December 2023

Vol. 44 No. 12
www.pedsinreview.org

Athlete Screening and

Sudden Cardiac Death
Ensuring Emergency
Readiness in the
Pediatric Primary
Care Setting:
An Updated Guideline
Fever: Three Patient
Cases
In Brief
Pneumocystis Pneumonia
Implications of Food and
Drug Administration
Approval of Respiratory
Syncytial Virus
Prophylactic Medication
Visual Diagnosis
Exfoliative Erythematous
Rash in an 11-day-old
Preterm Infant

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 Pediatrics in Review
ARTICLES ••
•••
• •

•
•
669 Athlete Screening and Sudden Cardiac Death
Robert Spencer, Shahed Quraishi
MOC

•
•
• •
••
•••

682 Ensuring Emergency Readiness in the Pediatric Primary Care Setting: An Updated Guideline
Maria Milla, Elisa Prebble, Gloria Riefkohl, Fernando Llopiz Martin, Danielle Altares Sarik, Paola Garcia-Herreros
To learn how
692 Fever: Three Patient Cases to claim MOC
692 Fever in a 40-day-old Infant points, go to:
Stelios Kasikis, Maame Hayfron, Despoina Galetaki, Risa Bochner https://publications.
aap.org/journals/
694 Ankle Pain 2 Days after a Febrile Illness in a 9-year-old Girl pages/moc-credit.
Maya Heled Akiva, Christos Karatzios, Marina I. Salvadori
697 Acute Right Lower Quadrant Abdominal Pain in a 2-year-old
Sagar D. Mehta, Carrie Ng STAY CONNECTED
701 Commentary: Fever Is Your Friend facebook.com/pedsinreview
Henry M. Adam

twitter.com/AAPJournals
INDEX OF SUSPICION
706 New-Onset Jaundice in an 11-month-old Boy
Sean E. Healton, Devon G. Lawrence, Noah J. Elkins, Leya Schwartz, Patricia A. Hametz
publications.aap.org/journals
710 Early Satiety and Nausea in a 12-year-old Girl
Alexandra S. Hudson, Amira Balbaa, Bryan J. Dicken, Matthew Carroll
713 Intermittent Fussiness in a Well-Appearing 5-week-old Girl
Elizabeth Wikle, Amani Sanchez, Arianna Nassiri, Francis Onyebuchi
716 Fatigue, Weight Loss, and Acute Chest Pain in a 15-year-old Boy
Madeline F.E. Parr, Katharine N. Clouser, Meghan Tozzi, Sejal M. Bhavsar

IN BRIEFS
720 Pneumocystis Pneumonia
Asif Noor, Leonard R. Krilov
723 Implications of Food and Drug Administration Approval of Respiratory Syncytial Virus
Prophylactic Medication
Ashley L. Saint-Fleur, Catherine Kier

VISUAL DIAGNOSIS
e33 Exfoliative Erythematous Rash in an 11-day-old Preterm Infant
Janani Rajkumar, Jamie B. Warren, Jina Park

Answer Key appears on page 719.

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 ARTICLE

Athlete Screening and Sudden

Cardiac Death
Robert Spencer, MD, MS,*† Shahed Quraishi, MD*
*Division of Pediatric Cardiology, Department of Pediatrics, Staten Island University Hospital, Northwell Health, Staten Island, NY
†Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, Hempstead, NY

EDUCATION GAP

Primary care providers play an instrumental role in preventing sudden

cardiac deaths in young athletes. Therefore, primary care providers should
be familiar with warning signs and risk factors of cardiac conditions that can
cause sudden death, preparticipation screening guidelines, and secondary
prevention measures.

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

1. Identify the causes of sudden cardiac death in young athletes. AUTHOR DISCLOSURE: Drs Spencer and
Quraishi have disclosed no financial
2. Describe screening guidelines and be aware of controversies in screening. relationships relevant to this article. This
commentary does not contain a
3. Recognize and promote secondary prevention measures. discussion of an unapproved/
investigative use of a commercial
product/device.

