SEPTEMBER 2017

Vol. 38 No. 9
www.pedsinreview.org

Management of Pediatric
Community-acquired
Bacterial Pneumonia
Messinger, Kupfer, Hurst, Parker

Pediatric Lymphoma
Buhtoiarov

Approach to
Hypertriglyceridemia
in the Pediatric Population
Valaiyapathi, Sunil, Ashraf

ONLINE

Visual Diagnosis:
Vesicular Rash
in a Neonate
Pavlek, Schmidt
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contents

Pediatrics in Review ®
Vol. 38 No. 9 September 2017

COMMENTARY
393 An Honor and Privilege
Deepak M. Kamat
ARTICLES
394 Management of Pediatric Community-acquired Bacterial Pneumonia
Amanda I. Messinger, Oren Kupfer, Amanda Hurst, Sarah Parker

410 Pediatric Lymphoma

Ilia N. Buhtoiarov

424 Approach to Hypertriglyceridemia in the Pediatric Population

Badhma Valaiyapathi, Bhuvana Sunil, Ambika P. Ashraf
INDEX OF SUSPICION
435 Case 1: Fever and Ataxia in a Toddler with Pica
Megan H. Tucker, Jonathan Holmes, Susan Harley, Maria Roca Garcia, Haidee Custodio

437 Case 2: Sternal Mass in an 18-year-old Boy

Erin Schaffner, Benjamin Hazen

438 Case 3: Abdominal Pain and Epididymitis in an 8-year-old Boy

Lauren W. Kaminsky, John P. Fletcher, Justen M. Aprile

439 Case 4: Suspected Sudden Visual Loss in a 2-year-old Girl

Hani Alsaedi, Katsuaki Kojima, Ajovi Scott-Emuakpor

440 Case 5: Large Amounts of Urine Bilirubin on Urine Dipstick

in a 14-year-old Girl
Yin Zhou, Paula Hertel, Jennifer Cu

441 Case 6: Dehydration and Electrolyte Abnormalities in an

11-year-old Boy
Filipa Almeida, Susana Lopes, Margarida Figueiredo, Filipe Oliveira,
Susana Sousa, Alexandra Sequeira

442 CME Quiz Correction

IN BRIEFS
443 Human Papillomavirus and HPV Vaccines
Allison Eliscu

445 Retractions
446 Sun Exposure
Melissa Long
ONLINE
e32 Visual Diagnosis: Vesicular Rash in a Neonate
Leeann Pavlek, John Schmidt

e35 Visual Diagnosis: A 3-week-old Girl with an Unusual Rash

Fatema Jaffery, Fatima Khan, Jose Bustillo

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Answer Key appears on page 447.

 Pediatrics in Review ®

Editor-in-Chief: Joseph A. Zenel, Sioux Falls, SD Editorial Fellow: Aamir Jeewa, Toronto, ON
Deputy Editor: Hugh D. Allen, Houston, TX Early Career Physician: Heather Campbell, Washington, DC
Associate Editor, Index of Suspicion: Philip R. Fischer, Rochester, MN Editor Emeritus: Lawrence F. Nazarian, Rochester, NY
Associate Editor, Visual Diagnosis: Mark F. Weems, Memphis, TN Founding Editor: Robert J. Haggerty, Canandaigua, NY
Associate Editor, In Brief: Henry M. Adam, Bronx, NY Managing Editor: Luann Zanzola
Associate Editor, In Brief: Janet Serwint, Baltimore, MD Publications Editor: Sara Strand
Associate Editor, CME: Rani Gereige, Miami, FL Medical Copyediting: Deborah K. Kuhlman, Lisa Cluver
EDITORIAL BOARD
Robert D. Baker, Buffalo, NY Michael Macknin, Cleveland, OH
Peter F. Belamarich, Bronx, NY Susan Massengill, Charlotte, NC
Eyal Ben-Isaac, Los Angeles, CA Elaine M. Pereira, Bronx, NY
Theresa Auld Bingemann, Rochester, NY Carrie A. Phillipi, Portland, OR
Stephen E. Dolgin, New Hyde Park, NY Peter Pizzutillo, Philadelphia, PA
Linda Y. Fu, Washington, DC
Mobeen Rathore, Jacksonville, FL
Lynn Garfunkel, Rochester, NY
Jennifer S. Read, Rockville, MD
Nupur Gupta, Boston, MA
Gregory A. Hale, St. Petersburg, FL E. Steve Roach, Columbus, OH
Thomas C. Havranek, Bronx, NY Sarah E. Shea, Halifax, Nova Scotia
Jacob Hen Jr., Trumbull, CT Andrew Sirotnak, Denver, CO
Jeffrey D. Hord, Akron, OH Miriam Weinstein, Toronto, ON
Neal S. LeLeiko, Providence, RI Shabana Yusuf, Houston, TX
PUBLISHER: American Academy of Pediatrics
Mary Lou White, Senior Vice President, Membership, Marketing and Publishing
Mark Grimes, Director, Department of Publishing
Joseph Puskarz, Director, Division of Journal Publishing
Pediatrics in Review® Print Issue Editorial Board Disclosures
The American Academy of Pediatrics (AAP) Policy on Disclosure of Financial Relationships and Resolution of Conflicts of Interest for AAP CME Activities is designed to ensure
quality, objective, balanced, and scientifically rigorous AAP CME activities by identifying and resolving all potential conflicts of interest before the confirmation of service
of those in a position to influence and/or control CME content. All individuals in a position to influence and/or control the content of AAP CME activities are required to
disclose to the AAP and subsequently to learners that the individual either has no relevant financial relationships or any financial relationships with the manufacturer(s)
of any commercial product(s) and/or provider(s) of commercial services discussed in CME activities. Commercial interest is defined as any entity producing, marketing,
reselling or distributing health-care goods or services consumed by, or used on, patients.
Each of the editorial board members, reviewers, question writers, PREP Coordinating Committee members and staff has disclosed, if applicable, that the CME content
he/she edits/writes/reviews may include discussion/reference to generic pharmaceuticals, off-label pharmaceutical use, investigational therapies, brand names, and
manufacturers. None of the editors, board members, reviewers, question writers, PREP Coordinating Committee members, or staff has any relevant financial relationships to
disclose, unless noted below. The AAP has taken steps to resolve any potential conflicts of interest.
Disclosures
• Nupur Gupta, MD, MPH, disclosed she has a financial relationship with Springer US as co-editor for MassGeneral Hospital for Children Handbook of Pediatric Global Health.
• Michael Macknin, MD, FAAP, disclosed that: he and his wife each receive a free cruise for his seven one-hour talks annually on general pediatric subjects for University at
Sea; he receives a grant from the Wendel Family Foundation to fund a randomized study comparing various diets, and one member of the Wendel Family produced the
film “Forks Over Knives,” which describes the virtues of a vegan diet.
• Janet Serwint, MD, FAAP, disclosed she has a clinical research grant from the Centers for Disease Control and Prevention for quality improvement for HPV vaccines.
• Andrew Sirotnak, MD, disclosed that he serves as an expert witness in cases of suspected child abuse.
• Miriam Weinstein, MD, has disclosed she receives research funding (through her hospital’s foundation) from LaRoche-Posay.
The journal extends special thanks to the following question writers and ancillary reviewers who contributed to this issue:
--Denise Bratcher, MD
--Youngna Lee-Kim, MD
--Catherine Wiley, MD
Pediatrics in Review offers 36 CME articles per year. A maximum of one AMA PRA Category 1 CreditTM is earned after achieving a 60% score on each designated quiz.
2017 Pediatrics in Review is approved for a total of 30 Maintenance of Certification (MOC) Part 2 credits by the American Board of Pediatrics through the AAP MOC
Portfolio Program.
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for physicians.
The AAP designates this journal-based CME activity for a maximum of 1.00 AMA PRA Category 1 CreditTM. Physicians should claim only the credit commensurate with the
extent of their participation in the activity.
This activity is acceptable for a maximum of 1.00 AAP credit. These credits can be applied toward the AAP CME/CPD* Award available to Fellows and Candidate Members of
the AAP.
The American Academy of Physician Assistants accepts certificates of participation for educational activities certified for AMA PRA Category 1 CreditTM from organizations
accredited by ACCME. Physician assistants may receive a maximum of 1.00 hour of Category 1 credit for completing this program.
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 ONLY BEXSERO CAN HELP PROTECT YOUR PATIENTS FROM MenB
IN AS FAST AS 1 MONTH WITH 2 DOSES1,2

1
that may be present on the surface of MenB are distinctly targeted by BEXSERO.

1
of BEXSERO are administered, each as a 0.5-mL prefilled syringe.

AS FAST AS
The dosing schedule for BEXSERO allows your patients to complete
1
the series within the span of 1 typical summer break.

Talk with your adolescent patients about vaccinating against MenB

Visit www.ChooseBEXSERO.com

Indication for BEXSERO

BEXSERO is a vaccine indicated for active immunization to prevent invasive disease caused by Neisseria meningitidis serogroup B.
BEXSERO is approved for use in individuals 10 through 25 years of age.
Approval of BEXSERO is based on demonstration of immune response, as measured by serum bactericidal activity against three
serogroup B strains representative of prevalent strains in the United States. The effectiveness of BEXSERO against diverse serogroup B
strains has not been confirmed.
Important Safety Information for BEXSERO
• BEXSERO is contraindicated in cases of hypersensitivity, including severe allergic reaction, to any component of the vaccine, or
after a previous dose of BEXSERO
• Appropriate observation and medical treatment should always be readily available in case of an anaphylactic event following the
administration of the vaccine
• The tip caps of the prefilled syringes contain natural rubber latex, which may cause allergic reactions in latex-sensitive individuals
• Syncope (fainting) can occur in association with administration of BEXSERO. Ensure procedures are in place to avoid injury from
falling associated with syncope
The persons depicted are models used for illustrative purposes only.
• The most common solicited adverse reactions observed in clinical trials were pain at the injection site (≥83%), myalgia (≥48%),
erythema (≥45%), fatigue (≥35%), headache (≥33%), induration (≥28%), nausea (≥18%), and arthralgia (≥13%)
• Vaccination with BEXSERO may not provide protection against all meningococcal serogroup B strains
• Vaccination with BEXSERO may not result in protection in all vaccine recipients

Please see accompanying brief summary of full Prescribing Information for BEXSERO.
©2017 GSK group of companies. References: 1. Prescribing Information for BEXSERO. 2. Prescribing Information for TRUMENBA.
All rights reserved. Printed in USA. 816247R0 February 2017
BEXSERO is a registered trademark of the GSK group of companies.
 BRIEF SUMMARY Reports of all serious adverse events, medically attended adverse events and Non-serious Adverse Events BEXSERO is a registered trademark of the GSK group of companies.
BEXSERO® (Meningococcal Group B Vaccine) adverse events leading to premature withdrawal were collected throughout the In the 3 controlled studies1,2,3 (BEXSERO N=2221, control N=2204), non-serious
Suspension for intramuscular injection study period for the studies conducted in Chile (12 months), UK (12 months), US/ unsolicited adverse events that occurred within 7 days of any dose were reported
Poland (8 months), and Canada/Australia (2 months). by 439 (20%) BEXSERO and 197 (9%) control recipients. Unsolicited adverse
The following is a brief summary only; see full prescribing information for Solicited Adverse Reactions events that were reported among at least 2% of participants and were more
complete product information. frequently reported in BEXSERO recipients than in control recipients were injection Manufactured by GSK Vaccines, Srl
The reported rates of local and systemic reactions among participants 10 through site pain, headache, and injection site induration unresolved within 7 days, and
25 years of age following each dose of BEXSERO administered 2 months apart or Bellaria-Rosia 53018, Sovicille (SI), Italy
1 INDICATIONS AND USAGE nasopharyngitis.
control in the US/Polish study1 are presented in Table 1. US License No. 1617
BEXSERO® is a vaccine indicated for active immunization to prevent invasive Serious Adverse Events
disease caused by Neisseria meningitidis serogroup B. BEXSERO is approved for Table 1: Percentage of US and Polish Participants 10 through 25 Years of Age Distributed by GlaxoSmithKline
Reporting Solicited Local and Systemic Adverse Reactions within 7 Days after Overall, in clinical studies, among 3,058 participants 10 through 25 years of
use in individuals 10 through 25 years of age. age who received at least 1 dose of BEXSERO, 66 (2.1%) participants reported Research Triangle Park, NC 27709
Approval of BEXSERO is based on demonstration of immune response, as measured BEXSERO or Control, by Dose
serious adverse events at any time during the study. In the 3 controlled studies1,2,3 ©2016 the GSK group of companies. All rights reserved.
by serum bactericidal activity against three serogroup B strains representative (BEXSERO N=2716, Control N=2078), serious adverse events within 30 days after
of prevalent strains in the United States. The effectiveness of BEXSERO against Dose 1 Dose 2b
any dose were reported in 23 (0.8%) BEXSERO recipients and 10 (0.5%) control BXS:1BRS
diverse serogroup B strains has not been confirmed. BEXSERO Placebo BEXSERO Menveo recipients.
Solicited Reactiona
4 CONTRAINDICATIONS (Saline) 6.2 Additional Pre-licensure Safety Experience ©2017 GSK group of companies.
Hypersensitivity, including severe allergic reaction, to any component of the N=110-114 N= 94-96 N=107-109 N=90-92 In response to outbreaks of serogroup B meningococcal disease at two universities All rights reserved. Printed in USA. 816247R0 January 2017
vaccine, or after a previous dose of BEXSERO. [see Description (11) of full in the US, BEXSERO was administered as a 2 dose series at least 1 month apart.
Local Adverse Reactions Information on serious adverse events was collected for a period of 30 days after
prescribing information]
Pain Any 90 27 83 43 each dose from 15,351 individuals 16 through 65 years of age who received
5 WARNINGS AND PRECAUTIONS Mild 27 20 18 26 at least 1 dose. Overall 50 individuals (0.3%) reported serious adverse events,
5.1 Preventing and Managing Allergic Reactions including one event considered related to vaccination, a case of anaphylaxis within
Moderate 44 5 37 9 30 minutes following vaccination.
Appropriate observation and medical treatment should always be readily available
in case of an anaphylactic event following the administration of the vaccine. Severe 20 2 29 8 6.3 Postmarketing Experience
5.2 Syncope Erythema Any 50 13 45 26 Adverse event reports received for BEXSERO marketed outside the US are listed
below. Because these events are reported voluntarily from a population of uncertain
Syncope (fainting) can occur in association with administration of BEXSERO. Ensure 1-25 mm 41 11 36 13 size, it is not always possible to estimate reliably their frequency, or to establish a
procedures are in place to avoid injury from falling associated with syncope. causal relationship to vaccination. This list includes serious events or events which
>25-50 mm 6 1 5 6
5.3 Latex have suspected causal association to BEXSERO.
The tip caps of the pre-filled syringes contain natural rubber latex which may cause >50-100 mm 3 0 5 4
allergic reactions in latex sensitive individuals. General disorders and Blisters at or around the injection site.
>100 mm 0 0 0 2 administration site conditions:
5.4 Limitation of vaccine effectiveness Induration Any 32 10 28 23 Immune System Disorders: Allergic reactions (including anaphylactic
BEXSERO may not protect all vaccine recipients. BEXSERO may not provide reactions), rash, eye swelling.
protection against all meningococcal serogroup B strains [see Clinical 1-25 mm 24 9 22 16
Nervous System Disorders: Syncope, vasovagal responses to injection.
Pharmacology (12.1) of full prescribing information]. >25-50 mm 7 0 4 0
5.5 Altered Immunocompetence > 50-100 mm 1 1 2 4 7 DRUG INTERACTIONS
Individuals with altered immunocompetence may have reduced immune responses Sufficient data are not available to establish the safety and immunogenicity of
> 100 mm 0 0 0 2 concomitant administration of BEXSERO with recommended adolescent vaccines.
to BEXSERO.
Systemic Adverse Reactions
6 ADVERSE REACTIONS 8 USE IN SPECIFIC POPULATIONS
Fatigue Any 37 22 35 20
The most common solicited adverse reactions observed in clinical trials were pain 8.1 Pregnancy
at the injection site (≥83%), myalgia (≥48%), erythema (≥45%), fatigue (≥35%), Mild 19 17 18 11 Pregnancy Category B:
headache (≥33%), induration (≥28%), nausea (≥18%), and arthralgia (≥13%). Moderate 14 5 10 7 Reproduction studies have been performed in rabbits at doses up to 15 times the
6.1 Clinical Trials Experience human dose on a body weight basis and have revealed no evidence of impaired
Severe 4 0 6 2
Because clinical trials are conducted under widely varying conditions, adverse fertility in females or harm to the fetus due to BEXSERO. There are, however,
reaction rates observed in clinical trials of a vaccine cannot be directly compared to Nausea Any 19 4 18 4 no adequate and well controlled studies in pregnant women. Because animal
rates in the clinical trials of another vaccine and may not reflect the rates observed Mild 12 3 10 3 reproduction studies are not always predictive of human response, BEXSERO
in practice. should be used during pregnancy only if clearly needed.
Moderate 4 1 5 1
In four clinical trials, 3058 individuals 10 through 25 years of age received at least Pregnancy Registry for BEXSERO
one dose of BEXSERO, 1436 participants received only BEXSERO, 2089 received Severe 4 0 4 0 GlaxoSmithKline maintains a surveillance registry to collect data on pregnancy
only placebo or a control vaccine, and 1622 participants received a mixed regimen Myalgia Any 49 26 48 25 outcomes and newborn health status outcomes following exposure to BEXSERO
(placebo or control vaccine and BEXSERO). during pregnancy. Women who receive BEXSERO during pregnancy should be
In a randomized controlled study1 conducted in US and Poland, 120 participants Mild 21 20 16 14 encouraged to contact GlaxoSmithKline directly or their healthcare provider should
10 through 25 years of age received at least one dose of BEXSERO, including 112 Moderate 16 5 19 7 contact GlaxoSmithKline by calling 1-877-413-4759.
participants who received 2 doses of BEXSERO 2 months apart; 97 participants 8.3 Nursing Mothers
received saline placebo followed by Menveo [Meningococcal (Groups A, C, Y, and Severe 12 1 13 4
It is not known whether BEXSERO is excreted in human milk. Because many
W-135) Oligosaccharide Diphtheria CRM197 Conjugate Vaccine]. Across groups, Arthralgia Any 13 4 16 4 drugs are excreted in human milk, caution should be exercised when BEXSERO is
median age was 13 years, males comprised 49% and 60% were White; 34% were Mild 9 3 8 2 administered to a nursing woman.
Hispanic, 4% were Black,<1% were Asian, and 2% were other.
Moderate 3 1 6 2 8.4 Pediatric Use
In a second randomized controlled study2 conducted in Chile, all subjects
(N=1,622) 11 through 17 years of age received at least one dose of BEXSERO. Severe 2 0 2 0 Safety and effectiveness of BEXSERO have not been established in children younger
This study included a subset of 810 subjects who received 2 doses of BEXSERO than 10 years of age.
1 or 2 months apart. A control group of 128 subjects received at least 1 dose of Headache Any 33 20 34 23 8.5 Geriatric Use
placebo containing aluminum hydroxide. A subgroup of 128 subjects received 2 Mild 19 15 21 8 Safety and effectiveness of BEXSERO have not been established in adults older
doses of BEXSERO 6 months apart. In this study, median age was 14 years, males than 65 years of age.
comprised 44%, and 99% were Hispanic. Moderate 9 4 6 12
In a third randomized controlled study3 conducted in the United Kingdom (UK), Severe 4 1 6 3 15 REFERENCES
974 university students 18 through 24 years of age received at least 1 dose of Fever ≥38°C 1 1 5 0 1. NCT01272180 (V102_03)
BEXSERO, including 932 subjects who received 2 doses of BEXSERO 1 month 2. NCT00661713 (V72P10)
apart. Comparator groups received 1 dose of Menveo followed by 1 dose of 38.0-38.9°C 1 1 4 0
3. NCT01214850 (V72_29)
placebo containing aluminum hydroxide (N=956) or 2 doses of IXIARO (Japanese 39.0-39.9°C 0 0 1 0
Encephalitis Vaccine, Inactivated, Adsorbed) (N=947). Across groups, median age 4. NCT01423084 (V72_41)
was 20 years, males comprised 46%, and 88% were White, 5% were Asian, 2% ≥40°C 0 0 0 0 5. Wang X, et al. Vaccine. 2011; 29:4739-4744.
were Black, <1% were Hispanic, and 4% were other. Clinicaltrials.gov Identifier NCT01272180. 6. Hosking J, et al. Clin Vaccine Immunol. 2007;14:1393-1399.
In an uncontrolled study4 conducted in Canada and Australia, 342 participants a Erythema, and induration: Any (≥ 1 mm). Pain and systemic reactions: mild
11 through 17 years of age received at least 1 dose of BEXSERO, including 338 (transient with no limitation in normal daily activity); moderate (some limitation 17 PATIENT COUNSELING INFORMATION
participants who received 2 doses of BEXSERO 1 month apart. The median age was in normal daily activity); severe (unable to perform normal daily activity) See FDA-Approved Patient Labeling.
13 years, males comprised 55%, and 80% were White, 10% were Asian, 4% were b Administered 2 months after Dose 1
Native American/Alaskan, and 4% were other.
Solicited adverse reaction rates were similar among participants 11 through 24
Local and systemic reactogenicity data were solicited from all participants in the studies years of age who received BEXSERO in the other three clinical studies,2,3,4 except
conducted in Chile, US/Poland, Canada/Australia, and in a subset of participants in for severe myalgia which was reported by 3-7% of subjects. Severe pain was
the UK study. Reports of unsolicited adverse events occurring within the first 7 days reported by 8% of university students in the UK3.
after each vaccination were collected in all studies. In the US/Poland study, reports of
unsolicited adverse events were collected up to one month after the second vaccination. (continued on next page)
eCigarette Use: One Trend You Can Halt

More data
emerging on
teens use of
#ecigs that leads
to #smoking

Adolescents and eCigarettes POLICY-BASED SOLUTIONS

Increase minimum age of sale to 21
(TOWN AND CITY, COUNTY, STATE,
Increase the price
(STATE AND FEDERAL TAXES
eCigarettes is the most commonly used tobacco product among young people and is becoming a public health concern concern. AND FEDERAL ACTIONS) AND FEES)

Health care professionals are on the frontline of protecting patients regarding the safety and risks of using eCigarettes. Make sure tobacco age of Adolescents are very price
sale laws include eCigarettes sensitive: The higher the
and any eCigarette laws price, the greater the effect
1 in 7
adolescents were smoking
10%
average percent of
300+
eCigarette brands
include traditional tobacco
products.
on use.

cigarettes or eCigarettes in adolescents smoking available.

2014. This is an increase from eCigarettes.
1 in 11 smokers in 2004.
Restrict sales locations Ban eCigarette use wherever
(TOWN AND CITY, COUNTY, combusted tobacco use is prohibited
STATE, AND FEDERAL ACTIONS) (INDIVIDUAL VENUE, TOWN, CITY, COUNTY,

SCHOOL-BASED SOLUTIONS CLINICAL CARE-BASED SOLUTIONS STATE, AND FEDERAL ACTIONS)

ase
Restricting sales location
to stores for ≥21 year olds Restrictions should be
would eliminate tobacco added to existing and

urch
Educate in health class Enact tobacco product-free zone Screen and counsel product sales in nascent regulations,
(MIDDLE AND HIGH SCHOOLS) (ELEMENTARY, MIDDLE, HIGH SCHOOL, (INPATIENT AND OUTPATIENT HEALTH CARE SETTINGS) pharmacies, gas stations, including workplaces,
AND COLLEGE GROUNDS) malls, and grocery and multi-unit housing, and

p
convenience stores. all indoor locations.

t
Present the science of Include eCigarettes in Screening for parent

n
early nicotine exposure and tobacco-free campuses. and adolescent

h pri
gateway drug phenomenon. eCigarette use will

Keep Current with NEW

ensure opportunity for
family and household

r wit
Inoculate against industry Include high schools intervention.
marketing messages, in tobacco-free
promotions, and images campus movement.
that make youth susceptible

oste
to eCigarette use.

F REE p Pediatric Collections from the

HI G H S CHO O L

American Academy of Pediatrics

Article: Winickoff JP and Winickoff SE. Potential Solutions to Electronic Cigarette Use Among Adolescents. Pediatrics. 2016;138(2):e20161502
DOI: 10.1542/peds.2016-1502
Link: pediatrics.org/content/early/2016/07/07/peds.2016-1502
Copyright © 2017 American Academy of Pediatrics

Order this special print Pediatric

Collection at shop.aap.org/eCigarettes
 Commentary
An Honor and Privilege
June 30, 2017, was my last day as the editor for the Index of Suspicion (IOS)
feature of Pediatrics in Review. Nine years ago, Dr Lawrence Nazarian, the former
Editor-in-Chief of Pediatrics in Review, offered me the honor and privilege of
serving as the editor for IOS, and I am forever indebted to him for this oppor-
tunity as well as his friendship and mentorship.
Over these 9 years, I had the opportunity to work with hundreds of medical
students, residents, fellows, and faculty. It was truly gratifying to guide first-time
writers, especially medical students and residents. Within a few weeks of being
appointed, I realized that medical students and residents are not trained for medical
writing. I still remember how my supervising faculty guided me through the process
of writing a good case report. Therefore, whenever an interesting but not so well
written case was submitted, instead of taking an easy route of “rejecting” the case for
poor writing, I decided to help and guide the authors. It did take a lot of time and
patience, but it was worth it because it gave me another valuable opportunity to teach.
I took advantage of these “teaching moments” to their fullest. When I attended any
of the national meetings, especially the session of the section of pediatric trainees at
the National Conference and Exhibition of the American Academy of Pediatrics,
many of the trainees thanked me for helping them with their case reports. Those
were humbling and gratifying moments for me, and I am going to truly miss
them!
I would like to thank Dr Joseph Zenel, the Editor-in-Chief of Pediat-
rics in Review, for his support and encouragement. I also thank all the authors
who submitted cases to Pediatrics in Review so that we could all learn from
their experiences. Finally, I thank my wife, Dr Ambika Mathur, and my chil-
dren, Dr Amol Kamat and Dr Aarti Kamat, for their support and understanding
when I was working late nights and over weekends to edit the cases.
Dr Philip Fischer, a good friend, will be taking over the editorship of IOS.
I strongly believe that the future of IOS is in good hands.
My sincere hope is that the cases we published over the last 9 years were
educational and helped residents and pediatricians provide better care to their
patients all over the world.
Deepak M. Kamat, MD, PhD*
*Children’s Hospital of Michigan, Detroit, MI.

EDITOR’S NOTE: Dr. Deepak Kamat, Professor of Pediatrics at Wayne State University, Detroit, MI,
served as the Pediatrics in Review Associate Editor for the Index of Suspicion column from 2008 to 2017.
Thanks to his dedication, the IOS column’s popularity continues to grow nationally and internationally.
He will be missed.

AUTHOR DISCLOSURE Dr Kamat has

disclosed no financial relationships relevant to
this article. This commentary does not contain
a discussion of an unapproved/investigative
use of a commercial product/device.

Vol. 38 No. 9 SEPTEMBER 2017 393

 Management of Pediatric Community-acquired
Bacterial Pneumonia
Amanda I. Messinger, MD,* Oren Kupfer, MD,* Amanda Hurst, PharmD,† Sarah Parker, MD‡
Divisions of *Pulmonary Medicine and ‡Infectious Diseases, Department of Pediatrics, University of Colorado Denver School of Medicine, Aurora, CO
†
Department of Pharmacy, Children’s Hospital Colorado, Aurora, CO

Practice Gaps
Management of pediatric community-acquired pneumonia should
focus on judicious use of antimicrobial medications, bacterial
diagnostics, and surgical drainage when complicated by large effusion
and empyema. Treatment in adherence to national guidelines produces
favorable outcomes.

Objectives After completing this article, readers should be able to:

1. Reinforce rational antibiotic use for bacterial community-acquired

pneumonia (CAP) in outpatient and inpatient settings.
2. Review and update techniques for microbial diagnosis of CAP.
3. Review medical and surgical management of complicated pneumonia.
4. Present specific considerations for CAP in patients with neuromuscular
disease.

INTRODUCTION

Community-acquired pneumonia (CAP) is the most common cause of death in

children worldwide, accounting for 15% of deaths in children younger than 5 years
of age. (1) Nearly 1 in 500 children will be hospitalized for CAP, which creates a
substantial economic burden. CAP is thus important to diagnose and appro- AUTHOR DISCLOSURE Drs Messinger,
Kupfer, Hurst, and Parker have disclosed no
priately treat. While viral causes of CAP are most common, differentiating financial relationships relevant to this article.
viral versus bacterial etiologies can be difficult. This leads to excessive use of This commentary does contain a discussion of
antimicrobial medications or susceptibility to feeling a pressure to prescribe. (2) an unapproved/investigative use of a
commercial product/device.
Overall, in the United States, 11.4 million antimicrobial prescriptions for pedi-
atric respiratory tract infections per year are avoidable. (3) Furthermore, broad- ABBREVIATIONS
spectrum but less effective antimicrobial agents are often prescribed when CAP community-acquired pneumonia
pharmacokinetically favorable narrow-spectrum agents are available. (4) Argu- CT computed tomography
ably, the untoward effects of overtreatment of CAP in those in whom treatment is IV intravenous
MIC minimum inhibitory concentration
unwarranted compounds the morbidity of this disease process. Because of
MRSA methicillin-resistant Staphylococcus
mounting knowledge of antimicrobial side effects, resistance, and microbiome aureus
effects, practitioners must adhere to the principles of judicious use when treating PCR polymerase chain reaction
CAP. In this regard, CAP, its epidemiology, various etiologic origins, clinical VATS video-assisted thorascopic surgery

394 Pediatrics in Review

presentations, and general diagnosis and treatment were
thoroughly reviewed in this journal (5) and are also dis-
cussed at length in national guidelines. (6) The intent of this
review is to supplement this excellent work by focusing on
specific treatment once a provider has weighed the risks and
benefits and decided that a child’s condition warrants treat-
ment of bacterial CAP and management of its complica-
tions. Salient details from both sources are summarized
throughout.
REVIEW OF INITIAL DIAGNOSIS
No standard of reference for diagnosis or single definition
of pneumonia exists. In this review, CAP is defined as an
acute lower respiratory tract infection acquired in a previ-
ously healthy individual. Associated symptoms include fever,
cough, dyspnea, and tachypnea with supporting evidence of
parenchymal infection and inflammation, diagnosed ac-
cording to findings at chest auscultation or the presence
of focal opacity seen on chest radiographs. (5)(7) Focal
opacity on chest radiographs is often held as a standard
of reference; however, some viral processes and atelectasis
can cause focal radiographic findings (though atelectasis
traditionally resolves in 48–72 hours). In addition, findings
on radiographs can lag behind clinical symptoms. Viral
pneumonitis accounts for most respiratory infections,
particularly in children younger than 5 years of age. Unfor-
tunately, no constellation of clinical symptoms or signs
(fever, tachypnea, hypoxemia, work of breathing) displays
good specificity or sensitivity for radiographic findings of
pneumonia, except that symptom severity and ill appear-
ance do correlate with focal infiltrates. To exclude pneumo-
nia, investigators in 1 study assessed the absence of cough,
crackles (rales), rhonchi, retractions, and nasal flaring in
young infants and found it useful in its negative predictive
value; but again, the presence of these findings was insen-
sitive in the prediction of pneumonia at radiography. (8) Left
with few alternatives, pediatricians typically use a combina-
tion of radiographic and physical findings to decide to treat a
patient for bacterial disease. Decisions on whether to hospi-
talize a patient are made by weighing the criteria presented in
Table 1, which were adapted from national guidelines and
prior review articles. (5)(6)
When to perform imaging in cases of acute pneumonia is
not well delineated, although some rules of thumb apply.
Chest radiographs are indicated in patients with more
severe respiratory distress, particularly those who meet
criteria for hospitalization. This imaging modality is used
to assess the presence of focal parenchymal opacities, as well
as screening for the presence of complications such as
effusion or empyema in patients who have not responded
to antibiotic treatment. Per Infectious Disease Society of Amer-
ica guidelines, other indications for chest radiography include
inconclusive clinical findings and ruling out other possible
causes of respiratory distress that can be diagnosed at radiog-
raphy (foreign body, pneumothorax, pleural disease, or cardiac
disease, including pulmonary edema and cardiomegaly). Imag-
ing is also indicated in febrile infants without a source who are
younger than 12 months of age, if there is evidence of leuko-
cytosis. Conversely, in patients with mild evidence of lower
respiratory tract infection (fever, cough) without hypoxemia or a
focal lung examination who are stable for outpatient treatment,
radiographs of the chest are not typically indicated. (9)(10)
Laboratory examinations are considered for all patients ill
enough to be hospitalized with suspected bacterial pneumo-
nia. These may commonly include blood cultures, inflamma-
tory markers, complete blood cell count, and nasopharyngeal
swab polymerase chain reaction (PCR) for viruses. Blood cul-
tures rarely yield positive findings in CAP, and they should not
be performed in patients treated on an outpatient basis or in
hospitalized patients with uncomplicated disease. However,
in patients with severe disease, the 10% to 18% yield is
arguably worthwhile. (11) Inflammatory markers (erythrocyte
sedimentation rate, C-reactive protein level, or procalcitonin)
may aid in clinical decision-making if measured longitudi-
nally, particularly in those with complicated CAP (discussed
later). (12) The complete blood cell count may provide infor-
mation on further complications, such as thrombocytopenia
or anemia from hemolytic uremic syndrome. (6) Nasopha-
ryngeal swabs for viral PCR should only be performed if the
results will change management. The number and types of
examinations performed depends on the severity and trajec-
tory of the illness. A thorough history may lead one to consider
testing for other unusual causes of lobar pneumonia. These
causes and their historical cues are listed in Table 2.
In the remainder of this review, it is assumed that a prac-
titioner has weighed the clinical, radiologic, and laboratory
evidence for their patient as discussed earlier, reviewed national
guidelines, and made a judicious decision to treat bacterial
causes of CAP. With this context in mind, we will discuss
pathogenesis, outpatient and inpatient management with re-
spect to routine and novel diagnostics, antimicrobial choices
and length of therapy, diagnosis and management of com-
plications, and recurrent lobar pneumonia and special CAP
considerations for patients with neuromuscular disease.
PATHOGENESIS AND BASIC DEFINITIONS
Pneumonia occurs as result of invasion of the lower respi-
ratory tract by a pathogenic organism. Bacterial infection
Vol. 38 No. 9 SEPTEMBER 2017 395
 TABLE 1. Criteria to Consider Hospitalization for Pediatric Pneumonia
• Hypoxemia (oxygen saturations <90% to 92% at sea level)
• Infants <3 to 6 months of age with suspected bacterial community-acquired pneumonia
• Tachypnea:
B
Infants <12 months of age: respiratory rate >70 breaths per min
B Children: respiratory rate >50 breaths per min
• Respiratory distress: apnea, grunting, difficulty breathing, and poor feeding
• Signs of dehydration or inability to maintain hydration or oral intake
• Capillary refill time >2 s
• Infants and children with toxic appearance
B Suspected or confirmed to have infection with a virulent organism (community-acquired methicillin-resistant Staphylococcus aureus or group
A Streptococcus)
• Underlying conditions/comorbidities that:
B May predispose patients to a more serious course (eg, cardiopulmonary disease, genetic syndromes, neurocognitive disorders,
neuromuscular disorders)
B
May be worsened by pneumonia (eg, metabolic disorder)
B May adversely affect response to treatment (eg, immunocompromised host, sickle cell disease)
• Complications (eg, effusion and/or empyema)
• Failure of outpatient therapy (48–72 h with no clinical response)
• Caretaker unable to provide appropriate observation or to comply with prescribed home therapy

