thyroid replacement makes them feel
better.
2534
Subclinical Thyroid Dysfunction and Fracture Risk
JAMA. 2015;313 (20):2055-2065

Blum, et al
• Subclinical hyperthyroidism was associated with an

increased risk of fractures, with highest risk in those
with suppressed TSH <0.10 mIU/L
• No association between subclinical hypothyroidism

and fractures
Why Everything you think About Aging May Be

Wrong
Wall Street Journal
Anne Tergesen
Nov. 30, 2014
2535
• Stereotype of later life as time of loneliness,

depression, decline, but research shows that in many
way, life gets better as we get older
• Moods and sense of well-being often improve with
age
• Expertise deepens, wisdom flourishes
• Many challenges, health related
• Several myths about aging:
Myths about Aging

1.Depression is more prevalent in Old Age
-Research shows emotional well-being improves until
the 70’s, when it levels off, even among centenarians
2. Cognitive Decline is Inevitable.
-Except in dementia, knowledge and wisdom help
people more in real-life than on tests.
3. Older Workers are Less Productive.

-People >55 YO make up 22% of the US labor force
-No relationship between age and job performance
2536
4. Loneliness is More Likely

-Older people report better marriages, better
friendships, higher rate of close ties
5. Creativity Declines with Age

Mark Twain, Cezanne, Frank Lloyd Wright, Robert
Frost, Virginia Woolf, Julia Childs, Laura Ingalls
Wilder, Benjamin Franklin, Mother Theresa, Ghandi,
Grandma Moses
2537
2538
NY Times Feb 11, 2017
• By Claire Cain Miller NEW YORK TIMES

• Women much more likely to work into 60s,
70s today, studies show
• 30% women 65-69 are working. 18% women
age 70-74 work
2539
Summary
• High-dose flu vaccine reduces respiratory hospitalizations from
N.H.residents > 65 years more than standard dose
• Shingrix vaccine prevents shingles in 90%,even in 90 YO
• Vaginal estrogen appears to be safe
• Methlyphenidate helps depression/apathy in Alz.patients
• Magnesium not effective for leg cramps,but ?placebo effect
• Exercise, vision, environmental factors,Ca+D decrease falls
• So far, no “magic bullet” to prevent Alzheimers]dementia
• Suppressed TSH may cause more problems than elevated TSH
• Growing older may not be as bad as you think!
2540
Obesity Management
Florencia Halperin, MD, MMSc

Co-Director, Center for Weight Management and Metabolic Surgery
Chief, Division of Endocrinology, Brigham and Women’s Faulkner Hospital
Division of Endocrinology, Brigham and Women’s Hospital
Instructor in Medicine, Harvard Medical School
None
2541
At the end of this class, participants will be able to:

Apply the approach that obesity is a disease, not a
behavioral problem
Understand how to formulate an effective obesity
treatment program with multiple components
Know indications for approved obesity treatments,
including lifestyle interventions, pharmacotherapy, and
surgery
Be familiar with recent obesity management guidelines
Jensen MD Circulation 2013; Apovian CM

JCEM 2015;Garvey WT Endocr Prac 2016
2542
Body Mass Index (BMI): kg / m2

Overweight: BMI 25.0 – 29.9
Obesity: BMI > 30.0
Class I: BMI 30.0 – 34.9
Class II: BMI 35.0 – 39.9
Class III: BMI > 40
Obesity is defined as a chronic, relapsing, multi-factorial,

neurobehavioral disease, wherein and increase in body fat
promotes adipose tissue dysfunction and abnormal fat mass
physical forces, resulting in adverse metabolic,
biochemical and psychosocial consequences
–American Society of Bariatric Physicians
Lizarbe B Front Neurogen 2013
2543
OBESITY
Neurobehavioral Psychological
Economic Endocrine
Immune
Developmental
Epi/Genetics Environment
Risk, not just BMI, should drive treatment decisions

Link weight loss goals to health goals
Earlier intervention
Chronic disease management
Individualized treatment approach(es)
2544
DIETARY INTERVENTIONS
PHARMACOTHERAPY
Placebo
Lorcaserin 10 QD
Lorcaserin 15 QD
EXERCISE INTERVENTIONS
Lorcaserin 10 BID
Gardner IJO 2012; Church PLoS

ONE 2009; Smith S NEJM 2010
DPP: Reduction in progression from IGT to T2DM
31% Reduction
(7.8 vs. 11%/yr)
58% Reduction
(4.8 vs. 11%/yr)
6.7%
Weight
Loss
DPP Research Group NEJM 2002;

Hamman Diabetes Care 2006
2545
Look AHEAD, 10 yrs: No difference in CV death, nonfatal

MI, CVA, hospitalization angina Look AHEAD Group NEJM 2013
Da Qing: 577 IGT, RCT 6 yrs, 23 yr follow up, CV death HR

0.59, all cause mortality HR 0.71 Li G Lancet Diab Endocrin 2014
Mediterranean Diet: 7000, HR 0.7 of major CV events

Estruch R NEJM 2013
2546
Broaching the subject: Counseling

Diet
Behavior Modification
Physical Activity
Medications
Surgery
Talk about it! Document it!

Obesity - a complex, multi-factorial disease
Initiating the conversation

◦ “We have not discussed your weight recently. What are your
thoughts about your weight and health at this time?”
Patient preferred term: “Weight”
Focus non-weight outcomes/health improvements with

5-10% weight loss
Wadden Obes Res 2003; AHA/ACC/TOS Guidelines Circulation 2013
2547
Motivational Interviewing:
◦ Patient-centered, collaborative counseling style
◦ Encourage personal reasons for change
◦ Explore ambivalence about change (behavioral change is a
process)
◦ Help identify and overcome individual barriers to success
◦ Can be effective in brief encounters
Core Practices
◦ Express empathy
◦ Reflective listening
◦ Collaboration – guiding and negotiating, not dictating
◦ Shared decision-making
◦ Support self-efficacy and autonomy
The clinician and patient should agree on whether weight loss

is appropriate and assess if the patient is prepared to
undertake the measures necessary to succeed:
◦ “How prepared are you to make changes in your diet, to be
more physically active, and to use behavior change
strategies such as recording your weight and food intake?”
If not prepared, counseling likely counterproductive

Periodically re-assess interest and readiness
Discuss avoiding additional weight gain to prevent risks
Evaluate and treat CVD risk factors
AHA/ACC/TOS Guidelines Circulation 2013
2548
“While weight loss treatment is ongoing, manage risk

factors such as hypertension, dyslipidemia, and other
obesity-related conditions.
This includes monitoring the patient’s requirements for

medication change as weight loss progresses,
particularly for anti-hypertensive and diabetes
medications that can cause hypoglycemia.”
5-10%
in 6 mos … BUT HOW?
AHA/TOS (2013)
2549
Dr. You
Caloric restriction
Portion controlled foods
Frequent follow up visits
Self monitoring
◦ Weight, diet, physical activity
Physical activity (exercise and NEAT)
Referral to a high-intensity comprehensive program
(including commercial programs, e.g. Weight
Watchers)
6 months: 6 kg (7%) weight loss

2 years: 3-4 kg weight loss
Irrespective of macronutrient composition
Sacks FM NEJM 2009

Bottom line for weight loss: Caloric restriction and
adherence (not macronutrient composition)
2550
1,200-1,500 kcal/d for women

1,500-1,800 kcal/d men
OR 500-750 kcal/d energy deficit
One of the evidence-based diets that restricts certain

food types (e.g. high-carb, high-fat) in order to create
an energy deficit by reduced food intake
Frozen diet meals

Liquid meals
Bars
Portion controlled
Calorie controlled
Convenient
Inexpensive
As part of a sensible
Wadden TA Obesity 2009
Well-planned menu
2551
Number of sessions attended (Look AHEAD)
Wadden TA Obesity 2009
Food, exercise, weight

Highest adherence to completing food intakes
greatest weight loss
www.wellocracy.com
2552
Low fitness independent predictor of mortality for any BMI
Exercise alone: limited effect on weight loss

Exercise plus diet: augments loss (modest)
Weight loss maintenance: More is better (>300 mins/week)
Pedometer use
◦ NEAT
◦ Increases
steps/d (~30%)
◦ Best predictor of
increased activity:
Step goal
Wadden TA Circulation 2012
Shaw K Cochrane 2006; Saris WH Obes Rev 2003; Bravata DM JAMA 2007
The most effective behavioral weight loss treatment is

a high intensity comprehensive program
◦ In-person
◦ High-intensity (i.e., ≥14 sessions in 6 months)
◦ Individual or group sessions by trained interventionist
The principal components include:

◦ Prescription of a moderately-reduced calorie diet
◦ Program of increased physical activity
◦ Use of behavioral strategies to facilitate adherence
2553
What are the approved weight loss medications?
When is it appropriate to consider use?
Which meds for which patients?
Obesity drugs
alter
physiology
not just
behavior(s)
Potential Mechanisms of Action

• Decrease appetite/cravings
• Decrease leptin resistance
• Increased energy expenditure
• Increase adherence by mitigating Ioannides-Demos LL J Obes 2011;
biological or genetic factors York DA. Nutrition 2000; Liu et al. Cell 2015
2554
*Above placebo
Weight
Name Mechanism Side Effects Dose Other
Loss*
Adrenergic/ 15-37.5
Phentermine 5% ↑HR, ↑BP Generic
CNS mg QAM
3.75/2 mg QMO U HCG;
Phentermine/
Adrenergic/ ↑HR, ↑BP,
(14d) 1mo chem↓CO2;
Topiramate Cognitive Not in CAD, CVA
7-9% CNS 7.5/46 mg
(Qsymia) Teratogenic in last 6mo
QAM
5-HT2c
Lorcaserin 10 mg
3.5% receptor Headache Not with SSRI
(Belviq) BID
agonist
Orlistat Lipase 60-120 Vitamin
3% Steatorrhea
(Alli,Xenical) Inhibitor mg QAC deficiencies
Naltrexone/ Nausea 8/90 mg: Not with other

Buproprion 4% CNS Constipation 2 tabs BID bupropion,
(Contrave) Headache (titration) opioids
Liraglutide GLP-1 Nausea, 3 mg SC

8-9%
(Saxenda) agonist/CNS Diarrhea QD
Adjunct to diet and exercise

Indication: BMI >30; BMI >27 with co-morbidities
If never participated in a comprehensive lifestyle

intervention program, undertake such a program prior
If unable to lose or sustain weight loss with

comprehensive lifestyle intervention and meets BMI
criteria, adjunctive therapies may be considered
◦ Maximized behavioral approaches
◦ Weight plateau
2555
Assessment monthly for first 3 mo, then every 3 mo
If effective (weight loss 5% at 3 mo) and safe,

recommend medication be continued
If ineffective (weight loss <5% at 3 mo) or
safety/tolerability issues, recommend medication be
discontinued and alternative medications or
approaches be considered
Apovian CM JCEM 2015
Effectiveness
Contra-indications
◦ Based on medical conditions or med-med interactions
Possible benefit for multiple medical conditions
◦ Headache prevention (topiramate)
◦ Diabetes/Pre-diabetes (liraglutide)
Cost
Patient Preference
2556
0
-1
-2 -2.8 -2.8 -2.8
Weight (kg)
-3 -3.6 -3.6 -3.3

-3.8
-4 -4.5
-5 -5.2 Cheapest
-5.6
-6 phentermine
-7 Most Effective
-8 -8.8 Phen+Top,
-9 Liraglutide
FDA-Approved Off-Label
-10
Witkamp RF Pharm Res 2011;Gadde K Arch Int Med 2013;

Powell AG Clin Pharm Ther 2011; Torgerson JS Diab Care 2004; Smith
NEJM 2010; Garvey WT AJCN 2012.
RCT, Liraglutide 3 mg vs placebo for DM prevention

BMI >27 (co-morbidities) or >30, pre-diabetes, n=2254
50% completed to week 160
At week 160:
HR 0.21 (95% CI 0.13–0.34) 6%
2%
LeRoux C Lancet Feb 2017
2557
Clinical Factors Avoid/Use Caution

Increased Seizure Risk Naltrexone/Bupropion
Kidney Stones Phentermine/Topiramate, Orlistat
Glaucoma Phentermine/Topiramate
Uncontrolled Hypertension Naltrexone/Bupropion
Phentermine
CAD/CVA Phentermine
Renal Insufficiency (mod-severe) Use half-dose: Phentermine/Topiramate,
Naltrexone/Bupropion
Avoid: Liraglutide, lorcaserin
Hepatic Insufficiency (mod-severe) Use half-dose: Phentermine/Topiramate
Use quarter dose: Naltrexone/Bupropion
Caution: Liraglutide, lorcaserin
SSRI use Caution: lorcaserin
Indications: BMI >40; BMI >35 with co-morbidities
(LAGB) (RYGB) (SG)

2011 2014
Total 158,000 193,000
RYGB 36.7% 26.8%
LAGB 35.4% 9.5%
SG 17.8% 51.7%
Ponce J SOARD 2015
2558
LAGB SG RYGB
Weight Loss
40-45% EBW 50-60% EBW 60-70% EBW
(2 yrs)
Length of
1 hour 1 hours 2 hours
Surgery
Time in Hospital 1 day 2 days 2 days
Risk of Death <0.05 % 0.1-0.3 % 0.3-0.5 %
Reversal of Yes, if medically
No Very Difficult
Procedure necessary
Inadequate loss; Dumping
Other Issues
Band removal syndrome
RCT
Absolute Difference in HbA1c (%)
 Lower in Surgery Lower in Control
5 Year Follow Up Data

Mingrone G et al Lancet 2015
Schauer PR et al NEJM 2017
Muller-Stich Ann Surg 2015
2559
Obesity is a disease, not a behavioral problem

One size does not fit all: long-term strategy/relationship
Goal of medical interventions is 5-10% lost in 6 mos
Calorie restriction, Behavioral Strategies, Exercise
Meds: adjunct to lifestyle therapy, re-assess effect and
need for (dis)continuation
Surgery: RYGB, SG highly effective in “diabesity”
Lots of new guidelines to review!
1. Jensen MD, et al. 2013 AHA/ACC/TOS Guideline for the Management of

Overweight and Obesity in Adults. Circulation. 2014 Jun 24;129(25 Suppl
2):S102-38.
2. Apovian CM, et al. Pharmacological Management of Obesity: An Endocrine
Society Clinical Practice Guideline. J Clin Endocrinol Metab. 2015
Feb;100(2):342-62.
3. Garvey WT, et al. American Association of Clinical Endocrinologists and
American College of Endocrinology comprehensive clinical practice
guidelines for medical care of patients with obesity. Endocr Pract.
2016;22(Suppl 3):1-203
4. Mechanik, JI, et al. Clinical practice guidelines for the perioperative nutritional,
metabolic, and nonsurgical support of the bariatric surgery patient--2013
update: cosponsored by American Association of Clinical Endocrinologists, The
Obesity Society, and American Society for Metabolic & Bariatric Surgery.
Obesity (Silver Spring). 2013 Mar;21 Suppl 1:S1-27
5. Heymsfield SB and Wadden TA. Mechanisms, Pathophysiology, and
Management of Obesity. N Engl J Med 2017; 376:254-266
2560
2561
A. Guidelines suggest prescribing caloric restriction for

weight loss: 1,200 -1,500 kcal/day for women and 1,500-
1,800 kcal/day for men
B. Guidelines suggest that a low-carbohydrate, low glycemic
index approach is preferred for diabetes risk reduction
and longer term weight loss maintenance
C. Self-monitoring by tracking food intake is associated with
successful weight loss, but monitoring weight is
associated with worse outcomes
D. Physical activity can augment weight loss, but beyond
150 mins/week little added benefit is observed
A
At this time, available evidence suggests that caloric
restriction and adherence (not a specific
macronutrient composition) is what matters the
most for weight loss
Monitoring weight, food intake and exercise are
recommended
Studies support that the more physical activity, the
more weight lost and maintained
2562
A. Discontinuation of the medication once the patient

has lost 5% of initial body weight
B. Discontinuation of the medication after 3 mos
(regardless of effect)
C. Discontinuation if the patient does not lose 5% of
initial body weight at 3 mos
D. Change to use as needed once the patient loses 5%
of initial body weight - to lower exposure/risks
C. Discontinuation of weight loss medications is

recommended if the patient does not lose 5% of initial
body weight at 3 mos
Close monitoring of patients on weight loss
medications is essential
There is a lot of biologic variability in response to
pharmacologic (and other) treatment approaches, so if
one approach is not working for an individual, it should
be re-addressed.
At all visits there should be an emphasis on
medications as adjunct to diet and exercise
2563
End of Life
Lisa Soleymani Lehmann, MD, PhD, MSc

VA National Center for Ethics in Health Care
LzsLehmann@gmail.com
Disclosures
No Disclosures
2564
Disclaimer
The views expressed in this presentation do not

represent those of the Federal Government,
Veterans Health Administration, or the National
Center for Ethics in Health Care.
Overview
• Advance care planning (ACP)
– Understand the utility of advance directives
– A process that should focus on patient’s goals
and values
• Explore how to effectively communicate with
patients about goals of care and values
• Identify common pitfalls in communication
and how to avoid them
• Provide a framework for ACP conversations
2565
What is Advance Care Planning (ACP)?
• Advance care planning is a process that

involves making decisions about the care
patients would want to receive if they
become unable to speak for themselves
– An advance directive is one outcome of process
• The decisions should be based on their
personal values, preferences, and discussions
with their loved ones and doctors
National Hospice and Palliative Care Organization (NHPCO)
Clinical Indications for ACP

• Routine indications
– Discussing poor prognosis
– Discussing treatment with low probability of success
– MD wound not be surprised if the patient died in 6-12
months
– Reviewing health care maintenance with patient
• Urgent indications
– Imminent death
– Patient talks about wanting to die
– Recently hospitalized for severe progressive illness
– Severe suffering and poor prognosis
T Quill, JAMA 2000;284(19): 2502-7
2566
Benefits of Advance Care Planning

• Promotes patient autonomy
– Gives voice to patients’ preferences even when
they cannot speak
– Gives patients peace of mind that their
preferences will be respected
• Benefits for healthcare providers
– Avoids future confusion and conflict
• Benefits for family
– Decreases family angst about end-of-life decisions
– Diminishes family guilt if treatment is limited
Clinical Outcomes &

Advance Care Planning
• Decreased ICU admission

• Improved quality of life
• Increased hospice
• Improves family bereavement outcomes
-Wright AA et al. JAMA. 2008;300(14):1665-7.

-Temel JS et al. N Engl J Med 2010;363:733-42.
-Wright AA et al. JAMA. 2016;315(3):284-292.
2567
Patients Want to Discuss

End-of-Life Preferences
• 80% of patients want to talk about end-of-life
(EOL) wishes
– Only 7% had a doctor discuss it
• 82% say it is important to put their wishes
in writing
– Only 23% have actually done so
• 60% believe it is extremely important not to
burden family with tough EOL decisions
– 56% have not communicated their EOL wishes
-Californians’ Attitudes Toward End-of-Life Issues. 2011.
A Step-Wise Approach to ACP

1. Solicit patient’s understanding of his/her illness
2. Assess if the patient has a health care agent
- Encourage communication between patient and agent
3. Elicit patient’s goals and values
4. Offer a prognosis
-Share information on outcomes
5. Make a recommendation based on goals & values
6. Summarize
7. Document goals and values
8. Apply the directives when indication arises
2568
Beyond Advance Directives:

Discussing Patients’ Goals of Care
• Cure
• Aggressive treatment aimed at life
prolongation at all costs
• Treatment aimed at restoring prior level of
function
• Symptom control or comfort care
Questions to Elicit Goals of Care
2569
Questions to Elicit Patient’s Values

• Is there anything I should know about your beliefs
or wishes that would help me be sure you get the
care you want?
• When you think about the future, what do you

hope for? Is there any thing you want to avoid?
• When you think about the possibility that you may

get sicker, what worries you the most?
• If your health gets worse, what are the most

important things to you?
2570
Prognosis: Survival to Hospital

Discharge after CPR in the Elderly
• Medicare data on 433, 985 patients who

underwent in-hospital CPR
• Patients >65 years
• Overall survival 18.3%
-Ehlenbach WJ, et al. NEJM 2009; 361:22-31.
Prognosis: Survival in Cancer

Patients Undergoing CPR
- Reisfield GM, et al. Resuscitation. 2006;71:152-160.
2571
Outcomes of In-hospital CPR

United States 2000-2009
• All patients > 18 years of age
• Survival increased from 20% to 29%
• Discharge home decreased 36% to 24%
• Discharge to hospice or long term care increased
– Hospice 0.4% to 7%
– Long term care 1% to 9%
• Neurologic compromise increased by 38%
• Feeding tube use increased by 28%
• Ventilator use increased by 58%
-Kazaure, Roman, and Sosa. Resuscitation. 2013
ePrognosis
• Estimating prognosis for elders
• Repository of geriatric prognostic indices
• Guide for clinicians about mortality outcomes
• Internally validated in 218,088 nursing home
residents
• www.eprognosis.ucsf.edu
-JAMA 2010;304 (17):1929-1935.
2572
Make a Recommendation
• As with other treatment decisions, it is appropriate
to offer your recommendations
• Base on clinical situation, goals of care & patient

values
• Offers guidance and relieves patients & families of

some of the burden of decision-making
• Does not undermine patient autonomy
Common Pitfalls
• Physicians:
– Talk too much
– Fail to respond to patient emotions
– Use jargon
– Misses opportunities for empathic connection
– Fail to elicit patient’s values and goals
– Jumping straight to code status and treatment
preferences
– Offering forms and reading material without
discussion
-JGIM 1995;10:436-442.
2573
Questions to Guide Conversation

• What is your understanding of your illness?
• How much information do you want about what is likely to
happen in the future with your illness?
• Who would you want to make decisions for you if you cannot
communicate?
• What are your goals for medical care?
• What are your biggest fears and worries?
• If you become sicker, how much are you willing to go through in
order to have the possibility of more time?
• Are there certain health situations you would find unacceptable
or make your life not worth living? E.g. feeding tube, unable to
care for self, etc.
• Have you discussed your preferences with your family?
Video of Goals of Care

Conversation
Conducting a Goals of Care Conversation with
a Patient
8:06 Elicit values

10:14 Goals of care
2574
Advance Care Planning: Summary Points

• More than just filling out a form
• A process of understanding values and goals
• Begin with what the patient understands
• Listen more and talk less
• Share prognostic information & data on CPR
outcomes
• Include family in conversations
• Make a recommendation & document
Question 1
You have a patient with advanced multiple sclerosis
who has developed renal failure secondary to diabetes. The
patient is DNR. She presents to the ED unconscious with a K
of 8 meq/L.
Which is the most appropriate next step?

a. No intervention because she is DNR
b. Discuss a reversal of the DNR order and dialyze
c. Proceed with dialysis
d. Give sodium polystyrene sulfonate (Kalexate, Kayexalate,
Kionex) until you can find the health care agent to discuss
dialysis
2575
Question 1
You have a patient with severe advanced multiple sclerosis
who has developed renal failure secondary to diabetes. The
patient is DNR. She presents to the ED unconscious with a K
of 8 meq/L.
Which is the most appropriate next step?

a. No intervention because she is DNR
b. Discuss a reversal of the DNR order and dialyze
c. Proceed with dialysis
d. Give sodium polystyrene sulfonate (Kalexate,
Kayexalate, Kionex) until you can find the health care
agent to discuss dialysis
Question 1
Correct answer is proceed with dialysis.
• “Do-Not-Resuscitate” (DNR) is specifically defined
as refraining from cardiopulmonary resuscitative
efforts
• A DNR order should prompt a conversation about
the patient’s goals of care and raise the question
of whether she intended comfort care only
• DNR does not mean do not treat
• Hyperkalemia is life threatening. Sodium
polystyrene sulfonate (Kalexate, Kayexalate,
Kionex)is an inferior therapy for the long-term
management of renal failure
2576
Question 2
A 29 year old man sustained a C1 and C2 spinal fracture
during a boxing champing championship 3 months ago. He
is paralyzed from the neck down and is ventilator dependent.
He is fully alert and understands his condition. He requests
removal from the ventilator and understands that he will die
as a result.
The most appropriate next step is:

a. Assess for depression and if no evidence remove the
ventilator as requested
b. Obtain a court order to continue the ventilator
c. Seek family consensus on removing the ventilator
d. Seek approval of the health care agent
Question 2
A 29 year old man sustained a C1 and C2 spinal fracture
during a boxing champing championship 3 months ago. He
is paralyzed from the neck down and is ventilator dependent.
He is fully alert and understands his condition. He requests
removal from the ventilator and understands that he will die
as a result.
The most appropriate next step is:

a. Assess for depression and if no evidence remove the
ventilator as requested
b. Obtain a court order to continue the ventilator
c. Seek family consensus on removing the ventilator
d. Seek approval of the health care agent
2577
Question 2
Correct answer is assess for depression and remove the
ventilator.
• Any adult patient with the mental capacity to understand
his medical condition and the implications of withdrawal
of treatment has the right to do what he wants to his own
body
• There is no ethical distinction between withholding and
withdrawing life sustaining treatment
• Patients are frequently depressed following a high c-spine
injury
• The patient is alert so no consent of the family or health
care agent is necessary
Resources
• http://www.ethics.va.gov/goalsofcaretraining.asp
• www.makingyourwishesknown.com
• Online decision aid to create personalized advance directive
• MyDirectives.com
• Universal advance digital directive
• www.knowyourwishes.com
• End of life discussion compass guide
• MOLST (MA Medical Orders for Life Sustaining Treatment)
• Written instructions from a clinician to other health professionals
based on patient preferences
• theconversationproject.org
• A guide with prompts to facilitate EOL conversations
• https://www.prepareforyourcare.org
2578
References
1. Dying in America: Improving Quality and Honoring Individual
Preferences Near the End of Life. Institute of Medicine. 2014.
2. Clayton JM, Hancock KM, Butow PN, Tattersall MH, Currow
DC, Adler J, et al. Clinical practice guidelines for
communicating prognosis and end-of-life issues with adults
in the advanced stages of a life-limiting illness, and their
caregivers. Med J Aust. 2007;186(12 Suppl):S77, S9, S83-108.
3. Dingfield LE, Kayser JB. Integrating Advance Care Planning
Into Practice. CHEST 2017; 151(6):1387-1393.
4. Gehlbach TH et al. Code status orders and goals of care in the
medical ICU. Chest 2011;1394:802-809.
5. Dalal S, Bruera E. End-of-Life Care Matters: Palliative Cancer
Care Results in Better Care and Lower Cost. The Oncologist.
2017;22:361-368.
2579
Psychiatry Overview
General Internal Medicine
Board Review
Ann L. Pinto, MD PhD
Staff Physician
Departments of Internal Medicine and Primary Care
• No disclosures
2580
Question 1
• A 65 yo woman comes to the office because her
brother has been diagnosed with stage IV lung
cancer. She wants to be screened for lung cancer
herself. She smoked one pack of cigarettes daily for
40 years and quit 8 years ago.
• Which of the following discussion points about lung
cancer screening in asymptomatic current or former
heavy smokers is true ?
Question 1 (con’t.)
A. Yearly screening chest x-rays reduce lung cancer
mortality.
B. Annual low dose CT scanning (LDCT) results in a
20% relative reduction in lung cancer mortality.
C. Most lung cancers detected by LDCT are stage III or
IV.
D. 5% of LDCT scans had positive findings
E. 50% of the positive screens in LDCT represent
cancer.
2581
Answer: B
Lung cancer screening
• National Lung Screening Trial
• Enrolled 53,000 asymptomatic high risk smokers
– Ages 55-64
– Greater than 30-pack-year history of smoking
– Currently smoking or quit within the last 15 years
• Annual low dose CT screening for 3 years versus
annual screening by x-ray
• Median follow-up 6.5 years; study terminated early
due to benefit.
Answer: B
• Results of National Lung Screening Trial
– 20% relative reduction in lung cancer mortality.
– 6.7% reduction in all cause mortality.
– 24% of scans had positive findings, 95% of which
were NOT cancer.
– Most cancers (70%) were stage I or II.
NEJM 2013; 368:1980
2582
Question 2
• 42 yo male complains of fatigue, low libido and
erectile dysfunction. His exam is notable for
gynecomastia. Total testosterone 180 mg/dL, normal
FSH and LH. What do you recommend as a next step?
A. Testosterone replacement therapy
B. Pituitary evaluation
C. Sildenafil
D. Relationship counseling
E. Semen analysis
Answer: B
Secondary hypogonadism
• Secondary hypogonadism: reproducibly low
testosterone with inappropriately low/normal FSH
and LH indicate a pituitary problem.
• Evaluation should include:
• Prolactin/other tests of pituitary function
• Iron studies (r/o hemochromatosis)
• Pituitary MRI
• Exclude excessive exercise/eating d/o.
• No semen analysis unless fertility is desired.
Lancet 2014; 383:1250-63.
2583
Question 3
• 83 yo F with an ischemic cardiomyopathy and EF15%
is admitted with pulmonary edema for the fourth
time this year. Despite aggressive diuresis, she
remains volume overloaded with declining renal
function.
• She wants to go home but her son disagrees and
wants aggressive care. You recommend a palliative
care consultation.
• Which of the follow is true regarding palliative care in
patients with advanced heart failure?
A. Patients should be referred when curative
therapies have been exhausted.
B. Palliative care requires discontinuation of active
treatment.
C. The onset of functional decline in heart failure
correlates strongly with 6 month prognosis.
D. Palliative care focuses on the psychosocial needs
of pts and families in addition to physical needs.
2584
Answer: D
Palliative care/advanced HF
• Heart failure has an unpredictable clinical trajectory,
unlike cancer.
• Palliative care focuses on maximizing QOL and does
not preclude therapies designed to prolong survival
• Can be initiated at any time.
• Shared decision making: patient’s goals and wishes
• Educates patients and families about the future and
encourages advance care planning.
• Eases transition to hospice care when needed.
Question 4
• 65 yo professor presents after a colleague found him
wandering, unable to find his office. His wife reports
several falls, 2 episodes where he thought he saw an
another person at the dinner table with them, and
that he thrashes around violently in his sleep. Only 1
year ago he was awarded a major prize for his
research.
• On exam he is orthostatic with slowed speech, and
some limb rigidity. No tremor. He has marked
difficulty with clock drawing. B12, TSH, RPR are nl.
2585
Question 4
• Based on these findings, the most likely diagnosis is:
A. Alzheimer’s disease
B. Parkinson’s disease
C. Lewy body dementia
D. Multi-infarct dementia
E. Normal pressure hydrocephalus
Answer: C
Lewy body dementia
• Early deficits in visuospatial and executive functioning
• Typically shorter course than AD, often with rapid decline.
• Visual hallucinations - highly specific for Lewy body
• REM sleep disorder: “acting out dreams”
• Parkinsonian symptoms, especially bradykinesia and
stiffness
• Onset of dementia and Parkinsonian symptoms typically
within 1 year of each other
• Cognitive fluctuations with variable attention/alertness
• Autonomic dysfunction (orthostasis -> falls are common)
2586
Question 5
• 27 yo M presents to the ER with a food impaction.
He notes worsening heartburn and difficulty
swallowing that has not responded to OTC
omeprazole. His medical history is significant only for
eczema. What is the most likely diagnosis?
A. Candida esophagitis
B. Achalasia
C. Diffuse esophageal spasm
D. GERD
E. Eosinophilic esophagitis
Answer: E
Eosinophilic esophagitis
• Male preponderance (M:F 3:1)
• Peak incidence: Childhood or 3rd-4th decade
• Patients typically have a history of atopy
• Most common presentation: dysphagia for solids
• Food impaction is common (33-50% of patients)
• Diagnosis: EGD with biopsy showing eosinophils PLUS lack of
response to PPI.
• Treatment:
– Swallowed inhaled corticosteroids
– Dietary modification
• Relapse is common if treatment is discontinued
Am. J. Gastroenterology 2013; 108:679-692
2587
Question 6
• 58-year-old M presents with burning neck pain that
radiates down his L arm. Despite high-dose NSAIDs,
his pain is 8/10 in severity. He has a history of
hypertension and chronic headache. Medications
include imipramine, lisinopril and trazodone. You
diagnose a cervical radiculopathy, refer him for PT
and prescribe tramadol for pain. 4 hours later he is
brought to the ER with altered mental status,
agitation and fever to 104oF. On exam he has dilated
pupils, hyperreflexia and spontaneous clonus.
• Based on this history, the most likely diagnosis
is:
A. Intracerebral hemorrhage
B. Bacterial meningitis
C. Anticholinergic toxicity
D. Serotonin syndrome
E. Neuroleptic malignant syndrome
2588
Answer: D
Serotonin syndrome
• Precipitated by use of serotonergic drugs
– Not just SSRIs!
– SSRI/SNRIs, MAOIs, TCAs, trazodone, opiates including
tramadol, drugs of abuse, some antibiotics (linezolid,
cipro)
• Symptoms
– fever, AMS, rigidity, spontaneous clonus, hyperreflexia,
autonomic instability
– usually within 24 hr of initiation/dose change of culprit
drug, commonly <6 hours
– can vary from mild to life-threatening and are often
missed/attributed to other causes
• Treatment: discontinue medication/supportive care
Question 7
• A 68-year-old male presents for follow-up
after a hospital admission for decompensated
CHF. His medical history is notable for CAD
with an ischemic cardiomyopathy and EF of
30%. He notes dyspnea with mild exertion and
worsening lower extremity edema.
2589
• Which of the following medications does not
have a mortality benefit in patients with class
III CHF?
A. Aliskiren
B. Candesartan
C. Metoprolol
D. Enalapril
E. Spironolactone
Answer: A
Management of CHF
• Aliskiren+enalapril led to more adverse effects vs.
enalapril alone without decrease in death or HF
hospitalization. Aliskiren alone did not meet criteria for
non-inferiority vs. enalapril. (ATMOSPHERE 2016)
• ACE-inhibitors improve mortality in pts with symptomatic
and asymptomatic LV dysfunction (CONSENSUS, SOLVD)
• Beta-blockers improve survival in pts with systolic
dysfunction, usually after stabilization on a diuretic and
an ACE-inhibitor (MERIT-HF)
• ARB use in ACE-inhibitor intolerant pts improves survival
in pts with CHF/reduced EF (CHARM-Alternative)
• Spironolactone has a mortality benefit in pts with Class III
or IV heart failure (RALES)
2590
Question 8
• A 19-year-old female with a history of IUD
placement 3 weeks ago presents with
complaints of crampy lower abdominal pain
and dyspareunia. She is afebrile. Her exam is
notable for cervical friability and bilateral
adnexal tenderness. Pregnancy test is
negative.
• What treatment to you recommend?
A. Azithromycin 2 g po ×1
B. Ciprofloxacin 500 mg b.i.d. + metronidazole 500
mg b.i.d. ×14 days
C. Ceftriaxone 250 mg IM + doxycycline 100 mg
b.i.d. + metronidazole 500 mg b.i.d. ×14 days
D. Drug regimen in answer C plus removal of the
IUD.
2591
Answer: C
Pelvic inflammatory disease
• Ascending infection of the female upper genital tract
• Major cause of infertility and ectopic pregnancy
• Polymicrobial infection: C. trachomatis and N.
gonorrhoeae, gram-negatives, anaerobes, and
streptococci
• Presentation: lower abdominal or pelvic pain
– Dyspareunia, intermenstrual or post-coital bleeding
– Vaginal discharge, dysuria also common
• Negative endocervical GC/chlamydia testing does not
rule out upper tract infection and treatment
regimens need to cover these
Answer: C
Pelvic inflammatory disease
• Treat if any one: uterine, adnexal or cervical motion
tenderness - microbial testing is not needed.
• Ceftriaxone 250 mg IM + doxycycline 100 mg bid x 14 days
(covers gonorrhea and chlamydia respectively)
• Replacing doxycycline, above, with azithromycin 2 g x1 is an
option for patients for whom compliance may be an issue.
• Increasing resistance of N. gonorrhoeae to fluoroquinolones
precludes use.
• Need for anaerobic coverage not definitive, BUT most
guidelines recommend addition of metronidazole (also covers
Trichomonas).
• IUDs do not need to be removed unless failure to improve.
• Always screen for HIV and other STDs in pts with PID.
2592
Question 9
A 33-year-old female presents to establish
care. Her medical history is significant for
Hodgkin’s lymphoma diagnosed at age 16 and
treated with ABVD (adriamycin, bleomycin,
vinblastine, dacarbazine) plus mantle
irradiation. She has been free of disease since
completion of therapy. She feels entirely well
and has no complaints.
• Which of the following screening tests is
indicated in this 31-year-old woman?
A. Annual mammograms
B. Annual breast MRIs
C. Echocardiogram every other year
D. Annual TSH
E. All of the above
2593
Answer: E
Hodgkin’s lymphoma survivorship
• General principles of pediatric cancer survivorship
– Childhood cancer survivors are at increased risk of
treatment-related toxicities – both malignant and
non-malignant
– Risk varies with treatment regimen
– Imperative to know specifics of treatment and
manage accordingly
– High index of suspicion for serious illness even in
young patients
Answer E
• 18-fold increased risk of secondary malignancy
– Risk of cancer: 26% at 30 years post tx; higher in women
– 13% of female survivors will get breast cancer by age 40
• Cardiovascular complications from mediastinal
irradiation increased with anthracycline treatment
– Accelerated atherosclerosis primary cause of death
– Important valvular disease, LV dysfunction, arrhythmias
• Thyroid dysfunction in as many as 30% of survivors
• Infertility/premature menopause common
• High incidence of anxiety and PTSD
2594
Answer E
• Female patients with chest irradiation
– Mammograms AND breast MRI annually from age 25 or 8
years post treatment (whichever is latest)
• Radiation (chest) + anthracycline treatment
– Echocardiogram/EKG at least q2yr
• Thyroid testing annually
• If pelvic or abdominal radiation (not this patient)
– Colonoscopy at 35 or 15 yr post treatment
• Don’t forget immunizations especially if s/p
splenectomy
• Clinical guidelines for follow up according to

specific treatment regimens: Children’s
Oncology Group Long-Term Follow-up
Guidelines for Survivors of Childhood,
Adolescent and Young Adult Cancer – great
resource
• www.survivorshipguidelines.org
2595
Question 10
• 46 yo M presents for follow-up of poorly controlled
hypertension. He takes lisinopril 40 mg, HCTZ 25 mg,
and amlodipine 10 mg. He is compliant with his
medications. BP is 152/92. What would be the best
choice of an additional medication to control his BP?
A. Aliskiren
B. Spironolactone
C. Doxazosin
D. Bisoprolol
E. Valsartan
Answer: B
Resistant hypertension
• Hypertension despite use of 3 anti-hypertensives of
different classes, one of which is a diuretic.
• PATHWAY-2 study (2015): for patients with resistant
hypertension (pts were on ACE/ARB, CCB and
diuretic), spironolactone was most effective
additional agent vs bisoprolol or doxazosin
• ACC/AHA 2017 hypertension guidelines:
spironolactone (or eplerenone) is the preferred
medication for resistant hypertension.
• Avoid dual blockade of renin-angiotensin system
(increased risk of AKI, hyperkalemia)
• Consider evaluation for secondary causes of HTN.
Lancet 2015; 386:2059
J Am Coll Cardiol 2018;71:e127-e248.
2596
Question 11
24 yo woman presents with dysuria and frequency
without fever, back pain or vaginal discharge. Exam
is notable only for mild suprapubic tenderness.
Which of the following is NOT recommended as first
line therapy?
A. Fosfomycin 3 g po x1
B. Ciprofloxacin 250 mg bid x 3 days
C. Bactrim DS 1 po bid x 3 days
D. Nitrofurantoin 100 mg po bid x 5 days
Answer: B
Acute uncomplicated cystitis
• Culture not necessary for uncomplicated cases
• Complicated UTI: male, pregnant or with structural
abnormalities
• 80% E.coli, 10% other GNR, remainder gram +
• Base treatment on local resistance, allergy, cost
• Hospital resistance data skew community estimates
• FQ highly effective but reserve use for more
serious infections – can cause collateral damage
• FQ use linked with infection with FQR GNRs, MRSA
• Tendinitis, QT-prolongation
IDSA guideline acute cystitis/pyelonephritis
Clinical Infectious Diseases ; 2011 ; 52 : e103 -e120
2597
Question 12
• Which of the following patients should be treated for
latent TB infection?
A. 58-year-old male starting hemodialysis with PPD
10 mm
B. 27-year-old student from Uganda with PPD 5 mm
C. 34-year-old injection drug user with cough,
weight loss
D. 24-year-old suburban teacher with PPD 10 mm
E. 45-year-old healthy spouse of patient with active
pulmonary TB and negative PPD
Answer: A
Latent TB infection
• 11 million people in US have LTBI; 5-10% will
reactivate if not treated
• Reactivation most common cause of new TB in US
• Goal: to screen those at high risk for reactivation:
– Recent PPD conversion
– HIV-positive
– Patients on immunosuppresion
– Patients on hemodialysis
– Close contacts of patients with active TB
2598
Answer: A
Latent TB infection
• Who should be treated for LTBI?
• PPD 5 mm:
– HIV positive,
– immunosuppressed,
– close contacts of pts with TB,
– patients with an abnormal CXR suggesting healed TB
• PPD 10 mm:
– IV drug users
– Homeless or residents/employees of congregate housing
– Pts with hematologic or head and neck cancer
– Patients on dialysis
– Recent arrivals from high incidence areas
Answer: A
Latent TB infection
Specific answer for this case:
A. Hemodialysis patients are at high risk for reactivation
and should be treated
B. Borderline positive test and likely acquired from early
exposure; low risk of reactivation
C. Symptoms of active pulmonary TB and should be tested
with sputum AFB testing
D. Low risk patients should not be tested but if they are,
should not be treated unless PPD>15 mm
E. This patient tested negative and does not need
treatment now; however, she is at high risk of
contracting TB and should be retested 8-10 weeks after
last exposure
2599
Question 13
• A 68-year-old male complains of urinary
urgency, frequency and awakening 3 times a
night to urinate. He denies hesitancy, dribbling
or weak stream. He has cut back on caffeine
and alcohol with no improvement. On exam,
his prostate is mildly enlarged, smooth and
symmetrical. Post void residual is 30 mL.
Urinalysis is unremarkable; PSA and renal
function are normal.
The best first choice of medication for him
would be:
A. Tamsulosin
B. Oxybutynin
C. Finasteride
D. Sildenafil
E. Bladder botulinum toxin
2600
Answer: B
Male lower urinary tract symptoms
• Lower urinary tract symptoms
– Bladder storage phase symptoms:
• Urgency, frequency , nocturia, involuntary loss of urine
– Bladder outlet obstruction symptoms:
• Hesitancy, incomplete emptying (elevated post void
residual), weak stream, dribbling
• This patient has an enlarged prostate but no
symptoms of bladder obstruction
• First choice for overactive bladder without bladder
outlet obstruction is an anti-cholinergic
Question 14
• Disease X has a prevalence of 10% in your
clinic. If you have a test for X that is 90%
sensitive and 90% specific, what fraction of
patients with a positive test truly have X?
A. 50%
B. 67%
C. 75%
D. 90%
2601
Answer: A
Biostatistics
With Without
disease disease
Positive 9 9 18
test
Negative 1 81 82
test
10 90 100
• SENSITIVITY: % patients with disease who test positive: 9/10 = 90%
• SPECIFICITY: % patients without disease who test negative: 81/90 = 90%
• POSITIVE PREDICTIVE VALUE: % patients with positive test who have the
disease: 9/18 = 50%
Biostatistics:
• Sensitivity quantifies avoiding false negatives.
Therefore a negative result from a high
sensitivity test is likely to be a true negative
and rules out disease
• Specificity quantifies avoiding false positives.
Therefore a positive result from a high
specificity test is likely to be a true positive
and rules in disease
• Neither are dependent upon prevalence
2602
Question 15
• 64 yo male with HTN, diabetes, obesity
presents with his 4th episode of acute gout
this year despite dietary modification. He is
anxious to treat his current symptoms and to
prevent further attacks. Exam today is notable
for erythema and exquisite tenderness of the
L 1st MTP joint and adjacent toe. No tophi are
noted. Renal function is normal.
Question 15 (con’t)
What is the best plan to treat his current
symptoms and prevent further attacks?
A. Indomethacin until flare resolves then
discontinue indomethacin and start allopurinol
B. Colchicine and allopurinol indefinitely
C. Febuxostat indefinitely
D. Colchicine indefinitely
E. Colchicine until flare resolves then add
allopurinol; discontinue colchicine after 3
months overlap, continue allopurinol indefinitely
2603
Answer: E
Management/prophylaxis of gout
• An acute attack should be treated within 24 hours
– NSAIDS
– Colchicine
– Oral corticosteroids (may consider intra-articular
steroids if 1-2 large joints affected)
• If a patient is already on urate-lowering therapy
(ULT), that should be continued without interruption
during treatment of an acute attack
• Consider starting ULT if ≥ 2 attacks/yr
Answer: E
• Urate lowering therapy (ULT) should not be initiated
until the acute flare has resolved
• Dose of ULT can be titrated up every 4 weeks; goal
serum urate <6 mg/dL
• Initiation of ULT can precipitate a gout flare and
should not be prescribed without inflammatory
prophylaxis (NSAIDs, colchicine).
• Anti-inflammatory prophylaxis should be continued
after initiation of ULT and continued for 3 months
after target serum urate is reached
2604
• Colchicine should not be used indefinitely due
to possible development of serious toxicities
(esp. in CKD) such as neuromyopathy.
• HCTZ can raise, and losartan decrease, uric
acid levels – modification of antihypertensives
may be useful.
• Caution using allopurinol in some Asian
populations.
Question 16a
• A 24 yo male camp counselor from
Massachusetts presents with 3 days of
intermittent fever as high as 104o, malaise,
myalgias and headache. Exam reveals a
temperature of 101.7 and a palpable spleen
tip.
• Lab testing: wbc 3.3, hct 32.3, plt 84, ALT 135,
AST 106, total bilirubin 2.8, direct bilirubin 0.3,
cr 0.9.
2605
Question 16a (con’t.)

• The most likely diagnosis is:
A. Tick-borne relapsing fever
B. Lyme disease
C. Rocky mountain spotted fever
D. Human granulocytic anaplasmosis
E. Babesiosis
Answer: E
Babesiosis
• Causative organism: Babesia microti in USA.
• Co-infection with Lyme common
• Asymptomatic to severe/life-threatening infection
• Asplenic/immunocompromised pts are at high risk
• Symptoms: fever, sweats, myalgias, arthralgias
• Laboratory testing: transaminitis, hemolytic anemia,
thrombocytopenia are common
• Confirmatory testing: PCR or thin smear showing
“Maltese cross” inclusions
2606
Question 16b
PCR confirms your diagnosis of babesiosis. What
is the best treatment for him?
A. Doxycyline
B. Cefuroxime
C. Amoxicillin-clavulanic acid
D. Clindamycin plus quinine
E. Azithromycin plus atovaquone
Answer: E
Babesiosis treatment
• Mild disease: atovaquone + azithromycin
• Severe disease (consider if elderly, immuno-
suppressed (medication/splenectomy/HIV+)):
clindamycin + quinine
• Doxycycline (used to treat Lyme) does not
cover babesiosis.
2607
Question 17
• 32 yo F presents for preconception counseling.
She has hypertension for which she takes
HCTZ. What is the best plan for managing her
hypertension given an anticipated pregnancy?
A. Continue HCTZ
B. Replace HCTZ with spironolactone
C. Replace HCTZ with nifedipine
D. Replace HCTZ with lisinopril
E. Replace HCTZ with atenolol
Answer: C
Chronic hypertension in pregnancy
• Chronic HTN: HTN that predates pregnancy.
• Pre-eclampsia: HTN associated with
– Proteinuria (no longer essential for diagnosis)
– Platelets <100,000
– Abnormal LFTs (transaminases ≥ 2x ULN)
– Renal impairment/pulmonary edema/visual
changes
• Gestational HTN: HTN that begins after the 20th
week of pregnancy without end-organ damage
2608
Chronic HTN in pregnancy

• First line choices in pregnancy: nifedipine, labetalol
and methyldopa.
• Diuretic use is controversial in absence of edema; not
favored
• Atenolol has possible increased risk of IUGR: avoid
• Avoid medication that affects the renin-angiotensin
system (Ace I, ARB, mineralocorticoid antagonists)
due to increased risk of fetal renal abnormalities,
IUGR, fetal death
ACOG Guidelines for Hypertension in
Pregnancy www.ACOG.org
Question 18
• A 48 yo male with hypertension, hyperlipidemia and
diabetes is found to have persistent mild elevation of
transaminases. His only medication is lisinopril. He
rarely drinks alcohol.
• BMI is 35 with notable central adiposity. There are
no stigmata of advanced liver disease. Hepatitis
serologies are negative, transferrin saturation is
normal and testing for autoimmune liver disease is
negative. Ultrasound shows diffuse hepatic steatosis.
2609
In addition to weight loss, what is the most
appropriate pharmacologic intervention?
A. Pioglitazone
B. Vitamin E
C. Atorvastatin
D. Ursodeoxycholic acid
E. Metformin
Answer: C
NAFLD spectrum
• Non-alcoholic fatty liver (20% US population)
– No inflammation, low risk of progression to cirrhosis
• NASH (non-alcoholic steatohepatitis) (1.5%-6.5%)
– + inflammation, +/- fibrosis
– 20% will progress to cirrhosis
• NASH cirrhosis
– 2-3% will develop HCC
• Risk factors for more serious disease: DM, high BMI/visceral
adiposity, metabolic syndrome
• Increased mortality: CVD is most common cause
– This patient should have aggressive risk factor reduction and statins should
NOT be avoided
2610
Answer: C
NAFLD spectrum
• Medication should be reserved for patient
with biopsy-proven NASH with fibrosis
• Pioglitazone improves histology in NASH
• long term safety concerns (heart failure, bone loss)
• Vitamin E improves histology in non-diabetic
patients
• possible increase in all cause mortality, prostate cancer
• Metformin, ursodeoxycholic acid have not been
shown to have benefit
AASLD guidelines:
Hepatology 2018;67:328-357
Question 19
• A 35-year-old female presents with complaints of
fever and ankle pain. Her exam is notable for clear
lungs, ankle swelling and dusky, tender nodules on
her lower extremities. A chest x-ray shows bilateral
hilar adenopathy. You diagnose her with acute
sarcoidosis. Which of the following statements
about sarcoidosis is true?
2611
Question 19 (con’t)
A. Sarcoidosis most commonly affects the lungs and
pulmonary function tests typically show obstruction.
B. Sarcoidosis frequently does not require treatment and it
is unclear if treatment helps prognosis.
C. Atrial fibrillation is the most common presentation of
cardiac sarcoidosis
D. A biopsy showing caseating granulomas is required for
diagnosis
E. Sarcoidosis is most commonly seen in white Americans
Answer: B
Sarcoidosis
• Idiopathic granulomatous disease
• 3-4x more common in blacks in the U.S.
• Biopsy: non-caseating granulomas.
• Can affect any organ system; lungs, skin, eyes most
common. Cardiac and CNS sarcoid have highest
morbidity.
• Clinical course ranges from asymptomatic to life-
threatening.
2612
Sarcoidosis
• Lungs most commonly affected (95%). PFTs are
frequently normal; most common abnormality is
restrictive lung disease.
• Most common cardiac symptom is heart block; VT is
the most common arrhythmia.
• Lofgren’s syndrome (case presentation) does not
require biopsy for diagnosis and typically does not
require treatment.
• Many cases do not require treatment and it is not
clear if treatment improves survival.
Question 20
• A 65 yo female presents with 2 weeks of progressive
knee pain that began after an evening of dancing at a
wedding. Pain is worse with climbing stairs. On exam
there is swelling and tenderness about 2 inches
below the joint, medially. The most likely diagnosis is:
A. Meniscal tear
B. Osgood-Schlatter syndrome
C. Iliotibial band syndrome
D. Anserine bursitis
E. Patellar teninditis
2613
Answer: D
Anserine bursitis
• Overuse injury – often develops after new activity
• Inflammation of bursa located between proximal
anteromedial tibia and conjoined tendon (medial
hamstring tendons)
• Risk factors: tight hamstrings, valgus knee
deformity, flat feet, female gender, obesity,
repetitive activities, OA
• Treatment: Icing, stretches, NSAIDs
Question 21
• A 67 yo male presents for follow up after a
spell of L arm weakness that lasted 30 minutes
then resolved spontaneously. His medical
history is significant for HTN and
hyperlipidemia. His neurologic exam is
completely normal. MRI brain/MRA head and
neck showed no infarct or hemodynamically
significant stenosis. Echocardiogram was
normal and 30 day event monitor showed no
arrhythmia.
2614
• Which of the following is the best option for
long-term secondary prevention of stroke in
this patient who has had a TIA?
A. Warfarin
B. Ticlopidine
C. ASA
D. Cilostazol
E. ASA + clopidogrel
Answer: C
Secondary prevention of stroke
• Antiplatelet agents are useful for secondary
prevention; current AHA/ASA guidelines recommend:
– ASA (low doses as effective as high doses)
– ASA + dipyridamole (Aggrenox)
– Clopidogrel
– On average, risk of stroke reduced by 22% with these
agents
• Long term use of ASA + clopidogrel led to an
increased risk of bleeding with no reduction in
vascular risk (MATCH trial)
2615
Answer: C
Secondary prevention of stroke
• Warfarin should not be used in patients with a non-
cardioembolic TIA/stroke
• Ticlopidine is effective for prevention but is
associated with significant side effects (severe
neutropenia, rash, diarrhea) that make it less
desirable.
• Cilostazol has shown some promise in early trials in
Asia but there is insufficient evidence to recommend
it at this time.
Question 22
• 44 yo male presents with pain/stiffness in his hands.
He also notes some erectile dysfunction. He has
recently been diagnosed with diabetes and is being
evaluated for abnormal liver function tests. On exam
he has bony enlargement of 2nd, 3rd MCPs but no
synovitis. What test is most likely to be diagnostic?
A. Anti-nuclear antibody
B. Transferrin saturation
C. Anti-cyclic citrullinated peptide antibody
D. Rheumatoid factor
E. No laboratory testing needed
2616
Answer: B
Hemochromatosis
• Iron overload as a result of mutations in HFE gene;
affects 1 in 200-500 people in US
• Symptoms:
– Early: arthropathy, fatigue, impotence
– Late: diabetes, cirrhosis, cardiomyopathy
• Polyarticular/symmetric arthritis: classic finding is
bony enlargement of 2nd/3rd MCPs without synovitis
• Screen: Fe/TIBC (>60% men, >50% women); positive
screens should be followed by genetic testing.
Question 23
• A 21 yo college student presents to your office
complaining of fever, cough, sneezing and
watery eyes. His medical history is
unremarkable and his immunizations are up to
date. He takes no medications and has no
allergies. Exam is significant for a temperature
of 104o, conjunctival injection, clear lungs.
You also note white spots on a red background
on the buccal mucosa.
2617
Koplik spots
CDC Public Health Image Library
• Which of the following is true regarding this case?
A. Diagnosis is clinical
B. Antiviral medication reduces the duration of
illness
C. Encephalitis is the most common cause of
associated death
D. The patient should be placed on contact
precautions
E. Post-exposure prophylaxis with ciprofloxacin
should be provided for susceptible contacts.
2618
Answer: A
Measles (rubeola)
• Incubation period: 10-12 days post-exposure
• Prodrome: fever (often high), cough, coryza,
conjunctivitis, Koplik spots (pathognomonic)
• Maculopapular rash: 2-4 days after onset of fever
• Rash starts at head and proceeds downwards to
trunk and then extremities
• Contagious 4 days before/4 days after rash develops
• Attack rate for susceptible patients is 90%
• 1 dose MMR 90% protective
• 2 doses MMR 97% protective
Answer: D
Measles (rubeola)
• In US in 2017: 118 cases in 18 states and D.C.
• Diagnosis is clinical with confirmation by PCR of
nasopharyngeal swab/serologies
• Treatment is supportive – anti-virals do not help
• Patients should be placed in respiratory isolation
• 30% of cases have complications
– Most common: otitis media, diarrhea
– Pneumonia most common cause of death
– Rare: encephalitis, seizure, death (0.2%)
2619
Answer: D
Measles (rubeola)
• Susceptible contacts should be vaccinated
within 72 hours of exposure
• IVIG for high risk/immunocompromised up to
6 days post exposure
• Report to local health authority or CDC
immediately
• NO ASSOCIATION between MMR vaccine and
autism
Question 24
Potential drawbacks to randomized controlled
trials include all but the following?
A. Internal validity
B. External validity
C. Selective dropout
D. Ethicality
2620
Answer: A
Trial design
Internal validity: confidence that we can place
in the cause and effect relationship in a
scientific study. Major design goal of RCT.
External validity: generalizability of results to
other populations.
Selective dropout: loss of particular, non-
random participants in a study.
Ethicality: potential conflict between research
goal and responsibility to individual patient.
2621
BIOSTATISTICS BOARD REVIEW
JULIE E. BURING, ScD

Senior Epidemiologist
Division of Preventive Medicine, Department of Medicine
No Disclosures
1
2622
Topics To Be Covered
• Screening (sensitivity, specificity,

predictive value, biases)
• Measuring data
• Frequency (incidence, prevalence)
• Association (ratio, difference)
• Interpretation of data
• Types of studies
• Valid statistical association
SCREENING
2
2623
Question 1
100 women over the age of 50 received mammograms

at a mobile breast cancer screening unit.
27 women had findings suspicious for malignancy on
the mammogram: 19 of these women were confirmed
as having breast cancer by biopsy (true positives).
1 woman had a negative mammogram but in the
subsequent year developed breast cancer, and is
assumed to have had the disease at the time of
screening (false negative).
What is the sensitivity of the mammogram? the
specificity? the predictive value of a positive test?
“truth”
Disease Status
Yes No
+ a b a+b
Screening
Test
- c d c+d
a+c b+d
T+ a
Sensitivity = =
Dx+ a+c
T- d
Specificity = Dx- = b + d
3
2624
Breast Cancer
+ -
+ 19 8 27
Mammogram
- 1 72 73
20 80 100
T+ 19
Sensitivity = Dx+ = = 95%
20
T- 72
Specificity = Dx- = 80 = 90%
“truth”
Disease Status
Yes No
+ a b a+b
Screening
Test
- c d c+d
a+c b+d
Dx+ a
Predictive Value (+) = PV(+) = = a+b
T+
Dx- d
Predictive Value (-) = PV (-) = = c+d
T-
4
2625
Breast Cancer
+ -
+ 19 8 27
Mammogram
- 1 72 73
20 80 100
Dx+ 19
PV (+) = = = 70%
T+ 27
Dx- 72
PV (-) = T- = 73 = 99%
What influences sensitivity,

specificity, and predictive value?
5
2626
Question 2
In a Mantoux tuberculosis screening program in a

high risk population, a positive test was defined as
10 mm of induration. If guidelines change, and a
positive test is now defined as only 5 mm of
induration, which of the following will be true?
More than one answer may be correct.
A. Sensitivity will increase
B. Specificity will decrease
C. Positive predictive value will increase
D. False positives will increase
E. False negatives will decrease
“Criterion of positivity” influences both

sensitivity and specificity of the screening test:
Criterion of positivity sensitivity

specificity
Criterion of positivity sensitivity

specificity
PV+ affected by sensitivity and specificity, but

increased mainly by increase in underlying
disease prevalence (like screening a higher risk
group).
6
2627
Question 2
In a Mantoux tuberculosis screening program in a
high risk population, a positive test was defined as
10 mm of induration. If a positive test is now
defined as only 5 mm of induration (i.e., ↓ the
criterion of positivity), which of the following will
be true? More than one answer may be correct.
A. Sensitivity will increase
B. Specificity will decrease
C. Positive predictive value will increase
D. False positives will increase
E. False negatives will decrease
Correct answers: A, B, D, E
What are issues in the interpretation

of screening results?
7
2628
Question 3
A randomized trial was conducted to evaluate the effectiveness of a

new screening program for colon cancer.
Among those patients whose cancers were detected by the screening
program, average age at diagnosis was 54 years and average age at
death was 60 years: thus, average survival from diagnosis to death
was 6 years.
For patients whose cancers were detected by clinical symptoms,
average age at diagnosis was 56 years and average age at death was
60 years: thus, average survival from diagnosis to death was 4 years.
The investigators reported a statistically significant 2 year increase in
survival from colon cancer associated with screening.
This mistaken conclusion is most likely due to:
A. The play of chance
B. Confounding by stage of disease at diagnosis
C. Lead time bias
D. Length bias
Lead Time
Death
screen symptoms
60 years
54 years
60 years
56 years
Incorrect Conclusion: 2 year increase in survival with

screening. Really just advanced diagnosis by 2 years.
Problem: Lead time bias (Correct answer “C”)
Solution: Compare age-specific (ex. at age 60) mortality
rates
8
2629
MEASURING DATA
Measuring Data
• Measures of disease frequency

• Measures of association
• How do we refer to these measures?
• How do we calculate these measures?
9
2630
Question 4
In each statement below, data are presented

based on the Framingham Study of coronary
heart disease. Chose the measure which best
describes each of these statements.
A. Prevalence measure
B. Incidence measure
C. Standardized morbidity ratio
D. Age-specific measure
E. Age-adjusted measure
number of existing cases at a point in time

Prevalence =
total population
number of new cases during a period of time

Incidence =
population at risk
Prevalence and incidence can be overall, or can be

category-specific (e.g. age-specific)
observed cases
Standardized morbidity ratio:
expected cases
10
2631
1. At the initial examination, 17 persons per

1,000 had evidence of coronary heart disease:
1. At the initial examination, 17 persons per 1,000

had evidence of coronary heart disease:
Prevalence measure
11
2632
3. During the first eight years of the study,

45 persons developed coronary heart disease
per 1,000 persons who entered the study free
of coronary heart disease:
3. During the first eight years of the study,

45 persons developed coronary heart disease
per 1,000 persons who entered the study free
of coronary heart disease:
Incidence measure
12
2633
4. At the initial examination, 31 persons aged

45 to 62 had coronary heart disease per
1,000 persons examined in this age group:
4. At the initial examination, 31 persons aged

45 to 62 had coronary heart disease per
1,000 persons examined in this age group:
Age-specific prevalence measure
13
2634
How do we calculate incidence

and prevalence?
Question 5
At the beginning of 2013, 800 people diagnosed

with diabetes lived in small town, which had a
mid-year population estimated at 10,000.
During that year, 200 new cases of diabetes were
diagnosed in the town and 40 people died of
complications of diabetes.
14
2635
• during 2013, 200 new cases diagnosed

• estimated midyear population = 10,000
• on 1/1/13, 800 diabetics in city
• during 2013, 40 died from diabetes
A. Incidence measure per 1,000 population

during 2013:
• in 2013, 200 new cases diagnosed

A. Incidence measure per 1,000 during 2013:

200 20
I= 10,000 = 1,000
15
2636

B. Prevalence measure per 1,000 on 1/1/13:

B. Prevalence measure per 1,000 on 1/1/13:

80
P = 800 =
10,000 1,000
16
2637

C. Prevalence measure per 1,000 on 12/31/13:

C. Prevalence measure per 1,000 on 12/31/13:
800+200-40 96
P = = 1,000
10,000
17
2638

D. Mortality due to diabetes per 1,000 general

population during 2013:

D. Mortality (differentiated from case-fatality)

due to diabetes per 1,000 during 2013:
40 4
M = =
10,000 1,000
18
2639
E. If the prevalence of diabetes in 2013 is

greater than that in 1950, this could be due
to:
A. A change in the incidence rate
B. A change in the duration of the
disease
C. Either (A) or (B) or both
The proportion of the population that has a

disease at a point in time (prevalence)
depends on both the rate of development of
the disease in the population (incidence) as
well as the duration of the disease from onset
to termination (death or cure). Under steady
state, P = I x D.
Thus, a change in prevalence can reflect a
change in incidence, a change in duration, or
both. (Answer “C“: either A or B or both).
19
2640
How do we calculate measures of

association?
Question 6
The table below gives the annual mortality rates

from lung cancer and coronary heart disease
among cigarette smokers and nonsmokers in a
cohort study of British male physicians.
Annual Mortality Rates per 100,000
Lung Coronary
Cancer Heart Disease
Cigarette smokers 140 669
Nonsmokers 10 413
20
2641
RELATIVE RISK (RR): Incidence in the

exposed group divided by Incidence in
nonexposed group: RR = Ie / Io
• Measure of the strength of association
• If no association, RR = 1
ATTRIBUTABLE RISK AMONG EXPOSED:
ARe = Ie - Io
• Assuming exposure causes outcome,
measure of public health impact among
the exposed
• If no association, AR = 0
Mortality rate/100,000
Coronary
Lung Cancer Heart Disease
Smokers 140 669
Nonsmokers 10 413
Ie 140/100,000
RR (Lung Cancer) = = = 14
Io 10/100,000
Those who smoke have 14x the risk of dying

from lung cancer as nonsmokers.
21
2642
Coronary
Smokers 140 669
Nonsmokers 10 413
Ie 669/100,000
RR (CHD) = = = 1.6
Io 413/100,000
Those who smoke have 1.6x the risk (or 60%

increased risk) of dying from CHD, compared to
nonsmokers.
Coronary
Smokers 140 669
Nonsmokers 10 413
ARe (Lung Cancer) = Ie- Io = 140/100,000 - 10/100,000

= 130/100,000 smokers
Assuming smoking causes lung cancer, for every
100,000 smokers, 130 cases of lung cancer are due
to their smoking, or could be eliminated if smoking
were eliminated.
22
2643
Coronary
Smokers 140 669
Nonsmokers 10 413
ARe (CHD) = Ie-Io = 669/100,000 - 413/100,000

= 256/100,000 smokers
Assuming smoking causes heart disease, for every
100,000 smokers, 256 cases of CHD are due to their
smoking, or could be eliminated if smoking were
eliminated.
Based on these data, is smoking a stronger risk

factor for lung cancer or CHD?
Lung cancer, since the RR for lung cancer is

greater than for heart disease.
23
2644
But if smoking were eliminated, could more

deaths be eliminated among smokers from lung
cancer or CHD?
Coronary heart disease, since the ARe for heart

disease (256/100,000 smokers) is greater than
for lung cancer (130/100,000 smokers). This
reflects that the baseline risk of CHD mortality
(413/100,000) is much higher than lung cancer
mortality (10/1000,000); thus even a small
decreased risk could affect a much larger
number of people on an absolute scale.
Number Needed to Treat
24
2645
Nonfatal MI or
Death from CHD
Pravastatin 212 1869 2081
Placebo 274 1804 2078
486 3673 4159
• RR = Ie = 212/2081 = 0.77
Io 274/2078
Those on pravastatin have a 33% lower risk of nonfatal
MI or death from CHD.
• ARe = Ie- Io = 212/2081 - 274/2078 = - 0.03
Note negative sign: 3 per 100 of the nonfatal MIs or
CHD deaths in the placebo group could have been
prevented by use of pravastatin, assuming causality.
• NNT = Number needed to treat = 1

ARe
= 1
0.03
= 33
We would need to treat 33 patients over 5 years
(median duration of follow-up) in order to prevent
one nonfatal MI or CHD death.
25
2646
INTERPRETATION OF DATA
• Types of studies
• Valid statistical association
Question 7
The association between low birth weight and
maternal smoking during pregnancy was
studied by obtaining smoking histories from
women at the time of their first prenatal visits
and comparing subsequent birth weights
among women with various smoking histories
What type of study is this?
A. Case-control study
B. Cohort study
C. Randomized clinical trial
D. Cross-sectional survey
26
2647
Case Control
Exp D
Cohort
Exp D
Clinical Trial (investigator allocates)
Exp D
Cross-sectional Survey
Exposure, Outcome
The association between low birth weight and

maternal smoking during pregnancy can be
studied by obtaining smoking status at time of
their first prenatal visit (EXPOSED VS
NONEXPOSED) and then comparing subsequent
birth weight (OUTCOME) with these smoking
histories. What type of study is this?
A. Case-control study
B. Cohort study
C. Randomized clinical trial
D. Cross-sectional survey
Correct answer: B
27
2648
Question 8
A case-control study was undertaken to evaluate the
relationship between maternal smoking during
pregnancy and low birth weight. A total of 350
mothers of low birth weight babies and 400 mothers
of normal weight babies were interviewed. Of the
mothers of low birth weight babies, 200 reported
smoking during the pregnancy, while 200 of the
mothers of the normal weight babies also reported
such a history.
What is the magnitude of the association between
smoking and birth weight? Is the observed
association valid?
Birth Weight
low normal
yes 200 200

a b
Smoking
no 150 200
c d
350 400
Measure of association in a case-control study is the odds

ratio (OR), which is a valid estimate of the relative risk:
ad
OR = bc
28
2649
Birth Weight
low normal
yes 200 200

a b
Smoking
no 150 200
c d
350 400
ad 200 (200)
A. OR = = = 1.3
bc 200 (150)
Mothers who smoke during pregnancy have 1.3 times the
risk, or a 30% increased risk, of having low birth weight
baby. Magnitude of association.
Validity of an Association
• To determine if an association observed in a

study is internally valid, we need to rule out
alternative explanations for the findings:
Chance
Bias
Confounding
• Versus external validity – generalizability of

study results
29
2650
• Chance: role of sampling variability.
• Bias: any source of systematic error in

the determination of the association.
• Confounding: mixture of effect between

the association under study and a third
variable, which may be responsible in
part or totally for the association seen.
1. In comparing the association between the two

groups (OR = 1.3), the p-value is found to be
0.20. The correct interpretation of this result is:
1. The null hypothesis is rejected.
2. The association is statistically significant.
3. The association did not occur by chance.
4. The association is compatible with the null
hypothesis.
5. Sampling variation is an unlikely explanation
of the association.
30
2651
The p-value is the probability that the observed

data (or data more extreme) would occur due to
the effects of chance alone, given that the null
hypothesis is true (H0, that there is truly no
difference, no association between the two
groups).
• If P <0.05, reject H0, association is statistically

significant at 0.05 level.
• If P >0.05, cannot reject H0, association is not

statistically significant at 0.05 level.
• P-value does not mean due to chance, or

mean chance is ruled out - relates to
likelihood of chance being an explanation of
the findings.
31
2652
1. In comparing the association between the two

groups, the p-value is found to be 0.20. The
correct interpretation of this result is:
NOTE: P-value GREATER THAN 0.05
1. The null hypothesis is rejected.
2. The associaton is statistically significant.
3. The association did not occur by chance.
4. The association is compatible with the
null hypothesis of no association.
5. Sampling variation is an unlikely
explanation of the association.
2. It is suggested that smoking mothers of

low-birth weight babies would tend to deny
such an activity due to feelings of guilt,
compared to nonsmoking mothers of low
birth weight babies, or smoking mothers of
normal weight babies. This would be an
example of the effects of:
1. Chance
2. Selection bias
3. Recall bias
4. Confounding
32
2653
2. It is suggested that smoking mothers of

low-birth weight babies would tend to
deny such an activity due to feelings of
guilt. This would be an example of the
effects of:
1. Chance
2. Selection bias
3. Recall bias – those with
outcome tend to recall/report exposures
differently than those without
4. Confounding
3. The effect of the situation described in (B)

(smoking mothers of low-birth weight babies
tend to deny such an activity) would be to
result in an observed relative risk which is
an:
1. Underestimate of the true relative risk.
2. Overestimate of the true relative risk.
3. The same as the true relative risk.
33
2654
3. The effect of the situation described in (B)

(smoking mothers of low-birth weight babies
tend to deny such an activity) would be to
result in an observed relative risk which is
an:
1. Underestimate of the true relative risk:
smoking won’t look as bad as it actually is.
2. Overestimate of the true relative risk.
3. The same as the true relative risk.
4. It was also observed that mothers of low

birth weight babies tended to be younger
than the mothers of the normal-weight
children. Moreover, smoking rates are
known to be higher in younger women in
this population. This would be an example
of the effects of:
1. Chance
2. Selection bias
3. Recall bias
4. Confounding
34
2655
SMOKING LOW BIRTH WEIGHT
MATERNAL AGE (3rd factor)
Correct answer: 4 - Confounding

If maternal age (the confounder) is uncontrolled,
will overestimate true association between
smoking and low birth weight.
TAKE HOME MESSAGE
• Limited number of necessary concepts in

Biostatistics for the Boards
• TRUST YOUR INSTINCTS
35
2656
No Disclosures
References
1. Fletcher RH, Fletcher SW. Clinical Epidemiology, The
Essentials. 5th Edition. Lippincott Williams and
Wilkins. 2012.
2. Glantz SA. Primer of Biostatistics. 7th Edition. McGraw-
Hill. 2011.
3. Hulley SB, Cummings SR, Browner WS, Grady DG,
Newman TB. Designing Clinical Research. 4rd Edition.
Wolters Kluwer. 2013.
36
2657
Morning Report 2018
Associate Program Director, Internal Medicine Residency
• I have no disclosures to report.
2658
Image of the Day

• 25 year old gentleman comes to see you for
better control of his diabetes.
• His past medical history is notable for type 2

diabetes first diagnosed 6 years ago and
hypertension diagnosed 3 years ago.
• Initially, he was placed on metformin but due to

gradually poorer control of his diabetes, he was
started on insulin.
Image of the Day

• Current regimen:
– Metformin 1000 mg bid
– Insulin glargine 20 U qhs
• Very motivated, carefully follows an ADA diet

and exercises on a regular basis.
• Frustrated that his lifestyle changes are not

making a difference in his diabetes control. His
blood sugars are in the 200s again.
2659
2660
Signs and Symptoms of

Acromegaly
• Enlarged jaw • Voice deepening
• Enlarged, swollen • Diabetes
hands and feet • Hypertension
• Coarse facial features • LVH
• Nose enlargement • Organomegaly
• Spreading of teeth • Colonic polyps and
• Joint pains colon cancer
• Skin tags • Sleep apnea
• Macroglossia
2661
Diagnosis of Acromegaly
• Insulin growth factor -1 (IGF-1)
• If IGF-1 elevated
– OGTT with growth hormone levels
– Suppression of GH to < 1ng/mL in normals
Patient Course
• IGF-1 and Growth Hormone levels were
elevated
• Imaging confirmed a pituitary tumor
• Transphenoidal surgery with cure
2662
Secondary Causes of
Hyperglycemia
• Acromegaly
• Cushing’s Syndrome
• Pheochromocytoma
• Adrenal Insufficiency
• Hyperthyroidism
• Glucagonoma
• Somatostatin-secreting tumors
• Pancreatic disease
• Medications (i.e. glucocorticoids, atypical
antipsychotics, HIV protease inhibitors)
Case
62 year old housewife and mother of four children came
in for evaluation of hair loss.
“If I go bald, I will kill myself.”
She was in good general health.
She did have a history of hypothyroidism. Positive

thyroid peroxidase antibodies. Euthyroid on replacement.
Tonsillectomy. Appendectomy. Scarlet fever as a child.
2663
First noticed symptoms 3 weeks ago-fair amount

of hair in her comb.
Two days prior, she saw her hairdresser who

told her “you have huge bald spots” and asked
her if she was ill.
No weight loss, fevers, chills, sweats, rash,

weight change, change in urinary or bowel
habits, bruising, change in skin pigmentation.
Her husband and children were well. Her

mother had died of breast cancer at age
56 and her father from pneumonia and
Alzheimer’s disease at age 82.
2664
BP 105/65 HR 64 RR 10
Several 2 to 6 cm bald spots with broken off

hairs at the edges.
No hair loss over her body.
Normal female escutcheon.
No thyroid nodules.
No lymphadenopathy.
Breast, lung, cardiovascular, and

abdominal exams were unremarkable.
Stool was brown and guaiac negative.
Gait, speech, and cranial nerves all intact.
2665
• WBC 3100/µL (62 P, 28 L, 7 M, 3 E)

• Hematocrit 36%
• Platelets 224, 000/µL
• Kidney and liver function tests normal.
• What additional tests would you want to

perform?
• Iron 18 µg/dL (40-159)

• TIBC 380 µg/dL (250-450)
• Transferrin saturation 5%
• B12 111 pg/mL (250-900)

• MMA 0.6 µmol/L (0-0.40)
2666
Hair Growth Cycle

• Anagen
– Growth phase
– 2-3 years
– 80-90% of follicles
• Catagen
– Involution phase
– 2-3 weeks
• Telogen
– Resting phase
– 3-4 months
– Hair shed at end of telogen (75/day)
– Mature root sheath or club at proximal end
Alopecia
• Scarring
– Associated fibrosis, inflammation, and loss of
hair follicles
– Smooth scalp with decreased # of follicular
openings
• Non-scarring
– Hair shafts gone but follicles preserved
– Potentially reversible
2667
Non-scarring and Scarring Hair Loss
Shapiro J. N Engl J Med 2007;357:1620-1630
Scarring Alopecia
• Discoid lupus
• Sarcoidosis
• Lichen Planus
2668
Non-scarring Alopecia
• Androgenetic telogen effluvium
• Alopecia areata
• Tinea capitis
• Traumatic alopecia
• SLE
• Secondary syphilis
• Hypothyroidism, hyperthyroidism
• Hypopituitarism
• HIV
• Deficiencies of protein, iron, biotin, zinc
• Medications
Androgenetic Alopecia
• Most common type of hair loss: 30-40% of adult men
and women
• Genetically determined shortening of anagen phase

(shorter, thinner hair shafts)
• Increased sensitivity of the hair follicles to androgens or

increased levels of androgens
• Anterior/midline scalp
• Polygenic inheritance/variable penetrance
2669
• Women less than men
– Fewer androgen receptors in hair follicles
– Less 5 α-reductase activity ( T DHT)
– Increased aromatase ( T E2)
• Rule out androgen excess in women

– Acne
– Hirsutism
– Male escutcheon
– Clitoromegaly
2670
Telogen Effluvian
• Most common cause of diffuse hair loss
• Diffuse shedding of normal hairs (clubbed hairs)
• Often follows major illness or postpartum
• Pull test
– Grasp around 30 hairs. If more than 5 club hairs come out –
abnormal
• Thyroid disease, iron deficiency, lupus
• Usually regrows in 3-4 months
Alopecia: Pull Test
2671
Alopecia Areata
• Common (1/1,000)
• T cell infiltrates around hair follicles
• Associated with other autoimmune diseases (vitiligo,

thyroiditis, and pernicious anemia)
• Smooth, circular discrete area of complete hair loss
• Black dots of hair broken a few mm from scalp at edge of

lesion
Alopecia Areata
• May have hair loss on body and/or pitted
nails
• Plucked hairs look like exclamation points

(narrow, rather than clubbed at the base)
• Develops over a few weeks, regrows in a

few months (90%)
2672
Clubbed Hairs
Springer et al, AFP, 2003
Alopecia Evaluation
• TSH
• Iron/TIBC
• Rule out trauma
• Meds: warfarin, heparin, PTU, vitamin A,
lithium, beta blockers, clonidine,
amphetamines
• ANA, VDRL
• Vitamin B12
2673
EKG of the day
Brugada Syndrome
•Elevated J point, ST segment in V1-2
•Brugada Syndrome vs. Brugada Pattern
•Inverted T Type 1; upright T in Types 2-3.
•Polymorphous VT/sudden death
•Often familial
•Channelopathy – usually Na+
•Occasionally can be provoked by Type 1 anti-
arrhythmics, stress
•See similar ST-T abnormalities in lateral leads in
hypothermia, hypercalcemia.
2674
Case
59 year old man with an extensive cardiac
history including CAD and VT, who presented
with epistaxis.
He had been quite ill over the last 4 weeks.
4 weeks previously
• The patient was hospitalized for AICD
interrogation due to multiple discharges.
• During his 10-day hospital stay both a

fractured lead and malfunctioning
epicardial patch were replaced via
thoracotomy.
2675
4 weeks previously
• Post-operative fevers were treated with 5
days of vancomycin, cefazolin and
levofloxacin. All cultures were negative,
and antibiotics were discontinued.
• The patient was still having low grade

temperatures when he was discharged.
Presentation
• In the post-discharge period, the patient
experienced malaise, fatigue, anorexia with an 8
lb weight loss, and diarrhea.
• He reported no tactile fevers.
• One day prior to admission, he developed a

right-sided headache, without visual changes,
nuchal rigidity, altered speech or local
weakness.
2676
Day of admission
• On the day of admission, the patient developed
new epistaxis that did not resolve with local
compression. He also noticed blood in the
sclera of his right eye.
• On route to the ED, family members noted left

leg and right arm shaking associated with mild
confusion but no loss of consciousness.
Additional ROS
• No bladder or bowel incontinence.
• No chest pain, orthopnea or palpitations.
• No head trauma.
2677
Past Medical History

• DM2
• CAD (s/p MI and CABG • CVA in 1997
in 1996) • Hypertension
• ICM (EF=40%) • Hypercholesterolemia
• VT (s/p AICD placement • Obesity
in 1999, revised 4 weeks
previously)
• Diverticulitis
Medications
• Lisinopril 40 mg po qd
• Atenolol 50 mg po qd
• Amiodarone 200 mg po qd
• Warfarin 5mg po qd
• Aspirin 325 po qd
• Ranitidine 150 mg po bid
2678
Allergies: NKDA
Soc Hx: Lived in the North End with a stable

male partner. No known TB risk factors. No
tobacco, intravenous drugs, or significant
alcohol use.
Fam Hx: Father- lung cancer, Mother - stroke
Physical Exam
T-101.4oF P-80 BP-146/60 RR-20
O2 sats - 96% on 2L oxygen by NC
General: Awake, diaphoretic, soaked through his

clothes, confused but followed simple
commands.
Skin: Multiple ecchymoses. Mild incisional

erythema, but no evidence of external chest
wound breakdown or drainage. Poor skin
turgor.
2679
Physical Exam (cont’d)

• HEENT: Right conjunctival hemorrhage.
EOMI.
• Neck: supple. JVP flat.
• Lungs: Bibasilar crackles.
• CV: RRR. 2/6 SEM. No peripheral edema.
• Neuro: Tremulous. Reflexes 3-4+.
Labs
10.5 139 107 55

9.5 243 132
31.2 4.4 27 1.1
MCV- 87
PTT- 55.6 Ca-9.5 Mg-1.6

INR – 12.7 PO4-4.4 TP-5.9
Alb-4.7 CKMB (-)
2680
Studies
CXR - Cardiomegaly, no infiltrates, AICD in place
ECG - Old anterior-septal MI. No change from

previous study
Head CT - Subdural hematomas affecting bilateral

frontal areas; right internal capsule CVA (likely
old)
Hospital Course
• FFP and vitamin K therapy were initiated.
• Persistent fevers developed with Temps 101-102oF.

Blood, sputum and stool samples were obtained for
microbiologic study. Pan CT scans showed no source on
infection.
• ID and Neurology consultations were obtained.
• Phenytoin was initiated for question of seizure-like

activity.
2681
Hospital Course (cont’d)

• The patient remained febrile.
• Blood cultures, lumbar puncture,

echocardiography and serologies for HIV and
syphilis failed to explain the fevers.
• By hospital day 5, severe hypernatremia

developed (Na 163) with worsening mental
status.
• Temp was 104.5. RR 40
2682
• >38.00C for 3 days
Roth, AFP, 2003
Roth, AFP, 2003
2683
Rare Miscellanous Causes

• Atrial myxoma
• Familial Mediterranean Fever
• Histiocytosis
• Whipple’s disease
• Thyroiditis and Thyrotoxicosis
Hospital Course
• TFTs ordered:
• TSH <0.01 (0.5 -5 uU/mL)
• T4 18.5 (4.5-10.9 ug/dL)
• THBI 2.51 (0.77-1.23)
• FT4I 46.4 (4.5-10.9)
• T3 343 (60-181 ng/dL)
• Concern was for amiodarone induced

hyperthyroidism
2684
Treatment
• Methimazole 30 mg per rectum q6 hrs was
initiated, but later changed to
propythiouracil (PTU) 400 mg pngt q 6 hrs.
• Methylprednisolone 60 mg iv q12 hrs
• Iopanoic acid 1 gm qd
Treatment
• Pulmonary aspiration was felt to have
occurred in the setting of delirium and
agitation.
• Despite anti-thyroid therapy, the patient

developed hyperpyrexia (T=107oF) and
increased clonus.
• A diagnosis of Thyroid Storm was made,

and the patient underwent
thyroidectomy.
2685
Follow-up
• The patient’s temp dropped quickly after
the thyroidectomy.
• The patient was discharged after a 3 week

hospital course.
• At follow-up, he had returned to his

previous level of function.
Thyroxine and Amiodarone
2686
Amiodarone
• 75 mg of iodine per 200 mg tablet
• 10% of iodine released as free iodide daily
• Average daily iodine intake in US is 0.15-0.30

mg.
• ½ life is 100 days
(Daniels, JCEM, 2001; Basaria and Cooper Am J Med, 2005)
Amiodarone and Thyroid Function
(Basaria and Cooper, Am J Med, 2005)
2687
Chronic Amiodarone Treatment
(Melmed et al. JCEM, 1981)
Probability of Thyroid Disease with

Amiodarone Treatment
(Trip MD et al., Am J Med, 1991)
2688
Amiodarone and Hyperthyroidism
(Daniels, JCEM, 2001)
Severe Hyperthyroidism -
Treatment
• Thyroid gland
– Inhibit synthesis – PTU, Methimazole
– Inhibit TH release – Iodine, Lithium
– Surgery
• Peripheral Effects of TH
– Inhibit T4 to T3 conversion – PTU, steroids, iopanoic acid,
propranolol
– Removal of excess thyroid hormone – plasmapheresis
• Systemic Decompensation
– Treat hyperthermia – Tylenol, cooling
– Correct dehydration and nutritional deficits – fluids, electrolytes
– Supportive therapy – pressors, treat CHF, steroids
2689
Anticoagulation and Hyperthyroidism

• Hyperthyroidism increases metabolism of
vitamin K-dependent clotting factors
• Altered protein binding of warfarin
• Enhanced affinity of warfarin for its

receptors
(Chute et al., Endo Practice, 1997)
Lab of the Day

• 36 year old woman with diabetes, liver disease,
and HIV comes to see you in follow-up.
• She says that her blood glucose has been very

elevated – consistently in the 250s.
• She believes this is due to poor diet.
• You counsel her regarding diet and exercise,

refer her to a nutrionist, and order a hemoglobin
A1c.
2690
Lab of the Day (cont’d)

• Her HgB A1c returns at 6.8%.
• You are surprised at this hemoglobin A1c.

What value did you expect?
Hemoglobin A1c (%) Average blood glucose

(mg/dL)
6 135
7 170
8 205
9 240
10 275
(Hemoglobin A1c x 33) - 60
2691
Lab of the Day (cont’d)

• Why is there a discrepancy?
– Glucometer
– Timing of testing
– Assay
– Treatment of iron, folate, or vitamin B12

deficiency
– Hemolysis
Hemoglobin A1c
• Red blood cells are freely permeable to glucose
• Glucose irreversibly attaches to the hemoglobin
• The hemoglobin A1c represents 3 months of

blood sugar readings because of the lifespan of
red blood cells
• Increases in red blood cell turnover falsely low

hemoglobin A1c
2692
Our patient
• Hct 36%
• Iron studies, folate, and B12 all normal and not on recent
treatment for deficiencies
• LDH 285 (107-235 U/L)

• Haptoglobin <8 (30-200 mg/dL)
• She has hemolysis – probably from her liver disease.
• How could you check her blood sugar control?
Fructosamine
• Measure of glycosolated end products
• Her level was 538 (0-285 umol/L).
2693
Case
44 year old private investor presented to
his PCP with low libido of one year’s
duration.
He has been married for seven years. Had

his first child one year ago.
The decline in his libido was gradual.
He is healthy and active, loves outdoor activities and

building ships.
Increasing fatigue over the past year has limited his time
outdoors.
Does not feel depressed. Has no other signs or

symptoms of a systemic illness including no fevers,
chills, headaches, weight changes, changes in his hair or
skin texture, bowel movements.
His only medical problem is mild hand arthritis.
2694
What more would you want to know?
Low libido
• Psychiatric: depression, anxiety disorder
• Medications: SSRIs, anticonvulsants, antihypertensive
medications
• Systemic illness
• Recreational drugs
• Androgen deficiency
• Thyroid disease
• Erectile dysfunction
2695
Normal pubertal development.
In addition to the low libido, he has noticed

decreased morning erections and decreased
ejaculatory volume.
No change in frequency of shaving, no breast

enlargement, or change in testicular size.
No headaches, vision changes.
No medications.
No tobacco, rare ETOH, no illicit drug use.
Family history unremarkable for thyroid

disease, delayed puberty, infertility.
2696
• Ht 6’4”, Wt 162 lb, BP 128/82, P 84, RR 10
• Gen: non-eunochoidal
• HEENT: PERRL, EOMI, Visual fields full
• Thyroid: normal in size and without nodules.
• No gynecomastia
• Lung, cardiovascular, and abdominal exams normal.
• GU: testes 10 cc bilaterally, nl phallus
• Hair: No change in male distribution of body hair
• Neuro: normal muscle bulk and strength.
Labs
• Testosterone 36 ng/dL (270-1190)
• TSH and prolactin normal
2697
Male Hypothalamic-Pituitary-Gonadal Axis
Hypothalamus
GnRH
Pituitary
LH
FSH Testosterone
Estradiol
Inhibin B
Testes
Male Hypothalamic-Pituitary-Gonadal Axis
Normal Secondary Primary
LH
FSH
2698
Labs
• Testosterone 40 ng/dL
• LH 1.5 U/L (2.4-5.9)
• FSH 1.3 (0.9-15.0)
Further Evaluation
• MRI of the pituitary gland revealed no
masses.
• Bone density scan: spine T score -2.5
• Semen analysis – azoospermia
• CBC Hct 36.1%
2699
Secondary Hypogonadism:
Acquired
• Benign tumors & cysts • Critical Illness

• Malignant tumors • Chronic systemic illness
• Infiltrative diseases • Glucocorticoids
• Infections • Chronic opiate use
• Pituitary apoplexy • Adult-onset
• Trauma Hypogonadotropic
• Radiation Hypogonadism
Infiltrative Diseases
• Hemochromatosis
• Sarcoidosis
• Eosinophilic granulomatosis
• Fe = 219 ug/dL (40-159 ug/dL)

• TIBC = 257 ug/dL (250-450 ug/dL)
• Transferrin saturation = Fe/TIBC = 85.2%
• Ferritin = 2435 ug/L (20-400 ug/L)
• HFE testing: C282Y homozygote
2700
Hemochromatosis and
hypogonadism
• Secondary
– Deposition in the pituitary gland
• Primary – much less common

– Deposition in the testes
Hemochromatosis and recovery

of function
• Little, if any, data
• Most say that if >40 years old, gonadal function

does not recover
(Cundy et al., Clin Endo, 1993)
2701
Summary
• Secondary causes of diabetes
• Acromegaly
• Alopecia evaluation
• Brugada Syndrome
• Fever of unknown origin
• Amiodarone and the thyroid
• Extreme hyperthyroidism/thyroid storm
• Potential inaccuracies in hemoglobin A1c
• Hypogonadism
• Hemochromatosis
References
• Bhasin S et al. Testosterone therapy in men with androgen deficiency syndromes: an
Endocrine Society clinical practice guideline. J Clin Endocrinol Metab 2010; 95: 2536.
• Brugada J et al. Right bindle-branch block and St-segment elevation in leades V1

through V3: a marker for sudden death in patients withour demonstrable stuctural
heart dissease. Circulation 1998; 97: 457.
• Daniels GH. Amiodarone-induced thyrotoxicosis. J Clin Endocrinol Metab 2001; 86: 3.
• Klubo-Gwiezdzinska J, Wartofsky L. Thyroid emergencies. Med Clin Norh Am 2012;

96: 385.
• Shapiro J. Clinical practice: har loss in women. NEJM 2007; 357: 1620.
2702
• I have no disclosures to report.
2703
General Internal Medicine

Cases and Questions
Lori Wiviott Tishler, MD
VP Medical Affairs
Commonwealth Care Alliance
Division of General Medicine
• Nothing to declare
2704
Case One
High Risk Breast Cancer

Screening
A healthy 38 year old woman

presents to your office for an
annual. Her 46 year old sister
was recently diagnosed with
breast cancer. She wonders,
“Should I have an MRI?”
2705
•Past Medical History: benign breast biopsy at

28, 2 normal pregnancies at 32 and 34.
Menarche at age 11. Regular periods.
•Medications: IUD
•Family history: sister as above, mother with
post menopausal breast cancer at 65,
maternal aunt with ovarian cancer. CAD on
the paternal side, and thyroid disease in a
3rd sibling.
•Social Hx: She’s married with 2 kids,

works as a teacher, active in her
synagogue. No dv, alcohol, or street
drugs. No tobacco.
•Her physical exam is completely

normal.
2706
What is her lifetime risk of

breast cancer?
A. 8%
B. 15%
C. 20%
D. 35%
E. 40%
What is her lifetime risk of

breast cancer?
A. 8%
B. 15%
C. 20%
D. 35%
E. 40%
2707
Risk Assessment
While in the office, you go to
www.cancer.gov/bcrisktool
and answer the following
questions
NCI Risk Model

Gail Model
• Race/Ethnicity White
• History of breast cancer,DCIS,LCIS No
• Age 38
• Age at Menarche 7-11
• Age at first live birth >30
• First Degree relatives >1
• Biopsies? Yes
• How many 1
• Any with atypical hyperplasia No
2708
Caveats
Underestimates risk for people who are
gene positive.
Developed for populations, not individuals
Does not factor in other risks,including

breast density, chest wall radiation.
What is the recommended

screening for our patient?
Annual clinical breast exam and:

A. Annual mammogram starting at 35?
B. Mammograms every 6 months starting at 35?
C. Mammogram one year; MRI the next?
D. Both MRI and mammogram every 6 months
E. Mammogram and MRI every year.
2709
What is the recommended screening for

our patient?
A. Annual mammogram starting at 35?