INTRODUCTION
ABBREVIATIONS
Sudden cardiac death (SCD) is defined as unexpected and abrupt death caused by a
cardiovascular condition, symptoms of which have begun within the past hour. Al- AAOCA anomalous aortic origin of a
coronary artery
though SCD is rare, each death has a significant and long-lasting effect on the vic- AAP American Academy of Pediatrics
tim's family and community. Athletes with preexisting cardiac conditions are at AC arrhythmogenic cardiomyopathy
increased risk for SCD during training and competition. (1) Conducting preparticipa- AED automated external defibrillator
AHA American Heart Association
tion physical evaluations (PPEs) of athletes is an important step in preventing SCD in ALCA anomalous left coronary artery
susceptible individuals, partly because many of the predisposing conditions would ARCA anomalous right coronary artery
otherwise not be noticeable. To ensure proper screening, primary care providers CERP Cardiac Emergency Response
Plan
should be familiar with cardiac conditions associated with SCD.
CMR cardiac magnetic resonance
Because no screening program can eliminate the risk of SCD, secondary pre- CPR cardiopulmonary resuscitation
ventive measures, such as increasing access to training in cardiopulmonary re- CPVT catecholaminergic polymorphic
ventricular tachycardia
suscitation (CPR) and automated external defibrillators (AEDs), as well as
ECG electrocardiogram
establishing emergency response plans at schools, are essential. This review pro- HCM hypertrophic cardiomyopathy
vides an overview of the epidemiology and causes of SCD in young athletes as ICD Implantable cardioverter-
defibrillator
well as preparticipation screening and secondary prevention.
LQTS long QT syndrome
LV left ventricular
EPIDEMIOLOGY PPE preparticipation physical
evaluation
SCD has an estimated incidence ranging from 1:917,000 to 1:3,000 athletes SCA sudden cardiac arrest
younger than 40 years in the United States per year. (2) Most cases occur at the SCD sudden cardiac death

