45

T
EBRA ING
EL

C
1979 ◾ 2024

JANUARY 2024
Vol. 45 No. 1
www.pedsinreview.org

Long-Acting Reversible
Etonogestrel Subdermal
Implant in Adolescents
Cushing Syndrome in
Childhood
Management of Acute
Sickle Cell Disease Pain
In Brief
Lice: Head, Body, Pubic
Spontaneous
Pneumothorax and
Pneumomediastinum
Online Only: Visual Diagnosis
Coral Fluorescing Axillary
Plaques Refractory to
Topical Antifungal and
Antibacterial Treatments

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 The power is in your hands—help prevent
respiratory syncytial virus (RSV) disease

Discover more
at Beyfortus.com

INDICATION
Beyfortus is indicated for the prevention of respiratory syncytial virus (RSV) lower
respiratory tract disease in:
• Neonates and infants born during or entering their first RSV season.
• Children up to 24 months of age who remain vulnerable to severe RSV disease
through their second RSV season.
IMPORTANT SAFETY INFORMATION
Contraindication
Beyfortus is contraindicated in infants and children with a history of serious
hypersensitivity reactions, including anaphylaxis, to nirsevimab-alip or to any of the
excipients.
Warnings and Precautions
• Hypersensitivity Including Anaphylaxis: Serious hypersensitivity reactions,
including anaphylaxis, have been observed with other human IgG1 monoclonal
antibodies. If signs and symptoms of a clinically significant hypersensitivity
reaction or anaphylaxis occur, initiate appropriate medications and/or
supportive therapy.

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 Beyfortus™ is the first and only long-acting antibody indicated for the
prevention of RSV lower respiratory tract disease in term and preterm infants1

Proven strong and consistent efficacy against MA RSV-LRTI1*

Healthy term and preterm infants ≥35 wGA (Trial 04) Healthy preterm infants ≥29 to <35 wGA (Trial 03)

74.9% RRR 70.1% RRR

(95% CI: 50.6, 87.3; P<0.001) (95% CI: 52.3, 81.2; P<0.001)
Beyfortus: 1.2% (12/994) Placebo: 5.0% (25/496) Beyfortus: 2.6% (25/969) Placebo: 9.5% (46/484)
Primary endpoint: Incidence of MA RSV-LRTI vs placebo through 150 days post one dose

Demonstrated safety profile versus placebo (Trials 04 and 03) and versus
palivizumab (Trial 05)1†
• The most common adverse reactions in Trial 04 and Trial 03 were rash (0.9%) and
injection site reactions (0.3%)
• Adverse reactions reported among Trial 05 subjects were similar to Trials 04 and 03
RSV disease protection that extends through 5 months based on clinical data1

IMPORTANT SAFETY INFORMATION (cont’d)

• Use in Individuals with Clinically Significant Bleeding Disorders: As with
other IM injections, Beyfortus should be given with caution to infants and
children with thrombocytopenia, any coagulation disorder or to individuals on
anticoagulation therapy.
Most common adverse reactions with Beyfortus were rash (0.9%) and injection site
reactions (0.3%).
Please see Brief Summary of full Prescribing Information on the following pages.
CI, confidence interval; IM, intramuscular; MA RSV-LRTI, medically attended respiratory syncytial virus
lower respiratory tract infection; RRR, relative risk reduction; wGA, weeks gestational age.
*Results of Trials 04 and 03 for infants entering their first RSV season. Trial 04 evaluated the efficacy
of a single dose of Beyfortus (50 mg IM if <5 kg weight, 100 mg IM if ≥5 kg weight) vs placebo in 1,490
healthy term and preterm infants (≥35 wGA). Trial 03 evaluated the efficacy of a single 50 mg dose
of Beyfortus vs placebo in 1,453 healthy preterm infants (≥29 to <35 wGA).
†
The Safety Population includes all infants who received the recommended dose of Beyfortus in
Trials 04 and 03: Primary and Safety cohorts from Trial 04; infants who weighed <5 kg and who received
the recommended dose of Beyfortus (single 50 mg IM dose) in Trial 03. Trial 05 was a Phase 2/3 study
that evaluated the safety of a single dose of Beyfortus (50 mg or 100 mg) in infants with chronic lung
disease (CLD) or congenital heart disease (CHD) and preterm infants (<35 wGA) entering their first
RSV season.
Reference: 1. Beyfortus (nirsevimab-alip). Prescribing Information. Sanofi.

©2023 Sanofi Pasteur Inc. All rights reserved.

SANOFI, 1 Discovery Drive, Swiftwater, PA 18370 MAT-US-2308449-v1.0-10/2023

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 BEYFORTUS™ Rx Only
(nirsevimab-alip) injection, for intramuscular use
Brief Summary of Prescribing Information
1 INDICATIONS AND USAGE
BEYFORTUS is indicated for the prevention of Respiratory Syncytial Virus (RSV)
lower respiratory tract disease in:
• Neonates and infants born during or entering their first RSV season.
• Children up to 24 months of age who remain vulnerable to severe RSV disease
through their second RSV season.
2 DOSAGE AND ADMINISTRATION
2.1 Recommended Dosage
Neonates and Infants: First RSV Season
For neonates and infants born during or entering the RSV season, administer
BEYFORTUS starting from birth. For infants born outside the RSV season,
administer BEYFORTUS once prior to the start of the RSV season considering
duration of protection provided by BEYFORTUS [see Clinical Pharmacology (12.2)
in the full prescribing information].
The recommended dosage of BEYFORTUS for neonates and infants born during
or entering their first RSV season is based on body weight (see Table 1) and is
administered as a single intramuscular (IM) injection.
Table 1 Recommended Dosage of BEYFORTUS in Neonates and Infants
Born During or Entering Their First RSV Season
Body Weight at Time of Dosing Recommended Dosage
Less than 5 kg 50 mg by IM injection
5 kg and greater 100 mg by IM injection
Children Who Remain at Increased Risk for Severe RSV Disease: Second RSV
Season
For children up to 24 months of age who remain at increased risk for severe RSV
disease in their second RSV season, the recommended dosage of BEYFORTUS is
a single 200 mg dose administered as two IM injections (2 x 100 mg).
Children Undergoing Cardiac Surgery with Cardiopulmonary Bypass
For children undergoing cardiac surgery with cardiopulmonary bypass, an additional
dose of BEYFORTUS is recommended as soon as the child is stable after surgery
to ensure adequate nirsevimab-alip serum levels. The recommended dosage of
BEYFORTUS is administered as an IM injection.
First RSV season:
• If surgery is within 90 days after receiving BEYFORTUS, the additional dose
should be based on body weight at the time of the additional dose. Refer
to Table 1 for weight-based dosing.
• If more than 90 days have elapsed since receiving BEYFORTUS, the
additional dose should be 50 mg regardless of body weight.
Second RSV season:
• If surgery is within 90 days after receiving BEYFORTUS, the additional dose
should be 200 mg, regardless of body weight.
• If more than 90 days have elapsed since receiving BEYFORTUS, the
additional dose should be 100 mg, regardless of body weight.
2.2 Administration Instructions
BEYFORTUS must be administered by a healthcare provider.
Parenteral drug products should be inspected visually for particulate matter and
discoloration prior to administration, whenever solution and container permit.
BEYFORTUS is a clear to opalescent, colorless to yellow solution. Do not inject
BEYFORTUS if the liquid is cloudy, discolored, or it contains large particles or
foreign particulate matter.
Do not use if the BEYFORTUS pre-filled syringe has been dropped or damaged, the
security seal on the carton has been broken, or the expiration date has passed.
BEYFORTUS is available in a 50 mg and a 100 mg pre-filled syringe. Check the
labels on the BEYFORTUS carton and pre-filled syringe to ensure the correct 50 mg
or 100 mg product is being used.
Co-administration with Childhood Vaccines and Immunoglobulin Products
BEYFORTUS can be given concomitantly with childhood vaccines [see Clinical
Pharmacology (12.3) in the full prescribing information]. When administered con-
comitantly with injectable vaccines, they should be given with separate syringes and
at different injection sites. Do not mix BEYFORTUS with any vaccines or medica-
tions in the same syringe or vial.
There is no information regarding co-administration of BEYFORTUS with other
immunoglobulin products. Palivizumab should not be administered to infants who
have already received BEYFORTUS in the same season. There are no data
regarding substitution of BEYFORTUS for palivizumab once prophylaxis treatment
is initiated with palivizumab for the RSV season. BEYFORTUS may be administered
prior to or during the second RSV season to children up to 24 months of age who
remain vulnerable to severe RSV disease, and who received palivizumab in their
first RSV season [see Adverse Reactions (6.1) and Clinical Studies (14.3) in the full
prescribing information].
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Administration Instructions for Single-Dose Pre-filled Syringe
BEYFORTUS 50 mg (50 mg/0.5 mL) BEYFORTUS 100 mg (100 mg/mL)
pre-filled syringe with a purple plunger pre-filled syringe with a light blue
rod. plunger rod.
Refer to Figure 1 for pre-filled syringe components.
Figure 1 Luer Lock Syringe Components
Step 1: Holding the Luer lock in one hand (avoid holding the plunger rod or syringe
body), unscrew the syringe cap by twisting it counter-clockwise with the other hand.
Step 2: Attach a Luer lock needle to the pre-filled syringe by gently twisting the
needle clockwise onto the pre-filled syringe until slight resistance is felt.
Step 3: Hold the syringe body with one hand and carefully pull the needle cover
straight off with the other hand. Do not hold the plunger rod while removing the
needle cover or the rubber stopper may move. Do not touch the needle or let it touch
any surface. Do not recap the needle or detach it from the syringe.
Step 4: Administer the entire contents of the BEYFORTUS pre-filled syringe as an
IM injection, preferably in the anterolateral aspect of the thigh. The gluteal muscle
should not be used as an injection site because of the risk of damage to the sciatic
nerve.
Step 5: Discard syringe into a sharps container.
If two injections are required, repeat Steps 1-5 in a different injection site.
4 CONTRAINDICATIONS
BEYFORTUS is contraindicated in infants and children with a history of serious
hypersensitivity reactions, including anaphylaxis, to nirsevimab-alip or to any of the
excipients [see Warnings and Precautions (5.1) and Description (11) in the full
prescribing information].
5 WARNINGS AND PRECAUTIONS
5.1 Hypersensitivity Including Anaphylaxis
Serious hypersensitivity reactions, including anaphylaxis, have been observed with
other human immunoglobulin G1 (IgG1) monoclonal antibodies. If signs and
symptoms of a clinically significant hypersensitivity reaction or anaphylaxis occur,
initiate appropriate medications and/or supportive therapy.
5.2 Use in Individuals with Clinically Significant Bleeding Disorders
As with any other IM injections, BEYFORTUS should be given with caution to infants
and children with thrombocytopenia, any coagulation disorder, or to individuals on
anticoagulation therapy.
6 ADVERSE REACTIONS
6.1 Clinical Trials Experience
Because clinical trials are conducted under widely varying conditions, adverse
reaction rates observed in the clinical trials of a drug cannot be directly compared
to rates in the clinical trials of another drug and may not reflect the rates observed
in practice.
A total of 3,224 pediatric subjects received the recommended dose of BEYFORTUS
in Phase 2 and Phase 3 clinical trials (Trials 03, 04, and 05) including 2,119 infants
who were born at 35 weeks gestational age (GA) or older, and 1,105 infants who
were born at less than 35 weeks GA. A total of 247 infants of any GA with chronic
lung disease (CLD) of prematurity or hemodynamically significant congenital heart
disease (CHD) in Trial 05 received the recommended dose of BEYFORTUS.
Neonates and Infants Entering Their First RSV Season (Trial 03 and Trial 04)
Trial 03 was a randomized, double-blind placebo-controlled trial conducted in
preterm infants born at a GA of greater than or equal to 29 weeks to less than 35
weeks. Subjects were randomized 2:1 to receive BEYFORTUS (N=968) or placebo
(N=479) by IM injection. All subjects randomized to BEYFORTUS received a single
50 mg IM dose regardless of body weight. Safety data in Trial 03 are presented only
for the infants in the BEYFORTUS arm who received the recommended dose
[infants who weighed less than 5 kg and who received a single dose of 50 mg
BEYFORTUS IM (N=572) or placebo (N=288)].
Trial 04 was a Phase 3, randomized, double-blind, placebo-controlled trial con-
ducted in late preterm and term infants born at greater than or equal to 35 weeks
 GA. Trial 04 enrolled subjects sequentially into two cohorts: the Primary Cohort was
used for the primary efficacy analysis [see Clinical Studies (14.3) in the full
prescribing information] and for assessment of safety, and the Safety Cohort was
used primarily for safety assessment. All subjects from both cohorts of Trial 04 were
included in the safety analysis (BEYFORTUS N=1,998 and placebo N=996).
Subjects in Trial 04 weighing less than 5 kg received a single 50 mg IM dose of
BEYFORTUS and infants weighing greater than or equal to 5 kg received a single
100 mg IM dose.
Infants who received the recommended dose in Trial 03 and infants in Trial 04 were
pooled to evaluate the safety of BEYFORTUS (N=2,570) compared to placebo
(N=1,284). At randomization, in this pooled Safety Population from Trials 03 and 04
cohorts, 22% of infants were born at less than 35 weeks GA, 10% of infants were
GA greater than or equal to 35 weeks and less than 37 weeks; 68% were GA greater
than or equal to 37 weeks; 52% were male; 57% were White; 15% were Black; 4%
were American Indian/Alaskan native; 4% were Asian; 1% were Pacific Islander; and
19% were Other or Mixed Race; 30% were Hispanic or Latino; 73% were from
Northern Hemisphere; and 53% weighed less than 5 kg. The median age was 2
months; 65% were less than or equal to 3 months; 28% were greater than 3 to less
than or equal to 6 months, and 7% were greater than 6 months of age. (Refer to
Sections 14.2 and 14.3, Clinical Studies, for a description of the efficacy populations
in Trials 03 and 04). In both trials, infants received a single dose of IM BEYFORTUS
or placebo on Study Day 1 and were monitored for at least 60 minutes post-dose.
Subjects were followed for 360 days post-dose to assess safety. Adverse reactions
were reported in 1.2% of subjects who received BEYFORTUS; most (97%) of
adverse reactions were mild to moderate in intensity.
Table 2 summarizes the adverse reactions that occurred in Trial 03 and Trial 04
(Safety Population) in subjects who received the recommended dose of
BEYFORTUS.
Table 2 Adverse Reactions Reported at an Incidence Higher Than
Placebo in the Safety Population* (Trials 03 and 04)
Adverse Reaction BEYFORTUS Placebo
N=2,570 N=1,284
% %
Rash† (occurring within 0.9 0.6
14 days post-dose)
Injection site reaction‡ 0.3 0
(occurring within 7 days
post-dose)
*The Safety Population includes all subjects who received the recommended dose
of BEYFORTUS in Trials 03 and 04: Primary and Safety cohorts from Trial 04;
infants who weighed less than 5 kg and who received the recommended dose of
BEYFORTUS (single 50 mg IM dose) in Trial 03.
†Rash was defined by the following grouped preferred terms: rash, rash macular,
rash maculo-papular, rash papular.
‡Injection site reaction was defined by the following grouped preferred terms:
injection site reaction, injection site pain, injection site induration, injection site
edema, injection site swelling.
BEYFORTUS™
(nirsevimab-alip) injection, for intramuscular use
safety profile of BEYFORTUS in these children during their second RSV season was
consistent with the safety profile of BEYFORTUS observed during their first RSV
season.
7 DRUG INTERACTIONS
7.1 Interference with RT-PCR or Rapid Antigen Detection RSV Diagnostic
Assays
Nirsevimab-alip does not interfere with reverse transcriptase polymerase chain
reaction (RT-PCR) or rapid antigen detection RSV diagnostic assays that employ
commercially available antibodies targeting antigenic site I, II, or IV on the RSV
fusion (F) protein. For immunological assay results which are negative when clinical
observations are consistent with RSV infection, it is recommended to confirm using
an RT-PCR-based assay.
8 USE IN SPECIFIC POPULATIONS
8.1 Pregnancy
BEYFORTUS is not indicated for use in females of reproductive potential.
8.2 Lactation
BEYFORTUS is not indicated for use in females of reproductive potential.
8.4 Pediatric Use
The safety and effectiveness of BEYFORTUS have been established for the
prevention of RSV lower respiratory tract disease in neonates and infants born
during or entering their first RSV season and in children up to 24 months of age who
remain vulnerable to severe RSV disease through their second RSV season. The
safety and efficacy of BEYFORTUS for this indication and populations are discussed
throughout the labeling.
Use of BEYFORTUS for this indication is supported by evidence from adequate and
well-controlled studies in neonates and infants from birth up to 12 months of age
with additional pharmacokinetic and safety data in children up to 24 months of age
[see Adverse Reactions (6.1), Clinical Pharmacology (12.3), and Clinical Studies
(14) in the full prescribing information].
The safety and effectiveness of BEYFORTUS have not been established in children
older than 24 months of age.
10 OVERDOSAGE
There is limited experience of overdose with BEYFORTUS.
There is no specific treatment for an overdose with BEYFORTUS. In the event of
an overdose, the individual should be monitored for the occurrence of adverse
reactions and provided with symptomatic treatment as appropriate.
Manufactured by: AstraZeneca AB, Södertälje, Sweden SE-15185
US License No. 2059
Distributed by: Sanofi Pasteur, Inc., Swiftwater, PA 18370 USA
BEYFORTUS is a trademark of the Sanofi group of companies.
©AstraZeneca 2023
NIR-BPLR-SL-JUL23 Revised: July 2023

Infants Born at <35 Weeks Gestational Age and Infants and Children with CLD of
Prematurity or Hemodynamically Significant CHD (Trial 05)
RSV Season One
The safety of BEYFORTUS was evaluated in Trial 05, a randomized, double-blind,
palivizumab-controlled multicenter trial in infants at high risk for severe RSV
disease. These subjects were randomized 2:1 to receive BEYFORTUS (N=614) or
palivizumab (N=304) by IM injection. The 614 infants who received BEYFORTUS
included 128 preterm infants born at GA less than 29 weeks, 390 preterm infants
who were born at 29 weeks or older to less than 35 weeks GA, and 96 late preterm
and term infants born at 35 weeks GA or older. Among infants enrolled during their
first RSV season, the number of infants with CLD of prematurity or hemodynamically
significant CHD were overall 214 and 103, respectively, regardless of gestational
age. Of these, 12 infants had both CLD and CHD.
Subjects in Trial 05 weighing less than 5 kg received a single 50 mg IM dose of
BEYFORTUS and infants weighing greater than or equal to 5 kg received a single
100 mg IM dose. BEYFORTUS was administered once on Study Day 1 followed by
4 monthly IM doses of placebo; palivizumab was administered IM monthly for 5
months. All subjects were monitored for at least 60 minutes post-dose. Subjects
were followed for 360 days post-dose to assess safety.
Adverse reactions reported among Trial 05 subjects who received BEYFORTUS in
their first RSV season were similar to those reported in subjects who received
BEYFORTUS in Trials 03 and 04.
RSV Season Two (Subjects with CLD of Prematurity and Hemodynamically
Significant CHD)
Subjects with CLD of prematurity or hemodynamically significant CHD could
continue in Trial 05 and receive BEYFORTUS or palivizumab prior to their second
RSV season. All subjects who received BEYFORTUS in the first RSV season also
received BEYFORTUS in the second RSV season (N=180). Subjects who received
palivizumab in the first RSV season were re-randomized to receive BEYFORTUS
(N=40) or palivizumab (N=42) in the second RSV season. Safety data were
available for 150 days after dosing in children with CLD or CHD who received
BEYFORTUS (N=220) or palivizumab (N=42) in their second RSV season. The

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 The official “I recommend
HealthyChildren.org
AAP website at every newborn visit
to new parents.
for parents. Great information
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Refer families here
—Kristin Sanders, MD, FAAP
Schneck Pediatrics
Seymour, IN

with confidence.

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*Get OUR Symptom Checker on YOUR practice web site! HealthyChildren.org/kidsdoc

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 Winter AAP
Virtual Career Fair
Y o u r
Find eart Wednesday, February 14

e th
(Noon – 6 pm ET)

Sw e !
Thursday, February 15

Job H e re (11 am – 2 pm ET)

Register at
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Featured Empl yers

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 Pediatrics in Review
COMMENTARY ••
•••
• •

1 45 Years of “Cognitive Basis” with a Touch of Humaneness

•
•
Joseph A. Zenel
MOC

•
•
• •
••
•••

ARTICLES To learn how

3 Long-Acting Reversible Etonogestrel Subdermal Implant in Adolescents to claim MOC
Neal D. Hoffman, Elizabeth M. Alderman points, go to:
https://publications.
14 Cushing Syndrome in Childhood aap.org/journals/
Anthony Parish, Clement Cheung, Anna Ryabets-Lienhard, Paul Zamiara, Mimi S. Kim pages/moc-credit.
26 Management of Acute Sickle Cell Disease Pain
Jason N. Payne, Beatrice E. Gee
STAY CONNECTED

INDEX OF SUSPICION facebook.com/pedsinreview

39 Persistent Bleeding in a 7-week-old Girl

twitter.com/AAPJournals
Leslie Saba, Matthew C. Authement
43 Severe Malnutrition in an Adolescent Girl
Doha Aboul-Fotouh, Marcella Donaruma-Kwoh, Gal Barak, Andrea Dean
publications.aap.org/journals
47 Cough, Neck Pain, and Right Facial Paralysis in a 14-year-old with Autism
Zhongbo Hu, Bradley Muller, Jeremy S. Slone, Hiroto Inaba
52 Facial Lesions and Rash in a 2-month-old Boy
Alexandra Curry, Anoop Khalsa, David Yi

IN BRIEFS
57 Lice: Head, Body, Pubic
Katherine A. Jordan, Stephanie N. Ferrin, Priyanka Rao
60 Spontaneous Pneumothorax and Pneumomediastinum
Molly Carney, Allison E Williams

VISUAL DIAGNOSIS
e1 Coral Fluorescing Axillary Plaques Refractory to Topical Antifungal and
Antibacterial Treatments
Brendan P. Stewart, Kayla Gonzalez, Caleb Wasser

Answer Key appears on page 62.

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 Pediatrics in Review
Editor-in-Chief Associate Editor, In Brief
Joseph A. Zenel, Bend, OR Linda Y. Fu, Washington, DC
Deputy Editor Associate Editor, CME
Hugh D. Allen, Houston, TX Rani Gereige, Miami, FL
Associate Editor, Index of Suspicion Managing Editor
Kriti Puri, Houston, TX Heidi Willis
Associate Editor, Visual Diagnosis Editorial Associate
Mark F. Weems, Memphis, TN Josh Sinason
Associate Editor, In Brief Medical Copyeditor
Janet R. Serwint, Baltimore, MD Lisa Cluver

EDITORIAL BOARD
Peter F. Belamarich, Bronx, NY Marta King, Saint Louis, MO
Eyal Ben-Isaac, Los Angeles, CA Stephanie Lauden, Columbus, OH
Roger L. Berkow, Atlanta, GA Priya Mahajan, Mission Viejo, CA
Rebecca C. Butterfield, Albany, NY Katie A. Meier, Cincinnati, OH
Heather Campbell, Washington, DC Norman Ramirez-Lluch, Mayaguez, PR
Cynthia Christy, Rochester, NY Jennifer S. Read, Burlington, VT
Steven Ciciora, Columbus, OH Jennifer A. Reed, Sioux Falls, SD
Cleavon Covington, Galveston, TX E. Steve Roach, Austin, TX
Daniel M. Fein, Bronx, NY Kanani Titchen, San Diego, CA
Naomi Fogel, Chicago, IL Samantha Vergano, Norfolk, VA
John G. Frohna, Charleston, WV Melissa Weddle, Portland, OR
Timothy Garrington, Aurora, CO Miriam Weinstein, Toronto, ON
Tamara Gayle, Washington, D.C. Shan Yin, Cincinnati, OH
Thomas C. Havranek, Bronx, NY Shabana Yusuf, Houston, TX
Bert Emil Johansson, El Paso, TX

PUBLISHER American Academy of Pediatrics

Benjamin D. Hoffman, President
Mark Del Monte, Chief Executive Officer/Executive Vice President
Mary Lou White, Chief Product Officer/Senior Vice President, Membership, Marketing and Publishing
Mark Grimes, Vice President, Publishing
Joseph Puskarz, Director, Journal Publishing
The journal wishes to extend special thanks to the following question writers and ancillary reviewers who contributed to
this issue:
Alaa Al Nofal, MD
Patricia Kelly, MD

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(ACCME) to provide continuing medical education for physicians.
The AAP designates this journal-based CME activity for a maximum of 36.0 AMA PRA Category 1 Credit(s)™. Physicians should
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 COMMENTARY

45 Years of “Cognitive Basis” with a Touch of

Humaneness
Joseph A. Zenel, MD
Editor in Chief, Pediatrics in Review

This January, Pediatrics in Review (PIR) enters its 45th year of publication, achieving an outcome founding Editor-
in-Chief Dr Robert Haggerty must have envisioned when he designed PIR for a pediatrician readership “with the hopes
that they will be interested in subscribing.” (1) In that first PIR issue in July 1979, Dr Haggerty reflected, “In starting
the new journal to assist in continuing medical education we know that information alone does not necessarily improve
a physician’s skill, humaneness, or effectiveness. But, cognitive information is the first step in maintaining or improving
competency.” (2) PIR’s primary mission was to provide that cognitive information, updated every five to six years, to
help pediatricians and pediatric practitioners stay current in their clinical practice. While PIR dutifully follows that mis-
sion, I think it was both Dr Haggerty’s and subsequent Editor-in-Chief Dr Larry Nazarian’s humaneness—that is, their
compassion and consideration for others—that made the information in PIR palatable, acceptable, and even enjoyable
these past 45 years, thereby ensuring the journal’s success and effectively teaching pediatrics throughout the world.
In particular, I believe PIR’s endurance as a CME journal is due to two of Dr Haggerty’s underlying philosophies.
The first was “to provide company yet not bore you bringing you up-to-date,” (2) which I rephrase to, “try not to lose the
readers’ attention.” Dr Haggerty once subtly suggested to me that some of my articles in PIR were way too long. His advice
was to keep PIR pertinent and practical, even personable, but not preachy.
The second and even more important philosophy was to avoid becoming “increasingly irrelevant to the health of
children.” (3)
In the October 1995 issue of Pediatrics, Dr Haggerty and Dr Nazarian wrote separate commentaries on the future of
pediatrics, raising issues then that now are powerfully relevant given today’s professed beliefs, values, and politics.
Twenty-five years ago, Dr Haggerty speculated there would be increasing ethnic and cultural diversity and beliefs, unex-
pected evolving family structures, increasing isolation of individuals from society, continuing advances in science and
technology, and a growing number of children with chronic diseases and children with psychosocial disorders, all of
which combined would “require pediatricians to understand and accept this diversity … to be more active in schools and
communities and participate with other disciplines and social support groups.” (3) Dr Nazarian opined that while the de-
mand of infectious diseases might decline, psychosocial disorders would demand more of a pediatrician’s time, more
children would have chronic conditions, prevention would occupy a central role in practice, and business systems would
have “both positive and negative impact on the quality of care and on the lifestyles of pediatricians.” (4) Perhaps both
Drs Haggerty and Nazarian foresaw that the pediatricians of 2024 would practice in a world peppered with strong, op-
posing views on health care, work/life balance, inequity, social media and its effects, family values, gender issues, men-
tal health, education, the business of medicine, artificial intelligence, and science and technology. Polarization on these
views risks separating pediatricians from their patients, making pediatricians irrelevant. I believe that deep down, when
Dr Haggerty and Dr Nazarian edited PIR and authored those 1995 commentaries, they followed the principles of the
Declaration of Geneva, a pledge of service to humanity taken upon medical school graduation. Within that pledge, one
phrase stands out: “I will not permit considerations of age, disease or disability, creed, ethnic origin, gender, nationality, politi-
cal affiliation, race, sexual orientation, social standing or any other factor to intervene between my duty and my patient.” (5) I
believe, as does the PIR editorial board, that behind PIR’s mission to help pediatricians and pediatric practitioners stay current
in their clinical practice is another mission: to provide information to help pediatricians be humane.

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 The editorial board and staff of PIR continue to explore ways to not bore you, yet keep you up-to-date. We try new ap-
proaches such as grouping case presentations around a single continuing medical education theme, or devoting a
month’s issue to a single subspecialty. We ask questions of ourselves, such as how to entice clinicians to pursue and un-
derstand new information on their own, when electronic medical records readily provide treatment algorithms or arti-
ficial intelligence can generate answers to questions typed on the spur of the moment? How many words should a
review article contain? How often should a subject be covered? How do we broach controversial medical topics that
pediatricians need to know, without being judgmental?
In an effort to appeal to all pediatricians, the editorial board remains diverse and forward-thinking, with its membership
ever-changing. We say good-bye to Dr Henry Adam, associate editor of “In Brief,” whose practical wisdom and unique wit will
be missed and welcome Dr Linda Fu as the new associate editor of “In Brief,” a general pediatrician whose NIH experience in
scientific research will provide new insights. We also say good-bye to Dr Lynn Garfunkel, associate editor of “Index of Sus-
picion,” who critiqued case submissions with grace and humor, and welcome Dr Kriti Puri as the new associate editor of
“Index of Suspicion,” a cardiologist intensivist who, at heart, is really a general pediatrician.
When he retired after 25 years as editor in chief, Dr Haggerty penned, “I have no doubt that PIR will continue to im-
prove and provide the cognitive base for the optimum health care of children.” (6) Twenty years later, PIR continues to edu-
cate, thanks to the American Academy of Pediatrics and to the many junior, mid-career, and senior pediatricians who guide,
advise, and contribute to the journal, all with just a touch of humaneness.

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 ARTICLE

Long-Acting Reversible Etonogestrel

Subdermal Implant in Adolescents
Neal D. Hoffman, MD,* Elizabeth M. Alderman, MD*
*Children’s Hospital at Montefiore/Albert Einstein College of Medicine, Bronx, NY

EDUCATION GAP

Pediatricians may not be confident in their ability to engage an adolescent

in shared decision-making if they are not knowledgeable about effective
birth control methods beyond the most prescribed oral contraceptive pills
and the injectable depot medroxyprogesterone acetate. Long-acting reversible
contraception, including the intrauterine device and the etonogestrel subdermal
implant, are important options to include in discussions with adolescents using
a reproductive justice framework that promotes autonomy.

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

1. Apply principles of effective and ethical counseling for adolescents

about effective birth control methods.
2. Explain the indications and effectiveness of the etonogestrel subdermal
implant.
3. Give examples of potential adverse effects of the etonogestrel subdermal
implant.
4. Discuss with an adolescent the advantages and disadvantages of the
etonogestrel subdermal implant.

