Pir June 2015, Volume 36, Issue 6

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2015 Report of the Committee on Infectious Diseases,

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Vol. 36 No. 6
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Vaccine Safety: Medical

Contraindications, Myths,
and Risk Communication
Smith
Hyperthyroidism
in Children
Srinivasan, Misra
Immunizations:
Vaccinations in General
Wiley
ONLINE
Visual Diagnosis:
Pinpoint, Nonfollicular,
Sterile Pustules on
Edematous Erythema in
a 15-year-old
Perinpanathan, Heilman,
Chamdawala
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contents
Pediatrics in Review
ARTICLES
227
Vaccine Safety: Medical Contraindications,

Myths, and Risk Communication
Michael Smith
239
Hyperthyroidism in Children
Shylaja Srinivasan, Madhusmita Misra
249
Immunizations: Vaccinations in General

Catherine C. Wiley
INDEX OF SUSPICION
260
Case 1: Recurrent Apneic Episodes in a

6-week-old Infant
Michal Feldon, Hilla Bahat, Shirly Gamsu, Noa Rosenfeld,
Zvi Bistritzer, Michael Goldman
262
Case 2: Fever and Neck Swelling in a

3-year-old Boy
Mahdi Alsaleem, Lina Saadeh, Eric McGrath
265
Case 3: Hepatosplenomegaly in a 2-year-old Boy

Rajeev Ramachandran
IN BRIEFS
268
Child Safety and Injury Prevention

Jennifer E. Sanders, Leora Mogilner
270
Chromosome 22q11.2 Deletion Syndrome

Elaine Pereira, Robert Marion
272
Erratum
e18
Visual Diagnosis: Pinpoint, Nonfollicular,

Sterile Pustules on Edematous Erythema in
a 15-year-old
ONLINE
Kirishanth Perinpanathan, Edward Heilman, Haamid Chamdawala

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Vol. 36 No. 6 June 2015

Editor-in-Chief: Joseph A. Zenel, Sioux Falls, SD
Associate Editor: Hugh D. Allen, Houston, TX
Editor, In Brief: Henry M. Adam, Bronx, NY
Consulting Editor, In Brief: Janet Serwint, Baltimore, MD
Editor, Index of Suspicion: Deepak M. Kamat, Detroit, MI
Editor, CME: Paula Algranati, Longmeadow, MA
Editorial Fellow: Mark F. Weems, Memphis, TN
Editor Emeritus: Lawrence F. Nazarian, Rochester, NY
Founding Editor: Robert J. Haggerty, Canandaigua, NY
Managing Editor: Luann Zanzola
Editorial Associate: Sara Strand
Medical Copyediting: Deborah K. Kuhlman
EDITORIAL BOARD
Robert D. Baker, Buffalo, NY
Peter F. Belamarich, Bronx, NY
Theresa Auld Bingemann, Rochester, NY
Denise Bratcher, Kansas City, MO
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Philip Fischer, Rochester, MN
Lynn Garfunkel, Rochester, NY
Rani Gereige, Miami, FL
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Nupur Gupta, Boston, MA
Jacob Hen, Bridgeport, CT
Jeffrey D. Hord, Akron, OH
Neal S. LeLeiko, Providence, RI
Michael Macknin, Cleveland, OH
Susan Massengill, Charlotte, NC
Jennifer L. Miller, Gainesville, FL
Carrie A. Phillipi, Portland, OR
Peter Pizzutillo, Philadelphia, PA
Mobeen Rathore, Jacksonville, FL
E. Steve Roach, Columbus, OH
Sarah E. Shea, Halifax, Nova Scotia
Andrew Sirotnak, Denver, CO
Miriam Weinstein, Toronto, ON
PUBLISHER: American Academy of Pediatrics
Joseph Puskarz, Director, Division of Journal Publishing
Pediatrics in Review offers 36 CME articles per year. A maximum
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Answer Key appears on page 272.
Vaccine Safety: Medical Contraindications, Myths,

Michael Smith, MD, MSCE*
*Division of Pediatric Infectious Diseases, University of Louisville School of Medicine, Louisville, KY.
Educational Gap
Some parents are more concerned about the safety of vaccines than the
diseases they are designed to prevent. To maintain high levels of
immunization, pediatricians must be familiar with vaccine safety and
vaccine risk communication. Formal training in these areas is lacking
(Williams SE, Swain R. Formal training in vaccine safety to address parental
concerns not routinely conducted in US pediatric residency program.
Vaccine. 2014;32(26):31753178).
Objectives
After completing this article, readers should be able to:
1. Recognize adverse reactions to various vaccine constituents and

manage them appropriately.
2. Plan an immunization regimen for a patient with egg allergy.
3. Plan an immunization regimen for a patient with an immune deciency,
including an immune deciency that results from chemotherapy.
4. Understand the basic mechanisms for assessing vaccine safety in the
United States.
5. Plan an appropriate approach to addressing the needs of the vaccinehesitant family.
INTRODUCTION
AUTHOR DISCLOSURE Dr Smith has

disclosed that he has received grants from
Sano Pasteur and Novartis. This commentary
does not contain a discussion of an
unapproved/investigative use of
a commercial product/device.
Vaccines are one of the most successful public health interventions of all time.
Diseases that once caused signicant morbidity and mortality in children are at
all-time lows in the United States. Although many parents and physicians no
longer have personal experiences with vaccine-preventable diseases, they remain
a short plane ight away. The largest measles outbreak in the United States in
more than 20 years occurred in 2014, and most cases occurred in unvaccinated
individuals.* Some were unvaccinated because they were not eligible for
*As of February 13, 2015, the Centers for Disease Control and Prevention reported 141 measles cases for
2015. Editor-in-Chief
Vol. 36 No. 6
JUNE 2015
227
vaccination, either due to age or an underlying medical

condition. However, many of these individuals remained
unvaccinated by personal choice.
The rst section of this article reviews medical contraindications and precautions for childhood immunizations.
This is followed by a discussion of current processes to
ensure vaccine safety in the United States. The nal section
summarizes some of the more common myths about vaccine safety and discusses strategies to communicate vaccine
safety to families.
The Advisory Committee on Immunization Practices
(ACIP) lists contraindications and precautions for each
vaccine. (1) ACIP denes a contraindication as a condition
in a recipient that increases the risk for a serious adverse
reaction. Vaccines should not be administered to individuals with a contraindication for that vaccine. In contrast,
a precaution is a condition in a recipient that might
increase the risk for a serious adverse reaction or that
might compromise the ability of the vaccine to produce
immunity. In general, vaccination should be deferred
when a precaution is present. However, in certain circumstances, such as an outbreak of a vaccine-preventable
disease to which an individual has a precaution but not
a contraindication, the benets of vaccination may outweigh the risks.
Contraindications are relatively uncommon. We review
two general contraindications in detail:
1) For all vaccines, a severe anaphylactic reaction to a prior
dose of a vaccine or vaccine component.
2) For live viral vaccines, administration to individuals with
a known severe immunodeciency.
commonly encountered allergens in vaccines are egg proteins, gelatin, yeast, and latex.
ANAPHYLAXIS
Gelatin
The risk of anaphylaxis after vaccine receipt is very low. A

review of 7.5 million administered vaccine doses from 1991
to 1997 identied only ve cases of anaphylaxis for an estimated 0.65 cases/1 million doses. More recently, only nine
cases of anaphylaxis were led with the National Vaccine
Injury Compensation Program between 2000 and 2009.
Even though the absolute risk of anaphylaxis is low, several
individuals each year may have an anaphylactic response to
vaccination because millions of Americans are vaccinated
annually. For this reason, the ACIP recommends that all
vaccines be administered in a facility with the appropriate
equipment and personnel trained to recognize and treat
anaphylaxis.
Many different components of a vaccine can be associated with an allergic reaction. These include the antigens
themselves, stabilizers, and preservatives. Some of the more
228
Egg Allergies
Egg proteins are present in vaccines against yellow fever,
inuenza, measles-mumps-rubella (MMR), and rabies. Of
these, only yellow fever vaccines have sufcient quantities to
cause clinically signicant reactions in most children with
egg allergies. For that reason, children with egg allergy who
require pre-travel vaccination against yellow fever should be
referred to an allergist.
Egg allergy was a contraindication for inuenza vaccine
for many years, but this is no longer true. Since 2011, the
ACIP has relaxed recommendations for inuenza vaccination among individuals with egg allergies. (2) The current
guidelines are summarized below and are based on severity
of the allergic response to eggs:
1) Children who can eat lightly cooked (ie, scrambled) eggs
may be vaccinated without any additional precautions.
Note that consumption of baked egg products does not
rule out an egg protein allergy because the heating may
denature proteins.
2) Children who develop hives only (and not cardiovascular,
respiratory, or gastrointestinal symptoms) may be vaccinated with inactivated inuenza vaccine if they are
observed for at least 30 minutes after vaccination.
3) Children who experience cardiovascular (hypotension),
respiratory (wheezing), or gastrointestinal (nausea/vomiting) symptoms or any reaction requiring epinephrine or
emergency medical attention should be referred to an
allergy specialist before vaccination.
Gelatin is used as a stabilizer in several vaccines, including

inuenza (Fluzone [Sano Pasteur, Swiftwater, PA] and
FluMist [MedImmune, Gaithersburg, MD]), MMR, measlesmumps-rubella-varicella (MMRV), rabies (RabAvert [Novartis
Vaccines, Cambridge, MA]), typhoid (Vivotif, Crucell Vaccines, Miami Lakes, FL), varicella, and zoster vaccines. Gelatin
is believed to be responsible for most of the reported anaphylactic responses to MMR vaccine. ACIP recommends exercising extreme caution when administering any of these
vaccines to children with a history of anaphylaxis to gelatin
or a gelatin-containing product.
Yeast
Hepatitis B and quadrivalent (but not bivalent) human
papillomavirus (HPV) vaccines include antigens that are
cultured in recombinant Saccharomyces cerevisiae (bakers
yeast). Although anaphylaxis after receipt of these vaccines
is uncommon, documented allergy to bakers yeast is a contraindication for these two vaccines.
Latex
Some vaccines use latex in vials or syringes. A recent list of
these vaccines is available at http://www.cdc.gov/vaccines/
pubs/pinkbook/downloads/appendices/b/latex-table.pdf
and in each vaccine-specic package insert. In general,
children with severe (anaphylactic) allergy to latex should
not receive vaccines supplied in vials or syringes that contain
natural rubber unless the benet of vaccination outweighs
the risk. Children with nonanaphylactic reactions may receive
these vaccines.
CONTRAINDICATIONS FOR LIVE VACCINES

Immunocompromised Patients
Data regarding the safety and immunogenicity of vaccines
for children with immune deciencies are limited. However, the Infectious Diseases Society of America (IDSA)
guidelines for vaccination of immunocompromised patients (3) and The American Academy of Pediatrics (AAP)
Red Book offer excellent summaries of the available evidence. (4) Generally, children with immune deciencies
may safely receive inactivated vaccines. Children with certain primary immune deciencies require additional pneumococcal and meningococcal vaccines above and beyond
the routine childhood immunization schedule. Although
live viral vaccines are contraindicated in certain immune
deciencies, this is not true for every vaccine and every
immune deciency state. The following section summarizes
general indications for live vaccines. Specic recommendations for individual patients should be made in conjunction
with a specialist in immunology or infectious diseases.
Primary Immune Deciencies

Live viral vaccines should be avoided in children with
antibody deciencies. Safety data are limited in this population and live vaccines are unlikely to be immunogenic due to
passive receipt of immune globulin intravenous (IGIV). An
exception is children with isolated immunoglobulin A deciency, who may receive live vaccines. In general, live vaccines
should also be avoided in children with T-cell deciencies.
However, children with incomplete DiGeorge syndrome may
receive vaccines if they have adequate immune function. The
IDSA guidelines suggest that live viral vaccines may be
administered to children with DiGeorge syndrome with
CD3 counts of at least 500, CD8 counts of at least 200,
and a normal mitogen response. (3)
Children with phagocyte cell deciencies (eg, chronic
granulomatous disease, leukocyte adhesion deciency) may
receive live viral vaccines, but they should not receive live
bacterial vaccines such as oral typhoid or Bacille Calmette
Gurin. Children with complement deciencies may receive
live vaccines.
Acquired Conditions
Infants with human immunodeciency virus (HIV) infection or perinatal HIV exposure may receive rotavirus vaccine. (3) MMR and varicella vaccines may be administered to
children aged 1 through 13 years with CD4 T-lymphocyte
percentages of 15% or greater and to children at least 14 years
old with absolute CD4 counts of at least 200. However,
children with HIV should not receive live attenuated inuenza vaccine (LAIV) or MMRV.
Live viral vaccines should not be administered during
chemotherapy. MMR and varicella vaccines may be administered 3 months after completion of chemotherapy except
for children who have received anti-B-cell regimens (eg,
rituximab). Vaccinations for these children should be deferred
until 6 months after therapy completion. It is safe to receive
inactivated vaccines during chemotherapy, but these vaccines
generally should not be administered during induction or
consolidation due to concerns about immunogenicity.
Inuenza Vaccine
The ACIP publishes recommendations for annual inuenza
vaccination each year. For the 20142015 season, LAIV is
recommended for healthy children 2 to 8 years of age if
available. (5) Immunocompromised children should not
receive LAIV. In addition, the following groups of children
should not receive LAIV:
1) Children younger than 2 years of age.
2) Children receiving aspirin or aspirin-containing products.
3) Children with egg allergy.
4) Children 2 to 4 years of age with asthma or a documented
episode of wheezing within the previous 12 months.
5) Children receiving inuenza-specic antivirals within
48 hours of vaccination.
The presence of asthma in individuals 5 years and older
or any other medical condition that increases the likelihood
of complications after natural inuenza infection (eg,
chronic pulmonary, cardiovascular, metabolic, or neurologic
conditions) is a precaution for administering LAIV.
Vaccination of Household Contacts of

Immunocompromised Children
Appropriate vaccination of household contacts is just as
important as vaccine recommendations for the immunocompromised children themselves. All household contacts
may receive inactivated vaccines. Household contacts may
also receive age-appropriate MMR, varicella, rotavirus, and
Vol. 36 No. 6
JUNE 2015
229
zoster vaccines if the contacts are immunocompetent. Household contacts of immunocompromised children may also
receive LAIV with a few exceptions. According to IDSA, LAIV
is contraindicated if:
1) The patient is a stem cell transplant recipient within
2 months after transplant.
2) The patient is a stem cell transplant recipient with graft
versus host disease.
3) The patient has severe combined immune deciency.
If any of the above criteria are met, inactivated inuenza
vaccine should be administered to household contacts. LAIV
may be considered if the vaccine recipient can avoid contact
with the immunocompromised patient for 7 days after
vaccination.
Other Contraindications
In addition to general vaccine contraindication, there are
vaccine- or condition-specic contraindications:
1) No pertussis-containing vaccine should be administered
to a patient who develops encephalopathy with no alternative explanation within 7 days of receiving a pertussiscontaining vaccine.
2) No Haemophilus inuenzae type b (Hib) vaccine should be
administered to infants younger than 6 weeks of age.
3) No rotavirus vaccine should be administered to children
with severe combined immunodeciency or a history of
intussusception.
4) No live viral vaccines should be administered during
pregnancy.
PRECAUTIONS FOR CHILDHOOD IMMUNIZATIONS

A full list of precautions is available from the ACIP, (1) but
some of the more common ones are summarized below.
The presence of moderate or severe acute illness with or
without fever is one precaution that applies to all vaccines.
The precaution is not based on a lack of efcacy but because
the expected adverse effects of vaccination might be confused with the natural progression of disease. For example,
if a child with a febrile upper respiratory tract infection is
vaccinated and develops fever the next day, it may be difcult
to differentiate between progression to bacterial otitis, sinusitis, or pneumonia and appropriate response to vaccine. On
the one hand, worsening disease progression may be missed.
On the other hand, a clinical change such as a rash may be
falsely attributed to the vaccine when it is, in fact, part of the
natural disease progression. Note that use of antimicrobial
therapy does not preclude vaccination per se. The only time
this is an issue is when a child requires therapy with an agent
that has activity against a specic live vaccine. Thus, children
230
receiving an inuenza antiviral should not receive LAIV,

children receiving acyclovir should not receive varicella vaccine, and children receiving an antibacterial with Gramnegative activity should not receive oral typhoid vaccine.
The immunogenicity of live viral vaccines may be
affected if they are administered in close succession. LAIV,
MMR, varicella, or zoster vaccines can be administered on
the same day. However, if they are not administered on the
same day, their administration should be separated by at
least 28 days. The immunogenicity of inactivated vaccines is
not affected by concomitant receipt of live viral vaccines.
Another frequently encountered precaution is deferral of
MMR and varicella vaccines in children who have received
antibody-containing products. These include IGIV, diseasespecic antibody, and some blood products. Doses of these
vaccines should be considered invalid if one of the previously noted antibody-containing products is administered
within 2 weeks after vaccination. The required interval
between antibody-containing products and receipt of live
viral vaccines varies by product and dose (Table 1).
PARENTAL VACCINE HESITANCY

It is equally important to review how pediatricians should
discuss vaccine safety with parents who are concerned about
vaccines and request delay of vaccination. The remainder of
this review focuses on some of the underlying reasons for
parental vaccine hesitancy and strategies and talking points
that may be used to reassure parents.
Perceived Risks of Vaccines

Perhaps the most challenging aspect of effective vaccine risk
communication in 2015 is related to the fact that vaccines
work. Because vaccine-preventable diseases are no longer
prevalent, many parents are not familiar with them and may
not perceive them as dangerous (Figure). At the same time,
vaccines are unique among pharmaceutical agents in that
they are administered to otherwise healthy children to
prevent future disease. In this context, the perceived risks
of vaccination outweigh the actual risks of disease for
some parents, and some opt to delay or avoid vaccines
completely.
When discussing vaccines with parents, it is important to
emphasize that not vaccinating is truly a risk, as evidenced
by the current measles epidemic. In 2014, there were 644
cases of measles in the United States, mostly among unvaccinated individuals. This represents the greatest number of
cases in 2 decades. Measles is one of the most contagious
vaccine-preventable diseases and is often the rst sign of
waning immunization rates in a community. (1)
TABLE 1.
Recommended Intervals Between

Antibody-containing Products and
Measles or Varicella Vaccine
DISEASE-SPECIFIC IMMUNOGLOBULIN
(IG)
RECOMMENDED
INTERVAL
Tetanus IG, hepatitis A IG, hepatitis B IG
3 mo
Rabies IG
4 mo
Varicella IG, measles IG prophylaxis in

nonimmunocompromised host
5 mo
Measles IG prophylaxis in
immunocompromised host
6 mo
Immunoglobulin Intravenous (IGIV)

Products
Cytomegalovirus IGIV
6 mo
IGIV replacement therapy for immune

deciencies, treatment of immune
thrombocytopenia purpura
(400 mg/kg), or varicella prophylaxis
8 mo
Treatment of immune thrombocytopenia

purpura (1000 mg/kg)
10 mo
Kawasaki disease
11 mo
Blood Transfusions
Washed red blood cells (RBCs)
None
RBCs with adenine-saline added
3 mo
Packed RBCs or whole blood
6 mo
Plasma or platelets
7 mo
Adapted from ACIP(1) and AAP(6) recommendations.
Nonetheless, vaccines are not completely without risk. Prelicensure randomized, controlled trials provide the strongest
evidence for the incidence of vaccine adverse events. However,
these studies are primarily designed to assess vaccine efcacy or
immunogenicity and may be underpowered for detecting rare
vaccine adverse effects. Following vaccine licensure, monitoring
continues to identify rare adverse events that may only become
evident after a vaccine is introduced at the population level.
These include the Vaccine Adverse Events Reporting System
(VAERS) and the Vaccine Safety Datalink (VSD).
VAERS is a passive postlicensure reporting system maintained jointly by the US Food and Drug Administration
(FDA) and the Centers for Disease Control and Prevention.
It allows any individual, including clinicians and parents, to
report a believed vaccine-associated adverse effect to the
system. VAERS includes data from the entire country but
has several important limitations. First, temporal association between vaccination and an adverse effect does not
imply causation. Only individuals who were vaccinated and

had the event of interest are included. Second, there is no
denominator that can be used to calculate the incidence of
adverse effects. Nevertheless, VAERS can quickly identify
potential vaccine-associated adverse events that may be
further evaluated using other epidemiologic methods.
The VSD partners with nine large managed care organizations and prospectively collects data on millions of individuals each year. Vaccinations are entered into the medical
record as part of routine medical care, and any subsequent
medical history, including adverse events, can be detected.
Unlike VAERS, VSD includes data from vaccinated children
who did not have an adverse event, which allows for a true
denominator to calculate the incidence of adverse reactions
after vaccination. Additionally, VSD includes children who
may not have received a certain vaccine. This means that VSD
can also be used to determine the relative risk of an adverse
event by comparing rates in vaccinated individuals to rates in
unvaccinated individuals. Several of the studies referred to in
this article are based on VSD data.
Fortunately, most vaccine adverse effects are transient
and mild. Fever and injection site redness and pain predominate. Although serious adverse events after vaccination
are rare, parents should be counseled about these potential
occurrences. In 2011, the Institute of Medicine (IOM)
published a consensus report on vaccine safety based on
a thorough review of thousands of studies. (7) Of 158
potential vaccine adverse events, the IOM found strong
evidence of a causal association between vaccines and
14 specic outcomes. The body of evidence favored acceptance of causal association for an additional four outcomes
and favored rejection for ve outcomes (Table 2).
Figure. In the decade before 1963 when a measles vaccine became

available, nearly all children contracted measles by the time they were
15 years old, according to the U.S. Centers for Disease Control and
Prevention. Some 3 to 4 million people in the U.S. were infected each
year, 400 to 500 people died, 48,000 were hospitalized, and 4,000
suffered encephalitis from measles. This 9-month-old boy with
a temperature of 40.5C (105F) exhibits a signicant measles rash.
Vol. 36 No. 6
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231
TABLE 2. Evidence
for Vaccine Adverse Events and Strength of Association
VACCINE(S)
ADVERSE EVENT
Outcomes for which evidence convincingly supports causality