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 high school or college level, often during practice or com-
petition. (3) The overall risk is higher in male compared
with female athletes, with a 9:1 ratio, and more than 3
times higher in black versus white athletes. (3)
Although some data suggest that SCD is more common
in nonathletes than in athletes, it is clear that intense
physical activity increases the risk of SCD in individuals
with predisposing cardiovascular disease. (4)(5)(6) Certain
sports are more strongly associated with SCD, such as
football, basketball, and baseball in male athletes. In con-
trast, female athletes are at greater risk while participating
in basketball, cross-country/track, and soccer. (3) Although
speculation attributes the increased risk of SCD in these
sports to each sport’s popularity, intensity of training, and
genetic predispositions of athletes, further studies are
needed to confirm this possibility.
CAUSES OF SUDDEN DEATH
Based on data from the US National Registry of Sudden
Death in Athletes from 1980 to 2011, 40% of sudden deaths
in young athletes occur in the absence of a preexisting cardiac
condition. Approximately half of these deaths are due to blunt
trauma (51%), with commotio cordis composing a much
smaller percentage (7%). (3)
In large autopsy-based studies of athletes in the United
States, hypertrophic cardiomyopathy (HCM) has consis-
tently been the most common confirmed cardiovascular
cause of sudden death, followed by coronary artery anoma-
lies. Table 1 lists the most common cardiac conditions as-
sociated with SCD. In this section, we highlight the most
prominent causes of SCD. An overview of these condi-
tions and some others is provided in Table 2.
Hypertrophic Cardiomyopathy
HCM is a genetic disorder affecting sarcomere proteins,
the basic contractile unit in cardiomyocytes. As previously
noted, it is the most frequently identified cause of SCD in
young athletes in the United States, with an estimated
prevalence of 1:500. (7)(8) However, as of 2019, only
1:1,250 individuals are clinically diagnosed, suggesting that
60% of affected individuals remain undiagnosed. (9)
More than 900 mutations have been identified in pa-
tients with HCM, most commonly located in the genes en-
coding b-myosin heavy chain (MYH7), cardiac myosin
binding protein C (MYPBC3), and cardiac troponin (TNNT2).
The clinical course of the disease varies considerably, with
some patients presenting in childhood and others remaining
asymptomatic through adulthood. Chest pain and dyspnea on
exertion are commonly reported symptoms. In addition, the
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Table 1. Cardiovascular Causes of Sudden Cardiac
Death (SCD) in Young Athletes
CONDITION SCD, %a
Hypertrophic cardiomyopathy 36
Anomalous coronary artery 19
Myocarditis 7
Arrhythmogenic cardiomyopathy 5
Coronary artery disease 4
Mitral valve prolapse 4
Aortic rupture 3
Aortic stenosis 2
Dilated cardiomyopathy 2
Otherb 18
a
Percentages are based on 842 young athletes in the United States
from 1980 to 2011 with confirmed cardiac causes of sudden death. (3)
b
Other conditions include (in decreasing order of frequency) left
ventricular hypertrophy of unresolved etiology, bridged left anterior
descending artery, long QT syndrome, congenital heart defect,
Wolff-Parkinson-White syndrome, myocardial infarction, sarcoidosis,
stroke, conduction system abnormality, cardiac rupture, cardiac tu-
mor, tetralogy of Fallot, electrolyte abnormality, ruptured cerebral
arteriovenous aneurysm.
physical examination may reveal a systolic murmur that be-
comes louder with reduced preload (eg, Valsalva maneuver or
standing) and quieter with increased preload (eg, squatting) or
afterload (eg, handgrip). A family history of sudden unex-
plained death is another important clue because HCM is usu-
ally inherited as an autosomal dominant trait. (10)
The 12-lead electrocardiogram (ECG) is abnormal in most
patients with HCM, with findings suggestive of left ventricular
(LV) hypertrophy and repolarization abnormalities (eg, T-wave
inversion). (10) Ambulatory ECG monitoring also provides
valuable information for risk stratification, as nonsustained
ventricular tachycardia is a risk factor for SCD. Other risk fac-
tors for SCD in patients with HCM include history of syncope
or cardiac arrest, family history of SCD, severe LV hypertrophy
(in adults, LV maximal wall thickness $30 mm), and abnor-
mal blood pressure response to exercise. (11) However, these
risk factors are extrapolated from adult data, and pediatric-
specific risk factors and calculators are currently under
investigation.
Echocardiography is the principal diagnostic imaging mo-
dality for HCM (Fig 1). Although diastolic LV wall thickness of
15 mm or greater without a known underlying cause is diag-
nostic in adults, a body surface–adjusted z score of 2 or greater
suggests HCM in children. (10)(12) Regardless of age, asym-
metrical septal hypertrophy is a common and distinctive fea-
ture of HCM. Cardiac magnetic resonance (CMR), which
offers enhanced spatial resolution and image quality, can be
helpful in patients with diagnostic uncertainty or poor echocar-
diographic imaging windows. Late gadolinium enhancement,
 a marker of replacement fibrosis found in approximately
half of patients, is a risk marker for adverse outcomes in
HCM. (13)
Screening is recommended for first-degree relatives of
patients with HCM, who can manifest at any age and thus
warrant surveillance imaging every 1 to 3 years. In addi-
tion, genetic testing with counseling is offered to individu-
als with HCM. If genetic testing reveals a pathogenic
variant, cascade genetic testing should be offered to first-
degree relatives, with clinical surveillance for those who
carry the pathogenic variant. If a pathogenic mutation is
not identified in the proband, cascade genetic testing is
not recommended for first-degree relatives. (10)
Guidelines, which have historically recommended against
participation in most competitive sports for patients with
HCM, are complicated and have recently evolved. Although
HCM is the most common cause of SCD in young athletes,
growing evidence shows that recreational exercise of mild to
moderate intensity is safe and beneficial in these patients.
(10)(14) As of 2020, class I recommendations permit mild to
moderate exercise in most patients with HCM. (10) Athletes
with HCM are encouraged to undergo a comprehensive eval-
uation and shared discussion of the potential risks and bene-
fits of sports participation with an expert. (10)(15) Although
participation in low-intensity competitive sports is reasonable
in most cases, if certain conditions are met, participation in
moderate- to high-intensity sports can also be considered
through shared decision-making. (10)
Coronary Artery Anomalies
Coronary artery anomalies are a diverse group of congenital
conditions with a wide range of clinical manifestations. An-
atomic variations in coronary anatomy are common and
range from benign and not causing myocardial ischemia or
SCD to life-threatening. (16)(17) In fact, anomalous aortic
origin of a coronary artery (AAOCA) is the second most
common cause of SCD in young athletes. (3)
Blood flow to the myocardium is derived from 2 main
coronary arteries, each arising from a different location of
the aorta. In most individuals, the right coronary artery
arises from the right aortic sinus and supplies blood to
the right side of the heart, whereas the left main coronary
artery arises from the left aortic sinus and bifurcates into
the left anterior descending and circumflex arteries, to-
gether supplying blood to the left side of the heart.
In patients with AAOCA, 1 of the coronary arteries arises
from an abnormal location on the aorta, creating an abnor-
mal coronary artery opening (ostium), take-off angle, and
course. If the coronary artery becomes stretched, kinked, or
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compressed, blood flow to the myocardium can be dis-
rupted and result in myocardial ischemia, ventricular ar-
rhythmias, and SCD. Due to the silent nature of coronary
anomalies, the true prevalence of AAOCA and absolute risk
of SCD are unknown. (18) However, studies suggest that
although anomalous left coronary artery (ALCA) is at least
6 times less common than anomalous right coronary artery
(ARCA), it has a much higher risk of SCD. (19)
Although half of SCD cases occur in previously asymptom-
atic individuals, patients may present with chest pain, exer-
tional syncope, or diminished exercise tolerance. (18) Results
of physical examination, ECG, and stress testing are often nor-
mal. Coronary anomalies are typically diagnosed by transtho-
racic echocardiography and advanced imaging modalities,
which should also be directed at identifying high-risk ana-
tomic features that increase the risk of SCD. These high-risk
anatomic features include slitlike ostium, acute take-off angle,
intramural course (within the wall of the aorta), and interarte-
rial course (between the aorta and the pulmonary trunk).
Restriction from competitive sports is recommended for
patients who have ARCA with high-risk features, symp-
toms, arrhythmias, or evidence of ischemia. Athletes can
generally resume competitive sports 3 months after repara-
tive surgery if they are asymptomatic and if testing reveals
no evidence of ischemia. For patients with ARCA without
symptoms or concerns for arrhythmias or ischemia, partici-
pation in competitive sports is acceptable with adequate
counseling and a discussion about the potential risk of car-
diac events. In athletes with ALCA, restriction from com-
petitive sports is generally recommended. As with ARCA,
athletes with ALCA may be cleared for competitive sports 3
months after surgery if they are asymptomatic and have no
evidence of ischemia. (20)
Myocarditis
Myocarditis, the third most common cause of SCD in young
athletes, is an inflammatory disease of the myocardium due
to infections, systemic diseases, drugs, and toxins. (3) Viral
infections, particularly due to enteroviruses (eg, coxsackievi-
ruses) and adenoviruses, are the most common causes of
myocarditis in the Unites States. Clinical manifestations vary
widely, ranging from asymptomatic cases to heart failure
and potentially fatal arrhythmias. Common symptoms asso-
ciated with myocarditis are fatigue, shortness of breath, nau-
sea (and/or abdominal pain), and chest pain. (21)(22) The
diagnosis is usually suspected due to the presence of cardiac
symptoms, elevated plasma troponin level, nonspecific ECG
abnormalities (ST/T-wave changes), and echocardiographic
findings, such as cardiac chamber enlargement and/or
Vol. 44 No. 12 D E C E M B E R 2 0 2 3 671
 672
Table 2. Cardiovascular Conditions Associated with Sudden Cardiac Death
PHYSICAL SPORTS GUIDELINES
CONDITION CAUSE EXAMINATION ECG/HOLTER ECHOCARDIOGRAM (USA)a MANAGEMENT NOTES
HCM Sarcomere mutations Systolic murmur LV hypertrophy and/ LV wall thickness $15 Restrict from high- Consider ICD if high High risk: previous cardiac
(mostly AD) or RV hypertrophy, mm or 2 SD for intensity sports, risk arrest or sustained VT;
large R or S waves; weight; small LV encourage mild- β-Blockers may family history of SCD;
left axis deviation; cavity size; abnormal intensity activity; improve symptoms syncope; nonsustained