AUTHOR DISCLOSURE: Drs Hoffman and

ABSTRACT Alderman have disclosed no financial
relationships relevant to this article. This
Several effective contraceptive options are available for use by adolescents, commentary contains discussion of an
including the long-acting reversible subdermal implant and intrauterine off-label use of the etonogestrel implant.
devices, which provide a high level of convenience, privacy, and effectiveness
for an adolescent. Knowledge of all the effective birth control methods is ABBREVIATIONS
essential for the pediatrician to be able to provide effective contraceptive
CDC Centers for Disease Control and
counseling for an adolescent. An approach to counseling using a reproductive Prevention
justice framework, which allows the provider and adolescent patient to engage COC combined oral contraceptive pill
in shared decision-making, is described. This article focuses on the long-acting DMPA depot medroxyprogesterone
acetate
reversible etonogestrel (ENG) subdermal implant for adolescents. The ENG ENG etonogestrel
implant is labeled for preventing pregnancy by suppressing ovulation. The IUD intrauterine device
ENG implant may also have a role in ameliorating dysmenorrhea and heavy MEC Medical Eligibility Criteria for
Contraceptive Use, 2016
menstrual bleeding. Postlabeling studies indicate that the ENG implant is POP progestin-only pill
effective for up to 5 years, although the device’s labeling states effectiveness VTE venous thromboembolism

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 up to 3 years. The main contraindication to using the ENG implant is pregnancy itself. Safe initiation of the ENG
implant is described, including an approach to determine whether an adolescent is pregnant. The main adverse
effect of the ENG implant is an unpredictable bleeding pattern that is most often ameliorated by use of nonsteroidal
anti-inflammatory medications, as well as estrogen, if not contraindicated for the patient. Details of the insertion and
removal procedures, including potential complications, are described to enable the pediatrician to provide effective
anticipatory guidance for the adolescent.
BACKGROUND
Range of Options for Contraception
This article focuses on the long-acting reversible etonoges-
trel (ENG) subdermal implant for adolescents. First ap-
proved by the FDA in 1999 as a single, 4-cm-long, ENG-
containing rod for subdermal placement, the ENG implant
was updated as a radiopaque implant with a special in-
serter to make insertions and management easier for
trained clinicians. (1)(2) Numerous reports indicate high
satisfaction, with at least 80% of users, including adoles-
cents, continuing its use for more than 12 months. (3) The
Contraceptive CHOICE Project demonstrated high accep-
tance of the ENG implant by adolescents in a prospective
cohort study that provided on-demand, no-cost contracep-
tion. More than one-third of 14- to 19-year-olds selected the
implant. (4) Although 1 study found that more than 45% of
trained providers were gynecologists, almost half were nurse
practitioners and general practitioners. (5)
However, note that several effective hormonal contracep-
tive options, in addition to barrier methods, exist and are
appropriate for use by adolescents. Each method has advan-
tages and disadvantages; no single option is perfect and
must be considered in the context of the individual adoles-
cent’s contraceptive needs, lifestyle, and medical history. (6)
In addition to the ENG implant, the intrauterine device
(IUD) is another long-acting reversible option, of which
there are 2 types: 1 without any hormones, known as the
copper IUD, and 1 with the hormone progestin, known as
the levonorgestrel IUD. Short-acting contraceptive meth-
ods include oral contraceptive pills, most of which are a
combination of estrogen and progestin. For those for
whom estrogen-containing regimens may be contraindi-
cated, a progestin-only pill (POP) is available. The other 2
short-acting alternatives to the combined oral contracep-
tive pill (COC), both of which are a combination of estro-
gen and progesterone, include the contraceptive skin
patch and the intravaginal ring. Finally, depot medroxypro-
gesterone acetate (DMPA) is an intermediate-acting method
that remains a very important contraceptive option, particu-
larly for those who cannot use estrogen and cannot tolerate
oral medication. Progestin-only methods, including long-
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acting methods such as the ENG implant, play an impor-
tant role in the contraception toolbox when estrogen is
medically contraindicated for the adolescent patient. (7)
Effectiveness of all family planning methods is shown in
Fig 1.
Contraceptive Counseling
Contraceptive counseling is an important skill for all clini-
cians working with adolescents to support access and
informed decision-making. (8) With so many options
available, it is tempting to use a hierarchical approach
when counseling an adolescent about choosing a method.
By hierarchical, we mean using an approach based on
tiered efficacy, usually emphasizing the long-acting meth-
ods. However, providing the best reproductive and sexual
health care requires each of us to first learn an adoles-
cent’s priorities and needs. (6) Patient-centered counseling
for reproductive health best starts with clarifying an ado-
lescent’s contraceptive needs: Are they sexually active?
What are the genders of their partners? Do they have a
specific intention regarding pregnancy in the next 12
months? It is also important to ask adolescents about their
previous experience with contraception and their current
knowledge about contraception, if any; what knowledge
does the adolescent have about other methods (ie, through
friends, relatives, or media); and if the adolescent has ex-
perienced any previous pregnancies. The 5 P’s (partners,
pregnancy prevention, sexually transmitted infection pro-
tection, sexual practices, and past sexually transmitted in-
fections) can be used as a guide for the basic framework
for obtaining a sexual history. (9) Once established that
pregnancy prevention is a desire and a priority, a common
approach to shared decision-making for an adolescent in-
cludes 3 domains: privacy concerns, current and preferred
menstrual pattern, and ease of use of a method. The com-
bined estrogen-progestin methods (COC, patch, and ring)
create a regular period, which may be a priority for the
young person. For some who find taking a pill daily to be
burdensome, the weekly patch and monthly ring may be
easier to use. However, there may be a concern for privacy
if patients are living with someone who might oppose
 Figure 1. Effectiveness of family planning methods.
their choice and could find the pill packet, the extra
patches, or the ring’s foil pack, for example. Longer-acting
methods such as the DMPA injection, the ENG implant,
and the IUD may be more appealing to the young person
who prioritizes a user-independent method. However, the
irregular bleeding or absence of bleeding that often comes
with the DMPA injection, the ENG implant, and the levo-
norgestrel IUD may impact privacy as well if the patient is
living with someone who might notice a change in the
adolescent’s menstrual pattern. In this case, the nonhor-
monal copper IUD may be more appealing given that it
does not change the person’s menstrual cycle. On the
other hand, the amenorrhea possibly caused by the DMPA
injection, the ENG implant, and the levonorgestrel IUD
may be very appealing to the young person with already
heavy periods or for the transmasculine or nonbinary
young person for whom menstruation creates dysphoria.
An important practical concern for adolescents, which has
implications for privacy as well, is cost and access, that is,
whether the patient has insurance they can use or can eas-
ily access state-funded insurance that covers family plan-
ning needs.
We also advocate using the framework of reproductive
justice to best assist an adolescent to make the best
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decision for themselves. (10) Reproductive justice is de-
fined by SisterSong as “the human right to maintain per-
sonal bodily autonomy, have children, not have children,
and parent children in safe and healthy environments.”
First developed by Women of African Descent for Repro-
ductive Justice, this framework acknowledges that many
communities have experienced structural discrimination
and coercion by individual practitioners and institutions,
as well as significant constraints on access to both contra-
ception and abortion care. Instead of valuing and respect-
ing individual autonomy, practitioners have often allowed
public health goals to supersede the individual’s needs.
(11) The reproductive justice framework provides us with a
tool to reverse this trend. Of note, a recent survey of pedi-
atric trainees, especially compared with their family medi-
cine and gynecology counterparts, showed a low level of
experience with contraceptive counseling and minimal ex-
posure to the reproductive justice framework. (12) One
can only assume the same experience for most pediatric
providers already out in the field, underscoring the need
for reproductive counseling as an important topic of con-
tinuing education for all of us. (13) The American Acad-
emy of Pediatrics has a resource, “Equitable Access to
Sexual and Reproductive Health Care for All Youth”
Vol. 4 5 No. 1 JANUARY 2024 5
 (https://www.aap.org/reproductivehealth), that provides best
practices and other resources to provide such care.
INDICATIONS AND USE OF THE ENG
SUBDERMAL IMPLANT
The ENG implant is labeled specifically for preventing
pregnancy, with the primary mechanism being suppres-
sion of ovulation. Ovulation is suppressed by the effect of
ENG (a progestin hormone) on the hypothalamus, provid-
ing negative feedback on gonadotropin-releasing hormone
release. With no release of gonadotropin-releasing hor-
mone, the anterior pituitary will not release luteinizing
hormone and follicle-stimulating hormone; therefore, no
ovarian follicle develops, and no egg is extruded from the
ovary to travel to the uterus. Additional mechanisms of
ENG that prevent pregnancy include increased viscosity of
cervical mucus and alteration of the endometrium to inhibit
implantation. The ENG implant has been shown to be safe
and effective for adolescents and adults. If a patient chooses
the ENG implant, it is essential to discuss the concurrent
need for condom use because the implant does not provide
protection against sexually transmitted infections.
Although not labeled for noncontraceptive indications,
studies show that the ENG implant is effective for a vari-
ety of noncontraceptive concerns. The most common sec-
ondary use is for treatment of severe dysmenorrhea, (14)
also via the mechanism of suppressing ovulation and,
therefore, preventing ovarian production of endogenous
progesterone. Progesterone is responsible for inducing the
prostaglandin synthesis cascade that results in the produc-
tion of oxygen radicals that contribute to uterine muscle
ischemia, causing menstrual cramps. Although not first-
line, the ENG implant may also be used to decrease men-
orrhagia or even cause full menstrual suppression as
some patients experience complete amenorrhea. However,
the ENG implant is often not as effective as other first-line
treatments because the implant may cause unpredictable
bleeding given the direct effect of ENG on the endometrial
lining (discussed further later herein). The ENG implant
is also sometimes used, although off-label, to prevent en-
dometrial hyperplasia in patients with polycystic ovary syn-
drome. Finally, some adolescents with acne benefit from
suppression of ovulation and endogenous hormone pro-
duction by the ENG implant. ENG, itself, is not very an-
drogenic compared with medroxyprogesterone. (15)
CONTRAINDICATIONS
There are relatively few contraindications to use of the ENG
implant. The most important contraindication to insertion
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of an ENG implant is a known or suspected pregnancy. Re-
gardless of reported sexual history, a negative pregnancy
test result is required on the day of insertion. Suspected
pregnancy, based on current symptoms and/or recent un-
protected intercourse, needs to be considered before pro-
ceeding and is discussed later herein in the “Initiation of
the Implant” section. If, after counseling a patient, the pa-
tient elects for ENG implant insertion on another day, the
patient should be advised not to have unprotected sex since
the last menses or within the previous week.
Bleeding diatheses such as Von Willebrand disease or
hemophilia should be addressed with a hematologist to
consider the safest preparation for the patient to use to
avoid significant bleeding.
Other important contraindications to the ENG implant,
similar to other progestin-only methods, include active liver
disease (such as hepatitis and hepatic tumors), known or
suspected breast cancer, or other progestin-sensitive can-
cers. Although the package insert mentions that a personal
history of thromboembolic disorders would prohibit its use,
the current Centers for Disease Control and Prevention’s
(CDC’s) US Medical Eligibility Criteria for Contraceptive
Use, 2016 (US MEC) guideline rates the ENG implant as
category 2, a condition for which the advantages of using
the method generally outweigh the theoretical or proven
risks. (7) Undiagnosed abnormal genital bleeding needs to
be evaluated before insertion, although abnormal genital
bleeding is rarely due to endometrial cancer in adolescents.
And, finally, although uncommon, previous allergic reac-
tion to any of the components of the current ENG implant
is also a contraindication to placement. Consultation with
an allergist would be helpful to provide appropriate counsel-
ing in this situation.
Potential drug interactions should be considered before a
patient decides to choose the ENG implant because this device
delivers a systemically distributed medication. Drugs or herbal
products that induce the cytochrome P450 enzymes may de-
crease the plasma concentrations of the progestin, resulting in
diminished effectiveness as well as breakthrough bleeding.
Some examples include antiepileptic drugs such as phenytoin,
antimicrobials such as rifampicin, and the herbal St. John’s
wort. Drugs or herbal products that inhibit cytochrome P450
enzymes, such as azole medications and grapefruit juice, may
increase plasma concentrations of the progestin. (16)
EFFICACY INCLUDING ONSET AND DURATION OF
ACTION AND RISK OF FAILURE TO PREVENT PREGNANCY
The ENG implant is a highly effective, non–user-dependent
method of contraception. (17) The initial determination of
 ENG implant efficacy in clinical trials was up to 3 years. This
remains the current duration stated in the Food and Drug Ad-
ministration (FDA) labeling. However, numerous postlabeling
studies definitively support a 5-year duration of effect. (18)
However, clinical trials suggest a 3 per 1,000 failure rate for
the device based on observed pregnancies during clinical tri-
als. Further analysis of the data suggests that pregnancies
likely occurred just before or within 2 weeks after removal of
the implant. In vivo efficacy is reported as greater than 99%
effective. (19) Concerns have been raised about the efficacy of
the ENG implant in persons with elevated BMI because indi-
viduals who weighed more than 130% of ideal body weight
were not included in clinical trials. One study of primarily
white women found that increasing BMI and longer duration
of implant use were associated with small decreases in serum
hormone levels. (20) However, 1 study of a community sam-
ple of mostly Hispanic women found comparable ENG levels
across a wide BMI range. (21) Of note, women on medi-
cations that induce hepatic enzymes were also excluded
from clinical trials. Pharmacokinetic studies show the
peak of mean serum concentrations 4 days after inser-
tion. (22) Serum concentrations drop precipitously at re-
moval of the implant. (20) Therefore, when removing the
ENG implant, another method of contraception should
be initiated if pregnancy is not desired at the time of re-
moving the implant.
INITIATION OF THE IMPLANT
The most important step before initiating the ENG im-
plant is to document a negative pregnancy test result on
the same day as insertion. The ENG implant, as for other
effective birth control methods, can be initiated using a
traditional start, that is, on days 1 to 5 of expected men-
struation. The implant can also be initiated at other times
during the patient’s menstrual cycle using the quick start
approach. (23) For quick start initiation, one must reliably
document that a person is not pregnant. See Figure 2 for
CDC recommendations to reasonably determine whether
a patient is pregnant. For example, if the patient’s last
menstrual period was within the previous 7 days, then one
does not need to be concerned about recent ovulation and,
therefore, pregnancy risk. However, if the patient’s last
menstrual period was more than 7 days earlier, and the
person had unprotected sex, then one cannot reliably rule
out recent ovulation. This situation requires counseling
the patient about the small, but real, possibility of having
an undetected early pregnancy since ovulation can occur
as early as 8 days after the first day of the last menstrual
period. (24) Although some patients may decide to defer
the insertion, it is safe to continue with insertion and re-
peat the pregnancy test 2 to 4 weeks later. In anticipation
of a possible positive pregnancy test result at the follow-up
visit, counseling to assist the patient in deciding whether
to continue or discontinue the pregnancy is needed. Safety
studies indicate that there is no harm to an early develop-
ing fetus if exposed to the ENG. However, removal of the
implant is indicated if the patient is pregnant and decides
to continue the pregnancy.
If a patient is currently using another hormonal form of
contraception, particularly one that is not used daily, the pa-
tient can easily switch to the ENG implant. There is no clini-
cal reason to delay the insertion unless the patient prefers to
“take a break” from all forms of hormonal birth control. The
optimal timing is to insert the implant at least 4 days before
stopping the other contraceptive method, except for the
DMPA injection, which is still medically active up to 15
weeks after the last dose. In this case, one ideally inserts the
implant at week 14 after the last DMPA injection. (25) The
ENG implant can also be safely started after a pregnancy
termination or immediately postpartum. Although small
amounts of contraceptive steroids or metabolites can be
found in human milk, including in the first few weeks post-
partum, studies have not shown that ENG affects human
milk volume or content in the first month. (26)(27)
There is currently no evidence that the ENG implant
is effective as emergency or postcoital contraception. If
the patient has had intercourse in the 5 days before the
appointment for insertion of the implant, emergency
contraception should be provided at that time using the

A health care provider can be reasonably certain that a woman is not pregnant if she has no
symptoms or signs of pregnancy and meets any one of the following criteria:

• is ≤7 days after the start of normal menses

• has not had sexual intercourse since the start of last normal menses
• has been correctly and consistently using a reliable method of contraception
• is ≤7 days after spontaneous or induced abortion
• is within 4 weeks postpartum
• is fully or nearly fully breastfeeding (exclusively breastfeeding or the vast majority
[≥85%] of feeds are breastfeeds), amenorrheic, and <6 months postpartum

Figure 2. How to be reasonably certain that a woman is not pregnant at the time of a contraceptive visit. https://www.cdc.gov/reproductivehealth/
contraception/mmwr/spr/notpregnant.html#Box2

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 levonorgestrel 1.5-mg tablet. Ulipristal, a progestin antag-
onist, is best avoided because it may decrease the efficacy
of the implant, as well as other progestin-containing
methods. (28)
INSERTION OF THE IMPLANT
Insertion of the ENG implant may be performed only by a
clinician formally trained by a certified trainer, which in-
cludes physicians, physician assistants, nurse practition-
ers, and nurses. (29) The procedure for insertion of the
ENG implant is safely performed in an outpatient setting.
Sedation is not indicated because of the brevity of the pro-
cedure, but a very anxious patient may benefit from relaxa-
tion techniques, often using music or mindfulness, to
tolerate the procedure. Local anesthesia with 1% lidocaine
before the implant’s insertion is all that is needed, al-
though some centers provide topical lidocaine before skin
infiltration. Using a special single-handed applicator, the
implant is inserted at the medial aspect of the upper arm
at least 3 cm below the groove between the biceps and tri-
ceps muscles to avoid deep nerves and blood vessels. Special
care is made to place the implant subdermally to keep it po-
sitioned as superficially as possible, allowing the implant to
remain palpable. This superficial placement facilitates the
subsequent removal of the implant when desired. Thin adhe-
sive strips are placed at the insertion site, and a small pres-
sure bandage is placed over the implant for 24 hours to
reduce bruising. The patient must keep the small pressure
bandage completely dry during this time to minimize the
risk of a skin infection. In addition to skin infection, poten-
tial complications include mild pain, paresthesia, bleeding,
hematoma, and scarring. Mild postprocedural pain responds
to acetaminophen or ibuprofen, as well as to cold packs.
BLEEDING PATTERNS EXPERIENCED WITH THE
IMPLANT
The most common adverse effect of the ENG implant,
and the most common reason for early removal, is irregu-
lar menstrual bleeding. (30) Advising patients of this
when counseling them about the ENG implant is crucial.
Unexpected bleeding is due to the ENG directly thinning
the endometrium. Approximately 60% of patients within
the first 90 days after insertion of the implant will experi-
ence a favorable bleeding pattern; this includes regular
(monthly or less than once a month) bleeding or complete
absence of bleeding (amenorrhea). Approximately 85% of
patients will maintain a favorable pattern for the next 3
months, although this decreases to 60% through the first
year. In contrast, 40% of patients within the first 90 days
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after insertion will experience unfavorable bleeding pat-
terns, including frequent or prolonged bleeding. The good
news is that almost 40% of these will revert to a favorable
bleeding pattern in the subsequent 3 months, and almost
half will revert to a favorable bleeding pattern through the
first year. Nevertheless, the unfavorable bleeding observed
for some patients with the implant is painless.
Most of the time, unexpected bleeding is a nuisance
and not medically concerning, but sometimes it can result
in anemia. In either case, bleeding can be controlled by
several treatments, and a stepwise approach is described
in a figure on the CDC’s website. (31)
The unfavorable bleeding associated with the ENG im-
plant often may be diminished or stopped somewhat with 5
to 7 days of treatment with nonsteroidal anti-inflammatory
medications (NSAIDs), including ibuprofen and naproxen.
(32) However, very prolonged bleeding often requires treat-
ment with an estrogen-containing medication, such as the
COC or supplemental estrogen, to temporarily thicken the
very thinned endometrium, in the absence of medical contra-
indications to using estrogen for the patient. The bleeding of-
ten responds within 48 hours and may require only 10 days
of COCs or 7 days of oral estrogen; in addition to stopping
the bleeding, it is hoped that these estrogen-containing regi-
mens will increase the interval between bleeding episodes.
In other words, the short course of estrogen is a temporizing
measure. Another reason for unexpected bleeding can be
cervicitis, and, therefore, if cervicitis is suspected, a gyneco-
logic examination and testing for sexually transmitted infec-
tions such as gonorrhea and chlamydia is warranted. (33)
With such a low contraceptive failure rate, pregnancy would
be unusual but should be considered, particularly if a patient
has other symptoms of pregnancy. (34)
OTHER ADVERSE EFFECTS
Other adverse effects from the ENG implant are minimal
and rarely occur. Some patients experience weight gain,
but a mean of only 2.8 lb (0.36 kg) of weight gain was re-
ported in the first year, and 3.7 lb (1.68 kg) over 2 years in
studies. (35)(36) Nevertheless, in 1 retrospective cohort
study of adolescent long-acting reversible contraception
users showed that preexisting obesity predicted a higher
BMI change for those using either the ENG implant or
the hormonal IUD. (37) Approximately 6% of ENG im-
plant clinical trial participants reported emotional lability,
and 5% reported depression; only 3% of participants cited
this as a reason for early removal. (38) ENG is one of the
least androgenic progestins, and less than 15% of clinical
trial participants reported acne. No decrease in bone
 density has been observed in persons using the ENG im-
plant, in contrast to the DMPA injection. This is likely be-
cause estradiol levels tend to remain physiologic in ENG
implant users. As with all progestin-only contraceptive
methods, there may be a slightly increased occurrence of
an ectopic pregnancy due to decreased tubal motility. (39)
Finally, it is unknown whether any increased thromboem-
bolic risk can be attributed to ENG alone, although there
are postlabeling reports of serious thrombotic events. As
noted previously herein, the CDC’s MEC classifies the
ENG implant as category 2. No incidents of increased ve-
nous thromboembolism (VTE) have been reported after
bariatric surgery for ENG implant users, and the CDC’s
US MEC classifies the ENG implant as category 1 (no re-
striction for use as contraception) after bariatric surgery.
COMPLICATIONS
The most serious complication of the insertion of an ENG
subdermal implant is the migration of the implant in the
arm away from the insertion site, which can include mi-
grating into the axillae and the thoracic cavity. (40) One
study documented that only 1 in 87 patients followed
1 year after insertion had a cranial migration of more than
2 cm. (40) These rare events are thought to result from in-
appropriately deep placement of the implant. It is impor-
tant to palpate the implant at follow-up visits to ensure it
remains where it was inserted. Patients can also be in-
structed to palpate the implant occasionally. More com-
mon but minor complications include paresthesia at the
insertion site. Previous concerns about deep blood vessel
or nerve damage have been allayed with the proper place-
ment of the implant at least 2 to 3 cm medial to the sulcus
between the biceps and the triceps.
REMOVAL
Implant removal may be indicated if the adolescent is not
satisfied for any reason with the implant or if the duration
of effect has been reached. If the patient is satisfied with
the method, a new implant can be immediately inserted at
the same site on the arm (unless the original placement
site was too close to the groove between the biceps and tri-
ceps muscles).
The removal procedure requires localization of the im-
plant. (13) If the implant cannot be palpated with one’s fin-
ger, then the implant is best located by radiographic
imaging given the presence of barium sulfate in the im-
plant rendering it radiopaque. Ultrasonography may also
be used to locate and mark the implant for removal. Simi-
lar to the insertion procedure, removal is safely performed
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in an outpatient setting. Sedation is not indicated because
of the brevity of the procedure, but a very anxious patient
may benefit from relaxation techniques, often using music
or mindfulness to tolerate the procedure. Local anesthesia
with 1% lidocaine and the vasoconstrictor epinephrine to
provide minimize bleeding is used to infiltrate the skin. A
sterile scalpel is used to make a 2-mm insertion along the
tip of the implant closest to the elbow, through which any
adherent fibrous tissue is teased apart from the implant,
and the implant removed. Thin adhesive strips are placed
at the insertion site, and a small pressure bandage is
placed over the implant for 24 to 48 hours to reduce bruis-
ing. The patient must keep the small pressure bandage
completely dry during this time to minimize the risk of a
skin infection. In addition to skin infection, potential com-
plications include mild pain, paresthesia, bleeding, hema-
toma, and scarring.
BILLING AND CODING
Understanding the billing process is essential to maintain-
ing both access to contraception and confidentiality for
adolescents, including use of the ENG implant. Current
Procedural Terminology codes and International Classifica-
tion of Diseases, Tenth Revision diagnostic codes exist for
both implant insertion and removal, and even for a failed
device placement. (41) A separate Healthcare Common
Procedure Coding System code exists for the device itself.
The American College of Obstetricians and Gynecologists
has an online resource for coding (www.acog.org/education-
and-events/publications/larc-quick-coding-guide). For unin-
sured or underinsured adolescents, programs such as the
federal government’s Title X Family Planning Program and
state government programs such as New York State’s Family
Planning Benefit Program and California’s Family Planning
Access, Care, and Treatment are very helpful. Adolescents
who cannot use their parent’s or guardian’s health insurance
due to confidentiality concerns are eligible for these pro-
grams. School health and college health centers often pro-
vide contraceptive services for free or at much lower cost.
The Kaiser Family Foundation has information online for
state-by-state coverage (https://www.kff.org/womens-health-
policy/report/medicaid-coverage-of-family-planning-benefits-
findings-from-a-2021-state-survey/).
CONTRACEPTIVE COUNSELING AND
MANAGEMENT
Pediatricians and other primary care providers play a cru-
cial role in counseling young people about contraceptive
choices. Using the principles of reproductive justice and
Vol. 4 5 No. 1 JANUARY 2024 9
 shared decision-making (as articulated previously herein),
the provider should emphasize the effectiveness, reversibility,
and safety of the implant and review the potential adverse ef-
fects, especially the effect on the menstrual pattern. (42)
Pediatricians can also assist an adolescent in assessing
their pregnancy risk before traditional or quick starting
the ENG implant, including advising patients to avoid un-
protected sex within 2 weeks of a scheduled insertion, if
possible. Pediatricians can also play a role in ensuring that
their patients complete the repeated pregnancy test 2 to
4 weeks after insertion, if indicated.
Although the primary care provider may not be trained
to insert (or remove) the implant, the provider plays an
important role in describing the procedure and in address-
ing any related concerns. (43) Practices that do not per-
form the procedure can develop a list of providers who
can and who are adolescent friendly. School health and col-
lege health services, as well as Title X clinics and Planned
Parenthood, are sites that can be included on this list.
At the contraceptive counseling visit, the pediatrician can
provide anticipatory guidance around the possibility of un-
scheduled bleeding, which is hoped will allow a young
woman to understand that bleeding is a likely adverse effect
and will seek advice and appropriate medication management
early. Anticipatory guidance may also ultimately decrease re-
quests for early discontinuation of the ENG implant. Never-
theless, the decision by a young woman to seek removal of
the implant should be respected and supported.
High-quality online resources for adolescents about the
ENG implant and other contraceptive methods include the
Center for Young Women’s Health (www.youngwomens
health.org), the Reproductive Health Access Project (www.
reproductiveaccess.org), Bedsider (www.bedsider.org), and
the North American Society for Pediatric and Adolescent
Gynecology (www.naspag.org/assets/docs/larc_2020.pdf).
Educational resources for providers include the Repro-
ductive Health Access Project (www.reproductiveaccess.
org) and the American College of Obstetricians and Gy-
necologists (www.acog.org/programs/long-acting-reversible-
contraception-larc).
EXAMPLE CASES
Case 1
A 19-year-old presents to discuss contraception with you
and is very interested in getting the ENG implant today.
She is in a new romantic relationship with a male partner.
What else do you need to know before proceeding with or re-
ferring the patient for an ENG implant insertion?
1. Concurrent medications, including contraception.
2. Medical history, including recent pregnancy.
3. Most recent unprotected intercourse.
4. Last menstrual period.
5. All of the above.
All these questions are important to ask and consider
when counseling an adolescent on contraceptive decision-
making. The request for an immediate insertion of the
ENG implant is best considered in the context of the ado-
lescent’s most recent menstrual period and the most re-
cent episode of unprotected intercourse. The primary
concern is the ability to rule out a current pregnancy with
certainty. If an adolescent has been consistently and cor-
rectly using an effective birth control method, then a nega-
tive urine pregnancy test is reliable. The same goes for a
situation in which the adolescent is currently menstruat-
ing, and this is a regular and expected menses. Further-
more, if the adolescent’s last menstrual period is less than
7 days ago, then the risk of ovulation is minimal to none
such that one can quick start the ENG implant safely.
Concerns are raised when the start of the adolescent’s
last menstrual period is more than 7 days earlier and the
adolescent has had unprotected sex since that time. Al-
though deferring the insertion until the adolescent’s next
menstrual period is a consideration, quick starting the
ENG implant remains a safe option for this patient. How-
ever, one needs to engage the adolescent in a discussion
about the possibility of missing the identification of an
early pregnancy. If the patient wants to proceed with the
ENG implant insertion, then a repeated pregnancy test
(either in the clinical office or at home) is needed in 2 to
4 weeks. (23)
If the most recent unprotected intercourse was within
the past 5 days, then the adolescent is also a candidate for
emergency contraception concurrent with the insertion. In
this case, the best option is the levonorgestrel emergency
contraceptive pill rather than ulipristal, which interferes
with the ENG progestin’s actions (see the CDC website:
2016 U.S. Selected Practice Recommendations for Contracep-
tive Use [http://www.cdc.gov/reproductivehealth/contraception/
contraception_guidance.htm].)
Case 2
A 16-year-old girl with sickle cell disease presents to dis-
cuss contraception with you. She has frequent vaso-occlu-
sive crises as well as cholelithiasis but no history of acute
chest disease or cerebrovascular events. Which methods
would be safest for her to consider? The options are

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 COCs, contraceptive patch, and vaginal ring; POP; DMPA;
ENG implant; hormonal IUD; and nonhormonal IUD.
All effective birth control methods are worth consider-
ing for an adolescent with sickle cell disease because of
the increased risk of pregnancy complications. However,
interdisciplinary input to engage the adolescent in shared
decision-making will afford the best outcome for the ado-
lescent to make the most informed decision. The proges-
tin-only methods—POP, DMPA, ENG implant, and
hormonal IUD—are the safest methods for this patient to
consider. The estrogen-containing methods (COC, patch,
and vaginal ring), which are designated by the US MEC as
category 2 (a condition for which the advantages of using
the method generally outweigh the theoretical or proven
risks) can be considered for a patient who has not previ-
ously had a stroke or VTE, but one needs to counsel the
patient in terms of risk of VTE, and one is strongly ad-
vised to consult with the patient’s hematologist before
proceeding with an estrogen-containing method. If this
patient has a history of cerebrovascular accident or other
VTE, then one should not prescribe an estrogen-containing
method. As previously stated, the progestin-only methods—
POP, DMPA, ENG implant—are the safest methods for this
patient to consider. Although in some patients, the ENG im-
plant causes frequent or prolonged bleeding, the bleeding is
generally light and decreases menstrual cramps significantly.
Of the 2 IUDs, the hormonal IUD is safer for a patient with
sickle cell disease than the nonhormonal IUD because, simi-
lar to the ENG implant, menstrual bleeding and cramping are
markedly decreased. The nonhormonal IUD is designated by
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the CDC’s US MEC as category 2 because of the known risk
of heavier and crampier periods; the concern is menorrhagia
worsening anemia and thus increasing the risk of vaso-occlu-
sive events. (44) Of note, the ENG implant, as well as other
contraceptive methods that suppress ovulation, may be helpful
for the noncontraceptive benefit of preventing catamenial
vaso-occlusive crises.
Summary
• The long-acting reversible etonogestrel (ENG)
subdermal implant is a very safe and effective option
for adolescents for contraception, especially for those
with estrogen contraindications, as well as those for
whom ease of use and privacy is a priority. (Based on
strong research evidence) (11)
• Pediatricians play a significant role in providing
birth control counseling and information to
adolescents using a reproductive justice framework
to assist adolescents in making informed decisions.
(Based on some research evidence as well as
consensus) (1)
Take the quiz! Scan this QR code to take the quiz,
access the references and teaching slides, and
view and save images and tables
(available on January 1, 2024).
Vol. 4 5 No. 1 JANUARY 2024 1 1
 PIR QUIZ

1. A 15-year-old girl presents to the school health clinic and is requesting birth
control pills for contraception. She became sexually active for the first time
3 months ago and has had 1 male partner. They have vaginal intercourse twice a
month and consistently use male condoms. Menarche occurred at age 13 years.
She reports that her periods usually occur every 26 days with 5 days of moderate
flow and cramps during the first 2 days. Her last menstrual period was 10 days
ago. She and her partner do not want her to become pregnant. She has never
used emergency contraception, used contraception for other indications, or
missed a period. She currently is not ready to discuss contraception with her
mother and requests confidential services. Which one of the following is the best
approach to initiate contraceptive counseling with this patient?
A. Agree with her choice for birth control, and if there are no contraindications, REQUIREMENTS: Learners can
take Pediatrics in Review quizzes
prescribe a combined oral contraceptive pill (COC). and claim credit online only at:
B. Ask about her preference for and knowledge about birth control pills http://pedsinreview.org.
and other contraceptive methods.
C. Tell her that adolescents have a high pregnancy rate with the use of To successfully complete 2024
Pediatrics in Review articles for
birth control pills and that a user-independent method is best for her.
AMA PRA Category 1 Credit™,
D. Tell her that the depot medroxyprogesterone acetate injection is best learners must demonstrate a
for her because it is available at the clinic, is a more effective method minimum performance level of
than COCs, and has the added benefit of amenorrhea. 60% or higher on this
E. Tell her that the highly effective long-acting etonogestrel (ENG) subdermal assessment. If you score less
than 60% on the assessment,
implant is the best contraceptive method for adolescents.
you will be given additional
2. A 15-year-old girl who has been taking COCs for 6 months for contraception opportunities to answer
asks about ENG implants, which she has read about. She asks about ENG questions until an overall 60%
or greater score is achieved.
implant indications in adolescents and other ENG implant noncontraceptive
benefits. The clinician explains to her that the most common and effective This journal-based CME activity
noncontraceptive benefit of ENG implants include treatment of which one of is available through Dec. 31,
the following noncontraceptive conditions? 2026, however, credit will be
recorded in the year in which
A. Bleeding diatheses (eg, Von Willebrand, platelet disorders). the learner completes the quiz.
B. Irregular menstrual cycles.
C. Menorrhagia associated with anemia.
D. Menstrual dysphoria.
E. Severe dysmenorrhea.