Varicella
1) Disseminated varicella infection (widespread chickenpox rash shortly after vaccination) without
other organ involvement
2) In individuals with immunodeciency, disseminated varicella infection with subsequent
infection resulting in pneumonia, meningitis, or hepatitis
3) Vaccine strain viral reactivation (appearance of chickenpox rash months to years after
vaccination) without other organ involvement
4) Vaccine strain viral reactivation with subsequent infection resulting in meningitis or encephalitis
(inammation of the brain)
5) Anaphylaxis
Measles-mumps-rubella (MMR)
1) In individuals with immunodeciency, measles inclusion body encephalitis

2) Febrile seizures
3) Anaphylaxis
Inuenza
Anaphylaxis
Hepatitis B
Anaphylaxis
Tetanus toxoid
Anaphylaxis
Meningococcal
Anaphylaxis
Injection-related events
1) Deltoid bursitis
2) Syncope
Outcomes for which evidence favors causal association

Human papillomavirus
Anaphylaxis
MMR
Transient arthralgia in women
MMR
Transient arthralgia in children
Outcomes for which evidence favors rejection of causal association

MMR
Autism
Inactivated inuenza
1) Bells palsy
2) Exacerbation of asthma or reactive airways disease
MMR
Type 1 diabetes
Diphtheria-tetanus
Type 1 diabetes
Tetanus toxoid
Type 1 diabetes
Acellular pertussis
Type 1 diabetes
Adapted from Adverse Effects of Vaccines: Evidence and Causality. (7)
A more recent systematic review included 67 additional

studies not reviewed in the IOM report. (8) These studies
were either published after the IOM report or were investigations of routine childhood vaccines (hepatitis A, Hib,
inactivated polio vaccine, pneumococcal conjugate vaccine
[PCV13], and rotavirus) that were not considered by the IOM.
This systematic review included ve studies of MMR vaccine
that were published after the IOM report. These studies
supported the ndings that MMR is associated with febrile
seizures but not with autism. The review also included four
high-quality studies assessing the relationship between vaccination and leukemia and found no association. The authors
232
did nd moderate evidence for associations between hepatitis

A vaccine and purpura in children aged 7 to 17 years, mild
gastrointestinal events and febrile seizures after inuenza
vaccination, anaphylaxis after meningococcal vaccination in
children allergic to the ingredients, febrile seizures after
PCV13 (especially when coadministered with inuenza vaccine), intussusception with rotavirus vaccines, and purpura
and varicella vaccine in children aged 11 to 17 years.
Although the clinician should acknowledge these potential
vaccine adverse effects, he or she must put their incidence into
context. The authors noted that the several identied vaccine
adverse events were extremely rare, especially when the
epidemiology of natural disease is considered. Worldwide, there

are 20 million cases of measles and 164,000 deaths each year
and the rate of adverse outcomes after natural infection is high.
Approximately 1 in 10 children with measles also gets an ear
infection and up to 1 in 20 develops pneumonia. About 1 in
1,000 contracts encephalitis and 1 or 2 in 1,000 die. By
comparison, the risk of MMR-associated immune thrombocytopenia purpura is approximately 1 in 40,000 doses and is
transient. Thus, when compared to the risks associated with
natural disease, vaccines emerge as the clear choice.
Cause or Coincidence
Fortunately, the number of children who have not received
any vaccines has remained below 1% for the past decade,
which is reassuring. On the other hand, any adverse health
outcome that occurs in the rst 2 years of a childs life most
likely will occur in a child who is vaccinated. Parents must be
reminded that temporal association between vaccination
and an adverse event does not mean that the association
is causal. This is particularly true for chronic diseases of
uncertain cause, such as autism, that are diagnosed at the
same age as many childhood vaccines are administered.
The Internet
Although the media perpetuates vaccine safety myths, the
primary source of information for many parents is the
Internet. Nearly 90% of United States adults report using
the Internet, with even higher rates among young adults with
college degrees. Several studies have demonstrated a growing
prevalence of vaccine misinformation on the Internet, in
large part due to antivaccine advocacy websites that are often
linked to each other. A simple Internet search is more likely to
lead to misinformation than reliable evidence-based facts
about vaccines. Social media sites are also lled with personal
anecdotes of alleged vaccine injuries.
The Internet does contain many excellent evidence-based
resources for both physicians and parents. However, distinguishing between reliable and unreliable Internet sites can be
difcult for parents. Table 3 lists websites that offer accurate,
science-based information about vaccines and vaccine safety.
Many of these websites have ready-to-print materials for
families that can be handed out in the ofce. For parents
who would like to conduct their own searches, the AAP offers
resources for evaluating vaccine websites: http://www2.aap.
org/immunization/families/evaluatingwebinfo.html.
SPECIFIC VACCINE SAFETY CONCERNS

Vaccines and Autism
The putative association between MMR and autism was rst
reported in 1998 in a small case series published in Lancet.
The report included 12 children, all of whom had inammatory bowel disease and eight of whom had autism. This
study had signicant aws, most notably that case reports do
not offer strong proof of causal association. Furthermore,
history of MMR receipt was based on parental recall.
Because these parents believed that MMR was responsible
for their childrens autism, it is not surprising that they
reported a temporal association between MMR vaccination
and the development of autistic symptoms. There are also
ethical concerns about this study based on its funding and
the fact that patients were not randomly enrolled. Because of
these ethical concerns, Lancet retracted the article in 2010.
Before retraction, the study received substantial media
attention, and rates of MMR vaccination signicantly decreased
in the United Kingdom, where the study was published, and to
a much lesser extent in the United States. The MMR-autism
hypothesis has never been conrmed. Many large epidemiologic studies that included hundreds of thousands of children
have failed to identify an association between MMR and autism.
In 2001, the IOM concluded there was no association between
MMR and autism and reafrmed this in 2004 and 2011.
The mercury-containing vaccine preservative thimerosal
has also been suggested to be linked to autism. This is based
on an FDA report from 1999 suggesting that the concentrations of ethylmercury, a thimerosal metabolite, exceeded
acceptable levels as determined by the Environmental Protection Agency (EPA). However, the EPA recommendations
are based on data for methylmercury, a common environmental toxin. In contrast, thimerosal is metabolized to ethylmercury, which is excreted much more quickly and has not
been associated with neurodevelopmental delay. Nevertheless,
because of the theoretical concern of thimerosal in childhood
vaccines, it has been removed from all childhood vaccines,
except some inuenza vaccines, for more than a decade. This
has not had an impact on rates of autism. Since then, multiple
large epidemiologic studies have conrmed that thimerosal
exposure is not associated with autism. Despite these reassuring data, some parents still have concerns about thimerosal in
inuenza vaccines. For these parents, LAIV, which is recommended for children as noted previously, or single-use vials
that do not contain thimerosal may be used.
Alternative Schedules
A newer parental concern relates to the safety of the immunization schedule. A study published a decade ago found
that nearly 25% of parents were concerned that children
receive too many vaccines and that these vaccines may overwhelm the developing immune system. Since that time, the
immunization schedule has become even more crowded,
with new vaccines against rotavirus, pneumococcal disease,
Vol. 36 No. 6
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233
TABLE 3.
Organizations Offering Credible Information About Vaccines

and Vaccine Safety
ORGANIZATION
URL
Professional
American Academy of Family Physicians (AAFP)
http://www.aafp.org
American Academy of Pediatrics (AAP)
http://www.cispimmunize.org
Association for Prevention Teaching and Research (APTR) (formerly the Association
of Teachers of Preventive Medicine)
http://www.atpm.org
Centers for Disease Control and Prevention
http://www.cdc.gov/vaccines
Infectious Diseases Society of America (IDSA)
http://www.idsociety.org
Pediatric Infectious Diseases Society (PIDS)
http://www.pids.org
Advocacy and Safety Assessment

Allied Vaccine Group
http://www.vaccine.org
Childrens Hospital of Philadelphia Vaccine Education Center
http://vec.chop.edu/service/vaccine-education-center
Every Child by Two (ECBT)
http://www.ecbt.org
Global Alliance for Vaccines and Immunization (GAVI)
http://www.gavialliance.org
Immunization Action Coalition (IAC)
http://www.immunize.org
Institute for Vaccine Safety, Johns Hopkins Bloomberg School of Public Health
http://www.vaccinesafety.edu
National Foundation for Infectious Diseases (NFID)
http://www.nd.org
Sabin Vaccine Institute (SVI)
http://www.sabin.org
For Parents
Childrens Hospital of Philadelphia Vaccine Education Center
http://vec.chop.edu/service/vaccine-education-center
Immunization Action Coalition (IAC)
http://www.vaccineinformation.org
National Network for Immunization Information (NNii)
http://www.immunizationinfo.org
Parents of Kids with Infectious Diseases (PKID)
http://www.pkids.org
Vaccinate Your Baby
http://www.vaccinateyourbaby.com
Voices for Vaccines
http://www.voicesforvaccines.org
and hepatitis A for young children and meningococcal, HPV,

and tetanus-diphtheria-pertussis (Tdap) vaccines for adolescents. These new vaccines represent a triumph for public
health but may overwhelm some parents and their clinicians.
Several reasons argue against alternative vaccine schedules. First, the current immunization schedule is designed
to protect children against diseases when they are most
susceptible; delay prolongs susceptibility to infection. It is
impossible for parents, pediatricians, or authors of published alternative immunization schedules to predict when
a child will come into contact with a vaccine-preventable
disease. Second, the concern that vaccines may overwhelm
the immune system is not science-based. From the moment
of birth, infants are bombarded with microbes from the
maternal genitourinary tract and the environment that
234
challenge the developing immune system. The additional

antigenic exposure from vaccines pales in comparison. In
fact, the neonatal immune system theoretically could respond
to up to 10,000 vaccines at a time. (9) Furthermore, although
the number of childhood immunizations has increased over
the past 2 decades, the total antigenic burden from vaccines
has decreased, largely due to discontinuation of whole-cell
pertussis vaccines. Finally, several studies have demonstrated
that children who receive their vaccines on time are no more
likely to develop autism or neurodevelopmental delay than
children whose vaccine receipt is delayed.
Human Papillomavirus and Promiscuity

In 2013, 57.3% of girls and 34.6% of boys received at least
one dose of HPV vaccine. Receipt of three vaccines was
much lower at 37.6% and 13.9%, respectively. Some parents

are concerned that this vaccine leads to sexual promiscuity.
However, a recent review of medical claims of 1,398 adolescent girls found no differences in rates of pregnancy, sexually
transmitted infection testing, diagnosis, or contraceptive
counselling between those who did and did not receive
HPV vaccine. (10) More importantly, thousands of Americans
die each year from HPV-associated cancers. This is nearly
1000 times as many as succumb to meningococcal disease,
yet rates for meningococcal vaccination approach 80%. Once
again, the key point is risk perception; it is critical for
clinicians to frame HPV vaccine as a cancer vaccine and
not just a vaccine against a sexually transmitted disease.
ADDRESSING VACCINE HESITANCY

Recommendations for discussing vaccine safety with concerned parents have been published. (11) The style and
approach needs to be tailored to each individual family.
Some parents may refuse all vaccines, others may have
concerns about specic vaccines, and still others may simply
have a few basic questions. The specic reasons for vaccine
concerns vary widely from parent to parent.
Parents whose primary concern is the number of injections may be reassured by the use of combination vaccines.
At the 2-month health supervision visit, for example, children receive vaccines against seven diseases: diphtheria,
tetanus, pertussis, polio, pneumococcus, Hib, and rotavirus.
One is an oral vaccine, and one is combination vaccine that
includes all of the other components except PCV. Framing
this encounter as two injections and a drink may be more
effective than immunization against seven diseases.
Other parents may be worried that multiple injections at the
same visit may cause excessive pain, and they wonder
whether this could be reduced by spreading the injections
out across several visits. Spacing out vaccines over two or
three visits may actually lead to more stressful stimuli in
addition to the inconvenience of extra visits to the ofce.
Clinicians should be familiar with strategies that have been
shown to reduce immunization pain. (12) These include use
of sucrose in children and young infants and age-appropriate
distraction techniques such as storytelling and blowing for
older children.
Some parents may object to vaccines on religious grounds.
For example, cells originally obtained from aborted fetuses
are used in certain vaccines, most notably rubella. It is
important to remind parents that these fetuses were not
aborted for the purpose of creating these vaccines. Indeed,
the Catholic Church has concluded that Catholics may receive
these vaccines because they do not contribute to current rates
of abortion and are important for the well-being of children

and the greater public health. Individuals of Islamic and
Jewish faith may have concerns about vaccines containing
gelatin as a stabilizer because it is of porcine origin. However,
because gelatin is cooked and not consumed as food, Muslim
and Jewish scholars have determined that gelatin-containing
vaccines are acceptable. (13)
Finally, some parents may have concerns about vaccine
mandates. For these parents, emphasizing the direct benet
of vaccination to their child, not just to society as a whole,
may be an effective strategy.
How to Deliver the Message?

The best method of communicating with parents who have
concerns about vaccine safety is an area in which further
research is needed. A recent meta-analysis of interventions
to reduce parental vaccine refusal and vaccine hesitancy
only identied 30 studies published between 1990 and
2012. (14) Half of the studies focused on the use of parentcentered information or education that was primarily
limited to brochures. Easy access to reliable vaccine information, such as the websites provided in Table 3, is clearly
important. A promising strategy is to introduce these
materials to parents before the health supervision visit.
This includes venues such as prenatal open houses or
during postpartum visits on the maternity ward. However,
the most critical element in effective vaccine risk communication may be how the message is delivered.
A handful of studies have begun to address this important question. Opel and colleagues (15) videotaped interactions between pediatricians and parents, some of whom
were vaccine-hesitant. The authors were particularly interested in how physicians initiated discussions about vaccines
and how the parents responded. Parental resistance was less
likely when physicians used a presumptive approach; that is,
presuming that the parents would agree with vaccination. In
contrast, when physicians used participatory approaches
that allowed for more parental decision-making, vaccine
resistance was more common. Physician response to parental vaccine resistance was also documented. Almost 50% of
the initially resistant parents ultimately accepted vaccination
when the physician persisted in recommendations. Of note,
though, only 50% of the physicians followed through with
their initial recommendations when faced with parental
concern.
Numerous studies have shown that a trusting relationship is the single most important element in effective
vaccine risk communication. This is true for all parents
but most especially for those who request exemptions. One
study of parents who were planning on deferring vaccines
Vol. 36 No. 6
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235
for their child determined that advice from their pediatrician changed their mind.
What If They Still Say No?

Some physicians may choose to dismiss vaccine-hesitant
families from their practice. The AAP recommends that
clinicians engage in ongoing dialogues with families who
are concerned about vaccine safety. (16) Because dismissing
such patients may result in families seeking care from providers who do not support routine immunization (who may
not have formal medical training), clinicians should make
their best efforts to engage these families. Furthermore, it is
unethical to dismiss patients actively under ones care without
a solid transition plan. That said, allowing a child who is not
up-to-date on vaccines to sit in a waiting room clearly places
other patients at risk. During the 2008 measles outbreak in
San Diego, California, four children were exposed to measles
in their pediatricians ofce when an intentionally unvaccinated 7-year-old child presented with fever, sore throat, and
a rash. The exposed children included three infants younger
than 1 year of age, one of whom was admitted to the hospital.
If a family refuses one or more vaccines at a given
ofce visit, consider scheduling a follow-up visit to administer any remaining vaccines. Clinicians also should
remain up-to-date on the local epidemiology of vaccinepreventable diseases. For example, the incidence of
pertussis and measles reached historical peaks in the
past 2 years. These outbreaks may convince some vaccinehesitant parents to immunize their children. If parents
continue to refuse vaccines, this should be documented

in the medical record. An AAP-approved template is available online at: http://www.aap.org/en-us/about-the-aap/
Committees-Councils-Sections/Section-on-infectiousdiseases/Documents/RefusaltoVaccinate.pdf.
Summary
On the basis of rst principles, anaphylaxis to a vaccine or
vaccine component is a contraindication to future receipt of that
vaccine. (1)
On the basis of strong evidence, live viral vaccines should not be
administered to severely immunocompromised children. (1) (3) (4) (7)
On the basis of some evidence with consensus, children with egg
allergies may receive inactivated inuenza vaccine. (2)
On the basis of strong evidence, neither measles-mumps-rubella
vaccine nor thimerosal causes autism. (7)
On the basis of some evidence with consensus, alternative
vaccination schedules have no benet and receipt of human
papillomavirus vaccines does not result in promiscuity. (9) (10)
On the basis of rst principles and consensus, vaccine risk
communication requires a tailored approach to each individual
family. (11) (14) (15) (16)
References for this article are at http://pedsinreview.aappublications.org/content/36/6/227.full.
Parent Resources from the AAP at HealthyChildren.org

http://www.healthychildren.org/English/safety-prevention/immunizations/Pages/Vaccine-Safety-The-Facts.aspx
Spanish: http://www.healthychildren.org/spanish/safety-prevention/immunizations/Paginas/Vaccine-Safety-The-Facts.aspx
236
PIR Quiz
1. You are seeing a 3-year-old child in November for his annual health supervision visit. His
parents tell you that he gets a mild-to-moderate perioral rash and occasional facial hives
when he eats scrambled eggs. He is able to eat baked egg products. Of the following,
which is the best strategy for inuenza vaccination for this child?
A. An egg allergy is a contraindication to inuenza vaccination.
B. The child may be vaccinated with inactivated inuenza vaccine and monitored for
at least 30 minutes.
C. The child may be vaccinated with live-attenuated inuenza vaccine and monitored
for at least 60 minutes.
D. The child should be referred to an allergy specialist for testing before
immunization.
E. Vaccination should be deferred until the child is old enough to receive the inactivated inuenza vaccine.
2. A 12-month-old child with congenitally acquired human immunodeciency virus (HIV)
infection comes to your ofce with his parents as a new patient. The boy has received all of
his vaccinations on time and is up to date. He has been generally healthy except for one
prior hospitalization at 3 months of age for respiratory syncytial virus bronchiolitis. The
parents tell you that their last doctor told them the child should not receive any live-virus
vaccines because of his HIV status. Which of the following is the next best step in
management?
A. Obtain a CD4 count and vaccinate the child with measles-mumps-rubella (MMR)
and varicella if the T-lymphocyte count is 15% or greater.
B. Obtain a CD4 count and vaccinate the child with MMR and varicella if the
B-lymphocyte count is 25% or greater.
C. Obtain a CD8 count and vaccinate the child with MMR and varicella if the
T-lymphocyte count is less than 15%.
D. Obtain a complete blood count and CD4/CD8 ratio before administering the MMR
and varicella vaccines.
E. Administer both the MMR and varicella vaccines at this time without any additional
testing.
3. A 12-year-old girl is receiving chemotherapy for acute lymphoblastic leukemia. Her
younger brother sees you today for his 4-year health supervision visit. He has been healthy
and growing well and today is due for several live-virus immunizations, including his
second MMR. The mother says that she was told by her daughters oncologist that her
daughter should not receive any live-virus vaccines. She is surprised that you plan to give
the MMR immunization to her son at this visit. What is your best response to her concerns?
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A. Household contacts of immunocompromised patients may only receive inactivated vaccines.

B. Household contacts of immunocompromised patients may receive ageappropriate MMR, varicella, rotavirus, and zoster vaccines as long as they are
immunocompetent.
C. The boy should only get the MMR or other live-virus vaccines if he can avoid contact
with immunocompromised individuals for at least 2 weeks.
D. The boy should only receive the rotavirus vaccine at this visit.
E. You will defer the boys 4-year vaccinations for at least 6 months.
4. A young woman comes to your ofce for her rst prenatal visit. She tells you she has read
a lot about vaccines on the Internet and would like to delay or omit some of the vaccines
that are usually given in the rst postnatal year. Of the following, which is your best
response to her concerns?
A. Although serious vaccine adverse events are common, the risks of not vaccinating
the child outweigh the benets.
B. Not vaccinating a child puts the child at risk for contracting vaccine-preventable
diseases, many of which are still seen in the United States, including measles.
Vol. 36 No. 6
JUNE 2015
237
C. The only vaccines that she needs to be concerned about are live-virus
immunizations.
D. Thimerosal use in immunizations is now limited to only MMR and diphtheriatetanus-pertussis (DTaP) vaccines.
E. You will work with her to develop a reasonable vaccine schedule that meets her
needs.
5. An 11-month-old child is hospitalized following 6 days of a temperature greater than
38.6C (101.4F), bilateral conjunctival injection, pharyngitis, cracked and red lips, a diffuse
maculopapular rash, and puffy hands and feet. He is diagnosed with Kawasaki disease and
treated appropriately with aspirin and immune globulin intravenous. His temperature
quickly decreases and he is about to be discharged home. You are discussing his discharge
instructions with his parents. Of the following, what would you advise his parents
regarding his 12-month vaccinations?
A.
B.
C.
D.
E.
238
He can receive his regularly scheduled 12-month vaccinations.