B. Mammograms every 6 months
starting at 35?
C. Mammogram one year; MRI the next?
D. Both MRI and mammogram every 6
months
E. Annual mammogram and annual MRI,
6 months apart
Key Points
These recommendations are mammogram and MRI for women with a lifetime
risk of breast cancer of 20% or more.
Consider referring for genetic counseling for people at high risk.
USPSTF recommendations would not apply to her because of her high risk.
Keep your eyes on data around breast density and new risk calculators, e.g
https://tools.bcsc-scc.org/BC5yearRisk/calculator.htm (not lifetime risk)
2710
My Mother-in-Law
On her way out of the office, she stops to

ask you about whether her mother-in-
law, now 86 with progressive dementia
and Parkinson’s Disease should still have
mammograms. Her mobility and
comprehension are severely limited and
she’s been living in a skilled nursing
facility.
Screen Mother-in-Law?
1.It’s up to the family and her mom

2.It’s up to the family and her mom,
but I recommend it!
but I really suggest that it’s not
necessary
2711
Screen Mother-in-Law?
1.It’s up to the family and her mom

but I recommend it!
but I really suggest that it’s not
necessary
When to Stop Screening?
There is no good evidence for screening after the age of 74.
What is the woman’s overall health status?
What is her preference?
Does she have a 5-10 year life expectancy?
How would she act upon a cancer diagnosis?
2712
Case Two
E-Cigarettes
“I’m smoking…Again”
But this time, I’m trying e-cigs. I
think they are better for me. What
do you think?
By the way, what’s a Juul? My

daughter mentioned that kids are
using them in high school.
2713
What do you think?
2714
Since you don’t think the “uh, I don’t know

would be a good answer,” you turn to your
desktop resource of choice and learn that
there is little good literature on e-cigs, but
that they function by delivering a nicotine-
containing vapor that contains fewer toxins
that a regular cigarette, that they are not FDA
approved, and that no one really knows if
they help people to quit smoking.
Are E-Cigarettes or Varenicline better at

24 weeks
A. E Cigarettes
B. Varenicline
2715
Are E-Cigarettes or Varenicline better

for sustained quitting in 24 weeks
A. E-cigs
B. Varenicline
E-Cigarettes
About 20.3% of current smokers who had tried to quit in

the last year were current e-cigarette users.
One study with e-cigarette users (only 40 patients) did

decrease smoking after 24 weeks
Varenicline for 24 weeks significantly increased quit rate

(37.8% vs. 12.5 for placebo)
JAMA Int Med, May 2014
2716
In addition to trying to figure out the

best method to quit, the patient is
very concerned about weight gain
after quitting smoking. She wonders
what the average weight gain is:
How much weight can I

expect to gain?
A. The average weight gain is
11 lbs over 5 months
B.16 lbs over 5 months
C.30 lbs in a year
D.20 lbs in a year
2717
How much weight can I

expect to gain?
A. The average weight gain
is 11 lbs over 5 months
B.16 lbs over 5 months
C.30 lbs in a year
D.20 lbs in a year
Weight Gain After Quitting

•It’s a reality.
•One of the most common reasons
for relapse
•Benefits usually outweigh the
downside
•Average is about 11 lbs
2718
Cases 3 and 4
Red Eyes
Case 3
50 year old man comes in with a huge
red area in his eye. He is in good health
and recently carried many boxes to the
attic. No pain in the eye. Vision is
20/20. He’s worried that this occurred
because he’s missed his
antihypertensive meds over the last few
days.
2719
What is Your Diagnosis?

A. Severe Conjunctivitis
B. Subconjunctival Hemorrhage
C. Herpes Keratitis
D. Hypertensive Urgency
E. Acute Angle Closure Glaucoma
2720

A. Severe Conjunctivitis
B. Subconjunctival Hemorrhage
C. Herpes Keratitis
D. Hypertensive Urgency
E. Acute Angle Closure Glaucoma
Case 4
50 year old woman with RA
comes in to see you. Her
disease has been active lately
and she is not feeling well.
Since yesterday, she has had
photophobia and two painful,
red eyes.
2721
On Exam
She’s clearly in pain, worse
with pressure to the eye
Photophobia on exam
ESR is 100
Phenylephrine drops don’t

clear it.

A. Herpes Keratitis
B. Acute Angle Closure Glaucoma
C. Scleritis
D. Episcleritis
E. Rheumatoid Eye
2722

A. Herpes Keratitis
B. Acute Angle Closure Glaucoma
C. Scleritis
D. Episcleritis
E. Rheumatoid Eye
Episcleritis vs. Scleritis

• Acute in onset, may be • Striking, highly
local or diffuse symptomatic course
• Associated with
• Resolves without rheumatologic disease in
treatment 50% of patients
• Vision is not affected • Painful, photophobia
• Phenylephrine drops • Threatens vision
leads to transient • Opthalmologic and
resolution. Sclera systemic treatment
normal underneath warranted urgently
2723
Case 5
Geriatrics: Falls in the Elderly
Case 5
92 year old community
dwelling elderly woman
brought by her 73 year old
daughter because she fell –
Again.
2724
Quickly ascertaining that her only injuries

are wounded pride and a sore bottom,
you review her history. The fall occurred
at home when she got up from the chair
and headed for the bathroom. She lives
alone, doesn’t drive, ignores her walker.
She takes multiple meds including
atenolol, hctz, lisinopril, insulin, and
metformin.
At night she takes amitryptiline

for her diabetic neuropathy.
She also drinks, though she’s
never admitted this to you
and you’ve learned this from
her daughter.
2725
On a Limited Physical Exam,

Which is Most Helpful?
A. Full Neurological Exam
B. Functional Exam
C. Vital Signs
D. Cardiac Exam
E. Joint Exam
On a Limited Physical Exam,

Which is Most Helpful?
A. Full Neurological Exam
B. Functional Exam
C. Vital Signs
D. Cardiac Exam
E. Joint Exam
2726
Functional Evaluation: The

Get Up and Go Test
Record the time that it takes for a
patient at risk to get up from a chair,
walk 10 feet, and return to the chair.
If this takes more than 30 seconds,
they have impaired mobility and are
at greater risk for a fall.
Results
You do the “up and go” test and she
scores 31 seconds, a marker of impaired
mobility. You send the visiting nurses in
to do a home safety assessment, stress
the importance of using her walker at all
times, stop the elavil and try something
else for her neuropathy. You address
the alcohol again as well.
2727
What is the Likelihood of

Recurrent Falls?
Of the 1/3 of elderly people who fall
every year,
A. 20%
B. 30%
C. 40%
D. 50%
E. 60%
have multiple falls.
What is the Likelihood of Recurrent

Falls?
Of the 1/3 of elderly people who fall every

year,
A. 20%
B. 30%
C. 40%
D. 50%
E. 60%
have multiple falls.
2728
• Fell in her bathtub and

sustained subdural. Age 88.
• Died from traumatic brain injury

after a fall at his Manhattan
home. Age 85
2729
Falls in the Elderly

Are responsible for 70% of accidental deaths in people 75
and over.
Increases with age and transcends ethnic groups
Cause significant morbidity, including decline of functional

status, risk for hospitalization
Cause serious injuries in 5-15% of falls. Hip fracture occurs

in 1-2% of falls.
Risk Factors
Intrinsic Extrinsic
• Muscle weakness
•Poor lighting
• Gait and balance
dysfunction •Clutter
• Visual impairment •Environmental
• Cognitive impairment obstacles
• Orthostatic hypotension •Bad shoes
• Meds
2730
Drinking in Elderly Patients in the ED
Lifetime alcohol abuse was 24%
14% had a drinking problem in the last year.
Elderly patients with GI complaints had a much higher rate

of alcohol issues (22%) than those who fell.
Physicians detected only 21% of the cases of current abuse

of alcohol.
Case 6
Chronic Pain
2731
A 69 Year Old Man with Back Pain
JM is a 69 year old woman with back

pain. She has had many studies
which show minimal reversible
problems. She has tried multiple
treatment modalities and adjunctive
therapy. She gets some relief, but
still suffers.
PMH: HTN and gout

Social: No tob, 3 drinks/week,
married, well-supported by
family. No history of substance
abuse.
2732
Trial of Narcotics?
You’ve been burned in the past
by people seeking narcotics.
What questions will be most
helpful in determining whether
she has a high risk of developing
problematic behavior around
these meds?
Opioid Risk
A. Family history of Substance Abuse
B. Personal History of Substance
Abuse
C. Preadolescent Sexual Abuse
D. A&B
E. All of the above.
2733
Opioid Risk
A. Family history of Substance Abuse
B. Personal History of Substance
Abuse
C. Preadolescent Sexual Abuse
D. A&B
E. All of the above
Opioid Risk
Family history of substance abuse
• Greatest for prescription drugs
Personal history of substance abuse

• Greatest for prescription drugs
Age between 16 and 45
Preadolescent sexual abuse (women)
Certain Psychiatric Diseases
2734
Opioid Addiction
Low incidence of iatrogenic addiction in
low risk groups
About 10% of the general population is at

risk for addictive disorders
Ask about risk factors!
Addiction Problem?
Our patient has been on a stable dose of
long and short-acting narcotics. You’ve
followed your state’s PMP and she is
obtaining meds appropriately. One day, she
comes in, obviously in pain, telling you she
strained his back helping her grandson learn
to swim, used up all her breakthrough
meds, borrowed some from her spouse,
and needs more (of a specific medicine).
2735
What should you do?

A. Her behavior is worrisome. Consider
weaning all narcotics.
B. She’s in violation of his contract. No
more meds.
C. Refill the meds, just this one time.
Make it clear to herthat he’s violating his
contract.
D. Refill the meds, she’s clearly in pain and
has been up front with you.
What should you do?

A. Her behavior is worrisome. Consider
weaning all narcotics.
B. She’s in violation of his contract. No
more meds.
C. Refill the meds, just this one time.
Make it clear to her that he’s violating
his contract.
D. Refill the meds, she’s clearly in pain
and has been up front with you.
2736
Pseudoaddiction
• Evidence of Physical Distress
• Change in frequency of drug use or unsanctioned
dose escalation
• Drug hoarding
• Requesting specific drugs
• Anxiety
• Openly acquiring drugs from others
• Asking for more meds or reluctance to change
regime
• Behavior stops with dose/med change
Friendly Reminder: Naloxone saves

lives
2737
Cases 7 & 8
Workplace Related Medicine
The patient following JM
Fell in her work at a local

discount store about 7-8 weeks
ago. She has been complaining
of pain in her lower back ever
since then.
2738
Treatment with NSAIDS and

muscle relaxants did not help.
Imaging was negative and PT,
likewise, did not make a
difference. Her symptoms are
out of proportion to her injury
and to your exam.
“I don’t think I can go back to

work yet, doctor,” she says
tearfully. “I’m just not ready.”
2739
What do you tell her now?

A. Tell her to stop malingering and get back to work.
B. Screen for and treat depression
C. Work with her and her company to come up with a
transition back to work plan.
D. Inquire about pending litigation
E. B, C, and D
What Do You Tell Her Now?
A. Tell her to stop malingering and get back to

work.
B. Screen for and treat depression
C. Work with her and her company to come up
with a transition back to work plan.
D. Inquire about pending litigation
E. B, C, and D
•
2740
Returning to Work after an Injury
Vast majority of people get better, go

back to work.
Patient factors include perception of

pain, injury, depression, lawsuits
pending, other secondary gain
Returning to Work after an Injury
Work factors include inability to provide transitional

employment.
MD factors include our own discomfort with when patients

are stable to return to work, desire to help a bad situation
Only 50% of workers ever return to work if they have been

out >6 months.
2741
Lead Astray?
A patient who has lead exposure in
his work as an instructor in the
police academy firing range comes
in to follow up after a
hospitalization department for a left
sided facial droop and a right-sided
hemiparesis.
While you discuss his recovery

from what appears to be a
CVA, his wife tells you that
she is sure that lead poisoning
caused his MCA stroke.
2742
Which is the Correct Response?
• A. She’s probably right. Check a lead level

immediately.
• B. She’s probably wrong. Lead exposure only
causes peripheral neuropathies.
• C. She’s probably wrong. It is uncommon for
occupational exposures to cause focal
neurological problems such as strokes.
• D. She’s right. Lead can cause encephalopathy,
why not strokes?
Which is the Correct Response?
• A. She’s probably right. Check a lead level

immediately.
• B. She’s probably wrong. Lead exposure only
causes peripheral neuropathies.
• C. She’s probably wrong. It is uncommon for
occupational exposures to cause focal
neurological problems such as strokes.
• D. She’s right. Lead can cause encephalopathy,
why not strokes?
2743
And, yet, it’s worth noting
Prevalence of CHD and stroke in

adults younger than 55 is highest
in those with service and blue
collar jobs, particularly
accommodation and food service.
(Nat’l Health Interview Survey).
Risks may include stress, shift

work, exposures to second hand
smoke and other particulates.
Case 9
After Gastric Bypass

Surgery
2744
A 45 year old female patient

Presents to your clinic to
establish care. She is new to
you. Past medical history is
notable for diabetes, which she
proudly tells you is “in
remission” after gastric bypass
surgery 5 years ago.
•She followed up with her

surgeon for a year or two, but
since then has not really been
seen by a physician. She has
maintained her weight loss.
2745
•She currently takes no

medicines, no herbal
supplements, and no vitamins.
•The remainder of her history and
exam are unremarkable.
What Labs Would You Order?

A. None, she’s fine
B. B12, A1C, CBC
C. B12, A1C, CBC, Vitamin D
D. B12, A1C, CBC, Chem-7
E. B12, A1C, Chem-7
2746
What Labs Would You Order?
A. None, she’s fine

B. B12, A1C, CBC
C. B12, A1C, CBC, Vitamin D
D. B12, A1C, CBC, Chem-7
E. B12, A1C, Chem-7
Late Complications of Gastric Bypass
Most common are anemia and b12 deficiency (30%) if not replaced.
Incisional hernia in 10%
Depression/Emotional disturbance (5-10%)
Rare ulcers at the anastomosis site (1-2%)
Very rare electrolyte abnormalities, sbo,
Cholelithiasis
2747
Case 10:Case 10
Unilateral Hearing Loss
Can You Talk to My Good Ear?
A 36 year old man calls your office with a complaint

that he woke up and can’t hear out of his left ear
very well. He has no history of ear problems, no
recent infections. He did travel recently on an
airplane and wonders if it’s because of the plane
trip. Your astute triage nurse had him hum and the
hum sound did not lateralize. He has no vertigo, but
he has tinnitus and a little bit of ear pain.
2748
What Do You Do Now?
A. Don’t worry. It’s the plane, take a

decongestant and call me in the
morning if you’re not better.
B. Don’t worry. See if you can come in
this week and we’ll take out the wax.
C. Worry a little. Maybe he has an otitis.
Add him on later or tomorrow.
D. Worry. See him today or refer to ENT.
What do you do now?

A. Don’t worry. It’s the plane, take a
decongestant and let me know if not
better.
B. Don’t worry. See if you can come in
this week and we’ll take out the wax.
C. Worry a little. Maybe he has an otitis.
Add him on later or tomorrow.
D. Worry. See him today or refer to ENT.
2749
Sudden Sensorineural Hearing

Loss
Rapid hearing loss. Usually noted over 12 hours or on
awakening in the morning.
Usually (but not always) unilateral
More than 90% of patients have tinnitus
Often patients have a sense of ear fullness
Etiologies for SSNHL
Myriad, but most commonly

autoimmune, microvascular, or viral
cochleitis.
Depending on the series, tumor

ranges from 3-30%. MRI to evaluate
the retrocochlear space is indicated.
2750
Treatment
No agreement on the best protocols.
Most ENT will treat with high dose glucocorticoids (60-

80mg/day) for 10 days. Some studies suggest faster healing.
Some data about intratympanitic steroids as well.
Subset of patients may improve with antivirals.
Prognosis
Generally, the prognosis is good.

• Better if it is high or low frequency loss and not across the
board.
• Better for younger patients
May take up to 4 months and not be complete
May be worse in people with vertigo
2751
Case 12: Transgender Medicine
You have a new patient coming to see

you. She is a transwoman, meaning she
was assigned male at birth (AMAB), but
has chosen to live as a woman since her
young adulthood. She has been taking
estrogen and testosterone blockers since
her late teens and is now 50. She has not
undergone gender affirmation surgery.
2752
What cancer screening is most appropriate

for this 53 year old woman?
A. Breast exam, mammogram, pap,
PSA
B. Breast exam, mammogram, colon
cancer screening
C. Breast exam, mammogram, colon
cancer screening, PSA
D. Breast exam, PSA
What Cancer Screening is Most Appropriate

for this 53 year old woman?
A. Breast exam, mammogram, pap,

PSA
B. Breast exam, mammogram, +/-
DRE
C. Breast exam, mammogram, DRE,
and PSA
D. Breast exam, PSA
2753
I’ve never seen a transgender patient
A phone survey in MA found a self-reported prevalence of .5%
Provide sensitive care
Empathic, non judgmental, don’t assume sexuality based on gender
Honor the patients gender identity (pronouns)
Provide care for the anatomy that is present.
Beyond the PHQ-2

Don’t assume that your patient is depressed, but DO be aware that
depression, anxiety, substance abuse, and trauma are more common in the
transgender population. No clear recommendations, but be aware:
16% have h/o Substance use disorder
Over 50% meet criteria for depression
May be increased risk of suicidal ideation
2754
Resources for Transgender Care
• https://oi.mgh.harvard.edu/pcoi/primary_care_guidelines/Transgend
er.asp#surg
• UCSF Center of Excellence for Transgender Health
• National LGBT Health Education Center
Best of Luck on the Boards!
• Nothing to declare
2755
Psychiatry Overview
Treating Opioid Use Disorder
Sarah E. Wakeman, MD, FASAM
Medical Director, Mass General Hospital Substance Use Disorder Initiative
Program Director, Mass General Addiction Medicine Fellowship
Clinical Co-Lead, Partners Healthcare Substance Use Disorder Initiative
Medical Director, RIZE Massachusetts
Disclosures
• None
2756
Drug overdoses now

leading cause of
death for Americans
under 50
Increase in
Opioid
Prescribing Was
Correlated with
Overdose & Rx
OUD
Paulozzi LJ, Jones C, Mack K, Rudd R. Vital signs: overdoses of prescription opioid pain
relievers—United States, 1999–2008. MMWR Morb Mortal Wkly Rep 2011;60:1487–92.
2757
Ongoing Death
Toll Due to
Heroin/Fentanyl
Dowell D. JAMA. Published online October 11, 2017. doi:10.1001/jama.2017.15971
National Opioid-Related Inpatient

Hospitalizations and ED Visits
2758
Prevalence of Substance Use Disorder
SAMHSA National Survey on Drug Use and Health. Retrieved from http://iusbirt.org/wp-content/uploads/2014/09/NSDUH14-0904_infographic.jpg
Case 1: Cindy
• New patient: 48 year-old woman with history of low
back pain previously on chronic opioid therapy with
extended release oxycodone
• Chart reports of early refill requests, lost prescriptions
• Toxicology positive for opiates
• PE notable for rhinorrhea, piloerection, myadriasis
• Comes to see you requesting oxycodone
2759
Case 1: Cindy
• What is the diagnosis?
1. Undertreated pain
2. Diversion
3. Opioid use disorder
4. All of the above
Differential diagnosis
• Aberrant drug-related behavior
2. Diversion
3. Substance use disorder
• Diagnostic tools
– Clinical history
– SUD dx criteria
– PMP
– Toxicology
2760
Case 1: Back to Cindy

• Describes initial back injury followed by escalating oxycodone use.
Transitioned to daily injection heroin use since last doctor stopped
prescribing oxycodone.
• Adult children worried, lost job due to missing work due to

withdrawal symptoms.
• Has experienced several non-fatal overdoses.
• “I’ve been to detox too many times to count, it never helps. I hate
AA meetings. I tried buprenorphine a couple of times and it helped
but taking that every day is just replacing one addiction with
another. Sure I wish I could stop using but heroin is the only thing
that makes me feel ok and helps with the pain.”
Patterns of Opioid use in the US
Cicero N Engl J Med 2015; 373:1789-1790
2761
DSM-5 Opioid Use Disorder

• Taking more or using longer than intended
• Not being able to cut down or stop
• Spending more time obtaining, using, or recovering
• Craving
• Role failure
• Use despite relationship problems
• Important activities given up
• Recurrent use in hazardous situations
• Use despite negative impact on physical or mental health
• Tolerance
• Withdrawal
2-3 mild, 4-5 moderate, 6 or more severe
Case 1: Cindy
2. Diversion
4. All of the above
2762
Case 1: Cindy
2. Diversion
4. All of the above
DSM-5 Opioid Use Disorder

Taking more or using longer than intended
Not being able to cut down or stop
Spending more time obtaining, using, or recovering
Craving
Role failure
Use despite relationship problems
Important activities given up
Recurrent use in hazardous situations
Use despite negative impact on physical or mental health
Tolerance
Withdrawal
2-3 mild, 4-5 moderate, 6 or more severe
2763
Case: Can We Help?

• You tell Cindy that she has a severe opioid use
disorder. What do you do next?
1. Give her a list of detox facilities to call.
2. Tell her that she is pre-contemplative. Advise her
to come back when she is ready to change.
3. Ask about her prior experiences with treatment
and consider buprenorphine initiation.
4. Offer her oxycodone for her back pain.
Case: Can We Help?

• You tell Cindy that she has a severe opioid use
disorder. What do you do next?
1. Give her a list of detox facilities to call.
2. Tell her that she is pre-contemplative. Advise her
to come back when she is ready to change.
3. Ask about her prior experiences with treatment
and consider buprenorphine initiation.
4. Offer her oxycodone for her back pain.
2764
Motivation: Neither Fixed nor

Linear
Ambivalence in Normal
2765
Listening for Change Talk

• “I’ve been to detox too many times to count,
it never helps. I hate AA meetings. I tried
buprenorphine and it helped but taking that
every day is just replacing one addiction with
another. Sure I wish I could stop using but
heroin is the only thing that helps with the
pain.”
Strengthening Change Talk

• Elaborate
– “Why did you decide to make that change?”
• Affirm
– “It takes a lot of strength to make those changes.”
• Reflect
– “It sounds like you are ready to stop using.”
2766
Responding to Change Talk

• “I’ve been to detox too many times to count,
it never helps. I hate AA meetings. I tried
buprenorphine and it helped but taking that
every day is just replacing one addiction with
another. Sure I wish I could stop using but
heroin is the only thing that helps with the
pain.” You are determined to stop using
heroin. What made you decide to
try medication treatment with
buprenorphine and go to detox
and AA meetings in the past?
“As we have seen repeatedly in the history of

medicine, science is one of the strongest allies in
resolving public health crises. Ending the opioid
epidemic will not be any different.”
2767
Understanding Addiction
• “The question is frequently asked: Why does a man
become a drug addict? The answer is that he usually
does not intend to. Junk wins by default. I tried it as a
matter of curiosity. I drifted along taking shots when
I could score. I ended up hooked. You don’t decide to
be an addict. One morning you wake up sick and
you’re an addict. ”
William S. Burroughs, Junky (1953)
Natural History of Opioid Use

Disorder
Using to feel good
Needing to use more to

feel normal
Using to keep from getting

sick
2768
Understanding Addiction
• Primary, chronic brain
disease characterized by
compulsive drug seeking
and use despite harmful
consequences
• Involves cycles of
recurrence and remission
• 40-60% genetic
American Society of Addiction Medicine. April 12, 2011. www.asam.org
NIDA. August, 2010. http://www.drugabuse.gov/publications/science-addiction
Substance Use Disorder is a Chronic, but

Treatable Illness
Decreased Heart Metabolism Decreased Brain
in Coronary Artery Disease Metabolism in Substance
High
Use Disorder
Low
Healthy heart Diseased Heart Healthy Brain Diseased Brain
Slide Courtesy of NIDA
2769
Visualizing Recovery
Volkow et al. J. Neurosci., December 1, 2001, 21(23):9414–9418
Treatment Outcomes as Good as for

Other Chronic Diseases
NIDA. Principles of Drug Addiction Treatment. 2012. McLellan et al., JAMA, 284:1689-1695, 2000 .
2770
• No cure
Similar to • Goal is to prevent acute
Management and chronic complications
of Diabetes • Individualized treatment

or HIV plans and goals
• Treatment includes:
– Medication
– Lifestyle changes
– Regular monitoring
for complications
– Behavioral support
Lessons
from
HIV/AIDS
• In the 1990s lifesaving
medication available;
fundamentally altered
the epidemic
• Sharp & sustained

declines in mortality
• Focus shifted to
adherence,
engagement in care
Sepkowitz KA. N Engl J Med 2001; 344:1764-1772
2771
Access & Adherence to Lifesaving Medication Can Fundamentally Alter

the Overdose Epidemic
Carrieri et al. Clinical Infectious Diseases, Volume 43, Issue Supplement_4, 15 December 2006, S197–S215
Medication
Methadone
Buprenorphine
Naltrexone
Psychosocial Interventions
What is Cognitive behavioral therapy
Effective Motivational enhancement therapy
Treatment? Contingency management
Recovery Supports
Recovery coaching
Mutual help organizations
2772
Medication Treatment Improves

Retention, Abstinence, Survival
Buprenorphine Maintenance
75% retained in treatment
75% abstinent by toxicology
Detoxification + counseling
20% died
Kakko et al. Lancet. 2003 Feb

22;361(9358):662-8
Goal of Medications for

Addiction Treatment
1 2 3 4
Relieve Block effects Reduce Restore
withdrawal of other cravings normal reward
symptoms opioids pathway
2773
Pharmacology of Treatments
Antagonist
(naltrexone)
Pharmacology of Treatments
Stable level of opioid

effect experienced as
neither intoxication
nor withdrawal, but as
“normal”
Antagonist
(naltrexone)
2774
Opioid Detoxification Ineffective
Chutuape et al. Am J Drug Alcohol Abuse. 2001

Feb;27(1):19-44.
What is Effective Treatment?
Treatment A
Treatment B
Kakko et al. Lancet. 2003 Feb 22;361(9358):662-8
2775
Opioid Agonist Therapy is Effective

Treatment
Buprenorphine Maintenance
75% abstinent by toxicology
Detoxification
20% died
Kakko et al. Lancet. 2003 Feb

22;361(9358):662-8
Treatment Retention Higher
Sees et al. JAMA. 2000;283(10):1303-1310.
2776
Opioid Use Lower
Mattick et al. Cochrane Database of Systematic

Reviews 2009, Issue 3. Art. No.: CD002209.
Mortality Decreased
All cause mortality rates (per 1000
person years):
•In methadone treatment: 11.3

•Out of methadone treatment: 36.1
•In buprenorphine treatment: 4.3

•Out of buprenorphine treatment: 9.5
Overdose mortality rates:
•In methadone treatment: 2.6

•Out of methadone treatment: 12.7
•In buprenorphine treatment: 1.4

•Out of buprenorphine treatment: 4.6
Sordo et al. BMJ 2017;357:j1550
2777
Buprenorphine vs. XR-NTX?
• The difference in opioid relapse-free survival between XR-NTX and BUP-NX
• Relapse events were greater for XR-NTX (65%) than for BUP-NX (57%)
• Only 72% of XR-NTX group started med (53% if randomized during detox)
• 94% of group assigned to buprenorphine started
Lee JD et al. The Lancet , Volume 391 , Issue 10118 , 309 - 318
Treatment Selection:
Belief versus Science
“We as a society… think [people with addiction]
should just get off drugs and by strenuously
hauling up on their own bootstraps should
stay off no matter what.
Policymakers and some clinicians continue to
promote detoxification as ‘treatment,’ even
though detoxification does nothing to help
people stay off drugs.”
Ling W. J Neuroimmune Pharmacol (2016)

11:394–400
2778
Medications for Addiction Treatment Work
Back to Cindy
• She has now been on buprenorphine/naloxone for 12
months and is doing well. She no longer meets criteria
for opioid use disorder, has started working, and
reconnected with family.
• How long does she need to stay on bup/nlx?

1. Medication treatments are best utilized as a bridge to
abstinence, she should begin a taper.
2. Medication treatments may be required long term or
even throughout life; so long as she is benefitting there is
no need to taper.
3. She should begin a taper after 2 years of treatment if she
continues to do well.
2779
Back to Cindy
• She has now been on buprenorphine/naloxone for 12
months and is doing well. She no longer meets criteria
for opioid use disorder, has started working, and
reconnected with family.
• How long does she need to stay on bup/nlx?

1. Medication treatments are best utilized as a bridge to
abstinence, she should begin a taper.
2. Medication treatments may be required long term or
even throughout life; so long as she is benefitting there
is no need to taper.
3. She should begin a taper after 2 years of treatment if she
continues to do well.
Long-term Treatment
• “In most cases, treatment will be required in

the long term or even throughout life. Such
long-term treatment, common for many
medical conditions, should not be seen as
treatment failure, but rather as a cost-
effective way of prolonging life and improving
quality of life, supporting the natural and
long-term process of change and recovery.”
World Health Organization http://apps.who.int/iris/bitstream/10665/43948/1/9789241547543_eng.pdf
2780
Long Term Outcomes with Buprenorphine
Engagement in agonist therapy associated with abstinence at Month 42:

Patients on agonist therapy: 79.6% abstinent
Not on agonist therapy: 50.8% abstinent
Weiss et al. Drug Alc Depend. 2015;150:112-9.
Treatment Takes Time
Hser et al. Addiction. 2016 Apr;111(4):695-705.
2781
Treatment Effective in Primary Care
No difference in self reported opioid use, opioid abstinence, study

completion, or cocaine abstinence between the 2 groups
Fiellin DA et al. Am J Med 126:1 2013
Hospitals Have Opportunity to Initiate

Treatment
• Initiating methadone in hospital:
– 82% present for follow-up addiction care
• Buprenorphine vs. detox among inpatients:

– Bupe: 72.2% enter into treatment after discharge
– Detox : 11.9% enter treatment after discharge
• Buprenorphine vs. referral in ED:

– Bupe: 78% engaged in treatment at 30 days
– Referral: 37% engaged in treatment at 30 days
J Gen Intern Med. Aug 2010; 25(8): 803–808; JAMA Intern Med 2014 Aug;174(8):1369-76.; D'Onofrio et al. JAMA 2015 Apr 28;313(16):1636-44
2782
Lack of Access to Treatment
Ann Fam Med 2015;13:23-26.
Despite Scientific Advances, Huge Gaps in Care
“[The] profound gap between the science of addiction and

current practice… is a result of decades of marginalizing
addiction as a social problem rather than treating it as a
medical condition. Much of what passes for “treatment”
of addiction bears little resemblance to the treatment of
other health conditions.”
Addiction Medicine: Closing the Gap between Science and Practice
www.casacolumbia.org
2783
The Need for Change

“For nearly a century, physicians were indoctrinated with the
societal attitude that addicts brought upon themselves the
suffering they deserve. Even after we began to regard addicts
as having a disease, our policies continued to reflect our
attitude: addicts are sick, they need help, but they also sin, so
do not help them too much. Until the correct mindset is
restored in the physician, the mere availability of an effective
medication will not make a difference. To put it another way,
for buprenorphine to succeed clinically, physicians themselves
must first change before they can help patients change their
lives.”
Ling. J Neuroimmune Pharmacol (2016) 11:394–400
Turning The Tide
2784
Evidence • Immediate access to all

types of medication for
Based Care OUD treatment
Checklist • Treatment based on

clinical need & patient
preference/experience
(i.e. not a one-size-fits-all
approach)
• Focus is on retaining
patients in care
Prevention
• Judicious opioid prescribing

• Address risk factors for
development of OUD
Systems Treatment
Based • Immediate access to medication for

OUD in all settings
• Reduce stigma
Checklist
Harm Reduction
• Naloxone
• Syringe exchange
• Safe consumption sites
2785
Take Home Points

• Fatal overdoses, the leading cause of death for
Americans under 50, are preventable
• Opioid use disorder is a diagnosable and

treatable disease
• Medications are the cornerstone of effective

treatment and can be successfully provided in
primary care and initiated in hospitals/EDs
Thank you!
• swakeman@partners.org
• @DrSarahWakeman
2786
References
• Carrieri et al. Clinical Infectious Diseases, Volume 43, Issue Supplement_4, 15 December 2006, S197–S215
• Chutuape et al. Am J Drug Alcohol Abuse. 2001 Feb;27(1):19-44.
• Cicero N Engl J Med 2015; 373:1789-1790
• Clark RE et al. J Subst Abuse Treat. 2015 Oct;57:75-80
• D'Onofrio et al. JAMA 2015 Apr 28;313(16):1636-44
• European Monitoring Centre for Drugs and Drug Addiction (2015)
• Fiellin DA et al. Am J Med 126:1 2013
• Hser et al. Addiction. 2016 Apr;111(4):695-705.
• Hutchinson et al. Ann Fam Med 2015;13:23-26.
• Kakko et al. Lancet. 2003 Feb 22;361(9358):662-8
• Katz J. 2017. https://www.nytimes.com/interactive/2017/06/05/upshot/opioid-epidemic-drug-overdose-deaths-are-rising-
faster-than-ever.html?_r=0
• Lee JD et al. The Lancet , Volume 391 , Issue 10118 , 309 - 318
• Leibschutz et al JAMA Intern Med 2014 Aug;174(8):1369-76
• Ling W. J Neuroimmune Pharmacol (2016) 11:394–400
• Mattick et al. Cochrane Database of Systematic Reviews 2009, Issue 3. Art. No.: CD002209.
• McLellan et al., JAMA, 284:1689-1695, 2000.
• Murthy V. https://addiction.surgeongeneral.gov/surgeon-generals-report.pdf
• Sees et al. JAMA. 2000;283(10):1303-1310.
• Sepkowitz KA. N Engl J Med 2001; 344:1764-1772
• Shanahan et al. J Gen Intern Med. Aug 2010; 25(8): 803–808
• Sordo et al. BMJ 2017;357:j1550
• Volkow N Engl J Med. May 31, 2017DOI: 10.1056/NEJMsr1706626
• Weiss et al. 2016. https://www.hcup-us.ahrq.gov/reports/statbriefs/sb219-Opioid-Hospital-Stays-ED-Visits-by-State.jsp
• Weiss et al. Drug Alc Depend. 2015;150:112-9.
• World Health Organization http://apps.who.int/iris/bitstream/10665/43948/1/9789241547543_eng.pdf
2787
Hyperlipidemia
Scott Kinlay, MBBS, PhD
Associate Chief Cardiovascular Division & Director of Vascular

Medicine, VA Boston Healthcare System
Associate Physician, Brigham & Women’s Hospital
Associate Professor in Medicine, Harvard Medical School
Disclosures
• Research Grants:
– VA CSP, VA MERIT, DoD
• Consultant:
– Colorado Prevention Center DSMB
• Speakers Bureau: None
• Advisory Committees:
– ACC PAD Council
• Ownership/ Other Financial Interest: None
2788
Learning Objectives
• Review effects of diet on lipids and
cardiovascular risk
• Review value and limitations of statin
therapy
• Review the implementation of current lipid
guidelines to reduce cardiovascular risk
• Review the new PCSK9 agents
Decreasing Cardiovascular Risk

Healthy Lifestyles
• Some lipid effects
• Non-lipid effects
– Vascular compliance
– Cardiac mechanics
– Muscle metabolism
2789
Fats and Coronary Artery Disease

• 1960-1980 Coronary Epidemic
• Response focused on fat as a
the causal “nutrient”
• Recommended dietary
allowances for saturated fat
and dietary cholesterol
• The food industry response
was predictable…
Low Fat Processed Foods
An Explosion of Processed
Foods with Refined Sugar
Instead of Fat
2790
Fat versus Sugar?

• Fat is a lubricant and more satiating
• Sugar is less satiating so the tendency is to
eat more more calories obesity
Modulators of High COH Diet Effects
Fiber
Whole Grain Content
Content
Glycemic
Index
Liquid versus
Accessibility
Solid COH
of Starch
and Sugars
Mozaffarian D. Circulation 2016; 133: 187
2791
Low Carb & Weight Loss Diets

• Atkins – 4 Phase Diet
– Very low COH, unlimited protein/fat
• Weight Watchers
– Calorie restriction by Physical Activity/Behav
Modification,
• Zone Diet and South Beach (3 Phase) Diets (similar)
– Low glycemic COH, Low-fat proteins, some monounsat FA
• Paleo Diet
– High protein, fruits, nuts, vegetables, organ meats, lard
– Low or no dairy, grains, sugars, legumes
Effects of Diets on Lipids

Short Term < 12 Mths Long Term > 12 Mths
Atkins ↓ 0-20% TG ↓ 10% TG
↑ 0-10% HDL ↑ 20% HDL
↑ 0-10% LDL ↔ 0% LDL
Atkins versus
Weight Watchers TG Less decline No difference
HDL Less increase
LDL about the same
Zone Both decrease TG No difference
No change HDL
LDL 10% lower
Paleo: Uncertain data
Effects on CV Risk Unknown
Atallah R. Circ Cardiovasc Qual Outcomes 2014; 7: 815
2792
Low Fat or Low Carb for Weight Loss?

609 Subjects in the DIETFITS RCT
Healthy Low Fat

Healthy Low Carb
-40 -30 -20 -10 0 10 20

12 Month Weight Change, kg
Note: Both Healthy Diets
Gardner CD, et al. JAMA 2018; 319: 667
Other Diets
• DASH Diet
– Designed to lower BP, but also lowers CVD
• Gluten-free diets
– For celiac disease, but no other evidence of benefit
• Ketogenic diet
– Low COH (± protein) to induce ketosis & weight loss
• Vegetarian diet
– Associated with low CVD if low in saturated fats
• Mediterranean diet
2793
“Mediterranean Diet”
• Food-based not nutrient-based diet
• High intake: fruits, nuts, non-starchy vegetables,
legumes, monounsat fats (olive/canola)
• Modest intake: whole grains, fish,chicken,
• Low intake: red meat, refined grains, starches, sugars
Life Magazine
Greece January 1948.
“Lunch! bread, one onion,
and olives”
PREDIMED: Mediterranean Diet

Primary Endpoint: Myocardial Infarction, Stroke, CV Death
Control Diet
Med Diet + Nuts
Med Diet +
Extra Virgin Olive Oil
Estruch R, et al. NEJM 2013; 368: 1279
2794
Low Fat Nutrient or Food-Based Diet?

Women’ Health Predimed
Initiative Low Fat “Mediterranean” Diet
Mozaffarian D. Circulation 2016; 133: 187

Estruch R, et al. NEJM 2013; 368: 1279
Howard BV, et al. JAMA 2006; 295: 655
Low Calorie Vegetarian vs Mediterranean

118 Subjects in the CARDIVEG RCT
Body Weight (kg) BMI Fat Mass (kg)
No Difference in Weight Loss
Opposite Changes in LDL and Trigs, but Small Differences

140
LDL p=0.01
140
Trigs p=0.01 Both
Trigs (mg/dL)
LDL (mg/dL)
130 130 Low

120 120
Calorie
110 110 Soti F, et al.

Circulation 2018,
100 100 Feb 26
T0 T2 T0 T2
2795
US Dietary Guidelines Advisory

Committee 2015
• The overall body of evidence identifies that a
healthy dietary pattern is
– Diets higher in vegetables, fruits: Strong Evidence
– Diets higher whole grains: Moderate to Strong
Evidence
– Diets higher low- or non-fat dairy, seafood, legumes,
and nuts: Moderate Evidence
– Diets with some alcohol (only among adults), but
increased risks of accidents: Moderate Evidence
– Diets lower in red and processed meat: Strong
Evidence
– Diets low in sugar-sweetened foods and drinks and
refined grains: Strong Evidence
http://www.health.gov/dietaryguidelines/2015-scientific-report/02-executive-summary.asp
Does Changing to a Healthy Diet Work?

20% Increase in 3 Healthy Diet Scores
48K Women in the Nurses Study & 25K Men Health Prof Fup Study
Lower Risk of Death
Decreased risk of death with a healthier diet with greater

decrease in risk with increasing years
Sotos-Prieto M, et al. NEJM 2017; 377: 143
2796
Features of a Healthy Diet

…our findings support the 2015 Dietary
Guidelines Advisory Committee that it is not
necessary to conform to a single diet plan to
achieve healthy eating patterns
These three dietary patterns, although

different…. Common food groups in each score
contributing most to improvements were
whole grains, vegetables, fruits, and fish….
Sotos-Prieto M, et al. NEJM 2017; 377: 143
LDL Lowering Medications

Important Adjunct to Healthy
Lifestyle in Higher Risk Groups
• Familial Hypercholesterolemia
• Clinically Evident Atherosclerosis
– CAD, PAD, CVD
• Diabetes Mellitus
• Multiple Risk Factors
2797
Decrease in LDL and Decrease in Risk

Relative Risk of Major Vascular Events
Relative Risk Reduction, %

Between-Group Difference in LDL-C, mmol/L
Silverman MG, et al. JAMA 2016;316:1289
LDL Lowering Therapies

All LDL lowering
therapies increase the LDL-R
expression of LDL
receptors on the liver
to increase LDL uptake,
Statins
and drive down serum Bile salt Binders
Ezetimibe
LDL levels. PCSK9 inhibitors
2798
Familial Hypercholesterolemia
Disorders of the LDL Receptor
• Autosomal dominant
• Strong association - premature CAD
• > 200 LDL receptor mutations:
– Phenotype influences course of disease
• Founder effect in certain populations:
– French Canadians, Lebanon
• Clinical diagnosis: Xanthomas, high LDL, FH
Homozygous vs Heterozygous FH
Homozygous Heterozygous
Mutant Alleles Both One
Frequency 1 : 1 million 1 : 500
LDL Receptor Activity < 2% 2 – 25%
Cutaneous Xanthomas as Child Xanthomas as Adult
LDL >> 190 mg/dL* > 190 mg/dL*
Myocardial Infarct Childhood – Early 40% by 50 years age
Adult
Treatment Apheresis, Drugs ± Apheresis
Liver Transplant, Genetic Counselling?
Drugs
* LDL 190 mg/dL ≈ 5.0 mmol/L
2799
Dutch Lipid Clinic Network Score

Patient History and Physical
Premature CAD (<55 men, < 60 women) 2
Premature cerebral or PVD 1
Tendon xanthoma 6
Arcus cornealis < 45 years old 4
First-degree relative
Premature CVD or LDL > 95th centile 1
Xanthoma, arcus cornealis, or children w LDL > 95th cent 2
LDL Cholesterol
> 330 mg/dL (8.5 mmol/L) 8
250-329 mg/dL (6.5-8.4 mmol/L) 5
190-249 mg/dL (5.0-6.4 mmol/L) 3
155-189 mg/dL (4.0-4.9 mmol/L) 1
DNA functional mutation of LDLR, apoB, or PCSK9 gene 8
Nordestgaard BG, et al. EHJ 2013;34:3478-3490a.
2800
Dutch Lipid Clinic Network Score

Diagnosis Total Points
Definite FH >8
Probable FH 6–8
Possible FH 3-5
Unlikely FH <3
Statins &
Cardiovascular Risk
They Work…
2801
Statins Work In….

• Acute coronary syndromes
• Stable coronary syndromes
• Coronary equivalent syndromes
• Diabetes
• Hypertension and other risk factors
• Peripheral artery disease
• Multiple risk factors with moderate to high
risk of cardiovascular disease over 10yrs
Statins and Primary vs Secondary

~175K Subjects
Prevention in 27 Trials
Rel Risk per 40 mg/dL
reduction in LDL
“Primary”
Prevention
Lower Risk
Higher Risk
Major
Vasc Event
“Secondary” RR ↓25%
Prevention
Lower Risk
Higher Risk Major

Vasc Event
RR ↓20%
CTT Collaborators. Lancet. 2012;380:581.
2802
How to Use Statins
Absolute LDL Change at 1 Year and

Percentage Reduction in Events
Major Coronary Events
50%
Reduction in Events
35%
25%
10%
0%
20% 20 40 60 80 mg/dL
(0.5) (1.0) (1.5) (2.0) (mmol/L)
Reduction in LDL
Cholesterol Treatment Trialists (CTT) Collaborators. Lancet 2005; 366:1267
2803
35% Relative Reduction Yields a Higher

Absolute Risk Reduction
For Higher Risk Patients
ACS Absolute
Benefit
SAP
from
CAD Equivalent Treatment
ASx Multi Risk Factor
ASx 0-1 Risk Factor
2804
2805
2806
35% Relative Reduction Yields a Higher

Absolute Risk Reduction
For Higher Risk Patients
ACS Absolute
Benefit
SAP
from
CAD Equivalent Treatment
ASx Multi Risk Factor
ASx 0-1 Risk Factor
2807
Adverse Effects Statins

• Myopathy
– Myositis↔Rhabdo
– Myalgia
• Cancer (No)
• Diabetes Mellitus Bosch X, et al. NEJM 2009; 361: 62
• Cognitive Changes
• Hepatitis (so rare only test if symptoms/signs)
• Use in the Elderly
Myositis
• Myositis (1:100)
– Muscle weakness/pain, ↑CK 5-10x ULN Symptoms/ CK
– Without renal involvement Rapidly
• Rhabdomyolysis (1:10,000) Reversible on
– Profound weakness, ↑CK > 10x ULN Statin
– Renal involvement and/or myoglobinuria Withdrawal
• Statin-Induced Necrotizing
Autoimmune Myopathy (1:100,000) Persistence of
– Profound proximal weakness Symptoms/ CK
– Ab to HMG CoA Reductase on Statin
– ELISA test & Consider immunotherapy Withdrawal
2808
Risk Factors for Myositis

• Hypothyroidism
• Vit D deficiency?
• High dose statins (esp. simvastatin)
• Advanced age
• Lower BMI
• Cytochrome P450 Inhibition
– Increases serum statin concentration but unpredictable
effect on risk of myositis
• Rare NSLCO1B1 polymorphisms
– Decrease statin uptake by the liver
Factors that Decrease CYP-450 3A4

PotenXally ↑ StaXn ConcentraXons but Side-Effects Unpredictable
• Gemfibrozil (esp with simvastatin)

• Cyclosporine
• Macrolide antibiotics
• Azole antifungals
• ART drugs in HIV (esp protease
inhibitors)
• Grapefruit juice
– Inhibits GI but not Liver CYP-450
2809
Other Potential Causes of CK↑

• Hypothyroid (also increases lipids)
• Idiopathic Hyper-CK-emia
– Benign elevation of CK (100’s to 1000’s)
• Injury or Excessive Exercise
– Focal muscle tear vs Diffuse myositis
• Alcoholism
– Pressure necrosis and dehydration
• Other Inflammatory Myopathies*
– Polymyositis, Dermatomyositis (heliotrope)
– Also present with ↑CK and Myopathic EMG
* Check out Clinical Problem Solving: NEJM 2016: 374: 1774
http://www.nejm.org/doi/full/10.1056/NEJMimc1508369
Statin Myalgia Without Myositis

• Muscle pain and aching
• CK normal or < 4 x ULN
• STOMP trial: 420 statin naïve patients
– 10% in atorva 80/d group vs 5% in placebo group
– So incidence probably about 5%
• Symptoms started on average 1 mth after
starting statin
• Resolved within 2 weeks of stopping drug
• Returned within 4 weeks of re-challenge
• Coenzyme Q10 not effective in one RCT
STOMP: Parker BA, et al. Circulation 2013; 27: 96
Taylor BA, et al. Atherosclerosis 2015; 238: 329
2810
GAUSS-3 Statin Intolerance

• 491 patients intolerant of Atorva 10mg/d or
another statin
• Rechallenged with Atorva 20mg/d or Placebo
Muscle Symptoms
50%
43%
40%
30% 27%
20% 17%
10%
10%
0%
Statin Only Placebo Only Statin & Placebo Neither
Nissen SE. JAMA 2016; 315: 1580
Management of Statin Myopathy

• Stop Statin until symptoms resolve
• Check for contributing factors
– Hypothyroidism, Vit D deficiency
– Drug interactions – e.g. new drugs
• Reassure patients of the safety of statins
– Try at least 2 other statins or lower doses
– Use alternate day dosing ( e.g. atorva/rosuva)
• Non-statin alternatives
– Ezetimibe 10mg/d (20% LDL lowering)
– PCSK9 inhibitors if FH or CVD “not at goal”
2811
Case: HyperCK and Myopathy

• 75 yr old African American man seen for lymphedema
• Right CEA 2014, DM on diet, HT, HL
• Rosuvastatin 40mg/d since 2013
• July 2015/ Feb 2016: Doing well
• Mar 2016: ER visit for palpitations, no muscle aches
but CK 1083. Rosuva stopped. TSH/VitD/ESR normal
• Apr 2016: On questioning he had mild muscle aches
and difficulty climbing stairs over 1 year “old age” –
symptoms gone now off statin
• Jun 2016: Started 10mg Rosuva /day
• Oct 2016: No muscle symptoms on Rosuv 5mg/d
Statin, CK and LDL

Date Rosuva Muscle Sx CK LDL
mg/d U/L mg/dL
Nov 2012 0 153
Feb 2016 40 Yes (retro) 44
Mar 2016 40 Yes 1084 42
(ER Visit) Stopped
May 2016 0 No 1036 120
Jun 2016 10 No 1296 72
Oct 2016 5 No 1334 94
2812
Case: Myopathy on High Dose Statin

• 46 yr old man with moderate renal a. stenosis
• Strong FH: Father SCD 45yrs, Mother CAD
• Non-alcoholic fatty liver treated with simva and
prava with mild increase in LFTs – statins stopped
• Oct 2015: Atorva 20/d Myalgias stopped
• Apr-Jun 2016: Dose ranging Rosuva
• Oct 2016: Rosuva 5 mg/d & doing well
– AST: 10/2015=27 10/2016=31
– ALT: 10/2015=48 10/2016=37
Statin Dose, Symptoms, Lab Work

Date Statin LDL mg/dL Myalgias CK
mg/d
Aug 2015 0 177 No
Oct 2015 A 20 77 Yes
Feb 2016 0 172 No ETT OK
11min
April 2016 R 10 71 No 91
May 2016 R 20 65 Yes 730
May 2016 0
Jun 2016 R5
Oct 2016 R5 85 No 251
Plan: If Symptoms and CK remain stable, consider adding Ezetimibe
2813
Statins and Diabetes

Jupiter Study: Rosuva vs Placebo
Major Risk Factors for Diabetes Mellitus
No major risk factors One or more risk factors
HR = 1.28 (1.07 – 1.54), p=0.01
HR = 0.99 (0.45 – 2.21), p=0.99
Years of Follow-up
Ridker PM, et al. Lancet 2012; 380: 565
Statins and Diabetes: Impact on CVD

Jupiter Study: Rosuva vs Placebo
Major Risk Factors for Diabetes Mellitus
No major risk factors One or more risk factors
HR = 0.67 (0.55 – 0.81)

p=0.0001
HR = 0.67 (0.53 – 0.85)
p=0.0007
Years of Follow-up
Ridker PM, et al. Lancet 2012; 380: 565
2814
~175K Subjects
Statins and Cancer
Rel Risk per 40 mg/dL
reduction in LDL
Cancer Incidence
Cancer Death
CTT Collaborators. Lancet. 2012;380:581.
Statins and Cognition

• High LDL a risk factor for stroke, multi-infarct
dementia, and Alzheimer's disease
• 60 cases reported to the FDA
of reversible cognitive
dysfunction with statins
• Observational meta-analyses
fail to show an effect of statins
on cognition
• In animal models, statins
decrease neuroinflammation
and amyloid-β concentrations Thompson PD, et al. JACC 2016; 67: 2395
2815
25 Statin RCTs and Cognition

Statins Better Statins Worse
Domain N (n)
Global 5 (26,515)
Attention 7 (732)
Executive 7 (26,926)
Memory 8 (26,850)
Processing Speed 10 (6,630)
Working Memory 3 (83)
All Domains 14 (27,643)
Standardized Mean Difference Ott BR, et al. J Gen Intern Med 2015; 30: 348
Statins in the Elderly Over 75 Years

• Clinical trials mostly < 75 yrs
Over 75 yrs age group
• Large number of CVD events
• Many trials support continued statins in
patients > 75 yrs
• But, acute pharmacokinetics/dynamics
– Very old have higher serum statin concentrations
– Cmax 50% higher, AUC 25% higher
– ?higher risk of side effects with maximum doses
2816
Statins Over 75 Years of Age
Good Life Expectancy Poor Life Expectancy

Clinically Evident CAD Muscle Weakness
Diabetes, PVD, isch CVA Frailty or Dementia
Drug Interactions
Consider Intermediate Dose
Where Statins May Not

Work
2817
RCTs No Benefit From Statins

• End-Stage Renal Disease on Dialysis 2+yrs
– AURORA (Rosuva), 4D (Atorva)
– InSHARP (Simva/Ezet) benefit, but some pre-HDx
• Aortic Stenosis
– Saltire (Atorva), SEAS (Simva/Ezet), Astronomer (Rosuva)
• CHF no CAD
– CORONA (Rosuva), GISSI-HF (Rosuva) all Negative
• ARDS/ COPD
– ARDS & COPD Clinical Research Networks - No benefit
• CABG
– STICS No benefit Rosuva 20mg for post-op AFib or MI
• Pre-PCI in ACS versus within 24 hours
– SECURE-PCI No benefit
Fellstrom B et al. N Engl J Med 2009;360:1395-1407 SALTIRE: Cowell JS, et al. NEJM 2005; 352: 2389
Kjekshus J et al. N Engl J Med 2007;357: 2248 SEAS: Rossebø AB, et al. NEJM 2008; 359: 1343
Astronomer: Chan KL, et al. Circulation 2010; 121: 306
Zheng Z, et al. N Engl J Med 2016; 374: 1744 Berwanger O, et al. JAMA 2018. March 11
Therapies for Low HDL and

High TGs
2818
Fibrates, Niacins, Omega-3

Fibrates: ACCORD Niacin: AIM-HIGH
No Significant Differences
In CV Events When Used With Statins
The ACCORD Study Group. N Engl J Med 2010;362:1563-1574 AIM-HIGH Investigators. NEJM 2011; 365: 2255
Niacin: HPS2-THRIVE Omega-3: ORIGIN
HPS2-THRIVE Investigators. NEJM 2014; 371: 203 ORIGIN Trial Investigators. NEJM 2012; 367: 309
CETP Inhibitors Raise HDL 2-3x

Torcetrapib: ILLUMINATE Dalcetrapib: Dal-OUTCOMES
Barter PJ, et al. NEJM 2007; 357: 2109 Schwartz GG, et al. NEJM 2012; 367: 2089
Evacetrapib: ACCELERATE
No Significant Differences
(or Worse)
In CV Events When Used
With Statins
Lincoff AM, et al.. NEJM 2017; 376: 1933
2819
Role for Non-LDL Lowering
• No role in combination with statins

• Maybe a role in statin intolerant subjects
• Gemfibrozil: Helsinki, VA-HIT
• Niacin: CDP, HATs
• Omega 3 FA: GISSI, small studies
• Better drugs available
Questions
• 52 yr old man with HIV tolerating highly active anti-retroviral
therapy (HAART) without any symptoms. He presents for a
routine follow-up including renewal of his medications. His
fasting lipid levels are:
– Total Cholesterol 253

– LDL cholesterol 170
– HDL cholesterol 41
– Trigs 210
• The most appropriate management is:

– Start simvastatin 40 mg/d Higher risk of HAART drug interaction
– Start fenofibrate Particularly with protease inhibitors
A: – Start atorvastatin 20 mg/d
– Strict dietary change to lower saturated fats and recheck lipids in 6
months Unlikely to achieve required lipid lowering
2820
Ezetimibe and Statins
IMPROVE-IT: Ezetimibe & Simva

Ezetimibe/Simva 10/40mg versus Simva 40-80mg
HR = 0.936 (95%CI: 0.89, 0.99)
p = 0.016 Statin Alone
ΔLDL
26% vs 43%
Event Rate (%)
Statin & Ezetimibe
Years Since Randomization Cannon C, et al. NEJM 2015
2821
Implications of IMPROVE-IT
Reduction in Major Vascular Events (%)
Implies the main effect
of statins and non-
statins is through LDL
lowering
Regenerates interest in
LDL targets?
Supports novel LDL

lowering therapies
Reduction in LDL (mmol/L) Cannon C, et al. NEJM 2015

Jarcho JA, Keaney, JF. NEJM 2015
The 2013 AHA/ACC

Lipid Guidelines
http://circ.ahajournals.org/content/early/2013/11/11/01.cir.0000437738.63853.7a.citation
DOI: 10.1056/NEJMms1314569
2822
Principles: What Do The RCTs Say?

• Who to Treat:
– Patients with Clinically Evident CVD
• ACS, Stable Angina, Prior MI
• HPS, PROVE-IT TIMI22, MIRACL, TNT, CARE, LIPID
– Patients with Diabetes Mellitus & LDL > 70mg/dL
• HPS, CARDS, CTT
– No Diabetes and 10 yr CVD Risk > 7.5%
• WOSCOPS, AFCAPS, ASCOT-LLA, JUPITER
– Patients with LDL > 190mg/dL (i.e. FH)
• Excluded from most RCTs due to high risk of
premature CVD
Principles: What Do The RCTs Say?

• How to Treat:
– Higher risk patients with high intensity statin
therapy to reduce LDL > 50%
• Atorva 40-80mg/d or
• Rosuva 20-40mg/d
– Moderate risk patients with moderate intensity
statin therapy to reduce LDL 30-50%
• Atorva 10-20mg/d, Rosuva 5-10mg/d,
• Simva 20-40mg/d, Prava 40-80mg/d, Lova 40mg/d
• Fluva ext rel 80mg/d, Fluva 40mg bid, Pitava 2-4mg/d
2823
Measuring CK, LFTs, Lipids

• Baseline pre-statin
– Measure CK only if there is an increased risk of statin
myopathy (history of statin myopathy, family history
of myopathy, drugs with potential interactions)
– Measure baseline LFTs and lipids
• Measurements after statin therapy
– No need to measure LDL (maybe for adherence)
– Remeasure CK only if muscle symptoms
– Remeasure LFTs only if suspicion of hepatotoxicity
(fatigue, jaundice, anorexia, weight loss)
iPhone App Android App

https://itunes.apple.com/us/app/ascvd- https://play.google.com/store/apps/
risk-estimator/id808875968?mt=8 details?id=org.acc.cvrisk&hl=en
http://www.acc.org/tools-and-practice-
support/mobile-
resources/features/2013-prevention-
guidelines-ascvd-risk-estimator
2824
New Algorithm
Patients > 21 Years of Age Without
- CHF (NYHA class II, III, IV)
- ESRD with Hemodialysis
Diabetes Mellitus No DM
Clinical Athero
40-75 yrs & LDL 40-75 yrs & LDL LDL > 190 mg/dL
CVD
70-189 mg/dL 70-189 mg/dL
High Intensity Calculate 10-yr Calculate 10-yr High Intensity

Statin CVD Risk CVD Risk Statin
CV Risk < 7.5%:

Moderate
CV Risk > 7.5%
Intensity Statin
Moderate - High
CV Risk > 7.5%
Intensity Statin
High Intensity
Statin
Keaney JF, et al. DOI: 10.1056/NEJMms1314569
Triglycerides and Pancreatitis

• 2013 AHA/ACC Lipid Guidelines
– Suggest specific treatment if > 500 mg/dL and
there is concern of increased risk of
atheroscerosis events
• 2012 Endocrine Society Clinical Guidelines
Committee
– Risk of pancreatitis increases above 1000 mg/dL
and consider treatment with concentrations
higher than this
Endocrine Society Clinical Guidelines Committee. JClinEndocrMetab 2012; 97: 2969
2825
Novel Therapies for LDL Lowering

• PCSK9 Monoclonal Ab Inhibitors
– Alirocumab (Praluent) Available
for Use
– Evolocumab (Repatha)
• PCSK9 RNA Interference Drugs
– Inclisiran – 6mth action in phase 1 trial
• Drugs Interfering with Apo B synthesis
– Lomitapide (↑LFTs, hepaXc steatosis)
– Mipomersen (Monoclonal Ab – injection site
reacXon, ↑LFTs, hepaXc steatosis
PCSK9 & LDL-Receptor Expression

• PCSK9 binds to the
LDL receptor
• LDL receptor degrades
• Prevents LDL receptor
recycling
• PCKS9 inhibitors block

PCSK9 binding to LDL
receptors
• Increase LDL receptor
recycling and
Fuster V. NatureRevCard 2014; 11: 671
expression
2826
ODYSSEY LONG TERM: Alirocumab

LDL Cholesterol Response: Primary Endpoint 24 months
LDL Cholesterol (mg/dL)
120
60
0
0 24 36 78
Week
Robinson JG, et al. NEJM 2015; 372: 1489
FOURIER: Evolocumab
LDL Cholesterol Response Over 3 Years
LDL Cholesterol (mg/dL)
100 Placebo + Statin
mean LDL = 96 mg/dL

(2.5 mmol/L)
50 Evolocumab + Statin
mean LDL = 30 mg/dL

(0.8 mmol/L)
0
0 1 2 3
Years
Sabatine MS, et al. NEJM 2017; 376: 1713
2827
FOURIER: Evolocumab
MACE: CV Events, Hospitalization UAP, Revascularization
What Happens with an Average LDL

of 30mg/dL (0.8 mmol/L)?
2828
FOURIER: Adverse Events

10%
8.1%
7.7%
8%
6% 5.0% 4.8%
4% p < 0.001 3.1% 2.9%

2.1%
2% 1.6% 1.6% 1.5%
0.1% 0.1%
0%
Injectn Site Allergic Reactn Muscle Event Rhabdomyolysis New Diabetes Neurocognitive
Reactn
Evolocumab Placebo
EBBINHAUS Substudy of FOURIER

Cambridge Neuropsychological Test Automated Battery
• 1974 Subjects
• 40-85 Years
No Difference in Cognitive Function Over 19 months
Giugliano R, et al.
NEJM 2017; 377: 633
2829
FDA Recommended Doses
• Alirocumab (Praluent)
– 75 mg subcut every 2 weeks
– 150 mg s/c every 2 weeks if inadequate response
• Evolocumab (Repatha)
– 140 mg s/c every 2 weeks, OR
– 420 mg s/c every month (3 x 140mg over 30 min)
• Measure LDL at 4-8 weeks and 6 monthly
Cost of PCSK-9 Inhibitors
• Alirocumab and Evolocumab cost $14,600/ person/ year

• If 100% reduction in CVD events
– 3 events prevented per 100 patients = $60,000
– Treatment of 100 patients = $1,460,000
– Net cost = $1,400,000 or $14,000 per patient
• If 5% of patients eligible, insurance premiums would
need to increased $124 per person
• Cost-effectiveness only acceptable if annual cost drops
to ≈ $4,500 per person
Schulman KA, et al. N Engl J Med 2015; 373:1591
Kazi DS, et al. JAMA 2016;11004 Nov 2016
2830
PCSK9: Prior Authorization
PCSK9 Access
> 45, 000 Patients
Prescribed PCSK9i in
Symphony Health
Solutions
• 53% Rejected
• 16% Approved
but not Filled
• 31% Approved
and Filled
Navar AM. JAMACard 2017; 2: 1217
2831
PCSK9 Access
As Copay Increases
Patients Filling Prescriptions, %
Less Likely to Fill Prescription
Number of Patients
Copay Range, $0 - > $500
Navar AM. JAMACard 2017; 2: 1217
Prescribing PCSK9 Inhibitors

Cost Usually Covered by 3rd Party Payers
• Heterozygous FH
– Abnormal gene or LDL > 250 with xanthomas or a
family history of premature ASCVD or Dutch Score>8
– AND, High dose atorva/rosuva and ezetimibe not
resulted in a > 50% reduction in LDL
– AND, Counseled on healthy lifestyle, other RF changes
• Homozygous FH
– Homozygous gene abnormality or untreated LDL > 500
mg/dL or max statin and ezetimibe LDL > 300 mg/dL
– AND, Counseled on healthy lifestyle, other RF changes
2832
Prescribing PCSK9 Inhibitors

More Difficult Cases for 3rd Party Payer Coverage
• Patients with ASCVD requiring further LDL
lowering
– Large trials yet to establish benefit
– Unclear what threshold defines “need for further
LDL lowering”, ? LDL > 100 mg/dL
– FDA concerned providers will skip high dose
statin/ezetimibe regimens
• Patients intolerant of statins
– Difficult to determine as a many patients with
symptoms tolerate some statin on rechallenge
Summary
• Lifestyle changes are fundamental
• New lipid guidelines emphasize statin therapy
of two intensities
• Omit LDL goals and non-statin therapies
among statin-tolerant subjects
• Avoid statins where they are of no benefit
• PCSK9 Inhibitors are powerful novel agents
but limited in their availability
2833
Question 1
A 59 year old woman presents to your outpatient clinic
with a history of diabetes mellitus 5 years treated with
diet and metformin and hypertension controlled by an
ACE inhibitor and HCTZ. She stopped smoking 2 years
ago. Her fasting LDL is 115 with triglycerides of 260 and
an HDL of 43 on simvastatin 10mg/d. Which of the
following therapies are indicated to reduce her CAD risk
A. Replace Simvastatin with Atorvastatin 40mg/d or
Rosuvastatin 20mg/d
B. Add Niacin 500mg/d escalating to 2g/d
C. Add Fish oil 1g/d
D. Increase Simvastatin to 20mg/d
Answer Q1
CAD risk equivalent with treated diabetes and
hypertension and an ex-smoker. Mildly elevated LDL,
elevated TGs and low HDL
A. Replace Simvastatin with Atorvastatin 40mg/d or
Rosuvastatin 20mg/d
Current guidelines recommend an intensive statin dose.

The recent randomized trials show no benefit from
adding niacin or fibrates to statin therapy. Doubling the
dose of simvastatin would decrease LDL by less than
10% and have a smaller effect on reducing CAD risk.
Statin therapy also reduces TGs
2834
Question 2
A 43 year old single man presents for a health checkup
after a screening cholesterol at a shopping center was
reported as high. He has no CAD symptoms, and no
diabetes, hypertension and is a non-smoker. His weight
has increased by 35 lb since college. His LDL is 135 with
triglycerides of 249 and an HDL of 43. Initial therapy
would include
A. Atorvastatin 40mg/d or Rosuvastatin 20mg/d
B. Simvastatin 20mg/d
C. An exercise prescription and dietary advice
D. Niacin 500mg/d
Answer Q2
Young man with no CAD risk equivalents. Bad Lifestyle is
the likely culprit for his weight gain and dyslipidemia.
C. An exercise prescription and dietary advice

Drug therapy is not recommended at this level of risk.
Lifestyle changes are recommended to reduce his
lifetime risk of ASCVD.
Myamericanheart.org/cvriskcalculator
2835
Question 3
A 69 year old woman man presents for an annual
physical exam. She has no symptoms and has a regular
exercise program of walking 30 minutes each morning.
Her blood pressure is 130/65 her BMI is 23. Her fasting
lipid panel shows an LDL of 135 mg/dL with triglycerides
of 195 and an HDL of 54. The appropriate dietary advice
would include which of the following
A. High in vegetables and fruit, and low in red meat
B. High in red meat and salad, and low in whole grains
C. High in sugar sweetened foods, and low in whole grains
D. High in coconut foods and oils, and low in wheat grains
Answer Q3
Current dietary guidelines support a “Mediterranean”
diet high in vegetables and fruits and low in red meat.
A. High in vegetables and fruit, and low in red meat
Answer B is similar to “Paleo” diets, which are high in animal protein and low
in carbohydrate. These are associated with short-term weight loss but may
have detrimental effects on the lipid panel particularly in non-obese
individuals.
Answer C is typical of the diets of industrialized countries and adverse to
health
Answer D is a variation on some “Paleo” diets which emphasize coconut based
foods and oils. Coconut oil is a saturated fat and can increase LDL levels. The
long-term health outcomes of diets high in coconut are unknown.
http://www.health.gov/dietaryguidelines/2015-scientific-report/02-executive-summary.asp
2836
References
• Review of Diets and Diet Guidelines. Mozaffarian D. Circulation 2016; 133: 187
• PREDIMED. Mediterranean Diet Trial. Estruch R, et al. NEJM 2013; 368: 1279
• US Dietary Guidelines Advisory. http://www.health.gov/dietaryguidelines/2015-
scientific-report/02-executive-summary.asp
• New AHA/ ACC Guidelines:
– http://circ.ahajournals.org/content/early/2013/11/11/01.cir.0000437738.63
853.7a.citation
– Keaney J, et al. NEJM 2014; 370: 275
• Old Guidelines
– ATPIII. JAMA. 2001;285:2486-2487. Grundy S, et al. Circulation 2004; 110:
227
• Tall A. NEJM 2006; 354: 1310
• FOURIER Trial of Evolocumab. Sabatine MS, et al. NEJM 2017; 376: 1713
2837
Update in Sepsis
Rebecca M. Baron, M.D.

No Conflicts
Thanks to Chanu Rhee for allowing me to
steal some of his slides.
2838
Case
A 47 yo woman with alcoholic cirrhosis is brought to

your ER with fevers, confusion, shortness of breath,
and worsening ascites. Temp is 37°C, SBP is 50
mmHg, HR 150 bpm, RR 40/min, CVP 4 mm Hg, and
O2 sat 90% (RA). CXR shows diffuse infiltrates, and
peritoneal fluid returns with a leukocyte count of
1000/µL (95% polys).
Question #1:
Does this patient have sepsis?
By what criteria?
2839
What is Sepsis (2001-15)?

Systemic Sepsis: SIRS +
Inflammatory Infection
Response Syndrome
(SIRS): Severe Sepsis:
Temp >38°C or <36°C Sepsis+ Organ
Heart Rate > 90 bpm Dysfunction
Resp Rate > 20/min
WBC >10000, <4000, Septic Shock:
or Bandemia>10% Sepsis+Refractory
Hypotension
Organ Dysfunction +/- Hypotension

(2001-2015)
2840
• 19-person SCCM/ESICM task force

• Meetings, Delphi processes, EHR records
• Endorsed by 31 Professional Societies
• Prior perceived shortcomings from prior:
• Focus on inflammation
• Continuum sepsis shock
• Vagueness of SIRS
• Severe sepsis is ‘redundant’
• SEPSIS: (>10% mortality)

• Life-threatening organ dysfunction
• Caused by dysregulated response to infection
• Increase SOFA score of ≥2
• SHOCK: (>40% mortality)
• Vasopressors for MAP≥65 mmg Hg
• Lactate>2 mmol/L
• In absence of hypovolemia
2841
SOFA Score: 6 Organ Systems, 0-4 Points

Points 0 1 2 3 4
<200 + mechanical <100 + mechanical
PaO2/FiO2 ≥400 <400 <300
ventilation ventilation
Platelets ≥150 <150 <100 <50 <20
Bilirubin <1.2 1.2-1.9 2.0-5.9 6.0-11.9 >12.0

Dopamine 5.1-15 Dopamine >15
Dopamine or or
Blood MAP MAP <5 Epinephrine <0.1 Epinephrine >0.1
Pressure ≥70 <70 or or or
Dobutamine Norepinephrine Norepinephrine
<0.1 >0.1
Glasgow
Coma 15 13-14 10-12 6-9 <6
Scale
3.5-4.9 >5.0
Creatinine <1.2 1.2-1.9 2.0-3.4 or or
<500cc urine/d <200cc urine/d
Vincent et al, Intensive Care Med 1996
qSOFA
• Out of hospital, ED, Ward settings
• Worse outcomes predicted from sepsis with 2 of:
• Respiratory Rate ≥ 22/min
• Altered mental status (GCS ≤ 13)
• SBP ≤ 100 mmHg
• Ongoing inquiry as to its validation
• LESS SENSITIVE but MORE SPECIFIC than SIRS
for sepsis screening.
2842
Limitations
Lab testing required (lactate, SOFA) not
feasible in low-resource settings
Prospective validation underway for
qSOFA score vs. other metrics
No use of biologic markers of sepsis to
help define subgroups or predictors
Practicality of definition for screening
patients vs. billing vs. epidemiologic vs.
research tools, etc.
In Part, from: Abraham E. JAMA 2016;315:757-759
SSC’s approach: essentially no different than before!
Step 1: Screen for Infection

• SIRS may be a sign of infection
Step 2: Screen for Organ Dysfunction
• Use organ dysfunction to target initial treatment and qSOFA to
target closer monitoring for deterioration from sepsis
Step 3: If hypotensive or lactate >=2.0 30 ml/kg crystalloid, with
reassessment of volume responsiveness or tissue perfusion
My bottom line: DON’T MISS SEPSIS. SCREEN with

SIRS, PROGNOSTICATE with qSOFA, Dx SEPSIS w SOFA
2843
Case, Question #2
1000/µL (95% polys). You initiate your sepsis bundle.
Initial management of hemodynamics should entail
use of:
a. Vasopressin
b. Norepinephrine
c. Norepinephrine + Furosemide
d. Intravenous fluids
e. Dobutamine
Case, Question #2
1000/µL (95% polys). You initiate your sepsis bundle.
Initial management of hemodynamics should entail
use of:
a. Vasopressin
b. Norepinephrine
d. Intravenous fluids
e. Dobutamine
2844
Question #2:
What are we supposed to be

doing with fluids in sepsis?
Sepsis: Source Control
EARLY, BROAD, EMPIRIC antibiotic therapy

Not the time to be elegant!
Think of sources needing SURGICAL
INTERVENTION
Catheter / device Remove it
Soft tissue abscess Drain it
Empyema Chest tube
Cholangitis ERCP
Endocarditis Abx/Valve replacement
Septic arthritis Joint debridement
Narrow therapy after 48 – 72H of cultures
2845
Septic Shock: EARLY Goal-Directed Therapy

2001- 2014
*Treatment began in E.D.: 6-hours

*A-line, Central line insertion
*Monitored: Mean arterial BP (MAP)
Central venous pressure (CVP)
Central venous O2 sat (SCVO2)
NEJM 2001; 345:1368 Hematocrit
EARLY Goal-Directed Therapy

INTERVENTION
500cc IVF Q 30 min!
NL arterial pH
NL base deficit Norepinephrine
NL lactate
ScvO2 > 70%
Dobutamine: dose
increased 2.5 mcg Q
15 min!
2846

HOW’D THEY DO THAT??

IT WORKED!!
However, what are the key components and broader applicability of EGDT?
2847
1341 Patients, Compared:

1. EGDT, vs.
2. Protocolized care without CVC, inotropes,
blood, vs.
3. Usual care
NO DIFFERENCE in Primary outcome of
60d in-hospital mortality or other outcomes
ProCESS*: What does it mean?

Mortality in usual care group substantially
lower than in EGDT in first trial (18% vs.
46%), thus “usual care” has evolved.
Severe sepsis without septic shock wasn’t
studied in ProCESS.
This trial and general practice supports
early antibiotics and fluids and uncertain re:
CVC for everyone, PRBCs**, dobutamine.
Targeted fluid resuscitation now the goal.
*ARISE, PROMISE trials, NEJM 2014-5 **TRISS trial, NEJM 2014: restrictive strategy
2848
CMS: (3h: plus

LA, cx, Abx)
(6h: f/u LA)
Surviving Sepsis Guidelines 2016, ICM 2017
From: Will This Hemodynamically Unstable Patient Respond to a Bolus of

Intravenous Fluids?
JAMA. 2016;316(12):1298-1309. doi:10.1001/jama.2016.12310
Figure Legend:
Effect of Increase in Preload on Stroke Volume of Ventricles With Normal and Decreased
Contractility. Frank-Starling curves illustrate that the effect of a given increase in preload
on stroke volume is dependent both on ventricular contractility and on baseline preload.
Copyright © 2016 American Medical
Date of download: 9/26/2017
Association. All rights reserved.
2849
Starting now at an ICU near you:

CLOVER trial design (PETAL Network)
What ‘flavor’ of fluid should we be

using in sepsis?
NO: Hetastarch
Mostly NO: Albumin
Yes: Crystalloid…moving toward
favoring LR over saline?
NEJM March 1, 2018
2850
FLUIDS in SEPSIS BOTTOM LINE:
Bolus crystalloid, but don’t overdo it.
Find your favorite way(s) to target

resuscitation.
Case, Question #3
You have administered broad-spectrum antibiotics to
treat presumed spontaneous bacterial peritonitis,
give her supplemental O2 (now saturating 90% on
100% FM), and after fluid resuscitation with 3L of
crystalloid, her HR comes down to 100 bpm, her SBP
has risen to 65 mm Hg with a mean arterial pressure
(MAP) of 50 mm Hg, and the CVP is 13 mm Hg. You
next order:
a. Vasopressin
b. Norepinephrine
d. 1 Unit of PRBCs
e. Dobutamine
2851
Case, Question #3
You have administered broad-spectrum antibiotics to
treat presumed spontaneous bacterial peritonitis,
give her supplemental O2 (now saturating 90% on
100% FM), and after fluid resuscitation with 3L of
crystalloid, her HR comes down to 100 bpm, her SBP
has risen to 65 mm Hg with a mean arterial pressure
(MAP) of 50 mm Hg, and the CVP is 13 mm Hg. You
next order:
a. Vasopressin
b. Norepinephrine
d. 1 Unit of PRBCs
e. Dobutamine
Question #3:
What’s up with pressors?
2852
Action of Vasoactive Catecholamines

2001- 2008
β1: HR, Contractility

β2: Vasodilation
Vasoconstriction
Chest 2007; 132:1678-1687; NEJM 2010; Lancet 2007* (Epi 2nd-line)
Vasopressin as a ‘Pressor’
Multi-center RCT with
~800 patients
No significant mortality
benefit in adding
vasopressin to
norepinephrine
Less sick people did
better with addition of
vasopressin
Widespread use as an
adjunctive support with
norepinephrine
VASST Trial
Russell et al. NEJM 2008; 358:877-887, Feb 28, 2008.
2853
New kid on the block:
Multi-center RCT with 344 patients (mostly sepsis; but NOT

low output states)
Add-on to conventional pressors increased MAP to 75
within 3h (69% vs. 23%, p<0.001)
Similar rates of adverse events
Intriguing as a new class of vasopressors
Surviving Sepsis Guidelines 2016, CCM 2017
2854
Question #2:
What are we supposed to be

doing with steroids in sepsis?
RELATIVE Adrenal Insufficiency

Basic Background
“High-dose” corticosteroids DO NOT improve
sepsis outcomes1
Absolute adrenal insufficiency in sepsis is RARE
What about RELATIVE adrenal insufficiency?

2002-2008: Cort-stim to select ‘nonresponders’
based upon a subgroup analysis
1NEJM 1984 311: 1137; Crit Care Med 1995 23: 1430; JAMA 2002
2855
Multi-center, double-blinded, placebo RCT
251 vs. 250 patients: Hydrocortisone or

Placebo q6h for 5d, then tapered 6d.
Primary outcome: Death 28 days.
2856
Low-Dose Steroids in Sepsis, 2018:
3800 patients, RCT 1241 patients, RCT

Less sick patients Activated Protein C
HC continuous infusion removed
No fludrocortisone Sicker patients
No mortality benefit 90d Included fludrocortisone
Faster resolution of shock 90d mortality benefit
Fewer blood transfusions Similar infections though
with steroids (unclear why) more viral with HC/FC
More hyperglycemia
with HC
March 1, 2018
Steroids in Sepsis Bottom Line?

“It is unlikely that in the near future sufficiently powered
trials will provide us with better data. Thus, clinicians
will have to use these data and subsequent meta-
analyses to decide how best to treat patients with
septic shock. Estimating 90-day mortality at the
bedside is not practical. It is likely that some
practitioners caring for a patient with a deteriorating
condition who is receiving escalating doses of
vasopressors, in whom other core interventions have
been instituted (i.e., appropriate antibiotics and
adequate volume resuscitation and source control), will
consider that the short-term benefits of low-dose
hydrocortisone may exceed any risks (e.g.,
antiinflammatory effects) as an added therapy in
selected patients.”
NEJM Editorial 2018
2857
Surviving Sepsis Guidelines 2016, CCM 2017
Adjunctive Sepsis Care
Tight Glucose Control2

Target glucose ≤180 mg/dl rather than tighter control.
Low Tidal Volume Ventilation in ARDS3
Judicious Fluid Management in Acute Lung Injury4
Protocolized Central Line Insertion and Care and
attention to ICU ‘bundles’ and prophylactic care5,6,7
1NEJM 2008;358:111; 2NEJM 2009;360:1283; 3NEJM 2000;342:1301;

4NEJM 2006;354:2564; 5NEJM 2006;355:2725; 6JAMA 2009;301:1231; 7CCM 2016
2858
Take-Home Points
Early Identification of Patients with Sepsis*
Source Control and Early Broad-Spectrum
Antibiotics
Early fluid resuscitation, primarily with crystalloid
(“Early Goal Directed Therapy” targeted fluids)
Norepinephrine as First Pressor of Choice
Consider Addition of Vasopressin to
Norepinephrine
Consider Epinephrine as 2nd-line Agent for
Refractory Hypotension to Norepinephrine
Limited role for Dopamine and Neosynephrine
as initial agents of choice; Angiotensin II is new.
*Note New Guidelines Consensus Guidelines, Crit Care Med 2016
Take-Home Points, Cont’d

Activated Protein C is no longer available.
Consider low-dose hydrocortisone for patients with
sepsis-induced refractory hypotension despite fluids and
pressors (without use of ACTH stim test to guide
decision-making) – perhaps in the sicker patients.
Uncertain goal of glucose control, but target ≤180 mg/dL
(instead of tighter control) suggested until more data
available. Hourly monitoring of glucose levels while on
an insulin drip is critical, and avoid hypoglycemia.
Attention to standard ICU care (e.g., ventilator bundle,
DVT and GI prophylaxis, central line care, etc).
CCM Consensus Guidelines, 2016
2859
Sepsis: Summary
NO rhAPC
To ICU High Risk of

Death Improving
Respiratory Check Cx’s ->

Start LD HC(??)
Support narrow Abx
0h 6h 24h 48h
Shock LOW Risk of Shock
starts Death resolving?
Antibiotics NO
? Debridement “Early Goal
NOT Septic? Source
Directed Rx”
Known?
Fluid End-of-life
Resuscitation No better discussion? Steroids?
No Conflicts
Thanks to Chanu Rhee for allowing me to
steal some of his slides.
2860
Selected Key References

Rhodes A, et al. Surviving Sepsis Campaign: International Guidelines for
Management of Sepsis and Septic Shock. Crit Care Med 2017; 45:486.
Annane D, et al. Hydrocortisone plus Fludrocortisone for adults with septic
shock. NEJM 2018; 378: 809.
Venkatesh B, et al. Adjunctive glucorticoid therapy in patients with septic
shock. NEJM 2018; 378: 797.
Khanna A, et al. Angiotensin II for the treatment of vasodilatory shock.
NEJM 2017; 377: 419.
Bentzer P, et al. Will this hemodynamically unstable patient respond to a
bolus of intravenous fluids? JAMA 2016; 12: 1298.
Singer M, et al. The 3rd international Consensus Definitions for Sepsis and
Septic Shock (Sepsis-3). JAMA 2016; 315: 801
The ProCESS Investigators. A randomized trial of protocol-based care for
early septic shock. NEJM 2014; 370: 1683.
Suggested Algorithm for PCT Use at BWH
2861
Suggested Algorithm for PCT Use at BWH, Cont’d
Oxygen Supply vs. Demand
Rivers, E. P. et al. CMAJ 2005;173:1054-1065
2862
Other “goals” of therapy

That can be monitored?
1818 patients : crystalloid vs.

crystalloid+20% albumin
Primary outcome: 28d mortality
NO DIFFERENCE in 28d mortality or other
secondary outcomes
2863
776 patients with septic shock: MAP 80-85

vs MAP 65-70 mm Hg
Primary endpoint 28d mortality
NO DIFFERENCE in 28d mortality, 90d
mortality, or adverse events
More new atrial fibrillation in high target group
Chronic HTN: less RRT in high target group
Multi-center, RCT, 1679 patients with shock

(858 patients DA; 821 NE)
Primary endpoint: 28d Mortality
No Significant Difference
(DA: 52.5%, NE: 48.5%)
2864
Secondary and Subgroup Analyses:
1. DA Increased arrhythmias
2. DA Increased 28d mortality in

cardiogenic shock subgroup
“Vasopressin Deficiency” in Sepsis?
2865
Norepinephrine vs. Vasopressin
About 400 septic shock subjects

Vaso/steroids vs. vaso vs. NE/steroids vs. NE
No difference in kidney failure free days at 28d
No clear renal protective effect demonstrated
Role for Epinephrine?
330 Patients with Septic Shock:

NE + Dobut (if needed) vs. Epi
Primary Outcome: 28d Mortality
No Difference
Similar secondary outcomes and adverse
events rates, as well
2866
Relative Adrenal Insufficiency

The ACTH-Stim Test Story
Annane et al. JAMA 2002 288: 862
300 septic patients
149 Patients: Placebo
151 Patients: Hydrocortisone 50 mg IV Q6h +
Fludrocortisone 50 µg PO QD x 7 days
All got:
Baseline, random cortisol levels
250 µg ACTH stimulation test
“Nonresponder”: Increase cortisol < 10 µg/dL
“Responder”: Increase cortisol ≥ 9 µg/dL
Relative Adrenal Insufficiency
+ STEROIDS
+ Relative Adrenal Insufficiency
+ STEROIDS
– Relative Adrenal Insufficiency

60
2867
Popular Topics for the Boards
Associate Physician
Department of Medicine, Division of Pulmonary and Critical Care
Harvard School of Medicine
Disclosures
• None
2868
Themes
• Medical statistics
• Decisional Capacity
• Iatrogenic problems
• Prolonged critical illness
• Weakness in ICU patients
• Disputes among surrogates/no HCP
Allow Me to Introduce You…

Mark Twain
There are three kinds of lies: lies, d—d lies,
and statistics
Thomas Bayes (professional clergyman and

amateur mathematician) – formulated
Bayes theorem
References for Images:

Mark Twain. The Biography Channel website. 2013.
Available at: http://www.biography.com/people/mark-twain-9512564.
Thomas Bayes: Celebrating Statisticians: Thomas Bayes
Available at: http://www.blogs.sas.com
2869
Case 1
• You are the attending for a 75yo woman admitted with diarrhea,
fever, tachycardia and leukocytosis
– Her symptoms started 1 week after completing a course of
antibiotics for a UTI
• Fortuitously, Grand Rounds this week reviewed C. difficile

– Approximately 60% antibiotic-associated
diarrhea is caused by C. difficile
• Your hospital has recently changed its laboratory assay for C. difficile
–The new assay has a sensitivity of 70% and a
specificity of 95%
• Your patient’s test comes back negative
Case 1
• What does the negative test mean?
– A. Specificity must be put into the context of the underlying
prevalence. Since both are high, the negative predictive value is
also high – the patient is unlikely to have C. difficile.
– B. A specificity of 95%, means that there is a 95% chance that
the negative test result is a true negative regardless of the
disease prevalence. The negative predictive value is therefore
95%
– C. The Negative predictive value is 68%.
– D. The population prevalence is 60%, so a specificity of 95%
gives a negative predictive value of 57%.
– E. The likelihood ratio of a negative test (LR-) in this assay is 4.9
2870
Case 1
• What does the negative test mean?
– A. Specificity must be put into the context of the
underlying prevalence. Since both are high, the
negative predictive value is also high – the patient is
unlikely to have D. difficile.
– B. A specificity of 95%, means that there is a 95%
chance that the negative test result is a true negative
regardless of the disease prevalence.
– C. The Negative predictive value is 68%.
– D. The population prevalence is 60%, so a specificity
of 95% gives a negative predictive value of 57%
– E. The likelihood ratio of a negative test (LR-) in this
assay is 4.9
Calculating Predictive Values

• Positive Predictive Value
– Probability of X (usually a disease) in all patients having a
positive test result
– True Positives/(True positives + False positives)
• Negative Predictive Value
– Probability of being without X (usually a disease) in all patients
with negative test result
– True Negatives/(True Negatives + False negatives)
• In our patient:
– Actual incidence of disease = 60%
– Test sensitivity = 70%
– Test specificity = 95% Disease
– For 100 patients: + - Totals
• 38/(38 + 18) = 0.68
Test + 42 2 44
Test - 18 38 56
60 40 100
2871
Medical Statistics: Definitions

• Sensitivity: Positive test in pts having X
– High sensitivity means few false negatives
– True Positive/(True positive + False negative)
• Specificity: Negative test in pts without X
– High specificity means few false positives
– True Negative/(True negative + False positive)
• Predictive Values: Probability that the test result
predicts the disease (or lack thereof)
• Odds Ratio and Likelihood Ratio
– Tests the test
– Useless tests have OR = 1 and LR = 1
More Definitions
• “Real-World” Example
• Absolute Risk
– Dabigatran vs. warfarin in
– Difference between patients with atrial fibrillation1
proportions of patients with
and without a characteristic • Annual incidence of serious
developing condition X bleeding in patients on 110 mg
dabigatran was 2.71%, vs.
• Number Needed to Treat (or 3.36% in patients on warfarin
Harm)
– Absolute risk reduction with
– 1/Absolute Risk dabigatran was 0.65%
• Relative Risk (Risk Ratio) – Number needed to treat =
– Comparison of the 1/0.0065 = 154
proportion of patients with – Relative Risk of serious
and without a characteristic bleed with dabigatran =
who develop condition X 0.0271/0.0336 = 0.81
• Confidence Intervals – The confidence intervals
– Distance away from 1 were 0.69 – 0.93, favoring
indicates strength of effect dabigatran over warfarin
Reference:
1. S.J. Connolly et al., NEJM 2009, vol. 361, pp. 1139 - 1151
2872
Another Consideration
• The Best Medical Journal has just published a non-
inferiority study on a new antihypertensive regimen
compared to a commonly used regimen.
– No overall superiority was shown compared to the usual therapy.
– Patients over 70 years old had significant decreases in both
systolic and diastolic BP on the new regimen.
– What is the significance of this?
• This is an example of “Post Hoc” Analysis

– Be careful! If the subgroup wasn’t included in the original
design, it can’t be relied upon for analysis
– Instead, it is “hypothesis generating” and requires further
testing
General Board Point

• There will be several questions
involving medical statistics
2873
Case 2
• You are the attending physician for a 74 year old woman who was
admitted 3 weeks ago with severe sepsis. Her comorbidities include
vascular dementia with mild functional impairment. Her course has
had multiple complications. Her adult daughter, who is her health
care proxy, her husband state that they feel that the patient would
want to continue full aggressive treatment of her illness.
Case 2
• This morning you receive an email from the night nurse, who writes
that, for the past week, the patient has been having episodes of
agitation during which she pulls at her IV lines and tracheostomy
tube. This behavior is new, and the night nurse is convinced that
the patient is trying to refuse medical treatment.
2874
Case 2
• This morning you receive an email from the night nurse, who writes
that, for the past week, the patient has been having episodes of
agitation during which she pulls at her IV lines and tracheostomy
tube. This behavior is new, and the night nurse is convinced that
the patient is trying to refuse medical treatment.
• When you ask the patient about this report, she turns away. When
her daughter visits, you mention the nurse’s concerns. The
daughter tells the patient, “We need you. You want to keep going,
don’t you?” The patient does not nod, but does squeeze her
daughter’s hand in response.
Case 2, continued
• Patient’s current exam
– VS Temp 99.2, HR 105, BP 115/65, RR 24, O2 sat
94% on FiO2 35%
– Chest: Bibasilar rales; Heart: Irreg Irreg; Abd: soft,
+BS; Ext: 1+ pedal edema; Neuro: Awake,
responds appropriately to Y/N questions, follows 1-
step commands; strength 3 - 4/5 bilat upper and
lower ext, MAE
2875
Case 2, continued
• Patient’s current meds include
– metoprolol
– inhaled albuterol/ipratropium
– ceftriaxone
– famotidine
– dalteparin
– trazodone
– lorazepam
Case 2, continued
• Of the following, the best next course of action
would be:
- A Ethics consult since the HCP is not acting on the
patient’s wishes
- B Assessing the patient’s ability to communicate and
her decision-making capacity
- C Continue aggressive therapy since that is the
guidance from the HCP, and patient’s dementia
precludes her from participating in this decision
- D Evaluating the patient for causes of delirium
- E Consulting psychiatry to evaluate for depression
2876
Case 2, continued
• Of the following, the best next course of action
would be:
- A Ethics consult since the HCP is not acting on the
patient’s wishes
- B Assessing the patient’s ability to communicate and
her decision-making capacity
- C Continue aggressive therapy since that is the
guidance from the HCP, and patient’s dementia
precludes her from participating in this decision
- D Evaluating the patient for causes of delirium
- E Consulting psychiatry to evaluate for depression
Case 2 - Explanation
• At this point, there is not enough information to evaluate
whether patient’s HCP is or is not acting on the patient’s
previously expressed wishes.
• It is not clear from the evidence presented what is
causing her nocturnal symptoms. The absence of
daytime symptoms do not rule out delirium.
• Ambivalence is common among patient who have a long
and burdensome course of therapy.
• Determining a critically ill patient’s decisional capacity is
difficult and time consuming; psychiatric consultation can
help in this assessment.
– Bedside assessment by Confusion Assessment Method-ICU
(CAM-ICU; Ely et al., Crit Care Med 2001)
2877
Decisional Capacity – Take Home

Points
• Intertwined with informed consent
• Requires
– Understanding and remembering choices
– Understanding consequences
– Being able to rationally consider choices
• May not arrive at the “right” choice
– Being able to indicate a choice
– A careful bedside assessment can be used
• Sliding scale
• Diagnosis of dementia per se does not rule out
decisional capacity
General Point for the Boards

• Be prepared for ethics and decisional
capacity questions - look for an option that
preserves a patient’s autonomy
2878
Case 3
• Your patient is a 68yo man with recurrent lung cancer who was
admitted to your ICU 2 days ago.
• He had been in his USOH and tolerating an outpatient
chemotherapy regimen (pembrolizumab and cyclophosphamide)
until 3 weeks PTA
– He had a sick contact (grandson with cold)
– His PCP started levofloxacin for possible pneumonia
• His symptoms include NP cough, fever, dyspnea
• His dyspnea progressed, and he required intubation last evening
– Bronchoscopy with lavage performed, Gram stain shows
neutrophils but no organisms
• His AM exam shows dependent rales, regular HR with a 2/6 systolic
murmur at the mid-axillary line, no JVD, no pedal edema
• Which would be the most reasonable next step?
Case 3
• A. Perform a CT angiogram to exclude PE
• B. Broaden antimicrobial therapy to
include anti-fungal (Aspergillus) coverage
• C. Float a PA line to exclude pulmonary
edema as a contributing factor
• D. Add solumedrol to treat possible drug-
induced pneumonitis
• E. Perform a non-contrast CT to evaluate
for lymphangitic spread of tumor
2879
Case 3
• A. Perform a CT angiogram to exclude PE
• B. Broaden antimicrobial therapy to
include anti-fungal (Aspergillus) coverage
• C. Float a PA line to exclude pulmonary
edema as a contributing factor
• D. Add solumedrol to treat possible
drug-induced pneumonitis
• E. Perform a non-contrast CT to evaluate
for lymphangitic spread of tumor
Case 3 - Explanation
• While the patient has a malignancy, the
subacute course would be atypical for PE
• The patient has not been severely
neutropenic for a prolonged period, and so
is not at risk for a fungal pneumonia
• The reported exam is not typical
pulmonary edema
2880
Case 3, Explanation
• Both cyclophosphamide and pembrolizumab have been
associated with drug-induced pneumonitis
• The incidence of pneumonitis with checkpoint inhibitors
is approximately 3 - 5%
– The incidence is higher, up to 10% with checkpoint inhibition
therapies combined with anti-CTLA4 therapy
– Approximately 25% of the patients developing pneumonitis will
have severe pneumonitis (grade 3 or 4)
• Treatment is to stop the offending drug and add steroids
General Points for the Boards

• Use all the clues provided in the question stem
– The set up may be tricky, but the needed information
will be there (somewhere)
• Be on the watch for a choice that is associated with an
iatrogenic problem
2881
Case 4
• Your patient, an 79 year old woman, passed away this morning. Her family
(spouse, 2 sons, and a daughter, who is her healthcare agent) was at her
bedside at the time of her death.
• She was admitted 12 weeks ago following a motor vehicle collision during
which she sustained a femur fracture. Her fracture was repaired by
Orthopedics with a ORIF. Her course was complicated by DVT on post-op
day 3 and prolonged respiratory failure. After her initial post-op course, she
was transferred to the medical intensive care unit (MICU) for management
of her prolonged respiratory failure. Her course in the MICU has been
significant for atrial fibrillation, ventilator associated pneumonia, urosepsis,
and delirium.
• Based on patient’s long-standing, consistent statements that she would not
want prolonged support by machines, her goals of care were changed to a
comfort-focused approach yesterday.
• You approach her family regarding consent for autopsy.
• The patient’s husband does not want an autopsy, but all of the children,
including her daughter who is the healthcare agent, want an autopsy
What is true regarding consent for autopsy for this patient?
Case 4
- A. The autopsy cannot proceed since a patient’s family

must give unanimous consent.
- B. Since the patient had several iatrogenic
complications during her hospitalization, the case must
be referred to the medical examiner.
- C. Since the patient’s admission was preceded by a
motor vehicle accident, the case must be referred to
the medical examiner.
- D. The autopsy can proceed since the health care
proxy has given permission.
- E. The autopsy cannot proceed since the next of kin
has refused permission.
2882
Case 4
- A. The autopsy cannot proceed since a patient’s family must give

unanimous consent.
- B. Since the patient had several iatrogenic complications during
her hospitalization, the case must be referred to the medical
examiner.
- C. Since the patient’s admission was preceded by
a motor vehicle accident, the case must be referred
to the medical examiner.
- D. The autopsy can proceed since the health care proxy has given
permission.
- E. The autopsy cannot proceed since the next of kin has refused
permission.
Case 4 - Answer
• The medical examiner must be notified since the
admission was precipitated by trauma.
– State laws for medical examiner notification vary
– State laws differ regarding permission for autopsy
– Some states allow HCP to consent, if explicitly
instructed in advance directive
– Most laws regarding autopsy permission follow
inheritance and property laws
2883
Autopsy Permission/Roles of HCP

– Take Home Points
• Authority for granting permission for
autopsy varies state by state
– Only a few states grant this to the HCP
• States frequently put constraints on this permission
– Generally the next of kin gives permission
• Medical examiner always has the authority
to perform an autopsy.
• The authority of the HCP is for decisions
regarding medical treatment.