2024 Pediatrics in Review is

approved for a total of 30
Maintenance of Certification
(MOC) Part 2 credits by the
American Board of Pediatrics
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 3. A 17-year-old girl is seen in the clinic for her annual health maintenance visit. Her
last menstrual period was 8 days ago, consisting of her typical period of 5 days
with moderate flow. She has had only 1 sexual partner. She and her male partner
of 6 months almost always use condoms for vaginal intercourse. In confidence
she reveals that she has an appointment in 2 weeks at a community clinic that
has a Family Planning Program (Title X) for contraceptive services. She wants an
ENG implant because it does not require her to remember to take a pill every
day and the ENG implant is effective for 3 years. She values the confidentiality of
both the ENG implant and the community clinic’s services. Screening for sexually
transmitted infections (STIs), availability and use of emergency contraception, and
the continued use of condoms are discussed with the patient. Which one of the
following should be included in a discussion with her about her plans for ENG
implant insertion at the community clinic?
A. After insertion, the implant will not migrate from its placed position.
B. For same-day insertion, she must present to the clinic during days 1 to
5 of her menstrual period.
C. Parental consent will be required for insertion of the implant.
D. Payment from her at the time of service will be required to ensure
confidential insertion.
E. Removal of the implant in the first year of use is performed only for
complications or adverse effects of the implant.
4. A 17-year-old girl presents to the family planning clinic for STI screening and
contraception. She has a steady male sexual partner, and they use condoms
inconsistently. She is interested in ENG implant for its contraceptive ease of
use. Her last menstrual period was 14 days ago. She denies substance use,
and her only medications are topical preparations for moderate facial acne.
Recommended STI screening tests are discussed with her and collected.
Results of a urine pregnancy test performed in the office are negative.
Which one of the following potential adverse effects of an ENG implant
should be addressed with this patient?
A. Breast tenderness during the first few months after insertion.
B. Decrease in bone density.
C. Expectation for worsening of acne.
D. Prolonged anovulation after removal of the implant.
E. Unpredictable menstrual bleeding pattern.
5. A 16-year-old patient had a quick start ENG implant inserted 3 months ago for
contraception. Today she reports that for almost 3 weeks she has been frustrated
by intermittent vaginal bleeding. Before insertion of the implant, her menses
were monthly with 4 to 5 days of moderate flow. Urine pregnancy test results at
insertion and 1 month later were negative. STI screening at insertion was
negative, and she has not had a new sexual partner. She has not experienced any
breast tenderness, nausea, vaginal discharge, or pelvic pain. There is no history of
substance use or the use of other medications or herbal products. The ENG
implant is palpable in a subcutaneous space 3 cm medial to the groove between
the biceps and triceps of her upper left arm. Which one of the following is the
best next step for the management of her bleeding?
A. Perform pelvic ultrasonography.
B. Perform a speculum examination for visualization of her cervix.
C. Prescribe a combined hormonal contraceptive for 1 month.
D. Remove the ENG implant.
E. Treat with a nonsteroidal anti-inflammatory medication for 5 to 7 days.

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 ARTICLE

Cushing Syndrome in Childhood

Anthony Parish, MD,* Clement Cheung, MD, PhD,* Anna Ryabets-Lienhard, DO,* Paul Zamiara, MD,†
Mimi S. Kim, MD, MSc*
*Pediatric Endocrinology, and †Pediatric Pathology, Children’s Hospital Los Angeles, Los Angeles, CA

PRACTICE GAPS

Differentiating Cushing syndrome (CS) from exogenous obesity can be

challenging for pediatricians because outpatient testing can be impractical
(eg, midnight salivary cortisol level, 24-hour urinary free cortisol level).
Although endogenous causes of CS are rare, early detection and treatment
are essential to reduce associated acute and long-term morbidity and
potential death. In a patient identified as having hypercortisolism, there are
additional challenges to differentiating corticotropin-independent from
corticotropin-dependent CS, including lengthy and involved inpatient
testing and difficulty with localization on imaging.

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

1. Recognize that the most common cause of Cushing syndrome (CS) in
childhood is from the exogenous administration of glucocorticoids;
endogenous CS is a rare disease.
2. Describe the underlying pathophysiology of CS.
3. Recognize that the first step in the diagnosis of CS is documentation of
hypercortisolism with a midnight salivary cortisol level, a 24-hour urinary
free cortisol level, and/or a low-dose dexamethasone suppression test, Author Disclosure: Drs Parish, Cheung,
Ryabets-Lienhard, Zamiara, and Kim have
which are complementary. disclosed no financial relationships
relevant to this article. This commentary
4. Develop a diagnostic evaluation to differentiate corticotropin-independent
does not contain a discussion of an
from corticotropin-dependent CS. unapproved/investigative use of a
commercial product/device.
5. List rare causes of corticotropin-independent and corticotropin-dependent
CS.
ABBREVIATIONS
6. List potential current therapies as well as interventions recommended
cAMP cyclic adenosine
for CS. monophosphate
7. Describe presenting clinical features and discuss long-term effects CRH corticotropin-releasing hormone
CS Cushing syndrome
of CS. CT computed tomography
DST dexamethasone suppression test
FDA Food and Drug Administration
ABSTRACT HPA hypothalamic-pituitary-adrenal
MRI magnetic resonance imaging
We describe a 15-year-old boy who presented with low back pain due to PPNAD primary pigmented nodular
vertebral compression fractures, growth deceleration, excessive weight gain, adrenocortical disease
UFC urinary free cortisol

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 rounded facies, dorsocervical fat pad, and hypertension. He was diagnosed as having Cushing syndrome (CS) due
to primary pigmented nodular adrenocortical disease resulting in excess cortisol produced by the adrenal glands,
leading to disruption of the hypothalamic-pituitary-adrenal axis. The most common cause of CS is exogenous
glucocorticoids, with endogenous causes being extremely rare, often leading to delay in diagnosis or misdiagnosis.
Herein, we review clinical presentation, screening for hypercortisolism, and decision-making in the diagnosis of CS,
as well as therapeutic approaches. The wide range of clinical presentations in pediatric CS and the rarity of the
condition can lead to difficulty in the recognition, diagnosis, and subsequent management of these patients. CS
can be difficult to differentiate from more common exogenous obesity, and outpatient screening of cortisol excess
is challenging. Early recognition and treatment of CS is necessary to avoid multisystemic complications, and
patients with suspected endogenous CS should be referred to a tertiary care center with experienced pediatric
endocrinology and surgery specialists. Further confirmatory diagnostic tests are necessary to distinguish corticotropin-
independent from corticotropin-dependent forms of CS, including a high-dose dexamethasone suppression test, a
corticotropin-releasing hormone stimulation test, and imaging. There can be challenges to the evaluation of CS,
including complex inpatient testing and difficulty with localization on imaging. Long-term sequelae of CS, including
adrenal insufficiency, obesity, hypertension, and mental health disorders, may remain despite definitive surgical
treatment, meriting close follow-up with the primary care clinician and subspecialists.

PATIENT CASE low-dose (1-mg) dexamethasone suppression test (DST) failed

A 15-year-old boy who was born at 28 weeks’ gestation pre- to suppress endogenous cortisol production. A high-dose
sented to the emergency department with acutely worsening (8-mg) DST also failed to suppress endogenous cortisol produc-
back pain and was noted to have excessive weight gain with tion, which further suggested a process that was independent
decreased linear growth for 2 years and hypertension. On of corticotropin release. This suspicion was confirmed
physical examination he was found to have facial plethora,
moon facies with a dorsocervical fat pad, skin bruising, cen-
tral obesity with proximal muscle wasting, elevated blood
pressure (141/107 mm Hg), and severe abdominal striae
(Fig 1). His weight was at the 92nd percentile, and his
height was less than the 1st percentile (z score, –3.61), which
placed his BMI in the class 3 obesity range. There were no
lentigines (flat spots of increased pigmentation) or blue nevi
on skin examination. He had Tanner stage 3 genitalia and
pubic hair. He had 7 of 10 back pain with tenderness to pal-
pation over the midline thoracic spine and was found to
have multiple vertebral compression fractures at the T7–T10
levels on radiography. He was not taking any medications
before presentation. He was born premature at 28 weeks’
gestation from a nonconsanguineous marriage and was de-
livered vaginally with no perinatal complications. There was
no known family history of endocrinopathies.
Further evaluation for hypercortisolism was performed
and revealed an elevated midnight serum cortisol level
(12.7 mg/dL [350.4 nmol/L]; reference range, 0.1–7.5 mg/dL
[2.8–206.9 nmol/L]) and midnight salivary cortisol level
(0.27 mg/dL [7.5 nmol/L]; reference range, 0.09–0.13 mg/dL
[2.5–3.6 nmol/L]), indicating a disturbance of the circadian
rhythm of cortisol production, and an elevated 24-hour uri-
Figure 1. A 15-year-old boy with classic stigmata of Cushing syndrome,
nary free cortisol (UFC) level (428.3 mg/24 h; reference including central obesity with proximal muscle wasting, rounded facies
range, 3–90 mg/d), confirming Cushing syndrome (CS). A with plethora, thin hair, and abdominal striae.

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 subsequently by undetectable corticotropin levels (<1 pg/mL
[<0.22 pmol/L]) at the time of elevated cortisol levels (Table 1).
To then help localize the source of autonomous cortisol, con-
trast-enhanced computed tomography (CT) of the abdomen
was performed, which revealed bilateral hyperplasia of the
adrenal glands. The right adrenal had a micronodule with cal-
cification, along with calcification in the right crus. The left
adrenal was most prominent and appeared thickened. Mag-
netic resonance imaging (MRI) of the abdomen showed possi-
ble nodularity of the superior limb of the left adrenal gland.
To further ascertain the etiology of the autonomous cortisol
production, a sequential classic Liddle test was performed in-
volving the administration of dexamethasone 0.5 mg every
6 hours for 48 hours, followed by dexamethasone 2 mg every
6 hours for another 48 hours. This in-depth testing revealed
an increase in UFC levels by 237% from baseline by day 5
(Table 1). Based on these findings, bilateral micronodular adre-
nocortical disease was highly suspected. Other pertinent labora-
tory results included 17-hydroxyprogesterone level, 101 ng/dL
(3.06 nmol/L) (reference range, 23–300 ng/dL [0.70–9.08
nmol/L]); dehydroepiandrosterone sulfate level, 38 mg/dL
(1.03 mmol/L) (reference range, 22–126 mg/dL [0.59–3.40
mmol/L]); androstenedione level, 94 ng/dL (3.28 nmol/L)
(reference range, 21–154 ng/dL [0.73–5.37 nmol/L]); and plasma
renin activity, 0.28 ng/mL per hour (0.28 mg/L per hour) (refer-
ence range, 1.2–2.4 ng/mL per hour [1.2–2.4 mg/L per hour]).
Luteinizing hormone, follicle-stimulating hormone, and total
testosterone levels were within the reference ranges for
Tanner stage 3 puberty.
The patient was discharged on low-dose ketoconazole
to suppress cortisol production while awaiting surgery
for 8 weeks but remained hypercortisolemic despite a dose
increase (from 200 to 400 mg/d). He underwent laparo-
scopic bilateral adrenalectomy, initially developing postopera-
tive hyponatremia, which normalized with supraphysiologic
glucocorticoid replacement (ie, hydrocortisone 50 mg/m2 per
day). Over the course of approximately 7 days, he was
weaned, based on his symptoms, to physiologic hydrocorti-
sone replacement. The postoperative period was otherwise
uneventful. He continues to receive lifelong hydrocortisone
and fludrocortisone replacement.
Pathological assessments of the resected tissue were con-
sistent with primary pigmented nodular adrenocortical disease
(PPNAD). On gross pathology, rather than forming a continu-
ous, thin, golden-yellow ribbon that is seen in the normal
adrenal cortex, the patient’s adrenal cortex was studded with
tan-brown nodules of varying size (Fig 2A). The left adrenal
gland weighed 19.6 g with attached tan-yellow lobulated peria-
drenal fat measuring 6.2 × 5.0 × 2.1 cm with golden-yellow pa-
renchyma and focal areas of hemorrhage. The right adrenal
gland weighed 27 g and measured 7.0 × 5.3 × 2.0 cm, with a
combined weight of 46.6 g for both adrenal glands (the aver-
age combined adrenal weight in adults is 11.8 g). (1) At high
magnification, hematoxylin and eosin staining showed well-
circumscribed but unencapsulated nodules of variably vacuo-
lated lipid-rich and eosinophilic lipid-poor cells among the
background cortex (Fig 2B). Fine golden pigment consistent
with lipofuscin was seen in both the lipid-rich and lipid-poor
cells, which compose the characteristic nodules of PPNAD.
PPNAD is often associated with the Carney complex, a disor-
der of multiple endocrine gland abnormalities, cardiac myxo-
mas, and lentigines. However, this patient did not have the
representative skin lesions, and an echocardiogram was nega-
tive for cardiac myxomas.

Table 1. Diagnostic Testing in our Adolescent Patient Case with Hypercortisolism

PATIENT’S AM
CORTICOTROPIN PATIENT’S AM
TEST UTILITY LEVEL(S) CORTISOL LEVEL(S)
Low-dose DST (30 mg/kg, Screening test for CS; 8 AM cortisol >1.8 lg/dL <5 pg/mL 16.7 mg/dL (460.72 nmol/L)
maximum 1 mg of (>49.66 nmol/L) is positive (<1.10 pmol/L)
dexamethasone)
High-dose DST (120 mg/kg, Corticotropin-dependent vs corticotropin- <5 pg/mL 17.2 mg/dL (474.51 nmol/L)
maximum 8 mg of independent CS; 50%–80% suppression of serum (<1.10 pmol/L)
dexamethasone) cortisol indicates Cushing disease
Classic sequential Liddle test Paradoxical rise of UFC >50% from baseline UFC % change from baseline: 237.8%
suggestive of autonomous adrenal secretion of
cortisol
CLASSIC LIDDLE DAY 1
TEST RESULTS (BASELINE) DAY 2 DAY 3 DAY 4 DAYS 4 1 5
Dexamethasone dose None 0.5 mg every 6 h 2 mg every 6 h
24-h UFC, lg/24 h 1154.4 1,253.7 1,659.5 2,811.7 3,900.5
Change from baseline, % 8.6 43.75 143.5 237.8

CS5Cushing Syndrome; DST5dexamethasone suppression test; UFC5urinary free cortisol.

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 Figure 2. A. Gross pathology of the adrenal cortex in an adolescent male patient with Cushing syndrome. The adrenal cortex was studded with tan-
brown nodules of varying sizes (arrows) rather than forming a continuous, thin, golden-yellow ribbon. B. Primary pigmented nodular adrenocortical dis-
ease (PPNAD) cell atypia (left) and lipofuscin (right). At higher magnification, cells composing the adrenal cortex nodules exhibited marked variation in
nuclear size and prominent nucleoli (black solid arrow). This contrasts with the smaller zona fasciculata cells (black open arrow). On the right, both lipid-
rich and lipid-poor cells composing the nodules exhibit fine golden pigment consistent with lipofuscin (yellow open arrow), which is responsible for the
“pigmented” nature of PPNAD nodules.

DISCUSSION younger patients and is potentially reversed in infants

CS is the consequence of prolonged exposure to excess circu-
lating glucocorticoids causing disruption of the hypothalamic-
pituitary-adrenal (HPA) axis. The most common cause of pe-
diatric CS is exogenous CS due to medications containing
glucocorticoids, in particular long-acting glucocorticoids such
as prednisone and dexamethasone. Very rarely, iatrogenic CS
can also occur with nonsystemic preparations (eg, inhaled
corticosteroids in those taking CYP450 inhibitors; overuse of
topical or ophthalmic corticosteroids). (2) Conversely, endoge-
nous CS is extremely rare in the pediatric population, with
an overall incidence of 0.7 to 2.4 per million adults, and
just 10% of new cases occur in children. (2)(3) Adolescents
with CS, similar to adults, have a slight female-to-male
predominance; however, this relationship is not present in
with CS. (4)(5)
Under usual physiologic conditions, the hypothalamus se-
cretes corticotropin-releasing hormone (CRH), which travels
to the anterior pituitary to induce the release of corticotropin,
which then acts on the zona fasciculata of the adrenal gland to
stimulate the synthesis and release of cortisol. The increase in
cortisol levels results in negative feedback on the hypothalamus
and anterior pituitary gland, and, thus, downregulation of
corticotropin and CRH production occurs. (4) These feed-
back pathways of the HPA axis get disrupted in CS by ex-
cess glucocorticoid exposure.
Etiologies of CS are typically categorized as corticotropin-
independent or corticotropin-dependent. Corticotropin-inde-
pendent CS, in which cortisol is autonomously produced by

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 the adrenal glands, accounts for approximately 10% to 15% of
CS in childhood and is caused by adrenocortical carcinomas
or adenomas, and bilateral nodular hyperplasia conditions
such as PPNAD and macronodular adrenal hyperplasia. (2)
Approximately one-third of all adrenal tumors manifest CS.
(6) Corticotropin-dependent CS is due to Cushing disease,
which is due to a corticotropin-secreting pituitary adenoma
leading to overproduction of cortisol by the adrenal glands or
to ectopic corticotropin production. Corticotropin-secreting pi-
tuitary adenomas are extremely rare in children younger than
6 years but account for more than 75% of cases among older
children and adolescents. (2) Ectopic corticotropin, exceed-
ingly rare in both adults and children, has been described in
carcinoid tumors in the bronchus, pancreas, or thymus; med-
ullary thyroid carcinoma; small cell lung carcinoma; pheo-
chromocytomas; and other pancreatic and gastrointestinal
neuroendocrine tumors and accounts for less than 1% of all
adolescents with CS. (7)
Cortisol has several multisystemic effects in metabo-
lism; the cardiovascular, immunologic, and inflammatory
systems; musculoskeletal and connective tissue; and fluid
and electrolyte homeostasis, as well as having neuropsy-
chiatric, behavioral, gastrointestinal, and developmental ef-
fects. (2, 8, 9)
Systemic Effects of CS
Hypercortisolemia results in many physical manifestations
in which clinical presentation plays an appreciable role in
guiding physicians toward appropriate evaluation and di-
agnosis of CS (Table 2). The most common symptom of
rapid weight gain is easily missed, especially given the cur-
rent childhood obesity epidemic. However, close growth
chart examination in skeletally immature children is pertinent
as patients with CS often have decreased growth velocity (ie,
slow growth) with dramatic weight gain in most cases. (2–4)
In contrast, linear growth in exogenous obesity is often typical
or accelerated. Cortisol suppresses growth hormone secretion
and interferes with insulin growth factor-1 action on growth
plates. Adolescents who are nearing or have completed growth
add to the challenges of diagnosis, so recognition of character-
istic CS features and a high index of suspicion are essential.
Approximately 75% of patients will have central adiposity with
increased dorsocervical fat pads and moon facies; however,
these findings are not specific to CS. Skin and subcutaneous
tissue changes can include acne and hirsutism from hyperan-
drogenism, plethora, bruising, skin atrophy, fungal infections,
and in cases of corticotropin-dependent CS, skin darkening
and purple striae due to high corticotropin levels. Cortisol ex-
cess also inhibits collagen synthesis and epidermal division to
cause striae in the case of low corticotropin levels, as seen in
our patient case, and so may be a feature in both forms of CS.
(2–5, 10)
Cortisol asserts several detrimental effects on the bone.
Osteoporosis is a likely underrecognized, but serious, conse-
quence of excess cortisol in children and is seen in more
than half of adult patients with CS. (11) Osteoporosis was a
distinguishing presenting feature in our patient. Exposure to
supraphysiologic glucocorticoids leads to early transient in-
crease in bone resorption through osteoclast activation and
to long-term suppression of bone formation via changes in
osteoblast and osteocyte function, as well as decreased intes-
tinal calcium absorption and renal reabsorption. (11–14)
These effects lead to low bone mineral density, which is evi-
dent on dual-energy absorptiometry. Compared with adults,
trabecular bone in children seems to be more sensitive to
the negative effects of glucocorticoids, making the spine more
vulnerable. (11) Severe skeletal pain can result from pathologic
fractures, and vertebral compression fractures are not un-
common. Studies have shown prevalence of osteoporosis
and vertebral compression fractures in pediatric CS of up
to 10%. (12) Thus, patients with CS should be screened
for presence of vertebral compression fractures with

Table 2. Clinical Manifestations of Pediatric Cushing Syndrome

SYSTEM CLINICAL MANIFESTATIONS
Dermatologic Facial plethora, acne, acanthosis nigricans, easy bruising, supraclavicular fat pads, moon facies, fungal infection,
hirsutism, fine downy hair, violaceous striae (>6 years old)
Neurologic Headaches
Cardiovascular Hypertension, hypertrophic cardiomyopathy, coagulopathy
Growth Growth deceleration with concomitant weight gain, central obesity, proximal muscle wasting
Gonadal Disruption of puberty (suppression of GnRH), amenorrhea, gynecomastia, virilization in corticotropin-independent
Cushing syndrome
Metabolic Glucose intolerance, insulin resistance (stimulation of gluconeogenesis), insulin suppression (b-cell dysfunction)
Bone Osteopenia, osteoporosis, fracture risk (# calcium absorption and renal tubular reabsorption, # bone formation,
" bone resorption)
Psychological Depression, anxiety, mood swings, irritability, fatigue

GnRH5gonadotropin-releasing hormone.

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 anteroposterior and lateral radiographs even if the patient is
asymptomatic. Although bone mineral density often recov-
ers after treatment of CS, bisphosphonate treatment for os-
teoporosis may be needed, especially in patients with
vertebral compression fractures. (14) Presence of unex-
plained severe osteoporosis, specifically, vertebral compres-
sion fractures in an obese child, should raise concerns for
evaluating for possible underlying CS.
In addition, cortisol increases the risk of dysglycemia by
stimulating gluconeogenesis, increasing peripheral insulin re-
sistance (caused by obesity), and directly suppressing insulin
release. (15) More than two-thirds of patients with corticotro-
pin-independent CS present with hirsutism and acne from
adrenal hyperandrogenism, with menstrual irregularities be-
ing common in adolescent females likely due to excess corti-
sol suppression of gonadotropin-releasing hormone, obesity,
and hyperandrogenism. (16) In corticotropin-dependent CS,
levels of dehydroepiandrosterone, dehydroepiandrosterone
sulfate, and androstenedione can be elevated or in the upper
reference range; however, if virilization is present, concern
for adrenal carcinomas should be raised. (17) Cortisol-induced
gonadotropin-releasing hormone suppression can lead to im-
paired gonadotropin release and disruptions in puberty pro-
gression. (5) Catabolic effects of excess glucocorticoids lead
many patients with CS to experience weakness and proximal
muscle wasting, exacerbated by inactivity. Weakness can be
further exacerbated by hypokalemia due to decreased renal
conversion of cortisol to cortisone by 11b-hydroxysteroid dehy-
drogenase type 2, allowing cortisol to exert mineralocorticoid
effects leading to renal potassium wasting. (9)
Notably, there are serious cardiovascular consequences
of elevated cortisol levels that may be seen at presentation
and if untreated can lead to mortality. Refractory hyperten-
sion may be present in children with CS and is likely to
be multifactorial in origin, including such causes as in-
creased adrenergic activation of peripheral vasculature, in-
creased hepatic production of angiotensinogen (substrate
of renin), and upregulation and activation of renal miner-
alocorticoid receptors by cortisol in cases of severe hyper-
cortisolism, which is usually due to ectopic corticotropin
secretion but can occur in all forms of CS. (18) Patients of-
ten have facial plethora and an increased risk of venous
thromboembolism, possibly attributed to glucocorticoid-in-
duced increases in plasma concentrations of clotting fac-
tors, factor VIII and von Willebrand factor complex in
particular, and decreases in fibrinolytic activity. (19) Elevated
serum homocysteine concentrations, which seem to be asso-
ciated with an increased risk of cardiovascular disease and ve-
nous thrombosis, have been reported in adult patients with
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CS. Hypercortisolemia in children is also associated with a
hypercoagulable state, although data are limited. (20, 21)
Although our patient case illustrated a rare cause of
CS, for primary pediatric clinicians, a vigilant awareness
of the physical manifestations of excess glucocorticoids is
critical for timely diagnosis of CS. After exogenous gluco-
corticoids have been ruled out, multiple approaches can
be used to differentiate CS from physiologic hypercortiso-
lism not due to CS, which can be seen in conditions such
as pregnancy, severe depression, obesity, or physical stress
(hospitalization, surgery, pain, etc).
Diagnosis of CS
Once patients with features of excess glucocorticoids are
identified, the next step is establishing a biochemical diag-
nosis of hypercortisolemia. Although our patient case in-
volved a rare form of corticotropin-independent CS, the
initial approach to the diagnosis of PPNAD is the same as
for any patient with suspected CS (Fig 3). Two separate el-
evated cortisol levels on first-tier screening tests are ini-
tially necessary in patients with suspected CS. (2–6, 8) A
24-hour UFC collection is the oldest and most cumber-
some method, ideally requiring 2 to 3 collections, and in
pediatrics has sensitivity of 89% and specificity of nearly
100%. (22) Levels greater than 90 mg/24 h (via radioim-
munoassay) are consistent with hypercortisolism. False-
positive elevations can occur due to physical and emo-
tional stress, severe exogenous obesity, pregnancy, polycys-
tic ovarian syndrome, exercise, depression, glycemia due
to diabetes, anorexia, alcoholism, anxiety, malnutrition,
and hyperhydration. (8) Inadequate collection can lead to
falsely low UFC levels. It is standard to not collect the first
void of the day, followed by collection of each void thereaf-
ter until the following first morning void and then stop-
ping collection. (8) In children, late-night salivary cortisol
level (collected between 11 PM and midnight) and low-dose
DST are superior to UFC level in making the initial diag-
nosis of CS and can be performed with a home collection
kit. (23) Loss of the normal diurnal rhythm of cortisol se-
cretion is a hallmark of CS, with abnormally elevated lev-
els of cortisol expected around midnight, which is the
time of the normal cortisol physiologic nadir. A salivary
cortisol sample obtained at midnight is nearly 100% sensi-
tive and 96% specific for CS when the level is greater than
0.13 mg/dL (>3.6 nmol/L). (24, 25) Patients who undergo
overnight low-dose DST are given 1 mg of dexamethasone
orally between 11 PM and midnight, which is normally ex-
pected to subsequently cause a low 8 AM cortisol level the
following morning; a value greater than 1.8 mg/dL
Vol. 4 5 No. 1 JANUARY 2024 1 9
 Figure 3. Diagnostic algorithm of Cushing syndrome showing screening for glucocorticoid excess. Initial screening for hypercortisolemia could include
a midnight salivary cortisol level, a 24-hour urinary free cortisol level, and a 1-mg overnight dexamethasone suppression test. If the results of at least 1
screening test are abnormal, the patient should be referred to endocrinology. RIA5radioimmunoassay.
(>49.7 nmol/L) despite dexamethasone suppression confers
95% sensitivity for CS but lower specificity of approximately
80%. (26) The gold standard cortisol measurement is a se-
rum cortisol level obtained at midnight with an indwelling
intravenous catheter in a minimally stressful environment.
(2) Accurate diurnal testing requires inpatient hospitalization
and is, therefore, not ideal for a screening test. Multiple tests
are necessary to make a firm diagnosis of CS given the limi-
tations of each test (Fig 3), and once high levels are con-
firmed, further testing is in order.
Differentiating Corticotropin-Independent vs
Corticotropin-Dependent CS
Once CS is diagnosed, the next step is to distinguish cortico-
tropin-independent from corticotropin-dependent CS (Fig 4).
A morning plasma corticotropin level of at least 29 pg/mL
($6.38 pmol/L) is 70% sensitive in identifying corticotropin-
dependent CS. A high-dose DST (Liddle test) can also be
used to differentiate between corticotropin-dependent and
corticotropin-independent CS. (2, 8) A baseline cortisol level
is measured at 9 AM, then patients are administered 120 mg/kg
(maximum dose 8 mg) of dexamethasone at 11 PM, and a
subsequent cortisol level is measured the following morn-
ing. A 20% decrease from baseline has been shown to be
100% specific for Cushing disease. Further differentiation
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from ectopic corticotropin secretion may require a CRH
stimulation test. (2, 8)
When suspecting corticotropin-independent CS due to
bilateral adrenocortical hyperplasia, the classic sequential
Liddle test involves low-dose dexamethasone (30 mg/kg
per dose; maximum 0.5 mg per dose) every 6 hours for 8
doses, followed by high-dose dexamethasone (120 mg/kg
per dose, maximum 2 mg per dose) every 6 hours for 8
doses. (27) A paradoxical rise of greater than 50% points
toward micronodular adrenocortical disease and is not typ-
ically seen in macronodular adrenal lesions.
Noninvasive diagnostic imaging is an essential tool to
further localize and distinguish causes of CS. Adrenal-pro-
tocol, contrast-enhanced CT is the most sensitive gold
standard to evaluate corticotropin-independent CS and dis-
tinguishing adrenal pathology; adrenal MRI may be a useful
addition (Fig 4). Adrenocortical adenomas and carcinomas
are more often unilateral, whereas bilateral lesions are sus-
picious for micronodular PPNAD or macronodular hyper-
plasia. High-resolution pituitary MRI in thin sections (1–2
mm) with contrast is useful in the evaluation of corticotro-
pin-dependent CS. In cases of ectopic corticotropin sources,
CT or MRI of the neck, chest, abdomen, and pelvis may be
used in addition to labeled octreotide scanning or positron
emission tomography.
 Figure 4. Diagnostic algorithm of Cushing syndrome (CS) showing the biochemical testing and imaging for localizing and differentiating between differ-
ent forms of CS. CRH5corticotropin-releasing hormone, CT5computed tomography, HDDST5high-dose dexamethasone suppression test,
MRI5magnetic resonance imaging.