His 12-month vaccinations should be deferred for 3 months.
His 12-month vaccinations should be deferred for 11 months.
He should receive his varicella vaccination, but not the MMR.
He should only receive his yearly inuenza vaccine.
Hyperthyroidism in Children
Shylaja Srinivasan, MD,* Madhusmita Misra, MD, MPH*
*Pediatric Endocrine Unit, Massachusetts General Hospital for Children and Harvard Medical School, Boston, MA.
Educational Gap
Hyperthyroidism is a rare but potentially serious disorder in childhood
with unique effects on growth and development. Clinicians should be
aware of the clinical manifestations of this condition, which can be subtle.
Timely identication and referral to pediatric endocrinologists can help
reduce associated morbidity.
Objectives
1. Describe the epidemiology and pathogenesis of hyperthyroidism.

2. Identify the various causes of hyperthyroidism.
3. Recognize the signs and symptoms of hyperthyroidism, including
neonatal hyperthyroidism.
4. Initiate an appropriate evaluation and know when to refer patients to
subspecialty care.
5. Understand the various modalities for treatment of hyperthyroidism
and the limitations of each option.
CASE STUDY
AUTHOR DISCLOSURE Dr Srinivasan has

disclosed no nancial relationships relevant to
this article. Dr Misra has disclosed that she
received an investigator-initiated grant from
Genentech. This commentary does not
contain a discussion of an unapproved/
investigative use of a commercial product/
device.
An 11-year-old girl with a history of asthma comes to your ofce with shortness of
breath, chest pain, and increased use of her albuterol inhaler for the past 2 weeks.
On physical examination, her blood pressure is 135/63 mm Hg and heart rate is
108 beats/min. She appears jumpy and anxious and has a tremor of her
extremities and tongue. Neck evaluation reveals a diffusely enlarged goiter with
a bruit. Laboratory testing documents an undetectable thyrotropin of less than 0.01
mIU/mL (normal range, 0.45.0 mIU/mL), free thyroxine of 7.8 ng/dL (100.39
pmol/L) (0.91.8 ng/dL [11.5823.17 pmol/L]), and very high total triiodothyronine
of more than 650 ng/dL (10.01 nmol/L) (60181 ng/dL [0.922.79 nmol/L]). On
further evaluation, she is diagnosed with Graves disease. Following treatment of
hyperthyroidism, her symptoms improve, including those of asthma.
EPIDEMIOLOGY
Hyperthyroidism is less common in children than in adults. Graves disease is the
most common cause for hyperthyroidism in children. Few studies have prospectively examined the incidence of childhood hyperthyroidism. In a national
Vol. 36 No. 6
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240
prospective surveillance study from the United Kingdom and

Ireland in children younger than 15 years of age, the incidence
of hyperthyroidism was 0.9 per 100,000. (1) Graves disease
accounted for 96% of cases. The authors reported an increasing incidence of hyperthyroidism with age in both sexes,
although girls had a signicantly higher incidence than boys
in the 10- to 14-year age group. In 2008, approximately 8000
children in the United States were being treated for Graves
disease at any time, with an estimated prevalence of 1 in
10,000 children. (2)
a somatic-activating mutation of the GNAS gene, resulting

in increased GS protein signaling that leads to hyperfunction of glycoprotein hormone receptors, autonomous cell
proliferation, and hormonal hypersecretion. The thyroid
gland is frequently involved and is the second most common endocrinopathy after precocious puberty.
Secondary causes of hyperthyroidism, including TSHsecreting pituitary adenomas and pituitary resistance to
thyroid hormone, are exceedingly rare in children and
caused by unregulated overproduction of TSH.
ETIOLOGY AND PATHOGENESIS
CLINICAL MANIFESTATIONS
Graves disease is the most common cause of hyperthyroidism in children, accounting for more than 95% of cases.
Other causes are described in the Table.
The pathogenesis of Graves disease is not completely
understood but is believed to include a complex interaction
of genetic, immune, and environmental factors. The contribution of genetic factors is suggested by disease clustering in families and ndings from twin studies. A
population-based study of Danish twins suggested that
nearly 80% of the risk of Graves disease is attributable
to genetic factors. (3) Graves disease occurs from formation
of stimulating antibodies to the thyrotropin (TSH) receptor
(TSHR) called TSH receptor-stimulating immunoglobulins
(TSIs). These antibodies were previously referred to as the
long-acting thyroid stimulators. They bind to and stimulate
the TSH receptor on thyroid follicular cells, causing
increased vascularity of the gland, follicular hypertrophy
and hyperplasia, and excessive synthesis and secretion of
thyroid hormone. Graves ophthalmopathy is also immunemediated and caused by cross-reactivity of TSI with a TSHRlike protein in retro-orbital tissue and extraocular muscles,
leading to local inammation and inltration of glycosaminoglycans. The resulting edema, muscle swelling, and
increase in intraorbital pressure causes the characteristic
features of Graves ophthalmopathy. Clinical manifestations
of ophthalmopathy are typically less severe in children than in
adults. A similar mechanism in the dermis may be responsible for Graves dermopathy, which is rarely seen in children.
Transient hyperthyroidism may result from destruction of
thyroid follicular cells by an autoimmune or infectious process,
leading to unregulated release of preformed hormone into the
circulation. Subacute thyroiditis from an infectious or inammatory cause usually resolves in a few months, with subsequent
normalization of thyroid function. Autoimmune thyroiditis
causing hyperthyroidism may be followed by hypothyroidism.
An uncommon cause of hyperthyroidism in children is
McCune-Albright syndrome (MAS). MAS is caused by
Hyperthyroidism in children can have a wide variety of

clinical manifestations, many of which are similar to those
seen in adults. However, hyperthyroidism has unique effects on growth and development and may cause pronounced neuropsychological manifestations in children.
Growth and Puberty

During infancy, excess circulating thyroid hormone can lead
to premature craniosynostosis. Longstanding hyperthyroidism from Graves disease may result in growth acceleration
and advancement in epiphyseal maturation. Children with
Graves disease are tall for age at presentation and their bone
age tends to be advanced. However, in a retrospective Italian
study of 101 children with Graves disease, although bone
age was advanced at presentation, there were no adverse
effects on subsequent growth, and adult height was consistent with genetic potential. (4) In severe cases of hyperthyroidism, pubertal onset and progression may be delayed.
Anovulatory cycles, oligomenorrhea, and secondary amenorrhea are common in postmenarchal girls. Hyperthyroidism causes an increase in plasma sex hormone-binding
globulin. As a result, total testosterone and estradiol concentrations are increased, but their unbound fractions are
normal or even decreased.
Cardiovascular and Respiratory

Hyperthyroidism causes an increase in heart rate and
cardiac output, widening of pulse pressure, and decrease
in peripheral vascular resistance. Systolic blood pressure
may increase. The classic water hammer pulse (a bounding pulse with a rapid upstroke and descent) may be seen in
acute stages of thyrotoxicosis. The patient may experience
palpitations, and dyspnea is common in severe thyrotoxicosis. Atrial brillation occurs in up to 20% of adults with
hyperthyroidism but is rare in children. The incidence of
mitral valve prolapse is more common in patients with
Graves disease than in the general population.
TABLE.
Causes of Hyperthyroidism
INCREASED TSH SECRETION OR TSH-LIKE ACTION
LABORATORY
FINDINGS
ANTIBODIES
RADIOACTIVE
IODINE OR
TECHNETIUM-99
UPTAKE
CONDITION
PREVALENCE
THYROID
EXAMINATION
RESULTS
TSH-secreting
pituitary
adenomas
Very rare
Normal
TSH[ or Normal
Negative
Diffusely [
Pituitary thyroid
hormone resistance
Very rare
Normal or
symmetric
goiter
TSH[ or Normal
Negative
Diffusely [
hCG-induced
(TSH-like action)
Physiologic
hyperthyroidism of
pregnancy (twin
pregnancy)
Gestational
trophoblastic
tumors
Familial gestational
hyperthyroidism due
to TSH receptor
mutations
Uncommon in
children
Normal
TSHY
[ serum
b-hCG
Negative
Diffusely [
INCREASED TSH RECEPTOR ACTIVATION OR ACTIVATION OF THE DOWNSTREAM SIGNALING PATHWAY
LABORATORY
FINDINGS
ANTIBODIES
RADIOACTIVE
IODINE OR
TECHNETIUM-99
UPTAKE
CONDITION
PREVALENCE
THYROID
EXAMINATION
RESULTS
TSH receptor-activating
or -stimulating
antibodies (Graves disease)
Most common
Diffuse goiter
TSHY
TSI /- anti-TPO
Diffusely [
Activating mutations of
the TSH receptor
Very rare
Normal or diffuse goiter
TSHY
Negative
McCune-Albright syndrome
Very rare
Normal or nodular or
diffuse goiter
TSHY
Negative
AUTONOMOUS THYROID HORMONE SECRETION
CONDITION
PREVALENCE
THYROID
EXAMINATION
RESULTS
LABORATORY
FINDINGS
ANTIBODIES
RADIOACTIVE
IODINE OR
TECHNETIUM-99
UPTAKE
Toxic adenoma
Less common in
children than in adults
Single nodule
TSHY
Negative
[ in a single focus;
suppressed uptake in the
rest of the gland
Toxic multinodular
goiter
Uncommon in
children
Multinodular
goiter
TSHY
Negative
[ multifocal uptake
Continued
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241
TABLE (Continued )
INCREASED RELEASE OF PREFORMED THYROID HORMONE (TRANSIENT HYPERTHYROIDISM)
RADIOACTIVE
IODINE OR
TECHNETIUM-99
UPTAKE
CONDITION
PREVALENCE
THYROID
EXAMINATION
RESULTS
Thyrotoxic phase of
chronic lymphocytic
thyroiditis (Hashitoxicosis)
Rare
Firm goiter
TSH Y
Anti-TPO, and/or
antithyroglobulin
in most
Lymphocytic thyroiditis
(silent, painless, and
postpartum thyroiditis)
Rare
Firm, nontender
TSH Y
Anti-TPO in most
Subacute thyroiditis
(painful, postviral,
granulomatous, and
de Quervain)
Rare
Tender gland
TSH Y
[ ESR
Negative
LABORATORY
FINDINGS
ANTIBODIES
DRUG-INDUCED (EXAMPLES)
THYROID
EXAMINATION
RESULTS
LABORATORY
FINDINGS
ANTIBODIES
RADIOACTIVE
IODINE OR
TECHNETIUM-99
UPTAKE
CONDITION
PREVALENCE
Amiodarone-induced
destructive thyroiditis
Very rare in
children
Normal
TSH Y
Negative
Contrast agents:
iodine-induced synthesis of
excess thyroid hormone
(Jod Basedow effect in an
underlying multinodular goiter)
Very rare in
children
Normal
TSH Y
Negative
OTHERS
CONDITION
PREVALENCE
THYROID
EXAMINATION
RESULTS
LABORATORY
FINDINGS
ANTIBODIES
RADIOACTIVE
IODINE OR
TECHNETIUM-99
UPTAKE
Factitious intake of
thyroid hormone
Rare
Normal
TSH Y
low serum thyroglobulin
Negative
Dermoid cysts with

thyroid tissue
Very rare in
children
Normal
TSH Y
Negative
Y in thyroid
Anti-TPOantithyroid peroxidase; hCGhuman chorionic gonadotropin; ESRerythrocyte sedimentation rate; TSHthyroid stimulating hormone
(thyrotropin); TSITSH receptor-stimulating immunoglobulin
Ocular
Children with hyperthyroidism may have lid retraction due to
increased adrenergic tone of the ocular muscles that can lead to
a prominent stare and lid lag (adrenergic stare). Lid lag is
assessed by asking the child to follow the examiners nger as
the nger moves downward in front of the eye. In the case of lid
lag, the upper eyelid lags behind the globe as the childs gaze
shifts slowly downward. True ophthalmopathy in Graves
242
disease is characterized by inammatory inltrates and edema

of retro-orbital tissue and extraocular muscles, resulting in
proptosis and impairment of ocular muscle function. Although
50% to 75% of children with Graves disease may have minor
features of Graves ophthalmopathy, such as pain, a foreign
body sensation in the eyes, or diplopia, symptoms are much
milder than in adults, and orbital disease severe enough to
compromise vision is extremely rare. In a retrospective review
of 152 children with Graves disease over a 3-year period, only

17% were referred to ophthalmology for prominent ophthalmic
manifestations. (5) Following resolution of hyperthyroidism in
children, the initial lid retraction or stare from increased
adrenergic tone resolves quickly. However, true proptosis from
Graves ophthalmopathy tends to persist or regress only slightly.
Gastrointestinal
Hyperthyroidism in children causes an increase in appetite.
However, weight loss occurs despite increased food intake
because of thyroid hormone-induced calorigenesis (heat
production). There is also an increased frequency of bowel
movements, although diarrhea does not occur. In children,
weight recovers with treatment of hyperthyroidism.
Muscle and Bone

Hyperthyroidism can cause fatigue. More specically, hyperthyroidism may cause proximal muscle weakness and difculty
climbing stairs or combing hair. Thyrotoxic periodic paralysis is
a complication of hyperthyroidism that is characterized by
muscle palsy and hypokalemia. Although hyperthyroidism is
more common in females, thyrotoxic periodic paralysis primarily affects males of Asian descent. Severe hyperthyroidism
increases osteoclastic bone resorption and the risk of fractures.
Bone density improves with treatment of hyperthyroidism.
Neuropsychological
Neuropsychological manifestations can be severe in children. Nervousness, sleep disturbances, and emotional lability are common. Children may have trouble focusing on
tasks that can result in a decline in school performance,
prompting an evaluation for attention-decit/hyperactivity
disorder. Neurologic examination reveals brisk reexes, and
a ne tremor of the hands and/or tongue may be seen.
Skin and Hair

The most characteristic change of hyperthyroidism is warm,
moist skin that results from cutaneous vasodilatation and
excessive sweating. This also causes heat intolerance. Hair
becomes ne and friable, and hair loss may increase. Nails
may become soft and friable. Graves dermopathy, which is
classically associated with Graves disease in adults, involves
bilateral nonpitting edema with associated thickening and
induration of the skin, typically seen over the ankles and feet.
This manifestation is rare in children.
DIAGNOSIS
The history, physical examination, and results from thyroid
function tests (TSH, free thyroxine [T4], and total triiodothyronine [T3]) contribute to the diagnosis of hyperthyroidism.
In children with primary hyperthyroidism, the serum TSH

concentration is suppressed and T4 and T3 values are elevated. Once the diagnosis of hyperthyroidism is conrmed
biochemically, evaluation should be undertaken to determine
the underlying cause, which may affect the choice of treatment. The thyroid examination, serum thyroid antibody
measurements, and radionucleotide uptake scan help differentiate the causes of hyperthyroidism (Table).
In Graves disease, examination of the neck usually
reveals a smooth, diffusely enlarged goiter without palpable
nodularity. Often, a thyroid bruit is heard on auscultation
due to increased vascularity of the gland. The diagnosis is
conrmed by measurement of TSI, which is positive in up to
90% of cases. For children with negative TSI results or
when the diagnosis is unclear, a radionucleotide uptake scan
can aid in differentiating conditions of increased thyroid
hormone production (such as Graves disease) from conditions of increased release of preformed hormone (such as
subacute thyroiditis or the early phase of autoimmune
thyroiditis). A radionucleotide uptake is performed with
radioactive iodide (123I) or 99-technetium (99mTc) pertechnetate.
The use of 99mTc pertechnetate is preferred for diagnosing
Graves disease because it is less expensive, is a faster test, and
involves less total body radiation exposure. The radionucleotide uptake scan shows diffusely increased uptake throughout
the gland in Graves disease, whereas conditions of increased
release of preformed hormone are associated with reduced
uptake. This differentiation becomes important in determining the appropriate therapeutic strategy.
In addition to TSI, endocrinologists often measure concentrations of other antibodies such as thyroid peroxidase
antibodies, which are helpful for diagnosis of autoimmune
thyroiditis and may be positive in up to 10% of patients with
Graves disease. Additional tests include liver function tests
and assessment of the absolute neutrophil count in anticipation of treatment with antithyroid medications.
MANAGEMENT
Treatment options for Graves disease in children include
antithyroid drugs, radioactive iodine therapy, and surgical
thyroidectomy. Although thyroidectomy leads to permanent
cure and subsequent hypothyroidism, it is typically not used
as rst-line therapy because of associated morbidity and
expense. Radioactive iodine therapy often leads to permanent cure and also hypothyroidism, but it is not recommended for very young patients. Lasting remission after
antithyroid medications does not occur in most patients
with pediatric Graves disease, even after years of treatment.
However, because some children experience remission over
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243
time, antithyroid medications are still considered rst-line

treatment. In the initial period, patients often require therapy with b-blockers for management of tachycardia and
hypertension because antithyroid medications may take
several weeks to normalize thyroid hormone values. Eventually, many pediatric patients require either radioactive
iodine or surgery.
Antithyroid Medications
The thionamides methimazole and propylthiouracil (PTU) are
used to treat Graves disease. Methimazole is considered rstline antithyroid treatment for children with Graves disease.
PTU has the unacceptable risk of hepatotoxicity in children;
there are reports of fulminant hepatic necrosis and liver failure
that may require liver transplantation or may be fatal. Therefore,
the Endocrine Society and the American Thyroid Association in
conjunction with the American Association of Clinical Endocrinologists (AACE) (6) strongly recommend against use of
PTU as rst-line treatment for Graves disease in children and
the US Food and Drug Administration has issued a black-box
warning regarding use of PTU, noting at least 32 (22 adult and
10 pediatric) cases of serious liver injury with PTU use.
The dose of methimazole is 0.2 to 0.5 mg/kg per day, with
a range of 0.1 to 1.0 mg/kg per day (maximal dose typically
does not exceed 30 mg/day). Methimazole is available as
5- and 10-mg tablets, and the dose is rounded off accordingly.
A higher dose is required at the initiation of treatment, and the
dose is reduced by 50% or more after thyroid hormone values
normalize to maintain the euthyroid state. Alternatively, some
physicians add levothyroxine to attain normal thyroid hormone values, a practice referred to as block and replace.
However, this regimen does not increase the likelihood of
sustained remission, and because of a possible higher risk of
dose-related complications with methimazole, this practice is
no longer recommended, except in special circumstances.
PTU is reserved for children who are allergic to or who
develop an adverse effect from methimazole that necessitates
drug discontinuation or when radioactive iodine or surgery is
not a suitable option. PTU is still used in life-threatening
thyroid storms because of its ability to act rapidly and inhibit
the peripheral conversion of T4 to T3 and in women in the
rst trimester of pregnancy due to the risk of embryopathy,
including aplasia cutis, with use of methimazole.
The adverse effect prole of methimazole and PTU is
similar. However, adverse effects tend to occur more often
and are more severe with PTU. Minor effects include a skin
rash, arthralgias, myalgias, nausea, and an abnormal taste
sensation. In children who develop a minor adverse effect, the
drug should be discontinued for a few days until the symptom
subsides and then may be restarted. Major adverse effects
244
include agranulocytosis, vasculitis with a lupus-like syndrome, hepatitis, and liver failure. Major adverse effects
occur in fewer than 2% of patients. Adverse effects to
methimazole usually occur within the rst 6 months of
starting therapy but can develop later. In contrast to PTU,
liver toxicity with methimazole usually manifests as cholestatic jaundice. The overall rate of both minor and major
adverse effects for antithyroid drugs in children is reported
to be 6% to 35%. Patients should be given written information regarding adverse effects of antithyroid drugs
before initiating therapy.
Before initiating antithyroid drug therapy, clinicians
should obtain a baseline absolute neutrophil count (ANC)
and liver function tests because the disease process itself can
cause a decrease in ANC and elevation in liver enzymes
before medications are started. After initiation of methimazole therapy, thyroid function tests are generally repeated in
2 weeks and then monthly until values normalize. Depending
on disease severity, thyroid function tests may not normalize
for several months. After normalization of thyroid hormone
concentrations, thyroid function tests should be monitored
every 3 to 4 months. As indicated previously, a potential
dangerous complication of antithyroid drug treatment is
agranulocytosis. For this reason, antithyroid medication
should be discontinued immediately and the ANC measured
in children who develop fever, mouth sores, or pharyngitis
during treatment. Agranulocytosis (<500/mm3) is a contraindication for future antithyroid drug treatment; the patient
should be considered for radioactive iodine or surgery.
The rate of remission of Graves disease in children
varies from 25% every 2 years to 40% over 8 or more years
based on different series of reports. (7) If methimazole is
chosen as rst-line treatment for Graves disease, clinicians
should attempt to reduce or discontinue the dose after
2 years to assess for remission. Children with Graves disease
not in remission following 2 years of methimazole therapy
should be considered for treatment with radioactive iodine or
thyroidectomy, although they may also be continued on
antithyroid drugs. Some of the predictors of remission
include older age, lesser disease severity at presentation,
small goiter size, higher body mass index Z-score, postpubertal status, and a decrease in TSI over time. (8)
Once remission occurs, the relapse rate in children varies
from 3% to 47%, based on different studies. Most relapses
occur within 1 year of treatment discontinuation, but later
relapses do occur. Risk of relapse is higher in non-Caucasians,
younger patients, and those who have higher initial free T4
concentrations at presentation. TSI is also a useful predictor
of outcome: positive antibodies after discontinuation of treatment are associated with relapse.
b-blockers
b-blockers such as propranolol are recommended for children who have palpitations and tremors, when the heart rate
exceeds 100 beats/min, and in those with hypertension.
b-blockers limit b-adrenergic activity and inhibit peripheral
T4-to-T3 conversion. In addition, because propranolol is
highly lipid-soluble and readily crosses the blood-brain
barrier, it may be benecial in those with neurologic symptoms. However, cardioselective b-blockers such as atenolol
should be used in children with reactive airway disease. In
acute settings such as thyroid storm and during surgery,
intravenous b-blockers such as esmolol are preferred due to
their rapid onset of action.
Glucocorticoids
Glucocorticoids inhibit peripheral conversion of T4 to T3
and reduce thyroid hormone secretion. They are used in
severe cases of hyperthyroidism and for treatment of thyroid
storm.
Radioactive Iodine Therapy