• Be prepared for a couple of questions on
health care proxies, including limits to their
authority, when and how a health care
proxy makes decisions, and who is eligible
to be a health care proxy.
2884
Case 5
• You are the attending for a 62yo woman who is

recovering from sepsis due to pyelonephritis.
– Her initial presentation was significant for
hypotension requiring pressors and altered mental
status.
• She was intubated for airway protection.
– Unfortunately, she aspirated during intubation, which
led to pneumonia and ARDS.
• Today is her tenth day on the ventilator, and she
still requires substantial support.
– You are meeting today with her family to discuss
possible tracheostomy placement.
Case 5
• What is true about patients who survive ARDS?
– A The use of sedatives with amnestic effects can minimize the
symptoms of later post-traumatic stress disorder.
– B Early enteral feeding is important to maintaining adequate
muscle mass in patients requiring prolonged ventilator
support. Unfortunately, full feeding goals (calories and/or
protein) are frequently not achieved due to GI intolerance.
– C Despite near normalization of their pulmonary function tests,
ARDS survivors report significant decrements in their
emotional and physical functioning for up to 5 years following their
illness.
– D Critical illness associated neuropathy/myopathy is strongly
associated with statin use.
– E With the exception of patients with spinal cord injuries,
patients with trauma-associated ARDS have a better
prognosis than patients with medical causes of ARDS
2885
Case 5 - Answer
• What is true about patients who survive ARDS?
– A The use of sedatives with amnestic effects can minimize the
symptoms of later post-traumatic stress disorder.
– B Early enteral feeding is important to maintaining adequate
muscle mass in patients requiring prolonged ventilator
support. Unfortunately, full feeding goals (calories and/or
protein) are frequently not achieved due to GI intolerance.
– C Despite near normalization of their pulmonary function tests,
ARDS survivors report significant decrements in their
emotional and physical functioning for up to 5 years following
their illness.
– D Critical illness associated neuropathy/myopathy is strongly
associated with statin use.
– E With the exception of patients with spinal cord injuries,
patients with trauma-associated ARDS have a better
prognosis than patients with medical causes of ARDS
Prolonged Critical Illness

• Prolonged critical illness is associated with significant
morbidity and healthcare costs
• Recent studies of survivors of ARDS show persistent
physical and neuropsychiatric limitations for up to 5
years after discharge from the acute hospital
– Near-normal pulmonary function tests by 1-year
– 6-minute walk test below range expected for age
– Over half of ARDS survivors report significant anxiety and/or
depression up to 5 years after their acute illness
• Predictors of decreased functioning after ARDS
– Age greater than 52
– Critical illness-associated weakness
– Comorbid disease
M. Herridge et al. NEJM 2011; vol. 364 pp.1293 – 1304
2886

• Be prepared for questions highlighting the
substantial personal and societal costs of
prolonged critical illness
Case 6
• You are the attending for a 56yo
man, h/o DM and asthma, who
was admitted 21 days ago for
pneumonia following H1N1
influenza.
• His initial hospital course included
an emergent traumatic intubation
• Hospital course was significant for
refractory hypoxemia requiring
paralysis (48hr) and ECMO.
• He gradually improved, and was
decannulated 2 days ago.
2887
This morning…
• On exam, he is afebrile with stable VS.
• Mental status exam shows him to be
awake, and nodding appropriately to Y/N
questions.
• His chest shows basilar crackles, and his
heart is regular and without murmurs.
• On neurologic exam, your patient cannot
lift either his arms or legs, although he can
move his fingers and toes to command.
The least likely cause would be

- A. Medications
- B. Low potassium
- C. Sequelae of traumatic intubation
- D. Undiagnosed premorbid neuromuscular
disease
- E. Critical illness associated weakness
2888
The least likely cause would be

- A. Medications
- B. Low potassium
- C. Sequelae of traumatic intubation
- D. Undiagnosed premorbid neuromuscular
disease
- E. ICU-Acquired weakness
ICU-Acquired Weakness
(ICU-AW)
• Approximately 75,000 patients annually develop
ICU-AW (Fan et al., AJRCCM, 2014)
• Patients with ICU-AW have 30% higher acute
hospital costs (Hermans et al. AJRCCM 2014)
than ICU patients without weakness
– This doesn’t count costs of rehabilitation,
readmission, post-rehabilitation support
• Patients with ICU-AW have higher mortality
compared to non-weak ICU patients
– Higher post-ICU mortality in first year: 28 vs 11%
– Possible higher in-hospital mortality (inconsistent
study results)
2889
Weakness Increases Mortality??

• Unknown mechanisms, probably multiple
– Difficulty swallowing
– Poor cough
– Prolonged ventilation
– Poor balance
– Difficult to move in bed so increased
decubitus ulcer incidence
– Possible persistent inflammatory process
ICU-Acquired Weakness
• Can occur very early in course
– Generally seen after 1 wk in ICU
• Common
– Clinically significant findings in up to 2/3 patients requiring
mechanical ventilator for over 1 week
– Depending on study >80% of patients on mechanical ventilation
have evidence
• Persists
– 6 minute walk test only 70% age-predicted maximum in ARDS
survivors 5yrs after acute illness (Herridge et al., NEJM 2003)
• Subtypes
– Myopathy
– Neuropathy
– Combined myopathy/neuropathy
2890
Risk Factors
• Age
• Sepsis
• Duration of organ failure
• Mechanical Ventilation
• Premorbid functional status
• Female gender (inconsistent)
• Medication (inconsistent)
– Aminoglycosides
– Neuromuscular blockers
– Glucocorticoids
Weakness in ICU patients -

Etiologies
• Primary neuromuscular disease
– Increases likelihood of critical illness
– Critical illness can unmask neuromuscular disease
• New, but separate, event complicating critical illness
– New CVA, embolism due to endocarditis, spinal cord ischemia
• Complication of therapy
– Meds
• Metabolic derrangements
– Hypokalemia
• Due to critical illness
– ICU-Acquired Weakness (ICU-AW)
2891
Diagnosis - Approach
• Differential can be summarized by MUSCLES
(Maramattom BV and Wijdicks EF, Critical Care Medicine 2006, vol.
34, pp 2835 – 2841)
– M: Meds – steroids, amiodarone, NMB,
aminoglycosides, lasix
– U: Undiagnosed primary neuromuscular disease
– S: Spinal cord problem such as ischemia
– C: Critical illness associated weakness
– L: Loss of muscle such as rhabodmyolysis
– E: Electrolytes: low K, low phos, high Mg
– S: Systemic illness: Hypthyroidism, adrenal
insufficiency, porphyria
General Board Point

• Weakness following critical illness is
common, and has a broad differential.
2892
Case 7
• You are on service at a Boston teaching hospital
• One of your patients is a 58yo diabetic woman
who was admitted 2wks ago with urosepsis
• Her initial shock has resolved, and she is
tolerating PS 12/5 for vent support
• Her course has been complicated by ATN
She is oliguric, and becoming volume overloaded
Renal is advising starting dialysis
Family Meeting
• You review your patient’s situation
• She has no written healthcare proxy
• Present at the meeting
– Husband (separated)
• She saw a news program on dialysis a year ago and said she’d never want it
– Sister
• Reports a recent conversation where the patient wanted her to be the HCP
• She states that her sister would definitely want dialysis because “she is a
fighter”
– 2 brothers
• No opinion regarding patient’s wishes, but both confirm she was
independent prior to current illness and enjoyed her quality of life
• During the meeting
– Her husband states he should be the HCP
– Her sister presents a living will from 5yr ago
• Specifies no mechanical support if terminal illness
2893
What is true about decision-making

for this patient?
- A. As the legal next of kin, patient’s husband is her HCP
- B. Her sister should be her health care proxy, since
that reflects the patient’s most recently stated wishes
- C. The patient’s advance directive should be used to
guide decision-making
- D. A legal guardian may be required for this patient
- E. Since there is no HCP, decisions require a consensus
among her family members
What is true about decision-making

for this patient? - Answer
- A. As the legal next of kin, patient’s husband is her HCP
- B. Her sister should be her health care proxy, since
that reflects the patient’s most recently stated wishes
- C. Her advance directive should be used to guide
decision-making
- D. A legal guardian may be required for this patient
- E. Since there is no HCP, decisions require a consensus
among her family members
2894
Explanation
• The Heath Care Proxy (HCP) is a legally designated role
– Paperwork requirement varies by state
• The default decision maker for patients lacking a HCP is determined
by state law
• Advance directives can be useful guides as to the patient’s wishes, if
– The patient anticipates the clinical situation at hand
– Can be more useful if general guidance provided
• “Five Wishes”, “Thinking Ahead”
– Some states allow durable orders for resuscitation preferences
• POLST/MOLST/LaPOST
• Even if there is no HCP, and no state-determined hierarchy of
surrogate decision makers, a consensus decision among people
who care for the patient provides a good basis for most clinical
decisions.
– Sometimes, a legal guardian is needed if no consensus
Healthcare Proxy – Take Home

Points
• A Health Care Proxy (HCP) has the same authority as a
decisionally capable patient
– Treatment decisions, not necessarily research (varies by state)
• Healthcare proxy uses “substituted judgment” as a basis
for decisions
– Most often uses “known or probable” wishes
– Other standards: “best interests”, “clear and convincing
evidence”
• State-specific guidelines if no written proxy
– Most states use “next of kin” as default proxy
– 7 states do not have defined hierarchy
• Authority applies only to healthcare matters
– Significant limits in some states
– Sometimes can be specifically directed to consent to autopsy
Adapted from C. Sabatino and E. Wood, “Decision-Making and Advance Directives –

Nuts & Bolts, National Aging and Law Conference, December 2010
2895
General Point for Boards

• Be prepared for questions regarding end
of life issues, ethics, surrogate decision
making
– Since state law guides these areas, look for
general principles
– Especially autonomy
Summary
• Statistical analyses are an integral part of evaluating medical data.
• The health care proxy (HCP) uses substituted judgment to make
decisions regarding medical therapy for an incapacitated patient. The
role of HCP ceases with the patient’s death. If there is no HCP
surrogate decision making is guided by state law.
• Decisional capacity is a continuum. Bedside testing can be helpful.
Impaired cognition does not always preclude decisional capacity.
• Iatrogenic injury is a favorite target for the boards – be on the lookout

for drug-associated syndromes, such as drug-induced pneumonitis.
• Survivors of prolonged critical illness experience many physical and

neuropsychiatric sequelae for several years after their acute illness.
• Weakness following critical illness is common, and can be severe.
It is an independent predictor of poor outcome.
2896
Disclosures
• None
References
• Medical Statistics
– J. A. Knottnerus et al. British Medical Journal 2002,
vol. 324, pp. 477 – 480.
• Advance Directives and Medical Decision
Making
– R.S. Olick, Chest 2012, vol. 141, pp. 232 – 238.
• Checkpoint-Associated Pneumonitis
– J Naidoo et al. J Clin Oncol 2017, vol. 35, pp709-717.
• Prolonged Critical Illness
– M. S. Herridge et al. NEJM 2011, vol. 364, pp.1293 –
1304.
2897
GOOD LUCK WITH YOUR

BOARDS !!
2898
Mechanical Ventilation
Basic to Advanced Concepts
Kathleen J. Haley, M.D.

Associate Physician
Department of Medicine, Division of Pulmonary and Critical Care
Harvard School of Medicine
Disclosures
• None
2899
Outline
• Indications
• Mechanical Ventilation Modes and Variables
• Lung Mechanics
• Complications of Mechanical Ventilation
• Liberation from Mechanical Ventilation
• Non-invasive Ventilation
Historical Perspective
2900
Indications for Mechanical Ventilation

• Hypoxemia
– Inability to achieve
adequate oxygenation
• Hypercapnea
– Inability to maintain
adequate alveolar
ventilation
• Reduce Work of Breathing
• Airway protection
– Intact laryngeal reflexes
are better
Goals of Mechanical Ventilation
• Maintain adequate oxygenation (pO2)

• Guarantee adequate alveolar ventilation (pCO2)
• Avoid harm
• Optimize patient comfort
• Extubate as soon as possible!!
2901
Important Variables
• Pressure
Compliance
(∆V/∆P)
• Volume Resistance • Triggering
(∆P/∆F)
• Flow • Cycling
• Time
Triggering
• Triggering – what causes the
ventilator to begin the
inspiratory phase
– Time – vent cycles at a
frequency determined by the
control rate
– Pressure – the vent senses
the pt’s inspiratory effort by
way of a decrease in the
baseline pressure
– Flow – vent senses the pt’s
inspiratory effort by way of a
deflection in the continuous
biased flow
2902
Cycling
• Cycling is how the ventilator switches from the
inspiratory phase to the expiratory phase.
– Time – such as in pressure control ventilation

– Flow – such as in pressure support ventilation
– Volume – such as in volume control ventilation
Modes of Ventilation:
Too many choices!!!!!!
AutoFlow
Auto Mode
VS SC
PPS
PCV
ECMO
2903
Commonly Used
Modes of Mechanical Ventilation
• Assist Control (AC)
– Can set either volume or pressure as the independent variable
– Respiratory drive not needed
– Patient-initiated breaths receive full support (volume or inspiratory pressure)
– When AC used without other description, refers to AC/volume-controlled
• Pressure Controlled (PCV) – usually done with AC mode
– Set both the inspiratory pressure and inspiratory time
– Allows control of the inspiratory:expiratory ratio
• Pressure Support Ventilation (PSV)
– Patient must have a reliable respiratory drive (spontaneous mode)
• Intermittent Mandatory Ventilation (IMV)
What Does AC Look Like?
2904
What Does IMV Look Like?
What Does PSV Look Like?
2905
Understanding
Mode Name What is set? Initiation

(triggering)
Assist Control (AC) Volume Patient or timer
IMV Volume Patient or timer
Pressure Control (PCV) Pressure Patient or timer
Pressure Support (PSV) Pressure Patient
Understanding
Mode Name What is set? Initiation Termination

(cycling)
AC/VC Volume Patient or timer Volume
IMV/VC Volume Patient or timer Volume
PCV Pressure Patient or timer Timer
PSV Pressure Patient Flow Rate
2906
Understanding Mechanical Ventilation

Other parameters to set:
Mode FiO2 Insp Flow Rate PEEP Inspiratory Time
AC Yes Yes Yes No (indirect)
IMV Yes Yes Yes No (indirect)
PCV Yes No Yes Yes
PSV Yes No Yes No
Assist Control/Volume Control

Ventilation
• Most commonly used mode of ventilation
• Pros:
– All breaths assisted
– Precise control of tidal volume and minute ventilation
• Important role in ventilation of unstable patients
• Con:
– Airway pressure is not controlled during inspiration
– Not a weaning mode
2907
Pressure Support Ventilation (PSV)
• Pro:
– Patient control of respiration
– Very comfortable for patients
– Excellent weaning mode of ventilation
• Cons:
– No guarantee of minute ventilation
– No backup respiratory rate
• Risk of apnea
Pressure Control Ventilation (PCV)
• Pro:
– Control of pressure during inspiratory phase of respiratory
cycle
– Easy to set ratio of inspiration and expiration
– Useful in cases of severe hypoxemia (inverse ratio
ventilation)
– High flows can be more comfortable in fibrotic lung
processes
• Cons:
– No guarantee of minute ventilation
2908
Lung mechanics and why we care
Lung Mechanics
Note: distending pressure is the total

pressure of the entire respiratory system.
2909
The ventilator as a diagnostic tool:

Clinical case
• 25 y.o. male with a narcotic overdose.

Intubated in emergency room for airway
protection and hypercarbia.
• Initial Vent Settings
AC, Rate=10, TV=500ml, PEEP=5, Flow=
60L/min, FiO2=1.0
• PIP=20 cm H20, Plateau=15 cm H20
• Determine compliance and resistance:
Compliance=
∆volume/∆pressure=
Tidal volume/plateau-PEEP
500/(15-5)=50
Normal: 50-100 ml/cm H20
2910
Resistance=
∆pressure/flow=
(PIP – plateau)/flow
(20 – 15)/1 = 5 cmH2O/L/sec
Normal: 5 -12 cmH2O/L/sec
Respiratory Mechanics
Elevated Peak Inspiratory Pressure
Resistance Compliance
Problem Problem
Problem with obstruction Problem with the

of the flow of gas into the stiffness of the lung
lung related to the tubes
or airway
2911
Elevated Peak Airway Pressures
• Increased resistance • Decreased compliance
Water/kink of ventilator tubing Pneumonia

Obstructed ETT/secretions ARDS
Asthma/bronchospasm Severe CHF
COPD Effusion
Pneumothorax
Right mainstem intubation
Complications of Mechanical Ventilation
• Ventilator-induced lung injury

• Ventilator associated pneumonia
• Oxygen toxicity
• Decreased cardiac preload
• Gastric stress ulceration
2912
Ventilator Strategies May Contribute to Lung Injury
Slutsky AS, Ranieri

VM. N Engl J Med
2013;369:2126-2136.
Complications of Mechanical Ventilation
(a) Capillary stress fracture with incipient (b) Higher power view of stress fracture
extravasation of erythrocyte. showing exposure of collagen filaments.
Crit Care. 2003 Dec;7(6):435-44. Epub 2003 Oct 17.
2913
Complications of mechanical ventilation:

(Tension) Pneumothorax
Strategies to Avoid Barotauma and Cyclic Recruitment:

Lung-Protective Ventilation
AACN Clin Issues. 2001 May;12(2):234-46.
2914
• Small tidal volume (6ml/kg) versus large tidal volume

(12ml/ kg)
• Inclusion criteria
– Mechanical ventilation
– paO2/FiO2 < 300
– Bilateral pulmonary infiltrates
– No evidence of LA hypertension
• PCWP < 18mm Hg
Main Outcome
Variables
The Acute Respiratory Distress Syndrome Network. N Engl J Med 2000;342:1301-1308
2915
Lung Protective Ventilation
• Low tidal volume

– 6 mL/kg
– Maximum plateau pressure
<30 cm H20
– FiO2 and PEEP adjusted to
keep PaO2 55-80 mm Hg
• PEEP
– Optimal PEEP remains
unclear
– Adjust to optimize
compliance (“best PEEP”)
– Use PEEP to get adequate
oxygenation
Auto (“intrinsic”)PEEP
Pressure will build in the chest if there is not adequate expiratory time to empty
each tidal volume
2916
Intrinsic or “Auto” PEEP
• Usually only clinically relevant in those with

obstructive lung disease (e.g. COPD)
• Can cause:
– Ventilator dyssynchrony
– Increased work of breathing
– Barotrauma
– Hypotension
How to treat auto-PEEP

• Decrease minute ventilation
– Decrease TV
– Decrease RR
• Increase expiratory time
– Increase inspiratory flow rate
• Increase extrinsic PEEP to facilitate synchrony
• Decrease airway resistance
– Optimize inhaled bronchodilators
2917
Prevention of
Ventilator-Associated Events, Including Infectious
Ventilator-Associated Events
• Recommended • Not Recommended
– Noninvasive ventilation – Selective gut
– Orotracheal intubation decontamination
– Ventilator circuit change for new – Early tracheostomy
patient or when soiled
– Hand washing • Controversial
– Closed endotracheal suction sustem – Chlorhexidine as the oral
– Continuous aspiration of subglottic cleaning agent
secretions
– Minimize sedation
– Oral hygiene
– Elevation of the head of bed
– Extubation as soon as feasible
The exit strategy

“Weaning” is rarely necessary
• Assess patient readiness
for extubation every day
– Hemodynamically stable
– Able to protect airway
– FiO2 < 60%
– PEEP < or = 7.5 cm H2O
• Spontaneous breathing
trial paired with “sedation
vacation”
AJRCCM 1994; 150:896
2918
Spontaneous awakening trial (SAT) paired with spontanous breathing trial (SBT)
Girard Lancet 2009
Non-invasive mechanical ventilation
Indications Contraindications
• Heart failure • Copious Secretions
• Hypercapnic respiratory • Altered mental status
failure (COPD • Need for secure airway
exacerbation)
2919
Summary
• Indications: guarantee adequate
– Ventilation, oxygenation, airway protection
• Goals: guarantee adequate
– Ventilation, oxygenation, comfort, avoid harm
• Variables
– Pressure, volume, flow, time. Triggering/cycling
• Mechanics
– Compliance and Resistance
• Complications
– Baro- and Volu- trauma, IVAC
• Lung protective strategy
– Tidal volume 6 ml/kg, plateau pressure < or = 30 mmHg, “optimal”
PEEP
• The exit strategy: the sooner, the better
Case 1.
25 y.o. gentleman with testicular cancer is admitted to the ICU

immediately after orchiectomy. Patient has no prior pulmonary
history.
Initial ventilator settings are FiO2=0.30, Mode = AC/VC, Rate =4,
TV=350, PEEP=5. Patient’s observed respiratory rate is 4.
Initial ABG reveals pH=7.24, pCO2=60, pO2=104
Which of the following ventilator changes will best correct the

respiratory acidosis?
a) Change mode to intermittent mandatory ventilation (IMV)

b) Change mode to pressure support ventilation (PSV)
c) Increase the respiratory rate
d) Decrease the FiO2
2920
Case 2.
60 y.o. woman (lifetime nonsmoker) is admitted to the ICU with

hypoxemic respiratory failure secondary to legionella pneumonia.
Patient has no prior pulmonary history.
Initial ventilator settings are FiO2=0.50, Mode = AC/VC, Rate =12,
TV=400, PEEP=5. Patient’s observed respiratory rate is 16.
Initial ABG reveals pH=7.38, pCO2=42, pO2=50
Which of the following ventilator changes will not correct the

hypoxemia?
a) Change mode to intermittent mandatory ventilation (IMV)

b) Increase the PEEP
c) Increase the FiO2
d) Change mode to PCV and prolong the inspiratory time
Disclosures
• None
2921
References
• Pham T et al. Mayo Clinic Proc. 2017; 92(9): 1382:1400.

• Carney D, DiRocco J, Nieman G. Crit Care Med. 2005;33(3
Suppl):S122-8.Med 2000;342:1301-1308.
• Habashi NM. Crit Care Med. 2005;33(3 Suppl)S228-40.
• Slutsky, AS. Chest 1999;116:9-15.
• Kompas, M. Am J Respir Crit Care Med 2015; vol 192: 1420-
1430
Thank you
2922
Highlights of the Pain, Agitation,

Delirium,
Immobility, and Sleep (PAD-IS)
Guidelines 2018
Associate Physician
Pulmonary and Critical Care Division, Dept of Medicine
Disclosures
• No financial disclosures
• I was a member of the PAD-IS committee
2923
Why organize a talk around these

guidelines?
• Extensively analyzed review of relevant literature
with an aim to guide clinical practice.
• Addresses 5 core clinical issues relevant to most

ICU patients and focused on outcomes
• International group of experts
• Patients included as collaborators and co-authors
Pain
• Pain is complex and influenced by psychological
and demographic variables
• Severe pain is associated with negative outcomes
• Implementation of assessment-driven
standardized pain management improves
outcomes
• Gold standard: self-report
2924
Pain
• Among those able to self-report, the Numeric
Rating Scale (0-10) is the best and is valid and
feasible
Pain
• Among those
unable to self-
report and in
whom behavior
is observable,
the Behavioral
Pain Scale(BPS)
in intubated and
non-intubated
(BPS-NI) and
Critical Care Pain
Observation Tool
are most reliable
and valid.
2925
Pain
• Proxy report:
– Family can be involved and their assessment is
closer to the patients’ then nurses’ and physicians’
but agreement between patient and family is still
only moderate.
• Physiologic measures:
– Vital signs are not valid indicators; can only be
used as cues to begin further assessment.
Pain—Pharmacologic management
• Opioids are the mainstay; however…
– Adjuncts to decrease pain and opioid

consumption, ie acetaminophen, low-dose
ketamine, neuropathic pain medications.
– Not for routine use:

• IV Lidocaine
• NSAID’s
2926
Pain—non-pharmacologic management
• Supported by the literature:

– Massage
– Music
• Not well-supported:
– Hypnosis
– Cybertherapy (virtual reality)
• Protocol vs no protocol (usual care)
Agitation/Sedation
• Light vs deep sedation in mechanically

ventilated critically ill patients
2927
Critical Care Medicine 2018;46:850-859.
Agitation/Sedation
• How do we coordinate sedation use with the
need to expeditiously liberate patients from
mechanical ventilation?
2928
Agitation/Sedation
Daily sedative interruption = nurse-driven protocolized targeted sedation
Agitation/Sedation:
Pharmacology Monitoring
• Bispectral index (BIS) for
• Propofol or dexmedetomidine deep sedation or
versus benzodiazepines neuromuscular blockade
Other
• Restraints: case by case
• Propofol versus risk/benefit assessment
Dexmedetomidine
2929
Delirium
Modifiable risk factors Non-Modifiable risk factors
• Benzodiazepine use • Age

• Blood transfusions • Dementia
• Prior coma
• Pre-ICU emergency or
trauma
• High APACHE score
Delirium
• A syndrome of acute (develops in hours to
days) alteration in consciousness accompanied
by change in cognition or perceptual
disturbance which fluctuates over time.
• Independently associated with outcomes in

the critically ill.
2930
Delirium
• Regular assessment with a validated
assessment tool is recommended
Delirium
Has not been consistently
Is associated with: associated with:
• Cognitive impairment at 3 • PTSD

and 12 months post- • ICU length of stay
discharge • Depression
• Functional dependence
• Mortality
Post intensive care syndrome (PICS): new or worsening impairments in

physical,cognitive, or mental health status arising after critical illness and
persisting beyond acute care hospitalization.
2931
Delirium--Pharmacology
• Prevention?
– Prophylactic use of medication to
prevent delirium is not supported by
the existing literature. It remains
somewhat controversial.
[haloperidol, atypical antipsychotic,
HMG-CoA reductase inhibitor
(statin), ketamine]
• Treatment?
– No pharmacologic treatment has
consistently demonstrated efficacy to
treat delirium or subsyndromal
delirium. For the mechanically
ventilated patient where agitation is
interfering with weaning/extubation
dexmedetomidine may be the best
sedative.
Delirium—Treatment
Multi-component, non-pharmacologic intervention

focused on risk reduction (i.e. prevention)
• Improve sleep
• Improve wakefulness (reduce sedation)
• Reduce immobility
• Reduce visual/hearing impairment
2932
Immobility
(Rehabilitation/Mobilization)
• Highlighted in the 2013 PAD guidelines as

beneficial as part of a delirium management
strategy
• A set of interventions designed to optimize

functioning and reduce disability.
• Rehabilitation or mobilization is recommended

for critically ill adults.
Immobility
• Ok to begin Ok if:
rehab/mobilization if HR 60-130/min
stability even if stability SBP 90-180 mmHg
is achieved with DBP 60-100 mmHg
vasoactive infusions or RR 5-40/min
mechanical ventilation. SpO2 > or = 88%
FiO2 < 0.6 and PEEP < 10 mmHg
• Rehab can be done in or Airway is secured
out of bed
2933
Sleep
• Why is sleep now part of the PAD-IS

guidelines?
– Sleep is considered a potentially modifiable risk

factor influencing recovery in critically ill adults.
– Whether it is a primary cause of some poor

outcomes or represents collateral damage from
brain failure in critical illness can be debated.
2934
Sleep and ICU outcomes
• Adversely affects ICU quality of life
• ? Delirium
– Sleep interventions lessen delirium occurrence
Flannery et al. Crit Care Med 2016
Sleep
• Should we/could we
monitor sleep in
critically ill adults?
But it is still worthwhile to

ask patients or caregivers
how they slept.
2935
Sleep
Non-pharmacologic
intervention
Mechanical ventilation
Aromatherapy,
acupressure, music
Noise and light reduction
Sleep
Pharmacologic interventions for
the sole purpose of improving
sleep.
Melatonin:
Propofol:
Dexmedetomidine:
2936
What about…
• Benzodiazepines and benzo-receptor agonists
– Not well studied for this indication, too many problems,
known negative effects on sleep architecture
• Antidepressants
– No data
• Antipsychotics
– No data
• Antihistamines
– Please don’t
Sleep
• Should a sleep-promoting protocol be used to improve
sleep in critically ill adults?
4 studies:
One RCT, 3 observational
Most were combinations of non-

pharmacologic strategies
Pooled analysis of the observational studies

showed reduction in delirium.
2937
ABCDEF
The ABCDEF bundle is the evidence
based framework created as a tool to
implement the PAD guidelines.
• A Assess, prevent, manage • Pain

pain
• B SAT coupled with SBT
• C Choice of analgesia, • Agitation
sedation
• D Delirium assessment, • Delirium
prevention, management
• E Early mobility and exercise • Immobility
• F Family engagement and
empowerment
• [? G Get sleep]
Take Home Messages
1. Pain is assessed regularly with validated tools and managed with

opioids along with adjuncts such as acetaminophen to decrease
opioid use
2. Agitation is managed with light sedation either with daily
interruption or nurse-driven protocol
3. Delirium is regularly assessed but there is no generally approved
pharmacologic therapy. Risk reduction/prevention is best
4. Immobility is treated with rehab/mobilization as long as the patient
is stable even if stability is maintained with mechanical ventilation
or vasopressor support
5. Sleep is best achieved by non-pharmacologic means such as noise
and light reduction via a sleep-promoting protocol
2938
Question #1
• A 65 yo man is admitted to the ICU in respiratory failure from
pneumococcal pneumonia. He is mechanically ventilated but agitated and
dyssynchronous with the mechanical ventilator. Which of the following is
not recommended:
• 1. Adjust the mechanical ventilator so he is more synchronous; maybe he

will be less agitated
• 2. Begin a continuous infusion of Propofol titrated as high as necessary to

make him stop moving so he will synchronize with the ventilator
• 3. Use opioids if he is assessed to be in pain
• 4. Assess him for delirium.
Question #2
• The patient in Question #1 was stabilized and 6 days after admission was
thought possibly to be ready to extubate. Which of the following is true?
• 1. His mechanical ventilatory support should be slowly weaned while he

remains on his sedation
• 2. He should be placed on an infusion of dexmedetomidine to help him

sleep at night so he will be more awake in the morning to give him the
best chance to extubate
• 3. Sedation should be held and he should have a “spontaneous breathing

trial” to see if he is ready for extubation
• 4. He cannot be extubated if he is delirious
2939
Acute Heart Failure and Cardiogenic Shock
Akshay S. Desai MD, MPH
Advanced Heart Disease Section
Boston, MA
Disclosures: Dr. Desai has been a paid consultant to St. Jude Medical, Inc.
Disclosures
• Dr. Desai has received honoraria for
consulting from Novartis, AstraZeneca,
Abbott, Relypsa, Signature Medical, and
DalCor Pharma
• Dr. Desai has received research grants from
Novartis
2940
Heart Failure is a Clinical Diagnosis
Congestion at Rest
No Yes Signs/symptoms
of congestion
No Warm & Dry Warm & Wet  Orthopnea/PND
Low  JVD
Perfusion  Ascites
at Rest  Edema
 Rales (rare in HF)
Yes Cold & Dry Cold & Wet
Possible evidence of low perfusion

 Narrow pulse pressure  Cool extremities
 Sleepy/obtunded  Hypotension with ACE inhibitor
 Low serum sodium  Renal dysfunction (one cause)
Stevenson LW. Eur J Heart Fail. 1999;1:251
No Difference in Outcomes between Care guided
by PA Catheter and Clinical Assessment
Hemodynamic Optimization with PAC guidance was safe and associated with
improvements in quality of life and reductions in MR, but had no impact on mortality
Routine Use of Invasive Hemodynamic Heart Monitoring Not Recommended
ESCAPE Investigators. JAMA 2005; 294: 1625
2941
When to consider PA Catheter?
• Uncertain fluid status, perfusion, systemic or pulmonary vascular
resistance
• Clinically significant hypotension or worsening renal function with
empiric therapy
• Evaluation of candidacy for advanced therapies such as VAD or
transplant
• Presumed cardiogenic shock
• Severe clinical decompensation with uncertain relative
contributions from elevated filling pressures, hypoperfusion,
abnormal vascular tone
• Apparent inotrope dependence or symptoms that persist despite
adjustment of recommended therapies
Hemodynamic Profiles in Acute HF
Congestion at Rest
No Yes
Warm & Dry Warm & Wet
No PCWP normal PCWP elevated
Low CI normal CI normal
Perfusion (compensated)
at Rest Cold & Dry Cold & Wet
Yes PCWP low/normal PCWP elevated
CI decreased CI decreased
2942
Hemodynamic Profiles in Acute HF
Congestion at Rest
No Yes
Warm & Dry Warm & Wet
No PCWP normal PCWP elevated
Low CI normal CI normal
Perfusion (compensated)
at Rest Cold & Dry Cold & Wet
Yes PCWP low/normal PCWP elevated
CI decreased CI decreased
Impact of Vasoactive
Medications on PV Loops
Normal PV Loop Vasoconstrictor/Vasodilator Positive/Negative Inotrope
SV
2943
Intravenous Vasodilator Drugs for Heart

Failure
Half‐Life Cardiac Systemic Pulmonary Central Mean

(mins) Output Vascular Vascular Venous Arterial
(CO) Resistance Resistance Pressure Pressure
(SVR) (PVR) (CVP) (MAP)
Nitroglycerine 3 ↑ ↓ ↓ ↓↓↓ ↓
Nitroprusside 1‐2 * ↑↑↑ ↓↓↓ ↓↓ ↓ ↓↓↓
Nesiritide 18 ↑↑ ↓↓ ↓↓ ↓↓ ↓↓
2013 ACC/AHA/HFSA HF Guidelines (IIb, A): Parenteral Vasodilators May be
considered an adjuvant to diuretic therapy for stable patients with heart failure
Intravenous Intropic Drugs
Drug α1 β1 β2 HR CO SVR PVR

Dobutamine (2‐10 µg/kg/min) + +++ ++ ↔↑ ↑↑ ↓ ↔
Dopamine
1‐2 µg/kg/min — — — ↔ ↔ ↔ ↔
2‐10 µg/kg/min + ++ — ↑ ↑↑ ↔↑ ↔
10‐20 µg/kg/min +++ ++ — ↑↑ ↔↑ ↑↑ ↔
Milrinone (0.1‐0.75 µg/kg/min) PDE 3 inhibitor ↑ ↑↑ ↓↓ ↓
Levosimendan Calcium Sensitizer ↑ ↑↑ ↓↓ ↓
2944
Mortality at 6 months by IV
medication use
0.8
Survival
0.6
Mortality with Inotropes increased
relative to vasodilators in acute HF
0.4
Use only as bridge to definitive
Inotrope therapy or for palliation in medically
0.2
Vasodilators refractory patients
Neither
0
0 30 60 90 120 150 180
Days
Elkayam U, et al. Am Heart J 2007; 153: 98-104
IV Milrinone In HF Patients: OPTIME‐CHF
N=951 pts, milrinone @ 0.5 µg/kg/min vs. placebo, 60 d F/U
12
*
% Patients During Hospitalization
10
8
Placebo
6
* Milrinone
4 †
0
MI A Fib VT/VF  BP Death
Cuffe et al. JAMA 2002;287:1541-7.
2945
ACC/AHA/HFSA 2013 Guidelines
Yancy C, et al. Circulation 2013; 128: e240
Cardiogenic Shock:
Definition
Clinically, a syndrome of diminished cardiac
output and vital organ hypoperfusion in the
face of adequate intracardiac filling pressures
Operationally,
Marked and persistent SBP < 80‐90 mm Hg
hypotension (> 30 mins)
Reduced Cardiac Index CI < 2.0‐2.2 L/min/m2
Normal or Elevated Cardiac PCWP > 18 mm Hg
Filling Pressure
Forrester JS, et al. N Engl J Med 1976; 295:1404-1

Hollenberg, et al. Ann Int Med 1999; 131:47-99
2946
Cardiogenic Shock: Etiology
• Acute MI
– Post‐MI complications
• Chronic heart failure
• Myocarditis
• Tako‐tsubo cardiomyopathy
• Hypertrophic cardiomyopathy
• Acute valvular regurgitation
• Aortic dissection
• Tamponade
• Pulmonary embolism
Circulation 2008;117:686-97
Pathophysiology of
Cardiogenic Shock
Myocardial infarction
Myocardial dysfunction
Systemic
Inflammatory Systolic Diastolic
response
syndrome
(IL-6, TNF-, NO) LVEDP
Cardiac output Pulmonary congestion
Stroke volume
Systemic Hypotension
perfusion
Coronary Perfusion
pressure
Hypoxemia
Ischemia
Compensatory Progressive
vasoconstriction myocardial
dysfunction
Reynolds HR, Hochman JS Circulation 2008; 117: 686-97. DEATH
2947
Question 1
A 60 year‐old man presents to the EW with 2 hours of crushing substernal chest pain radiating
to his left arm, nausea, and diaphoresis.
On examination, his BP is 82/60 mm Hg, heart rate is 110 bpm, and oxygen saturation is 95% on
4L of oxygen. He is in severe respiratory distress and has marked jugular venous distension,
bilateral rales, an S3 gallop, and cold clammy extremities.
Electrocardiogram reveals sinus tachycardia with ST elevation in the anterolateral leads and ST
depression in the inferior leads. The patient is given aspirin, clopidogrel, nitroglycerin,
heparin, and IV fluids. He remains hypotensive despite dopamine.
Urgent Coronary angiography is planned. Which of the following additional steps is most
appropriate?
A. Initiate low dose beta‐blocker
B. Add a phosphodiesterase inhibitor
C. Insert an intra‐aortic balloon pump
D. Administer thrombolytic therapy
E. Endomyocardial biopsy
Grading Shock Severity
Increasing severity of cardiogenic shock
90.0%
Pre-shock ‘Mild’ ‘Moderate’ 80.0%
‘Refractory’
80.0% Need
for
70.0% MCS
60.0%
50.0% 42.0%
40.0%
Mortality
30.0% 21.0%
20.0%
10.0% 7.5%
3.0%
0.0%
Kar, et al. Circulation 2012; 125: 1809-1817.

Inotrope Dose
2948
Potential Benefits of MCS in
Cardiogenic Shock
• Maintain End‐Organ Perfusion
• Reduce Intracardiac Filling Pressures
• Reduce ventricular volumes, wall stress, and myocardial
oxygen consumption
• Augment coronary perfusion
• Limit Infarct Size
Rihal, et al. J Am Coll Cardiol 2015; 65: e7-26.
Considerations in Device
Selection
• Etiology of Shock
• Anticipated Duration of Support
• Left Ventricular Support, Right Ventricular Support, or Both?
• What is the Goal?
• Bridge to Recovery
• Bridge to Durable VAD
• Bridge to Transplant
• Bridge to Decision
2949
Options for Temporary MCS
LV Support Only*
IABP Impella TandemHeart ECMO
Percutaneous
Less Support More support
TandemHeart Abiomed Centrimag ECMO

Surgically Implanted
BVS 5000
Intra‐Aortic Balloon Counterpulsation (IABP)
•Traditional mainstay of mechanical therapy for
cardiogenic shock
•Inflates in diastole
• Augments coronary and peripheral perfusion
•Deflates in systole
• Reduces afterload
•Effective in acute hemodynamic stabilization,
though no definitive impact on mortality in shock
•Patients with a good hemodynamic response to
IABP experience better outcome2
Willerson JT, et al. Am J Med 1975; 58: 183-91

Ramanathan K, et al. Circulation 2003; 108(suppl I): I-672
2950
Physiological Effects of IABP
Cardiac Index  40% Cardiac Output  500 ml/min

(L/min/M2)
Heart Rate  7 bts/min
Arterial Lactate  42%
(mmol/L) Systolic BP  20 mmHg
Coronary  34% Diastolic BP  30 mmHg

Blood Flow
(M2/100g/min)
Sheidt, NEJM 1973; Mueller, Circ 1972
Use of IABP
• Consider for • Contraindications
– patients with STEMI when – Significant AI
cardiogenic shock is not – Severe PAD
rapidly reversed with – Abdominal aortic aneurysm
pharmacologic therapy
– Aortic Dissection
– inotrope‐refractory heart
failure in patients with
cardiomyopathy
– Medically refractory
ventricular tachycardia
– Mechanical MI complication
(VSD, Papillary muscle
rupture)
2951
Question 2
You are called to the CCU to see a 47 y/o man
being supported with an IABP following an AMI
with cardiogenic shock. The nurse notes a change
in the IABP waveform. What manipulation should
be made to correct the timing:
a. Nothing, the timing is optimal
b. Increase the inflation delay
c. Increase the inflation time
d. Reduce the inflation time
IABP Timing
Unassisted
Diastolic and
Systolic Pressures Augmented Pressure
in Early Diastole
ECG
Lower end-diastolic
Aortic and systolic
Pressure pressures on
subsequent beat
Inflation at dicrotic notch

(onset diastole)
Deflation at End-Diastole
Krishna and Zacharowski, Contin Educ Anaesth Crit Care Pain 2009;9:24-28
2952
Suboptimal Timing
Early Inflation Late Inflation
Use R‐wave
(ECG) trigger
rather than
Early Deflation Late Deflation pressure
waveform
trigger in
patients with
arrhythmias
Krishna and Zacharowski, Contin Educ Anaesth Crit Care Pain 2009;9:24-28
IABP SHOCK-2 Trial: Primary

Outcome
30-Day Mortality
HR 0.96, 95% CI: 0.79 – 1.17, p=0.69
Control: 41.3%
IABP: 39.7%
Thiele et al, NEJM 2012
2953
Trends in MCS Use
Kapur and Esposito, Heart Failure Clinics 2015
Percutaneous MCS Devices
TandemHeart Impella
21F LA- 15F FA Access 12F-21F

Centrifugal, 3.5-4 l/min Flow Axial 2.5-5.0 l/min
Yes Anticoagulation Yes
Short-term Approved Short-term
2954
Device Comparison
IABP Impella TandemHeart
Ease of Implantation
  X
Support LV only LV, (RV) LV, RV, BiV
Mode of Cannulation Percutaneous Percutaneous Percutaneous or
Surgical
Cannula Size 7F 12-14F 21F
Trigger ECG/Arterial Pressure Asynchronous Asynchronous
Cardiac Output 0.5 L/min 2.5-4.0 L/min 4-6 L/min
Augmentation
Pulsatile Flow Yes No No
Duration of Support Short up to 7 days up to 14 days

Limb Ischemia + ++ +++
Hemolysis + ++ ++
Insertion site bleeding + ++ ++
Adapted from Myat, et al. JACC Cardiovasc Interv 2015; 8: 229-44.
IABP vs Percutaneous LVAD
Cardiac Index
LVAD IABP Cardiac Index P(heterogeneity) = 0.22

meansd meansd Mean Difference I2 = 34.0%
Thiele et al. 2.30.6 1.80.4 0.55 (0.23 ; 0.87)
Burkhoff et al. 2.20.6 2.10.2 0.16 (-0.14 ; 0.46)
Seyfarth et al. 2.20.6 1.80.7 0.36 (-0.16 ; 0.88)
Pooled 0.35 (0.09 ; 0.61)
-2 -1 0 1 2
Favors IABP Favors LVAD
Cheng et al: EHJ 2009; 30:2102
2955
Pulmonary Capillary Wedge Pressure
LVAD IABP Pulmonary Wedge Pressure P(heterogeneity) = 0.01

meansd meansd Mean Difference I2 = 76.6%
Thiele et al. 165 227 -5.6 (-9.2 ; -2.1)
Burkhoff et al. 164 253 -8.4 (-11.0 ; -5.8)
Seyfarth et al. 195 206 -1.0 (-5.2 ; 3.2)
Pooled -5.3 (-9.4 ; -1.2)
-20 -10 0 10 20
Favors LVAD Favors IABP

30 Day Mortality
2956
Question 3
30‐year old female at 37 weeks’ gestation of a previously uncomplicated pregnancy presents
with a 3‐day history of pleuritic chest pain. Upon admission, due to concern for fetal distress
she is taken to urgent Caesarean section without obstetrical complication. On closure of the
abdomen, she suffers complete cardiovascular collapse with PEA arrest. Cardiopulmonary
resuscitation is initiated with recovery of spontaneous circulation within 20 minutes. Blood
pressure is 80/60 with PaO2 40 mm Hg despite an FIO2 of 1.0. the extremities are mottled and
clammy. You are called to discuss options for urgent mechanical circulatory support for
stabilization.
Which of the following is the best strategy?
A. Intra‐aortic Balloon Pump
B. Veno‐Venous ECMO
C. Veno‐Arterial ECMO
D. Percutaneous Right Ventricular Assist Device
E. Percutaneous Left Ventricular Assist Device
Extra‐Corporeal Membrane Oxygenation
• Centrifugal, non-pulsatile pump for blood

propulsion linked to a membrane oxygenator for
gas exchange
• 2 broad configurations
• Veno-Venous  Oxygenation/pulmonary support
• Veno-Arterial  Cardiopulmonary Support
• Cannulation at bedside without fluoroscopic

guidance
• ≥ 4.5 L/min depending on cannula size

• Inflow: RA via femoral vein (18-31 F)
• Outflow: Descending aorta via femoral artery (15-22F)
• Anticoagulation required (ACT 180-250)
Cheng R, et al. Ann Thorac Surg 2014; 97(2): 610-16

Kapur and Esposito, Heart Failure Clinics 2015
2957
ECMO Configurations
Veno-Venous ECMO Veno-Arterial ECMO

(Pulmonary Blood Flow Intact) (Cardiopulmonary Bypass)
ECMO: Accepted Indications
• Hypoxemic respiratory failure with PaO2/FiO2 of <100 mmHg
despite optimization of the ventilator settings, including the tidal
V‐V ECMO
volume, positive end‐expiratory pressure (PEEP), and inspiratory to
expiratory (I:E) ratio
• Avoid in those mechanically ventilated for > 7 days
• Hypercapnic respiratory failure with an arterial pH less than 7.20
• Refractory cardiogenic shock
V‐A ECMO
• Cardiac arrest
• Failure to wean from cardiopulmonary bypass after cardiac surgery
• As a bridge to either cardiac transplantation or placement of a
ventricular assist device
2958
ECMO vs. Mechanical Ventilation for
Respiratory Failure/ARDS
Munshi, et al. Ann Am Thorac Soc 2014; 11(5):802–810
ECMO vs. Mechanical Ventilation for
Respiratory Failure/ARDS
Overall, no definitive mortality benefit seen
Potential benefit in subgroup of studies examining

VV ECMO in patients with H1N1-related ARDS
Munshi, et al. Ann Am Thorac Soc 2014; 11(5):802–810
2959
V‐A ECMO in Cardiogenic
Shock/Cardiac Arrest
• Efficacy
• No Randomized Trials, only Observational Studies
• Median Survival to Hospital Discharge: 41% (IQR 13‐78%)
• Best median survival in myocarditis (73%)
• Benefit in cardiac arrest greatest if door to ECLS times < 30 minutes
– Concerns
• LV/Aortic Stasis
• Pulmonary Hemorrhage
• Coronary/Cerebral Hypoxia
• Complications in practice
• Kidney Injury (56%)
• Bleeding (41%)
• Significant Infection (30%)
• Lower extremity ischemia (17%)
• Neurologic Complications (13%)
Cheng R, et al. Ann Thorac Surg 2014; 97(2): 610-16
Options for RV failure
• TandemHeart RVAD / BiVAD
• Impella RP (investigational)
• Surgical (Centrimag) RVAD / BiVAD
• Veno‐Venous ECMO (isolated RV failure)
• RA‐LA ECMO (Pulmonary + RV failure)
• Veno‐arterial ECMO (biventricular failure)
2960
Increasing severity of cardiogenic shock
Pre-shock ‘Mild’ ‘Moderate’ ‘Refractory’

IABP Impella 5.0
90.0% Impella CP Centrifugal LVAD 80.0%
ECMO
80.0%
70.0%
60.0%
Mortality
50.0% 42.0%
40.0%
30.0% 21.0%
20.0%
10.0% 7.5%
3.0%
0.0%

Inotrope Dose
Selection of Percutaneous MCS for
Refractory CS
2961
Take Home Points
• Options for management of cardiogenic shock are
expanding
• For medically refractory patients, early institution of
mechanical circulatory support is key
• Device selection must be tailored to the needs of the
individual patient and local expertise
• Consider ultimate goals of care before transitioning
to mechanical support
• Patients that stabilize on mechanical support may be
candidates for durable VAD as destination therapy or
bridge to cardiac transplant
Thank You!
www.brighamandwomens.org/heart
2962
Critical Care: Take Home Messages

and Clinical Pearls
Elizabeth Gay, MD
Associate program director, Brigham and Women’s Hospital Pulmonary
and Critical Care Medicine Fellowship
Assistant professor of medicine, Harvard Medical School
• No disclosures
2963
Case 1
A 38 year old man with a history of a traumatic splenectomy presents with
fever and confusion. He was well until a few hours before presentation,
when he suddenly felt light-headed, became febrile and per his wife, not
his usual self. The day before he had taken his young daughter to the park.
• PMH: Spleen removed after shrapnel injury during Iraq tour

• No allergies, no medications
• Married to a woman he met while in Iraq and lives with her and their
four year old daughter. Discharged from Army and working in
management for construction firm. No travel recently.
• ROS: No headaches, rash, abdominal pain, cough, diarrhea, nausea
Physical exam
T38.9, RR 25, HR 130, BP 90/65, SaO2 94% on room air
General- ill appearing, mild increase in work of breathing
Oropharynx- clear
Chest- a few basilar crackles
CV- tachycardic, regular, no mrg
Abd- soft, NT
Ext- no edema
No rashes
Oriented to self and hospital, but missed year
Neurologic exam non-focal, no meningeal signs
2964
Question 1
Which of the following is the next best step in care for this
patient?
A) Obtain blood cultures and CXR

B) Obtain blood cultures and CXR, and start broad spectrum antibiotic
coverage
C) Obtain blood cultures, CXR, and lumbar puncture, then start broad
spectrum antibiotic coverage
D) Obtain blood cultures and CXR, then start broad spectrum antibiotic
coverage and 2 L of normal saline
Teaching points
• Recent studies have called into question the need for care
bundles around sepsis, but strong data supports that early
antibiotics decrease mortality.
• Whether or not early fluids are important is harder to tease
out, but the bulk of the evidence suggests that early
resuscitation is important.
• A qSOFA score of 2 suggests increased mortality and in this
patient without a spleen, sepsis is an emergency.
2965
Case 1 continued. . .
• Labs return with lactate of 5, Cr of 2, mildly elevated AST and ALT, wbc of
20 with left shift, plt of 102. CXR is clear.
• He receives antibiotic therapy with vancomycin and piperacillin-

tazobactam and 4 L of fluid, but rapidly becomes more hypotensive.
Within 2 hours he is on 30 mcg/min of norepinephrine, .04 U/min of
vasopressin, 400 mcg/min of phenylephrine and epinephrine is being
hung.
• Bedside ultrasound does not show hydronephrosis, nor gallbladder

pathology. Common bile duct is not dilated. Echo shows hyperdynamic LV
without compromise. Detailed skin exam does not reveal any lesions.
Question 2
What is the next best step in care?
A) Broaden antibiotics to meropenem and gentamycin

B) Obtain pan-CT scan
C) Add dobutamine
D) Start stress dose steroids
2966
Teaching points
• Patient risk factors for drug resistant organisms, not severity of illness,
should determine antibiotic choice.
• Refractory septic shock merits best possible work-up for surgical source.
Ultrasound at the bedside may be the safest option if a patient is too
unstable to travel.
• Some septic patients may have additional element of cardiogenic shock,
but without evidence for this, adding an inotrope may worsen
hypotension.
• Stress dose steroids may decrease duration of shock (and potentially have
a mortality benefit in some select patient population). This is a
reasonable option in refractory shock. There is no need to check a cortisol
stimulation test. You can also consider fludracortisone in addition to
hydrocortisone 50 mg IV q6 hours.
Case conclusion
• The patient died of refractory shock 6 hours
after arrival in ICU. All of his blood cultures
grew pneumococcus. He had not been
vaccinated after his splenectomy.
2967
Case 2
A 71 year old man with a history of chronic lymphocytic
leukemia (never requiring treatment) presents with abdominal
pain and is found to have pancreatitis, thought secondary to a
gallstone which had passed. He is admitted to the general ward
and given a 1 L NS bolus on arrival. Overnight he develops a new
oxygen requirement and is given furosemide. The next morning
on rounds he is noted to be more confused, with increased work
of breathing. Stat labs reveal a lactate of 4, increasing
leukocytosis and Hb of 17, as well as Cr of 2.5 (from 1.2
baseline). K is 3. Urine output is 10 cc/hour.
Physical Exam
T38.1 HR 125 BP 101/65 RR 30 SAO2 92% on 40% NRB
General- alert, but confused, diaphoretic, accessory muscle use
Chest- diminished at the bases with some proximal rhonchi
Abd- distended, tense, non-tender, hypoactive bowel sounds
Ext- trace edema, warm
Oriented x 2, neurologic exam grossly non-focal
2968
Question 1
Which of the following is the best initial fluid management
strategy?
A) Start NS at 200 cc/hour
B) Bolus 50 grams of albumin
C) Bolus 2 L of NS
D) Bolus 2 L of LR
Teaching points
• Correction of hypovolemia in severe pancreatitis likely
improves outcomes and may decrease extent of necrosis.
• Too much fluid may predispose to pulmonary edema, bowel
wall edema, and abdominal compartment syndrome.
• There is a lack of data to suggest that colloids should be
preferred over crystalloids in sepsis or pancreatitis.
• LR may be associated with less renal injury than NS.
2969
Case continued
The patient is admitted to the ICU and intubated for respiratory
distress. He does not require high ventilator settings, but PEEP is
set at 12 to help with significant atelectasis. Bladder pressure is
14. Over the next two days in the ICU, he receives a total of 6 L
of LR. Lactate normalizes and HR is the 80s with a systolic blood
pressure of 120. He requires 40% fio2 on the ventilator.
Over the next day, urine output decreases to 25 cc an hour and
Cr increases to 3, but electrolytes are in order. UA shows muddy
brown casts. He continues to spike fevers to 102. CT abdomen
shows more necrosis around pancreas but no fluid collection.
Bladder pressure remains 12 to 14.
Question 2
Which of the following is the next best strategy for management
of this patient’s renal failure?
A) Start continuous venovenous hemofiltration (CVVH)
B) Start a furosemide drip, aiming to increase urine output to
50 cc/hour
C) Continue to follow expectantly
D) Start intermittent hemodialysis
2970
Teaching points
• Evidence to date does not support that routine early initiation
of renal replacement therapy provides a benefit over waiting
for traditional indications for dialysis.
• Diuresis in ATN likely does not change the course of the
disease so can be attempted as needed for clinical
management of volume overload or electrolyte disarray.
Case 3
A 49 year old man is transferred to your ICU for refractory
hypoxemic respiratory failure. He has no clear preceding
pulmonary diagnosis, but had been noted to have abnormal
chest imaging 6 months before presentation. His current
presentation was marked by a febrile illness, then rapid
development of bilateral infiltrates requiring intubation. He has
received antibiotics and steroids at the outside hospital.
2971
Physical exam
T36 HR 75 BP 110/68, breathing with vent , SaO2 92%
Vent settings: AC, R16, TV 540 (8 cc/kg IBW), fio2 95%, PEEP 5
ABG 7.24/paCO2 70/paO2 62
Plateau 30, Peak 35
General- intubated, sedated on propofol
ETT in place
Chest- bilateral harsh breath sounds and some basilar crackles
CV- rrr, S1, 2, no mrg
Ext- warm, no edema, no rashes
http://courses.washington.edu/med620/images/mv_c3fig1.jpg
2972
Question 1
What is the next best step in ventilator management?
A) Increase RR to 20
B) Increase TV to 600
C) Decrease TV to 450, increase RR to 20
D) Decrease TV to 250
Teaching point
• The primary management for ARDS remains a low tidal
volume strategy, targeting a plateau pressure less than 30,
pa02 of 60 and pH of 7.15 or higher.
• We don’t know if higher PEEP is better, so a bedside
evaluation of each patient remains the best strategy.
Complications from high PEEP include hypotension from
decrease in preload and barotrauma.
2973
Case continued. . .
• TV is decreased to 5 cc/kg and with increase in RR, pH remains
around 7.2 with pa02 of 60
• He is started on a cisatracurium drip.
• At attempt at diuresis leads to hypotension and is aborted.
• Overnight he becomes extremely hypoxemic after a turn, with
pa02 of 52 on blood gas. CXR is unchanged. Mechanics show
further decrease in compliance.
Question 3
What is the next best step in care?
A) Change to pressure control ventilation
B) Change to high frequency oscillatory ventilation
C) Prone positioning
D) Call ECMO team
2974
Teaching points
• For refractory ARDS, prone positioning may provide a survival
benefit in patients with the most severe disease.
• ECMO is an appropriate consideration for an otherwise
healthy patient with single organ failure and should be
considered early.
• Other modes of ventilation have not been shown to be
helpful and in the case of HFOV may be harmful in adults.
References
• Venkatesh, Balasubramanian, et al. "Adjunctive Glucocorticoid Therapy in Patients with Septic
Shock." New England Journal of Medicine (2018)
• Semler, Matthew W., et al. "Balanced crystalloids versus saline in critically ill adults." New England
Journal of Medicine378.9 (2018).
• Chaudhuri, Dipayan, et al. "Early Renal Replacement Therapy Versus Standard Care in the ICU: A
Systematic Review, Meta-Analysis, and Cost Analysis." Journal of intensive care medicine (2017)
• Guérin C, Reignier J, Richard JC, et al. Prone positioning in severe acute respiratory distress
syndrome. N Engl J Med (2013)
2975
Critical Care Board Review

Elizabeth Gay, MD
Associate program director, Harvard-Brigham and Women’s

Hospital Fellowship in Pulmonary and Critical Care Medicine
Boston, MA
Disclosures
• None
2976
Case #1
A 68 year-old man with a history of CAD, COPD, and diastolic
heart failure presents with worsening dyspnea for two days,
associated with wheezing. No chest pains or palpitations.
T 36, P 110/min, BP 100/95 mmHg, RR26

Oxygen saturation 95% on non-rebreather, 40% fiO2
Mild JVD, no HJR, +accessory muscle use
Chest- bilateral wheezes and rales throughout both lungs
Abd- soft, NT
CV- tachycardic, regular, no mrg, nl S1, 2
Ext- Warm, + symmetric LE edema
Case #1
2977
Case continued. . .
• In the ED he is given broad spectrum

antibiotics, albuterol and ipratropium
nebulizers, and IV solumedrol.
• They then increase the FiO2 to 60%.
• He is still unable to speak in full sentences.
• ABG: 7.25/paC02 55/pa02 89
Acute: Increase paCO2 by 10,

decrease pH by .08. Interpret this ABG.
Chronic: Increase by 10,
decrease by .03
Question 1: What would be the most

appropriate intervention at this time?
• A. Intubate and begin assist control ventilation

• B. Decrease the FiO2
• C. Apply non-invasive positive pressure ventilation
• D. Decrease the rate of IV fluid administration
• E. Begin bicarbonate IV
2978
Indications for non-invasive positive pressure

ventilation:
– Acute-on-chronic respiratory failure (exacerbation of COPD)
– Patients with acute asthma
– Acute congestive heart failure (not caused by an acute myocardial

infarction)
– Patients who are immunocompromised with pneumonia
– To facilitate weaning from invasive ventilation in difficult to wean

patients with COPD
– Post operative patients
– Obesity hypoventilation, neuromuscular weakness
– Palliative care for dyspnea
Question 1: Explanation
NIV contraindications:
– Unstable: ischemia, hypotension, arrhythmia, upper GIB,

profuse emesis, etc
– Agitated, altered MS
– Unable to protect airway
– Swallowing impairment
– Excessive secretions
– Recent upper airway or GI surgery
2979
• Goals of NIV:
– Ventilation: reduce PaCO2
– Improve oxygenation
– Reduce work of breathing
– Reduce dyspnea
Question 1 Answers: What would be the most

appropriate intervention at this time?
• A. Intubate and begin assist control ventilation.
NIV may allow you to avoid intubation.
• B. Decrease the FiO2
Although there is no need to over-oxygenate, decreasing fio2 in the face of hypoxemia
will not improve the situation.
• C. Apply non-invasive positive pressure ventilation
• D. Decrease the rate of IV fluid administration
This may be reasonable, but is unlikely to quickly correct respiratory failure.
• E. Begin bicarbonate IV
Creating a metabolic alkalosis will decrease the need for ventilation, but risks volume
overload and doesn’t address the underlying respiratory failure.
10
2980
NIV in the ICU
• Predictors of failure in hypoxemic respiratory failure:

– No improvement in PaO2/FiO2 in 1-2 hours
– Older patients (> 40!)
– APACHE >34
– ARDS
– Pneumonia: Observational studies suggest NIV NOT useful
in hypoxemia respiratory failure secondary to CAP in the
absence of COPD
– Multi-organ failure
11
NIV versus standard Rx
Nava et al, 2009 Lancet
2981
Case #1: The story continues. . .
• Despite NIV, the patient does not seem to be

improving.
• Labs have now come back and troponin is elevated,
ECG unchanged.
• BP 85/40 mmHg, Pulse 105/min
• SaO2 93% on bi-level 10/5 cmH2O with 100 % FiO2
13
CXR- ARDS
What
condition
appears to
be
developing?
2982
Question 2: What is the next best step in

management?
A. Transfer to CCU
B. Increase IVF due to low BP
C. Intubate the patient
D. Add sedation to improve synchrony with NIV
15
Failure of NIV indicated by:

No improvement in blood gas.
No improvement or worsening respiratory
distress.
Worsening mental status.
Worsening hemodynamics.
16
2983
Question 2 Answers: What is the next best

step in management?
A. Transfer to CCU
This may be reasonable but should not delay intubation.
B. Increase IVF due to low BP
You should re-evaluate volume status before increasing fluid
administration in the setting of developing ARDS.
B. Intubate the patient
C. Add sedation to improve synchrony with NIV
NIV is a spontaneous mode of ventilation and adding sedation may
decrease respiratory drive and lead to worsening acidosis.
17
Case #2
A 67 year-old man with a history of hypertension,
peripheral vascular disease, and chronic renal
insufficiency is post-operative day two from a
femoral-popliteal bypass graft. He becomes
increasingly restless and combative with nursing.
Social history notable for a 45 pack-year history of
smoking cigarettes and 1-2 drinks with dinner,
perhaps more on weekends. He is a high level
executive in the financial industry.
Current medications: Fentanyl PCA, Metoprolol 12.5 mg
BID, furosemide 20 mg IV daily
18
2984
Case #2 continued
BP 140/95 mmHg, HR 90/min, RR 20, Sa02 95% on RA

Uncooperative, belligerent, paranoid ideation
No jvd, MM dry
Chest- clear throughout
Ext- trace symmetric edema, bypass site is clean and dry with no
evidence of bleeding
Neuro- won’t follow commands, pupils equal and reactive,
normal and symmetric reflexes
19
Question 1 Answers: What is the most

likely diagnosis?
A. Alcohol withdrawal
B. Non-alcohol related delirium
C. Medical disorder (infection, stroke, etc)
D. Psychiatric disorder (psychosis)
E. Insufficient information
20
2985
Case #2 Explanation:
Key points about ICU delirium
Agitation ≠ Delirium
• 3 delirium phenotypes
– Hyperactive
– Hypoactive
– Mixed
• Delirium is defined (DSM IV) by:
– Disturbance in consciousness
– Change in cognition or development of perceptual disturbance not
accounted for by pre-existing or evolving dementia
– Disturbance develops over hours-days and fluctuates in severity
21
Core points about ICU delirium
Predisposing factors:
• Advanced age
• Dementia
• Functional impairment in activities of daily living
• High medical comorbidity
• History of alcohol abuse
• Male gender
• Sensory impairment (blindness, deafness)
22
2986
ICU Delirium
• Differential diagnosis
– Psychiatric disorders: schizophrenia, depression,
mania, dementia
– Medical disorders: endocrinopathy, infection, CNS
injury, sepsis, renal failure, hypoxia, hypoglycemia,
electrolyte imbalance
– Substances: intoxication, adverse effect,
withdrawal
23
ICU Delirium
• Implications:
– 3 times higher risk of death by 6 months
– $15k to $25k higher hospital costs
– 5 fewer ventilator free days (days alive and off
vent)
– 9 times higher incidence of cognitive impairment
at hospital discharge
Ely et al, JAMA 2004
24
2987
ICU Delirium
• Diagnosis based on a • Treatment: the 4 “P’s”

combination of: • Prevention
• History* • Prevention
• Assessment tool • Prevention
• Exclusion of • ?Dexmedetomidine
medical/psychiatric • Psychotropics
illness
• Avoid Polypharmacy
Question 1: What is the most likely

diagnosis?
A. Alcohol withdrawal
This is a possible diagnosis here, but you need more information both to understand
drinking history and to rule out other medical problems. He does not have clear
signs of autonomic hyperactivity which are typically associated with alcohol
withdrawal.
B. Non-alcohol related delirium
You need to rule out a medical disorder and obtain more history of about alcohol use.
C. Medical disorder (infection, stroke, etc)
You would want more information (labs) to rule out a new medical complication.
D. Psychiatric disorder (psychosis)
A new onset psychosis would be unlikely.
E. Insufficient information
26
2988
Case #3
A 28 year-old woman in her 34th week of pregnancy

presents with acute dyspnea. This started suddenly
one morning when she was doing some chores in her
house. She has some pleurisy but no cough,
palpitations, or fevers.
• Pregnancy has been uneventful until now

• No PMH
• Medications: Prenatal vitamins
27
27
Case 3 continued. . .
BP 95/70 mmHg, RR 20, Pulse 100/min, SaO2 97% on
RA
Alert, mild increase in work of breathing
There is no JVD or HJR
Chest- clear throughout
CV- tachycardic, regular, soft systolic murmur
Abd- gravid, soft
Ext- warm, no c/c/e
No rashes
Oriented x 4
28
2989
Question 1: Which of the following is the

A. Asthma exacerbation
B. Perinatal cardiomyopathy
C. Anxiety
D. Pulmonary embolism
29
Case #3
Causes of Maternal Mortality

– Pulmonary embolism 20%
– Hypertensive disorders (including eclampsia) 15%
– Ectopic pregnancy 12%
– Bleeding 11%
– CVA 10%
– Anesthesia 8%
– Cardiomyopathy 5%
30
2990
Case #3
• Pulmonary Embolism
– Leading cause of peri-partum maternal mortality
– AA>Caucasians
– Risk factors: older age, c-section
– DVT present in 0.3% of all deliveries
– Factors V, VII, VIII, IX, X, XII and fibrinogen are all
increased during pregnancy
31
Case #3 continued. . .
• Despite heparin gtt and supplemental oxygen, her

condition worsens.
• BP 80/40 mmHg, P120/min, RR 35, SaO2 88% on 100
% non-rebreather
• Lungs: clear throughout
• Echo at bedside: Dilated and hypokinetic RV, RVSP
50
• Doppler US shows femoral DVT
What is the next best step in management?
32
2991
Case #3
• INTUBATE
– Hypoxia can be harmful to the fetus
– Maternal SaO2 > 95%
– TREAT the Patient!
• Sedatives, antibiotics, other medications generally ok to
use
33
Thrombolysis?
Ahearn, Gregory S., et al. Archives of Internal Medicine 162.11 (2002): 1221-1227.
2992
Case #4
An 81 year-old man with a history of CAD and CRI is admitted with pleuritic
chest pain, fevers and cough of 2 days duration. He is also mildly confused
per his wife.
T-101.8 BP 100/60 mmHg HR 110/min RR 32 SaO2 91% on RA

General- frail, thin, mild respiratory distress, oriented x 2
No jvd, MM dry
Chest- Rales upper right and mid lung zones
Ext- no edema, warm
Initial labs:
– WBC-12K with left shift
– Electrolytes normal except for Cr 1.5 (baseline)
– Blood glucose 260 mg/dl
35
Case #4
2993
Case continued. . .
• You diagnosis the patient with community

acquired pneumonia and start ceftriaxone and
azithromycin after obtaining sputum and
blood cultures. He is admitted to the ICU for
close monitoring.
What would you recommend for glucose

control? What is your target blood sugar?
37
Question 1: Which of the following is the most accurate

statement about glucose control in the critically ill
patient?
A. Tight glucose control (80-110 mg/dl) is associated with a mortality
benefit compared with a goal of < 180 mg/dl.
B. Hyperglycemia in the critically ill is associated with increased mortality.
C. Tight glucose control is associated with fewer days on mechanical
ventilation.
D. Episodes of hypoglycemia in patients managed with tight glucose
control are insignificant if the protocols are done properly.
E. Tight glucose control is only beneficial for critically ill diabetics.
38
2994
Glycemic control in the critically ill
• Targeting < 180 mg/dl resulted in
lower mortality then 80-110
mg/dl.
• Severe hypoglycemia, < or = 40
mg/dl, was observed in the 80-
110 mg/dl group (6.8%) vs the <
180 mg/dl (0.5%).
• In this trial, the absolute risk of
death at 90 days increased by 2.6
percentage points; hence, the
number needed to harm = 38.
• Presently, tight or “intensive”
glucose control is not
recommended.
Question 1 Answers: Which of the following is the most

accurate statement about glucose control in the
critically ill patient?
A. Tight glucose control (80-110 mg/dl) is associated with a mortality benefit compared with
a goal of < 180 mg/dl.
More recent studies have not shown improved mortality with tight control.
B. Hyperglycemia in the critically ill is associated with increased mortality.
C. Tight glucose control is associated with fewer days on mechanical ventilation.
Glucose control has not been shown to change days on the ventilator.
D. Episodes of hypoglycemia in patients managed with tight glucose control are insignificant if
the protocols are done properly.
Even in studies with detailed protocols, hypoglycemia was an important issue.
E. Tight glucose control is only beneficial for critically ill diabetics.
Even in patients with diabetes the data does not support tight control during critical illness.
40
2995
Case #5
A 41 year-old man presents with dyspnea and chest

tightness. Shortly after arrival to the ED he is
intubated for respiratory distress.
Past medical history: obesity (BMI 39), DM2, asthma
41
Case continued. . .
• Physical Exam
T36 BP 160/75 mmHg HR 125/min RR26 Sa02 92 on 50% fiO2
General- intubated, over-breathing the vent and mildly agitated
Large neck, difficult to appreciate JVD
Chest- poor air movement, no wheezes
Ext- symmetric trace edema
42
2996
Question 1: Which of the following is the most accurate

statement about the role of this patient’s obesity in the
ICU?
A. His tidal volume should be based on his current weight

rather than his ideal body weight.
B. His ICU mortality is higher then someone of normal weight
C. He is likely to have more days on mechanical ventilation
then someone of normal weight.
D. His weight is not relevant to his ICU care.
43
Obesity and prognosis in the critically ill
• No effect on mortality
until BMI < or = 18.5
or > or = 40
• Effects on: Duration
of Mechanical
Ventilation and LOS
in post-op patients.
Crit Care Med 2008;38:151
2997
Question 1 Answers: Which of the following is the most

accurate statement about the role of this patient’s
obesity in the ICU?
A. His tidal volume should be based on his current weight rather than his ideal
body weight.
Lung size doesn’t change with increasing BMI, so you should use ideal body weight.
B. His ICU mortality is higher then someone of normal weight
Between a BMI of 30 and 39, mortality does not appear to be higher and may actually
be improved in some populations (obesity paradox).
C. He is likely to have more days on mechanical ventilation then someone of
normal weight.
D. His weight is not relevant to his ICU care.
Obesity is important for ICU care, influencing things like procedures, imaging studies
and drug dosing.
45
Summary points
• Case #1:
– NIV may prevent intubation for COPD exacerbations.
– Co-morbidities or worsening of respiratory function obligate
intubation.
– Myocardial infarction and hemodynamic instability are absolute
contraindications to NIV.
• Case #2:
– Agitation with cognitive dysfunction has a broad differential and is
best diagnosed with a good history, exclusion of reversible
medical/psychological causes, and application of validated assessment
tools.
• Case #3:
– Pulmonary embolism is a leading cause of maternal mortality.
– In general, critical illness in pregnancy should not be treated
differently than in non-pregnant adults.
46
2998
Summary Points
• Case #4:
– Hypoglycemia is associated with poor outcomes for critically ill
patients but so are aggressive attempts at glycemic control.
• Case #5:
– Obesity is not necessarily associated with higher ICU mortality but
may be associated with longer time on mechanical ventilation.
47
2999
Board Review Practice 3

Sanjay Divakaran, M.D.
Fellow, Division of Cardiovascular Medicine
Clinical Fellow in Medicine
sdivakaran@bwh.harvard.edu
Disclosures:
None
3000
CASE 1
A 70-year-old woman presents with pain in her hands and wrists for 9 months.
Her hands are stiff in the morning for 15 minutes. She has pain with sewing and
typing. She has not noticed any joint swelling. Her vital signs are normal. Her
bilateral proximal interphalangeal joints are tender to palpation and have bony
enlargements. The first carpometacarpal joints are also tender and have bony
squaring bilaterally. Her metacarpal squeeze test is negative. The remainder of
the exam is normal.
Which of the following studies should be done to establish the diagnosis?
A) ANA
B) Uric acid
C) Radiography of the hands
D) Rheumatoid factor
E) No additional studies are needed
The correct answer is E

• This patient with first carpometacarpal joint tenderness and squaring has
osteoarthritis.
• While symmetric and polyarticular arthritis seem to suggest rheumatoid arthritis,
the joints involved are not consistent with rheumatoid arthritis, and there are no
clinical indicators of joint inflammation.
• The DIP joints are almost always involved in degenerative arthritis, and rarely in
RA. PIP joints can be involved in either. The MCP joints are involved almost
exclusively RA.
• At the wrist, involvement of the first carpometacarpal joint is almost always a
sign of osteoarthritis, while involvement of ulnar styloid is almost always a sign
of rheumatoid arthritis.
• Morning stiffness less than 30 minutes indicates degenerative rather than
inflammatory arthritis.
• ACR criteria for diagnosing OA of the hands:
– Hand pain, aching, or stiffness, plus 3 of…
• Hard tissue enlargement of two or more of 10 selected joints
• Fewer than three swollen metacarpophalangeal joints
• Hard tissue enlargement of two or more DIP joints
• Deformity of two or more of 10 selected joints
Arthritis Rheum 1990;33:1601-10.
3001
Osteoarthritis Rheumatoid Arthritis

Courtesy of Dr. Sara Tedeschi McGonagle D et al. Rheumatology 2008;47:1278-1285.
CASE 2
A 68-year-old man with a history of hypertension and gout presents for his annual
exam. He was a past smoker for 20 years but quit 30 years ago. He drinks one glass
of red wine daily. He exercises regularly. He has no specific complaints. He gets his
influenza vaccination annually and he received his pneumococcal vaccine 3 years
ago. He had a normal colonoscopy 7 years ago. He is on amlodipine and
allopurinol. His vital signs are normal and his physical exam including
cardiopulmonary, abdomen, prostate, and peripheral pulses are all unremarkable.
Which of the following screening tests is most appropriate for this patient based
on most evidence of benefit?
A) CT Coronary Calcium Imaging

B) Prostate Specific Antigen
C) Thyroid Stimulating Hormone
D) Abdominal Ultrasound
E) Exercise Treadmill Test
3002
The correct answer is D

• USPSTF recommends that men between the ages of 65 and 75 with any
current or past history of smoking undergo a one time screening for AAA
with an abdominal ultrasound.
• Several studies have demonstrate survival benefit of screening including a
population based study of over 67,800 men aged 65 and 74 that were
randomized to AAA screening with surgery for those found to have AAA
>5.4cm vs. no screening that showed AAA related-mortality was reduced by an
average of 42% (95% CI, 22%-58%) in the screened population compared with
the non-screened population. Several studies have shown no benefit in male
non-smokers and in women.
• CT coronary calcium imaging has insufficient data to determine whether the
association of coronary calcium with coronary artery disease risk warrants
screening in asymptomatic men.
• The ability of prostate cancer screening tests to prolong life is uncertain.
• There is not enough evidence to recommend routine screening for thyroid
disease. However, screening high risk populations such as patients with
diabetes, down syndrome, and postmenopausal women may be justified.
Lancet 2002;360(9345):1531-9.
Ann Intern Med 2005;142:203-11.
CASE 3
A 20-year-old woman with a history of systemic lupus erythematosus
diagnosed two years earlier presents to the emergency department with
fatigue and fevers to 100.5 for several days.
Home medications include metoprolol succinate 25mg daily, lisinopril 10mg

daily, prednisone 15mg daily, hydroxychloroquine 200mg daily, azathioprine
50mg daily, and dapsone 100mg daily.
Initial evaluation reveals a young woman in no acute distress. Vital signs are
notable for a temperature of 100.5, heart rate of 60, blood pressure 110/70,
respiratory rate of 16, and an oxygen saturation of 80% on room air. Oxygen
saturation increases to 88% with a non-rebreather mask. Chest X-ray and CT
scan of the chest are unremarkable. CBC reveals a WBC 5.42, Hemoglobin 10
(at her baseline), Plt 273. Chemistry panel is unremarkable. Arterial blood gas
shows a pH of 7.38, PaCO2 32, and PaO2 527 on 100% oxygen via the non-
rebreather mask.
3003
CASE 3 (cont.)
The next best step in management is:
A) Endotracheal intubation and mechanical ventilation

B) Transfuse 2 units PRBCs
C) Treat with hyperbaric oxygen
D) Stop the dapsone
E) Treat with trimethoprim sulfamethoxazole and prednisone
The correct answer is D.

• This is a case of methemoglobinemia caused by dapsone.
• Methemoglobin is a form of hemoglobin that does not bind oxygen.

– It is normally present at <1% due to the activity of anti-oxidant enzymatic
pathways.
• Acquired methemoglobinemia is caused by exogenous oxidizing drugs, including

trimethoprim, sulphonamides, dapsone, local anesthetics, and aniline dyes.
– Most people are asymptomatic except for cyanosis, and possibly headache
and fatigue.
– Severe methemoglobinemia can cause shortness of breath, mental status
changes, dysrhythmias, seizures, coma, and death.
• The diagnosis should be suspected in the setting of a normal PaO2 despite a low
peripheral oxygen saturation.
– Patients may or may not have cyanosis.
• Treatment: stop the offending medication.

– Severe cases may be treated with IV methylene blue.
3004
CASE 4
A 37-year-old woman with no significant past medical history presents to the
emergency department with 2 days of days of nausea, vomiting, and
abdominal pain. Her only medication is acetaminophen, which she has been
taking for low back pain. She has not been taking any calcium supplements.
Labs reveal calcium 15.4, phosphate 4.9, and creatinine 1.6. Her PTH level is
low and her PTH-RP is undetectable.
All of the following would be appropriate initial therapy for her hypercalcemia
in the acute setting EXCEPT:
A) Hydration with intravenous normal saline

B) Zolendronate 4mg IV
C) Furosemide 40mg IV
D) Calcitonin 4 units/kg IM
The correct answer is C.

•The recommended approach for the treatment of severe hypercalcemia
(calcium > 14 mg/dL) includes:
– Hydration with normal saline.
– Bisphosphonates (zolendronate or pamidronate).
– Calcitonin.
• Loop diuretics such as furosemide (Choice C) are no longer recommended.

– Risks:
• Electrolyte abnormalities.
• Volume depletion resulting from over-diuresis.
• Loop diurectics should be considered in cases of fluid overload in order to

restore euvolemia.
LeGrand SB, Leskuski D, Zama ISO. Ann Intern Med. 2008;149(4):259.
3005
CASE 4 – Part II
CT scan of the chest, abdomen, and pelvis reveals diffuse lytic lesions in the
spine, pelvis, long bones, and ribs. No other abnormalities are noted.
Additional workup demonstrates a normal serum protein electrophoresis,
normal serum angiotensin converting enzyme level, and a mildly elevated
LDH of 450.

A) Multiple myeloma
B) Sarcoidosis
C) Metastatic breast cancer
D) Diffuse large B-cell lymphoma
E) Langerhans Cell Histiocytosis

• All of the choices listed can cause lytic bone lesions and hypercalcemia.
• The most likely diagnosis in a 37 year old woman with no other CT findings is metastatic
breast cancer.
– CT of the chest may miss breast lesions.
• The median age at diagnosis for multiple myeloma (Choice A) is 66 years, and only ~2% of
patients are younger than 40 years old.
• Sarcoidosis (Choice B) of bone occurs in approximately 5% of patients with the disease,

but this usually occurs in advanced disease and rarely without pulmonary manifestations.
• Diffuse large B-cell lymphoma (Choice D) is a rare cause of bony lesions. The CT scan
would have been expected to show lymphadenopathy as well.
• Langerhans cell histiocytosis (Choice E) is a rare disorder (2 in 1 million) that may present
with bony lesions. Other presenting symptoms may include rash, diabetes insipidus,
lymphadenopathy, ataxia, and memory difficulty.
3006
CASE 5
A 32-year-old man with no significant past medical history
presents with low-grade fevers, anorexia, headache, and neck
stiffness of 4 days’ duration, which started shortly after a dental
procedure. The night prior to presentation he had one episode
of emesis and a worsening posterior headache. This morning, his
wife noticed that he seemed “not quite himself” and was
“walking into walls,” prompting her to bring him into the
Emergency Department. In the ED, he undergoes the following
head imaging.
Non Contrast Head CT
3007
Axial T2 Flair MRI
CASE 5 (cont.)
What is the most likely diagnosis and best next management
choice?
A) Meningitis; Treatment with ceftazidime, vancomycin, and

micafungin
B) Meningitis; Treatment with ceftriaxone, vancomycin, and
ampicillin
C) Brain abscess; Treatment with ceftazidime, vancomycin,
micafungin, and acyclovir
D) Ruptured brain abscess; Treatment with ceftriaxone,
vancomycin, and metronidazole with neurosurgery consultation
if symptoms do not improve with 24h of antibiotics
E) Ruptured brain abscess; Treatment with ceftriaxone,
vancomycin, and metronidazole with emergency neurosurgery
consultation
3008
The correct answer is E.

• The patient’s initial clinical syndrome of fevers, anorexia,
headache, and neck stiffness is consistent with a diagnosis of
meningitis.
• An abrupt change in symptomatology and focal neurological
symptoms are an indication for emergent head imaging (non-
contrast head CT).
• The head CT demonstrates a brain abscess with likely
surrounding vasogenic edema.
• The MRI demonstrates pus within the ventricle, indicating
rupture of the brain abscess, a neurological emergency with a
very high mortality rate
• Emergency neurosurgical consultation and broad spectrum
antibiotics are indicated in this case.
Mathisen and Johnson, Clinical Infectious Diseases, Vol. 25, No. 4, Oct., 1997
CASE 5 (cont.)
Which of the following is not indicated in the
management/workup of this patient?
A) Blood culture
B) Consideration of ventricular drainage
C) Serial lumbar punctures to evaluate opening pressure
D) TTE with bubble study
E) Careful physical examination of the sinuses and
tympanic membranes
3009

• Blood cultures (choice A) can be helpful in identification of causative
organism of central nervous system infections by hematogenous spread.
• Emergency neurosurgical consultation for consideration ventricular drainage

(choice B) is indicated, as intracranial pressure can lead to brainstem
herniation.
• Serial lumbar punctures (choice C) to evaluate opening pressure are not

indicated in the management of these patients.
– Serial lumbar punctures are used in the management of cryptococcal meningitis.
• TTE with bubble (choice D) is indicated, as patients with cyanotic heart

disease have a higher incidence of CNS infections.
– The presence of a right-to-left intracardiac shunt in a patient with a brain abscess may be
an indication for closure of the cardiac defect.
• Careful physical examination of the sinuses and tympanic membranes

(choice E) is indicated, as the possibility of direct spread of infection from the
paranasal/frontal sinuses or from otitis media must be evaluated.
CASE 6
A 30-year-old woman with ulcerative colitis and autoimmune hepatitis
complicated by cirrhosis, ascites, and esophageal varices presents with
dyspnea and left-sided back pain. Abdominal ultrasound shows minimal
ascites and chest X-ray reveals the following:
3010
CASE 6 (cont.)
Which of the following would not be appropriate in the
evaluation and management of this pleural effusion?
A) Thoracentesis
B) Chest tube
C) Diuretics
D) TIPS (transjugular intrahepatic portosystemic
shunt)
E) Evaluation for liver transplantation
The correct answer is B.

• This patient most likely has a pleural effusion due to cirrhosis and ascites.
- Secondary to diaphragmatic defect(s), which can be microscopic.
- 85% right-sided, 13% left-sided, and 2% bilateral.
• Thoracentesis (choice A) should be performed to assess for other possible

etiologies of the pleural effusion and to rule out infection.
• Diuretics (choice C) can be used to manage the pleural effusion.
• TIPS (choice D) is used to manage refractory pleural effusions.
• Patients with hepatic hydrothorax should be evaluated for liver

transplantation (choice E).
• A chest tube (choice B) should not be placed in the setting of hepatic

hydrothorax as it can cause massive protein and electrolyte depletion,
infection, renal failure, and bleeding.
Aliment Pharmacol Ther 2004; 20 :271
3011
CASE 7
A 56-year-old woman with hypertension presents to the Emergency
Department with left lower quadrant abdominal pain and no bowel
movements for several days. Her medications include hydrochlorothiazide
and omeprazole. Her vital signs, including her blood pressure, are normal.
Her physical examination is not revealing. Abdominal CT suggests
constipation. The CT also shows a 3.5cm right adrenal lesion.
All of the following tests for the evaluation of this adrenal lesion are
appropriate except?
A) Dexamethasone suppression test

B) Plasma aldosterone and renin
C) 24 hour urine fractionated metanephrines and catecholamines
D) Cosyntropin stimulation test
E) Adrenal protocol CT or MRI

• This is an adrenal nodule incidentally discovered during the course of
abdominal imaging performed for other reasons in a patient with mild
hypertension.
• Appropriate laboratory evaluation includes:

-Dexamethasone suppression test to evaluate for Cushing Disease (choice
A).
- 24-hour urine fractionated metanephrines and catecholamines (or
plasma free metanephrines) to evaluate for pheochromocytoma (choice
C).
- Plasma aldosterone and renin if the patient has hypertension (choice B).
• An adrenal-protocol CT or MRI (choice E) should be performed to identify

benign features or those concerning for malignancy.
A cosyntropin stimulation test (choice D) evaluates for adrenal insufficiency

and is not a standard part of the evaluate of an adrenal lesion.
Young WF. NEJM 2007; 356: 601
3012
CASE 8
A 42-year-old man with a history of morbid obesity status-post
bariatric surgery with 75 pound weight loss presents for a follow-up
visit. He complains of 5 years of progressive gait instability and
numbness and weakness in his distal extremities. He now has
trouble holding a cup and his handwriting is deteriorating. His family
history is unremarkable. He takes high vitamin supplements
including B-complex and zinc.
On examination, he has an unsteady gait, Romberg sign, spasticity in

the bilateral lower extremities, bilateral hyperreflexia, and Babinski
sign bilaterally. There is impaired vibration and position sense in the
feet. Pain and temperature sensation in the lower extremities are
normal. His labs reveal leukopenia, neutropenia, normocytic anemia,
high serum zinc, and low ceruloplasmin. Levels of Vitamin B12,
folate, homocysteine, and methylmalonic acid are normal.
CASE 8 (cont.)
Which of the following is the most likely cause of
his condition?
A) Vitamin B12 deficiency

B) Paraneoplastic polyneuropathy
C) Copper deficiency
D) Vitamin B6 toxicity
E) Lead toxicity
3013

• The patient has findings suggestive of progressive impairment of the
corticospinal tracts and posterior columns of the spinal cord (subacute
combined degeneration).
– In a patient with history of bariatric surgery, deficiencies of either copper
or Vitamin B12 should be suspected.
– However, the Vitamin B12, methylmalonic acid, and homocysteine levels
in this case are normal, which rules out Vitamin B12 deficiency (choice A).
• Copper deficiency (choice C) affects the corticospinal tract (hyperreflexia and

Babinski sign) and posterior column (impaired vibration sensation).
– Zinc competes with copper for intestinal absorption, and the patient is
taking supplemental zinc.
• There are no signs or symptoms to suggest an underlying neoplasm (choice B).
• Vitamin B6 toxicity (choice D) causes peripheral neuropathy, but not upper

motor neuron signs. Toxicity is very rare at doses less than 100mg daily.
• Adults with lead poisoning (E) choice can have many symptoms, including a
peripheral neuropathy that manifests as wrist or ankle weakness; however,
lead toxicity does not cause upper motor neuron signs.
Neurology 2007;68(21):1843-1850.
CASE 9
A 56-year-old woman presents with dyspnea on exertion and fatigue
for 2 months. She has a history of hypertension and Stage 4 chronic
kidney disease. She has no nausea, vomiting, anorexia, or chest pain.
Her weight is stable and she is adherent to a renal diet. Her
medications include furosemide and lisinopril. Her health care
maintenance is up-to-date, including a recent colonoscopy.
On examination, her BP is 118/62. BMI is 24. Her conjunctivae are

pale. Her cardiac and lung exams are unremarkable. She has 1+
lower extremity edema. Labs reveal hemoglobin 9.6, MCV 92, eGFR
18, ferritin 190, iron 57, TIBC 257, and transferrin saturation 22%.
Urinalysis reveals 1+ protein. Her stool is guaiac negative, and
treatment with erythropoietin is begun. Four weeks later, her fatigue
and exercise tolerance has improved and her hemoglobin is now
12.6 with transferrin saturation 21%.
3014
CASE 9 (cont.)
What is the most appropriate next step in the
A) Stop erythropoietin
B) Stop lisinopril
C) Change lisinopril to HCTZ
D) Add IV ferrous gluconate
E) Schedule EGD
The correct answer is A.