Indications for intensive care unit admission include:

• Severe respiratory distress or impending respiratory failure that requires:
B Intubation and mechanical ventilation
B Positive pressure ventilation
• Recurrent apnea or slow irregular respirations
• Cardiopulmonary monitoring due to cardiovascular compromise secondary to:
B Sustained tachycardia
B Inadequate blood pressure
B Requirement of pharmacological support for blood pressure or perfusion
B Altered mental status due to hypercarbia or hypoxemia
B
Pulse oximetry measurement of <92% on fractional inspired oxygen concentration of >0.50
• Pediatric Early Warning Score >6

Reproduced with permission from Gereige RS, Laufer PM. Pneumonia. Pediatr Rev. 2013;(34):19. (5)

represents a failure of many layers of extrinsic and intrinsic
defense. Physical barriers to infection include upper respi-
ratory tract nasal hairs and turbinate architecture, as well as
complex respiratory airway branching that inhibits access to
distal airways. In the large airways, cough and mucociliary
clearance of secretions and humoral and cell-mediated
defenses work to defend the lower respiratory tract from
invasion. Secreted and humoral immunoglobulins, as well as
intrinsic antimicrobial properties of alveolar fluid, work with
the phagocytic alveolar macrophages to eradicate bacteria.
When these defenses are overwhelmed in some capacity,
bacterial pathogens penetrate and cause disease. (13)
Many factors may contribute to overwhelming of these
defenses and subsequent pneumonia, but the influence of

396 Pediatrics in Review

TABLE 2. Unusual Causes of Pneumonia in Children: A Summary of
Historical Clues
SUMMARY OF INCUBATION, DIAGNOSTICS, AND
AGENT HISTORICAL CLUES TREATMENT (CONSULT REFERENCES FOR DETAILS)a

Bacillus anthracis Exposure to contaminated hides (including drum covers); Incubation: 2–43 d
often will have skin manifestation (eschar), as well Diagnostic: cultureb and PCR
Treatment: ciprofloxacin, doxycycline
Blastomyces Travel to Central United States Incubation: 2 wk to 3 mo
dermatitidis Diagnostic: cultureb, serologic analysis
Treatment: amphotericin
Chlamydophila Exposure to sick birds Incubation: 5–14 d
psittaci Diagnostic: serologic analysis
Treatment: doxycycline, azithromycin second line
Coccidioides immitis Travel to endemic area (Arizona, Nevada, California, Texas, Incubation: 1–4 wk for primary infection, disseminated
Utah, Mexico, Central and South America) disease weeks to years
Diagnostic: cultureb, serologic analysis
Treatment: not always needed, but fluconazole,
itraconazole, amphotericin B
Coxiella burnetti Exposure to infected birthing fluids or excreta (including Incubation: 14–22 d
unpasteurized milk) from sheep, cattle, and goats Diagnostic: PCR and serologic analysis, best if acute and
convalescent
Treatment: doxycycline best, second-line TMP-sulfa
Cryptococcus gatii Travel to endemic area (Pacific Northwest) Incubation: 8 wk to 13 mo
Diagnostic: cultureb
Treatment: amphotericin
Entamoeba Exposure to contaminated food, most commonly in Incubation: days to years, most commonly 2–4 wk
histolytica resource-limited settings, institutionalized settings, or Diagnostic: identification of organisms in sample,
men who have sex with men; occurs in conjunction serology
with liver abscess or triad of liver abscess, Treatment: metronidazole plus luminal amebicide
parapneumonic effusion, pericardial effusion
Francisella tularensis Exposure to ticks and potentially horseflies or sick animals Incubation: 1–21 d (typically 3–5 d)
(most notoriously rabbits); history of lawn-mowing Diagnostic: cultureb, PCR of blood or source, serologic
over carcasses analysis
Treatment: aminoglycoside, ciprofloxacin
Hantavirus Exposure to mice feces and/or urine in endemic area Incubation: 1–6 wk
(Colorado, Utah, New Mexico, Arizona); often Diagnostic: serologic analysis
hemoconcentration with thrombocytopenia Treatment: supportive
Histoplasmosis Travel to endemic area (Central United States), exposure Incubation: 1–3 wk for primary infection, disseminated
to birds and/or bird excrement disease weeks to years
Diagnostic: cultureb, serologic analysis, urine antigen
Treatment: not always needed, but if so amphotericin B,
itraconazole
Legionella Exposure to contaminated water supply Incubation: 2–10 d
pneumophila Diagnostic: culture, antigen in urine, serologic analysis
Treatment: azithromycin, levofloxacin
Leptospira spp Exposure to urine (or water contaminated with urine) of Incubation: 2–30 d, usually 5–14 d
infected animals; usually some liver involvement, as Diagnostic: serologic analysis
well Treatment: penicillin
Mycobacterium Exposure to infected persons or high-risk settings or to Incubation: highest risk for disease first 2 y after infection,
tuberculosis persons with chronic cough with such exposures but can be years
Diagnostic: culture, rapid diagnostics, clinical
Treatment: 4 drugs, see references
Mycoplasma Exposure to infected person 1–4 weeks ago Incubation: 1–4 wk (usually 2–3 wk)
pneumoniae Diagnostic: PCR (preferred), serum immunoglobulin M
Treatment: azithromycin
Continued

Vol. 38 No. 9 SEPTEMBER 2017 397

 TABLE 2. (Continued )

SUMMARY OF INCUBATION, DIAGNOSTICS, AND

AGENT HISTORICAL CLUES TREATMENT (CONSULT REFERENCES FOR DETAILS)a

Yersinia pestis Exposure to infected animals, including prairie dogs, Incubation: 1–8 days
squirrels, ill cats and dogs, fleas
85% of US cases are in New Mexico, Colorado, Arizona, Diagnostic: cultureb, PCR, serologic analysis
and California
— Treatment: doxycycline, ciprofloxacin second-line TMP-
sulfa

TMP-sulfa¼trimethoprim/sulfamethoxazole.
a
Information for consideration of differential only; practitioners should refer to the AAP Red Book and national guidelines. Timing of positive serologic
findings varies, and some diseases require acute and convalescent sera. Some organisms require specific culture conditions. Treatment regimens may
depend on location and severity of disease.
2
Alert the laboratory if a specimen will be sent for culture that has a high risk of infection for laboratory personnel.

viral coinfection on bacterial pneumonia is an important
concept. Animal models suggest that respiratory viruses
destroy the respiratory epithelium and change the landscape
of the cell surface to exhibit more antigen receptors. These
changes impair the cough reflex and mucociliary clearance.
In addition, viruses may inhibit normal macrophage func-
tion. Influenza is most commonly associated with subse-
quent bacterial superinfection, but suspicion for this entity
should be high in any child with a viral prodrome who
exhibits abrupt worsening of clinical status in a time frame
in which a viral infection should be resolving. (14) A public
health example of this viral-bacterial interplay is readily avail-
able, in that pneumococcal vaccines decrease the morbidity
of influenza infections, while some viral vaccines decrease
the incidence of radiographic findings of pneumonia. (15)
Bacterial pneumonia can be classified according to sev-
eral pathophysiological definitions based primarily on radio-
logic and physical findings. Lobar pneumonia involves a
single discrete lobe or lung segment of parenchymal inflam-
mation, a discrete opacity on chest radiographs, and focal
findings of crackles, bronchial breath sounds, and dimin-
ished aeration at auscultation. This classic pattern is typical
of pneumococcal infection. Bronchopneumonia involves
inflammation of the airways and interstitium and appears
more diffuse on images, with scattered crackles, rhonchi,
and asymmetrical aeration at examination, commonly asso-
ciated with Streptococcus pyogenes or Staphylococcus aureus.
Mixed peribronchial and interstitial disease with focal
parenchymal inflammation is observed in cases of viral
pneumonia that become subsequently bacterial (in patients
with influenza, for example). Cavitary pneumonia is a result
of tissue necrosis associated with Mycobacterium tuberculo-
sis, although it can occur with other pathogens. (13) Com-
plicated pneumonia includes parapneumonic effusions,
pulmonary abscesses, bronchopleural fistulas, and necro-
tizing pneumonia.
CAUSATIVE PATHOGENS AND THEIR IDENTIFICATION
Definitive identification of bacterial etiologic origins in CAP
is limited by lack of a primary sample for culture or PCR
from the lower respiratory tract. This in turn limits our
ability to describe with confidence the microbial and epi-
demiological patterns of bacterial pneumonia. That said,
bacterial causes of CAP continue to include Streptococcus
pneumoniae, S aureus, and S pyogenes. Overall, with the
advent of S pneumoniae vaccines, the incidence of unequiv-
ocal bacterial CAP is decreasing, although of those who
develop CAP, S pneumoniae remains the most common
cause. Multiple studies in which antigen detection and
nucleic acid PCR were used on culture-negative empyemas
demonstrated that most culture-negative empyemas are
caused by penicillin-susceptible, nonvaccine serotypes of
S pneumoniae. (13)(16)(17) For S aureus, there is some
evidence that pediatric lung infections from methicillin-
resistant S aureus (MRSA) are increasing. (18)(19)(20)
Because of immunization, herd immunity, and partial
immune responses to even 1 dose of vaccine, invasive
disease due to Haemophilus influenzae type B is now exceed-
ingly uncommon. Nontypeable H influenzae strains are
now responsible for most cases of invasive Haemophilus dis-
ease, including pneumonia. (21) Between 2003 and 2012,
the annual incidence of invasive, nontypeable H influenzae
disease was 1.6 cases per 100,000 children younger than 5
years of age. Invasive disease with Moraxella catarrhalis
is similar. Studies on the evaluation of the role of these
organisms are marred by easy contamination from the
upper airway, and results are difficult to interpret. It is likely

398 Pediatrics in Review

that these organisms play a small role in unequivocal
bacterial CAP, and that when they do, disease is likely to be
less severe. Mycoplasma undoubtedly causes CAP and can
cause lobar disease and effusions, although the role of
treatment remains controversial (as discussed later). A list
of less usual causes for pneumonia and when to consider
them is presented in Table 2.
Inexpensive, reliable, noninvasive methods for establish-
ing a bacterial etiologic origin in pediatric pneumonia are
highly desirable to promote selection of the most narrow
and effective antimicrobial treatment. Options for pathogen
discovery include upper and lower airway samples, coupled
with traditional culture methods, targeted PCR, and targeted
relative quantitative PCR (although these PCR methods are
not yet available except in research settings).
Upper-airway samples include nasopharyngeal washes
and swabs and throat samples. These samples are useful
in the detection of various bacteria, including Mycoplasma
pneumoniae, Chlamydophila pneumoniae, Bordetella pertussis,
and Bordatella parapertussis. Sputum expectoration is com-
monly used in adults but has been a challenge in pediatrics.
In theory, sputum includes a lower airway sample. Sputum
samples are informative in adults and have been studied
with success in children as young as 1 month of age. (22)
Coordination with a respiratory therapist to use specialized
techniques to improve sputum expectoration and/or nasal
aspiration may be required in children younger than 6 years
of age to obtain a successful, high-quality specimen (fewer
than 10 squamous epithelial cells per low-power field).
While sputum collection is not necessary for evaluation
in a patient treated on an outpatient basis, attempts should
be made to obtain sputum in children with moderate to
severe pneumonia who are hospitalized. (6) Low-quality
sputum specimens are not meaningful, can be misleading,
and should not be cultured. (13)(23) Studies of PCR of
sputum and upper-airway samples are plagued by the bias
of pretreatment and lack of comparison to the lower airway.
In theory, these are improved by using quantitative PCR but
are still problematic and are not yet readily available. (24)
Sampling techniques for the lower respiratory tract in-
clude direct pleural sampling, pleural fluid aspiration after
placement of a chest tube or video-assisted thorascopic
surgery (VATS), bronchoalveolar lavage via flexible bron-
choscopy, or (rarely performed) direct biopsy of the paren-
chyma or open thoracotomy.
Sampling of pleural fluid without placement of a chest
tube (thoracentesis) is the most direct way of obtaining more
information but has become unfamiliar for many practi-
tioners. For a period of time, it was believed that identifying
the microorganism did not change the treatment, and amid
concerns about surgical complications such as pneumotho-
rax, bleeding, and pain, the practice has become much less
common. In the current era of antimicrobial resistance, this
should be reconsidered. Ideally, sampling should occur before
treatment with antibiotics. Procedural instructions for thora-
centesis and recommendations for radiologic assistance are
available. (25) Commonly, pleural fluid is obtained with
therapeutic procedures such as chest tube placement or VATS,
which almost always occur after some period of antimicrobial
therapy, often resulting in negative culture findings.
When pleural fluid is obtained, it should be sent for
Gram stain and bacterial culture, as well as cell count and
differential, to allow differentiation of bacteria from other
causes of effusion (ie, mycobacterial, oncologic). Modified
criteria, originally proposed by Light et al, (26) in 1972, allow
differentiation of exudate from transudate on the basis of
fluid pH level, presence of leukocytes, protein, glucose, and
lactate dehydrogenase ratios. However, international guide-
lines do not recommend these tests because they rarely
change management in pediatric cases with a high pretest
probability of bacterial pneumonia. Culture of the fluid is
crucial; however, if the patient is pretreated, 70% of findings
are negative. (10) S pneumoniae is a particularly difficult
bacterium to culture because of its propensity for autolysis
and relative fragility during sample transport. (27) Other
cultures should be based on unusual exposure history or
clinical situations (Table 2).
Efforts to better characterize the bacterial components of
pleural fluid with culture-independent methods are under-
way. Many studies focus on identification of S pneumoniae in
culture-negative pleural samples via PCR-based identifica-
tion. Antigen testing and PCR testing of pleural fluid greatly
increase diagnostic yield, although these are not yet readily
available. (15) A study in which uniplex PCR was used in
pleural fluid demonstrated a causative organism in 82% of
56 children. (28) In addition to targeted PCR, relative
quantitation of PCR, PCR for the gene-encoding bacterial
16S ribosomal RNA subunit, and deep sequencing are all
up-and-coming techniques. (29) Urinary antigen tests for
S pneumoniae are not recommended for children because
of the high rate of false-positive results. (6)
In patients receiving mechanical ventilation, 2 additional
options exist for obtaining lower respiratory tract specimens:
bronchoscopy and tracheal aspirate. Tracheal aspirates are likely
of similar utility to sputum and are most useful if obtained
early, prior to colonization of the endotracheal tube with pa-
tient or hospital flora. The use of bronchoscopy to obtain a
bronchoalveolar lavage sample is an option if other sources of
microbial diagnosis cannot be obtained and should be partic-
ularly considered in complicated and/or immunosuppressed
Vol. 38 No. 9 SEPTEMBER 2017 399
 hosts who may have unusual pathogens or in children who are
not improving despite receiving adequate therapy for usual
pathogens. In pediatrics, nonbronchoscopic bronchoalveolar
lavage or mini–bronchoalveolar lavage has been studied for
safety in older children (30) with ventilator-associated pneu-
monia but is not commonly used because of the size of the
pediatric airway. (31)
OUTPATIENT MANAGEMENT
Uncomplicated bacterial pneumonia is an entity that can be
effectively treated in most children on an outpatient basis
with oral antibiotics and supportive care. Cough and fever
are often present in any patient in whom pneumonia is
being considered, but the degree of respiratory distress is
important to assess for each patient. (32)
For management of outpatient mild to moderate bacterial
pneumonia, treatment with antibiotics is empirical; it is not
recommended to pursue tests to assess for a cause if the
patient does not meet criteria for inpatient treatment. Cri-
teria for hospitalization include hypoxemia, moderate respi-
ratory distress, age younger than 12 months, and presence of
a moderate to large pleural effusion, in addition to the
criteria in Table 1. (5)(6) A child who meets the criteria
for outpatient management will thus be relatively well and
amenable to oral therapy but at risk for progression; thus,
close follow-up is warranted.
A key to success in the outpatient realm is an appropriate
choice and dose of an antimicrobial agent. Selection of
appropriate oral antibiotics is based on assessment of pre-
sumed pathogens, patient age, exposures, prior medical
history, medication allergies, and community bacterial resis-
tance patterns. The key organism to cover in this setting is
S pneumoniae because it remains the most common cause,
despite vaccination. (15) The cornerstone of oral antimicro-
bial treatment for S pneumoniae is amoxicillin. Practitioners
commonly presume that oral cephalosporins are superior to
amoxicillin for S pneumoniae; this likely stems from knowl-
edge that some S pneumoniae penicillin nonsusceptible
isolates are susceptible to ceftriaxone and assume that oral
cephalosporins are superior to amoxicillin. Indeed, the op-
posite is true. Oral cephalosporins have short half-lives, are
poorly absorbed, are highly protein bound, and are often
dosed at long intervals. This results in serum concentrations
that do not provide enough killing time (serum concentra-
tion over minimum inhibitory concentration [MIC]) to treat,
except for organisms with a low MIC to a selected drug.
Amoxicillin reaches higher levels and is less protein bound,
thus giving it more time with a drug concentration over
the MIC for many pathogens, provided the MIC is in the
400 Pediatrics in Review
susceptible or intermediate drug level range. Because the
pharmacokinetics of the oral cephalosporins are far inferior
to amoxicillin, their use in CAP should be reserved for
patients who are allergic to penicillin or patients with a cause
known to be resistant to amoxicillin but susceptible to
cephalosporins (ie, M catarrhalis or b-lactamase–positive H
influenzae). (6)(33)
Another consideration for treatment with b-lactam anti-
biotics is the dosing interval. Many practitioners are un-
aware that more frequent dosing will provide more killing
time and have the potential to treat organisms with slightly
higher MICs. For example, for S pneumoniae with a peni-
cillin MIC of 2.0 mg/mL, 90 mg per kilogram of body weight
divided into doses administered twice daily will achieve cure
in approximately 65% of patients, while if divided into doses
administered 3 times daily, it is estimated to provide cure
in 90%. (34) Thus, when amoxicillin is used, pharmacoki-
netics are superior if used in high doses (90–100 mg/kg per
day) divided into doses administered 3 times a day, instead
of twice daily. This dosing strategy should be selected where
higher rates of nonsusceptible S pneumoniae exist or argu-
ably in all patients with lobar CAP in whom room for error
with outpatient treatment should be minimized. (35) Al-
though twice-daily dosing is successful in otitis media
because of the prolonged half-life of the drug in the ear
fluid (and thus creating more time with a drug level over the
MIC of the offending organism) when compared to serum
(4 vs 1.2 hours, respectively), this cannot be safely extrap-
olated to true bacterial pneumonia. (36)
Although empirical coverage of H influenzae and M
catarrhalis is not warranted in most patients, it is important
to note that 30% of H influenzae and 100% of M catarrhalis
produce a b-lactamase, rendering those isolates resistant to
amoxicillin. They are routinely susceptible to amoxicillin–
clavulanic acid and cephalosporins. Other microbial causes
of CAP include S aureus and S pyogenes, although these
bacteria do not usually cause disease mild enough to be
treated in an outpatient setting. Oral antimicrobial selec-
tions are discussed in Fig 1.
M pneumoniae is known to cause diffuse or lobar CAP,
but the benefits of treatment remain controversial. (37)(38)
The ability of a practitioner to differentiate Mycoplasma from
other etiologic origins by using clinical history and exam-
ination findings is not reliable and can lead to overtreatment
of this pathogen. Although national guidelines recommend
consideration of treatment in patients older than 5 years of
age, (6) this may lead to undue pressure to treat, given the
lack of proven benefit. The judicious practitioner should be
allowed room to align with national reviews (38) and not
routinely treat this entity empirically, particularly if symptoms
Figure 1. Complicated CAP empirical antibiotic therapy algorithm. Adapted from Complicated Community Acquired Pneumonia, Clinical Care
Guidelines, Children’s Hospital Colorado, updated October 11, 2016. (71) CAP¼community-acquired pneumonia, CDC¼Centers for Disease Control and
Prevention, IV¼intravenous, MRSA¼methicillin-resistant Staphylococcus aureus, PO¼per os, TID¼3 times daily.

are also consistent with viral disease or if providers are already
treating the patient for other bacterial causes. In adult popula-
tions, the desire to cover both Mycoplasma and bacterial causes
has led to a crisis in the overuse of fluoroquinolones, a practice
the Food and Drug Administration has strongly discouraged.
(39) Though azithromycin is largely ineffective against the
traditional CAP pathogens mentioned earlier, it is often used
in an attempt to treat both typical and atypical infections, which
contributes to the fact that it is the second most commonly
prescribed antimicrobial agent in outpatient pediatrics. (40)
Despite a recent publication in which investigators suggest that
azithromycin may decrease subsequent wheezing when used
in early childhood, (41) the difficulties of this research make the
results inconclusive, and any potential benefit must be weighed
against the need for dual therapy, side effects, development of
resistance, and detrimental effects on the microbiome. (42)(43)
Many centers now have rapid diagnostics to target M pneumo-
niae, so treatment might logically be reserved for hospitalized
patients with positive PCR test findings.
Length of therapy for uncomplicated bacterial CAP
should not exceed 7 days, and there are data to support 3
days for nonsevere CAP. (44) Studies have demonstrated
similar success rates of 7 days when compared with 10 days
and 5 days. (45)(46) Although all studies involving CAP
are subject to the Pollyanna phenomenon (positivity bias),
(47) the number and consistency of the shorter therapy
studies increase the quality of the evidence such that the
benefits (in terms of mitigating resistance, decreased side
effects, and compliance) of 5 or 7 days should make these
lengths standard.
A patient is considered to have failed outpatient antimi-
crobial therapy for CAP when clinical worsening occurs,

Vol. 38 No. 9 SEPTEMBER 2017 401

 despite 48 hours of properly chosen and dosed antimicro-
bial agents. Notably, fever may persist (for an average of 48
hours), (48) but if a patient is improving in other ways
(better oral intake, lower respiratory rate, increased normal
activities), this would not be deemed a failure. If failure
occurs, repeat chest radiography and consideration of hos-
pitalization are in order. If the patient is hospitalized, it is not
necessary to expand coverage unless resistant organisms are
suspected (ie, rapid progression suggestive of S aureus or S
pyogenes), since intravenous (IV) ampicillin reaches much
higher serum levels than amoxicillin and provides extended
killing time for S pneumoniae. One may suspect highly
resistant S pneumoniae in children who have not received
the pneumococcal conjugate vaccine PCV13, since they are
not immunized against serotype 19A.
INPATIENT MANAGEMENT
Inpatient management of CAP can be separated into 2
patient scenarios: those who are admitted with viral pneu-
monitis and who might have superimposed CAP and those
with a clear need-to-treat bacterial CAP, with or without a
parapneumonic process. For the first category, the discus-
sion of diagnosis, outpatient management, and hospitaliza-
tion criteria in Table 1 was addressed earlier. For those with
an undisputed need-to-treat bacterial CAP as the primary
diagnosis, a few management principles apply. These in-
clude diligence in solidifying a microbial diagnosis, thought-
ful antimicrobial therapy, and management of complicated
disease.
Although inpatient bacterial CAP is still most likely to be
S pneumoniae, other causes should be considered in certain
inpatient settings. S aureus should be particularly consid-
ered in patients with influenza and superimposed CAP. S
aureus and S pyogenes should be considered in those with
rapidly progressive disease or signs and/or symptoms of
sepsis or toxic shock. While ampicillin provides adequate
coverage of S pyogenes, coverage for inpatients may need to
be expanded for S aureus with consideration of MRSA
coverage, depending on severity of disease and local resis-
tance patterns. The need to cover H influenzae or M catar-
rhalis specifically in the inpatient setting in normal hosts is
debatable, and hospitals that choose to prioritize the use of
ampicillin and/or amoxicillin (which lack coverage for 30%
of H influenzae and all M catarrhalis) demonstrate similar
outcomes when compared to the historical use of more ex-
panded regimens. (49) S pneumoniae, S aureus, and S pyogenes
can all cause parapneumonic processes. For antibiotic treat-
ment guidelines for inpatient CAP, please see Fig 1 on
antibiotic choice (IV and oral step-down).
402 Pediatrics in Review
Studies support the use of standardized inpatient CAP
guidelines. Per the Centers for Disease Control and Pre-
vention Study of Etiology of Pneumonia in the Community
on pneumonia causes, the use of inpatient clinical care
guidelines improved the use of ampicillin and decreased use
of cephalosporins and macrolides without negatively affect-
ing outcomes. (50) In this study, investigators also looked at
combined clinical physiological parameters (respiratory
rate, oxygen saturation) for “time to clinical stability” and re-
ported that guidelines were also helpful in determining
timing of discharge. (51)
Given that moderate to severe CAP involves bacteria-
triggered inflammation, investigations into adjunctive anti-
inflammatory therapies have included macrolides and
corticosteroids. Adjunctive corticosteroid use is supported
in adults with severe CAP, with studies showing shorter
time to clinical stability, shorter hospital lengths of stay, and
possible decreased mortality. There were no clinically sig-
nificant side effects identified in relation to corticosteroids
in these patients. (52)(53) The use of corticosteroids has not
yet been studied in pediatric CAP and should thus be
approached with caution. A short steroid course (5–7 days)
should be strongly considered in patients with CAP who
received a diagnosis of asthma if they exhibit signs of
reversible airway obstruction. Use of azithromycin as an
anti-inflammatory agent in acute CAP remains controver-
sial and is not recommended at this time. (54)(55)
COMPLICATED PNEUMONIA
There is substantial variability in admission rates for children
seen in the emergency department for CAP independent of
illness severity, and there is little to help clinicians predict
which patients will go on to develop moderate to severe com-
plications. In a recent study in Pediatrics, in which the Centers
for Disease Control and Prevention Study of Etiology of
Pneumonia in the Community data were also used, predictive
analytics were used to develop 3 prognostic models to esti-
mate risk for severe pneumonia outcomes in children. A
simple electronic health record model in which 9 predictors
were aggregated, including data on age, race, temperature,
vital signs, and partial pressure of arterial oxygen to fractional
index of oxygen ratio, was used to accurately identify risk for
intensive care unit admission and severe outcomes, including
the need for invasive mechanical ventilation and death. This
work, despite requiring more validation, may provide an
important tool for clinicians in determining those at highest
risk for complications from CAP. (56)
Despite decreasing incidence of bacterial pneumonia
and invasive pneumococcal disease attributed to vaccination
against H influenzae and S pneumoniae, studies indicate that
the rate of empyema and other complications of bacterial
CAP are increasing, particularly in preschool-aged patients.
(18)(57) This is possibly due to pneumococcal serotype
replacement and/or antibiotic resistance. (58) Complications
of CAP include parapneumonic effusion, empyema, pulmo-
nary abscess, bronchopleural fistula, necrotizing pneumonia,
acute or impending respiratory failure, and sepsis. Please
refer to Fig 2 for radiographic examples of some of these
complications. Parapneumonic effusion refers to an exuda-
tive process that results in a pleural fluid collection due
to pneumonia. Parapneumonic effusions develop in stages
on the basis of duration. In the first several days, effusions are
exudative and free flowing. By the second week, they become
fibropurulent with fibrin deposition over the pleurae. Fluid
can become septated. By 10 to 14 days, the effusion becomes
organized, with a stiff pleural membrane. Empyema is a
purulent effusion, with leukocytosis and/or bacteria in the
pleural space. Effusions are categorized by size to aid in
clinical decision-making (Fig 3). A bronchopleural fistula
occurs when an erosion in the airway or parenchyma com-
municates directly with the pleura, such that air enters the
pleural space. Necrotizing pneumonia occurs as a compli-
cation of both lobar and bronchopneumonia and is defined
by a combination of parapneumonic effusion, loculation,
and septation of the effusion and abscesses. These patients
Figure 2. Radiologic progression of complicated pneumonia. A.
Radiograph obtained on August 24 shows right upper lobe opacity and
small right pleural effusion. B. Radiograph obtained on August 29 shows
right middle and lower lobe consolidation and right-sided pleural
effusion with chest tube. C. Radiograph obtained on August 30 shows
worsening consolidation of the right upper lobe with minimal central
lucencies, likely an underlying component of pleural effusion. A chest
tube is in place. D. Radiograph obtained on September 3 shows
improved aeration with lucencies within the consolidation of the right
upper lobe, which suggests cavitation with small right effusion.
have a combination of the findings discussed earlier, exhibit
diminished or absent aeration and crackles at auscultation,
and typically appear ill and even toxic, with high fevers,
hypoxemia, and malaise. Complicated CAP should be sus-
pected in cases of previously healthy children with pro-
longed and persistent fever or deteriorating clinical status,
despite receiving appropriate antibiotic treatment. Other
clinical scenarios—such as rapid progression to impending
or fulminant respiratory failure—or the presence of chronic
comorbid illness—such as immunodeficiency, chronic lung
disease, or anatomic abnormalities—should prompt earlier
consideration and evaluation with imaging and laboratory
diagnostics.
Indications for chest computed tomography (CT) in
complicated CAP include concern for abscess or other pa-
renchymal abnormality. Identification of pleural septations
as evidence of organized pleural effusion or empyema is not
reliable and does not correlate with outcomes of specific
interventions (ie, chest tube drainage, intrapleural fibrino-
lytics, or VATS). Therefore, chest CT is not indicated on a
routine basis for evaluation of mild to moderate pneumonia
or even in cases of simple pleural effusion. When indicated,
CT should be performed with IV contrast material to allow
differentiation of thoracic structures.
The utility of lung ultrasonography in diagnosing com-
plicated pneumonia is controversial, in both the literature and
clinical practice. Lung ultrasonography in combination with
initial chest radiography can demonstrate small pneumonic
consolidations and allow early diagnosis of pleural effusion.
(59) Evaluation of pleural effusion with chest ultrasonography
may (a) allow localization, (b) demonstrate the presence of
loculations or septations to further characterize empyema,
and/or (c) guide thoracentesis and drain placement. However,
the presence or absence of septations on ultrasonography does
not enable prediction of a response to specific therapies or
indicate a need for surgical intervention over medical manage-
ment. Ultrasonography is highly user dependent, and images
should be acquired and interpreted by experienced personnel.
Management of parapneumonic effusions may be solely
medical or may involve a range of procedures to drain fluid
and physically disrupt fibrosis and inflammation. The deci-
sion of type and timing for percutaneous drainage or surgical
intervention often depends on local expertise and the indi-
vidual clinical scenario. Long-term outcomes of children with
pleural empyema are good, regardless of the treatment ap-
proach used during the acute phase of illness, (58) although
drainage procedures that meet the criteria as outlined in
national recommendations may shorten hospital stays. (13)
An example of an algorithm based on these guidelines is
provided in Fig 3 and is used at our institution. The goal of
Vol. 38 No. 9 SEPTEMBER 2017 403
 drainage is to debulk disease to provide symptomatic relief
and to allow antimicrobial agents to penetrate poorly perfused
areas.
Criteria for surgical intervention in cases of parapneu-
monic effusion and empyema involve consideration of the
size and duration of the effusion on images and the degree
of respiratory compromise and illness severity. Patients with
clinically significant hypoxemia, hypercapnia, and positive
pressure requirements or with complete respiratory failure
that requires intubation and ventilation will likely benefit
from drainage. Other indications for drainage of the pleural
space include the finding of thick pus at diagnostic thor-
acentesis, presence of fever and systemic illness after 5 to 7
days of therapy, presence of effusion for more than 10 days,
and, in cases of toxic shock with S aureus, debulking disease
and thus toxins.
Data are limited regarding an optimal drainage proce-
dure; therefore, the procedure type is often based on insti-
tutional expertise, availability, and provider comfort.
Options include thoracentesis, chest tube placement with
or without fibrinolytics, VATS, and thoracotomy for open
decortication. Randomized controlled trials in which VATS
was compared to the use of a chest tube with fibrinolytics
indicated that the therapies are equivalent in terms of length
of stay but favored the chest tube with fibrinolytics in terms
of cost and favored VATS in terms of rates of need for

Figure 3. Management of pneumonia with parapneumonic effusion. Adapted from Bradley et al. Clinical Infectious Disease 2011 and from Complicated
Community Acquired Pneumonia, Clinical Care Guidelines, Children’s Hospital Colorado, updated October 11, 2016. (71) CT¼computed tomography,
IR¼interventional radiology, IV¼intravenous, PO¼per os, tPA¼tissue plasminogen activator, US¼ultrasonography, VATS¼video-assisted thorascopic
surgery.