Treatment with 131I is an effective therapy for Graves disease
and may be considered for children not in remission after at
least 1 to 2 years of treatment with antithyroid drugs or in
those who have had a major adverse effect to these medications. Children with severe Graves disease (total T4 >20
mg/mL [341.88 nmol/L] and free T4 >5 ng/dL [64.36 pmol/L])
should be pretreated with b-adrenergic blockade and
methimazole until thyroid hormone values are near normal
before proceeding with radioactive iodine therapy because
of concern for thyroid storm based on rare reports. The
present guidelines state that the goal of 131I therapy for
Graves disease is to induce hypothyroidism rather than
euthyroidism with a single adequate dose, based on a possible increased risk for development of thyroid neoplasm in
the residual partially irradiated thyroid and poor remission
rates with low doses of 131I.
There are few adverse effects from 131I therapy other than
lifelong hypothyroidism, the goal of therapy. Permanent
hypothyroidism develops 2 to 3 months after treatment,
at which time levothyroxine administration is necessary in
replacement doses. Mild tenderness can occur over the
thyroid in the rst few days after therapy from radiationinduced thyroiditis, which responds well to treatment with
nonsteroidal anti-inammatory agents. There are rare reports of thyroid storm occurring in children after radioactive
iodine treatment.
Radioactive iodine is excreted in saliva, urine, and stool,
and signicant radioactivity is retained within the thyroid for
several days. Therefore, children should follow local radiation
safety recommendations following treatment, which include

absence from school for 1 week, not sharing cups or utensils
with others, and not kissing or sitting next to pregnant
women and babies for this duration.
Concern for thyroid malignancy from use of 131I therapy is
based on the increased incidence of thyroid neoplasms in
children after the nuclear disasters at Hiroshima and Chernobyl. However, those exposures were to external ionizing
radiation and are not directly applicable to the use of radioiodine in Graves disease. It is notable that thyroid cancer
rates were not increased among 3,000 children exposed to
only 131I from the Hanford nuclear reactor site (9) or in 6,000
children who received 131I for diagnostic scanning. (10)
Further studies have not revealed an increased risk of thyroid
cancer, leukemia, or other cancers. There has also not been an
increase in the rate of infertility, spontaneous abortions, or
congenital anomalies in offspring of patients treated with
radioactive iodine. However, because of the relatively small
number of young children treated with radioactive iodine and
for theoretical cancer risk concerns, the American Thyroid
Association and AACE recommend that 131I therapy be avoided
in very young children (<5 years) and that the dose be limited
to 10 mCi in children who are 5 to 10 years of age. (6)
Surgery
Based on current guidelines, thyroidectomy is the preferred
treatment in children younger than 5 years of age when
denitive therapy is required and in children with large
goiters who experience major adverse effects to antithyroid
drugs because the response to 131I may be poor in these
cases. If surgery is planned, the patient should be pretreated
with b-blockers and antithyroid drugs or inorganic iodine.
Use of inorganic iodine for 7 to 10 days reduces the
vascularity of a large goiter and is particularly important
when antithyroid drugs cannot be used because of their
adverse effects. Near-total or total thyroidectomy is the
recommended procedure for management of Graves disease to reduce the risk of persistent hyperthyroidism. Surgery must be performed by a highly experienced surgeon to
reduce the rate of complications, which include postoperative hemorrhage, wound infection, transient or permanent
hypoparathyroidism, and vocal cord paralysis from injury to
the recurrent laryngeal nerve.
Management for Other Causes of Hyperthyroidism

The management of other causes of hyperthyroidism in
children, such as the various forms of thyroiditis (autoimmune thyroiditis and subacute thyroiditis), does not involve
specic treatments other than observation, symptomatic
treatment if necessary, and monitoring of thyroid function
Vol. 36 No. 6
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245
tests. Symptomatic treatment is rarely required because

symptoms are mild and short-lived. b-blockers can be used
in children with palpitations, tremors, signicant tachycardia,
and hypertension. In subacute thyroiditis, nonsteroidal antiinammatory agents or glucocorticoids are used for pain and
tenderness, if present. Thyroid function tests are monitored
to assess for the resolution of hyperthyroidism and to detect
subsequent transient or permanent hypothyroidism.
Methimazole can be used to control biochemical effects
of hyperthyroidism in MAS and activating mutations of the
TSH receptor. However, this is a temporary measure; radioactive iodine or surgery is eventually necessary for permanent treatment. Treatment options for toxic adenomas and
toxic multinodular goiters include radioactive iodine or
surgery, although surgery is preferred in children. Therapies for TSH-secreting pituitary adenomas are directed at
treatment of the pituitary tumor.
THYROID STORM
Thyroid storm is a rare and life-threatening condition that is
an extreme manifestation of hyperthyroidism and an endocrine emergency. In adults, thyroid storm is estimated to
occur in fewer than 1% of patients with hyperthyroidism, and
the incidence in children is not clear. Thyroid storm is
characterized by multisystem organ failure and clinical features that include nausea, vomiting, diarrhea, tachycardia,
hyperpyrexia, hepatic dysfunction, hypotension, arrhythmias,
and congestive heart failure. Among the neuropsychiatric
manifestations are agitation, delirium, psychosis, stupor, and
coma. Factors that can precipitate thyroid storm include
abrupt cessation of antithyroid drugs, thyroid or nonthyroid
surgery in a patient with unrecognized or inadequately
treated hyperthyroidism, radioactive iodine therapy, and
acute illnesses such as diabetic ketoacidosis. In children,
thyroid storm has also been reported after inadvertent or
purposeful ingestion of levothyroxine. (11)
A high index of suspicion for thyroid storm should be
maintained in children with hyperthyroidism who demonstrate evidence of systemic decompensation. Guidelines
from the American Thyroid Association and AACE suggest
a multimodality treatment approach with close monitoring in an intensive care unit. Treatment should include
b-adrenergic blockade with propranolol or esmolol (parenteral therapy is usually necessary), antithyroid drug
therapy with PTU, inorganic iodine solutions for acute
inhibition of thyroid hormone secretion and synthesis, and
corticosteroid therapy. Supportive measures include aggressive cooling with cooling blankets, use of acetaminophen, volume resuscitation, and respiratory support.
246
NEONATAL THYROTOXICOSIS
Neonatal thyrotoxicosis is almost always the result of neonatal Graves disease caused by transplacental passage of
maternal TSI antibodies. This condition is transient and
self-limiting but can have severe clinical manifestations
and long-term sequelae. Graves disease occurs in approximately 0.2% of women, and neonatal thyrotoxicosis occurs in approximately 1% to 5% of infants born to affected
mothers. Based on these data, the incidence of neonatal
Graves disease is estimated to be 1 in 25,000 neonates.
The likelihood of neonatal Graves disease is related to the
titer of maternal TSI, with hyperthyroidism most likely
when the maternal TSI titer exceeds 500%. Neonatal
thyrotoxicosis typically occurs in infants of mothers with
active Graves disease but can also occur in infants of mothers
with a history of Graves disease previously treated with
radioactive iodine or surgery due to the persistence of TSI.
During pregnancy, fetal thyrotoxicosis is monitored by
assessing for the presence of a fetal goiter on ultrasonography
and for fetal tachycardia. Intrauterine growth restriction can
cause small-for-gestational age births, and preterm births may
occur. Very severe cases can lead to intrauterine heart failure,
fetal hydrops, and intrauterine demise. Clinical manifestations of neonatal thyrotoxicosis include irritability, hyperactivity, restlessness, poor sleep, diarrhea, and poor weight gain.
Physical examination may reveal warm and moist skin,
tachycardia with bounding pulses, arrhythmias, frontal bossing with triangular facies, hepatosplenomegaly, a diffuse
goiter, and an adrenergic stare. Severe neonatal thyrotoxicosis
may be complicated by congestive heart failure.
The time of onset and severity of symptoms vary, depending on whether the mother received treatment with antithyroid
drugs during pregnancy. Infants born to mothers not treated
with antithyroid drugs during pregnancy can exhibit hyperthyroidism at birth. Infants of mothers treated with antithyroid
drugs may be euthyroid or even hypothyroid at birth from
transplacental passage of the antithyroid drug and may
become hyperthyroid several days later, after the antithyroid
drug clears from the neonates circulation. Thyroid function
tests should be obtained in infants born to mothers with
Graves disease after birth and additionally if symptomatic.
If neonatal thyrotoxicosis is detected, treatment should be
initiated promptly.
For the management of severe cases of neonatal thyrotoxicosis, inorganic iodine (such as Lugol solution) is administered in pharmacologic doses to inhibit organication of
iodide and thyroid hormone release. The advantage of
inorganic iodine over methimazole is its rapid onset
of action. Effects of inorganic iodine wear off after 4 to 6
weeks, but neonatal Graves disease is usually in the process

of resolving by this time. Treatment options also include
b-blockers and sometimes methimazole. As mentioned,
there is a black-box warning against the use of PTU for
treatment of Graves disease in children. Glucocorticoids
are used in severe cases, and digoxin is helpful if heart
failure occurs. Transient hypothyroidism rarely occurs from
prolonged suppression of TSH that persists even after
thyroid hormone secretion has decreased. Affected infants
may require a short duration of levothyroxine replacement
therapy until TSH concentrations normalize.
Neonatal Graves disease typically resolves spontaneously
3 to 12 weeks after birth, although it occasionally persists for
a longer period. Long-term sequelae include poor growth,
craniosynostosis, hyperactivity, developmental and behavioral problems, and very rarely persistent hypothyroidism.
On the basis of some research evidence and consensus, history,

physical examination, and thyroid function tests help diagnose
hyperthyroidism. The condition is characterized by suppressed
serum thyrotropin and elevated serum triiodothyronine and
thyroxine. Radioactive iodine (or technetium-99) uptake and
serum thyroid antibody measurements help determine the cause
of hyperthyroidism. (6)
On the basis of some research evidence and consensus, treatment
options for Graves disease in children include antithyroid
medications, radioactive iodine, and surgery. Antithyroid
medications are commonly used as the rst-line therapy in
children. However, because of the low rates of spontaneous
remission, (7) most children eventually require permanent
treatment with radioactive iodine or surgery. Of the available
antithyroid medications, current guidelines recommend use of
methimazole and not propylthiouracil because of the unacceptable
risk of hepatotoxicity associated with propylthiouracil. (6)
On the basis of strong research evidence, thyroid storm is a rare
life-threatening endocrine emergency that should be suspected
in children with hyperthyroidism who demonstrate evidence of
systemic decompensation.
Summary
On the basis of strong research evidence, hyperthyroidism is
a rare (1) but potentially serious disorder in childhood that, if
uncontrolled, can lead to a wide range of complications,
including effects on growth and development.
On the basis of strong research evidence, Graves disease is the
most common cause of hyperthyroidism in children, accounting
for greater than 95% of cases. (2) It is caused by stimulating
antibodies to the thyroid-stimulating hormone receptor.
On the basis of strong research evidence, neonatal

hyperthyroidism can occur in infants born to mothers with
a history of Graves disease due to transplacental passage of TSH
receptor stimulating antibodies.
References for this article are at http://pedsinreview.aappublications.

org/content/36/6/239.full.

http://www.healthychildren.org/English/health-issues/conditions/chronic/Pages/Thyroid-Disorders-Treatment.aspx
Vol. 36 No. 6
JUNE 2015
247
PIR Quiz
1. Which of the following thyroid examination ndings, thyroid function tests, serum thyroid
antibody measurements, and radionuclide uptake scan results are most commonly seen in
patients with Graves disease:?
A. Diffuse goiter, decreased thyrotropin (TSH), positive serum thyroid antibody,
diffusely increased radionuclide uptake.
B. Firm goiter, decreased TSH, positive serum thyroid antibody, decreased radionuclide uptake.
C. Multinodular goiter, decreased TSH, negative serum thyroid antibody, increased
multifocal radionuclide uptake.
D. Normal thyroid examination, decreased TSH, negative serum thyroid antibody,
diffusely increased radionuclide uptake.
E. Tender thyroid gland, decreased TSH, negative serum thyroid antibody, decreased
radionuclide uptake.
2. Graves disease results from:
A.
B.
C.
D.
E.
Autonomous thyroid hormone secretion.

Excessive production of thyrotropin-releasing hormone in the hypothalamus.
Formation of stimulating antibodies to the TSH receptor.
Increased release of preformed thyroid hormone.
Increased TSH secretion.
3. A 13-year-old girl comes to your ofce for a routine health supervision visit. During the
physical examination, you palpate a rm thyroid gland. You also notice a tremor of her
extremities and tongue. Because of these physical examination ndings, you order
laboratory tests. Results include: TSH <0.01 mIU/L (normal, 0.45.0 mIU/L), free thyroxine 5
ng/dL (64.36 pmol/L) (normal, 0.91.8 ng/dL [11.5823.17 pmol/L]), and triiodothyronine
350 ng/dL (5.39 nmol/L) (normal, 60-181 ng/dL [0.922.79 nmol/L]). Which of the following
additional physical examination ndings best supports the diagnosis of hyperthyroidism?
A.
B.
C.
D.
E.
Bilateral ptosis.
Hepatomegaly.
Muscle weakness.
Decreased pulse pressure.
Truncal obesity.
4. Methimazole is used as rst-line antithyroid treatment for children with Graves disease
because propylthiouracil has an unacceptable risk of hepatotoxicity associated with its use.
However, liver toxicity is a major adverse effect of methimazole. Liver toxicity with
methimazole usually manifests as:
A.
B.
C.
D.
E.
Cholestatic jaundice.
Fulminant hepatic necrosis.
Hepatitis.
Hepatoblastoma.
Steatosis.
5. A new admission to the newborn nursery is an infant who was born to a mother with
Graves disease. When reviewing the mothers chart, the presence of which of the following
ndings on prenatal ultrasonography would be most concerning for fetal thyrotoxicosis?
A.
B.
C.
D.
E.
248
Adrenergic stare.
Craniosynostosis.
Edema of the lower extremities.
Fetal tachycardia.
Frontal bossing.
learners must
or higher on this
assessment, which
than 60% on the
given additional
achieved.
which the learner
completes the quiz.
Immunizations: Vaccinations in General

Catherine C. Wiley, MD*
*Associate Professor of Pediatrics, University of Connecticut School of Medicine, Connecticut Childrens Medical Center, Hartford, CT.
Educational Gap
Despite the great success of the national childhood immunization
program, gaps in coverage remain, and vaccine-preventable diseases
continue to occur.
Objectives
1. Describe the indications, contraindications, and schedule for each of

the routine childhood immunizations.
2. Recognize the enhanced immunogenicity of conjugate vaccines.
INTRODUCTION
Immunization is one of the most frequent, complex, and costly activities in the
pediatric ofce. The routine childhood immunization schedule published by the
Centers for Disease Control and Prevention (CDC) has burgeoned from vaccines
protecting against nine diseases, supplemented by one-half page of explanatory
footnotes, 2 decades ago to 16 diseases, three pages of footnotes, and a host of
combination vaccines in 2014. Although electronic health record decision support
holds promise for streamlining vaccine administration, currently pediatricians
must rely on intimate knowledge of immunizations and ready access to resources
that address the nuances of the schedule and other special considerations such as
contraindications and precautions.
This article reviews the routine childhood vaccine schedule, contraindications
and precautions to immunization, and common special considerations in immunization. A full discussion of special circumstances and high-risk populations is
beyond the scope of this review. A companion article in this issue of Pediatrics in
Review Vaccine Safety: Medical Contraindications, Myths and Risk Communication, by Dr Michael Smith addresses vaccine hesitancy and catch-up
schedules for unimmunized and underimmunized children.
GENERAL CONCEPTS
AUTHOR DISCLOSURE Dr Wiley has disclosed
no nancial relationships relevant to this
article. This commentary does not contain
a discussion of an unapproved/investigative
use of a commercial product/device.
The childhood immunization schedule is reviewed, updated, and approved

annually by the Advisory Committee on Immunization Practices (ACIP), the
American Academy of Pediatrics, and the American Academy of Family Practice.
The schedule is published annually in the Morbidity and Mortality Weekly Report.
The CDC Recommended Immunization Schedule for Persons Aged 0 through 18
Vol. 36 No. 6
JUNE 2015
249
years United States 2015, catch-up schedules, and adult

immunization schedules are available at www.cdc.gov/
vaccines/schedules. The recommended schedule takes into
account available evidence regarding vaccine efcacy and
safety, immunogenicity (including persistence of passive
maternal antibody), and disease prevalence. Although standard recommended intervals should be followed routinely to
maximize protection, minimal intervals may be used to
catch up children with delayed immunizations or if there
is concern that a child may not return.
Timeliness of immunization is a challenge. A 2002 study
demonstrated that by the age of 24 months, approximately
90% of children had received at least one vaccine late or too
early to be considered valid. (1) When immunization is
delayed, no routine immunization dose needs to be repeated.
For immunizations administered too early, the dose should
be repeated at the recommended minimum age and interval
following the invalid dose. In accordance with ACIP guidelines, vaccines given within a grace period of 4 or fewer days
below the minimum interval may be accepted as valid, but
local and state regulations may not recognize this exception.
Most vaccines may be administered simultaneously, but
when live vaccines are not given simultaneously, administrations should be separated by at least 28 days. Antigenic
content of various vaccine products varies and evidence
concerning the interchangeability of products is limited.
The same product should be continued if practical, but
vaccines should not be delayed if the same product is not
available.
Other than local reactions and fever, adverse events to
immunization are relatively rare. Parents should be counseled
about possible adverse events and provided with the current
Vaccine Information Statements published by the CDC.
Signicant adverse events should be reported to the CDC
through the Vaccine Adverse Event Reporting System. (2)
Vaccines should not be administered in the presence of
a true contraindication. Only one contraindication is common to all vaccines: anaphylaxis to a previous dose or
vaccine component. When a precaution is present, immunization is generally deferred. However, vaccines may be
given if the benet outweighs the risk (eg, community
outbreak). The only precaution to all vaccines is moderateto-severe acute illness at the time that the immunization is
due. In these situations, immunization may resume as the
acute illness begins to resolve. Deferring vaccines in the
absence of true contraindications or precautions (eg, during
minor illness) is an important cause of missed opportunities
for immunization.
Most routine childhood vaccines contain inactivated subunit antigens or toxins. The introduction of conjugate vaccine
250
technology has been an important advance in the protection

of children younger than 2 years of age as well as immunocompromised individuals. Bacterial polysaccharides, which
are poorly immunogenic in younger children, are conjugated
to carrier proteins (typically capsular or outer membrane
antigens). These proteins improve immune responsivity by
triggering T-cell-dependent immunity to polysaccharides,
thereby strengthening immune memory.
Live attenuated vaccines include vaccines against measlesmumps-rubella (MMR), varicella, rotavirus, and inuenza.
Live vaccines generally induce stronger mucosal immunity
than inactivated products. Because viral replication occurs,
live vaccines are generally contraindicated in immunocompromised patients, in pregnancy, and following recent receipt
of antibody-containing blood products (up to 11 months,
depending on the dose of antibody received).
INFLUENZA VACCINES
Immunization against inuenza poses unique challenges
because of the changing circulation of antigenically distinct
inuenza viruses from year to year. Antigenic drift, due to
continual minor inuenza virus mutations, is particularly common among inuenza A strains. In contrast, antigenic shift
introduces a markedly novel inuenza strain following a sudden
major change in antigens to which there is little or no preexisting immunity in the population. (3) Antigenic shift is much less
common than antigenic drift but has the potential to result in
pandemics (eg, Spanish u of 1918 and H1N1 in 2009).
Inuenza vaccine is developed annually based on the
antigenic composition of strains predicted to circulate most
widely in the coming year. Trivalent vaccine historically
included one B strain and two A strain lineages. Beginning
with the 2013-2014 season, quadrivalent inuenza vaccine
became available to cover both inuenza B strain lineages. In
the prior 10 years, the circulating B strain was included in the
trivalent vaccine in only 50% of seasons. (3) Quadrivalent
inuenza vaccines eventually should replace trivalent vaccines.
Childhood inuenza immunization historically targeted
children 6 months to 2 years of age, who experience severe
illness and death at rates similar to other high-risk groups
(such as adults >65 years of age), and children with chronic
illnesses, including persistent asthma and other chronic
respiratory diseases as well as cardiac, neurologic, metabolic, hepatic, renal, and immunologic disorders. However,
routine inuenza immunization for all children older than
6 months of age has been recommended since 2010. This
recommendation is based on the following observations:
Excess severe illness burden also occurs in children ages 2
to 5 years.
Inuenza causes preventable severe illness and death in