• Therapy with erythropoietin has been shown to effectively treat anemia
in patients with CKD and may reduce fatigue and the need for blood
transfusions.
• Normalizing hemoglobin levels with erythropoiesis stimulating agents in

patients with anemia due to CKD is associated with increased risk of
death, non-fatal MI, stroke, CHF and thrombosis.
– The FDA recommends that erythropoietin should not be used once
hemoglobin is higher than 12.
– The rate of hemoglobin increase should not exceed 1g/dL over 2 weeks.
– Therefore, treatment with the erythropoiesis stimulating agent should be
stopped (choice A).
• Iron saturation of >20% is adequate. IV iron (choice D) is not necessary.

Oral iron may be beneficial, as increased red cell production over time
may deplete iron stores in the future.
• ACE inhibitors can slow the progression of chronic kidney disease,

particularly those associated with proteinuria, and should therefore not
be stopped (choices B and C).
Lancet 2007;369(9559):381–388.
3015
CASE 10
A 44-year-old man is brought to the emergency department after brief loss of
consciousness at work lasting for approximately 30 seconds. He has had a 5-
day history of dyspnea on exertion and chest pain. On the morning of
presentation, he had difficulty walking to work because of shortness of breath
and worsening chest pain.
On presentation, his ECG demonstrates 1mm ST segment elevations in leads I,

II, and aVL. Laboratory values are notable for a troponin-T of 0.22, normal CK
and CK-MB, WBC 4.1, Hgb 7, plt 11. The LDH is elevated at 1300, and PT and
PTT are normal.
A peripheral blood smear is shown.
(Image source: library.med.utah.edu)
CASE 10 (cont.)
The most appropriate initial treatment for this
condition is:
A) Platelet transfusion
B) Cardiac catheterization
C) Rituximab
D) IVIG
E) Plasma exchange
3016
The correct answer is E.

• This is a case of thrombotic thrombocytopenic purpura (TTP), given the concurrence of
microangioapathic hemolytic anemia and thrombocytopenia without an alternative explanation.
– It is now rare to encounter all five manifestations of the classic pentad of TTP
(microangiopathic hemolytic anemia, thrombocytopenia, renal failure, neurologic changes,
and fevers).
– Plasma exchange (choice E) should be initiated even if there is uncertainty about the
diagnosis of TTP, since the risks of progressive TTP generally outweigh the risks of
exchange.
• Platelet transfusion (Choice A) is contraindicated in TTP, as it may lead to progressive

consumption of infused platelets and production of thrombi, causing worsening neurologic
symptoms and/or renal failure.
•Cardiac catheterization (Choice B) might be reasonable for this patient later in his course, but is
not the most appropriate initial treatment. The ischemic signs and symptoms are most likely due
to microthrombi in the coronary circulation, which are treated by exchange.
• Rituximab (Choice C) may be used in addition to plasma exchange for refractory or recurrent
TTP, but at present is not indicated for up-front treatment of de novo TTP.
•IVIG (Choice D) may also be used as an adjunctive therapy in TTP, but not as an alternative to
plasma exchange.
CASE 11
A 42-year-old man presents to the emergency department for evaluation one
week after an episode of severe left-sided chest pain in the setting of cocaine
use. The chest pain persisted for approximately 24 hours, and then resolved.
He has not had any further chest pain, is currently chest pain free, and has no
exam features of heart failure.
His ECG in the emergency department is shown below:
Cardiac biomarkers are notable for a normal CK and CK-MB, and an elevated
troponin-T at 13.2.
3017
CASE 11 (cont.)
CASE 11 (cont.)
A 42-year-old man presents to the emergency department for evaluation one
week after an episode of severe left-sided chest pain in the setting of cocaine
use. The chest pain persisted for approximately 24 hours, and then resolved.
He has not had any further chest pain, is currently chest pain free, and has no
exam features of heart failure.
His ECG in the emergency department is shown below:
Cardiac biomarkers are notable for a normal CK and CK-MB, and an elevated
troponin-T at 13.2.
3018
CASE 11 (cont.)
The best next step in management is:
A) Echocardiogram
B) Anticoagulation with heparin
C) Urgent cardiac catheterization
D) Clopidogrel
E) Pharmacologic stress test

• The clinical history of chest pain in the setting of cocaine use one week ago and his ECG
suggests a missed anterior MI.
– Following a myocardial infarction, cardiac biomarkers peak in 18-24 hours.
• CK and CK-MB remain elevated for 48 hours, while troponins may remain elevated for 10
days.
• The pattern of biomarkers here is consistent with a missed MI one week ago.
• The ECG demonstrates ST elevations in leads V1-V4, suggestive of an anterior ST-elevation

MI. There are also Q-waves in leads V1-V4.
• The presence of anterior Q-waves plus persistent ST-elevations with a clinical story of a
cocaine-induced MI one week ago is suggestive of a left ventricular aneurysm.
– An echocardiogram should be performed to look for the presence of a ventricular
aneurysm and ventricular thrombus (choice A).
– Left ventricular aneurysms are common complication of anterior MIs.
– Left ventricular aneurysms are treated with afterload reduction and anticoagulation.
• Late catheterization of STEMI (after 24-48hrs) (Choice C) should only be done for severe
heart failure, electrical or hemodynamic instability, or persistent ischemia.
3019
CASE 12
A 28-year-old woman with no significant past medical history presents with
nausea and vomiting after completing her first marathon. She was able to
complete the marathon and thereafter immediately rehydrated. She took
four 200mg ibuprofen tablets and was at a post-marathon party when she
started to feel ill, saying unusual things to her friends such as, “I made a
terrible mistake” and “I am drowning.” Her friends brought her to the
emergency department. On examination, she is tired appearing and mildly
confused, and has an otherwise non-focal neurological exam. Her jugular
venous pressure is 6 cmH2O
What is the best next step in the workup and management of this patient?
A) Administration of 1L intravenous normal saline

B) Oral rehydration with an electrolyte replacement sports drink
C) STAT electrolyte panel
D) Administration of hypertonic saline at a rate of 1cc/kg/hr
E) Measurement of an ibuprofen level

• This patient likely has symptomatic, acute hyponatremia, likely caused
by extreme loss of hypotonic fluid (sweat) from exercise and
replacement of the hypotonic fluid with free water.
• The first step in this emergency situation should be to obtain a STAT

electrolyte panel to confirm hyponatremia and to help guide further
treatment (choice C).
• In the setting of euvolemia, rehydration with normal saline and PO

hydration is inadequate to correct hyponatremia and can result in
worsening hyponatremia (choices A and B).
• Empiric administration of hypertonic saline should be avoided in a

clinical setting where labs can be obtained rapidly as correcting
hyponatremia too quickly can lead to an osmotic demyelination
syndrome or central pontine myelinolysis (choice D).
• The patient’s signs and symptoms are inconsistent with ibuprofen

overdose (choice E).
3020
CASE 13
A 36-year-old woman with depression, mild asthma, and obesity
presents with three weeks of a non-productive cough. She also
has paroxysms of coughing and post-tussive vomiting. She
denies significant wheezing. She works at a day care. She got her
vaccinations as a child. Vital signs, lung exam, complete
metabolic panel, and chest X-ray are unremarkable.
The best treatment at this time would be?
A) Albuterol inhaler
B) Azithromycin
C) Prednisone
D) Anti-tussive agents
E) Admission to the hospital for IV antibiotics

• The clinical presentation suggests pertussis, which can be a cause
of persistent cough in adults, even those who received vaccinations as
child.
-Paroxysms of coughing and post-tussive vomiting are
suggestive of pertussis.
- The clinical course of pertussis in adults is usually less severe
than in children.
- Treatment for pertussis with a macrolide antibiotic (i.e.
azithromycin, choice B) is advised within 4 weeks of symptom
onset in order to contain the spread of infection.
• Albuterol inhaler (choice A) and prednisone (choice C) might be used

for an asthma attack, but are not indicated for this patient.
• There is no clinical indication for hospitalization or IV antibiotics for

this patient (choice E).
3021
CASE 14
A 25-year-old man who recently moved to the US from France (and had not
seen physicians there) presents with a headache, and on imaging is found to
have a superior sagittal sinus thrombosis. On examination, he is noted to be
tall and thin, and to have pectus excavatum and arachnodactyly. No
murmurs are appreciated on cardiac auscultation.
Which of the following tests would you expect to be abnormal in this

patient?
A) Activated protein C resistance

B) Fibrillin-1 mutation
C) Protein S activity
D) Homocysteine level
E) Prothrombin G20210A mutation

• The patient likely has homocystinuria, which can be diagnosted by an elevated
homocysteine level in the blood (choice D). These patients have a clinical phenotype
that can be similar to Marfan Syndrome, but there are some key differences:
- Patients with homocystienuria can be tall and thin, and have pectus excavatum and
arachnodactyly, similar to Marfan Syndrome. However, they do not have the
cardiovascular problems associated with Marfan Syndrome.
- Patients with homocystinuria may have associated venous thromobsis, which is
not present in Marfan Syndrome.
- Patients with homocystinuria have associated neuro-psychiatric disorders, venous
thrombosis, osteoporosis, and skin hypopigmentation.
- Patients with homcystinuria have downward lens dislocation while those with
Marfan Syndrome have upward lens dislocation.
- Most patients with Marfan Syndrome have a mutation in Fibrillin-1 (choice B).
• He was likely born in an environment where newborn screening for homocystinuria

(which now commonly exists) was not done.
• Factor V Leiden (resistance to activated protein C), prothrombin gene (G20210A)

mutation, and protein S deficiency are causes of a prothrombotic state, but do not
explain his other physical findings.
http://emedicine.medscape.com/article/1115062-overview
3022
CASE 15
A 38-year-old woman with a history of diffuse cutaneous systemic sclerosis
presents with lower extremity edema for one week. Her baseline blood pressures
are 120-140/70-80. She is on nifedipine and omeprazole.
On examination, she is afebrile. Her HR is 98 and BP is 170/100. She has skin

thickening over the face, hands, arms, chest and abdomen. There are
telangiectasias on her face and palms. Her cardiac examination is notable for an
S4. Her lungs are clear. She has 2+ lower extremity edema. Laboratory evaluation
reveals hemoglobin 9.8, platelets 95, BUN 40, creatinine 2.4, and albumin 3.4.
Urinalysis shows 2+ protein and 10 RBCs/high-powered field. A peripheral blood
smear shows 2+ schistocytes.
Along with admitting the patient to the hospital, what is the most appropriate
next step in management?
A) Increase the nifedipine dose

B) Begin captopril
C) Start oral labetalol
D) Begin IV methylprednisolone
E) Start oral prednisone

• The patient has scleroderma and now has hypertension, lower
extremity edema, renal failure with proteinuria, and
microangiopathy consistent with scleroderma renal crisis.
• The drug of choice for scleroderma renal crisis is an ACE

inhibitor with rapid titration to reduce blood pressure.
– ACE inhibitors are the most effective medication to
preserve or improve renal function in scleroderma renal
crisis.
– ACE inhibitors have shown a significant reduction in
mortality in this setting.
• Corticosteroids are not indicated (choices D and E) for

scleroderma renal crisis.
Rheum Dis Clin North Am 2003;29:315-333.
3023
CASE 16
A 36-year-old man presented to his primary care physician with a week-long
history of severe pain in his left Achilles tendon. Over the past few days, he
has also developed pain and swelling in his fingers and toes (see photographs
below). He has been having difficulty walking and bearing weight. Of note,
two weeks ago, he developed a week-long course of diarrhea accompanied by
chills and sweats following a weekend camping trip.
CASE 16 (cont.)
The most appropriate treatment is:
A) Ceftriaxone 1g IV
B) Methylprednisolone 1000mg IV
C) Prednisone 60mg PO
D) Indomethicin 50mg PO
E) Observation
3024

• This is a presentation of reactive arthritis, which presents as an asymmetric mono/oligo-
arthritis, predominantly of lower extremity joints.
–Classically, it also presents with enthesitis (inflammation of the insertion of ligaments,
tendons, joint capsule, or fascia to bone -- typically the Achillies tendon) and dactylitis
(“sausage digits”).
–Extra-articular involvement may include urethritis, conjunctivitis, uveitis, oral ulcers, and
rashes.
• Reactive arthritis may occur following genitourinary or enteric infections caused by Chlamydia
trachomatis, Yersinia, Salmonella, Shigella, Campylobacter, and possibly Clostridium difficile.
• Treatment for reactive arthritis is with NSAIDs, such as indomethicin, for at least two weeks.
• Gonococcal arthritis (for which ceftriaxone, choice A, would be an appropriate treatment) may
present with the abrupt onset of a mono- or oligo-arthritis, but typically does not cause sausage
digits, and frequently presents with a rash.
• Intravenous (Choice B) or oral (Choice C) steroids may be used to treat numerous rheumatologic
conditions, but are not the treatment of choice for reactive arthritis.
• Observation (Choice E) is not the best choice given the severity of symptoms in this case.
CASE 17
A 39-year-old woman of Greek descent presents to the emergency
department after experiencing a brief loss of consciousness while at work.
Workup in the emergency department reveals a WBC 4, Hgb 6.5, Plt 207.
She notes that she had a viral syndrome one week ago, which subsequently
resolved. She has no history of bleeding. She recently moved into a new
house three months ago. She notes that she has had a propensity to chew ice
for the past one year. She has no family history of anemia.
Additional workup reveals: MCV 55, Iron < assay, Ferritin 1, TIBC 400, ESR 8.
Normal haptoglobin, LDH, B12, and folate levels.
Blood smear shows microcytic, hypochromic red blood cells of varying

shapes.
Of note, CBC three years ago showed a Hgb of 9.5 with an MCV of 85.
3025
CASE 17 (cont.)
A) Thalassemia
B) Iron deficiency anemia
C) Lead toxicity
D) Hemolysis
E) Anemia of chronic inflammation

• This is a case of profound iron-deficiency anemia, as evidenced by microcytic anemia
with very low ferritin level.
• Common causes of microcytic anemia include iron deficiency, thalassemia, and chronic
inflammation (i.e. anemia of chronic disease). Rarer causes include copper deficiency,
lead poisoning, and sideroblastic anemia.
• Iron deficiency may have an insidious onset, with typical presenting symptoms including
fatigue, weakness, exercise intolerance, headache, and irritability. Additional signs and
symptoms include tongue pain, dry mouth, pica/pagophagia, and restless leg syndrome.
• Thalassemia (Choice A) typically presents with very low MCVs, as in this case, but iron
stores should be normal to increased. The prior MCV of 85 also makes thalassemia highly
unlikely, as it is an inherited disorder.
•Lead poisoning (Choice C) may cause microcytic anemia. Basophilic stippling is often
(but not always) evident on peripheral blood smear. Other manifestations include
abdominal pain, joint and muscle aches, memory problems, and irritability.
• The normal haptoglobin and LDH make the diagnosis of hemolytic anemia (Choice D)
less likely.
• Anemia of chronic disease (Choice E) typically presents with low iron and low TIBC, but
an increased ferritin. The ESR would also be expected to be elevated.
3026
CASE 18
A 19-year-old man with no significant past medical history presents with a
new, non-productive cough of five months duration. He was seen by his PCP
when the cough began, was diagnosed with bronchitis, and was treated with
a course of antibiotics. His symptoms did not improve, the cough worsened,
and it is now accompanied by dyspnea and wheezing. He feels dyspneic on
exertion and often coughs with exertional activity. Examination is notable for
an oxygen saturation of 91% on RA and scattered expiratory wheezes. WBC is
15.6 with an absolute eosinophil count of 1890/µL. Review of systems is
notable for a 25-pound weight loss in the last five months. His social history is
notable for marijuana use.
What is the most likely diagnosis?

A) Asthma
B) Chronic bronchitis
C) Eosinophilic granulomatosis with polyangiitis (Churg-Strauss Syndrome)
D) Allergic bronchopulmonary aspergillosis (ABPA)
E) Invasive aspergillosis

• ABPA (choice D) should be suspected in a patient with new onset asthma as
an adult in the presence of peripheral eosinophilia.
• While this constellation of symptoms can also be seen in eosinophilic

granulomatosis with polyangiitis (Churg-Strauss Syndrome), the historical
feature of marijuana use heavily sways the diagnosis in favor of ABPA, as
marijuana is often contaminated with Aspergillus.
• Eosinophilic granulomatosis with polyangiitis (choice C) is characterized by

sinus disease, asthma, end-organ damage from peripheral and tissue
eosinophilia, including cardiac dysfunction and neuropathy.
• Chronic bronchitis (choice B) is unlikely to explain the patient’s eosinophilia

or end-expiratory wheezing.
• Invasive aspergillosis (choice E) is usually seen in patients with underlying

immunocompromise and is associated with fevers and occasionally with frank
hemoptysis or blood tinged sputum.
3027
CASE 18 – Part II
All of the following are reasonable next steps in the workup and
treatment of this patient except?
A) Start prednisone at a dose of 0.5-1.0 mg/kg/day

B) Check strongyloides serology
C) Check IgE level and consider initiation of omalizumab
D) Encourage patient to stop marijuana usage
E) Check for FIP1L1-PDGFRα translocation

• The treatment for ABPA includes:
– Cessation of offending agents (choice D).
– Oral steroids (choice A).
• It is important to rule-out occult stronglyoidiasis (choice B) in a
patient with eosinophilia prior to the initiation of steroids, so as to
avoid precipitating life-threatening strongyloides hyperinfection
syndrome.
• The test for the presence of FIP1L1-PDGFRα translocation (choice E) is a

molecular diagnostic tool that is used in the diagnosis of chronic eosinophilic
leukemia.
• Omalizumab (choice C) is a monoclonal antibody directed at IgE that is

FDA-approved for the treatment of refractory asthma in the setting of an
elevated IgE level. It is not currently indicated in the treatment of ABPA.
3028
CASE 19
A 64-year-old man with hypertension presents with three days of right upper
quadrant abdominal pain. Labs show ALT 927, AST 1048, alkaline phosphatase
132, total bilirubin 7.8, direct bilirubin 5.7, WBC 8.62, Hct 42.5, platelets 270,
albumin 3.5, and INR 1.1. He denied acetaminophen ingestion and chronic alcohol
use. Hepatitis A IgM, hepatitis B surface antigen, and hepatitis B core IgM are
negative. Hepatitis C viral load is 5,041,727 with genotype 1B. Anti-neutrophil
antibody, anti-smooth muscle antibody, and testing for herpes simplex virus,
cytomegalovirus, and Epstein-Barr virus are negative. RUQ ultrasound with
Doppler shows no cirrhosis or hepatomegaly, and patent portal and hepatic veins
with normal flow. He later admitted to recent IV heroin use. Which of the
following is the best management of this patient at this time?
A) Monitor hepatitis C viral load in 3 months and consider treatment if the

virus has not not cleared
B) Tenofovir
C) Ledipasvir/sofosbuvir
D) N-acetylcysteine
E) Prednisolone

• This patient likely has acute hepatitis C virus infection, given the recent exposure to IV
drugs, the positive viral load, and the lack of another cause for his hepatitis.
• Hepatitis C accounts for 20% of acute hepatitis in the US, but is often asymptomatic
(approximately 25% of patients present with symptoms). The RNA viral load becomes
detectable from days up to 8 weeks after infection, while the IgG serology is detectable
after 8 weeks. There is no IgM for hepatitis C.
• There is limited evidence for the treatment of acute hepatitis C, but the general
recommendations are to monitor the viral load again at 3 months (choice A), as those
patients who present with symptomatic acute hepatitis C infection are more likely to
clear the infection without treatment within the first few months.
• If treatment for chronic HCV infection is subsequently indicated, then

ledipasvir/sofosbuvir would be an option at that time (choice C).
• Tenofovir (choice B) is a treatment for hepatitis B. N-acetylcysteine is a treatment for

acetaminophen hepatotoxicity (choice D). Prednisolone (choice E) is a treatment for
alcoholic hepatitis.
J Hepatology 2005; 42: S108
3029
CASE 20
A 27-year-old woman originally from Brazil who is 25 weeks pregnant (G1P0)
presents with dyspnea, blood tinged-sputum, and pleuritic chest pain. Her HR is
86 bpm, BP is 126/73 mmHg, and O2 saturation is 82% on RA. Examination reveals
diffuse rales bilaterally and a difficult-to-auscultate, low-pitched diastolic rumble
at the apex. Electrocardiogram shows sinus tachycardia. A chest X-ray shows
diffuse bilateral infiltrates. Echocardiography reveals a normal ejection fraction, a
diffusely thickened mitral valve, moderate-to-severe mitral stenosis, and elevated
pulmonary artery systolic pressures. She is intubated for respiratory support. Fetal
ultrasound is reassuring.
The most appropriate regimen for medical management is:

A) Beta-blocker and gentle diuresis
B) Digoxin
C) Dopamine
D) ACE inhibitor
E) Hydralazine and nitrates

• This patient likely had rheumatic fever as a child resulting in rheumatic heart
disease and mitral stenosis, which was asymptomatic until her pregnancy.
• Medical management of symptomatic mitral stenosis in pregnancy involves

beta-blockade (to slow the heart rate, which improves diastolic filling) and
gentle diuresis. If this is not adequate, percutaneous mitral valvuloplasty can
be considered.
• Positive inotropes (such as digoxin, choice B, and dopamine, choice C) should

be avoided in mitral stenosis.
• Vasodilators (such as ACE inhibitors, choice D, and hydralazine and nitrates,

choice E) are not first line agents in the setting of decompensated mitral
stenosis.
• The safety of medications during pregnancy should also be considered.

Carabello BA. Circulation. 2005;112:432-437.
Bonow RO et al. J Am Coll Cardiol. 2006 Aug 1;48(3):e1-148.
3030
CASE 21
A 29-year-old woman presents to the emergency department
with sore throat, fever, and recurrent hematuria.
She was in her usual state of health until one month ago, when
she developed a sore throat and a fever of 101 F. The following
day, she noticed frank blood in her urine and went to the
emergency department. She was diagnosed with a presumed
urinary tract infection and given a seven day course of
cephalexin. After several days of antibiotics, her fevers resolved
and her urine cleared. She remained in good health until one
week ago, when she again developed fever, sore throat and
bloody urine, and returned to the emergency department. She
notes that she had a similar episode about three years ago.
CASE 21 (cont.)
Urinalysis is notable for 3+ blood and 2+ protein.
Urine sediment shows 493 dysmorphic RBCs. No casts are seen.
Laboratory values are notable for a creatinine of 3.4. Complement
components C3 and C4 are normal.
Renal ultrasound shows no evidence of obstruction, hydronephrosis, or
perinephric fluid collection.
Which of the following is the most likely diagnosis:
A) Post-streptococcal glomerulonephritis
B) IgA nephropathy
C) Carcinoma of the bladder
D) Urinary tract infection
E) Nephrolithiasis
3031

• IgA nephropathy is the most common cause of primary glomerulonephritis in the
developed world. It usually presents with recurrent gross hematuria, usually less
than five days after an upper respiratory infection or bacterial tonsillitis, though it
may present with microscopic hematuria and mild proteinuria.
• Post-streptococcal GN (Choice A) is an immune-complex disease from specific

nephritogenic strains of Group A streptococcus. It usually occurs one to three
weeks after pharyngitis and three to six weeks after skin infection. Children ages
5-12 and adults over 60 years of age are at highest risk. Complements are usually
decreased, and this may persist for four to eight weeks. Renal function resolves
within three to four weeks; hematuria may persist for three to six months. Unlike
IgA nephropathy, it post-streptococcal GN rarely recurs.
• Proteinuria and dysmorphic RBCs suggest glomerular (rather than extraglomerular)

pathology, making the remaining choices unlikely.
– Carcinoma of the bladder (Choice C) typically affects older patients, with a
mean age at diagnosis of around 70.
– Urinary tract infections (Choice D) and nephrolithiasis (choice E) would be
expected to present with additional signs and symptoms.
Selected References
• Altman R, Alarcón G, Appelrouth D, Bloch D, Borenstein D, Brandt K, et al.
The American College of Rheumatology criteria for the classification and
reporting of osteoarthritis of the hand. Arthritis Rheum 1990; 33: 1601–10
• Ashton HA, Buxton MJ, Day NE, et al; Multicentre Aneurysm Screening
Study Group. The Multicentre Aneurysm Screening Study (MASS) into the
effect of abdominal aortic aneurysm screening on mortality in men: a
randomised controlled trial. Lancet. 2002 Nov 16;360(9345):1531-9
• Fleming C, Whitlock EP, Beil T, Lederle F. Screening for abdominal aortic

aneurysm: a best-evidence systematic review for the U.S. Preventive
Services Task Force. Ann Intern Med 2005;142:203-11.
• LeGrand SB, Leskuski D, Zama ISO. Narrative review: furosemide for

hypercalcemia: an unproven yet common practice. Ann Intern Med.
2008;149(4):259.
• Young WF. The Incidentally Discovered Adrenal Mass. N Engl J Med 2007;
356:601-6
3032
Board Review Practice 3

Sanjay Divakaran, M.D.
Fellow, Division of Cardiovascular Medicine
Clinical Fellow in Medicine
sdivakaran@bwh.harvard.edu
3033
Joslin Diabetes Center

Diabetes 2008: From Research to Clinical Practice
Hypertension, Renal Disease, and Cardiovascular Disease in Diabetes:
Current Approach to Diagnosis and Treatment
Diabetes Update 2018
ROBERT C. STANTON, MD
Chief of Kidney and Hypertension Section
Disclosure
I have been a Consultant to Janssen

Pharmaceuticals on the Global Renal
Advisory Board.
3034

Learning Objectives
Understand the Risks of Diabetes
Review the World of Medications for Diabetes
Understand the Emerging Roles of the Newer Medications –GLP1-RAs

and SGLT2 Inhibitors
Know the Role of Metformin, Lactic Acidosis Risk, and How to Dose
Metformin
Appreciate the Role of New Diabetes Technologies
Know Current Recommendations for Management of Type 2 Diabetes
- Glucose control has greatest

impact on Microvascular
disease
- Macrovascular impact of
glucose control takes longer, is
only modest, but is real; Other
approaches are more potent
3035

Quality of Diabetes Care in the US

Data from:
CDC’s National
health interview
survey;
National hospital
discharge
survey;
US Renal Data
System; National
Vital statistics
System
What is the A1c Goal?
American College of Physicians Recommends 7-8% for

Most Non-Pregnant Adults with Type 2 Diabetes. And to
lower Medications if A1c is <6.5%
The American Diabetes Association Recommends <7%

for most people. But <6.5% or as high as 8% may be
appropriate.
The Best Approach: Aim for <7% but Individualize goals!

Riddle et al Diabetes Care 41:1121-1124, 2018
3036

Which of the following medications are currently

most recommended as initial drugs for treatment
of newly diagnosed type 2 diabetes.
A) Metformin, Sulfonylureas, DPP-4 inhibitors

B) Metformin, SGLT-2 inhibitors, GLP-1 Receptor Agonists
C) Metformin, GLP-1 Receptor Agonists, Insulin
D) Metformin, TZDs, DPP-4 Inhibitors
Which of the following medications are currently most

recommended as initial drugs for treatment of newly
diagnosed type 2 diabetes.
A) Metformin, Sulfonylureas, DPP-4 inhibitors
B) Metformin, SGLT-2 inhibitors, GLP-1 Receptor Agonists
C) Metformin, GLP-1 Receptor Agonists, Insulin
D) Metformin, TZDs, DPP-4 Inhibitors
The answer is B. In fact, any of these medications could be used

depending on the presenting blood glucose levels and
glycohemoglobin A1c. Current guidelines recommend metformin.
And there is increased support for starting with SGLT-2 Inhibitors or
GLP-1 Receptor Agonists.
3037

Garber et al Endocrine Practice 24:91-120, 2018
Lifestyle Modification in the Diabetes

Prevention Program Outcomes Study
16-session curriculum with individual sessions
Goal – 7% weight loss
• Healthy, low-fat, low-calorie diet
• 150 min per week of moderate-intensity physical activity
• After the first 24 weeks, individual and group sessions were used
to reinforce the lifestyle modification behaviours
DPPOS – Quarterly Sessions for All Participants
• Supplementary sessions for DPP Lifestyle Participants
• Twice a Year Visits.
Nathan et al The Lancet: Diabetes and Endocrinology 3:866-875, 2015
3038

Lifestyle Intervention or Metformin Prevents
Development of Diabetes – 15 Year Follow Up
Placebo Metformin
Lifestyle Intervention
Nathan et al The Lancet: Diabetes and Endocrinology 3:866-875, 2015
3039

Multiple Complex Pathophysiological
Abnormalities in T2DM
pancreatic
incretin insulin
effect secretion
pancreatic
glucagon
- secretion
gut
carbohydrate
delivery & HYPERGLYCEMIA
absorption
+
hepatic renal peripheral
glucose glucose glucose
production excretion uptake
Adapted from: Inzucchi SE, Sherwin RS in: Cecil Medicine 2011
Multiple Pathophysiologically-Based
Therapies for T2DM
GLP-1R Insulin
agonists pancreatic
incretin Glinides insulin
SUs secretion
effect
DPP-4 Amylin pancreatic
inhibitors mimetics glucagon
- secretion DA
agonists
gut A G I s
carbohydrate
absorption
Metformin TZDs
Bile acid
-
sequestrants
+ SGLT-2
inhibitors
3040

Major Pathophysiologically-Based
Therapies for T2DM
GLP-1R Insulin
agonists pancreatic
incretin insulin
SUs secretion
effect
DPP-4 pancreatic
inhibitors glucagon
- secretion
gut
carbohydrate
absorption
Metformin TZDs
+ SGLT-2
inhibitors
GLP-1R Insulin
agonists “insulin
SUs providers”
DPP-4
inhibitors
“incretin
enhancers”
Metformin
“insulin TZDs
sensitizers”
SGLT-2
inhibitors “glucose
excreter”
3041

Hypoglycemia Risk
Any Medication May Cause Hypoglycemia but of Particular

Risk are Sulfonylureas and Insulin
3042

Mechanism of Action of Sulfonylureas
Sola et al Archives of Medical Science 11:840-848, 2015
Hypoglycemic Risk of Sulfonylureas Increases as

GFR Declines (as Compared to Metformin)
Van Dalem et al British Medical Journal 354:i3625, 2016
3043

All of the glucose lowering medication classes

below have been shown to lower cardiovascular or
stroke risk in prospective randomized trials except
one. Identify the exception.
A) SGLT-2 Inhibitors
B) GLP-1 Receptor Agonists
C) Thiazolidinedione
D) Metformin
3044

All of the glucose lowering medication classes below have
been shown to lower cardiovascular or stroke risk in
prospective randomized trials except one. Identify the
exception.
A) SGLT-2 Inhibitors
B) GLP-1 Receptor Agonists
C) Thiazolidinedione
D) Metformin
The answer is D) metformin. SGLT-2 inhibitors and GLP-1 receptor
agonists have been shown to significantly lower cardiovascular risk in
multiple trials. Pioglitazone has been show to lower stroke and non-
fatal MI risk in one study. Metformin has never been shown to lower
cardiovascular or stroke risk.
Thiazolidinediones
Available since 1997.
Pioglitazone is the TZD mostly available
Mechanism: PPAR-γ activation, increased peripheral glucose

uptake, decrease lipolysis.
Dosing: daily, takes weeks-months for full effect, max effective

dose = max dose.
A1c lowering: 1-2%

Pros: efficacy, metabolic effects, daily dosing, no
hypoglycemia, ?preservation of beta-cell function.
Cardiovascular benefit shown in Proactive trial
Cons: cost, weight gain, edema/CHF, CV controversy,
fractures, urologic cancers?
Kernan et al. New England Journal of Medicine 374:1321–1331, 2016

Bril et al. Clinical Gastroenterology and Hepatology 16:558-566, 2018
3045

Thiazolidinediones
Available since 1997.
Pioglitazone is the TZD mostly available
Mechanism: PPAR-γ activation, increased peripheral glucose

uptake, decrease lipolysis.
• Pioglitazone lowered progression to liver fibrosis in Nonalcoholic
Steatohepatitis (NASH)
Dosing: in weeks-months
daily, takes people withfor
Type 2 Diabetes
full effect, (Cusi, 2018)
max effective
dose = max dose.
• Lowered risk of stroke in Non-Diabetic Patients(Kernan, 2016)
• Prevented A1c
progression from Prediabetes to Diabetes (Kernan, 2016)
lowering: 1-2%
Pros: efficacy, metabolic effects, daily dosing, no
hypoglycemia, ?preservation of beta-cell function.
Cardiovascular benefit shown in Proactive trial
Cons: cost, weight gain, edema/CHF, CV controversy,
fractures, urologic cancers?
Kernan et al. New England Journal of Medicine 374:1321–1331, 2016

Bril et al. Clinical Gastroenterology and Hepatology 16:558-566, 2018
Thiazolidinediones
The Principal Risks are Edema and Weight Gain
Association Studies have Suggested Increased Bone Loss

and Fracture Risk
• (Possibly due to Decreased Osteoblast Activity)
Low Hypoglycemia Risk
Wang et al Scientific Reports &;1717; 2017

Riche and King Pharmacotherapy 30:716-727, 2010
3046

TZDs and Edema
Wang et al Scientific Reports &;1717; 2017
3047

GLP-1 Source
Muskiet et al Nature Reviews Nephrology 13:605-628, 2017
GLP-1 Agonists/DPP4 Inhibitors

Gut Derived Hormone GLP-1 Has Multiple Actions Including
Increasing Insulin Secretion
DPP4 is a Peptidase that Cleaves GLP-1
• Main Antidiabetic Action of DPP4 Inhibition is thought to

be due to Increasing GLP-1, but DPP4 has many
substrates so there may well be many other actions.
Mann et al New England Journal of Medicine 377:839-848, 2017

Thomas et al Diabetes Therapy 7:439-454, 2016
3048

GLP-1 Actions
Muskiet et al Nature Reviews Nephrology 13:605-628, 2017
Liraglutide Reduced CV Risk

(LEADER Trial)
Marso et al New England Journal of Medicine 375:311-322, 2016
3049

Semaglutide Reduced CV Risk

(SUSTAIN-6 Trial)
Marso et al New England Journal of Medicine 375:311-322, 2016
3050

Effects of SGLT2 Inhibitors
*Changes Cellular
Fuel Metabolism
van Bommel et al Clinical J. Amer. Soc. Nephrol. 12:700-710, 2017

*Mudaliar et al Diabetes Care:1115-1122, 2016
EMPA-REG Improved 3-Point MACE

(CV related death, non-fatal MI and non-fatal stroke)
N=7070,
14% rel. risk
DM and reduction
CV
disease
Zinman et al New England Journal of Medicine 373:2117-2128, 2015

]
3051

EMPA-REG: Improved Hospitalization for Heart Failure
EMPA-REG Improved Cardiovascular Mortality
38% rel. risk

reduction
38
.Re):131.
2016 Dec;16(12):131.
3052

Canagliflozin Decreases CV Events:

3 Point MACE (CANVAS Trial)
Neal et al New England Journal of Medicine 377:644-657, 2017
SGLT2 Inhibitors Side Effects
The Principal Side Effects are Urinary Tract Infections and

Genital Mycotic Infections
3053

SGLT2 Inhibitors Side Effects

Amputations - CANVAS Trial (Canagliflozin) Reported a Rate of
6.3/1000 patient-years for amputations (primarily toe and metatarsal)
as compared to 3.4/1000 in Control Group1
• Amputations occurred in those with preexisting peripheral vascular disease
Diabetic Ketoacidosis – Recent Publication Reports Double the Rate

of DKA in Initiation of SGLT2 Inhibitors as Compared to DPP4. But
overall rates were very low2
Bone Loss and Fracture Risk has been Reported – But overall Risk
is Unclear at this time3
1) Neal et al New England Journal of Medicine 377:644-657, 2017

2) Fralick et al New England Journal of Medicine 376:2300-2302, 2017
3) Tang et al Diabetes, Obesity, and Metabolism 18:1199-1206, 2016
Are SGLT-2 Inhibitors Renoprotective?
3054

Effects of SGLT2 Inhibitors
*Changes Cellular
Fuel Metabolism
van Bommel et al Clinical J. Amer. Soc. Nephrol. 12:700-710, 2017

*Mudaliar et al Diabetes Care:1115-1122, 2016
Empagliflozin (SGLT2 Inhibitor) Slowed Decline in

eGFR
Normal Rate of GFR Decline: 0.5 – 1 ml/year
Wanner et al NEJM 375:323-334, 2016
3055

Empagliflozin Decreased Glomerular Hyperfiltration in 8 Week Study in People
with Type 1 Diabetes Possibly by Altering Tubulo-Glomerular Feedback
Cherney et al Circulation 129:587-597, 2014
Thoughts about SGLT2 Inhibitors and Diabetic

Kidney Disease
SGLT2 Inhibitors May be RenoProtective
• (Secondary Analysis of EMPA-REG Cardiovascular Study)
• (Secondary Analysis of CANVAS Cardiovascular Study)
Outstanding Issues:
• Does Empagliflozin really prevent the decline in eGFR due to normal
aging as it appeared to do in EMPA-REG Study?
• Is it Safe to Have High Levels of Glucose in the Nephron for Many
Years? – No answer for 10 Years or More
• CREDENCE Study - Canagliflozin (To be Completed 2019) will answer
some of these questions
• New Empagliflozin and Dapagliflozin Studies: Chronic Kidney Disease
with and without Type 2 Diabetes Mellitus
3056

Metformin
Metformin is Considered the First Drug of Choice for People

with Type 2 Diabetes Mellitus
Phenformin was taken off the market due to lactic acidosis

in 1978
Until 2016, Recommendations had been to Stop Metformin

at Serum Creatinine (>1.5 mg/dl for men and >1.4 mg/dl for
women – about an eGFR of 60 ml/min) to prevent lactic
acidosis
DeFronzo et al Metabolism 65:20-29, 2016
3057

Metformin Mechanism of Action
Rena et al Diabetologia 60:1577-1585, 2017
Biochemistry of Lactate Production
DeFronzo et al Metabolism 65:20-29, 2016
3058

Metformin Mechanism of Lactic Acidosis
Rena et al Diabetologia 60:1577-1585, 2017
Arguments For Metformin Use in Patients to

an eGFR of 30 ml/min
Metformin is an Excellent Antidiabetic Medication with
Multiple Beneficial Actions and Few Side Effects
Lactic Acidosis is Very Rare

– For example Systematic Review of about 150,000 patients –
Risk was 3.3/100,000 (Sulfonlyureas had 4.8 cases/100,000)
Bakris and Molitch Diabetes Care 39:1287-1291, 2016

Lu et al Annals of Pharmacology 47:1488-1497, 2013
3059

Risk of Lactic Acidosis is Very Low
Inzucchi et al JAMA 312: 2668-2675, 2014
Arguments Against Metformin Use in Patients

with an eGFR of <45 ml/min
Metformin Associated Lactic Acidosis (MALA) is Very
Serious and Often Leads to Death
Conditions Predisposing to MALA are those Associated

with an Acute Decline in eGFR (Dehydration, Sepsis,
Acute Kidney Injury)
These Conditions are Common and Unpredictable
Kalantar-Zadeh and Kovesdy Diabetes Care 39:1281-1286, 2016
3060

Metformin–CKD Prescribing
Guidelines (April 2016)
• Obtain eGFR before starting metformin and annually, more
frequently in those at risk for renal impairment (e.g., elderly).
• Metformin contraindicated in patients with an eGFR <30.
• Starting metformin in patients with an eGFR between 30-45 not
recommended.
• If eGFR falls <45, assess the benefits and risks of continuing
treatment. D/C if eGFR falls <30.
• Hold metformin at the time of / before iodinated contrast
procedure if eGFR 30-60; if h/o liver disease, alcoholism, or heart
failure; or if intra-arterial contrast. Recheck eGFR 48 hrs after
procedure and restart if renal function stable.
http://www.fda.gov/Drugs/DrugSafety/ucm493244.htm (accessed 4-8-16)
Recommendations
Metformin Can be Safely Used to eGFR of 30 ml/min
• If GFR is <45 ml/min maximal recommended dose is 500 mg twice
a day
Hold Metformin in Situations of eGFR Decline (Dehydration,

AKI, etc)
Hold Metformin in Situations of Increased Risk for eGFR

Decline (e.g. Contrast Dye Studies)
Stanton American Journal of Kidney Disease 66:193-195, 2015
3061

Metformin
GLP-1 RA
SGLT-2i
DPP-4i
TZDs
SU/GN
3062

Advances in Insulin Therapy
1. Newer basal insulins (early data show less

hypo), that are also available in concentrated
formulations (e.g., glargine U-300, degludec U-
100, U-200). Note: PD/PK change with U-300
2. Combination basal insulin + GLP-1 receptor agonist
fixed combinations (e.g. glargine + lixisenatide,
degludec + liraglutide) – insulin dose is the one
titrated. (Less hypo, no weight gain, lower insulin dose)
3. Combination basal insulin + fast acting dose

– ex: iDegAsp – one injection daily to cover
main meal + basal
4. Inhaled insulin : outcomes needed
3063

Advances in Insulin Therapy

5. Increasing utilization of
continuous glucose monitoring
(CGM, or ‘sensors’) to guide
therapy in those on insulin pumps
and/or intensive insulin regimens
(mainly T1DM.). Can now reduce
need for fingersticks
6. Significant advances in the
‘artificial’ or ‘bionic’ pancreas that
links a CGM sensor to an insulin
(& glucagon?) pump (T1DM.) First
‘hybrid closed-loop pump’ available
now in US (Medtronic 670G device)
CGM and Insulin Pump Placement
https://www.niddk.nih.gov/health-information/diabetes/overview/managing-diabetes/continuous-
glucose-monitoring
3064

Insulin Pump Improves Glucose Control
Hirsch and Skylar

http://diabetesmanager.pbworks.com/w/page/17680318/The%20Management%20of%20Type%201%20Di
abetes%20, 2009
CGM Provides A Large Amount of Data
Danne et al Diabetes Care 317:1631-1640, 2017
3065

CGM Use Improved A1c (DIAMOND Trial)

24 Week Study
Beck et al JAMA 317:371-378, 2017
https://www.niddk.nih.gov/health-information/diabetes/overview/managing-diabetes/continuous-
glucose-monitoring
3066

Atkinson et al The Lancet 383:69-82.2014
Diabetes Update 2018 Summary
Lifestyle Modifications and Metformin remain the mainstay of

treatment.
Trials with GLP-1RAs and SGLT-2 Inhibitors showing significant
cardiovascular risk reduction are making these likely second line
agents and possibly first line.
Weigh the risks & benefits of each agent to design a treatment regimen
individualized to each patient.
Major advances in technology are having a large impact on insulin
therapy, especially in T1DM
3067

Selected References
Garber et al Consensus Statement by the American Association of Clinical Endocrinologists

and American College of Endocrinology on the Comprehensive Type 2 Diabetes Management
Algorithm Summary – 2018 Executive SummaryEndocrine Practice 24:91-120, 2018
Inzucchi SE, et al. Management of hyperglycemia in type 2 diabetes, 2016: a patient-centered

approach: Diabetes Care. 38:140-149, 2015
Zinman et al Empagliflozin, Cardiovascular Outcomes, and Mortality in Type 2 Diabetes New

England Journal of Medicine 373:2117-2128, 2015
Marso et al Liraglutide and Cardiovascular Outcomes in Type 2 Diabetes New England Journal
of Medicine 375:311-322, 2016
Riddle et al A1C Targets Should Be Personalized to Maximize Benefits While Limiting Risks
Diabetes Care 41:1121-1124, 2018
3068

Diabetes: Managing Common

Complications
ROBERT C. STANTON, MD
Chief of Kidney and Hypertension Section
Disclosures
I have served as a consultant to Janssen

Pharmaceuticals in the past 12 months.
3069

Learning Objectives
Know the Complications of Diabetes Mellitus
Understand the Importance and Goals of Blood Sugar and Blood

Pressure Control for Managing Complicatios
Know How to Screen for and Manage Diabetic Complications
- Glucose control has greatest

impact on Microvascular
disease
- Macrovascular impact of
glucose control takes longer, is
only modest, but is real; Other
approaches are more potent
- Tailoring regimens to reduce

CV disease is the next frontier
in diabetes management
3070

Complications of Diabetes in the United States
#1 cause of blindness in Developed Countries

#1 cause of end-stage kidney disease in U.S. (and soon
the World)– 53% of all new cases
20-30% of people with diabetes develop kidney disease
~60% to 70% of people with diabetes have mild to severe
forms of nervous system damage
Major factor leading to lower-extremity amputations
Cardiovascular disease is the cause of death in 75% to
80% of people with type 2 diabetes
Afkarian et al JAMA 2016;316(6):602-10
USRDS.ORG 2018 Annual Data Report
Diabetes Care: Standards of Medical Care - 20187
Which one of the goals below are recommended

current best practices to prevent diabetic
complications for all patients.
A) BP <130/80, A1c <8%, RAAS Inhibitor

B) BP<140/80, A1c <7%
C) BP<130/80, A1c <6%, RAAS Inhibitor
D) BP<130/80, A1c <7%
3071

Which one of the groups below reflect current best

practices to prevent diabetic complications.
A) BP <130/80, A1c <8%, RAAS Inhibitor

B) BP<140/80, A1c <7%
C) BP<130/80, A1c <6%, RAAS Inhibitor
D) BP<130/80, A1c <7%
The answer is D. Current goals (although there is

some controversy) are BP<130/80 and A1c of <7%.
There is no unique role for RAAS inhibitors
although there may be good reasons to start with
them or add them early on for BP control.
No Primary Prevention of Development of

Microalbuminuria by Enalapril or Losartan
Mauer et al N Engl J Med.; 361:40-51, 2009
3072

Biopsy Study Shows No Primary Prevention of

Mesangial Expansion by Enalapril or Losartan
Mauer et al N Engl J Med.; 361:40-51, 2009
Comparison of Prevention Trials for Type 2

Diabetes
Trials Showing
Prevention Benefits had
Higher Baseline BPs
Bilous et al Ann Intern Med.151:11-20, 2009
3073

Diabetic Complications: Blood Sugar Control
25 Year Follow Up of DCCT/EDIC (Type 1 Diabetes) –

50% Reduction of Microalbuminuria in Original
Intensively Treated Group
De Boer
Diabetes Care
37: 24-30,
2014
3074

25 Year Follow Up of DCCT/EDIC (Type 1 Diabetes) –
50% Reduction of Microalbuminuria in Original
Intensively Treated Group
De Boer
Diabetes Care
37: 24-30,
2014
30 Year Follow Up of DCCT/EDIC –

32% Reduction in MACE (CV Outcomes) in
Original Intensively Treated Group
DCCT/EDIC Study Group. Diabetes Care 39: 686-693, 2016
3075

10 Year Follow Up of UKPDS (Type 2 Diabetes)
Holman et al New England Journal of Medicine 359: 1577-1589, 2008
3076

A1c Goal
Aim for <7% but Individualize goals!
UKPDS vs ACCORD and ADVANCE
• ACCORD/ADVANCE Participants were 8 and 12 years older than

UKPDS and were Considered to be at High Risk
• UKPDS were newly diagnosed
3077

Diabetic Complications: Blood Pressure

Control
Blood Pressure Goal
JNC 8 Recommended <140/90

(As did Many Other Organizations Until Recently)
Goal Blood Pressure IS:

<130/80
3078

ACCORD Blood Pressures
Accord Study Group. N Engl J Med;362:1575-1585, 2010
ACCORD Trial: No Benefit of Tight BP

Control on Cardiovascular Outcomes
Accord Study Group. N Engl J Med;362:1575-1585, 2010
3079

Low Blood Pressures Appear to Increase

Cardiovascular Mortality
Cooper-DeHoff RM et al JAMA 304: 61-68, 2010
SPRINT – Systolic Blood Pressure Intervention Trial - (Improved CV

Outcomes in Intensive BP Group (<120 mmHg) vs Less Intense
Control (<140 mmHg) in Subset with CKD
COMBINED CV OUTCOMES
SPRINT Participant
Characteristics:
>75 yo
Increased CV Risk
No Diabetes ALL CAUSE MORTALITY

Mellitus
Cheung et al J Am Soc Nephrol 28: 2812-2823, 2017
3080

Analysis of ACCORD Study (Type 2 DM Participants) Study Using
SPRINT Criteria Show Improved CV Outcomes in Intensive BP
Group (<120 mmHg) vs Less Intense Control (<140 mmHg)
COMBINED CV OUTCOMES:
CV Death, Nonfatal MI, Nonfatal Stroke
Buckley et al Diabetes Care September 25, EPUB, Ahead of Print, 2017
ALL OFFICE BLOOD PRESSURES (INCLUDING

THOSE TAKEN IN MY OFFICE) ARE WRONG
PROPER WAY TO TAKE BLOOD PRESSURE:
RESTING FOR AT LEAST 5 MINUTES
USE PROPER CUFF SIZE
USE BARE ARM RESTING AT HEART LEVEL
TAKE MULTIPLE MEASUREMENTS AND AVERAGE

RESULTS
CHECK ORTHOSTATIC BLOOD PRESSURE

Drawz and Ix J Am Society of Nephrology October 19 EPUB, Ahead of Print, 2017
DeBoer et al Diabetes Care 40:1273-1284, 2017
3081

What is the Initial Drug Choice for Hypertension
Control in Diabetes?
Individualize!!
It will take at least 2 likely 3 or more medications to reach

goal
ADA Recommends Using a Medication that Lowers CV Risk

– ACE Inhibitors, ARBs, Dihydropyridine Calcium Channel
Blockers, or Thiazide-Like Diuretics. But if there is
increased urine albumin then start with ACE-I or ARB
Choose a medication on the following:

• Cost
• Age
• Co-morbidities
• Side Effects
Diabetes Care 41:Supplement 1, 2018
Diabetic Kidney Disease
3082

Quality of Diabetes Care in the US

Data from:
CDC’s National
health interview
survey;
National hospital
discharge
survey;
US Renal Data
System;
National Vital
statistics System
29
Numbers of Patients on Dialysis-USA: 1992
www.usrds.org
3083

Numbers of Patients on Dialysis-USA: 2002
www.usrds.org
vol 2 Figure 1.9 Map of the adjusted prevalence of ESRD, by Health

Service Area, in the U.S. population, 2011-2015*
Data Source: Special analyses, USRDS ESRD Database. Standardized for age, sex, and race. The standard population was
the U.S. population in 2011. *Three Health Service Areas were suppressed because the ratio of unadjusted rate to
adjusted rate or adjusted rate to unadjusted rate was greater than 3. Values for cells with 10 or fewer patients are
suppressed. Abbreviation: ESRD, end-stage renal disease.

32
Volume 2, Chapter 1
3084

Figure 1.16 Trends in adjusted* prevalence (per million) of ESRD, by primary cause of
ESRD, in the U.S. population, 1996-2014
DIABETES
HYPERTENSION
GLOMERULONEPHRITIS
CYSTIC KIDNEY DISEASE
Data Source: Reference Table B.2(2) and special analyses, USRDS ESRD Database. *Point prevalence on December 31 of each
year. Adjusted for age, sex, and race. The standard population was the U.S. population in 2011. Abbreviation: ESRD, end-stage
renal disease.
2016 Annual Data Report, Vol 2, ESRD, Ch 1 33
vol 2 Figure 1.11 Trends in adjusted prevalence of ESRD, by race, in

the U.S. population, 2000-2015
NATIVE HAWAIIAN/PACIFIC ISLANDER
AFRICAN-AMERICAN
AMERICAN INDIAN/ALASKA NATIVES

ASIAN
WHITE
Data Source: Reference Table B.2(2) and special analyses, USRDS ESRD Database. Point prevalence on December 31 of
each year. Standardized for age and sex. The standard population was the U.S. population in 2011. Abbreviations NH/PI:
Native Hawaiian/Pacific Islander; AI/AN: Americans Indian/Alaska Natives; ESRD, end-stage renal disease.

34
Volume 2, Chapter 1
3085

vol 2 Figure 1.12 Trends in the adjusted prevalence of ESRD, by
Hispanic ethnicity, in the U.S. population, 2000-2015
HISPANIC
NON- HISPANIC
Data Source: Reference Tables B.1, B.2(2). Point prevalence on December 31 of each year. Standardized for age, sex,
and race. The standard population was the U.S. population in 2011. Abbreviation: ESRD, end-stage renal disease.

35
Volume 2, Chapter 1
Diabetic Kidney Disease: 2015 Data

About 14.8% of the U.S. population has chronic kidney disease (CKD) as
defined as GFR of < 60 mL/min or elevated urine albumin level
Most CKD patients die of heart disease before reaching end stage kidney
disease
About 700,000 patients are on dialysis or have a kidney transplant
Death rates are 15-20% per year for dialysis patients
Medicare spent $37 billion in 2015 on ESRD , which is about 7.3% of the
Medicare budget. And an additional $50 billion was spent on CKD
Patients
www.usrds.org
3086

Excess Mortality in Type 2 Diabetes is Due to

Kidney Disease
Afkarian et al J Am Soc Nephrol 24: 302–308, 2013
Diagnose Kidney Disease Early:

Measure eGFR and Spot Urine
Albumin/Creatinine Ratio
(microalbumin test)
Yearly
Use Nephelometry to Measure
Microalbumin as Dipsticks are Relatively
Insensitive and May Miss Low (but
significant) Increases in the Urine
Abumin Level
3087

Value of Graphing GFR

Creatinine was 1.0 in 2004 and now 1.5
GFR Declined from 60 to 35 over 9 Years
-2.8 ml/min/year
People with Diabetes and Kidney

Disease May NOT have Diabetic
Kidney Disease
3088

Reasons to Consider Kidney Diseases Other

than Diabetes in People with Diabetes
Type 1 Diabetes Duration of <5 years
Absence of Diabetic Retinopathy (especially in Type 1 DM
Persistently Low Hemoglobin A1c
Active Urine Sediment (especially many RBCs or WBCs)
Rapidly Declining GFR
Rapidly Increasing or Very High Urine Protein Level
Any of These May Be an Indication for Kidney Biopsy
Liang et al PLOS ONE 1 May 2013 | Volume 8 | Issue 5 e64184
Causes of Non-Diabetic Kidney Disease in

Patients with Diabetes
Clin J Am Soc Nephrol 8: 1718–1724, 2013
3089

Albuminuria/Proteinuria
Normal total protein renal excretion is about 200
mg/day (up to 20 mg is albumin) – Most of the
protein comes from tubular cells – Intact Albumin
is from Glomerular Filtration
Normal Albumin Excretion by Nephelometry is an

Albumin/Creatinine Ratio of <30 mg/g
Microalbuminuria – 30–300 mg/g
Macroalbuminuria – >300 mg/g
Increasing Albuminuria and Decreasing GFR

Are Associated with Increased
Cardiovascular and Renal Events in Type 2
Diabetes
Ninomiya T et al J. Am. Soc. Neph. 20:1813-1819 (2009)
3090

Albuminuria appears to be a marker of

generalized inflammation and
endothelial dysfunction.
Prevention of Diabetic Kidney Disease
Blood Glucose Control

• Goal is A1c <7%
Blood Pressure Control

• Goal is <130/80
Stop Smoking
Measure eGFR and urine albumin/creatinine ratio at least

Yearly
3091

Treatment of Diabetic Kidney Disease
Blood Pressure Goal - <130/80
Blood Sugar Control - A1c < 7.0%
Lower Urine Albumin – Use RAAS Inhibitors

(Especially if >300mg/g)
Stop Smoking
Measure eGFR and urine albumin/creatinine ratio at

Every Visit
All of the following are effects of ACE Inhibitors

and Angiotensin Receptor Blockers except one.
Identify the exception.
A) Decrease Blood Pressure

B) Lower Urine Albumin Level
C) Increase eGFR
D) Increase Potassium
3092

All of the following are effects of ACE Inhibitors

and Angiotensin Receptor Blockers except one.
Identify the exception.
A) Decrease Blood Pressure

B) Lower Urine Albumin Level
C) Increase eGFR
D) Increase Potassium
ACE Inhibitors and ARBs lower GFR
(increase creatinine) by causing vasodilation
of the efferent arteriole
The greater the initial decline in GFR after

starting Losartan, the slower the rate of
decline in long term GFR
Holtkamp FA et al Kidney International 80:282-287, 2011
3093

Use Of ACE Inhibitors/ARBS
There is no unique role for ACE inhibitors/ARBs for

prevention of diabetic kidney disease.
For patients with diabetic kidney disease - All patients

with increased urine albumin (generally a urine
albumin/creatinine ratio >300 mg/g) should be on an
ACE-inhibitor or an Angiotensin Receptor Blocker even if
the patient has excellent blood pressure
Eye Diseases and Diabetes
Nonproliferative diabetic retinopathy (NPDR)

Proliferative diabetic retinopathy (PDR)
Glaucoma at earlier age
Cataract formation at earlier age
Retinal detachment
Macular edema more common
Best prevention: A1C, BP, LDL in target; yearly dilated eye

exams and early intervention
Recent Study – 60% of People with Diabetes do not have
Yearly Exams
Beaser RS and the Staff of Joslin Diabetes Center. Joslin’s Diabetes Deskbook: A Guide
for Primary Care Providers, 3rd Edition. Boston: Joslin Diabetes Center, 2014.
Murchison et al. Nonadherence to Eye Care in People with Diabetes. Abstract Presented
at American Academy of Ophthalmology Annual Meeting 2016.
3094

Diabetes and Neuropathy
Symptoms are usually in the feet first, and can consist of:
• Numbness, paresthesias to severe pain
• Mild weakness
• Loss of position and vibratory sensation
• Sleep disturbance, depression
Examine Feet for Signs of Neuropathy – Use a filament
Treatment is Mainly for Pain
• ADA Recommends pregabalin or duloxetine as initial treatment
Beaser RS and the Staff of Joslin Diabetes Center. Joslin’s Diabetes Deskbook: A Guide for
Primary Care Providers, 3rd Edition. Boston: Joslin Diabetes Center, 2014.
Diabetes Care 41:Supplement 1, 2018
Diabetes and Foot Problems:

Factors Increasing Risk
High blood glucose levels
Prior ulcerations or amputations
PVD, neuropathy, retinopathy
Smoking
Structural deformities
Can’t see, feel, or reach the foot
Best Prevention: 50% of amputations can be

prevented by protecting the feet, daily foot
care, daily foot checks, referrals for problem
feet
Beaser RS and the Staff of Joslin Diabetes Center. Joslin’s Diabetes
Deskbook: A Guide for Primary Care Providers, 3rd Edition. Boston: Joslin
Diabetes Center, 2014.
3095

Filament Exam
Boulton et al Diabetes Care 31:1679-1685, 2008
Other Complications
Sexual dysfunction in men and women

• Marker for high risk of heart disease in men,
associated with vascular problems
Gastroparesis
• Slowing of the emptying of the stomach
Autonomic dysfunction
• Orthostatic hypotension
3096

Smoking and Diabetes
People who smoke are 40%–60 % more likely
to get diabetes than people who do not smoke
Smoking with diabetes
• Increases the risk of severe kidney damage
and nerve problems
• Greatly increases the risk of heart attack,
stroke, and foot amputations
• Increases insulin resistance and blood
glucose levels
• Worsens gum disease and tooth loss
Willi, et al. JAMA. 2007;298:2654-2664. | CDC, Smoking and Diabetes

http://www.cdc.gov/tobacco/campaign/tips/diseases/diabetes.html?mobile=false | Demmer, et al. Diabetes Care.
2012;35:2036-2042
Management Issues for Macrovascular

Disease: CV Disease, Stroke, and Peripheral
Vascular Disease in Type 2 Diabetes
Dyslipidemia (low HDL, high triglycerides)
Hypertension (2½ times more common in diabetes)
Nephropathy
Obesity/sedentary lifestyle
Altered coagulation, platelet function, and fibrinolysis
Hyperinsulinemia/hyperproinsulinemia/insulin resistance
Cigarette smoking
Hyperglycemia
Bierman EL. Arterioscler Thromb. 1992;12:647-656.
3097

Reducing Risk: Changing One Risk Factor Helps
Controlling A1C BP < 130/80 LDL-C Microalbumin Smoking

< 7% < 100
Reduction in
Heart/ related
Circulation
Nephropathy
related
Retinopathy
related related
Neuropathy
related
Copyright © 2017 by Joslin Diabetes Center. All Rights Reserved.
Office Management of Diabetic Complications Summary
Blood pressure control <130/80

• Check Orthostatic Blood Pressure
Blood sugar control (A1c <7%)

Manage Cardiovascular Risk Factors – Screen for CVD/PVD
Yearly Dilated Eye Exams
Calculate eGFR and Measure Urine Albumin/Creatinine Ratio
at least Yearly
Foot Exam at least Yearly – Use Filament
Screen for Neuropathy, Sexual Dysfunction, and
Gastroparesis
Stop smoking
3098

Selected References
Standards of Medical Care. Diabetes Care Volume 14 (Supplement
1), 2018
www.USRDS.org
Buckley LF et al. Intensive versus standard blood pressure control
in SPRINT-eligible participants of ACCORD-BP. Diabetes Care
40:1733–1738, 2017
De Boer et al Kidney Disease and Related Findings in the Diabetes
Control and Complications Trial/Epidemiology of Diabetes
Interventions and Complications Study. Diabetes Care 37:24-30,
2015
Holman et al 10-Year Follow-up of Intensive Glucose Control in
Type 2 Diabetes. New England Journal of Medicine 359: 1577-1589,
2008
3099
Thyroid Disease
Psychiatry Overview
Matthew Kim, M.D.
Clinical Director
Division of Endocrinology, Diabetes and Hypertension
Assistant Professor
No disclosures to report
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Topics
• Hypothyroidism
• Hyperthyroidism
• Non‐thyroidal illness
• Thyroiditis
• Thyroid nodules
‐
TRH
+
T4 T3
‐
TSH
T4 T3
+
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T4
1, 5’ ‐ Deiodinase
T3
0.03% T4 0.1% T3
T4 T3
T4 T3
T4 T3
Thyroxine‐Binding Thyroxine‐Binding
Globulin T4 Globulin T3
99.97% T4 99.9% T3
T4 T3
T4 T3
Thyroxine‐Binding
T4 T3
Prealbumin
T4 Albumin T3
Albumin T4 T3
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Hypothyroidism
Hypothyroidism: Etiologies
• Iodine deficiency
• Autoimmune thyroiditis 95%
• Post‐ablative hypothyroidism
• Post‐surgical hypothyroidism 4%
• Drug‐mediated inhibition
• Insufficient TRH and/or TSH secretion
• Congenital absence of thyroid tissue < 1%
• Resistance to thyroid hormone
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Autoimmune Thyroiditis
• Hashimoto’s thyroiditis, chronic lymphocytic
thyroiditis
• Marked female predominance, increasing
prevalence with age
• Associated with increased rates of infertility and
miscarriage
• Association with other autoimmune disorders
– Type 1 diabetes
– Addison’s disease
– Vitiligo
– Premature gray hair
Hypothyroidism: Diagnosis
1. Check a TSH level
• Normal = euthyroid
• Elevated = primary hypothyroidism
• Low = possible secondary hypothyroidism
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2. If the TSH level is elevated, check a total T4
or free T4 level
• Elevated TSH: low total T4 and/or free T4 =
primary hypothyroidism
• Elevated TSH: normal total T4 and free T4 =
subclinical (mild) hypothyroidism
3. If the TSH level is low and you suspect
hypothyroidism, check a free T4 level
• Low TSH: low free T4 = secondary
hypothyroidism
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4. If no obvious underlying cause for primary
hypothyroidism is evident, check anti‐thyroid
peroxidase and/or anti‐thyroglobulin
antibody titers
• Elevated anti‐thyroid peroxidase and/or anti‐
thyroglobulin antibody titers = autoimmune
thyroiditis
Hypothyroidism: Treatment
• Levothyroxine (Synthroid®, Levoxyl®, Unithroid®,
Levothroid®, Tirosint®)
• Taken once daily
• Starting dose
– Healthy young adults 0.8 mcg/lb daily
– Age > 60 25‐50 mcg daily
– Cardiac ischemia 12.5‐25 mcg daily
• Reduce daily dose by 25% when administered IV
• Check a TSH level 6 weeks after starting or
adjusting a dose
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• Subclinical (mild) hypothyroidism
– Indications for treatment are controversial
– Usually treated if
• TSH > 10‐15 mIU/L
• Concomitant hypercholesterolemia
• Pregnancy
– Doses usually need to be increased during early
stages of pregnancy
– Try to maintain TSH levels between 0.5‐2.5 mIU/L
during the first trimester
• Agents that block absorption
– Iron sulfate
– Sucralfate
– Bile acid resins (Welchol®, cholestyramine)
• Agents that increase metabolism
– Rifampin
– Phenytoin
– Phenobarbital
– Carbamazepine
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Hyperthyroidism
Hyperthyroidism: Definitions
• Thyrotoxicosis – A systemic syndrome
characterized by exposure to excessive levels
of thyroid hormone
• Hyperthyroidism – A systemic syndrome
characterized by exposure to excessive levels
of thyroid hormone produced by overactive
functional thyroid tissue
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Thyrotoxicosis
Hyperthyroidism
Hyperthyroidism: Etiologies
• Graves’ disease 88%
• Toxic adenoma
• Toxic multinodular goiter 11%
• Iodine exposure
• Struma ovarii
< 1%
• TSH‐secreting pituitary adenoma
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Non‐Hyperthyroid Thyrotoxicosis:
Etiologies
• Subacute thyroiditis
• Autoimmune thyroiditis
Graves’ Disease
• Marked female predominance
• Commonly presents between 15‐35 years of
age
• Complications
– Thyroid eye disease
(Graves’ ophthalmopathy)
– Dermopathy (pretibial myxedema)
– Acropachy
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Toxic Adenoma
• Hyperthyroidism caused by growth of a single
autonomously functioning hyperplastic
thyroid nodule
• Usually large
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Toxic Multinodular Goiter
• Hyperthyroidism caused by growth of multiple
autonomously functioning hyperplastic
thyroid nodules
• May develop in the setting of a previously
euthyroid multinodular goiter
• Nodules may vary in size
• Hyperthyroidism may be precipitated by
exposure to iodine (Jod‐Basedow
phenomenon)
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Hyperthyroidism: Diagnosis
1. Check a TSH level
• Normal = euthyroid
• Low = thyrotoxicosis
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2. If the TSH level is low and you suspect
hyperthyroidism, check a total T4 or free T4
level and a total T3 level
• Low TSH: elevated total T4, free T4, or total T3 =
thyrotoxicosis
• Low TSH: normal total T4, free T4, and total T3 =
subclinical (mild) thyrotoxicosis
3. Check for clinical evidence of complications
of Graves’ disease
• Goiter
• Symptoms and signs of thyroid eye disease
• Dermopathy
• Acropachy
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4. If no complications of Graves’ disease are
clinically evident, consider checking anti‐TSH
receptor antibodies or radionuclide testing
with a thyroid uptake and scan
Anti‐TSH Receptor Antibodies
• Thyroid stimulating immunoglobulin (TSI)
– Bioassay that measures activation of cells that
express TSH receptors
• Thyrotropin‐binding inhibitory
immunoglobulin (TBII)
– Immunoassay that detects antibodies that bind to
TSH receptors
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Radionuclide Testing
• Thyroid uptake study
– Used to measure level of activity
– High uptake (usually > 25%) = increased iodine uptake
and organification consistent with hyperthyroidism
– Low uptake = non‐hyperthyroid thyrotoxicosis
• Thyroid scan
– Generates images that reflect distribution of activity
– Can help to distinguish between causes of
hyperthyroidism
Graves’ disease
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Toxic adenoma
Toxic multinodular goiter
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Hyperthyroidism: Management
• Beta blockers
– Atenolol: 25‐50 mg daily
– Propranolol LA: 60‐80 mg daily
• Antithyroid drugs
• Radioactive iodine
• Thyroid surgery
Antithyroid Drugs
• Methimazole
– Agent of choice in most cases
– Can be taken once daily
– Started at a dose of 5‐40 mg daily
– Recheck thyroid hormone levels 3‐4 weeks after
starting or changing a dose
– Adverse effects
• Common ‐ pruritis, rash
• Rare ‐ agranulocytosis, hepatotoxicity, vasculitis
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Antithyroid Drugs
• Methimazole
– Graves’ disease
• 30‐60% chance of remission after 12‐18 months of
treatment
• 50% chance of relapse within 18 months of stopping
treatment
– Toxic adenoma and toxic multinodular goiter
• Require continuous treatment
• Doses may need to be increased over time
Antithyroid Drugs
• When to use propylthiouracil
– Prior to conception and during the first trimester
of pregnancy
• Methimazole has been associated with aplasia cutis
• Consider switching to methimazole during the second
trimester
– In cases of thyroid storm
• Acts to block peripheral conversion of T4 to T3
– When a patient who is allergic to methimazole
declines radioactive iodine treatment or surgery
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Radioactive Iodine
• Iodine‐131
– May be given immediately or after a period of
treatment with antithyroid drugs
– Can’t be given while pregnant or breastfeeding
– May cause transient inflammation and
thyrotoxicosis
– Can take up to 2‐6 months to work
– Delay conception until 6 months out from
treatment due to risk of fetal thyroid damage
Radioactive Iodine
• Graves’ disease
– Dose based on uptake and gland weight
– Treatment may exacerbate thyroid eye disease
• Toxic adenoma
– Usually shrinks size without impairing function of
normal tissue
• Toxic multinodular goiter
– May relive compressive symptoms caused by
substernal extension
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Thyroid Surgery
• Graves’ disease
– In cases of severe hyperthyroidism (thyroid storm)
– When a patient who is allergic to antithyroid drugs
can’t be or refuses to be treated with radioactive
iodine
• Toxic multinodular goiter
– When there is substernal extension causing
significant compressive symptoms
Non‐Thyroidal Illness
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• “Euthyroid sick syndrome”
• Transient changes in hypothalamic‐pituitary
function, thyroid hormone secretion, and
deiodinase activity that occur in the setting of
acute physiologic stress
• Combinations of changes may suggest
underlying thyrotoxicosis and/or
hypothyroidism
• TSH
– Initially suppressed due to decreased
hypothalamic‐pituitary secretion
– May rebound to high levels during recovery
• T4
– Decreased due to diminished secretion
• T3
– Decreased due to inhibition of deiodinase activity
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TSH
reverse T3
Normal
T4
T3
Mild Moderate Severe Recovery
Thyroiditis
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Subacute Thyroiditis
• Onset is often preceded by a nonspecific viral
illness
• Patients present with pain localized to the
thyroid gland which may radiate upwards to
the neck and jaw
• Thyroid gland may be slightly enlarged and
exquisitely tender to palpation
• Inflammation may spread from one lobe to
the other
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• Low thyroid uptake
• Lab tests may reveal an elevated ESR
• Thyrotoxic phase lasting 1‐4 weeks caused by
release of thyroid hormone, followed by a
resolving hypothyroid phase lasting 1‐3
months
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• High dose ibuprofen, aspirin, celecoxib, or
prednisone 20‐40 mg daily for pain control
• Symptoms may flare up as doses are tapered
• Beta blockers to attenuate thyrotoxic
symptoms
• Temporizing treatment with levothyroxine
during hypothyroid phase
• Lymphocytic thyroiditis, painless thyroiditis, or
silent thyroiditis
• May develop in 5‐8% of all women following
pregnancy (postpartum thyroiditis)
• Usually asymptomatic
• Thyroid gland may be slightly enlarged, but is
not tender
• Most cases resolve completely within 6
months, though 10% may recur
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• Low thyroid uptake
• ESR is normal
• Thyrotoxic phase caused by release of thyroid
hormone (90% of cases), followed by a
resolving hypothyroid phase (50% of cases)
• Beta blockers to attenuate thyrotoxic
symptoms
• Temporizing treatment with levothyroxine
during hypothyroid phase
Checkpoint Inhibitors
• Immunomodulatory antibodies that inhibit
programmed cell death receptor 1 and
receptor ligand 1 (PD‐1, PD‐L1) and cytotoxic
T‐lymphocyte‐associated antigen 4 (CTLA‐4)
• Immunologic enhancement can trigger new‐
onset autoimmune thyroiditis
• May present with severe thyrotoxicosis
followed by rapid progression to overt
hypothyroidism
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Checkpoint Inhibitors
Thyrotoxicosis Hypothyroidism
Atezolizumab (Tecentriq®) 8.0% 13.2%
Nivolumab (Opdivo®) 3.2% 7.0%
Ipilimumab (Yervoy®) 1.7% 3.8%
Pembrolizumab (Keytruda®) 0.6% 3.9%
Thyroid Nodules
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Thyroid Nodules
• 54,000 new cases of thyroid cancer in the U.S.
in 2018
• 300,000 new palpable thyroid nodules
detected annually
• Incidental nodules noted on 13% of carotid
doppler studies
• Discrete nodules identified on 67% of thyroid
ultrasounds
Thyroid Nodules: Evaluation
• TSH level
– Assess functional status
• Thyroid ultrasound
– Confirm presence
– Characterize
– Detect additional non‐palpable nodules
– Identify lymphadenopathy
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TSH and thyroid ultrasound
Low TSH Normal TSH High TSH
Anti‐thyroid
Toxic adenoma Thyroid scan
antibodies
Toxic multinodular Autoimmune
Graves’ disease Nodule
goiter thyroiditis
Cold nodule Fine needle aspiration biopsy
Thyroid Nodules: FNA Criteria
• > 1.0 cm
– Hypoechoic nodules
– Nodules with suspicious features
• > 1.5 cm
– Isoechoic nodules
– Hyperechoic nodules
• > 2.0 cm
– Spongiform nodules
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Thyroid Nodules: FNA Criteria
• Suspicious features
– Irregular margins
– Microcalcifications
– Coronal height > width
– Extrathyroidal extension
– Extrusion through a rim of calcification
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Bethesda System for Reporting Thyroid
Cytopathology
Malignant
Benign 0 ‐ 3%
Atypia of undetermined significance 10 ‐ 30%
Suspicious for a follicular neoplasm 25 ‐ 40%
Suspicious for malignancy 50 ‐ 75%
Malignant 97 ‐ 99%
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Thyroid Nodules: Management
• Benign
– Monitor with serial imaging
• Atypia of undetermined significance
– Repeat biopsy +/‐ genetic profiling (Afirma®, ThyroSeq®)
• Suspicious for a follicular neoplasm
– Repeat biopsy +/‐ genetic profiling
• Suspicious for malignancy
– Hemithyroidectomy or total thyroidectomy
• Malignant
– Total thyroidectomy
Question 1
A 33 year‐old male is noted to have palpable
enlargement of the right side of his thyroid.
Ultrasound reveals a 3.1 cm nodule with smooth
borders. Lab tests show TSH 0.1 mU/L (0.5 ‐ 5.2
mU/L) and T4 11.5 µg/dL (4.6 ‐ 10.7 µg/dL). He
reports a history of symptomatic palpitations and
weight loss of 5 lbs over the course of 3 months,
despite an increase in his appetite. He is not taking
any medications and has not noted any problems
with dysphagia or dysphonia.
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Question 1
A. Perform a fine needle aspiration biopsy of the
right sided nodule
B. Administer a 15 mCi dose of I‐131
C. Refer the patient to a thyroid surgeon
D. Start methimazole at a dose of 5 mg daily
E. Check a radioiodine scan and uptake
Question 1
A. Perform a fine needle aspiration biopsy of the
right sided nodule
B. Administer a 15 mCi dose of I‐131
C. Refer the patient to a thyroid surgeon
D. Start methimazole at a dose of 5 mg daily
E. Check a radioiodine scan and uptake
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Question 2
A 74 year‐old male with a history of hypertension and
hypercholesterolemia is hospitalized after presenting with
a three month history of progressive fatigue and dyspnea
on exertion. His weight is 164 lbs, his pulse is 44 bpm, and
lab tests show CPK 528 U/L (22 ‐ 198 U/L), TSH 65 mU/L
(0.5 ‐ 5.2 mU/L), free T4 0.2 ng/dL (0.9 ‐ 1.7 ng/dL), and
T4 2.3 µg/dL (4.6 ‐ 10.7 µg/dL). A nuclear stress test
reveals findings consistent with ischemia. Coronary
angiography reveals diffuse three vessel disease that is
not amenable to stenting. A cardiologist recommends
that he undergo coronary artery bypass surgery.
Question 2
A. Start levothyroxine at a dose of 125 mcg daily
B. Administer a 60 mcg intravenous dose of
levothyroxine daily
C. Check anti‐thyroid peroxidase and anti‐
thyroglobulin antibodies
D. Start levothyroxine at a dose of 12.5 mcg daily
E. Defer treatment with thyroid hormone
replacement until after he has undergone
revascularization
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Question 2
A. Start levothyroxine at a dose of 125 mcg daily
B. Administer a 60 mcg intravenous dose of
levothyroxine daily
C. Check anti‐thyroid peroxidase and anti‐
thyroglobulin antibodies
D. Start levothyroxine at a dose of 12.5 mcg daily
E. Defer treatment with thyroid hormone
replacement until after he has undergone
revascularization
Key Points
• The TSH level is the most sensitive index of
thyroid function
• Graves’ disease is usually diagnosed clinically
• Pregnancy is associated with increased
levothyroxine dose requirements
• Treatment of subclinical thyroid disease is
optional in most cases
• Fine needle aspiration is the most informative
approach to the evaluation of thyroid nodules
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References
• Durante C et al. The Diagnosis and Management
of Thyroid Nodules. JAMA. 2018 Mar 6;319(9):
914‐924
• Peeters RP. Subclinical Hypothyroidism. N Engl J
Med. 2017 Jun 29;376(26):2556‐2565
• Smith TJ, Hegedüs L. Graves' Disease. N Engl J
Med. 2016 Oct 20;375(16):1552‐1565
• Samuels MH. Subacute, silent, and postpartum
thyroiditis. Med Clin N Am. 2012. 96(2):223‐33
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ADRENAL DISORDERS
Anand Vaidya, MD MMSc
Director, Center for Adrenal Disorders
Division of Endocrinology, Diabetes, & Hypertension
Disclosures
None
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Learning Objectives
1. Review the role of the adrenal gland in physiology and

pathophysiology
2. Evaluation of adrenal insufficiency
3. Evaluation of an adrenal mass
4. Biochemical work up for hyperaldosteronism,

hypercortisolism, and pheochromocytoma
TUTORIAL VIDEOS:
ADRENAL PHYSIOLOGY: https://www.youtube.com/watch?v=bM6rhEuOtBM
ADRENAL INSUFFICIENCY: https://www.youtube.com/watch?v=SgckxKvccKo
PRIMARY ALDOSTERONISM: https://www.youtube.com/watch?v=db9v9kNIiXU
PHEOCHROMOCYTOMA: https://www.youtube.com/watch?v=0tZ8kJ6dN3A
Take Home Points

• The adrenal glands synthesize and secrete hormones that play a vital
role in hemodynamic homestasis. Understanding the physiology of
adrenal hormone feedback and the relative interpretations of adrenal
testing is crucial for accurate assessments.
• Carefully timed cortisol and ACTH measurements can help decipher

whether the HPA axis is functioning appropriately
• The prevalence of adrenal masses increases with age, and their

incidental discovery has increased.
• All adrenal masses should be carefully evaluated for malignant potential

and hormone hyperfunction
• Consider involving endocrine/adrenal colleagues at any time in the

evaluation
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Case 1
• 28yoF presents to ER 6 weeks after having a baby
• Cannot breastfeed well
• Presents with progressive fatigue, dizziness, orthostasis,
salt craving, hyperpigmentation, anorexia, and weight loss
• BP=60/40 mmHg
• IV saline (8L) and BP improves
• Cortisol 0.80 mcg/dL

• (60mins after 250 mcg cosyntropin)= 1.0 mcg/dL
• ACTH>1000pg/mL
Question 1
A) Primary adrenal insufficiency

B) Acute secondary adrenal insufficiency
C) Chronic secondary adrenal insufficiency
D) Ectopic ACTH syndrome
E) Cushing’s disease
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Question 1
This most likely diagnosis is:
A) Primary adrenal insufficiency

B) Acute secondary adrenal insufficiency
C) Chronic secondary adrenal insufficiency
D) Ectopic ACTH syndrome
E) Cushing’s disease
Adrenal Cortex: Steroidogenesis

Cholesterol
Zona Glomerulosa Zona Fasciculata Zona Reticularis
Pregnenolone 17-Hydroxypregnenolone DHEA
Progesterone 17-Hydroxyprogesterone Androstenedione
11-Deoxycorticosterone 11-Deoxycortisol Testosterone
Corticosterone Cortisol Estradiol
Aldosterone
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Hypothalamic-Pituitary-Adrenal Axis
P
Glucocorticoid
Receptor
Target
Organ
Cell
Adrenal
Mineralocorticoid
Receptor
The Glucocorticoid Receptor

Physiologic Activation of the GR
Increase Blood Glucose

• Increase gluconeogenesis
• Promote protein breakdown
• Augment epinephrine-mediated lipolysis
Increase Cardiovascular tone

•Increase pressor response to NE, AngII
•Stimulate synthesis of Epi
•Inhibit synthesis of NO
Immune Modulation
CNS Effects
•Appetite
•Mood
•Sleep/wake
Promote fetal tissue and development
Involved in parturition
Many other magical things…
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The Mineralocorticoid Receptor
Physiologic Activation of the MR

• Sodium reabsorption
• Expansion of plasma volume
• Urinary potassium secretion
• Urinary hydrogen secretion
Hypothalamic-Pituitary-Adrenal Physiology:
NEWTON’s 3rd LAW: For every action, there is an equal and opposite reaction (feedback)
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Hypothalamic-Pituitary-Adrenal Physiology
H CRH
Glucocorticoid
Receptor
P
Cortisol
POMC
• ACTH
• (MSH)
Cortisol
Glucocorticoid
Receptor
Adrenal
Mineralocorticoid
Receptor
11βOH-steroid dehydrogenase 2 Target
Inactivates cortisol to cortisone Organ
Cell
Hypothalamic-Pituitary-Adrenal Physiology
H CRH
ACTH
Glucocorticoid
Receptor
Adrenal Mineralocorticoid
Receptor
AGT Target
Ang-II Aldosterone Organ
Renin Ang-I ACE K+ Cell
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The HPA axis
1) Cortisol secretion is entirely dependent on ACTH
2) Aldosterone is not dependent on ACTH. It is regulated

in part by:
• Angiotensin II (Renin-angiotensin system)
• K+ balance
• ACTH
3) HPA axis responds to:

• Diurnal variation/clock
• “stress”: ACTH & cortisol secretion is augmented
“relative” to the degree of stress
Hypothalamic-Pituitary-Target Organ Physiology:
25
Cortisol (µg/dL)
20
15
10
0
2400 0400 0800 1200 1600 2000 2400
TIME
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Testing the HPA axis
STATIC TEST (entire HPA axis):

•Morning cortisol (and ACTH)
•An “appropriate” AM cortisol should ideally be >15-18 µg/dL, reflecting
a morning peak, but values > 10-12 µg/dL when pre-test probability is
low
Vaidya et al. NEJM 2010; 362(6): e16
Testing the HPA axis
STATIC TEST (entire HPA axis):

•Morning cortisol (and ACTH)
•An “appropriate” AM cortisol should ideally be >15-18 µg/dL, reflecting
a morning peak, but values > 10-12 µg/dL when pre-test probability is
low
PROVOCATIVE TEST (adrenal glands):

•250 µg cosyntropin stimulation test
Vaidya et al. NEJM 2010; 362(6): e16
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Primary Adrenal Insufficiency

(Addison’s Disease)
Manifestations/Characteristics:
H CRH
Labs:
• low cortisol
P • high ACTH
• low aldosterone
-hyperkalemia, hyponatremia,
ACTH hypovolemia
Physical Exam:
Cortisol
• fatigue/lethargy/anorexia Glucocorticoid
Aldosterone
• hypotension/orthostasis/salt craving Receptor
Adrenal • weight loss Mineralocorticoid
• hyperpigmentation Receptor
• abdominal pain
• many many more Target
Organ
Cell
Primary Adrenal Insufficiency

(Addison’s Disease)
Response to Cosyntropin:
H CRH
• sub-optimal
P EXAMPLE:
60 mins following
Morning
250 µg cosyntropin
ACTH Cosyntropin Cortisol (µg/dL) 1.8 2.1
ACTH (pg/mL) 1100
Glucocorticoid
Cortisol Receptor
Adrenal
Mineralocorticoid
Receptor
Target
Organ
Cell
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Primary Adrenal Insufficiency (Addison’s)
Causes:
• Autoimmune
• Infiltrative infections (TB, fungal)
• Hemorrhage
• Infiltrative malignancy
Medications:
• Anti-fungal medications
• Heparin
• Etomidate
ACUTE Secondary Adrenal Insufficiency
H CRH
Labs:
P • low basal cortisol
• inappropriately low ACTH
• ± hyponatremia
ACTH
• Normal K and aldosterone regulation
Physical:
Cortisol
• completely normal Glucocorticoid
Adrenal • mild, progressive, fatigue at baseline Receptor
• severe fatigue, orthostasis, Mineralocorticoid
Receptor
hypotension, in situations of stress
Target
Organ
Cell
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H CRH
• NORMAL
P EXAMPLE:
60 mins following
Morning
250 µg cosyntropin
ACTH Cosyntropin Cortisol (µg/dL) 2.2 26.0
ACTH (pg/mL) 10
Cortisol Glucocorticoid
Receptor
Adrenal
Mineralocorticoid
Receptor
Target
Organ
Cell
CHRONIC Secondary Adrenal Insufficiency
With chronic ACTH deficiency, adrenal cortex

H CRH
(ZF) will atrophy, and will progressively
respond less to cosyntoprin stimulation
EXAMPLE:
P 60 mins following
Morning
250 µg cosyntropin
Cortisol (µg/dL) 2.2 4.5
ACTH Cosyntropin
ACTH (pg/mL) 10
Glucocorticoid
Cortisol Receptor
Adrenal
Mineralocorticoid
Receptor
Target
Organ
Cell
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Secondary Adrenal Insufficiency
Causes:
• Pituitary mass: adenoma or metastatic lesion
• Pituitary infection
• Pituitary infiltration (granulomatous disease, iron)
• Pituitary trauma
Medications:
• Glucocorticoids
• Megesterol
• Opioids
Case 1
• Diagnosed with primary adrenal insufficiency (Addison’s)

• Treated with IV saline (8L)
• IV hydrocortisone initially
• Transitioned to PO hydrocortisone/fludrocortisone
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Case 2
• 46 year old pre-menopausal woman was in a car accident.
• No known medical conditions
• Brought to ER and complained of some abdominal pain. Had

a rapid unenhanced Abdominal CT that revealed no
hemorrhage or other injuries
• Incidental discovery of a 2.2 cm R adrenal mass, with 5 HU

unenhanced density
What, if anything, do you tell her about the

incidental adrenal mass??
Incidentally Disovered Adrenal Masses

• Adrenal tumors are incidentally discovered in 1-10% of adults.
• A minority represent malignant entities (primary adrenal malignancy or extra-

adrenal metastasis)
• The majority are determined to be benign and “nonfunctional” and therefore

are considered to pose no health risk.
• In contrast, ~10-15% of adrenal tumors autonomously secrete adrenal

hormones. These “functional” tumors are associated with an increased risk
for cardiometabolic outcomes, such as CV disease, diabetes, and
osteoporosis/fracture.
• Therefore, all incidentally discovered adrenal tumors should be carefully

evaluated to determine whether they are: 1) malignant and/or 2) functional.
Nieman LK. JCEM 2010; Young et al. NEJM 2007; Zeiger et al. Endocr Pract 2009; Fassnacht EJE 2016
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Differential Diagnosis of Adrenal Mass
NON-FUNCTIONAL FUNCTIONAL
BENIGN
MALIGNANT
(85-95%) (5-15%)
Adrenocortical Adenoma
Myelolipoma
Neuroblastoma
BENIGN Ganglioneuroma
(~90-95%)
Cyst
Hemorrhage
Infection (fungal, tuberculous)
Hemangioma
MALIGNANT
(~5%)
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(85-95%) (5-15%)
Adrenocortical Adenoma Adrenocortical Adenoma
Myelolipoma Aldosterone producing
Neuroblastoma Cortisol producing
BENIGN Ganglioneuroma Micro- or Macro-nodular Disease

(~90-95%)
Cyst Aldosterone producing
Hemorrhage Cortisol producing
Infection (fungal, tuberculous) Pheochromocytoma
Hemangioma
MALIGNANT
(~5%)
(85-95%) (5-15%)
Adrenocortical Adenoma Adrenocortical Adenoma
Myelolipoma Aldosterone producing
Neuroblastoma Cortisol producing
BENIGN Ganglioneuroma Micro- or Macro-nodular Disease

(~90-95%)
Cyst Aldosterone producing
Hemorrhage Cortisol producing
Infection (fungal, tuberculous) Pheochromocytoma
Hemangioma
Adrenocortical carcinoma Adrenocortical carcinoma
MALIGNANT
Metastatic cancer from a non-
(~5%) Pheochromocytoma
adrenal primary
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General Diagnostic Approach

1. Is there evidence for malignancy?
2. Is there adrenal hormone excess?
Clinical Biochemical Radiographic

Phenotype Phenotype Phenotype
History and physical exam Laboratory evaluation for Radiographic evidence

for evidence of hormone evidence of adrenal supportive of a benign or
excess or malignancy hormone excess malignant mass
Clinical Phenotype
Overt Overt Overt
Cortisol Excess Catecholamine Excess Aldosterone Excess
• Obesity/weight gain • Episodic symptoms • Hypertension
• Lipodystrophy o Hypertension • Hypokalemia
oCentral adiposity o Palpitations • Alkalosis
oSupraclavicular fat pads o Anxiety/Panic
oDorsocervical fat pad o Sweats/Tremors
oRounded face o Headache
• Hyperglycemia/Diabetes o Arrhythmia
• Hypertension
• Insomnia
• Mood disorder/Psychosis
• Osteoporosis
• Immunesuppression
• Platelet dysfunction
• Hypercoagulable state
• Myopathy
• Atrophic skin
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Case 2 – Clinical Phenotype
• No symptoms
• No signs to suggest hypercortisolism,
pheochromocytoma, hyperaldosteronism, or Clinical
hirsutism. Phenotype
• No evidence of weight loss, abdominal

distention, or androgen excess, to suggest
metastatic cancer or hyperfunctioning
adrenocortical carcinoma
Unrevealing
Case 2 – Radiographic Phenotype

Normal comparison Patient’s non-contrast CT
2.2cm right adrenal mass

5 Hounsfield units
Round, homogenous
3155
Question 2
A 2.2 cm adrenal nodule with an unenhanced density of 5 HU
on CT is most suggestive of:
A)Myelolipoma
B)Adrenocortical adenoma
C)Pheochromocytoma
D)Metastatic lung cancer to the adrenal gland
E)Adrenocortical carcinoma
Question 2
A 2.2 cm adrenal nodule with an unenhanced density of 5 HU
on CT is most suggestive of:
A)Myelolipoma
B)Adrenocortical adenoma
C)Pheochromocytoma
D)Metastatic lung cancer to the adrenal gland
E)Adrenocortical carcinoma
3156

Likely Potentially
Characteristic
Benign Malignant
Size < 4 cm > 4-6 cm
Attenuation on
<10 HU > 10 HU
unenhanced CT
Contrast washout on
CT protocol at 15
Absolute>60% Absolute<60% Radiographic
minutes
Relative >40% Relative<40%
Phenotype
MRI chemical shift
suggestive of lipid-rich Yes No
content
FDG avidity on PET No Yes
Irregular Borders No Yes
Heterogeneous content No Yes BENIGN: Suggestive of

Necrosis No Yes adrenocortical adenoma
Calcifications No Yes
Rate of Growth < 1cm/y >1cm/y
Miller. Nature Rev Endo 2014

Vaidya. Scientific American Medicine 2015
Case 2 – Biochemical Phenotype
Suggested screening biochemical evaluation for adrenal masses:
Condition Patients Test Abnormal Value

1 mg Nonfunctional: ≤1.8 mcg/dL
Autonomous
ALL Dexamethasone Possible: 1.9-5.0 mcg/dL
cortisol secretion
Suppression Test Autonomous: 5.0 mcg/dL
Serum aldosterone
Primary HTN and/or • Suppressed PRA
to plasma renin
Aldosteronism hypokalemia • ARR>20-25
activity ratio (ARR)
Plasma (or urinary)

Pheochromocytoma ALL (almost) fractionated >2-4x ULRR
metanephrines
Adrenal androgen Hirsutism or DHEAS
Higher than ULN
excess virilization Total Testosterone
Fassnacht EJE 2016
3157

• 1mg DST #1 => cortisol: 8.0 µg/dL
• 1mg DST #2 => 7.8 µg/dL, ACTH<5 pg/mL
• 8mg DST => 8.1 µg/dL, ACTH<5 pg/mL Biochemical
Phenotype
• 24h Urine Free Cortisol: 45 µg/24h (<45)
•Midnight Salivary Cortisol:

3.7, 3.9, 4.6, 4.3 nmol/L (<4.3)
• Random ACTH: 5 pg/mL

• Plasma metanephrines: normal
Autonomous
• Aldosterone/PRA: not suggestive cortisol
• DHEAS: normal secretion?
Case 2 – Clinical Diagnosis
Benign adrenocorticol adenoma
Autonomous cortisol secretion
No clinical signs of hypercortisolism
Should surgery be recommended?
3158
Case 2 – Outcome
• BP = 122/75 mmHg
• Fasting Blood Glucose = 99 mg/dL
• HbA1c = 5.8%
• Bone Mineral Density:
• Spine T= -3.2
• Femoral Neck T= -2.2
• Total Hip T= -2.0
• INDIVIDUALIZED DECISION: Laparoscopic R adrenalectomy
• Peri-operative IV hydrocortisone considered, but not given
• Pathology revealed 2.5 cm adrenal cortical adenoma
• Post-op AM cortisol 4 mcg/dL, ACTH<10 pg/mL (asymptomatic)
• 1 week post-op, morning cortisol = 17 µg/dL
Suggested Diagnostic Algorithm for Incidentally Discovered Adrenal Mass

Adrenal Mass
Clinical Phenotype
(+) Biochemical Phenotype (-/+)

Confirm Overt Hormone
Excess with Clinical
Radiographic Phenotype
Syndrome
Radiographic Phenotype Suspicious Benign Appearing

>4-6cm, >10 HU, contrast avid, <10HU, <4cm, non-contrast avid,
and Localization heterogeneous homogeneous
Surveillance Considerations:
Consider surgery If initially “nonfunctional”:
((Consider alternative imaging: • No strong evidence for repeated biochemical
CT with washout, MRI)) testing
• Repeat biochemical testing if worsening
If Unilateral: Consider surgery comorbidities (HTN, DM, low BMD)
?Metastases or infection: Biopsy If autonomous cortisol secretion without
•Growth>0.5cm/year or +20%
•Suspicious radiographic features clinical syndrome:
Unsure? =>Surveillance: repeat • Individualized consideration for surgery
•New or worsening hormonal excess imaging in 3-6 months based on comorbidities and other factors.
• Repeat biochemical testing annually
•No firm evidence for radiographic
surveillance
3159
Adrenal Tumors with Autonomous Cortisol Secretion
&
Risk for CVD, Diabetes, Skeletal Disease
Comorbidities associated with adrenal tumors with

autonomous and “subclinical” cortisol secretion
Comorbidities
Hypertension
Glucose intolerance/type 2 diabetes
Obesity
Dyslipidemia
Osteoporosis/Vertebral Fracture
Fassnacht et al. EJE 2016
3160
Autonomous Cortisol Secretion
Stable “nonfunctional”
DST≤1.8 mcg/dL
Proportion with Cardiovascular Mortality (%)

Proportion with Cardiovascular Disease (%)
Worsening Stable,
≤1.8 => 1.8-5.0 but Any Autonomous Cortisol
or DST 1.8-5.0 mcg/dL
1.8-5.0 => >5.0 DST >5.0 mcg/dL
Stable,
Worsening
but Any Autonomous Cortisol
DST 1.8-5.0 mcg/dL
≤1.8 => 1.8-5.0
DST >5.0 mcg/dL or
1.8-5.0 => >5.0
Stable “nonfunctional”
DST≤1.8 mcg/dL
Di Dalmazi et al. Lancet Diabetes & Endo 2014
Most deaths due to cardiovascular or infectious causes
DeBono et al. JCEM 2014

Morelli et al. JCEM 2015
3161
• Participants with adrenal incidentalomas who developed incident subclinical

vertebral fractures detected on BMD and higher 1mg DST (2.7 vs 2.0 mcg/dL).
• Autnomous cortisol secretion associated with ~10-fold higher risk of incident (~3y
follow-up) vertebral fracture.
DeBone et al. JCEM 2014

Morelli et al. JCEM 2015
50
Adjusted HR: 2.36 (1.45, 3.84)
45 Absolute Risk: 15.6 % (6.9, 24.3)
Composite Diabetes (%)
Adrenal Tumor with

40
Subclinical Hypercortisolism
35 32.0% (1mg DST 1.9-5.0 mcg/dL)
Incident
30 27.3%
“Non-Functional”
25
Adrenal Tumor
20 (1mg DST ≤ 1.8 mcg/dL)
15 11.7%
No Adrenal Tumor
10
0
0 5 10 15 20
Years of Follow-Up
3162
Lopez et al. Ann Int Med 2016
Continuum of Cardiometabolic Risk
Adrenal Tumor
With Overt
Cushing Syndrome
Adrenal tumor
with Autonomous Cortisol
Secretion but no Cushing
syndrome
“Nonfunctional”
adrenal tumor
Morphologically Normal
with no hormone excess
Prevalence of Condition
Should Intervention be Performed?
HTN
Improved
SBP
DM
Improved FBG
Bancos et al. EJE 2016
3163
Case 3
• 42yoF healthy woman

• New HTN 130-140/80
Clinical
• Spontaneous headache => BP 200/100 Phenotype
• Over several months treated with:
– Lisinopril+amlodipine+labetolol: BP still
140/90
• Hypokalemia (2.3 mmol/L) on more than
one occasion Concerning for excess
aldosterone
No clinical signs of
hypercortisolism
Hyperaldosteronism: who to screen?
• Severe or Resistant Hypertension

– BP>150/100 mmHg x3; or >140/90 mmHg on 3 medications; or <140/90 mmHg on 4+
medications
• HTN + spontaneous or diuretic-induced hypokalemia
• HTN + adrenal mass
• HTN + sleep apnea
• HTN and family member with PA
• HTN + Family history of early-onset HTN or cerebrovascular

accident (<40yrs)
Funder et al. JCEM 2016
3164

Diagnostic Testing for Adrenal Aldosterone Excess:
Goal Test Method Desired Value

Screening Aldosterone-to-Renin Peripheral blood • suppressed
Ratio (ARR) Plasma renin
activity (PRA)
• ARR>20-25
Confirmation Salt Suppression Test Oral salt x4-5 days Non-suppressible
to achieve 24h aldosterone
UNa>200mmol/24h
IV saline
Localization CT imaging CT: surgical CT: N/A
planning
AVS AVS: lateralization
AVS: lateralization or non-
of hormone function lateralization
Biochemical
• Aldosterone 22 ng/dL (on anti-HTNives) Phenotype
• PRA <0.6 ng/mL/h
• ARR >>>40
Highly suggestive of
Primary Aldosteronism
3165
Oral Salt Suppression Test:

Biochemical
Phenotype
• 24h Urine Na: 378mmol/24h
• 24h Urine Aldosterone: 25.5 mcg/24h
Primary
Aldosteronism
3166
Suggested Diagnostic Algorithm

Adrenal Mass
1. Clinical Phenotype
2. Biochemical Phenotype
(+)
Confirm Aldosterone
Excess
3. Radiographic Phenotype Bilateral Medical therapy

and Localization Disease with MRA
•Improve BP and reduce

Unilateral Disease Surgery anti-HTN medications
•Lower CVD risk
Case 3 Outcome
• Laparoscopic L adrenalectomy
• Pathology revealed 2.4 cm adrenal cortical adenoma
• Post-op, BP 105/60 mmHg on lisinopril 10mg daily; no

hypokalemia
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• Primary Aldosteronism
• Benign L adrenal cortical adenoma (Conn’s
tumor)
Case 4
• 28yo healthy, athletic, woman

• Runs 4-6 miles a day Clinical
• Excessive sweating Phenotype
• Anxiety
• BP 140/90mmHg (new)
• No palpitations, chest pain, tremors, etc Concerning for

pheochromocytoma?
3168
Who should you evaluate for Pheo-PGL?

