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Sickle Cell Disease/Acute Chest Syndrome

Chairmans Rounds August 13, 2010


David H. Rubin, MD Department of Pediatrics, St. Barnabas Hospital Professor of Clinical Pediatrics, Albert Einstein College of Medicine

OBJECTIVES
Case presentation History of sickle cell disease Pathophysiology Complications Treatment Competency Based Summary

CASE PRESENTATION
12 month old SC patient with fever for 2 days; tmax 103F + rhinorrhea, no cough Reduced oral intake and activity PE: T105.2F, P198, R62, O2sat:97%

Chest reduced breath sounds R base

Chest xray: R base infiltrate

HISTORY OF SICKLE CELL DISEASE

1910 First description (in western literature) of sickle cell disease by Chicago physician James B. Herrick Patient from West Indies with anemia characterized by unusual red cells: sickle shaped 1927 Hahn and Gillespie showed sickling of red cells was related to low oxygen

HISTORY OF SICKLE CELL DISEASE

1948
Janet Watson (pediatric hematologist in New York) noted newborn fetal hemoglobin lacked abnormal sickle hemoglobin seen in adults Linus Pauling and Harvey Itano showed that hemoglobin from patients with sickle cell disease is different from normals First disorder in which abnormality in protein known to be at fault

HISTORY OF SICKLE CELL DISEASE

1984
Bone marrow transplantation in a child with sickle cell disease produced the first reported cure Transplantation was performed to treat acute leukemia-child's sickle cell disease was cured as a side-event

1995
Hydroxyurea became the first (and only) drug proven to prevent complications of sickle cell disease in the Multicenter Study of Hydroxyurea in

Sickle Cell Anemia

HEMOGLOBIN MOLECULE

Hemoglobin - two pairs of nonidentical globin and polypeptide chains; each chain associated with one heme group Four polypeptide chains (alpha, beta, gamma and delta) in the globin portion HbA - 2 alpha and 2 beta chains HbF - 2 alpha and 2 gamma chains HbA2 - 2 alpha and 2 delta chains Heme group - iron containing pigment responsible for oxygen transport

Hemoglobin A

SICKLE CELL DISEASE


The chain of colored boxes represent the first eight amino acids in the beta chain of hemoglobin. The sixth position in the normal beta chain has glutamic acid, while sickle beta chain has valine. This is the sole difference between the two.

SICKLE CELL DISEASE


1/400 African American infants 8% of African Americans are heterozygous carriers of the gene they have trait Also found in: African, Mediterranean, Middle Eastern, Indian, or Caribbean ancestry Pathology directly related to polymerization

of deoxygenated sickle hemoglobin


Distortion of erythrocyte morphology Reduced RBC life span Increased viscosity Episodes of vasoocculsion

SICKLE CELL DISEASE


Antenatal diagnosis by amniocentesis or chorionic villus DNA Hb S identified by electrophoresis and solubility testing
Affected newborns express small quantities of Hb S even with

predominance of Hb F

SICKLE CELL DISEASE

Clinical course:

ischemic changes intermittent crises

Anemia, increased reticulocyte count Splenomegaly in early childhood High risk of bacterial sepsis

PATHOPHYSIOLOGY

OXYGEN SATURATION CURVES in (a) 41 normals and (b) 53

subjects with sickle cell anemia. For any given pO2, the saturation for Hb SS cells is less than that for normal erythrocytes. (Johnson CS,

Verdegem TV. Pulmonary complications of sickle cell disease. Semin Resp Med 1988;9:291)

LABORATORY FINDINGS

Hemoglobin: 5-9 g/dl Target cells, poikilocytes, sickled cells Reticulocyte count 515% WBC count: 1215,000/mm3 Platelet count increased Increased LFTs, bilirubin

DIFFERENTIAL DIAGNOSIS
Surgical

abdomen Rheumatic fever Rheumatoid arthritis Osteomyelitis Leukemia

COMPLICATIONS I
Priapism - GU tract infarction Retinopathy sequestration of blood in conjunctival vessels; retinal hemorrhage Cholelithiasis - chronic hemolysis Osteonecrosis of femoral head

COMPLICATIONS II
Hematuria, hyposthenuria, renal failure - papillary necrosis Jaundice - hepatic infarct Stroke, seizures, weakness, sensory hearing loss - CNS ischemia Respiratory distress pulmonary infarction