previously healthy older children and young adults.
Inuenza immunization confers health benets for all
age groups.
Children serve as a vehicle of transmission of inuenza to
unimmunized and unprotected individuals, including
very young infants, immunocompromised individuals,
and patients with contraindications to immunization.
Immunization of all health-care personnel and ofce
staff is essential to protect vulnerable patients and to keep
staff healthy and available to treat patients during community outbreaks. To ensure patient protection, compliance
with annual inuenza immunization is a condition of
employment at many health-care facilities.
Inuenza vaccine is administered annually to children
ages 6 months and older, beginning as soon as vaccine
becomes available. Although waning immunity late in the
season is a consideration, missed opportunities to immunize and the challenging logistics of immunizing large
numbers of patients in a narrow window of time support
early immunization. Continuing immunization throughout
the inuenza season is also advised (Table 1).
Children ages 9 years and older require one dose of
inuenza vaccine annually. Younger children receiving
either live or inactivated vaccine may require two doses
separated by at least 28 days; recommendations vary from
year to year. Currently, two doses are indicated if the child
has not received two doses before the start of the current
inuenza season. The only exception to this rule is children
who received one dose of inuenza vaccine in the 2013-2014
season, who need only one dose in the 2014-2015 season.
Because H1N1 has continued to circulate since the
2009-2010 season, children younger than 9 years also need
two doses in the current season if at least one prior dose did
TABLE 1.
not contain H1N1 antigen. H1N1 antigen has been included

in all vaccines since 2010 and in monovalent H1N1 vaccine
during the 2009-2010 season.
There are few true contraindications to inuenza vaccine.
Both inactivated and live attenuated inuenza vaccines are
contraindicated in patients with severe egg allergy. Patients
with mild egg allergy without anaphylaxis may receive
inactivated inuenza vaccine, followed by 30 minutes of
in-ofce observation.
A small increase in the risk of febrile seizures among
children ages 6 months to 5 years has been observed in some
seasons, particularly with simultaneous administration of
pneumococcal conjugate vaccine. Although surveillance for
an association between inuenza vaccine and febrile seizures
continues, current recommendations have not changed. However, one brand of inuenza vaccine was more denitively
associated with increased incidence of febrile seizures (Auria,
Merck and Co, Inc, Whitehouse Station, NJ) and is not routinely
recommended for children younger than 9 years of age. (3)
Guillain-Barr syndrome (GBS) was associated with the
1976 swine inuenza vaccine, but recent studies suggest at
most a small increased risk of GBS following inuenza
immunization (approximately 1 additional case per 1 million
doses). (4) Immunization of patients with a past history of
GBS deserves careful consideration; the potential small
increased risk of recurrent GBS must be balanced against
the risk of inuenza disease, particularly in individuals with
other high-risk conditions.
Quadrivalent live attenuated inuenza vaccine (LAIV4)
has a similar safety prole and efcacy as compared to
inactivated inuenza vaccine, and is an option for healthy
children 2 years of age and older. Adverse events following
LAIV4 administration are uncommon and include minor
respiratory and gastrointestinal symptoms such as
Inuenza Vaccines Approved for Use in Children 6 Months to 17

Years of Age, 2014-2015 Season
TRADE NAME
MANUFACTURER
FORMULATION
AGES INDICATED
ROUTE
Fluzone
Sano Pasteur
IIV3, IIV4, inactivated
6 mo
Intramuscular
FluMist
MedImmune
LAIV4, live attenuated
2 y (to 49 y)
Intranasal
Fluarix
GlaxoSmithKline
3 y
Intramuscular
FluLaval
ID Biomedical Corporation of Quebec
3 y
Intramuscular
Fluvirin
Novartis Vaccines and Diagnostics
IIV3, inactivated
4 y
IIV4, inactivated
5 y
Auria
CSL Limited
Intramuscular
*
Intramuscular
*American Academy of Pediatrics does not recommend routine use before age 9 years due to risk of febrile seizures.
Vol. 36 No. 6
JUNE 2015
251
rhinorrhea, cough, abdominal pain, and fever. LAIV4 is

contraindicated in pregnancy, egg allergy, and immunosuppression; in recipients of antiviral agents in the preceding
48 hours; and in children being treated with aspirin.
Asthma and other underlying conditions that might be
associated with a higher risk of inuenza complications
are precautions for LAIV4 due to the lack of safety evidence
in affected patients. Children 2 to 4 years of age who have
a history of wheezing in the last 12 months also should not
receive LAIV4. Contacts of immunosuppressed patients
may receive LAIV4, with the exception of caregivers of
individuals with severe immunosuppression requiring
a protected environment (eg, bone marrow transplant unit).
CONJUGATE VACCINES
Meningococcal Vaccines
Two quadrivalent conjugate vaccines (Menactra [MCV4-D],
Sano Pasteur, Inc, Swiftwater, PA and Menveo [MCV4CRM], Novartis Vaccines, Cambridge, MA) are currently
available to protect against meningococcal strains A/C/Y
and W-135. Nearly 75% of meningococcal infections in children 11 years and older involve these strains. (5) Two nonconjugate vaccines targeting serogroup B have recently been
licensed for children and young adults ages 1025 years
(Bexsero, Novartis and Trumenba, Wyeth Pharmaceuticals
Inc, Philadelphia, PA). Bexsero is administered in two doses
one month apart; Trumenba requires three doses at 0, 2, and
6 months. While these vaccines have been used in outbreaks
in New Jersey, California, Rhode Island, and Oregon, formal
recommendations for use have not yet been published.
Indications will likely include outbreak control and immunocompromise (complement deciencies and asplenia). (6)
Conjugate meningococcal vaccines are preferred due to
strong anamnestic responses to a subsequent booster dose,
reduced nasopharyngeal carriage of meningococcus, and
longer duration of clinical protection. (7) Quadrivalent meningococcal polysaccharide vaccine (Menomune [MPSV4], Sano)
may be used when there is a contraindication to MCV4 (eg,
severe allergy to diphtheria toxoid). Immunization is recommended at 11 to 12 years of age, with a booster dose at 16 to
18 years of age, at least 8 weeks after the rst dose. Cases of
meningococcal disease and deaths are signicantly fewer
with this two-dose regimen. Individuals receiving a rst dose
of vaccine at 16 years of age or older do not require a second
dose, but unimmunized college freshman living in dormitories and those who received a single dose before age 16 years
should receive one dose of vaccine. There has been a small
increase in GBS clustered 14 days after administration of
Menactra (but not Menveo). The risk of GBS is outweighed by
252
the benet of protection against meningococcal disease.

Accordingly, a prior history of GBS was removed as a precaution to meningococcal vaccination in 2010. (6)
Routine immunization of children younger than 11 years
of age is not recommended. Recommendations for meningococcal immunization for patients at increased risk vary
with patient age and the specic indication for immunization (eg, potential exposure vs immune compromise). (7) In
general, two doses of MCV4 separated by 8 to 12 weeks are
recommended for children 2 years of age and older with
immunodeciency and adolescents 11 years of age or older
with human immunodeciency virus (HIV) infection. Only
MCV4-D is approved for infants 2 to 9 months old at
increased risk of meningococcal disease; either conjugate
vaccine may be administered to infants and children older
than 9 months. Children with functional or anatomic asplenia,
including sickle cell disease, should not receive MCV4-D
until after 2 years of age due to immune interference with
13-valent pneumococcal conjugate vaccine (PCV13). (7)
HibMenCY (MenHibrix, GlaxoSmithKline Biologicals,
Rixensart, Belgium) is a bivalent meningococcal vaccine
conjugated to Haemophilus inuenzae b (Hib) that protects
against strains C and Y. It is approved as a four-dose series
for infants 6 weeks to 18 months of age at high risk due to
functional or anatomic asplenia (including sickle cell disease), complement deciencies, or exposure due to local
outbreaks. When infants are immunized with HibMenCY,
this vaccine should be used for all four doses, and other Hibcontaining vaccines should not be given. For high-risk children 2 to 6 years of age, a booster dose with MCV4 is required
3 years after the primary series. Thereafter, and for children
7 years of age and older, a booster of MCV4 is required
every 5 years. (7)
Pneumococcal Vaccines
Streptococcus pneumoniae is an important cause of respiratory tract disease (pneumonia, sinusitis, and otitis media),
bacteremia, and meningitis. In 2010, PCV13 replaced the
former 7-valent vaccine. The polysaccharide capsular antigens in PCV13 are individually conjugated to a diphtheria
membrane protein. PCV13 is indicated for immunization of
healthy children at 2, 4, 6, and 12 to 15 months of age as well
as children and adults with immune compromise and other
conditions that increase the risk for invasive pneumococcal
disease. (8) Healthy children 15 to 59 months of age and
children with underlying medical conditions younger than
72 months of age who were previously fully immunized
with PCV7 should receive one dose of PCV13. Older children with immune compromise and other specic high-risk
conditions for invasive disease (eg, cochlear implants,
cerebrospinal uid leaks, and asplenia) should be immunized with one dose of PCV13 if not previously immunized.
A nonconjugate, 23-valent pneumococcal vaccine (PPS23)
is also available for high-risk patients to protect against the 13
serotypes in PCV13 as well as 10 additional serotypes. PPS23
is poorly immunogenic in children younger than 24 months
of age and is not used in this age group. PPS23 is indicated
for patients 2 years of age and older with the following
conditions:
Chronic illnesses such as chronic lung disease (including
asthma for those 19 years and older)
Chronic cardiac, renal, and hepatic disease and diabetes
Immunocompromising conditions such as sickle cell
disease, HIV, and malignancy
For immunocompromised patients, PPS23 should be
administered at least 8 weeks following a dose of PCV13.
In childhood, only one additional dose of PPS23 is recommended, 5 years after the rst dose (eg, for children with
timely immunizations, PPS23 is administered at 2 years and
7 years). Pneumococcal vaccine administration is nuanced
in patients with chronic disease and immunocompromise,
and the reader is directed to the references for additional
information. (8)(9)
Haemophilus Inuenzae Type B Vaccines

Hib was a leading cause of bacteremia, meningitis, cellulitis,
and epiglottitis in the prevaccine era. Hib capsular antigen is
conjugated to either a tetanus or Neisseria meningitidis-derived
carrier protein. Hib vaccine is given in three or four doses
(determined by brand) at 2, 4, (6) and 12 to 15 months, either as
a monovalent vaccine or in combination with diphtheriatetanus-acellular pertussis-inactivated poliovirus. A single dose
is sufcient for children ages 15 to 59 months of age who have
delayed immunizations; a catch-up schedule is available for
younger children with incomplete immunizations. Immunization may also be indicated for some older children with
immune compromise. Adverse events following Hib vaccine
are uncommon and largely limited to minor local reactions.
NONCONJUGATE INACTIVATED VACCINES

Hepatitis Vaccines
Hepatitis B infection is a common cause of acute and
chronic liver disease, hepatocellular carcinoma, and death
worldwide. Hepatitis B vaccine, composed of recombinant
DNA-produced hepatitis B surface antigen (HBsAg), was
the rst vaccine to provide protection against cancer through
prevention of infection with hepatitis B virus. Hepatitis B
infection in newborns is rarely symptomatic but results in
a chronic carrier state in more than 90% of infected infants.
Prompt neonatal immunization is highly efcacious in

preventing neonatal acquisition of hepatitis B. Therefore,
for infants weighing at least 2 kg, hepatitis B vaccine is
administered at birth, 1 to 2 months, and 6 months of age,
with catch-up for unimmunized older children. Combination vaccines should not be used for the birth dose. The nal
dose should be provided no earlier than 24 weeks of age, at
least 8 weeks following the second dose and at least 16 weeks
following the rst dose. For preterm infants weighing less
than 2 kg, hepatitis B immunization is deferred until the
infant reaches 1 month of age or hospital discharge (whichever comes rst), unless the mother is HBsAg-positive or
her status is unknown. In these situations, hepatitis B
vaccine is given at birth, but the dose is not counted
and is repeated when the infant reaches 1 to 2 months of
age. (10)
Hepatitis B immune globulin (HBIG) is coadministered
with hepatitis B vaccine within 12 hours of birth to infants
born to hepatitis B-infected mothers and to preterm infants
weighing less than 2 kg if the mothers results will not be
available by 12 hours of age. For infants weighing more
than 2 kg, HBIG administration may be deferred for up to 7
days or until the mother is determined to be HBsAgpositive. HBIG should be administered no later than 7 days
after birth if the mothers results remain unavailable. Original
maternal laboratory reports should be viewed directly; failure
to recognize maternal hepatitis B infection and deferral of
immunization outside of the perinatal period have been
associated with preventable neonatal hepatitis B infection
and rare deaths from fulminant neonatal hepatitis B. Infants
born to HBsAg-positive mothers should be tested for hepatitis B surface antibody and HBsAg following the nal dose
of hepatitis B vaccine (typically at 9 to 12 months).
Hepatitis A infection is also an important cause of preventable liver disease. Two single-antigen inactivated hepatitis A vaccine (HAV) products are currently available for
use in children: Havrix (GlaxoSmithKline) and VAQTA
(Merck and Co, Inc). HAV is recommended for all children
12 months of age, with a booster dose 6 to 18 months later
and catch-up for older children. Immunization is also
recommended for household contacts of children adopted
from countries with moderate-to-high rates of hepatitis A
infection (currently applies to most international adoptees).
Adverse events are uncommon. HAV and hepatitis A
immune globulin are recommended for postexposure prophylaxis for unimmunized patients.
Diphtheria, Pertussis, and Tetanus Vaccines

Pertussis illness has a variety of presentations, including
a nondescript upper respiratory tract infection, the classic
Vol. 36 No. 6
JUNE 2015
253
triphasic 100-day cough syndrome, pneumonia, apnea (in

young infants), seizures, and encephalopathy, with mortality
occurring predominantly in infants. Tetanus is characterized by severe muscle spasms provoked by a neurotoxin,
often progressing to respiratory failure. Diphtheria infection causes an acute membranous pharyngitis that may lead
to airway obstruction. Although diphtheria and tetanus are
now rare in the United States, pertussis infections remain
endemic, with cyclic peaks occurring every 3 to 5 years.
Acellular pertussis vaccines have entirely replaced wholecell pertussis vaccines. Although acellular pertussis vaccines
contain varying pertussis antigens and quantities (Table 2),
currently available products are believed to be equivalent in
efcacy and safety. These products are associated with fewer
adverse effects than whole-cell pertussis vaccines, but recent
data also suggest a more rapid decline in immune protection
following immunization with acellular pertussis vaccine. (11)
Reported cases of pertussis have been increasing, particularly
among children 10 years of age and older. Complete protection against pertussis is 98% at 1 year following the fth
dose of pertussis-containing vaccine, declining to 70% at 5 or
more years following immunization.
Diphtheria-tetanus-acellular pertussis (DTaP) vaccine is
administered in a ve-dose series at 2, 4, and 6 months of
age; at 15 to 18 months (at least 6 months following the third
dose); and upon school entry (4-6 years). Only four doses are
required if the fourth dose is given after 4 years of age. DTaP
is often administered as a component of combination
TABLE 2.
vaccines containing inactivated polio vaccine (IPV) and

Hib or hepatitis B vaccine. DTaP and diphtheria-tetanus
(DT) are not recommended for children 7 years or older.
Beginning in 2005, a single dose of Tdap replaced Td for
adolescents 11 to 18 years of age. Since 2010, ACIP has also
recommended a single dose of Tdap for unimmunized/
underimmunized children 7 to 10 years of age due to lack
of a licensed pertussis-containing vaccine for this age group.
(12) Tdap is preferred for children 7 years of age and older
because it is less reactogenic than DTaP (due to its reduced
diphtheria and pertussis antigenic content) (Table 2). A single
dose of Tdap is followed by up to three doses of Td for children
who require additional doses to complete the routine series.
When indicated, Tdap may be administered with no
minimum interval following the last dose of DTaP, DT, or
Td. To achieve high antibody concentrations during pregnancy and passive protection of the newborn, mothers should
be immunized with Tdap during each pregnancy, preferably
during the third trimester. (13) With the exception of pregnancy, no booster doses of Tdap are recommended; subsequent doses should be administered as Td. Booster doses of
Tdap may be recommended in the future as additional longterm safety and efcacy data become available.
A booster dose of a tetanus-containing vaccine is recommended for patients with clean wounds incurred 10 or more
years since their last tetanus dose and for major or contaminated wounds seen 5 or more years since the last dose.
Vaccine should also contain diphtheria and pertussis
Comparison of Selected Diphtheria and Pertussis-containing

Vaccines
TRADE NAME
DAPTACEL
DTaP
INFANRIX
DTaP
KINRIX
DTaP-IPV
ADACEL
Tdap
BOOSTRIX
Tdap
PENTACEL
PEDIARIX
DTaP-IPV-HIB DTaP- IPV-HEP B
Manufacturer
Sano Pasteur GlaxoSmithKline GlaxoSmithKline Sano Pasteur GlaxoSmithKline Sano Pasteur GlaxoSmithKline
Age approved
6 wk 6 y
6 wk 6 y
46y
10 64 y
10 y
6 wk 4 y
6 wk 6 y
Tetanus toxoid
5 Lf
10 Lf
10 Lf
5 Lf
5 Lf
5 Lf
10 Lf
Diphtheria toxoid
15 Lf
25 Lf
25 Lf
2 Lf
2.5Lf
15 Lf
25 Lf
Filamentous
hemagglutinin
5 mg
25 mg
25 mg
5 mg
8 mg
20 mg
25 mg
Inactivated
pertussis toxin
10 mg
25 mg
25 mg
2.5 mg
8 mg
120 mg
25 mg
Pertactin
3 mg
8 mg
8 mg
3 mg
2.5 mg
3 mg
8 mg
Fimbriae
Types 2 & 3
5 mg
5 mg
5 mg
Pertussis Antigens:
Lflimit of occulation (units)
254
antigens, unless specically contraindicated. Tetanus

immune globulin is indicated only in isolated circumstances:
massive or contaminated wounds in patients with unknown
immunization status or who received fewer than three doses
of tetanus-containing vaccine, persons with HIV or other
severe immunocompromise regardless of immunization status, and potential umbilical cord contamination in an infant
born to an unimmunized mother outside of a hospital. (14)
The most common reactions to DTaP are local and febrile.
A temperature greater than 40.5C (104.9F), seizures,
hypotonic-hyporesponsive episodes, and inconsolable crying are much less common after DTaP than was observed
for whole-cell pertussis vaccine, but such occurrences represent precautions to subsequent doses of DTaP. These
events are not associated with later epilepsy or other sequelae.
Current evidence does not support a causal relationship
between acellular pertussis vaccines and acute neurologic
illness, but encephalopathy within 7 days of receipt of any
pertussis-containing vaccine remains a contraindication to
further pertussis immunization. Vaccination is typically
deferred in young infants with evolving neurologic illnesses.
If the indication for deferral persists beyond 1 year of age,
immunization with DT is recommended up to the age of 7
years, after which time Td is advised. GBS and brachial
neuritis are rare adverse events following tetanus toxoid
administration but not after DTaP. GBS occurring within
6 weeks following Td or Tdap is a precaution to further doses.
Generally, Td or Tdap are not administered in such situations,
but individual circumstances should be considered.
The spectrum of illness ranges from asymptomatic infection to genital warts, genital cancers (particularly cervical
cancer), anal and head-and-neck cancers, and rarely,
laryngeal papillomatosis (via vertical transmission during
vaginal delivery). Two licensed vaccines (Gardasil, Merck
and Co, Inc, and Cervarix, GlaxoSmithKline) provide
protection against HPV types 16 and 18, which together
cause approximately 70% of cervical cancers. Gardasil
also provides protection against types 6 and 11, which
cause 90% of genital warts. (15) Immunization is recommended routinely for both boys and girls at age 11 to 12
years, ideally before initiation of sexual activity. (16) A
newly licensed 9-valent HPV vaccine (Gardasil 9, Merck
and Co, Inc) targets the four HPV types in Gardasil, as
well as types 31, 33, 45, 52, and 58; these additions extend
coverage to approximately 90% of cervical cancer cases.
(17) Recommendations for series completion and reimmunization for recipients of Gardasil have not yet been
released. HPV immunization can be initiated as early as
age 9 years and up to 26 years for those not previously
immunized. For all three formulations, three doses are
administered, with subsequent doses given 2 months and
6 months following the rst dose. Because Gardasil
contains Saccharomyces cerevisiae, it is contraindicated
for those with allergy to bakers yeast. Data on vaccination
during pregnancy are limited and, therefore, immunization during pregnancy is not recommended. Observation
of patients for 15 minutes following vaccination is advised
due to an association with syncope. Syncope is not a contraindication to future administration of any vaccine.
Polio Vaccines
Polio vaccine has eliminated paralytic polio from the Western Hemisphere. Only IPV is available in the United States,
due to the small but avoidable risk of vaccine-associated
paralytic poliomyelitis caused by the live attenuated vaccine
strain. The possibility of transmission of vaccine virus to
unimmunized or immunocompromised household contacts is also eliminated by use of IPV.
IPV is administered in a four-dose series at 2, 4, 6 to
18 months, and 4 to 6 years of age. Only three doses are
required if the third dose is given after 4 years of age, provided
that at least 6 months have elapsed since the second dose. IPV
is well tolerated and adverse events are rare. Adults are generally presumed to be immune to polio and are only immunized if they are at increased risk of infection (eg, travelers
and those with occupational exposures).
Human Papillomavirus Vaccines