1. Paroxysmal constellation of symptoms/signs, or episodic “spells”, strongly
suggestive of catecholamine excess
• palpitations, sweating, anxiety/panic, elevations in blood pressure,
headache/visual symptoms, pallor
2. Provocation/precipitation of symptoms by culprit medications

• dopamine antagonists, beta-blockers, sympathomimetics, opioids,
NERI/SSRI, MAO inhibitors, glucocorticoids
3. Incidentally discovered adrenal mass (>10 HU on CT)
4. Known or suspected hereditary predisposition for syndromic Pheo-PGL
5. Known history of prior Pheo-PGL
Lenders et al. JCEM 2014
Desired Value in true

Test catecholamine- Comment
producing tumors
Plasma fractionated
metanephrines Excellent Screening tests
(metanephrine, normetanephrine) >2-4x ULRR in (LC-MS/MS)
clinically apparent
24h urinary fractionated functional tumor Sensitivity: 95-100%,
metanephrines (and creatinine) Specificity: ~85-90%
~10-15% of individuals who do not

have a catecholamine-producing
tumor will have “positive” biochemistry
~100% negative predictive value
Lenders et al. JCEM 2014
3169
Biochemical
• Plasma metanephrines: 20 (<62)
• Plasma normetanephrines 615 (<145) Phenotype
• 24h urine NE: 1508 (<135)

• 24h urine Normetanephrines 3156 (<1050)
• 24h urine Epi: 2 (<20)
• 24h urine metanephrines: 151 (<460)
Pheochromocytoma
RIGHT
2 cm mass
35 HU
T2 hyperintense
on MRI
3170
Suggested Diagnostic Algorithm for Suspected or Known Adrenal Mass

Adrenal Mass
Clinical Phenotype

Syndrome

surveillance
AACE guidelines 2009, Young NEJM 2007, Vaidya. Scientific American Medicine 2015
Case 4 Outcome
• Alpha-blocked and hydrated in preparation for surgery

• Laparoscopic R adrenalectomy
• Pathology revealed pheochromocytoma
• Post-op: sweats, anxiety, hypertension all resolved
3171
Case 5
• 37yo healthy woman had an abdominal CT for RLQ
pain
• No cause of pain found
• Incidental RIGHT 2.8cm Adrenal mass (<10HU), LEFT

~3cm adrenal mass (18HU)
• Was told that these are likely benign “adenomas” and

to follow up in 1 year.
3172
R: 2.8 cm, <10 HU L: 3.0 cm, 18 HU
Suggested Diagnostic Algorithm for Suspected or Known Adrenal Mass

Adrenal Mass
Clinical Phenotype

Syndrome

surveillance
AACE guidelines 2009, Young NEJM 2007, Vaidya. Scientific American Medicine 2015
3173
Case 5
• She returned 1.5 years later
• Has new hirsutism on face and upper chest
• Repeat imaging was performed
R: Unchanged L: 4.3 cm, 30 HU

2.8 cm, <10 HU Larger
Heterogeneous
Nodular
Fat stranding
3174
Case 5
• Underwent a radical L adrenalectomy
• Pathology revealed a high grade stage I

Adrenocortical carcinoma…
Case 5 – Clincial Diagnosis

• STAGE I, HIGH GRADE, ADRENOCORTICAL CARCINOMA
• Adrenal carcinomas are rare, highly aggressive, fast growing, and can
produce multiple adrenal hormones
• Only known cure is early recognition and radical surgery
• 50-70% are metastatic at time of presentation
• Median survival < 12 months from time of diagnosis; can be prolonged

with cytoreduction (surgery/IR)or adjuvant mitotane/EDP therapy
• Morbidity and mortality associated with rapid tumor growth and spread,
but also uncontrolled hormone excess states (i.e. Cushing’s syndrome,
mineralocorticoid excess).
3175
Take Home Points

• The adrenal glands synthesize and secrete hormones that play a vital
role in hemodynamic homestasis. Understanding the physiology of
adrenal hormone feedback and the relative interpretations of adrenal
testing is crucial for accurate assessments.
• Carefully timed cortisol and ACTH measurements can help decipher

whether the HPA axis is functioning appropriately
• The prevalence of adrenal masses increases with age, and their

incidental discovery has increased.
• All adrenal masses should be carefully evaluated for malignant potential

and hormone hyperfunction
• Consider involving endocrine/adrenal colleagues at any time in the

evaluation
Supplemental References
TUTORIAL VIDEOS:
ADRENAL PHYSIOLOGY: https://www.youtube.com/watch?v=bM6rhEuOtBM
ADRENAL INSUFFICIENCY: https://www.youtube.com/watch?v=SgckxKvccKo
PRIMARY ALDOSTERONISM: https://www.youtube.com/watch?v=db9v9kNIiXU
PHEOCHROMOCYTOMA: https://www.youtube.com/watch?v=0tZ8kJ6dN3A
Fassnacht et al. Management of adrenal incidentalomas: European guidelines.
European Journal of Endocrinology 2016
Young WF, Jr. Clinical practice. The incidentally discovered adrenal mass.
New England Journal of Medicine 2007;356:601-10.
Vaidya A, Hamrahian AH, Auchus RJ. Genetics of Primary Aldosteronism. Endocrine Practice 2015; 21(4): 400-5.
Funder JW, et al. Case Detection, Diagnosis, and Treatment of Patients with Primary Aldosteronism: An Endocrine Society
Clinical Practice Guideline.
Journal of Clinical Endocrinology and Metabolism 2016
Lenders JWM, Duh QY, Eisenhofer G, et al. Pheochromocytoma and Paraganglioma: An Endocrine Society Clinical Practice
Guideline.
Journal of Clinical Endocrinology and Metabolism 2014; 99: 1915-1942
Bornstein et al. Diagnosis and Treatment of Primary Adrenal Insufficiency: An Endocrine Society Clinical Practice Guideline.
Journal of Clinical Endocrinology and Metabolism 2015
3176
ADRENAL DISORDERS
Anand Vaidya, MD MMSc
Director, Center for Adrenal Disorders
Division of Endocrinology, Diabetes, & Hypertension
3177
Pituitary Disorders
Ursula B. Kaiser, M.D.

Chief, Division of Endocrinology, Diabetes,
and Hypertension
Disclosures
BMS, Ferring – research grant funding

NovoNordisk – scientific advisory board
Chiasma – clinical trial investigator
3178
Learning Objectives
Lecture is a general neuroendocrine review.

Goal is to discuss:
Neuroendocrine physiology
Diagnostic approach and management of
pituitary disorders
Outline
I. Pituitary Physiology
II. Causes of Pituitary Disease
III. Approach to Evaluation and Management of
Pituitary Disease
A. Pituitary Hormone Excess
B. Pituitary Hormone Deficiency
C. Mass Effects
3179
Pituitary Gland
Anterior Pituitary Posterior Pituitary
Adenohypophysis Neurohypophysis
80% of the gland 20% of the gland
Derived from Rathke’s pouch Direct extension of the
(oral ectoderm) hypothalamus
Comprised of 5 cell types Axon terminals from SON and
Secretes 6 hormones PVN of hypothalamic neurons
Controlled by neuropeptides Hormone produced in
from the hypothalamus & hypothalamus, stored in
feedback from target organs pituitary
Pituitary Physiology
Anterior Pituitary Posterior Pituitary
Hypothalamic Hypothalamus
Releasing/Inhibiting
Supraoptic nucleus
Neuropeptide
Paraventricular nucleus
Axons
Anterior Pituitary
Hormone
Posterior Pituitary
Target
Organ
AVP Oxytocin
3180
Approach to Pituitary Disorders
Evaluate:
Pituitary hyperfunction
Baseline and “Suppression tests”
Pituitary hypofunction
Baseline and “Stimulation tests”
Mass effects
Approach to Pituitary Disorders
Posterior Pituitary
Overproduction of AVP
• Syndrome of Inappropriate Antidiuretic
Hormone Secretion (SIADH)
Underproduction of AVP
• Diabetes Insipidus (DI)
- Central (pituitary)
- Nephrogenic
- Primary polydipsia
3181
Clinical Case 1
39 year old female presented for pituitary

evaluation of headaches
MRI scan revealed 2x3.2 cm sellar mass,
extending suprasellarly to the optic
chiasm and into the L cavernous sinus.
Normal Adenoma Normal Adenoma
Differential Diagnosis of Sellar/Parasellar Lesions
Benign Tumors Granulomatous, Infectious, and

Pituitary adenoma (carcinoma) Inflammatory
Meningioma Lymphocytic hypophysitis
Cell Rest Tumors Abscess
Craniopharyngioma Sarcoidosis
Rathke’s cleft cyst Tuberculosis
Epidermoid Eosinophilic granulomatosis
Chordoma Mycoses
Lipoma Metastatic Tumors
Colloid cyst Vascular Lesions
Primitive Germ Cell Tumors Hematologic Malignancies
Germinoma Miscellaneous
Teratoma Empty sella syndrome
Dysgerminoma Arachnoid cyst
Oligodendroglioma
Ependymoma
Astrocytoma
3182
Pituitary Adenomas: Epidemiology
Pituitary adenomas are the 3rd most common brain tumor.

They account for 10-15% of all intracranial tumors.
MRI studies 14.4%
Autopsy series 12-22.5%
They are classified according to size.

Microadenomas < 10mm
Macroadenomas > 10 mm
Ezzat Cancer 101: 613, 2004

Daly JCEM 91: 4769, 2006
Pituitary Tumorigenesis
Lactotrope Gonadotrope Somatotrope Corticotrope Thyrotrope
Daly et al. JCEM 91:4769, 2006
3183
Patient Evaluation
History:
Questions regarding endocrine hypo- or hyper-function.
Think of anterior & posterior pituitary.
Hyperfunction: Hypofunction:
Cushings syndrome Adrenal insufficiency
Hyperthyroidism Hypothyroidism
GH excess GH deficiency
Prolactin excess Hypogonadism
Neurological symptoms: headache, visual disturbance.
Standard Pituitary Laboratory Tests
Thyroid
TSH, free T4
Reproductive
Prolactin
FSH, LH, testosterone (men) or estradiol (women)
GH
Critical to assess prolactin prior
IGF-I
proceeding to surgery
Adrenal Extra tests required if GH or ACTH
Cortisol excess is suspected
3184
Clinical Case 2-1
24 yr old woman G2P2, menses never

resumed after d/c OCP’s. ROS: HA’s, no
visual or other neuro c/o. + fatigue,
depression, and cold intolerance. Can’t
seem to lose weight she gained with last
pregnancy. + galactorrhea x 6 mos.
Meds: none.
What should you look for on exam?
PE: normal. What is the differential diagnosis?
Clinical Case 2-2
Labs What is the single most

E2 11; LH 6; FSH 5 important test to order
to exclude a physiologic
IGF-1 nl 183, GH 1.0 cause of elevated
α-subunit 0.8 (nl) prolactin?
cortisol 8.2 Hematocrit
Ferritin
FT4 1.0, TSH 1.5 Pregnancy test
Prolactin 283 Chest Xray
3185
Clinical Case 2-3
Labs What is the single most

E2 11; LH 6; FSH 5 important test to order
to exclude a physiologic
IGF-1 nl 183, GH 1.0 cause of elevated
α-subunit 0.8 (nl) prolactin?
cortisol 8.2 Hematocrit
Ferritin
FT4 1.0, TSH 1.5 Pregnancy test
Prolactin 283 Chest Xray
HCG negative
Clinical Case 2-4
Labs How do you interpret

E2 11; LH 6; FSH 5 the lab values?
IGF-1 nl 183, GH 1.0 What is the next step?
α-subunit 0.8 (nl)
cortisol 8.2
FT4 1.0, TSH 1.5 What are the treatment
Prolactin 283 options?
HCG negative
3186
Clinical Presentation of
Hyperprolactinemia
Galactorrhea **
Hypogonadism **
Oligo/amenorrhea
Infertility
Erectile dysfunction
Growth arrest / delayed puberty
Mass effects if tumor is large
DDx: Hyperprolactinemia
Physiologic states:
Suckling
Pregnancy, Lactation, Exercise, Stress, Sleep TRH DA
Medications E2
Lactotrope
Primary hypothyroidism
Systemic disorders: Prolactin
Neurogenic chest wall lesion, renal failure, cirrhosis,
seizures
Hypothalamic-pituitary stalk damage Breast
Radiation, infiltrations, cysts, tumors, trauma
Prolactinoma
Idiopathic
Macroprolactinemia
3187
Medications and Hyperprolactinemia

More Common Less Common
DA receptor blockers Antihypertensives
Phenothiazines, haloperidol, Methyldopa, reserpine,
resperidone, olanzepine verapamil
Domperidone, metoclopromide
Antidepressants
DA synthesis inhibitors Tricyclics, SSRIs (minimal)
Methyldopa
Opiates
Estrogens
Antihistamines
Cimetidine
Prolactinomas
Account for 30-40% of pituitary tumors

More common in women (3 fold higher) than men
Premenopausal women usually present earlier with clinical
symptoms and microadenomas.
Postmenopausal women and men usually present later with
macroadenomas
3188
Prolactinomas: Treatment Options
General Treatment Options:

Medical therapy with DA agonists
– Cabergoline (preferred), bromocriptine
Transsphenoidal resection
– Second line therapy in most cases
Radiation
– Generally reserved for resistant or aggressive tumors
Melmed et al. JCEM. 96: 273-288, 2011
Clinical Case 3-1
57 yr old male with multiple medical problems

who recently presented to PCP with SOB,
CP. Found to have new onset CHF, hypoxia
– LVEF 25%, cardiac cath normal.
PMH: Rheumatoid arthritis, gout, nephrolithiasis, colon polyps,

carpal tunnel syndrome, COPD.
Meds: Captopril, allopurinol, ASA, prednisone 5mg/d,

methotrexate.
3189
Clinical Case 3-2

PE: 126/88 P82.
HEENT: PERRLA, EOMI, VF full to confrontation, Fundoscopic exam
normal. Large tongue. Upper/lower dentures.
Neck: moderate symmetrical thyromegaly, no nodules palpated.
Lungs: bibasilar rales. RRR +S3
Abd: obese, o/w normal.
Ext: Large doughy hands. Shoe size 13, wide. No active joint inflammation.
Multiple skin tags.
What diagnosis are you considering?

What lab tests would you like?
Clinical Features of Acromegaly

Soft tissue hypertrophy
Arthritis / carpal tunnel
syndrome
Increased head, hand, foot
size.
Organomegaly
– Cardiomegaly with CHF
Metabolic Disturbances
– Diabetes mellitus
Obstructive sleep apnea
Dental malocclusion
Colon polyps/cancer
Increased mortality
3190
Clinical Case 3-3

Labs:
GH 2.4; IGF-1 985 (high)
FT4 = 0.7 (normal 0.7-2.7), TSH 0.4
FSH 11, LH 7.4, testosterone 234 (low normal)
Prolactin 7 (normal)
What diagnosis are you considering now?

Would you order any radiologic tests at this time?
Clinical Case 3-4
What test can be used to confirm GH

hypersecretion?
A. Midnight salivary GH
B. Oral glucose tolerance test for GH
suppression
C. Urinary IGF-1
D. Serum IGFBP-3
3191
Clinical Case 3-4
What test can be used to confirm GH

hypersecretion?
A. Midnight salivary GH
B. Oral glucose tolerance test for GH
suppression
C. Urinary IGF-1
D. Serum IGFBP-3
Acromegaly: Treatment
Surgery
Medical Therapy
Somatostatin analogs
– Octreotide LAR
– Lanreotide
– Pasireotide
Cabergoline
Pegvisomant
Radiation Goal is “biochemical cure”:

Normal IGF-I
Conventional
Normal GH suppression
Radiosurgery
3192
Clinical Case 4-1

50 yr old woman referred to PE: 176/90 P72
evaluate weight gain. Moon face, dorsocervical
Reports rapid 50lb wt gain. and supraclavicular fat pads
No HA, visual, neuro Thyroid 30g pebbly
complaints.
CTA B, RRR
“Dr. you must do something
about this weight!!!” Central obesity
PMH: hypothyroidism, HTN, Abd: +purple striae
“borderline DM.” 1+ edema
FMH: obesity, thyroid Neuro: normal
disease
Meds: L-T4, lisinopril, ASA What would you recommend?
Clinical Features of Cushing’s

Syndrome
Central obesity
Skin changes
Hirsutism
Menstrual irregularities
Hypertension, CAD
Muscle weakness
Clinical
Osteoporosis
presentation
can vary Mood disturbances
dramatically
3193
Clinical Case 4-2

You are concerned about Cushing’s syndrome in
this patient. What is the best first step in
evaluating this patient?
A. Screen for hypercortisolism
B. Obtain a pituitary MRI
C. Obtain a CT scan of the adrenal glands
D. Perform inferior petrosal sinus sampling to
determine if the source of excess cortisol is an
ACTH producing pituitary adenoma
Clinical Case 4-2

You are concerned about Cushing’s syndrome in
this patient. What is the best first step in
evaluating this patient?
A. Screen for hypercortisolism
B. Obtain a pituitary MRI
C. Obtain a CT scan of the adrenal glands
D. Perform inferior petrosal sinus sampling to
determine if the source of excess cortisol is an
ACTH producing pituitary adenoma
3194
Obesity and Cushing’s Syndrome
Many signs/symptoms/co-morbidities overlap and are

common in the general population:
Obesity / weight gain
Hypertension
DM
Sleep apnea / sleep disorders
Depression / “stress”
This is a rare disease.

The challenge is deciding who to screen for CS.
Screening for Cushing’s Syndrome

Endocrine Society Clinical Guidelines
Patients with “unusual” features for age
Osteoporosis, hypertension, etc
Patients with multiple and progressive clinical

features of Cushing’s syndrome
Children with decreasing height percentile and
increasing weight
Patients with adrenal incidentalomas
Nieman L et al. JCEM 93(5): 1526-40. 2008.
3195
Cushing’s Syndrome
Step 1: Document syndrome of hypercortisolism
Screening tests for hypercortisolism include:
– 24 hour urine free cortisol (x2)
– Late night salivary cortisol levels (x2)
– 1 mg overnight dexamethasone test
Step 2: Determine whether it is ACTH dependent or

independent.
Step 3: Localize tumor and remove.
Thyrotropinomas
Very rare! (approx. 0.5-1% of pituitary adenomas)
Clinical presentation:
Hyperthyroidism, goiter
– Patients often treated previously with thyroidectomy / I131
70% present with macroadenomas
Diagnosis:
– elevated T4, T3
– Inappropriately NORMAL or elevated TSH *******
– elevated α-subunit, molar ratio α-subunit/TSH>1
Treatment:
– Surgery (treatment of choice), somatostatin analogs
3196
“Nonfunctioning” Adenomas
Appear clinically inactive.
Often secrete α−subunit, FSHβ or LHβ subunit or intact
gonadotropins.
One third of all pituitary tumors.
Often present with mass effect symptoms only and

no evidence of hormonal overactivity.
Some patients with large tumors present with

panhypopituitarism.
Treatment of choice is surgery
Pituitary Adenomas:
Therapeutic Considerations
Treat symptoms related to mass effects.

Restore or preserve vision
Neurologic improvements – cranial nerves, headaches
Correct pituitary hyperfunction.

Aim for biochemical cure
Medical hormone replacement for hypopituitarism.
3197
Perioperative Management
Preoperative Evaluation: Long Term Management
Assess pituitary function Patients typically evaluated
Replace as needed 1, 6, 12 weeks post-
Thyroid & cortisol most important operatively.
Stress-dose glucocorticoids if MRI typically repeated at 12
necessary
week visit to serve as new
baseline.
Early Inpatient Management: Follow-up annually or as
dictated by clinic status.
Assess for complications:
Hormone assessment
Neurologic status
MRI
Endocrine
Diabetes insipidus Long term assessment of
SIADH hormone status and tumor
Adrenal insufficiency recurrence required
Woodmansee WW et al. AACE Clinical Review Endoc Prac. 21:832-838. 2015.
Hypopituitarism
Management
Treatment based on correcting hormone deficiencies.
Adrenal - hydrocortisone or prednisone. Use lowest dose possible.
– Stress dose coverage
– Mineralocorticoid replacement not necessary.
Thyroid – levothyroxine, after adrenal replacement
– ** remember TSH cannot guide Rx.
Gonadal - Men require testosterone, women may require estrogen-
progestin replacement. Gonadotropins for fertility.
Growth hormone – Need provocative testing. Can treat with rhGH.
Prolactin - no replacement available or required.
Posterior pituitary – desmopressin (DDAVP).
Medical Alert Jewelry
3198
Pituitary Disease Summary

“Take Home” Messages:
When evaluating patients with pituitary disorders, let pituitary
physiology be your guide. Evaluate:
Pituitary hyperfunction
– GH (acromegaly)
– ACTH (Cushing’s disease – hypercortisolism)
– Prolactin (galactorrhea, menstrual disorders, erectile dysfunction)
– TSH (hyperthyroidism)
Pituitary hypofunction – all hormone systems
Mass effects (headache, visual dysfunction)
Treatment is aimed at restoring normal pituitary function and can

include: surgery, hormone replacement, medications
Thank You
3199
General References/
Additional Reading
Prolactinomas/ hyperprolactinemia
Melmed S et al. Diagnosis & Treatment of Hyperprolactinemia: An Endocrine Society Clinical
Practice Guideline. J Clin Endocrinol Metab 2011. 96: 273-288.
Klibanski, A. Prolactinomas. N Engl J Med 2010. 362:1219-26.
Acromegaly
Katznelson L. et al. Acromegaly: An Endocrine Society Clinical Practice Guideline. J Clin Endocrinol
Metab 2014. 99: 3933-3951.
Cushing’s Syndrome
Nieman LK et al. The Diagnosis of Cushing’s Syndrome: An Endocrine Society Clinical Practice
Guideline. J Clin Endocrinol Metab 2008. 93: 1526–1540.
Nieman LK et al. Treatment of Cushing’s Syndrome: An Endocrine Society Clinical Practice
Guideline. J Clin Endocrinol Metab 2015. 100: 2807-2831.
Hypopituitarism
Fleseriu M et al. Hormonal Replacement in Hypopituitarism in Adults An Endocrine Society Clinical
Practice Guideline. J Clin Endocrinol Metab 2016. 101: 3888-3921.
Peri-operative Management
Woodmansee WW et al. AACE/ACE Disease State Clinical Review: Postoperative Management
Following Pituitary Surgery. Endocrine Practice. 2015. 21: 832-838.
3200
Take-Home Messages and Clinical

Pearls
Carolyn Becker MD
Master Clinician Educator
Division of Endocrinology, Diabetes and
Hypertension
Disclosures
• Royalties from UpToDate for 2 chapters
on Premenopausal Osteoporosis
($1800/yr)
3201
Topics to be Reviewed
Diabetes/Obesity
Thyroid
Adrenal
Pituitary
Hypoglycemia
Case 1
• A 54 year old man presents to you for follow up
of T2DM, HTN, hyperlipidemia, and obesity (BMI
44 kg/m2).
• Six months ago, you added sitagliptin to
metformin and glipizide for HgbA1C of 8.2%.
• A1C improved to 7.6% but he wants help with
weight loss. He refuses to consider bariatric
surgery.
• In addition to prescribing a diet and exercise
program, you plan to switch from sitagliptin
to liraglutide 3.0 mg daily to help him lose
weight.
3202
Current Medications
• Metformin 1000 mg twice daily with meals
• Glipizide 5 mg twice daily with meals
• Sitagliptin 100 mg once daily to be
stopped and switched to liraglutide 3.0 mg
daily
• Lisinopril 20 mg daily
• Atorvastatin 40 mg daily
If You Make No Other Medication Changes

After Switching to Liraglutide, What is the
Patient At Greatest Risk For?
A. Rhabdomyolysis
B. Hypotension
C. Hypoglycemia
D. Hypertriglyceridemia
E. Hyperkalemia
3203
If You Make No Other Medication Changes

After Switching to Liraglutide, What is the
Patient At Greatest Risk For?
A. Rhabdomyolysis
B. Hypotension
C. Hypoglycemia
D. Hypertriglyceridemia
E. Hyperkalemia
Davies MJ. 2015 JAMA 314:687

Pi-Sunyer X. 2015 NEJM 371:11
Proper Use of GLP-1 Agonists

• GLP-1 agonists (eg. liraglutide) are used at a dose of 1.8
mg daily to improve glycemic control in patients with
T2DM.
• At a dose of 3.0 mg daily, liraglutide also is approved for
weight loss and can be an adjunct to diet and exercise
• However, in patients with T2DM on other glucose-
lowering medications there is a significantly higher risk of
hypoglycemia when liraglutide 3.0 mg is added.
• Hypoglycemic risk was ~25% for either metformin or
pioglitazone and ~43% with a sulfonylurea + liraglutide
3.0 mg daily
• Take home message: reduce sulfonylurea by 50% (or
stop completely) when starting high dose liraglutide
to help in weight loss in patients with T2DM
3204
Case 2
• A 28 year old woman comes to you for help in
losing weight.
• She gained 20 lbs after college due to a more
sedentary lifestyle and increased caloric intake
• She gained another 30 lbs in the past year
despite trying to cut back on food and increase
exercise. Her only medication is paroxetine for
depression.
• She started paroxetine 18 months ago
After Stopping Paroxetine, Which of the

Following Would You Begin for her
Depression?
A. Amitriptyline
B. Mirtazapine
C. Venlafaxine
D. Fluoxetine
E. Sertraline
3205
After Stopping Paroxetine, Which of the

Following Would You Begin for her
Depression?
A. Amitriptyline
B. Mirtazapine
C. Venlafaxine
D. Fluoxetine
E. Sertraline
Obesity and Anti-Depressants

• The SSRI paroxetine (Paxil) is associated with
the greatest weight gain in this list
• Of the tricyclics, amitriptyline (Elavil) promotes
the greatest weight gain.
• Mirtazapine (Remeron), venlafaxine (Effexor),
and duloxetine (Cymbalta) can all promote
weight gain though milder
• Sertraline (Zoloft), citalopram (Celexa), and
escitalopram (Lexapro) are weight neutral
• Fluoxetine (Prozac) and buproprion (Wellbutrin)
promote weight loss
3206
When Lifestyle Fails:

Weight Loss Medications for Obesity
• Phentermine (Adipex)
• Phentermine/topiramate (Qysmia)
• Orlistat (Xenical)
• Lorcaserin (Belviq)
• Naltrexone/bupropion (Contrave)
• Liraglutide (Saxenda)
Thyroid Case
• A 30 year old woman presents with mild fatigue,
5-lb weight gain, and occasional constipation
• She is 2 months postpartum and plans to breast-
feed for 1 year
• Her only medication is a prenatal MVI
• FH is positive for hypothyroidism in her mother
• On exam, she appears well, though tired
– Wt 130 lbs (60 kg), BMI 22, pulse 70 and regular
– Thyroid gland: normal in size and consistency
• Labs: TSH 30 mU/L (nl 0.5 – 5.0), free T4 1.2
(nl 0.8 – 1.5)
3207
What Would You Do Next?
A. Order a radioiodine scan and uptake

B. Begin levothyroxine 50 mcg daily
C. Begin levothyroxine 100 mcg daily
D. Ask her to return for a repeat TSH in 1
month
E. Check anti-thyroid antibodies
What Would You Do Next?
A. Order a radioiodine scan and uptake

B. Begin levothyroxine 50 mcg daily
C. Begin levothyroxine 100 mcg daily
D. Ask her to return for a repeat TSH in 1
month
E. Check anti-thyroid antibodies
3208
Postpartum Thyroiditis
A.RAI scan and uptake is indicated for evaluation
of thyrotoxicosis, not hypothyroidism, and is
contraindicated during lactation
B. and C. In a symptomatic hypothyroid patient,

levothyroxine 100 mcg/d (or 0.8 mcg/lb) would
be a good starting dose. Given her normal free
T4, a lower starting dose such as 50 mcg/d
might be considered.
Postpartum Thyroiditis
D. In the postpartum setting with minimal
symptoms, no goiter, and normal free T4, the
most likely diagnosis is postpartum thyroiditis
which will resolve 50% of the time without rx.
Monitoring TSH in this case is reasonable.
E. Positive anti-thyroid antibodies can be present

in both postpartum thyroiditis and Hashimoto’s
so will not help distinguish between the 2
possibilities.
3209
Case 3
• A 60 year old Caucasian woman admitted
with acute abdominal pain and sepsis is
found to have a ruptured appendix.
• She is treated with antibiotics and
emergency appendectomy via
laparotomy and does well intraoperatively.
• Over the next 48 hours, she experiences
nausea, vomiting and hypotension
requiring intravenous saline and pressors.
Case (cont)
• Her PMH is positive for arthritis of both
knees and spinal stenosis. She denies any
history of oral prednisone use.
• ROS: She noted some fatigue and mild
decreased appetite over the past 2 months
months.
• PE: she has generalized obesity with mild
facial plethora
3210
Case (cont)
• Labs as outpatient prior to surgery: Normal
complete metabolic panel, TSH, free T4
and FSH 55 (c/w menopause)
• Now: serum Na+ 130, K+ 3.8, serum
cortisol 1.8 mcg/dL, ACTH < 10 pg/mL.
• After 250 mcg of cosyntropin IV, her
serum cortisol rises from 2.0 to 3.5 mcg/dL
at 60 minutes.
Which Diagnosis is Most Likely to Explain

Her Adrenal Insufficiency?
A. Bilateral adrenal hemorrhage
B. Perioperative opiate exposure
C. Acute pituitary infarction
D. Exogenous glucocorticoids
E. Addison’s disease
3211
Which Diagnosis is Most Likely to Explain

Her Adrenal Insufficiency?
A. Bilateral adrenal hemorrhage
B. Perioperative opiate exposure
C. Acute pituitary infarction
D. Exogenous glucocorticoids
E. Addison’s disease
Exogenous Glucocorticoids
• This patient had received multiple injections of
methylprednisolone into her spine and several
joints over the past 15 months.
• When asked about taking “prednisone”, she did
not associate this with her steroid injections.
• Following her last injection 4 months ago, she
had mild symptoms of steroid withdrawal but
compensated until her acute sepsis, surgery and
anesthesia when she decompensated.
3212
Exogenous Glucocorticoids
• Her labs are consistent with chronic secondary
adrenal insufficiency.
• Opiates can transiently suppress the HPA axis
but cortisol post-cosyntropin should have
stimulated normally.
• ACTH would be HIGH in both adrenal
hemorrhage and Addison’s as these cause
primary adrenal insufficiency
• Acute pituitary infarction should have impacted
the other anterior pituitary hormones and
cosyntropin stimulation would be normal.
H CRH
Labs:
P • low basal cortisol
• inappropriately low ACTH
• ± hyponatremia
ACTH
• Normal K and aldosterone regulation
Physical:
Cortisol
• completely normal Glucocorticoid
Adrenal • mild, progressive, fatigue at baseline Receptor
• severe fatigue, orthostasis, Mineralocorticoid
Receptor
hypotension, in situations of stress
Target
Organ
Cell
3213
H CRH
• NORMAL
P EXAMPLE:
60 mins following
Morning
250 µg cosyntropin
ACTH Cosyntropin
ACTH (pg/mL) 10
Cortisol
Glucocorticoid
Receptor
Adrenal
Mineralocorticoid
Receptor
Target
Organ
Cell
CHRONIC Secondary Adrenal Insufficiency
With chronic ACTH deficiency, adrenal cortex

H CRH
(ZF) will atrophy, and will progressively
respond less to cosyntoprin stimulation
EXAMPLE:
P 60 mins following
Morning
250 µg cosyntropin
ACTH Cosyntropin
ACTH (pg/mL) 10
Glucocorticoid
Cortisol Receptor
Adrenal
Mineralocorticoid
Receptor
Target
Organ
Cell
3214
Causes of Hyperprolactinemia
I. Physiologic II. Pharmacologic III. Pathophysiologic
Menstrual cycle Dopamine antagonists Primary hypothyroidism
Pregnancy - phenothiazines Chronic renal failure
Nursing - haloperidol Chest wall lesions
Nipple stimulation - risperidone Polycystic ovary syndrome
Stress - metoclopromide Idiopathic
- domperidone Macroprolactinemia
Amitriptyline Hypothal/pituitary lesions
Antihypertensives Prolactinoma
- methyldopa
- reserpine Other medications?
Verapamil Birth control pills?
Cimetidine Check TSH
Estrogens Stalk compression?
Evaluation of the Non-Diabetic Patient

with Low Glucose & Symptoms
Must get labs when the glucose is LOW
Glucose
Insulin
C-peptide
Sulfonylurea (SFU) screen
Others
3215
Proinsulin is Cleaved into Insulin and

C-Peptide and Secreted
Proinsulin
B Chain C-peptide A Chain
Insulin C-peptide
A Chain C-peptide
S S +
B Chain
When Glucose is Low (<50)

• INSULIN HIGH
– C-peptide high
• SFU negative insulinoma
• SFU positive sulfonylurea effect
– C-peptide low surreptitious insulin use
• INSULIN LOW
– Liver, heart, or kidney failure; sepsis, ETOH,
Cortisol or GH deficiency, nonpancreatic
tumors, inborn errors of metabolism,
inanition
3216
Disclosures
• Royalties from UpToDate for 2 chapters
on Premenopausal Osteoporosis
($1800/yr)
THANK YOU!
3217
Endocrine Board Review

Alexander Turchin, MD, MS
Associate Professor of Medicine, Harvard Medical School
Director of Quality in Diabetes, Division of Endocrinology,
Disclosures:
Brio Systems
Eli Lilly
Merck
Monarch Medical Technologies
3218
Case 1
A 68-year-old man is being treated with heparin for
pulmonary embolism. Four days after admission, he has
sudden onset of severe abdominal / flank pain and
tenderness. He is found to be hypotensive. Labs show
hyponatremia and hyperkalemia, and his hematocrit is
35 percent, as compared with 40 percent at the time of
admission.
The most appropriate next step is to:

A. Measure serum aldosterone
B. Measure serum cortisol
C. Measure serum cortisol before and after
administration of corticotropin (ACTH)
D. Measure urinary cortisol excretion
E. Start total fluid restriction at 1,200 cc / 24 hours
Case 1
A 68-year-old man is being treated with heparin for
pulmonary embolism. Four days after admission, he has
sudden onset of severe abdominal / flank pain and
tenderness. He is found to be hypotensive. Labs show
hyponatremia and hyperkalemia, and his hematocrit is
35 percent, as compared with 40 percent at the time of
admission.

A. Measure serum aldosterone
B. Measure serum cortisol
C. Measure serum cortisol before and after
administration of corticotropin (ACTH)
D. Measure urinary cortisol excretion
E. Start total fluid restriction at 1,200 cc / 24 hours
3219
Case 1: Explanation
This patient has acute primary adrenal insufficiency.
ACTH stimulation test (C) is the best way to make this
diagnosis.
A random cortisol measurement without ACTH
stimulation (B) can be difficult to interpret.
Decreased production of aldosterone (A) does not
necessarily indicate decreased production of cortisol,
which is potentially life-threatening.
Urinary cortisol excretion (D) is not a reliable test for
diagnosis of adrenal insufficiency.
Fluid restriction (E) is not indicated in treatment of
hyponatremia caused by adrenal insufficiency and can,
in fact, exacerbate the patient’s condition.
Case 2
A 52-year-old woman is brought to the office after falling and
striking her abdomen on the edge of a chair. She had
abdominal pain soon thereafter, but it has subsided. She is
normotensive. Physical examination is unremarkable except
mild abdominal tenderness. CT of the abdomen reveals a 3-
cm hypodense left adrenal mass with smooth borders. Serum
electrolytes are normal.
A. Measure plasma metanephrines
B. Fine needle aspiration of the mass
C. Measure 8 AM serum cortisol following 1 mg
dexamethasone at midnight
D. Both A and C
E. Repeat abdominal CT in six months
3220
Case 2
A 52-year-old woman is brought to the office after falling and
striking her abdomen on the edge of a chair. She had
abdominal pain soon thereafter, but it has subsided. She is
normotensive. Physical examination is unremarkable except
mild abdominal tenderness. CT of the abdomen reveals a 3-
cm hypodense left adrenal mass with smooth borders. Serum
electrolytes are normal.
A. Measure plasma metanephrines
B. Fine needle aspiration of the mass
C. Measure 8 AM serum cortisol following 1 mg
dexamethasone at midnight
D. Both A and C
E. Repeat abdominal CT in six months
Case 2: Explanation
Subclinical Cushing syndrome and pheochromocytoma
are relatively common in patients with adrenal
incidentalomas and must be ruled out (D).
Fine needle aspiration of an adrenal mass (B) can only
detect a metastatic lesion and is not indicated in a
patient without a known primary malignancy.
A repeat CT (E) to ensure that the nodule is not growing
will be helpful but is not the first priority – ruling out
hormonal overproduction is more urgent.
3221
Case 3
A 24-year-old veterinary student has had symptoms of
hypoglycemia before breakfast for several months.
Laboratory studies early one morning reveal the
following:
Serum glucose 28 mg/dl
Serum insulin 65 µU/ml (normal, 5-15)
Serum C-peptide 0.1 ng/ml (normal, 0.5-3.0)
Serum cortisol 27 µg/dl (normal, 8-25)
The most likely cause of these results is
A. Adrenal insufficiency
B. Non-islet-cell tumor
C. Insulinoma
D. Surreptitious administration of insulin
E. Surreptitious ingestion of glyburide
Case 3
A 24-year-old veterinary student has had symptoms of
hypoglycemia before breakfast for several months.
Laboratory studies early one morning reveal the
following:
Serum glucose 28 mg/dl
Serum insulin 65 µU/ml (normal, 5-15)
Serum C-peptide 0.1 ng/ml (normal, 0.5-3.0)
Serum cortisol 27 µg/dl (normal, 8-25)
The most likely cause of these results is
A. Adrenal insufficiency
B. Non-islet-cell tumor
C. Insulinoma
D. Surreptitious administration of insulin
E. Surreptitious ingestion of glyburide
3222
Case 3: Explanation
Elevated insulin and low C-peptide levels (D) are
consistent with exogenous insulin administration.
Adrenal insufficiency (A) is ruled out by a normal cortisol
level.
Hypoglycemia caused by a non-islet cell tumor (B) is
characterized by low insulin and elevated IGF-2 level.
Both an insulinoma (C) and sulfonylurea overdose (E)
would result in elevated insulin as well as C-peptide
levels.
Case 4
A 32-year-old man comes to see you for work-up of
infertility after he was found to have a low sperm count
and low testosterone. He is significantly taller than both
of his parents. His testicles are small and firm.
What is the best next step in the diagnostic workup:
A. Measure serum follicle stimulating hormone (FSH)

B. Measure serum luteinizing hormone (LH)
C. Order a pituitary MRI
D. Measure serum prolactin level
E. Examine his karyotype
3223
Case 4
A 32-year-old man comes to see you for work-up of
infertility after he was found to have a low sperm count
and low testosterone. He is significantly taller than both
of his parents. His testicles are small and firm.
What is the best next step in the diagnostic workup:
A. Measure serum follicle stimulating hormone (FSH)

B. Measure serum luteinizing hormone (LH)
C. Order a pituitary MRI
D. Measure serum prolactin level
E. Examine his karyotype
Case 4: Explanation
Based on the physical examination, the index of
suspicion is high that the patient has Klinefelter
syndrome (XXY). While this syndrome is characterized
by primary hypogonadism leading to elevation of FSH
(A) and LH (B), neither test is diagnostic. Karyotype (E)
is the best way to make the diagnosis. Prolactin (C) is
not affected in Klinefelter syndrome and there is no
anatomic pituitary pathology that could be visible on the
MRI.
3224
Case 5
A 71-year-old man comes to see you for follow-up. He
complains of gradually progressive burning pain in both feet
that is worse at rest and is relieved with walking; it is
interfering with his sleep. He has had type 2 diabetes for
over 20 years, poorly controlled over most of this time, but
more recently with A1c in upper 6s. His physical examination
reveals intact pulses but absent ankle reflexes in both feet.
Any of the medications below would be appropriate to offer
him except:
A. Oxycodone 5 mg every 6 hours as needed
B. Amitriptyline (Elavil) 25 mg at bedtime
C. Pregabalin (Lyrica) 50 mg every 8 hours
D. Capsaicin cream 3-4 times per day
E. Duloxetine (Cymbalta) 60 mg daily
Case 5
A 71-year-old man comes to see you for follow-up. He
complains of gradually progressive burning pain in both feet
that is worse at rest and is relieved with walking; it is
interfering with his sleep. He has had type 2 diabetes for
over 20 years, poorly controlled over most of this time, but
more recently with A1c in upper 6s. His physical examination
reveals intact pulses but absent ankle reflexes in both feet.
Any of the medications below would be appropriate to offer
him except:
A. Oxycodone 5 mg every 6 hours as needed
B. Amitriptyline (Elavil) 25 mg at bedtime
C. Pregabalin (Lyrica) 50 mg every 8 hours
D. Capsaicin cream 3-4 times per day
E. Duloxetine (Cymbalta) 60 mg daily
3225
Case 5: Explanation
This patient has painful diabetic neuropathy, as
evidenced by the quality of the pain, improvement with
activity and evidence of neuropathy (absent ankle
reflexes) on physical examination, as well as history of
poorly controlled diabetes.
While painful diabetic neuropathy can be self-limiting,
his symptoms are severe and are interfering with his
sleep, so treatment would be advised. Pregabalin (C),
and duloxetine (E) are FDA approved for treatment of
painful diabetic neuropathy, and there is strong evidence
for efficacy for amitriptyline (B) and capsaicin (D).
Opioids such as oxycodone (A) are not recommended
as the first line treatment of painful diabetic neuropathy.
Case 6
A 44-year-old woman has had weakness and nervousness
for several months. She also has noted occasional
palpitations and has lost 5 lbs. Her pulse rate is 108
beats/minute. She has mild eyelid retraction and a tremor of
her hands, but no thyroid enlargement or nodules.
Her serum TSH is 0.01 µU/ml (normal, 0.4-4.0) and serum
free thyroxine concentration is 2.0 ng/dl (normal, 0.8-1.6). Her
thyroid radioiodine uptake at 24 hours is 52 percent (normal,
15-35) with diffuse pattern. Pregnancy test is negative.
The next step is to:
A. Measure serum C-reactive protein
B. Administer I-123 radioiodine isotope
C. Administer I-131 radioiodine isotope
D. Start propylthiouracil
E. Start methimazole
3226
Case 6
A 44-year-old woman has had weakness and nervousness
for several months. She also has noted occasional
palpitations and has lost 5 lbs. Her pulse rate is 108
beats/minute. She has mild eyelid retraction and a tremor of
her hands, but no thyroid enlargement or nodules.
Her serum TSH is 0.01 µU/ml (normal, 0.4-4.0) and serum
free thyroxine concentration is 2.0 ng/dl (normal, 0.8-1.6). Her
thyroid radioiodine uptake at 24 hours is 52 percent (normal,
15-35) with diffuse pattern. Pregnancy test is negative.
The next step is to:
A. Measure serum C-reactive protein
B. Administer I-123 radioiodine isotope
C. Administer I-131 radioiodine isotope
D. Start propylthiouracil
E. Start methimazole
Case 6: Explanation
This patient has mild Graves disease. First line
treatment for Graves disease are thionamides, and
specifically methimazole (E).
Propylthiouracil (D) is associated with an increased risk
of liver failure.
Measurement of C-reactive protein level (A) does not
assist in management of Graves disease.
Treatment with I-131 isotope (C) usually leads to
permanent hypothyroidism and is therefore not
recommended as first line choice in most cases.
When radioiodine is used, I-131 isotope is preferred to
I-123 (B) because the former emits a large fraction of its
radiation as beta rays (electrons) which have a short
penetration depth and do not affect organs other than
the thyroid.
3227
Case 7
A 32-year-old woman has had erratic menstrual periods
since adolescence and amenorrhea for about 4 months. She
has had mild facial hirsutism for more than 10 years. She
recently gained about 5 pounds, and has had less energy
than in the past. She takes no medications. She has mild
facial hirsutism, but no striae, central adiposity, hot flashes, or
galactorrhea. Her prolactin is measured to be 52 ng/mL (nl 4-
30), and the pregnancy test is negative.
The most appropriate next step is to order:
A. Ovarian ultrasonography
B. Serum follicle stimulating hormone (FSH)
C. Pituitary MRI
D. Serum testosterone
E. Serum TSH
Case 7
A 32-year-old woman has had erratic menstrual periods
since adolescence and amenorrhea for about 4 months. She
has had mild facial hirsutism for more than 10 years. She
recently gained about 5 pounds, and has had less energy
than in the past. She takes no medications. She has mild
facial hirsutism, but no striae, central adiposity, hot flashes, or
galactorrhea. Her prolactin is measured to be 52 ng/mL (nl 4-
30), and the pregnancy test is negative.
The most appropriate next step is to order:
A. Ovarian ultrasonography
B. Serum follicle stimulating hormone (FSH)
C. Pituitary MRI
D. Serum testosterone
E. Serum TSH
3228
Case 7: Explanation
Mild hyperprolactinemia associated with secondary
amenorrhea can be due to primary hypothyroidism (E)
as low free T4 stimulates increased TRH production
from the hypothalamus which stimulates secretion of
both TSH and prolactin from the pituitary.
Ovarian ultrasonography (A) and measurement of
testosterone levels (D) are not helpful in diagnosing the
etiology of hyperprolactinemia.
FSH (B) will be suppressed in patients with
hypothalamic amenorrhea. She does not have hot
flashes so premature ovarian insufficiency is unlikely
and it would not be associated with hyperprolactinemia.
Hypothyroidism is more common than pituitary masses
and should be ruled out before a pituitary MRI (C) is
considered.
Case 8
A 68-year-old woman was found unresponsive at home by
her daughter. In the Emergency Department, her temperature
was 103.2, oxygen saturation 70% on room air, blood
pressure 90/40 and heart rate 115. When given oxygen she
was sleepy, but arousable. Her thyroid exam was normal. She
was hospitalized and treated with intravenous fluids and
antibiotics.
On day 2 TFTs were drawn because of persistent sinus
tachycardia. TSH was 0.15 µU/ml (nl 0.5-5.0) and free
thyroxine was 0.6 ng/dL (nl 0.8-1.6). The best next step is:
A. Pituitary MRI
B. Thyroid ultrasound
C. Thyroid I-123 scan and uptake
D. Levothyroxine 100 mcg daily
E. Re-evaluate in 4-6 weeks
3229
Case 8
A 68-year-old woman was found unresponsive at home by
her daughter. In the Emergency Department, her temperature
was 103.2, oxygen saturation 70% on room air, blood
pressure 90/40 and heart rate 115. When given oxygen she
was sleepy, but arousable. Her thyroid exam was normal. She
was hospitalized and treated with intravenous fluids and
antibiotics.
On day 2 TFTs were drawn because of persistent sinus
tachycardia. TSH was 0.15 µU/ml (nl 0.5-5.0) and free
thyroxine was 0.6 ng/dL (nl 0.8-1.6). The best next step is:
A. Pituitary MRI
B. Thyroid ultrasound
C. Thyroid I-123 scan and uptake
D. Levothyroxine 100 mcg daily
E. Re-evaluate in 4-6 weeks
Case 8: Explanation
This patient’s thyroid function tests are consistent with
both sick euthyroid syndrome and secondary
hypothyroidism. However, in a setting of critical illness in
a patient without a known pituitary lesion, sick euthyroid
syndrome is much more likely, and expectant
management (E) is recommended.
Pituitary MRI (A) would only be indicated if the patient’s
thyroid hormone levels do not normalize as she recovers
from her illness.
Thyroid ultrasound (B) and radioiodine scan and uptake
(C) are not helpful in diagnosing the etiology of
hypothyroidism.
Levothyroxine supplementation (D) has not been shown
to be of benefit in patients with sick euthyroid syndrome.
3230
Case 9
A 67-year-old woman comes for a follow-up visit two years
after initiating alendronate (Fosamax) for treatment of
osteoporosis. She takes calcium 500 mg twice daily and
vitamin D 800 units daily. She takes alendronate on Sunday
mornings together with the rest of her medications. She walks
a mile 5 days a week. Her 25-OH-D level is 32 ng/mL
(normal). Two years ago her T-score in the left hip was -2.6. A
week ago follow-up bone densitometry showed a 6%
decrease in the left hip (significant). The best next step is:
A. Ask her to skip the morning calcium on Sundays
B. Double her calcium dose
C. Double her vitamin D dose
D. Add raloxifene (Evista)
E. Add ibandronate (Boniva)
Case 9
A 67-year-old woman comes for a follow-up visit two years
after initiating alendronate (Fosamax) for treatment of
osteoporosis. She takes calcium 500 mg twice daily and
vitamin D 800 units daily. She takes alendronate on Sunday
mornings together with the rest of her medications. She walks
a mile 5 days a week. Her 25-OH-D level is 32 ng/mL
(normal). Two years ago her T-score in the left hip was -2.6. A
week ago follow-up bone densitometry showed a 6%
decrease in the left hip (significant). The best next step is:
A. Ask her to skip the morning calcium on Sundays
B. Double her calcium dose
C. Double her vitamin D dose
D. Add raloxifene (Evista)
E. Add ibandronate (Boniva)
3231
Case 9: Explanation
This patient has a failure of treatment with an oral
bisphosphonate. She takes alendronate together with
calcium which can decrease bisphosphonate absorption.
Therefore the first step is to make sure calcium and
alendronate are taken separately (A).
She already takes adequate calcium (B) and vitamin D
(C) doses. Increasing these is unlikely to be of clinical
benefit and could have adverse effects.
Neither raloxifene (D) nor ibandronate (E) have been
shown to reduce the risk of hip fractures.
Case 10
A 62-year-old man comes for follow-up of diabetes. He
used to be treated with metformin 1000 mg bid and glipizide
10 mg bid but two years ago glipizide was stopped and
glargine (Lantus) insulin started. He now takes 30 units of
glargine at night. He wakes up from hypoglycemia 2-3 times a
week but his daytime glucose ranges between 150-220
mg/dL. His A1C is 7.5%. The best next step is:
A.Stop glargine and restart glipizide
B.Take glargine in the morning instead of at night
C.Decrease glargine and add a rapid acting insulin before
every meal
D.Stop glargine and start detemir (Levemir) insulin at night
E.Ask him to eat a snack before going to bed
3232
Case 10
A 62-year-old man comes for follow-up of diabetes. He
used to be treated with metformin 1000 mg bid and glipizide
10 mg bid but two years ago glipizide was stopped and
glargine (Lantus) insulin started. He now takes 30 units of
glargine at night. He wakes up from hypoglycemia 2-3 times a
week but his daytime glucose ranges between 150-220
mg/dL. His A1C is 7.5%. The best next step is:
A.Stop glargine and restart glipizide
B.Take glargine in the morning instead of at night
C.Decrease glargine and add a rapid acting insulin before
every meal
D.Stop glargine and start detemir (Levemir) insulin at night
E.Ask him to eat a snack before going to bed
Case 10: Explanation

This patient has excessive basal insulin dose as
evidenced by nocturnal hypoglycemia; his
hyperglycemia is likely post-prandial. Therefore basal
insulin dose should be decreased and prandial insulin
added (C).
Replacing glargine with glipizide (A) will further increase
his daytime glucose levels.
Administering glargine in the morning instead of at night
(B) is unlikely to make a difference.
Replacing glargine with evening detemir (D) will not
reduce nocturnal hypoglycemia.
Bedtime snack (E) will reduce nocturnal hypoglycemia
but will not improve his overall glycemic control.
3233
Case 11
A 57-year-old woman is evaluated for severe hypertension
resistant to treatment with three anti-hypertensive
medications (ACE inhibitor, calcium channel blocker, and
HCTZ) and hypokalemia. She is found to have serum
aldosterone 24 ng/dL (nl 4.0 – 21.0) and plasma renin activity
0.2 ng/mL/hr (nl 0.6 – 3.0). Plasma metanephrine and
normetanephrine levels are normal. A 24 hour urine
aldosterone level is 20 mcg with urine sodium of 220 mEq.
Abdominal CT shows a 2-cm benign appearing nodule in the
right adrenal gland. The best next step is:
A. Abdominal MRI
B. Repeat the CT in 6 months
C. Refer to an experienced surgeon for right adrenalectomy
D. Adrenal vein sampling
E. Stop all anti-hypertensives and repeat biochemical tests
Case 11
A 57-year-old woman is evaluated for severe hypertension
resistant to treatment with three anti-hypertensive
medications (ACE inhibitor, calcium channel blocker, and
HCTZ) and hypokalemia. She is found to have serum
aldosterone 24 ng/dL (nl 4.0 – 21.0) and plasma renin activity
0.2 ng/mL/hr (nl 0.6 – 3.0). Plasma metanephrine and
normetanephrine levels are normal. A 24 hour urine
aldosterone level is 20 mcg with urine sodium of 220 mEq.
Abdominal CT shows a 2-cm benign appearing nodule in the
right adrenal gland. The best next step is:
A. Abdominal MRI
B. Repeat the CT in 6 months
C. Refer to an experienced surgeon for right adrenalectomy
D. Adrenal vein sampling
E. Stop all anti-hypertensives and repeat biochemical tests
3234

This patient has primary hyperaldosteronism. However,
adrenal nodules are common in this age group, while
excess aldosterone production could have a different
source (e.g. bilateral adrenal hyperplasia). Therefore
confirmation of laterality of aldosterone production (D) is
the first step and adrenalectomy (C) is premature.
Abdominal MRI (A) will not provide any additional
information.
Deferral of definitive treatment (B) of primary
hyperaldosteronism is not appropriate.
The diagnosis of primary hyperaldosteronism is
definitive and no further biochemical workup (E) is
needed.
Case 12
A 41-year-old man comes to your office complaining of
progressive erectile dysfunction over the last several years.
Evaluation shows testosterone 1,200 pg/ml (nl 1,800 – 6,900)
and prolactin of 68 ng/ml (nl 4-23), confirmed by dilution.
Pituitary MRI shows a 2.5-cm intrasellar mass consistent with
pituitary adenoma. He denies headaches; his neurological
examination is normal and visual fields are intact. Morning
cortisol is 12 mcg/dl, IGF-1 is normal, and LH and FSH are
low. The best next step is:
A.Refer to a neurosurgeon
B.Start bromocriptine (Parlodel)
C.Start cabergoline (Dostinex)
D.Start testosterone patch
E.Repeat pituitary MRI in 6 months
3235
Case 12
A 41-year-old man comes to your office complaining of
progressive erectile dysfunction over the last several years.
Evaluation shows testosterone 1,200 pg/ml (nl 1,800 – 6,900)
and prolactin of 68 ng/ml (nl 4-23), confirmed by dilution.
Pituitary MRI shows a 2.5-cm intrasellar mass consistent with
pituitary adenoma. He denies headaches; his neurological
examination is normal and visual fields are intact. Morning
cortisol is 12 mcg/dl, IGF-1 is normal, and LH and FSH are
low. The best next step is:
A.Refer to a neurosurgeon
B.Start bromocriptine (Parlodel)
C.Start cabergoline (Dostinex)
D.Start testosterone patch
E.Repeat pituitary MRI in 6 months

This patient has a non-secretory pituitary
macroadenoma and should be referred to a
neurosurgeon for resection (A) to prevent further
complications, such as optic chiasm compression.
Deferral of treatment (E) is not appropriate.
Prolactin elevation is mild and thus due to pituitary stalk
compression rather than production by the tumor.
Consequently treatment with bromocriptine (B) or
cabergoline (C) is not the appropriate therapy.
Gonadotropin production may recover after resection of
the tumor, and therefore testosterone supplementation
(D) is premature.
3236
Case 13
A 56-year-old previously healthy woman reports intense
flushing (her face turns purple) that’s been going on for 6
months. She underwent menopause 4 years ago and was
asymptomatic at the time. She also complains of frequent
watery bowel movements. She takes no medications. She
has one of the episodes during her visit and her blood
pressure falls to 102/61 down from 127/74. The best next
step is:
A.Magnetic resonance imaging of the brain
B.24-hour urine collection for catecholamines and
metanephrines
C.24-hour urine collection for 5-hydroxyindoleacetic acid (5-
HIAA)
D.24-hour urine collection for tryptase
E.Start estrogen supplementation
Case 13
A 56-year-old previously healthy woman reports intense
flushing (her face turns purple) that’s been going on for 6
months. She underwent menopause 4 years ago and was
asymptomatic at the time. She also complains of frequent
watery bowel movements. She takes no medications. She
has one of the episodes during her visit and her blood
pressure falls to 102/61 down from 127/74. The best next
step is:
A.Magnetic resonance imaging of the brain
B.24-hour urine collection for catecholamines and
metanephrines
C.24-hour urine collection for 5-hydroxyindoleacetic acid
(5-HIAA)
D.24-hour urine collection for tryptase
E.Start estrogen supplementation
3237

This woman’s symptoms are most consistent with
carcinoid syndrome; therefore 24-urine collection for
5-HIAA (C) is the best way to confirm the diagnosis.
Pituitary tumors do not typically cause flushing and thus
pituitary MRI (A) will not be helpful.
Pheochromocytomas (B) rarely cause flushing and are
not usually associated with diarrhea.
Serum (rather than urine) tryptase (D) measurement can
be used to diagnose systemic mastocytosis.
New onset of flushing several years after the
menopause is unlikely be due to estrogen deficiency (E).
Case 14
A 25-year-old man comes in for routine physical. He had
craniopharyngioma resection at the age of 12 and has been
taking levothyroxine ever since. His current dose is 112 mcg
daily. Blood tests show TSH of 0.05 µU/ml (nl 0.5-5.0) and
free thyroxine 0.7 ng/dL (nl 0.8-1.6). The best next step is:
A. Decrease levothyroxine to 88 mcg daily
B. Increase levothyroxine to 125 mcg daily
C. Radioactive iodine uptake
D. Pituitary MRI
E. Re-evaluate in 6 months
3238
Case 14
A 25-year-old man comes in for routine physical. He had
craniopharyngioma resection at the age of 12 and has been
taking levothyroxine ever since. His current dose is 112 mcg
daily. Blood tests show TSH of 0.05 µU/ml (nl 0.5-5.0) and
free thyroxine 0.7 ng/dL (nl 0.8-1.6). The best next step is:
A. Decrease levothyroxine to 88 mcg daily
B. Increase levothyroxine to 125 mcg daily
C. Radioactive iodine uptake
D. Pituitary MRI
E. Re-evaluate in 6 months

This patient with a known pituitary lesion that has been
surgically resected has secondary hypothyroidism. In
these circumstances, TSH is not a useful indicator of
thyroid hormone adequacy. His free thyroxine levels are
low and his levothyroxine dose should be increased (B)
rather than decreased (A). Deferral of treatment (E) is
not appropriate.
As hyperthyroidism is not suspected, radioactive iodine
uptake (C) will not be helpful.
His pituitary disease is well established and there is no
reason to suspect any changes that could be revealed
by a pituitary MRI (D).
3239
Case 15
A 71-year-old man returns to see you for follow-up of type 2
diabetes. He also has hypercholesterolemia, heart failure,
hypertension, osteoarthritis, remote history of pancreatitis and
bladder cancer and family history of medullary thyroid cancer.
His current medications include glipizide 10 mg bid and
simvastatin 20 mg qhs. His hemoglobin A1c is 8.2% and
fasting blood glucose 130-150 mg/dL. The best next step is to
add the following medication to glipizide:
A. metformin 1000 mg daily
B. liraglutide (Victoza) 0.6 mg SQ daily
C. sitagliptin (Januvia) 100 mg daily
D. pioglitazone (Actos) 15 mg daily
E. glargine (Lantus) insulin 15 units SQ qhs
Case 15
A 71-year-old man returns to see you for follow-up of type 2
diabetes. He also has hypercholesterolemia, heart failure,
hypertension, osteoarthritis, remote history of pancreatitis and
bladder cancer and family history of medullary thyroid cancer.
His current medications include glipizide 10 mg bid and
simvastatin 20 mg qhs. His hemoglobin A1c is 8.2% and
fasting blood glucose 130-150 mg/dL. The best next step is to
add the following medication to glipizide:
A. metformin 1000 mg daily
B. liraglutide (Victoza) 0.6 mg SQ daily
C. sitagliptin (Januvia) 100 mg daily
D. pioglitazone (Actos) 15 mg daily
E. glargine (Lantus) insulin 15 units SQ qhs
3240

In this patient metformin (A) and pioglitazone (D) are
contraindicated because of history of heart failure,
liraglutide (B) and sitagliptin (C) are contraindicated
because of history of pancreatitis, and pioglitazone (D) is
also contraindicated because of history of bladder
cancer. Liraglutide (B) is additionally contraindicated
because of family history of medullary thyroid cancer.
Therefore glargine insulin (E) is the only remaining
treatment option.
Case 16
A 65-year-old woman comes to see you as a new patient.
She has type 2 diabetes, hypertension and hypothyroidism.
She takes metformin XR 2000 mg daily, glimepiride 4 mg
daily, lisinopril 20 mg daily, and diltiazem XR 240 mg daily.
Her fasting lipid profile shows LDL cholesterol of 120 mg/dL,
HDL cholesterol 51 mg/dL, and triglycerides 167 mg/dL. The
best next step is:
A. Start ezetimibe (Zetia) 10 mg daily
B. Start niacin extended release 500 mg daily
C. Start fenofibrate (Tricor) 145 mg daily
D. Start simvastatin (Zocor) 40 mg daily
E. Start atorvastatin (Lipitor) 20 mg daily
3241
Case 16
A 65-year-old woman comes to see you as a new patient.
She has type 2 diabetes, hypertension and hypothyroidism.
She takes metformin XR 2000 mg daily, glimepiride 4 mg
daily, lisinopril 20 mg daily, and diltiazem XR 240 mg daily.
Her fasting lipid profile shows LDL cholesterol of 120 mg/dL,
HDL cholesterol 51 mg/dL, and triglycerides 167 mg/dL. The
best next step is:
A. Start ezetimibe (Zetia) 10 mg daily
B. Start niacin extended release 500 mg daily
C. Start fenofibrate (Tricor) 145 mg daily
D. Start simvastatin (Zocor) 40 mg daily
E. Start atorvastatin (Lipitor) 20 mg daily

This woman needs to lower her LDL (guidelines
recommend at least moderate intensity statin therapy for
most patients with diabetes).
Niacin (B) and fenofibrate (C) have not been
unequivocally shown to decrease the incidence of
cardiovascular events in patients with elevated
cholesterol, while ezetimibe (A) benefits are relatively
weak; they are therefore not recommended as first line
treatment.
Simvastatin (D) has significant drug-drug interactions
with many calcium channel blockers and is
contraindicated in doses greater than 10 mg daily in
patients who take diltiazem.
Consequently atorvastatin (E) is the best treatment
choice.
3242
Case 17
A 53-year-old woman comes to see you for follow-up of
type 2 diabetes. She also has hypertension and obstructive
sleep apnea. She has struggled with obesity for many years
and her current BMI is 37.5 kg/m2. She takes metformin 2,000
mg/day. Her A1c is 9.2%. Her blood pressure is well
controlled on lisinopril 20 mg daily, amlodipine 10 mg daily
and hydrochlorothiazide 25 mg daily. She has tried multiple
weight loss diets over the years but has always regained the
weight she loses. The best next step is:
A. Start glipizide 10 mg daily
B. Start glargine (Lantus) insulin 15 units at bedtime
C. Recommend that she consider a bariatric procedure
D. Start phentermine 30 mg daily
E. Start empagliflozin (Jardiance) 10 mg daily
Case 17
A 53-year-old woman comes to see you for follow-up of
type 2 diabetes. She also has hypertension and obstructive
sleep apnea. She has struggled with obesity for many years
and her current BMI is 37.5 kg/m2. She takes metformin 2,000
mg/day. Her A1c is 9.2%. Her blood pressure is well
controlled on lisinopril 20 mg daily, amlodipine 10 mg daily
and hydrochlorothiazide 25 mg daily. She has tried multiple
weight loss diets over the years but has always regained the
weight she loses. The best next step is:
A. Start glipizide 10 mg daily
B. Start glargine (Lantus) insulin 15 units at bedtime
C. Recommend that she consider a bariatric procedure
D. Start phentermine 30 mg daily
E. Start empagliflozin (Jardiance) 10 mg daily
3243

This woman needs to improve her glycemic control. She
is obese and has several reversible complications of
obesity; it would therefore be ideal for her to also lose
weight.
A bariatric procedure (C), such as a Roux-en-Y gastric
bypass or a sleeve gastrectomy, will achieve both of
these goals. Glipizide (A) and glargine (B) will lead to
weight gain. Phentermine (D) will achieve modest weight
loss, but is only recommended for short-term use and
will not improve her glucose control. Empagliflozin (E)
will only result in modest weight loss and is unlikely to
bring her A1c below 7.0%.
GOOD LUCK!
54
3244
Disclosures:
Brio Systems
Eli Lilly
Merck
Monarch Medical Technologies
55
REFERENCES
1. Williams Textbook of Endocrinology, 13th edition.
2. Werner & Ingbar's The Thyroid: A Fundamental and
Clinical Text, 10th edition.
3. American Diabetes Association. Standards of
Medical Care in Diabetes – 2018. Diabetes Care
2018; Volume 41; Supplement 1.
3245
Rheumatoid Arthritis: Diagnosis and Treatment
Paul F Dellaripa MD
Boston MA
Disclosures
• Genentech
• Up to Date
• Bristol Myers Squibb
3246
Rheumatoid Arthritis
• RA is a systemic diseases that primarily affects joints and untreated
or undertreated disease can lead to significant pain, disability and
higher risk of death
• RA has extra-articular effects in the lung and other organs, and a
higher risk of cardiovascular disease
• Recognition of early disease offers the opportunity at early
intervention and control of disease and better functional outcomes
as well as the potential for lower mortality
• There are many treatment options in 2018 but early intervention with
defined goals and targets of therapy while minimizing risk is key
What is RA ?
3247
But RA is also this!
RA: clinical findings

• Female predominance (3:1)
• General peak of onset is 25-50 years
• Although can occur at any age
• Symmetric synovitis
• Small joint involvement is most common
• Hands especially wrists, MCP and PIP
• Cervical spine disease can occur;atlanto-axial instability or superior migration of the dens.
• LS spine is spared
• Disease may start or remain asymmetrical
• Extra-articular involvement
• Lung - Interstitial lung disease
• Higher risk of lymphoma
• Cardiovascular
• Vasculitis
• Pericarditis
• Coronary artery disease
3248
Other diagnosis to consider

• Seronegative spondyloarthritis (Psoriatic arthritis, ankylosing
spondylitis, reactive, IBD related)
• Infection (viral, Lyme, less common septic)
• SLE
• Polymyalgia rheumatica
• Sarcoid
• Crystalline disease (gout/pseudogout)
• Vasculitis
2010 Classification Criteria from ACR/EULAR

• Who should be tested?
• Patients with synovitis of at least one joint which has no other explanation
• Point system
• ≥6/10 points required to make the diagnosis of RA
• Points given based on
• Number of joints involved
• Serology (Rheumatoid factor and CCP/ACPA)
• Acute phase reactants
• Duration of symptoms
3249
Re-defining RA: 2010 Classification

Criteria from ACR/EULAR
Score
Descriptor
A. Joint involvement (use highest applicable category)
1 large joint 0
2-10 large joints 1
1-3 small joints (with or without large joint involvement) 2
4-10 small joints (with or without large joint involvement) 3
>10 joints (at least 1 small joint) 5
B. Serology (high-positive: ≥ 3x upper limit normal for the test)
Negative RF and negative ACPA 0
Low-positive RF or low-positive ACPA 2
High-positive RF or high-positive ACPA 3
C. Acute phase reactants
Normal CRP and ESR 0
Abnormally elevated CRP or ESR 1
D. Duration of symptoms
<6 weeks 0
≥6 weeks 1
RA and increased mortality risk

Age-Standardized Mortality 1976-2012 in NHS
200
200
150
150
10,000)
All RA
10,000
Seropositive RA
non-RA
(per
Seronegative RA
100
Deaths per
all-RA
100
sero+ RA
Non-RA
Deaths
sero- RA
50
50
0
0
1976 1980 1984 1988 1992 1996 2000 2004 2008

Calendar Sparks et al, presented at ACR 2014
Calendaryear
year
Sparks et al, Arthritis Care Res, 2016
3250
Mortality and RA – why the increased risk?

• Increased risk of cardiovascular disease (CVD)
• 2008 meta-analysis looking at 24 studies (111,758 patients) suggests 50%
increased risk of CVD deaths in RA
• Study by Wasko et al examining 5625 patients for 25 years
• Found 70% decreased risk of mortality in those taking methotrexate >1year
• This may be related to decreased CAD risk in patients who start
methotrexate
Avina-Zubieta et al, Arth Care Res, 2008

Wasko et al, Arth Rheum 2014
Mortality of RA-ILD
R
A
RA-ILD
Olson AJRCCM 201111

Bongartz Arth Rheum 2010
Park AJRCCM 2007
Kim Chest 2009
3251
What happens when you delay treatment?

• 598pts from EARLY RA LEIDEN COHORT of 1674 pts
• Consecutive pts enrolled between 1993-2006
• Study evaluated assessment delay and disease outcome defined as
rate of joint destruction and sustained DMARD free remission
• In pts with RA 69% were assessed >12 weeks after symptoms/referral
was associated with less DMARD free remission and more xray
progression over 6 yrs
• Those pts seen within 12 wks of symptom onset had greater DMARD
free remission and less progression (Van der Linden Arthritis Rheum
2010; 62:3537-3546)
Long-term impact of delay in assessment of patients with early arthritis
Arthritis & Rheumatism

Volume 62, Issue 12, pages 3537-3546, 30 NOV 2010 DOI: 10.1002/art.27692
http://onlinelibrary.wiley.com/doi/10.1002/art.27692/full#fig2
3252
Reductions in Radiographic Progression in Early Rheumatoid Arthritis Over Twenty-

Five Years: Changing Contribution From Rheumatoid Factor in Two Multicenter UK
Inception Cohorts (Carpenter L et al. Arthritis Care Res 69(12);1809-17 2017)
• 2 longitudinal inception cohorts in the UK

• 1465 pts between 1986-2001 (ERAS) and 1236 pts between 2002-
2013 (ERAN)
• RA- within 3yrs of symptoms onset
• XRAY – lower erosion scores at baseline in newer cohort ERAN and
lower progression rates, progression in 74% of ERAS and 27% ERAN
• DMARD use major factor in decline of progression, adequate
treatment may remove the predictive value of RF on xray progression
Reductions in Radiographic Progression in Early Rheumatoid Arthritis Over Twenty-Five Years: Changing
Contribution From Rheumatoid Factor in Two Multicenter UK Inception Cohorts
Arthritis Care & Research

Volume 69, Issue 12, pages 1809-1817, 6 NOV 2017 DOI: 10.1002/acr.23217
http://onlinelibrary.wiley.com/doi/10.1002/acr.23217/full#acr23217-fig-0001
3253
Reductions in Radiographic Progression in Early Rheumatoid Arthritis Over Twenty-Five Years: Changing
Contribution From Rheumatoid Factor in Two Multicenter UK Inception Cohorts
Arthritis Care & Research

Volume 69, Issue 12, pages 1809-1817, 6 NOV 2017 DOI: 10.1002/acr.23217
http://onlinelibrary.wiley.com/doi/10.1002/acr.23217/full#acr23217-fig-0003
So we know RA is bad for you and once you have

made the diagnosis you should treat ASAP….Then
what?
How can you assess risk to identify those with who will develop more
severe disease?
Based on that risk assessment, what agents should you start and how
to assess for efficacy?
In simplest terms, the goal is to start therapy within 3
months of disease onset if not sooner and methotrexate is
the preferred DMARD in the vast majority of patients.
3254
What constitutes poor prognosis?

• Functional limitation
• Extraarticular disease
• Rheumatoid factor positivity or presence of anticyclic citrullinated
peptide (CCP) antibodies
• Bony erosions documented radiographically
How do we do assessments?
• Disease Activity Score 28 joints (DAS28) =DAS28-ESR = ( 0.56 *
sqr(TJC)) + (0.28 * sqr(SJC)) + ( 0.7 * ln(ESR)) + (0.014 * GH)
• Simplified Disease Activity Index (SDAI)= SJC + TJC +PGA + EGA + CRP
• Clinical Disease Activity Index (CDAI) =SJC + TJC + PGA + EGA
• MD HAQ score.
• The patient-reported outcome measures include:

• Routine Assessment of Patient Index Data 3 (RAPID3)
• Patient Activity Scale (PAS) and PAS-II
3255
RAPID 3: patient centered measure of

function, pain and global status. ( Pincus et al
2009)
• RAPID3 (routine assessment of patient index data 3) is a pooled index
of the 3 patient-reported American College of Rheumatology
rheumatoid arthritis (RA) Core Data Set measures: function, pain, and
patient global estimate of status.
• Each of the 3 individual measures is scored 0 to 10, for a total of 30/3.
• Disease severity may be classified on the basis of RAPID 3 scores: >4 =
high; 2.1-4 = moderate; 1.1-2 = low; < or =1 = remission.
• RAPID3 scores are correlated with the disease activity score 28
(DAS28) and clinical disease activity index (CDAI)
2015 American College of Rheumatology Guideline for the Treatment of Rheumatoid Arthritis
Arthritis & Rheumatology

Volume 68, Issue 1, pages 1-26, 6 NOV 2015 DOI: 10.1002/art.39480
http://onlinelibrary.wiley.com/doi/10.1002/art.39480/full#art39480-fig-0003
3256
Methotrexate
• Very effective – standard of care as first choice in most cases of RA for
over 30 years
• Can be given orally or subcutaneously.
• Found to:
• Change natural history of RA
• Decrease extra-articular manifestations
• Increase QOL and even potentially survival
Methotrexate: potential toxicities

• Gastrointestinal discomfort (most common)
• Liver enzyme abnormalities (role of fibroscan)
• Hematologic abnormalities
• Opportunistic infections
• Effect on reproduction ( need to stop for at least 3 months before
attempting conception)
• Rare complications:
• Lung toxicity ( less than 1%)
• Nephrotoxicity
• ? Malignancy ( lymphoma)
3257
Methotrexate – what if patient cannot

tolerate MTX ?
• Leflunomide; mechanism of action similar to MTX, daily oral dose,
similar level of efficacy as MTX; need to monitor LFTs;teratogenic
• Sulfasalazine: slow onset of action, not used as a single agent but
often in triple therapy combination
• Hydroxychloroquine; milder agent, often used as part of combination
therapy, ocular toxicity risk.
• Targeted synthetic DMARDs (tofacitinib)
What to ensure your patient has before

starting immunosuppressive therapy
• Lab baseline
• LFTs, creatinine, CBC
• Hepatitis B and C screening
• TB testing (PPD or T spot/quantiferon gold)
• Inactivated vaccines
• Influenza
• Pneumonia (PCV13 and PPSV23)
• Live vaccines
• Most contraindicated when on immunosuppressive therapy
• If given prior to initiation must wait at least one month before starting therapy
• Exception is zoster
• Safe to give: azathioprine (<3mg/kg), methotrexate (<0.4mg/kg) or those taking prednisone <20 mg/d
• New vaccine available but information on side effect in rheumatic disease pts not available
3258
If someone doesn’t respond to MTX alone

then what?
• Combination therapy either other conventional DMARDs with MTX
• Biologic agent (TNFi or other)
• Combination of biologic agent with MTX
• Combination of conventional and synthetic DMARD
Population Early RA (< 3 yrs)

Type of study Randomized, double-blind trial
Treatment Groups -(IE) Immediate MTX plus etanercept

-(IT) Immediate triple therapy (MTX plus SSA plus HCQ)
-(SE) Step-up from MTX to MTX plus etanercept
-(ST) Step-up from MTX to triple therapy
Step-up if DAS28 > 3.2 at week 24
Length of study 2 years

Primary Outcome DAS28-ESR values from week 48 to week 102
Conclusion No difference in DAS28-ESR between 48-102 weeks in any group, IE and IT (equally)
more effective than SE and ST at week 24
Less radiographic progression in SE group as compared to ST
3259
• Based on the RACAT study

• Etanercept-MTX combination would result in 0.15
additional quality adjusted life year, but this would
cost 77,290 dollars
Anti-TNF Therapy
• 5 FDA approved TNF modulators in RA
• All have similar effects—with roughly a response rate of 60-70%
• Work in early disease and late disease—clinical outcomes better in
early disease possibly related to the presence of more inflammation
• Stabilize radiographic progression
• While can be used as monotherapy, often and most effectively used
in combination with MTX or other conventional DMARD and there are
multiple studies to support their efficacy (see next slide) .
3260
(A) Sustained remission (sREM), sustained low disease activity (sLDA) and American College of
Rheumatology (ACR)50 response at Week 52. in patients with early RA and poor prognostic
factors
P Emery et al. Ann Rheum Dis 2017;76:96-104
©2017 by BMJ Publishing Group Ltd and European League Against Rheumatism
Anti-TNF Therapy – adverse events

• Cutaneous
• Injection site reactions
• Diffuse rashes
• Infectious
• Sepsis, septic joints, pneumococcal infections
• Tuberculosis
• Cardiac
• Increased risk class III-IV CHF
• Neurologic
• Demyelination
• Oncologic
• Worry in the past has been increased risk of lymphoma and
other malignancies
3261
Malignancy and anti-TNF

• Skin cancers may be increased in patients taking anti-TNF but recent study shows
no identifiable increased risk of melanoma with anti-TNF (Ann Rheum Dis 2017;
76:386). We still recommend once yearly skin checks by dermatology in patients
on these medications
• Lymphoma and TNF inhibitors: Large cohort studies with no clear evidence of
increased risk (Arthritis Rheum 2006;54(9):2757-2764)
• Risk of malignancy in general is lower with TNFi and cDMARD compared to MTX
and abatacept and RTX (Solomon D Semin Arthritis Rheum. 2014 Feb;43(4):489-
97)
Rare potential side effects

• Pancytopenia and aplasia
• Autoimmune manifestations
• Granulomatous pulmonary disease
• Vasculitis
• SLE-type glomerulonephritis
• Psoriasis
3262
Absolute contraindications to
TNF-Blockers
• Heart failure: CHF III/IV

• Active/latent Tuberculosis
• Active infection
• Demyelinating disease - MS/optic neuritis
• Consider
• Malignancy – speak with oncologist prior to initiating
Abatacept – mechanism of action:blocks

activation of co-stimulatory pathway
3263
Abatacept
• Monthly infusions or weekly injections
• Similar risks to anti-TNF but less TB risk
• May be used with or without methotrexate
• Usually after TNF “failure”—response rate 50%
• Onset 4-16 weeks
Genovese M. N Engl J Med 2005;

353(11):1114-23.
1Kremer JM, et al. Ann Intern Med.
2006;144:865-876.
Rituximab
• B cell depletion though may have other effects on immune system

• Works about 50% in anti-TNF failures
• Onset 6-12 weeks-may have long term effect
• 2 infusions—1000mg vs 500mg
• For use mainly in seropositive pts
• Taylor R ,Lindorfer M
• Nature Rev 2006
3264
Rituximab: Adverse events

• Infections including PML ( due to JC virus) , HepB, others
• Rashes including psoriasis
• Low cell counts ( WBC)
• Low IgG for long durations--?significance
• Need to check Hep B core IgM prior to starting RTX
Tocilizumab
• Monoclonal antibody that blocks IL-6r
• 50% response rate in TNF failures
• Onset 2-12 weeks
• Impressive improvements in CRP, QOL, fatigue
• Adverse events:
• Infections
• ? GI perforation - avoid in patients with history of diverticulitis
• Lipid, leukocyte and liver test abnormalities
3265
Mechanism of Tocilizumab
(Kim GW et al Archives of Pharmacal Research 2015)
Gerd R Burmester et al. Ann Rheum Dis 2016;75:1081-1091
©2016 by BMJ Publishing Group Ltd and European League Against Rheumatism
3266
Tofacitinib:a new synthetic DMARD

• First oral biologic agent targets Janus Kinase molecule 1 and 3
• Indication- Active moderate to severe RA, inadequate response or
intolerance to MTX
• Monotherapy or in combination with MTX
• Combination of tofacitinib (5 mg twice daily) with MTX (15 to 25 mg
per week) similar in efficacy to adalimumab plus MTX and appears
more efficacious than tofacitinib alone (Fleischmann R et al Lancet.
2017;390(10093):457)
JAK inhibition
3267
JAK inhibitors-potential complications

• Infections
• Opportunistic infections
• Herpes Zoster ( risks inc steroid use, age, Asia , duration of use)
• Lipid abnormalities
• Neutropenia
• Anemia
• Gastrointestinal perforation
• Increase serum creatinine –
• Clinical significance?
• LFTs
• Malignancy
Corticosteroids in RA: there is controversy

• Use in early disease to control inflammation is reasonable though
long term use is fraught with hazard and significant adverse events
including bone fragility, hypertension,infection, glaucoma
• Some advocate for use of low dose steroids (5-7.5 mg) in addition to
DMARD and biologic use
• Our goal is to limit use of CS to lowest possible dose or none at all.
3268
If remission is achieved, can you with withdraw or lower

doses of biologics? The answer is you may be able to lower dose but
most patients will flare if you withdraw drug entirely (Smolen J et al Lancet
381:2013)
• PRESERVE trial:604 (72·4%) of 834 enrolled patients who achieved
remission on MTX/etanercept were eligible for the double-blind period, of
whom 202 were assigned to 50 mg etanercept plus methotrexate, 202 to
25 mg etanercept plus methotrexate, and 200 to placebo plus
methotrexate.
• At week 88, 166 (82·6%) of 201 patients who had received at least one
dose of 50 mg etanercept and one or more DAS28 evaluations had low
disease activity, compared with 84 (42·6%) of 197 who had received
placebo (mean difference 40·8%, 95% CI 32·5–49·1%; p<0·0001).
• Additionally, 159 (79·1%) of 201 patients given 25 mg etanercept had low
disease activity at week 88 (mean difference from placebo 35·9%, 27·0–
44·8%; p<0·0001).
Phase III Study Evaluating Continuation, Tapering, and Withdrawal of

Certolizumab Pegol After One Year of Therapy in Patients With Early
Rheumatoid Arthritis (Weinblatt ME et al. Arthritis Rheumatol 2017 Oct; 69(10): 1937–1948)
3269
Take home points

• Rheumatoid arthritis is a treatable disease with improved outcomes
when the disease is treated early
• Methotrexate is the cornerstone of therapy in most patients
• There are a variety of combinations of therapies that involve
conventional DMARDS, biologics and synthetic DMARDS that can be
used in combination with methotrexate in those with poor prognostic
factors.
• Attention to vaccine use and risk for infection is paramount
• Early referral to a rheumatologist is encouraged.
Question 1
• A 44 year-old man who is doing well on methotrexate 25mg/week for
18 months develops a cough, fever and malaise. CXR reveals a diffuse
infiltrate and small pleural effusions.
3270
Question 1
The next interventions should all be performed EXCEPT:
• A. Cessation of methotrexate
• B. Chest CT scan
• C. Emergency Bronchoscopy
• D. Broad Spectrum antibiotics and steroids
• E. Sputum for culture/sensitivity and methenamine silver as well as
1,3 beta glucan
Question 1: Answer C
• Emergency bronchoscopy
• While this may be needed eventually, other interventions should be
initiated first. If opportunistic infection ( PJP, fungal) is suspected then
bronchoscopy may be warranted. A transbronchial biopsy is useful if
granulomatous disease is suspected.
3271
Question 2
• A 50 yo female with a history of MS and sulfa allergy presents with 2
months of joint pain in her hands and feet. She is RF and CCP + high
titer , CRP 20. The patient is started on Methotrexate and increased
to 25 mg (orally then changed to subcutaneous) and 4 months later
has a modest improvement in her pain and function. Her RAPID 3
score went from 8 to 5. and CRP of 8. Her liver enzymes have been
normal except with one elevation less than 2X normal which is now
no longer present
What therapeutic options would you

consider to be the best option at this time?
• A. Begin triple therapy with MTX/HCQ/SSZ
• B. Add a TNF inhibitor
• C. Add leflunomide
• D. Add abatacept sq weekly
3272
The best answer is D

• In this pt with RA with a higher risk for poor prognosis and MS and
partial response to MTX , adding an additional agent makes sense.
• In this case TNF inhibitors are not recommended in pts with MS,
triple therapy cannot be used due to sulfa allergy
• leflunomide which can be used in combination with MTX but does
have a higher risk of liver inflammation and there were liver enzyme
abnormalities in this patient
• In this case, the best available option is to add abatacept.
Question 3
• A 50 yo female developed painful swollen joints in the wrists, hands,
knees and feet 1 year ago, high titer CCP antibody. X-rays show small
erosions in the MCPs of the hands. She is initially started on
methotrexate and then adalimumab is added with remission within 9
months. She is doing well but doesn’t like taking all of these
medications and wants to know if she can get off of them soon
3273
How would you advice this patient?