Primary Pigmented Nodular Adrenocortical Disease
Our patient case of PPNAD demonstrated the paradoxical
rise in cortisol secretion (as percentage change in UFC)
during the classic Liddle test that is indicative of micro-
nodular disease, in contrast to macronodular adrenocorti-
cal disease in which there is not a rise in cortisol secretion.
(26) In 90% of patients, PPNAD is associated with the Car-
ney complex, which is inherited in an autosomal dominant
fashion approximately 75% of the time, but PPNAD can
also arise in isolation, such as was seen in our patient case.
(27–30) PPNAD is characterized by pigmented adrenocorti-
cal nodules of various sizes ranging in diameter from sub-
microscopic to 10 mm, although notably, imaging findings
can often be normal. On microscopy, the cortical nodules
are unencapsulated and the globular cells contain pigment-
laden eosinophilic cytoplasm, which appears black to brown
in color, with an atrophic-appearing cortex between nodules,
as was seen in our patient case (Fig 2A). (28)
Most cortisol-producing adrenal hyperplasia conditions,
including PPNAD and related adrenal tumors, are caused

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 by defects in the cyclic adenosine monophosphate (cAMP)/
protein kinase A (PKA) signaling pathway, which regulates
free cholesterol availability and steroidogenic enzyme ex-
pression. Several genes have been implicated in this path-
way, with the most common underlying variant in PPNAD
occurring in PRKAR1A, which encodes a regulatory subunit
that activates PKA and results in unregulated cell prolifera-
tion in cAMP-responsive tissues along with tumor forma-
tion in tissues that are affected in the Carney complex.
(29)(31) Pathogenic variants in PRKAR1A, PDE11A, PRKACB,
PRKACA, and PDE8B involved in the cAMP/PKA pathway
have also been identified in isolated PPNAD. Most of these
affected genes are inherited in an autosomal dominant fash-
ion approximately 75% of the time. Our patient case had a
PRKACA variant, with a 349-kb copy number gain and germ-
line duplication on chromosome 19p13 involving duplication
of the entire PRKACA. In addition, pathogenic variants of
GNAS1 cause constitutive activation of the Gsa protein, in-
creasing cAMP production and leading to hypersecretion of
cortisol. Notably, this is an underlying mechanism in
McCune-Albright syndrome, a condition strongly associated
with infantile CS. (31, 32) Additional surveillance for patients
with the Carney complex includes annual thyroid ultraso-
nography given the risk of nodules, prolactin levels to screen
for pituitary adenomas, and testicular ultrasonography given
the risk of calcifying Sertoli cell tumors in males. (30)
Treatment of CS
Treatment of endogenous CS depends on the underlying
etiology, and pediatric-specific clinical practice guidelines
are lacking. For CS caused by benign adrenal tumors, the
preferred treatment is surgical resection. For a unilateral
adrenal mass, single adrenalectomy has a nearly 100%
cure rate. (33) Bilateral, exceedingly rare nodular disease,
such as PPNAD, most often requires bilateral adrenalec-
tomy. Medications such as ketoconazole or mitotane can
be used to suppress cortisol production in the case of sur-
gical delay or failure or in cases of ectopic corticotropin se-
cretion without a localized source. (34)
In children with Cushing disease, transsphenoidal surgi-
cal resection of the corticotropin-secreting pituitary tumor at
a specialized center with experienced neurosurgeons has a
success rate greater than 90%. Among patients who require
repeated surgery due to recurrent disease, the success rate
falls to 60%. (2, 33) Although the mortality rate is low, post-
operative complications can be serious, including destruction
or damage of the pituitary gland, leading to diabetes insipi-
dus, syndrome of inappropriate antidiuretic hormone secre-
tion, panhypopituitarism, infection, bleeding, and pituitary
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apoplexy (hemorrhage or infarction of the pituitary). Radio-
therapy of the pituitary gland is generally avoided in children
due to the serious adverse effects. Pharmacotherapy for
Cushing disease is reserved for unsuccessful pituitary re-
section, in which selected medications act to modulate cor-
ticotropin release (somatostatin analogues), inhibit
steroidogenesis (ketoconazole, mitotane), and block the
glucocorticoid receptor (mifepristone). Although approved
in adults, off-label use of drugs such as ketoconazole,
which inhibits CYP enzyme activity and reduces cortisol
synthesis, administered at a starting dose of 400 to 600
mg/d for children older than 12 years is frequently used
given the lack of medications approved for children with
Cushing disease by the Food and Drug Administration
(FDA). (2, 33) Early bilateral adrenalectomy in patients with
refractory corticotropin-dependent CS may help improve
adverse events but can also lead to complications from loss
of feedback inhibition of the hypothalamus. CRH stimulat-
ing excessive pituitary corticotropin production can result in a
pituitary adenoma in up to 25% of patients, resulting in hy-
perpigmentation from proopiomelanocortin production in
the anterior pituitary's corticotropic cells, a condition known
as Nelson syndrome. (33) During the immediate postopera-
tive period for Cushing disease, stress dosing of gluco-
corticoids is recommended, with subsequent weaning to
physiologic replacement doses. (35) The mean ± SD time to
recovery of the HPA axis after transsphenoidal surgical re-
section in children is 12.6 ± 3 months, with early recovery
(<6 months) associated with recurrence of disease. (36)
Adrenal insufficiency must be anticipated after success-
ful surgical resection of a pituitary adenoma for Cushing
disease or after bilateral adrenalectomies, and daily gluco-
corticoid replacement is imperative. In the case of a bilat-
eral adrenalectomy, patients will require lifetime daily
replacement of both glucocorticoids and mineralocorti-
coids. (35) In addition, it is compulsory that patients re-
ceive stress-dose glucocorticoids in the setting of acute
illness, trauma, and surgical procedures given the risk of
provoking an adrenal crisis.
Long-term Sequelae of CS
Children with CS can have long-term adverse health outcomes
associated with prolonged exposure to excessive glucocorti-
coids, as well as postsurgical complications. Posttreatment
challenges include optimization of growth and pubertal devel-
opment, normalization of metabolism and body composition,
and promotion of psychosocial health. Children and adoles-
cents with CS have a high risk of continuing to be overweight
or obese after successful treatment for their disease and
should be followed closely. (37) No clear associations have
 been shown between treatment and final adult height or
catch-up growth; however, children with continued suboptimal
growth should be further evaluated for growth hormone axis
recovery and possible recurrent CS. (38) The most common
psychiatric conditions associated with CS include anxiety, de-
pression, and emotional lability, which may not resolve with
treatment of hypercortisolemia. Importantly, suicidal ideation
has been reported in approximately 6% of children after treat-
ment of CS, highlighting the necessity of screening for ad-
verse psychological effects unmasked or activated by excess
cortisol levels. (39) Diligent screening for deterioration of
school and cognitive performance is also necessary because
children with CS may experience a decline in cognition, with
younger patients at diagnosis demonstrating lower IQ scores
and persistent forgetfulness, unclear thinking, and diminished
attention span despite curing their CS. (40)
Conclusion
Due to its rarity in both children and adults, endogenous
causes of CS, such as PPNAD, can be difficult to diagnose
in a timely manner and thus carry significant morbidity
and mortality. Hypercortisolism manifests as a multiorgan
problem; therefore, primary care clinicians should consult
subspecialists, in particular endocrinologists, in the diag-
nosis, clinical care, and subsequent follow-up of these
patients. Early recognition of key features can lead to
successful treatment of hypercortisolism, although clinicians
and caregivers should be aware that there are long-term con-
sequences of prolonged excess glucocorticoid exposure.
Summary
• Cushing syndrome (CS) is the result of sustained
exposure to excess circulating glucocorticoids
causing disruption of the hypothalamic-pituitary-
adrenal axis. The most common cause of pediatric
CS is exogenous due to longer-acting glucocorticoid
treatment for inflammatory conditions.
• Most children with CS classically present with
arrest of linear growth and rapid weight gain,
which can help differentiate from exogenous
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childhood obesity. Early recognition is key to
preventing severe morbidities. (Based on strong
research evidence)
• The first step in the diagnosis of CS is documenting
hypercortisolism with at least 2 separate screening
tests, including midnight salivary cortisol level,
24-hour urinary free cortisol level, and/or a low-dose
dexamethasone suppression test. (Based on strong
recommendation)
• CS is a complex clinical syndrome affecting multiple
organ systems, and a multidisciplinary approach
(eg, primary care, endocrinology, surgery) can be
essential. Patients require lifelong follow-up. (Based
on strong evidence and consensus)
• Primary pigmented nodular adrenocortical disease
is a very rare cause of pediatric CS. Our patient case
illustrates the multitiered approach required for
screening, diagnosis, differentiation of corticotropin-
independent or corticotropin-dependent CS,
and anatomical localization of the causative
lesion(s). (Based on strong research evidence
and consensus)
• Surgical intervention generally offers the best
potential for the cure of CS; however, medical
adjunctive treatment options may be used when
surgery is not feasible or curative. (Based on strong
research evidence and consensus)
• Posttreatment challenges include optimization of
growth and pubertal development, normalization
of metabolism and body composition, and
promotion of psychosocial health. (Based on
strong research evidence and consensus)
Take the quiz! Scan this QR code to take the quiz,
access the references and teaching slides, and
view and save images and tables
(available on JANUARY 1, 2024).
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 PIR QUIZ

1. In a prepubertal patient with significant central obesity, which one of the

following clinical or laboratory findings most likely helps to rule out Cushing
syndrome?
A. Absence of osteoporosis.
B. Accelerated linear growth.
C. Normal blood glucose level.
D. Normal blood pressure.
E. Urinary free cortisol (UFC) excretion of 50 lg/24 h (via
radioimmunoassay).
2. A 14-year-old boy with obesity is brought to the clinic by his parents
because of severe low back pain. On physical examination he is noted to REQUIREMENTS: Learners can
have rounded facies and a dorsocervical fat pad. His weight has increased take Pediatrics in Review quizzes
33 lb (15 kg) during the past 12 months despite watching his diet and and claim credit online only at:
joining the swim team. He has not experienced any trauma, and his pain http://pedsinreview.org.
began suddenly when he woke up from sleep. Spinal radiography shows
To successfully complete 2024
vertebral body compression fractures at T12-L1. Which one of the following Pediatrics in Review articles for
is the most likely underlying cause of his vertebral body compression AMA PRA Category 1 Credit™,
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minimum performance level of
A. 1,25-dihydroxyvitamin D resistance. 60% or higher on this
B. Decreased dietary calcium absorption in the intestine. assessment. If you score less
C. Early increase in bone resorption with subsequent inhibition of than 60% on the assessment,
osteoblastic activity. you will be given additional
opportunities to answer
D. Inhibition of 1a-hydroxylase activity reducing 1,25 vitamin D levels.
questions until an overall 60%
E. Loss of muscle strength leading to decreased tension on bone. or greater score is achieved.
3. A 16-year-old boy presents to the clinic with a weight gain of 44 lb (20 kg)
This journal-based CME activity
over the past 12 months. He reports weakness when climbing stairs. His
is available through Dec. 31,
blood pressure today is 139/95 mm Hg. His BMI is at the 99th percentile, 2026, however, credit will be
and his height is at the 3rd percentile. On physical examination his face is recorded in the year in which
rounded, he has striae on his abdomen and back, and he has a prominent the learner completes the quiz.
dorsocervical fat pad. He does not drink soda or juices and is on the high
school basketball team. Of the following evaluation measures, which one is
the most appropriate next step in this patient?
A. Fasting lipid panel alone.
B. Hemoglobin A1c and fasting lipid panel.
2024 Pediatrics in Review is
C. Two separate 24-hour urine collections for UFC measurements. approved for a total of 30
D. Two separate hemoglobin A1c measurements. Maintenance of Certification
E. Two separate random serum cortisol measurements. (MOC) Part 2 credits by the
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4. The patient in vignette 3 is found to have 2 elevated UFC levels of 110 lg/dL
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 5. A 12-year-old girl is brought to the clinic by her parents for a second
opinion regarding the treatment of her Cushing syndrome. Her treating
physician recommended bilateral adrenalectomy. You discuss with the parents
that bilateral adrenalectomy is the most appropriate treatment recommended
for Cushing syndrome caused by which one of the following etiologies?
A. Corticotropin-secreting pituitary adenoma.
B. Adrenocortical carcinoma.
C. Corticotropin-releasing hormone–secreting tumor.
D. Ectopic corticotropin secretion from gastrointestinal carcinoid tumor.
E. Primary pigmented nodular adrenocortical disease.

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 ARTICLE

Management of Acute Sickle Cell Disease

Pain
Jason N. Payne, MD, MSPH,*† Beatrice E. Gee, MD*‡
*Children’s Healthcare of Atlanta, Atlanta, GA
†
Morehouse School of Medicine, Atlanta, GA
‡
Emory University School of Medicine, Atlanta, GA

EDUCATION AND PRACTICE GAPS

This article, directed toward general pediatricians and trainees, provides

recommendations for the treatment of acute pain in children and adolescents
with sickle cell disease (SCD). Structural racism has been a major problem in
the treatment of people with SCD, which can be remedied through clinical
practice. (1)(2)

OBJECTIVES After completing this article, readers should be able to

1. Diagnose acute pain episodes in children and adolescents with sickle

cell disease.
2. Describe the use of multimodal therapy in the management of acute
sickle cell pain.
3. Describe nonpharmacologic approaches and disease-modifying therapies
for preventing sickle cell pain.
4. Describe how bias has historically affected medical treatment of pain in AUTHOR DISCLOSURE: Drs Payne and
racialized minorities and detect and avoid stigmatizing behavior when Gee have disclosed no financial
treating people with sickle cell disease. relationships relevant to this article. This
commentary does not contain discussion
of an unapproved/investigative use of a
commercial product/device.
ABSTRACT
Pain is a common complication of sickle cell disease. Sickle cell pain can ABBREVIATIONS
often be effectively managed by pediatricians in outpatient and hospital ACS acute chest syndrome
settings. Acute pain management should be initiated quickly. Patients ED emergency department
need to be evaluated for sickle cell complications and other causes of pain. ESI Emergency Severity Index
Hb hemoglobin
Nonsteroidal anti-inflammatory drugs and opioids are the mainstay of pain IV intravenous
treatment, but additional therapies include hydration, local pain control, MME morphine milligram equivalent
muscle relaxants, and nonpharmacologic approaches. Healthy lifestyle NSAID nonsteroidal anti-inflammatory
drug
habits and good behavioral and mental health are important for preventing PCA patient-controlled analgesia
and coping with sickle cell disease pain. Disease-modifying therapies, such as RBC red blood cell
hydroxyurea, can help prevent sickle hemoglobin polymerization and acute RCT randomized controlled trial
SCD sickle cell disease
pain episodes. Because sickle cell disease largely affects people who are
VOE vaso-occlusive pain episode

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 racialized minorities in the United States, health-care providers need to be aware of how their own personal biases
may affect care of these patients.
CASE PRESENTATION
A 10-year-old boy with hemoglobin (Hb) SS disease pre-
sents with lower leg and back pain for 3 days. He recently
returned from a vacation where he went swimming and
played outside. He has no fever or cough, but oral intake
has been low; his parents think he is dehydrated. He has
been using warm compresses and taking ibuprofen and
hydrocodone/acetaminophen. The pain has worsened, and
he came to the emergency department (ED) for additional
treatment. What is the best approach for managing this
patient?
EPIDEMIOLOGY
Sickle cell disease (SCD) is the most commonly inherited
blood disorder, affecting more than 100,000 persons in
the United States and millions of people globally, particu-
larly those with ancestors from sub-Saharan Africa. (3)
SCD is also seen in other ethnic groups, which may have
other SCD haplotypes with varying severity of disease.
SCD should be recognized as a potentially life-threatening
condition among different racial and ethnic groups, and
not “just Black Americans.” (4) SCD is defined by the
presence of at least 1 b-globin mutation responsible for
creating Hb S (coding for glutamic acid instead of valine
at amino acid 6). Homozygous Hb SS disease, also known
as sickle cell anemia, accounts for approximately 60% to
65% of SCD. The sickle mutation can also be inherited in
the compound heterozygous state with other b-globin mu-
tations, such as Hb C or b-thalassemia, leading to Hb SC
disease (35%–30% of SCD) or Hb S with b-thalassemia
(Sb0 or Sb1, 5%–10% of SCD). (5)
PATHOPHYSIOLOGY
Hb S polymerizes reversibly in deoxygenated environ-
ments, and repeated episodes of polymerization can cause
the red blood cell (RBC) to be irreversibly sickled. (5) Sick-
led RBCs can lead to vaso-occlusion, resulting in tissue is-
chemia and nociceptive pain, caused by visceral or somatic
tissue injury. (6) Leukocytosis is also not uncommon in
patients with SCD because sickled RBCs can activate vari-
ous tissue components, including the vascular endothe-
lium, leukocytes, and platelets. (5) Due to microvascular
vaso-occlusion, sickle RBCs also contribute to oxidative
stress due to tissue reperfusion, and last, intravascular
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and extravascular hemolysis also contributes to ongoing
anemia, oxidative stress, and shortened RBC life span. (5)
Management of sickle cell pain is challenging due to these
poorly understood and complex mechanisms. (7)
Episodic pain occurs throughout the life span of people
with SCD and tends to increase as children age. Diary
studies have shown that by adolescence, opioid use was
higher in youth 14 to 19 years old, 57% of days compared
with 10% to 11% of days in younger children. (8)(9) Vaso-
occlusive pain episodes (VOEs) are the leading cause of
hospital utilization for people with SCD. (10)
Some patients and advocates have recommended the
terminology pain episodes instead of the older term crises.
Crisis may imply higher risk of bad outcomes and/or diffi-
culty controlling pain. On the other hand, others feel that
crisis best describes the severity of events and that the
term episode underplays the significance of the pain.
Herein, we use vaso-occlusive pain episode (VOE).
CLINICAL ASPECTS
History and Physical Examination
Patients presenting with sickle cell pain should be thor-
oughly assessed for other medical issues that may be pre-
sent, such as infection, trauma, or other SCD complications,
such as stroke or acute chest syndrome (ACS). Splenic seques-
tration should be considered in younger children who have
abdominal pain, irritability, and drop in hemoglobin. History
should include a description of painful sites, attempted treat-
ments, and exploration of triggers, such as injury, dehydra-
tion, overexertion, infection, stress, or recent menstrual cycles
that may provoke acute pain. Some triggers are preventable,
which can be helpful for the patient’s self-management. Physi-
cal examination may show tenderness, redness, warmth, or
swelling of painful sites, but some patients have no overt find-
ings owing to the pain being deep in bone, soft tissue, or
viscera.
Differential Diagnosis
The diagnosis of VOE is often one of exclusion. Not all
pain in a person with SCD is due to VOEs, and the clini-
cian should keep an open mind about the differential diag-
nosis. Examples of diagnoses include severe headache,
especially with visual changes or motor weakness, which
may be signs of stroke; chest, abdominal, or back pain
may be symptoms of ACS; abdominal pain may result
Vol. 4 5 No. 1 JANUARY 2024 2 7
 from gallstones, pancreatitis, constipation, or pelvic infec-
tion or pregnancy in females; back pain may occur with
urinary tract infection or constipation; or bone pain may
be from fractures or osteomyelitis. Table 1 provides an
overview of other conditions that may be present in a per-
son with SCD who has pain and suggests appropriate di-
agnostic evaluations.
Laboratory Evaluation
A complete blood cell count, a reticulocyte count, and a
chemistry panel should be performed to evaluate for hy-
dration status, renal function, and hemolysis. Due to in-
creased risk of sepsis from functional asplenia, all patients
with SCD presenting with fever require blood cultures and
treatment with empirical broad-spectrum antibiotics per
institutional guidelines, such as administering ampicillin,
levofloxacin, or third-generation cephalosporins. Children
with SCD are at higher risk for infection by encapsulated
organisms. For patients with SCD in the United States,
the most common bacteria isolated from infection include
Streptococcus pneumoniae, Salmonella, Escherichia coli, and
Staphylococcus aureus. (13) Most institutions recommend
ceftriaxone as the treatment of choice because of its long
half-life and coverage of encapsulated organisms. (14)
However, there is a rare, potentially fatal complication of
repeated exposure to ceftriaxone that can cause life-threatening
hemolysis. (15) For this reason, our institution prefers am-
picillin as first-line therapy for empirical antibiotic coverage.
Not all pain requires imaging, but obtaining a chest radio-
graph is useful for patients with chest, abdominal, or back
pain to evaluate for possible ACS, and bone radiographs
are useful when there is a history of trauma. ACS is clini-
cally defined as finding a new pulmonary infiltrate on a
chest radiograph accompanied by the patient having fever
and/or respiratory signs and symptoms such as hypoxia,
tachypnea, or dyspnea.
Pain Assessment
The initial assessment of pain should include using a pain
intensity rating; in 2000, The Joint Commission consid-
ered pain as the fifth vital sign. Commonly used pain
scales for children include unidimensional tools such as
the Numeric Rating Scale (pain ratings from 0 to 10, for
patients $8 years old) and the Bieri Faces Pain Scale, for
patients 3 years or older (https://www.iasp-pain.org/resources/
faces-pain-scale-revised). (16)(17)(18)(19) Functional pain as-
sessment is another tool to measure pain, which includes ob-
servation or self-report of a person’s ability to perform
activities of daily living; this can be a helpful addition in
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understanding the impact of pain on a person’s functionality,
but functional pain assessment tools are not widely used and
have limited utility in the emergency setting. (20)(21)(22)
Daily functional assessment may help to monitor patient
progress, especially when there is little to no change in nu-
meric pain ratings.
It is crucial to believe a patient’s report of pain and to
not judge whether patients “look like they are hurting.”
There are no diagnostic markers of SCD pain, and we de-
pend on self-reporting in verbal patients. (16) Patients
with SCD pain may lack focal findings of tenderness,
swelling, or warmth; those with frequent or chronic pain
may have become inured to pain and may not have
changes in vital signs or emotional responses to pain; and
when patients with SCD are able to use personal devices,
they may be using distraction techniques for coping with
pain. Patients who need to prove that they are hurting may
even learn to exaggerate their symptoms to get treated.
AVOIDING RACIAL BIAS AND STIGMATIZATION
Structural racism in medicine has been well-described and
brought to the forefront in medicine after the death of
George Floyd and during the COVID-19 pandemic. (4)(23)
Racialized minority patients (people who could be per-
ceived as being socially different from the racial or ethnic
majority) are more likely to be labeled as “drug seeking,”
to not be believed about the level of pain described, or to
be thought to have higher pain tolerance. (24) As a result,
racialized minority patients may be treated with less anal-
gesics than white patients with similar painful conditions
and have undertreated pain. (25)
The American Medical Association and the Association of
American Medical Colleges recommend attention to language
as a basic component to promoting health equity, including
avoiding dehumanizing language and blaming. (26) One
should avoid saying “sickler,” and instead identify a per-
son’s sickle cell genotype, such as Hb SS or Hb SC, and
the SCD haplotype if known because such information
provides significant information (eg, Hb S Senegal haplo-
type has a less severe course and higher Hb F levels). Peo-
ple with many health-care encounters should not be called
“frequent fliers.” (4) The need for frequent pain treatment
may be due to high disease severity and/or ineffective
symptom management, and patients should not be assumed
to be seeking opioids. Although consideration of social deter-
minants of health and stressors is necessary to identify pain
triggers or barriers to treatment, it should not be assumed
that every patient who is from a racial or ethnic minority
group has social problems as the root cause of their pain. In
 Table 1. Differential Diagnosis and Evaluation of Pain in People with Sickle Cell Disease by Body Site
DIFFERENTIAL HISTORY,
SITE DIAGNOSIS SYMPTOMS SIGNS TESTS TREATMENT
Common pain Uncomplicated pain "Typical" pain site and May or may not have All patients should See text
location episode characteristics focal findings of have a CBC count,
tenderness, differential count,
redness, warmth, reticulocyte count
or swelling
Any location Fracture or strain Trauma Point tenderness, Radiography of site Injury treatment as
swelling needed,
nonopioid
analgesic preferred
Head Migraine headache Headache with aura, Migraine treatment
photophobia,
nausea, family
history
Stroke Weakness Focal neurologic Head CT or brain MRI Stroke treatment if
The “worst headache signs, altered to evaluate for needed (13)
ever” may be a mental status stroke
cerebral hemorrhage
Skull bone infarct Tender skull, swelling CT scan of skull Same treatment as
for acute VOE,
but pain may be
prolonged
Chest Acute chest syndrome URI, fever, shortness of Tachypnea, hypoxia, Chest radiography, Oxygen
(can also present breath abnormal breath respiratory viral Respiratory
with abdominal or sounds testing treatments
back pain) Antibiotics (13)
Abdomen Epigastric: GERD, Burning, acid in throat, Epigastric or upper Upper GI series, Antacids or proton
peptic ulcer disease nausea, vomiting, abdominal Helicobacter pylori pump inhibitor
coughing, and tenderness testing; GI consult if
wheezing severe or persistent
RUQ: gallstones, Increased jaundice, Worsened jaundice, Fractionated bilirubin, GI or surgical
biliary disease nausea and RUQ tenderness liver function tests, consult for bile
vomiting, pain worse (Murphy sign) abdominal duct obstruction
with fatty meals ultrasonography
LUQ: splenomegaly Spleen larger than Spleen larger or Ultrasonography for May need red
or splenic usual, pallor, fatigue tender, pallor spleen size if blood cell
sequestration examination is transfusion (13)
difficult
CBC count,
reticulocyte count:
hemoglobin and/or
platelet count may
be lower with
sequestration
Lower or diffuse: Infrequent or hard Abdominal distention, Rectal examination, Laxatives, enema
constipation (can stool stool masses abdominal
also present with radiography
low back pain)
Lower Urinary tract infection Urinary frequency, Suprapubic Urinalysis, urine culture Antibiotics if
abdomen, burning, odor tenderness needed
pelvis, STI Sexually active, pelvic Penile or vaginal Pelvic examination Antimicrobials if
genitourinary pain, penile or vaginal discharge with cultures, urine needed
tract discharge, odor testing for STI
Pregnancy Sexually active, missed Enlarged uterus, Pregnancy test Prenatal care, avoid
menstrual period breast swelling NSAIDs after 20
weeks’ gestation
Back Flank: pyelonephritis Fever, urinary Costovertebral angle Urinalysis, urine and Antibiotics if
(see also urinary frequency, burning, tenderness blood cultures needed
tract infection) odor
Vertebrae: sickle cell Recurrent back pain Focal vertebral Spine radiography may May not be
bone disease tenderness show loss of volume responsive to
of vertebral bodies, opioids; may
osteopenia need chronic
pain treatment
(7)
Continued

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 Table 1. Differential Diagnosis and Evaluation of Pain in People with Sickle Cell Disease by Body Site (Continued)
DIFFERENTIAL HISTORY,
SITE DIAGNOSIS SYMPTOMS SIGNS TESTS TREATMENT
Extremities Bone infarct Severe, prolonged Bone tenderness, Radiography, MRI Same treatment as
bone pain swelling for acute VOE,
but pain may be
prolonged
Viral infection Flulike, myalgias, fever, Flulike appearance, Viral testing Acetaminophen or
respiratory muscle tenderness NSAIDs may be
symptoms more helpful for
myalgias
Osteomyelitis, Focal redness, warmth, Tenderness, swelling, Radiography, CT, or Antibiotics
cellulitis swelling, fever warmth, or MRI of bone, blood
redness culture, tissue biopsy
Venous Swelling, pain, history Extremity swelling, Doppler Anticoagulants
thromboembolism of catheter venous cord ultrasonography for
placement flow
Any location or Multiorgan "Worse pain ever" Multiple sites of pain CMP, organ function May need red
multisite dysfunction or organ evaluation (image blood cell
syndrome dysfunction organs as needed) exchange
transfusion and/
or plasma
exchange (14)

CBC5complete blood cell, CMP5comprehensive metabolic panel, CT5computed tomography, GERD5gastroesophageal reflux disease,
GI5gastrointestinal, LUQ5left upper quadrant, MRI5magnetic resonance imaging, NSAID5nonsteroidal anti-inflammatory drug, RUQ5right
upper quadrant, STI5sexually transmitted infection, URI5upper respiratory infection, VOE5vaso-occlusive pain episode.

addition to avoiding biased language, health-care providers
should reflect on whether they treat patients with SCD dif-
ferently from people with other painful conditions and/or
treat racially minoritized patients differently from white
patients. (24)(27)
MANAGEMENT OF ACUTE SICKLE CELL PAIN
Treatment of Mild to Moderate Pain
Although there is no one-size-fits-all approach to manag-
ing sickle cell pain, there are strategies to help improve
pain treatment efficiency and efficacy. The World Health
Organization introduced the concept of a Pain Ladder in
1986, with the first level of treatment for mild pain using
adjuvant or nonpharmacologic therapies (rest, warmth, or
massage) and nonopioid medications, the addition of
weak (oral) opioids for moderate pain, and reserving the
use of strong (parenteral) opioids for severe pain. (28) Ice
is discouraged for VOEs because of the possibility of causing
vasoconstriction and worsening perfusion. Nonopioid thera-
pies include oral or topical nonsteroidal anti-inflammatory
drugs (NSAIDs), topical anesthetics such as lidocaine cream
or patches, and muscle relaxants (cyclobenzaprine or metho-
carbamol). Weak oral opioids such as acetaminophen with
codeine and tramadol are not widely used in pediatrics. Acet-
aminophen with codeine is not recommended in children
because of the substantial genetic variability of the presence
of the hepatic enzyme CYP2D6, which is responsible for the
conversion of codeine to morphine, a variability that can
manifest as underdosing or overdosing. Commonly used
oral opioids include hydrocodone or oxycodone in combi-
nation with acetaminophen, or oxycodone alone (see
Table 2 for opioid dosing). Oral morphine has similar
potency as hydrocodone (1 morphine milligram equivalent
[MME]) but is less available in pharmacies, and the tablet
formulations are prepared in the dose range recommended
for adults.
The concept of MME is critical in opioid prescribing be-
cause it provides a standardized method for comparing
opioid doses and assessing the risk of overdose. MME allows
health-care providers to compare the potency of different
opioids with morphine, which is considered the benchmark
for opioids. This helps providers choose the appropriate opi-
oid dose for each patient and avoid the risks associated with
overdosing or underdosing. The use of MME also helps to
ensure consistent dosing and to avoid errors that can occur
when converting between different opioids, especially when
transitioning from intravenous to oral. In addition, MME
is a useful tool for tracking opioid prescriptions and monitor-
ing patients for potential misuse or abuse of opioids. Overall,
the use of MME is essential for safe and effective opioid
prescribing and for helping mitigate the ongoing opioid
epidemic.
Oxycodone and hydromorphone are higher potency and
should be reserved for patients who have demonstrated lack
of response to hydrocodone/acetaminophen. When pre-
scribing opioid and acetaminophen combination products,

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 Table 2. Opioid Dosing for Acute Pain Management
MORPHINE MILLIGRAM
MEDICATION ROUTE EQUIVALENTS DOSAGE COMMENTS
Hydrocodone Oral only 1 ! Patient weight <50 kg: 0.0.5–0.2 mg/kg Be aware of total daily
with per dose every 4–6 h as needed acetaminophen dosage
acetaminophen ! Patient weight $50 kg: oral, initial dose: Forms:
5–10 mg every 4–6 h as needed ! Elixir 7.5/325 per 15 mL
! Tablets 5/325, 7.5/325, 10/325
Oxycodone Oral only 1.5 ! Patient weight <50 kg: 0.05–0.2 mg/kg Forms:
per dose every 4–6 h as needed (usual ! Elixir 5 mg per 5 mL
maximum dose range: 5–10 mg) ! Tablets 5, 7.5, 10 mg
! Patient weight $50 kg: 5–10 mg every
4–6 h as needed (maximum dose:
20 mg)
Oxycodone with Oral only 1.5 Same dosing per oxycodone component Be aware of total daily
acetaminophen acetaminophen dosage
Forms:
! Elixir 5/325 per 5 mL
! Tablets 5/325
Morphine Oral 1 ! Infants <6 mo: 0.08–0.1 mg/kg per Forms:
dose every 3–4 h as needed ! Elixir 2 mg/mL or 4 mg/mL
! Infants >6 mo, children, and ! Tablets 15, 30 mg
adolescents:
- Patient weight <50 kg: 0.2–0.5 mg/kg per
dose every 3–4 h, maximum 15–20 mg
- Patient weight $50 kg: 15–20 mg every
3–4 h
IV Oral to IV ratio 3:1 Patient weight <50 kg ! Suggested first choice for IV
! Intermittent: 0.1–0.2 mg/kg per dose therapy
every 2–4 h, maximum 5 mg per ! Infants aged <3 mo and
dose opioid naive may be more
! Infants <3 mo, opioid naive: 0.05 mg/kg susceptible to respiratory
per dose depression
Patient weight >50 kg: 2–5 mg every
2–4 h
PCA: 0.01–0.04 mg/kg per hour
continuously; patient-controlled dose
0.01–0.04 mg/kg
Hydromorphone Oral 4 Patient weight <50 kg: 0.03–0.08 mg/kg Forms:
per dose every 3–4 h as needed Tablets 2, 4, 8 mg
Patient weight $50 kg: 2–4 mg every
3–4 h as needed. Opioid naive:
1–2 mg every 3–4 h as needed
IV Oral to IV ratio 5:1 Patient weight <50 kg: 0.015 mg/kg per
dose every 3–6 h as needed
Patient weight $50 kg: 0.2–0.6 mg per
dose every 2–4 h as needed
PCA: 1–4 lg/kg per hour continuously;
patient-controlled dose 1–4 lg/kg
Nalbuphine IV only NA Infants >6 mo, children, and ! Consider for use in opioid-
adolescents: 0.1–0.3 mg/kg per dose naive patients
every 3–4 h as needed, maximum ! Avoid in patients who are taking
dose: 20 mg, 160 mg/d daily or long-acting opioids
PCA: 0.01–0.04 mg/kg per hour because antagonist may
continuously; patient-controlled dose displace the other opioids from
0.01–0.03 mg/kg receptors and increase pain
Fentanyl Intranasal NA Children >10 kg and adolescents: ! Using parenteral preparation
1.5–2 lg/kg once, may repeat second
dose 0.5–0.75 lg/kg within
10–20 min; maximum dose 100 lg
IV NA Patient weight <50 kg: 1–2 lg/kg per ! Short half-life: needs frequent
dose, every 1–2 h dosing every 30 min to 2 h, or
Patient weight $50 kg: 25–50 lg every PCA
1–2 h ! May be tolerated by people
PCA: 0.5–1 lg/kg per hour (limited with adverse reactions to
available data) other opioids

IV5intravenous, NA5not available, PCA5 patient-controlled analgesia.