404 Pediatrics in Review

additional drainage procedures. (60)(61) Fibrinolytics
should be considered with chest tube placement to address
loculated infection and to facilitate effluent drainage. Choice
of fibrinolytic is dictated in part by availability, with tissue
plasminogen activator being the most commonly used in
the United States. Dosages have not been fully validated in
children and are variable in the literature. (60)(62) By
extrapolating the adult dosages, our center uses tissue
plasminogen activator of 0.1 mg/kg, given in 3 total doses
(every 24 hours) with a dwell time of 1 hour (Fig 3). (6)
Lung abscesses are increasingly rare in pediatric com-
plicated pneumonia because of increased access to care and
treatment with antibiotics. They may occur as a complica-
tion within necrotizing pneumonia but can also occur in
cases of more subacute scenarios. Lung abscesses are char-
acterized by the presence of a well-defined “rim” of fibrosis
around liquefaction necrosis, with or without air fluid levels.
The primary parenchymal infection that leads to a lung
abscess may originate hematogenously, via aspiration of oral
flora, or secondary to an inhaled foreign body. Owing to their
rarity in previously healthy children, lung abscesses should
trigger further consideration of underlying conditions or
predisposing risk factors, including aspiration (acute or
chronic), foreign body, and structural abnormality, such
as a pulmonary sequestration or congenital pulmonary
airway malformation (formerly known as congenital cystic
adenomatoid malformation). Immunodeficiency or chronic
infection should be considered when M tuberculosis or en-
demic fungi are identified. It is difficult to differentiate lung
abscess from other structurally similar complications, such
as loculated pneumothorax, pneumatocele, or cavitary
necrosis. Chest CT is the imaging modality of choice.
There is not strong evidence that surgical drainage of small
to moderately sized abscesses improves outcomes over pro-
longed medical therapy alone. (63) Aspiration and culture of
fluid from lung abscesses are typically reserved for patients
who do not respond to appropriate antibiotics within 5 to 7
days because drainage carries risk, and most abscesses will
drain spontaneously via the bronchial tree. Antibiotic treat-
ment must often be initiated without a specimen or before
identification of specific bacteria. Parenteral therapy should
reflect the empirical recommendations in Fig 1, with care
given to considering additional anaerobes and gram-negative
organisms if aspiration is suspected as the etiologic origin of
the abscess. Duration of treatment is typically 4 to 6 weeks,
with at least 1 to 2 weeks of therapy after resolution of fever
and until normalization of inflammatory markers. Perform-
ing repeat imaging to follow up resolution is indicated.
When lung necrosis and abscess develop near the pleural
boundary, inflammation and infection can erode from the
airway and enter the pleural space, creating an air leak
known as a bronchopleural fistula. This complication is rare
in pediatric pneumonia, but some single-center retrospec-
tive case reviews have indicated increasing rates associated
with specific pneumococcal serotypes. (64) Care of this
complication is not straightforward and requires a multi-
specialty approach, including surgical consultation.
Round pneumonia is a separate complication from an
abscess, although also very rare. It has a distinctive radio-
logic pattern, described as an opaque round shape, and a
study of children with round pneumonia typically demon-
strated the consolidations to have well-defined borders, to be
located posteriorly, and to be solitary in their distribution.
Round lesions on chest radiographs should trigger consid-
eration of a broader differential diagnosis, including fungal
infection, lung abscess, and congenital or acquired pulmo-
nary malformations such as cysts, congenital pulmonary
airway malformation, or pulmonary sequestration, as well
as a range of neoplasms, including lymphoma and neuro-
blastoma. (65) Primary pulmonary malignancies are rare in
pediatrics.
Necrotizing pneumonia is an inexact term used to denote
evidence of parenchymal necrosis in the lung. It is commonly
a precursor for a range of complications, including lung
abscess and pneumatocele. Radiologically, these changes
appear as focal lucencies on chest radiographs, often with an
accompanying parapneumonic effusion. CT scans, when
obtained, show areas of low attenuation within the paren-
chyma that are attributed to liquefaction; these areas can be
patchy or continuous, with an area of consolidation. Impor-
tantly, the term necrotizing pneumonia conveys an assessment
of clinical severity out of proportion to traditional symptoms
of severe pneumonia, since some of these patients progress
rapidly to septic shock and respiratory failure. Necrotizing
pneumonia is thought to be caused by particularly virulent
bacterial strains of S pyogenes, S pneumoniae, or S aureus, par-
ticularly S aureus harboring Panton-Valentine leukocidin, a
toxin associated with neutrophil lysis. (66) Similar to patients
with lung abscess discussed earlier, most cases of necrotizing
pneumonia resolve with medical treatment alone.
Antimicrobial therapy of complicated pneumonia should
include coverage for S pneumoniae for all patients, and for
very ill patients or those with influenza, therapy should
include coverage for S pyogenes and S aureus, with consid-
eration for empirical MRSA coverage. Antimicrobial agents
should be narrowed as soon as possible, (67) as directed by
culture results and local epidemiology (Fig 1). Two to 4
weeks of antibiotic therapy is typical for treatment of com-
plicated pneumonia; however, there is a lack of data to
support a definitive length of treatment. Length of therapy
Vol. 38 No. 9 SEPTEMBER 2017 405
 should be determined by the clinical course and response to
therapy. Parenteral antibiotics are recommended for initial
therapy to optimize antimicrobial concentrations in the lung
tissue and pleural fluid. The decision to transition a patient
with complicated CAP to oral antibiotics is best guided by
clinical response, including improved respiratory status,
decreasing fever, and decreasing inflammatory markers.
In a recent study, there were no differences in complications
related to infection in patients treated with IV versus oral
antibiotics. (61)
Severe pneumonias have other well-described associa-
tions worth mentioning that may complicate care in the
acute setting. These include syndrome of inappropriate
antidiuretic hormone and hemolytic-uremic syndrome (par-
ticularly with S pneumoniae). Another rare complication of
pneumonia is empyema necessitans. This occurs when
infected fluid in the chest erodes into the chest wall, causing
local symptoms where the erosion occurs. Empyema neces-
sitans is seen in more indolent infection that has gone
undetected, such as with actinomycetes or mycobacteria
or, rarely, inadequately treated traditional bacterial compli-
cated pneumonia.
USE OF FOLLOW-UP RADIOLOGY
Repeat chest radiography is indicated in cases of clinical
deterioration or instability after 24 to 48 hours of antibiotics.
Identification of effusion or worsening infiltrate can inform
decisions about broadening antibiotic coverage or consid-
eration of pleural drainage.
In patients with a chest tube in place, standards vary from
institution to institution about serial chest imaging, with
some supporting daily radiographs to be acquired to be able
to monitor chest tube placement, while others only repeat
chest radiography in cases of clinical deterioration or pos-
sible tube malfunction.
In the outpatient realm, repeat chest radiographs are not
indicated in most cases of mild, moderate, or even severe
pneumonia. Because recurrent pneumonia in a specific
location may suggest underlying anatomic abnormalities,
chest imaging should be repeated 6 to 8 weeks after clinical
resolution of pneumonia. Complete radiologic resolution of
acute pneumonia occurs by 2 months in more than 90% of
cases. (68) Radiographic resolution of a lung abscess and
round pneumonia should be documented.
RECURRENT BACTERIAL PNEUMONIAS
Recurrent pneumonia is defined by more than 2 episodes of
pneumonia in 1 year or more than 3 episodes in a lifetime.
406 Pediatrics in Review
Approximately 8% of patients hospitalized for pneumonia
meet these criteria. (68) Regardless of the age of the patient,
recurrent pneumonia should trigger further evaluation for
underlying microbiological, functional, anatomic, and chronic
disease factors. (69)(70) Conducting radiologic follow-up at
2 months to distinguish persistent from recurrent pneu-
monias is reasonable to assist in determination of a differ-
ential diagnosis and to direct further imaging, laboratory
testing, and procedural evaluation. (68)
Diagnosis of recurrent or persistent pneumonia is con-
firmed by means of persistent findings of opacification on
chest radiographs. Further evaluation of persistent localized
consolidation starts with direct visualization and sampling
of the affected region by means of flexible bronchoscopy and
bronchoalveolar lavage. Cytologic analysis and culture of
the fluid can demonstrate persistent pathogens or suggest
aspiration if a high burden of lipid-laden macrophages
is seen. CT with contrast material is used to evaluate the
parenchyma and distal airways. Pathologic changes such as
airway bronchiectasis, cystic changes, and congenital se-
questrations and infectious complications, such as cavitary
abscesses or pleural effusion with loculations, can direct
further evaluation and therapies.
Consolidations that persist and/or recur in the same area
suggest a persistent pathogen or a focal anatomic abnor-
mality. Persistent infectious causes include less common
pathogens, such as tuberculosis, endemic fungal infections,
Actinomyces, and nocardiosis. Focal anatomic abnormalities
include obstructing lesions of the airway, including a re-
tained foreign body, compressing lymph node or tracheal
growth, compressing vascular rings or slings, and dynamic
obstruction due to compressive tracheal tracheomalacia or
bronchomalacia. Other focal abnormalities lead to poor
clearance, such as segmental bronchiectasis, tracheal bron-
chus, pulmonary sequestration, or airway cyst, can lead to
poor mucociliary clearance. Right middle lobe syndrome de-
scribes the presence of recurrent right middle lobe con-
solidations that likely occur because of poor collateral
ventilation due to the acute angle to that lobe from the right
mainstem bronchus. This lobe is more susceptible to atel-
ectasis, aspiration, and lymph node compression.
Infiltrates that recur, but in anatomically distinct areas,
invoke concern for immune defects or difficulties with air-
way clearance. Asthma causes recurrent atelectasis and in-
filtrates due to airway inflammation and mucus plugging.
Associated symptoms of airway reactivity, including night-
time cough and wheeze that is worse with activity, can
suggest uncontrolled asthma. Other defects and/or diseases
to consider include cystic fibrosis, ciliary defects, surfactant
protein defects, HIV, and congenital immune deficiencies.
A negative newborn screening test finding for cystic fibrosis
should not deter the provider from pursuing a sweat chlo-
ride test. If results are positive, the provider should contact
the nearest cystic fibrosis center for further evaluation.
Another unusual cause to consider is recurrent bacterial
seeding of the lungs in patients with cardiac defects, espe-
cially valvular disease and septal defects.
The tempo of the evaluation is dictated by the severity of
the illness. For example, chronic hypoxemia, hypoventila-
tion, weight loss, persistent fevers, anemia, leukopenia or
leukocytosis, or digital clubbing would all trigger a more
aggressive approach. Recurrent pneumonia evaluation can
be aided by referral to specialists, including an infectious
disease specialist, pulmonologist, and otolaryngologist.
DIAGNOSIS AND MANAGEMENT OF PNEUMONIA IN
PATIENTS WITH NEUROMUSCULAR DISEASE
Pneumonia in patients with neuromuscular disease (in-
cluding spinal muscular atrophy and Duchenne muscular
dystrophy) requires additional diagnostic considerations
and management recommendations. Because of persistent
muscle weakness that leads to restrictive lung physiology,
most patients with neuromuscular disease have decreased
total lung capacity. Compounding this physiology, these
patients often have impaired cough function at baseline,
and bulbar weakness may increase the risk for aspiration
into the lungs. Thus, these patients are at high risk for
developing pneumonia in general, and it can be community
acquired, hospital acquired, or health care associated. Once
infected, the decreased pulmonary reserve accelerates dete-
rioration to respiratory failure in these patients. (71)
Initial diagnosis and stabilization should include early
consideration of chest radiography, electrocardiography,
blood gas analysis, and assessment of electrolyte levels.
Patients with spinal muscular atrophy are at risk for hypo-
glycemia if they receive nothing by mouth for 4 to 6 hours
and should be started on IV dextrose, regardless of hydration
status, if they receive nothing by mouth. Empirical antibiotic
coverage includes traditional CAP coverage, but based on
clinical history, risk factors, and past microbiology, may
need to be expanded to cover anaerobes, gram-negative find-
ings (including resistant gram-negative findings), and/or
MRSA. A diagnostic bronchoalveolar lavage should be
considered in intubated patients. Supportive care with oxy-
gen and biphasic noninvasive ventilation is often essential,
being mindful that increasing fractional index of oxygen
alone or instituting continuous positive airway pressure
may blunt the hypoxic respiratory drive response in the
setting of chronic hypercapnia. Airway clearance regimens
that include mechanical insufflation-exsufflation are impor-
tant in aiding mucus clearance and airway recruitment.
Admission criteria for patients with neuromuscular disease
are more conservative, requiring assessment of each patient
in relationship to his or her pulmonary baseline. If the
patient requires continuous nasal intermittent positive
pressure ventilation, new or increased oxygen requirement,
or new or worsened hypercapnia or if suctioning and cough
augmentation requirements are frequent, the patient should
be admitted with consideration of critical care services.
Consider cardiac dysfunction as either primary or secondary
to respiratory distress, since many of these patients develop
cardiomyopathy (particularly with Duchenne muscular
dystrophy).
Summary
• On the basis of some research evidence, as well as consensus,
treatment of uncomplicated community-acquired pneumonia
can reasonably be achieved in 7 days or less. (43)(44)(45)
• On the basis of strong evidence, narrow-spectrum treatment is
the preferred therapy in almost all settings. (6)(33)(35)
• On the basis of consensus and moderate evidence, in this era of
antimicrobial resistance, efforts to obtain a specimen for
pathogen identification may be beneficial.
• On the basis of strong evidence, consideration of surgical and/or
procedural management of complicated pneumonia should be
based on size of effusion and clinical severity. (6)(13)
• On the basis of moderate evidence, patients with recurrent
pneumonia require further evaluation.
• On the basis of expert consensus, patients with a neuromuscular
disorder are particularly susceptible to severe disease and more
resistant pathogens and may require broader antibiotic coverage
and aggressive airway clearance.
References for this article are at http://pedsinreview.aappublications.
org/content/38/9/394.
Vol. 38 No. 9 SEPTEMBER 2017 407
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1. A previously healthy 13-month-old girl who lives in Arizona is brought to the office with a REQUIREMENTS: Learners
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physical examination, there is no grunting or chest retractions. There are crackles heard
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2017 Pediatrics in Review
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C. Outpatient amoxicillin.
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D. Outpatient azithromycin.
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E. Outpatient cefdinir.
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saturation increases to 98%. There are crackles at the left lung base. A chest
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408 Pediatrics in Review

5. A 2-year-old girl is admitted to the hospital with fever for 3 days with a right middle lobe
consolidation. She has had a cough for the past 3 months with 2 prior admissions for
pneumonia, with the same location of the infiltrate noted on chest radiographs. She
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A. a1-antitrypsin deficiency.
B. Chronic granulomatous disease.
C. Cystic fibrosis.
D. Retained foreign body.
E. Wiskott-Aldrich syndrome.

Additional Resources for Pediatricians

AAP Textbook of Pediatric Care, 2nd Edition
• Chapter 315: Pneumonia - https://pediatriccare.solutions.aap.org/chapter.aspx?sectionid=124995320&bookid=1626
Point-of-Care Quick Reference
• Pneumonia - https://pediatriccare.solutions.aap.org/content.aspx?gbosid=165559

Parent Resources from the AAP at HealthyChildren.org

• Pneumonia: https://www.healthychildren.org/English/health-issues/conditions/chest-lungs/Pages/Pneumonia.aspx
For a comprehensive library of AAP parent handouts, please go to the Pediatric Patient Education site at http://patiented.aap.org.

Vol. 38 No. 9 SEPTEMBER 2017 409

 Pediatric Lymphoma
Ilia N. Buhtoiarov, MD*
*Pediatric Leukemia and Lymphoma Clinic, Cleveland Clinic Children’s Hospital, Cleveland, OH

Education Gaps
Painless lymphadenopathy is one of the commonest presentations
of pediatric lymphoma. Absence of the absolute lymphoma-specific
signs and symptoms makes it a particular diagnostic challenge. Lack
of systemic symptoms does not preclude a malignant transformation.
High level of suspicion is critical for timely patient referral to a
pediatric oncologist. Outstanding survival rates may be
compromised by a substantial prevalence of the therapy-related
side effects.

Objectives After completing the article, readers should be able to:

1. Recognize genetic and environmental factors contributing to

development of lymphoma.
2. Identify clinical parameters that can be used to predict the nonbenign
nature of lymphadenopathy.
3. Recognize lymphoma-associated oncologic emergencies.
4. Diagnose tumor lysis syndrome and propose prophylactic and
AUTHOR DISCLOSURE Dr Buhtoiarov has
therapeutic interventions. disclosed no financial relationships relevant to
this article. This commentary does not contain
5. Discuss therapeutic options and recognize therapy-related side effects.
a discussion of an unapproved/investigative
use of a commercial product/device.

ABBREVIATIONS
INTRODUCTION CAR chimeric antigen receptor
cHL classic Hodgkin lymphoma
Lymphoma is the third most frequent childhood malignancy (prevalence rate of CNS central nervous system
12%–15%), closely following acute leukemia and central nervous system (CNS) CT computed tomography
tumors. Most pediatric patients with lymphoma will survive their disease into EBV Epstein-Barr virus
HIV human immunodeficiency virus
adulthood. Having a high threshold of clinical suspicion at the time of first
HL Hodgkin lymphoma
assessment, along with performing problem-oriented initial tests, followed by
HRSC Hodgkin Reed-Sternberg cell
prompt referral to the pediatric lymphoma expert for further evaluation and HSCT hematopoietic stem cell
specialized treatment, are the pillars of therapeutic success. This review will serve transplantation
to update the readership on pediatric lymphoma epidemiology and known Ig immunoglobulin
predisposition factors, clinical presentation, diagnostic tests, and therapeutic LN lymph node
NHL non-Hodgkin lymphoma
options, as well as treatment-related side effects that may need to be recognized
NLPD nodular lymphocyte–predominant
while taking care of lymphoma survivors. SVC superior vena cava
Lymphoma is a neoplasm caused by malignant transformation of lymphoid TLS tumor lysis syndrome
cells. Advances in the understanding of lymphoma biology led to development of UA uric acid

410 Pediatrics in Review

risk- and response-adapted therapies, which caused lym-
phomas to be one of the most curable pediatric cancers. The
disease-free survival after completion of therapy exceeds
85% for most patients with lymphoma.
BIOLOGY AND EPIDEMIOLOGY OF LYMPHOMA
There are 2 clinicopathologic lymphoma types: Hodgkin
lymphoma (HL) and non-Hodgkin lymphoma (NHL), with
distinct clinical subtypes within each of those types. Varia-
tions in lymphoma incidence, age, and sex distribution occur
in different pediatric populations according to geographic lo-
cation and socioeconomic environment.
HL accounts for approximately 6% to 8% of all pediatric
neoplasms. In developed countries, HL is the most prevalent
lymphoma, as well as the most prevalent neoplasm in patients
aged 10 to 19 years (Table 1 [1]). In developing counties, the
overall HL prevalence in older children is about the same
but occurs significantly more frequently in younger patients
(aged 0–9 years). HL incidence has a bimodal age distribu-
tion: the early peak occurs in the mid-20s, with the second
peak in the late 50s; however, in developing countries, the
early peak occurs before adolescence. In early childhood, HL
is more frequent in boys (male to female ratio of approx-
imately 5:1), whereas in adolescents, it is more frequent
in girls (male to female ratio of approximately 0.8:1.0). In
younger patients, the increased HL prevalence correlates
with larger family size and socioeconomically disadvantaged
status. For the older group, the greater HL risk correlates
with higher socioeconomic status, smaller sibship size, and
late birth order. These patients commonly experience fewer
childhood infections or experience them at older ages, which
potentially affects the timing of immune system maturation.
HL incidence is similar among young African American and
white patients; it is less frequent among African American
adolescents (ratio of 0.8:1.0).
There are 2 biologically distinct HL variants: classic HL
(cHL) and nodular lymphocyte–predominant (NLPD) HL.
The diagnostic hallmark of cHL is the multinucleated (at
least 2 nuclei in 2 separate lobes) Reed-Sternberg cell or its
mononuclear variant, the Hodgkin cell (Fig 1A). These
malignant cells of B-cell origin constitute less than 1% of
the tumor bulk; most of the tumor mass is a variable mixture
of nonneoplastic reactive leukocytes of a certain lymphoma-
specific architecture. Hodgkin Reed-Sternberg cells (HRSCs)
express B-cell lineage–specific antigens CD30 and CD15. On
the basis of characteristics of the reactive infiltrate and HRSC
morphology, 4 cHL subvariants are recognized: nodular
sclerosis (most frequent in older patients [>10 years of
age]); mixed cellularity (more frequent in younger children
[<10 years of age]), lymphocyte rich (rare), and lymphocyte
depleted (also rare). These histologic variants have some
prognostic implications; patients with the mixed cellularity
cHL seem to have a better outcome.
NLPD HL accounts for approximately 10% of all HL cases
and affects girls more frequently than boys (female to male
ratio of 3:1). The malignant cells of NLPD HL are called
lymphocyte-predominant cells (Fig 1B). They are large cells
with single, folded, multilobulated nuclei with small nucle-
oli. Unlike classic HRSC, the lymphocyte-predominant cells
uniformly express CD20 but not CD30 or CD15.
After the onset of HL at a single lymphoid organ, the
HRSC contiguously spreads to the adjacent lymphoid tissues
and to distant lymphoid and nonlymphoid organs through
both lymphatic and hematogenous routes. Since HRSCs are
terminally differentiated cells with a limited proliferation and
extravasation potential, the role of HRSC “precursors”
homing into “metastatic niches” is being debated. (2)

TABLE 1. Pediatric Lymphoma Incidence (Per 100,000 Person-Years)

MALE PATIENTS FEMALE PATIENTS
<5 Y 5–9 Y 10–14 Y 15–19 Y <5 Y 5–9 Y 10–14 Y 15–19 Y

Hodgkin lymphoma <1 6 12 28 <1 2 9 31

Non-Hodgkin lymphoma 3.2 6 6.1 2.8 0.8 1.1 0.8 1.2
Burkitt lymphoma
Lymphoblastic 1.6 2.2 2.8 2.2 0.9 1.0 0.7 0.9
Diffuse large B-cell <1 1.2 2.5 6.1 0.6 <1 1.4 4.9
lymphoma
Anaplastic large-cell 2.3 3.3 4.3 7.8 1.5 1.6 2.8 3.4
lymphoma and other

According to reference 1. Data are number of patients.

Vol. 38 No. 9 SEPTEMBER 2017 411

 Figure 1. Photomicrographs (H&E stain; original magnification,
40) demonstrate the histomorphology of different types of lymphoma. A. Classic
Hodgkin lymphoma is shown. The arrowhead indicates the Reed-Sternberg cell; the arrow indicates the Hodgkin cell, surrounded by reactive
lymphocytes. B. Nodular lymphocyte–predominant Hodgkin lymphoma is shown. The arrowhead indicates the lymphocyte-predominant “popcorn”
cell, which is the cell surrounded by reactive lymphocytes. C. Burkitt lymphoma is shown. The arrowhead indicates a macrophage surrounded by
morphologically uniform malignant lymphoma cells (also known as “the starry sky” appearance). D. T-cell lymphoblastic lymphoma is shown.
Morphologically uniform malignant cells form the bulk of the tumor.

Although early exposure to pediatric infections has a
protective effect, Epstein-Barr virus (EBV) has been impli-
cated in HL development; EBV positivity can be observed in
approximately 70% to 80% cases of mixed-cellularity HL,
the commonest histologic cHL subvariant of early child-
hood. Children with a medical history of infectious mono-
nucleosis have increased risk of developing EBV-positive
cHL; EBV can still be detected in the tumors of more than
50% of these patients. However, such patients are not at
increased risk for EBV-negative cHL. (3) In contrast, NLPD
HL has no strong association with EBV.
Familial HL comprises approximately 4% of all cHL
cases. HL history in a parent or a sibling is a recognized risk
factor. Age (<45 years) of the affected parent or sibling
is critical and results in a sevenfold increased risk of HL
development. Brother-brother and sister-sister pairs have
the highest risks for developing cHL. Monozygotic twins of
patients with HL demonstrate the greatest risk. (4) In many
cases of familial cHL, certain inherited or acquired immune
system abnormalities exist, such as autoimmune lympho-
proliferative syndrome, ataxia-telangiectasia, sarcoidosis,
juvenile rheumatoid arthritis, systemic lupus erythemato-
sus, Sjögren syndrome, ulcerative colitis, immune throm-
bocytopenic purpura, acquired immune deficiencies caused
by EBV, and human immunodeficiency virus (HIV) infec-
tions. A long latency from the onset of the autoimmune
condition (mean, 15.4 years) to HL diagnosis has been
observed. This underscores the role of long-term immuno-
logic dysregulations as a pathogenetic factor in HL.
In children without underlying immunologic disarrays,
the recessively inherited human leukocyte antigen–linked
susceptibility genes may be found in approximately 60%
of cases. Familial HL cases demonstrate only 1 major
incidence peak between 15 and 34 years of age. The afore-
mentioned factors seem to play a minimal role in NLPD HL
development.
Secondary HL—that is, HL that develops after therapy
administered for another malignancy—is extremely rare and,
in reported cases, follows the treatment of acute lymphoblas-
tic leukemia.
NHL is a heterogeneous group of neoplasms that ac-
counts for approximately 7% of all pediatric malignancies; it
originates from either immature (lymphoblastic) or mature
B, T, or natural killer cells: lymphoblastic lymphoma; mature
B-cell NHL (Burkitt lymphoma, diffuse large B-cell lym-
phoma, primary mediastinal B-cell lymphoma); and
anaplastic large-cell lymphoma. There are several other
infrequent types, including primary CNS NHL. Similar
to HL, there is a variability in NHL incidence rates according
to sex, age, and ethnicity. The overall incidence rate appears to
be increasing with age (Table 1). Male patients are affected
more frequently than female patients (male to female ratio
3.5:1). (1) NHL incidence in white children is the highest
when compared to other ethnic groups.
In NHL, the bulk of the tumor is composed predominantly
of the uniform malignant cells (Fig 1 C and D). Conceptually,
any lymphoma that lacks the morphologic features of HL
should be classified as NHL, although in some cases, the
distinction is challenging to make.
The spreading of NHL to different sites and organs is a
phylogenetically conserved phenomenon that relies on lym-
phocyte biology; it uniquely depends on lymphoma cells’
expression of various adhesion molecules and the reciprocal
receptors expressed in the target organs. (5)
Previous exposure to pediatric infections does not af-
fect NHL incidence. However, there is a strong association
of endemic Burkitt lymphoma with EBV and malaria
(and possibly schistosomes and arbovirus) in some African
countries (Uganda, Malawi, Congo, and Nigeria, known
as the “African lymphoma belt”). Exposure to Euphorbia
tirucalli spurge, also known as “milk bush,” which is used
in many rituals, has been attributed to reactivation of latent

412 Pediatrics in Review

EBV infection. Poor socioeconomic conditions lower the
age of initial EBV infection, which could be the trigger for
Burkitt lymphoma. However, EBV can be isolated in only 10%
to 15% of cases of sporadic Burkitt lymphoma. The afore-
mentioned factors play no role in the incidence of other NHL
types.
The retrospective studies performed by the Interna-
tional Lymphoma Epidemiology Consortium demonstrated
increased NHL risk for patients with a first-degree relative
with previous NHL history, a first-degree relative with
history of cHL, or a first-degree relative with acute leukemia.
Prospective cohort studies confirmed the association of
B-cell NHL with a history of lymphoma in first-degree
relatives. Unlike cHL, no human leukocyte antigen class I or
II alleles were characterized as having NHL risk-modifying
effects. Recently, certain genetic variations within or near
the candidate genes have been identified. (6)
Similar to cHL, congenital or acquired immune deficien-
cies are strong risk factors for childhood NHL. Patients with
ataxia-telangiectasia, Wiskott-Aldrich syndrome, severe
combined immune deficiency, X-linked lymphoproliferative
disease, autoimmune lymphoproliferative syndrome, com-
mon variable immune deficiency, and X-linked hyper–
immunoglobulin (Ig) M syndrome have a 10- to 200-fold
increased risk of NHL development. Many children demon-
strate evidence of preceding EBV infection. HIV infection is one
of the commonest acquired immune deficiencies that increases
risk of NHL by more than 150 times. Sjögren syndrome,
systemic lupus erythematosus, and hemolytic anemia are asso-
ciated with increased risk of B-cell lineage NHL, whereas
psoriasis was reported to increase the risk for cutaneous T-cell
lymphoma by 3.5-fold. Juvenile rheumatoid arthritis and the
concomitant use of corticosteroids or other immunosuppres-
sants are also associated with increased NHL risk.
Interestingly, patients who were previously treated for
HL are at risk for developing secondary NHL, the risk of
which is higher after treatment than that of any other cancer.
The biology of such a phenomenon is unclear. Chromo-
somal instability documented in patients with HL before
any therapy might render these patients particularly sensi-
tive to the genotoxic effect of chemotherapy and radiation.
Risk of secondary NHL increases after the first 5 years after
completion of chemotherapy and persists for decades.
Exposure to various environmental factors prenatally
or in early childhood has always been considered one of
the putative key elements of lymphomagenesis. Thus, it
was found that maternal consumption of heavy liquors (ie,
alcoholic beverages other than wine and beer) (7) during
pregnancy might be associated with NHL but not HL.
However, no statistically significant relationship between
alcohol dose and lymphoma incidence was documented.
Preconception paternal smoking but not maternal smoking
before or during pregnancy was also observed to be asso-
ciated with NHL; this had a tendency to increase with the
number of cigarettes smoked. However, parental smoking
history was not associated with increased frequency of HL.
(7) In addition, residential exposure to household pesticides,
(8)(9) paternal preconception exposure to organic solvents and
petrol exhaust, (10) and in utero exposure to benzene and
nitrogen dioxide (11) have been proposed as possible causative
factors for lymphoma development.
Similarly, in utero exposure to ionizing radiation (diag-
nostic radiography, computed tomography [CT]), although
extremely rare, has also been suggested to be associated with
increased frequency of lymphoma. (12) In contrast, expo-
sure to ionizing radiation in early childhood or exposure to
diagnostic ultrasonography in utero has not been found to
be associated with increased lymphoma incidence later in
life. (12) Exposure to chemotherapy agents used for other
malignancies, as discussed previously, also increases the
risk of lymphoma development.
Hence, both genetic susceptibility and environmental
factors may play a role in the development of lymphoma.
However, it is unclear if there is any cross-potentiation be-
tween different factors. It remains to be elucidated whether
additional pathogenetic factors, resulting in postnatal gene-
tic alterations, are necessary to trigger lymphomagenesis, as
pediatric lymphoma remains an infrequent condition. Sim-
ilarly, it remains to be studied if active avoidance of exposure
to the aforementioned environmental factors could have a
prophylactic effect on development of pediatric lymphoma.
CLINICAL PRESENTATION
Lymphoma is traditionally perceived as a malignancy that
predominantly involves the lymph nodes (LNs). Whereas
this is true for most cases, there are occurrences where
lymphoma originates from primary lymphoid tissues (bone
marrow and thymus) or various secondary lymphoid tissues
other than LN (spleen, mucosa-associated lymphoid tis-
sue) or nonlymphoid organs (skin, bone, brain, lungs, liver,
salivary glands, etc). It is extremely important to remember
that there are no lymphoma-specific signs or symptoms
other than those related to growth of the lymphoma mass. It
is also difficult to distinguish HL from NHL solely on the
basis of clinical presentation.
Lymphadenopathy in a well-appearing child is always
a diagnostic challenge. In many patients, lymphadenopathy
is secondary to self-limited transient processes that resolve
without interventions (Table 2). Regardless, despite the
Vol. 38 No. 9 SEPTEMBER 2017 413
 TABLE 2. Common Causes of Lymphadenopathy
CAUSE SOURCE

Infection Bacterial: Staphylococcus aureus, group A Streptococcus, Brucella spp, Borrelia spp, Bartonella henselae, Francisella
tularensis, Mycobacterium spp
Viral: Epstein-Barr virus, cytomegalovirus, HIV, herpes simplex virus, human papillomavirus, human herpesvirus-8,
measles, rubella
Fungal: Histoplasma capsulatum, Cryptococcus spp, Coccidioides spp
Protozoan: Toxoplasma gondii, Plasmodium spp
Autoimmune disease Juvenile rheumatoid arthritis, systemic lupus erythematosus, autoimmune lymphoproliferative syndrome
Storage disease Gaucher disease, Niemann-Pick disease
Drug reaction Allopurinol, atenolol, captopril, carbamazepine, cephalosporins, hydralazine, penicillins, phenytoin, quinidine,
sulfonamides
Malignancy Lymphoma, leukemia, solid tumor metastases
Miscellaneous Postvaccination reaction, Langerhans cell histiocytosis, Kawasaki disease, sarcoidosis, Castleman disease, Kikuchi
disease, Rosai-Dorfman disease

relative infrequency of childhood cancers, careful consid-
eration must be made to rule out lymphadenopathy as an
initial presentation of malignancy. There is no agreement on
what LN size should indicate an abnormality. In pediatric
oncology practice, a persistently enlarged LN larger than 1
cm should merit further investigation. However, it also
depends on the age of the child, as well as anatomic location.
For example, epitrochlear LNs, which are usually not pal-
pable, are considered enlarged if larger than 0.5 cm; ingui-
nal LNs are considered enlarged if larger than 1.5 cm.
Localized lymphadenopathy involves a single nodal area;
generalized lymphadenopathy involves at least 2 noncon-
tiguous nodal groups. Chronic lymphadenopathy is the LN
enlargement that persists for more than 3 weeks.
A diagnostic approach to lymphadenopathy includes the
following:
• History: duration, associated symptoms, contact with ill
persons, infections, medications, vaccinations, and site
of vaccine inoculation (Table 2)
• Physical examination: size, number, anatomic location,
pain and/or tenderness, consistency, matting (ie, forming
conglomerates that feel and move together during
lymph node palpitation), overlying skin changes
• Minimally invasive testing, including the following:
n Laboratory tests: complete blood cell count; serum
lactate dehydrogenase, alkaline phosphatase,
uric acid (UA), and C-reactive protein levels; and
erythrocyte sedimentation rate
n Radiologic imaging: chest radiography, LN ultra-
sonography, CT
The ultimate goal is to determine whether biopsies of
LNs should be performed. Patients with unremarkable clinical
history and physical examination findings do not require
immediate biopsy; such patients should be re-evaluated in 3
to 4 weeks. Children with chronic or generalized lymph-
adenopathy or those with new-onset systemic symptoms
should be advised to undergo biopsy without delay.
Factors that have high predictive value for the nonbenign
nature of lymphadenopathy are as follows (13):
• Age of more than 10 years
• Duration of lymphadenopathy longer than 6 weeks
• LN size larger than 2.5 cm
• Supraclavicular site (left side in particular)
• Matting and limited motility to palpation
• More than 1 noncontiguous LN area involved
HL commonly appears with an LN conglomerate at
presentation, which is frequently located in the cervical
or supraclavicular area. It is usually painless, unless the
mass compresses other anatomic structures, and has “rub-
bery” firmness, with no inflammatory changes of overlying
skin. Involvement of other organs may be symptomatic on
the basis of the anatomic compartment: chest discomfort,
superior vena cava (SVC) syndrome, tachypnea and orthopnea
in the case of large mediastinal masses; abdominal discomfort
due to hepatomegaly or splenomegaly or large intra-abdominal
tumor; musculoskeletal pains; and headaches or focal neu-
rological signs in cases of CNS involvement.
Constitutional signs include fatigue, anorexia, and so-
called B symptoms:
• Fever of at least 100.4°F (38°C) for 3 consecutive days,
occurring mostly at night in an undulant pattern and
progressively becoming worse (Cardarelli-Pel-Ebstein
fever)
• Drenching night sweats
• Unexplained body weight loss of 10% or more over the
preceding 6 months