ROUTINE TREATMENT
Maintain full immunization status Administer polyvalent pneumococcal vaccine (may be

poorly immunogenic in children with Hb SS and < 5 yrs of age) Administer H. influenzae vaccine

Folic acid daily

ROUTINE TREATMENT
Prophylactic penicillin 4 mo- 5 yrs (<5y: 125mg/12h; >5y: 250mg/12h) Aggressive ED approach to temperature >38.5C:

laboratory studies (CBC, culture, UA and culture, chest x-ray) admission antibiotics

SPECIFIC PROBLEMS IN SICKLE CELL PATIENTS

Bacterial sepsis
Other infections

Acute chest syndrome Vasoocclusion crises Splenic sequestration crises Aplastic crises Hemolytic crises Treatment

BACTERIAL SEPSIS
Impaired immunologic function, functional asplenia Increased risk from: streptococcus

pneumoniae, H. influenzae, n. meningitidis, salmonella, E. coli, mycoplasma pneumoniae, staphylococcus aureus

Greatest risk 6 months - 3 years of age

BACTERIAL SEPSIS

Impaired immunologic function


Loss of splenic activity Fulminant nature of illness Most dangerous period: 6m-3y (protective antibodies limited with diminished splenic function)

Risk of sepsis = 100X normal population Streptococcus pneumoniae, h. influenza most common in young children E. coli and salmonella most common in older children

BACTERIAL SEPSIS

Differentiating the patient with viral illness vs serious bacterial illness (SBI) difficult ONLY a blood culture can identify difference MUST obtain rapidly and administer antibiotics Clinical deterioration is VERY rapid Treat for septic shock EARLY

BACTERIAL SEPSIS

Emergence of penicillin resistant

streptococcus pneumoniae

Rapid blood work and IV ceftriaxone or cefotaxime and vancomycin (if area of high resistance) If not acutely ill on physical exam (no pallor, rales, increased spleen, rales) with guaranteed follow-up within 24H, may treat with ceftriaxone 50 mg/kg, otherwise admit

BACTERIAL SEPSIS

Short stay outpatient unit also appropriate If low risk for SBI, may give PO or IV antibiotics and discharge.BUT MUST SEE WITHIN 24 HRS for FOLLOWUP Older child with any fevermay not have high WBC and may not have high fever.BEWARE admit for antibiotics and close observation

BACTERIAL BLOOD CULTURES IN CHILDREN WITH SCD


(Rogovik 2009)

Retrospective chart review of 692 pediatric SCD patients with or without fever from 2005-2007 in Toronto Sick Childrens Hospital (inclusion in study limited to 530 with blood cultures) 77% of febrile children admitted; 7 positive cultures; 3 in febrile children No s.pneumoniae species all identified microorganisms part of normal skin or oral flora and could be contaminants
Thought to be due to 7-valent pneumococcal vaccine

SEPTIC ARTHRITIS/OSTEOMYELITIS
VERY difficult to diagnose clinically; similar to bone infarction Diagnostic tests prior to antibiotics: Gram stain and culture

bone aspiration (osteomyelitis) joint aspiration (septic arthritis)

Antibiotics

INFLUENZA A (H1N1) AND SICKLE CELL DISEASE


(Inusa 2010)

Review of cases of H1N1 disease in patients with SS disease in children in London: April August 2009 21 positive cases among 2200 patients with SCD; 19 were admitted; 11 needed blood transfusions due to falling Hg and ACS (10 patients had acute chest syndrome) All successfully treated with oseltamivir

ACUTE CHEST SYNDROME


(Vichinsky 2000)

Defined as a new infiltrate on a chest radiograph associated with one or more symptoms such as
Fever Cough Sputum production Tachypnea Dyspnea New onset hypoxia

ACUTE CHEST SYNDROME


(Vichinsky 2000)

Clinical and radiological similarity to bacterial pneumonia


Fever, leukocytosis Pleuritic chest pain Pleural effusion Cough with purulent sputum

Clinical course is unique

Multiple lobe involvement possible Duration of clinical illness and of radiologic clearing of infiltrates prolonged (10-12 days)

ACUTE CHEST SYNDROME/Pathophysiology

Process may be initiated by


Microbial infection In situ vaso-occlusion Fat embolism from ischemic/necrosis bone marrow Thomboembolism

?Activation of endothelium by oxygen radicals of erythrocytes or infection process that induces secretion of inflammatory cytokines