Reprinted with permission from Lexi-Drugs, Lexi-Comp Inc. (11)

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 patients should be advised regarding not taking additional
acetaminophen.
ED Treatment
By the time most patients with SCD pain arrive at the hos-
pital, they have already attempted mild and moderate pain
treatment at home and are likely to need parenteral ther-
apy. Rapid assessment and medication administration are
recommended, ideally with a door-to-analgesia time of less
than 60 minutes. (7) The National Heart, Lung, and Blood
Institute recommends that patients with SCD and VOE be
assigned an Emergency Severity Index (ESI) of 2 to help
prioritize their rapid triage and management. (11)(30)(31)
The ESI is a 5-level triage tool used in most hospital EDs
to help provide more effective treatment for time-critical
emergencies by assigning lower scores to the patients with
the most emergent needs such that an intubated patient
would have an ESI of 1 and a patient with a minor com-
plaint such as only a sore throat would have an ESI of 5.
The use of standardized pain treatment protocols can
initiate timely care and decrease provider treatment vari-
ability that may be influenced by biases. (7)(31) Standard-
ized protocols for treatment in the ED should include
tiered assessment and management, with less severe pain
treated initially with nonopioid therapies and more severe
pain with oral or intravenous (IV) opioids. (11)(28) Once
the severity of pain is determined, a weight-based or indi-
vidualized pain management plan should be used. Rapid
delivery of analgesics should be followed by repeated as-
sessment and treatment every 15 to 30 minutes until the
patient reports or demonstrates improvement in pain.
(11)(31) Reassessment should focus on pain relief as well
as adverse effects of opioids, which include oversedation
and respiratory depression.
Many ED protocols include intranasal fentanyl as an
initial analgesic, which can be given before or during IV
placement and is associated with reduced pain within the
first 30 minutes. (32) Additional pharmacologic manage-
ment includes 3 major classes of medicines: nonopioids,
opioids, and adjuvants. (7)(33) IV ketorolac, an NSAID,
can be very helpful for reducing pain caused by inflamma-
tion in SCD, but NSAIDs are contraindicated in people
who have a history of gastrointestinal ulcers, bleeding, or
renal disease. In those situations, acetaminophen can be a
helpful adjunctive therapy with opioids.
At our institution, morphine is the most commonly
used IV opioid, with well-understood dosing guidelines.
For opioid-naive patients, providers could consider using
lower doses of morphine or IV nalbuphine, which has
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mixed opioid agonist-antagonist effects and may be associ-
ated with a lower likelihood of developing ACS compared
with morphine (see Table 2 for opioid dosing). (34) In the
case of all opioids, it is recommended to use the lowest
potency/dose and shortest duration possible that is effective
for pain relief. Repetitive doses of IV opioid in the ED
should be given cautiously because cumulative sedative ef-
fects can be delayed. In patients who have already received
0.2 mg/kg of morphine, successive doses should be smaller,
such as 0.05 mg/kg per dose every 2 to 3 hours. Patients
should have continuous cardiorespiratory and oximetry mon-
itoring while receiving frequent or continuous opioids.
Adjunctive therapies include administering agents to
counteract opioid-induced adverse effects, such as pruritis
and/or nausea and vomiting. Oral antihistamines, such as
diphenhydramine or hydroxyzine, can be helpful to con-
trol itching. Ondansetron can be effective in preventing or
relieving nausea and vomiting. Nonpharmacologic man-
agement in the ED could include heating pads and dis-
tracting activities. Pain treatment should also include
hydration with oral and/or hypotonic IV fluids to achieve
1× the maintenance rate and IV opioids as needed to con-
trol pain. Bolus infusions of isotonic fluids, such as nor-
mal saline or lactated Ringers, are not recommended in
the absence of dehydration to prevent overhydration and
to minimize risk of subsequent ACS. (35) Specifically, in
in vitro models, suspending sickle RBCs in normal saline,
a hyperosmolar IV fluid, has been associated with in-
creased RBC stiffness, cellular dehydration, and increased
capillary transit times. (36)
American Society of Hematology guidelines in 2020
for the management of SCD pain recommend the use of
individualized care plans that are co-developed by clini-
cians and patients and include recommended medicines
and doses that have been effective for a given patient. (7)
These plans inform ED staff of medications that may be
less commonly used or have dosing outside the usual
range (low doses for sensitive patients, higher doses for
the opioid tolerant). These individualized care plans can
be helpful to prevent situations in which a clinician may
not believe or accept when a patient states that hydromor-
phone or another medication works best for their pain in-
stead of the more typically prescribed morphine.
The decision to discharge the patient home or not from
the ED is made based on the response to therapy, whether
the patient and family are comfortable managing the pain
at home, and whether other complications are present that
need hospital treatment or close monitoring, such as fever,
hypoxia, ACS, or worsened anemia. Some institutions
 have guidelines for admission, such as a patient requiring
more than 3 IV doses of opioid within 2 hours or pain unre-
lieved after 4 hours of treatment. If the patient is discharged,
the patient should be prescribed adequate analgesics for at
least 72 hours of continued home treatment. When available,
reviewing both the patient’s electronic medical record and
the Prescription Drug Monitoring Program (an electronic da-
tabase that tracks controlled substance prescriptions in a
state) can help determine whether a patient has had recent
opioid prescriptions.
Inpatient Pain Treatment
Once a patient is admitted, individualized pain plans can
continue to be used to guide treatment and have the po-
tential to reduce length of admission, increase patient sat-
isfaction, and improve quality of life. (7)(37)(38) Whether
or not the patient has an individualized plan, the general
concepts of pain treatment are similar to those used at home
and in the ED. If not obtained in the ED, chemistry laboratory
tests are recommended at admission to ascertain baseline re-
nal and hepatic function, and these tests should be followed
1 to 2 times a week during prolonged admissions. Daily com-
plete blood cell counts and reticulocyte counts for at least
72 hours on admission are suggested to monitor whether the
patient is experiencing anemia exacerbation.
Prescribing nonopioids can include continuation of
scheduled IV ketorolac or acetaminophen. The maximum
recommended number of doses of ketorolac is 20 (5-day
course) every 30 days to reduce the risk of gastrointestinal
bleeding. If this limit has been reached, then oral NSAIDs
can be given, such as ibuprofen, naproxen, or meloxicam.
Muscle relaxants given around-the-clock and topical lido-
caine can also be used during hospitalization.
Patients who were treated with IV opioids in the ED
will likely need to continue IV opioids during hospitaliza-
tion. It is important that there not be a delay in dosing of
IV opioids while transitioning the patient from the ED to
the inpatient unit because a delay can lead to poorly con-
trolled pain. The patient should be assessed soon after ar-
rival at the inpatient unit, which includes a review of
when the last pain medication was given in the ED, the
current pain intensity rating, and level of consciousness.
We suggest aiming for a “floor-to–assessment and anal-
gesia” time of less than 60 minutes.
There are 3 primary dosing strategies for opioids: sched-
uled intermittent dosing, basal/continuous IV opioid infu-
sion, and on-demand dosing. Opioid delivery via patient-
controlled analgesia (PCA) has been associated with shorter
length of hospitalization, lower total opioid consumption,
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and better patient satisfaction; however, most recent guide-
lines do not reflect a recommendation on this delivery
method due to lack of evidence in individuals with SCD.
(7)(39)
We suggest scheduled intermittent opioid dosing every
3 hours for patients who are opioid naive, are developmen-
tally immature, or have demonstrated good relief with in-
termittent dosing in the ED. Additional opioid doses may
be needed for breakthrough pain. If intermittent dosing is
not effective, we recommend transitioning the patient to
receive PCA delivery instead of higher amounts or more
frequent dosing to every 2 hours.
Starting doses for PCA-delivered opioid should follow
institutional pharmacologic guidelines and a patient’s indi-
vidualized pain plan. Opioid-tolerant patients may need
higher doses to achieve pain relief or improvement (Table 2).
Continuous opioid infusion prevents sedation associated
with higher opioid doses delivered intermittently during
peaks of pain, and continuous infusion treats pain during
troughs of intermittent opioid dosing. The patient-initiated
“demand” bolus for breakthrough pain allows for control of
medication when it is needed and avoids waiting for a
nurse to be available to give as-needed doses. A common
approach is to divide the total amount of opioid prescribed
and give up to half of the total by continuous infusion per
hour and the remainder as on-demand boluses. Bolus dos-
ing is not recommended for young or developmentally
delayed children. Some institutions have shown clinical
benefit with demand-only dosing, with shorter hospitaliza-
tion, decreased opioid exposure, and rapid improvement
in pain scores (40); however, patients often report that
they may awaken in pain after not receiving boluses dur-
ing sleep. For nonverbal patients or those who are not de-
velopmentally able to understand PCA bolus use, they can
be treated with continuous infusion only. Some institu-
tions have the option of nurse-administered boluses. We
do not recommend having the bolus option for a parent or
guardian to administer opioids.
Naloxone should be available for all patients on sched-
uled or continuous IV opioids. Although there are standard
doses for naloxone reversal of opioid overdose, naloxone
should be given cautiously in patients receiving acute pain
treatment. Rapid naloxone administration can be associated
with onset of severe pain, anxiety, and seizures due to dis-
placement of opioid from its receptors. Gradual titration of
naloxone for opioid reversal to achieve adequate respiratory ef-
fort and mental status is recommended.
Adjunctive therapies are often necessary to prevent treat-
ment adverse effects. Famotidine, an H2 antihistamine, or
Vol. 4 5 No. 1 JANUARY 2024 3 3
 proton pump inhibitors can be prescribed to treat or pre-
vent gastritis associated with NSAID use. Opioid-induced
adverse effects, including pruritis, nausea and vomiting,
and constipation, should be addressed. For pruritis not re-
lieved by oral antihistamines, intermittent low-dose nalbu-
phine or continuous low-dose infusion naloxone can be
effective. A daily stimulant laxative should be scheduled un-
less the patient is experiencing diarrhea, and dosing should
be adjusted to prevent constipation. Intravenous hypotonic
fluids at 1x maintenance rate are suggested.
Preventive respiratory treatments, such as incentive spi-
rometry, are recommended to prevent atelectasis and the
development or worsening of ACS. Patients who have
asthma can be treated with scheduled albuterol and their
asthma and/or allergy controller medications continued.
Usual SCD medications, such as folic acid, hydroxyurea, or
other disease-modifying therapy, should be continued, along
with any other daily medications for other conditions.
Nonpharmacologic pain management includes warm
packs, warm baths, activities to help with coping and dis-
traction, psychosocial support, and physical therapy when
available. Healthy dietary choices and a typical daily sched-
ule of activities, including hygiene, schoolwork, and sched-
uled bedtime, are recommended to promote a normative
experience, to avoid excess snacking or sweetened drinks,
and to maintain a day-night circadian cycle. Functional
pain assessment may be useful in inpatient settings.
In some hospitals, severe acute pain not responsive to
opioids may be treated with IV ketamine, IV lidocaine,
and regional or epidural anesthesia, usually administered
and managed by anesthesiologists. (41)
Transition to Discharge
When patients have relief of their pain and have improved
functionality, parenteral opioids are reduced, eventually
transitioning to equianalgesic oral opioids. At our institu-
tion, we reduce to a 4-hour cumulative MME to the pa-
tient’s usual dose of hydrocodone or oxycodone every
4 hours, a regimen that most families can usually manage
at home. For example, a patient who weighs 88 lb (40 kg)
and is currently receiving morphine continuous infusion
of 1 mg/h is receiving 4 mg of IV morphine over 4 hours,
which is the equivalent of 12 MME (IV to oral morphine
equivalence of 3:1) (Table 2). If the usual dose of hydroco-
done/acetaminophen is 5 mg hydrocodone/325 mg acet-
aminophen (5 MME), then a change from the current
continuous infusion would be a dose reduction of 7 MME
per dose, which would likely be ineffective for pain control.
In this example, it is recommended to gradually reduce the
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morphine infusion rate from 1 mg/h to 0.4 mg/h over the
following 12 to 16 hours (0.4 mg/h × 4 h 5 1.6 mg/4 h ×
3 5 4.8 MME), as tolerable to the patient, before changing
to oral hydrocodone/acetaminophen.
Patients with SCD who have been treated with IV
opioids for more than 7 days may be at risk for opioid
withdrawal if they change to as-needed dosing or stop
their opioids at home. In this case, we prescribe a home
taper of oral opioids, starting with a schedule of 4 times a
day and gradually reducing the frequency over 5 to 7 days,
and educating families on signs and symptoms of opioid
withdrawal. Most patients are discharged within 24 hours
of transitioning to oral pain medicines. They are encour-
aged to continue to manage their pain at home with
scheduled NSAIDs, opioids, and other adjunct therapies
as outlined in their individualized pain management plan.
A prescription of nasal naloxone with instructions for its
use and administration is recommended for patients who
take opioids daily.
PAIN PREVENTION
Healthy lifestyle practices that are recommended for all
children can help people with SCD reduce pain. The Cen-
ters for Disease Control and Prevention and the National
Institutes of Health recommend good hydration, avoiding
pain triggers, pursuing physical activity, maintaining a
heart healthy diet, achieving adequate sleep, and having
support systems and ways to manage stress. (42)(43) All
patients with SCD should be followed by their general pe-
diatricians, who can help promote these healthy lifestyle
practices and follow their patients’ overall development.
Although general pediatricians can be fantastic partners in
their care, general pediatricians should not be managing
these patients on their own. Where available, patients with
SCD should be referred to a local pediatric hematology
team, whose expertise can ensure that the patients have ac-
cess to the latest therapies and receive the most up-to-date
care recommended per professional society guidelines.
Rapid diagnosis and treatment of febrile illnesses and
infections are important for reducing inflammation as a
trigger to pain and life-threatening infectious complica-
tions. Providing oxygen to treat hypoxia caused by acute
respiratory illnesses, chronic lung disease, and/or obstruc-
tive sleep apnea can reduce sickle Hb polymerization and
vaso-occlusion.
Although there are few clinical trials specifically for
SCD pain, integrative therapies such as acupuncture, med-
itation, massage, and/or yoga have been shown to have
benefit for the treatment of some painful conditions, such
 as chronic back pain or headaches. (44) The National Center
for Complementary and Integrative Health recommends that
patients discuss the use of mind-body practices or dietary
supplements with their health-care provider and not use an
integrative approach either to delay or to use as a sole substi-
tute to conventional medical treatment. The National Center
for Complementary and Integrative Health’s framework of
“whole person health” (https://www.nccih.nih.gov/health/
whole-person-health-what-you-need-to-know) is useful for SCD
pain management, taking into consideration the complex
interplay among pathophysiology, physical function, mental
health, and social factors. (45)
DISEASE-MODIFYING THERAPIES
Hydroxyurea was FDA-approved to reduce SCD complica-
tions for adults in 1998 and for children in 2017 (but had
been used off-label for many years). Hydroxyurea is a che-
motherapeutic agent that increases the presence of Hb F
and reduces sickle Hb polymerization, leading to a higher
total Hb level and reduction of SCD pain and ACS. Hy-
droxyurea is also used to prevent stroke. (46) Hydroxyurea
is now recommended for all children with Hb SS or S/b0-
thalassemia older than 9 months to reduce the development
of pain and to delay organ injury. (11)
Long-term RBC transfusions are used to prevent severe SCD
complications, such as stroke, recurrent ACS, or splenic seques-
tration, and are not typically used to treat pain without other
complications. However, a short course of monthly RBC trans-
fusions may be helpful in patients who have bone infarcts or
who are in the early stages of disease-modifying therapies. In-
definite use of transfusions to prevent pain is not recommended
due to the eventual development of transfusional iron overload,
which necessitates treatment with iron chelation.
Since 2017, there have been 3 additional FDA-approved
therapies for SCD. L-glutamine is an amino acid that increases
antioxidant activity in RBCs and is approved for children 5
years of age to adults. In a randomized controlled trial (RCT),
participants who took L-glutamine had 25% fewer VOEs com-
pared with a placebo-treated group, as well as fewer episodes
of ACS. (47) L-glutamine is given orally twice daily.
Crizanlizumab was approved in 2019 for people with
SCD 16 years and older. Crizanlizumab is a monoclonal
antibody directed against P-selectin, an adhesion molecule
on platelets and endothelial cells that mediates the adher-
ence of platelets and leukocytes to blood vessels, which
can be an early event in VOEs. In an RCT, individuals re-
ceiving crizanlizumab had 45% fewer VOEs per year com-
pared with those receiving placebo. (48) Crizanlizumab is
given by IV infusion every 4 weeks.
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Voxelotor was also approved in 2019, for people with
SCD 12 years and older. Approval was extended to 4 years
and older in 2021. Voxelotor binds directly to Hb and in-
creases its oxygen affinity. In SCD, this results in reduced
Hb S polymerization and sickling, hemolysis, and anemia.
(49) In an RCT, 51% of patients who received voxelotor had
an increase in Hb greater than 1 g/dL (>10 g/L) from base-
line in 24 weeks compared with 6.5% of those who were pla-
cebo-treated. Voxelotor has not been demonstrated to
reduce VOEs in clinical trials, but medical claims database
analysis showed that among people with SCD and voxelotor
prescriptions, 61% had an increase in Hb level greater than
1 g/dL and 34% had a reduction in VOE-related hospitaliza-
tions. (50) Voxelotor is given orally once a day.
Early and reliable use of hydroxyurea can be an effective
means of reducing sickle cell pain and the transition from
episodic pain to frequent or chronic pain. The newer thera-
pies are helpful options for those who do not have adequate
response to hydroxyurea or who prefer not to take it.
CANNABIS FOR SICKLE CELL PAIN
In some states, cannabis is legal for medical and/or recreational
use, and some adults with SCD use cannabis for pain treatment.
Cohort studies show variable association of cannabis use and
hospitalizations, with fewer admissions in Wisconsin and more
in New York among cannabis users versus nonusers. (51)(52) An
RCT of vaporized cannabis vs placebo showed no statistically sig-
nificant difference in chronic daily pain. (53) Cannabis products
(smoked, vaped, or ingested) should be avoided for treatment of
SCD pain in children and adolescents due to lack of evidence of
safety or benefit, its status as an unregulated illicit substance in
many states, and its effects on neurologic development and the
potential for significant adverse effects, including neuropsychiat-
ric symptoms or cannabinoid hyperemesis syndrome. (54)
RISK OF OPIOID DEPENDENCE AND ADDICTION
The effective relief of sickle cell pain needs to be balanced by the
safe use of opioids and avoidance of overuse and overdose. The
entire nation has an opioid crisis with growing numbers of opi-
oid overdose deaths in the past decade, a crisis that involves both
illicit and prescription opioids. Patients with SCD are often
found guilty by association and are labeled as drug-seeking.
(55) Federal agencies and state governments have guidelines
regarding opioid prescribing, such as limits of maximum
MME per day, or number of days/doses of medication per
prescription. People with cancer are usually exempt, but not
people with SCD. These limits may make it difficult for pa-
tients with severe pain to get sufficient medication to relieve
their symptoms. In reality, opioid-associated deaths among
Vol. 4 5 No. 1 JANUARY 2024 3 5
 people with SCD between 1999 and 2018 accounted for 348
of 15,765 total deaths (2%). (56) This 20-year number is com-
pared with 100,000 drug overdose deaths nationally from
May 2020 to April 2021, indicating that opioid overdose
death is relatively infrequent among people with SCD and
should not be used as a reason to limit prescription opioids
to people with SCD who need them.
All forms of opioids can be abused or can be associated with
physical dependence or addiction. Opioid use disorder and ad-
diction are a result of activation of brain reward circuits by
opioids, which has been described as causing a cycle of addic-
tion. (57) Some useful concepts can be applied to the treatment
of SCD pain to reduce the potential of opioid dependence. First,
clinicians should become knowledgeable about the relative po-
tency (MME) of the various medications. Clinicians should pre-
scribe the lowest dose and potency of opioid and the shortest
duration of therapy that effectively relieves pain. Clinicians
should track the number of outpatient opioid prescriptions us-
ing the state’s Prescription Drug Monitoring Program. Clini-
cians can reduce activation of the brain’s reward circuits by
euphoric effects by avoiding rapid IV infusions (“push”) of
opioids, and instead administering opioids by slow infusion
over 10 to 15 minutes using a syringe pump. Antihistamines
should be given orally to avoid euphoric effects with IV admin-
istration. Giving opioids on a schedule during the initial phases
of acute pain, rather than waiting until they are needed, re-
duces unrelieved pain, withdrawal, and negative affective
symptoms, as well as opioid craving.
ACKNOWLEDGMENTS
We thank the children and families living with sickle cell disease
with whom we have had the privilege to work and learn; our
many colleagues at Children’s Healthcare of Atlanta, who are
dedicated to providing high-quality and compassionate care to
patients; and our families for supporting our work.
Summary
• Where available, patients with sickle cell disease
(SCD) should be referred to a local pediatric
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hematology team whose expertise can ensure
that patients have access to the latest therapies
available and receive up-to-date care per professional
society guidelines.
• Hydroxyurea is strongly recommended as a
disease-modifying therapy for SCD to reduce the
frequency of vaso-occlusive pain episodes in
children and adolescents. (Based on strong evidence
from randomized controlled trials and cohort studies)
(46)
• Standardized protocols (11)(28) and individualized
plans (7) for SCD pain treatment are recommended.
(Based on moderate evidence from observational
studies and expert opinions)
• Integrative therapies such as acupuncture, meditation,
or yoga are additional options for treatment and
prevention of SCD pain. (Based on very limited
evidence, but no reports of adverse outcomes)
• Cannabis should not be used to treat SCD pain in
children and adolescents due to lack of supporting
evidence of effectiveness and the substantial risks
for adverse outcomes. (54)
SUGGESTED QUALITY IMPROVEMENT
ACTIVITIES
1. Achieve door-to–first analgesic treatment of 60 minutes
for children and adolescents with sickle cell disease
vaso-occlusive pain episode seen in emergency depart-
ments or urgent care centers.
2. Home naloxone prescriptions and education for all chil-
dren and adolescents with sickle cell disease who are
taking daily opioids.
Take the quiz! Scan this QR code to take the quiz,
access the references and teaching slides, and
view and save images and tables
(available on January 1, 2024).
 PIR QUIZ

1. During the routine yearly evaluation of a 13-year-old boy of sub-Saharan

African decent, the parents discuss the patient’s frequent need for
hospitalizations due to vaso-occlusive pain episodes. He is taking
hydroxyurea as prescribed, and episodes are often provoked by illness or
dehydration. The family can describe his individualized care plan. Review of
your clinic’s standard questions for social determinants of health reveals no
concern of food insecurity. The patient has up-to-date insurance coverage.
Which one of the following is the most likely cause of the patient’s frequent
hospitalizations?
A. High disease severity.
B. Opioid-seeking behavior.
C. Poor access to care. REQUIREMENTS: Learners can
take Pediatrics in Review quizzes
D. Poor adherence to care plan. and claim credit online only at:
E. Social determinants of health. http://pedsinreview.org.
2. A 6-year-old boy with known sickle cell disease is brought to the emergency
To successfully complete 2024
department by his parents because of leg pain over the past day. The Pediatrics in Review articles for
parents report no improvement of the pain after trying warm compresses AMA PRA Category 1 Credit™,
and oral hydrocodone and acetaminophen. According to the National Heart, learners must demonstrate a
Lung, and Blood Institute, which one of the following is the most minimum performance level of
60% or higher on this
appropriate Emergency Severity Index recommended to assign this patient
assessment. If you score less
during emergency department triage? than 60% on the assessment,
A. Level 1. you will be given additional
opportunities to answer
B. Level 2.
questions until an overall 60%
C. Level 3. or greater score is achieved.
D. Level 4.
E. Level 5. This journal-based CME activity
is available through Dec. 31,
3. A 10-year-old girl with known sickle cell disease is admitted with a vaso- 2026, however, credit will be
occlusive pain episode. She has not been drinking well since admission but recorded in the year in which
was drinking before admission and does not appear clinically dehydrated. the learner completes the quiz.
She weighs 70.5 lb (32 kg). Which one of the following types of intravenous
fluids is most appropriate for this patient?
a. 0.9% saline bolus of 640 mL.
b. 0.9% saline bolus of 320 mL.
c. D5 lactated ringer at 72 mL per hour.
2024 Pediatrics in Review is
d. D5 0.9% saline at 72 mL per hour. approved for a total of 30
e. D5 0.45% saline at 72 mL per hour. Maintenance of Certification
(MOC) Part 2 credits by the
4. During a routine evaluation, the parents of a 4-week-old infant with a recent American Board of Pediatrics
diagnosis of sickle cell disease (hemoglobin SS) inquire about when to begin (ABP) through the AAP MOC
using medications to prevent pain episodes that their 7-year-old child with Portfolio Program. Pediatrics in
sickle cell disease has had. You discuss the first-line agent, hydroxyurea, and Review subscribers can claim up
to 30 ABP MOC Part 2 points
inform the family that it is recommended to begin this treatment when their
upon passing 30 quizzes (and
child is older than which of the following ages? claiming full credit for each
a. 6 months. quiz) per year. Subscribers can
start claiming MOC credits as
b. 9 months.
early as October 2024. To learn
c. 12 months. how to claim MOC points, go
d. 18 months. to: https://publications.aap.org/
e. 24 months. journals/pages/moc-credit.

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 5. A 16-year-old boy with sickle cell disease is hospitalized for a vaso-occlusive
pain episode. He is being treated appropriately with intravenous fluids,
intravenous pain medications, and adjunctive pain medications. The family
inquires about methods to decrease the risk of opioid addiction. You explain
to them that decreasing the experience of euphoria is the best way to
minimize risk of addiction. Which one of the following is an effective
method to decrease euphoria associated with intravenous opioids?
a. Administration of intravenous antihistamine.
b. Administration of opioids over 10 to 15 minutes.
c. Avoiding intravenous opioids until pain occurs.
d. Avoiding scheduled opioids for initial treatment.
e. Use of more potent opioids initially.

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 INDEX OF SUSPICION

Persistent Bleeding in a 7-week-old Girl

Leslie Saba, MB BCh BAO,* Matthew C. Authement, MD*
*Department of Pediatric and Adolescent Medicine, Mayo Clinic, Rochester, MN

PRESENTATION
A 7-week-old girl presents with bruising, hematemesis, and persistent bleeding
from venipuncture sites. She was born at 38 weeks’ gestation via spontaneous
vaginal home delivery to consanguineous parents. After birth, the infant had no
screening or prophylactic care performed, such as critical congenital heart dis-
ease screen, newborn screen, bilirubin check, hearing screen, hepatitis B immu-
nization, erythromycin ointment, or vitamin K injection. She has had
regurgitation of feeds since birth, but streaks of dark blood in her vomit were
first noticed 3 weeks ago and progressed to bright red blood 6 days before pre-
sentation. She had 1 episode of a bright red dime-sized amount of blood in her
diaper, but her stool has otherwise been yellow in color. She also has bruising
on her back and head, with no history of trauma. She is exclusively breastfed
but has been more lethargic, with decreased feeding. She initially presented to
her pediatrician, where she had laboratory blood specimens drawn from her an-
tecubital fossa. This site continued to ooze, prompting presentation to a local
emergency department the following day, where she had additional laboratory
specimens drawn revealing a hemoglobin level of 7.5 g/dL (75 g/L), which de-
creased by 1.9 g/dL (19 g/L) compared with the previous day. Red blood cell in-
dices show a decreased hematocrit level of 21.9%, a decreased erythrocyte count
of 2.38 × 106/mL (2.38 × 1012/L), a normal mean corpuscular volume of 92 mm3
(92 fL), and a normal red blood cell distribution width of 14.3%. Platelet and
white blood cell counts are normal. Blood smear shows atypical lymphocytes,
polychromasia, and poikilocytosis. Alanine aminotransferase, aspartate amino-
transferase, and alkaline phosphatase levels are elevated compared with age-ap-
propriate norms of 93 U/L (1.55 mkat/L), 127 U/L (2.12 mkat/L), and 954 U/L
(15.93 mkat/L), respectively, with a total bilirubin level of 5.3 mg/dL (90.65 mmol/L).
Prothrombin time (PT), international normalized ratio (INR), and activated partial
thromboplastin time (aPTT) are collected, and the result was “recollection of speci-
men collection” due to an error message on the laboratory machine. She was subse-
quently transferred from the emergency department to our hospital for further
evaluation and management.
Vital signs at presentation include a temperature of 97.2! F (36.2! C), heart rate
of 164 beats/min, respiratory rate of 35 breaths/min, blood pressure of 84/67 mm
AUTHOR DISCLOSURE: Drs Saba and
Hg, and oxygen saturation of 100% on room air. Weight is at the 11th percen- Authement have disclosed no financial
tile for age. Physical examination reveals a jaundiced, lethargic infant. Anterior relationships relevant to this article. This
commentary does not contain a
fontanelle is flat. She has moist mucosal membranes. On auscultation, a sys-
discussion of an unapproved/
tolic flow murmur heard loudest at the left upper sternal border is present. Ab- investigative use of a commercial
dominal palpation reveals hepatomegaly 4 cm below the costal margin, and no product/device.