Approximately 40 types of human papillomaviruses (HPVs)
infect humans, predominantly through sexual contact.
LIVE VACCINES
Measles-Mumps-Rubella Vaccines and Varicella Vaccine
Measles, mumps, and rubella have been largely eliminated
from the United States. However, a record-breaking resurgence of measles occurred in 2014, with most case reports
related to international travel and importation of disease by
unimmunized individuals, followed by spread in unimmunized/underimmunized communities. (18) Varicella infection (chickenpox), varicella meningoencephalitis, and
secondary complications of cellulitis and pneumonia have
also declined. Because approximately 5% to 10% of individuals fail to seroconvert following immunization, two doses
of MMR and varicella are given in childhood (at 12 months
and 4 to 6 years of age). However, cases of measles, mumps,
and varicella do occur, even in patients who have received
two doses of vaccine. (18)(19) The minimum interval
between doses is 28 days for MMR and varicella vaccine
given at 13 years of age and older and 3 months for measles-
Vol. 36 No. 6
JUNE 2015
255
TABLE 3.
Additional Vaccines Indicated for Certain International Travelers
VACCINE
TYPE
AGE INDICATED SCHEDULE
BOOSTER1
Japanese
encephalitis
Inactivated
2 mo
2 doses 28 d apart
Duration of protection unknown, possibly

boost after 12 y in adults
Measles2
Live attenuated 12 mo
6 <12 mo
2 doses at least 28 d apart

Single dose
Not needed
After 12 mo of age: 2 doses at least 28 d apart
Meningococcal Inactivated
2 18 mo
7 23 mo
9 23 mo
24 mo
2, 4, 6, and 1415 mo
1 dose in 3 y; then every 5 y thereafter
As above
2 doses 3 mo apart (MCV4-CRM3)
2 doses 3 mo apart, (MCV4-CRM or As above
4
MCV4-D ) 1 dose MCV4
Every 5 y
Polio
Inactivated
6 wk
If needed, accelerated schedule,

doses #2 and #3 in 4-wk
intervals, #4 6 mo
One dose after 4 y of age, one dose <12 mo

before leaving polio-infected or
polio-exporting country
Rabies
Inactivated
All
Day 0, 7, 21, or 28
Depends on risk, yes if exposed
Typhoid fever
Live attenuated 6 y
Inactivated
2 y
Day 0, 2, 4, 6
1 dose
Every 5 y
Every 2 y
Yellow Fever
Live attenuated 9 mo
1 dose
Every 10 y
If risk continues.
Given as MMR in United States; monovalent measles vaccine may be available in other countries.
3
MCV4-CRM:Quadrivalent meningococcal conjugate vaccine (Menveo)
4
MCV4:Quadrivalent meningococcal vaccine (Menactra)
5
Series may be continued in other countries if needed as inactivated polio vaccine or live attenuated oral polio vaccine.
Wallace GS, Seward JF, Pallanasch MA. Interim CDC guidance for polio vaccination for travel to and from countries affected by wild poliovirus. Morb
Mortal Wkly Rep. 2014;63(27):591-594.25
2
mumps-rubella-varicella (MMRV) (ProQuad, Merck and Co,

Inc), and varicella vaccine given to children younger than 13
years of age. Immunization may be accomplished by administering the trivalent MMR and monovalent varicella vaccines separately (but simultaneously) or MMRV to children
younger than 13 years. Because MMRV is associated with
a higher risk of febrile seizures than MMR, children with
a personal or family history of seizure should generally be
immunized with MMR and varicella separately for the rst
dose. (20) Varicella vaccine is contraindicated in individuals
with neomycin or gelatin allergy. Egg allergy is not a contraindication because MMR is derived from tissue culture.
During outbreaks, age-appropriate receipt of recommended vaccine should be assured. Postexposure prophylaxis may be efcacious in reducing measles and varicella
infection (but not rubella or mumps) if administered within
72 hours of exposure. Potentially exposed children 13
months and older may be given a second dose of vaccine
at least 28 days following receipt of the rst dose. MMR can
be administered to infants at least 6 months of age who are
at increased risk of exposure, including international travelers. Because the immune response may be reduced in this
age group, a dose of MMR administered before 12 months of
256
age is not counted as one of the two required doses. The role
of a third dose for outbreak control is an area of investigation
and is not routinely recommended at present.
MMR and varicella vaccines are not recommended in
pregnancy, and pregnancy should be avoided for 28 days
following receipt of these vaccines. (20) If either vaccine is
inadvertently given, termination of the pregnancy is not
specically advised, but the mother should be counseled
that there is a theoretical risk of harm to the fetus. Prior
history of idiopathic thrombocytopenic purpura is a precaution to MMR vaccine because affected individuals may be at
increased risk for recurrence following immunization. As
live attenuated vaccines, MMR and varicella vaccines are not
TABLE 4.
Resources for International Travel
CDC Travelers Health Website: www.cdc.gov/travel/

CDC : 1-800-CDC-INFO
CDC Yellow Book: Health Information for International Travel, 2014
(updated every 2 years)
World Health Organization: www.who.int/ith/
recommended for use in immunocompromised individuals, except those with HIV who do not have severe immunosuppression. Measles inclusion body encephalitis has
been described rarely in individuals with immunodeciency. (20) Zoster (shingles) may occur following varicella
vaccine administration, but the risk is greatly reduced
compared to zoster following wild-type chickenpox, and
symptoms are substantially milder.
Varicella immune globulin should be administered as
soon as possible (up to 10 days following exposure) to highrisk individuals exposed to varicella virus. High-risk individuals include nonimmune pregnant women, neonates
born to mothers with varicella infection from 5 days prior
to 2 days after delivery, all hospitalized preterm infants born
before 28 weeks gestation or whose birthweight is 1,000 g
or less, and hospitalized preterm infants 28 weeks gestation
or older born to nonimmune mothers. (21)
Rotavirus Vaccines
Rotavirus vaccine is indicated for the prevention of acute
diarrheal disease due to rotavirus infection in healthy infants. The vaccine is administered orally on a two-dose
(Rotarix, GlaxoSmithKline) or three-dose schedule (Rotateq,
Merck and Co, Inc) at 2, 4, (and 6) months of age. The rst
dose should not be administered after 14 weeks and 6 days
of age, and the nal dose should not be administered after
8 months of age. Another rotavirus vaccine, RotaShield
(Wyeth Laboratories, Inc, Marietta, PA), was withdrawn
from the market in 1999 due to an association with intussusception. Reports of intussusception with current rotavirus vaccine cluster 3 to 7 days following the rst dose only.
(22) The increased risk of intussusception is estimated at
1 to 5 per 100,000 doses. In contrast, rotavirus vaccine
prevents 40,000 hospitalizations in the United States annually. Rotavirus vaccine is contraindicated in patients with
a history of intussusception due to increased risk of recurrence in this group (23) and in patients with severe combined immunodeciency. (24)
VACCINES FOR INTERNATIONAL TRAVELERS

Travelers should allow at least 8 weeks before international
travel to accomplish appropriate health planning and allow
sufcient time for development of immune protection from
vaccines. (26) International travelers should be up to date
with all routine immunizations. Additional vaccines (Table 3)
or immune globulin may be indicated under special
circumstances. Yellow fever vaccine is only available at
designated clinics, and cholera and tickborne encephalitis

vaccines are currently not available in the United States.
Child age, duration of travel, season, presence of infectious
disease outbreaks, and contact with local populations (eg,
home stay with relatives vs resort accommodations) may inuence immunization decisions. The CDC provides excellent,
regularly updated resources to assist with immunization and
other health considerations for travel planning (Table 4). Consultation with an infectious disease specialist or travel clinic may
also be of benet, particularly for travel to higher-risk areas such
as developing countries. In general, written documentation of
vaccines administered outside of the United States may be
considered valid.
Summary
The childhood immunization schedule is complex and nuanced.
Although serious adverse reactions to immunizations are
uncommon, clinicians must be well-versed in these reactions as
well as the contraindications and precautions to each vaccine.
Conjugate vaccine technology links polysaccharide antigens to
carrier proteins, triggering T-cell-dependent immunity to
polysaccharides, thereby strengthening immune memory.
On the basis of some research evidence and consensus, live
vaccines are generally contraindicated in immunocompromised
patients and in pregnancy. (8)(20) Most live vaccines can be
administered to household contacts of immunocompromised
patients. (8)(20)
On the basis of some research and consensus, modied
administration of meningococcal, pneumococcal, and less
commonly, other vaccines may be indicated to protect
immunocompromised patients. (2)(3)(7)(8)(20)
On the basis of disease epidemiology and consensus,
international travelers should be up-to-date with all routine
immunizations; depending on destination, additional vaccines or
immune globulin may be required. (26)
RESOURCES FOR HEALTH-CARE PROFESSIONALS AND

FAMILIES:
American Academy of Pediatrics: www.healthychildren.org
Centers for Disease Control and Prevention: www.cdc.gov/
vaccines
Immunization Action Coalition: www.immunize.org
Vol. 36 No. 6
JUNE 2015
257
PIR Quiz
1. A mother brings her 12-month-old boy in your ofce for a routine health supervision visit.
He has been generally healthy and is up-to-date on his immunizations. During your
discussion with the mother, you mention that the boy will be getting two immunizations
that day: varicella vaccine and measles-mumps-rubella vaccine. The mother states that she
does not want her infant to get two vaccines in 1 day and asks if she can bring him back in 2
weeks for the second immunization. After you state that it is best to give all immunizations
at the same time, the mother insists on separating the two vaccines and again asks if she
can bring her infant back in 2 weeks for the second immunization. Which of the following is
the best response?
A. If live vaccines are not given simultaneously, administrations should be separated
by at least 28 days.
B. Live vaccines may be given within 4 days of one another.
C. There is an increased risk of adverse reactions if more than one live vaccine is given
on the same day.
D. Live vaccines may not be given simultaneously with inactivated vaccines.
E. If administration is separated, the measles-mumps-rubella vaccine should be
administered before the varicella vaccine.
2. You are discussing with medical students the different vaccines that are available to
children. One of the students asks why the 13-valent pneumococcal conjugate (PCV13)
vaccine is better than the 23-valent pneumococcal polysaccharide (PPS23) vaccine since
the PPS23 vaccines covers more strains of Streptococcus pneumoniae. Which of the
following is the best response?
A. Unconjugated polysaccharide vaccines induce T-lymphocyte-dependent immunity after the third dose.
B. Conjugation of bacterial polysaccharides with a protein carrier improves the
effectiveness by inducing T-lymphocyte-dependent immunologic function.
C. Unconjugated polysaccharide vaccines should not be given to immunocompromised individuals.
D. A single dose of PCV13 is sufcient for healthy children ages 15 to 59 months of age
who have delayed immunizations.
E. PCV13 should not be given if PPS23 has already been administered to a patient
regardless of age.
3. The parents of a 15-month-old girl come to your ofce for inuenza vaccination. The child
attends day care and has been generally healthy except for an episode of acute otitis
media 1 month ago during which she had a febrile seizure. The parents also report that the
child often gets a mild facial rash after eating scrambled eggs. She has no other reported
allergies. Which of the following is a contraindication to inuenza vaccine?
A.
B.
C.
D.
E.
A past history of febrile seizures.

A maternal past history of Guillain-Barr syndrome.
Anaphylaxis after eating egg products.
Chronic lung disease (including asthma).
Allergy to amoxicillin.
4. You are seeing a 5-month-old boy in your ofce after he was briey hospitalized for
respiratory syncytial virus bronchiolitis. The infant was born at term and without
complications. He has been doing well and the parents have no complaints today. In
reviewing the immunization record, you note that the infant has received one hepatitis B
dose after birth. Of the following, which is the best management strategy for administering
the hepatitis B vaccine to this infant?
A. No further vaccinations are required.
B. Administer a second dose of hepatitis B after the infant is at least 24 weeks of age.
C. Test the infant for hepatitis B surface antigen before any further vaccination with
hepatitis B.
258
learners must
or higher on this
assessment, which
than 60% on the
given additional
achieved.
which the learner
completes the quiz.
D. Administer a second dose of hepatitis B vaccine today and the third dose in 8
weeks.
E. Administer a second dose of hepatitis B vaccine today and a third dose at 12
months of age.
5. A mother brings her 12-month-old daughter to your ofce for a routine health supervision
visit. She tells you that the childs grandfather, who is being treated for lung cancer, is
currently living with them. She read that immunocompromised individuals should not
receive live vaccines and she knows that her daughter is scheduled to receive several
vaccines today. Of the following, what is the most appropriate strategy?
A. Defer any live vaccines for the child until after the grandfather is no longer
considered immunocompromised.
B. Explain that only inactivated vaccines are administered at the 1-year health
supervision visit.
C. Explain that only the varicella vaccine is contraindicated.
D. Explain that the grandfathers immune status to varicella should be tested before
vaccinating the 12-month-old.
E. Explain that live vaccines can be given to household contacts of immunocompromised individuals.
Vol. 36 No. 6
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259
Recurrent Apneic Episodes in a 6-week-old

Infant
Michal Feldon, MD,* Hilla Bahat, MD,* Shirly Gamsu, MD,*
Noa Rosenfeld, MD,* Zvi Bistritzer, MD,* Michael Goldman, MD*
*Department of Pediatrics, Asaf Harofe Medical Center, Zrifn, Israel.
CASE PRESENTATION
EDITORS NOTE
We invite readers to contribute case
presentations and discussions. Please use
the Submit and Track My Manuscript link
on the Pediatrics in Review homepage:
http://pedsinreview.aappublications.org.
AUTHOR DISCLOSURE Drs Feldon, Bahat,
Gamsu, Rosenfeld, Bistritzer, and Goldman
have disclosed no nancial relationships
relevant to this article. This commentary does
not contain a discussion of an unapproved/
investigative use of a commercial product/
device.
A 6-week-old infant is brought to the hospital after apparent life-threatening

events. She has had three different episodes on three consecutive days that
consisted of apnea (lasting between 20 and 30 seconds), cyanosis, and, on one
occasion, muscle limpness. The episodes are not directly related to meals. She is
exclusively breastfed and experiences food regurgitations. She has no history of
abnormal limb movements, vomiting, or diarrhea, and the mother denies use of
medication by the infant or herself. Her perinatal history is uneventful. Her
weight gain is normal (birthweight was 3.840 kg, weight on admission is
4.870 kg). The parents are of Ashkenazi origin, and no consanguinity is noted.
There is a family history of early vascular strokes, kidney failure, and nephrolithiasis.
The babys vital signs (heart rate 135 beats/min, respiratory rate 40 breaths/
min, blood pressure 85/42 mm Hg, and oxygen saturation 100% in room air) and
ndings on physical examination are normal. She is admitted to the pediatric
intensive care unit for monitoring and evaluation.
Results of her laboratory evaluation, including complete blood cell count, electrolytes, renal function tests, liver enzymes, and urinary dipstick testing, are normal.
However, an arterial blood gas shows metabolic alkalosis (pH 7.56, bicarbonate
36 mEq/L [36 mmol/L], partial pressure of carbon dioxide 35 mm Hg). Findings on
additional tests, including electrocardiography and renal ultrasonography, are normal. One additional test suggests the diagnosis.
CASE DISCUSSION
Metabolic alkalosis is generally divided into two primary types: chloride-responsive,
which is typied by a low urinary chloride that is maintained by volume depletion
and corrected by volume repletion; and chloride-resistant, which is characterized by
an elevated urinary chloride that does not respond to volume repletion. Chlorideresistant alkalosis typically results from potassium depletion or mineralocorticoid
excess and is further divided according to blood pressure elevation (Table).
Metabolic alkalosis in children is most commonly due to emesis or diuretic use. In
neonates and young infants, metabolic alkalosis is usually related to an inherited
syndrome such as Bartter syndrome or signicant emesis from gastrointestinal
obstruction, as in hypertrophic pyloric stenosis. Chronic metabolic alkalosis in neonates
is typically related to prolonged hypercapnia and respiratory acidosis.
260
TABLE.
Causes of Metabolic Alkalosis

CHLORIDE-RESISTANT (URINARY CHLORIDE >20 mEq/L [20 mmol/L])
CHLORIDE-RESPONSIVE (URINARY CHLORIDE

<15 mEq/L [15 mmol/L])
ELEVATED BLOOD PRESSURE
NORMAL BLOOD PRESSURE
1. Gastric losses (emesis, nasogastric suction)
1. Adrenal adenoma/hyperplasia
1. Gittelman syndrome
2. Diuretics use
2. Glucocorticoid-remediable aldosteronism
2. Bartter syndrome
3. Cystic brosis
3. Renovascular disease
3. Base administration
4. Chloride-losing diarrhea
4. Renin-secreting tumor
4. EAST syndrome
5. Chloride-decient formula
5. Cushing syndrome
5. Autosomal dominant
hypoparathyroidism
6. Posthypercapnia
6. Licorice ingestion
7. Liddle syndrome
8. 17b-Hydroxylase deciency
9. 11b-Hydroxylase deciency
10. 11b-Hydroxysteroid dehydrogenase
deciency
This patient was obviously not dehydrated, based on her

normal weight, vital signs, physical examination ndings,
and electrolytes, and she had no history of emesis or diarrhea.
Her urinary chloride measured 28 mEq/L (28 mmol/L). Her
lack of low potassium concentrations or high blood pressure
raised the possibility of base excess (exogenous base).
On repeat questioning, the mother reported treating the
infant with gripe water and simethicone drops. Apparently,
she gave 10 drops of gripe water every few hours. Testing of
the commercial product she used revealed a high concentration of sodium bicarbonate.
mother administered to the infant caused the severe metabolic alkalosis, which eventually induced apnea.
Management
Medical intervention is usually necessary only for children
with moderate or severe metabolic alkalosis. The most
effective approach is to address the underlying cause. In
this case, 2 days after cessation of gripe water use, the infant
was symptom-free and repeat blood gas analysis showed
normal results. When metabolic alkalosis is due to base
excess, terminating the source of the base excess should be
sufcient for cure.
The Condition
Base excess in infants has been reported in cases involving
the use of electrolyte-enhanced water in infant formulas and
erroneous use of baking soda, but no cases have been
reported with over-the-counter food supplements. In the
past, most of the observed cases were due to the milk-alkali
syndrome, seen when peptic ulcer disease was treated with
calcium carbonate and the Sippy diet (a bland diet to treat
peptic ulcer disease consisting of milk and other ingredients). The frequency of milk-alkali syndrome decreased
dramatically after the introduction of histamine-2 blockers
and hydrogen potassium ATPase inhibitors.
Several different studies have shown that metabolic alkalosis can induce apnea in infants and adults after bicarbonate
intoxications and acid loss, such as in hypertrophic pyloric
stenosis. We believe that the high concentration of bicarbonate in the gripe water combined with the overdosage that the
Lessons for the Clinician

In all cases of chloride-resistant metabolic alkalosis with
no signs of potassium depletion or blood pressure
abnormalities, the possibility of an external source of base
excess should be suspected.
Ingesting over-the-counter medications, food supplements,
and simple household products can result in serious adverse effects when used inappropriately.
Gripe water is a commonly used product designed to treat
infantile colic. Its composition varies according to the
country of manufacture. Originally, it was composed from
dill seed oil, sodium bicarbonate, and alcohol. In the
United States, where it is regarded as a drug, gripe water
was banned in 1982.
Vol. 36 No. 6
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261
Fever and Neck Swelling in a 3-year-old Boy