ACUTE CHEST SYNDROME


Most cases are infectious origin Difficult to identify organism although more common organisms are Mycoplasma pneumoniae S pneumoniae Chlamydia trachomatis

ACUTE CHEST SYNDROME Clinical Presentation


(Johnson 2005)

Fever > 38.5C and cough most common especially in children compared with adolescents Tachypnea and bronchospasm more common in children However 35% of patients had normal PE; additional data support unreliability of the physical examination in the detection of ACS

ACUTE CHEST SYNDROME

Symptoms: tachypnea, rales, ronchi, ?lobar consolidation Workup: oxygen saturation, CBC, blood culture, chest x-ray (may be negative in 50% of cases) Treatment:

Start antibiotics early Initiate IV ampicillin or ceftriaxone (plus erythromycin in young child); consider streptococcus pneumoniae or Mycoplasma RBC transfusion or exchange transfusion for severe anemia (Hg < 5), hypoxia, radiographic evidence of rapidly progressive disease Therapy with steroids may prevent clinical deterioration in ACS

STEROIDS AND ACS


(Strouse 2008)

Retrospective cohort study to examine risk factors for readmission and prolonged hospitalization at Johns Hopkins in patients < 22 yrs of age 1998-2004 Identified 65 patients with 129 episodes of ACS (mean age 12.5 yrs) Readmission strongly associated with use of corticosteroid (OR 20, p<.005) Suggest limited use of steroids

STEROIDS AND ACS


(Kumar 2010)

Retrospective study of 63 patients with 78 episodes of ACS from 2005-2007 at SUNY Downstate Asthma Regimen of prednisone used (2mg/kg/d max 80 mg in 2 divided doses for 5 days 15% of 53 children receiving steroids and 8% of the 25 children who did not receive steroids were readmitted (NS) No significant readmission rate from steroids

STEROIDS AND ACS


(Sieff 2010)

Therapy

with steroids not usually needed unless patient has a history of asthma and signs of asthma exacerbation.

ACUTE CHEST SYNDROME


(Kikiska 2004)

Increased incidence following abdominal surgery (15-20%) ACS was associated with Age (young vs old) Weight (lighter over heavier) Operative blood loss (more > less) Lower final temperature

CAUSES OF ACUTE CHEST SYNDROME


1. Hb SRelated *Direct consequences of Hb S
Pulmonary vaso-occlusion (16.1%) Fat embolism from bone marrow ischemia/infarction (8.8%) Hypoventilation secondary to rib/sternal bone infarction or to narcotic use Pulmonary edema induced by narcotics or fluid overload

*Indirect consequences of Hb S Infection Atypical bacterial

Chlamydia pneumoniae (7.2%) Mycoplasma pneumoniae (6.6%) Mycoplasma hominis (1.0%)

Bacterial Staphylococcus aureus, coagulase-positive (1.8%) Streptococcus pneumoniae (1.6%) Haemophilus influenzae (0.7%) Viral Respiratory syncytial virus (3.9%) Parvovirus B19 (1.5%) Rhinovirus (1.2%) 2. Unrelated to Hb S Fibrin thromboembolism Other common pulmonary diseases (eg, aspiration, trauma, asthma)

CAUSES OF ACUTE CHEST SYNDROME*

*Vichinsky et al., NEJM, 2000 and Johnson, Semin Resp Med, 1988

POOR PROGNOSIS/POTENTIAL INDICATIONS FOR EXCHANGE TRANSFUSION IN ACUTE CHEST SYNDROME


(Vichinsky 2000, Johnson 1988, Fine 1997)

Altered mental status and other acute neurologic findings Persistent tachycardia >125/min Persistent respiratory rate >30/min or increased work of breathing (nasal flaring, use of accessory muscles, sternal retractions) Temperature >40C Hypotension compared with baseline

POOR PROGNOSIS/POTENTIAL INDICATIONS FOR EXCHANGE TRANSFUSION IN ACUTE CHEST SYNDROME


(Vichinsky 2000, Johnson 1988, Fine 1997)

Arterial pH <7.35 Arterial oxygen saturation persistently <88%, despite aggressive ventilatory support Serial decline in pulse oximetry or increasing A-a gradient Hemoglobin concentration falling by 2 g/dL or more Platelet count <200,000/L Evidence for multiorgan failure Pleural effusion Progression to multilobe infiltrates

ASTHMA AND ACS


(Boyd 2004)