• A. you have severe erosive RA and you will be on these meds or
similar for the rest of your life
• B. Given that you are in remission, we can begin to taper one med at
a time and you should be able to get off both meds
• C. stop the methotrexate
• D. Withdrawal of medication in RA can be done but the rate of flare is
high (>60-70%) though some patients may be able to maintain
remission with less medication.
The correct answer is D

• Withdrawal of medication in RA is challenging in many patients
though recent data (3 trials so far) suggest patients may tolerate
lower doses of their medication.
3274
References
• Wasko MC, Dasgupta A, Hubert Het al. Propensity-adjusted association of methotrexate with overall survival in
rheumatoid arthritis. 2013 Feb;65(2):334-42.
• Singh JA, Saag KA, Bridges SL, et al . American College of Rheumatology Guideline for the Treatment of Rheumatoid
ArthritisArthritis & Rheum 2015; 68(1) :1-26
• O’Dell J, Mikuls T, Taylor TH et al. Therapies for Active Rheumatoid Arthritis after Methotrexate Failure N Eng J Med 2013
2013 :369(4) ;307
• Weinblatt ME et al. Phase III Study Evaluating Continuation, Tapering, and Withdrawal of Certolizumab Pegol After One
Year of Therapy in Patients With Early Rheumatoid Arthritis Arthritis Rheumatol 2017 Oct; 69(10): 1937–1948
• Solomon DH, Kremer JM, Fisher M et al. Comparative cancer risk associated with methotrexate, other non-biologic and
biologic disease-modifying anti-rheumatic drugs.2014 Feb;43(4):489-97
• Fleischmann R , Mysler E, Hall S et al Lancet. Efficacy and safety of tofacitinib monotherapy, tofacitinib with methotrexate,
and adalimumab with methotrexate in patients with rheumatoid arthritis (ORAL Strategy): a phase 3b/4, double-blind,
head-to-head, randomised controlled trial.Lancet 2017 Jul 29;390(10093):457-468.
3275
Update in Rheumatic Diseases:

Scleroderma/Sjögrens/Myositis
Laura L Tarter MD

Division of Rheumatology
Disclosures
None
3276
Outline
1. Scleroderma
2. Sjögren’s syndrome
3. Myositis
• Clinical manifestations and diagnosis

• Treatment options
Systemic Sclerosis (SSc/Scleroderma)

• Complex systemic disease that affects the
skin, lung, heart, GI tract, and kidney
• Incidence = 19 cases / million
• Pathophysiology
• Vascular and endothelial dysfunction
• Autoimmunity
• Fibroblastic activation and proliferation
3277
Scleroderma = Hardening of the Skin

• Localized scleroderma
• Morphea
• Linear scleroderma
• Systemic sclerosis
• Diffuse
• Limited (CREST)
• Sine scleroderma
• Overlap Syndrome
Katz KA, Derm Online
Limited Systemic Sclerosis: CREST

• Calcinosis
• Raynaud’s
• Esophageal Dysmotility
• Sclerodactyly
• Telangiectasias
ACR Image Bank
3278
Limited vs Diffuse SSc

Limited Diffuse
Skin thickening Face, forearms, lower Face, trunk, entire

legs, hands and feet arms/legs, hands and
feet; tendon friction rubs
Raynaud’s phenomenon Progressive disease Rapid onset following RP:
following onset of RP months to 3 years
Autoantibodies Association with anti- Association with anti-Scl
centromere Ab (50-60%) 70 ab (30%)
Internal organ Late: primarily pulmonary Early: ILD (75%),

involvement HTN (10-30%), myocardial disease,
esophageal dysmotility diffuse GI involvement,
scleroderma renal crisis
(10-15%)
Prognosis 10-yr survival > 70% 10-yr survival 40%
Skin Thickening
3279
Puffy Hands of Early SSc
Sclerodactyly
ACR Image Bank
3280
Mauskopf Facies
Natural History of Skin Tightening in SSc
Medsger TA et al. Rheum Dis N Am 2003
3281
Raynaud’s Phenomenon
• Not an infrequent initial presentation of CTDs

• Episodic, reversible digital skin color change
• White to blue to red
• Well-demarcated
• Due to vasospasm
• Usually cold-induced
3282
• Primary Raynaud’s
• Common in young women (<age 30)
• Often have + family history
• ANA mostly negative
• Secondary Raynaud’s
• Onset in > age 35
• Digital ulcers, pitting scars in fingers
• Abnormal capillary micrscopy
• Presence of autoantibodies
3283
Secondary Raynaud’s Phenomenon

• Connective tissue diseases
• SSc, SLE, MCTD, Undifferentiated CTD,
Sjogren’s syndrome, Dermatomyositis
• Occlusive arterial disease
• Atherosclerosis, Antiphospholipid Syndrome,
Buerger’s disease
• Vascular injury
• Frostbite, vibratory trauma
• Vinyl chloride, bleomycin, amphetamines,
cocaine
• Hyperviscosity/ cold-reacting proteins
Digital Ulcer in SSc
3284
Nailfold Capillaroscopy: Periungual Changes
SSc: Autoantibodies
• ANA + in nearly all cases
• Often nucleolar
• Anti-centromere
• 50-60% limited SSc
• Anti-Scl-70 (anti-topoisomerase ab)
• 30% diffuse SSc
• Anti-RNA polymerase III
• Associated with increased risk of renal crisis
• Other antibodies: anti-DNA polymerase, anti-U3-
RNP, anti-PM-Scl
• Often seen in overlap disease
3285
SSc: Internal Organ Involvement

• Interstitial lung disease
• Leading cause of mortality
• Occurs in 75% diffuse SSc
• Often within the first 4 years
• Pulmonary hypertension
• More common in limited SSc (10-30%)
• Usually occurs years into illness
• Concomitant pulmonary hypertension and ILD
• Extremely challenging clinical scenario
• Increased rate of malignant lung neoplasms
SSc: Internal Organ Involvement

• Renal Disease
• 60-80% diffuse SSc in autopsy studies
• Microalbuminuria, HTN, mild Cr rise ~ 50%
• Renal crisis 10-15% (early diffuse SSc)
• Cardiac Involvement
• Congestive heart failure, myocardial fibrosis
• Pericarditis (10-20%)
• Arrhythmias
• GI Involvement (90%)
• Esophageal hypomotility/ LES incompetence
• Gastroparesis
• Watermelon stomach (vascular ectasia in the antrum)
3286
Interstitial Lung Disease in SSc
SSc: Esophageal Dysmoliity (?Role in ILD)
3287
SSc Treatment: ILD

• Current standard of care
• Modest improvement lung function/skin scores with
Cyclophosphamide
• MMF
• Anti-fibrotics in IPF: FDA approved 2014

• Pirfenidone
• Nintedanib
• Ongoing trials in CTD ILD
• Numerous other trials in CTD ILD
SSc Treatment: Ther Has Been Progress!

• Renal: ACE inhibitors
• PAH: Prostacyclin, Endothelin antagonists,
Phosphodiesterase inhibitors
• Reflux: PPI high dose, anti reflux surgery
• Raynaud’s: Endothelin antagonists, Prostacyclin,
Phosphodiesterase inhibitors, Surgery, Botox
• Lung transplant
3288
Sullivan KM et al., SCOT Study Investigators

January 4, 2018
Key Points in Scleroderma

• ILD remains the leading cause of mortality
• Treatment options have improved
• Raynaud’s that develops > age 35 raises
concern for a rheumatic disease
• The presence of concomitant Raynaud’s and
GERD should raise suspicion for limited SSc
• Pulmonary HTN is a complication of long
standing limited SSc; screening is essential as
treatments are available that improve morbidity
and possibly mortality
3289
Sjögren’s Syndrome (SS)

• Autoimmune disorder characterized by
salivary and lacrimal gland dysfunction
• Decreased production of tears and saliva
• Primary and secondary

• Prevalence primary SS = 2-10 per 10,000
• Pathophysiology
• Proliferation and infiltration of lymphocytes in
exocrine glands
• Autoantibody production and the role of B cells in
the pathophysiology of this disease are the
source of ongoing investigation
Sicca Syndrome Manifestations

• Keratoconjunctivitis sicca
• Ocular dryness
• Corneal injury
• Xerostomia
• Oral dryness, dysphagia
• Dental caries, thrush
• Nasal dryness and epistaxis

• Vaginal dryness
• Dyspareunia
• Candidiasis
3290
Classification Criteria for Primary SS

Item Weight/Score
Labial salivary gland with focal lymphocytic 3
sialadenitis and focus score of > 1 foci/4 mm2
Anti-SSA/Ro positive 3
Ocular Staining Score >5 in at least 1 eye 1
Schirmer’s test <5 mm/5 min in at least 1 eye 1
Unstimulated whole saliva flow rate <0.1 1

mL/min
Score of >4 needed to establish dx
* exclusions: active hepatitis, head/neck xrt, sarcoidosis AIDS,
amyloidosis, IgG4-related disease
Shiboski CH et al., Ann Rheum Dis 2017
SS: Parotid Gland Enlargement
3291
SS: Corneal Abrasions
SS: Salivary Hypofunction
3292
Primary SS: Extraglandular Disease
• Peripheral neuropathy
• Vasculitis
• Interstitial lung disease (LIP, NSIP)
• Synovitis
• Risk factors for more aggressive disease:
+RF, low C4, cryoglobulinemia
• Increased risk of lymphoma
50 yo with Known SS with 8 lb Weight Loss

Lung biopsy c/w Marginal Zone Lymphoma
3293
SS: Associated Conditions

• Connective tissue diseases
• SLE
• RA
• Systemic sclerosis
• Hypothyroidism
• Autoimmune hepatitis
Sjögren’s Syndrome: Treatment

• Exocrine gland dysfunction
• Xerostomia: oral hygiene and agents to
stimulate salivary secretion
(pilocarpine/muscarinic agonist )
• KCS: cellulose products to augment tear
replacement and topical cyclosporine
• Treatment of extraglandular disease is difficult
• Trials are ongoing, mostly in the area of B cell
directed therapy
• Hydroxychloroquine may be useful in those with
fatigue and arthralgias
3294
Key Points About Sjögren’s Syndrome

• Higher risk of non-Hodgkins lymphoma in
primary Sjögrens (up to 44 fold or 5% lifetime)
• Most cases are secondary to other rheumatic
diseases
• Treatment geared towards managing sicca
symptoms and promoting oral hygiene
• Treatment of extraglandular disease is
challenging
• Patients with low titer ANA, fatigue, and eye or
mouth dryness are a significant challenge
diagnostically
Inflammatory Myopathies
• Group of autoimmune disorders
• Common feature = immune-mediated muscle injury
• Usually present with muscle weakness and
elevated muscle enzymes (CK/aldolase)
• Disorders include
• Dermatomyositis (DM)
• Polymyositis (PM)
• Overlap myositis (with another systemic
rheumatic disease)
• Inclusion body myositis (IBM)
• Necrotizing autoimmune myositis (NAM)
• Histopathologic and clinical distinctions
Senecal et al., Arth Rheum 2017
3295
Inflammatory Myopathies: DDx

• Inflammatory myopathies • Amyloid myopathy
• Drug-induced myopathies • Sarcoid myopathy
• Steroids • Metabolic myopathies
• Statins • Disorders of carbohydrate
• Colchicine and lipid metabolism
• Hydroxychloroquine • Hypothyroidism
• Alcohol • Electrolyte disturbances
• Zidovudine • Hyper/hyponatremia
• Infections • Hypokalemia
• Viral • Hypophosphatemia
• Toxoplasmosis • Hypocalcemia
• Trichinosis • Neurologic disorders
• Bacterial pyomyositis • Myasthenia gravis
• Systemic vasculitis • Motor neuron disease
• PAN, GPA, eGPA • Muscular dystrophy
Inclusion Body Myositis v

Idiopathic Inflammatory Myopathy
Inclusion Body Myositis IIM
Sex Male > female Female > male
Age Usually > 50 Common before 50
Onset Slowly progressive Acute or sub-acute
Weakness Distal and asymmetric Proximal and symmetric

muscle weakness
EMG Myopathic and neuropathic Myopathic changes
changes
Muscle biopsy Mononuclear cell infiltrates Inflammation, fiber necrosis
and vacuoles containing
amyloid
Response to Generally poor Generally good
immunosuppression
3296
IIM (Photomicrograph)
Inclusion Body Myositis (Photomicrograph)
3297
DM and PM: Clinical Features

• Proximal muscle weakness
• > 90% PM patients
• 50-60% DM patients at presentation; skin
features may precede weakness
• Amyopathic DM
• Skin findings
• Classic DM
• Not found in PM
DM: Gottron’s Papules
3298
DM: Heliotrope Rash
3299
DM: Poikiloderma (Shawl and V Signs)
DM: Nailbed
3300
DM and PM: Clinical Features

• ILD (10%)
• Cardiac disease
• Myocarditis—frequently subclinical
• 3-4x increased risk MI
• Esophageal disease
• Weakness of striated muscle of upper 1/3rd of
esophagus aspiration
ILD and Pneumomediastinum
3301
DM and PM: Autoantibodies

~ 80% ANA +
Myositis-specific Clinical syndrome Prevalence
autoantibodies
Antisynthetase Antisynthetase syndrome 20%
antibodies,
including anti-Jo-1
Anti-signal Severe myopathy, aggressive disease that 5%
recognition particle may be difficult to control
(SRP)
Anti-Mi-2 Acute onset DM, classic skin findings, good 7-30%
prognosis
Anti-MDA-5 Rapidly progressive ILD, cutaneous

ulceration involving Gottron’s papules,
arthritis, alopecia, oral ulcers, amyopathic
Antisynthetase Syndrome
• Fever
• Raynaud’s
• Inflammatory arthritis
• Mechanics hands
• ILD (can be severe)
3302
Treatment Regimens in IIM

• Corticosteroids (often with DMARD)
• DMARDs
• Methotrexate
• Calcineurin inhibition (Tacrolimus)
• Azathioprine
• Mycophenolate
• Cyclophosphamide (mostly in ILD)
• Rituximab (recent trial efficacy unclear but may
be useful in antisynthetase syndrome)
• IVIG (refractory cases)
• Abatacept (T cell co-stimulatory inhibitor)
Summary
• Scleroderma
• Recognize clinical patterns
• Major morbidity/mortality = lung disease
• There are newer treatment options!
• Sjögrens syndrome
• Recognize clinical manifestations
• Sometimes marked by systemic disease
• Higher risk for lymphoma
• Inflammatory myopathy
• Recognize clinical patterns
• Newer antibodies may help with diagnosis
• Major morbidity = lung disease
3303
Board Question #1
• 53 yo female with 20 year hx of Raynaud’s
develops fatigue and dyspnea over the
preceding 6 months
• On Nifedipine
• BP 115/80
• Exam notable for prominent P2
• PFTs show DLCO 48% predicted (low)
• 02 sat is 96% rest, 93% with activity (abnormal)
• Echo shows mild TR, PASP 48 mmHg
Board Question #1
What is the appropriate next test for

this patient?
• A. CT angiogram of the chest

• B. HRCT of the chest
• C. Pulmonary artery catheterization
• D. Exercise stress test
3304
Board Question #1
• Correct answer: C
• The longstanding history of Raynaud’s
raises the question of a CTD. Given the
decline in DLCO and echo findings, PAH
remains the greatest concern.
Board Question #2
• 51 yo man with diffuse cutaneous SSc is

admitted with new onset hypertension
associated with anemia and
thrombocytopenia
• On admission: BP 180/105; skin
thickening over face, chest, hands, legs;
lungs clear; heart RRR normal S1 S2; 1+
edema in legs
3305
Board Question #2
• Hgb 9.8 Plt 101K Cr 1.4

• UA 2+ protein, no casts
• Smear: 2+ schistocytes
• Started on captopril 6.25mg every 8hrs
• Captopril escalated to 25 mg every 8hrs
• 3 days later, BP 140/95, Cr now 2.1
• UA 2+ protein
Board Question #2
Which of the following is the most

• A. Discontinue captopril, begin nifedipine

• B. Continue to increase the captopril
• C. Start plasmapheresis
• D. Angiography to assess for RAS
• E. Order the RNA polymerase III ab
3306
Board Question #2
• Correct answer: B
• This patient has systemic sclerosis with
diffuse skin disease and is at significant
risk for renal crisis which is the case here.
Despite the continued increase in
creatinine, the ACE inhibitor should be
continued.
• The RNA poly III ab confers increased risk
for renal crisis
References
• Bournia VK, Vlachoyiannopoulus PG, Selmi C, Moutsoupoulus HM Gerswin
ME. Recent advances in the treatment of systemic sclerosis. Clin Rev
Allergy Immunol 2009:36(2-3):176-200
• Tashkin DP, Elashoff R, Clements PJ et al. for the Scleroderma Lung Study.
Cyclophosphamide versus placebo in scleroderma lung disease. N Eng J
Med 2006;354:2655-2666
• Tashkin DP, Roth M, Clements PJ et al. Mycophenolate in Scleroderma:SLS
II. Lancet 2016;4(9):708-719
• Coghlan JG, Pope J, Denton C. Assessment of endpoints in pulmonary
arterial hypertension associated with connective tissue disease. Curr Opin
Pulm Med 2010:16(suppl) S27-34.
• Meijer JM et al. Effectiveness of rituximab treatment in primary Sjogrens
syndrome: a randomized, double blind placebo controlled trial. Arthritis
Rheum 2010:62(4):960
• Dalakas M. Inflammatory Muscle disease. N Eng J Med. 2015:372:1734-47
• King TE, Jr., Bradford WZ, Castro-Bernardini S, et al. A phase 3 trial of
pirfenidone in patients with idiopathic pulmonary fibrosis. N Engl J Med
2014;370:2083-92.
• Richeldi L, du Bois RM, Raghu G, et al. Efficacy and safety of nintedanib in
idiopathic pulmonary fibrosis. N Engl J Med 2014;370:2071-82.
3307
Vasculitis/GCA/PMR
• Internal Medicine Board Review
• Paul F Dellaripa MD, Rheumatology,
Brigham and Women’s Hospital, Boston
MA
• Associate Professor of Medicine, Harvard
Medical School
Disclosures
• Up to Date
• Genentech
3308
Vasculitis: Summary
• A heterogeneous group of disorders
characterized by vascular inflammation
leading to vessel occlusion and tissue
ischemia and necrosis.
• Difficult but improving treatment options
• Pattern recognition is key to early
diagnosis and early therapeutic
intervention.
Vasculitis:Outline
• Polyarteritis nodosa: abdominal pain, skin ulcers,
neuropathy
• Microscopic polyangiitis:pulm/renal syndrome, MPO
ANCA
• Granulomatosis with polyangiitis (Wegeners
granulomatosis): upper and lower respiratory tract,
pulm/renal syndrome, PR3 ANCA predominate
• Eosinophilic Granulomatosis with Polyangiitis
(Churg Strauss):asthma, eosinophilia, pulmonary
infiltrates
• Cryoglobulinemic vasculitis:cutaneous vasculitis
• Behcets:oral and/or genital ulcers, rash, uveitis
• Takayasus arteritis: pulseless syndrome affected
females.
• Giant Cell Arteritis;headache, jaw claudication, visual
loss, PMR
3309
Vasculitis:Classification
•Small vessels (venules, arterioles) • Small and medium muscular
arteries
–Drug-induced and serum
sickness – Classic PAN
–Ig A vascullitis ( Henoch- – Microscopic polyangiitis
Schönlein purpura) – GPA (Wegener’s
–Cryoglobulinemia granulomatosis)
–Vasculitis associated with – EGPA( Churg-Strauss
systemic rheumatic diseases vasculitis)
–Vasculitis associated with – Kawasaki syndrome
malignancy – Rheumatoid vasculitis
–Hypocomplementemic – SLE
urticarial vasculitis
–Vasculitis associated with • Large arteries
infections – Giant cell or temporal
arteritis
– Takayasu arteritis
Vessel Size and Clinical Disease

Correlates
• Large vessel (GCA, Takayasu)
• Medium vessel (PAN, Kawasaki) PAN is
REALLY RARE
• Small vessel (ANCA disease (GPA (WG) or
MPA, IgA/HSP, Goodpastures,
SLE/RA/CTD,cryoglobulinemia)
• Small and Medium (Buergers, Cogan’s,
Primary CNS vasculitis, sometimes ANCA
vasculitis )
• Any or all types of blood vessels (Behcet’s,
Relapsing Polychondritis, Cogan’s)
3310
When to suspect vasculitis: clinical

features
• Multisystem disease
• Unexplained constitutional signs and symptoms
• Skin lesions (palpable purpura)
• Ischemic vascular changes (gangrene, claudication, Raynaud’s

• phenomenon, livedo)
• Glomerulonephritis
• Mononeuritis multiplex
• Myalgia, arthralgia/arthritis
• Abdominal (intestinal angina) or testicular pain
Hard to classify vasculitis

(Lamprecht, Clin Exp Rheum 2011)
• Goodpastures syndrome (DAH, glomerulopnephritis)
• Behcet’s disease ( oral/genital ulcers, arthritis,vasculitis)
• IgG4 related systemic disease (autoimmune pancreatitis,
chronic sclerosing sialadenitis, orbital inflammatory pseudotumour,aortitis,and
retroperitoneal fibrosis)
• Cogan's syndrome (vestibulitis, hearing loss, vasculitis)

• Primary CNS vasculitis
• Intestinal vasculitis
• Chronic periaortitis
• Thromboangiitis obliterans (Burger’s disease)
3311
Conditions that mimic systemic

vasculitis
• Atheroembolic disease
• Cardiac myxoma
• Thrombotic disorders
– Anti-phospholipid antibody syndrome
– Thrombotic thrombocytopenic purpura
• Drug-induced vascular damage
– Ergot derivatives
– Cocaine
– Amphetamines
• Infective endocarditis
What is this ?
• Raynauds/acral
necrosis
• Antiphospholipid Ab
• Endocarditis
• Small vessel
vasculitis (including
RA)
• Medium vessel
vasculitis
3312
Pathogenesis
• Immune complex deposition ( SLE, cryos,
HSP)
• Ab vs vascular structures ( antiGBM)
• Ab against no vascular structures (ANCA)
• Cell mediated tissue injury, Th1, IL-6,
TH17 (GCA, TA)
ACR 1990 criteria for classification of

polyarteritis nodosa (1-4)
• Must have at least 3 of the 10 criteria present.
– Weight loss > 4 kg
– Livedo reticularis
– Testicular pain or tenderness
– Myalgias, weakness, or leg tenderness
– Mononeuropathy or polyneuropathy
– Diastolic BP > 90
– Elevated BUN/creatinine
– Hepatitis B virus
– Arteriographic abnormality
– Biopsy of small or medium artery containing PMN
• Sensitivity 82.2% and Specificity 86.6%
3313
Real world considerations for

PAN
• Middle aged male
• Fever, weight loss, and abdominal pain
• Elevated inflammatory markers
• Hypertension
• Neuropathy
• No glomerulonephritis
• Can be associated with Hepatitis B
3314
Polyarteritis nodosa: wrist drop
PAN: sural nerve
3315
Case
• 26 yo presented in the spring 2010 with
right flank pain, CT scan showed a right
renal infarct. Pt treated with
anticoagulation after an unremarkable
evaluation for hypercoagulability and then
developed a hematoma. He had mild
fatigue but otherwise was well.
• An MRI/A was performed
3316
3317
ANCA associated vasculitis

• Include Granulomatosis with Polyangittis (Wegener's
Granulomatosis ), microscopic polyangitiis and
EGPA (Churg Strauss) and drug induced vasculitic
syndromes (PTU, allopurinol, levamisole tainted
cocaine)
• Morbidity associated with these diseases typically
related to renal failure due to do glomerulonephritis
or pulmonary hemorrhage/respiratory failure
• Mortality often related to disease progression but
more often treatment associated infection. In
fact,vasculitis that appears to be worsening
should be considered an infection until proven
otherwise.
ANCA Associated Vasculitis

• C-ANCA with PR3 reactivity most commonly found in
GPA (Wegener’s ), though p-ANCA-MPO has been
noted in 10% of cases of WG
• P-ANCA-MPO most often seen in microscopic
polyangitiis. Occasionally ANCA and anti-GBM can
be concurrent
• Very high titer ANCA (esp MPO ) raises possibility of
drug induced vasculitis (including cocaine)
• In initial treatment, the ANCA type is irrelevant,
though mortality is higher with PR3 ANCA
• ANCA is useful diagnostically but does not
necessarily predict relapse
3318
Anticytoplasmic autoantibodies
Granulomatosis with Polyangiitis

(formerly Wegener's Granulomatosis)
• Classic patterns include upper respiratory
symptoms, sinusitis, epistaxis, hearing loss, otitis
media (remember, adults otherwise rarely get otitis
media)
• Lower respiratory symptoms ( bronchitis,
hemoptysis due to capillaritis)
• Glomerulonephritis
• Mononeuritis multiplex, cranial neuropathy, orbital
pseudotumor
• Constitutional symptoms (fever, weight loss,fatique)
3319
Immunohistopathology: ANCA
reuslts in a pauci-immune
patholgy
• GPA(Wegeners): scant or no immune
deposits
• SLE: clumpy immune complex
deposition
• Goodpastures:linear IgG deposition
along the glomerular basement
membrane
3320
3321
3322
3323
Microscopic polyangiitis
• Present with GN as major clinical
finding
• Mononeuritis multiplex
• Alveolar hemorrhage
• Sometimes difficult to distinguish from
GPA(WG)
• ANCA in pANCA pattern (MPO ab)
Eosinophilic Granulomatosis with

Polyangiitis ( Churg Strauss
Syndrome)
• Asthma
• Eosinophilia
• Non fixed pulmonary infiltrates
• Paranasal sinus abnormality
• Extravascular eosinophils (biopsy)
• Mononeuropathy or polyneuropathy
3324
Clinical features of CSS

• Phase I: adult onset asthma, most require
steroids for control
• Phase II: eosinophilic infiltrates in the lung
and GI tract. Lung infiltrates are typically
peripheral, patchy and asymmetrical.
• Phase III:constitutional symptoms and
systemic disease, peripheral neuropathy, CNS
vasculitis, mesenteric ischemia, cutaneous
vasculitis
• cardiac involvement with myocarditis is
the leading cause of death.
3325
3326
What could this be?

• PAN ( necrotic lesions, often nodular)
• Cocaine associated ANCA disease (
typically skin disease)
ACR classification criteria:

Takayasu arteritis (13,14)
• Must have at least 3 of the 6 criteria present.
– Age < 40 years at disease onset
– Claudication of extremities
– Decreased brachial artery pulse
– BP difference > 10 mm Hg between arms
– Bruit over subclavian arteries or aorta
– Arteriogram abnormality: occlusion or narrowing in
aorta or main branches
– Think young female, pulseless, constitutional
symptoms!
3327
Takayasu’s arteritis
Criteria for diagnosis of Behçet’s

disease (15,16)
• Recurrent oral ulceration plus two of the
following:
– Recurrent genital ulceration
– Eye lesions (anterior/posterior uveitis or cells
in vitreous or retinal vasculitis)
– Skin lesions (E. Nodosum, pseudofolliculitis,
papulopustular lesions or acneiform nodules)
– Positive pathergy test
• Sensitivity 91% and specificity 96%
3328
Behçet’s syndrome: ulceration,

tongue
Folliculitis in Behcet’s
3329
Ulcerations on scrotum in
Behcet’s
Cryoglobulinemia
• 3 types ( I, II, III) with Type II ( hepatitis C)
and III (CTDs)
• Immune complex mediated vasculitis with
complement consumption (low C4)
• Mixed cryo associated with both IgG and IgM
• IgM is often monoclonal and specific for Fc of
the IgG ( presence of rheumatoid factor)
• Nerve, skin and rarely renal and lung
involved.
• Need to treat the Hep C infection long term
to control the vasculitis
3330
Cryoglobulinemia: ear
necrosis
Cryoglobulinemia
3331
Treatment regimens:Vasculitis
• May need to start Treatment prior to having a clear
diagnosis. Always rule out infection!
• Rituximab effective in ANCA associated disease; non
inferior compared to CYC in both new onset and relapsing
disease (RAVE trial NEJM 2010) with steroids
• Oral cyclophosphamide 2mg/kg/day adjusted for renal
function in severe cases or intravenous CYC .5 mg/m2 q3-4
weeks , which may be safer
• Plasmapheresis: may be useful in ANCA associated
disease/cryoglobulinemia where standard regimen is not
effective or renal disease is rapidly progressive (renal
failure Cr >5.7 perhaps in DAH)
• Corticosteroids and now IL-6 inhibition in Takayasu
• In Behcets TNFi like infliximab and adulimumab.
• Other therapies include mycophenolate, azathioprine,
methotrexate,abatacept
• Antiviral therapy in Hep C associated cryoglobulinemia
Board Question
• 74 yo male is hospitalized with diffuse
alveolar hemorrhage over a period of a
few days. He had a prodrome of malaise
and arthralgia for several weeks.
• In the ICU his serum creatinine is 7.4
mg/dl, urinalysis shows 3+protein, many
RBCs, scattered red cell casts.
• He is intubated, with copious bloody
secretions evident from the ETT.
3332
Which of the following antibodies is the

patient most likely to have
• A. AntiSm antibodies
• B. AntiGBM antibodies
• C. p-ANCA MPO (myeloperoxidase)
• D. c-ANCA PR3
• E all of the above
Correct answer
• E is correct
• This case is an example of the
pulmonary renal syndrome. This clinical
pattern can be seen in SLE, ANCA
associated disease, and Goodpastures
and so all of the antibody testing are
reasonable.
3333
Board Review
• 45yo male with long standing asthma
• New onset fever, fatigue , skin rash and
worsening dyspnea.
• Using albuterol inhaler more frequently and
requiring more oral steroids and was recently
started on a leukotriene antagonist.
• Complains of diffuse abdominal pain
• CXR shows bilateral patchy infiltrates, and
WBC count is 15,000/ul with 25% eos.
Which of the following is the

correct next step
• A. Increase inhaled steroids
• B. Begin plasmapheresis
• C. Increase the prednisone from 10 mg
to 20 mg orally per day
• D Begin intravenous corticosteroids.
• E. perform an open lung biopsy
3334
• Correct answer is D
• This patient has Eosinophilic
Granulomatosis with Polyangiitis ( CSS) .
• He has severe systemic manifestations
with mononeuritis and should be treated
with intravenous steroids in high doses.
• The decision to use steroid sparing agents
or cytotoxic therapy depends on severity
of disease
Giant Cell Arteritis

• Systemic vasculitis of large and medium vessels
of unknown etiology characterized by
transmural inflammation, granuloma formation,
and luminal occlusion of the cranial blood
vessels (16).
• Annual incidence is North America is 19-32 per
100,000 in persons > 50 yrs
• Cell mediated immune processes are important
in this disorder. IL-6, IL17, interferon gamma,
IL1B and TH-17 play important but varying roles
in pathogenesis and clinical manifestations.
3335
GCA: Clinical manifestations

• Headache (scalp tenderness, including
posterior)
• Jaw claudication due to facial artery
involvement ( sometimes rarely presenting as
trismus)
• Visual loss due to retinal and posterior ciliary
artery vasculitis. ( blurriness, diploplia)
• Permanent visual loss noted in up to 15% of
cases
• Though rare, there is a long term risk of thoracic
aneurysm
Giant Cell Arteritis:other

manifestations
• Weight loss
• Fever ( including FUO)
• Polymyalgia rheumatica
• Ischemia of the head, neck or extremities
due to occlusive disease of the carotid,
subclavian and vertebral arteries
• Carotidynia
• Cough
3336
Giant Cell arteritis: Diagnosis

three of the following five criteria was associated with a 94% sensitivity and 91%
specificity)
• Age greater than or equal to 50 years at time of

disease onset
• Localized headache of new onset
• Tenderness or decreased pulse of the temporal
artery
• Erythrocyte sedimentation rate greater than 50
mm/h (Westergren)
• Biopsy which includes an artery, and reveals a
necrotizing arteritis with a predominance of
mononuclear cells or a granulomatous process
with multinucleated giant cells
Headache in GCA
• Scalp pain
• Location can be temporal, posterior,
occipital
• “My hair hurts to brush”
• Tongue pain
• Ear, nose pain, jaw pain, trismus
• “throat pain”
3337
Retinal ischemia due to GCA
3338
Aortic dissection: a rare

complication of GCA
Diagnosis: GCA
• Laboratory markers: ESR, CRP, alkaline
phosphatase, IL-6 though inflammatory
markers may be normal or low in a small
number of cases
• Whenever there is a reasonable suspicion of
GCA, a temporal artery biopsy should be
performed. The morbidity of a biopsy is low
• It is preferable to obtain a biopsy prior to starting
therapy but pathologic findings can persist for up
to several weeks after starting steroids, so
therapy should not be delayed if a biopsy cannot
be obtained promptly
• Ultrasound emerging as a diagnostic test
though false negative and positives have
been noted
3339
3340
Treatment of GCA
• Prednisone 40-80 mg per day for 4 weeks
• Reduce to 20 mg per day by third month
• Reduce by 5 mg every 2-4 weeks and then at 10 mg
reduce by 1 mg every 4-6 weeks, total therapy up to 2
years
• Benefit of intravenous corticosteroids with visual
symptoms is unclear but reasonable to consider
• IL-6 inhibition: FDA approved for GCA with shortened
course of steroids ( Stone et al NEJM 2017)
• Methotrexate as steroid sparing not effective
• No evidence that TNF blockade is effective
• Low dose ASA may reduce ischemic events in GCA
• Th1 and Th-17 blockade:(Ustekinumab) ?role in
refractory GCA (Conway et al Ann Rheum Dis 2016)
Board question
• 82 year old healthy female ( no meds) is
evaluated for a 2 week history of headache and
neck pain. She also complains of achiness of the
shoulders, neck , and lower back. She had two
episodes of blurriness in her right eye transiently
last week but none now.
• On exam the scalp is diffusely tender,
carotidynia noted , ROM limited due to pain in
shoulders. Vision normal.Reflexes normal in
UEs.
• ESR 24 mm/h, CRP 1.0 Hgb 11.7 CK 150
3341

appropriate next step at this time?
• A MRI of head
• B EMG
• C Prednisone 1 mg/kg per day
• D Prednisone 15 mg per day
• E Doppler US of the carotid artery
• F Temporal artery biopsy
• Correct answer C
• This patient has a significant risk for GCA
and should be treated immediately
regardless of access to biopsy
• The low ESR and CRP can be seen in
GCA and should not dissuade treatment
and further diagnostic testing
3342
Pearls : GCA
• GCA is a strong consideration in the elderly with new
onset headache, neck ache , visual changes or
unexplained fatigue or anemia
• Jaw claudication is the most specific sign of GCA,
followed by visual loss and TA tenderness
• A more robust inflammatory response is correlated with a
lower risk for visual loss.
• Patients with a low or normal ESR and CRP can have
GCA If one biopsy is negative, the additional yield of a
contralateral biopsy is modest but is reasonable to
consider performing.
• A rising ESR in a treated for GCA does not necessarily
suggest that GCA is returning
• IL-6 inhibition is the first FDA approved treatment in GCA
Polymyalgia Rheumatica
• Age>50
• 1 month duration of morning stiffness in 3
or more areas ( shoulders, hips, thighs
and neck)
• ESR >40 mm/hr
• Exclusion of other diseases
3343
3344
PMR: Differential diagnosis

• Polymyositis
• Rotator cuff tendonitis
• Parkinson's disease
• Giant cell arteritis
• Fibromyalgia
• Malignancy
PMR treatment
• Corticosteroids should result in substantial and often
gratifying improvement in symptoms in low dose ( <20
mg/day prednisone). If response is underwhelming
reconsider diagnosis
• With resolution of symptoms and normalization of ESR (
typically 1-2 months) , taper steroids by 2.5 mg every 2-4
weeks until 10mg/day and then taper by 1 mg per month.
Typical duration of treatment is up to 2 years or longer.
Relapse is not uncommon.
• Unknown benefits though anectodes for DMARDsand
biologics (hydroxychloroquine, MTX or Tocilizumab)
3345
PMR treatment
• In patients with high clinical suspicion of
disease where prednisone is not effective,
consider the use of methylprednisolone, as
some patients do not metabolize prednisone.
• Other agents, including MTX,
hydroxychloroquine, other DMRDS and now IL-6
inhibition may be helpful but limited trials
PMR pearls
• Synovitis of the hands can occur in PMR
• A normal ESR does not exclude the diagnosis
• 15-20% of patients with PMR will develop GCA
• Consider a temporal artery biopsy if persistent
constitutional symptoms or inflammatory
markers remain high.
3346
Vasculitis: Take home Points

• A heterogeneous group of disorders
characterized by vascular inflammation
leading to vessel occlusion and tissue
ischemia and necrosis.
• Emerging, more targeted treatment
options on the horizon
• Pattern recognition is key to early
diagnosis, early therapeutic intervention
and limiting end organ damage.
References
• Stone JH et al. Rituximab versus cyclophosphamide for ANCA-associated
vasculitis. N Engl J Med. 2010;363(3):221.
• Yates M, Watts RA Bajema IM et al. EULAR/ERA-EDTA recommendations for

the management of ANCA-associated vasculitis. Ann Rheum Dis 2016;75:1583-
1594
• Guivellin L et al Rituximab versus azathioprine for maintenance in ANCA-

associated vasculitis. N Eng J Med. 2014;371(19):1771-80
• Stone JH et al. Trial of tocilizumab in giant cell arteritis. N Eng J Med

2017;377:317-328
• Alibaz-Oner F, Aydin SZ, Direskeneli H. Recent advances in Takayasu arteritis

• Eur J Rheumatol.2015;2(1):24-30
• Hatemi G et al. Behçet's syndrome: a critical digest of the 2014-2015 literature.

Clin Exp Rheumatol. 2015 33(6 Suppl 94):S3-14
3347
Soft Tissue Rheumatism
Elinor Mody, MD
Chief, Division of Rheumatology
Reliant Medical Group
Some problems are difficult, but diagnosing

and treating most causes of joint pain are not!
3348
Common areas of pain
• Shoulder
• Elbow
• Wrist
• Hip
• Knee
• Ankle
Some definitions
• Tendon: The collagenous portion of a muscle at the

origin and insertion.
• Enthesis: The attachment of a tendon to bone.
• Bursa: Two membranes and the lubricated space
between, that allows near-frictionless motion of soft
tissue over bone.
• Ligament: Collagenous tissue connecting two bony
structures.
• Fascia: A layer or sheet of fibrous tissue that
separates or covers various soft tissues or organs.
3349
Tendinitis
• History
Pain with active motion
Weakness
May elicit an overuse history
• Exam
Little discomfort with passive ROM
Isometric contraction is always tender.
Palpable tendons usually tender
Bursitis
• History
Weakness not prominent
May elicit an overuse history
• Exam
Passive ROM more uncomfortable than tendinitis
Isometric contraction is tender
Palpable bursae tender
3350
Arthritis
• History
Weakness only related to pain
AM stiffness
• Exam
Passive ROM as uncomfortable as AROM
Isometrics not tender (the joint isn’t moving)
Crepitus in OA
Joint aspirate often inflammatory
Shoulder: Common causes of shoulder pain
• Tendinitis: Rotator cuff (+/- Ca2+), biceps

• Bursitis: Subacromial and subdeltoid bursae
• Adhesive capsulitis
• Arthritis: Glenohumeral, AC
• Neuropathy: Cervical, notalgia
• Dislocation/trauma: GH, AC separation, Fx
• Other: Cellulitis, pneumonia, cardiac
3351
Shoulder: Normal anatomy
3352
“Empty Can Test
» Tests Supraspinatus
» Arm abducted 90 degrees in pronation
» Downward pressure applied
3353
Napoleon Test
» Tests subscapularis
» Press belly with elbow at 90 degrees
» Pain or inability to perform suggests
subscapularis tendonitis/derangement
External Rotation Lag
» Tests Infraspinatus
» Hold arm in external rotation with elbow at
90 degrees
» Inability to maintain suggests infraspinatus
tendonitis/derangement
3354
Hawkins- Kennedy
» Tests for subacromial impingement

» Hold arm at 90 degrees flexion, with elbow
at 90 degrees.
» Forcibly internally rotate shoulder
» Pain with this maneuver suggests
impingement
Shoulder: Subacromial approach
3355
Shoulder: Posterior approach
Shoulder: Normal arthrogram
3356
Shoulder: Chondrocalcinosis and AC

osteophytes
Other therapies
• Systemic Steroids or NSAIDs
• Disease-specific therapy, e.g. colchicine for
crystal disease
• MR imaging indicated primarily to guide
surgery. Not needed for diagnosis or
treatment.
3357
Elbow
• Lateral epicondylitis (actually an enthesitis)

• Olecranon bursitis
• Arthritis is uncommon
Elbow: Lateral epicondylitis
3358
Elbow: Tennis elbow strap
Elbow: Olecranon bursitis
3359
Elbow: Olecranon bursitis
Other therapies
• Steroids or NSAIDs
• Disease-specific therapy, e.g. colchicine for
crystal disease, antibiotics for infection, etc.
• Steroid injection of olecranon bursa should
be avoided, due to risk of infection
3360
Wrist
• Fracture: Colle’s
• Arthritis: Crystal
• Median neuropathy: carpal tunnel syndrome
• deQuervain’s tenosynovitis
Carpal tunnel syndrome
• Often overweight, middle-aged patient

• May have history of overuse/misuse
• Night pain, numbness in median distribution
• Tinel’s & Phalen’s signs
• EMG/NCS only necessary prior to surgery
• Therapeutic options include splint, rest, steroid
injection, surgery
3361
Wrist: rest
Wrist: splint
3362
Wrist: Aspiration/Injection
Hip
• Bursitis
• Tendinitis
• Groin “pull”
• Arthritis
• Referred from spine
3363
Hip: Bursitis
Hip: Trochanteric bursitis
3364
Hip: Trochanteric bursa injection
Knee
• Trauma: meniscal or ligamentous tear, Fx

• Arthritis: Inflammatory and OA
• Bursitis: Pre-patellar, pes anserine, etc.
The knee is the first joint we’ve discussed

today where routine plain films are often
helpful!
3365
Knee: Normal Anatomy
Knee: Normal Anatomy
3366
Knee: Chondrocalcinosis
Knee: Osteoarthritis
3367
Ankle
• “Sprain” = traumatic ligamentous tear
• Fracture
• Arthritis
– OA is uncommon in the ankle
– Crystal arthritis is common
• Tendinitis
– Peroneus longus et brevus
– Tibialis posterior/FHL
– Tibialis anterior
• Neuropathy, e.g. Tarsal tunnel syndrome
Ankle: Normal
3368
Ankle & Foot: Normal
Ankle: Aspiration/Injection
3369
Summary
• Joint, tendon, and bursal pain are among the most

common reasons patients seek medical attention.
• A diagnosis is frequently evident after a proper
history and exam. Usually, a film or other test is
NOT required for accurate diagnosis and treatment.
• Embrace the principle of local therapy for a local
problem.
3370
SLE and the Antiphospholipid Syndrome
Susan Y. Ritter MD, PhD

Associate Physician
Division of Rheumatology, Immunology and Allergy
Disclosures
• Spouse is employee of Pfizer
3371
Overview
• SLE – different presentations and severity
• Classification criteria
• Cutaneous and drug induced
• Treatment
• Antiphospholipid Syndrome
SLE Epidemiology
• Prevalence ~1 in 1000
• Most common in females in reproductive
years
• 9:1 female : male ratio
• More common in Black, Latino and Asian
3372
What is Lupus?
• Great imitator
• Many different organ-systems may be involved
• Disease occurs in the presence of
autoantibodies—most commonly ANA
Many faces of SLE

• 51 yo white male—glomerulonephritis (GN), + ANA, +
dsDNA, seizures
• 32 yo black female—arthritis, discoid rash, pleurisy, +

ANA, + Ro
• 52 yo female— thrombocytopenia, hemolytic anemia,

renal disease, +ANA, + APLA
• 27 yo female –fevers, class V GN, low WBC, + ANA, +

dsDNA, low complements, arthritis
3373
What is shared?
• Positive autoantibodies
• Clinical manifestations suggestive of SLE
Classification Criteria for SLE

4 are necessary, and 1 should be + ANA
• Malar Rash • Neurologic: seizures or psychosis
• Discoid Rash
• Photosensitivity • Hematologic: anemia, leuko or
• Apthous ulcers lymphopenia, thrombocytopenia
• Arthritis • Immunologic: anti-DNA, anti-

Smith, antiphospholipid antibody
• Serositis (pericarditis or pleuritis)
• Positive ANA
• Renal (proteinuria or casts)
3374
Other common symptoms

• Fatigue
• Headaches
• Malaise
• Cognitive impairment “lupus fog”
• Myalgias
Case 1
• 33 yo woman comes to see you.
• She has mouth sores and a rash over the
bridge of her nose that looks like this:
3375
3376
Case 1: continued
• Her PCP sent off an ANA that was positive at a
titer of 1:320 and she had dsDNA at 45 units.
• Does she have SLE?
Case 1:
• Malar rash
• Photosensitivity
• Aphthous ulcers
• Positive ANA
• Positive anti-dsDNA
3377
Other skin manifestations of SLE
Discoid lupus
3378
Cutaneous Lupus: Discoid Lupus

• Patient have defined plaques that become
thickened over time. Can scar and leave
hypopigmented lesions
• 10-15% of patients develop systemic lupus—in
those that are ANA positive
• In SLE patients, 10-15% will have discoid lesions
• Treatment: sun avoidance, antimalarials,
dapsone, immunosuppressive agents,
thalidomide
Cutaneous Lupus: SCLE (subacute

cutaneous lupus erythematosus)
• More common in Caucasians
• 75% are women
• Lesions occur in sun-exposed areas
• Two types of lesions:
– Papulosquamous
– Polycyclic annular
3379
SCLE
Other Skin Findings in SLE

• Alopecia
• Vasculitis
• Raynaud’s
• Bullous lesions
• Urticarial lesions
• Panniculitis
• Nail lesions
3380
Alopecia
Raynaud’s
3381
Case 2
• 40 yo man whom you have been following for
several years with SLE (malar rash, positive
serologies and renal disease) complains of
chest pain when he takes a deep breath
• Is this related to lupus?
Pulmonary Manifestations of SLE

• Pleuritis
• Lupus pneumonitis
• Chronic interstitial lung disease
• Pulmonary hemorrhage (high mortality)
• Shrinking lung syndrome (secondary to
diaphragmatic paralysis and lung disease)
3382
Case 3
• 35 yo female whom you have followed for SLE
for many years (joint symptoms, renal disease,
positive serologies, requiring steroids) has
read on the internet that she is at risk for
having a heart attack
• How do you counsel her?
Cardiovascular Manifestations of SLE

• Accelerated atherosclerosis
– Disease + drugs
• Pericarditis
• Valvular heart disease—usually in conjunction
with the antiphospholipid syndrome
• Coronary vasculitis—rare
• Myocarditis—rare
3383
Case 4
• 32 yo woman referred from her PCP with one
month of joint swelling affecting her PIPs and
MCPs. She has a history of psoriasis and her
PCP believes she has psoriatic arthritis.
Case 4: continued
• Despite being placed on NSAIDs and low dose
steroids, she continues to feel unwell.
• Calls your office with fevers 102, feels terrible
• Initial labs reveal a WBC 2.8.
• You decide to send off an ANA which returns
at 1:1280 and dsDNA is 84.
3384
Jaccoud’s arthropathy
Musculoskeletal manifestations of SLE

• 95% will have musculoskeletal complains
• Arthralgias and arthritis
• Septic arthritis
• Osteonecrosis—risk increases with steroid use > 20
mg per day
• Myositis—more commonly seen in patients with
Mixed Connective Tissue Disease (MCTD)
• Myopathy—secondary to steroids—proximal muscle
weakness
3385
Case 5
• 25 yo woman referred to you with anemia and
thrombocytopenia
– Hemocrit 25
– Platelet count 90,000
• She has a history of pleuritis
• Positive ANA and false positive VDRL
Hematologic manifestations of SLE

• Anemia—usually Coomb’s positive
• Leukopenia—WBC < 4000
• Lymphopenia—Lymphocytes < 1500
• Thrombocytopenia—Platelets < 100,000
3386
Case 6
• 29 yo woman with history of mild SLE
(arthritis, malar rash, positive serologies)
presents with edema, proteinuria, and RBC in
her urine
• What do you do?
Renal disease in SLE

• Proteinuria > 500 mg protein/24 hr urine
• Presence of casts
3387
WHO Classification
• Class I: Normal or Minimal Change
• Class II: Mesangial glomerulonephritis
• Class III: Focal proliferative glomerulonephritis
• Class IV: Diffuse proliferative
glomerulonephritis
• Class V: Membranous glomerulonephritis
• Class VI: Global sclerosis > 90% sclerosed
lesions
Activity vs. Chronicity

• Look for the degree of activity in the involved
renal specimen
• High disease activity implies better response
to therapy
• Chronic lesions are scarred, and will not
improve with immunosuppression
3388
Case 7
• 25 yo woman with history of SLE (hematologic
and arthritis) presents with altered mental
status
Neuropsychiatric Manifestations of SLE
Neurologic Psychiatric
• CVA • Psychosis
• Seizures • Cognitive disorder
• Transverse myelitis
• Pseudo dementia
• Optic neuritis
• Meningitis • Functional
• Headaches
• Organic brain syndromes
• Neuropathies
• Associated with
antiphospholipid antibodies
3389
Other SLE manifestations

• Sjogren’s Syndrome
• GI abnormalities
– Abdominal pain
– Anorexia
– Peritonitis
– Pancreatitis
– Hepatitis
• Secondary fibromyalgia
Case 8
• You are asked to see a 38 yo woman with a
history of a rash over the bridge of her nose
which she has been told is acne rosacea and
some joint achiness
• She has an ANA sent that is positive at 1:40
• Does she have lupus?
3390
Few notes about ANA test

• ANA test was not designed as a screening test
• Up to 20% of healthy adults, particularly women, have
a low titer ANA and do not go on to develop rheumatic
diseases
• Causes of false positive tests:
– viral infections
– family history of rheumatic disease
– other autoimmune disease like GI or thyroid disease
• Once a patient has a positive ANA, it does not need to
be retested, unless symptoms change and there is an
increased suspicion for a rheumatic disease.
Autoantibodies in SLE
• ANA found in 95% of patients
• Anti-dsDNA in 40-80% of patients
• Anti-Sm 25% of patients
• Anti-histone—seen in drug induced SLE
• Anti-Ro(SSA), Anti-La(SSB)– Sjogren’s, SCLE
• Anti-RNP—Mixed Connective Tissue disease
• False positive VDRL—antiphospholipid
antibody
3391
Choosing Wisely Campaign

Don’t test ANA sub-serologies without a positive ANA and
clinical suspicion of immune-mediated disease.
• Tests for anti-nuclear antibody (ANA) sub-serologies are

usually negative if the ANA is negative.
• Exceptions include anti-Jo1, which can be positive in
some forms of myositis, or occasionally anti-SSA, in the
setting of lupus or Sjögren’s syndrome.
• Broad testing of autoantibodies should be avoided;
instead the choice of autoantibodies should be guided by
the specific disease under consideration.
www.rheumatology.org/FiveThings
Case 9
• 63 yo man started on procainamide for an abnormal
heart rhythm.
• He develops joint pain and a skin rash
• Work-up reveals a positive ANA and anti-histone
antibody
3392
Drug Induced SLE

• Patients present with lupus-like illness
• Usually arthritis, rash and serositis
• Positive ANA and anti-histone antibody
• Rare to have renal, neuropsychiatric or
vasculitic disease
• Often responds to drug withdrawal, NSAIDs or
low dose prednisone
Drugs Involved in Drug-Induced SLE
3393
Drugs Involved in Drug-Induced SLE

Common Rare
• Procainamide • Beta-blockers
• Hydralazine • D-Penicillamine
• INH
• Quinidine
• PTU
• Hydantoins
• Trimethadione
• Chlorpromazine
General Treatment Advice in SLE

• Sun avoidance and protection
• Diet
• Exercise
• Smoking cessation
3394
Lupus Flare
• A flare is a measurable increase in disease
activity in one or more organ systems
involving new or worse clinical signs and
symptoms and/or laboratory measurements.
It must be considered clinically significant by
the assessor and usually there would be at
least consideration of a change or an increase
in treatment.
International consensus for a definition of disease flare in lupus. Ruperto et al. Lupus. 2011 Apr;20(5):453-62.
Treatment: Mild Disease

• Symptoms: low grade fever, rash, arthralgia, fatigue
• NSAIDs
• Antimalarials—hydroxychloroquine most common
• Low dose prednisone < 10 mg/day
3395
Treatment: Severe Disease

• Steroids: 0.5-1 mg/kg/day—renal, CNS
• Cyclophosphamide—monthly pulses 500-1000
mg/m2 or biweekly for 12 weeks—renal, CNS
• Azathioprine—renal
• Mycophenolate mofetil—renal, skin
• Tacrolimus –renal, skin
• Methotrexate – arthritis, skin
• Belimumab– steroid resistant serositis and
arthritis
Other therapies (off label)

• Cyclosporine A
• Rituximab
• Abatacept– joint symptoms, in trials for renal
disease
• Bone marrow transplant
3396
Summary of SLE
• SLE is a multi-system autoimmune disorder
• SLE can look like many different disease entities
• To diagnose SLE, the ANA should be positive
• A positive ANA dose NOT make a diagnosis of SLE
• Direct treatment towards the underlying system
involved
• All patients unless contraindicated should be offered
hydroxychloroquine
• Can use steroids and other immunosuppressives
• Biologics other than belimumab are under
investigation
Antiphospholipid Antibody
Syndrome
3397
When to think about antiphopholipid

antibodies?
• Early miscarriages
• Stroke/TIA in younger patients
• DVT/PE
• Patients with lupus
Antiphospholipid Antibody Syndrome:

Major criteria
• Presence of an anticardiolipin antibody (IgG or
IgM) and/or lupus anticoagulant on 2 separate
occasions 12 weeks apart PLUS one of the
following clinical events:
• Arterial thrombotic event
• Venous thrombotic event
• Recurrent pregnancy losses
– 2 or more 1st trimester losses
– 2nd trimester loss or severe intrauterine growth
restriction
3398
Other clinical features

(not part of criteria)
• Coomb’s positive hemolytic anemia
• Livedo reticularis
• Raynaud’s phenomenon
• Migraines and cognitive dysfunction
• Valvular vegetations or thickening
• Renal disease—thrombotic microangiopathy
Associated medical conditions

• Sneddon’s syndrome: Strokes and livedo
reticularis in young women
• Evan’s syndrome: Thrombocytopenia and
Coomb’s positive hemolytic anemia
• CVAs and MIs in individuals under 40
• SLE
• Catastrophic APS (CAPS)—sudden multisystem
occlusive disease
3399
Antiphospholipid Antibody Tests

• Lupus Anticoagulant
• Anti-Cardiolipin
• Beta-2 glycoprotein I
Lupus Anticoagulant
• In vitro prolongation of clotting test
– In vivo it is a pro-coagulant
• Activated PTT, platelet neutralizing procedure,
dilute Russell Viper Venom time are used
• Lupus anticoagulant should be confirmed by
adding phospholipid and normalizing the test
result
3400
3 Possibilities
Lupus Anticoagulant Confirmatory What dose it mean?
- Negative
+ - Negative
+ + Positive
Anticardiolipin Antibodies
• ELISA test: standardized using international
standard—GPL units
• All subsets: IgG, IgM, IgA, IgD can be seen, but
IgG is the most clinically relevant
• Clinically relevant titer is ≥ 40 units
3401
Anti-beta-2 glycoprotein I
• ELISA test
• IgG and IgM forms
• Clinically relevant titer is ≥ 40 units
• dRVVT (used with LAC) is sensitive to the
presence of anti-beta-2-glycoprotein I
• Closely correlated with thrombotic events
Antibodies in Various Patient

Populations
• Healthy controls: 1-2%
• Recurrent miscarriage population: 5-10%
• SLE: 20-40%
• SLE with livedo or Raynaud’s: 80%
• Stroke, MI under age 40: 20%
• HIV infected: IgM 50-60%
3402
Who should be evaluated for

antiphospholipid antibodies?
• SLE patients
• Patients under age 40 with CVA, MI, no
obvious risk factors
• Recurrent venous or arterial clots
• Women with recurrent first trimester
pregnancy losses, or second trimester loss
Treatment: Patients with documented

clot + antibodies
• Lifelong anticoagulation—generally warfarin
• Target INR 2.5
• Recurrent episodes, severe arterial episodes,
target INR 3-3.5
• There is insufficient data regarding the efficacy

of direct oral anticoagulants in this condition.
3403
Treatment: Antibodies in the absence

of clinical events
• Some advocate the use of prophylactic aspirin
therapy in those with positive antibodies. This
therapy has NOT been shown to decrease the
risk of clotting episodes except in patients
with co-existing SLE
Catastrophic Antiphospholipid
Syndrome (CAPS)
• Consider when multiple clots over 7 days
– Renal failure, diffuse alveolar hemorrhage, adrenal
hemorrhage, encephalopathy can be seen
– Can look similar to other thrombotic
microangiopathies
• Treatment with anticoagulants,
corticosteroids, IVIG and plasma exchange
– Some use Rituximab or Eculizumab (off label) if
refractory
3404
Summary of APS
• The antiphosholipid syndrome is defined as:
– Arterial clots, venous clots or obstetrical
complications in the presence of an
antiphospholipid antibody
– The antibody testing needs to be positive on 2
separate occasions at least 12 weeks apart
– Treatment for the arterial or venous complications
is life-long anticoagulation
Question 1
• 23 F with a history of malaise, facial rash and
achiness. Appropriate work-up includes:
• A) ANA
• B) CBC w/ diff, LFTs, creatinine and urinalysis
• C) dsDNA
• D) All of the above
3405
Answer
• B) CBC, LFTs, renal function screen
• As a first pass for the evaluation of suspected

SLE, a complete history and physical should be
performed. Appropriate laboratory testing
includes a CBC with differential, liver function
tests, creatinine and urinalysis. Avoid sending
an ANA and/or dsDNA unless there is a strong
suspicion of SLE.
Question 2
• 43 F presents with a DVT with no clear
precipitant. PMHx is notable for 2 first trimester
miscarriages and one second trimester
miscarriage. Appropriate testing includes:
• A) Lupus anti-coagulant
• B) Anticardiolipin antibody
• C) VDRL
• D) A, B, and C
• E) A and B only
3406
Answer
• E) A and B should be sent
• The history is suggestive of antiphospholipid

syndrome
• Send off both the lupus anticoagulant and
anticardiolipin antibody when you have a high
suspicion for the antiphospholipid antibody
syndrome
• VDRL is not a good screening assay for this
disorder
References
• Classification criteria for systemic lupus erythematosus: a
review. Petri M, Magder L. Lupus. 2004;13(11):829
• Guidelines for referral and management of systemic lupus

erythematosus in adults. American College of Rheumatology
Ad Hoc Committee on Systemic Lupus Erythematosus
Guidelines. Arthritis Rheum. 1999 Sep; 42(9): 1785-96
• Diagnosis and Management of the Antiphospholipid

Syndrome. Garcia D and Erkan D. NEJM. 2018 May 24; 378
(21): 2010-2019.
3407
Mono-articular Joint Complaints
Derrick J. Todd, M.D., Ph.D.

Associate Physician
Department of Rheumatology, Immunology, and Allergy
Instructor of Medicine
Disclosures
• UpToDate: Author, Reviewer
• Optum: Consultant
3408
“When an arthritis
patient walks in the
front door, I feel like
leaving by the back…”
Objectives
1. Approach to the patient with monoarthralgia
2. Septic arthritis in detail
3. Microcrystalline arthritis in detail
4. Interspersed: Case-based questions
3409
Question 1:
58 y.o. alcoholic man presents to clinic with rapid
severe knee pain, swelling, and altered gait. He
has psoriatic arthritis, on adalimumab. No other
complaints. Imaging as shown. Joint aspiration:
30 cc non-bloody cloudy fluid, crystals (shown),
50,000 WBC/mm3, 95% PMN.
What is the most appropriate next step?
A. Contact orthopedics for “washout”
B. Send home with Rx for cefalexin
C. Intra-articular steroid injection
D. Wait for gram stain results before A-C
Knee Radiograph
3410
Crystal Analysis
Question 2:
A 42 year old otherwise healthy woman presents
with mild left knee discomfort but lots of swelling.
The swelling has been progressing for weeks,
without much pain or any associated systemic
symptoms. Joint aspiration: 90 cc non-bloody
slightly cloudy fluid with 12,000 WBC/mm3, 65%
PMN, no crystals, and negative Gram stain.
Which of the following would be most likely to
provide a diagnosis?
A. Serum uric acid level
B. Serum lyme serology
C. Serum ANA test
D. MRI of the affected knee
3411
Making a Diagnosis
Clinical Assessment
Diagnostic
Laboratory
Imaging
Testing
3412
Clinical Assessment
1. Pathophysiology
• Inflammatory or non-inflammatory
2. Anatomy
• Articular or not
• Joint distribution
3. Chronology
• Acute/explosive (hours or days)
• Sub-acute (weeks)
• Chronic/insidious (months or years)
4. Co-morbidities and risk factors
Acute Inflammatory Monoarthritis
Pain, warmth,
swelling, and
erythema,
involving only
one joint
3413
Acute Monoarthritis: Likely Causes

1. Septic arthritis
• Staph and Strep species (>90%)
• Neisseria species
• Other gram negatives
2. Microcrystalline disease
• Acute gouty arthritis
• Acute pseudo-gouty arthritis
3. Systemic rheumatic disease of one joint
• Spondyloarthritis (PsA, ReA, AS, IBD)
4. Trauma or hemarthrosis
Acute Monoarthritis: Presentation
1. Acute onset: days, not weeks

2. Joint is swollen, red, warm, and painful.
3. Worry about septic if there is involvement of:
• The knee
• A prosthetic joint
• Proximal joint: shoulder or hip
• Axial joint: TMJ, SC, SI, pubis, spine
3414
Exam: Confirm “Mono” “Arthritis”
1. Perform a complete joint exam

2. How do you assess for effusion?
3. Examination should distinguish arthritis from
peri-arthritis (bursitis or tendonitis)
4. Why is active versus passive ROM important?
5. Search for infection sources and for tophi.
It’s swollen, now what?

1. Arthrocentesis (pre-antibiotics)
2. What do you need?
• Syringes, needles, and tubes
• Someone who knows how to do it.
• Universal precautions
• Prep: cleanser, lidocaine, gauze, and chuck
• Give anesthesia time!
3. Any word of advice?
4. What do you send it for?
3415
Fluid WBC Analysis
Not Sterile Septic

Normal Inflamed Inflamed Inflamed
WBC <200 Up to 1K 1K – 100K >30K
% PMN <25% 25 – 50% 25 – 90% >90%
Fluid Crystal Analysis
3416
Fluid Crystal Analysis

Calcium Pyrophosphate Dihydrate
(Pseudogout)
Monosodium Urate
(Gout)
Interpretation of Inflamed Fluid
Crystal Analysis
Negative Positive
Gram Stain
Negative
Positive
3417
Crystal Analysis
Negative Positive
Gram Stain
Negative
Positive Septic Joint
Crystal Analysis
Negative Positive
Gram Stain
Negative Crystal
Disease
Positive Septic Joint
3418
Crystal Analysis
Negative Positive
Gram Stain
Negative Crystal
Disease
Positive Septic Joint Crystals AND
Septic Joint
Crystal Analysis
Negative Positive
Gram Stain
Negative Many Options: Crystal

RA,PsA,Lyme Disease
Positive Septic Joint Crystals AND
Septic Joint
3419
Empiric Treatment
Crystal Analysis
Negative Positive
Gram Stain
Negative Consider Crystal

Empiric Abx Therapy
Positive Empiric Abx Empiric Abx
Gout Therapy
Additional Workup
1. Blood cultures
2. CBC with diff
3. Metabolic profile
4. Imaging (especially if history of trauma or prior
prosthesis is present)
5. Consider serologic workup for RA or lyme
6. Hunt for other sources of infection
3420
Risk Factors for Septic Arthritis

1. Immune-suppressed patient
• Medications: steroids, chemotherapy, DMARDs
• Co-morbidities: diabetes mellitus, cirrhosis, renal
disease, asplenism, inherited immunodeficiency, HIV
2. Prosthetic joint: recent or established
3. Recent sepsis or invasive procedure
4. Intravenous drug user
5. Pre-existing damaged joints
6. Coagulopathy
Management: Septic Arthritis

1. Antibiotics
• Empiric therapy: 3rd gen cephalosporin + vancomycin
• Tailored therapy is ideal (beta-lactam)
• Inferior alternatives: aminoglycosides, quinolone
2. Serial drainage with WBC analysis
3. Review all joints daily
4. Get orthopedics on board if…
• Any prosthetic joint is involved
• Any joint other than the knee
• The knee in a young person
• Refractory to drainage and Abx
• Osteomyelitis is present
3421
Myth-Busting: Gout 2018
Basic Principles of Gout

1. Clinical gout results from the convergence of
two processes
• Chronic hyperuricemia, with crystal deposition
• Inflammatory response to the crystals
• NO SINGLE MEDICATION ADDRESSES BOTH
2. There are different stages of gout
• Clinically silent hyperuricemia
• Intermittent acute gouty arthritis/tendinitis/bursitis
• Chronic gouty arthropathy (with or without tophi)
3422
Uric Acid
1. Uric acid level stratifies a patient’s risk for
developing clinical gout over a lifetime
• Hyperuricemia is not diagnostic of gout
• Normal uric acid does not exclude gout
2. Many factors affect a spot serum uric acid
• Hydration and dietary status
• Acute changes in renal function
• Medications (esp. diuretics)
• Active gout attack
3. Uric acid should also be used as a target of
treatment in a patient with established gout.
• Goal: uric acid <6 mg/dL, or <5 mg/dL if tophi
Hyperuricemia: Risk Factors

1. Un-modifiable risk factors
• Family history of gout or hyperuricemia
• Age and male gender
• Co-morbidities: cardiac disease, renal insufficiency,
heme malignancy, inherited metabolic defects
2. Modifiable risk factors

• Diet: alcohol (beer), shellfish, organ meat, red meat,
heavy dairy, high-fructose corn syrup
• Medications: diuretics, cyclosporine, HAART
• Obesity
• Lead exposure
3423
Acute Gouty Arthritis

1. Acute inflammatory arthritis/tendinitis/bursitis
• Usually mono- or oligo-articular
• Aspirate: inflammatory fluid with uric acid crystals
• DON’T FORGET ABOUT PSEUDOGOUT!
2. Triggers are mostly innocuous or unpredictable
• Recent trauma or repetitive overuse
• Systemic inflamed state: surgery, infection
• Fluctuations in uric acid: fluid shifts, diuretics, or
someone messed with the allopurinol
• Dietary indiscretion?
3. Treatment: Target the inflammation!
Pseudogout Arthritis: Risk Factors

1. History of pseudogout
2. Presence of chondrocalcinosis may be helpful
3. Concurrent trauma or inflamed state
4. Usually limited to the elderly
5. Altered metabolic states
• Hemochromatosis
• Hyper-PTH
• Thyroid abnormalities
• Low phosphate or magnesium
• Acromegaly
3424
Chondrocalcinosis
Acute Crystalline Arthritis: Basics
Management principles for gout or pseudogout

1. Early treatment is the most successful
2. It gets better on its own with time
3. Rest, ice, and analgesics help almost everyone
4. Try to avoid the orthopedics service
5. Don’t mess with the allopurinol in patients with gout
3425
Acute Crystalline Arthritis: Medications

1. NSAIDS: assess co-morbidities and risks
2. Corticosteroids: low doses are safe and effective
• Intra-articular: directed therapy
• Oral: 20 mg daily, tapered by 5 mg every 4 days
• Quick: IM/IV methylprednisolone 40 mg x1, then oral
3. Oral colchicine
• NEVER give intravenously
• 0.6 mg BID-TID for 1-2 days, then QD-BID
• CAUTION in renal compromise
• CAUTION with medication interactions
• Do NOT dose to the point of diarrhea…
Acute Crystalline Arthritis: Helpful Facts

1. Uric acid level is not always helpful in acute gout.
2. Distribution of involvement may be helpful:
• Most common site: Peripheral extremities
• Can include tendon sheaths and bursae
• Rarely occurs centrally: SI joints, pubis, or discs
3. May co-exist with septic arthritis or other forms of
crystalline arthritis (CPPD)
4. In bad polyarticular disease, patients can
demonstrate features of sepsis.
5. Management of hyperuricemia is often
unnecessary in the acute setting.
3426
Chronic/Recurrent Gout
THE GOUCH
3427
Chronic/Recurrent Gout
1. A disease of hyperuricemia
• Treating only inflammatory episodes is effective for
symptomatic gout but insufficient for chronic disease
• Hyperuricemia associated with many disease states:
chronic arthropathy, chronic kidney disease,
cardiovascular disease
2. When to direct treatment at hyperuricemia?
• All patients with clinical gout should be encouraged to
modify risk factors: weight, diet, and possibly diuretics
• Indicators for anti-hyperuricemic medication: tophi,
erosive arthropathy, multiple attacks, high recurrence
risk, uric acid nephropathy, or nephrolithiasis
Role of Imaging in Diagnosis of Gout

1. Radiography
• Rarely diagnostic for
gout, but can be
suggestive
• Useful to determine
extent of gouty
arthropathy
3428

1. Radiography
– Rarely diagnostic for gout, but can be suggestive
– Useful for determining extent of any gouty arthropathy
2. Ultrasound (MSKUS)
– Advantages: relatively inexpensive; no radiation;
assess multiple sites; sensitive to gouty changes
– Disadvantages: operator dependent
I Got a Bridge to Sell Ya’
3429
MSKUS: Subclinical Tophus
3430
3431
Negative Birefringence

1. Radiography
– Rarely diagnostic for gout, but can be suggestive
– Useful for determining extent of any gouty arthropathy
2. Ultrasound
– Advantages: relatively inexpensive; no radiation;
assess multiple sites; sensitive to gouty changes
– Disadvantages: operator dependent
3. Dual energy CT scan (DECT)

– Advantages: standardized; can assess entire
foot/ankle; can see “through” bone
– Disadvantages: cost; radiation; availability; familiarity
3432
Dual-Energy CT
http://www.dsct.com/index.php/dual-energy-imaging
Gout: Dual-Energy CT
A Huppertz 2014, Rheumatol Int
3433
Medications for Chronic Gout

1. Treat hyperuricemia!
• Explain that treatment is usually “for life”
• Goal uric acid: <6 mg/dL, or <5 mg/dL if tophi present
• Almost all compliant patients can achieve this!
• Early in treatment: patients at high risk for gout attack
• Almost always co-prescribe an anti-inflammatory such
as low-dose colchicine, typically for months.
2. The agents
• Xanthine oxidase inhibitors: allopurinol, febuxostat
• Uricosurics: probenacid, losartan, lesinurad (new)
• Recombinant uricase: pegloticase, rasburicase
Allopurinol: Myth-busting
1. Properly used, allopurinol is the most effective and
safest agent for almost all patients.
• Inadequate dose is most likely reason for treatment failure
• Allopurinol is generally safe, even at high doses.
• Start low and go slow, especially in CKD.
• I will titrate to >300 mg daily, even in patients with CKD.
• Rapid change in allopurinol can trigger gout attack!
2. Allopurinol toxicity
• Renally excreted, and only very rarely nephrotoxic
• Changes in LFTs or blood counts can be dose limiting
• Rash is rare, but can portend a more serious reaction
• Hypersensitivity: SJS, TEN, DRESS, DIL, ANCA vasculitis
• HLA-B*5801 high-risk allele (Korean, Han Chinese, Thai)
3434
Conclusions: Gout
1. Try to secure a crystal-proven diagnosis
2. Non-invasive imaging modalities help diagnose
gout and determine extent of disease burden
3. Treat inflammatory phase of acute gouty
arthritis with anti-inflammatory agents
• NSAIDs, corticosteroids, colchicine, ice, rest
4. Use anti-hyperuricemic agents when indicated
• Tophi, erosions, nephrolithiasis, multiple attacks
• Allopurinol, febuxostat, probenecid, pegloticase
5. Overlap #3 and #4, often for months
6. PLEASE don’t mess with my allopurinol
Question 1:
50,000 WBC/mm3, 95% PMN.
3435
Question 1:
50,000 WBC/mm3, 95% PMN.
Question 2:
C. Serum ANA test
3436
Question 2:
C. Serum ANA test
3437
Comments on Lyme Testing

1. Too big a topic for this talk
2. Proper sequence: Start with a screening
ELISA, and then do a Western blot only as a
confirmatory test.
3. Lyme result can be negative in early disease
(immunologic window), but are invariably
positive in established disease.
4. Avoid fishing expeditions and “specialty lyme
laboratories”, especially in patients without
clinical features of Lyme disease.
5. Be prepared to interpret a positive result!
When to Call Us
1. Any rheumatology patient
2. Any complex patient
3. The exam is equivocal
4. You would like to have procedural oversight or
to review synovial fluid yourself.
5. Tap is dry, but exam suggests fluid is present
6. At 2 A.M., remember that ortho is in-house ☺
3438
Summary
1. History and exam should prove that acute
monoarthritis is “acute” “mono” and “arthritis.”
2. A hot joint is septic until proven otherwise.
3. Arthrocentesis with synovial fluid analysis is the
procedure of choice and guides empiric therapy.
4. Don’t mess with the allopurinol.
Disclosures
None
3439
Additional Reading for William Osler

1. Baker DG, Schumacher HR. “Acute monoarthritis” N
Engl J Med. 1993;329(14):1013-1020.
2. Schlesinger N. “Diagnosing and treating gout: A review
to aid primary care physicians.” Postgrad Med.
2010;122(2):157–61.
3. Sharff KA, Richards EP, and Townes JM. “Clinical
Management of Septic Arthritis.” Current
Rheumatology Reports. 2013;15(6):332.
4. Wilson JF. “In the clinic. Gout.” Ann Intern Med.
2010;152(3):ITC21. Erratum Ann Intern Med.
2010;152(7):479–80.
3440
Take home messages

Rheumatology
Paul F Dellaripa MD
Disclosures
• Up To Date
• Genentech
3441
Teaching point:Distinguishing Bursitis

vs arthritis on examination
• The ability to fully extend the knee with limited
flexion indicates the process is outside the joint (
ie bursa) . In bursitis, intrabursal pressures
increase with flexion and decrease with
extension.
• In a intra-articular process (ie synovitis in a joint)
the patient lacks the ability to fully extend the
knee because intra-articular pressure increases in
extension and is lowest in semiflexion.
Acute Monoarthritis: Likely causes

• Septic arthritis (Staph, Strep mostly, Neisseria,
Gram negatives less likely)
• Micro crystalline disease ( gout, pseudogout)
• Systemic rheumatic disease of one joint or
starting in one joint (RA, spondyloarthritis)
• Trauma or hemarthrosis
3442
Synovial fluid analysis:

interpretation of cell count/diff
• <1-2,000 wbc/cc: noninflammatory fluid

– O.A., trauma, other
• >2,000 wbc/cc: inflammatory fluid
– DDx is extensive; basically includes all
the systemic rheumatic diseases
Synovial fluid analysis:

interpretation of cell count/diff [cont.]
• >30-100,000 wbc/cc:
suggestive of septic arthritis
• But may also be seen with
gout and pseudogout and occasionally with
R.A. and so-called “reactive arthritis”
3443
Synovial fluid analysis: what to send-make

every attempt to obtain!
• 1. Gram stain, C&S
• 2. Cell count and differential
(anticoagulated tube)
• 3. Analysis for crystals by compensated
polarized microscopy
(anticoagulated tube;
crystals will “keep” for hours)
---------------------------------------------------------------
(Glucose, total protein, LDH, etc.
don’t add anything)
Treatment of rheumatoid arthritis

• MTX - 1st line DMARD for most patients
- weekly dosing 15-25 mg PO or SQ
- folic acid 1 mg daily to reduce side
effect risks or leucovorin weekly 5-15mg
- CBC, LFT, Cre monitoring
• “treat to target” (frequent monitoring +
medication adjustment) improves
longterm outcomes
• optimize treatment with current agent
before making changes
3444

• second line agents (typically added to Mtx):
- TNF inhibitors
- IL-6 inhibitors
- B cell depletion (Rituximab)
- T cell co-stimulatory blockade
- oral Jak inhibitors
- traditional DMARD (Sulfasalazine,
Hydroxychloroquine “triple therapy”)
• role of corticosteroids:
- useful adjunct at low doses (<10 mg)
Singh Arthritis
Rheumatol 2016
- many side effects
Singh Arthritis Rheumatol 2016
3445
Take home message in RA
• Remember that there are new criteria for the diagnosis of RA

• Maximizing MTX is still a cornerstone of Rx in RA and likely lowers
mortality in RA
• Patients starting on DMARDs like MTX or leflunomide or any
biologic need to have an assessment of Hep B and C status.
• Assess for prior history of TB prior to DMARD or biologic therapy
• Pneumovax/flu vaccine advocated for such patients.
• Consideration for timing of vaccinations such as zoster are
important before beginning drugs for RA
• The Use of triple therapy may become more prominent compared
to MTX/biologic combination based on recent data
Spondyloarthritis
• psoriatic arthritis
• IBD
• Reactive arthritis
• ankylosing spondylitis
• Role of TNF inhibitors in
axial disease
• Newer agents now
approved that affect
TH17 pathway ( IL-17
and IL-12/23 inhibition)
3446
Adequate NSAID
trial:
- lack of response
(or intolerance) to
≧2 different NSAIDs
over 1 month
- incomplete
responses to ≧2
different NSAIDs
Ward Arthritis Rheum 2016 over 2 months
SLE and Autoantibodies

• ANA- found in >95% of patients
• Anti-ds-DNA- 40% -80% of patients
• Anti-Sm- 25% of patients
• Anti-histone- seen in drug induced SLE
• Anti-Ro, Anti-La - Sjogren’s, SCLE
• Anti-RNP- Mixed Connective Tissue Disease
• False positive VDRL- an anti-phospholipid antibody
3447
The Antiphospholipid Syndrome is

defined as:
• Arterial clots, venous clots or obstetrical
complications in the presence of an
antiphospholipid antibody. The antibody
testing needs to be positive on two separate
occasions at least 12 weeks apart.
• Treatment for the arterial or venous
complications is life-long anti-coagulation
Patients who should be evaluated for

antiphospholipid antibodies
• SLE patients
• Patients under age 40 with CVA, MI no obvious risk
factors
• Recurrent venous or arterial clots
• Women with recurrent first trimester pregnancy
losses, or second trimester loss
• Some advocate the use of prophylactic aspirin
therapy in those with positive antibodies. This
therapy has not been shown to decrease the risk of
clotting events except in patients with co-existing
SLE.
3448
Osteoarthritis:treatment options
• Acetominophen
• NSAIDS, tramadol (careful in the elderly, interaction tramadol with
SSRI)
• Steroid Injections Evidence based data: Steroid injection for osteoarthritis of the hip: a
randomized, double-blind, placebo-controlled trial. (Lambert RG, et al Arthritis Rheum. 2007;56(7):2278)
• Splinting of small joint like the CMC joint of the thumb can be very
useful
• Viscosupplemenation (controversial)
• Chondroitan (data not supportive)
• Arthroscopic lavage/debridement of the knee ( data not
supportive)
• Narcotics (avoid)
• Weight loss and knee OA *
Patient has features of secondary OA. JSN narrowing at MCPs
•cartilage calcification
• OA type changes at wrist and

MCPs with joint space narrowing
Chondrocalcinosis------->>
The Differential Diagnosis of Secondary OA:
Hemochromatosis
Hypothyroidism
Hyperparathyroidism
Rarely : Wilson’s Disease; Ochronosis
18
3449
Uric acid
• The serum uric acid (SUA) ranges widely in

gout, from “normal” to elevated
• A very low SUA (< 4-5 mg %)
makes diagnosis less likely
• SUA may drop by 1-2 mg %
during an acute attack
Clinical presentation: gouty arthritis

• Typical presentation:
- acute
- monoarticular or oligoarticular
- lower extremity joints
• 1st MTP: involved in 50% of initial attacks;
95% involvement in recurring gout
• BUT: any joint and tendon in the body
lined with synovium may be affected
3450
A caveat about gout treatment

• Important: don’t treat the serum uric acid during an acute attack of
gout-usually
• If the SUA is changing rapidly (up or down), risk of acute gout is
increased
– so never start hypouricemic Rx (e.g., allopurinol)
in the midst of an acute attack—but…
– obvious corollary: if a patient is already on alllopurinol and
flares, and has been on allopurinol don’t stop it
– Add on Colchicine for acute disease is reasonable in addition to
steroids/NSAIDS
Chronic Rx: maximal dose of allopurinol is not known

Febuxostat: used when intolerant to allopurinol
Uricase: used only where severe burden of tophi
Anakindra: very useful in recalcitrant cases, but expensive.
Clinical presentation: acute pseudogout
• Older adults
• Typically presents as an acute monarticular
arthritis, most commonly at the knee,
shoulder.
– big toe (gout) :: knee (pseudogout)
• Can be febrile
• Chondrocalcinosis is common
3451
Chondrocalcinosis
Pseudogout [cont.]
– remember chondrocalcinosis is a
radiologic diagnosis
– and pseudogout is a
clinical diagnosis
3452
Raynauds phenomenon
• Primary Raynauds common in young women (teens
and twenties), may have a family history of this as
well, ANA mostly negative.
• Onset of Raynauds in adults after the age of 35
concerning for the development of a rheumatic
syndrome and is termed secondary Raynauds.
Digital ulcers, pitting scars in fingers, abnormal
capillary microscopy and presence of autoantibodies
suggest the development of an underlying rheumatic
syndrome.
Key points in Scleroderma

• Recognize the presence of concomitant Raynauds and
GERD as a possible clinical manifestation of underlying
limited scleroderma and therefore the longterm risk
of pulmonary hypertension
• ILD occurs in diffuse SSc>limited SSc but can occur in
both
• Avoid steroids in SSc especially high dose, in SSc pts. (
increased risk of renal crisis)
• Pulmonary hypertension is a complication of long
standing scleroderma of mostly the limited variant and
treatment that improve morbidity and possible
mortality are available now.
• Newer treatments and clinical trials underway
3453
Newer classification in myositis

• Inclusion body myositis (IBM)
• DM ( prob or definite)
• PM (prob or definite)
• Amyopathic DM
• Nonspecific myositis
• Necrotizing myopathy
• If you have a pt being treated for “inflammatory
myositis” and they are not improving consider the
possibility of inclusion body myositis
Fibromyalgia
Non-inflammatory
Pain without objective findings
Sleep disturbance
Mood disorders
Normal labs
Polymyositis
Painless weakness
Proximal>Distal
CK elevated
EMG - insertional irritability
28
3454
Antisynthetase syndrome
Dermatomyositis: “mechanic’s hands”
• Fever
• Raynauds
• Inflammatory Arthritis
• Mechanics hands
• ILD (can be severe)
• Myositis
• Typically associated with Jo-1, PL-12, PL-
7 ab amongst others recently discovered
ANCA associated vasculitis

• Include Granulomatosis with Polyangittis (Wegener's
Granulomatosis ), microscopic polyangitiis and EGPA
(Churg Strauss) and drug induced vasculitic syndromes
(PTU, allopurinol, levamisole tainted cocaine)
• Morbidity associated with these diseases typically related
to renal failure due to do glomerulonephritis or pulmonary
hemorrhage.
• Mortality often related to disease progression but more
often treatment associated infection. In fact,vasculitis
that appears to be worsening should be considered
an infection until proven otherwise.
• Rituximab established therapy for ANCA vasculitis but
other agents such as MTX, Azathioprine or abatacept
may be used in limited cases or as maintenance
therapy
3455
GCA Pearls
• GCA is a strong consideration in the elderly with new onset
headache, neck ache , visual changes or unexplained fatigue or
anemia
• Jaw claudication is the most specific sign of GCA, followed by visual
loss and TA tenderness
• A more robust inflammatory response is correlated with a lower
risk for visual loss. (33)
• Patients with a low or normal ESR and CRP can have GCA If one
biopsy is negative, the additional yield of a contralateral biopsy is
modest but is reasonable to consider performing. Treat if needed—
have about 2 weeks to change pathology
• A rising ESR in a treated for GCA does not necessarily suggest that
GCA is returning
• Ultrasound can help but a negative study does not rule out the
diagnosis
• Tociluzimab now FDA approved for GCA and can allow more rapid
taper of steroids ( Stone et al NEJM 2017)
PMR pearls
• Synovitis of the hands can occur in PMR-a
subset of these patients evolve into RA
• A normal ESR does not exclude the diagnosis
• 15-20% of patients with PMR will develop GCA
• Consider a temporal artery biopsy where
persistent constitutional symptoms or
inflammatory markers remain high.
3456
Final case: 40 yo male Bilateral ankle pain and

painful red nodules on shins..what is the next
test to order
Lofgrens syndrome: Acute form of sarcoid, typically

responds to NSAIDS, rarely steroids and rarely progress
to chronic sarcoidosis
3457
Rheumatology Board Review
Joerg Ermann, MD
Instructor in Medicine, Associate Physician
Disclosures
• Consulting/Scientific Advisory Boards:

Boehringer Ingelheim, Eli Lilly, Novartis
• Research Grants:
Boehringer Ingelheim, Pfizer
3458
Question 1
A 38 yo woman with a recent diagnosis of seropositive

rheumatoid arthritis has been treated with oral
Methotrexate 12.5 mg weekly for the past 4 months. She
has had only modest improvement. According to your
notes, the number of swollen joints has dropped from 15
to 11 and the number of tender joints has dropped from
18 to 13.
Labs:
RF and anti-CCP positive
Hct 36.1
ESR 50, CRP 14.1 mg/l
A. add a TNF inhibitor

B. begin Rituximab infusions
C. switch MTX to Tofacitinib
D. increase MTX to 25 mg weekly
E. add prednisone 20 mg daily
3459
A. add a TNF inhibitor

B. begin Rituximab infusions
C. switch MTX to Tofacitinib
D. increase MTX to 25 mg weekly
E. add prednisone 20 mg daily
Singh Arthritis Rheumatol 2016; 68:1-26
3460
• Methotrexate
- 1st line DMARD for most patients
- weekly dosing 15-25 mg PO or SQ
- folic acid 1 mg daily reduces side effects
- CBC, LFT, Crea monitoring
• T2T = “treat to target” improves longterm outcomes
• optimize treatment with current agent before changing
drugs
• second line agents, typically added to Methotrexate:

- cytokine inhibitor (TNF, IL-6)
- B cell depletion
- T cell co-stimulatory blockade
- oral Jak inhibitors
- conventional DMARDs (Hydroxychloroquine,
Sulfasalazine)
• role of corticosteroids:
- useful adjunct at low doses (≦10 mg)
- many side effects
3461
Question 2
Since the introduction of monoclonal antibodies into

clinical practice ~20 years ago, biologics have
revolutionized the care of patients with rheumatic
diseases, cancer and other illnesses.
Within the next few years, the patents for several of the
original biologics will expire opening the market to
biosimilars produced by competing manufacturers.
Which of the following statement regarding biosimilars is
correct?
Compared with the reference product,

biosimilars…
A. are structurally identical

B. have similar efficacy
C. are ~90% cheaper
D. are cheaper but may not be as effective
E. all of the above
3462
Compared with the reference product,

biosimilars…
A. are structurally identical

B. have similar efficacy
C. are ~90% cheaper
D. are cheaper but may not be as effective
E. all of the above
Biosimilars
• identical amino acid sequence as originator (reference)

drug but structure may differ slightly due to post-
translational modifications
• biosimilars ≠ generic drugs
• must be highly similar to an approved biological
product (originator) in terms of structure, function,
quality, clinical efficacy and safety
• at least 1 clinical trial in 1 indication → extrapolation to
other indications
Lyman NEJM 2018; 378:2036-44
3463
Question 3
A 52 yo female with seropositive rheumatoid arthritis

comes for her annual physical examination. She was
diagnosed with the disease 10 years ago and is currently
taking 20 mg methotrexate PO weekly and injects a TNF
inhibitor every other week.
She denies any significant joint problems (joint swelling,
pain, morning stiffness) and feels generally well.
She plans to travel to South America later in the year. You
review her vaccination records.
Which of the following vaccines should be avoided

in this patient?
A. Hepatitis A
B. Hepatitis B
C. Td booster
D. yellow fever
E. recombinant Zoster vaccine
3464
Which of the following vaccines should be avoided

in this patient?
A. Hepatitis A
B. Hepatitis B
C. Td booster
D. yellow fever
E. recombinant Zoster vaccine
Vaccination of patients on
immunosuppressive drugs
• live-attenuated vaccines are contraindicated

- MMR
- live-attenuated influenza
- yellow fever
- zoster live vaccine (recombinant zoster vaccine is
safe)
• all patients on immunosuppressive drugs should
receive
- annual recombinant influenza
- pneumococcal vaccine (PCV13 + PPSV23), ideally
prior to initiation of immunosuppression
- other vaccines as indicated by age or other
circumstances
https://www.cdc.gov/vaccines/hcp/acip-recs/general-recs/immunocompetence.html
3465
Question 4
A 28 yo kindergarten teacher presents with 1 week of

pain, swelling and morning stiffness in her hands and
knees. 3 weeks ago, she had a cold with nasal discharge,
fever, malaise, and muscle aches. Several children in her
class had similar symptoms accompanied by an
erythematous rash on the cheeks.
Exam:
Mild soft tissue swelling of several PIPs and MCPs.
Minimally swollen + tender wrists and knees bilaterally.
Labs:
CBC unremarkable, ESR 40
ANA 1:40, RF 24 IU
What initial treatment would you

recommend?
A. Naproxen 500 mg BID

B. Hydroxychloroquine 400 mg daily
C. Methotrexate 15 mg qweek + folic acid 1 mg daily
D. Prednisone 20 mg daily
E. Doxycycline 100 mg BID for 1 week
3466
What initial treatment would you

recommend?
A. Naproxen 500 mg BID

B. Hydroxychloroquine 400 mg daily
C. Methotrexate 15 mg qweek + folic acid 1 mg daily
D. Prednisone 20 mg daily
E. Doxycycline 100 mg BID for 1 week
• presentation highly suggestive of Parvovirus B-19

infection (viral arthritis)
- acute mild symmetric synovitis
- exposure to sick children with facial rash
• generally a self limited disease, improvement over
several weeks, minimal intervention required
• RF may be mildly elevated,
ANA of 1:40 is generally not significant
Marks Clin Med (London) 2016; 16:129-34
3467
Question 5
A 25 yo female medical student presents to the ED with

fever, chills and a diffuse rash. This started the day after
she returned from Haiti where she had spent one month
volunteering in a health clinic. Within hours, she also
developed severe widespread joint pain (affecting her
PIPs, MCPs, wrists, MTPs, ankles, knees, hips).
Exam:
T 103°F, HR 130/min, BP 130/71, O2 98% on room air
diffuse, blanchable erythematous rash on trunk and limbs,
swollen MCPs and MTPs, multiple tender joints
Laboratory:
CRP elevated, Wbc 3.6, Hct 30, Plt 140
LFT WNL
Which of these viruses could be the cause

for the patient’s symptoms?
A. Zika
B. Chikungunya
C. Borrelia
D. O’nyong’nyong
E. Ross River
3468
Which of these viruses could be the cause

for the patient’s symptoms?
A. Zika
B. Chikungunya
C. Borrelia
D. O’nyong’nyong
E. Ross River
Chikungunya arthritis
• consider viral arthritis in context of travel history

Chikungunya - Caribbean, Central Africa, SE Asia
O’nyong'nyong - East Africa
Ross River - Australia
• arbovirus (arthrophod-born) transmitted by mosquitoes
→ acute disease with fever, rash, arthritis, myalgias,
typically self-limited
• confirmation by antibody testing (IgM, IgG)
• treatment - NSAIDs
Waymouth Semin Arthritis Rheum 2013; 42:273-8, Weaver NEJM 2015; 372:1231-9, Sutaria Curr Opin Rheumatol 2018; 30:256
3469
Origin, spread and distribution of

Chikungunya virus and its vectors
Weaver NEJM 2015; 372:1231-9
Question 6
A 72 yo female presents with 6 weeks of stiffness in the

neck and both shoulder. She has shoulder pain when
dressing herself in the morning. She also reports pain at
night and sleeps poorly. Symptoms improve as the day
progresses but then return in the early evening. No
significant PMH except for HTN.
Exam:
Mildly decreased passive ROM in the shoulders. Mild OA
changes in the hands. No synovitis. No muscle weakness.
Labs: CBC unremarkable, ESR 12 mm/h
3470
A. polymyositis
B. early rheumatoid arthritis (RA)
C. fibromyalgia
D. polymyalgia rheumatica (PMR)
E. metabolic myopathy
A. polymyositis
B. early rheumatoid arthritis (RA)
C. fibromyalgia
D. polymyalgia rheumatica (PMR)
E. metabolic myopathy
3471
Polymyalgia rheumatica (PMR)
• clinical diagnosis
• pain and morning stiffness in neck, shoulders, hips
age >50, +/- constitutional symptoms
• shoulder girdle (60%)
hip girdle (5%)
both (35%)
• Labs: ESR and/or CRP elevated in 80%
anemia 15%
• associated with GCA (headache, visual loss, FUO)
Kermani Lancet 2013; 381:63-72, Helfgott Arthritis Rheum 1996; 39:304-7
Question 7
An 80 yo woman was hospitalized two days ago for upper

GI bleeding. She was found to have a peptic ulcer and
was placed on omeprazole plus IV normal saline for
hydration.
Today, she presents with acute painful swelling of the
right knee. PMH is significant for OA of the hands and
knees, for which she took Ibuprofen at home.
Exam:
T 100.0
Heberden + Bouchard nodes in both hands
warmth and a large effusion in the right knee
knee aspiration → 60 ml of yellow cloudy fluid
(+ intracellular rhomboid positively birefringent crystals)
3472
What is the likely cell count in the synovial

fluid of this patient?
A. 500 cells/µl
B. 500 cells/ml
C. 15,000 cells/µl
D. 15,000 cells/dl
E. 15,000 cells/ml

A. 500 cells/µl
B. 500 cells/ml
C. 15,000 cells/µl
D. 15,000 cells/dl
E. 15,000 cells/ml
3473

A. 500 cells/µl
B. 500 cells/ml
C. 15,000 cells/µl
D. 15,000 cells/dl
E. 15,000 cells/ml
Synovial fluid analysis
• informative tests:
- cell count + differential
- Gram stain + culture
- crystal analysis
• not informative: albumin, protein, glucose
• “inflammatory” >2,000 cells/µl
• septic arthritis more likely with
- high cell count (>50,000 cells/µl)
- high neutrophil fraction (>95%)
Courtney Best Pract Res Clin Rheumatol 2009; 23:161-92
3474
Question 8: What is the serum uric acid target

for patients on uric acid lowering drugs?
A. less than 4 mg/dl

B. less than 5 mg/dl
C. less than 6 mg/dl
D. less than 7 mg/dl
E. less than 8 mg/dl
Question 8: What is the serum uric acid target

for patients on uric acid lowering drugs?
A. less than 4 mg/dl

B. less than 5 mg/dl
C. less than 6 mg/dl
D. less than 7 mg/dl
E. less than 8 mg/dl
3475
Allopurinol dosing
• treat to target: serum uric acid <6 mg/dl in all patients

• alternative target:
<5 mg/dl in severe gout for faster dissolution of
crystals
• Flare prophylaxis during initiation!
(e.g. low dose Colchicine)
• patients may require >300 mg daily to achieve target
• repeat uric acid test 1 month after dose adjustments
Khanna Arthritis Care Res 2012; 64:1431-46, Richette Ann Rheum Dis 2017; 76:29-42
Allopurinol toxicity
• clinical features:
- rashes (mild → Stevens-Johnson syndrome)
- LFT abnormalities
- Allopurinol hypersensitivity syndrome
• low starting dose reduces risk for severe toxicity
• consider screening for HLA-B*58:01 in Asians
• alternatives
- desensitization
- Febuxostat
- uricosuric drugs
Khanna Arthritis Care Res 2012; 64:1431-46
3476
Question 9
A 68 yo man with HTN and tophaceous gout returns for

follow-up. He was started on Allopurinol + Colchicine
6 months ago. Following Allopurinol titration (current dose
400 mg daily), his serum uric acid has been <6.0 mg/dl
for the last 3 months without gout flare.
Exam:
Moderate-sized tophus over the left elbow, two small
tophi on DIPs. No swollen or tender joint.
Lab:
uric acid 4.9 mg/dl
CBC, CMP unremarkable

appropriate next step in management?
A. add Probenecid
B. change Allopurinol to Febuxostat
C. reduce the Allopurinol dose
D. discontinue Colchicine
E. continue current gout medications
3477

appropriate next step in management?
A. add Probenecid
B. change Allopurinol to Febuxostat
C. reduce the Allopurinol dose
D. discontinue Colchicine
E. continue current gout medications
Khanna Arthritis Care Res 2012; 64:1431-46, Richette Ann Rheum Dis 2017; 76:29-42
Flare prophylaxis during initiation of uric

acid lowering therapy
• recommended for all gout patients, continue until no

evidence of gout activity (no gout flare in 3 months, no
tophi)
• minimum duration
- 6 months
- 3 months after achieving serum target (if no tophus)
- 6 months after achieving serum target (if tophi were
present)
• options
- Colchicine (renally dosed)
- low dose NSAIDs
- low dose Prednisone (≦10 mg daily)
Khanna Arthritis Care Res 2012; 64:1447–61
3478
Question 10
A 45 yo male presents with painful swelling of the 3rd and