Mahdi Alsaleem, MD,* Lina Saadeh, MD,* Eric McGrath, MD*
*Department of Pediatrics, Childrens Hospital of Michigan, Detroit, MI.
CASE PRESENTATION
AUTHOR DISCLOSURE Drs Alsaleem, Saadeh,

and McGrath have disclosed no nancial
relationships relevant to this article. This
commentary does not contain a discussion of
an unapproved/investigative use of
A 3-year-old previously healthy boy presents to the emergency department (ED)

with a high temperature (39C [102.2F]) despite taking acetaminophen and leftsided neck swelling. He has decreased activity and oral intake. He has had clear
rhinorrhea with an occasional cough for 1 week but no sore throat or headache.
Two days ago, he was seen at the ED and complete blood cell count, rapid
streptococcal antigen test, and chest and neck radiographs were normal. He was
treated with azithromycin and sent home. However, he has since remained febrile
over 2 days and developed swelling and erythema of the left side of his neck,
prompting his return to the ED.
On physical examination, his temperature is 38.6C (101.5F), heart rate is 140
beats/min, respiratory rate is 23 breaths/min, and blood pressure is 100/56
mm Hg. His left posterior cervical region has a tender, rm, freely mobile, enlarged
mass measuring 32 cm, with induration and overlying erythema. The remainder
of his examination ndings are unremarkable.
Laboratory evaluation reveals a white blood cell count of 22,400/mL (22.4109/L)
with 80% neutrophils, no bands, and 13% lymphocytes; hemoglobin of 10.2 g/dL
(102 g/L), and platelet count of 352103/mL (352109/L). C-reactive protein is
elevated at 117 mg/L (1,114.31 nmol/L). Ultrasonography of the neck reveals multiple
lymph nodes in the left cervical region, the largest measuring 3.12.9 cm.
Hospitalization and further evaluation lead to the diagnosis.
CASE DISCUSSION
The patient was hospitalized with the diagnosis of acute bacterial cervical
lymphadenitis. He received intravenous (IV) clindamycin but developed a rash
on his chest and face following the fourth dose. Clindamycin was replaced with IV
vancomycin, but he remained febrile. Findings on neck computed tomography
were consistent with those of ultrasonography (Figure). On the sixth day of fever,
he developed markedly erythematous conjunctivae bilaterally, swelling of both
hands, and cracked lips with erythema. Due to the history of previous rash,
unilateral lymphadenopathy, erythematous conjunctivae, edema of hands,
cracked lips, and fever for 6 days, the diagnosis of Kawasaki disease (KD) was
considered. He was treated with high-dose IV immunoglobulin (IVIg) and highdose aspirin (ASA). Echocardiography showed prominent left coronary vessels
without aneurysm. His conjunctivitis improved dramatically overnight with
therapy. His fever resolved within 24 hours of treatment. Therapy was continued
262
with low-dose ASA. Follow-up echocardiography showed

normal coronary arteries.
The Condition
KD is best described as a vasculitis that can involve multiple
body systems. Diagnosis is clinical, based on a high index of
suspicion and exclusion of other possible diagnoses via
meticulous laboratory evaluation. Early diagnosis and treatment with IVIg and ASA are important to decrease morbidity and mortality. The diagnostic criteria require the
presence of fever for at least 5 days and at least four of
the following ve classic signs:
1) A bilateral nonpurulent bulbar conjunctival injection
2) Changes in lips and oral cavity such as erythema, cracked
lips, strawberry tongue, and diffuse injections of oral and
pharyngeal mucosa
3) Changes in the peripheral extremities, including erythema
of palms and soles and edema of the hands or feet
4) A rash, primarily truncal, that is polymorphous but
nonvesicular
5) Cervical adenopathy 1.5 cm, usually unilateral
Common laboratory ndings in KD include leukocytosis,
anemia, elevated erythrocyte sedimentation rate, thrombocytosis (mostly after the rst week of illness), sterile pyuria,
low albumin, and possible hyponatremia. Elevated serum
liver transaminase values are common, as are elevated
serum bilirubin and alkaline phosphatase values.
Children suspected of having KD who do not fulll
diagnostic criteria (fever 5 days, but fewer than four signs
of mucocutaneous inammation) may have incomplete disease. A diagnosis in such cases is often supported by echocardiographic ndings of coronary artery abnormalities. Most
authors use the terms incomplete and atypical KD interchangeably. However, the American Heart Association recommends reserving the term atypical KD for those patients
Figure. Computed tomography scan of the neck with contrast shows

numerous posterior triangle enlarged lymph nodes on the left side of
the neck.
who have a problem that generally is not seen in KD, such as

developing renal impairment during the disease.
There are two important observations regarding cervical
lymphadenopathy in KD. First, despite being one of the
major criteria, cervical lymphadenopathy is the least common nding and only presents in 50% of all cases. Second,
some cases of KD present with only cervical lymphadenopathy and fever; other clinical criteria develop later.
Such clinical presentations often lead to a delay in the
diagnosis.
Differential Diagnosis
Viral infections such as those caused by cytomegalovirus
(CMV), Epstein-Barr virus (EBV), and adenovirus may present with clinical manifestations similar to KD, although
patients do not typically have edema of the hands and feet
and the lymphadenopathy is usually bilateral. In these cases,
viral serology for CMV and EBV, polymerase chain reaction
(PCR) for adenovirus, and nasal wash samples for respiratory viral antigen or PCR testing aid in making the diagnosis. Bacterial lymphadenitis is usually unilateral and may
be associated with fever and lymph node swelling in the
neck. However, bacterial lymphadenitis is unlikely to cause
swelling of the hands or feet and should respond to IV
antibiotics (and surgical drainage if an abscess develops).
Stevens-Johnson syndrome and other drug reactions can
present similarly to KD, but prolonged fever and lymphadenopathy are less prominent features. Systemic-onset
juvenile idiopathic arthritis lacks the oral features seen
with KD, and the lymph node enlargement is usually
generalized.
Treatment and Prognosis

The aim of KD treatment is to reduce damage due to the
vascular inammation associated with the disease. Highdose (2 g/kg) IVIg administered within the rst 10 days of
the disease has been shown to reduce the risk of coronary
artery aneurysm from approximately 25% to less than 5%.
ASA, which has anti-inammatory and antithrombotic
activities, is given in high doses (80100 mg/kg per
day), then reduced to low doses (35 mg/kg per day) if
the patient remains afebrile for 2 to 3 days. The low dose
should be maintained until the patient shows no evidence
of coronary abnormalities by 6 to 8 weeks after the onset of
illness.
Clinicians should have high index of suspicion for KD in
any child with fever and a neck mass or other associated
features that is unresponsive to antibiotic therapy for a suspected bacterial infection. If the diagnosis of KD, either
classic or incomplete, is established or strongly suspected,
Vol. 36 No. 6
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treatment with IVIg and ASA should begin as soon as

possible to prevent the morbidity and mortality associated
with the coronary artery aneurysms that can develop with
this condition.
Mortality in KD is between 0.1% and 0.3% and mostly
occurs during the rst 2 months of the disease. Morbidity
depends on the degree of coronary artery involvement. Patients
who develop aneurysms are at higher risk for myocardial
infarction due to sluggish ow and subsequent stenosis in
the aneurysmal space and may need long-term ASA or other
antiplatelet medications.
Measles and varicella vaccines should be deferred for 11
months after high-dose IVIg administration for KD, and
varicella vaccine should be avoided during ASA therapy. The
264
patient and household contacts should receive inuenza

vaccine.

KD should be considered in children with cervical lymphadenitis and fever, especially when there is a poor response to
antimicrobial therapy for suspected bacterial lymphadenitis.
Serial thorough examinations of a patient with a persistent fever and neck swelling are necessary because the
classic features of KD may only become evident over time
in cases of asynchronous presentation.
Suggested Readings for this article are at http://pedsinreview.
aappublications.org/content/36/6/262.full.
Hepatosplenomegaly in a 2-year-old Boy

Rajeev Ramachandran, MD*
*Department of Pediatrics, National University Hospital, Singapore.
CASE PRESENTATION
AUTHOR DISCLOSURE Dr Ramachandran has

disclosed no nancial relationships relevant to
this article. This commentary does not contain
A 2-year-old boy is admitted for evaluation of massive hepatosplenomegaly. He

has had a fever for the past 2 days. He was previously healthy, with no history of
jaundice, loss of appetite, or weight loss. He is the only child of nonconsanguineous parents and was born at term after an uncomplicated pregnancy, with
birthweight at the 50th percentile. He had regular health supervision visits for
vaccinations until 1 year of age, at which his growth, development, and physical
examination ndings were normal. He has been healthy and has not seen a doctor
for almost 1 year. Family history is noncontributory.
Physical examination reveals a febrile child who looks well. Other vital signs
are normal for his age. His weight is above the 97th percentile and his height and
head circumference are at the 75th percentile. He is scratching his skin and
sweating excessively but has no rashes. He has a protuberant abdomen with
distended veins and massive hepatosplenomegaly. The rest of the examination
ndings are normal.
Laboratory evaluation reveals a normal basic metabolic panel, liver function
test shows elevated aspartate aminotransferase of 82 U/L (1.37 mkat/L) (normal,
2060 U/L [0.331.00 mkat/L), alanine aminotransferase of 52 U/L (0.87 mkat/L)
(normal, 1035 U/L [0.170.58 mkat/L), and alkaline phosphatase of 401 U/L
(6.70 mkat/L) (normal, 130350 U/L [2.175.85 mkat/L]). In addition, the bilirubin
measurement is normal and lactate dehydrogenase is elevated at 1089 U/L
(18.19 mkat/L) (normal, 250580 U/L [4.189.69 mkat/L]). Hemoglobin
is 10.4 g/dL (104 g/L), hematocrit is 30.5% (0.35), mean corpuscular volume is
74.4 mm3 (74.4 fL), and red cell distribution width is 17.9. Reticulocyte count is
normal. Platelet count is low at 66103/mL (66109/L). White blood cell count
is 3900/mL (3.9109/L), with an absolute neutrophil count of 570/mL (0.57109/L)
and mild monocytosis at 144/mL (1.44109/L). Computed tomography (CT) scan of
the abdomen demonstrates nodular, hypodense, nonenhancing lesions in the liver,
spleen, and kidneys (Figure). Further procedures help in conrming the diagnosis.
CASE 3 DISCUSSION
The differential diagnoses considered for this 2-year-old boy with massive
hepatosplenomegaly were: 1) storage disorders, including glycogen storage disease, Gaucher disease, and Niemann-Pick type A disease; 2) myeloproliferative
diseases; 3) malignancies, including leukemia, lymphoma, and hepatoblastoma;
and 4) granulomatous diseases such as sarcoidosis. Ultrasonography and CT scan
Vol. 36 No. 6
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265
Figure. Computed tomography scan of the abdomen showing

nonenhancing hypodense lesions scattered throughout the liver and
spleen, which are grossly enlarged.
of the abdomen showed nodular lesions in the liver,

spleen, and kidneys suggestive of malignancies such
as leukemia, lymphoma, or hepatoblastoma. Juvenile
myelomonocytic leukemia was a possibility due to the
presence of peripheral monocytosis. The peripheral
blood smear did not show any blast cells, and bone
marrow aspiration and trephine biopsy results were
normal, making leukemia an unlikely diagnosis. The
alpha-fetoprotein value was normal, making hepatoblastoma unlikely, and the angiotensin-converting enzyme
value was high, indicating sarcoidosis. The differential
diagnoses at this point were lymphoma, secondary malignancies, and sarcoidosis.
Following liver biopsy, histology showed diffuse inltrates
of large lymphocytes positive for CD20, CD79A, CD10, and
BCL6. They were negative for CD30, ALK1, TDT, CD56,
TIA1, BCL2, and MUM1. MYC was positive in fewer than
40% of cells. Ki67 proliferation was approximately 60%. The
patient was diagnosed with diffuse large B-cell lymphoma
(DLBCL) with B symptoms (fever, sweating, and pruritus).
The phenotype supported a germinal center B cell origin.
Whole-body positron emission tomography/CTscan revealed
extensive udeoxyglucose-avid lymphadenopathy above and
below the diaphragm; multiple lesions within the liver,
spleen, and both kidneys; bony lesions involving the spine;
and a right retroperitoneal deposit adjacent to the right psoas
muscle (stage IV disease). Cytologic and chemical analysis of
cerebrospinal uid obtained by lumbar puncture yielded
normal ndings.
The Condition
Non-Hodgkin lymphoma (NHL) represents approximately
60% of all lymphomas in the pediatric population. DLBCL
is a form of NHL that is seen predominantly in adults.
DLBCL can arise in lymph nodes or outside of the lymphatic
system in the gastrointestinal tract, testes, thyroid, skin,
266
breast, bone, or brain. DLBCL can be divided into three

clinically relevant groups using gene-expression proling:
germinal center type, activated B-cell type, and mediastinal
large B-cell lymphoma.
DLBCL is an aggressive tumor with a tendency to metastasize; the majority of cases eventually show some extranodal
component. The bone marrow is involved in only about 10%
of cases. DLBCLs are positive for B-cell markers such as
CD19 and CD20, and most express BCL-6 protein, with some
demonstrating a rearrangement of the BCL-6 gene. DLBCLs
that express germinal center markers CD10 or BCL-6 tend to
have a better prognosis than those that express activated B-cell
markers MUM1/IRF4 or CD138. In the nongerminal center
group, expression of BCL-2 and cyclin D2 are considered
adverse predictors.
Management
Because DLBCL is an aggressive tumor, treatment should
begin immediately. A combination of chemotherapy and the
monoclonal antibody rituximab with or without radiation
therapy has led to cure in a large number of patients. The
current standard treatment for DLBCL is R-CHOP, which is
a combination of rituximab and chemotherapy drugs (cyclophosphamide, doxorubicin, vincristine, and prednisone).
DLBCL is fatal if left untreated and can now be cured in
more than 50% of patients. A cure is generally dened as
5-year disease-free survival.
Autologous hematopoietic stem cell transplantation is
the treatment of choice for patients who relapse. High-dose
chemotherapy coupled with a stem cell transplant can be
used to treat patients with DLBCL who fail initial chemotherapy but are responsive to a second-line chemotherapy
regimen.
Patients Clinical Course

This patient was offered chemotherapy with R-CHOP, but
the parents requested more time to take a decision. He is
clinically stable at this time.

Massive hepatosplenomegaly has a short differential
diagnosis list for children that includes storage disorders
such as glycogen storage disease, Gaucher disease, and
Niemann-Pick disease; malignancies such as leukemia
and lymphoma; parasitic infections such as malaria and
leishmaniasis; and hematologic conditions that include
myelobrosis with myeloid metaplasia and thalassemia
major.
A stepwise approach toward diagnostic evaluation helps
to minimize trauma and cost.
Constitutional B symptoms (fever, night sweats,

pruritus, fatigue, and weight loss) may be features of
lymphoma in children and their presence indicates
a poorer prognosis.
The presence of nodular lesions in the liver and
spleen and B symptoms even in the absence of
signicant peripheral lymphadenopathy should
prompt consideration of a malignant tumor such as

lymphoma.
DLBCL is rare in children. Patients with extranodal tumors
should undergo a thorough evaluation, including computed
tomography scan of the chest and abdomen, bone marrow
analysis, cerebrospinal uid studies, and positron emission
tomography scan to screen for other organ involvement.
Vol. 36 No. 6
JUNE 2015
267
in
Brief
Child Safety and Injury Prevention
Jennifer E. Sanders, MD, Leora Mogilner, MD
Icahn School of Medicine at Mount Sinai, New York, NY
AUTHOR DISCLOSURE Drs Sanders and

Mogilner have disclosed no nancial
Bright Futures: Guidelines for Health

Supervision of Infants, Children, and
Adolescents, 3rd ed. Hagan JF, Shaw JS,
Duncan PM, eds. Elk Grove Village, IL:
American Academy of Pediatrics; 2008
In-Line Skating Injuries in Children and
Adolescents. American Academy of
Pediatrics Committee on Injury and Poison
Prevention and Committee on Sports
Medicine and Fitness. Pediatrics. 1998;101
(4):720722
Child Passenger Safety. American Academy
of Pediatrics Committee on Injury, Violence
and Poison Prevention. Pediatrics. 2011;127
(4):788792
SIDS and Other Sleep-Related Infant
Deaths: Expansion of Recommendations
for a Safe Infant Sleeping Environment. Task
Force on Sudden Infant Death Syndrome.
Pediatrics. 2011;128(5):10301039
National Action Plan for Child Injury
Prevention. Centers for Disease Control and
Prevention, National Center for Injury
Prevention and Control. Atlanta, GA: CDC,
NCIPC; 2012
268
Unintentional injuries are the leading cause of death in the United States among
children older than 1 year of age, adolescents, and young adults. Each year, nearly
9 million pediatric patients are treated in emergency departments for unintentional
injuries, and more than 9,000 die from their injuries, amounting to approximately
25 children each day. Common causes of fatal and nonfatal unintentional injury
include motor vehicle collisions, drownings, res, falls, and sports-related injuries.
Aside from their morbidity and mortality, these injuries and their treatment result
in signicant nancial burdens for families and society.
Children and adolescents are particularly vulnerable to injury because of their
size, immature development, natural curiosity, and inexperience. Males have a higher
risk of injury compared to females, and the male death rate from injury is twice that
of females. A number of social factors suggestive of family stress and disorganization
are associated with greater childhood injury, including lower socioeconomic status,
lower maternal age, lower maternal education, and an increased number of people
living in one household. Injury rates also vary based on geographic location. Fire and
burn-related injuries and deaths are greatest in the southern states, while trafcrelated injuries are greatest in the Great Plains states and the South. Motor vehicle
crashes are a leading cause of preventable deaths across all age groups.
Patient visits to the ofce or the emergency department provide physicians
with the opportunity to educate parents and children on safety and injury prevention. The specic anticipatory guidance provided to families should depend on
the age of the child because the risk and type of injury vary with age. Promoting
safety and preventing injury during a childs rst year after birth can be difcult
because infants are rapidly developing during this time. Families often underestimate infants motor skills and overestimate their cognitive skills. Suffocation and
motor vehicle crashes are the most common causes of injury and death. Parents
must pay special attention to restricting infants exposure to choking and suffocation hazards such as small toys, balloons, and plastic bags. Infants and toddlers
should ride in rear-facing safety seats until they reach the age of 2 years or the
highest height and weight allowed by the car seat manufacturer.
Infants are also at risk of falls, burns, choking, poisoning, and drowning.
Reinforcing the importance of providing constant supervision for infants is
critical. All medications, hazardous household products, and dangerous objects
should be stored locked in high places, out of the sight and reach of children.
Parents should ensure that there are window guards on all windows in the home,
working smoke detectors, and re extinguishers. Staircases in homes should be
gated at both the top and bottom to prevent falls.
Infant walkers have been proven to be a cause of signicant injuries. Most of
the injuries and deaths associated with walkers occurred from falls down stairs.
Furthermore, infant walkers provide no developmental benets; the use of
walkers can actually delay the motor skills required for walking.
Sudden infant death syndrome (SIDS), a diagnosis of

exclusion that cannot be explained through medical investigations, is the leading cause of death in infancy beyond the
neonatal period. The American Academy of Pediatrics (AAP)
recommends that all infants be placed on their backs in their
parents room (but not the parents bed) for every sleep. Soft
objects and loose bedding should be kept out of the crib to
reduce the risk of suffocation, entrapment, and strangulation.
Evidence suggests that pacier use is linked with lower rates of
SIDS, so infants should be put to sleep with a pacier after 1
month of age.
Children ages 1 to 4 years old are at high risk for injury
because their physical abilities exceed their cognitive abilities to understand the consequences of their actions. The
leading cause of preventable death in this age group is
drowning. Children should never be unsupervised in any
body of water, including bathtubs. Home swimming pools
and hot tubs should have fencing around all four sides with
a self-latching gate. Burns are also a signicant cause of
injury in this age range. Hot water temperature in the home
should be checked and should be no higher than 48.9C
(120F). Hot pots and pans should be kept out of the reach of
children. The safest approach is to keep children out of the
kitchen while cooking. Children who are older than 2 years
of age or those who have outgrown the rear-facing car seat
weight or height limit should ride in a forward-facing safety
seat with a harness until they reach the highest height and
weight recommendations for the seat, at which time they
should transition to a belt-positioning booster seat.
Middle childhood (ages 5 to 10 years) is a time for intellectual development and gaining independence. Ensuring a safe home environment and appropriate supervision
continues to be important during this phase of a childs
life. Parents should be asked about the presence of rearms in their homes or in the homes that their children
visit. Guns should be removed from environments where
children live and play, and if rearms are present, they must be
stored unloaded in a locked place to which children do not have
access, with the ammunition locked in a separate location.
Physical activity and play are also important activities in

a childs life during middle childhood and adolescence.
Parents should ensure that children on any wheeled recreation device (eg, bicycles, scooters, inline skates, skateboards, rollerblades) wear properly tting helmets to help
prevent head injury. Some physicians ofces and emergency departments provide helmets to patients, and many
communities offer bicycle rodeos or events where helmets
are distributed for free. Children using inline skates and
skateboards should also wear wrist guards, elbow pads, and
knee pads. Most injuries from wheeled toys without a handlebar occur in the wrists from falls onto outstretched
hands. Belt-positioning booster seats for car use are recommended for children in this age group until the vehicle lapand-shoulder seat belt ts properly, which usually occurs at
a height of 4 feet 9 inches or between 8 and 12 years of age.
Pediatricians can have a signicant impact on injury
prevention by counseling parents and children. Every visit,
either in the ofce or in the emergency department, can
incorporate counseling and guidance on injury prevention.
COMMENT: Each year in the United States, about 10,000
children suffer gunshot wounds, and about 3,000 of these
children die. Children in the United States are 10 times more
likely to commit suicide by rearm and 9 times more likely
to die from an accidental gunshot than children in other
industrialized countries. The AAP urges pediatricians to ask
families about guns in the home and to counsel them that the
safest policy is to have none. If a family does keep a rearm, it
should be kept unloaded in a locked place, with its ammunition stored separately, also under lock. Given the ubiquity of
civilian guns in the United States, estimated to be about
300,000,000 or approximately the same as the total population, the AAPs position makes sense. However, Floridas state
legislature has made it illegal for physicians to ask routinely
about guns in the home. So much for the safety of our
children, not to mention the rst amendment!
Henry M. Adam, MD
Editor, In Brief

http://www.healthychildren.org/English/safety-prevention/Pages/default.aspx
Spanish: http://www.healthychildren.org/Spanish/safety-prevention/Paginas/default.aspx
Vol. 36 No. 6
JUNE 2015
269
in
Brief
Elaine Pereira, MD,* Robert Marion, MD*
*Childrens Hospital at Monteore, Bronx, NY.
AUTHOR DISCLOSURE Drs Pereira and