Does asthma increase the risk of ACS in children with sickle cell disease? Retrospective case control study (cases: ACS, controls: no ACS) Cases of physician diagnosed asthma 4 times (95% CI: 1.7, 9.5) more likely to develop ACS and longer hospitalization

ACS AND LUNG FUNCTION


(Sylvester 2006)

Hypothesis: children with sickle cell disease hospitalized with ACS have poor lung function compared with those with SCD not hospitalized with ACS Results
Higher resistance, TLC and RV in ACS group No difference in PFTs pre/post bronchodilator therapy, but ACS group had lower FEV25 and FEF75 pre and lower FEF75 post

Conclusion ACS hospitalized children had significant differences in PFT

VASOOCCLUSION
Infarction of bone, soft tissue, and viscera by sickled red cells Young children: usually painful crises involve extremities Older children/adolescents: head, chest, abdominal, back pain Intercurrent illness may precipitate crisis

HAND-FOOT SYNDROME

Acute sickle dactylitis 1st manifestation of disease Pain symmetrical swelling of hands and feet Ischemic necrosis of small bones; rapidly expanding bone marrow chokes off blood supply Radiographs helpful in chronic stage

VASOOCCLUSION

Occlusion of mesenteric vessels vs. appendicitis; pain may mimic acute surgical condition Hepatic infarction - acute onset of jaundice and abdominal pain (similar

to hepatitis, cholycystitis and biliary obstruction)

GU Tract - renal papillary necrosis, priapism


Antifibrinolytic drugs -aminocaproic acid or tranexamic acid may cause ureteral clot

VASOOCCLUSION/

Treatment

Mild/Moderate Pain
1 maintenance with oral or IV fluids or D5NS or D5NS Acetaminophen with or without codeine Admit if poor pain control, poor hydration status, or repeated ED visits

Severe Pain
1 maintenance with oral or IV fluids or D5NS or D5NS Morphine 0.1-0.15 mg/kg IV Admit

CNS INFARCTION

Spectrum of initial complaints: mild symptoms of TIA to seizures, coma, hemiparesis, death Cortical infarction seen on MRI or CT Immediately start 1 - 2 volume exchange to reduce Hb S to < 30% of total Hb
whole blood < 5 days old OR packed red cells < 5 days reconstituted with fresh frozen plasma

Preserve pre-transfused sample for red cell antigen identification

PRIAPISM

Admit with severe pain or persistent erection Hydration: 1 - 2X maintenance for 24-48 hours with IV fluids D5NS or D5NS If swelling does not decrease, transfuse with red cells to raise Hb to 9-10g/dl If no improvement, exchange transfusion to reduce Hb S to < 30% of total Hb If no improvement, corporal aspiration or surgical procedure

SPLENIC SEQUESTRATION CRISIS


Symptoms: left upper quadrant pain, pallor, lethargy Signs: hypotension, tachycardia, enlarged and firm spleen Laboratory: severe anemia, thrombocytopenia, neutropenia, increased reticulocytes Treatment: Immediate volume replacement, transfusion with packed red cells or whole blood

APLASTIC CRISIS
Symptoms: progressive pallor, lethargy, may be caused by parvoviral infection Signs: absence of jaundice Laboratory: severe anemia, decreased reticulocytes Treatment: transfusion with packed red cells or whole blood

HEMOLYTIC CRISIS

Symptoms: viral/bacterial infection Signs: sudden pallor, jaundice, scleral icterus Laboratory: severe anemia, increased reticulocytes, active hemolysis Treatment: rarely needs transfusion; await resolution of infection

TREATMENT
(Sieff 2010)

Fluids
Primarily for vaso-occlusive crisis 1 maintenance with oral or IV fluids or D5NS or D5NS

Pain management
Mild/moderate: oral medications acetaminophen with codeine or oxycodeine Severe: IV morphine or hydromorphine, patient controlled analgesia, NSAIDs

TREATMENT
(Sieff 2010)

Sepsis antibiotics
Due to emergence of resistant strains of s. pneumoniae, treat with 3rd generation cephalosporin (cefotaxime or ceftriaxone) and vancomycin Watch for secondary organ damage due to sickling in presence of acidosis, stasis, and hypoxia consider transfusion (packed RBC or exchange transfusions)

Acute chest syndrome cover for appropriate organisms

TREATMENT
(Roseff 2009)

Transfusion
Consider in patients with signs and symptoms of anemia Increases patient hemoglobin Dilutes Hg S with Hg A