414 Pediatrics in Review

 These signs, present in about one-third of patients,
usually signify advanced-stage disease and are secondary
to inflammatory cytokine release by the tumor. Fever is an
independent prognostic factor for bone marrow involve-
ment. The “B symptoms” are uncommon in patients with
NLPD HL. Absence of “B symptoms” does not rule out HL.
NHL clinical presentation greatly varies because of bio-
logical difference of distinct NHL variants, and depends on
the NHL type; any organ, tissue, and anatomic area can
be involved. Unlike HL, NHL frequently manifests with a
rapidly enlarging mass (Burkitt lymphoma doubling time is
approximately 5 days vs approximately 30 days for HL). The
most common presenting sites are the abdomen, the head
and neck region (parotid glands, Waldeyer ring of lymphoid
tissue, cervical LN), and the mediastinum; bones, kidneys,
and skin may also be involved. Gonadal involvement is
present in approximately 5% of cases, with no sex-related
differences. CNS and bone marrow involvement are more
common than in patients with HL; these patients require
more intensive treatment to attain the same survival rate.
The bone marrow involvement in patients with Burkitt lym-
phoma and lymphoblastic lymphoma may become a source of
diagnostic confusion; patients with fewer than 25% lymphoma
cells in the bone marrow are still considered to have Burkitt
lymphoma or lymphoblastic lymphoma, whereas those who
have at least 25% bone marrow lymphoma cells will be
classified as having the Burkitt type or acute lymphoblastic
leukemia with extramedullary disease, respectively.
ONCOLOGIC EMERGENCIES IN NEWLY DIAGNOSED
LYMPHOMA
Children with newly diagnosed lymphoma may present
with life-threatening conditions that necessitate immediate
therapeutic interventions:
• Anterior mediastinal mass presenting as SVC syn-
drome, airway obstruction, or pleural effusion with
resultant acute cardiorespiratory insufficiency
• Abdominal masses complicated with intestinal obstruc-
tion, intussusception, inferior vena cava syndrome, ure-
teral obstructions, or postrenal failure
• CNS lymphoma manifesting with cranial nerve
palsies, spinal cord compression, or lymphomatous
meningitis
• Metabolic derangements due to rapid tumor cell break-
down in the settings of compromised renal function, also
known as tumor lysis syndrome (TLS)
Other infrequent life-threatening conditions are acute
hemolytic anemia and coagulopathy. This review will focus
only on the most frequent oncologic emergencies.
Respiratory distress (stridor, shortness of breath, orthopnea)
is a frequent initial presentation of a rapidly enlarging
mediastinal mass. When children initially present to a
pediatrician’s office with these signs, the frequent first
therapeutic interventions are b-adrenergic agonists and
glucocorticoids. Since lymphoma cells are exquisitely sen-
sitive to glucocorticoids, the rapid tumor size reduction,
followed by transient symptomatic improvement, can soon
be seen. It has to be remembered that therapy with gluco-
corticoids in a patient with atypical presentation (asymmetrical
chest wall anatomy and excursion, as well as asymmetrical
air entry, concomitant neck vein distention, lymphadenop-
athy, and other systemic signs or symptoms, including “B
symptoms”) should be preceded by chest radiography,
which might demonstrate the mediastinal mass with or
without pleural effusion (Fig 2).
SVC syndrome appears at presentation with dilated neck
veins, asymmetrical facial swelling, plethora, and altered
mental status; children with SVC syndrome are at high risk
for venous thrombosis and strokes.
For patients with the aforementioned conditions, (a) emer-
gency cytoreduction chemotherapy with prednisone or cyclo-
phosphamide or (b) radiation therapy should be initiated.
The staging and diagnostic evaluation, including tumor
biopsy, can be completed within 48 to 72 hours from onset
of the treatment; the quality of the specimen will not be
substantially compromised, but the risk of severe cardio-
respiratory morbidity would be markedly reduced.
Figure 2. A chest radiograph of a 8-year-old male with newly diagnosed
NHL is shown. The child was initially treated with nebulized albuterol
and enteral prednisolone for presumed exacerbation of reactive airway
disease. The black and white brackets indicate a mediastinal mass; the
dashed vertical line highlights the airways that deviate from midline; the
arrowheads indicate left hemithorax pleural effusion.
Vol. 38 No. 9 SEPTEMBER 2017 415
 Cranial nerve or spinal cord compression (direct invasion
occurs rarely) appears at presentation with focal neurological
deficits, paraplegias, or generalized convulsions; emergency
chemotherapy or surgical decompression via vertebral lam-
inectomy and intracanalar tumor resection are therapeutic
alternatives.
TLS is a life-threatening condition that can be seen in
patients with Burkitt lymphoma, diffuse large B-cell lym-
phoma, and B-cell lymphoblastic lymphoma—that is, neo-
plasms with both high proliferation rate and large tumor
burden. TLS occurs when the intracellular components of
the tumor cell cytoplasm (nucleic acids, which are metab-
olized into UA, phosphorus, and potassium) are released
into the blood after the lymphoma cell breakdown, either
spontaneously or after the onset of treatment. Under normal
physiological circumstances, these substances are excreted
in the urine. In patients with bulky lymphomas, the amount
of the released content overwhelms the excretory kidney
capacity. This becomes an even greater problem when the
kidneys are already infiltrated by malignant cells or com-
pressed by the intra-abdominal tumor. The acute kidney
injury, which leads to progressively worsening electrolyte
and fluid imbalance, is the pathogenetic cornerstone of TLS.
The distinction should be made between laboratory TLS
and clinical TLS. Laboratory TLS is asymptomatic metabolic
disarray; it includes 2 or more of the following, occurring
simultaneously within 3 days prior to and up to 7 days after
therapy onset (14):
• Hyperuricemia (>8.0 mg/dL [>475.88 mmol/L])
• Hyperkalemia (>6.0 mmol/L)
• Hyperphosphatemia (>4.5 mg/L)
• Hypocalcemia (corrected calcium <7.0 mg/dL [<1.75
mmol/L], ionized calcium <1.12 mg/dL [<0.28 mmol/L]).
Unlike all other abnormalities, hypocalcemia results from
excess of serum UA and phosphorus precipitating calcium
into calcium urate and calcium phosphate crystals in the
kidneys. The clinical TLS is laboratory TLS, along with lab-
oratory and clinical evidence of end-organ damage, includ-
ing neuromuscular symptoms secondary to hypocalcemia,
uremia, increased creatinine level, oliguria, hypertension,
cardiac dysrhythmia, pulmonary edema, altered mental
status, seizures, and death.
It should be assumed that any patient with lymphoma is
at high risk for TLS, especially before the histopathologic
variant and the extent of the disease are established. Serum
lactate dehydrogenase level can be regarded as the surrogate
marker of the tumor bulk; patients with lactate dehydroge-
nase level more than 2 times the upper limit of normal are at
high risk for TLS. Once the histologic variant is confirmed,
the patients may be restratified according to risk: Burkitt
416 Pediatrics in Review
lymphoma, diffuse large B-cell lymphoma, and B-cell
lymphoblastic lymphoma are the conditions with high risk
for TLS, whereas anaplastic large-cell lymphoma and HL are
the conditions with low risk for TLS.
TLS management should be initiated without delay. The
evolution of TLS must be monitored via serial measurement
of serum potassium, creatinine, UA, calcium, and phosphorus
levels. In the absence of any electrolyte disarrays, all patients
must receive prophylactic therapy with xanthine oxidase (the
rate-limiting enzyme that metabolizes purines into UA) inhib-
itors allopurinol or febuxostat, as well as intravenous hydration to
facilitate removal of the breakdown metabolites by urine. Until
recently, aggressive urine alkalinization was recommended to
prevent tubular precipitation of calcium urate crystals;
nowadays, this practice is discouraged, since calcium phos-
phate, as well as hypoxanthine and xanthine (intermediate
metabolites of nucleic acid degradation, increased in con-
centration when allopurinol is used) are poorly soluble
in the alkalinized urine. Hence, the neutral or minimally
alkalinized urine pH level is preferred.
Patients who demonstrate a picture of laboratory TLS
must be treated more aggressively to prevent organ damage.
Rasburicase, the recombinant urate oxidase, is used to rapidly
degrade UA in serum. It is contraindicated in patients with
glucose-6-phosphate dehydrogenase deficiency. Because ras-
buricase does not inhibit UA formation, it should be admin-
istered in parallel with allopurinol.
Hyperkalemia should be treated aggressively, as it may
precipitate fatal arrhythmia. Bedside electrocardiographic
monitoring must be established without delays. Serum
potassium concentration above 5.5 mEq/L (5.5 mmol/L) is
associated with myocardial repolarization abnormalities.
Peaked T waves on an electrocardiogram are the earliest
sign of hyperkalemia. Serum potassium level higher than
6.5 mEq/L (6.5 mmol/L) is associated with imminent
paralysis of the atria and manifests as progressive P wave
widening and flattening, as well as PR segment lengthen-
ing. Calcium gluconate should be administered promptly
to protect myocardial excitability. Other pharmacologi-
cal interventions to decrease potassium concentration in
serum must also be implemented, including administra-
tion of b-adrenergic agonists (inhaled or enteral), insu-
lin and sodium bicarbonate (both intravenous) to shift
potassium into the intracellular compartment, loop diuretics
(intravenous; may not be feasible in patients with kidney
lymphomatous infiltration), and sodium polystyrene sul-
fonate (enteral) to facilitate renal or intestinal potassium
excretion.
Hyperphosphatemia is managed by limiting the dietary
phosphorus absorption (calcium acetate, sevelamer).
 Hypocalcemia does not need to be managed pharmaco-
logically unless the patient is symptomatic; serum calcium
level usually normalizes once the UA and phosphorus
concentrations are under control. Patients with clinical
TLS and renal failure require hemodialysis, which improves
hyperkalemia, azotemia, and fluid balance.
APPROACHES TO DIAGNOSIS
As mentioned previously, there are no lymphoma-specific
signs or symptoms, laboratory tests, or imaging tests.
Hence, the differential diagnosis can be broad and includes
infectious, autoimmune, and lymphoproliferative disor-
ders, as well as nonspecific reactive conditions (Table 2).
Only pathomorphologic evaluation of the tissue (excisional
biopsy is preferred over fine-needle aspiration or core-
needle biopsy, as it allows evaluation of the histologic
architecture of the LN or tumor) can be used to reliably establish
the diagnosis. Additional tests may be used to identify all
body sites involved, stratify the disease risk, and assign correct
treatment. Table 3 summarizes suggested investigations.
LYMPHOMA THERAPY: RISK- AND RESPONSE-
ADAPTED THERAPEUTIC APPROACHES
When patients with limited disease (serum lactate dehydro-
genase concentration increase less that two-fold above upper
normal limit; lower stage, Table 4) and rapid early response
to initial chemotherapy (as determined by tumor viabil-
ity and/or size decrease measured with fluorine 18 (18F)
fluorodeoxyglucose positron emission tomography/CT)
receive less intensive treatment, this usually results in
unprecedented reduction of the treatment-related adverse
effects while maintaining a high survival rate (>85%) in the
patients with lymphoma across all age groups. (15)(16)
Multiagent chemotherapy is the mainstay of treatment
for both HL and NHL; it is based on the clinical protocols
proven to be effective in multi-institutional clinical trials.
The protocols differ in the number (4)(5)(6)(7)(8) and dura-
tion (21–28 days) of cycles, various agents used together,
doses of the agents, and frequency of their use within the
cycle. There may be some variability between the cycles
within 1 protocol, too. Traditionally, chemotherapy is deliv-
ered during the first 8 to 15 days; the reminder of the days
within the cycle is allowed for recovery from treatment-
related immediate (nausea, vomiting, fatigue, fever, etc; 1–2
days from receiving the drug) and prompt (suppressed
blood cell counts, loss of appetite, mucositis, diarrhea,
constipation, etc; 1–2 weeks) side effects. Late side effects
(any time after completion of the therapy) are discussed
herein. Lymphoblastic lymphomas are treated by using
acute lymphoblastic leukemia protocols, which are com-
pletely different. All patients undergoing chemotherapy
receive prophylactic therapy with antifungal azoles and with
trimethoprim/sulfamethoxazole or pentamidine for Pneu-
mocystis jirovecii. In addition, patients frequently require
blood product (packed red blood cells, platelets) transfusions,
as well as granulocyte colony-stimulating growth factor (for
neutrophil recovery) and recombinant human keratinocyte
growth factor (palifermin, for treatment-induced mucositis)
support to ensure uncomplicated transition through the
treatment cycles.
Radiation therapy plays an important role in the treat-
ment of HL but is reserved for patients who did not
demonstrate rapid response after the first several chemo-
therapy cycles. It is administered only to areas initially

TABLE 3. Recommended Investigations for Lymphoma Evaluation

STUDY TYPE PROTOCOL

Laboratory studies Complete blood cell count, renal and liver function tests
Erythrocyte sedimentation rate; C-reactive protein, uric acid, lactate dehydrogenase, and alkaline phosphatase
levels
Imaging studies Chest radiography, posteroanterior and lateral views
Computed tomography of the neck, chest, abdomen, and pelvis
Magnetic resonance imaging of the brain, abdomen, and pelvis
Fluorodeoxyglucose positron emission tomography/computed tomography, whole body
Staging tests Bone marrow biopsy: uniformly for patients with non-Hodgkin lymphoma
Patients with classic Hodgkin lymphoma, patients with extensive disease and skeletal involvement by
fluorodeoxyglucose positron emission tomography/computed tomography
Cerebrospinal fluid studies, only for patients with non-Hodgkin lymphoma
Miscellaneous Pulmonary function tests, electrocardiography, echocardiography
Fertility preservation (sperm banking, ovarian tissue cryopreservation)

Vol. 38 No. 9 SEPTEMBER 2017 417

 TABLE 4. Pediatric Lymphoma Clinical Staging
STAGE HODGKIN LYMPHOMA ANN ARBOR STAGING
I Single lymphatic site or localized single extralymphatic site
without regional LN involvement
II ‡2 LN regions on the same side of the diaphragm or
Localized single extralymphatic site with regional LN
involvement on the same side of the diaphragm
III LN involvement on both sides of the diaphragm or
Localized extralymphatic extension with adjacent LN
involvement or
Spleen
IV Diffuse involvement of ‡1 extralymphatic site with or without
associated LN involvement or with involvement of distant
site(s) or
Liver, bone marrow, lungs, central nervous system
LN¼lymph node.
“affected by lymphoma” (so-called involved field radiation),
which allows minimizing the exposure of the whole body.
Both noncorpuscular (photon) and corpuscular (proton)
radiation can be used. For NHL, radiation therapy is used
infrequently, usually in patients with lymphoma refractory
to first- and second-line therapies and with primary CNS
lymphomas. It remains an emergency treatment of choice
in patients who present with SVC syndrome, spinal cord
compression, and large splanchnic tumors that cause pain
or obstruction. The commonest immediate and prompt side
effects are radiation-induced dermatitis, transient myelo-
suppression, malaise, nausea, diarrhea, and xerostomia.
Surgery, in contrast to chemotherapy and radiation ther-
apy, has a limited role in lymphoma treatment. Only patients
with stage I NLPD HL and stage I (nodal) and II (primary
gastrointestinal) Burkitt lymphoma and anaplastic large-cell
lymphoma benefit from primary tumor excision. However,
these patients still require chemotherapy and/or radiation
therapy to attain stable remission. Total splenectomy, which
was used in the past for staging and therapeutic purposes,
used to result in overwhelming and frequently fatal infec-
tions (17); nowadays, it is not a treatment of choice. Instead,
the radiation therapy or low-intensity chemotherapy can be
used to attain rapid size reduction and symptomatic relief in
patients with extreme splenomegaly.
Hematopoietic stem cell transplantation (HSCT) plays an
important role in the therapy of both HL and NHL. It is used
in conjunction with second- and third-line therapies for
primary treatment-resistant or recurrent lymphoma; HSCT
facilitates hematopoietic recovery after highly intensive
418 Pediatrics in Review
NON-HODGKIN LYMPHOMA ST JUDE CHILDREN’S
RESEARCH HOSPITAL (MURPHY) STAGING
Single tumor or LN involvement outside of the abdomen
and mediastinum
Single tumor with regional LN involvement or ‡2 sites on
one side of the diaphragm or
Primary gastrointestinal tract tumor (completely resected)
with or without regional LN involvement
Tumors or LN involvement on both sides of the diaphragm
Primary intrathoracic tumor or primary intra-abdominal
disease
Paraspinal or epidural tumors
Bone marrow or central nervous system, with or without any
other sites involved
chemotherapy and mediates remission consolidation via
graft-versus-lymphoma effect, when the cells of the recov-
ered immune system perform immunologic surveillance
and destroy residual microscopic lymphoma. Autologous
HSCT involves the use of patients’ own hematopoietic stem
cells harvested from peripheral blood between chemother-
apy cycles after the hematopoietic stem cells’ mobilization
with granulocyte colony-stimulating factor with or without
plerixafor, a reversible CXCR4 chemokine receptor antag-
onist that allows the release of hematopoietic stem cells
from the bone marrow. Patients with lymphoma who
undergo autologous HSCT benefit primarily from accelerated
hematologic recovery after extremely aggressive chemother-
apy. Autologous HSCT is a preferred stem cell–based therapy
for pediatric patients with lymphoma. In contrast, the allo-
geneic HSCT involves the use of hematopoietic stem cells
from human leukocyte factor–matched related or unrelated
donors; the source of the hematopoietic stem cells can
be either peripheral blood or bone marrow. In addition to
hematologic reconstitution, the stem cell–derived immune
cells can recognize the residual lymphoma cells as “foreign”
and effectively destroy them. This type of HSCT is used for
treatment of aggressive, treatment-refractory, and relapsed
lymphomas. Patients whose disease progresses after autolo-
gous HSCT may still benefit from allogeneic HSCT.
As expected, HSCT-related toxicities uniquely depend
on the donor type; allogeneic HSCT is frequently compli-
cated with graft-versus-host disease, when recovered
immune cells attack the recipient’s body cells as “foreign.”
Therapy for graft-versus-host disease requires prolonged
immunosuppression to mitigate immunologic attack of the
recipient’s body by alloreactive cytotoxic T-cells. However,
the same mechanism underlies the curative graft-versus-
lymphoma effect. Patients who undergo autologous
HSCT can also develop graft-versus-host disease; however,
this disease is milder and has unique clinicobiological
characteristics.
Biological therapy has truly revolutionized lymphoma
treatment. It involves the use of principles of selective
targeting of neoplastic cells that share unique biological
characteristics that are distinct from other normal cells.
Lymphoma cell antigen–specific monoclonal antibodies
and cytotoxic T-cells, as well as small molecules that target
intracellular signaling pathways, are now in use. Monoclo-
nal antibodies that target CD19 (denintuzumab mafodotin
[CD19a antibody-cytotoxic drug conjugate]; blinatumomab
[CD19/CD3 bispecific T-cell engager]), anti-CD20 monoclo-
nal antibodies (rituximab, ofatumumab, obinutuzumab),
and anti-CD30 monoclonal antibody (brentuximab vedotin
antibody-cytotoxic drug conjugate) are used either as single
agents or in combination with conventional chemotherapy.
The mechanisms of killing lymphoma cells with the afore-
mentioned biological agents involve direct cytotoxic effect,
as well as engaging the activated immune cells to mediate
lymphoma cell killing.
There are many other agents that demonstrated effec-
tiveness in preclinical trials but have not yet been included
in major pediatric lymphoma protocols. Nivolumab and
pembrolizumab, the antagonists of programmed cell death
receptor 1—stimulation of which results in intratumoral
immune suppression—hold particularly strong clinical
promise.
Chimeric antigen receptor (CAR) cytotoxic T-cells, which
are capable of recognizing and selectively killing CD19-,
CD20-, and CD30-expressing lymphoma cells (ie, virtually all
HL and NHL subvariants), are the culmination of targeted
immune therapy of lymphoma. The T lymphocytes, har-
vested from either the patient or a donor via leukapheresis,
are transfected in vitro with the virus vector–caring gene
sequence encoding an artificial chimeric receptor that enables
high affinity and specificity binding to CD19, CD20, and CD30
antigens on the lymphoma cell surface. The CAR T-cells
become activated upon encountering the CD19-, CD20-, or
CD30-expressing lymphoma cells, and mediate the lymphoma
cell killing in a selective fashion. Of practical importance, the
activated CAR T-cells produce large quantities of proin-
flammatory cytokines (interferon-g, interleukin-6, inter-
leukin-10), which may lead to the development of toxic
side effects that manifest as high fever, myalgia, hypotension,
capillary leak and pulmonary edema, cardiac dysfunction,
renal and hepatic failure, and disseminated intravascular
coagulation.
The CAR T-cells are most effective in the setting of
minimal residual disease and are used for treatment of relapsed
lymphomas that are resistant to conventional therapies.
DISEASE SURVEILLANCE AFTER THERAPY
COMPLETION
After therapy completion, every 3 months for the first year,
patients undergo complete physical examination and labo-
ratory testing (complete blood cell count; comprehensive
metabolic panel; erythrocyte sedimentation rate; and C-reactive
protein and lactate dehydrogenase levels), in addition to 18F
fluorodeoxyglucose positron emission tomography/CT (or
just CT). The disease surveillance should be performed
every 4 months during the second and third years and every
6 months thereafter until 5 years after therapy, by conduct-
ing physical examination and laboratory blood tests. Imag-
ing should be performed only if clinically indicated, given
the increasing awareness of the potential risks related to
imaging-related radiation exposure. After 5 years, the patients
usually follow up with the oncologist at a dedicated long-term
follow-up clinic semiyearly. Additional screening tools (echo-
cardiography, pulmonary function tests) aim at timely detec-
tion and treatment of the side effects summarized herein.
LATE EFFECTS OF THERAPY
Due to the high rate of cure of lymphoma, the likelihood
of treatment-related long-term side effects is considerably
high, as well. Much of what is seen today is the result of
treatment approaches used in the past; fewer side effects are
expected in patients who receive therapy with current pro-
tocols. The risk-adapted approaches allow for substantial
reduction in exposure to radiation, whereas they introduce
some novel therapies upfront. Since these novel therapies
are not side effect free, we have yet to learn what the long-
term consequences would be. All patients must be screened
for late-onset side effects (Table 5) during their follow-up
visits. A multidisciplinary (endocrinology, cardiology, etc)
approach must be used to provide care for patients with
organ-specific side effects.
Premature gonadal failure and infertility are always a big
concern. Owing to differences in chemotherapy agents and
regimens, fertility in patients with HL is affected more
frequently than in patients with NHL. The rate of infertility
after chemotherapy is higher in male patients than in female
patients and demonstrates dose dependence for certain
agents (cyclophosphamide, procarbazine). (18) Regardless,
Vol. 38 No. 9 SEPTEMBER 2017 419
 TABLE 5. Therapy-related Late Side Effects
LATE EFFECT RADIATION THERAPY
Musculoskeletal side effect Yes
Cardiovascular side effect Yes
Pulmonary side effect Yes
Hypersplenism and hypoimmuneglobulinemia Splenic irradiation
Thyroid dysfunction Yes
Female gonadal dysfunction Yes
Premature ovarian failure Yes
Male infertility Irradiation of inguinal
and pelvic areas
Myelodysplastic syndrome and secondary leukemia
Secondary cancers (breast, thyroid) Yes
every patient with lymphoma should be counseled for sperm
banking or egg harvesting and/or ovarian tissue cryopreserva-
tion. If gamete procurement is not feasible, administration of
leuprolide, the gonadotropin-releasing hormone agonist, to
adolescent female patients before or during chemotherapy
may also be used; it results in a significantly lower rate
(approximately 10%) of premature ovarian failure. At the same
time, the use of leuprolide, with or without testosterone, results
in sperm count recovery in fewer than 20% of male patients.
Secondary malignancies are a devastating late side effect
of lymphoma treatment. Death from secondary malignan-
cies is the second leading cause of mortality after death from
the primary disease. Similar to infertility, it occurs more
frequently in patients with HL (cumulative risk up to 25%)
than in patients with NHL (cumulative risk, 2%–5%) and
depends on the therapy that the patient received. Acute
leukemia, NHL, and lung cancer are the commonest sec-
ondary malignancies in patients with HL who underwent
chemotherapy alone; breast cancer becomes the leading
secondary malignancy in female patients treated with a
combination of chemotherapy and radiation therapy. Acute
myelogenous leukemia is the most frequent secondary malig-
nancy in patients with NHL. The peak period of secondary
malignancy risk is between 5 and 9 years after therapy but may
extend beyond 25 years for patients who underwent concom-
itant chemotherapy and radiation therapy.
Infection is another cause of morbidity of patients with
lymphoma, primarily due to lymphopenia and hypogam-
maglobulinemia secondary to intensive chemotherapy,
spleen irradiation, (19) and biotherapy selectively targeting
B-cells. (20) All patients with lymphoma must receive yearly
420 Pediatrics in Review
CHEMOTHERAPY
No
Anthracyclines
Bleomycin
Rituximab immunotherapy
No
Yes
Alkylating agents
Alkylating agents
Procarbazine
Cyclophosphamide, ifosfamide, dacarbazine,
procarbazine, etoposide
Yes
inactivated influenza vaccine between the chemotherapy
cycles, provided they do not have absolute severe leukopenia
(<0.2
109/L). It remains a rule not to administer any live
vaccines (measles, mumps, rubella, varicella, live attenuated
influenza, rotavirus) during this period. If spleen irradiation
is planned, the patient should receive vaccination for Strep-
tococcus pneumoniae and meningococcal infections at least 2
weeks before radiation therapy. At treatment completion,
the patients should be tested for IgG titers against hepatitis
B, measles/mumps/rubella, and S pneumoniae. Interest-
ingly, many patients selectively lose their IgG titers to
hepatitis B and components of measles, mumps, and
rubella. Repeat vaccination is recommended when lympho-
penia improves. Patients who received rituximab frequently
demonstrate profound hypogammaglobulinemia, which is
treated with intravenous IgG.
Cardiovascular morbidity, which most frequently mani-
fests as myocardial infarction or valvular structural changes,
is prevalent in lymphoma patient survival, as much as
45.5% (95% confidence interval, 36.6%–54.3%); high-dose
radiation therapy but not exposure to anthracyclines is
associated with the most severe complications. (21)
CONCLUSIONS AND FURTHER DIRECTIONS
Advances in understanding of cellular biology of lymphoma,
a risk-adapted approach to therapy, refining of elements
of supportive care, and use of novel therapeutics results
in outstanding survival outcomes for patients with lymphoma.
However, many important questions have yet to be answered.
Clarification of interaction of genetic predisposition to
lymphoma and environmental factors merits further in-
vestigations. Rapid development of the concept of preci-
sion medicine and targeted cancer therapy widens the
potential of making lymphoma therapy even more effi-
cient, with potentially minimal late side effects.
• On the basis of strong research evidence (level A) in the form of
multiple clinical studies, treatment of patients with lymphoma
with contemporary protocols results in fewer treatment-related
side effects; however, these late adverse effects require life-long
monitoring and multidisciplinary medical management. (17)(18)
(19)(20)(21)

Summary
• On the basis of strong research evidence (level A) in the form of To view teaching slides that accompany this article,
numerous epidemiological retrospective studies, (2)(4)(5)(6)(7) visit http://pedsinreview.aappublications.org/content/
(8)(9)(10)(11)(12) both inherited genetic predisposition and 38/9/410.supplemental.
exposure to various potentially genotoxic environmental
factors may contribute to increased incidence of lymphoma
in children.
• On the basis of strong research evidence (level A) in the form of
published reports of thorough analysis of lymphadenopathy-
associated signs and symptoms, (13) certain lymph node clinical
features could be predictive of a possible malignant process.
However, it remains to be understood that there are no absolute
lymphoma-specific symptoms or signs. Of utmost importance,
absence of systemic symptoms does not rule out the diagnosis of
lymphoma.
• On the basis of strong research evidence (level A) in the form of
multiple clinical observations, tumor lysis syndrome, either
spontaneous or treatment induced, remains one of the
commonest emergency presentations of lymphoma. (14) References and Suggested Readings for this article are at http://
pedsinreview.aappublications.org/content/38/9/410.

Additional Resources for Pediatricians

AAP Textbook of Pediatric Care, 2nd Edition
• Chapter 225: Cancers in Childhood - https://pediatriccare.solutions.aap.org/chapter.aspx?sectionid¼124994555&bookid¼1626
Point-of-Care Quick Reference
• Cancers in Childhood - https://pediatriccare.solutions.aap.org/content.aspx?gbosid¼165492

Parent Resources from the AAP at HealthyChildren.org

• https://www.healthychildren.org/English/health-issues/conditions/cancer/Pages/Childhood-Cancer.aspx
For a comprehensive library of AAP parent handouts, please go to the Pediatric Patient Education site at http://patiented.aap.org.

Vol. 38 No. 9 SEPTEMBER 2017 421

 PIR Quiz
There are two ways to access the journal CME quizzes:
1. Individual CME quizzes are available via a handy blue CME link under the article title in the Table of Contents of any issue.
2. To access all CME articles, click “Journal CME” from Gateway’s orange main menu or go directly to: http://www.aappublications.
org/content/journal-cme.

1. A 14-year-old African American female adolescent presents to your office with fever, REQUIREMENTS: Learners
weight loss, and neck swelling. Her father is concerned because his brother recently can take Pediatrics in Review
received a diagnosis of non-Hodgkin lymphoma (NHL) at 48 years of age after a similar quizzes and claim credit
presentation. The patient’s past medical history includes systemic lupus erythematosus, online only at: http://
which was initially managed with corticosteroids; asthma, for which she has undergone pedsinreview.org.
multiple chest radiographic examinations; and recurrent ear infections during early
To successfully complete
childhood. Which of the following factors is most likely to increase the risk for development
2017 Pediatrics in Review
of NHL in this child?
articles for AMA PRA
A. Ethnicity. Category 1 CreditTM, learners
B. Exposure to diagnostic radiography in childhood. must demonstrate a minimum
C. Family history of lymphoma. performance level of 60% or
D. History of autoimmune disease. higher on this assessment,
E. History of recurrent infections. which measures achievement
2. A 7-year-old boy presents to your office with a mass near his neck. His mother first noticed of the educational purpose
the mass when he received a diagnosis of group A streptococcal pharyngitis 1 month ago. and/or objectives of this
Since then, the mass has doubled in size. There is no history of fever, night sweats, or activity. If you score less than
weight loss. On physical examination, the patient is well appearing and in no distress. 60% on the assessment, you
There is a 2-cm nontender, fixed lymph node (LN) in the left supraclavicular region. There will be given additional
are no other enlarged LNs observed. Which of the following factors is most predictive of opportunities to answer
the nonbenign nature of lymphadenopathy in this child? questions until an overall 60%
A. Age of the patient. or greater score is achieved.
B. Duration of LN enlargement. This journal-based CME
C. Lack of lymphadenopathy in other areas. activity is available through
D. Location of lymphadenopathy. Dec. 31, 2019, however, credit
E. Size of the LN. will be recorded in the year in
3. A 16-year-old male adolescent presents to the emergency department with fever and which the learner completes
respiratory distress. He has had intermittent fever for several weeks and 20-pound weight the quiz.
loss. On physical examination, he is lethargic and has decreased breath sounds on the right
side, with ipsilateral neck vein distention and facial swelling. Which of the following is the
most likely cause of the neck and facial findings in this patient?
A. Bacterial lymphadenitis.
B. Pulmonary embolism.
C. Septic thrombophlebitis. 2017 Pediatrics in Review now
D. Superior vena cava syndrome. is approved for a total of 30
E. Tumor lysis syndrome (TLS). Maintenance of Certification
(MOC) Part 2 credits by the
4. A 7-year-old boy, who is a recent refugee from the Congo, presents with fever for 1 week
American Board of Pediatrics
and a 10-cm jaw mass. You suspect Burkitt lymphoma and order initial laboratory tests.
through the AAP MOC
Which of the following findings is most consistent with TLS?
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422 Pediatrics in Review

5. A 15-year-old male adolescent has just completed therapy for stage 2 Hodgkin lymphoma
with rapid early response and is now in remission. Which of the following late effects is he
at the highest risk for experiencing?
A. Graft-versus-host disease due to hematopoietic stem cell transplantation.
B. Growth failure due to radiation therapy.
C. Infertility due to chemotherapy.
D. Secondary leukemia due to immunotherapy.
E. Sepsis due to splenectomy.

Vol. 38 No. 9 SEPTEMBER 2017 423

 Approach to Hypertriglyceridemia in the
Pediatric Population
Badhma Valaiyapathi, MBBS,* Bhuvana Sunil, MBBS,† Ambika P. Ashraf, MD‡
*Department of Epidemiology, School of Public Health, University of Alabama at Birmingham, Birmingham, AL
†
Department of Pediatrics, Harlem Hospital Center, New York, NY
‡
Division of Pediatric Endocrinology and Metabolism, Department of Pediatrics, Children’s of Alabama, University of
Alabama at Birmingham, Birmingham, AL

Practice Gaps
There is paucity of information regarding identification and management
of hypertriglyceridemia in children. In this review article, we discuss the
etiologic origin, diagnosis, and therapeutic approach of a commonly
encountered pediatric problem that lacks clear-cut guidelines.