4th toe of the right foot and a rash under the soles of his
feet for 4 weeks. He denies fever, recent dysuria,
diarrhea, eye problems, or a h/o psoriasis or back pain.
He is sexually active. He takes no medications.
Exam:
Dactylitis of the right 3rd and 4th toes. Yellow-brown
nodular/hyperkeratotic crusty rash under both feet.
Laboratory + Imaging:
CRP 8 mg/l
CBC unremarkable
X-ray foot - soft tissue swelling
3479

appropriate diagnostic test?
A. anti-CCP
B. ANA
C. urine PCR test for Chlamydia trachomatis
D. HLA-B27
E. X-ray of the pelvis

appropriate diagnostic test?
A. anti-CCP
B. ANA
C. urine PCR test for Chlamydia trachomatis
D. HLA-B27
E. X-ray of the pelvis
3480
Reactive arthritis
• within 4 weeks after UTI or infectious diarrhea

Chlamydia, Yersinia, Salmonella, Shigella,
Campylobacter
• synovial fluid: Gram-stain and culture negative
other microbial analysis also often negative
• self-limited (50%) or chronic (50%)
- asymmetric oligoarthritis, enthesitis, dactylitis
- sacroiliitis
- keratoderma blennorrhagica, circinate balanitis
• treatment with NSAIDs (+ DMARDs if chronic)
no role for antibiotics
Carter Best Pract Res Clin Rheumatol 2011; 25:359-74
HLA-B27
• strongly associated with SpA

- ankylosing spondylitis ~90%
- reactive arthritis 30-70%
- psoriatic arthritis 40-50%
• prevalence of HLA-B27+ in US
6.1% overall
7.5% non-Hispanic White
4.6% Mexican American
1.1% non-Hispanic Black
• HLA-B27 never makes a diagnosis of SpA
Khan Curr Rheumatol Rev 2010; 12:337-41, Reveille Arthritis Rheum 2011, 64:5, 1407-11
3481
Question 11
A 28 yo male presents with chronic pain in the low back

and buttocks for about 3 years. The pain is worse in the
morning and associated with stiffness. Symptoms
improve with exercise. Ibuprofen provides some relief.
The patient denies peripheral joint pain or swelling,
rashes, GI complaints, eye symptoms. A sibling has
psoriasis.
Exam:
Tenderness to palpation over the SI joints, otherwise
unremarkable. ROM in the lumbar spine is normal.
Labs and Imaging:
HLA-B27 negative, CRP 7 mg/l
No evidence for sacroiliitis on pelvic X-ray.
What is the most appropriate diagnostic

test?
A. X-ray cervical, thoracic, lumbar spine

B. CT pelvis
C. U/S of SI joints
D. MRI of the SI joints
E. 99mTc bone scan
3482
What is the most appropriate diagnostic

test?
A. X-ray cervical, thoracic, lumbar spine

B. CT pelvis
C. U/S of SI joints
D. MRI of the SI joints
E. 99mTc bone scan
Axial spondyloarthritis
• includes patients with AS + ‘non-radiographic’ disease

• characteristic features
- chronic back pain (>3 months), onset before age 45
- inflammatory back pain
- association with HLA-B27, psoriasis, IBD, uveitis
- good response to NSAIDs
- M:F = 1:1 (2-3:1 in AS)
• initial tests - CRP, HLA-B27, X-ray pelvis
MRI of SI joints if X-ray negative
• recognize and refer to Rheumatology for evaluation
Rudwaleit Ann Rheum Dis 2009; 68:777-83, Sieper Arthritis Rheum 2013; 65:543-551
3483
2009 ASAS classification criteria for axial SpA

(in patients with back pain ≥3 months and age at onset <45 years)
Sacroiliitis on imaging HLA-B27

plus or plus
≥1 SpA feature ≥2 other SpA features
• inflammatory back pain Sacroiliitis on imaging

• arthritis • active (acute) inflammation
• enthesis (heel) on MRI highly suggestive of
• uveitis sacroiliitis associated with
• dactylitis SpA
• psoriasis OR
• Crohn’s disease/ulcerative • definite radiographic
colitis sacroiliitis according to mNY
• good response to NSAIDs criteria
• family history for SpA
sensitivity 82.9%, specificity 84.4% (overall)
• HLA-B27 sensitivity 66.2%, specificity 97.3% (imaging
• elevated CRP arm)
Rudwaleit Ann Rheum Dis 2009;

68:777-83
Bilateral sacroiliitis on MRI (STIR)
3484
Question 12
A 29 yo male with ankylosing spondylitis diagnosed

2 years ago presents with worsening low back and
buttock pain over the last 6 months. Morning stiffness
lasts 3 hours. ROS is negative except for fatigue.
Symptoms had previously been well-controlled with
physical therapy and Naproxen.
A switch to Indomethacin 50 mg TID one month ago was
without benefit.
Exam:
Tenderness to palpation over the SI joints.
Schober test 4 cm. Otherwise unremarkable.
Labs:
CRP 10 mg/l
What is the most appropriate addition

to this patient’s medical therapy?
A. Tramadol
B. Methotrexate
C. Sulfasalazine
D. Adalimumab
E. Prednisone
3485
What is the most appropriate addition

to this patient’s medical therapy?
A. Tramadol
B. Methotrexate
C. Sulfasalazine
D. Adalimumab
E. Prednisone
Management of ankylosing spondylitis
• first line: NSAIDs and physical therapy

• inadequate NSAID response:
- no response/intolerance to ≥ 2 NSAIDs over 1 month
- incomplete response to ≥ 2 NSAIDs over 2 months
• second line: TNF inhibitors, IL-17A antagonists
• no role for systemic corticosteroids or conventional
DMARDs (e.g. Methotrexate)
Ward Arthritis Rheumatol 2016; 68:282-98, van der Heijde Ann Rheum Dis 2017; 76:978-
991
3486
Question 13
A 42 year-old man is evaluated for pain and swelling of
his left wrist. This started suddenly four days ago. No
history of trauma.
The patient has insurance through ‘HMO Cheap’. In
addition to radiographs, they will only pay for only one
blood test.
Which of the following tests should be

ordered?
A. transferrin saturation
B. serum calcium
C. rheumatoid factor
D. ANA
E. serum uric acid
3487
Which of the following tests should be

ordered?
A. transferrin saturation
B. serum calcium
C. rheumatoid factor
D. ANA
E. serum uric acid
• pertinent information:
- chondrocalcinosis
- acute wrist arthritis (pseudogout)
- degenerative changes in wrist and MCP2/3
• presentation c/w CPPD + secondary osteoarthritis
• differential diagnosis:
- hemochromatosis
- hyperparathyroidism
- hypothyroidism
- acromegaly
- diabetes mellitus
- Wilson’s disease, Ochronosis (rare)
Husar-Memmer Curr Rheumatol Rep 2013; 16:393
3488
Question 14
A 45 yo high school teacher is evaluated for low back

pain that started insidiously 3 weeks ago and has
become worse over the last week. It is now constant,
worse with movements and does not respond to OTC
ibuprofen. He denies a history of trauma, malignancy,
fever, weight loss, numbness, tingling or weakness in the
legs, bladder or bowel symptoms. He does not use IV
drugs.
Exam:
uncomfortable, reduced ROM in L spine
sensation, strength, DTR in legs are symmetric and WNL
straight-leg-raise test → lumbar pain
A. X-ray lumbar spine

B. MRI lumbar spine
C. corticosteroid taper
D. bedrest for 3 days, then graded exercise program
E. change NSAID
3489
A. X-ray lumbar spine

B. MRI lumbar spine
C. corticosteroid taper
D. bedrest for 3 days, then graded exercise program
E. change NSAID
Nonspecific low back pain
• pain without evidence for a serious underlying

condition (e.g. cancer, infection, cauda equina
syndrome), spinal stenosis, radiculopathy, or other
specific spinal cause (e.g. compression fracture, AS)
• imaging not recommended
• management
- education + reassurance
- superficial heat, other non-pharmacological
interventions
- NSAIDs or muscle relaxants
Chou Ann Int Med 2007; 147:478-91, Qaseem Ann Int Med 2017; 166:514-530
3490
Question 15
A 44 yo colleague sees you for left shoulder pain. She is

an avid tennis player and has had pain in the left deltoid
area for the past 3 weeks. The pain is worse with
movements and has prevented her from playing tennis.
Exam:
Subacromial tenderness. The AC joint is nontender.
Full passive ROM in the glenohumeral joint. Resisted
shoulder abduction causes pain, there is no weakness.
Resisted forearm flexion is unremarkable.
X-ray: normal
A. supraspinatus tendonitis
B. rotator cuff tear
C. bicipital tendonitis
D. calcific tendonitis
E. AC joint sprain
3491
A. supraspinatus tendonitis
B. rotator cuff tear
C. bicipital tendonitis
D. calcific tendonitis
E. AC joint sprain
cervical radiculopathy
AC joint calcific tendonitis

pathology frozen shoulder
rotator cuff impingement syndrome
(supraspinatus tendonitis, subacromial bursitis)
supraspinatus tear
OA of the glenohumeral joint
crystal-induced arthritis
bicipital tendonitis
referred pain
(heart,
gall bladder)
Beach NEJM 2016; 375:e24
3492
Question 16
A 42 yo female with long standing asthma maintained on

oral corticosteroids for frequent flares complains about a
new problem. She is having increasing difficulties
climbing stairs, getting up from a chair has become
difficult. She denies upper extremity weakness, joint pain,
muscle pain, stiffness. Her breathing is at baseline.
Exam: moon face, abdominal striae, unable to get up
from chair without using her hands
Labs: CBC, CPK, TSH, ESR are WNL
You suspect she has corticosteroid-induced myopathy.
Which statement is correct regarding

corticosteroid-induced myopathy?
A. muscle pain and stiffness are typical

B. serum CPK may be raised 2-3 times normal
C. patients often describe difficulty rising from chairs
D. shoulder girdle symptoms are generally greater than
hip girdle symptoms
E. the development of this condition is independent of
the corticosteroid dose
3493
Which statement is correct regarding

corticosteroid-induced myopathy?
A. muscle pain and stiffness are typical

B. serum CPK may be raised 2-3 times normal
C. patients often describe difficulty rising from chairs
D. shoulder girdle symptoms are generally greater than
hip girdle symptoms
E. the development of this condition is independent of
the corticosteroid dose
Classification of myopathies associated

with systemic disorders
• Endocrine myopathies
• Inflammatory myopathies
• Paraneoplastic myopathy
• Myopathy from infectious disease
• Drug- and toxin-induced myopathies
• Critical illness myopathy
• Metabolic myopathies
Chawla Front Neurol 2011; 2:49
3494
Corticosteroid myopathy
• Can develop an any time following the initiation of

corticosteroid therapy.
• More common with higher doses of corticosteroids and
longer term use of the drug.
• Commonest complaint is difficulty rising from chairs.
Patients note weakness (typically LE > UE ).
No pain or stiffness. Serum CPK is not elevated.
Chawla Front Neurol 2011; 2:49
Question 17
A 25 yo female presents with episodic painful color

changes in her hands. This started after she moved to
Boston three years ago to attend graduate school.
Episodes are triggered by cold exposure. Typically, her
fingers turn white and later blue.
She has no relevant past medical history and takes no
medications except for birth control. She feels chronically
fatigued. ROS is otherwise unremarkable (no joint pain or
swelling, rashes, photosensitivity, dry eyes or mouth,
mucosal lesions, SOB, weakness).
Physical examination is unremarkable.
3495
What is the next step in evaluating this

patient?
A. perform nailfold capillary microscopy

B. check ANA
C. check antiphospholipid antibodies
D. check scleroderma antibodies (Scl-70, anti-
centromer)
E. no additional tests needed
What is the next step in evaluating this

patient?
A. perform nailfold capillary microscopy

B. check ANA
C. check antiphospholipid antibodies
D. check scleroderma antibodies (Scl-70, anti-
centromer)
E. no additional tests needed
3496
normal
pathological
Wigley NEJM 2016; 375:556-65
Question 18: Which of the following is not included in

the classification criteria for anti-phospholipid
syndrome?
A. h/o venous thromboembolism

B. h/o premature delivery due to pre-
eclampsia/eclampsia
C. positive anti-cardiolipin antibody test
D. positive anti-β2 microglobulin antibody test
E. presence of lupus anticoagulant
3497
Question 18: Which of the following is not included in

the classification criteria for anti-phospholipid
syndrome?
A. h/o venous thromboembolism

B. h/o premature delivery due to pre-
eclampsia/eclampsia
C. positive anti-cardiolipin antibody test
D. positive anti-β2 microglobulin antibody test
E. presence of lupus anticoagulant
Classification criteria for definite anti-phospholipid syndrome (APS)
Miyakis J Thromb Haemost 2006; 4:295-306, Schreiber Nat Rev Dis Primers 2018; 4:17103
3498
Question 19
A 52 yo man presents with several episodes of

hemoptysis over the past day.
He had been well until 3 weeks ago when he developed
myalgia, arthralgia, epistaxis, and diminished hearing.
One week ago he developed a rash and weakness in his
right hand.
Past medical history is otherwise unremarkable. The
patients takes no medications.
Exam:
T 100.4, BP 152/100, HR 72, RR 24
bilateral conjunctival injection, tender maxillary sinuses
decreased hearing in both sides
diffuse rhonchi
reduced grip strength right hand
palpable purpura over the lower extremities
Labs:
Wbc 12,300
ESR 84
Crea 2.1
UA: 3+ protein, 50 Rbc, 20 Wbc, mixed cellular casts
3499
Which of the following tests is most likely to

establish the diagnosis?
A. anti-dsDNA
B. cryoglobulins
C. complement levels (C3, C4)
D. ANCA
E. urine electrophoresis
Which of the following tests is most likely to

establish the diagnosis?
A. anti-dsDNA
B. cryoglobulins
C. complement levels (C3, C4)
D. ANCA
E. urine electrophoresis
3500
ANCA in the Diagnosis of Vasculitis
• useful test, especially when strongly positive,

c-ANCA is more specific than p-ANCA
• indirect immunofluorescence: p-ANCA c-ANCA
ELISA: anti-MPO anti-PR3
• ANCA-associated vasculitides:
- GPA (Wegener’s): c-ANCA, rarely p-ANCA
- MPA (Microscopic polyangiitis): p-ANCA
- EGPA (Churg-Strauss): c-ANCA or p-ANCA
Jennette Arthritis Rheum 2013; 65:1-11
3501
Question 20
An 84 yo male without significant PMH presents with

fatigue and malaise for 6 weeks. He tires easily and has
difficulties completing routine daily activities. He reports a
4 lb weight loss. ROS is negative for fever, night sweats,
SOB, chest pain, changes in urinary or bowel habits. He
denies joint pain, stiffness, headaches, visual complaints.
Exam:
Tired looking but otherwise unremarkable.
Labs:
Wbc 5.0, Hct 28.4, MCV 90, Plt 186
ESR 120
A. biopsy of a single temporal artery

B. biopsy of both temporal arteries
C. trial of Prednisone 60 mg daily
D. trial of Prednisone 15 mg daily
E. serum protein electrophoresis
3502
A. biopsy of a single temporal artery

B. biopsy of both temporal arteries
C. trial of Prednisone 60 mg daily
D. trial of Prednisone 15 mg daily
E. serum protein electrophoresis
• pertinent information
- normocytic anemia and high ESR
- fatigue, not stiffness
- no headache or visual changes
- normal exam
• What are the features of PMR/GCA?
- age >50
- shoulder and hip girdle stiffness + pain
- cranial/visual symptoms in GCA
- fatigue is not the primary issue
• need to r/o dysproteinemia, myeloma
no role for empirical corticosteroids in this case
Weyand NEJM 2014; 371:50-7
3503
Question 21: The Anti-Ro antibody is

associated with all of the following
EXCEPT:
A. Sjogren’s syndrome
B. neonatal lupus
C. subacute cutaneous lupus
D. diffuse proliferative glomerulonephritis
E. congenital heart block
Question 21: The Anti-Ro antibody is

associated with all of the following
EXCEPT:
A. Sjogren’s syndrome
B. neonatal lupus
C. subacute cutaneous lupus
D. diffuse proliferative glomerulonephritis
E. congenital heart block
3504
Anti-Ro/SSA antibodies are associated

with:
• Sjogren’s syndrome
• congenital heart block
• other forms of neonatal lupus
e.g. cutaneous lesions and thrombocytopenia
• subacute cutaneous lupus
• SLE with glomerulonephritis is not typically associated
with this antibody!
Yoshimi Clin Dev Immunol 2012: 606195
Question 22
A 69 yo woman is admitted to the hospital with increasing

shortness of breath on exertion.
The patient has a long history of Raynaud’s and was told
to have scleroderma several years ago. She has lost 30 lb
over the last year in the setting of dysphagia. Facial
telangiectasia and sclerodactyly are clearly present.
While obtaining the history you consider the differences
between diffuse and limited cutaneous systemic sclerosis.
3505
Which of the following is a characteristic feature

of limited cutaneous systemic sclerosis?
A. skin involvement of proximal limbs and trunk

B. interstitial lung disease
C. pulmonary hypertension
D. increased risk for scleroderma renal crisis
E. anti-Scl70 (topoisomerase) antibodies
Denton Lancet 2017; 390:1685-99
Which of the following is a characteristic feature

of limited cutaneous systemic sclerosis?
A. skin involvement of proximal limbs and trunk

B. interstitial lung disease
C. pulmonary hypertension
D. increased risk for scleroderma renal crisis
E. anti-Scl70 (topoisomerase) antibodies
Denton Lancet 2017; 390:1685-99
3506
Question 23
A 23 year old female college student is seen in the ER for

acute bilateral ankle swelling and pain over both shins for
5 days. Symptoms have been getting worse and she has
now difficulties walking. She denies any trauma or recent
travel. No significant PMH.
Exam:
T 100.1, BP 110/65, P 85 reg, RR 18
bilateral swelling of ankles, diffusely tender
bilateral lesions over the tibia, painful to palpation
Labs:
Hct 35, ESR 35
3507
What test would you order next?
A. chest X-ray
B. skin biopsy
C. ACE level
D. RF
E. urinalysis and ANCA
What test would you order next?
A. chest X-ray
B. skin biopsy
C. ACE level
D. RF
E. urinalysis and ANCA
3508
Lofgren syndrome
Lofgren Acta Med Scan 1952
• acute presentation of sarcoidosis

- erythema nodosum
- bilateral hilar lymphadenopathy
- ankle arthritis
• complete triade - 95% specific for sarcoidosis
(DD coccidioidomycosis in endemic areas)
• 1st line treatment - NSAIDs
O’Regan Ann Intern Med 2012; 156
Courtesy of Dr Christoph Berliner, Radiopaedia.org, rID: 22067
3509
Question 24: What do rheumatoid arthritis,

psoriatic arthritis, AS and SLE have in common?
A. largely overlapping genetic risk factors

B. similar prevalence (~1%)
C. more common in women than in men
D. TNF inhibitors are first-line therapy
E. increased risk for cardiovascular disease
Question 24: What do rheumatoid arthritis,

psoriatic arthritis, AS and SLE have in common?
A. largely overlapping genetic risk factors

B. similar prevalence (~1%)
C. more common in women than in men
D. TNF inhibitors are first-line therapy
E. increased risk for cardiovascular disease
3510
Patients with inflammatory rheumatic diseases

have an increased risk for cardiovascular
disease
Nurmohamed Nat Rev Rheumatol 2015; 11:693-704
Questions?
3511
Board Review Practice

Images
Part 2
Ajay K. Singh, MBBS, FRCP
Disclosure
• GSK
Consultant
3512
Question 14
This patient pulled out a tick
from her skin 30 minutes after
a trek in a conservation area in
Barnstable in Cape Cod.. What
is the most likely diagnosis?
A. Bed bug bite

B. Deer tick bite
C. Kissing bugs
D. Deadly Brown Recluse
Spiders
E. Flea bite
http://lymediseaseguide.org/lyme-disease-rash
Question 14
This patient pulled out a tick
from her skin 30 minutes after
a trek in a conservation area in
Barnstable in Cape Cod.. What
is the most likely diagnosis?
A. Bed bug bite

B. Deer tick bite
C. Kissing bugs
D. Deadly Brown Recluse
Spiders
E. Flea bite
http://lymediseaseguide.org/lyme-disease-rash
3513
Deadly Brown Recluse Spiders

Fleas are insects that form the order
Siphonaptera. They are wingless, with
mouthparts adapted for piercing skin and
cimicids or, loosely, bed bugs sucking blood.
Body louse, female Blattodea is an order of insects that contains

the cockroaches and the termites. Formerly
Deer Tick
https://en.wikipedia.org/wiki/Lyme_disease
3514
http://cid.oxfordjournals.org/content/43/9/1089.f
ull
Lyme Facts
• Lyme disease is the most common tickborne infection in both North
America and Europe.
• In the US - Lyme disease is caused by Borrelia burgdorferi, transmitted
by bite from tick species Ixodes scapularis and Ixodes pacificus.
• Clinical manifestations - commonly: skin, joints, nervous system, and
heart.
• Early cutaneous infection with B. burgdorferi is called erythema migrans
-most common clinical manifestation of Lyme disease.
• I. scapularis may also be infected with and transmit Anaplasma
phagocytophilum (previously referred to as Ehrlichia phagocytophila)
and/or Babesia microti, the primary cause of babesiosis.
Abite from an I. scapularis tick may lead to the development of Lyme
disease, human granulocytic anaplasmosis (HGA, formerly known as
human granulocytic ehrlichiosis), or babesiosis as a single infection or, less
frequently, as a coinfection.
HGA and babesiosis should be included in the differential diagnosis of
patients who develop fever after an Ixodes tick bite in an area where these
infections are endemic
3515
Treatment of Early Lyme

• Early localized or early disseminated Lyme disease
associated with erythema migrans (in the absence of
specific neurologic manifestations or advanced atrioven-
tricular heart block (A-I))
Doxycycline (100 mg twice per day) x14 d
Amoxicillin (500 mg 3 times per day) x14-21
Cefuroxime axetil (500 mg twice per day) 14–21 days l
• Doxycycline has the advantage of being effective for
treatment of HGA (but not for babesiosis), which may
occur simultaneously with early Lyme disease.
• Doxycycline is relatively contraindicated during
pregnancy or lactation and in children !8 years of age.
http://lymediseaseguide.org
3516
Question 15
A 62 year old woman on dialysis undergoes a total
parathyroidectomy for tertiary hyperparathyroidism
(PTH 1200 pg/mL). Post-operatively (≈6 hrs post op)
she complains of tingling around her lips and around the
mouth. Approximately 9 hours later she has carpopedal
tetany. Both Trousseau’s and Chvostek’s signs are
positive. An ECG is done. Which one of the following is
most consistent with her likely serum calcium level
A B C
3517
Question
• A
• B
• C
✔A B C
SOURCE:
http://www.angelfire.com/un/al6a/presentation/REsearch/electrolyte_and_metabolic_abnorm.
htm
3518
ECG Changes in Hypo-and Hypercalcemia
• Hypercalcemia and hypocalcemia predominantly alter the

action potential duration.
• Hypercalcemia shortens the ventricular action potential
duration by shortening phase 2 of the action potential.
Hypocalcemia prolongs phase 2 of the action potential.
• Hypercalcemia – shorter QT interval (ST segment portion)
• Hypocalcemia – longer QT interval
• Severe hypercalcemia (e.g., serum Ca2+ ³15 mg/dl) can also
be associated with decreased T wave amplitude, sometimes
with T wave notching or inversion.
• Hypercalcemia sometimes produces a high takeoff of the ST
segment in leads V1 and V2 and can thus simulate acute
ischemia.
• Hypocalcemia generally does not cause T-wave changes
because it does not affect phase 3 of the action potential.
RuDusky, BM Chest Journal 2001
Question 16
A.Lead toxicity
B.Copper toxicity
C.Zinc toxicity
D.Mercury toxicity
3519
https://en.wikipedia.org/wiki/Wilson%27s_disease
A.Lead toxicity
Copper toxicity
A.Zinc toxicity
B.Mercury toxicity
Wilson’s Disease
• Wilson's disease, also called Wilson disease or hepatolenticular
degeneration
• Autosomal recessive disease, mutation in Wilson’s disease protein
gene (ATP7B), accumulation of copper in tissues – accumulation
in liver, brain.
• Also eyes (Kayser-Fleischer rins – copper deposition in
Descemet’s membrane); kidneys (type 2 RTA), heart
(cardiomyopathy)
• Named after Samuel Wilson a British neurologist who first
described the condition in 1912
• A single abnormal copy of the gene is present in 1 in 100 people,
who do not develop any symptoms (carrier)
• If a child inherits the gene from both parents, the child may
develop Wilson's disease. Symptoms usually appear between the
ages of 6 and 20 years, but cases in much older people have been
described. Wilson's disease occurs in 1 to 4 per 100,000 people
3520
SOURCE: http://www.eurowilson.org/en/living/guide/what/index.phtml
Question 17
A 48 year old white male with chronic kidney disease
(CKD) with a serum creatinine of 1.5 mg/dL presents to
you complaining of weakness and fatigue and an
episode of palpitations. The patient is on furosemide 40
mg BID, lisinopril 20 mg QD, atorvostatin 20 mg QD and
aspirin 81 mg QD. You do an ECG and draw labs.
Based on the ECG, what is the most likely diagnosis?
A.) Patient has hypomagnesemia, Mg 1.4 mg/dL
B.) Patient has hypokalemia, K 2.0 mEq/L
C.) Patient has hyperkalemia, K 6.8 mEq/L
D.) Patient has hypocalcemia, Ca 7.1 mg/dL
3521
https://cardiologyboardreview.wordpress.com/page/2/
Question 17
A 48 year old white male with chronic kidney disease
(CKD) with a serum creatinine of 1.5 mg/dL presents to
you complaining of weakness and fatigue and an
episode of palpitations. The patient is on furosemide 40
mg BID, lisinopril 20 mg QD, atorvostatin 20 mg QD and
aspirin 81 mg QD. You do an ECG and draw labs.
Based on the ECG, what is the most likely diagnosis?
A.) Patient has hypomagnesemia, Mg 1.4 mg/dL
B.) Patient has hypokalemia, K 2.0 mEq/L
C.) Patient has hyperkalemia, K 6.8 mEq/L
D.) Patient has hypocalcemia, Ca 7.1 mg/dL
3522
SOURCE:
https://fluidandelectrolyteimbalances.wordpress.com/2013/04/19/potassi
um/
Hypokalemia
• PR interval may be prolonged
• Flat T wave
• Prominent U wave
• ST depression
• QT prolongation, but often difficult to
measure as T wave flattens
3523
Question 18
A 55-year-old man presented with a 2-
year history of painful jaw enlargement
and progressively ill-fitting dentures.
The serum level of alkaline
phosphatase and bone-specific alkaline
phosphatase were elevated (154 IU per
liter [normal level, <120] and 92 IU per
liter [normal range, 15 to 41],
respectively). He has an elevated
alkaline phosphatase and a normal
Q: serum creatinine. Which one of the
following tests would confirm the
diagnosis?
A. Bone scan
B. Insulin-like growth factor-1 level
C.Serum calcium
D.Abdominal ultrasound
E.Testing the function of the facial nerve
SOURCE: Patel MB, et al N Engl J Med 2008; 358:625
A. Bone scan
Q:
Paget's disease, acromegaly, and
renal osteodystrophy are among
the causes of jaw enlargement,
Answer: visible in this image. An elevated
alkaline phosphatase makes
Paget's disease the most likely
diagnosis; the diagnosis can be
confirmed with a bone scan and a
mandibular biopsy. Treatment with
a bisphosphonate normalized the
serum level of alkaline
phosphatase. Earlier diagnosis
and treatment might have limited
further mandibular hypertrophy
and pain
3524
Paget’s Disease of the Bone

• Chronic disorder that can result in enlarged and misshapen
bones; named after Sir James Paget; affects 1.5-8% of
population; presentation >age 55
• Caused by the excessive breakdown and formation of bone,
followed by disorganized bone remodeling.
• Affected bones weaken, resulting in pain, misshapen bones,
fractures and arthritis in the joints near the affected bones.
Rarely, can develop into a primary bone cancer known as
Paget's sarcoma.
• Often Paget's disease is localized to only a few bones in the
body. The pelvis, femur, and lower lumbar vertebrae are the
most commonly affected bones.
• Early diagnosis and treatment is important, after age 40,
siblings and children of someone with Paget's disease should
have an alkaline phosphatase blood test every two or three
years.
https://en.wikipedia.org/wiki/Paget%27s_disease_of_bone
Question 19
A 30 year patient returns with
fever after a visit trekking in
several sub-saharan countries.
He has high fever (39.5oC), low
normal blood pressure and
lethargy. He complains of a stiff
neck and photophobia. The
rash began 2 days before the
visit to the ED and 8 days after
his return.
A.) Erythema multiforme
B.) Meningococal meningitis
C.)Henoch Schonein purpura
D.) Microscopic polyangitis
3525
A 30 year patient returns with

fever after a visit trekking in
several sub-saharan countries.
He has high fever (39.5oC), low
normal blood pressure and
lethargy. He complains of a stiff
neck and photophobia. The
rash began 2 days before the
visit to the ED and 8 days after
his return.
A.) Erythema multiforme
B.) Meningococal meningitis
C.)Henoch Schonein purpura
D.) Microscopic polyangitis
Erythema multiforme (EM) is an

acute, self-limited, and sometimes
recurring skin condition that is
considered to be a type IV
hypersensitivity reaction associated
with certain infections, medications,
and other various triggers.
SOURCE: http://emedicine.medscape.com/article/1122915-overview
https://en.wikipedia.org/wiki/Erythema_multiforme#/media/File:Erythema_multiforme_minor_of_the_hand.j
pg
HSP – is a systemic vasculitis with IC’s
depositing with IgA
In the skin, the disease causes
palpable purpura
Also, kidney and joint involvement and
abdominal pain (small bowel vasculitis
Classic Triad: purpura, abdominal pain

and arthritis
SOURCE:
http://www.cfp.ca/content/54/8/1117/F1.expansion
3526
Microscopic polyangiitis (MPA)

is vasculitis of small vessels:
small vessels, including
arterioles, capillaries, and
venules.
Consitutional features: Fever,
anorexia, weight loss, fatigue
Glomerular involvement: RPGN

SOURCE: Rheum: myalgias, arthralgias
https://o.quizlet.com/tA5nW9BXhJwEPC1fHclg
BA_m.jpg and arthritis
GI: Abdominal pain and GI
bleeding
Lung hemorrhage
Peripheral neuropathy
Meninogococcal Meningitis
• Gram-negative diplococcus Neisseria meningitidis
• Presents with intense headache, fever, N/V, Photophoba, stiff neck,
lethargy, altered mental state, rash
• Meningococcal septicemia - rapid circulatory collapse and a hemorrhagic
rash, is a more severe, but less common, form of meningococcal disease.
• cerebrospinal fluid (CSF) usually confirms the presence of meningitis.
Typical CSF abnormalities in meningitis include the following:
Increased opening pressure (>180 mm water)
Pleocytosis of polymorphonuclear leukocytes (white blood cell [WBC]
counts between 10 and 10,000 cells/µL, predominantly neutrophils)
Decreased glucose concentration (< 45 mg/dL)
Increased protein concentration (>45 mg/dL)
• Culture of CSF and blood specimens - To identify N meningitidis and the
serogroup of meningococci, as well as to determine the bacterium’s
susceptibility to antibiotics
• Polymerase chain reaction (PCR) assay - For confirmation of the diagnosis
http://emedicine.medscape.com/article/1165557
-overview
3527
Meningococcal belt
SOURCE: Aguado T, et al Nature Reviews Microbiology 3, 10-11 (January

2005)
Question 20
A 19-year-old man presented with a 10-month
history of Raynaud's phenomenon, fever,
abdominal pain, and hypertension. On
examination, he had multiple subcutaneous
nodules on his forehead, and his blood
pressure was 150/100 mm Hg. Laboratory
findings included a normal urine sediment, an
elevated erythrocyte sedimentation rate, mild
anemia, and leukocytosis, with negative tests
for antineutrophil cytoplasmic autoantibody,
hepatitis B surface antigen, and hepatitis C
antibody. What diagnosis is suggested by the
findings on his angiogram?
A. Takayasu's arteritis
B. Wegener's granulomatosis
C. Paraganglioma
D. Systemic lupus erythematosus
E. Polyarteritis nodosa
SOURCE: Das CJ , et al .N Engl J Med 2006; 355:2574
3528
E. Polyarteritis nodosa
The angiogram reveals multiple

microaneurysms involving the
parenchymal branches of the hepatic
artery, splenic artery, renal artery. Biopsy
of a subcutaneous nodule revealed
necrotizing inflammation of medium-
sized arteries, and vasculitis in renal
biopsy specimens — findings consistent
with a diagnosis of polyarteritis nodosa.
The patient was treated with
corticosteroids, resulting in the resolution
of his symptoms, including the skin
nodules, fever, and abdominal pain.
Multiple aneurysmal dilatations up to 1
cm in diameter, involving the bifurcations
and branches of small- and medium-size
arteries, are characteristic of polyarteritis
nodosa.
Polyarteritis nodosa
• Classic polyarteritis nodosa (PAN or c-PAN) - systemic
vasculitis characterized by necrotizing inflammatory lesions
that affect medium-sized and small muscular arteries,
preferentially at vessel bifurcations, resulting in
microaneurysm formation, aneurysmal rupture with
hemorrhage, thrombosis, and, consequently, organ ischemia
or infarction.
• Kussmaul and Maier first described PAN in 1866.
• Affects skin (see the image below), joints, peripheral nerves,
the gut, and the kidney. affects skin joints, peripheral nerves,
the gut, and the kidney
3529
Question 21
These lesions were neither
pruritic nor painful. What is
the diagnosis?
A. Pyoderma gangenosus
B. Phlegmasia cerulea dolens
C. Pretibial myxedema
D. Necrobiosis lipoidica
diabeticorum
Q: E. Erythema nodosum
Q:
These lesions were neither
pruritic nor painful. What is
the diagnosis?
Answer:
D. Necrobiosis lipoidica
diabeticorum
This patient was diagnosed

with necrobiosis lipoidica
diabeticorum.
3530
Necrobiosis lipoidica
• Necrobiosis lipoidica is a disorder of collagen degeneration
with a granulomatous response, thickening of blood vessel
walls, and fat deposition.
• The main complication of the disease is ulceration, usually
occurring after trauma. Infections can occur but are
uncommon.
• There have been rare reported cases of squamous cell
carcinomas developing in chronic lesions of necrobiosis
lipoidica.
• The condition was first described in 1929, by Oppehhein, who
called it dermatitis atrophicans lipoidica diabetica; in 1932,
however, the disease was renamed necrobiosis lipoidica
diabeticorum (NLD), by Urbach.
• In 1935, Goldsmith reported the first case in a nondiabetic
patient.
Question 22
58 year old woman presents with bright red blood per rectum,
fatigue and dyspnea. PMH- recurrent episodes of spontaneous
epistaxis. Mother has similar history. Labs – severe iron deficiency
anemia.
The most likely cause is:
A.) Essential telangiectasia
B.) Osler-Weber-Rendu syndrome
C.) Scleroderma
D.) Neurofibromatosis
3531
58 year old woman presents with bright red blood per rectum,
fatigue and dyspnea. PMH- recurrent episodes of spontaneous
epistaxis. Mother has similar history. Labs – severe iron deficiency
anemia.
The most likely cause is:
A.) Essential telangiectasia
B.) Osler-Weber-Rendu syndrome
C.) Scleroderma SOURCE: Perez-Belmonte LM, et al, NEJM N Engl J
Med 2015; 373:e15
D.) Neurofibromatosis http://www.nejm.org/doi/pdf/10.1056/NEJMicm1414035
Osler-Weber-Rendu Syndrome
• Osler-Weber-Rendu disease (OWRD) - rare autosomal dominant disorder that

affects blood vessels throughout the body (causing vascular dysplasia) and results in
a tendency for bleeding. (also known as hereditary hemorrhagic telangiectasia [HHT]
• HHT is manifested by mucocutaneous telangiectases and arteriovenous
malformations
• Lesions can affect the nasopharynx, central nervous system (CNS), lung, liver, and
spleen, as well as the urinary tract, gastrointestinal (GI) tract, conjunctiva, trunk,
arms, and fingers
• Recurrent and severe epistaxis is the most common presentation, frequently leading
to severe anemia that necessitates transfusion, GI bleeding is also prevalent.
• diagnosis of HHT is made clinically on the basis of the Curaçao criteria (1999):
Epistaxis
• Telangiectasias
• Visceral lesions
• Family history (a first-degree relative with HHT)
3532
Question 23
25-year-old man with human immunodeficiency virus (HIV) infec-

tion who was receiving highly active antiretroviral therapy presented with a
1-week history of diplopia and headache. The CD4 count was 218 cells per
Q:
cubic millimeter, and the viral load was 50,000 copies per milliliter. The
neurologic examination revealed an inability to abduct the right eye with
horizontal gaze: What is the likely diagnosis?
A. Internuclear ophthalmoplegia
B. Left fourth cranial nerve palsy
C. Left sixth cranial nerve palsy
D. Right fourth cranial nerve palsy
E. Right sixth cranial nerve palsy
SOURCE: Dhillon, WS et al N Engl J Med 2010; 362:e52
E. Right sixth cranial nerve palsy

(VIth cranial nerve palsy or Abducens nerve palsy)
The neurologic examination reveals an inability to abduct the

right eye with horizontal gaze to the right, a finding that is
consistent with an isolated right abducens nerve palsy.
Causes: Vasculopathi (HTN, DM), trauma, idiopathic

cavernous sinus mass, raised intracranial pressure, giant cell
arteritis
3533
Question 24
This 41 year old patient
with a history of alcohol
abuse developed alopecia
with fine, brittle scalp
hair, diarrhea, and angular
cheilitis. Measurement of
which one of the
following metals is most
Q: likely to be diagnostic?
A. Chromium
B. Copper
C. Manganese
D. Selenium
E. Zinc
E. Zinc
This scaly erythematous

eruption that preferentially
Answer:
involved the distal
extremities and the
perineum is most
consistent with
acrodermatitis
enteropathica, confirmed
by measurement of the
Acquired Acrodermatitis Enteropathica zinc level. The patient's
symptoms resolved after
zinc supplementation.
• SOURCE: Wang LC et al N Engl J Med 2005;

352:1121http://www.nejm.org/doi/full/10.1056/NEJMicm030844?vie
wType=Print&viewClass=Print
3534
Question 25
A 19-year-old woman presented to
the emergency department with a
10-day history of intermittent
odynophagia, voice changes, and
fever. Before her visit to the
emergency department, she was
treated with azithromycin and
prednisone for pharyngitis and,
subsequently, with 2 days of
penicillin and a tapered dose of
prednisone. She was otherwise
Q: healthy. Examination revealed
bilateral swelling of the soft palate
with a midline uvula pushed
anteriorly What is the diagnosis?
A. Ludwig's angina
B. Glossopharyngeal nerve palsy
C. Pharyngeal gonorrhea
D. Bilateral peritonsillar
abscesses
E. Infectious mononucleosis
D. Bilateral peritonsillar
Q: What is the diagnosis? abscesses
Bilateral swelling of the

soft palate is visible with a
Answer:
midline uvula pushed
anteriorly. A CT of the
neck after the
administration of
intravenous contrast
material showed bilateral
peritonsillar abscesses
This is most consistent
with a diagnosis of
bilateral peritonsillar
abscesses.
SOURCE: Fiechtl, JF et al N Engl J Med 2008; 358:e27

http://www.nejm.org/doi/pdf/10.1056/NEJMicm072980
3535
Hospital Medicine:
What’s New in the Literature
Psychiatry Overview Christopher Roy, MD

Director of Hospital Medicine
Division of General Medicine, Department of Medicine
3536
Case 1
68 year-old female smoker admitted with cough
and purulent sputum, wheezing, and dyspnea
consistent with an acute exacerbation of COPD.
She is afebrile and chest radiograph is normal.
On hospital day #3, she has stabilized and is off

oxygen, remains afebrile. Your medical student
tells you that her procalcitonin (Vidas assay) is
0.15 mcg/L.
Case 1
You should:
a. Continue azithromycin
b. Repeat blood cultures
c. Add ceftriaxone IV
d. Stop azithromycin and discharge home
e. Ask the medical student to prepare a
presentation on procalcitonin for the team
3537
Case 1
You should:
a. Continue azithromycin
b. Repeat blood cultures
c. Add ceftriaxone IV
d. Stop azithromycin and discharge home
e. Ask the medical student to prepare a
presentation on procalcitonin for the team
Procalcitonin: Overview
• Biomarker of bacterial infection
• Shown to help safely curb antibiotic utilization in
ICU patients with suspected or documented
infection/sepsis, and respiratory tract infections
• FDA approved for:
– Sepsis diagnostic aid (2006)
– Assessment of 28-day sepsis mortality (2016)
– NEW: Guide to antibiotic therapy initiation /
discontinuation in respiratory infections, and
discontinuation in sepsis (2017) (Vidas assay)
3538
Procalcitonin and Acute Respiratory

Infection
• Cochrane review/metaanalysis of 32 RCTs,
6708 patients who had acute respiratory
infection, randomized to PCT guided therapy
vs usual care
• Mortality was lower in the PCT group (8.6% vs
10%) and antibiotic exposure was 2.4 days
lower. Treatment failure was similar
• Bottom line: PCT algorithms might be useful in
ARI to reduce abx usage and mortality
Cochrane Database of Systematic Reviews,
Published online October 12, 2017
Suggested Algorithm for PCT Use
3539
Cautions with Procalcitonin

• False positives: inflammation: major
trauma/burns/surgery/pancreatitis
• False negatives: early sepsis or contained
infection, repeat within 6-24 hrs if abx withheld
• Severely immunocompromised patients were
excluded, as were patients with cystic fibrosis or
pregnancy
• Should never replace clinical judgment (clinical
judgment override in sepsis trials used >50%)
Newer trials suggesting PCT not so

great…
• AE COPD study from France
• ProACT study NEJM May 2018
3540
COPD and Procalcitonin

• Antibiotics are indicated for most acute
exacerbations of COPD requiring
hospitalization
• Triggers of AE COPD are often not bacterial
• Could PCT be used to distinguish bacterial
trigger from viral, environmental etc and
decrease antibiotic utilization?
www.goldcopd.com
AE COPD and Procalcitonin

• RCT of 302 patients admitted to ICU with AE
COPD in France
• PCT guided antibiotic rx vs. usual care
• Failed to safely reduce antibiotic use
• Initiation of antibiotics improved 3 month
survival regardless of PCT level
• Bottom line: don’t use PCT algorithm to
reduce abx for AE COPD
Intensive Care Med (2018) 44:428–437
3541
• Use of PCT guided rx algorithm for suspected lower resp

infection did not result in less use of antibiotics vs usual care
• Included 1656 pts with final dx of COPD flare, asthma, acute
bronchitis, pneumonia presenting to ED
• “Real world” study, PCT algorithm did not beat usual
care/clinical gestalt Published online NEJM May 20, 2018
Case 2
78 year-old male assisted living resident is
admitted with pneumonia. At baseline he uses
a walker to ambulate. You begin his admission
orders and consider choices for his activity
orders:
a. Ambulate with assistance
b. Fall precautions
c. OOB as tolerated
d. Bedrest
e. PT evaluation
3542
Case 2
78 year-old male assisted living resident is
admitted with pneumonia. At baseline he uses
a walker to ambulate. You begin his admission
orders and consider choices for his activity
orders:
a. Ambulate with assistance
b. Fall precautions
c. OOB as tolerated
d. Bedrest
e. PT evaluation
Case 2
• Hospitalized elders
are OOB only 4% of
waking hours with
usual care
• A lack of early
mobilization to
contribute to
functional decline
and frailty,
prolonged delirium,
longer LOS, lower
likelihood of
discharge to home
• Structured program
to increase early
mobilization could
reduce these risks
Creditor et al Ann Int Med 1993;

118:219-23
3543
Let’s MOVE ON
• 10,000 elderly patients admitted
to 14 acute care hospitals in
Ontario
• Quasi experimental time series
approach with visual audits to
assess mobilization rates
• No added resources,
implemented with existing care
team
– Assessed for early mobilization
within 24 hours of admission
– Mobilized 3 times a day
– Progressive and scaled, tailored
to patient’s abilities
From: Outcomes of Mobilisation of Vulnerable Elders in Ontario (MOVE ON): a multisite interrupted time
series evaluation of an implementation intervention to increase patient mobilisation
Age Ageing. 2017;47(1):112-119. doi:10.1093/ageing/afx128
Age Ageing | © The Author 2017. Published by Oxford University Press on behalf of the British Geriatrics Society.This is an
Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License
(http://creativecommons.org/licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any
medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.com
3544
MOVE ON
• 10% increase in patients out of bed
• Significant decrease in median LOS (-6.1 days)
in the intervention and post intervention
phases
• No change in % discharged to home
Case 3
68 year-old female is brought by her husband
to the ED for an episode of syncope. She has a
history of HTN and hyperlipidemia. Syncope
was sudden in onset and there was no
prodrome. She awoke within seconds and was
alert, denied chest pain, dyspnea, or
palpitations. Physical exam including VS, O2
saturation, and 12 lead ECG were normal.
3545
Case 3
• In addition to cardiac monitoring and
echocardiogram, you should consider:
a. EEG
b. Head CT
c. D-dimer
d. CTA of the coronary arteries
e. Carotid non-invasive studies
f. None of the above
Case 3
• In addition to cardiac monitoring and
echocardiogram, you should consider:
a. EEG
b. Head CT
c. D-dimer
d. CTA of the coronary arteries
e. Carotid non-invasive studies
f. None of the above
3546
Pulmonary Embolism in
Patients with Syncope
• PESIT study
• 11 hospitals in Italy
• 560 pts with first episode of
syncope
• PE ruled out in 59% with
low prob Wells score and
neg d-dimer
• Prevalence of PE in
remaining pts was 42.2%, in
the entire cohort it was
17.3% (about 1 in 6)
• But higher risk cohort than
syncope pts admitted in
U.S.?
n engl j med 375;16 October 20, 2016
But is the prevalence of PE in patients

with syncope really that high??
• Retrospective observational study of 5 databases in
4 different countries over 6.75 years
• 1,671,944 patients with ED visit for syncope
• Prevalence of PE at ED or hospital discharge and
within 90 days
• Prevalance of PE only 0.06% for all patients and
0.15% for hospitalized patients, and only 0.14-
0.35% at 90 days
• Conclusion: PE was rarely identified, and not all
patients need evaluation for PE
JAMA Int Med. Published online Jan 29, 2018
3547
Case 4
55 year old female presents with fevers, flank
pain, nausea, vomiting, and confusion. Exam is
notable for T 102.5, HR 130, BP 75/50 R 32.
There is R flank tenderness and she is lethargic
and confused. Urinalysis shows >100 WBC and
4+ bacteria.
Case 4
In addition to starting aggressive volume
resuscitation and IV antibiotics for presumed
urosepsis, which of the following is indicated:
a. Vitamin D, thiamine, and
hydrocortisone
b. Normal saline instead of lactated
ringers for resuscitation
c. Hydrocortisone plus fludrocortisone
3548
Case 4
In addition to starting aggressive volume
resuscitation and IV antibiotics for presumed
urosepsis, which of the following is indicated:
a. Vitamin D, thiamine, and
hydrocortisone
b. Normal saline instead of lactated
ringers for resuscitation
c. Hydrocortisone plus fludrocortisone
Corticosteroids in Sepsis:
the Final Word?
• Over the past 55 years (!) there have been multiple small
studies and metaanalyses of CS in sepsis, with
equivocal/disparate findings
• 2 very large studies this year, probably will be the last word on
this
• Australian study (ADRENAL) 3,658 pts, (1/3 surgical), with abd
infection or pneumonia as source, received cont infusion of
HC (200 mg/d)
• French study (APROCCHSS) of 1,241 pts (80% medical) most
with pneumonia, rec’d HC 50mg q6h + fludrocortisone 50 mcg
qd Venkatesh et al. NEJM. 2018; 378:797-808.
Annane et al. NEJM. 2018;378:809-18.
3549
Corticosteroids in Sepsis
• Both studies found that HC shortened the
duration of septic shock (faster resolution and
more pressor-free days)
• The French study showed a reduction in 90d
mortality (43% vs 49.1%, p=0.03) in the HC +
fludrocort arm
• The Australian study showed no 90d mortality
benefit
• Bottom line: treat the sickest pts with HC and
(possibly) fludrocortisone
Venkatesh et al. NEJM. 2018; 378:797-808.
Annane et al. NEJM. 2018;378:809-18.
Face-off: Lactated ringers

vs Normal Saline
NEJM 2018; 378(9)
3550
Lactated ringers vs normal saline

• In non-critically ill patients presenting to the
ED, use of LR did not increase hospital-free
days but did decrease major adverse kidney
events (4.7% vs 5.6% adj OR 0.82, p=0.01)
• In critically ill patients presenting to the ICU,
use of LR lowered major adverse kidney
events (14.3% vs 15.4%, OR 0.90, p=0.04) and
30d in-hospital mortality (10.3% vs 11.1%,
p=0.06)
NEJM 2018; 378(9)
Vitamin C???
3551
• 47 pts in single center

• Retrospective
before/after study design
• Cocktail of Vit C 1.5 mg
q6h, HC 50mg q6h,
Thiamine 200mg q12h
• 9% vs 40% mortality (!!!)
• Too good to be true?
CHEST. 2017; 151(6):1229-1238
Case 5
65 yo male is admitted for elective cervical
laminectomy. Perioperatively he receives
prophylactic cefazolin and develops severe
diarrhea on POD#3, WBC 7 26, and fever. C.
diff is sent and positive.
3552
Case 5
What is the best treatment regimen:
a. Metronidazole 500 mg orally q8h

b. Fidaxomicin 200mg orally bid
c. Vancomycin 500 mg orally q6h
d. IVIG
e. Fecal Microbiome Transplant
Case 5
What is the best treatment regimen:
a. Metronidazole 500 mg orally q8h

b. Fidaxomicin 200mg orally bid
c. Vancomycin 500 mg orally q6h
d. IVIG
e. Fecal Microbiome Transplant
3553
New 2018 IDSA Guidelines for C diff
• Fidaxomicin
recommended
alternative to
vanco orally
• Metronidazole
downgraded, and
is only weakly
recommended for
mild disease if
fidaxomicin and
vanco unavailable
Clin Infect Dis. 2018 Feb 15
Case 6
You are asked to consult on a 45 year-old male
admitted to the trauma service with pelvic and
rib fractures after a MVA for an elevated TnT. He
developed substernal chest discomfort in the
setting of being transferred to a chair and ECG
was normal but troponin T was 38. The hospital
recently changed to a high sensitivity TnT assay.
3554
Case 6
What would be your next best diagnostic step?
a. Coronary angiography
b. Dobutamine MIBI
c. CT angiography
d. No further testing required
Case 6
What would be your next best diagnostic step?
a. Coronary angiography
b. Dobutamine MIBI
c. CT angiography
d. No further testing required
3555
High sensitivity TnT
Hochholzer W, Morrow DA, Giugliano RP, AHJ 2010
Many causes of hsTnT elevation
3556
Many types of MI
• Type I: Ischemic due
to plaque rupture
(ACS)
• Type 2: Ischemic due
to supply/demand
mismatch
• Type 3: Sudden
cardiac death
• Type 4: Procedure
related (PCI)
• Type 5: CABG related
Even normal people have a number
3557
Use of HEART Score in Suspected ACS
Partners (BWH/MGH) ED Pathway
3558
Case 7
45 year old male with DM and HTN admitted
with cholecystitis and has a laparoscopic
cholecystectomy. You are called on POD #2
because his hsTnT (sent because of post-op ECG
changes) is elevated at 38. On exam he is
sedated on fentanyl PCA but denies SOB or CP.
Vital signs have been stable and he did not have
extremes of BP in OR. Rest of exam is normal
and ECG shows non-specific ST-T wave changes
in the lateral leads.
Case 7
a) Elevation of hsTnT after non-cardiac surgery has no bearing on
30d mortality
b) Patients with myocardial injury after non-cardiac surgery (MINS)
usually have ischemic symptoms
c) There are no published studies of effective treatment of MINS
d) Elevation of hsTnT has similar prognostic value as elevation of a 4th
generation troponin assay
e) I’ve never heard of MINS so I can’t answer the question
3559
Case 7
a) Elevation of hsTnT after non-cardiac surgery has no bearing on
30d mortality
b) Patients with myocardial injury after non-cardiac surgery (MINS)
usually have ischemic symptoms
c) There are no published studies of effective treatment of MINS
d) Elevation of hsTnT has similar prognostic value as elevation of a
4th generation troponin assay
e) I’ve never heard of MINS so I can’t answer the question
Myocardial injury after non-cardiac

surgery (MINS)
• Elevated postop TnT (4th or 5th generation) is a marker for worse
prognosis and increased mortality after non-cardiac surgery
• MINS includes MI and isolated ischemic troponin elevation that
occur within first 30 days after surgery
• MINS does not include non-ischemic myocardial injury
– sepsis, rapid AF, PE, chronically elevated troponin
• MINS affects ≥8 million adults worldwide annually
• MINS is independently associated with increased risk of CV events
and death over first 2 years after surgery
• Without measuring troponin, most MINS will be missed as most do
not have sx
• ?treatment
3560
Elevated hsTnT after non-cardiac surgery

predicts increased 30d mortality
And most patients had no ischemic symptoms!

Devereaux JAMA 2017 317(16):1642-51
Dabigatran in
myocardial injury after
noncardiac surgery
Dr. PJ Devereaux on behalf of MANAGE Investigators
Population Health Research Institute, Hamilton, Canada
3561
MANAGE Trial design

• Multicenter/multinational RCT of 1754 patients with MINS
within 35 days
– randomized to dabigatran 110mg bid or placebo
– Trial stopped early due to loss of funding and slow enrollment
• Partial 2X2 factorial design
– patients not already on PPI
• randomize to omeprazole or placebo
• Primary outcome: major vascular complication (vascular
mortality, nonfatal MI, non-hemorrhagic stroke, peripheral
arterial thrombosis, amputation, and VTE)
Primary efficacy outcome

Outcome Dabigatran Placebo HR P
n=877 n=877 (95% CI) value
no. (%) no. (%)
composite of vascular death
and nonfatal MI, 97 (11) 133 (15) 0.72 0.012
non-hemorrhagic stroke, (0.55-0.93)
peripheral arterial
thrombosis, amputation, and
symptomatic VTE
• There was no significant effect of omeprazole study drug on results of dabigatran primary
efficacy analysis (interaction P=0.79)
• But, study drug was stopped in >40%, and use of ASA and statin was lower than average
• More studies needed
3562
Case 8
23 year-old female with sickle cell anemia is
admitted with pain crisis. On prior admissions
for the same issue she has been treated
successfully with a high-dose PCA. 5 minutes
after ordering the PCA, pharmacy calls you to
ask if you could switch her to bolus dosing and
maximize non-opioid adjuvants given the
national opioid shortage.
National Shortage of
Injectable Opioids
3563
Background
July 10, 2017
• As of July 2017, national shortage
of IV administered opioids.
• Medications in short supply
include hydromorphone, fentanyl,
remifentanil, sufentanil,
meperidine, methadone, and
morphine
• All hospitals experiencing the
same shortages, though shortages
may be more severe in some
regions and may vary over time
• Could take over a year for the
supply chain issues to work out
Courtesy of John Fanikos, PharmD
3564
OPIOID SPARING STRATEGIES
Is my patient on a PCA and able Is my patient on a Is my patient on a opioid

to take oral medications? PCA and NPO? infusion and NPO?
Optimize short acting opioids:* Optimize opioids:* Optimize opioids:*
• D/C PCA and transition to oral opioids (tablet or elixir) • D/C PCA and transition to IV boluses of opioid • Consider discontinuing infusion and transitioning to
• Consider Fentanyl TD IV boluses of opioid
Optimize use of long acting opioids if needed: • Consider Fentanyl TD
• Oxycontin, MS Contin, Fentanyl TD Consider additional adjuvants:**
• If Methadone is considered, consult palliative, postop or chronic pain • Acetaminophen IV Consider additional adjuvants:**
service • Ketorolac • Acetaminophen IV
• Clonidine patch • Ketorolac
Consider additional adjuvants:** • Lidocaine patch • Clonidine patch
• Acetaminophen PO or IV • Lidocaine patch
• Ibuprofen PO or Ketorolac iv or other NSAID Consider creative use of local anesthetics:
• Gabapentin • Can patient have a nerve block? Consider creative use of local anesthetics:
• Clonidine patch • Can patient get an epidural? • Can patient have a nerve block?
• Lidocaine patch • Can patient get an epidural?
Consider opioid sparing IV infusions:
Consider creative use of local anesthetics: (POPS, Chronic, Palliative Pain Service approval Consider opioid sparing IV infusions:
• Can patient have a nerve block? required if out of ICU) (POPS, Chronic, Palliative Pain Service approval
• Can patient get an epidural? • Dexmedetomidine infusion (ICU only) required if out of ICU)
• Lidocaine infusion • Dexmedetomidine infusion (ICU only)
Consider opioid sparing IV infusions: • Ketamine infusion • Lidocaine infusion
(POPS, Chronic, Palliative Pain Service approval required if out of ICU) • Ketamine infusion
• Lidocaine infusion Consider consulting Pain, Palliative Care, or
• Dexmedetomidine infusion (ICU only) Pharmacy Consider consulting Pain, Palliative Care, or Pharmacy
• Ketamine infusion • If pain is difficult to manage • If pain is difficult to manage
• If you need help with conversion to oral opioids • If you need help with conversion to oral opioids
Consider consulting Pain, Palliative Care, or Pharmacy *If your patient is NOT in an acute pain crisis and is able to
• If pain is difficult to manage tolerate POs, IV opioids are NOT available. BWH Department of Anesthesiology, Perioperative and Pain
• If you need help with conversion to oral opioids **Always review contraindications for your patients prior to Medicine, 2018
starting any of these medications. Ver 2018.3 Last update 3/12/2018
3565
Case 9
82 year-old female with chronic AF, CHF with
EF 25%, HTN, h/o TIA, PVD now admitted to
ortho service for elective THR. You are asked
to comment on management of her
anticoagulation periop. She is on warfarin 2.5
mg daily and her INR is 2.0.
Case 9
With regards to her warfarin anticoagulation, you
should recommend:
a. Stop/reverse warfarin preop and use low molecular

weight heparin or UF heparin bridge pre and post op
b. Stop/reverse warfarin preop and use oral
rivaroxaban as a bridge pre and post op
c. Stop/reverse warfarin and resume postop without a
bridge
3566
Case 9
With regards to her warfarin anticoagulation, you
should recommend:
a. Stop/reverse warfarin preop and use low molecular

weight heparin or UF heparin bridge pre and post op
b. Stop/reverse warfarin preop and use oral
rivaroxaban as a bridge pre and post op
c. Stop/reverse warfarin and resume postop without a
bridge
Case 9
• CHADS2 score: 5 (CHF, HTN, Age>=75, h/o
TIA)=high risk, 12.5% stroke rate
• CHA2DS2-VASc score: 8 (CHF, HTN, Age>=75,

Vasc dz, TIA, female sex) =high risk=>10% risk
of stroke, 15.2% risk of stroke, TIA, systemic
embolism
3567
N Engl J Med 2015; 373:823-833
_____
High risk underrepresented
Journal of the American College of Cardiology Jan 2017, 23217;

DOI:10.1016/j.jacc.2016.11.024
3568
But bridging rarely needed for DOACS…
JACC Jan 2017, 23217; DOI:10.1016/j.jacc.2016.11.024
JACC Jan 2017, 23217;

DOI:10.1016/j.jacc.2016.
11.024
3569
JACC Jan 2017, 23217;

DOI:10.1016/j.jacc.2016.
11.024
Case 10
63 year-old female with HTN, DM, CHF and
recent DVT/PE on rivaroxaban presents with
rapidly expanding swelling and pain of her R
thigh. On exam she is lethargic, afebrile, HR 130
BP 85/60. Her R thigh is tensely swollen and
ecchymotic and tender. Distal R pulses are
diminished. Hct 26. CT demonstrates a large
anterior compartment hematoma.
3570
Case 10
In addition to volume resuscitation and transfusion
of pRBC, the best next step would be:
a) Fresh frozen plasma 10-15 ml/kg
b) Idarucizumab 5g IV
c) 4 factor PCC 50 units/kg IV
d) aPCC 50 units/kg IV
e) Andexanet alfa 400 mg IV bolus followed by 480
mg infusion over 2 hours
Case 10
In addition to volume resuscitation and transfusion
of pRBC, the best next step would be:
a) Fresh frozen plasma 10-15 ml/kg
b) Idarucizumab 5g IV
c) 4 factor PCC 50 units/kg IV
d) aPCC 50 units/kg IV
e) Andexanet alfa 400 mg IV bolus followed by 480
mg infusion over 2 hours
3571
Tomaselli GF. J Am Coll Cardiol.2017 Dec

19;70(24):3042-3067. PMID: 29203195
Tomaselli GF. J Am Coll Cardiol.2017 Dec

19;70(24):3042-3067. PMID: 29203195
3572
New reversal agents in development

• Andexanet alfa
– Similar structure to Factor Xa and binds Factor Xa
inhibitors
– Being studied currently in ANNEXA-4 trial
– Interim analysis presented at ACC in March
• 132 patients presenting with major bleeding while taking
Factor Xa inhibitor (apixaban, rivaroxaban, edoxaban,
enoxaparin)
• 88% reduction in anti-Factor Xa activity, excellent or very
good hemostasis in 83%
• Safety: at 30d 12% died, 11% had thrombotic event
• Ciraparantag (PER977)
– another direct and indirect Fxa inhibitor binding
molecule, still in very early stages of development.
One dose fully reverses for 24 hrs.
Thank You!
3573
Emerging Topics for the Boards: Bringing Health Equity

Research into Your Practice

Cheryl R. Clark MD, ScD
Director, Health Equity Research & Intervention
Center for Community Health and Health Equity
Division of General Internal Medicine and Primary Care
Disclosures
• No Disclosures
3574
Today’s Presentation
• Review frameworks and current literature for
translating health disparities research into practice
– Definitions: differences vs. disparities vs. inequities
– Topic updates:
• Addressing social determinants of health in clinical settings
• Supporting “Cultural Humility” in clinical practice
• Managing implicit bias in clinical care
– Examples of effective clinical interventions in practice
Take Home Points

• Movement toward addressing social factors in
clinical care settings, including new tools and
incentives
• New data to understand needs of diverse groups
• There are strategies we can use to improve

disparities and inequities in clinical settings
3575
Definitions
Difference vs. Disparities vs. Inequities
Question 1:
Using the National Academy of Medicine (IOM)
framework from Unequal Treatment, which of
the following is a health care disparity?
A. Differences in prescribing adjuvant estrogen therapy
between black and white women
B. Differences in opioid prescribing for chronic pain by race or
ethnicity
C. Differences in patient preferences for skilled nursing facility
use post-hospitalization by race or ethnicity
D. Differences in opioid prescribing for long-bone fracture
by race or ethnicity
3576
Question 1:
Using the National Academy of Medicine (IOM)
framework from Unequal Treatment, which of
the following is a health care disparity?
B. Differences in opioid prescribing for chronic pain by race or
ethnicity
C. Differences in patient preferences for skilled nursing facility
use post-hospitalization by race or ethnicity
D. Differences in opioid prescribing for long-bone fracture
by race or ethnicity
“Disparities” and “Inequities”
3577
National Academy of Medicine (IOM)

Framework
Disparity:
Differences not
due to clinically
appropriate care
or patient
preferences
Contributors: lack of
interpreters, time
pressure,
payment models,
insurance
coverage
Question 1:
*Need more information about tumor data to determine
whether this is clinically appropriate
B. Differences in opioid prescribing for chronic pain by
race or ethnicity
*Overuse of opioid prescribing
C. Differences in patient preferences for skilled nursing
facility use post-hospitalization by race or ethnicity
D. Differences in opioid prescribing for long-bone
fracture by race or ethnicity
3578
Disparities in Prescribing Opioids to

Control Acute Pain
Table. Percentage of Emergency Department Visits at Which an Opioid was
Prescribed, by Race/Ethnicity, National Hospital Ambulatory Medical Care Survey
(NHAMCS) 1993-2005
Weighted Proportion of Visits at Which an Opioid

Analgesic Was Prescribed, % (95% Confidence Interval)
Asian/ P
Type of Pain No. White Black Hispanic Other Value
Any 156,729 31 (32-32) 23(22-24) 24 (23-26) 28 (26-30) <.001
Long-bone 4348 52 (50-55) 45 (39-50) 51 (44-57) 43 (32-54) 0.02
fracture
Nephrolithiasis 2215 72 (69-75) 56 (44-68) 68 (61-76) 67 (52-82) 0.02
No injury or 161,224 9.9 (9.4-10) 6.6 (6-7) 6.4 (5.8-6.9) 7.2 (6-8) <.001
pain
Source: Pletcher et al. JAMA 2008
What Can We Do to Address Disparities?

• Use population health data
to identify differences and
clinical needs
• Standardize care to
minimize uncertainty
• Expand diversity of the care

team to check bias and
discrimination
• Incentivize change through

payment models
Anderson et al. Health Affairs 2018
3579
Eliminating Disparities in Practice

Example: Kaiser Permanente
Population health medical record data review to
identify patients not meeting quality metrics
Single pill combination therapy improved adherence
Medical assistants also followed up with patients two
to four weeks after medication adjustments
– Hypertension control increased from 44% to 90%
– Eliminated racial disparities in hypertension, LDL and
glycated hemoglobin control
Sources: Ayanian et al. NEJM 2014

Jaffe et al. Journal of Clinical Hypertension 2016
Question 2
According to the American College of Physicians April
2018 position paper on Addressing Social Determinants
of Health, which of the following is most likely to
address a health inequity?
A. A physician-led press conference describing clinical data
on patient blood lead levels
B. Opening a grocery store to improve access to fresh
foods in an underserved neighborhood
C. Screening patients for social needs at every clinic visit
D. Placing low-income housing near highways to improve
transportation access
3580
Question 2
According to the American College of Physicians
April 2018 position paper on Addressing Social
Determinants of Health, which of the following is
most likely to address a health inequity?
A. A physician-led press conference describing clinical
data on patient blood lead levels
B. Opening a grocery store to improve access to fresh
foods in an underserved neighborhood
What Are Social Determinants Of Health?
• World Health Organization Framework:

– Circumstances in which people are born, grow, live, work,
and age
– Systems put in place to deal

with illness.
– Circumstances and systems
shaped by economics,
social policies, and politics
3581
What is a Health Inequity?

World Health Organization Framework
Definition of Health Inequities: • Equity from the start
– Maternal and child health
Human Rights and Social Justice
• Healthy places and people
• Differences between individuals – Environmental conditions
and groups that are avoidable
and unfair • Fair employment and safe work
– Living wages, occupational conditions
• Arise from social and economic • Social safety net protections
conditions within and between – Protected standard of living
societies • Health in all policies
– Make the healthy thing the easy thing
• Differences in illness are to do
contingent on social and • Fair financing
economic actions taken to – Progressive tax system
prevent and respond to illness • Rights of women
• Collect and monitor data
Multiple Dimensions of Risk
Source: Closing the Gap in a Generation

Amended from Solar & Irwin, 2007
3582
Social Determinants of Health:

Multiple Dimensions of Risk
• Affect patients across the life course
• Affect patients via psychosocial, behavioral and
material pathways
– Require multiple or “multi-level” intervention
components, “upstream” investments, and systems
changes
• Physicians can observe inequities in practice and

address them in significant ways
Question 2
Which of the following is most likely to address a health inequity?
A. A physician-led press conference describing clinical data on patient blood lead levels
B. Opening a grocery store to improve access to fresh foods in
an underserved neighborhood
- Simply increasing access to stores may not be impactful without
multi-level interventions to support behavior change
- Systems for intervention are needed to act on screening results;
tailor timing of screening to clinic resources and patient needs
-potential childhood asthma risk associated with automobile
exhaust near high-traffic areas
Source: American College of Physicians Annals of Int. Med 2018
3583
Question 2
Which of the following is most likely to address a
health inequity?
A. A physician-led press conference describing clinical
data on patient blood lead levels
- ACP highlights social, environmental and public health actions as
contributors to patient health, and underscores the role of clinical
data and physician advocacy in addressing determinants of health
B. Opening a grocery store to improve access to fresh foods in an
underserved neighborhood
Physician as Advocate
Pediatrician Dr. Mona Hanna-Attisha giving a press conference to recommend

issuing a water advisory due to high lead blood levels found in her patient panel
Story: https://www.nytimes.com/2018/06/09/opinion/sunday/flint-water-pediatrician-detective.html
Press Conference: https://youtu.be/6tELb594WTw
Timeline: https://www.cnn.com/2016/01/20/health/flint-water-crisis-timeline/index.html
3584
What Can We Do to Eliminate

Inequities in Clinical Care?
ACP statement of 9 recommendations
• Implement public policy interventions to promote health equity
• Health care professionals should be knowledgeable about
screening and identifying social determinants in practice
• Use team-based care approaches
• Invest in evidenced-based programs and social services
• Support research and include diverse participants in research
• Support “health in all policies” in community planning
• Use electronic health record systems to improve health
• Adjust payment and performance metrics for social risk
• Screen and collect social data to aid evidence-driven decisions
Source: American College of Physicians Annals of Int. Med 2018
Example in Practice
Social Screening and Referral System
in Primary Care
• Adapted a social screening tool to document
social needs (e.g. housing instability, food
insecurity)
• Built a screening survey in the EHR to facilitate
data collection
• Used the EHR to refer patients for services
Source: Gold et al. JABFM August 2017
3585
Topic Updates
• Social determinants of health in clinical settings

• Cultural humility
• Implicit bias in clinical care
Question 3:
Which of the following are currently available tools and
incentives to assist clinicians in addressing social
determinants of health (SDOHs) in clinical settings?
A. New delivery system and payment models, including
Medicaid Accountable Care Organizations (ACOs)
B. Electronic Health Record-integrated screening tools
C. An evidence base of practical strategies to guide
intervention in clinical practice
D. All of the above
3586
Question 3:
Which of the following are currently available tools and
incentives to assist clinicians in addressing social
determinants of health (SDOHs) in clinical settings?
A. New delivery system and payment models, including
Medicaid Accountable Care Organizations (ACOs)
B. Electronic Health Record-integrated screening tools
C. An evidence base of practical strategies to guide
SDOH intervention in clinical practice
D. All of the above
Delivery/Payment Model: Medicaid

Accountable Care Organizations (ACOs)
- Financial incentive to reduce
total costs of care for populations
- Federal authority: 1115
demonstration waiver
Some state models require
screening and intervening on SDOHs
Models encourage or require
partnerships with community-
based organizations
States with active Medicaid ACOs
Waivers allow payment for select States pursuing Medicaid ACO
services to address SDOHs programs
Sources: Center for Health Care Strategies, Inc.
Resource: https://sirenetwork.ucsf.edu/ (Gottlieb et al.)
3587
Question 4:
Compared to Cis-gender populations, gender
minority populations (including transgender and
gender non-conforming groups) are more likely
to:
A. Have fair or poor self-rated health
B. Be unemployed or out of the labor force
C. Both A and B
D. We do not have data collected to understand issues
related to gender minority populations
Question 4:
Compared to Cis-gender populations,
gender minority populations
(including transgender and gender
non-conforming groups) are more
likely to:
A. Have fair or poor self-rated health
B. Be unemployed or out of the labor
force
C. Both A and B Sexual and Gender Minority
(SGM)-related questions
D. We do not have data collected to available for use by states
understand issues related to gender from 2014-present
minority populations
Source: Streed et al. JAMA Int Med 2017
3588
Collecting Data
Demonstrates Cultural Humility
Definition of “Cultural Humility” in medical education:
Commitment to life-long (1) learning about aspects of
cultural identity, (2) addressing power dynamics, and
(3) developing partnerships with patients and their
advocates
In practice
• Attitude: Being willing to say “I don’t know” and being
interested in asking individuals what is important to them
• Action: Collecting and analyzing population data to plan for
resources that address patients’ needs and assets.
Source: Tervalon and Murray-García 1998
Resource: https://www.hospitalmedicine.org/practice-
management/the-5-rs-of-cultural-humility/
2015 CMS Equity Plan for Medicare

• Priority 1: Expand • Resources:
collection, reporting, and
analysis of standardized
data
– Sexual orientation and
gender identity (SOGI) data
– Race, ethnicity and
language (REaL) data
– Disability status
Sources: https://www.cms.gov/About-CMS/Agency-Information/OMH/OMH_Dwnld-
CMS_EquityPlanforMedicare_090615.pdf
https://aspe.hhs.gov/basic-report/hhs-implementation-guidance-data-collection-standards-race-
ethnicity-sex-primary-language-and-disability-status
3589
Question 5:
There is compelling evidence that a provider’s
implicit bias influences which of the following
outcomes or processes?
A. Clinical outcomes
B. Doctor-patient communication
C. Patient adherence
D. Process measures of quality care delivery
Question 5:
There is compelling evidence that a provider’s
implicit bias influences which of the following?
(Data are emerging on other outcomes)
A. Clinical outcomes
B. Doctor-patient communication
C. Patient adherence
D. Process measures of quality care delivery
Source: Mania et al. Soc Sci Med 2018
3590
Definition of Implicit Bias
Definition:
“Unexamined cultural stereotypes that are
automatically activated in ways that bypass
deliberate thought and influence one’s judgement
in unintended and unacknowledged ways”
Source: Chapman et al JGIM 2013
Data on Impact of Implicit Bias
• All 7 studies that examined the impact of

implicit bias on communication showed that
stronger provider bias was associated with
poorer patient-provider communication
Source: Mania et al. Soc Sci Med 2018
3591
Communication Example: Hagiwara et al.

Soc. Sci & Medicine 2016
• IAT used to measure
Physician Talk-Time Ratio

implicit bias for
physicians (n=14),
perceived
discrimination scale in
patients (n = 112)
Physician Implicit Bias
• Physician bias
influenced talk-time
ratio
What Do We Do to Address Implicit

Bias?
• Attention to
communication
• Awareness of implicit
bias and other
cognitive biases
3592
Culturally and Linguistically

Appropriate Services (CLAS)
• Standard 4. Health care
organizations must offer
and provide language
assistance services,
including bilingual staff and
interpreter services, at no
cost to each
patient/consumer with
limited English proficiency
at all points of contact, in a
timely manner during all
hours of operation.
Professional Interpreters
Improve Outcomes
• Professional interpreters vs. ad hoc
interpretation:
– Reduction in communication errors
– Increase in patient comprehension
– Equalize health care utilization & clinical

outcomes
– Increase satisfaction with communication

Source: Karliner et al. Health Services Research 2007
3593
Recognizing Implicit Bias is Difficult
Source: Green et al. JGIM 2007
Cognitive Biases in Health Care

(Diagnostic biases)
• Ascertainment bias: a physician’s
thinking is shaped by prior
expectations
• Visceral bias: our feelings affect
decision making
• Fundamental attribution error:
we may blame patients for
illnesses, rather than investigating
contributing circumstances
Sources: Croskerry, Academic Medicine 2003,
The Joint Commission October 2016
3594
Emerging: What to do About

Cognitive Bias
• Structural interventions
– Standardizing care
– Explicit communication
– Reducing time pressures
• Awareness of Cognitive Bias
– See Crosskerry, Academic Medicine (2003)
• Mindfulness practice
– Lovingkindess and empathy for self
– Curiosity and compassion for patients
Summary
• Health disparities and inequities are multi-factorial,
and include social and medical contributors
• There is a movement toward addressing social
determinants of health in clinical care. Physicians are
increasingly incentivized to have the skills, knowledge,
attitudes and systems in place to address these issues.
• Cultural humility and work to acknowledge implicit
bias contribute to good data and good communication
needed to eliminate disparities and inequities
3595
References and Resources

• Anderson, Andrew C., et al. "Promoting Health Equity And
Eliminating Disparities Through Performance Measurement
And Payment." Health Affairs 37.3 (2018): 371-377.
• Social Interventions Research & Evaluation Network (SIREN):

https://sirenetwork.ucsf.edu/
• Tervalon, Melanie and Jann Murray-García. "Cultural
humility versus cultural competence: A critical distinction in
defining physician training outcomes in multicultural
education." Journal of health care for the poor and
underserved 9.2 (1998): 117-125.
• Implication Association Test for implicit bias:

https://implicit.harvard.edu/implicit
3596
General Dermatology Review

Clinical Pearls for Common Problems
Co-Director, Merkel Cell Carcinoma Center of Excellence
Department of Dermatology,
Brigham & Women’s Hospital
Center for Cutaneous Oncology,
Dana-Farber/Brigham & Women’s Cancer Center
Instructor of Dermatology, Harvard Medical School
Disclosures
• No Disclosures
3597
Lecture Goals
• Recognize and treat common rashes

• Recognize common benign skin lesions
• Recognize skin cancers
• Know when to refer
Top 10 Problems in Dermatology
• Rashes: • Lesions
– Acne – Benign growths
– Fungi / Tinea – Actinic keratoses
– Seborrheic – BCC
dermatitis – SCC
– Psoriasis – Melanoma
– Eczema
3598
Common Rashes
ACNE
3599
Acne: Epidemiology
• Typically presents first

in children/teens, and
resolves by age 25
• However, 12% of
women and 3% of
men have acne until
their 40s
• First acne outbreak
not uncommonly
occurs between age
20-35
Acne: Classification
• Classification is based • Important to also note:

on the morphology: – Scarring
– Comedonal – Hormonal distribution
• Open comedones -
“blackheads”
• Closed comedones -
“whiteheads”
– Inflammatory
• Papules, pustules
– Nodulocystic
• Nodules, cysts
Photo courtesy of Elizabeth Buzney, MD
3600
Acne: Morphology
inflammatory papules
open comedones
closed comedones
pustule
Acne: Morphology
open comedones on the nose
3601
Acne: Morphology
inflammatory and cystic acne with scarring
Photo courtesy of Harley Haynes, MD
Acne: Morphology
nodulocystic acne with
scarring
3602
Acne: Pathogenesis
• Acne is multifactorial!
– Keep this in mind – most pts require more than one
treatment modality
• Key Components:
1. Defective keratinization
- Results in plugging of the hair follicle, giving rise to comedones
2. Androgens
- Stimulate sebaceous glands oil production
3. Bacteria (Propionibacterium acnes)
- Lives in the follicle, turns oils into free fatty acids, causing inflammation
4. Inflammation
- In response to keratinous debris, FFAs, and P. acnes
Acne: General Treatments Principles
• Main classes of therapy:

– Retinoids - topical and systemic
– Antibiotics - topical and systemic
– Hormonal - systemic only
– Misc - keratolytics, intralesional steroids,dapsone
• Goal:
– #1 – prevent scarring
– #2 – clear skin
3603
Acne: Treatments Principles
• Combination therapies are most effective

• Treatment is based on Morphology & Severity…
Comedonal Inflammatory Nodulocystic
(black-/whiteheads) (papular, pustular)
Mild Topical retinoid Topical abx
+/- BP + BP
+/- Topical retinoid
Moderate Topical retinoid Oral abx Oral abx
+ BP + BP + Topical retinoid
+ Topical retinoid + BP
Severe (Or if Derm Derm Derm Referral
Presence of Referral Referral (Oral isotretinoin)
Scarring)
• …and also Distribution

– hormonal distribution? Y OCPs, spironolactone
– can pt reach affected body areas? N oral treatments
Acne: Consider the Distribution
3604
Acne: Topical Retinoids
• Retinoids:
– Tretinoin cream / gel 0.025%, 0.05%, 0.1%
• name brands Retin-A, Retin-A Micro, Atralin, Renova
– Adapalene cream / gel / lotion 0.1% and 0.3%
• Better for those with drier, more sensitive skin
• name brand Differin
– Tazarotene
• Strongest, difficult for most pts to tolerate
• Sig: Apply pea-sized at night, start 1-2x/week and
advance to QHS as tolerated
– SE: redness*, irritation/itching*, scaling*, +/-
photosensitivity
*usually a result of advancing too quickly rather than a medication
intolerance/allergy
– Pea-sized amount sufficient for entire face
Acne: Topical Antibiotics
• Clindamycin 1% lotion, solution, gel, foam

• Erythromycin 2% solution, gel
• Azelaic acid 15% or 20% gel
– Naturally occurring saturated dicarboxylic acid
– Bacteriocidal against P acnes
– Useful in pts with post-inflammatory hyperpigmentation
• Benzoyl Peroxide washes, creams, gels, lotions

– Has both antibacterial and comedolytic properties
– Use in combo with abx above - prevents resistance
– Use in the AM, to avoid oxidizing retinoids (applied PM)
– Pts w/ truncal acne: Keep an extra BP wash in the shower
– SE: bleaching of hair/clothes, dryness, irritation
3605
Acne: Treatment with Oral Antibiotics
• Tetracyclines are the antibiotic of choice:

– Minocycline – dizziness, dyspigmentation, drug-ind SLE
– Doxycycline – photosensitivity
– Know your SE, counsel appropriately – all can cause GI
upset, pill esophagitis – take with a full glass of water, stay
upright, and ok to take with food if needed for tolerability
• Other options: cephalosporins, macrolides, sulfa
• Strategies:
– Try to taper off oral antibiotics as pt improves
switch to topical regimen as maintenance
– If no benefit after 3 mo at full dose, switch to another abx
– If no benefit after at least 6 mo of 2 different abx
consider isotretinoin
Acne, Simplified
• Most common type: mixed inflamm. & comedonal

• Most common regimen (worth memorizing):
– BPO 2-5% wash otc 1-2x/week in the mornings
– Mild non-medicated wash otherwise BID
– Clindamycin lotion BID
– Tretinoin 0.025% cream QHS, start slowly (e.g. 1-2x/week)
• Unless very dry skin Adapalene 0.1%
• If pain / scarring / nodulocystic
lesions:
– Start oral antibiotics, refer to derm
• Hormonal distribution
– Consider OCPs or spironolactone
3606
Acne: Last Thoughts
• Unless your patient is extremely oily at baseline,

most patients will do better with creams and
lotions, rather than solutions and gels, as many
of the topical therapies for acne have xerosis as a
side effect
• Tell patients new meds may take 6-8 wks to work

– Retinoids may cause initial flaring
– Oral antibiotics have faster onset
SUPERFICIAL
FUNGAL & YEAST
INFECTIONS
3607
Superficial Fungal Infections
• Three groups of fungi can cause superficial

infections of the skin (epidermis):
– Dermatophytes
– Candida spp. (yeast)
– Malassezia spp. (yeast)
• “Tinea” = Dermatophytoses = superficial fungal

infection of keratinized tissues, e.g., stratum
corneum, hair, and nails
– Three genera:
• Microsporum
• Trichophyton
• Epidermophyton
Tinea: Diagnosis
• KOH prep – most cost effective means of dx

– You’ll need: 15-blade, alcohol swab, and slide
– Wipe area w/ alcohol swab
– Scrape until sufficient scale on slide, then cover
scale w/ coverslip
• Edge of plaque is highest yield
– Apply a few drops of KOH at edge to get
underneath coverslip
– Light a match! Hold under slide for a few
seconds
– 10x scan to find hyphae, 40x for detail if needed
3608
Tinea: KOH prep

parallel lines longer than surrounding keratinocytes
branching
Tinea: Another KOH prep
First, scan at 10x…
Then, zoom in to 40x to

precisely identify structures
Photos courtesy of Adam Lipworth, MD
3609
Photo courtesy of Dermquest.com
Tinea Pedis
• “Athlete’s foot”
• Most common fungal
infxn
• Risk factor for Photo courtesy of Faloonb
development of
cellulitis
• Three clinical
patterns:
– Interdigital
– Moccasin (aka chronic
hyperkeratotic)
– Vesiculobullous
Photo courtesy of Adam Lipworth, MD
Tinea Pedis: Moccasin type
• Often associated with

nail involvement
• Look for the “One
hand, two feet”
syndrome
Photos courtesy of Janice Lin, MD
3610
Tinea Manus
Look for fine scale in the creases – great place to KOH!
Tinea Manus
3611
Tinea: Treatment
• Hygiene (T. pedis):

– Dry feet: cotton socks, frequent changes, powders
– Shoes: alternate shoes worn, consider sandals
• Topical antifungals:
– Use at least for 2 weeks, not just until appears resolved
– Many to choose from:
• Imidazoles – clotrimazole, miconazole, econazole,
oxiconazole (note, not ketoconazole)
• Allylamines – terbinafine, butenafine, naftifine
• Ciclopirox
• Discuss, recurrences are common, but should
clear with treatment
Tinea Corporis
• Annular
erythematous scaly
patches, often with
advancing scaling
edge
• Topicals generally
sufficient, unless:
– Heavily hair bearing
areas
– Large surface area
involved
– Animal source
Photos courtesy of Ruth Ann Vleugels, MD
3612
Tinea Corporis
• Annular
erythematous scaly
patches, often with
advancing scaling
edge
• Topicals generally
sufficient, unless:
– Follicular involvement
– Large surface area
– Animal source
• DDx: nummular
eczema
Photos courtesy of Adam Lipworth, MD
Tinea Cruris
• Scaling erythematous
to hyperpigmented
patch on upper and
inner thighs
– Dry looking
– Central clearing
– Raised scaly border
• Scrotum/Penis rarely
involved
• Topicals effective
• DDx: inverse psoriasis
3613
Tinea Cruris / Corporis (in pt with AIDS)
Tinea Faciei
• Erythematous
plaque with
distinctive
edge-active
scale,
asymmetrical
Photo courtesy of Grook Da Oger
3614
Case 1
• Frances is a 52 yo
female with a history
of obesity and
diabetes, who
presents with a 3
month history of
itching, burning, red
inframammary rash,
not relieved by triple
antibiotic ointment.
It’s starting to really
worsen now that it’s
finally warm outside.
Case 1
• What is the most likely

cause of Francis’s
rash?
A – Candida intertrigo
B – Inverse psoriasis
C – Seborrheic dermatitis
D – Tinea corporis
3615
Case 1

cause of Frances’s
rash?
Case 1

cause of Frances’s
rash?
Note presence of satellite lesions, itching
and burning, made worse by sweating
Good location, and can look similar.
Plaques lack satellite lesions, and are
often not as bright red.
Wrong distribution
Expect to see raised rim, usually with
scale.
3616
Candida Intertrigo
• Red moist plaques, often with satellite lesions

Candida intertrigo
– distinguish from inverse psoriasis
• Often more sore than itchy
• Promoted by:
– Diabetes
– Obesity
– Heat inc sweating
– Occlusive clothing inc sweating Inverse psoriasis
– Limited mobility inc sweating
Candida Intertrigo: Treatment Principles
• Can always be treated topically

• Powders don’t work well for treatment
– Penetration poor
– But are great for dz maintenance
• Creams are preferred
• Ointments are a good choice when skin is
macerated or starting to break down
3617
Candida Intertrigo: Treatment
• Polyenes: nystatin
– notably comes in an ointment – prevent maceration
• Azoles: ketoconazole*, clotrimazole,
econazole, miconazole
• Ciclopirox
– has mild anti-inflammatory properties, and has activity
against Gram positive and Gram negative bacteria that
often co-exist
• Keep it dry to keep it from coming back!
– Corn starch
– Antifungal powders: miconazole, nystatin,
undecylenic acid, tolnaftate, 12% benzoic acid
Seborrheic Dermatitis
• Common, affects 2-5%

• Rash is caused by
inflammatory reaction to
Malassezia globosa
Photo courtesy of Roymishali
3618
Seborrheic Dermatitis: Clinical
• Erythematous patches
and thin plaques with
overlying yellowish dry
or greasy scales
• In areas w/ increased
sebaceous gland activity
– Scalp (“dandruff”)
– Face: eyebrows,
nasolabial folds, ears
– Trunk: chest / sternal area
• Worse in pts with HIV
Seborrheic Dermatitis: Treatment
• Antidandruff shampoos (scalp, chest)

– Ketoconazole 1% (otc) or 2% (Rx), selenium sulfide,
zinc pyrithione, ciclopirox
– Lather, leave shampoos on x 10 minutes, rinse, repeat
QOD till clear
• Antidandruff creams (face)
– Ketoconazole 2%, ciclopirox
• +/- a low potency topical steroid
– Hydrocortisone 2.5%, desonide, fluocinolone
solution
• Calcineurin inhibitors (3rd line, concurrent rosacea)
– Pimecrolimus cream, tacrolimus ointment
3619
Tinea Versicolor
• Misnomer - Not a true

dermatophyte infxn!
• Malassezia furfur
– (formerly Pityrosporum
ovale)
• Well-demarcated
hypopigmented, tan,
pink, or salmon
patches on the trunk
• Scale is inducible by
rubbing w/ finger/blade
The Many Colors of Tinea Versicolor

Hypopigmented
Hyperpigmented
Pink or Salmon-colored
Photo courtesy of Margaret Kopelman, MD
3620
Tinea Versicolor: Treatment
• Shampoos:
– E.g. selenium sulfide, ketoconazole, pyrithione zinc
– Cover larger area
– Leave on 5-10 minutes, then rinse
• Creams:
– E.g. ketoconazole, clotrimazole, miconazole,
econazole
– Easier for limited disease
• Recurrences are common
– Plan to retreat in summer months
• Scale resolves quickly; dyspigmentation weeks to
months
PSORIASIS
&
ECZEMA
3621
Psoriasis
• Classification by body
surface area (BSA)
– Mild: <5%
– Moderate: 5-10%
– Severe: >10%
• 20% of patients have
moderate to severe disease
– Generally requires
phototherapy or systemic
medications to clear
Psoriasis - Not only a skin disease
• Psoriatic Arthritis 7-42%

– Destructive arthropathy
• Obesity (OR 1.66) &
Metabolic Syndrome
• Cardiovascular risks
– Independent, non-modifiable
risk factor for MI and stroke
– Increased incidence of
arrhythmia
• Malignancy risks
– NMSCs, lymphoma, lung
3622
Eczema
• Not just one disease!