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 splenomegaly. There are 2 bruises 1.5 cm in diameter on
her middle upper back, 1 bruise 1 cm in diameter on her
occiput, and dried blood around her fingernails. She has
normal skin turgor. She has continuous oozing from ve-
nipuncture sites on her left and right antecubital fossae
that is saturating gauze dressings changed 20 minutes
earlier. Peripheral intravenous access is obtained for urgent
management. Additional laboratory testing and imaging re-
veal the diagnosis.
DISCUSSION
Differential Diagnosis
The differential diagnosis for persistent bleeding in a neo-
nate includes acquired bleeding disorders and inherited
bleeding disorders. Acquired bleeding disorders include
disseminated intravascular coagulation, especially due to
sepsis, vitamin K deficiency, and liver disease. Inherited
bleeding disorders include hemophilia, von Willebrand
disease, and congenital platelet disorders such as Bernard-
Soulier syndrome and Glanzmann thrombasthenia. An-
other diagnosis to consider when an infant has hemateme-
sis or bloody stools includes swallowed maternal blood
from breastfeeding. In addition, nonaccidental trauma can
be considered in a nonmobile infant with bruising and el-
evated transaminase levels.
Evaluation of conjugated and unconjugated bilirubin
levels can be used to further identify causes of acquired
coagulopathies, some of which may be associated with
liver disease. Unconjugated hyperbilirubinemia can result
from hemolytic disease processes, breast milk jaundice,
lactation failure jaundice, or inherited disorders of biliru-
bin metabolism, such as Crigler-Najjar and Gilbert syn-
dromes. Causes of conjugated hyperbilirubinemia include
biliary atresia, Alagille syndrome, idiopathic neonatal hep-
atitis, a1-antitrypsin deficiency, and inherited metabolic
diseases such as galactosemia and tyrosinemia. Infectious
causes, including sepsis and perinatal TORCH infections
such as congenital toxoplasmosis, cytomegalovirus, and
herpes simplex virus, should also be part of the differen-
tial diagnosis because they may present with jaundice, pe-
techiae, and hepatomegaly.
Actual Diagnosis
This infant was clinically diagnosed as having vitamin K
deficiency bleeding (VKDB), formerly known as hemor-
rhagic disease of the newborn. She had notably not re-
ceived vitamin K at her home birth. Coagulation studies
revealed an elevated INR of 29, as well as prolonged PT
greater than 320 seconds, aPTT greater than 400 seconds,
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thrombin time of 28.1 seconds, and reptilase time of
24.8 seconds. Vitamin K–dependent coagulation factors
II, VII, IX, and X were undetectable. D-dimer level, fibrino-
gen level, and von Willebrand factor antigen and activity
were normal.
Due to this patient’s elevated total bilirubin level, a di-
rect bilirubin level was obtained to differentiate between
conjugated and unconjugated causes of hyperbilirubine-
mia. Direct hyperbilirubinemia (bilirubin level, 3.4 mg/dL
[58.15 mmol/L]) prompted further evaluation for liver
disease. Abdominal ultrasonography revealed a small and
irregular gallbladder consistent with a gallbladder ghost
sign, and an atretic common hepatic duct measuring
0.9 mm. Gallbladder ghost sign describes the triad of an
atretic gallbladder measuring less than 1.9 cm, thin or ab-
sent mucosal lining with an indistinct wall, and an irregu-
lar gallbladder contour. (1) This raises concern for biliary
atresia; however, a hepatobiliary iminodiacetic acid scan
showed no scintigraphic evidence of biliary atresia. Fur-
ther tests for causes of direct hyperbilirubinemia were per-
formed. Blood cultures, urinalysis, and cytomegalovirus
urine polymerase chain reaction were negative for infec-
tion. Total serum bile acid and urine bile acid levels were
elevated, consistent with cholestasis. Additional analysis of
urine bile acids was obtained by fast atom bombardment
mass spectrometry to screen for inborn errors of bile acid
metabolism, and the findings were normal. Testing for
galactosemia using urine-reducing substances was nega-
tive. Lactate dehydrogenase, haptoglobin, and cholesterol
levels were normal. The newborn screen was sent before
transfusion but was unsatisfactory, perhaps due to anemia
or sample collection error, and will be repeated in the
future. The underlying cause of direct hyperbilirubine-
mia was revealed by a decreased a1-antitrypsin level of
33 mg/dL (6.07 mmol/L) with ZZ phenotype, indicative
of a1-antitrypsin deficiency. Cholestatic liver disease,
such as a1-antitrypsin deficiency, is a known cause of vita-
min K deficiency due to impaired ability to synthesize vita-
min K–dependent coagulation factors as well as impaired
absorption. (2)
The Condition
Vitamin K has an essential role in the synthesis of factors
II, VII, IX, and X in the coagulation cascade. Deficiency of
vitamin K leads to decreased activity of these clotting fac-
tors and, therefore, an increased risk of bleeding. New-
borns have reduced stores of vitamin K due to insufficient
placental transport, and in addition, breastfed infants are
at increased risk of deficiency due to decreased amounts
 of vitamin K in human milk compared with standard in-
fant formulas. (3) In addition, newborns have a sterile gut
and lack the gut bacteria that contribute to the synthesis
of vitamin K. (4) VKDB, previously known as hemorrhagic
disease of the newborn, is divided into 3 groups based on
the age at onset: early (within the first 24 hours after
birth), classic (between days 2 and 7), and late (between
weeks 2 and 12). (3) Early-onset VKDB is associated with
maternal use of medications that inhibit or decrease vita-
min K activity, such as antiepileptics, antitubercular drugs,
or warfarin. (5) Classic VKDB is typically idiopathic but oc-
curs at a higher incidence in breastfed newborns. Hepato-
biliary and malabsorptive diseases, such as biliary atresia,
cystic fibrosis, and a1-antitrypsin deficiency, can precipi-
tate late-onset VKDB due to decreased bile and pancreatic
enzymes, which aid in the absorption of fat-soluble vita-
mins such as vitamin K. (6)
VKDB can present with bleeding from the mucous
membranes, the gastrointestinal tract (melena, hemateme-
sis), or the skin (bruising, petechiae) or after circumcision,
cutting of the umbilical cord, and vaccinations. Intracra-
nial bleeding is seen in more than 50% of late VKDB
cases and should be considered in babies with lethargy, al-
tered consciousness, seizures, feeding difficulties, or bulg-
ing fontanelles. (6)
VKDB affects both the extrinsic (factor VII) and intrin-
sic (factors II, IX, X) coagulation pathways, thereby lead-
ing to increased PT and aPTT, respectively. INR is also
elevated and typically greater than 4. (4) Platelet count and
fibrinogen level remain normal. Proteins induced by vita-
min K absence or antagonism (PIVKA) are functionally
defective vitamin K–dependent coagulation factors that are
formed when vitamin K is deficient. (6) The detection of
any amount of PIVKA indicates vitamin K deficiency. (4)
PIVKA levels are detectable for approximately 5 days after
vitamin K administration and can be used to make a retro-
spective diagnosis of VKDB even after treatment. (6) Imaging
should be performed if there is concern for intracranial or
intrathoracic bleeding.
Management
Prompt administration of vitamin K is key in the manage-
ment of VKDB, and treatment should not be delayed for
laboratory results. Vitamin K can be administered subcuta-
neously, intramuscularly, or intravenously; however, intra-
muscular injection can lead to hematoma formation.
Vitamin K–dependent coagulation factors rapidly increase
within 20 to 30 minutes after vitamin K administration, with
normalization of the coagulopathy within 2 to 3 hours. (7) For
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severe or life-threatening bleeding, blood transfusion, fresh
frozen plasma, or prothrombin complex concentration should
be considered.
The American Academy of Pediatrics recommends ad-
ministration of intramuscular vitamin K at a dose of 0.5 to
1.0 mg to all newborns for the prevention of VKDB. Oral
vitamin K is less effective at preventing VKDB, particularly
the late-onset type, due to malabsorption. (6) Parental re-
fusal of intramuscular vitamin K in the United States is
estimated to be up to 3.2% in hospitals, 14.5% in home
births, and 31% in birthing centers. (8) This highlights an
important collaborative role between physicians and mid-
wives in educating families in the perinatal period, especially
given differing state regulations regarding prophylaxis refusal.
VKDB led to the incidental diagnosis of a1-antitrypsin
deficiency in this case as the patient’s bleeding prompted
a thorough medical evaluation, which revealed hepatomegaly,
elevated transaminase levels, and direct hyperbilirubinemia.
a1-Antitrypsin deficiency is an autosomal codominant genetic
disorder, and children of consanguineous parents are at
greater risk for inheriting the disease, as seen in this case.
There is no specific treatment for a1-antitrypsin–associated
liver disease, and management focuses on strategies to pre-
vent hepatic injury. Patients should receive hepatitis A and B
vaccinations, avoid alcohol intake, and eat healthy diets to pre-
vent obesity. (9) Definitive treatment for end-stage liver dis-
ease is liver transplant, with 5-year survival of 80% after liver
transplant. (10) a1-Antitrypsin level also affects the lungs and
increases the risk of emphysema; therefore, patients should
be advised to abstain from smoking and are monitored with
regular spirometry testing. Intravenous administration of
pooled human a1-antitrypsin is the primary method of treat-
ing the associated lung disease in patients with declining lung
function. (11)
Patient Course
The infant’s bleeding resolved after the administration of
vitamin K and fresh frozen plasma with correction of INR
to 1.1, PT to 11.6 seconds, and aPTT to 32 seconds. Blood
transfusion was performed given symptomatic anemia
with tachycardia and poor feeding. On examination the
following morning she appeared alert, and venipuncture
sites at the antecubital fossae were no longer bleeding.
Hepatomegaly improved to 1.5 cm below the costal margin
without splenomegaly. Left upper sternal border flow mur-
mur was still audible. She was discharged and was referred
to outpatient pediatric gastroenterology for follow-up of newly
diagnosed a1-antitrypsin deficiency. Additional laboratory test-
ing revealed improving anemia with a hemoglobin level of
Vol. 4 5 No. 1 JANUARY 2024 4 1
 10.1 g/dL (101 g/L) and a direct bilirubin level of 2.1 mg/dL
(35.92 mmol/L). She was feeding well, gaining weight, and
had no further bleeding episodes at the 2-week follow-up
appointment. Pediatric gastroenterology plans to continue to
follow her with biannual laboratory checks and office visits.
Lessons for the Clinician
• Consider underlying hepatobiliary or malabsorptive dis-
orders in patients presenting with late-onset vitamin K
deficiency bleeding.
4 2 Pediatrics in Review
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• If there is strong clinical suspicion for vitamin K deficiency
bleeding, initiate immediate treatment while awaiting test
results.
• Vitamin K can be administered for vitamin K deficiency
bleeding subcutaneously, intramuscularly, or intrave-
nously; however, intramuscular injection can lead to he-
matoma formation.
References for this article can be found at
https://doi.org/10.1542/pir.2021-005492.
 INDEX OF SUSPICION

Severe Malnutrition in an Adolescent Girl

Doha Aboul-Fotouh, MD,* Marcella Donaruma-Kwoh, MD,* Gal Barak, MD, MEd,* Andrea Dean, MD*
*Department of Pediatrics, Baylor College of Medicine, Texas Children’s Hospital, Houston, TX

PRESENTATION
A 17-year-old adopted girl with a reported history of prediabetes, hyperlipidemia,
and in utero human immunodeficiency virus exposure presents to an endocri-
nology clinic for poor growth and primary amenorrhea. Her mother reports
2 unrevealing evaluations for poor growth that had remained poor despite high
appetite and regular meals. She recently was seen for routine care and was re-
ferred for further evaluation. Her mother describes mood and behavior changes
over the past 7 months and abnormal behaviors, including eating cat food and
food left in the trash. Her mother further reports that the patient has had diffi-
culty self-regulating her appetite and never seems to feel full, which the patient’s
mother attributes to trauma and neglect in her birth home. Both deny food inse-
curity. Review of symptoms is negative for fever, abdominal pain, emesis, diar-
rhea, hematochezia, and melena.
The patient was adopted at age 10 years and lived with her adoptive mother
and 7 adoptive sisters, all of whom were adopted separately from foster care.
Two additional older sisters moved out after reaching adulthood. The family at-
tended religious services regularly. They have moved frequently but always lived
rurally, and all the children were homeschooled after adoption. In a private inter-
view, the patient denies attempts to lose weight, drug use, sexual activity, feeling
unsafe at home, depression, and suicidal ideation.
On physical examination the patient’s heart rate is 46 beats/min, blood pres-
sure is 107/76 mm Hg, weight is 78.0 lb (35.4 kg), height is 60.4 in (153.5 cm),
and BMI is 15.0 (Z score 5 –4.5). She is polite, thin, and clean, and she appears
younger than her stated age, with roughly shorn hair and baggy clothes. Tanner
stage of both breast and pubic hair is II. Her examination findings are otherwise
normal, including thyroid, lymph node, abdominal, and neurologic examina-
tions. Her examination shows fine lanugo on her extremities but no abnormal
dental findings and no calluses on her knuckles.
Initial laboratory values are normal, including complete metabolic panel (carbon
dioxide level, 30 mEq/L [30 mmol/L]; reference range, 25–35 mEq/L [25–35 mmol/L]),
blood cell counts (hemoglobin level, 14.0 g/dL [140 g/L]; white blood cell count, AUTHOR DISCLOSURE: Drs Aboul-
3,110/mL [3.11 × 109/L]; platelet count, 241 × 103/mL [241 × 109/L]), thyroid levels Fotouh, Barak, and Dean have disclosed
no financial relationships relevant in this
(thyrotropin level, 2.308 mIU/mL [reference range, 0.5–3.4 mIU/mL]; free thyroxine
article. Dr Donaruma-Kwoh previously has
level, 0.9 ng/dL [11.58 pmol/L] [reference range, 0.8–2.0 ng/dL (10.38–25.74 pmol/L)]), provided expert witness consultation in
lipid levels, hemoglobin A1c levels, and inflammatory markers. Levels of folli- the field of child abuse pediatrics for a
fee. This commentary does not contain a
cle-stimulating hormone (4.8 mIU/mL [4.8 IU/L]; range for Tanner stage II,
discussion of an unapproved/
0.7–5.8 mIU/mL [0.7–5.8 IU/L]) and luteinizing hormone (1.6 mIU/mL [1.6 IU/L]; investigative use of a commercial
range for Tanner stage II, 0.2–2.3 mIU/mL [0.2–2.3 IU/L]) were consistent with her product/device.

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 sexual maturity assessment. Human immunodeficiency virus
antibody testing is nonreactive. The patient is admitted to the
pediatric hospital medicine service for treatment of severe
malnutrition with bradycardia.
DISCUSSION
Differential Diagnosis
The leading diagnosis was inadequate caloric intake on the
child's part, including primary psychiatric disorders and
disordered and/or restricted eating. Lower on the differen-
tial diagnosis were high-output conditions such as hyper-
thyroidism, type 1 diabetes, chronic infection, malignancy,
and malabsorptive diseases such as celiac disease and in-
flammatory bowel disease. Medical evaluation was initiated,
beginning with gathering input and recommendations from
subspecialty consultants.
Psychiatry was consulted to assess for a mood or behavior
disorder that would lead to restrictive eating, including
obsessive-compulsive disorder, psychosis, or autism spectrum
disorder. The patient’s mother provided additional history
of repetitive behaviors and limited interests. However, in
speaking with and observing the patient, these behaviors
were not detected.
Adolescent medicine was consulted to evaluate for a pri-
mary eating disorder. Although the patient reported hypera-
wareness of caloric content of meals, and guilt associated
with eating, she had no distorted body image and no desire
to lose weight. In fact, she described feeling stronger at a
previous higher weight. She expressed concern about eating
more than appropriate, and shame for eating garbage and
cat food, as well as hoarding or stealing food. Nonetheless,
she did not express any thoughts or behaviors consistent with
binging or purging.
Although evaluation was underway, the patient was ob-
served in the hospital and the information gathered by the
multidisciplinary team was synthesized. She ate normally
and gained weight during her observation period and, over
subsequent interviews, gradually offered subtle insights into
her home life. For example, she reported that at each meal,
her mother fixed her plate, and she was made to eat in the
bathroom while the rest of the family members gathered at
the dinner table and served themselves. Later, she told an-
other staff member that she was encouraged to refrain from
eating all the food provided to her to learn self-control.
Actual Diagnosis
A diagnosis of deprivational abuse was made with the as-
sistance of the child protection team. The patient’s peculiar
behaviors, although initially concerning for primary eating
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disorder or psychiatric illness, including food obsession and
intensive food-seeking, were manifestations of hunger. Her
mother’s controlling behavior in the context of her physio-
logical starvation was abusive, and she demonstrated no un-
usual eating behaviors while admitted. Her diagnosis was
further supported by normal eating behaviors and rapid
weight gain accompanied by refeeding syndrome when pro-
vided regular access to food.
During her prolonged hospitalization, aberrant mother-
child interactions became apparent, such as repeated re-
fusal to bring in the patient’s glasses so that she could
read, and the removal of snacks from the room. Eventu-
ally, the mother’s out-of-state extended family sought out
hospital staff to report long-standing concern for the children
and volunteered collateral information, including previous re-
ports of neglect and abuse. Throughout the hospitalization,
the patient provided new details of her mother’s disciplinary
practices, including unusual punishments, such as shearing
her hair and isolating her from her family for long periods.
However, she did not endorse abuse, instead explaining
these occurrences as fair consequences and limitations to
curve her own excessive desires.
The Condition
Deprivational abuse, which refers to withholding a child’s
basic needs for control, punishment, or intimidation, is in-
frequently discussed in the recent literature. Subtle forms
are common, and the psychological effects from these aber-
rant caregiver-child interactions impact children throughout
their lifetimes. (1) Deprivation of food and support is typi-
cally housed under the category of neglect, which refers to
the failure of a caregiver to meet the child’s needs due to
stress, competing priorities, lack of knowledge or education,
or financial constraints. (2)(3) However, such categorization
contributed to diagnostic and communication challenges
in this case, in which the child was deliberately starved for
purposes of control and discipline. Therefore, the more
apt diagnosis of deprivational abuse was used to convey the
malevolence of the caregiver and the intentional neglect that
this patient faced. (3)(4)
It is important to recognize that other well-known cate-
gories of abuse besides neglect, such as medical child
abuse (MCA; ie, Factitious Disorder Imposed on Another,
formerly known as Münchausen syndrome by proxy) and
torture, also do not accurately capture the nature of this
patient’s experience. For example, this case is clearly not
MCA because this caregiver did not exaggerate, fabricate,
or induce the child’s illness, in this case, starvation with
the intent to seek or obtain medical attention. (5)(6) On
 the contrary, the parent was resistant to obtaining care for
her child, which she ultimately sought only due to delayed
menses. Furthermore, although deprivation is included as
one of many possible manifestations of torture, of which this
case does share some aspects, it did not meet the full diag-
nostic criteria of child torture. (5)(7) Therefore, from a medi-
cal and legal standpoint, it is inaccurate and ineffective to
discuss the patient in terms of neglect, MCA, or torture. This
child’s case highlights how a better understanding of inten-
tional deprivation as a presentation of neglect could benefit
its survivors through earlier recognition and diagnosis. More-
over, a shared knowledge of deprivation and, arguably, a
more robust utilization of the term deprivational abuse would
improve communication with stakeholders and equip clinicians
to advocate for patient well-being and removal from harm.
An index of suspicion would have aided in the collec-
tion and interpretation of the history provided by the pa-
tient and caregiver, which obscured the true diagnosis. In
retrospect, the history provided by the caregiver included
high-yield factual information, including complaints of the
patient’s intense food-seeking, including eating pet food
and garbage, which is a documented trait of deprivation
and could serve as a clue to the presence of abuse. (7) In
addition to incomplete information, reliance on the care-
giver history, which although routine in pediatrics, introduced
implicit bias that was difficult to overcome for diagnosis as
well as in advocating for the patient. Similar to MCA, the
parent gained sympathy from hospital staff and Child Protec-
tive Services (CPS) by sharing her personal story and indicat-
ing overwhelming concern for the patient. (6) However,
unlike MCA, where there is a shared awareness of this trait,
an incomplete understanding of deprivational abuse and lack
of language to discuss it made it difficult to overcome this
bias that favored the caregiver. The term neglect made it
seem that with enough education and resources, the parent
could safely care for the patient.
In addition, viewed through the lens of deprivational
abuse, the patient’s initial and persistent denial of mistreat-
ment would have been expected. Although pediatricians rou-
tinely consider neglect in infants or immobile children who
present with failure to thrive, it is assumed that an ambula-
tory, neurotypical adolescent could fulfill basic needs in the
absence of food insecurity. Therefore, this patient’s denial
of abuse was taken for granted, and disordered eating and
psychiatric diagnoses, prevalent in adolescent girls, led the
differential diagnosis well into her observation period and
serial interviews.
Although the patient objectively described her mother’s
abusive actions, she perceived them as fair consequences
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and, therefore, defended her mother vehemently. Living in
near-total isolation from the outside world and peer inter-
action, she had normalized the actions of her parent. Fur-
thermore, she suggested that her mother had “saved her”
from an unloved existence and was helping her because
“foster kids can be sneaky.” This internalized scapegoating
is well documented in victims of child torture (5)(7) and is
common in older abused children, who fail to recognize
their experience as abusive because it has defined their en-
tire upbringing. (1) Clinicians and social service workers
must be aware that these children are rendered ineffective
advocates for their own protection, despite being more ver-
bal than infants and young children.
Treatment/Management
Treatment aims to address acute and chronic consequences of
deprivation, in this case, her malnutrition, as well as removal
from the abusive caretaker and permanent placement into a
safe, stable, and nurturing environment. Long-term trauma
counseling is recommended.
Patient Course
The patient gained 30 lb (13.6 kg) and grew 1 in (2.54 cm)
in height during her 4-week admission, after receiving
age-appropriate access to food and regular meals. Her re-
feeding syndrome was managed with electrolyte repletion.
She experienced menarche within weeks of reaching typi-
cal weight-for-age parameters.
A report was made to CPS. Despite lengthy multidisciplin-
ary meetings attempting to explain the nature of her abuse,
CPS ultimately returned her to her mother’s home. Her dis-
position demonstrated the challenges of removing a child
with intentional neglect, manifested as starvation in this case,
from their abusive environment. Her abuse was difficult to
discuss without agreed-on terminology, its effects were rapidly
erased (eg, weight gain), and the patient was unable to recog-
nize, attest to, or remove herself from her own abuse. (1) In-
deed, our patient’s expressed desire to return to the care of
her mother heavily influenced CPS’s final decision.
The patient became a missing person several months after
discharge after she was abandoned by her mother at a bus sta-
tion on her 18th birthday. After several months of homeless-
ness, the patient was recovered. She was welcomed into the
home of her extended family, enrolled in occupational school,
and is now actively processing her abuse in counseling.
Lessons for the Clinician
• Although deprivation is a subcategory of neglect, it differs
in the deliberate nature of the withholding of a child’s
Vol. 4 5 No. 1 JANUARY 2024 4 5
 physical or emotional needs and is often delivered as
punishment. Deprivational abuse is infrequently used ter-
minology that was used in this case to convey the malevo-
lence of the caregiver and the harm done to the patient.
• Deliberate starvation by a caregiver should remain on the dif-
ferential diagnosis for failure to thrive or severe malnutrition
in infants, children, and adolescents, especially when there
is a history of bizarre behavior or intense food-seeking.
• Although pediatricians depend on parent- or guardian-
provided history, providers’ assumptions must be confronted
in the process of integrating information from caregivers.
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• Survivors of abuse, especially deprivation and torture,
may not always be able to recognize abusive behavior as
abuse but may be able to deliver factual statements
(such as discipline and punishment, content of meals,
access to care) to describe their home environment.
Even if the survivor is an adolescent, they may be an
ineffective advocate for their own protection due to the
nature of the abuse.
References for this article can be found at
https://doi.org/10.1542/pir.2021-005416.
 INDEX OF SUSPICION

Cough, Neck Pain, and Right Facial Paralysis in a

14-year-old with Autism
Zhongbo Hu, MD, PhD,* Bradley Muller, MD,† Jeremy S. Slone, MD, MPH,*‡ Hiroto Inaba, MD, PhD§
*Hospitalist Medicine Program, Department of Oncology,
†
Department of Hematology and Oncology,
‡
Global Pediatric Medicine, and
§
Department of Oncology, St. Jude Children’s Research Hospital, Memphis, TN

PRESENTATION
A 14-year-old boy with autism presents to the emergency department for intermittent
cough and neck pain for 5 weeks and worsening dyspnea for 3 days. Five weeks ago, he
started with an intermittent dry and harsh cough and neck pain, but without a docu-
mented fever. Three weeks ago, he experienced significant fatigue and dizziness at school
and presented to his primary pediatrician. Initial evaluation showed normal complete
blood cell counts, normal chemistries, and a negative mononucleosis test result. The day
after the visit to the pediatrician’s office, he woke with difficulty moving the right side of
his face and right eyebrow and presented to urgent care. A head computed tomographic
(CT) scan was performed with normal results, and his condition was diagnosed as Bell’s
palsy (peripheral facial nerve palsy), for which he was prescribed valacyclovir and predni-
sone (30 mg for 2 days, 20 mg for 3 days, and 10 mg for 3 days). After an 8-day course of
treatment, his fatigue and appetite improved, but his cough, neck pain, and facial droop-
ing remained unchanged. Three days ago, the patient noticed dyspnea on exertion, but it
was not noted by his parents. In the evening of presentation, he developed shallow and fast
breathing, and his parents brought him to the emergency department. Review of systems
showed continued intermittent cough, chest pain, and palpitation.
His medical history is significant for high-functioning autism diagnosed at age 3 years;
he does well in school. He does not have a herpes infection history. He lives with his
parents with no ill contact in a non–Lyme disease–endemic area and is fully immunized.
His vital signs show weight of 125.4 lb (56.9 kg) (70th percentile), height of 67.5 in
(171.5 cm) (82nd percentile), temperature of 99.1! F (37.3! C), heart rate of 78 beats/min,
respiratory rate of 26 breaths/min, oxygen saturation of 98%, and blood pressure of
133/93 mm Hg. The patient is alert and oriented. His cranial nerve examination exhibits
mainly right-sided facial paralysis, including no eyebrow movement, no forehead wrin-
kle, no nasolabial fold, inability to close his right eye tightly, and an asymmetrical smile.
His visual acuity is 20/20 bilaterally. Pupils are round and reactive to light and accom-
modation. Extraocular movements are intact, without ptosis. His hearing is normal.
Gag reflex presents but decreases on the right. Tongue is midline. He has normal
AUTHOR DISCLOSURE: Drs Hu, Muller,
speech and tongue movement as well as normal and symmetrical strength. Shoulder Slone, and Inaba have disclosed no
shrug is symmetrical. His sensation is intact bilaterally to pain and light touch except financial relationships relevant to this
article. This commentary does not
aching numbness on the right side of the face. Biceps, triceps, and plantar reflex are nor-
contain a discussion of an unapproved/
mal. The neck is supple, the trachea is midline, and there is no jugular vein distention. investigative use of a commercial
There are palpable bilateral cervical and right axillary lymph nodes. He has symmetrical product/device.

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 chest wall expansion, and the lungs are clear to auscultation
with intermittent tachypnea. Heart sounds are slightly muffled.
The abdomen is soft, nontender, and nondistended, with no
hepatosplenomegaly. The complete blood cell count shows a
white blood cell count of 7,000/mL (7 × 109/L); neutrophils,
48.3%; immature granulocytes, 0.4%; lymphocytes, 31.8%;
monocytes, 17.6%; eosinophils, 1.0%; basophils, 0.9%; hemo-
globin level, 14.0 g/dL (140 g/L); and platelet count, 205 × 103
/mL (205 × 109/L). Blood smear does not have any blasts. The
blood chemistry analysis shows a creatinine level of 2.11 mg/dL
(186.52 mmol/L) (reference range, 0.2–0.7 mg/dL [17.68–61.88
mmol/L]); urea nitrogen level of 14 mg/dL (5.0 mmol/L) (8–21
mg/dL [2.86–7.5 mmol/L]) and electrolyte levels (sodium, 141
mEq/L [141 mmol/L] [134–143 mEq/L (134–143 mmol/L)]; potas-
sium, 3.5 mEq/L [3.5 mmol/L] [3.5–5.0 mEq/L (3.5–5.0 mmol/
L)]; chloride, 103 mEq/L [103 mmol/L] [96–109 mEq/L
(96–109 mmol/L)]; carbon dioxide, 27 mEq/L [27 mmol/L]
[20–31 mEq/L (20–31 mmol/L)]; calcium, 9.7 mg/dL [2.42 mmol/
L] [8.8–10.8 mg/dL (2.2–2.7 mmol/L)]; and phosphorus, 4.5 mg/
dL [1.45 mmol/L] [2.9–5.4 mg/dL (0.94–1.74 mmol/L)]); uric
acid level, 12.2 mg/dL (0.73 mmol/L) (2.4–7.8 mg/dL
[0.14–0.46 mmol/L]); lactate dehydrogenase level, 1,506 U/
L (25.15 mkat/L) (360–730 U/L [6.01–12.19 mkat/L]); erythrocyte
sedation rate, 23 mm/hr (0–13 mm/hr); and C-reactive protein
level, 3.21 mg/dL (32.1 mg/L) (#0.9 mg/dL [#9.0 mg/L]). A
rapid antigen test for severe acute respiratory syndrome corona-
virus 2 is negative. A chest radiograph shows a mediastinal
mass. The patient is admitted for further evaluation and man-
agement. Pediatric oncology is consulted for co-management.
DISCUSSION
Differential Diagnosis
Bell’s palsy is idiopathic and the most common cause of periph-
eral facial nerve paralysis. It causes weakness of the ipsilateral
muscles involving facial expression. Most of the symptoms will
naturally resolve within weeks to months, with more than 70%
of patients experiencing complete recovery. (1) Some patients
may experience severe facial weakness and inability to blink or
close the eyes, resulting in corneal ulceration and permanent vi-
sual impairment. Bell’s palsy is a disease that is diagnosed by ex-
clusion, requiring elimination of etiologies such as trauma,
neoplasm (acoustic neuroma and lymphoma), congenital or
syndromic disorders (Melkersson-Rosenthal syndrome, Albers-
Sch€onberg disease [osteopetrosis], and Goldenhar syndrome
[oculoauriculovertebral dysplasia]), surgical complication with
facial nerve injury, and infection (herpes zoster [Ramsay Hunt
syndrome], otitis media, and Lyme disease). (2)
The differential diagnosis of a mediastinal mass (Table) in an
adolescent includes lymphoma (lymphoblastic, Hodgkin, pri-
mary mediastinal large B cell), germ cell tumor, and thymoma.
(3) The most frequent tumors in the anterior compartment are
thymoma, teratoma (germ cell tumor), thyroid tumor, and
“terrible” lymphoma (ie, the four Ts). (4) Approximately 75% of
patients with mediastinal tumors are male, and the median on-
set age is 13 years. Of all mediastinal tumors, lymphomas are
the most common (47.5%), followed by germ cell tumors and
neuroblastoma (12.5% each), and thymoma (7.5%). (5)
Actual Diagnosis
Posteroanterior and lateral chest radiography showed an en-
larged anterior mediastinum. Computed tomography of the
chest, abdomen, and pelvis showed a “large mediastinal mass
and enlargement of the kidneys. There is mass effect with com-
pression of the superior vena cava (SVC), trachea, right main-
stem and right upper lobe bronchus” (Fig 1). Biopsy of the left
cervical lymph nodes showed diffusely positive CD3, CD5,
terminal deoxynucleotidyl transferase; positive CD10, BCL-2,
c-MYC; and significantly increased Ki67/MIB-1. Flow cytometry
of the lymph node specimen identified 97.4% blasts with posi-
tive CD45 (dim), CD2, CD7, CD10, CD5, CD7, CD1a, cytoplas-
mic CD3, and terminal deoxynucleotidyl transferase. Bilateral
bone marrow aspiration and biopsies were performed and
showed that approximately 2% of the total analyzed cells in the
bone marrow expressed markers similar to those of the nodal
blasts. His condition was diagnosed as T-cell lymphoblastic lym-
phoma (T-LLy) with peripheral facial paralysis. His laboratory

Table. Differential Diagnoses of a Mediastinal Mass in a Child

ANTERIOR MEDIASTINAL MASS MIDDLE MEDIASTINAL MASS POSTERIOR MEDIASTINAL MASS
Leukemia/lymphoma (T-cell lymphoblastic Foregut duplication cysts, eg. bronchogenic Thoracic neuroblastoma
leukemia/lymphoma, Hodgkin cyst
lymphoma, anaplastic large-cell
lymphoma, B-cell lymphoma)
Solid tumor (germ cell tumor, teratoma) Tuberculosis Neurofibroma
Thymic cyst Fungal chest infection Extramedullary hematopoiesis
Enlarged thymus Vascular malformation Vascular malformation
Tuberculosis Lymphadenopathy

Adapted from Green K, Behjati S, Cheng D. Fifteen-minute consultation: obvious and not-so-obvious mediastinal masses. Arch Dis Child Educ
Pract Ed. 2019;104(6):300. Copyright notice 2022 with permission from BMJ Publishing Group Ltd.