Objectives After completing this article, readers should be able to:

1. Describe the pathophysiology of hypertriglyceridemia.

2. Recognize causes of hypertriglyceridemia.
AUTHOR DISCLOSURE Drs Valaiyapathi and
3. Discuss management of pediatric hypertriglyceridemia. Sunil have disclosed no financial relationships
relevant to this article. Dr Ashraf has disclosed
that she has a research grant from Merck, she
serves as mentor to the principal investigator
Abstract on a grant from Thrasher Research Fund, and
her spouse is on the speakers’ bureaus of
Hypertriglyceridemia is increasingly identified in children and Pfizer, Bristol-Myers Squibb, and Celgene. This
commentary does contain a discussion of an
adolescents, owing to improved screening and higher prevalence of unapproved/investigative use of a
childhood obesity. Hypertriglyceridemia can result from either increased commercial product/device.
triglyceride (TG) production or reduced TG clearance. The etiologic origin
ABBREVIATIONS
can be primary (genetic) or secondary, but it is often multifactorial. ApoB-48 apolipoprotein B-48
Management is challenging because of the interplay of genetic and ApoB-100 apolipoprotein B-100
secondary causes and lack of evidence-based guidelines. Lifestyle DHA docosahexaenoic acid
EPA eicosapentaenoic acid
changes and dietary interventions are most important, especially in
FA fatty acid
hypertriglyceridemia associated with obesity. Dietary restriction of fat FDA Food and Drug Administration
remains the mainstay of management in primary hypertriglyceridemia. FFA free FA
When fasting TG concentration is increased above 500 mg/dL (5.65 mmol/L), HDL high-density lipoprotein
IDL intermediate-density
fibrates may be used to prevent pancreatitis. Omega-3 fatty acids are
lipoprotein
often used as an adjunctive therapy. When the fasting TG concentration is LDL low-density lipoprotein
less than 500 mg/dL (5.65 mmol/L) and if the non–high-density LPL lipoprotein lipase
lipoprotein cholesterol level is above 145 mg/dL (3.76 mmol/L), statin NHLBI National Heart, Lung, and Blood
Institute
treatment can be considered. OTC over-the-counter
TG triglyceride
VLDL very low-density lipoprotein

424 Pediatrics in Review

INTRODUCTION
The term hypertriglyceridemia indicates an increased plasma
fasting triglyceride (TG) concentration that is above the 95th
percentile for age and sex. (1)(2) A TG level greater than or
equal to 100 mg/dL (1.13 mmol/L) and a level greater than
or equal to 130 mg/dL (1.47 mmol/L) are considered above
the 95th percentile for children of ages 0 to 9 years and
10 to 19 years, respectively. (3)(4)(5) An estimated 10% of US
children and adolescents between 12 and 19 years of
age have increased serum TG levels greater than 150
mg/dL (1.69 mmol/L). (3)(6)(7) By extrapolating the adult
guidelines, hypertriglyceridemia can be considered mild to
borderline high (150–199 mg/dL [1.69–2.25 mmol/L]),
moderate to high (200–499 mg/dL [2.26–5.64 mmol/L]),
very high (500–999 mg/dL [5.65–11.29 mmol/L]), se-
vere (1000–1999 mg/dL [11.30–22.59 mmol/L]), and very
severe (>2,000 mg/dL [>22.60 mmol/L]). (5)(6)(7) Hyper-
triglyceridemia in children parallels the increasing incidence
in childhood obesity, metabolic syndrome, type 2 diabetes,
sedentary lifestyle, high-fat and high-carbohydrate diet, and
medication use. (8) There is a paucity of literature on pediatric
hypertriglyceridemia. With increased universal lipid screen-
ing, the number of cases of hypertriglyceridemia identified
will increase.
BRIEF OVERVIEW OF TG METABOLISM
Understanding TG metabolism is fundamental for prompt
identification and management of hypertriglyceridemia.
Factors that stimulate hepatic lipoprotein synthesis or in-
hibit TG removal generally lead to increased plasma cho-
lesterol and TG levels. Hypertriglyceridemia results from
an increase in the circulating TG-rich lipoproteins (ie,
plasma very low-density lipoprotein [VLDL], chylomicrons),
which are produced by the liver or absorbed from food.
Chylomicrons transport dietary lipids and are synthesized
within enterocytes. Chylomicrons contain a truncated form
of apolipoprotein B, called apolipoprotein B-48 (ApoB-48),
which is only 48% of the length of the complete molecule.
ApoB-48 allows for production and secretion of chylomi-
crons. VLDL is synthesized within the hepatocytes and
contains atherogenic apolipoprotein B-100 (ApoB-100), chy-
lomicron remnants, free fatty acids (FFAs), and de novo fatty
acids (FAs). (5) Both chylomicron and VLDL transport and
deliver TGs to tissues to use as FFAs for energy and storage
(Fig 1).
Dietary cholesterol, FAs, and fat-soluble vitamins are
absorbed in the proximal small intestine. TGs are formed
in the enterocytes upon hydrolysis of these dietary fats. The
longer-chain FAs are incorporated into nascent chylomi-
crons in the intestinal mucosal cells, whereas medium-
chain FAs with fewer than 10 carbon atoms directly enter
the liver through the portal vein. The chylomicron consists
of 80% to 95% TGs, along with cholesteryl esters, retinyl
esters, phospholipids, cholesterol, ApoB-48, and other apo-
lipoproteins. Chylomicrons enter the thoracic duct via the
lymphatic system, then travel to the vena cava and circulate.
In the lymph and blood, chylomicrons acquire other apo-
liporoteins, such as apolipoprotein C-II, apolipoprotein
C-III, and apolipoprotein E. (5) Depending on the fat con-
tent of a meal, TG levels can increase as much as 100%
postprandially.
VLDL is synthesized in the hepatocytes and transport
TGs and cholesterol to peripheral tissues. The VLDL TG
content is derived from chylomicron remnants, plasma
FFA, and de novo FAs synthesized from carbohydrates
(Fig 2). VLDL has more cholesterol relative to TGs, with
a TG-to-cholesterol ratio of 5:1, in comparison to chylomi-
crons, which have a TG-to-cholesterol ratio of 10:1. (5) Both
endothelial lipoprotein lipase (LPL) and hepatic TG
lipase can release FFA and glycerol from VLDL TGs. The

Figure 1. Triglyceride synthesis. ANGPTL¼angiopoietin-like, apoB-48¼apolipoprotein B-48, apoB-100¼apolipoprotein B-100, apoC-II¼apolipoprotein

C-II, apoC-III¼apolipoprotein C-III, FA¼fatty acid, FFA¼free FA, LPL¼lipoprotein lipase, PL¼phospholipid, VLDL¼very low-density lipoprotein.

Vol. 38 No. 9 SEPTEMBER 2017 425

 remaining VLDL (ie, VLDL remnants), also referred to as
intermediate-density lipoproteins (IDLs), become TG depleted,
decrease in size, and form cholesterol-enriched small, dense
low-density lipoprotein (LDL) particles. ApoB-100 is the
principal apolipoprotein on all atherogenic lipoprotein par-
ticles (ie, LDL, VLDL, and IDL).
The Role of LPL
LPL located on the capillary endothelial cells breaks down
TGs from TG-rich lipoproteins into FFAs and monoglycer-
ides. LPL is activated by apolipoprotein C-II and inhibited by
apolipoprotein C-III and angiopoietin-like proteins 3 and 4
(Fig 1). Glycosylphosphatidylinositol-anchored high-density
lipoprotein (HDL)-1 transports LPL into the luminal surface
of capillary endothelial cells, and this complex interacts with
lipase maturation factor. Thus, defects in apolipoprotein
C-II or LPL can lead to defects in chylomicron clearance.
Insulin is a potent activator of LPL and, hence, insulin-
resistant and/or insulinopenic states are associated with
reduced LPL activity. Lack of LPL enzyme activity, lack of LPL
protein production, or both can result in hypertriglyceride-
mia (predominantly hyperchylomicronemia).
Obesity and Dyslipidemia
There is increased VLDL TG production in the setting of
visceral obesity and insulin resistance due to excess FFA flux
to the liver from high-fat diets, excess adipose tissue release
of FFAs, and increased de novo TG production from high
carbohydrate intake and hyperinsulinemia. Simple sugars
undergo glycolysis to generate acetyl coenzyme A mole-
cules, which are the building blocks for FA synthesis.
Figure 2. Synthesis of very low-density lipoprotein. apoB-
100¼apolipoprotein B-100, CoA¼coenzyme A, FA¼fatty acid, FFA¼free
FA, VLDL¼very low-density lipoprotein.
426 Pediatrics in Review
Atherogenic Dyslipidemia
LPL is the major enzyme involved in hydrolysis of TGs and
is primarily expressed in myocyte and adipocyte vascular
beds. LPL hydrolyzes TGs trafficked in the large TG-rich
chylomicrons and VLDLs. Lipolysis reduces the particle size
and releases apolipoprotein A-I molecules on chylomicron
surfaces, which become available for lipidation or renal ca-
tabolism. A large quantity of phospholipids is also released,
which attaches to phospholipid transfer proteins and serves
as a reservoir for use by maturing HDL particles. Since LPL is
the primary enzyme involved in the hydrolysis of TGs, LPL
deficiency and/or inhibition leads to severe hypertriglyceri-
demia. Increased TG levels are associated with decreased
HDL cholesterol levels and increased concentrations of proa-
therogenic small, dense LDL particles. (9)
CAUSES OF HYPERTRIGLYCERIDEMIA
Hypertriglyceridemia is secondary to either increased TG
production or reduced TG clearance. The etiologic origin
could be primary or secondary and is often multifactorial.
Primary Causes
Table 1 illustrates the causes of primary (genetic) hyperlipid-
emias. The traditional Fredrickson classification describes the
pattern of increased lipoproteins as type I (chylomicrons), type
IIa (LDL), type IIb (LDL and VLDL), type III (IDL), type IV
(VLDL), and type V (VLDL and chylomicrons). (10) All except
type IIa exhibit increased serum TG levels. A 2-hit hypothesis is
often proposed for the manifestation of hypertriglyceridemia, the
first “hit” being genetic predisposition and the second “hit” being
hormonal or environmental factors (such as obesity, hypothy-
roidism, estrogen status, or diabetes) that play a permissive role.
Type I Hyperlipoproteinemia (Hyperchylomicronemia
Syndrome). Type I hyperlipoproteinemia usually manifests in
infancy and childhood (a) secondary to homozygous or com-
pound heterozygous mutations in the LPL gene, causing LPL
deficiency, (11) or (b) owing to loss of function mutations in the
genes that encode the cofactors essential for LPL activity—that
is, APOC2, APOA5, LMF1, and GP1HBP1. (11)(12) These result
in decreased hydrolysis of TGs transported in chylomicrons
and VLDL at the tissue capillary endothelial surface. (13)(14) Af-
fected patients experience recurrent attacks of acute pancreatitis,
eruptive xanthomas, and lipemia retinalis. Inheritance is auto-
somal recessive, and history of consanguinity may be present.
LPL deficiency has a prevalence of 1:106 in the US population.
Rarely, type I hyperlipoproteinemia could be due to circulating
LPL autoinhibitors, (11)(15)(16)(17)(18)(19)(20)(21)(22)(23) which
impair LPL activity as described in the context of autoimmunity.
TABLE 1. Characteristics of Primary Hyperlipidemias
FREDRICKSON
CLASSIFICATION INHERITANCE LIPID ABNORMALITYa CLINICAL FEATURES CAUSES

Type Ib Autosomal recessive TG [ (chylomicron [) Chylomicronemia syndrome: LPL deficiency

TC:TG ratio >10:1 eruptive xanthomas, recurrent ApoC-II deficiency
— pancreatitis, lipemia retinalis LMF1 deficiency
— GP1HBP1 deficiency
— ApoA5 deficiency
Type IIa Autosomal dominant LDL [, TG normal Premature CVD, tendon Familial
xanthomas hypercholesterolemia
Type IIb Polygenic TG [ (VLDL [) Early CVD in family members Familial combined
ApoB-100 [ hyperlipidemiac
HDL Y, LDL normal or [
Type III Polygenic TG [ (VLDL [, chylomicrons [), Premature CVD, palmar or Dysbetalipoproteinemiac
ApoE2/E2 IDL [, TC [, LDL normal tuberoeruptive xanthomas
homozygosity
Type IV Autosomal dominant TG [ (VLDL [), Hypertriglyceridemia in family Familial
ApoB-100 normal members, may have increased hypertriglyceridemiac
HDL Y or normal, LDL normal or Y CVD risk
Type V Autosomal dominant TG [ (VLDL [, chylomicron [) Hypertriglyceridemia in family Familial
members hypertriglyceridemiac
Minimal CVD risk

ApoA5¼apolipoprotein A-5, APoB-100¼apolipoprotein B-100, ApoC-II¼apolipoprotein C-II, ApoE2¼apolipoprotein E2, CVD¼cardiovascular disease,
GP1HBP1¼glycosylphosphatidylinositol-anchored HDL-1, HDL¼high-density lipoprotein, IDL¼intermediate-density lipoprotein, LDL¼low-density
lipoprotein, LMF1¼lipase maturation factor-1, LPL¼lipoprotein lipase, TC¼total cholesterol, TG¼triglyceride, VLDL¼very low-density lipoprotein.
a
Predominant type of TG-containing lipoprotein (ie, VLDL vs chylomicron) increase is depicted in parentheses.
b
Patients with heterozygous mutations may present with mild to moderate TG level increases.
c
Manifests in childhood owing to complex interactions of genetic and environmental factors (ie, weight gain, medications, metabolic
perturbations)—that is, the second “hit.”

Familial Hypertriglyceridemia. Familial hypertriglyceri-
demia is caused by excessive TG synthesis, which can mani-
fest as type IV or type V hyperlipoproteinemia and is thought
to affect 1% of the population. Those with type IV hyper-
lipoproteinemia have increased concentration of VLDL in the
circulation, due to either increased production or decreased
catabolism of VLDL, (6) and can have a TG level between 250
and 1,000 mg/dL (2.82–11.30 mmol/L). Type V hyperlipo-
proteinemia results from an increased production of both
VLDL and chylomicrons. These patients have a TG level that
exceeds 1,000 mg/dL (11.30 mmol/L) (similar to type I hyper-
lipoproteinemia), with pancreatitis as a major concern. These
are autosomal dominant disorders. There will be a history of
pancreatitis in multiple family members but a variable history
of premature cardiovascular disease, likely dependent on
whether they have predominant increases in chylomicrons
and/or VLDL. Although familial hypertriglyceridemia is gen-
erally not fully expressed until adulthood, hypertriglyceride-
mia manifests at younger ages in patients with familial
hypertriglyceridemia because of complex interactions of
genetic and environmental factors, such as childhood obe-
sity, diabetes, and medications (ie, the second “hit”).
Familial Combined Hyperlipidemia. Familial combined
hyperlipidemia is also known as type IIb hyperlipoproteinemia
and is characterized by an overproduction of VLDL and ApoB-
100 by the liver and a decrease in clearance of chylomicron
remnants. (6) The prevalence is around 1% to 5.7% of the
population. Patients present with increased levels of ApoB-100
(>130 mg/dL) and non–HDL cholesterol. Patients may man-
ifest an increase in either TG or LDL cholesterol level or both.
Familial combined hyperlipidemia is associated with a strong
family history of premature cardiovascular disease. Patients
and family members can have increased LDL cholesterol and
TG levels, increased TG levels alone, or increased LDL cho-
lesterol levels alone.
Dysbetalipoproteinemia (Type III Hyperlipoproteinemia).
Manifests with accumulation of IDL with near-equivalent
increase of both cholesterol and TGs, usually in the range
of 300 to 500 mg/dL (3.39–5.65 mmol/L). This is rare
(prevalence of 1 in 10,000). It is due to homozygous mutation

Vol. 38 No. 9 SEPTEMBER 2017 427

 in apolipoprotein E (ApoE2/E2 homozygosity). Usually, this
manifests after 20 years of age and, rarely, a second “hit” may
precipitate the hypertriglyceridemia earlier. (24)
Mutations in the nuclear bile acid receptor “FXR” (farnesoid
X receptor) cause progressive familial intrahepatic cholestasis
and can manifest as moderate hypertriglyceridemia. (25) Pri-
mary hypoalphalipoproteinemias, including Tangier disease
(lecithin cholesterol acyltransferase deficiency), can appear
with moderate hypertriglyceridemia at presentation. (26)
Secondary Causes
Secondary causes are listed in Table 2. Oftentimes, second-
ary hypertriglyceridemia is due to an interplay of combina-
tions of these conditions (hormonal and environmental),
along with genetic causes. (6)(27)(28)(29)
Dyslipidemia of Obesity and Insulin Resistance. Insulin
resistance promotes FFA release from adipose tissue into
the portal circulation, which, in turn, increases hepatic TG
production and secretion of TG-rich VLDL. Thereupon,
excessive TG deposition in the liver, skeletal muscle, and
visceral adipose tissue promotes insulin resistance. Con-
sumption of a high-carbohydrate diet in the face of an
insulin-resistant state begets chronic stimulation of VLDL
overproduction. Insulin is a potent stimulator of LPL, which
TABLE 2. Causes of Secondary
Hypertriglyceridemia
Obesity
Metabolic syndrome
Uncontrolled diabetes
Hypothyroidism
Hypercortisolemia
Nonalcoholic fatty liver disease
Liver disease
Glycogen storage disorders
Lipodystrophy: genetic or acquired
Renal disease
Excessive alcohol intake
Infections
Autoimmune disease: eg, dermatomyositis
Medications: steroids, glucocorticoids, oral estrogens, diuretics,
thiazides, protease inhibitors, antipsychotics, antidepressants,
estrogen-receptor blockade, retinoids, immunosuppressants
(eg, rapamycin, cyclosporine), b-blockers, bile acid sequestrants
428 Pediatrics in Review
regulates postprandial TG excursions, and therefore, LPL
activity is impaired in insulin-resistant individuals.
Diabetes Mellitus. Both type 1 and type 2 diabetes melli-
tus can cause hypertriglyceridemia. LPL activity will be
reduced in poorly controlled type 1 diabetes mellitus. Owing
to insulinopenia, there is increased FFA flux from adipose
tissue, which drives hepatic VLDL production. Patients with
type 2 diabetes mellitus also have all these metabolic dis-
turbances, along with an array of biochemical perturbations
related to obesity and insulin resistance.
COMPLICATIONS OF HYPERTRIGLYCERIDEMIA
Pancreatitis
The risk of pancreatitis is far more worrisome once serum TG
concentrations exceed 1,000 mg/dL (11.30 mmol/L). (5)(7)
The mechanisms include pancreatic capillary bed ischemia
due to TG-rich chylomicron sludge; subsequent release of
pancreatic lipases from the damaged pancreatic acini further
increasing production of proinflammatory FFAs, which leads
to free radical damage and inflammation; and premature
activation of pancreatic trypsinogen to trypsin, which pro-
motes activation of other digestive enzymes, resulting in
autodigestion of the gland. (30)(31)(32) If pancreatitis is sus-
pected, hospitalization is required for rapid lowering of TG
levels. Noncompliance with a low-fat diet can cause recurrent
pancreatitis in those with quantitative or qualitative defects of
LPL, as seen in type I hyperlipidemia. Pancreatitis is associ-
ated with clinically significant morbidity and mortality, (33)
and recurrent pancreatitis may lead to chronic exocrine and
endocrine pancreatic insufficiency (ie, fat malabsorption,
failure to thrive, and insulin-dependent diabetes).
Cardiovascular Risk
Hypertriglyceridemia is considered to be an independent risk
factor for coronary artery disease. (34) Increased TG levels are
associated with decreased HDL cholesterol levels; increased
concentrations of proatherogenic small, dense LDL particles;
increased non–HDL cholesterol levels; and increased con-
centrations of ApoB-100. (7)(9) Cardiovascular risk is asso-
ciated with atherogenic dyslipidemia and other diseases with
cardiovascular risk, such as diabetes and obesity. (6)(7)
Nonalcoholic Fatty Liver Disease
Nonalcoholic fatty liver disease is associated with obesity
and visceral adiposity. Even though metabolic syndrome
is associated with nonalcoholic fatty liver disease, hyper-
triglyceridemia is not universally reported in pediatric non-
alcoholic fatty liver disease. Hypertriglyceridemia in this
scenario can be associated with fat accumulation in the liver LIFESTYLE MODIFICATION
and increased transaminase levels.
Patients with secondary hypertriglyceridemia should follow
a 6-month trial period of weight management, including
MANAGEMENT dietary counselling and physical activity, since obesity and
insulin resistance play a central role (NHLBI expert panel
There is a paucity of data on a systematic approach to
recommendation). (4) A multimodal intervention involving
management of hypertriglyceridemia in pediatric patients
dietary modification, increasing physical activity, and behav-
and therefore, the approach is mostly based on current
ioral changes is recommended. Children and adolescents
adult hypertriglyceridemia management guidelines that
with both primary and secondary hypertriglyceridemia are
are tailored for the pediatric population. (4)(7)(29)(35)
advised to follow a restricted diet with less than 25% to 30%
There are no specific screening guidelines for hyper-
of calories from fat, less than 7% of calories from saturated
triglyceridemia, per se. There is also controversy regarding
fat, less than 200 mg per day of cholesterol, and avoidance of
the existing guidelines. Table 3 summarizes the National
trans fats consumption. Current guidelines also advocate
Heart, Lung, and Blood Institute (NHLBI) expert panel
replacement of simple carbohydrates with complex carbo-
guidelines (4) for dyslipidemia screening. These have been
hydrates, limiting intake of sugar and sugar-sweetened
endorsed by the American Academy of Pediatrics and the
beverages, and increasing the dietary intake of fish to in-
American Heart Association. NHLBI guidelines recom-
crease omega-3 fatty acid consumption. (4) A high intake of
mend universal screening for all children between 9 and
natural dietary fiber, especially water-soluble fiber, is advo-
11 years of age and again between ages 17 and 21 years by
cated. Institute of Medicine Dietary Reference Intake
using a nonfasting lipid profile. Selective (targeted) screen-
recommends consumption of 14 g of dietary fiber per
ing is recommended between ages 2 and 8 years and 12
1,000 kcal.
and 16 years for children with risk factors for prema-
The more common forms of increased TG levels are
ture cardiovascular disease. (4) The US Preventive Ser-
usually secondary to de novo hepatic TG synthesis
vices Task Force determined that there is insufficient
and production of VLDL, in which restricting intake of
evidence for or against lipid screening in children and
dietary carbohydrates—especially simple sugars—and in-
adolescents. (36)
creasing dietary fiber intake will be effective. Intake
When using nonfasting lipid profiles, risk assessment
of mono- and polyunsaturated FAs and omega-3 FAs is
determination is performed by using the non–HDL cho-
encouraged.
lesterol component (calculated by subtracting the HDL
Performing moderate to intense physical activity for 30
cholesterol level from the total cholesterol level). There
to 60 minutes daily can reduce the TG level. Weight loss
is more emphasis on recognition of non–HDL choles-
is expected to improve insulin sensitivity, reduce FFA
terol because it represents all atherogenic lipopro-
release from adipose tissue, and enhance activity of LPL,
tein particles. Since dietary fats and carbohydrates can
leading to better clearance of TGs. Moreover, a healthy
increase serum TG concentrations, fasting for 8–12 hours
diet with fewer refined carbohydrates and less saturated
prior to testing is recommended for evaluation of hypertri-
fat will reduce endogenous synthesis of VLDL and LDL
glyceridemia. (7) It is important to keep in mind that if the TG
cholesterol.
concentration is more than 400 mg/dL (4.52 mmol/L),
LDL cholesterol calculation by using the Friedewald equa-
tion [LDL ¼ Total cholesterol  HDL  (TGs O 5)] is
PHARMACOLOGICAL MANAGEMENT
inaccurate. (5)
Primary hypertriglyceridemia diagnosis is based on There are no Food and Drug Administration (FDA)–
increased fasting TG concentration in association with approved TG level–lowering medications for use in children
family history of dyslipidemia, pancreatitis, and cardiovas- younger than 18 years of age, and there are no established
cular disease, along with associated risk factors and clinical indications for their use in children. (6) Nevertheless, ex-
features. It is important to exclude secondary causes of trapolation of adult guidelines is judiciously applied in this
hypertriglyceridemia in all patients. (7) Patients with hy- scenario. (6)(7)(29) When fasting TG concentration is
pertriglyceridemia associated with obesity and metabolic greater than 500 mg/dL (5.65 mmol/L), primary pharma-
syndrome need to be evaluated for other associated co- cological agents for treating hypertriglyceridemia, such as
morbid conditions, such as hypertension, diabetes, and fibrates, niacin, and omega-3 FAs, are used to prevent
nonalcoholic fatty liver. pancreatitis. (28) However, the safety and effectiveness data

Vol. 38 No. 9 SEPTEMBER 2017 429

 TABLE 3. NHLBI Guidelines for Pediatric Dyslipidemia Screening
TYPE OF SCREENING LIPID
AND AGE PROFILE CRITERIA TO SCREEN WHEN TO REPEAT

Universal Normal: repeat at 17–21 y of age

9–11 y Nonfastinga/fasting Universal Borderline: repeat after 1 y
17–21 y Nonfastinga/fasting Universal Abnormalb: perform FLP twicec
Selective
2–8 y Fasting Positive family history of premature CVDd Abnormalb: perform FLP twicec
Parent has TC ‡240 mg/dL (‡6.22 mmol/L) or known
dyslipidemia
Child has diabetes, hypertension, BMI ‡ 95th percentile,
smokes cigarettes, or is exposed to secondhand smoke
Child has a moderate- to high-risk medical conditione
12–16 y Fasting New knowledge of positive family history of premature CVDd Abnormalb: perform FLP twicec
New knowledge of parent with TC ‡240 mg/dL (‡6.22
mmol/L) or known dyslipidemia
Patient has diabetes, hypertension, BMI ‡85th percentile or
smokes cigarettes
Patient has a moderatee- or high-riskf medical condition

According to reference 4. BMI¼body mass index; CVD¼cardiovascular disease; FLP¼fasting lipid profile; HDL¼high-density lipoprotein; LDL¼low-density
lipoprotein; NHLBI¼National Heart, Lung, and Blood Institute; TC¼total cholesterol; TG¼triglyceride.
a
Disregard TG and LDL cholesterol in the nonfasting sample.
b
Abnormal lipid screening results are as follows: For nonfasting screening, results are abnormal if non-HDL level is >145 mg/dL (>3.76 mmol/L) or if HDL
level is <40 mg/dL (<1.04 mmol/L); for fasting screening, results are abnormal if LDL cholesterol level is >130 mg/dL (>3.37 mmol/L), if non–HDL
cholesterol level is >145 mg/dL (>3.76 mmol/L), if HDL cholesterol level is <40 mg/dL (<1.04 mmol/L), if TG level is >100 mg/dL (>1.13 mmol/L) if the child is
<10 years of age, or if TG level is >130 mg/dL (>1.47 mmol/L) if the child is >10 years of age.
c
Repeat fasting lipid profile after 2 weeks but within 3 months (average the results).
d
Positive family history of CVD indicates that a parent, grandparent, aunt/uncle, or sibling has a history of myocardial infarction, angina, stroke, or
coronary artery bypass graft, stent, or angioplasty at <55 years of age for male patients or <65 years of age for female patients.
e
Moderate-risk condition indicates Kawasaki disease with regressed coronary aneurysms, chronic inflammatory disease (systemic lupus erythematosus,
juvenile rheumatoid arthritis), HIV infection, or nephrotic syndrome.
f
High-risk condition indicates diabetes mellitus type 1 and type 2, chronic kidney disease and/or end-stage renal disease or postrenal transplant,
postorthotopic heart transplant, or Kawasaki disease with current aneurysms.

for these agents for treating hypertriglyceridemia in chil-
dren are lacking. (37)(38) For patients with moderate hyper-
triglyceridemia (200–499 mg/dL [2.26–5.64 mmol/L]),
treatment is targeted toward reducing the non-HDL cho-
lesterol level (3)(7)(39) by using a statin. (28)
Fibrates
Fibrates, a class of lipid level–lowering drugs, are the first-
line management when the TG concentration is greater
than 500 mg/dL (5.65 mmol/L) to reduce the pancreatitis
risk. (6)(12)(38) This is not an FDA-approved indication for
patients under 18 years of age; for these patients, a pediatric
lipid specialist should be consulted. Fibrates activate the
peroxisome proliferator–activated receptor-a and reduce
hepatic VLDL synthesis. Fibrates also augment the activity
of LPL, leading to enhanced hydrolysis of TG-rich lipopro-
teins. In adults with isolated hypertriglyceridemia, fibrates
reportedly reduce plasma TG concentration by 40% to 60%.
(15) Gemfibrozil (600 mg administered twice daily) and
fenofibrates (nanocrystal formulation administered at a
dose of 145 mg daily or micronized capsules administered at
a dose of 200 mg daily as fenofibric acid 135 mg) are the
available fibrate therapies. Fibrates can cause myopathy,
especially when used in conjunction with a statin. They
have to be used with caution in patients with mild to
moderate renal disease and are contraindicated in severe
renal impairment. Fibrates can be used in patients with
dyslipidemia and nonalcoholic fatty liver disease. Owing to
their risk for development of cholesterol gallstones, fibrates
are contraindicated in patients with gallbladder disease. (20)
Niacin (Nicotinic Acid)
Nicotinic acid reduces plasma TG levels by 5% to 40%. It
also reduces LDL cholesterol and lipoprotein(a) levels.

430 Pediatrics in Review

Niacin increases the plasma HDL cholesterol level by
10% to 40%. (35) Niacin curtails TGs by inhibiting
diacylglycerol acyltransferase-2, which is an enzyme that
converts diacylglycerol to TGs, thereby reducing FFA
flux from the adipose tissue. It can increase the break-
down of TG-rich lipoproteins ApoB-100 and ApoB-48.
The main adverse effect of niacin is the flushing that
occurs 15 minutes after ingestion, due to the release of
prostaglandin F2, which can be prevented in adults by
giving the patient aspirin 15 minutes before administering
niacin. (35)(40) However, owing to concerns of Reye syn-
drome, aspirin is not advocated for use in children. To date,
there has been only 1 clinical trial in pediatrics involving
the use of niacin (41), in which numerous adverse effects
were reported in 76% of patients, including flushing,
abdominal pain, vomiting, headache, and increased liver
enzyme levels. (37)(41)
Omega-3 FAs
Long-chain omega-3 FAs can be used as an adjunctive
therapy when TG concentration is greater than 500 mg/dL
(5.65 mmol/L). It has to be kept in mind that a TG-lowering
effect is entirely dependent on the omega-3 content (ie,
eicosapentaenoic acid [EPA] and docosahexaenoic acid
[DHA] content). When compared to prescription fish oil
products that contain specific amounts of EPA and DHA
and/or a capsule, over-the-counter (OTC), unregulated fish
oil supplements vary in concentration of EPA and DHA. In
adults, when used in the form of EPA and DHA (approx-
imately 465 mg EPA and 375 mg DHA), these therapies
reduced TG levels by 20% to 50%. (35)(42) There are no
pediatric dosing guidelines available. So far, to our knowl-
edge, there have been 2 pediatric clinical trials in which
omega-3 FAs were used. (43)(44) Even though the low-dose
OTC fish oil trial (44) in patients with TG levels greater
than 140 mg/dL (1.58 mmol/L) did not show TG level–
lowering effectiveness, the trial in which 3 to 4 g of pre-
scription omega-3-acid ethyl esters were used (approximately
3,360 mg DHA plus EPA administered per day) (43) dem-
onstrated responders and nonresponders. However, there
was no statistically significant improvement. Prescription-
strength or OTC fish oil capsules may be used after
confirming (a) that a patient has severe hypertrigly-
ceridemia by obtaining several fasting baseline measure-
ments and (b) a failure to control TG levels by means
of diet and weight loss. Depending on the response, a
decision can be made whether to continue or stop the
treatment. Prescription fish oil products do not cause
the fishy taste and burping experienced with OTC fish
oil capsules. (35)
Statins
When TG levels are between 200 and 499 mg/dL
(2.26–5.64 mmol/L), it is important to evaluate the non–
HDL cholesterol level, as this reflects all atherogenic
lipoprotein particles. (8) Statins are 3-hydroxy-3-methyl-
glutaryl-coenzyme A reductase inhibitors and can be used
for persistently increased non–HDL cholesterol levels, even
after implementation of dietary and lifestyle changes. (8)(45)
Commonly used statins include simvastatin 5 to 40 mg per
day, atorvastatin 10 to 20 mg per day, rosuvastatin 5 to
20 mg per day, and pravastatin 20 to 40 mg per day. To
our knowledge, there have not been many large, long-
term studies on statin use in the pediatric population.
The common side effects include headache, myalgia, and
gastrointestinal symptoms, all of which eventually dis-
appear with continued use. Some uncommon but poten-
tial side effects include muscle disorders (ie, myalgia,
myopathy, rhabdomyolysis, myonecrosis, and myositis),
increased serum transaminase levels, increased inci-
dence of new-onset type 2 diabetes, and ill-defined
cognitive dysfunction. These unstudied long-term risks
in the pediatric population should be compared to the
benefits when initiating statin treatment. Statins should
be used cautiously in female patients because of poten-
tial teratogenicity. Drug interactions (ie, those that affect
cytochrome P450) need to be kept in mind when prescrib-
ing statins.
SEVERE HYPERTRIGLYCERIDEMIA
Acute pancreatitis can be consequent to severe hypertri-
glyceridemia (ie, TG level > 1,000 mg/dL [11.30 mmol/L]).
(5) Ideally, serum TG concentration should be less than
500 mg/dL (5.65 mmol/L) to prevent pancreatitis. Patients
with severe hypertriglyceridemia tend to have exponential
increases postprandially because of defective and already
maximized LPL activity. (30) Children with pancreatitis can
present with acute abdominal pain, nausea, vomiting, and
ileus. Even though there are no established guidelines,
oftentimes patients with severe hypertriglyceridemia are
hospitalized on the basis of the presence or absence of
symptoms. A TG level higher than 1,000 mg/dL (11.30
mmol/L) with abdominal pain or pancreatitis necessi-
tates hospitalization. Severe hypertriglyceridemia in
patients with uncontrolled diabetes and those with pre-
vious episodes of pancreatitis require admission when
the TG level is higher than 1,000 mg/dL (11.30 mmol/L)
(2). Insulin activates LPL and facilitates degradation and
clearance of TG from the circulation (46) and, hence,
insulin therapy is often used in the management of severe
Vol. 38 No. 9 SEPTEMBER 2017 431
 hypertriglyceridemia, (47)(48)(49)(50)(51) especially in
patients with uncontrolled diabetes. Plasmapheresis
can reduce serum TG levels rapidly and can be used in
symptomatic patients with severe hypertriglyceridemia and
pancreatitis. Plasmapheresis is not required in the care
of asymptomatic patients with severe hypertriglyceridemia.
When the TG level is higher than 1,000 mg/dL (11.30
mmol/L), the predominant lipoprotein is chylomicron
(52), the levels of which could be further worsened by any
additional dietary fat intake; therefore, patients with TG
levels higher than 1,000 mg/dL (11.30 mmol/L) should
refrain from having dietary fat for 72 hours. Since chy-
lomicrons are produced in the small intestine and are
dependent on dietary fat for formation, (53) fasting will
result in a rapid and robust decline in TG levels. When TG
levels are lower than 1,000 mg/dL (11.30 mmol/L), the
patient can then be placed on a diet that contains less than
10% to 15% of daily calories from fat.
CONCLUSIONS
A lack of pediatric-specific protocol and FDA-approved TG
level–lowering drugs makes the management of hypertrigly-
ceridemia in children difficult. Dietary restriction remains
the mainstay of management, supplemented by TG level–
lowering medications. A more rational approach needs to be
followed in the pediatric setting.
432 Pediatrics in Review
SUMMARY
• On the basis of epidemiological studies and expert opinion, (3)(7)
an estimated 10% of US children and adolescents between 12
and 19 years of age have increased serum TG concentrations (TG
level >150 mg/dL [>1.69 mmol/L]).
• On the basis of expert opinion, (5)(7) hypertriglyceridemia
diagnosis is based on fasting TG concentrations.
• On the basis of expert opinion, (5)(7) it is important to exclude
secondary causes of hypertriglyceridemia in all patients.
• On the basis of expert opinion, (5)(7) the risk of pancreatitis is
lower when TG concentration is less than 1,000 mg/dL (11.30
mmol/L).
• On the basis of expert opinion, (4) a 6-month trial period of weight
management, including dietary counselling and physical activity, is
recommended in patents with secondary hypertriglyceridemia—
especially where obesity and insulin resistance play a central role.
• On the basis of some research evidence, consensus statements,
and expert opinions, (3)(7)(39) for patients with TG levels between
150 and 499 mg/dL (1.69–5.64 mmol/L), the treatment goal is to
target non-HDL cholesterol.
• On the basis of expert opinion, (5,7) for patients with very high
triglycerides, (above 500 mg/dL), a fibrate can be used to reduce
the pancreatitis risk.
References for this article are at http://pedsinreview.aappubli-
cations.org/content/38/9/424.
PIR QUIZ
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1. A 9-year-old girl was found to have a fasting triglyceride level of 352 mg/dL (3.98 mmol/L) REQUIREMENTS: Learners
at a routine lipid profile screening. Her height and weight are at the 25th percentile, and can take Pediatrics in Review
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2. You have been evaluating a 6-year-old boy for hypertriglyceridemia. The patient’s family must demonstrate a minimum
history is clinically significant for severe hypertriglyceridemia in his father and uncle and performance level of 60% or
the death of his maternal grandmother at 45 years of age due to myocardial infarction. The higher on this assessment,
boy’s fasting triglyceride level is 553 mg/dL (6.25 mmol/L). You began dietary and physical which measures achievement
activity modifications and referred him to an endocrinologist. The boy’s parents return of the educational purpose
today to discuss the endocrinologist’s recommendations for treatment options. In and/or objectives of this
discussing with them the potential side effects of the various pharmacological treatments activity. If you score less than
of hypertriglyceridemia, which of the following is the most appropriate statement? 60% on the assessment, you
A. Aspirin should be routinely given to children 15 minutes before niacin to prevent will be given additional
flushing. opportunities to answer
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B. Immediate hospitalization.
B. Immediate plasmapheresis.
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Maintenance of Certification
4. A 10-year-old boy with a history of mood disorder, gastroesophageal reflux disease,
(MOC) Part 2 credits by the
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American Board of Pediatrics
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5. A 9-year-old girl is seen in the clinic as a new patient. A screening fasting lipid profile shows
a triglyceride level of 250 mg/dL (2.82 mmol/L). She is otherwise healthy, with a body mass
index at the 40th percentile. Her family history is unremarkable. Which of the following is
the most appropriate next step in the care of this patient?