– Atopic dermatitis
– Contact dermatitis
– Asteatotic eczema
– Dyshidrotic eczema
– Neurodermatitis
– Nummular dermatitis
– Stasis dermatitis
Eczema and Psoriasis
• Some pearls:
– Consider surface area you are treating:
• 30 g tube covers the entire body of an adult once
• Clobetasol >50g/wk – pt at risk of HPA suppression
• Estimate the BSA affected:
1 palm = 1% BSA
(pt’s palm, not yours)
• Then estimate how much you’ll need to give:

1 fingertip unit = ½ g treats 2% BSA (2 palms)
So, if you’re treating a 4% BSA rash (1g/treatment)

with a BID medication (2g/day), and planning 2 weeks
of treatment, dispense 30g
3623
• Rule of Nines
– Quick way to estimate
BSA in adults
– Divide body into 9%
sections:
• Head – 9%
• Chest – 9%
• Abdomen – 9%
• Back – 9% x 2
• Upper ext – 9%
• Lower ext – 9% x 2
• Groin – 1%
• More pearls…
– Consider the base: What? There’s a difference!?!
• Ointments are greasy, but have fewer potential
irritants, and are generally more potent
• Creams rub in better, don’t mess up clothes as
much, and may be preferred by many patients
• Lotions, gels may be better for acne-prone skin,
hair-bearing areas
• Solutions, foams easier to use in the scalp
3624
• And more pearls…

– Consider the base:
The Effect of Vehicle on Potency:
Generic name Betamethasone dipropionate Potency Class
Trade name Diprolene ointment 0.05% 1
Diprolene gel 0.05% 1
Diprolene cream 0.05% 2
Trade name Diprosone ointment 0.05% 2
Diprosone cream 0.05% 3
Diprosone lotion 0.05% 5
• Emphasize intermittent therapy to avoid

tachyphylaxis, atrophy, etc – “burst and taper”
Common Dermatologic Growths
• Benign neoplasms Butchart Gardens in Vancouver
– Seborrheic keratoses
– Cherry angiomas
– Sebaceous hyperplasia
• Actinic keratoses
• Basal cell carcinoma
• Squamous cell carcinoma
• Moles and melanoma
Photo courtesy of NorwegianMarcus on wikipedia
3625
BENIGN NEOPLASMS
OF SKIN
Seborrheic Keratoses
• Common, benign
lesions
• Appear in 30s
• Usually in sun-
exposed distribution
3626
Seborrheic Keratoses
• Waxy, sometimes velvety, sometimes

verrucous, “stuck-on” appearance,
very well-demarcated
Cherry Angiomas
• Most common
acquired vascular
proliferation
– Dilated, congested
capillaries and post-
capillary venules
• Bright red, dome
shaped papules
• Trunk + extremities
• Appear in teens, 20s,
and beyond
– Increase during
pregnancy
3627
Sebaceous Hyperplasia
• Not a true neoplasm fd

fdfd afsd
• Benign enlargement of
sebaceous lobule
around follicular
infundibulum
• Yellowish soft papules,
+/- telangectasias,
central dell
• Central / upper face
ACTINIC KERATOSES
3628
Actinic Keratoses
• AKA, solar keratoses,

senile keratoses
• Precancerous lesions
for SCC
– Similar rates of
transformation as
cervical intraepithelial
neoplasia
– Emphasize, low risk!
Actinic Keratoses: Presentation
• Head, neck, upper

trunk, forearms/hands
• Typical patient:
– Elderly, chronic sun
exposure, light skin
• Rough, erythematous,
scaly thin papule
– Scale can be gritty, white,
yellow, hyperkeratotic, or
a “horn”
Tenderness on palpation,
esp if indurated bx for
invasive SCC
3629
Actinic Keratoses: Treatments
• Consider number, location, thickness, and your pt

– Local therapies – e.g. cryotherapy
• Preferred when lesions are few or scattered; pt not interested in
field treatments, or not expected to be compliant
• Advantages: quick procedure, short down time (~1-2 week),
physician control
• Disadvantages: painful, can miss pre-clinical lesions, can
inappropriately treat something (e.g. amelanotic melanoma)
– Field therapies – e.g. 5-FU, imiquimod, PDT
Cryotherapy
• AKs
– Single freeze-thaw cycle of 8-10 seconds
• Hypertrophic AKs may require longer or multiple
treatments
• Atrophic AKs or areas of thinner skin may require less
– 1-2mm freeze margin around the lesion
3630
Actinic Keratoses: Treatments
• Consider number, location, thickness, and your pt

– Local therapies – e.g. cryotherapy
• Preferred when lesions are few or scattered; pt not interested in
field treatments, or not expected to be compliant
• Advantages: quick procedure, short down time (~1-2 week),
physician control
• Disadvantages: painful, can miss pre-clinical lesions, can
inappropriately treat something (e.g. amelanotic melanoma)
– Field therapies – e.g. 5-FU, imiquimod, PDT
• Advantages: treat wide area, prevent new lesions from arising,
“new skin”, ?cosmetic benefits, patient control
– With proper counseling, always a safe option, minimal
scarring
• Disadvantages: longer down time (usually about 1 month), need
for counseling, patient control
Actinic Keratoses: Field Therapies
• 5-fluorouracil
– Generic 5% cream, 2% & 5% solution
– Brands – Efudex 5% cream, Carac 0.5% cream
– Micromedex directions:
• 2 or 5% cream or solution BID x 2-6 wks
• 0.5% microsphere formulation daily x 4 weeks
– My directions: generic 5% cream 1-2x/day x ~3 weeks
• Titrate to erythema, slight irritation
• Counsel patients on expected side effects
• Apply petrolatum to soothe irritated skin
• If too unpleasant – call for ANTIDOTE!
– Topical steroid Rx
• Imiquimod, ingenol mebutate, PDT (photodynamic
therapy) – refer
3631
Actinic Keratoses: Topical 5-Fluorouracil
– Post-2.5 weeks of
Efudex BID
– Patient presented with
erythema, crusting,
shallow erosions, pain,
and itching. Distressed!
– Management:
• Petrolatum liberally
• Class V topical steroid (in
an ointment base) for 1-2
weeks
Case 2
• Fred is a 86 year old Caucasian gentleman with a history

of multiple skin cancers. He comes in with a 6+ month
history of a slowly growing, pearly lesion below,
occasionally bleeding.
What genetic mutation is associated

with this skin lesion?
A – BRAF
B – CDKN2A gene
C – MLH1/MSH2 DNA mismatch repair
D – Sonic hedgehog / patched (PTCH1)
3632
Case 2
• Fred is a 86 year old Caucasian gentleman with a history

of multiple skin cancers. He comes in with a 6+ month
history of a slowly growing, pearly lesion below,
occasionally bleeding.
What genetic mutation is associated

with this skin lesion?
A – BRAF
B – CDKN2A gene
Case 2
• What genetic mutation is associated with the skin

lesion below? Lesion is a BCC.
A – BRAF
acquired mutation in this gene is the most common event
leading to melanoma, present in ~2/3 of melanomas
Inhibitors: vemurafenib and dabrafenib
B – CDKN2A gene
most common cause of inherited melanoma
defect leads to Muir Torre syndrome (HNPCC)
3633
Basal Cell Carcinoma: Genetics

• BCCs are caused by loss of function mutations in PTCH (tumor
suppressor gene) and activating mutations in smoothened (oncogene)
– Aquired - from DNA damage to basal keratinocytes from UV
– Heritable - Basal Cell Nevus Syndrome (aka Gorlin Syndrome)
• mutation in PTCH
• 100s of BCCs, broad nasal root, palmar pits, and jaw cysts
• Vismodegib, Sonidegib
– hedgehog pathway
inhibitors
– Recently approved for
treatment of advanced
and metastatic BCC
– Blocks smoothened
receptor
Illustration courtesy of Peter Znamenskiy
Nonmelanoma skin cancers
• NMSCs:
– Basal cell carcinoma (75-80%)
– Squamous cell carcinoma
– (Merkel cell carcinoma (<<<1%, although rising incidence))
• 1/5 Americans will develop skin cancer in their
lifetime
• Incidence increases with age
• Other risk factors: Fair skin*, UV exposure,
ionizing radiation, chemical exposures,
occupation, immunosuppression
– Chronic, long term UV SCC
– Intermittent, intense episodes of burning BCC
3634
BASAL CELL CARCINOMA
BCC: Epidemiology
• Most common type of cancer

– > 1 million cases annually
– 25% of all cancers in the US
• Risk factors:
– UV exposure
• Intermittent holiday > chronic occupational
– Fitzpatrick Type I and II skin
• i.e., light skin/eyes, always burns, zero to minimal ability to tan
– Northern European ancestry
– Immunosuppression
• Patients with BCC at higher risk for melanoma
3635
BCC: Presentation
• Most commonly on head and neck

• Variable appearance depending on type
– Classic nodular (60%) – favors the face
• Ulcerated variants
• Pigmented variants
– Superficial – favors the trunk/ext
– Morpheaform – scarlike
• Historical Clues:
– Slow growing – develop over months to years
– Friable, bleed easily
BCC Presentation
3636
BCC Types:
Nodular Superficial
Pigmented Nodular Ulcerated Morpheaform
BCC Types:
Nodular
Nodular
3637
BCC Types:
Pigmented Nodular
BCC Types:
Morpheaform
Ulcerated
Superficial
3638
Ulcerated BCCs
SQUAMOUS CELL
CARCINOMA
3639
Squamous Cell Carcinoma In Situ
• Bowen’s disease, aka

SCC in situ
– Scaly erythematous
patch or thin plaque,
sometimes crusted
– DDx: AKs, superficial
BCC, SCC, psoriasis,
nummular eczema

SCC in situ
sometimes crusted
nummular eczema
3640

SCC in situ
sometimes crusted
nummular eczema
Squamous Cell Carcinoma
• Invasive SCC
– Erythematous keratotic
papule/nodule
– +/- Tenderness
– More rapid growth
– Immunosuppression
– Higher risk for
metastases/death
3641
How Much Risk:

- 2.0 - 5.8% risk of nodal mets
- 2.1% risk of disease specific
death
Risk Factors:
– Tumor diameter > 2 cm
– Invasion beyond fat
– Poor differentiation
– Perineural invasion
– Ear, temple, anogenital
JAMA Dermatology May 2013

Bateman’s purpura
(actinic purpura, formerly
senile purpura)
3642
Case 3
Lucy, a 60 year old Caucasian woman with a history

of breast cancer, presents for an 8 week history
of an enlarging nontender, nonpruritic 8mm
lesion on the left calf. She is an avid runner.
A – Basal cell carcinoma

B – Melanoma
C – Seborrheic keratosis
D – Squamous cell carcinoma
Case 3
Lucy, a 60 year old Caucasian woman with a history

of breast cancer, presents for an 8 week history
of an enlarging nontender, nonpruritic 8mm
lesion on the left calf. She is an avid runner.

B – Melanoma
3643
Case 3
Lucy, a 60 year old Caucasian woman with a history of

breast cancer, presents for an 8 week history of an
enlarging nontender, nonpruritic 8mm lesion on the left
calf. She is an avid runner. The most likely diagnosis is:
Although you can have pigmented varieties, this is growing too rapidly
B – Melanoma
Note the Asymmetry, Border irregularity, Color variation, Diameter over
6mm, and Evolution (growth) in a pt with sun exposure history
Doesn’t have classic, “stuck-on” appearance
Lacks scale and has pigment
Case 3, continued
• Lucy’s pathology:
– Melanoma, Breslow’s depth 1.6mm (intermediate)
• Ulceration: Absent
• Mitoses: 1 mit per sq mm
• Vascular/Lymphatic Invasion: Absent
– Treatment:
• Sentinel lymph node biopsy and wide local excision
– SLNB was negative
• Follow-up:
– Routine skin & lymph node monitoring by Dermatology
– Routine self-skin exams (monthly)
– Sun protection
3644
Case 3, continued
• 1 year after her treatment,

Lucy returns urgently to your
office, because she suddenly
noted this lesion “overnight.”
• The first thing you do is:

A – Ask to take a closer look
B – Reassure her. You don’t know what it is,
but melanoma never strikes twice in the
same patient.
C – Reassure her. This is a classic cherry
angioma.
D – Tell her to call her dermatologist
immediately because she has a deadly
melanoma.
Case 3, continued
• 1 year after her treatment,

Lucy returns urgently to your
office, because she suddenly
noted this lesion.
• You:
A – (Astutely) Ask to take a closer look
B – Reassure her. You don’t know what it is,
but melanoma never strikes twice in the
same patient.
C – Reassure her. This is a classic cherry
angioma.
D – Tell her to call her dermatologist
immediately because she has a deadly
melanoma.
3645
Case 3, continued
• Talon Noir – “black heel”

– hemorrhage in the stratum
corneum caused by trauma
– perfectly defined border
– no actual pigment, only blood
c/o Virtual Grand Rounds 2.0
c/o Virtual Grand Rounds 2.0
MELANOMA
3646
Melanoma: Epidemiology
• Increasing incidence:
– 1/1500 – born in 1935
– 1/600 – born in 1960
– 1/150 – born in 1980
– 1/62 – born in 2006
• 1/34 – if including in situ melanoma
• Represents 5% of all new cancer cases*
– 5th most common cancer type*
– Most common cancer type in Caucasian women 25-29
• Accounts for 79% of all skin cancer deaths
– 1 American dies from melanoma every hour
– ~9700 in 2014
*excluding BCC and SCC
Melanoma: Risk Factors
• Genetic factors
– Sun-sensitive genotype
• “Skin type”: ability to tan / likelihood of sunburn
– Specific melanoma genes
• First degree relative with melanoma
• Multiple family members with melanoma, regardless of degree
• Families with dysplastic nevi + 2 members with melanoma
• Environmental factors
– Intermittent exposure hypothesis
• Just 1 blistering sunburn in childhood more than doubles lifetime
risk of developing melanoma!
– Tanning bed use
• Whener et al 2014: 13% of adults, 43% of college students
admitted to using a tanning bed in the past year.
3647
Melanoma: Risk Factors
• Phenotypic characteristics
– Blue or green eyes
– Red or blond hair
– >100 typical nevi
– Atypical nevi (any)
– Large congenital nevus (>20cm in adults)
– Fitzpatrick Skin Type I or II
• Burn easily
• Tan rarely or never
Melanoma: Diagnosis
• ABCDs, revamped:
– A – Asymmetry
– B – Borders irregular, notched, scalloped,
poorly defined
– C – Colors, varying shades
– D – diameter > 6mm
– D – Different
• The “ugly duckling” sign
– E – Evolving
• Changing in size, shape, color, or development of
symptoms
3648
Melanoma: Examples With Dermoscopy
Melanoma: Examples With Dermoscopy
3649
Melanoma: Diagnosis
PATHOLOGIC DIAGNOSIS:
MALIGNANT MELANOMA, invasive to a depth of 0.5 mm, anatomic level III/early IV.
Mitotic rate 1 per sq. mm
Melanoma: Diagnosis
PATHOLOGIC DIAGNOSIS:
MELANOMA, with nevoid cytomorphology, invasive to a depth of 0.38 mm,
anatomic level II, with regression-like stromal changes. No dermal mitoses seen.
3650
Melanoma: Diagnosis
June 2011 September 2011 - X
August 2012
(-) family hx/o melanoma

(+) hx/o tanning booth exposure (approx 10
lifetime)
Melanoma 1.35mm, 1 mitosis/mm2
Stage 1B
Case 4
• You referred Andrea to

Plastic Surgery for removal
of a small, firm, persistently
tender growth on her right
upper arm.
• She is a healthy 28 yo
woman with a history of
fibroids and no other
medical problems. The
following pathology report
is sent back to you:
“Pilar leiomyoma.”
3651
Case 4
You referred Andrea to Plastic Surgery
for removal of a small, firm, persistently • Pilar leiomyoma
tender growth on her right upper arm.
She is a healthy 28 year old woman • The next best step in
with a history of multiple fibroids and no management is:
other medical problems. The following
pathology report is sent back to you:
“Pilar leiomyoma.”
A – Do nothing, benign
lesion.
B – Excise other similar
lesions
C – Re-excision with
narrow margins
D – Refer to Genetics
Case 4
• Pilar leiomyoma
• The next best step in
management is:
A – Do nothing, benign
lesion. True, benign, however…
B – Excise other similar
lesions Can consider, but often can
be managed medically
C – Re-excision with
narrow margins Not necessary
D – Refer to Genetics
Reed’s Syndrome
3652
Case 4: Reed’s Syndrome

You referred Andrea to Plastic Surgery
for removal of a small, firm,
• Pilar leiomyoma
persistently tender growth on her right – Benign, smooth muscle growths
upper arm. She is a healthy 28 year old arising from arrector pili muscles
woman with a history of multiple – Medical management if patient
fibroids and no other medical
has multiple
problems. The following pathology
report is sent back to you: • Calcium channel blockers
“Pilar leiomyoma.” • Gabapentin
• Phenoxybenzamine
• Reed’s syndrome
– AD genetic condition
– Multiple cutaneous and uterine
leiomyomas
– Defect in fumarate hydratase
gene
– ~20% of patients develop renal
cell carcinoma
Case 4: Take Home Point
• Cutaneous leiomyomas (piloleiomyoma) + uterine

leiomyomas (fibroids) Genetic referral
fumarate hydratase defect (Reed’s synd)
early detection of RCC
save lives
pass the boards
• It is impossible to be familiar with every diagnosis
• There’s no shame in
consulting “Dr. Google”!
3653
Parting Tips for Skin Success
• Patient education is key

– Most treatment failures are a result of noncompliance
– Set patient expectations
• Set your own expectations
– Get comfortable with a few medications of each type
– Decide what you feel most comfortable managing
– Anticipate when you’re out of your comfort zone and
need to refer
• It is impossible to be familiar with every diagnosis
– Know your resources, including the neighborhood BCD
• Don’t forget your ABCDEs!
Supplemental Reference Slide
• Schmults CD et al. JAMA Derm; 149(5):541-7.

• Whitmore SE et al. JAMA Derm; 2001;44:775-80.
• Wehner MR et al. JAMA Derm. 2014;():.
doi:10.1001/jamadermatol.2013.6896.
• Habif. Clinical Dermatology: A Color Guide to Diagnosis
and Treatment. 5th edition.
– 1 volume text, ideal for the Internal Medicine clinician
• Bolognia, Jorizzo, Schaffer. Dermatology. 3rd edition
– Detailed text, a favorite of most dermatology trainees
• www.aad.org
– Excellent resource for clinicians and patients
• www.merkelcell.org
– If you are interested in what I do, outside of Gen Derm
3654
Disclosures
• No Disclosures
3655
Allergy/Immunology Overview
David E. Sloane, M.D., Ed.M.

West Roxbury VA Medical Center
No Disclosures
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Allergy/Immunology
• Immunology background
• Allergic Rhino-conjunctivitis
• Allergic Asthma
• Angioedema and Urticaria
• Anaphylaxis
• Drug Hypersensitivity and Desensitization
• Food Allergy and Oral Immunotherapy
• Mastocytosis and Mast Cell Activation Syndromes
• Common Variable Immunodeficiency
Our world….
http://voices.nationalgeographic.com/2014/01/07/dung-beetles-use-the-sun-to-navigate/
So why do we not all die of sepsis?
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The Immune System as a

Matter Processing Network
Where it is from:
How bad it is:
The Mast Cell + IgE Paradigm
Slide courtesy of Dr. Tse Wen Chang
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Mast Cell Mediators
Simons FER et al. Risk assessment in anaphylaxis: Current and future approaches. J Allergy Clin Immunol 2007;120:S2-24.
Allergic Rhino-Conjunctivitis
• Symptoms: • Signs:
• Sneezing • Clear bilateral nasal
• Nasal congestion discharge
• Runny nose • pale and edematous
• Nasal itching turbinate mucosa
• Ocular itching, • conjunctival injection
• Increased tearing • clear to while ocular
discharge
• Palatal itching,
• hyper-lacrimation
• Ear blockage
• Ear itching
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Allergic Rhino-Conjunctivitis
• Importance: • Seasonal Allergens:
• Prevalence approximately 15-20% • pollens from trees, grass,
of the population weeds
• Relationship between AR and • Perennial Allergens:
asthma
• dust mites, cat/dog dander
• In one study, 28% of patients with
asthma had AR and 17% of • Diagnosis:
patients with AR had asthma • prick/epicutaneous and
intradermal skin test
• DDx:
• Infectious rhinitis (PMN’s vs.
Eos in smear), cholinergic
rhinitis
Allergic Rhino-Conjunctivitis: Treatment
• Environmental Control/Allergen Avoidance

• Medications:
• Intranasal Steroids: e.g., fluticasone, budesonide
• Intranasal Antihistamine: e.g., azelastine
• Non-sedating antihistamines:
• E.g., Loratidine, Desloratidine, Fexofenadine, Cetirizine,
Levocetirizine,
Decongestants = α adrenergic agonists
• Mast cell Stabilizers: e.g., Cromolyn
• Ocular Agents: e.g., Olpatidine, Ketotifen
• Intranasal Anticholinergics: e.g., Ipratropium
• Combined antihistamine and anti-PAF agents rupatadine
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Immunotherapy for Allergic

Rhino-Conjunctivitis and Asthma
Immunotherapy: Allergen Specific “Vaccine”
beneficial in randomized trials for pollens, Alternaria, dust mites, and cat
dander allergens (Durham NEJM 1999, 2008; Ross RN 2000)
high affinity and specificity pollen-biding IgG4 with IgE blocking ability (James
LK JACI 2012)
generation of Th0 and T reg responses.
Modified/Recombinant hypoallergenic proteins and

chimeras (cat Fel d1/Fc) (Saxon JACI 2011)
Anti-IgE : approved 3/2003 (omalizumab) for treatment of asthma

(NEJM 1999)
moderate to severe persistent allergic asthma
FEV1 < 80%, specific allergen IgE
Sublingual/oral Immunotherapy 2015

•Targeted at children/adolescents and patients
with fear of needles
•Tablets with recombinant major allergens
taken daily or during high pollen season for
grass, ragweed, and dust mites
•Ragweed Tablet in 1871 patients was effective
in decreasing symptoms by 27% during pollen
season (Nelson H Allergy 2013)
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Asthma
• A syndrome, not single disease
– Allergic
– Exercise induced
– Cough variant
• Endotypes or subtypes may co-occur
• Newer biologic therapies
– Omalizumab = anti-IgE for allergic
– Meoplizumab, Reslizumab = anti-IL-5 for eosinophilic
predominant
– Benralizumab = anti-IL-5Rα chain
– (Lebrikizumab = anti-IL-13 in patients with elevated serum periostin
concentrations)
Asthma and Aspirin Sensitivity
AERD = Aspirin Exacerbated Respiratory Disease (Samter’s triad/tetrad):

• Asthma (often steroid dependent)
• Nasal polyposis (loss of smell)
• Aspirin and NSAIDS intolerance (decreased FEV1>12% upon exposure)
• Chronic rhino-sinusitis
Pathobiology:
– NOT IgE mediated
• LT overproduction because PGE2 inhibition of 5-LO pathway (and thus LT
production) is insufficient; COX-1 inhibition further decreases PGE2 generation. LT’s
such as LTC4 produced by mast cells and eos;
• In some patients, eos overexpress LTC4 synthase
• Platelets aggregate with eos, pmns, monos;
• Low concentrations of PGE2.
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AERD
Management:
- Leukotriene blockade (5-LO, LTR antagonists)
- Surgery (polyps, sinuses)
- Aspirin desensitization
Case 1
• A 23-year-old man was evaluated for asthma
and bilateral pulmonary infiltrates. He had had
asthma since childhood. Although he had
occasionally received oral corticosteroids for
asthmatic exacerbations as a child, he had
never required hospitalization for asthma. Of
note is that in the past two years he had been
treated for pneumonia on two occasions. His
current medications included inhaled
corticosteroids and an oral antihistamine.
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Allergic Bronchopulmonary Aspergillosis

Criteria:
Asthma
Pulmonary infiltrates/central bronchiectasis
Elevated total serum IgE >1000 ng/ml
Peripheral eosinophilia
Positive skin test and RAST (IgE) to Aspergillus
Precipitins against Aspergillus
Treatment: Oral steroids, consider anti-fungals
Associations: cystic fibrosis and HLA DR2

.
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Urticaria and Angioedema

• Urticaria
Acute < 6 weeks , Chronic > 6 weeks
• Urticaria :
pruritic geographic macular lesions with central
clearing of short duration (<24h) and variable size
• Angioedema :
swelling ± pain, associated to urticaria in 40-50% of
cases
Acute Urticaria
A cause is found in 20% of cases:
• Drugs: aspirin and NSAIDS, Abx

• Foods: egg, milk, peanut and nuts, seafood,
shellfish
• Infections (viral/bacterial: HBV and HCV)
• Contact Allergies (animal dander and saliva; pollen
from trees, grass, weeds)
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Chronic Urticaria
(a cause is found in < 10% of cases)
Physical Urticarias
•Symptomatic Dermatographism
•Pressure (delayed)
•Exercise Induced
•Cold, solar, aquagenic, vibratory
Autoimmune :
IgG Anti-IgE Receptor (35-40%) or Anti-IgE (5-10%) autologous serum skin
test positive (CIU index)
Hashimoto’s Thyroiditis
elevated anti-peroxidase (TPO) and anti-microsomal antibodies, Graves
disease
Connective tissue disorders, Malignancy

SLE, leukocytoclastic vasculitis, multiple myeloma, plasmocytoma,
cryoglobulinemias
Urticaria: Treatment
• H1 antagonists nonsedating→sedating
• H2 antagonists ranitidine, famotidine,
cimetidine
• Doxepin (combined H1 and H2 antagonist)
• Leukotriene antagonists Montelukast
• Corticosteroids (alternate day ≤ 20mg)
• Others: Colchicine, Dapsone,
Hydroxychloroquine, Sulfasalazine, Cyclosporine,
Plasmapheresis, IVIG, Levothyroxine
Omalizumab Anti-IgE (Chronic idiopathic urticaria/Cold-
induced urticaria, Boyce 2007 JACI, Kaplan 2009, Maurer
2013 NEJM)
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Less itch
Omalizumab in CIU :
150 mg to 300 mg
every 4 weeks
Less hives
Maurer et al NEJM 2013
Case 2
22 y male with recurrent
episodes of abdominal pain
and lip swelling, not pruritic,
no associated hives, and not
responding to corticosteroids
or anti-histamines. Two other
family members have similar
episodes and one uncle died of
asphyxiation at early age
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Angioedema (non mast cell mediated)

Hereditary
• C1inh deficiency : Type I
decreased level due to point/frame shift mutations of the SERPIN gene
• C1inh dysfuntion: Type II
normal serum concentration but non-functional protein
C1Inh/C1Q Nl,
Type III:
Factor XII mutation
Females, familial, menstrual periods (estr/prog)
Acquired
• Inhibitor(s) of C1inh : anti-idiotypic Abs
B cell lymphomas
Excessive consumption (malignancies, connective
tissue diseases SLE, HIV )
Treatment of HAE
From http:/www.ajmc.com/journals/supplement/2013/ace010_13jun_hae_ce/ace010_13jun_lumry1_s103to10
accessed 20 November 2015
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Hereditary and Acquired Angioedema

• Symptoms
episodic swelling of the head, face, neck, extremities and GI (abdominal
pain, nausea and vomiting responsive to fluids and narcotics)
• Diagnosis
C4 C1INH C1q C2
Hereditary ↓ nl/↓ nl +/-
Acquired ↓ nl/↓ ↓ +/-
• Therapy :
Purified C1inh (FDA 2009): Cinryze, Berinert
Kallikrein inhibitor (Kalbitor, ecallantide, 10 mg sq X3)
Bradykinin receptor 2 Inh (Icatabant) 30 mg sq
(Cicardi et al. 2010, NEJM)
androgenic steroids (danazol, stanazolol)
epsilon amino caproic acid, tranexamic acid, FFP
Case 3: Is this anaphylaxis?

• 46 y o m from India eating at a Chinese restaurant, on no meds,
mild intermittent asthma, avoids seafood (fish allergy)
• Felt itchy and flushed after a bite of beef,
• developed urticaria, SOB, and severe wheezing
• Patient collapse within 15 min, 911 called
• 5 attempts fail to intubate due to laryngeal edema
• Epi given, dead upon arrival ED (45 mi)
• Tryptase post mortem sample: 32 ng/ml (NL: 15ng/ml)
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Case 4: is this anaphylaxis?

• 42 y o healthy male stung by wasp while working in yard
• Within 15 min has severe flushing, dizziness and syncope
• 911 called: BP 50/? Mm Hg
• Epinephrine IM is administered by EMT
• Full Recovery
• Tryptase 42 ng/ml in ER
• Tryptase baseline 2 months later 20 ng/ml
• Skin test positive for Hymenoptera venom
Anaphylaxis Definitions
• “A systemic, immediate hypersensitivity reaction
caused by immunoglobulin E (IgE) mediated
immunologic release of mediators from mast cells
and basophils.” (Lieberman, 2003)
• Anaphylaxis = “a severe , potentially fatal systemic

allergic reaction that occurs suddenly after contact
with an allergy-causing substance.” (Second Symposium, JACI
2006;117:391-397)
• “A serious allergic reaction that is rapid in onset and

might cause death” (Simons, 2010)
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Anaphylaxis Clinical Manifestations

1. Acute onset of an illness (min to hrs) with involvement of the skin and/or
mucosae (hives, pruritus, flushing) and at least one of the following
1. Respiratory compromise (dyspnea, wheeze, bronchospasm, stridor, reduced
PEF, hypoxemia)
2. Reduced BP or symptoms (syncope)
2. Two or more of the following that occur rapidly after exposure to a likely
allergen for that patient (min to hrs)
1. Skin and/or mucosae
2. Respiratory compromise
3. Reduced BP
4. GI symptoms (colic, diarrhea)
3. Reduced BP after exposure to a known allergen for that patient (min to hrs)
Table I from Sampson et al JACI 2006 117:391-397.
Frequency of Manifestations
• Cutaneous 90%
– Urticaria and Angioedema 85-90%
– Flushing 45-55%
– Pruritus 2-5%
• Respiratory 40-60%
– Dyspnea and Wheeze 45-50%
– Laryngeal Angioedema 50-60%
– Rhinitis 25-20%
• Dizziness, syncope, hypotension 30-35%
• Abdominal (n, v, colic, diarrhea) 25-30%
• Misc (HA 5-8%, SSCP 4-6%, Sz 1-2%)
Liberman P et al JACI 2005;115(3):S483-S523
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TRYPTASE
TRYPTASE
Swartz 1987 NEJM, 2006; Stevens 2007, Prieto Garcia 2013
Anaphylaxis: Epidemiology
Fatal Anaphylaxis:
Previously “Severe Anaphylaxis” (Sampson Asthma 1992, NEJM, 2006)
Allergy to: Peanuts, Tree Nuts, Fish or Shellfish (transgenic foods)
Patients on ß-Blockers/ACE-inhs
Non Fatal Anaphylaxis:

1/2700 hospitalizations
repeated antibiotics exposure (CF)
0.5% Hymenoptera Stings
1/10,000 RCM Exposure
1% PCN and antibiotics beta lactams and others
1/5,000-25,000 General Anesthetic Exposure
1/3,000-5,000 Hemodialyses
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Anaphylaxis: Pathobiology
IgE /Mast Cell mediated
Foods: Peanuts, Tree Nuts, Seafood, Eggs, Milk
Allergen Extracts, Vaccines, antisera
Hymenoptera Venom: Bees, Wasps, Yellow Jackets, Hornets, Fire Ants
Hormones (Progesterone Autoimmune Dermatitis), Enzymes
Monoclonal Abs :anti-TNFa, anti-CD20
Chemotherapy: platins, taxenes
Beta lactams, ASA and other NSAIDS (COX1>COX2), vancomycin (red person syndrome)
Radio Contrast Media, opiates (direct mast cell activators)
Anesthetics: Curare Derivatives
Dialysis membranes
Anaphylaxis: Diagnosis
Acute :
Tryptase : total >11ng/ml, mature > 1 ng/ml
N-Methyl Histamine in 24h urine collection
Prostaglandin D2 metabolites (PG 11-β-F2-α) in urine
Retrospective :
Antigen-Specific IgE
Specific IgE in serum (in vitro)
Skin Testing (in vivo)
Basophil activation FACS: CD69/CD203
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Management of
Anaphylaxis
Epinephrine IM (not sq) 0.3-0.5cc
recumbent position, quadriceps
Observation for a Minimum of 6 Hours
Obtain a serum Tryptase
Oxygen
Anti-histamines H1 and H2,
Steroids: single dose (IV or oral)
Delayed, protracted anaphylaxis may occur 6 to 24 hours; late phase or
secondary reaction requires repeat Epi in 16-36% of patients.
If ß Blockade: Glucagon 5 - 15 µg/min IV (after trying epi)
ACE inhibitors are implicated in severe/refractory
Education
Allergy evaluation
Auto injectable epinephrine
World Allergy Organization anaphylaxis guidelines: summary. Simmons, F, et al. JACI, 2011;
127: 587-593
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Epi: Take the Right Route
Exercise Induced Anaphylaxis

Associated with food allergy in >30% cases (wheat)
• Specific IgE, Skin Test Food
Management:
Discontinue Exercise Earliest Symptom : Flushing, Pruritus
• Limit Exercise on Hot, Humid Days,
• Exercise with a companion
• Avoid Exercise 4-6 hrs Post Prandial
• Avoid Exercise Post Allergy Immunotherapy
• Avoid Beta-Blockers and ACE Inhibitors
• Use Epinephrine promptly
• Have a Medi-Alert Bracelet
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Drug Hypersensitivity
Common Drugs:
PCN and related Abx: IgE-mediated
- Cross reactivity with cephalosporins (10 % first generation, 1-2% 3th -4th
generation)
aztreonam is non- crossreactive (except ceftazidime)
ASA and NSAID’s: COX-1/COX-2 blockade, universal cross-reactivity
ACE-I (Kininase II): Bradykinin Mediated angioedema
Sulfonamides: no cross-reactivity with non-antibiotic
medications (NEJM 2007)
Diagnosis:
• Skin test (Pre-Pen for PCN: FDA 2010)
• Challenge
Management
Avoidance, MediAlert Bracelets
Desensitization (Antibiotics, Aspirin,Chemotherapy, Mo)
MRGPRX2 Human Receptor for Peptidergic Drugs

Mrgprb2 mediates mast cell
responsiveness and side effects
of peptidergic therapeutic drugs
(Icatibant, ciprofloxacin,
rocuronium, atracuronium).
a, Percentage of responding cells

from wild-type (WT) and
Mrgprb2MUT (MUT) peritoneal mast
cells after drug
b, Left, representative images of

Evans blue stained extravasation
15 min after intraplantar injection
of icatibant. Right, quantification of
Evans blue leakage into the paw
after 15 min.
c, Total histamine release from

wild-type (red diamonds) and
Mrgprb2MUT (black squares) mice
after incubation with named
substances.
Note that no significant difference

between wild-type and
Mrgprb2MUT cells
was found at any dose of anti-IgE
antibody.
Nature 2015
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Mrgprb2 mediates mast cell

responsiveness and side effects of
small molecules therapeutic drugs.
a, Structures of 48/80 and a cyclized

variant. The THIQ motif is highlighted in
blue.
b, Structures of representative members of

all NMBD classes. THIQ
motifs are highlighted in blue. Note that
only succinylcholine lacks a bulky
hydrophobic group.
c, Percentage of responding cells from wild-

type(WT) and Mrgprb2MUT(MUT) peritoneal
mast cells after application of various
NMBDs.
d, Structure of ciprofloxacin,
with the motif common to all
fluoroquinolones highlighted in blue.
e, Percentage of responding cells

from wild-type and Mrgprb2MUT peritoneal
mast cells after fluoroquinolone
f, Changes in n body temperature after

intravenous injection of ciprofloxacin (1.5
mg in125 ml saline) at time 0. n 54 mice
per genotype.
Drug Desensitization
First line therapy for all patients
Prolonged life span (cancer)
Increased QOL (chronic inflammatory diseases)
Protection against anaphylaxis
• Is desensitization for everybody (risks/indications)?
• Can all drugs be desensitized (chemo, MoAbs, antibiotics, ASA)?
• What are the indications (symptoms)?
• What are the contraindications (severe cutaneous, beta blockers)?
• Are they safe (fatalities)?
• What are the outcomes (effectiveness)?
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Castells et al 2008, Sloane et al 2016
PAIN
Safety of Rapid Desensitizations 413 cases and 2177 cases

Castells et al. JACI 2008
Sloane et al JACI IP 2016
Mild Reaction: 27%

(111/413)
Severe Reaction: 6%
No Reaction: 67% (24/413)
(278/413)
94 % of cases with mild or no reactions

No deaths
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Paclitaxel Desensitization
Feldweg A et al Gyn Onc 2005
Step Solution Rate Time (min) Administered dose Cumulative dose (mg)
1 1 1 15 0.0003 0.0003
2 1 2 15 0.0006 0.0009
3 1 5 15 0.0015 0.0024
4 1 10 15 0.0030 0.0054
5 2 2 15 0.0060 0.0060
6 2 5 15 0.0150 0.0210
7 2 10 15 0.0300 0.0510
8 2 20 15 0.0600 0.1110
9 3 5 15 0.1500 0.2610
10 3 10 15 0.3000 0.5610
11 3 20 15 0.6000 1.1610
12 3 40 15 1.2000 2.3610
13 4 10 15 2.9764 5.3374
14 4 20 15 5.9528 11.2902
15 4 40 15 11.9056 23.1957
16 4 75 186 276.8043 300.0000
-----------------------------------------
Total time = 411 minutes
Non-IgE Hypersensitivity Reactions to

Medications
• DRESS syndrome:
eosinophlia, rash, systemic symptoms, LAN, LFT elevations
anti-convulsants: cross-reactivity is high (HLA-B* 1502)
phenytoin, phenobarbital, carbamazepine
role of HHV6-7 reactivation
• Delayed Maculopapular Rashes: EM/SJS/TEN
sufonamides, beta-lactams
Abacavir: fever, rash, systemic involvement (HLA-B*5701)
Quinolones: universal cross-reactivity
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Specific HLA Alleles in Drug

Hypersensitivity
•Abacavir (reverse transcriptase termination
HIV) :
HLA-B 57-01 exclusive
•Carbamazepine
(anti-convulsant):
HLA-B 15:02
Carbamazepine induced
Stevens-Johnson Syndrome
Toxic Epidermal Necrolysis
Abacavir Hypersensitivity
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The New York Times Magazine

June 7th, 2009
•“Mommy, I’m afraid”(impending sense of doom)
• The mother, a 32 yo W, was found lying
unconscious in a public bathroom in a pool of
bloody stool after feeling, hot, dizzy and
having a sensation of “fluttering heart.”
• She told the ER doctors that her only medical
problem was occasional panic attacks, flushing
and a rash.
Urticaria Pigmentosa
Darier’s sign
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Systemic Mastocytosis
Diagnostic Criteria
Major Criteria :
multifocal infiltrates of 15 or more mast cells
in bone marrow and/or extracutaneous organs
Minor Criteria:
1. > 25% spindle shaped mast cells
2. c-kit mutations (codon D816V)
3. aberrant expression of CD2 and CD25
4. Tryptase >20 ng/ml
Systemic Mastocytosis
Spindle shape mast cells
Mast cell aggregates
Tryptase staining
KIT mutation D816V

Aberrant CD25 and CD2
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Classification of Disease associated with Mast

Cell Activation (Akin, Metcalf, Valent JACI 2010)
Non Clonal Mast Cell Activation

Syndrome
Hamilton et al JACI 2011
Go back to case 4
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Common Variable Immunodeficiency

• Sinusitis (>2) , Pneumonia (>2), UTI (>3-4), Deep seated
infections
• Low IgG, IgA, IgM (– 2 SD)
• Poor response to vaccines : Pneumovax, H.Influenza,
Hepatitis, Strep pneumo (Prevnar-13)
• Gammaglobulin replacement:
IVIG or SQ 400mg/kg q 3-4 weeks
(TACI defect, association with autoimmune diseases and
lymphoma)
Summary Pearls for the IM Boards

• Allergic Rhino-conjunctivitis: IT
• Asthma/AERD: ASA desensitization
• Allergic Bronchopulmonary Aspergillosis: IgE
• Angioedema and Urticaria : C4, TPO
• Anaphylaxis: TRYPTASE
• Adverse Drug Reactions/Desensitization: Pre-Pen
• Mastocytosis: c-KIT D816V mutation
• Common Variable Immunodeficiency: IgG
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Board Question 1
• An 18 yo patient presents with an episode of
angiodema of face and abdominal pain. He has no
itching or associated hives. Which test would be
most appropriate?
a) Serum tryptase
b) Serum C4
c) CT abdomen
d) CBC
Board Question 1
• An 18 yo patient presents with an episode of
angiodema of face and abdominal pain. He has no
itching or associated hives. Which test would be
most appropriate?
a) Serum tryptase
b) Serum C4
c) CT abdomen
d) CBC
Explanation: The clinical presentation of angioedema without
associated pruritus, in conjunction with this family history, suggests
hereditary angioedema (HAE). The best single test for HAE is the
serum C4 concentration.
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Board Question 2
• A 50 yo male with CAD presents to the ER with
hypotension , tachycardia, SOB and
generalized hives after a wasp sting. The most
important action in the acute setting is:
a) Perform skin test to Hymenoptera venom
b) Obtain a serum tryptase
c) Administer epinephrine
d) Administer venom immunotherapy
Board Question 2
• A 50 yo male with CAD presents to the ER with
hypotension , tachycardia, SOB and
generalized hives after a wasp sting. The most
important action in the acute setting is:
a) Perform skin test to Hymenoptera venom
b) Obtain a serum tryptase
c) Administer epinephrine
d) Administer venom immunotherapy
Explanation: While all these measures are appropriate, the most
pressing issue acutely is patient safety. Timely administration of
epinephrine is life saving, while a delay in administration is the most
important risk factor for death from anaphylaxis.
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References
• Castells et al JACI 2008 , 2012 Desensitizations
• Boyce et al JACI 2009 Xolair use in Urticaria, Maurer
2013
• Escribano et all 2009 Mastocytosis
• Durham et al NEJM 2008 Immunotherapy for AR
• Cunningham Rundles 2007 Common Variable
immunodefiency
• Simons FE 2011 : World Allergy Organization
anaphylaxis guidelines: J Allergy Clin Immunol
• LEAP peanut allergy study NEJM 2015
• Mast Cell Anaphylactoid receptor Nature 2015
No Disclosures
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Depression Update
Russell G. Vasile MD
Director, Affective Disorders Consultation Service,
Department of Psychiatry
Associate Professor of Psychiatry
Psychiatry Overview
Disclosures
No Disclosures
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Learning Objectives
• Understand the spectrum of depressive

disorders and treatment implications
• Appreciate recent developments in the

psychopharmacologic management of
depression, including refractory
depression
• Enhance skills in suicide risk assessment
Emerging Issues - 2018

• Suicide Risk and antidepressants – the
role of occult bipolar depression
• Treatment Resistant Depression –
Augment, Switch, Combine?
• Novel neuroleptic/antipsychotic
medications as antidepressant boosters
• What role for TMS and brain stimulation
techniques?
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Prevalence of Mood Disorders
1 Year (%) Lifetime (%)

Major Depressive
10.3 17.1
Episode
Manic Episode 1.3 1.6
Dysthymia 2.5 6.4
Any Mood Disorder 11.3 19.3
Kessler RC, et al. Arch Gen Psychiatry. 1994;51:8.
DSM- 5 Classification
of Mood Disorders
Mood disorders
Bipolar disorders Depressive disorders
Bipolar I CyclothymicBipolar Major Dysthymic Depressive

disorder disorder disorder depressive disorder disorder
NOS disorder NOS
Bipolar II Single Recurrent

disorder episode
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Screening for Mood Disorders

• Patient Health Questionnaire 2 (PHQ-2);longer
version PHQ-9
• Quick Inventory of Depressive Symptoms
• Beck Depression Rating Scale
– Self-report
• Hamilton Rating Scale for Depression
– Clinician administered
• Young Mania Rating Scale
• Columbia Classification Algorithm for Suicide
Assessment ( C-CASA)
PHQ-2
• Little interest or pleasure in doing things
• Feeling down and depressed or hopeless
0 - Not at all
1 - Several days
2 - More than half the days
3 - Nearly every day
Score of 6 or more correlates 78% with major

depression.
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Subtypes of
Depressive Disorders
• Bipolar/Unipolar
– Rapid Cycling as a sub-variant
• Melancholic/Non-Melancholic
• Psychotic/Non-Psychotic
• Agitated/Retarded
• Responsive/Non-responsive
• Atypical
– Rejection Sensitive Dysphoria
• Seasonal Affective Disorder
DSM-5 Criteria for

Melancholic Features
A. Either of the following, occurring during the
most severe period of the current episode:
1. Loss of pleasure in all, or almost all, activities
2. Lack of reactivity to usually pleasurable stimuli
B. Three or more of the following:
1) Distinct quality of depressed mood (ie, different from
feelings experienced after loved one’s death)
2) Depression regularly worse in the morning
3) Early morning awakening
4) Marked psychomotor retardation or agitation
5) Significant anorexia or weight loss
6) Excessive or inappropriate guilt
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Recurrence is Common
Rate of recurrence per episode
100 90
80
Recurrence Rate (%)
70
60 50
40
20
0
After 1 After 2 After 3
Depressive Episode(s)
DSM-IV: 1994;341-342.
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Detecting Bipolar Disorder

• History of mood elevation
• Family history of bipolar disorder
• Sub-syndromal mood elevation
• Mixed states/racing thoughts
• Antidepressant associated mania
• Response to mood stabilizers
• No biological markers established
NIMH Collaborative Depression Study

-Depression as the Unmet-Need
Wks depressed Wks manic

BP I 31% 10%
n=135
BP II 52% 1.4%
n=71
10 years follow-up; BP II-- greater chronicity and comorbidity

Judd et al., Arch Gen Psych 2002; 59:- 530 537
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Factors Affecting the Choice

of Antidepressant
• Side effect profile
• History of previous response
• Family history of response
• Safety in overdose
• Differential effects in subtypes

of depression
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Selecting Among
Antidepressants
• Initial choices – SSRI/SNRI
– Half-life considerations
– Activation – sedation
• Secondary options
– Tricyclic antidepressants
– Mirtazapine
– Bupropion
• MAO-inhibitors
– Phenelzine, Tranylcypromine
Treatment Recommendations
• In first episode patients
– Use maximum tolerated dosage, Continue
treatment for 6 months following remission.
Discontinue medications gradually over 2-4 weeks.
• In patients with recurrent depression

– Maintenance treatment for patients with three or
more episodes of depression, or two severely
disabling episodes.
3696
Differences between the SSRIs

• Half-life of fluoxetine much greater than paroxetine
• Inhibition of P450 2D6 enzymes much greater with

paroxetine and fluoxetine as compared to sertraline or
citalopram
• Inhibition of P450 34A

– Fluvoxamine delays clearance of alprazolam
• Inhibition of P450 1A2, 3A4, 2C9

– Fluvoxamine delays clearance of warfarin,
theophylline,propranolol, clozapine
SSRI Side Effects

• Jitters, fatigue, insomnia, headache
• Sexual dysfunction, erectile dysfunction,
anorgasmia
• Weight gain may occur
• Rare risk of GI bleeding possibly due to
inhibition of platelet function
• Inappropriate SIADH in the elderly
• Switch to mania, agitation
• Osteoporosis, risk of non-vertebral fracture in
elderly (Diem et al, Arch Intern Med, 2007)
3697
Serotonin Syndrome
• GI – cramping, diarrhea, bloating
• Neurological – Tremor, dysarthria
• Cardiovascular –tachycardia, hypertension
• Psychiatric – confusion, mania, restless
• Medications that may contribute:

– Isoniazid, Linezolid
– Tramadol, Dextromorphan, St. John’s Wort
SSRI Withdrawal
• CNS Symptoms
– Sleep disturbance, vivid dreams
– Anxiety, restlessness
– Headache
• Parasympathetic Symptoms
– Sweating, sialorrhea
– Nausea, vomiting, cramps, diarrhea
3698
Citalopram
• Highly selective SSRI; Minimal
NE/Dopamine activity
• Dosage range 10 – 40 mg; QT
prolongation FDA warning
• Metabolized by liver; No active metabolites
• SSRI side effects generally well tolerated
• Rare side-effects – hyponatremia, SIADH
• No in-patient depression studies
conducted
Escitalopram (Lexapro)
• Active S- enantiomer of racemic citalopram – twice as
potent as the racemic mixture
• Absorption unaffected by food
• Plasma peak at 5 hours –steady state one week
• 10 mg/day standard dosage
• Little effect on CYP isoenzymes
• Relatively few medication interactions
• In large studies, 10 or 20 mg/day of Escitalopram were
as effective as 40 mg/day of citalopram.
• Theoretical advantages over citalopram, possibly fewer
side effects.
3699
Venlafaxine
• SNRI – serotonin effects at lower dosages;
• Norepinephrine effects at higher dosages
• Dosage range – 75 mg – 300 mg
• Monitor BP at higher dosage range
• FDA approved for generalized anxiety and major
depression.
• Probable greater antidepressant efficacy at
higher dosage
• Extended release formulation available
Wellbutrin (Bupropion)
• Dopaminergic/Noradrenergic agonist
• Stimulating antidepressant -75 -375 mg qd
– Sustained and Extended Release options
• No sexual dysfunction
• Contraindicated in patients with seizures
• Effective in ADHD
• Avoid concurrent use of stimulants
• Insomnia may be a side-effect
• Limited anti-anxiety properties; may cause
anxiety
3700
Duloxetine (Cymbalta)
• SNRI Dosage range 20-30 mg bid; 60-90
mg in refractory patients
• Avoid use in patients with renal or hepatic
impairment
• May increase anti-arrythmic blood levels
• May be useful in pain syndromes
• Side –effects – dry mouth, nausea,
constipation, dizziness, fatigue
• Avoid in pregnancy
Mirtazapine
• Alternative to SSRI/SNRI
• Less sexual dysfunction
• Sedation and weight gain side-effects
• Anti-anxiety properties
• Dosage range 15-60 mg qd
• Excellent for sleepless, underweight
patients, including elderly
• NE and 5HT1 agonist
3701
Heterogeneity of Treatment
Resistant Depression
• Bipolar Depression and Latent Bipolar
• Axis II Co-morbidity
• Substance Abuse
• Anxiety Disorders
• Trauma, Abuse and Psychosocial Crisis
• Occult Medical Disorders
• Undiagnosed Sleep Apnea
• Schizoaffective, Schizophrenia Spectrum
Adapted from Fagiolini and Kupfer, Biol Psychiatry 2003;53:640-648
Standard MAOIs are

Particularly Effective for:
• Atypical Depression
• Resistant Depression
• Elderly Depressives (maintenance effects)
• Social Phobia
• Neuroticism
• Interpersonal Hypersensitivity
• Phobic Avoidance
3702
Augmentation Medication
Strategies for TRD
• Lithium – best established (7/9 controlled studies)
Lower blood levels -0.4-0.6 meq/l effective
• T3 – 25-50 mcg. Efficacy established with TCAs
• Novel neuroleptics – Aripiprazole (Abilify), 5-10
mg (FDA approved)
• Olanzapine-Fluoxetine combination in bipolar
depression
Switch Strategies for TRD

• Changes within class – uncontrolled
studies show variable response rates
• SSRI to TCA – 40% response in open
study (SSRI to nortriptylene)
• SSRI to Venlafaxine (43% remission)
• SSRI to Mirtazapine – open study after 8
weeks, 48% respond
3703
Atypical Antipsychotics in TRD

• Aripiprazole Augmentation; Brexpiprazole
augmentation dosage 2-4 mg qd
• SSRI augmentation with risperidone or
ziprasidone-may facilitate response
• Lurasidone and quetiapine for bipolar
depression; Cariprazine dosage 1.5 mg qd
• Olanzapine – fluoxetine combination –
large meta analysis demonstrates efficacy
in TRD
Lurasidone for Bipolar I Depression
• Lurasidone dosage 20-120 mg qd

• Studied as adjunctive agent to lithium or
Valproate in bipolar depression
• Studied as monotherapy for bipolar
depression – 53% response to low dose
therapy (20-60 mg qd); 51% response
for high dose (80-120) versus 30% for
placebo
• Also effective utilized adjunctively with
lithium or Depakote
3704
Lurasidone for bipolar depression
• Side effects –Nausea, somnolence, headache,

akasthesia
• Treatment emergent suicidality 9% versus 6%
for placebo in adjunctive study; 14 % in
monotherapy for all three groups.
• Minimal changes in lipids, weight and glycemic
control
• Significantly more patients achieved remission
in the lurasidone treated group
• Treatment emergent hypomania not significant
Electroconvulsive Therapy
• Key indications – Psychotic Depression, Suicidal Press,
Food Refusal, Treatment Refractory Depression,
Parkinson’s Disease, Refractory Manic Excitement.
• Medical Concerns – 4 deaths/100,000 treatments.

Cardiac risks- recent myocardial infarction, unstable
angina, hypertension, atrial fibrillation, post-
cerebrovascular accident, intracranial aneurysm or
space-occupying lesions or other causes of increased
intracranial pressure.
• Post ECT maintenance – High rate of relapse particularly

with psychotic depression; Post ECT medications -
nortriptylene and lithium, MAO-I, Maintenance ECT.
3705
Suicidal Behavior and Depression

• 20-40% of patients with an affective disorder
exhibit nonfatal suicidal behaviors, including
thoughts of suicide1
• Estimates associate 16,000 suicides in the US
annually with depressive disorder2
• 18% of those with a history of major depressive
disorder (MDD) attempt suicide2
• 15% of patients with severe primary MDD of at
least 1 month’s duration eventually commit
suicide2
1. Review of Psychiatry. Washington, DC: American Psychiatric Press; 1988;7:353-385
2. Am J Psychiatry. 1988;145:1351-1357.
Risk Factors for Suicide

• Previous Attempts
• Psychosis
• Major Depression or Bipolar Diagnosis
• Alcohol or Drug Abuse
• Losses, deaths, shame, poverty
• Social isolation, unmarried, homosexual
• Lack of access to clinical care
• Access to firearms, toxins, medicines
• History of violence or impulsivity
• Prominent anxiety or agitation
3706
Suicide Risk Assessment

• Press
– The sense of urgency to die
• Perturbation
– The degree of stress imposed on the patient
• Pain
– The subjective sense of anguish
• Risk-Rescue Assessment
– Previous attempts-assessment of lethality
• Guns, jumping, hanging, drowning are particularly
malignant
– Previous attempts-assessment of attempts to obtain help
• Psychosis
– Command hallucinations
• Personality Disorder, Depression, Substance Abuse
From Schneidman, Multidimensional Approach to Suicide, In Suicide:

Understanding and Responding, IU Press, 1989
Antidepressants and Suicide Risk

• Increased risk of suicidal ideation and behavior
in children, adolescents and adults age 24 and
younger
• No effect on suicidal ideation or behavior in
adults age 25-65
• Reduction in suicidal ideation and behavior in
adults 65 and older.
• Risk appears secondary to emerging hypomania
or agitation
Stone et al. BMJ 2009:339 2880

Liberon Neuropsychopharmacology:35 1619
3707
Summary – Key Points

• Assess the Depressive Spectrum –
Appreciate the longitudinal history and co-
morbidity
• Watch for latent bipolarity
• Careful follow-up to assess early side-
effect experience –particularly in young
adults and adolescents
• Watch for latent psychosis in the elderly
• Follow-up phone calls after beginning
antidepressants - Outreach
Question 1
• Which of the following is not an appropriate
treatment for bipolar depression?
A. Lurasidone
B. Lithium Carbonate
C. Buproprion as a stand alone medication
D. Low dose anti-depressant covered by a mood
stabilizer anti-manic medication.
E. Quetiapine in a dosage of 300 mg per day.
ANSWER : C
Antidepressants can trigger mania if not combined
with a mood stabilizer.
3708
Question 2
• What is the most rapid and effective

treatment for psychotic depression with
command hallucinations in the elderly?
• A. Antidepressant medication
• B. Antipsychotic medication
• C. Electroconvulsive therapy
• D. Antidepressant combined with
antipsychotic medication
• ANSWER: C
• Antidepressant medications may take 2-4 weeks to
become effective.
References
• Chandler V: Google and suicides; what can we learn about the use of the internet to
prevent suicides. Public Health 154 (2018) 144-150
• McIntyre RS et al: Treatment-resistant depression: Definitions, review of the evidence

and algorithmic approach. Journal of Affective Disorders 156 (2014); 1-7
• Gobbi et al. Antidepressant combination versus antidepressant plus second-

generation antipsychotic augmentation in treatment-resistant unipolar depression.
International Clinical Psychopharmacology 2018, 33:34-43.
• Nelson, J. Craig: Adjunctive Ziprasidone in Major Depression and the Current Status
of Adjunctive Atypical Antipsychotics. Am J Psychiatry 2015;172: 1176-1178
• Loebel et. Al.: Lurasidone as adjunctive therapy with lithium or valproate for the
treatment of bipolar depression; A randomized, double blind, placebo-controlled
study. Am J Psychiatry 2014; 171:169-177
3709
Disclosures
No Disclosures
3710
Diagnostic Errors in Medicine

Gordon D. Schiff MD
Associate Director Center for Patient Safety Research and Practice
Brigham and Women's Hospital Div. General Medicine
Safety Director – Harvard Center for Primary Care

Academic Improvement Collaborative
Associate Professor of Medicine Harvard Medical School
Financial Conflicts/Disclosures
• None relevant to talk
• Commercial
– None related (Medaware software evaluation)
• Other/Grant Funding
– CRICO Malpractice Grants–Diagnostic Errors/Pitfalls
– Gordon & Betty Moore Foundation- Diagnostic Error Projects
– SIDM/PCORI Research Mentor honorarium
– AHRQ –HIT Safety Grant –Drug Indications
– Gold Foundation- Boundaries Issues
2
3711
7 Key Points
1. Dx Errors frequent, important, yet underappreciated
2. Growing interest, recognition
Especially 2o NAM Improving Dx 2016 Report
3. Traditional approaches limited
Low leverage, misapplied, often counterproductive
4. HIT: important role in preventing as well as causing
5. Metrics: elusive, illusive; Need for new Culture
6. More Conservative Dx: not counter to missing Dx
7. Patients: ↑ engagement
Enhanced role understanding uncertainty, co-producing dx
3712
21% Experienced Medical Error

IHI/NPSF 2017
Survey
3713
Misdiagnosis
Leading
Type of Error
Patient
Identified
Factors
3714
Patient
Identified
Factors
10
Schiff et al JAMA Intern Med 2013
3715
3716
Diagnosis-Related Closed Claims
Top Allegation Categories
13 Selection: N=10693 closed claims from 2013-2017
Top Allegation Details
Selection: N=3466 closed claims from 2013-2017 with a Diagnosis-Related allegation
14
3717
Injury Severity

Footnote: Injury severity based on National Association of Insurance Commission (NAIC) codes.
15
Top Specialties
16
3718
Top Risk Management Categories
17
Top Risk Management Details – Diagnosis-Related Closed Claims

Clinical Judgment
Clinical Judgment – Percentage of Claims
21% 19% 17% 10% 8%

Narrow Inadequate / Misinterpretation Failure to Failure to
Diagnostic Inappropriate of Diagnostic Adequately Obtain
Focus Testing Studies Assess Specialty
Patient’s Consult or
Condition Referral
Selection: Closed PL claims from 2013-2017, N=1840 with a Diagnosis-Related allegation and a Clinical Judgment
Risk Management issue
18
3719
Schiff & Graber Diagnosis Errors in Acute Care Setting. Principles and Practice of Hospital Medicine McGraw Hill 2012
Top Risk Management Details – Diagnosis-Related Closed Claims

Clinical Systems
Clinical Systems – Percentage of Claims
17% 16% 13% 10% 8%

Failure to Manage Insufficient Results/Specimen Lack of Failure to Inform
Patient’s Follow- Studies (e.g., Lost, Misfiled, or Coordination of Patient of Test
up Care Imaging) MD Unaware of Care Results
Results
Selection: Closed PL claims from 2013-2017, N=550 with a Diagnosis-Related allegation and a Clinical Systems
Risk Management issue
20
3720
IOM Report
September
2015
8 IOM Goals to Improve Diagnosis and

Reduce Diagnostic Error
GOAL 1 Facilitate more effective teamwork in the diagnostic process among
health care professionals, patients, and their families
GOAL 2 Enhance health care professional education and training in the

diagnostic process
GOAL 3 Ensure that health information technologies support patients and

health care professionals in the diagnostic process
GOAL 4 Develop and deploy approaches to identify, learn from, and reduce
diagnostic errors and near misses in clinical practice
3721
8 IOM Goals to Improve Diagnosis and

Reduce Diagnostic Error
GOAL 5 Establish a work system and culture that supports the diagnostic
process and improvements in diagnostic performance
GOAL 6 Develop a reporting environment and medical liability system that

facilitates improved diagnosis through learning from diagnostic errors
and near misses
GOAL 7 Design a payment and care delivery environment that supports the
diagnostic process
GOAL 8 Provide dedicated funding for research on the diagnostic process and
diagnostic errors
3722
What is a Diagnosis Error?
Adverse
Outcomes Diagnostic
Process
Failures
Delayed,
Missed,
Misdiagnosis
Modified from
Schiff Advances in Patient Safety AHRQ 2005,
Schiff & Leape Acad Med 2012
3723
Marshal Wolf
Brigham
27
Sherlock Holmes
Dr. Gregory House
28
3724
Don Berwick
Former President and CEO

Institute for Healthcare
Improvement (IHI)
Former Director Centers for
Medicare & Medicaid Services
29
Genius diagnosticians make great stories,

but they don't make great health care.
The idea is to make accuracy reliable,
not heroic
Don Berwick
Boston Globe 7/14/2002
30
3725
2 Key Improvement Concepts
• Situational Awareness
• Safety Nets
Diagnostic Risk
Situational Awareness
• Specialized type of situational awareness
• High reliability organizations/theory
– High worry anticipation of what can go wrong
– Preoccupied w/ risks recognizing/preventing
• Appreciation diagnosis uncertainty, limitations
– Limitations of tests, systems’ vulnerabilities
– Knowing when “over head” need for help
• Making failures visible
• Don’t miss diagnoses, red flag symptoms
• Diagnostic pitfalls – potentially useful construct
32
3726
• Perhaps the most important distinguishing feature of

high-reliability organizations is their collective
preoccupation with the possibility of failure. They
expect to make errors and train their workforce to
recognize and recover them. They continually
rehearse familiar scenarios of failure and strive hard
to imagine novel ones. Instead of isolating failures,
they generalize them. Instead of making local repairs,
they look for system reforms
Reason Human error: models and management West J Med. 2000;
What is a Diagnostic Pitfall?
Need for/Value of Situational Awareness
3727
GENERIC TYPES of PITFALLS

• Disease A repeatedly mistaken for Disease B
• Bipolar disease mistaken for depression
• Failure to appreciate test/exam limitations
• Pt w/ breast lump and negative mammogram and/or ultrasound
• Atypical presentation
• Addison’s disease presenting with cognitive difficulties
• Presuming chronic disease accounts for new symptoms
• Lung cancer: failure to pursue new/unresolving pulmonary sx in patient
with pre-existing COPD
• Overlooking drug, other environmental cause
• Pancreatitis from drug; carbon monoxide toxicity fail to consider
• Failure to monitor evolving symptom
• Normal imagining shortly after head injury, but chronic subdural
hematoma later develops
BREAST CANCER PITFALLS: MALPRACTICE CASES
Pitfall N Example
1. Family History - Failure to obtain family history of breast cancer
4
Issues - Under-weighing family history of breast cancer
- Underestimating risk of BC in young symptomatic
2. Atypical patients
- Fast-growing cancers arising during MMG interval
Presentation/
6 - Under-weighing complaints of patients with
Cognitive psychiatric diagnoses
Challenges - Prioritizing chronic medical or social issues over
screenings in complex patients
- Lump felt to be benign on physical exam
3. False Negative
2 - Bias in wanting to reassure patient, due to low
Physical Exam likelihood of BC
- Fibrocystic breast tissue can obscure underlying BC
in MMG
4. Fibrocystic/Dense - Not recognizing changes in breast density over time
9
Breast Dilemmas - Failure to investigate unilateral fibrocystic changes
- Failure to investigate breast lump with FNA in
patient with dense breasts and negative U/S
3728
Pitfall N Example
5. Screening vs.
- Ordering/performing a screening MMG, rather than
Diagnostic 2
a diagnostic MMG
Mammogram Order
- False negative MMG in pt with fibrocystic breasts
- Failure to reevaluate breast complaints in light of
previously negative MMG
6. False Negative
9 - Misreading of MMG by radiologists
Mammogram - Failure to follow-up on nipple retraction observed
on MMG, attributing it to imaging technique
- Falsely reassuring negative “additional views”
7. False Negative - Falsely reassuring negative U/S in pts with breast
2
Ultrasound lump
- Failure to refer to breast surgeon
8. Surgical Referral 4 - Breast lump appearing benign to surgeon palpation
- Patient failure to follow-up on referral
Schiff et al. Unpublished data Coverys/CRICO Closed Claims review 2016
Pitfall N Example
9. Biopsy Performance/ - Inability to recognize missed sampling due to
1
Interpretation bleeding/complications and failure to repeat biopsy
- Failure to order diagnostic imaging studies (MMG
10. Failure to Order
2 and U/S)
Further Studies - Failure to recommend excisional biopsy
11. Diffusion of - Failure to document/ensure pt was receiving
screening MMGS and breast exams
Responsibility/ 4
- Failed coordination/communication between PCP
Coordination Issues and GYN
- Failure to follow-up on resolution of mastitis
- Failure to pursue etiology of persistent galactorrhea
- Pursuing lymphoma as cause of lymphadenopathy
12. Other Symptoms 8
- Axillar lymphadenopathy lost due to fact that not
incorporated into BIRADS coding (revised now)
- Failure to work up persistent painful cyst
Schiff et al. Unpublished data Coverys/CRICO Closed Claims review 2016
3729
Diagnostic Situational Awareness Model
Diagnostic Risk
Safety Nets
• Recognizing inherent uncertainties/risks, build
in mitigation, protections, recovery structures
and processes
• Proactive, systematic follow-up, feedback via
closed loop systems
• Major role for HIT to hard-wire
– To automate, ensure reliability, ease burden on
staff/memory, ensure loops closed and outliers
visible
40
3730
41
El-Kareh
Schiff
BMJ QS 2013
42
3731
43
Clinical Documentation
CYA
3732
Canvass for
Your
Assessment
-Differential Diagnosis
-Weighing Likelihoods
-Etiology Canvass for
-Urgency
-Degree of Your
certainty
Assessment
3733
Open Loop System
Water goes on the

same time each day,
regardless of whether
it is raining or lawn is
flooded
Schiff A J Med 2008

47
48
3734
49
55/338 (16%) not improved

of whom only 21 (38%)
had contacted any clinician
50
3735
Feedback –Key Role in Safety

• Structural commitment patient role to play
• Embodies/conveys message: uncertainty, caring,
reassurance, access if needed
• Allows deployment of test of time, more conservative
diagnosis
• Enables differential diagnosis
• Emphasizes that disease is dynamic
• Reinforces culture of learning & improvement
• Illustrates how much disease is self limited
• Makes invisible missed diagnoses visible
51
Examples of Feedback Learning

Feeding back to upstream hospital Tracking persistent mysteries
- spinal epidural abscess
Chart correction by patients
IVR follow-up post urgent care visit
Radiology/pathology
- UAB Berner project
- systematic second reviews
Dedicated Dx Error M&M
2nd opinion cases
- Best Doctors dx changed
Autopsy Feedback
- 7/32 MDs aware disseminated CMV Linking lab and pharmacy data
- to find signal of errors (missed ↑ TSH)
ED residents post admission tracking
Urgent care
Feedback to previous service - call back f/up systems
Malpractice
52
- knock on the door
3736
Feedback- Challenges
• Effort, time, support required
• Discontinuities
• Can convey non-reassuring message
• Feedback fatigue
• Non-response not always good predictor of
misdiagnosis as multiple confounders
• Tampering – form of availability bias
53
Role for Patient

In Minimizing and Preventing Diagnosis Error and Delay
• Push for timely access • Being patient: time & tests
• Reliable follow-up, continuity • Recruiting family for support
• Keen observer, reporter sx • Respecting limits on staff time,
• Proactive on test results society resources
• Sharing hunches • Agreeing to disagree
• Curiously reading on own • Help in building, maintaining
• Meticulously adhering w/ trust and communication
empiric trial regimens • Getting involved with patient
• Active as co-investigator organizations
54
3737
Role for Patient

In Minimizing and Preventing Diagnosis Error and Delay
• Push for timely access • Being patient: time & tests
• Reliable follow-up, continuity • Recruiting family for support
• Keen observer, reporter sx • Respecting limits on staff time,
• Proactive on test results society resources
• Sharing hunches • Agreeing to disagree
• Curiously reading on own • Help in building, maintaining
• Meticulously adhering w/ trust and communication
empiric trial regimens • Getting involved with patient
• Active as co-investigator organizations
Key question is:

What will it take at the provider and institutional end
to support these roles and help them flourish? 55
Ricardo Levins Morales Art Studio
56
3738
Summary Question #1
• Which of the following are examples of
“Situational Awareness” constructs that hold
potential for helping clinicians and patients
anticipate, recognize, and/or prevent diagnostic
errors
A. Red flag symptoms
B. Context-relevant lists of Don’t Miss diagnoses
C. Just-in-time reminders about potential pitfalls
D. All of the above
Question #1 Answer Slide

• Answer is D- All of the above
• Red flag symptoms, context-relevant lists of
don’t miss diagnoses, and reminders about
potential pitfalls can help the clinician in real
time with being more aware of critical factors
to consider or mistakes to try to avoid
3739
Summary Question #2
Which of the following statements regarding diagnostic
errors is not true:
A. Patient surveys reveal at least 1 in 5 have experienced a

medical error, the majority of which are diagnostic errors
B. The best way to decrease diagnostic errors is to order more
tests to screen for all possible diagnosis
C. Improving patient follow-up by phone to check how symptoms
are evolving is an example enhanced follow-up and feedback
D. Better clinical documentation goes beyond “CYA”, and
includes improving recording of differential diagnosis, degree of
certainty, follow-up contingencies
Question #2 Answer Slide

• Answer is B- Order lots of tests.
This is not a good idea owing to the fact that
unselected tests without proven screening value in
low probability situations/populations are highly
vulnerable to false positive errors.
It is much better to focus on the patient, their history
and more likely diagnoses. This more conservative
and appropriate approach also avoids overdiagnosis
errors and uncovering low risk incidental-omas.
• All the others choices are true.
3740
Further Reading/Resources
• National Academy of Medicine: Improving Diagnosis in
Health Care Report. Free online viewing. Especially
recommend Executive Summary pp. 1-18.
• AHRQ PSNet Website Topics Safety Target Diagnostic
Errors. Up-to-date collection of articles on Dx Error.
• Society for Improving Diagnosis in Medicine (SIDM)
Website, International Conferences, resources
• Schiff & Ruan. The Elusive and Illusive Quest for Diagnostic
Safety Metrics. Jl of Gen Internal Med 2018
• Schiff. Diagnostic Error: Time for a New Paradigm.
BMJ Quality and Safety 2013
DIAGNOSTIC ERROR IN MEDICINE 11TH

INTERNATIONAL CONFERENCE NEW ORLEANS
3741
Supplemental
Slides
JGIM 7/18
3742
Culture of Diagnostic Safety & Improvement
1. Driving out fear so no one afraid to ask questions,

question a diagnosis, share when things go wrong
– Dealing w/ adverse events replacing blame & fear, w/ learning & improvement
2. Organization-wide commitment to improving diagnosis,
learning from diagnosis delays, diagnostic process errors
– Leadership/organizational recognition that misdiagnosis is the
#1 top cause of patient-reported errors
– Aggressive reporting, appreciative investigation, of adverse events
– Relentless curiosity/worry/conferencing: what is wrong with patient; what
might be missing, what can go wrong in system?
– Obsession w/ details of dx process: what can go wrong, limitations of tests
Culture of Diagnostic Safety & Improvement

3. Recognition uncertainty inherent in diagnoses, tests, illness
presentation and evolution; anticipation of common pitfalls
– Situational awareness local, disease specific, literature reported
vulnerabilities/pitfalls.
– Reliable, proactive, follow-up safety nets & feedback systems to detect and protect
– Conservative approaches to testing, imaging
• Enabled by shared decision-making and reliable follow-up
4. Respect human limitations, need for cognitive, process support

– Decreased reliance on human memory, minimizing negative effects of stress,
fatigue, fear, recognizing limited ability to truly multitask.
– Redesign EMRs & communication systems to support cognition, collaborative
diagnosis, and follow-up
5. Enhanced role for patient in co-producing diagnosis
– Working collaboratively to formulate history, diagnosis, monitor course,
raise and research questions
3743
Evaluation of Cardiac and Pulmonary Risk in the Preop

Patient
Adam C. Schaffer, MD, MPH

Associate Physician, Hospital Medicine Unit, Brigham and
Women‘s Hospital
Conflicts of Interest
I have no conflicts of interest to declare
3744
Clinical Case
76-year-old male with severe COPD, on 3 liters of home
oxygen and chronic prednisone 7.5 mg daily, DMII on
metformin, dyspnea with minimal exertion.
He has no history of MI or CHF. His EKG is essentially
normal.
He has metastatic colon cancer, with a single metastasis
to the brain causing left arm weakness
You are seeing him on the office for a preop evaluation
prior to neurosurgery scheduled for the following week to
resect the metastasis causing the left arm weakness
He underwent successful resection of a colon mass
three years ago
Introduction
The role of the clinician performing preoperative
evaluations is not to provide medical “clearance”
prior to surgery
Instead, the clinician should:
– Provide an assessment of the patient’s cardiac and
other risks going into the procedure
– Decide whether additional preoperative testing, such
as a cardiac stress test, is needed
– When indicated, recommend measures to reduce the
perioperative risk, such as beta blockers and statins
– Assist the surgeon in deciding whether to go forward
with the procedure
3745
New Preop Guidelines were

Published in 2014
ACC/AHA 2007 Periop Guidelines
Source: Fleisher LA, et al. ACC/AHA 2007 guidelines…. Circulation. Oct 23 2007;116(17):e418-499.
3746
ACC/AHA 2014 Periop Guidelines
Fleisher LA, Fleischmann KE, Auerbach AD, et al. ACC/AHA Clinical Practice Guideline 2014 ACC/AHA ...Circulation. published
online before print August 1, 2014.
Comparison of the old and the

new guidelines
3747
Risk assessment in the

New Guidelines
For risk assessment, the new guidelines recommend
estimating the preoperative risk of a major adverse
cardiac event (MACE), which here are defined as death
or MI
The risk of MACE is a function of the both the risk
associated with the procedure and the risk associated
with the patient
If there is a low risk of MACE, which is defined as < 1%,
then one goes to surgery
Risk assessment in the

New Guidelines
The new guidelines suggest three way to
determine if the MACE is < 1% or not:
1. ACS NSQIP Surgical Risk Calculator
(http://www.riskcalculator.facs.org/)
2. Perioperative Cardiac Risk Calculator
(http://www.surgicalriskcalculator.com/miorcardi
acarrest)
3. RCRI score (though one of the two options
above is preferred because they outperform the
RCRI score)
3748
ACS NSQIP
Surgical Risk Calculator
Cohen ME, Ko CY, Bilimoria KY, et al. Optimizing ACS NSQIP modeling for evaluation of surgical quality and risk: .... Journal of the
American College of Surgeons. Aug 2013;217(2):336-346.e331.
ACS NSQIP
Surgical Risk Calculator
Cohen ME, Ko CY, Bilimoria KY, et al. Optimizing ACS NSQIP modeling for evaluation of surgical quality and risk: .... Journal of the
American College of Surgeons. Aug 2013;217(2):336-346.e331.
3749
Gupta Perioperative Cardiac

Risk Calculator
Gupta PK, Gupta H, Sundaram A, et al. Development and validation of a risk calculator for prediction of cardiac risk after surgery.
Circulation. Jul 26 2011;124(4):381-387.
Risk Assessment: RCRI

Risk Factor Definition
1. High-risk type of surgery Intraperitoneal, intrathoracic, or suprainguinal

vascular procedures
2. Ischemic heart disease History of MI, positive stress test, current
cardiac CP, nitrate usage, ECG with pathologic
Q waves
3. History of congestive heart failure History of CHF, pulmonary edema, or PND;
rales or S3 on exam; chest x-ray with
pulmonary edema
4. History of cerebrovascular disease History of transient ischemic attack or stroke
5. Insulin therapy for diabetes
6. Preoperative serum creatinine > 2.0

mg/dL
“A patient with 0 or 1 [RCRI] predictor(s) of risk would have a low

risk of MACE. Patients with ≥ 2 predictors of risk would have
elevated risk.”
Source: Lee TH, Marcantonio ER, Mangione CM, et al. Derivation and prospective validation of a simple index for prediction of
cardiac risk of major noncardiac surgery. Circulation. Sep 7 1999;100(10):1043-1049.
3750
The new preop evaluation guidelines

Under the new
guidelines, if your risk
of MACE is low
(< 1%), then you go
to surgery
If you risk is elevated
(≥ 1%), then you
consider the patient’s
functional capacity

Under the new
guidelines, if your
functional
capacity is ≥ 4
METs, then you
proceed to
surgery
This is similar to
the old guidelines
3751

In a patient whose
MACE risk is ≥ 1%
and whose functional
capacity is < 4 METs,
under the new
guidelines, you would
consider a stress test
if it would alter
decision making

Consider the following patient: a 78 y.o. M with a
hx of ESRD on HD, MI, HTN, current smoker
with COPD, who is largely wheelchair bound due
to severe OA, is scheduled for a knee
replacement
Under the 2007 guidelines, this patient has an
RCRI score of 2, and is undergoing intermediate
risk surgery, and so no stress test is
recommended
3752

Consider the following patient: a 78 y.o. M with a
hx of ESRD on HD, MI, HTN, current smoker
with COPD, who is largely wheelchair bound due
to severe OA, is scheduled for a knee
replacement
Under the 2014 guidelines, this patient has a
MACE risk of ≥ 1% (using his RCRI ≥ 2 or the
risk calculator) and he does not make 4 METs,
thus the guidelines suggest considering a stress
test if it will alter management
Why are we now considering stress tests

in more patients under the new guidelines?
The DECREASE-II Trial (2006) by Poldermans
et al found no benefit to preop stress testing,
with revascularization if positive, in intermediate
risk patients undergoing vascular surgery
The DECREASE-V Pilot Study (2007) by
Poldermans et al found no benefit to preop
revascularization in high-risk patients (with
positive stress tests) undergoing vascular
surgery
3753
Why are we now considering stress

tests in more patients under the new
guidelines?
Concerns have been raised about the scientific integrity

of the studies published by Poldermans group
The authors of the 2014 Guidelines said evidence from
the DECREASE trials, conducted by Poldermans’s
group, would not form the basis of any recommendations
Preoperative ECGs in the

New 2014 ACC/AHA Guidelines
Class IIa: Preoperative resting 12-lead ECG is
reasonable for patients with known coronary heart
disease, significant arrhythmia, peripheral arterial
disease, cerebrovascular disease, or other significant
structural heart disease, except for those undergoing
low-risk surgery
Class IIb: Preoperative resting 12-lead ECG may be
considered for asymptomatic patients without known
coronary heart disease, except for those undergoing low-
risk surgery
Class III: Routine preoperative resting 12-lead ECG is
not useful for asymptomatic patients undergoing low-risk
surgical procedures
3754
Perioperative Beta Blockers:

2014 Recommendations
Perioperative beta blockade appears to be of
benefit in selected patients who are at elevated
risk of perioperative cardiac events
Per the ACC/AHA 2014 Periop Guidelines,
there is one class I indication for perioperative
beta-blocker use:
– “Beta blockers should be continued in
patients undergoing surgery who have been
on beta blockers chronically”
What to do in patients who are not
already on beta blockers in controversial

The POISE Trial
The PeriOperative ISchemic Evaluation (POISE) Trial enrolled 8351
patients undergoing noncardiac surgery with at least one cardiac
risk factor
Patients were randomized to either placebo or controlled-release
metoprolol (CR metoprolol) 100 mg orally 2 – 4 hours prior to
surgery, a postoperative dose of CR metoprolol based on heart rate
and blood pressure, and then 200 mg of CR metoprolol orally daily
for the next 30 days
The beta blocker arm had a lower rate of the primary outcome (30-
day cardiac events): 5.8% in the beta blocker arm versus 6.9% in
the placebo arm (P=0.04)
However, the total mortality was higher in the CR metoprolol group
(3.1%) than in the placebo group (2.3%) (P=0.03)
The higher mortality in the beta blocker arm was driven by an
increase in the stroke rate in this group
The general view of this trial is that the dose of periop beta blockers
given was too large, and so led to the increased stroke rate
Source: Poise Study Group. Effects of extended-release metoprolol succinate in patients undergoing non-cardiac surgery (POISE
trial)…. Lancet. May 31 2008;371(9627):1839-1847.
3755

How (not) to Use them
“Routine administration of high-dose beta

blockers in the absence of dose titration is not
useful and may be harmful to patients not
currently taking beta blockers who are
undergoing noncardiac surgery”
Source: Fleisher LA, et al. 2009 ACCF/AHA focused update on perioperative beta blockade incorporated into the ACC/AHA 2007
guidelines on perioperative cardiovascular… . Circulation. Nov 24 2009;120(21):e169-276.

Retrospective Data
Lindenauer et al. performed a large retrospective
cohort study examining the benefits of periop beta
blockers based on the cardiac risk of the patient
Patients undergoing noncardiac surgery (mainly
orthopedic and abdominal procedures), both routine
and emergent, were included
Patients receiving prophylactic periop beta blockers
were compared with patients not receiving beta
blockers
This study is debated:
– On the one hand, it was quite large (n=663,635)
– On the other hand, it was retrospective, and based on the use
of an administrative database. No charts were reviewed. Beta
blockers started on hospital day 1 or 2 were considered
prophylactic.
Source: Lindenauer PK, et al. Perioperative beta-blocker therapy …. New England Journal of Medicine. Jul 28 2005;353(4):349-361.
3756

Retrospective Data
Patients without cardiac risk factors who got
periop beta blockers seemed to be harmed by
them
Patients with an RCRI of at least 2, and
certainly with an RCRI of 3, appeared to
benefit from beta blockers
Source: Lindenauer PK, et al. Perioperative beta-blocker therapy …. New England Journal of Medicine. Jul 28 2005;353(4):349-361.

The 2014 AHA guidelines are offer mainly IIb
recommendations about when to start periop beta
blockers in those who are not on them
In patients with an RCRI score of 3 or more, it may be
reasonable to begin beta blockers prior to surgery
(class IIb recommendation)
“In patients with a compelling long-term indication for
beta-blocker therapy but no other RCRI risk factors,
initiating beta blockers in the perioperative setting as
an approach to reduce perioperative risk is of
uncertain benefit”
Beta-blocker therapy should not be started on the day
of surgery (class III recommendation)
3757

Which One to Use
One retrospective study from April 2011 examined
perioperative atenolol versus metoprolol
3787 high-risk patients undergoing inpatient surgery at
the San Francisco VAMC were included
1011 patients received atenolol and 2776 patients
received metoprolol
Patients who received atenolol, versus metoprolol, had
lower 30-day mortality (1% versus 3%, P < 0.0008) and
lower 1-year mortality (7% versus 13%, P < 0.0001)
This was thought to be due to the risk of missing doses
of the shorter-acting metoprolol, with resultant
beta-blocker withdrawal effect
Wallace AW, Au S, Cason BA. Perioperative β-blockade: atenolol is associated with reduced mortality when compared to metoprolol.
Anesthesiology. Apr 2011;114(4):824-836.
Periop Beta Blockers

Take Home Points
In patients who are already on beta blockers,
continue them on beta blockers perioperatively
You want to avoid beta blocker withdrawal
In patients not already on beta blockers with an
RCRI score of ≥ 3 “it may be reasonable to
begin beta blockers before surgery”
If beta blocker are being started in preparation
for surgery, you want to start them well ahead of
surgery and not on the day of surgery
3758
Perioperative Statins
The DECREASE-III trial enrolled 497 patients, age > 40,
at elevated cardiac risk, scheduled to undergo
noncardiac vascular surgery
All patients had to be statin naïve
All patients were on beta blockers
– Patients who were already taking a beta blocker were continued
on this beta blocker
– Patients who were not on a beta blocker were started on one,
and their dose was titrated based on their HR
Patients were randomized to fluvastatin 80 mg daily or a
placebo. This statin was started on average 37 days
prior to surgery and continued for at least 30 days after
surgery
Source: Schouten O, Boersma E, Hoeks SE, et al. Fluvastatin and perioperative events in patients undergoing vascular surgery. New
England Journal of Medicine. Sep 3 2009;361(10):980-989.
DECREASE III Trial
Perioperative Myocardial Ischemia: Perioperative death from CV cause or MI:

10.8% in the statin arm vs. 19.0% in the 4.8% in the statin arm vs. 10.1% in the
placebo arm (P = 0.01) placebo arm (P = 0.03)
Placebo
Placebo
Fluvastatin
Fluvastatin
Source: Schouten O, Boersma E, Hoeks SE, et al. Fluvastatin and perioperative events in patients undergoing vascular surgery. New
England Journal of Medicine. Sep 3 2009;361(10):980-989.
3759
Perioperative Statins:
Statins should be continued in patients currently
taking statins and scheduled for noncardiac
surgery (class I)
Perioperative initiation of statin use is
reasonable in patients undergoing vascular
surgery (class IIa)
Perioperative initiation of statins may be
considered in patients with clinical indications
according to GDMT who are undergoing
elevated-risk procedures (class IIb)
Perioperative Aspirin
The POISE 2 Trial, an RCT published in the
NEJM in April 2014, looked at the effect of
perioperative ASA
The trial enrolled 10,010 patients undergoing
noncardiac surgery who were at risk for vascular
complications
Patient within the coronary stent critical periods
were excluded
The primary endpoint was death or nonfatal MI
at 30 days
Devereaux PJ, Mrkobrada M, Sessler DI, et al. Aspirin in patients undergoing noncardiac surgery. New England Journal of
Medicine. Apr 17 2014;370(16):1494-1503.
3760
The patients were stratified by whether they were
already taking ASA (continuation group) or not (initiation
group)
There was no benefit to ASA in the primary outcome or
any of the secondary outcomes
The negative results were the same for the continuation
group and the initiation group
Taking ASA was associated with an increased risk of
major bleeding
Starting at POD#8, there was no significant difference in
the bleeding risk between and ASA and placebo groups
Medicine. Apr 17 2014;370(16):1494-1503.
Medicine. Apr 17 2014;370(16):1494-1503.
3761
Perioperative Clonidine
As a companion to the periop ASA trial, there was a
parallel periop clonidine trial
The trial, as RCT, enrolled 10,010 patients undergoing
noncardiac surgery who were at risk for vascular
complications
The primary endpoint was death or nonfatal MI at 30
days
There was no benefit to periop clonidine in reducing the
primary endpoint
Patients in the clonidine arm had an increase the risk of
clinically important hypotension and nonfatal cardiac
arrest.
Devereaux PJ, Sessler DI, Leslie K, et al. Clonidine in patients undergoing noncardiac surgery. New England Journal of Medicine.
Apr 17 2014;370(16):1504-1513.
Bridging Anticoagulation
The BRIDGE trial randomized 1884
patients with Afib on coumadin who were
scheduled for an elective procedure to
either bridging with LMWH (dalteparin) or
placebo.
Patients had to have at least 1 of the
CHADS2 risk factors.
The mean CHADS2 score was 2.3
Source: Douketis JD, Spyropoulos AC, Kaatz S, et al. Perioperative Bridging Anticoagulation in Patients with Atrial
Fibrillation. New England Journal of Medicine. June 22, 2015 (published on-line ahead of print).
3762
3763
Perioperative Pulmonary Complications

Tested on 5,859 patients
in 63 centers
Respiratory complications
were defined as:
– Respiratory infection or
failure
– Bronchospasm
– Atelectasis
– Pleural effusion
– Pneumothorax
– Aspiration pneumonitis
Score:
– < 26 denotes a 3.4% risk
– 26-45 denotes a 13.0% risk
– >45 denotes a 38.0% risk
Mazo V, Sabate S, Canet J, et al. Prospective external validation of a predictive score for postoperative pulmonary complications.
Anesthesiology. 2014;121(2):219-231.
3764
Perioperative Pulmonary Risk

Reduction Strategies: Lung Expansion
In patients at elevated risk, such as those undergoing
abdominal surgery, a lung expansion maneuver is
appropriate, and is more effective than no intervention
Options include incentive spirometry, lung expansion
exercises, and continuous positive airway pressure
There is no compelling evidence favoring one lung
expansion intervention over another
Continuous positive airway pressure may be appropriate
in patients who are unable to undergo either incentive
spirometry or lung expansion exercises. CPAP is
advisable in OSA patients.
Source: Lawrence VA, et al. Strategies to reduce postoperative pulmonary complications after noncardiothoracic surgery: systematic
review for the American College of Physicians. Annals of Internal Medicine. Apr 18 2006;144(8):596-608.
Perioperative Pulmonary Risk

Reduction Strategies
Smoking cessation
– May help reduce the incidence of postop pulmonary
complications
– However, smoking cessation immediately (< 8 weeks) prior to
surgery may increase the risk of postop pulmonary complications
Anesthesia techniques need to be considered
– Patients who had residual muscle blockade after receiving the
long-acting neuromuscular-blocking agent pancuronium had an
increased rate of postop pulmonary complications compared to
patients without residual muscle blockade
– Use of either spinal or epidural anesthesia, as compared to
general anesthesia, may also reduce the incidence of postop
pulmonary complications
Source: Lawrence VA, et al. Strategies to reduce postoperative pulmonary complications after noncardiothoracic surgery: systematic
review for the American College of Physicians. Annals of Internal Medicine. Apr 18 2006;144(8):596-608.
3765
The Timing of Surgery for Hip

Fracture Patients
Retrospective cohort analysis of 42,230 hip fracture
patients in Ontario
Mean age around 80, around 70% female
Primary outcome was 30-d mortality
Source: Pincus D, Ravi B, Wasserstein D, et al. Association Between Wait Time and 30-Day Mortality in Adults Undergoing Hip
Fracture Surgery. JAMA. Nov 28 2017;318(20):1994-2003..
Periop Issues for OSA Patients

Both respiratory and cardiovascular periop
complications are more common in
patients with untreated OSA than
comparable patients without OSA
Prescribing CPAP for patients with OSA
perioperatively reduced the risk of
cardiovascular but not pulmonary
complications
Mutter TC, Chateau D, Moffatt M, Ramsey C, Roos LL, Kryger M. A matched cohort study of postoperative outcomes in
obstructive sleep apnea: could preoperative diagnosis and treatment prevent complications? Anesthesiology. Oct
2014;121(4):707-718.
3766
Periop Issues for Obese Patients

There are an increasing number of case reports
of obese patients having postop rhabdomyolysis
after surgery
It is likely that the immobilization and weight on
the gluteal muscle results in necrosis
If an obese patient has postop AKI, consider
rhabdomyolysis and check a CK
Obese patients has restrictive lung physiology,
and so consider CPAP in hypoxic obese patients
postop
The Value of
Medical Consultation Itself
A retrospective cohort study, using an
administrative database, included almost
270,000 patients undergoing elective
intermediate- or high-risk noncardiac surgery
38.8% of these patients underwent medical
consultation
Propensity scores were used to produce a
matched-pairs cohort that reduced differences
between patients who did and did not undergo
preoperative consultation
Source: Wijeysundera et al. Outcomes and processes of care related to preoperative medical consultation. Archives of Internal
Medicine. Aug 9 2010;170(15):1365-1374.
3767
The Value of
Undergoing medical consultation was
associated with:
– Increased new beta-blocker usage (95% CI:
2.36-2.65)
– Increased new statin usage (95% CI: 1.34-
1.54)
– Increased preop cardiac stress testing (95%
CI: 2.33-2.47)
– Increased 30-day mortality (95% CI: 1.07-1.25)
– Increased 1-year mortality (95% CI: 1.04-1.12)
Medicine. Aug 9 2010;170(15):1365-1374.
The Value of
Possible conclusions to draw from this study:
– Using propensity scores does not always give you
matched cohorts
– We do not do a good job selecting which patients
should undergo medical consultation
– We do not do a good job with medical consultation
itself
Medicine. Aug 9 2010;170(15):1365-1374.
3768
Clinical Case
76-year-old male with severe COPD, on 3 liters of home
oxygen and chronic prednisone 7.5 mg daily, DMII on
metformin, dyspnea with minimal exertion.
He has no history of MI or CHF. His EKG is essentially
normal.
He has metastatic colon cancer, with a single metastasis
to the brain causing left arm weakness
You are seeing him on the office for a preop evaluation
prior to neurosurgery scheduled for the following week to
resect the metastasis causing the left arm weakness
He underwent successful resection of a colon mass
three years ago
Clinical Case
1.8%
3769
Clinical Case
What actually happened:
– The neurosurgeon cancelled the case
– The patient was scheduled for brain XRT
instead
– Surgery remains on the table as an option
If the patent undergoes surgery, consider cort
stim versus stress dose steroids
Multiple Choice Question 1

A 71-year old male with a history of
hypertension, diabetes mellitus, and atrial
fibrillation on warfarin is scheduled for a
left knee arthroplasty.
3770

Which one of the following is the preferred
recommendation for handling his anticoagulation
perioperatively?
A. He should receive bridging anticoagulation with low
molecular weight heparin
B. He should receive bridging anticoagulation with
unfractionated heparin
C. He should receive bridging anticoagulation with
fondaparinux
D. His warfarin should be continued
E. No bridging anticoagulation is indicated

The correct answer is (E), no bridging
anticoagulation is indicated. The BRIDGE trial
showed no benefit (and increased bleeding) with
bridging anticoagulation with low molecular
weight heparin in patients with a CHADS2 score
of 2.3, which is similar to this patient (who has a
CHADs 2 score of 2). Bridging with other agents
would be expected to have a similarly
unfavorable risk-benefit profile.
3771

You are performing a pre-operative
evaluation on a 77-year-old male with a
history of diabetes mellitus on insulin,
ESRD, and hypertension for which the
patient takes metoprolol. He is scheduled
for partial colon resection for recurrent
diverticulitis. His MACE risk is 2.1%. He
can walk up two flights of stairs briskly
without difficulty.

Which one of the following is the most
appropriate preoperative recommendation in this
patient?
A. His metoprolol should be changed to clonidine
B. No preoperative stress test is indicated
C. He should undergo a resting cardiac echo
D. He should undergo a exercise nuclear stress
test
E. He should undergo a pharmacologic nuclear
stress test
3772

The correct answer is (B), no preoperative stress test is
indicated.
The patient has a MACE risk ≥ 1%, but his functional
capacity is > 4 METs, and so no preop stress test is
indicated. Thus answers (D) and (E) are incorrect. The
patient has no symptoms of valvular or other heart
disease that would support a cardiac echo, making
answer (C) incorrect. Clonidine is not effective in preop
cardiac risk reduction, and so answer (A) is incorrect.
Key References
1. Fleisher LA, Fleischmann KE, Auerbach AD, et al. 2014 ACC/AHA guideline on
perioperative cardiovascular evaluation and management of patients undergoing
noncardiac surgery: a report of the American College of Cardiology/American Heart
Association Task Force on Practice Guidelines. Circulation. Dec 9
2014;130(24):e278-333.
2. Cohen ME, Ko CY, Bilimoria KY, et al. Optimizing ACS NSQIP modeling for
evaluation of surgical quality and risk: patient risk adjustment, procedure mix
adjustment, shrinkage adjustment, and surgical focus. Journal of the American
College of Surgeons. Aug 2013;217(2):336-346.e331.
3. POISE Study Group, Devereaux PJ, Yang H, et al. Effects of extended-release
metoprolol succinate in patients undergoing non-cardiac surgery (POISE trial): a
randomised controlled trial. Lancet. May 31 2008;371(9627):1839-1847.
4. Devereaux PJ, Mrkobrada M, Sessler DI, et al. Aspirin in patients undergoing
noncardiac surgery. New England Journal of Medicine. Apr 17 2014;370(16):1494-
1503.
5. Douketis JD, Spyropoulos AC, Kaatz S, et al. Perioperative Bridging
Anticoagulation in Patients with Atrial Fibrillation. New England Journal of Medicine.
August 27 2015;373(9):823-833.
3773

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• Incidence, mortality, costs of AKI

• Approach to the patient with AKI

• Specific clinical scenarios

Acute Kidney Injury

> 0.3 mg/dL increase

25% increase to at least 2.0 mg/dL within 48h

“Sudden” rise of > 2.0 mg/dL

New consensus definition

Chertow, G. M. et al. J Am Soc Nephrol 2005;16:3365-3370

AKI is increasingly common

50% of ICU pts

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.DUL3%UDDWHQ0'03+ Ellen W. Seely, M.D

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