Marion have disclosed no nancial
22q11.2 Microdeletion Syndrome (VeloCardio-Facial Syndrome, DiGeorge

Syndrome, Shprintzen Syndrome). In: Jones
KL, Crandall Jones M, del Campo M, eds.
Smiths Recognizable Patterns of Human
Malformation. 7th ed. Philadelphia, PA:
Elsevier Saunders; 2013:358361
(DiGeorge Syndrome/Velocardiofacial
Syndrome). McDonald-McGinn DM, Sullivan
KE. Medicine (Baltimore). 2011;90(1):118
Practical Guidelines for Managing Patients
with 22q11.2 Deletion Syndrome. Bassett
AS, McDonald-McGinn DM, Devriendt K, et al;
International 22q11.2 Deletion Syndrome
Consortium. J Pediatr. 2011;159(2):332-9.e.1
Functional Outcomes of Adults With
22q11.2 Deletion Syndrome. Butcher NJ,
Chow EW, Costain G, Karas D, Ho A, Bassett AS.
Genet Med. 2012;14(10):836843
270
In recognition of their unifying molecular etiology, the conditions previously

known as velocardiofacial syndrome, DiGeorge syndrome, Shprintzen syndrome, and conotruncal anomaly face syndrome have been grouped into what
is now termed the 22q11.2 deletion syndrome (22Q11.2DS). The disorder that
results from this microdeletion and demonstrates an autosomal dominant
inheritance pattern has a nearly equal distribution among males and females.
Although its prevalence is quoted as between 1 in 3,000 and 1 in 6,000, the
phenotype may be subtle, leading to underdiagnosis of the most mildly affected
individuals.
The 22Q11.2DS is a contiguous gene syndrome; the critical region includes up
to 40 genes. Currently, the actual cause of the phenotypic features is unclear.
TBX1, one of the genes deleted in most affected individuals, is believed to play
a major role during embryonic development of the heart, thymus, parathyroid
gland, palate, and craniofacies.
Much of the 22Q11.2DS phenotype results from abnormal differentiation of
the third and fourth pharyngeal pouches, embryonic structures that form the
thymus and parathyroid gland. Third and fourth pharyngeal pouch hypoplasia
affects development of the rst and second pharyngeal arches, which leads to
maxillary and mandible formation. Disruption of embryogenesis in 22Q11.2DS
can result in characteristic facial features, abnormalities of the palate and great
vessels, congenital heart disease (CHD), hypoparathyroidism, and immune
deciencies.
Facial features in individuals with 22Q11.2DS include a characteristic nose
with a bulbous tip. Ears are often asymmetric, with overfolded helices and other
minor anomalies. The eyes show narrowing of the palpebral ssures with slight
upward obliquity and allergic shiners. The jaw is usually small or retruded,
resulting from mandibular hypoplasia, and the malar region is decient. The face
is long, often with microcephaly and abundant scalp hair. Poor facial muscle tone
can result in a masklike appearance with an open mouth posture.
Between 75% and 85% of individuals with 22Q11.2DS have CHD. The defects,
usually derived from the embryonic conotruncal primordia, can range from
clinically asymptomatic (right-sided aortic arch, seen in w50%) to requiring
intervention in the newborn period (interrupted aortic arch, specically type B).
The spectrum includes tetralogy of Fallot (w20%), ventricular septal defect
(w60%), and vascular ring. CHD is the leading cause of mortality, accounting
for more than 90% of deaths.
Aberrations of vascular structures are common in individuals with 22q11.2DS.
Medial placement, tortuosity, and other abnormalities of the internal carotid
arteries are seen in 25% of patients. Imaging these vessels before craniofacial
plastic surgery is vital to avoid unexpected encounters of an unidentied pulsatile
mass in an unfamiliar region during surgery.
Abnormalities of the soft and hard palate are seen

in approximately 70% of patients. Defects range from
overt clefts of the secondary palate to submucous clefts
that may not be detectable on routine examination and
bid uvulas. Whether or not a frank cleft is present, most
individuals have velopharyngeal insufciency caused
by poor movement of the palatal muscles, resulting in
hypernasal speech that is worsened by lymphatic tissue
hypoplasia.
Independently of the cardiac or palatal issues, one third
of patients have feeding difculties related to dysphagia.
Involvement of speech and language therapists with aggressive feeding protocols is essential. Nasogastric or gastrostomy feeding may be needed to assure proper energy
intake, especially in infancy and childhood, when most
corrective surgeries take place.
Immunologic abnormalities, usually involving T lymphocytes, are common in individuals with 22Q11.2DS. Most
patients have thymus hypoplasia, which can result in
impaired T-cell function; at its most extreme, thymus aplasia
can lead to life-threatening infections in early infancy. Most
affected children have an increased frequency of infections
(including respiratory infections and otitis media) in the
rst 3 years after birth. Later, infections tend to abate and
T cells function properly, but the absolute lymphocyte count
can be moderately low for age.
The parathyroid glands can also be affected. Some patients manifest severe hypocalcemia with tetany in the
newborn period that can be intractable to treatment. However, most children have normal serum calcium concentrations, although hypocalcemic events, especially in neonates
or during times of stress, can occur.
The syndrome can also involve the genitourinary tract,
with renal hypoplasia or agenesis being the most common
defects. Multicystic dysplasia and obstructive uropathy have
also been associated with 22Q11.2DS.
As with the other phenotypic features, developmental
and behavioral abnormalities are extremely variable in
children with 22q11.2DS. Although most have learning
disabilities, with delays in speech and gross motor skills,
a smaller percentage have frank intellectual disabilities.
Approximately 20% are diagnosed with an autistic spectrum disorder. Recent studies, however, suggest that the
actual prevalence of autism spectrum disorder may approach
50%.
A serious concern for individuals with 22q11.2DS is the
development of psychiatric disorders in later childhood and
adolescence. Between 10% and 20% develop conditions that

include chronic schizophrenia, schizoaffective disorder, and
bipolar disorder. Milder behavioral conditions, including
attention-decit/hyperactivity disorder, anxiety and depression, and cyclothymia, are seen in most affected people.
Close follow-up assessment is necessary to screen for the
development of one or more of these conditions, and intervention is important. Recent studies suggest that
although functional ability for adults is not signicantly
inuenced by surgery for CHD or palatal repair, quality of
life is affected by intellectual level and the presence of
schizophrenia.
Most cases of 22Q11.2DS are diagnosed by 5 years of age,
but the markedly variable phenotype can result in the initial
diagnosis being made in adulthood, often in the parent of an
infant or young child who is manifesting more severe
symptoms and signs. In the great majority of patients,
the deletion occurs as a de novo event. Originally, uorescence in situ hybridization was used to identify the microdeletion. Approximately 85% of affected individuals have
a deletion of approximately 3 megabases; the remaining
have atypical smaller deletions. Because chromosomal microarrays can identify smaller deletions, they are becoming
the diagnostic tool of choice for 22Q11.2DS. Prenatally,
fetuses found to have CHD are routinely screened for the
deletion; postnatally, cardiac and palatal disorders are common indications for genetic testing. Even though the deletion is inherited in only 7% of cases, parents of affected
children should be tested for the purpose of genetic
counseling.
Considering the broad effects of 22Q11.2DS, a multidisciplinary team approach for management is recommended.
Available practical guidelines can be tailored to individual
patient needs. Recently, syndrome-specic growth charts have
been developed (http://www.vcfscenter.com/GrowthChart).
At the time of diagnosis, referral for cardiac, immunologic,
and renal evaluation is essential as well as endocrine evaluation for calcium, parathyroid hormone, and thyrotropin.
The palate must be examined for overt and submucous
clefts in infants; in older children and adults, more emphasis should be placed on evaluations for hypernasal speech
and velopharyngeal insufciency. Before and during any
surgery, special precautions should be taken to monitor for
hypocalcemia or immunologic abnormalities. At all ages,
screening for developmental, socialization, and emotionalbehavioral issues is indispensable; consultation with a developmental behavioral pediatrician should be sought. Aided by
Vol. 36 No. 6
JUNE 2015
271
the guidelines, subspecialists and the pediatrician can work

together to create a secure medical home for children with
22Q11.2DS.
COMMENT: Let me share an interesting sidelight associated with the history of 22Q11.2DS. In 1993, a British
geneticist, John Burn, took the title of Joseph Hellers novel
to create the mnemonic CATCH-22 for the primary
features of the syndrome:
Cardiac abnormality
Abnormal facies
Thymic aplasia
Cleft palate
Hypocalcemia/Hypoparathyroidism
22 (a reminder of the involved chromosome)
A few years later he chose another Heller title, Closing

Time, to urge that use of the mnemonic, which had been
greeted with enthusiasm by the genetics community, be
dropped. Aside from the realization that Abnormal facies
was disparaging, Burn had it pointed out to him that a catch-22
had come to mean a no-win situation. In Hellers novel,
insanity was grounds for discharge from combat duty, but to
request discharge was proof that the soldier was sane.
The practice of good medicine must be about more than
genetics. If our science is not informed by humanism, we
cannot meet all the needs of our patients.
Henry M. Adam, MD
Editor, In Brief
Erratum
In the August 2010 In Brief Hepatitis A, (Kojaoglanian T. Pediatrics in Review. 2010;31(8):348350, doi:10.1542/pir.31-8348), the authors name was misspelled. The correct spelling should be Tsoline Kojaoghlanian. The journal regrets the
error.
ANSWER KEY FOR JUNE 2015 PEDIATRICS IN REVIEW:

Vaccine Safety: Medical Contraindications, Myths, and Risk Communication: 1. B; 2. A; 3. B; 4. B; 5. C.
Hyperthyroidism in Children: 1. A; 2. C; 3. C; 4. A; 5. D.
Immunizations: Vaccinations in General: 1. A; 2. B; 3. C; 4. D; 5. E.
272
Pinpoint, Nonfollicular, Sterile Pustules

on Edematous Erythema in a 15-year-old
Kirishanth Perinpanathan, MD,* Edward Heilman, MD, FAAD,
Haamid Chamdawala, MD, MPH
*Department of Family Medicine, The Brooklyn Hospital Center, Brooklyn, NY.
Departments of Dermatology and Pathology, SUNY Downstate Medical Center, Brooklyn, NY.
Department of Pediatrics, The Brooklyn Hospital Center, Brooklyn, NY.
PRESENTATION
A 15-year-old previously healthy teen comes to the emergency department with a 2week history of a generalized pustular rash. The rash initially appeared while she was
on a cruise to the Bahamas as multiple red, itchy, raised, pinpoint lesions over her
inguinal areas accompanied by a fever. Within the next 24 hours, the rash rapidly
progressed to involve her entire body, and both of her feet and ankles swelled. She
was evaluated by her pediatrician and prescribed hydroxyzine and hydrocortisone
cream, which provided little relief. She visits the emergency department today due to
the worsening of her symptoms and is admitted for further evaluation.
She reports taking dimenhydrinate for motion sickness 2 days before her rash
appeared. She has not been exposed to new soaps or skin emollients. She has no
history of any viral illness. She had used the cruise swimming pool but had not
swum in the ocean. She has no known drug allergies and no family history of
atopic dermatitis or autoimmune disease.
On physical examination, she has a temperature of 38.5C (101.3F) and is in
mild discomfort from the pruritic rash. Skin examination reveals numerous
small (pinhead-sized), nonfollicular pustules over a diffuse erythematous and
edematous base (Fig 1) accompanied by generalized scaling and active desquamation of the skin (Fig. 2). She has no palpable lymph nodes. There is no
AUTHOR DISCLOSURE Drs Perinpanathan,

Heilman, and Chamdawala have disclosed no
nancial relationships relevant to this article.
This commentary does not contain
e18
Figure 1. Numerous small (pinhead-sized), nonfollicular pustules over a diffuse erythematous and
edematous base on the lower extremities.
Figures 2. Generalized scaling and active

desquamation on the upper extremity (A)
and torso (B).
mucous membrane involvement and Nikolsky sign is

negative on both affected and healthy skin.
Laboratory results reveal leukocytosis (16,500/mL
[16.5109/L]) with neutrophilia (80%) and normal eosinophil count (4%). Cultures of blood and pustular uid are
negative. Results of a complete metabolic panel are unremarkable. The erythrocyte sedimentation rate is 10 mm/hr.
A punch biopsy of the lesion reveals the diagnosis.
of the lymph nodes has been reported in a few cases, but major
internal organs are often not affected.
The precise mechanism of AGEP remains unknown.
Results of in vitro studies suggest the involvement of CD4
and CD8 T-cells in the pathogenesis of the disease. The
activated T-cells release a number of factors, including
interleukin-8/CXCL8. This results in recruitment of
DIAGNOSIS
Skin biopsy shows the presence of subcorneal and intraepidermal pustules composed of neutrophils with mild
spongiosis. The papillary dermis is edematous, with neutrophil and eosinophil inltration in the perivascular areas
(Fig. 3). Based on the clinical presentation and histologic
examination of a skin biopsy, the diagnosis of acute generalized exanthematous pustulosis (AGEP) is conrmed.
Discussion
AGEP is an uncommon but severe cutaneous eruption presenting as multiple, small (<5 mm), aseptic pustules on an
erythematous background. AGEP can occur in all age groups,
with an annual occurrence of approximately ve cases per 1
million and a slight female preponderance. Most cases are
drug-related. Frequently associated medications are antibacterial agents, particularly those of the penicillin and quinolone
groups. Other drugs with weaker associations include antifungals, nonsteroidal anti-inammatory agents, macrolides,
and antiepileptic drugs. Infectious agents, such as enterovirus
and parvovirus, have also been implicated as triggers for AGEP.
Before histologic examination, the diagnosis of AGEP heavily
depends on clinical ndings. Pustular lesions originate on the
face or intertriginous areas within 2 days after intake of the
offending drug. Fever and leukocytosis are commonly associated
with the skin manifestations. The mucous membranes, particularly buccal mucosa, are affected in 20% of cases. Involvement
Figures 3. A. Intraepidermal pustule with accompanying supercial

perivascular and interstitial dermatitis. B. Magnied view better
demonstrates the intraepidermal location of the pustule composed of
predominately neutrophils.
Vol. 36 No. 6
JUNE 2015
e19
neutrophils and eosinophils, which form pustules through

destruction of keratinocytes.
Cutaneous lesions of AGEP resolve spontaneously about
2 weeks after discontinuation of the offending agent. AGEP
has a good prognosis. The mortality rate has been reported
to be approximately 5%, mostly due to superinfections in
elderly patients with comorbidities.
Differential Diagnoses
The most common differential diagnoses for AGEP are
acute pustular psoriasis, erythema multiforme (EM), and
Stevens-Johnson syndrome (SJS).
Pustular psoriasis is very similar to AGEP and can be
difcult to differentiate via clinical symptoms alone. Histologic ndings of both show subcorneal or intraepidermal
pustules. A family or personal history of psoriasis, more
generalized pattern of pustular eruptions, longer duration of
fever and pustules, and histologic nding of pustules with
diffuse epidermal hyperplasia and papillomatosis favor
a diagnosis of pustular psoriasis. A history of recent drug
administration, no history of psoriasis, pustular eruptions
beginning at intertriginous areas, shorter duration of fever,
and histologic ndings of pustules with edema of papillary
dermis, vasculitis, exocytosis of eosinophils, or necrotic
keratinocytes indicate a diagnosis of AGEP.
Atypical targetoid lesions, as in SJS and EM, are sometimes
present with AGEP. Coalescence of pustules during the resolution phases of the disease may also mimic blisters and vesicles
found in SJS. However, the dissemination pattern of the lesions,
mucosal involvement, and histologic features can differentiate
the diseases. SJS begins on the face and thorax and spreads
symmetrically to distal areas; AGEP begins on the intertriginous
folds or face and spreads caudally. Mucosal involvement is seen
in 90% of SJS cases but in fewer than 20% of AGEP cases.
Finally, skin tenderness is present in SJS and absent in AGEP.
Depending on the stage, a histology specimen of SJS shows
leukocyte extravasation around the vasculature, lymphocyteinduced necrolysis of keratinocytes at dermoepidermal junction, or vesiculation within fully necrotic epidermis.
EM presents as target lesions formed by the erythematous maculopapules with a darker-colored center. The
lesions are usually 1 to 3 cm in diameter and present
primarily on the extremities. In comparison, the vesicles
and surrounding erythema are much smaller in AGEP.
EM often arises after herpes simplex virus or Mycoplasma
infections.
Management
Because AGEP is a self-limiting condition, discontinuation
of the offending drug and supportive care are sufcient
e20
management. Antipyretics can be administered if they are

not the suspected cause of the condition. Corticosteroid
treatment is best avoided due to the spontaneous remission of the condition. In addition, there is no evidence that
they alter the disease course. Application of moist dressings, topical corticosteroids, and moisturizers can help
relieve symptoms and facilitate skin repair. Topical antibiotics can be used to prevent superinfection on wound
sites.
After disease resolution, the offending agent must be
identied and the patient informed to avoid it in the future. If
patients are taking multiple medications and the causal agent
of AGEP is not clear, patch testing may reveal the offending
drug. However, the test has poor sensitivity despite a high
specicity.
Patient Course
This girl initially received a course of empiric antibiotics
due to suspicion of an infectious origin. After biopsy
ndings conrmed the diagnosis of AGEP, antibiotics
were discontinued and she was only given supportive
therapy. Because the disease was already at the resolution
stage at the time of diagnosis, she was discharged home
with emollients and a scheduled follow-up appointment at
the dermatology clinic.
Development of AGEP following the administration of
dimenhydrinate has not been reported previously. The time
between exposure to the medication and appearance of the
rash, the clinical presentation, and histologic ndings in this
patient point toward the drug as the offending agent.
Furthermore, a recently reported case of AGEP was caused
by diphenhydramine, which is a major constituent of dimenhydrinate. Because our patient did not return for follow-up
patch testing, the specic drug association was not
conrmed.
Summary
AGEP is a rare skin reaction that causes the formation of numerous
aseptic pustules on an erythematous base. In most cases, it presents
after exposure to drugs, more often antibiotics. Fever and
leukocytosis are common. The history, clinical appearance, and
histology of the pustules conrm the diagnosis of AGEP. Pustular
psoriasis, SJM, and EM must be ruled out. The lesions heal
spontaneously within 2 weeks after discontinuation of the
offending agent, an occurrence that further supports the diagnosis.
Immediate withdrawal of the causative agent and supportive
therapy is the mainstay of treatment for AGEP.
Suggested Reading
1. Halevy S. Acute generalized exanthematous pustulosis. Curr Opin
Allergy Clin Immunol. 2009;9(4):322328
2. Hanafusa T, Igawa K, Azukizawa H, Katayama I. Acute generalized

exanthematous pustulosis induced by topical diphenhydramine. Eur
J Dermatol. 2011;21(6):994995
Vol. 36 No. 6
JUNE 2015
e21
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Vol. 36 No. 6 June 2015

Answer Key appears on page 272.

Vaccine Safety: Medical Contraindications, Myths,

After completing this article, readers should be able to:

1. Recognize adverse reactions to various vaccine constituents and

AUTHOR DISCLOSURE Dr Smith has

vaccination, either due to age or an underlying medical

The risk of anaphylaxis after vaccine receipt is very low. A

Gelatin is used as a stabilizer in several vaccines, including

CONTRAINDICATIONS FOR LIVE VACCINES

Primary Immune Deciencies

Vaccination of Household Contacts of

PRECAUTIONS FOR CHILDHOOD IMMUNIZATIONS

receiving an inuenza antiviral should not receive LAIV,

PARENTAL VACCINE HESITANCY

Perceived Risks of Vaccines

Recommended Intervals Between

Tetanus IG, hepatitis A IG, hepatitis B IG

Varicella IG, measles IG prophylaxis in

Immunoglobulin Intravenous (IGIV)

IGIV replacement therapy for immune

Treatment of immune thrombocytopenia

RBCs with adenine-saline added

Packed RBCs or whole blood

Adapted from ACIP(1) and AAP(6) recommendations.

imply causation. Only individuals who were vaccinated and

Figure. In the decade before 1963 when a measles vaccine became

for Vaccine Adverse Events and Strength of Association

Outcomes for which evidence convincingly supports causality

1) In individuals with immunodeciency, measles inclusion body encephalitis

Outcomes for which evidence favors causal association

Transient arthralgia in women

Transient arthralgia in children

Outcomes for which evidence favors rejection of causal association

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