Vol. 38 No. 9 SEPTEMBER 2017 433

 A. Prescribe a statin.
B. Prescribe niacin.
C. Recommend a diet containing less than 10% to 15% dietary fat.
D. Recommend supplementation of omega-3 fatty acids with fish oil capsules.
E. Repeat the fasting lipid profile and plan further care based on the mean of the 2
results.

434 Pediatrics in Review


EDITOR’S NOTE
We invite readers to contribute Index of
Suspicion cases through the PIR manuscript
submission system at: https://mc.
manuscriptcentral.com/pir.
AUTHOR DISCLOSURE Drs Tucker, Holmes,
Harley, and Roca Garcia have disclosed no
financial relationships relevant to this article.
Dr Custodio has disclosed that she is principal
investigator for a clinical trial sponsored by
Allergan. This commentary does not contain a
discussion of an unapproved/investigative
use of a commercial product/device.
1 Fever and Ataxia in a Toddler with Pica
Megan H. Tucker, MD,* Jonathan Holmes, MD,† Susan Harley, MD,‡
Maria Roca Garcia, MD,§ Haidee Custodio, MD¶
*Pediatrics, Children’s Mercy Hospitals and Clinic, Kansas City, MO
†
Children’s Medical Group, Mobile, AL
‡ § ¶
Division of Pathology, Division of Pediatrics, Division of Pediatric Infectious Diseases, University of
South Alabama College of Medicine, Mobile, AL
PRESENTATION
A 2-year-old boy with developmental delay and a history of geophagia residing in
Mobile, AL, presents to a local emergency department with 3 weeks of intermittent
fever and 3 days of irritability, ataxia, and strabismus. He has no history of
international travel. Other than a temperature of 101°F (38.3°C), vital signs are
within normal limits. On physical examination, the patient is noted to have
bilateral cranial nerve 6 palsy, slurred speech, and an ataxic gait. Extreme irrita-
bility is observed when sitting the patient upright and with bright lights.
Ophthalmologic examination reveals bilateral papilledema.
Laboratory analysis reveals C-reactive protein of 0.2 mg/dL (1.90 nmol/L),
erythrocyte sedimentation rate of 48 mm/h, and peripheral white blood
cell (WBC) count of 9,500/mL (9.50  109/L) with an absolute eosinophil
count of 32% (0.32). Computed tomography scan of the boy’s head yields
unremarkable results; magnetic resonance imaging of the brain reveals
nonspecific inflammatory changes. The opening pressure on lumbar punc-
ture (LP) is greater than 20 mm Hg, and the manometer is emptied 3 times
before obtaining a normal closing pressure. The cerebrospinal fluid (CSF)
Figure. A hypercellular specimen with numerous eosinophils (arrow) in a background of mixed
inflammation, including lymphocytes, neutrophils, and mono/histiocytes. (Cerebrospinal Fluid
Cytospin; Papanicolaou stain, 1000)
Vol. 38 No. 9 SEPTEMBER 2017 435
 shows a white blood cell count of 823 /mL (0.82109/L),
glucose of 41 mg/dL (2.28 mmol/L), and protein of
0.65 g/dL (6.5 g/L). Manual differentiation of the CSF
shows the presence of 27% eosinophils (Figure). Following
the LP, substantial clinical improvement is noted. The patient
is more alert, interactive, and less irritable, although improve-
ments regress within days. Three subsequent LPs are per-
formed to relieve increased intracranial pressure (ICP), and
436 Pediatrics in Review
each shows significant CSF eosinophilia ranging from 73% to
100%. Bone marrow biopsy reveals increased eosinophilic
precursors supportive of a reactive rather than a malignant
process. Further laboratory evaluation establishes the diagnosis.
The Case Discussion and References appear with the online
version of this article at http://pedsinreview.aappublications.
org/content/38/9/435.
DISCUSSION
Based on the findings of CSF eosinophilic pleocytosis,
neurologic symptoms, and history of geophagia, helmin-
thic infection resulting in eosinophilic meningitis was
considered. This is the most common cause of eosino-
philic meningitis worldwide. This suspicion was further
raised when extensive evaluation for other infection, auto-
immune disorder, and malignancy returned negative.
On hospital day 6, the patient was treated with albendazole
and a 10-day course of methylprednisolone. His irritability
resolved, and his gait normalized within 1 week. He com-
pleted a 20-day course of albendazole. Angiostrongylus
cantonensis polymerase chain reaction (PCR) assay per-
formed on the CSF through the Centers for Disease
Control and Prevention (CDC) returned positive. Tests
for Baylisascaris procyonis and other known causes of
eosinophilic meningitis were negative.
Differential Diagnosis
Eosinophilic meningitis is defined as the presence of 10
or more eosinophils per microliter in the CSF or at least
10% eosinophils of the total CSF leukocyte count. (1) The
differential diagnosis for eosinophilic meningitis encom-
passes infectious and noninfectious causes. Helminthic par-
asites such as A cantonensis, Gnathostoma spinigerum, and
B procyonis are the most common causes worldwide. (2)(3)
Angiostrongylus and Gnathostoma are not considered
endemic in the United States. Baylisascaris are round-
worms known to infect raccoons in North America,
although documented infections are very few and are
typically associated with geophagia. Patients infected
with B procyonis typically present with signs of menin-
goencephalitis, including ataxia, paralysis, and ocular
involvement with choroidal infiltrates and neuroretinitis.
The presentation is often severe, resulting in death or
permanent neurologic sequelae. Brain imaging in A can-
tonensis infection yields nonspecific or normal results,
whereas infection with B procyonis commonly shows dif-
fuse periventricular white matter disease on imaging,
which can aid in differentiating between the 2 parasites.
(2)(4)(5)(6)
Other parasitic infections, such as toxocariasis, schisto-
somiasis, paragonimiasis, and neurocysticercosis, and central
nervous system involvement in infections with Coccidioides
immitis, Rickettsiae, and neurosyphilis can also be associated
with eosinophilic meningitis. (2)
Noninfectious causes of eosinophilic meningitis include
myelography contrast agents, medications such as ciproflox-
acin and ibuprofen as well as intraventricular vancomycin
and gentamicin, certain malignancies, ventriculoperitoneal
shunts, and hypereosinophilic syndrome. (2)
The Condition
A cantonensis is a rat lungworm that has mollusks as
intermediate hosts. Crustaceans may serve as transport
hosts and humans as accidental hosts. A cantonensis is
the most common cause of eosinophilic meningitis world-
wide, with most cases reported in Asia and the Caribbean.
However, there have been reports of infection in Hawaii
and Louisiana. (7) Studies have found infected rodents and
mollusks on the Gulf Coast of the United States, especially
in port cities, likely due to the transportation of rats from
endemic areas to the United States on ships and airplanes.
(4)(7)(8)
Infection with A cantonensis occurs with ingestion of raw
or undercooked snails and seafood that harbor the parasite
or consumption of contaminated produce. (7)
There are 3 primary clinical manifestations of angio-
strongyliasis: 1) meningitis, the most common manifes-
tation, usually with a good prognosis; 2) encephalitis
with alteration of consciousness, which is rare but fatal;
and 3) ocular involvement (optic neuritis, papilledema,
uveitis). (9)
In a review of pediatric cases in Thailand, the most
common presentation was severe headache (seen in all
patients), followed by fever, nausea, vomiting, papilledema,
cranial nerve palsy, and abnormal cerebellar signs. (10) Chil-
dren are more likely than adults to exhibit papilledema,
a high opening CSF pressure, and cranial nerve abnor-
malities. Hyperesthesia has been reported as a specific
sign for A cantonensis infection in adults but not in chil-
dren, likely due to a child’s inability to communicate this
sensation.
Diagnosis
The diagnosis of infection with A cantonensis, a neurotropic
parasite, is primarily clinical but is suggested when a patient
presents with neurologic symptoms and laboratory findings
consistent with CSF eosinophilic pleocytosis. Exposure to an
infectious source, such as a history of consumption of raw
snails or contaminated produce in an endemic area within
the past month, is crucial in establishing the diagnosis. (7)
In our case, no such history was elicited. We can only
surmise that because the child had geophagia, he may have
eaten contaminated matter, a not so remote possibility for
a child living in a port city on the Gulf Coast.
Definitive diagnosis is difficult because cases in the
United States are rare, symptoms are nonspecific, and
diagnostic tests are not readily available. In addition, serologic
tests may yield positive results only during the convalescent
stage. PCR of the CSF can confirm the diagnosis, but it is
available only through specialized laboratories, in this case
through the CDC. (3)
Treatment
Because A cantonensis cannot survive for a prolonged period
of time in the human body, most infections resolve spon-
taneously. (2)(7) For this reason, treatment is generally
supportive, with analgesics administered for pain and cor-
ticosteroids provided to decrease the inflammatory reaction.
Repeat LPs may be performed to relieve ICP. Antihel-
minthic drugs are not routinely administered because of
uncertainty about their effectiveness and concerns for exac-
erbation of symptoms due to an inflammatory response
from dying organisms. However, some evidence suggests
that the use of antihelminthic medications decreases the
duration of symptoms.
Our patient showed significant improvement without
exacerbation of symptoms with the use of albendazole
as well as a course of methylprednisolone. At follow-up
evaluation 4 months later, he was at his pre-illness
baseline.
Lessons for the Clinician
• The presence of eosinophils in the cerebrospinal fluid is
unusual and should alert clinicians to infectious and
noninfectious diagnostic possibilities.
• Angiostrongylus cantonensis is the most common cause
of eosinophilic meningitis worldwide. It should be con-
sidered in the differential diagnosis, especially in the
Parent Resources from the AAP at HealthyChildren.org
• Meningitis: https://www.healthychildren.org/English/health-issues/conditions/head-neck-nervous-system/Pages/Meningitis.aspx
For a comprehensive library of AAP parent handouts, please go to the Pediatric Patient Education site at http://patiented.aap.org.
context of recent travel to endemic areas or with high-risk
behavior such as geophagia.
References
1. Ramirez-Avila L, Slome S, Schuster FL, et al. Eosinophilic
meningitis due to Angiostrongylus and Gnathostoma species. Clin
Infect Dis. 2009;48(3):322–327
2. Lo Re V III, Gluckman SJ. Eosinophilic meningitis. Am J Med.
2003;114(3):217–223
3. Miller MA, Menowsky M, Leeson K, Leeson B. Eosinophilic meningitis:
what’s the “diff”? Am J Emerg Med. 2014;32(1):107.e5–107.e7
4. Wang QP, Lai DH, Zhu XQ, Chen XG, Lun ZR. Human
angiostrongyliasis. Lancet Infect Dis. 2008;8(10):621–630
5. Tsai HC, Liu YC, Kunin CM, et al. Eosinophilic meningitis caused by
Angiostrongylus cantonensis associated with eating raw snails:
correlation of brain magnetic resonance imaging scans with clinical
findings. Am J Trop Med Hyg. 2003;68(3):281–285
6. Tsai HC, Tseng YT, Yen CM, et al. Brain magnetic resonance
imaging abnormalities in eosinophilic meningitis caused by
Angiostrongylus cantonensis infection. Vector Borne Zoonotic Dis.
2012;12(2):161–166
7. Centers for Disease Control and Prevention (CDC). Parasites –
Angiostrongyliasis (Also known as Angiostrongylus infection).
2010. Available at: https://www.cdc.gov/parasites/angiostrongylus/
index.html. Accessed June 16, 2017
8. Teem JL, Qvarnstrom Y, Bishop HS, et al. The occurrence of the rat
lungworm, Angiostrongylus cantonensis, in nonindigenous snails in
the Gulf of Mexico region of the United States. Hawaii J Med Public
Health. 2013;72(6 suppl 2):11–14
9. Sawanyawisuth K, Sawanyawisuth K. Treatment of angiostrongyliasis.
Trans R Soc Trop Med Hyg. 2008;102(10):990–996
10. Sawanyawisuth K, Chindaprasirt J, Senthong V, et al. Clinical
manifestations of eosinophilic meningitis due to infection with
Angiostrongylus cantonensis in children. Korean J Parasitol. 2013;51
(6):735–738

AUTHOR DISCLOSURE Drs Schaffner
and Hazen have disclosed no financial
relationships relevant to this article. This
commentary does not contain a discussion of
an unapproved/investigative use of a
commercial product/device.
2 Sternal Mass in an 18-year-old Boy
Erin Schaffner, MD,* Benjamin Hazen, MD†
*Diagnostic Referral Service, and
†
Department of Pediatrics, Children’s Hospital of Pittsburgh of UPMC, Pittsburgh, PA
PRESENTATION
An 18-year-old previously healthy boy presents to the emergency department with
a 1-day history of an anterior chest wall mass and a 1-week history of chest pain and
fever. One week ago, he sought care at a referring hospital, where he was treated
with naproxen for presumed muscle strain. Two days later, he was admitted to
the referring facility after he developed fever, and chest computed tomography
(CT) scan findings raised concern for left lower lobe pneumonia. After 2 days
of intravenous antibiotic therapy, he was discharged with a prescription for
amoxicillin/clavulanic acid from the referring hospital. Later on the day of dis-
charge, he developed a tender mass over his right anteroinferior chest. There is no
history of trauma.
On physical examination, the boy has a temperature of 101.12°F (38.4°C), heart
rate of 90 beats/min, respiratory rate of 36 breaths/min, and blood pressure of
113/69 mm Hg. His growth parameters are within normal ranges for age. He has
decreased breath sounds at the lung bases bilaterally but no crackles. A 4-cm firm,
tender mass is present lateral to his xiphoid process on the right. He has no
lymphadenopathy. The remainder of the physical examination yields normal
results.
Laboratory studies reveal a normal comprehensive metabolic panel, except for
albumin of 2.8 g/dL (28 g/L). His complete blood cell count is remarkable for a
leukocytosis of 20,800/mL (20.8  109/L) with 80% neutrophils and thrombo-
cytosis of 441  103/mL (441  109/L). His C-reactive protein is elevated at greater
than 19 mg/L (180.96 nmol/L). Chest CT scan shows an ill-defined soft-tissue
mass in the anterior mediastinum surrounding the costal cartilage. Additional
procedures and imaging studies reveal the diagnosis.
The Case Discussion and Suggested Readings appear with the online version of this
article at http://pedsinreview.aappublications.org/content/38/9/437.
Vol. 38 No. 9 SEPTEMBER 2017 437
DISCUSSION
Ultrasound-guided aspiration of the mass revealed purulent
fluid, and the patient was treated empirically with vanco-
mycin and ceftriaxone while awaiting culture results.
Subsequent chest magnetic resonance imaging (MRI) dem-
onstrated focal bone marrow edema of the inferior right
fifth sternal segment extending into the xiphoid process
and costochondral cartilage with local spread to retrosternal
soft tissues. A large inflammatory multiloculated phlegmon
(6.54.38.8 cm) circumferentially surrounded the inferior
sternum and xiphoid, extending inferiorly to the subcutaneous
tissue anterior to the liver without breaching the abdominal
peritoneum. MRI findings confirmed the presence of sternum
and xiphoid osteomyelitis. Methicillin-resistant Staphylococcus
aureus (MRSA) grew from aspirate culture, and the patient
was transitioned to oral clindamycin to complete a 6-week
antibiotic course based on culture sensitivities. Blood cultures
remained negative throughout his hospitalization, and the
patient experienced defervescence before discharge.
The Condition
Primary sternal osteomyelitis (PSO) is very rare in children,
accounting for approximately 0.2% of the cases of osteo-
myelitis. Boys are affected twice as often as girls. The
prevalence of PSO has a bimodal distribution; most cases
occur before the age of 1 year or between adolescence and
early adulthood. PSO and acute hematogenous osteomye-
litis (AHO) are primarily diseases of young children because
they have a more robust vascular supply, which is needed for
bone growth. The most common sites of AHO are the long
bones of the lower extremities. Within the long bones,
metaphyseal localization is most frequent because the vascu-
lature at these sites has slower blood flow, a decreased number
of phagocytic cells lining the capillaries, and fenestrations
in the endothelium that can promote propagation of infec-
tion during transient bacteremia. Neonates are at particularly
increased risk of concomitant septic arthritis because osteo-
myelitis infection can easily breach the epiphyseal growth
plate through vessels that do not atrophy until after age 1 year.
A variety of organisms are responsible for cases of
AHO. The most common causative organism is S aureus. In
recent years, the prevalence of AHO caused by community-
acquired MRSA (CA-MRSA) has increased markedly,
although methicillin-sensitive S aureus remains the pre-
dominant organism. Streptococcus pyogenes and Streptococcus
pneumoniae are also considered common pathogens in
AHO. Since the introduction of universal vaccination, the
rates of S pneumoniae and Haemophilus influenzae type b
osteomyelitis have decreased substantially. Less commonly,
fastidious organisms, such as Kingella kingae, should be
considered, particularly in children younger than age 4 years.
Clinical Presentation and Diagnosis
Acute osteomyelitis often presents with focal pain, ery-
thema, and swelling over the affected site along with fever
and impaired function such as ambulation if a long bone is
affected. Supporting laboratory findings include leukocyto-
sis and elevated inflammatory markers. Osteoclastic bone
demineralization cannot be seen on radiographs until
approximately 10 to 14 days of active infection and inflam-
mation. Other modalities, such as ultrasonography, are
helpful to define the characteristics of soft-tissue collections
and periosteal involvement. Triphasic radioisotope scanning
with 99mtechnetium can detect AHO earlier than plain
radiography but can yield false-negative results in the first
3 days of infection. MRI is particularly useful in early
diagnosis of AHO because it can identify early marrow
edema that may be missed by other imaging modalities.
MRI is considered the gold standard imaging modality for
AHO diagnosis when available. The definitive diagnosis of
AHO can be established by performing a culture of bone
or subperiosteal abscess aspirate to identify the pathogen,
and subsequent antibiotic therapy can be tailored based on
culture results. Identification of the pathogen can be further
supported by a positive blood culture, although blood cul-
tures identify the pathogen in fewer than 40% of cases.
Treatment
AHO infections regularly require hospitalization for admin-
istration of parenteral antibiotics and, in severe cases,
surgical intervention. Empiric therapy should be directed
against S aureus based on local susceptibility patterns.
Clindamycin, vancomycin, and b-lactams all achieve
therapeutic concentrations in the bone. Historically,
first-generation cephalosporins, clindamycin, and nafcil-
lin were used as first-line therapy, but this choice has been
complicated by the increased prevalence of CA-MRSA.
Clindamycin remains an effective option in areas where
fewer than 10% of CA-MRSA isolates are resistant, but in
areas with higher levels of resistance, vancomycin is the em-
piric antibiotic of choice for presumed CA-MRSA AHO.
Because the prevalence of CA-MRSA has a significant
impact on the selection of initial empiric therapy, some have
attempted to develop algorithms for predicting CA-MRSA
infection based on laboratory results and symptoms, but
these have not been well studied. Therefore, the gold
standard treatment guideline remains direct bone sampling
when clinically possible. Antibiotic therapy should be tai-
lored to bone aspirate and blood culture pathogen growth
and antibiotic susceptibilities. Transition from parenteral to
oral antibiotic should be based on clinical and laboratory
response. Shorter durations of parenteral antibiotics have
not been associated with higher levels of treatment failure
when clinical response is considered. Short-course intrave-
nous antibiotics (minimum 3-4 days) for uncomplicated
AHO have had similar cure rates in 2 systematic reviews.
The transition from parenteral to oral antibiotics and dis-
charge from the hospital can be based on clinical improve-
ment, particularly resolution of fever, improving physical
examination findings, decreasing C-reactive protein values,
and ability to tolerate oral antibiotic. The duration of therapy
should be a minimum of 3 weeks and may range to 6 weeks
or longer, based on clinical response. Treatment endpoints
include regain of function and resolution of systemic signs
of infection. Normalization of inflammatory markers can
be expected in 7 to 10 days for C-reactive protein and 3 to 4
weeks for erythrocyte sedimentation rate.
Prognosis
Conservative treatment with antibiotics can be effective in
approximately 90% of cases of AHO. The remaining cases
require more aggressive forms of treatment, including
surgical debridement. Chronic osteomyelitis, characterized
by long periods of episodic pain and persistent infection
despite prolonged antibiotic therapy, can occur in up to 5%
of cases. Additional complications include joint damage,
pathologic fractures, and permanent growth plate disrup-
tion leading to limb length discrepancy.
Lessons for the Clinician
• Community-acquired methicillin-resistant Staphylococcus
aureus (CA-MRSA) is increasing in prevalence, leading
Additional Resources for Pediatricians
AAP Textbook of Pediatric Care, 2nd Edition
• Chapter 304: Osteomyelitis - https://pediatriccare.solutions.aap.org/chapter.aspx?sectionid=136093940&bookid=1626
Point-of-Care Quick Reference
• Osteomyelitis - https://pediatriccare.solutions.aap.org/content.aspx?gbosid=165550
For a comprehensive library of AAP parent handouts, please go to the Pediatric Patient Education site at http://patiented.aap.org.
to more severe infections with a wider range of clini-
cal manifestations and complications, including acute
hematogenous osteomyelitis.
• Until effective prediction models can be established, it is
imperative that CA-MRSA osteomyelitis be detected early
and treated adequately to prevent chronic infection and
permanent sequelae.
Suggested Readings
McMullen BJ, Andresen D, Blyth CC, et al; ANZPID-ASAP Group.
Antibiotic duration and timing of the switch from intravenous
to oral route for bacterial infections in children: systematic
review and guidelines. Lancet Infect Dis. 2016; 16(8):e139-e152
Peltola H, Pääkkönen M. Acute osteomyelitis in children. N Engl J Med.
2014;370(4):352–360
Peltola H, Pääkkönen M, Kallio P, Kallio MJ; Osteomyelitis-Septic
Arthritis Study Group. Short- versus long-term antimicrobial
treatment for acute hematogenous osteomyelitis of childhood:
prospective, randomized trial on 131 culture-positive cases. Pediatr
Infect Dis J. 2010;29(12):1123–1128
Schweitzer A, Della Beffa C, Akmatov MK, et al. Primary osteomyelitis
of the sternum in the pediatric age group: report of a new case and
comprehensive analysis of seventy-four cases. Pediatr Infect Dis J.
2015;34(4):e92–e101
Scott RJ, Christofersen MR, Robertson WW Jr, Davidson RS, Rankin L,
Drummond DS. Acute osteomyelitis in children: a review of 116
cases. J Pediatr Orthop. 1990;10(5):649–652
Tseng MH, Lin WJ, Teng CS, Wang CC. Primary sternal osteomyelitis
due to community-associated methicillin-resistant Staphylococcus
aureus: case report and literature review. Eur J Pediatr. 2004;163
(11):651–653
Wood JB, Johnson DP. Prolonged intravenous instead of oral antibiotics
for acute hematogenous osteomyelitis in children. J Hosp Med.
2016;11(7):505–508
Yagupsky P, Porsch E, St Geme JW III. Kingella kingae: an
emerging pathogen in young children. Pediatrics. 2011;127
(3):557–565

AUTHOR DISCLOSURE Drs Kaminsky,
Fletcher, and Aprile have disclosed no
financial relationships relevant to this article.
This commentary does not contain a
discussion of an unapproved/investigative
use of a commercial product/device.
438 Pediatrics in Review
Abdominal Pain and Epididymitis in an
3 8-year-old Boy
Lauren W. Kaminsky, MD, PhD,* John P. Fletcher, DO,* Justen M. Aprile, MD*
*The Pennsylvania State University Milton S. Hershey Medical Center and College of
Medicine, Hershey, PA
PRESENTATION
An 8-year-old boy is hospitalized after 5 days of abdominal pain, vomiting,
diarrhea, and poor oral intake. Results of a rapid Strep test are positive, and
he receives intramuscular penicillin. Scrotal pain, swelling, and hematuria
develop, and ultrasonography reveals epididymitis. The epididymitis fails to
improve with antibiotics, and the abdominal pain continues. After 3 days, he is
transferred to a tertiary care hospital. During transfer by ambulance, the patient’s
father notices a new dark purple rash. On admission, the boy has severe episodic
abdominal pain, scrotal pain, and gelatinous bloody stool.
On physical examination, his temperature is 97.9°F (36.6°C), heart rate is 115
beats/min, and blood pressure is 129/90 mm Hg. His abdomen is nondistended,
with tenderness and guarding on palpation. The scrotum is edematous, ery-
thematous, and tender, with bilateral cremasteric reflex. A palpable, non-
blanchable petechial and purpuric rash is present on the upper extremities and
buttocks.
Laboratory results include:
• White blood cell count: 29,730/mL (29.73
109/L)
• Hemoglobin: 15.6 g/dL (156 g/L)
• Platelet count: 421
103/mL (421
109/L)
• Prothrombin time: 15.7 seconds
• International normalized ratio: 1.3
• Partial thromboplastin time: 24 seconds
• C-reactive protein: 1.56 mg/L (1.56 mg/dL)
• Complement component 3 (C3): 112 mg/dL
• Complement component 4 (C4): 20 mg/dL
• Blood urea nitrogen: 9 mg/dL (3.21 mmol/L)
• Serum creatinine: 0.32 mg/dL (28.29 mmol/L)
• Urinalysis:
– Hemoglobin: large
– Protein: 100 mg/dL
– Red blood cell count: 50þ per high-power field
– Protein/creatinine ratio: 1.01
The Case Discussion and Suggested Readings appear with the online version of this
article at http://pedsinreview.aappublications.org/content/38/9/438.
DISCUSSION
Renal ultrasonography yields normal results. Abdominal
ultrasonography shows a probable small bowel intussus-
ception in the left abdomen, prompting consultation with
pediatric surgery. Urology is consulted for epididymitis, and
nephrology is consulted for nephropathy. His initial diag-
nosis was unclear. However, following the development
of the palpable purpuric rash, the combination of the
patient’s age, palpable purpura with a normal platelet count,
abdominal pain, and hematuria pointed to the diagnosis
of Henoch-Schönlein purpura (HSP), meeting both the
American College of Rheumatology and the EULAR/PRINTO/
PRES criteria without the need for confirmational biopsy.
The Condition
HSP is a common systemic vasculitis in children. This
immune-mediated vasculitis is characterized by immuno-
globulin A (IgA) deposition. The cause of HSP is unknown,
but the condition has been noted to follow infections. As in
this case, a minority of patients with HSP test positive for
group A Streptococcus, but there is no evidence of a direct
link. HSP resolves spontaneously in most children, although
relapses can occur.
Differential Diagnosis
Assessment of platelet count and coagulation studies can aid
in differentiating HSP from leukemia, idiopathic thrombo-
cytopenic purpura, and coagulopathies with findings of
purpura and petechiae. Purpuric rash with a normal platelet
count and coagulation study results occurs in other vascu-
litides. In the setting of abdominal pain, appendicitis should
be considered. Hematuria can also be found in IgA ne-
phropathy and poststreptococcal glomerulonephritis. The
differential diagnosis for scrotal pain and swelling includes
testicular torsion, epididymitis, and orchitis.
Clinical Manifestations
Patients with HSP may present with a palpable purpuric
rash, arthritis/arthralgias, abdominal pain, and/or renal
disease. Signs and symptoms can arise over several days but
often develop over weeks to months. The purpuric rash is
frequently distributed symmetrically in pressure-dependent
areas, such as the lower extremities and buttocks. Arthritis
is nondeforming, often transient, and more likely to occur
in the large joints of the lower extremities, although it does
occur in the upper extremities. Gastrointestinal involve-
ment can include nausea, vomiting, abdominal pain, hem-
orrhage, ischemia, and intussusception. Intussusception is
classically associated with HSP, but its presence is rare. In
HSP, most cases of intussusception occur in the small
bowel in contrast to idiopathic cases of intussusception,
which are more likely ileocolic. Nephritis is indicated by
hematuria with or without proteinuria and can result in
hypertension. Renal manifestations resolve in most patients,
however a minority of patients progress to end-stage renal
disease. Scrotal and testicular pain and/or edema may
develop as approximately one-fifth of boys with HSP can
have scrotal involvement. Epididymitis and orchitis should
also be considered. Central nervous system involvement is
rare, but symptoms can include headache, altered mental
status, seizures, and neuropathy.
Diagnosis
HSP is a clinical diagnosis, with biopsy reserved for unusual
presentations. Confirming biopsy shows leukocytoclastic
vasculitis with IgA deposition. Laboratory findings are
nonspecific and may include elevated concentrations of
serum IgA and inflammatory markers with decreased levels
of C3 and C4. In the setting of a purpuric rash, a normal
platelet count and normal coagulation studies should be
confirmed. Urinalysis can be used to assess for renal
involvement.
Management
HSP is often self-limited and resolves spontaneously in
most patients. Management involves supportive care and
monitoring for complications. Acetaminophen or nonste-
roidal anti-inflammatory drugs (NSAIDs) can be considered
for pain management. Glucocorticoids may reduce the
duration of severe abdominal pain and joint pain. However,
because glucocorticoids have not been found to alter the
disease course substantially, either prednisone or methyl-
prednisolone generally is considered if the patient is hos-
pitalized, has poor oral intake, and/or is unable to perform
activities of daily living. Routine use of glucocorticoids is not
recommended due to potential adverse effects, including
the risk of obscuring evidence of complications, such as
intussusception.
Hospitalization should be considered for patients who
are unable to tolerate oral intake, perform activities of daily
living, have severe renal involvement, altered mental status,
abdominal pain, or gastrointestinal bleeding. Vital signs,
urine output, urinalysis, hematocrit, the presence of blood
in stool, and serial abdominal examinations should be
monitored. A nephrologist should be consulted for man-
agement of renal involvement because renal disease can be
progressive in a minority of patients.
Approximately one-third of children with HSP experi-
ence recurrence of symptoms. Because the risk of recurrence
lasts for months after presentation, monitoring for hyper-
tension and renal involvement with blood pressure evalu-
ations and urinalysis should be considered for at least 1 year
from initial presentation. Renal manifestations most com-
monly occur within the first 6 months.
Conclusion
This patient was started on glucocorticoids for severe
abdominal pain. Intussusception did not require surgery.
Because his blood pressure was elevated on multiple eval-
uations, a calcium channel blocker was prescribed. He was
discharged from the hospital following resolution of abdom-
inal symptoms. Follow-up care was planned with nephrol-
ogy and with his pediatrician to monitor blood pressure, a
complete metabolic panel, urinalysis, and urine protein/
creatinine ratio.
The patient experienced recurrence of symptoms. He
was readmitted to the hospital 6 times for complications,
including joint pain, abdominal pain, hematuria, inability to
tolerate oral intake, and ureterolithiasis. For joint pain relief,
he was started on choline salicylate/magnesium salicylate,
an NSAID that has minimal adverse renal effects. The dose
of glucocorticoids was increased due to continued abdom-
inal pain. A stent was placed by urology for an obstructing
ureteral stone. Ureterolithiasis was likely due to dehydration
(there is no evidence supporting a link with HSP). The
recurrence of this patient’s symptoms underscores the
importance of follow-up care. As exemplified in this case,
other etiologies should still be considered in the differential
diagnosis when the patient presents with recurrent symp-
toms. This patient had abdominal pain from both HSP
recurrence and ureterolithiasis.
Additional Resources for Pediatricians
AAP Textbook of Pediatric Care, 2nd Edition
• Chapter 264: Henoch-Schönlein Purpura - https://pediatriccare.solutions.aap.org/chapter.aspx?sectionid=124509885&bookid=1626
Point-of-Care Quick Reference
• Henoch-Schonlein Purpura - https://pediatriccare.solutions.aap.org/content.aspx?gbosid=165520
Parent Resources from the AAP at HealthyChildren.org
• Henoch-Schonlein Purpura: https://www.healthychildren.org/English/health-issues/conditions/skin/Pages/Henoch-Schonlein-
Purpura.aspx
Lessons for the Clinician
• Henoch-Schönlein purpura (HSP) is the most common
systemic vasculitis in children and is a self-limited disease
managed with supportive care and symptomatic treat-
ment. Follow-up care should include blood pressure
evaluations and urinalysis because clinical manifestations
can take weeks to months to develop.
• The diagnosis of HSP is based on clinical manifestations
of purpuric rash, arthritis/arthralgia, abdominal pain,
and renal disease. Confirming biopsy can be performed in
unusual presentations.
• Recurrence of signs and symptoms of HSP is common for
weeks to months after initial presentation.
Suggested Readings
Ha TS, Lee JS. Scrotal involvement in childhood Henoch-Schönlein
purpura. Acta Paediatr. 2007;96(4):552–555
McCarthy HJ, Tizard EJ. Clinical practice: Diagnosis and management
of Henoch-Schönlein purpura. Eur J Pediatr. 2010;169(6):643–650
Park SJ, Suh JS, Lee JH, et al. Advances in our understanding of the
pathogenesis of Henoch-Schönlein purpura and the implications
for improving its diagnosis. Expert Rev Clin Immunol. 2013;
9(12):1223–1238
Piram M, Mahr A. Epidemiology of immunoglobulin A vasculitis
(Henoch-Schönlein): current state of knowledge. Curr Opin
Rheumatol. 2013;25(2):171–178
Saulsbury FT. Henoch-Schönlein purpura in children. Report of 100
patients and review of the literature. Medicine (Baltimore). 1999;
78(6):395–409
Trnka P. Henoch-Schönlein purpura in children. J Paediatr Child Health.
2013;49(12):995–1003
Yang YH, Yu HH, Chiang BL. The diagnosis and classification of
Henoch-Schönlein purpura: an updated review. Autoimmun Rev.
2014;13(4-5):355–358