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 Figure 1. A, Posteroanterior radiograph of the chest demonstrates a large mediastinal mass (line with arrowheads) measuring up to 15 cm in transverse
dimension with a mediastinal ratio greater than 50%. B, Axial computed tomographic (CT) scan with intravenous contrast demonstrates the large medi-
astinal mass (outlined in white) narrowing the right and left main bronchi (arrows) and surrounding and narrowing the superior vena cava (SVC) (arrow-
heads). Bilateral pleural effusions are also noted (asterisks). C, Coronal CT scan with intravenous contrast demonstrates a large mediastinal mass (small
white arrows) surrounding and narrowing the SVC (arrowheads). Also noted are a right pleural effusion (asterisk) and diffuse enlargement of the kidneys,
with the renal parenchyma replaced by low-density lobulated lesions (black arrows).

results, with significant elevation of uric acid and creatinine lev-
els, indicated a diagnosis of tumor lysis syndrome (TLS). The
TLS with hyperuricemia and acute kidney injury (AKI) were
likely exacerbated by recent prednisone treatment. His cerebro-
spinal fluid was evaluated on day 5 of treatment and was nega-
tive for lymphoma cells.
The Condition
LLy, the second most common type of non-Hodgkin lym-
phoma in childhood and adolescence, accounts for 25% to
35% of cases. (6) T-cell lymphoblastic origin is seen in
70% to 80% of patients with LLy, with 60% to 70% presenting
with a large mediastinal mass. (7) T-LLy with a mediastinal
mass is often accompanied by cough, chest pain, shortness of
breath, wheezing, stridor, swelling of the head and neck, or
dysphagia due to compression of the trachea, SVC, or esopha-
gus or to development of a pericardial or pleural effusion. Bone
marrow or peripheral blood blast percentage less than 20% indi-
cates LLy, whereas 20% or more blasts indicates acute lympho-
blastic leukemia (ALL). T-LLy and T-cell ALL are both
transformed from immature precursor T cells and are treated
with similar treatment protocols. The overall survival rates are
approximately 80% in the pediatric population. (8)
When a facial palsy is present in the setting of lymphoma,
the clinician must determine whether this represents a central
palsy that could be a result of CNS infiltration by the lymphoma
or a peripheral seventh nerve palsy due to compression of the
facial nerve by tumors or enlarged lymph nodes (Fig 2). (1) A
central facial palsy spares the forehead because the musculature
receives innervation from both sides of the motor cortexes. A

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 Figure 2. Symptoms to distinguish peripheral from central facial nerve palsy. Peripheral facial palsy (including Bell’s palsy) shows loss of forehead and
eyebrow movement, inability to close eye, eyelid droops, loss of nasolabial folds, and lower lip droops. Central facial palsy preserves the eyebrow and
forehead movement, with loss of only nasolabial folds and lower lip droops. (Adapted with permission from Garro A, Nigrovic LE. Managing peripheral
facial palsy. Ann Emerg Med. 2018;71[5]:620.)

peripheral seventh nerve palsy, as seen in this case, involves the
musculature of the upper and lower face. Several case reports de-
scribe T-cell lymphoma with or without mastoid involvement that
presented with peripheral seventh cranial nerve palsy. (9)(10)
T-LLy/ALL, especially with a large mediastinal mass, Burkitt
lymphoma, and other acute leukemias with hyperleukocytosis
(B-cell ALL: white blood cell count, $100,000/mL [$100 × 109
/L]; acute myeloid leukemia: white blood cell count, $50,000/mL
[$50 × 109/L]) account for the 3 most common pediatric diseases
with the highest risk of TLS. TLS is a life-threatening complica-
tion that can occur before or after initiation of therapy, when the
rapid lysis of malignant cells releases intracellular ions (mainly
potassium and phosphorus), nucleic acids, proteins (including
cytokines), and their metabolites into the bloodstream. The me-
tabolites cause hyperuricemia, hyperkalemia, hyperphosphate-
mia, hypocalcemia, and uremia. (11) The definition of laboratory
TLS requires 2 or more of the previously mentioned metabolic
abnormalities. Clinical TLS is manifested when laboratory TLS is
accompanied by signs of organ failure, such as increased creati-
nine level, seizure, cardiac dysrhythmia, multiorgan failure, or
death. (12) TLS leading to AKI is a primary concern because AKI
is associated with short- and long-term mortality. (11)(12) TLS-in-
duced AKI is due mainly to crystal precipitation of uric acid and
calcium phosphate causing renal tubular injury and obstruction.
The AKI can occasionally be due to xanthine nephropathy
and nephrolithiasis after allopurinol administration. (13)
Management
Corticosteroids reduce the risk of unsatisfactory facial recovery
and are recommended as the first line of treatment for Bell’s
palsy, (14)(15) with maximum benefit when given within 72 hours
of disease onset. A methylprednisolone dose pack is recom-
mended for adults, with prednisone or prednisolone (2 mg/kg
per day) for 10 days recommended for children. (1) However,
treatment of Bell’s palsy with corticosteroids should be consid-
ered only after a thorough diagnostic evaluation to exclude other
etiologies, such as malignancy, especially in patients with respi-
ratory signs or symptoms that might indicate mediastinal mass.
(16)(17)A very thorough history and physical examination is par-
ticularly needed in an autistic patient because of inability to ade-
quately communicate. Pretreatment of leukemia/lymphoma
with corticosteroids may obscure and delay the diagnosis.

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 Patients with lymphoma or leukemia can present with periph-
eral facial palsy. In that case, chemotherapy should be started af-
ter the diagnosis is established. Note that corticosteroids might
mask the diagnosis by reducing the tumor burden and cause
TLS with AKI without any awareness by the clinician, as de-
scribed herein. Regarding T-LLy management, although the
overall survival rate for pediatric LLy is greater than 80%, initial
management of T-LLy with mediastinal mass is still challenging,
with both high morbidity and late sequelae due to compressions
of the trachea and SVC. A mediastinal location is frequent at pre-
sentation and relapse in patients with T-LLy. Per current stan-
dard-of-care treatment protocols, stage II through IV T-LLy is
treated similar to T-cell ALL, with 4-drug induction (corticoste-
roids, vincristine, asparaginase, and daunorubicin) and consoli-
dation therapy including cyclophosphamide, cytarabine, and
mercaptopurine. (6) In patients with significant cardiorespiratory
compromise, prediagnostic treatment with corticosteroids (eg,
methylprednisolone 20 mg/m2 in 4 divided doses for 1 day) or ra-
diotherapy to the mediastinal mass (eg, 180 rad/dose with 3
doses) should be considered; however, histologic diagnosis, stag-
ing, and prognosis may be compromised. Ultrasonography with
Doppler is needed in a patient with a large mediastinal mass to
rule out thrombosis. Diagnostic procedures should start from less
invasive sites, from peripheral blood followed by bone marrow,
pleural effusion, and lymph node biopsy of cervical or supraclavic-
ular regions to minimize anesthesia risk. Attempted resection of
a mediastinal mass is not recommended unless procedures in
other sites fail to establish a diagnosis. Intrathecal chemotherapy
may be delayed if a large mediastinal mass is compromising the
airway or causing severe AKI.
Early recognition of patients at risk for TLS and initiation of
therapy are important to prevent AKI. Hyperhydration with in-
travenous non–potassium-containing fluid (2,500–3,000 mL/
m2 per day in patients at highest risk) is the key for prophylaxis.
Prophylaxis with allopurinol (300–450 mg/m2 per day in 3 di-
vided doses up to 400 mg daily) should begin 1 to 2 days before
chemotherapy and continue for 3 to 7 days after chemotherapy
is started. Allopurinol, which can cause xanthine nephropathy,
is not preferred after TLS diagnosis is established. Rasburicase
at 0.2 mg/kg with single or repeated dosages is indicated if the
uric acid level is greater than 7.5 mg/dL (>0.45 mmol/L), or 6.5
mg/dL (0.39 mmol/L) in patients younger than 13 years with no
history of glucose-6-phosphate dehydrogenase (G6PD) defi-
ciency or ongoing pregnancy. (18) Patients at high risk for TLS
may be considered for low-intensity initial therapy, such as a
week of prednisone for childhood ALL or LLY, or low-dose cyclo-
phosphamide, vincristine, and prednisone for a week for Burkitt
lymphoma. (12) The described prophylactic methods, combined
with close monitoring of TLS laboratory results every 4 to 8 hours
and electrolyte imbalance management, is the routine regimen.
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Urinary alkalinization is not recommended in patients with TLS
because it decreases the solubility of calcium phosphate. If the
measures fail to prevent renal deterioration, significant fluid over-
load, or worsening electrolyte imbalance, then early continuous
renal replacement therapy is recommended. (19)
Patient Course
The patient was initially treated for a Bell’s palsy, delaying his pri-
mary lymphoma diagnosis. In addition, treatment with corticoste-
roids may lead to AKI and TLS-associated hyperuricemia without
notice until his presentation to a pediatric oncology subspecialty.
After G6PD testing to avoid rasburicase-induced G6PD deficien-
cy–associated hemolytic anemia, (20) the patient received hydra-
tion with 2 times maintenance intravenous fluid, rasburicase,
and then allopurinol. After 2 days of hydration, respiratory dis-
tress with worsening pleural effusion developed, and the patient
was transferred to the ICU for oxygenation with high-flow nasal
cannula and chest tube placement. When corticosteroid treat-
ment was restarted, worsening TLS-induced AKI and electrolyte
imbalance developed, with hyperphosphatemia and hypocalce-
mia. Corticosteroids were temporarily held while continuous renal
replacement therapy was started. The patient’s AKI and general-
ized edema and effusion improved, enabling him to resume the
treatment regimen.
Lessons for the Clinician
• Bell’s palsy is typically diagnosed by exclusion. After exclud-
ing secondary facial nerve palsy, first-line management is
initiate corticosteroid therapy within 72 hours to obtain max-
imal benefit.
• Be thoughtful about conditions that might require addi-
tional evaluation before corticosteroid initiation, espe-
cially in the setting of any respiratory symptom.
• The diagnostic process for mediastinal mass must be
carefully planned, starting with the least-invasive proce-
dure to minimize the risk of anesthesia.
• Fluid management in a patient with tumor lysis syndrome,
acute kidney injury, and superior vena cava syndrome may
be challenging because hyperhydration can worsen the supe-
rior vena cava syndrome. Consider early continuous renal re-
placement therapy or extracorporeal membrane oxygenation
in life-threatening situations.
Acknowledgments
We thank Dr Cherise Guess for her assistance in editing
this manuscript and Dr Cara Morin for providing the ra-
diologic imaging.
References for this article can be found at
https://doi.org/10.1542/pir.2022-005512.
Vol. 4 5 No. 1 JANUARY 2024 5 1
 INDEX OF SUSPICION

Facial Lesions and Rash in a 2-month-old Boy

Alexandra Curry, DO,* Anoop Khalsa, MD,* David Yi, DO*
*Department of Pediatrics, University of California San Francisco–Fresno, Fresno, CA

PRESENTATION
A 2-month-old former term boy with no known medical conditions presented
with a 1-month history of persistent scabbed lesions on his face and scalp and
2 weeks of a worsening rash on his arms, legs, palms, and soles. According to
the mother, the scalp lesion was present at birth, and she continues to peel the
scab during bathing. There was no scalp probe, vacuum, or forceps used at de-
livery. The facial lesions were initially ulcerative and then developed scabs but
did not heal completely. The rash began on the extremities and spread proxi-
mally. He has no other symptoms. His sister was recently diagnosed as having
scabies and is currently being treated. Per mom, there has not been any recent
travel, hiking or camping, animal exposures, tick bites, or ingestions other than
his regular formula.
Two weeks before delivery, his mother developed a painful vesicular vaginal
lesion without associated regional lymphadenopathy after unprotected intercourse
with a new partner. She received no testing of her lesion but was prescribed em-
pirical acyclovir during the last 2 weeks of pregnancy because she was positive for
herpes simplex virus (HSV) type 2 IgG antibody. The lesion was reportedly still
present but was healing the day of delivery, when mom had a precipitous vaginal
delivery. Mom had no other pertinent medical history. Her prenatal laboratory
test results were negative for hepatitis B, human immunodeficiency virus, and
group B streptococcus. She also had 3 negative fluorescent treponemal antibody
absorption (FTA-Abs) test results at 31, 35, and 38 weeks’ gestation, the last test be-
ing the day of delivery. At birth, the patient’s examination findings were normal
except for a round, 2-cm, raised lesion on his scalp. HSV surface cultures and
HSV blood polymerase chain reaction were negative at that time.
On presentation to the emergency department he is afebrile and his other vi-
tal signs are within normal limits, with weight at 5,578 g (36th percentile) and
height at 23.8 in (60.5 cm) (69th percentile), on track with his birth percentiles.
On physical examination there is a diffuse, papulosquamous, blanchable, ery-
thematous, targetoid, well-circumscribed, partially crusted rash that includes the
palms, soles, and scalp, without mucosal involvement (Figs 1–3). He has several
soft, palpable cervical lymph nodes less than 1 cm each, and the liver is palpable
2 cm below the subcostal margin.
AUTHOR DISCLOSURE: Drs Curry, Khalsa,
Laboratory evaluation shows a white blood cell count of 10,700/mL (10.7 × 109/L), and Yi have disclosed no financial
a hemoglobin level of 7.9 g/dL (79 g/L) with a mean corpuscular volume of 86.7 fL relationships relevant to this article. This
commentary does not contain a
(86.7 mm3), and a platelet count of 150 × 103/mL (150 × 109/L). The differential count
discussion of an unapproved/
is 63% lymphocytes and 22% neutrophils, 1% bands, 8% monocytes, 5% eosino- investigative use of a commercial
phils, and 1% basophils. The C-reactive protein level is 10.75 mg/dL (107.5 mg/L) product/device.

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 Figure 2. Scabbed facial chancre over the bridge of the nose and lateral
to the left eye.

postnatal HSV evaluation at birth was negative. Coxsackievi-

rus, rickettsia, bacterial endocarditis, toxic shock syndrome,
measles, and meningococcemia are potential organisms that
could cause a rash on the palms, but the patient did not

Figure 1. Healing scalp chancre over the right parietal bone.

(reference range, 0–1.5 mg/dL [0–15.0 mg/L]). The procalcito-

nin level is 315 ng/dL (3.15 mg/L) (reference range, 0–30 ng/dL
[0.3 mg/L]). His metabolic panel is within the reference range,
including normal hepatic enzyme levels. COVID-19 polymer-
ase chain reaction is negative. No imaging is performed. Pend-
ing laboratory results from his outside pediatrician and our
facility ultimately help reveal the diagnosis.

DISCUSSION
Differential Diagnosis
The differential diagnosis includes rheumatologic, allergic,
and infectious causes. Neonatal lupus erythematosus and
psoriasis were considered but were less likely given a nega-
tive family history and the wide distribution and appearance
of the rash. The skin targetoid lesions on the trunk and ex-
tremities were similar to a hypersensitivity response such as
erythema multiforme, which could have been secondary to
potential HSV infection. However, the crusted facial lesions
were inconsistent with erythema multiforme, and his previous Figure 3. Generalized rash on the legs and soles.

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 have a fever, mucosal involvement, or other systemic symp-
toms that are seen with these infections. Given his sister’s
recent infection, we considered scabies; however, it is usually
a pruritic rash with 3- to 5-mm papules often in the presence
of pustules, unlike our patient’s more confluent, targetoid
rash. Maternal syphilis testing was negative, and her genital
lesion was painful, which is more consistent with an HSV le-
sion. However, congenital syphilis was considered because
the facial lesions exhibited a chancrelike appearance, and his
painless maculopapular rash involving the palms and soles
resembled a syphilitic infection, especially in the setting of
his lymphadenopathy, anemia, and hepatomegaly. In addi-
tion, negative syphilis test results are possible, especially if
testing is performed early in the disease process. The mom’s
new sexual encounter was approximately 2 weeks before
delivery, and the FTA-Abs treponemal assay can take 3 to
4 weeks to become positive in primary syphilis. (1)(2)
Actual Diagnosis/Clinical Course and Management
On hospital day 2, the patient’s rapid plasma reagin (RPR)
titer was reactive at 1:256. Based on the laboratory and ex-
amination findings in the setting of a positive RPR, our
patient was diagnosed as having early congenital syphilis.
Of note, during our patient’s admission, his mom tested
positive for syphilis with an RPR of 1:128, therefore con-
firming that the infant was exposed to untreated maternal
syphilis. He was not tested for syphilis at birth secondary
to negative maternal testing because she was too early in
her infection for the assays to accurately detect infection.
A lumbar puncture was completed, and he was started on
penicillin treatment. He was also treated empirically with
acyclovir for HSV until the HSV blood culture, cerebrospinal
fluid (CSF), and mucosal cultures were finalized as negative.
Two hours after the first dose of intravenous penicillin
G, he became tachycardic, hypertensive, and febrile, with
increased fussiness. A Jarisch-Herxheimer reaction was
suspected. The patient was given 1 dose of acetaminophen,
and he improved. There were no further reactions with
subsequent penicillin G doses. The plain radiograph bone
survey showed periostitis consistent with congenital syphilis;
however, his remaining evaluation was largely negative. He
had a nonreactive CSF-VDRL test result. Given the lack of
pleocytosis or increased protein in the CSF, we had a low
suspicion for neurosyphilis and, therefore, did not obtain a
brain magnetic resonance image. (3)(5) The ophthalmologic
examination findings and auditory brainstem response were
normal. He completed a 10-day course of penicillin G. (6)
He was discharged with scheduled follow-up. He missed his
3-month appointment, but testing 6 and 9 months after
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treatment showed significant improvement; however, he con-
tinues to be seropositive, with an RPR at 1:2. He will follow
up next at 12 months.
The Condition
Treponema pallidum is the spirochete that causes congenital
syphilis. The incidence in the United States has continued to
increase since 2013 and is currently 125 to 180 cases per
100,000 live births, highest among non-Hispanic American
Indian or Alaskan Native, Pacific Islander, and Black or Afri-
can American populations. (7)(8) In 2020, preliminary data
show more than 2,000 cases of congenital syphilis, includ-
ing 139 stillbirths or infant deaths. (7) In 2019, 50% of coun-
ties in the United States reported at least 1 case of syphilis
(all stages) among women of reproductive age (15–44 years),
which serves as an important reminder that congenital syph-
ilis can be seen almost anywhere. (7)(8) Globally, congenital
syphilis is a leading cause of preventable stillbirth, highlight-
ing the importance of prenatal screening. (9)(10)
Syphilis is transmitted through the placenta or contact
with infectious lesions during birth. Untreated syphilis dur-
ing pregnancy has a rate of perinatal transmission of 60% to
100%. (3)(4)(5)(11) This rate is increased during the second
half of pregnancy and is higher in mothers with primary or
secondary syphilis. (12) Fetal or perinatal death occurs in
40% of infants born to infected and untreated moms. (3)(11)
Patients may present as severe as hydrops fetalis and still-
birth, or they may be asymptomatic at birth and only develop
signs and symptoms weeks to months later.
Because spirochetes widely disseminate, nearly all organ
systems can be infected. Early findings (within the first 2 years
after birth) include maculopapular erythematous rash involving
copper red spots on the palms and soles; skin peeling; per-
sistent copious rhinitis (snuffles); diffuse lymphadenopathy;
pneumonitis; jaundice; hepatosplenomegaly; and pseudopar-
alysis of Parrot caused by painful osteochondritis or periostitis,
which manifests as decreased movement of the extremities,
mainly the upper limbs. Laboratory evaluation at birth or
within the first 4 to 8 weeks of age most commonly reveals
Coombs-negative hemolytic anemia, thrombocytopenia associ-
ated with platelet trapping in an enlarged spleen, and elevated
liver enzyme levels secondary to bile stasis or fibrosis. (3)(6)
Late manifestations (after 2 years but within the first
2 decades) can be prevented by treatment of early infec-
tion. These manifestations include frontal bossing, kerati-
tis, Hutchinson teeth, saddle nose, saber shins, gummas,
and juvenile paresis, which occurs during adolescence and
manifests as behavior changes, focal seizures, and loss of
intellectual function. (3)(6)
 Laboratory Diagnosis
There are 2 types of tests used to diagnose syphilis: non-
treponemal and specific treponemal antibody tests. There
are 2 algorithms used to determine management. (6) The
classic or traditional pathway first uses a nontreponemal
assay (eg, RPR and VDRL, which measure host antibodies
made in response to phosphatidylcholine taken up from
mammalian tissue by T pallidum during an active infec-
tion) and if positive is confirmed with a treponemal test
(eg, manual FTA-Abs and T pallidum particle agglutination
assay or automated enzyme immunoassay and chemilumines-
cence immunoassay, which measure antibodies to T pallidum).
It takes 4 to 6 weeks after the initial infection for an RPR
test to become reactive. Because the RPR is a marker of
active infection, it may be negative in the setting of latent
or late syphilis. The reverse algorithm, more often used
now especially in endemic areas, performs a treponemal as-
say first, and should that be positive, is followed by a non-
treponemal test. Treponemal antibodies appear earlier than
nontreponemal antibodies, allowing for earlier detection of
syphilis with the reverse algorithm. (1)(2)(3) Even still, it
takes 3 to 4 weeks for the treponemal assays to be reactive
in the setting of an infection, and in some literature, FTA-
Abs testing was found to be less sensitive than other trepo-
nemal assays for primary syphilis (Table). (10)(13)(14) To
this end, patients in high-risk areas with a history of a sexual
encounter with a new partner late in pregnancy may need
follow-up testing for syphilis because initial testing could
have been before the ability of the assay to detect antibodies.
In addition, symptomatic patients should receive both
treponemal and nontreponemal testing. The FTA-Abs test
involves the addition of fluorescein isothiocyanate–labeled
anti–human globulin antibody to a patient’s serum for the
detection of anti–T pallidum antibody. The degree of fluores-
cence is then manually read based on the degree of
Table. Sensitivity and Specificity of Nontreponemal
and Treponemal Testing in Primary Syphilis (13)(14)(19)
SYPHILIS TEST SENSITIVITY, % SPECIFICITY, %
Nontreponemal
RPR 77–99 93–99
VDRL 74–87 96–99
Treponemal
FTA-Abs 78.2–100 87–100
TP-PA 86.2–100 99.6–100
CIA 84.9–98.9 93.0–97.3
Treponema pallidum EIA 84.9–98.9 78.4–86.1
Note: The sensitivity and specificity vary based on time since infection.
Abbreviations: CIA5chemiluminescence immunoassay, EIA5enzyme
immunoassay, FTA-Abs5fluorescent treponemal antibody absorption,
RPR5rapid plasma reagin, TP-PA5Treponema pallidum particle aggluti-
nation assay.
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fluorescence and is graded 11 to 14. False-negatives within
the period of reactivity are rare and difficult to quantify but
are due to either a human failure to quantify fluorescence
on the slide or a decreased specificity of the fluorescein iso-
thiocyanate–labeled anti–human globulin antibodies. (2)
Of note, qualitative treponemal tests should not be used in
the diagnosis or treatment of infants because passive trans-
placental transfer of IgG maternal antibodies may persist un-
til 15 months. (6)(15) Therefore, 1 of the diagnostic criteria for
congenital syphilis is that the infant’s nontreponemal titer
(eg, RPR) is at least 4-fold greater than the mother’s titer at
birth, indicating fetal antibody synthesis. It is important to
consider the history of maternal treatment and her nontre-
ponemal titer response while planning the infant evaluation
and management. The following evaluation is warranted
when congenital syphilis is suspected: CSF-VDRL test, cell
count and protein level; complete blood cell count with differ-
ential count; and other tests as clinically indicated, including
liver function tests, human immunodeficiency virus testing,
long-bone and chest radiographs, abdominal ultrasonography,
neuroimaging, and ophthalmologic and auditory brainstem
examinations.
Management/Treatment
Parenteral penicillin G is the only effective treatment for
congenital syphilis. (6)(15) T pallidum has shown no resis-
tance to penicillin, which has proved to be effective in main-
taining the minimal concentration needed for treponemicidal
levels over the treatment period. The frequency of penicillin
dosing depends on age due to renal clearance because the se-
rum half-life of penicillin G correlates inversely with age.
(6)(16) Current treatment for infants older than 1 month is
aqueous crystalline penicillin G 200,000 to 300,000 U/kg
per day, intravenously administered as 50,000 U/kg every 4
to 6 hours for 10 days. (6)
Awareness of the Jarisch-Herxheimer reaction is impor-
tant. Most commonly seen during treatment of primary
and secondary seropositive syphilis, this reaction is due to
a release of endotoxinlike antigens during bacterial lysis
on starting penicillin. (3)(17) Symptoms include fever, hy-
potension, hyperventilation, headache, flushing, and vom-
iting. There is a reported increased risk with higher RPR
titers ($1:32). (18) Mild reactions are self-limiting and may
resolve within the first 24 hours. Symptoms can usually
be treated with only antipyretics or intravenous fluids if
there is vital sign instability. If necessary, corticosteroids,
vasopressors, or inotropic support may be used. This is
not a contraindication to continuing treatment. (3)(18)
Vol. 4 5 No. 1 JANUARY 2024 5 5
 After initial treatment, patients with congenital syphilis
should be followed every 2 to 3 months for repeated non-
treponemal VDRL or RPR testing until it is nonreactive.
The serologic response to treatment is often slower in in-
fants diagnosed and treated beyond the neonatal period.
However, should the patient continue to remain positive
12 months after treatment, repeated evaluation, including
CSF examination, and repeated treatment with 10 days of
parenteral penicillin G may be indicated. (6)
Lessons for the Clinician
• Syphilis can yield a negative test result if the mother is in-
fected late in the pregnancy because treponemal assays take
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3 to 4 weeks and nontreponemal assays take 4 to 6 weeks
to detect antibodies.
• Consider syphilis for any rash involving the palms and
soles with unknown etiology even if the history seems to be
reassuring (eg, negative maternal prenatal syphilis testing).
• A Jarisch-Herxheimer reaction can occur during initiation
of treatment with penicillin, usually resolves within the first
24 hours, and is not an indication for stopping treatment.
• After treatment for congenital syphilis, patients should
be followed closely with repeated rapid plasma reagin titers
every 2 to 3 months until their titer becomes nonreactive.
References for this article can be found at
https://doi.org/10.1542/pir.2021-005372.
 IN BRIEF

Lice: Head, Body, Pubic

Katherine A. Jordan, MD,* Stephanie N. Ferrin, MD,* Priyanka Rao, MD*
*Department of Pediatrics, University of North Carolina School of Medicine, Chapel Hill, NC

INTRODUCTION AND EPIDEMIOLOGY

Lice are one of the most common ectoparasites that the general pediatrician will
encounter. Head lice (Pediculus humanus capitis), body lice (Pediculus humanus
corporis), and pubic lice (Pthirus pubis) can all cause infestations in humans,
their only host. These lice all feed on human host blood, spread between hu-
mans without animal vectors, and have predictable reproductive cycles.
Most frequently occurring in young children and their caregivers, head lice is
estimated to occur in 6 to 12 million patients annually in the United States, can
affect patients from all socioeconomic groups, and spreads by head-to-head
contact. In contrast, body lice infestations are quite rare in the United States
and occur almost exclusively in the homeless population, spreading between
people on unwashed clothing and bedding. Body lice infestations may also occur
in other groups of people living closely together, such as victims of war or natural
disasters. Unlike head lice, body lice have been associated with the spread of addi-
tional pathogens, most notably epidemic typhus and louse-borne relapsing fevers.
Pubic lice, colloquially called “crabs,” are most often found in adolescents and
young adults. Most commonly spread by close bodily contact, especially sexual
AUTHOR DISCLOSURE: Drs Jordan,
contact, pubic lice can also be transmitted through infested towels, bedding, and
Ferrin, and Rao have disclosed no
unwashed clothes. Although not associated with the transmission of disease, other financial relationships relevant to this
sexually transmitted infections are frequently present among individuals with pubic article. This commentary does not
contain a discussion of an unapproved/
lice infestation.
investigative use of a commercial
product/device.
PRESENTATION
Head Lice. Devore CD, Schutze GE;
Severe itching is the most common presenting symptom of a louse infestation. Council on School Health and Committee
Lice feed on small amounts of blood from the scalp, body, or other areas with on Infectious Diseases, American
Academy of Pediatrics. Pediatrics.
hair. Salivary deposits from their feeding causes sensitization and subsequent 2015;135(5):e1355–e1365
pruritis. Pruritis may be delayed in initial infestations because sensitivity can
Pediculosis Corporis (Body
take up to 4 to 6 weeks to develop. Thus, itching often signifies that a primary Lice); Pediculosis Capitis (Head Lice);
infestation is well established. Subsequent infestations may result in more rapid Pediculosis Pubis (Pubic Lice). In: Red
development of symptoms. Other signs can include reports of the sensation of Book: 2021–2024 Report of the Committee
on Infectious Diseases. 32nd ed. Kimberlin
“something moving in the hair,” difficulty with sleep, sores due to scratching, DW, Barnett ED, Lynfield R, Sawyer MH,
or, in severe cases, lichenification of areas of the skin/scalp due to the severe eds. Itasca, IL: American Academy of
Pediatrics; 2021
itch-scratch cycle.
A diagnosis of lice occurs from identification of adult lice, eggs, or nits. Lice What’s Bugging You? An Update on
avoid light and can move quickly, making a visual diagnosis challenging. Head the Treatment of Head Lice Infestation.
Tebruegge M, Pantazidou A, Curtis N.
and body lice are often white with elongated bodies that are about the size of a Arch Dis Child Educ Pract Ed. 2011;
sesame seed. Utilization of a fine-tooth comb in combination with lubrication of 96(1):2–8