RBCs with Hg A - longer survival than Hg S

Suppresses patients own erythropoiesis

TREATMENT
(Roseff 2009)

Simple transfusion (peripheral IV)


Technical ease, low risk of exposure, dilution of Hg S Increases viscosity, risk of Fe overload

Exchange transfusion (automated machine)


Rapid reduction in Hg S, no risk of Fe overload Requires large gauge catheter, expertise in special equipment, higher risk of exposure

TREATMENT
(Roseff 2009)

Indications for transfusion


Aplastic crisis Hemolytic crisis (extremely rare) Splenic sequestration Priapism Presurgical prophylaxis Acute chest syndrome Stroke

OTHER TREATMENT
(Sieff 2009, Steinberg 2010)

Stem cell transplantation Hydroxyurea


Introduced 25 years ago based on ability to increase fetal hemoglobin (Hg F) Observational studies in children have shown benefits and safety Often used for maintenance therapy in patients with stroke In long term study (17.5 years f/u) mortality reduced in those treated with hydroxyurea

TRANSITION TO ADULT CARE


(Hunt 2010)

30 day rate of return to acute care


10-17 yrs: 27.4% 18-30 yrs: 48.9%

Why the increase?


Lack of insurance Poor follow-up contacts Too much reliance on emergency departments for ongoing care

SUMMARY
Chronic

hemolytic anemia Crises: vasoocclusive (any organ, acute chest syndrome, stroke), hemolytic, sequestration, aplastic Watch for sepsis Continuity of care critical: immunizations, antibiotics

COMPETENCY BASED OBJECTIVES

Medical Knowledge
knowledge about the established and

evolving biomedical, clinical, and cognate (epidemiological and socialbehavioral) sciences and their application to patient care

Diagnosis, management of sickle cell disease

COMPETENCY BASED OBJECTIVES

Patient Care
family centered patient care

developmentally and age appropriate compassionate and effective for treatment of health care problems and promotion of health

Medical home for treatment of multispecialty disease

COMPETENCY BASED OBJECTIVES

Practice Based Learning


investigation and evaluation of patient

care, and the assimilation of scientific evidence

Communication Skills
interpersonal and communication skills

resulting in effective information exchange and learning with patients, families and professional associates

COMPETENCY BASED OBJECTIVES

System Based Practice understanding systems of health care

organization, financing, and delivery, and the relationship of ones local practice and these larger systems responsibilities, adherence to ethical principles, and sensitivity to diverse patient populations

Professionalism carrying out professional

REFERENCES

Vichinsky et al., NEJM, 2000 Fine et al, NEJM 1997 Johnson CS. The acute chest syndrome. Hematol Oncol CLin N am 19 (2005) 857-879. Sylvester KP et al. Impact of acute chest syndrome on lung function of children with sickle cell disease. J Pediatr 2006;149:17-22. Sylvester KP. Airway hyperresponsiveness and acute chest syndrome in children with sickle cell anemia. Pediatr Pulmonol 2007;42:272-276. Sieff, CA. Hematologic emergencies. In Fleisher Ludwig. Pediatric Emerg Med 6th ed., Phila, Lippincott. 2010

REFERENCES

Caboot JB and Allen JL. Pulmonary complications of sickle cell disease in children. Curr Opin Pediatr 2008;20:279-287. Boyd JH et al. Asthma and acute chest in sickle cell disease. Pediatr Pulmonol 2004;38:229-232. Kumar R et al. A short course of prednisone in the management of acute chest syndrome of sickle cell disease. J Pediatr Hematol Oncol 2010;32:e91-e94. Strouse JJ et al. Corticosteroids and increased risk of readmission after acute chest syndrome in children with sickle cell disease. Pediatr Blood Cancer 2008;50:1006-1012.

REFERENCES

Inusa B et al. Pandemic influenza A (H1N1) virus infections in children with sickle cell disease. Blood 2010;115;110:2329-2340. Rogovik AL et al. Bacterial blood cultures in children with sickle cell disease. Amer J Emerg Med 2010:28:511-514. Roseff SD. Sickle cell disease: a review. Immunohematol 2009;25:67-74. Steinberg et al. Risks and benefits of long term use of hydroxyurea in sickle cell anemia; a 17.5 year followup. Am J Hematol 2010;85:403-408. Hunt SE. Transition from pediatric to adult care for patients with sickle cell disease. JAMA 2010;304:408409.