AUTHOR DISCLOSURE Drs Alsaedi, Kojima,
and Scott-Emuakpor have disclosed no
financial relationships relevant to this article.
This commentary does not contain a
discussion of an unapproved/investigative
use of a commercial product/device.
Suspected Sudden Visual Loss in a 2-year-old
4 Girl
Hani Alsaedi, MD,* Katsuaki Kojima, MD, PhD,* Ajovi Scott-Emuakpor, MD, PhD*
*Departments of Pediatrics and Human Development, College of Human Medicine, Michigan State
University, East Lansing, MI
PRESENTATION
This case concerns a 28-month-old girl with a history of polycythemia,
bronchopulmonary dysplasia, and pulmonary hypertension who was being treated
with sildenafil. She is brought to a community hospital emergency department by
her parents for evaluation of a suspected sudden-onset right-sided visual loss. On
the day of admission, the patient’s parents notice that she is clumsy, as evidenced
by reaching out several inches off to the left of her target. Additionally, she walks
into the infant gate instead of through it. She has no seizurelike activity, weakness,
or facial drooping. She has several episodes of “explosive” diarrhea. This infant
is the product of a pregnancy that was complicated by premature labor, leading
to a premature delivery at 24 weeks’ gestation. She consequently spent several
weeks in the NICU.
At initial presentation, she is afebrile with a heart rate of 139 beats/min, a
respiratory rate of 56 breaths/min, blood pressure of 100/67 mm Hg, and oxygen
saturation greater than 95% in room air. Physical examination reveals a well-
nourished, toxic-appearing girl. Her pupils are equal, round, and reactive to light
bilaterally. Her oral mucosa is dry. Extraocular movement appears intact, although
she is ignoring the right side of her visual field. Strength, sensation, and deep
tendon reflex are intact. She has a normal gait.
Laboratory results reveal a white blood cell count of 11,900/mL (11.9  109/L)
with 60% segmented neutrophils, 28% lymphocytes, and 9% monocytes;
hemoglobin level of 17.6 g/dL (176 g/L); hematocrit concentration of 51.1%;
and platelet count of 172  103/mL (172  109/L). Head computed tomographic
scan is a limited study due to motion artifacts. It does not show intracranial
bleeding.
The Case Discussion and Suggested Readings appear with the online version of this
article at http://pedsinreview.aappublications.org/content/38/9/439.
Vol. 38 No. 9 SEPTEMBER 2017 439
DISCUSSION

Acute vision loss with dehydration in a patient with a history

of polycythemia raised concern for an acute stroke. Normal
saline bolus was given in the emergency department due to
concern for dehydration. Brain magnetic resonance imag-
ing (MRI) revealed left parieto-occipital acute infarct (Figs 1
and 2). She was admitted to the PICU for further manage-
ment. Aspirin treatment was started after brain MRI. She
also received supportive care, including intravenous hydra-
tion. Her visual symptoms improved after hospital admis-
sion. Magnetic resonance angiography (MRA) of the brain
and neck showed no vascular malformations, occlusions, or
stenosis. The results of hypercoagulation evaluation were
normal. Her symptoms lasted for 48 to 72 hours and sub-
sequently seemed to have subjectively resolved, although
formal visual field testing could not be conducted given her
age. She was discharged from the hospital on day 5 of
admission.

The Condition
Arterial ischemic stroke (AIS) is a sudden brain dysfunction
caused by decreased cerebral blood supply. It can occur in Figure 2. Brain magnetic resonance image (apparent diffusion
any stage of life, but its characteristics, including presen- coefficient map) showing left parieto-occipital acute infarct.
tation, pathophysiology, and prognosis, vary depending on

the age at onset. For example, atherosclerosis is the most

important mechanism and prevention target of adult stroke,
which rarely exists in pediatric stroke. There are a few case
reports suggestive of an association between sildenafil use
and the development of stroke in the adult population. In
contrast, risk factors for pediatric AIS are sickle cell disease,
cardiac disorders, arteriopathies, trauma, infection, and hy-
percoagulable states. However, in many pediatric stroke
patients, the underlying etiology remains unclear even after
an extensive evaluation. The incidence of pediatric stroke is
estimated to be 1 to 6 per 100,000 children each year.
Pediatric stroke is a significant cause of a lifelong dis-
ability. Affected patients may experience neurologic deficits
for many years. It is also associated with significant acute
and chronic health care costs. However, pediatric stroke
remains underrecognized by caregivers and health care pro-
viders due to subtle and nonspecific presentation as well as
a wide range of differential diagnosis.

Figure 1. Brain diffusion-weighted magnetic resonance image showing
left parieto-occipital acute infarct.
Diagnosis
Acute onset of neurologic abnormality in patients with risk
factors needs to be recognized as stroke until proven other-
wise. Median time between symptom onset and radiologic
diagnosis of pediatric stroke is reported to be 25 hours.
Computed tomography is frequently performed emergently
to rule out hemorrhagic stroke, mass effect, or large estab-
lished infarction. Diffusion-weighted MRI is the gold stan-
dard and can identify small and early infarction in infants
and children. Differential diagnosis of stroke includes
complicated migraine, prolonged postictal paresis, tumors,
intracranial infection, demyelinating conditions, and psy-
chogenic conditions.
Once a diagnosis of stroke is established, evaluation to
investigate underlying etiology should be considered, includ-
ing MRA of the head and neck, cardiologic evaluation such as
electrocardiography and echocardiography, prothrombotic
evaluation, and hemoglobin electrophoresis, depending on
clinical presentation.
Management
Guidelines regarding treatment of pediatric stroke are
largely based on adult data due to lack of randomized
controlled trials in the pediatric population. Emergency
thrombolysis for children is not recommended outside of
research because effectiveness, safety, and dose have not
been established. After excluding hemorrhagic stroke, an-
tithrombotic therapy should be started for pediatric AIS to
prevent secondary stroke. Anticoagulation therapy may be
recommended depending on the etiology, but safety and
efficacy data in children are limited.
Patients with AIS should receive supportive care to
minimize ischemic brain injury. Blood glucose, tempera-
ture, and blood pressure should be optimized. Seizures
should be controlled to prevent secondary brain damage.
Additional Resources for Pediatricians
AAP Textbook of Pediatric Care, 2nd Edition
• Chapter 103: The Newborn With Hematologic Abnormalities - https://pediatriccare.solutions.aap.org/chapter.aspx?
sectionid=107789585&bookid=1626
Parent Resources from the AAP at HealthyChildren.org
• Warning Signs of Vision Problems in Infants & Children: https://www.healthychildren.org/English/health-issues/conditions/eyes/Pages/
Warning-Signs-of-Vison-Problems-in-Children.aspx
For a comprehensive library of AAP parent handouts, please go to the Pediatric Patient Education site at http://patiented.aap.org.
Rehabilitation for survivors of pediatric stroke is important
due to the plasticity of the brain in this population. Reha-
bilitation targets motor, language, and intellectual damage
and is expected to improve the quality of life as well as the
emotional health of both the child and the family.
Lessons for the Clinician
• Acute onset of neurologic abnormality in patients with
risk factors needs to be recognized as stroke until proven
otherwise.
• Brain diffusion-weighted magnetic resonance imaging is
the gold standard for the diagnosis of arterial ischemic
stroke.
• Antithrombotic therapy should be started after excluding
hemorrhagic stroke.
Suggested Readings
Monagle P, Chan AK, Goldenberg NA, et al. Antithrombotic therapy in
neonates and children: Antithrombotic Therapy and Prevention of
Thrombosis, 9th ed: American College of Chest Physicians
Evidence-Based Clinical Practice Guidelines. Chest. 2012;
141(2)(suppl):e737S–e801S
Roach ES, Golomb MR, Adams R, et al; American Heart Association
Stroke Council; Council on Cardiovascular Disease in the Young.
Management of stroke in infants and children: a scientific
statement from a Special Writing Group of the American Heart
Association Stroke Council and the Council on Cardiovascular
Disease in the Young. Stroke. 2008;39(9):2644–2691
Rosa M, De Lucia S, Rinaldi VE, et al. Paediatric arterial ischemic stroke:
acute management, recent advances and remaining issues. Ital J
Pediatr. 2015;41:95

AUTHOR DISCLOSURE Drs Zhou and Cu have
disclosed no financial relationships relevant to
this article. Dr Hertel has disclosed that she is
co-investigator on a U01 National Institutes of
Health grant and is site principal investigator
for a Lumena/Shire Pharmaceuticals trial
unrelated to this article topic. This
commentary does not contain a discussion
of an unapproved/investigative use of a
commercial product/device.
440 Pediatrics in Review
Large Amounts of Urine Bilirubin on Urine
5 Dipstick in a 14-year-old Girl
Yin Zhou, MD,* Paula Hertel, MD,* Jennifer Cu, MD*
*Texas Children’s Hospital, Houston, TX
PRESENTATION
A 14-year-old girl is referred to a liver clinic by her primary care physician (PCP)
for large amounts of urine bilirubin on repeated urine dipstick analysis. She
notes very mild abdominal pain that occurs occasionally after meals. She denies
jaundice, bleeding, easy bruising, vomiting, diarrhea, or fevers. She visited her
PCP in the previous month for labial cyst and urinary tract infection and was
treated with cephalexin. Her urine dipstick at that time and during a sub-
sequent visit showed large amounts of bilirubin. She uses amphetamine/
dextroamphetamine salts and a methylphenidate patch for attention-deficit/
hyperactivity disorder. She also takes etodolac (a nonsteroidal anti-inflammatory
drug [NSAID]) for tendonitis and a vitamin B supplement.
On physical examination, she appears comfortable. Her blood pressure is
102/66 mm Hg, her pulse is 93 beats/min, and she is afebrile. Her sclerae are
anicteric. Her abdomen is not tender, and there is no hepatomegaly. Her skin is
not jaundiced. Other findings on physical examination are completely normal.
The evaluation performed by her PCP showed alanine aminotransfer-
ase, 18 IU/L (0.30 mkat/L); aspartate aminotransferase, 24 IU/L (0.40 mkat/
L); g-glutamyltransferase, 8 IU/L (0.13 mkat/L); direct bilirubin, 0.2 mg/dL
(3.42 mmol/L); and indirect bilirubin, 0.4 mg/dL (6.84 mmol/L). Her complete
blood cell count was also normal. Abdominal ultrasonography showed normal
liver, biliary tree, spleen, and pancreas. Repeated urine dipstick studies contin-
ued to show large amounts of bilirubin.
The Case Discussion, References, and Suggested Reading appear with the online version
of this article at http://pedsinreview.aappublications.org/content/38/9/440.
DISCUSSION
This patient did not have evidence of hepatocellular
disease or hemolysis, and she never had elevated se-
rum bilirubin levels. Therefore, the presence of large
amounts of bilirubin in urine on urine dipstick was
quite puzzling. During a quick literature search regarding
substances producing false-positive bilirubin in urine on
urine dipstick, we came across a similar case, in an older
adult, with positive urine bilirubin when serum bilirubin
levels were normal that was attributed to etodolac, an
NSAID. (1) Our patient was also taking etodolac for ten-
donitis. After a discussion with her orthopedic surgeon,
etodolac use was discontinued, and a repeated urine dip-
stick test performed subsequently was negative for
bilirubin.
Differential Diagnosis
Direct hyperbilirubinemia has many causes. To understand
the pathologic conditions resulting in hyperbilirubinemia,
it is important to understand the physiology of bilirubin
production and excretion. Bilirubin is a product of heme
catabolism during red blood cell breakdown that occurs
in the reticuloendothelial system. Unconjugated biliru-
bin is carried by albumin in the plasma to hepatocytes
and is conjugated with glucuronic acid by the enzyme glucu-
ronyl transferase in the liver, and then is excreted through
the bile ducts into the duodenum. In the intestine, bacterial
b-glucuronidase deconjugates the conjugated bilirubin into
urobilinogen and urobilin. The bulk of urobilinogen and
urobilin is excreted in the stool, which gives stool its color.
Small amounts of urobilinogen are reabsorbed and circulate
back to the liver or are excreted in the urine. Hence, urine
normally contains urobilinogen but not conjugated bili-
rubin. Therefore, conjugated bilirubin, which is normally
not found in urine, signifies cholestasis when found on
urine dipstick study. Our patient had normal urobilinogen
on dipstick, which means that she did not have hemolysis
or increased turnover of bilirubin in the enterohepatic
circulation.
The etiologies of cholestasis, reflected by conjugated
hyperbilirubinemia, include conditions causing extrahe-
patic biliary obstruction, such as choledochal cyst or gall-
stones blocking the common bile duct; conditions causing
intrahepatic cholestasis, such as Alagille syndrome, pro-
gressive familial intrahepatic cholestasis, oral contracep-
tive use, and congenital conditions such as Dubin-Johnson
syndrome or Rotor syndrome. In the neonate, serious
conditions such as biliary atresia, Alagille syndrome, cystic
fibrosis, and inborn errors of metabolism also have to be
ruled out as causes for conjugated hyperbilirubinemia.
Our patient never had elevated direct bilirubin levels on
any liver function tests, and her abdominal ultrasonogra-
phy findings were normal. Therefore, cholestasis could be
ruled out.
Another cause of conjugated hyperbilirubinemia is end-
stage liver disease caused by hepatocellular conditions
such as viral hepatitis, autoimmune hepatitis, Wilson
disease, hemochromatosis, and a1-antitrypsin deficiency.
Hepatocellular injury is usually initially detected in the
form of elevated liver enzyme levels, and, in the late
stages, elevated prothrombin time and low albumin levels.
Cirrhosis also leads to portal hypertension, which can
present with splenomegaly, thrombocytopenia, ascites,
and/or varices. This patient did not have any stigmata
of chronic liver disease on physical examination or labo-
ratory evaluations. After eliminating hepatocellular injury
and cholestasis, the only option left was a false-positive
bilirubin finding in the urine. This was determined to be
the most likely explanation for positive bilirubin on urine
dipstick after a negative test result when the drug was
discontinued.
The Mechanism for a False-Positive Result
Urinalysis by dipstick is a quick and efficient tool used in the
office setting to check urine for pH, specific gravity, protein,
glucose, ketones, bilirubin, urobilinogen, nitrite, and leu-
kocyte esterase. Bilirubin is detected by the diazo method,
which involves a reaction between bilirubin and a diazo-
nium salt found on the dipstick, forming a compound called
azobilirubin, which gives a distinct color. Etodolac is an
NSAID that has been shown in previous reports to give
positive results for bilirubin measured by the diazo method.
(2)(3) In these studies, urinary metabolites of etodolac were
extracted and purified using high-performance liquid chro-
matography, (2) and the metabolites were incubated with the
diazo reagent, which gave positive results for bilirubin. The
2 specific metabolites of etodolac are 6- and 7-hydroxylated
etodolac, and the hydroxyl group is essential for the false-
positive reaction because the metabolite without the
hydroxyl group gives a negative reaction. (2) Another sub-
stance that gives false-positive urine bilirubin on dipstick
testing is the investigational antifibrotic agent lufironil
(HOE 077). (1)
Lessons for the Clinician
• Positive urine bilirubin on dipstick without serum hy-
perbilirubinemia should prompt a search for medica-
tions that may give false-positive results on urine dipstick
testing.
• Etodolac produces urinary metabolites that react with
reagent on the dipstick to give false-positive results for
bilirubin on urine dipstick study.
References
1. Mehta P, Lukacs M, Abraham SM. Normal in the blood, abnormal in
the urine. Q JM. 2012;105(10):1001–1002
2. Ferdinandi ES, Sehgal SN, Demerson CA, et al. Disposition and bio-
transformation of 14C-etodolac in man. Xenobiotica. 1986;16(2):153–166
3. Sho Y, Ishiodori T, Oketani M, et al. Effects of urinary
metabolites of etodolac on diagnostic tests of bilirubin in urine.
Arzneimittelforschung. 1999;49(7):572–576
Suggested Reading
Baader E, Bickel M, Damm D, et al. Interference in clinical laboratory
tests, with special regard to the bilirubin assay: effects of a
metabolite of the new prolyl 4-hydroxylase inhibitor, Lufironil. Eur J
Clin Chem Clin Biochem. 1994;32(7):515–520

AUTHOR DISCLOSURE Drs Almeida, Lopes,
Figueiredo, Oliveira, Sousa, and Sequeira have
disclosed no financial relationships relevant to
this article. This commentary does not contain
a discussion of an unapproved/investigative
use of a commercial product/device.
Figure. Skin hyperpigmentation on the extensor surfaces of the fingers.
Dehydration and Electrolyte Abnormalities in
6 an 11-year-old Boy
Filipa Almeida, MD,* Susana Lopes, MD,* Margarida Figueiredo, MD,*
Filipe Oliveira, MD,* Susana Sousa, MD,* Alexandra Sequeira, MD*
*Pediatric Department, Centro Hospitalar Médio Ave, Vila Nova de Famalicão, Portugal
PRESENTATION
A previously healthy 11-year-old white boy presents to the emergency department
with a 3-day history of nausea, anorexia, weakness, abdominal pain, and an ep-
isode of vomiting. He has no history of fever, diarrhea, constipation, respiratory or
urinary symptoms, or use of laxatives or diuretics.
Physical examination reveals a thinly built boy with signs of dehydration
(sunken eyes and slightly dry mucous membranes) and generalized skin hyper-
pigmentation, especially noticed on the extensor surfaces of the fingers of both
hands (Fig). He is afebrile, with capillary refill time of less than 2 seconds, blood
pressure of 94/68 mm Hg, and a heart rate of 116 beats/min. His weight is 32 kg
Vol. 38 No. 9 SEPTEMBER 2017 441
 (70.5 lb) (weight loss of 6% in the previous 3 days). Findings
on the rest of the physical examination are normal.
Initial laboratory evaluation reveals the following values:
sodium, 118 mEq/L (118 mmol/L) (reference range, 136–145
mEq/L [136–145 mmol/L]); potassium, 6.1 mEq/L (6.1 mmol/L)
(reference range, 3.5–5.1 mEq/L [3.5–5.1 mmol/L]); chloride,
92 mEq/L (92 mmol/L) (reference range, 101–111 mEq/L
[101–111 mmol/L]); blood urea nitrogen, 109 mg/dL (38.9
mmol/L) (reference range, 0–48 mg/dL [0–17.1 mmol/L]);
and serum creatinine, 0.81 mg/dL (71.6 mmol/L) (refer-
ence range, 0.1–1.0 mg/dL [8.8–88.4 mmol/L]). He has
mild metabolic acidosis (pH 7.33; bicarbonate, 18 mEq/L
[18 mmol/L]), and he is normoglycemic (glucose, 94 mg/
dL [5.22 mmol/L]). His complete blood cell count and liver
enzyme, uric acid, lactate dehydrogenase, and C-reactive
protein levels are within normal limits. Results of urine
drug screen also are negative.
He is diagnosed as having hyponatremic dehydration and
is given an intravenous bolus of 20 mL/kg of isotonic (0.9%)
sodium chloride solution. He is hospitalized for monitoring
and further evaluation. Right after hospitalization, he develops
hypotension and is administered another bolus of normal
saline solution. His blood pressure does not improve, and he
is, therefore, started on inotropic support with dopamine.
Additional laboratory evaluation reveals the cause of fluid-
resistant hypotension and abnormal laboratory results.
The Case Discussion and Suggested Readings appear with the online
version of this article at http://pedsinreview.aappublications.org/
content/38/9/441.

CME Quiz Correction

Several Pediatrics in Review readers raised questions about the CME quiz for “Environmental Risks to Children:
Prioritizing Health Messages in Pediatric Practice” (Galvez MP, Balk SJ. Pediatrics in Review. 2017;38(6):263–279, DOI:
10.1542/pir.2015-0165). As a result, the journal has changed the preferred response for Question 4 to “D” and for
Question 5 to “E.” The journal regrets the errors.

442 Pediatrics in Review

DISCUSSION
In the presence of hypotension unresponsive to initial resus-
citation efforts and abnormal electrolyte values, the diagnosis
of acute adrenal insufficiency was considered. An early-
morning blood sample was collected for hormonal study,
and the patient was treated with intravenous hydrocortisone
(70 mg/m2). Clinical improvement was noticed. An abdom-
inal computed tomographic scan revealed no abnormali-
ties in the adrenal glands. The measurement of a plasma
corticotropin (ACTH) level greater than 1,250 pg/mL (275
pmol/L) (reference range, 9–52 pg/mL [2–11 pmol/L]) and a
serum cortisol level of 1 mg/dL (28 nmol/L) (reference
range, 3–21 mg/dL [83–579 nmol/L]) confirmed the diagnosis
of primary adrenal insufficiency (PAI). His aldosterone level,
although within normal limits (2.1 ng/dL [58.3 pmol/L]; ref-
erence range, 2–22 ng/dL [55.5–610.3 pmol/L]) was low for
the degree of hyperreninemia (plasma renin activity, 8.36
ng/mL per hour; reference range, 0.15–2.33 ng/mL per
hour; and renin level >500 mU/mL; reference range, 2.8–
40 mU/mL), confirming mineralocorticoid deficiency. Adre-
nal antibodies were detected (1/160; reference range, <1/10),
confirming an autoimmune etiology (Addison disease).
Other causes of PAI, such as infections with M tuberculosis,
cytomegalovirus, Epstein-Barr virus, and human immuno-
deficiency virus (HIV), were excluded. Results of the
investigation for other autoimmune diseases were nega-
tive: calcium, phosphorus, and parathyroid hormone levels
were normal; thyroid function was normal, and thyroid
peroxidase and thyroglobulin antibodies were negative; anti-
tissue transglutaminase immunoglobulin A antibodies spe-
cific for celiac disease were also negative.
The Condition
Addison disease, also known as PAI, is an uncommon disease
in children, with an incidence of approximately 0.8 in 100,000
general population. Addison disease results from impaired
synthesis and release of adrenocortical hormones (glucocor-
ticoids and/or mineralocorticoids) despite elevated levels of
corticotropin. It can be a consequence of the impaired function
of the adrenal cortex due to abnormal adrenal development
(adrenal hypoplasia congenita), steroidogenesis disorders
(congenital adrenal hyperplasia), or adrenal destruction. The
adrenal destruction of the adrenal cortex can be caused by
autoimmune process, infections, infiltrative or metastatic
diseases, hemorrhage of the adrenal gland, metabolic disor-
ders, or the effects of drugs. Autoimmune destruction is the
most common cause of Addison disease in children and can
occur as an isolated condition or as a component of autoim-
mune polyglandular syndromes (APSs): APS type 1 consists
of the triad of hypoparathyroidism, chronic mucocutaneous
candidiasis, and Addison disease, and APS type 2 is defined
by Addison disease, thyroiditis, and type 1 diabetes.
Clinical presentation is variable and can be insidious.
Symptoms often are nonspecific and include loss of appetite,
generalized weakness, nausea, abdominal pain, vomiting,
weight loss, and salt craving. These symptoms can be easily
confused with a viral gastroenteritis or a psychiatric disorder,
especially depression, and, thus, results in delay in the
diagnosis. Classic clinical signs include weight loss, ortho-
static hypotension, hyperpigmentation, and shock. The skin
and mucosal hyperpigmentation is a classic finding and
results from increased secretion of melanocyte stimula-
tion hormone (MSH). The pituitary secretes large quan-
tities of corticotropin in response to low cortisol level.
Pro-opiomelanocortin is a precursor for both corticotro-
pin and MSH. Thus, when corticotropin production
increases, there is increased production of MSH as well.
Classic biochemical abnormalities of Addison disease
include hyponatremia, hyperkalemia, hypoglycemia, and
metabolic acidosis. Acute presentation of Addison disease
is a true medical emergency, and the outcome can be fatal
if not promptly recognized and treated.
Diagnosis
Diagnosis of Addison disease requires a high degree of sus-
picion, and definitive diagnosis is based on checking hormonal
levels.
The initial screening for adrenal insufficiency should
include the measurement of electrolytes, early morning
cortisol, corticotropin, renin or plasma renin activity, and
aldosterone. Diagnosis of PAI is confirmed by an elevated
plasma corticotropin concentration (frequently >100 pg/mL
[22 pmol/L]) in the presence of a low serum cortisol con-
centration (usually <10 mg/dL [276 nmol/L]). When the
diagnosis is in doubt, a stimulation test with synthetic
corticotropin should be performed, and in patients with
PAI there will not be an increase in the cortisol level. Min-
eralocorticoid deficiency is confirmed in the face of a rela-
tively low aldosterone value despite hyperreninemia.
If PAI is diagnosed, further evaluation should be per-
formed to determine the underlying cause. Antibodies should
be checked to evaluate for autoimmune PAI. If adrenal
antibodies are positive, the patient should be screened for
autoimmune polyglandular syndromes by measuring serum
calcium, phosphorus, parathyroid hormone level, and anti-
bodies against thyroid and islet cells. In addition, screening
for other autoimmune disorders, such as celiac disease and
autoimmune atrophic gastritis, should be performed. If
autoimmune evaluation is negative, then other causes of
PAI, such as infections (tuberculosis, HIV, cytomegalovirus,
candidiasis), infiltrative diseases (hemochromatosis, pri-
mary amyloidosis), adrenal hemorrhage (associated with
sepsis, anticoagulants), and adrenal metastases or tumors
should be looked for. A computed tomographic scan of the
adrenals may be useful in these cases. Males with negative
antibodies should be screened for adrenoleukodystrophy by
measuring very-long-chain fatty acids. In early infancy, the
most common cause of PAI is congenital adrenal hyperpla-
sia, and 17-OH-progesterone should be measured (a value
greater than 1,000 ng/dL is diagnostic for 21-hydroxylase
deficiency, the most common cause of congenital adrenal
hyperplasia).
Treatment
Primary adrenal insufficiency in its acute presentation
(adrenal crisis) is a life-threatening condition. Even when
the diagnosis is uncertain, the treatment should be initiated.
Management of acute adrenal insufficiency involves initial
fluid resuscitation with a 20-mL/kg bolus of normal saline
(repeated bolus may be required) and the administration of
intravenous stress doses of hydrocortisone (50–100/m2) as
early as possible. Electrolyte abnormalities and hypoglyce-
mia need to be corrected appropriately.
Long-term treatment of Addison disease consists of
exogenous corticosteroid replacement. The preferred glu-
cocorticoid replacement is oral hydrocortisone (the current
recommendation for a total starting daily dose of hydro-
cortisone in children is 8 mg/m2 divided into 3 or 4 doses),
and mineralocorticoid replacement is performed with
fludrocortisone at a dose of 0.1 to 0.2 mg/day.
The aim of the treatment in children is to control the
symptoms of adrenal insufficiency with a dose that allows
adequate growth and pubertal development. The current
guidelines suggest monitoring adequacy of glucocorticoid
replacement by clinical assessment by checking growth
velocity, body weight, blood pressure, and energy level.
Patients with adrenal insufficiency are recommended to
wear medic-alert jewelry (either bracelet or necklace). They
are also provided an “emergency letter” that they are rec-
ommended to always carry with them because it details
management of their condition in situations of physical
stress or illness.
Patient Course
After intravenous hydrocortisone therapy, our patient was
started on oral fludrocortisone therapy. He responded well
to this therapy, with normalization of serum electrolyte levels.
He is being followed by a pediatric endocrinologist. There was
a progressive decrease of skin hyperpigmentation, with full
resolution after 4 months and a decrease of plasma cortico-
tropin levels (203 pg/mL [45 pmol/L]; reference range, 9–52
pg/mL [2–11 pmol/L]). The plasma renin activity and renin
levels also normalized. Approximately 10 months later, adrenal
antibody titers had decreased (1/40; reference range, <1/10).
Currently, with 3 years of follow-up, this patient main-
tains normal growth and pubertal development and has not
developed any other autoimmune diseases.
Lessons for the Clinician
• If a patient has symptoms of asthenia, signs of dehydra-
tion disproportionate to estimated losses, and hyperpig-
mentation of skin, the index of suspicion for adrenal
insufficiency should be high, even in the absence of
the characteristic electrolyte abnormalities.
• Any patient with hypotension or shock unresponsive to
initial resuscitation efforts and/or an abnormal electro-
lyte profile (hyponatremia, hyperkalemia, hypoglycemia,
or metabolic acidosis) should be considered to have ad-
renal insufficiency until proved otherwise.
• Follow-up of adrenal insufficiency is required not only
for monitoring response to therapy and treatment adher-
ence but also for monitoring for development of other
autoimmune disorders.
Suggested Readings
Antal Z, Zhou P. Addison disease. Pediatr Rev. 2009;30(12):491–493
Auron M, Raissouni N. Adrenal insufficiency. Pediatr Rev. 2015;36(3):92–102,
quiz 103, 129
Bornstein SR, Allolio B, Arlt W, et al. Diagnosis and treatment of
primary adrenal insufficiency: an Endocrine Society clinical
practice guideline. J Clin Endocrinol Metab. 2016;101(2):364–389
Oelkers W. Adrenal insufficiency. N Engl J Med. 1996;335(16):1206–1212