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 the hair with water or oil to slow lice movement may
make detection easier. Small eggs, or the empty egg cas-
ing known as nits, are often more visible because they are
white in color. Eggs or nits will be firmly glued to the hair
shaft, which helps to distinguish them from dandruff, hair
casts, dirt, or dried hair care products, which will be visible
more directly on the scalp. Pubic lice typically present with
the lice and nits in pubic hair, but they may also be found
on other areas of the body, such as axilla, eyelashes, eye-
brows, and the head, including facial hair. These lice have a
different appearance from the more common head or body
louse. Often tan to greyish white, their oval bodies have a
crablike appearance, and the use of a magnifying lens may
be helpful for identification.
TREATMENT
Both head lice and pubic lice are treated by topical pedicu-
licides, and preferred initial treatment is with permethrin
1% lotion or pyrethrin-based shampoo products. These
products are preferred due to better safety profiles, although
louse resistance to these products is increasing. Topical treat-
ment should be applied after hair has been washed with
shampoo but not conditioner and then rinsed. A sufficient
amount of lotion or cream should be applied to saturate the
hair and scalp, particularly behind the ears and the nape of
the neck. Leave treatment on hair for 10 minutes and rinse
off with warm water. Use of a fine-tooth comb or nit comb
helps to remove dead or remaining live lice and nits from
hair after treatment. An additional treatment at 7 to 10 days
is recommended if lice or nits are still present. Pediatricians
should consider treatment with an alternative agent when
medication resistance is suspected based on the presence
of abundant live lice 24 hours after initial treatment or
persistence of infestation after the second application of
the first-line agent. The presence of nits alone is not a sign
of treatment failure.
Additional pediculicides authorized in the United States
include malathion 0.5% lotion, spinosad 0.9% suspension,
abametapir 0.74% lotion, and ivermectin 0.5% lotion.
Treatment cost ranges from $12 to $35 for over-the-counter
treatment, and preparations are readily available at many
pharmacies. Malathion is highly flammable, so it is crucial
to council families using malathion to avoid combustibles
such as hair dryers, smoking, or open flame during applica-
tion. The safety of malathion has not been assessed in chil-
dren younger than 6 years, and it is not approved for pubic
lice. Spinosad, ivermectin, and abametapir are not recom-
mended for use in infants younger than 6 months owing
to the potential for central nervous system toxicity. Use of
5 8 Pediatrics in Review
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lindane is not recommended by the American Academy of
Pediatrics owing to concerns for neurotoxicity. For pedicu-
losis involving the eyelashes, an ophthalmic-grade petrola-
tum ointment may be prescribed and administered to the
eyelashes and eyelid margins 2 to 4 times a day for 10 days.
Erythema, irritation, and itching are common after topical
therapies and can be mitigated with oral antihistamines or
topical corticosteroids.
Owing to rising resistance rates, alternative treatments
for lice are being evaluated. In vitro studies for natural
products such as essential oils from eucalyptus, lavender,
and tea tree are promising. However, because the Food
and Drug Administration (FDA) does not regulate these
products and there is a paucity of clinical evidence, use of
these products in children should be limited. There is not
good evidence for hot air or electric combs. There is some
evidence that wet combing with a fine-tooth comb has good
success rates, with regimens consisting of combing out nits
and lice every 3 days for 14 days. This method can be tedious
and difficult to complete for young children but is without
the adverse effects of pediculicides. Many recommend wet
combing after a pediculicide application, and although evi-
dence is not robust, it is thought that this may help reduce
repeated infestation.
When a patient presents with head lice, physicians should
treat contacts with signs of infestation as well as those who
share a bed with infested individuals, regardless of their
symptoms. Spread of head lice is uncommon in school
settings, and the American Academy of Pediatrics recom-
mends against sending children home from school for
head lice, and schools should not require all nits to be ab-
sent before return because most nits are nonviable. Teach-
ers and health-care providers should attempt to preserve
children’s privacy as much as possible. For pubic lice, all
sexual contacts that the patient has had within the past
month should be notified and treated.
Both head and pubic lice cannot live for more than 1 or
2 days off the human body and are thought to have limited
spread through personal items. However, to be cautious, it
is typically recommended to wash clothing, bedding, and
stuffed animals/toys on hot water cycles with hot air drying
at the same time that topical treatment is initiated. Items
can also be placed in a plastic bag and sealed for 2 weeks
or be exposed to temperatures greater than 130! F (>54.5! C)
for more than 5 minutes, either by soaking in hot water or
through pressing with a hot iron.
In contrast, body lice live almost exclusively in clothing
and bedding and can live away from their blood source for
5 to 7 days. For this reason, treatment of body lice requires
 environmental decontamination as described previously herein.
Treatment with a pediculicide is rarely indicated but is some-
times used when a patient has persistent symptoms or has
abundant body hair. In places with widespread outbreaks
linked to epidemic disease such as typhus, fumigation with
chemical insecticide is sometimes used.
CONCLUSION
Lice are a group of ectoparasites that cause head lice, body
lice, and pubic lice infestations. General pediatricians will
most commonly see head lice and pubic lice, for which
they can diagnose and begin treatment and eradication
measures in the outpatient setting. While alternative thera-
pies are being researched, primary treatment continues to
be topical pediculicides.
Comments: Here is a mistake I never made again. I
was working in an emergency department in a community
hospital and an adolescent-aged patient was being admitted
for skin cellulitis. I also noted that she had profuse white
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“specks” in her hair and assumed that she had bad dandruff.
Well, once she was admitted to the floor, a skilled nurse
paged me to tell me that this patient had a significant case
of head lice infestation. Needless to say, the nurses were a
bit upset with me for not initiating treatment before admis-
sion, but I had not thought of that diagnosis. On closer in-
spection it was clear. The white “specks” (or nits) were distal
on the hair shaft and not on the scalp as you would expect
for dandruff. It was a lesson I always remembered.
Diagnosing live head lice was one of my favorite teach-
ing points with medical students and residents. I would
take a piece of scotch tape and trap a louse. Because they
are only 2 to 3 mm in length, it was astounding how large
they looked under the microscope magnification. It always
resulted in a wonderful teaching opportunity and also
made more apparent how problematic the head louse is to
the infected patient.
Janet Serwint, MD
Associate Editor, In Brief
Vol. 4 5 No. 1 JANUARY 2024 5 9
 IN BRIEF

Spontaneous Pneumothorax and Pneumomediastinum

Molly Carney, MD,* Allison E Williams, MD, FAAP*†
*UPMC Children’s Hospital of Pittsburgh, Pittsburgh, Pennsylvania
†
University of Pittsburgh, Pittsburgh, Pennsylvania

Pneumothorax and pneumomediastinum both represent accumulation of air

within extraluminal tissue. However, they differ in their etiology, presentation
and treatment. Although relatively rare in the pediatric population, prompt rec-
ognition, diagnosis and understanding of treatment principles can prevent un-
necessary testing and hospital admissions.

PNEUMOTHORAX
Pneumothorax is an accumulation of air between the visceral and parietal
pleura, which can occur because of trauma, medical procedures or spontane-
ously. Spontaneous pneumothorax is further divided into primary spontaneous
pneumothorax (PSP), which occurs in otherwise healthy patients and secondary
spontaneous pneumothorax (SSP), which occurs in the setting of underlying AUTHOR DISCLOSURE: Drs Carney and
lung disease such as asthma, cystic fibrosis, connective tissue disease, smoking Williams have disclosed no financial
relationships relevant to this article. This
or vaping. Tension pneumothorax leads to compression of essential organs commentary does not contain a
within the cardiopulmonary system, which is a surgical emergency that is be- discussion of an unapproved/
yond the scope of this review. The incidence of PSP in pediatric patients is esti- investigative use of a commercial
product/device.
mated at 4 per 100,000 children with a bimodal peak during the neonatal
period and adolescence (ages 13- 22 years). During adolescence, there is a 2-4- Pneumothorax, Pneumomediastinum, and
fold increased risk for males compared to females with the highest rates occur- Pulmonary Embolism. Johnson NN, Toledo
ring in tall, thin adolescent males postulated to be due to increased distending A, Endom EE. Pediatr Clin North Am.
2010;57(6):1357–1383. doi:10.1016/j.
pressures at the pulmonary apices, which predisposes to rupture of bullae. pcl.2010.09.009
The classic presentation for pneumothorax is sudden onset of unilateral chest
pain and dyspnea. Vital sign changes such as tachycardia, tachypnea, or hypox- Management of Spontaneous
emia can be observed depending on the size of pneumothorax. Key findings on Pneumothorax: British Thoracic Society
Pleural Disease Guideline 2010. MacDuff
physical exam include decreased breath sounds, hyperresonance to percussion, A, Arnold A, Harvey J. Thorax. 2010;65(supp 2):
and vocal fremitus. Regardless of size, symptoms are generally more pro- ii18–ii31. doi:10.1136/thx.2010.136986
nounced in SSP. The gold standard for diagnosis is use of a chest X-ray reveal-
Management of Spontaneous
ing an absence of lung markings to the peripheral pleural line. The best
Pneumothorax in Children: A Systematic
imaging modality for detecting a pneumothorax is an erect AP film taken during Review and Meta-Analysis. Miscia ME,
inspiration, which can be challenging to obtain, especially in younger patients. Lauriti G, Lisi G, Riccio A, Lelli Chiesa P.
Recent literature has supported the use of ultrasound and chest computed to- European Journal of Pediatric Surgery.
2020;30(1):2–12. doi:10.1055/
mography (CT). Although typically reserved for traumas where erect chest X-ray s-0039-3402522
cannot be obtained, meta-analyses of adult trauma patients reveal that with a
trained operator, ultrasound can be highly accurate (AUC 0.979). Conversely, re- Management and Outcomes of
Spontaneous Pneumomediastinum in
gardless of operator, ultrasound is equally specific to chest X-ray (1.00 vs 0.99)
Children. Noorbakhsh KA, Williams AE,
with a lower sensitivity (0.52 vs 0.88). Chest CT is the most sensitive and spe- Langham JJW, et al. Pediatric Emergency
cific modality, however given the associated radiation, it is typically reserved for Care. 2021;37(12):e1051–e1056

6 0 Pediatrics in Review

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 high-risk patients, those with recurrent pneumothoraces
or planning surgical intervention.
Given the lack of pediatric specific guidelines and the
wide variation in the literature for the treatment of a pedi-
atric pneumothorax, management is typically based on
clinical presentation and provider preference, as well as ex-
trapolation from the adult guidelines proposed by the Brit-
ish Thoracic Society (BTS) and the American College of
Chest Physicians (ACCP). For patients diagnosed with
PSPs that have only mild symptoms without vital sign
changes, patients may be observed in the emergency de-
partment for 3-6 hours then discharged home with follow-
up care in 1-2 days to ensure no worsening symptoms or
exam findings. On average, the pneumothorax should re-
solve in 8 days. If resolution was not documented upon
discharge, both BTS and AACP recommend a repeat chest
X-ray at follow-up. Conversely, all patients with SSP
should be admitted for monitoring given the increased
risk of significant respiratory compromise. Oxygen admin-
istration at 2-4 L/min in adolescents can result in an in-
creased rate of reabsorption for large pneumothoraces, but
is ineffective at relieving chest pain. Any patient with ei-
ther PSP or SSP who presents with significant dyspnea or
vital sign instability should undergo acute decompression
of the pneumothorax. Whereas, BTS recommends initial
therapy with needle aspiration based on studies revealing
similar efficacy to chest tube placement with a shorter hos-
pital stay, AACP recommends initial chest tube placement
given the risk of additional procedures should needle aspi-
ration fail and the risk for a persistent air leak with needle
aspiration. Consistent with AACP guidelines, a retrospec-
tive study found that of pediatric patients presenting with
a spontaneous pneumothorax, 54% of patients were ob-
served without intervention and 41% underwent chest
tube insertion but no patients received needle aspiration
alone.
Recurrence of PSP is common, occurring in 40%-60% of
children, typically within 1 month, whereas recurrence of SSP
varies based on underlying pathology. This results in debate re-
garding the benefit of definitive surgical intervention following
first time spontaneous pneumothorax. Most surgeons agree
upon surgical intervention for pediatric patients if an air leak
persists for more than 3 to 5 days or there are episodes of recur-
rent PSP. However, guidelines regarding surgical intervention
for initial pneumothorax vary; whereas AACP only recom-
mends surgical intervention for initial SSP, many surgical pub-
lications argue for early video-assisted thoracoscopic surgery
(VATS) in both initial PSP and SSP to decrease both hospitali-
zation time and recurrence risk.
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PNEUMOMEDIASTINUM
Pneumomediastinum is extraluminal air anywhere through-
out the mediastinum, which can occur spontaneously, or be
acquired during medical procedures. Spontaneous pneumo-
mediastinum occurs in the setting of excessive Valsalva
such as coughing, screaming, emesis, choking or inhaled
drug use. The proposed mechanism is prolonged or exces-
sive Valsalva resulting in alveolar rupture that allows track-
ing of free air from the hilum into the mediastinal space
and subcutaneous tissue. Similar to pneumothorax, primary
spontaneous pneumomediastinum occurs in otherwise
healthy children, whereas secondary spontaneous pneumo-
mediastinum can occur in the setting of asthma, COVID,
pneumonia, or vaping. Although potentially underrecognized
and underreported, pneumomediastinum is considered rela-
tively rare in children affecting approximately 1 in 12,000-
14,000 children per year. There is a bimodal distribution
with peaks in children 6 months to 7 years and again in ado-
lescents, but no reported gender difference.
Unlike pneumothorax, which has a classic presentation,
the presentation of pneumomediastinum is widely variable
with the most common complaints being chest pain, neck
pain, and dyspnea or more infrequently dysphagia, dys-
phonia, torticollis, and cough. Physical exam findings in-
clude subcutaneous emphysema with palpable crepitus,
neck edema, and precordial crepitus auscultated in syn-
chrony with systole, referred to as Hamman’s sign. Chest
X-ray is frequently used to confirm the diagnosis. Al-
though anterior view chest X-ray is typically sufficient, lat-
eral views and neck radiographs can also reveal alternative
pockets of trapped air. Other imaging studies such as CT
scans, esophagrams, laryngoscopy, or esophageal endos-
copy are largely unnecessary. An esophagram is often ob-
tained in the setting of emesis to rule out serious
complications of pneumomediastinum such as esopha-
geal perforation, otherwise known as Boerhaave syn-
drome. However, this is exceedingly rare in children and
if present, is often associated with tachycardia or pleural
effusions on X-ray. One study of pneumomediastinum in
children found that 75% of children underwent secondary
imaging following diagnosis, however no patient had ad-
ditional findings or diagnoses identified on these scans,
suggesting that additional imaging may not be necessary.
This is especially true in children with only mild pain
symptoms and no vital sign changes.
Treatment is largely supportive including rest, pain con-
trol, and avoidance of aggregating factors such as cough or
Valsalva. Oxygen is rarely indicated unless the patient is ex-
hibiting oxygen desaturations. Hospital admission is only
Vol. 4 5 No. 1 JANUARY 2024 6 1
 necessary in patients with desaturations or respiratory dis-
tress, which are more often associated with secondary pneu-
momediastinum. Pneumomediastinum typically resolves
within 2 to 15 days without complication. Rare, but potential,
complications include development of pneumothorax, media-
stinitis, air within the spinal canal otherwise called pneumo-
rrhachis, or compression of mediastinal structures resulting
in cardiac or respiratory compromise and recurrence. The
most common reason for return to the emergency depart-
ment following discharge is persistent chest pain.
Although pneumothorax and pneumomediastinum are
both air leak syndromes, the clinical presentations and
treatments of these two syndromes are different. Whereas
the treatment of pneumomediastinum is mainly support-
ive with a low risk of complications, further research
needs to be done on pediatric pneumothoraces to decrease
risk of recurrence and other serious complications.
Comments: While rare, both pneumothorax and pneu-
momediastinum are important diagnostic considerations in
ANSWER KEY FOR JANUARY PEDIATRICS IN REVIEW
Long-Acting Reversible Etonogestrel Subdermal Implant in Adolescents: 1. B; 2. E; 3. B; 4.E; 5. E.
Cushing Syndrome in Childhood: 1. B; 2. C; 3.C; 4. B; 5. E.
Management of Acute Sickle Cell Disease Pain: 1. A; 2. B; 3. E; 4. B; 5. B.
6 2 Pediatrics in Review
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the more common complaint of chest pain in pediatric
aged patients. These diagnoses support the importance of a
careful physical exam, something I sometimes worry may
be abbreviated in the current fast-paced practice settings.
The findings of decreased breath sounds, hyperresonance
to percussion and vocal fremitus in pneumothorax and the
palpable crepitus in pneumomediastinum are essential to
appreciate. This is also an example where no formal pediat-
ric guidelines currently exist for treatment of pneumothora-
ces and we rely on adult guidelines. Yet we all know that
children are not just small adults and physiologically there
may be differences to consider. Pediatric systematic reviews
of pneumothorax (the best data we have to date without pe-
diatric guidelines) have led to some important suggestions
as to when to intervene surgically, and ways to choose ra-
diologic imaging to minimize morbidity from radiation.
Janet Serwint, MD
Associate Editor, In Brief
 VISUAL DIAGNOSIS

Coral Fluorescing Axillary Plaques Refractory to

Topical Antifungal and Antibacterial Treatments
Brendan P. Stewart, MD,* Kayla Gonzalez, MD,† Caleb Wasser, DO, FAAP‡
*UConn General Surgery Residency, University of Connecticut School of Medicine, Farmington, CT
†
University of Connecticut Pediatrics Residency Program, Farmington, CT
‡
Connecticut Children’s Medical Center, Hartford, CT

PRESENTATION
An 8-year-old boy with a medical history significant for obesity (BMI, 34.75) and anxiety
presents to the clinic with a bilateral axillary rash. The rash began under the right arm
2 months before presentation, and he simultaneously developed a similar, but less ex-
pansive, lesion in the left axilla. The rash is a 2- to 3-in (5.1- to 7.6-cm) circular plaque
with beefy red coloration and raised macerated edges; the right axilla is worse than the
left axilla. The patient is prescribed clotrimazole topical 1% cream for a presumed fun-
gal infection to be applied twice a day and is advised to follow up in 1 month.
At the follow-up visit 1 month later, the patient is still experiencing the bilateral
rash, which is now associated with pruritis. At this visit, the rash still appears as a
beefy red color with overlying thick hyperkeratotic scaling and macerated edges.
During this visit, the rash is examined under a Wood’s lamp, which displays coral
fluorescence (Fig 1). An aerobic skin culture is also performed at this visit. The pa-
tient is prescribed topical clindamycin for a presumed bacterial infection or eryth-
rasma, and follow-up is scheduled in the clinic in 2 weeks.
Two weeks later the patient presents with continued rash that is still itchy. The aero-
bic skin culture, collected at the previous visit, grew heavy growth of methicillin-sensitive
Staphylococcus aureus. The patient reports using no new lotions or creams and that the
rash is slightly improving. On examination the patient still has the bilateral erythema-
tous rash appearing as circular plaques with hyperkeratotic scales on the outer edges,
which remains fluorescent under the Wood’s lamp. The patient is prescribed an addi-
tional week of topical clindamycin gel and is instructed to return in 1 week.
One week later, he presents with a worsening rash. The right axilla now has sur-
rounding erythematous macular skin irritation, and the initial plaque is still beefy red
with hyperkeratotic scaling and macerated edges that fluoresces under a Wood’s
lamp (Fig 2). Because the topical antibiotic ointment was ineffective, the patient is
treated with oral erythromycin and referred to a dermatologist. Two weeks later, the
patient presents to dermatology with the initial plaques surrounded by expanding ery-
thematous urticarial papules associated with pruritis. The patient undergoes two
AUTHOR DISCLOSUURE: Drs Stewart,
4-mm skin punch biopsies at sites 1 and 2 in the left axilla (Fig 3). Site 1 histopathol- Gonzalez, and Wasser have disclosed no
ogy shows orthohyperkeratosis, parakeratosis, neutrophils, and serum in the stratum financial relationships relevant to this
corneum; neutrophils in the upper epidermis; hypogranulosis; pseudocarcinomatous article. This commentary does not
contain a discussion of an unapproved/
epidermal hyperplasia; thinning of suprapapillary plates; dilated and tortuous vessels investigative use of a commercial
in the papillary epidermis; and superficial, perivascular, and interstitial infiltrate of product/device.

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 Figure 1. The patient’s left axilla before treatment with topical clindamycin seen under normal light (A) and Wood’s lamp (B).
lymphocytes, histiocytes, and neutrophils. Immunostaining
for human papillomavirus types 6, 11, 16, 18, 31, 33, 42, 51,
52, 56, and 58 is negative. Periodic acid–Schiff stain for fun-
gal elements and Gram-stain for bacteria are negative. Site 2
histopathology showed parakeratosis, epidermal acanthosis,
and subcorneal collections of neutrophils with a superficial
and mid-dermal infiltrate of lymphocytes, histiocytes, and
neutrophils. Gram-stain and periodic acid–Schiff stain were
also negative at site 2. Histopathology confirms the diagnosis.
DIAGNOSIS
Based on review of the histopathologic findings from the
skin punch biopsies and clinical assessment, a final diag-
nosis of inverse psoriasis is made.
Figure 2. The patient’s right axilla after treatment with topical clindamycin. A. Beefy-red, macerated, hyperkeratotic scaling seen under normal light. B.
Coral-red fluorescence visualized under Wood’s lamp.
e2 Pediatrics in Review
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DISCUSSION
On initial presentation, common diagnoses to be consid-
ered for plaques of this nature include fungal intertrigo,
bacterial (erythrasma), psoriasis, eczema, and granular
parakeratosis. Fungal etiologies were less likely after there
was no improvement with clotrimazole treatment. Our
suspicion for dermatitis was low given no history, lack of
lichenified lesions with excoriations, and the overall size
and thickness of the plaques on presentation. (1) Granular
parakeratosis was also considered; however, the patient
had no recent changes in deodorants, lotions, soaps, or
other possible irritants, which made us less likely to con-
sider this reaction as an etiology of the patient’s present-
ing symptoms. (2) Our leading diagnoses were erythrasma
 Figure 3. The patient’s left and right axillae after treatment with oral erythromycin and topical clindamycin. A. The patient’s left axilla with circles marked
1 and 2 indicating the 2 locations of skin biopsies. B. The patient’s right axilla.
and psoriasis. However, after both topical and oral antibi-
otics were ineffective, we considered erythrasma less likely
despite our Wood’s lamp findings. In addition, our patient
did not display signs of systemic psoriasis and inflamma-
tion, such as nail pitting, inflammatory bowel disease, dia-
betes, or arthritic pains, which would have helped cement
a diagnosis of psoriasis. (3) This leaves the most likely di-
agnosis as an abnormal presentation of psoriasis.
Psoriasis and erythrasma are commonly included together
in the differential diagnosis of plaquelike lesions similar to our
patient. (4) Psoriasis is an inflammatory skin disease found in
approximately 1% of children, with the most typical onset be-
ing around 7 to 10 years of age. (5) In the pediatric population,
psoriasis is most commonly found on the scalp, face, trunk,
and extremities. (5) Compared with the adult population, pla-
que psoriasis in pediatrics is usually less scaly and not as thick.
(5) Inverse psoriasis, as present in our patient, is a subclass of
psoriasis commonly located around skin folds. (6) Numerous
risk factors have been proposed for developing psoriasis, in-
cluding stress and skin trauma. (5) Obesity has also been the
focus of recent research as a comorbidity of psoriasis, with
obesity being associated with more severe psoriasis. (5) Various
medications have also been linked to causing a psoriasiform
drug reaction, including b-blockers, lithium, and antimalarial
medications. In addition, note that a diagnosis of psoriasis is
more commonly made in patients with lighter skin types com-
pared with patients with darker skin types. (7)
Erythrasma is a skin condition most commonly caused
by Corynebacterium minutissimum. (8) More commonly seen
in adult populations, erythrasma is rare in the pediatric pop-
ulation. (9) Erythrasma is frequently located in the axillary
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or inguinal regions, and there is increased risk for individu-
als who are obese or diabetic. (8–11) Additional risk factors
predisposing patients to erythrasma infections include male
sex, hot/humid climates, and living in populated areas such
as college dormitories. (8) Our patient presented with an
obese body habitus and a BMI of 34.75, putting him at risk
for both psoriasis and erythrasma. He presented in December
through March in the Northeast, ruling out climate as a con-
tributing factor. In addition, he lived at home with his parents
and sibling with no pets. There was no report of new medica-
tions or trauma to the bilateral axilla.
Despite resembling fungal infections such as candidiasis or
dermatophyte infection, dermatitis, or inflammatory reactions
such as psoriasis, a diagnosis of erythrasma and psoriasis can
made via examination with a Wood’s lamp. Erythrasma will ex-
hibit characteristic coral-red fluorescence under the blue light
due to production of porphyrins by C minutissimum. (8, 11, 12)
Although it has also been historically reported that psoriasis
will display a similar red fluorescent color under Wood’s lamp,
in more recent studies, patients with inverse psoriasis with
fluorescence under Wood’s lamp has been attributed to eryth-
rasma. (13, 14) However, note that psoriasis can present differ-
ently depending on the patient’s skin color. In patients with
lighter skin types, psoriasis will present with more pink/red
hues, whereas patients with darker skin types present with le-
sions of more violaceous pigmentation. (7)
As evident in Figs 1 and 2, our patient’s lesions displayed
coral-red fluorescence under the Wood’s lamp in both axil-
lae. A definitive diagnosis of erythrasma can be determined
with a skin biopsy or culture, which will show Gram-positive
coccobacilli in the stratum corneum, the most superficial
Vol. 4 5 No. 1 JANUARY 2024 e3
 dermal layer. (9, 11, 15) Skin cultures should be performed if
the Wood’s lamp evaluation is inconclusive and the clinician
still suspects a bacterial infection. (16) On the other hand, if
a clinician is suspecting psoriasis, diagnosis is most often
made from clinical scoring systems; skin biopsy is rarely re-
quired. (17) However, biopsy is definitive, and histopathology
will display hyperkeratosis, parakeratosis, elongated epider-
mal ridges, dilated blood vessels in the dermis, and inflam-
matory infiltrates in the dermis and epidermis. (17) Skin
biopsies are typically indicated when there is suspicion for a
serious condition, when diagnosis cannot be made in a less-
invasive manner, when treatment will be guided based on
histopathologic findings, or when a patient fails to respond
to initial therapies. (18) With our patient, the decision was
made to also test the biopsy samples for human papillomavi-
rus immunostaining given the hyperkeratotic nature of the
lesion on biopsy. (19)
Erythrasma can be treated with topical or oral antibiotics,
with macrolides serving as the treatment of choice. (11) Cla-
rithromycin, erythromycin, and clindamycin have all been
used as treatments. (11, 15, 16, 20) Macrolides are bacterio-
static antibiotics that inhibit the 50s subunit of bacterial ribo-
somes, preventing protein translation and synthesis. (21)
Topical macrolides are commonly preferred to prevent adverse
effects, including gastrointestinal complaints such as nausea,
vomiting, and diarrhea; cardiac effects such as prolonged QT
interval; and cutaneous reactions such as Stevens-Johnson
syndrome or toxic epidermal necrolysis. (21, 22) Most recently,
fusidic acid and mupirocin have been used with success in
treating erythrasma. Mupirocin inhibits protein synthesis by
binding to isoleucyl-tRNA synthesis and inhibiting protein
synthesis, and fusidic acid binds elongation factor G and in-
hibits protein synthesis. (8, 11, 12, 23, 24) Treatment of eryth-
rasma has proved to be difficult, with infection commonly
recurring after a full course of antibiotics. (8, 11)
Our patient had failed initial therapy with topical clindamy-
cin and oral erythromycin, and we ultimately decided to refer
him for a biopsy. The biopsy of the main plaques was negative
for stains of any bacteria or fungal component and more
closely resembled the histologic description of psoriasis. No
culture was sent of the samples; however, given that the pa-
tient was treated with both topical and oral antibiotics, it is pos-
sible that there were no viable bacteria on the lesions at the
time of biopsy. The initial skin swab for our patient did not
show results consistent with C minutissimum on Gram-stain
but did show heavy growth of methicillin-sensitive S aureus,
which has been shown to be associated with psoriasis. (25)
Psoriasis, as well as inverse psoriasis, in both the adult and
pediatric populations is initially treated with topical therapies,
e4 Pediatrics in Review
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by Almoosa Hospital user
including topical glucocorticoids. (5, 17) Topical corticosteroids
are not without harm, and common adverse effects that must
be considered include skin atrophy, acne, skin infections, and
changes in pigmentation. (5, 17, 26) In addition, UV light has
additionally been proved as a treatment for psoriasis; however,
safety in pediatric patient populations is still lacking. (27, 28)
Absolute contraindications to UV therapy include systemic lu-
pus erythematosus, basal cell nevus syndrome, and xeroderma
pigmentosum, and relative contraindications include history
of skin cancers, photosensitivity disorders, and use for psoria-
sis in the genital areas. (28–30)
Last, note that histopathology showed secondary subcorneal
pustular dermatitis as satellite lesions surrounding the hyper-
keratotic plaques in our patient at biopsy site 2. Given that
these lesions appeared after treatment with oral erythromycin,
a possible cause is a drug reaction that has been reported
after the use of topical clindamycin and oral erythromycin.
(22, 31, 32) However, it is also possible that the satellite
lesions were from progression of the psoriasis. For the
previously stated reasons, we believe that the patient was
experiencing inverse psoriasis complicated with probable
erythrasma, which resolved with topical treatments.
PATIENT COURSE
The patient reported that the rash fully resolved bilaterally
on administration of triamcinolone 0.1%. Because our pa-
tient did not display signs of systemic inflammation, topi-
cal treatments were solely used as opposed to systemic
therapies. On cessation of topical treatment, the rash be-
gan to recur in both axillae. Due to recurrence, the patient
was prescribed triamcinolone 0.1% to use for 2 weeks for
eruptions as needed with maintenance treatment of tacro-
limus 0.03% topical cream to use twice daily.
Summary
• This case highlights the role of skin biopsies to
differentiate between inflammatory and microbial
causes of plaques that may appear similar even
under UV Wood’s lamp examination.
• Especially with pediatric rashes, it is important to
consider both the presenting symptoms and the
patient’s risk factors and comorbid conditions to
help elucidate the underlying cause.
• If a patient does not respond to medications to
treat the initial diagnosis, a broader differential
diagnosis should be considered.