Human Papillomavirus and HPV Vaccines
Allison Eliscu, MD*
*Stony Brook Children’s Hospital, Stony Brook, NY
AUTHOR DISCLOSURE Dr Eliscu has
disclosed no financial relationships relevant to
this article. This commentary does not contain
a discussion of an unapproved/investigative
use of a commercial product/device.
Human Papillomavirus. American Academy
of Pediatrics. In: Kimberlin DW, Brady MT,
Jackson MA, Long SS, eds. Red Book 2015
Report of the Committee on Infectious Diseases.
30th ed. Elk Grove Village, IL: American
Academy of Pediatrics; 2015:576–583
Sexually Transmitted Diseases Treatment
Guidelines, 2015. Workowski KA, Bolan GA;
Centers for Disease Control and Prevention.
MMWR Recomm Rep. 2015;64(RR-3):1–137.
Erratum in MMWR Recomm Rep. 2015;
64(33):924
Human Papillomavirus Vaccination:
Recommendations of the Advisory
Committee on Immunization Practices
(ACIP). Markowitz LE, Dunne EF, Saraiya
M, et al. MMWR Recomm Rep. 2014;63
(RR-05):1–30
Human Papillomavirus: Know the Facts.
Centers for Disease Control and Prevention;
2017. Available at: http://www.cdc.gov/hpv/
hcp/know-facts.html. Accessed January
26, 2016
A 9-Valent HPV Vaccine Against Infection
and Intraepithelial Neoplasia in Women.
Joura EA, Giuliano AR, Iversen OE, et al. N
Engl J Med. 2015;372(8):711–723
in
Brief
Human papillomavirus (HPV) is the most common sexually transmitted infec-
tion in the United States, with more than 14 million new cases each year. Most
infections are subclinical and undiagnosed, so the exact prevalence is unknown.
However, it has been suggested that almost all sexually active individuals acquire
HPV at some point during their lifetimes. Factors that increase an individual’s
risk of becoming infected with HPV include age younger than 25 years, sexual
debut before 16 years of age, having multiple sexual partners, and having a partner
who has had multiple partners. More than 120 strains of HPV have been identified,
more than 40 of which are sexually transmitted and can infect the genital re-
gions. HPV strains are divided into oncogenic (high-risk) types and nononcogenic
(low-risk) types based on their potential to cause cancer.
Infection with high-risk or oncogenic types (most commonly types 16 and 18)
may lead to cellular changes of the cervix, which can be detected on Papanicolaou
smear. These cellular changes are asymptomatic and usually self-resolve, espe-
cially among healthy adolescent females. In a study of 187 adolescent females with
low-grade squamous intraepithelial lesions on Papanicolaou smear, the median
time to complete resolution of the lesions was 8 months, and only 3% of the study
participants progressed to a high-grade squamous intraepithelial lesion. Fur-
thermore, a high percentage of high-grade lesions also self-resolve in this age
group, with very few females younger than age 21 years progressing to cervical
cancer (0.15 per 100,000 females). Because most HPV-induced cellular changes
are transient and rates of cervical cancer in this population are low, initial
Papanicolaou smear testing is not recommended before age 21 years. Delaying
the initial Papanicolaou smear to age 21 years reduces the chance of detecting an
abnormality that would likely self-resolve with no clinical consequence but may
lead to unnecessary, costly, and anxiety-provoking diagnostic or therapeutic
procedures.
Infections with low-risk HPV subtypes (most commonly types 6 and 11) have
the potential to cause genital warts, also known as condylomata acuminata.
Condylomata are usually flesh-colored cauliflower-like genital lesions, although
they may also appear flat, smooth, thorny, or hyperpigmented. Genital warts are
most commonly detected on the external genitals (penis, scrotum, and perianal
area in males; vulva, perineum, and perianal area in females) and less commonly
in the urethral meatus, vagina, or cervix. Warts tend to be asymptomatic but
occasionally may cause mild itching or irritation. Additional symptoms may
develop, depending on the size and location of the warts. For example, warts
located within the urethral meatus may cause dysuria or hematuria, vaginal
warts may cause irregular vaginal bleeding, and perianal warts may cause
hematochezia or pain with defecation.
Genital warts are primarily diagnosed by clinical inspection and must be
differentiated from similar-appearing normal variants, such as pearly penile
Vol. 38 No. 9 SEPTEMBER 2017 443
 TABLE. Treatment Options for Genital Warts
CATEGORY TREATMENT
Patient Applied Imiquimod 5% (or 3.75%*)
cream
Podofilox 0.5% solution or gel
Sinecatechins 15% ointment
(green tea extract)
Clinician Applied Cryotherapy (liquid nitrogen)
Trichloroacetic acid or
bichloracetic acid 80%-90%
solution
papules (asymptomatic flesh-colored papules in rows along
the corona of the penis) and vestibular papillae (pink
frond-like papules symmetrically lined along a female’s
vestibule). Warts should also be differentiated from mol-
luscum contagiosum (small, firm, clustered viral lesions
with a central umbilication) and condylomata lata (a sequela
of secondary syphilis that appears flatter, smoother, and
moister than warts).
Application of 5% acetic acid to a wart produces a whit-
ening appearance, but routine use is not recommended to
make a definitive diagnosis because many other common
conditions, such as candidiasis and herpes, can also produce
a positive result. Biopsy of typical lesions is not necessary,
although biopsies of atypical-appearing lesions or those not
responding to therapy may be performed to rule out malignancy.
HPV DNA testing for genital warts is also not recommended.
Multiple treatment options are available for genital warts,
primarily to remove symptomatic lesions or those causing
cosmetic concerns. Genital warts may regress spontane-
ously, so patients with asymptomatic lesions may opt to
delay treatment. Furthermore, treatment does not erad-
icate the underlying virus, and it is not known if viral
transmission is diminished by treatment. Warts generally
improve within 3 months of treatment, although they fre-
quently recur within a few months. Treatment modalities
are separated into patient-applied and clinician-applied
methods (Table). Because no specific treatment has been
shown to be most effective, the choice of method should
be based on the clinician’s experience, cost of treatment,
and number and location of warts.
444 Pediatrics in Review
USE ADVERSE EFFECTS
Apply at bedtime 3/week Skin irritation, vesicles,
(*or every night), wash off in hypopigmentation,
morning; use up to 16 weeks may weaken condom
Apply twice daily for 3 days, no Pain or irritation
therapy for 4 days; may repeat
up to 4 weeks
Apply 0.5 cm ointment strand Skin erythema, itching,
3/day, do not wash off; use burning, rash, pain
up to 16 weeks
Must be trained appropriately Pain, necrosis, blistering
Apply small amount to wart, allow Pain, irritation
to dry, will see white frost on
tissue; repeat weekly if
necessary
The only vaccine approved by the Food and Drug Admin-
istration and available in the United States is the 9-valent
vaccine. This vaccine is approved for use in both males and
females and protects against the nononcogenic HPV strains
6 and 11 (responsible for approximately 90% of genital
warts) and 7 oncogenic strains including strains 16 and
18 (responsible for approximately 70% of cervical cancers).
The 9-valent vaccine has replaced the bivalent vaccine
(which protected against strains 6 and 11) and the quadri-
valent vaccine (which protected against strains 6, 11, 16, and
18), both of which have been discontinued in favor of the
newer 9-valent vaccine. The American Academy of Pediat-
rics and the Advisory Committee on Immunization Prac-
tices (ACIP) recommend vaccination against HPV for all
adolescent females and males at age 11 to 12 years. All
unvaccinated females (age 13 to 26 years) and males (age
13 to 21 years) and immunocompromised or high-risk males
(such as men sexually active with men) age 21 to 26 years
should also be vaccinated, as should unvaccinated adoles-
cents who have genital warts or abnormal cervical changes.
The Centers for Disease Control and Prevention’s ACIP has
recently recommended that individuals initiating the vaccine
series at 9 through 14 years of age should receive only 2 doses,
administered 6 to 12 months apart. Older patients receiving
the initial HPV vaccine after 15 years of age should continue
to receive the 3-dose series on a 0, 1 to 2 months, and 6 months
schedule. Vaccination series do not need to be restarted if
patients are late for the second or third doses, and patients who
have received 3 doses of the bivalent or quadrivalent vaccine
do not require extra doses of the newer 9-valent vaccine.
 The HPV vaccines have been shown to be effective in
preventing more than 95% of precancerous cervical changes
from types 16 and 18, more than 90% of genital warts in
males and females, and more than 96% of precancerous
cervical changes from the 5 additional oncogenic types
covered by the 9-valent vaccine. In addition, the HPV
vaccine is safe and well tolerated, with a safety profile
similar to those of other routine vaccines. The most
common adverse effects are pain, edema, and erythema
at the injection site. Adolescents may occasionally develop
dizziness or syncope following an injection, so they should
be observed for 15 minutes following vaccination.
Rates of HPV vaccination among adolescents in the
United States remain low for several reasons: lack of knowl-
edge about the vaccine, less-than-strenuous recommenda-
tions by clinicians, parental perception that the vaccine is
not necessary, and discomfort about vaccinating preteens
against a sexually transmitted infection. Clinicians should
counsel patients and parents that the vaccine is most effec-
tive when administered at a younger age and before patients
have become sexually active. They should stress that the
vaccines are very safe and effective in preventing cancer and
that receiving the vaccine does not influence an adolescent’s
decision to initiate sexual activity.
COMMENT: A vaccine to prevent cancer is something of a
medical holy grail, and the pity is that this one really works
(even better than originally predicted) and we’re not close to
taking full advantage. By 2012, 6 years after its introduction,
the quadrivalent HPV vaccine had reduced the prevalence of
its 4 covered strains of virus among girls ages 14 to 19 years
by nearly two-thirds. Yet fewer than 50% of adolescent girls
and only about 20% of teenage boys in the United States
have received a full course of the vaccine. Further, only 2
states, Rhode Island and Virginia, as well as Washington
DC, require it. Although the vaccine has primarily been
promoted for its role in preventing cervical cancer, which
currently kills more than 4,000 women each year, HPV can
also cause anal, penile, and oropharyngeal cancers, provid-
ing the rationale for immunizing boys along with girls. Another
rationale is that, as with all vaccines, the larger the immunized
population, the smaller the pool of virus in the community. We
have an effective tool at hand, and other countries are using it far
more efficiently than we. Australia has an immunization rate
greater than 70% among teenage girls, and Rwanda has a rate
greater than 90%. Overcoming unreasonable resistance to the
HPV vaccine is well worth the effort.
– Henry M. Adam, MD
Associate Editor, In Brief

Retractions

1. NOTICE OF RETRACTION: Visual Diagnosis: 7-year-old Girl With Swelling in the Arm. Shahnawaz M. Amdani,
Magda Mendez. Pediatrics in Review. May 2015; 36(5):e14-e17, DOI: 10.1542/pir.36-5-e14. The American Academy of
Pediatrics has removed this article from circulation because it contained citation and attribution errors. We apologize to
our readers.
2. NOTICE OF RETRACTION: Visual Diagnosis: 3-Year-Old Boy With Persistent Right Chest Wheezing. Shahnawaz M.
Amdani, Naresh Reddivalla, Magda Mendez, Orlando Perales. Pediatrics in Review. Dec. 2014; 35(12):e61-e63, DOI:
10.1542/pir.35-12-e61. The American Academy of Pediatrics has removed this article from circulation because it
contained citation and attribution errors. We apologize to our readers.
3. NOTICE OF RETRACTION: Index of Suspicion: Rash, Recalcitrant Tachycardia, and Hypertension in a 16-Year-Old
Girl. Seshashree Seshadri, Samhar Al-Akash, Salam Gharaybeh. Pediatrics in Review. Jan. 2015; 36(1):31-32, DOI:
10.1542/pir.36-1-31. The American Academy of Pediatrics has removed this article from circulation because it contained
citation and attribution errors. We apologize to our readers.

Vol. 38 No. 9 SEPTEMBER 2017 445

 in
Brief
Sun Exposure
Melissa Long, MD*
*Children’s National Medical System, Washington, DC
AUTHOR DISCLOSURE Dr Long has disclosed
that she owns stock in Masimo and that she
has a family member on the company’s Board
of Directors. This commentary does not
contain a discussion of an unapproved/
investigative use of a commercial product/
device.
The Surgeon General’s Call to Action to
Prevent Skin Cancer. US Department of
Health and Human Services. Washington, DC:
Office of the Surgeon General; 2014
Ultraviolet Radiation: A Hazard to Children
and Adolescents. Council on Environmental
Health and Section on Dermatology,
American Academy of Pediatrics. Pediatrics.
2011;127(3):e791–e817
New Insights About Infant and Toddler
Skin: Implications for Sun Protection. Paller
AS, Hawk J, Honig P, et al. Pediatrics. 2011;
128(1):92–102
Pediatric Sunscreen and Sun Safety
Guidelines. Julian E, Palestro A, Thomas J. Clin
Pediatr. 2015;54(12):1133–1140
446 Pediatrics in Review
Skin cancer is the most commonly diagnosed cancer in the United States, with
more than 5 million people treated annually. Although melanoma accounts for
only 5% of skin cancer cases, it accounts for more than 75% of the morbidity,
and the incidence is increasing faster than for any other solid tumor. Yet, it is
not just a cancer afflicting older adults. It is the second most common form of
cancer in women aged 15 to 29 years.
There is strong evidence that UV radiation (UVR) causes skin cancer. Since
2009, the World Health Organization has classified UVR from sunlight
and tanning devices as a class I human carcinogen. Whereas UV-B rays are
responsible for sunburn, UV-A rays lead to photoaging (ie, wrinkles, discol-
oration), and, importantly, both types contribute to the pathogenesis of skin
cancer. However, the degree to which UVR contributes to an individual’s risk of
cancer depends on a variety of factors, including his or her skin type, the age of
the individual, chronicity of sun exposure, and use of sun protection measures.
It is thought that intermittent but intense UVR exposure, especially in child-
hood, is important in the pathogenesis of melanoma and basal cell carcinoma,
whereas cumulative exposure is more important for the development of squa-
mous cell carcinoma. Use of indoor tanning devices, especially in young people,
can increase the risk of melanoma by up to 60%, and risk increases with each
use. It is estimated that more people worldwide will develop skin cancer from
tanning devices than will develop lung cancer from smoking.
Evidence is mixed as to whether sun protection measures can prevent skin
cancer. However, the US Preventive Services Task Force has found evidence that
counseling young people in the primary care setting promotes increased sun
protection behaviors. Recommendations from the American Academy of Pedi-
atrics (AAP) include the following: 1) avoid sunburns and tanning parlors; 2)
avoid midday sun exposure (10 AM–4 PM) and seek shade during that time; 3)
wear tightly woven and dark-colored clothing that covers the body; 4) wear UV-
blocking sunglasses; 5) wear a wide-brimmed hat or a cap with a brim that
shades the face; and 6) apply and reapply sunscreen every 2 hours. In addition,
the AAP recommends that infants younger than 6 months stay out of direct
sunlight completely with the use of shade, a protective hat and clothing, and
sunscreen on the face and hands when sun exposure is unavoidable.
Because there are thousands of sunscreen products for sale, patients may
benefit from additional counseling regarding selection of a sunscreen. There are
2 classes of active ingredients in sunscreen: 1) inorganic or physical blockers (eg,
zinc oxide or titanium dioxide) that deflect both UV-A and UV-B rays and 2)
organic or chemical blockers that absorb UVR and eliminate the energy as heat.
Most chemical-blocking sunscreens protect against UV-B rays only; a few, such
as oxybenzone, protect against both UV-A and UV-B rays. The AAP recommends
a sunscreen with broad-spectrum coverage (ie, one that pro-
tects against both UV-A and UV-B rays) and one with a sun
protection factor (SPF) of 15 or higher. It is important to note
that a sunscreen’s SPF is a measure of UV-B protection alone.
A child wearing sunscreen with an SPF of 15 can be out in the
sun 15 times longer before getting a sunburn than if he or she
were not wearing any sunscreen. However, the UV-B–blocking
benefits of sunscreen eventually plateau. A sunscreen rated
as SPF 30 filters 97% of UV-B rays, whereas one rated as
SPF 50 blocks 98% of UV-B rays. As a result, the Food and
Drug Administration (FDA) limits sunscreen manufac-
turers from claiming any greater than an SPF of 50.
In addition to counseling about sunscreen selection,
patients may also benefit from counseling about how
sunscreen should be applied. An average adult requires
about 1 oz of sunscreen to effectively cover his or her
exposed body, and this application amount approximates
the size of a golf ball. There is no set amount for a child, but
some suggest an amount that fills the child’s cupped hand.
Sunscreen should be applied 15 to 30 minutes before sun
exposure and reapplied at least every 2 hours. If a sun-
screen is intended for use during sports or in water,
patients should be advised to check the product’s water-
resistance rating because products are rated for effective-
ness of either 40 or 80 minutes in the water.
The safety of sunscreen ingredients has received sub-
stantial media attention, driven by highly vocal consumer
and environmental advocacy groups. Concerns have been
raised that when absorbed by the body, sunscreen ingre-
dients may cause hormonal alterations or skin cancer.
Chemical blockers are absorbed by design, but some posit
that even nanoparticles in physical blockers may be
absorbed by the skin and thus pose health risks. Accord-
ing to the American Academy of Dermatology, there are
no studies that show that any of the FDA-approved sun-
screen ingredients cause any significant health problems
in humans, and the high risk of skin cancer from sun
exposure far exceeds other theoretical health risks from
the sunscreen products themselves.
ANSWER KEY FOR SEPTEMBER 2017 PEDIATRICS IN REVIEW
Management of Pediatric Community-acquired Bacterial Pneumonia: 1. E; 2. C; 3. B; 4. A; 5. D.
Approach to Hypertriglyceridemia in the Pediatric Population: 1. E; 2. E; 3. E; 4. E; 5. E.
Counseling about sun protection measures is a key part
of a pediatrician’s anticipatory guidance. A comprehensive
approach to limiting sun exposure is important but must
be balanced against other priorities, such as obesity pre-
vention and ensuring adequate vitamin D levels. Pediatri-
cians should ensure that counseling on sun exposure is not
understood as a prohibition on outdoor activity and should
discuss alternative measures to ensure adequate vitamin D
intake during childhood.
COMMENTS: Dr Long’s In Brief has reviewed the dangers
of sun exposure and the preventive anticipatory guidance
that pediatricians need to provide. Although 90% of pedi-
atricians who responded to a national AAP survey acknowl-
edged that skin cancer is an important risk and sun exposure
prevention can reduce cancer, most of these pediatricians
ranked counseling on sun exposure guidance as a lower
priority than many other preventive topics. Hence, pedia-
tricians need to adopt these principles in their anticipatory
guidance. One approach is to ensure that sunburn preven-
tion is discussed at least yearly with children and parents.
Several studies have noted that patients apply only 25%
to 50% of the amount of sunscreen recommended by the
FDA for optimal protection, resulting in enhanced risk of
sunburn and exposure. Parents also need to navigate the
various formulations of sunscreen products. Use of sun-
screen sprays may be appealing, but they may result in
inhalation risks in young children, and also the added step
to still need to rub in the product to ensure appropriate
distribution over all of the exposed skin. Pediatricians need
to remain vigilant in completing an extensive skin inspec-
tion during the physical examination to identify any wor-
risome skin lesions that may result in early identification
of skin cancer. Finally, pediatricians should be on the
forefront in advocating for legislature to prevent minors’
access to tanning booths as a measure to reduce melanoma
risks in children and adolescents.
– Janet R. Serwint, MD
Associate Editor, In Brief
Pediatric Lymphoma: 1. D; 2. D; 3. D; 4. B; 5. C.
Vol. 38 No. 9 SEPTEMBER 2017 447
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 Vesicular Rash in a Neonate
Leeann Pavlek, MD,* John Schmidt, MD*
*Department of Pediatrics, University of Michigan C.S. Mott Children’s Hospital, Ann Arbor, MI

PRESENTATION

A 3-day-old girl presents to the emergency department with a vesicular rash on her
left leg. She was born at 39 weeks’ gestation via an uncomplicated vaginal delivery
and went home after 24 hours. No skin findings or any other physical abnor-
malities were noted at birth. Her mother received appropriate prenatal care and
was started on valacyclovir prophylaxis at 36 weeks’ gestation after testing positive
for herpes simplex virus (HSV) serologies. The infant’s mother has no history of
genital or oral ulcers, and no lesions were noted at the time of delivery. The mother
took no other medications during pregnancy, and she reports no history of
alcohol, tobacco, or illicit drug use. The infant’s rash developed on the morning
of presentation. She has otherwise been feeding well and has had no fevers. There
has been no exposure to any plants, animals, or lotions.
On physical examination, she appears well and is afebrile, with vital signs
within age-appropriate limits. Growth parameters include a weight of 3,200 g
(38th percentile), length of 52 cm (84th percentile), and head circumference of
34 cm (45th percentile). Skin examination is positive for crusted vesicular lesions
arranged in a linear pattern on the posterior left leg, extending from the gluteal
fold to the Achilles tendon (Figs 1 and 2). The remainder of her physical exam-
ination findings are normal.
A full sepsis evaluation is performed. Laboratory tests reveal a normal complete
blood cell count and urinalysis findings. Blood and urine culture samples are
obtained. A lumbar puncture is unsuccessful, so she is scheduled to have a repeated

AUTHOR DISCLOSURE Drs Pavlek and

Schmidt have disclosed no financial
relationships relevant to this article. This
commentary does not contain a discussion
of an unapproved/investigative use of a
commercial product/device. Figure 1. Vesicles in a linear pattern on the posterior leg.

e32 Pediatrics in Review


Figure 2. Close-up view of the vesicular lesions with crusting.
lumbar puncture performed by the interventional radiology
department. She is started on empirical ampicillin, cefotax-
ime, and acyclovir therapy.
Given that she appears clinically well, the dermatology
department is consulted to evaluate for an etiology other
than HSV. The results of a skin punch biopsy confirm the
suspected diagnosis.
DIAGNOSIS
Histopathologic evaluation of the punch biopsy reveals a
spongiotic dermatitis with large dyskeratotic cells and many
eosinophils, consistent with a diagnosis of incontinentia
pigmenti (IP).
Discussion
IP is a rare X-linked dominant disorder, with 65% of cases
associated with deletions in the IKBKG gene on chromosome
Xq28. IP can be inherited and can also be caused by a de novo
mutation in the affected child. Approximately 1,000 cases of
IP have been reported in females; it is generally regarded as
fatal in males, although cases have been reported in males
with a 47,XXY karyotype or somatic mosaicism. IP is char-
acterized by skin lesions, as well as various abnormalities of
the nails, teeth, eyes, and central nervous system (CNS). The
skin lesions progress through 4 distinct stages, with the first
stage beginning in utero or shortly after birth. The lesions
initially present as erythematous vesicles and pustules that
develop along the lines of Blaschko. Next, the initial lesions
develop a hyperkeratotic verrucous appearance. The third
stage usually occurs between 6 and 12 months and consists
of swirled and linear areas of hyperpigmentation, some-
times described as a “marble cake” appearance. The final
stage is characterized by linear hypopigmentation of the
extremities with associated hair loss. Patients may also
develop alopecia of the scalp or trunk.
Dental involvement is another common finding in
patients with IP. Patients can have a delay in eruption of
primary teeth, congenital absence of primary or secondary
teeth, microdontia, or peg- or cone-shaped teeth. Nail changes
can include thickness, ridges, pitting, or complete absence of
the nails. Neovascularization of the retina can occur in some
patients, and this predisposes them to retinal detachments
if preventive laser photocoagulation is not performed. Man-
ifestations in the CNS can include seizures, delay in motor
development, intellectual disability, and muscle spasticity.
Differential Diagnosis
The differential diagnosis for a vesicular rash in an infant
includes a variety of infectious, genetic, and benign self-
limited etiologies. Several of the possible diagnoses are life-
threatening if untreated, so making the correct diagnosis is
critical. Several viruses, especially HSV and varicella zoster
virus, can also present with vesicles that appear in the first
few days after birth. Bacterial infection with Staphylococ-
cus aureus or Streptococcus species can manifest as pus-
tular or vesicular skin lesions. An infant infected with
scabies may develop pustules and vesicles, although these
commonly involve the palms and soles and are pruritic.
Congenital blistering disorders may present in a similar
manner as IP, with vesicular or bullous lesions present
at birth or in the first weeks after birth; these disorders
include epidermolysis bullosa, congenital bullous pem-
phigoid, and epidermolytic hyperkeratosis. Finally, be-
nign newborn rashes, including erythema toxicum and
transient neonatal pustular melanosis, can mimic the ap-
pearance of IP.
Treatment and Prognosis
The management of IP consists of treating the various
manifestations of the condition and preventing known com-
plications. The skin lesions usually resolve without inter-
vention, but standard measures should be taken to keep the
skin hydrated and prevent secondary infections. Examina-
tion by an ophthalmologist should be performed soon after
diagnosis to evaluate for retinal neovascularization. Photo-
coagulation can be performed to decrease the risk of retinal
detachment if this is detected early. Surveillance eye exam-
inations are recommended monthly for the first 4 months
after birth, every 3 months until 1 year old, every 6 months
until 3 years old, and then yearly.
Pediatric neurology should be involved to evaluate for
spasticity, seizures, and focal neurologic deficits. A brain
Vol. 38 No. 9 SEPTEMBER 2017 e33
 magnetic resonance image (MRI) can identify structural
abnormalities that may be contributing to any neurologic
symptoms. Brain anomalies reported with IP include agen-
esis of the corpus callosum, gray matter heterotopias, and
periventricular leukomalacia. IP can predispose patients to
hemorrhagic strokes, likely secondary to issues with micro-
vasculature. Early involvement of physical and occupational
therapy is beneficial for children with any of these issues.
Routine dental care is essential for all children, especially
those with dental manifestations of IP. Depending of the
severity of the tooth issues, children may need dental im-
plants to assist with speech and nutrition. Involvement of a
speech language pathologist can help patients who develop
speech difficulties as a result of dental abnormalities.
It is recommended that families affected by IP meet with
a genetic counselor because the condition can be inherited
in an X-linked dominant fashion. Testing can determine
whether an affected female inherited the gene from her
mother or whether she developed a de novo mutation.
Thorough history and physical examinations may identify
previously undiagnosed family members who also have IP.
Life expectancy for those with IP is thought to be normal,
other than those patients who develop substantial compli-
cations of the disease during infancy. Women with IP have
an increased incidence of miscarriages, thought to be due to
the low viability of male fetuses affected by IP.
Patient Course
Our patient is admitted to the general pediatrics team for
further evaluation and treatment. Blood and urine culture
results remain negative. A sample of CSF is obtained by an
interventional radiologist, and results of culture and HSV
polymerase chain reaction are also negative. Use of antibiotics
and acyclovir is discontinued after 48 hours of negative
culture results. On diagnosis, the genetics department is
consulted and recommends molecular testing for the involved
Additional Resources for Pediatricians
AAP Textbook of Pediatric Care, 2nd Edition
• Chapter 95: Neonatal Skin - https://pediatriccare.solutions.aap.org/chapter.aspx?sectionId=139978906&bookId=1626
Parent Resources from the AAP at HealthyChildren.org
• Baby Birthmarks & Rashes: https://www.healthychildren.org/English/ages-stages/baby/bathing-skin-care/Pages/Your-Newborns-Skin-
Birthmarks-and-Rashes.aspx
For a comprehensive library of AAP parent handouts, please go to the Pediatric Patient Education site at http://patiented.aap.org.
e34 Pediatrics in Review
genes, brain MRI to assess for associated structural abnor-
malities, and evaluation by the ophthalmology and neurology
departments. Results of the brain MRI are abnormal, show-
ing multiple areas of restricted diffusion, consistent with the
typical CNS manifestations of IP. Electroencephalography
does not record any seizures but demonstrates excessive
negative sharps, conferring an increased risk of seizures.
An eye examination performed during admission is normal,
and she is currently followed as an outpatient with the pedi-
atric retina specialists.
Summary
• Incontinentia pigmenti (IP) should be considered in the
differential diagnosis for any infant presenting with vesicular
or pustular lesions, along with other congenital and infectious
disorders, including herpes simplex virus infection.
• When IP is diagnosed, specialists in ophthalmology, genetics,
neurology, and dentistry should be involved early to evaluate
for multisystem involvement and provide necessary treatment.
• Patients with IP who develop sudden vision changes need to
be evaluated immediately for retinal detachment.
Suggested Readings
Ardelean D, Pope E. Incontinentia pigmenti in boys: a series and review
of the literature. Pediatr Dermatol. 2006;23(6):523–527
Cohen PR. Incontinentia pigmenti: clinicopathologic characteristics
and differential diagnosis. Cutis. 1994;54(3):161–166
Meuwissen ME, Mancini GM. Neurological findings in incontinentia
pigmenti: a review. Eur J Med Genet. 2012;55(5):323–331
Minic S, Novotny GEK, Trpinac D, Obradovic M. Clinical features
of incontinentia pigmenti with emphasis on oral and dental
abnormalities. Clin Oral Investig. 2006;10(4):343–347
Poziomczyk CS, Recuero JK, Bringhenti L, et al. Incontinentia pigmenti.
An Bras Dermatol. 2014;89(1):26–36
 A 3-week-old Girl with an Unusual Rash
Fatema Jaffery, MD,* Fatima Khan, MD, MBA,* Jose Bustillo, MD*
*Department of Pediatrics, Newark Beth Israel Medical Center, Newark, NJ

PRESENTATION

A 3-week-old girl presents to the pediatric outpatient department for evaluation of

a rash that has been present since age 2 weeks. The rash is found on the infant’s
face, arms, feet, and trunk and does not seem to bother her. No history of fever or
other behavioral changes are noticed. There is no history of contact with anyone
who has a similar rash.
On presentation to the outpatient clinic, the infant appears well and is not in
any distress. Her current weight is 3,674 g, length is 20 in (50.8 cm), and head
circumference is 13.8 in (35 cm). On physical examination, she has multiple
annular discoid lesions with central hypopigmentation with no discharge on
various parts of the body. The sizes of the lesions vary from 1 to 3 cm (Figs 1–3).

AUTHOR DISCLOSURE Drs Jaffery, Khan,

and Bustillo have disclosed no financial
relationships relevant to this article. This
commentary does not contain a discussion
of an unapproved/investigative use of a
commercial product/device. Figure 1. Annular discoid lesions found on sole of the foot.

Vol. 38 No. 9 SEPTEMBER 2017 e35


Figure 2. Annular discoid lesions found on sole of the trunk.
The infant was born to a 20-year-old gravida 3, para 0-0-
2-0 mother at 40 weeks and 1 day of gestation via cesarean
delivery. The pregnancy was complicated by a category III
fetal heart rate tracing that prompted an emergency cesarean
section. The baby’s Apgar score was 9 at 1 and 5 minutes. Her
birthweight was 2,975 g. The mother’s prenatal care was
normal, and laboratory tests revealed that rapid plasma reagin
was nonreactive, human immunodeficiency virus was neg-
ative, and rubella titers showed immunity.
On further questioning, the mother denied any his-
tory of lupus, joint pains, or rash. The infant’s complete
blood cell count and comprehensive metabolic panel results
were normal. Sjogren antibody, anti-SSA, and anti-SSB titers
were all elevated at greater than 8.0 antibody index (AI)
(reference range, 0.0-0.9 AI). Antinuclear antibodies were
also positive. Results of echocardiography and electrocardiog-
raphy were normal.
The mother’s anti-SSA and anti-SSB titers were also
positive (each >8.0 AI). Her antinuclear antibody titer
was positive at 1:640. Her anti-Smith and anti-dsDNA were
negative. Erythrocyte sedimentation rate was elevated at
53 mm/hour.
Figure 3. Annular discoid lesions found on the head.
e36 Pediatrics in Review
Diagnosis
Neonatal lupus (NL) is an autoimmune phenomenon in which
antibodies are passively transferred from mother to fetus in
the second and third trimesters. Mothers of these infants have
a primary autoimmune disease, such as systemic lupus ery-
thematosus, Sjogren syndrome, rheumatoid arthritis, or mixed
connective tissue disorder. (1) According to some studies, less
than one-third of women are symptomatic in affected fetuses.
The diagnosis can be made by positive antibodies to SSA/Ro,
SSB/La, or anti-U1RNP in the newborn. (1) Anti-Ro has shown
greater than 99% sensitivity with infants who have been diag-
nosed as having congenital heart block, but it has poor specifi-
city. Anti-La was shown to have only 30% sensitivity. Screening
has been shown not to be effective in infants born to mothers
with positive anti-La and negative anti-Ro. (2) NL presents with
cutaneous lesions, anemia, thrombocytopenia, elevated liver
enzyme levels, or possibly heart block. The incidence is 1% in
newborns with seropositive mothers. Forty percent of women
who have a child with NL are asymptomatic. (3) The most
common clinical manifestation is a discoid-type rash seen at
birth that resolves within a couple of months; however, heart
block can be seen in up to 15% to 30% of patients. (4)
NL is due to a transplacental transfer of immunoglob-
ulins of the mother to the fetus. Ten percent of these new-
borns are serum positive for anti-U1RNP, and 90% are serum
positive for SSA/SSB. Interestingly, patients who are positive
for anti-U1RNP have only cutaneous manifestations. (3)
Rarely, these patients can also have first-, second-, or
third-degree heart block. Dilated cardiomyopathy has also
been reported but is rare. Pacemakers have been placed in
patients with heart block (5).
All infants diagnosed as having NL should undergo an
evaluation that includes, but is not limited to, a complete
metabolic panel, complete blood cell count, electrocardiog-
raphy, and echocardiography. Differential diagnoses include
erythema toxicum, seborrheic dermatitis, tinea skin infec-
tion, miliaria rubra, and urticaria.
In most patients, the rash resolves on its own without
treatment, but it can be treated with topical corticosteroids.
Avoidance of sun exposure is recommended as well. (3) For
heart block, some case reports have shown improvement with
intravenous immunoglobulin and systemic corticosteroids, but
there is no definitive treatment. (2) At times, a pacemaker has
been used for third-degree heart block. (5)
Patient Course
The infant was prescribed topical corticosteroids, and the rash
improved within 6 months. She is growing and developing
normally. The mother had recently started to have general joint
pain and is undergoing further evaluation.

Summary
• Neonatal lupus is a disease in which the mother’s antibodies
are passively transferred to a fetus and can manifest in a
newborn as a rash, anemia, elevated liver enzyme levels, and,
in rare cases, heart block.
• Diagnosis can be made clinically, but one must do appropriate
laboratory tests to detect antibodies for the benefit of the
patient and the mother.
• Fifty percent of asymptomatic women who are serum positive
go on to have a primary autoimmune disease.
• The rash can be treated by simple avoidance of sun exposure or
topical corticosteroids. However, for congenital heart block,
intravenous immunoglobulin and systemic corticosteroids have
been suggested and, if needed, a pacemaker for heart block.
Additional Resources for Pediatricians
AAP Textbook of Pediatric Care, 2nd Edition
• Chapter 324: Rheumatologic Diseases - https://pediatriccare.solutions.aap.org/chapter.aspx?sectionId=124995829&bookId=1626
For a comprehensive library of AAP parent handouts, please go to the Pediatric Patient Education site at http://patiented.aap.org.
References
1. Lee LA. Neonatal lupus: clinical features and management. Paediatr
Drugs. 2004;6(2):71–78
2. Silverman E, Buyon J, Jaeggi E. Neonatal lupus erythematosus. In:
Petty RE, Laxer RM, Lindsley CB, Wedderburn L, eds. Textbook of
Pediatric Rheumatology. 7th ed. Philadelphia, PA: Elsevier;
2016:336–350.
3. McKinlay JR, Cooke LM, Cunningham BB, Gibbs NF.
Neonatal lupus erythematosus. J Am Board Fam Med. 2001;14
(1):68–70
4. Hurwitz S, ed. Neonatal lupus erythematosus. In: Clinical
Pediatric Dermatology: A Textbook of Skin Disorders of Childhood
and Adolescence. 2nd ed. Philadelphia, PA: WB Saunders;
1993:567–569
5. Pike JI, Donofrio MT, Berul CI. Ineffective therapy, underpowered
studies, or merely too little, too late? risk factors and impact of
maternal corticosteroid treatment on outcome in antibody-associated
fetal heart block. Circulation. 2011;124(18):1905–1907.
Vol. 38 No. 9 SEPTEMBER 2017 e37