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Pediatrics in Review
ventricular mitral valve 1/ shared decision- but do not reduce VT; abnormal blood
arrhythmias mitral regurgitation; makingb mortality pressure response to

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LV outflow tract exercise; severe LV
obstruction hypertrophy
AAOCA Abnormal coronary Normal Usually normal; Abnormal coronary Anomalous left coronary artery Coronary angiography is
embryogenesis ischemic changes; artery Restrict from Surgical repair recommended
arrhythmias competitive sports Stress tests may yield
false-negatives
Anomalous right coronary artery Consider sports
Restrict from Surgical repair if participation 3 mo
competitive sports high-risk features, after reparative surgery
if asymptomatic and
if symptoms, symptoms,
arrhythmias, or arrhythmias, or no evidence of
evidence of evidence of ischemia
ischemia ischemia
Myocarditis Acquired; usually Evidence of Nonspecific ST- Wall motion Restrict from sports for Supportive Clearance depends on
viral infection cardiogenic shock, segment and T- abnormalities; at least 3–6 mo normalization of serum
sinus tachycardia wave ventricular markers of cardiac
or abnormalities; dysfunction; mitral injury, normalization of
tachyarrhythmias, ectopy/ regurgitation; systolic function, and
gallop or arrhythmias pericardial effusion resolution of any
hepatomegaly arrhythmias on
exercise ECG
AC Mutations in Normal Epsilon wave; Enlarged RV, LV, or Restrict to low- ICD if high risk Cardiac MRI is
desmosomal localized QRS both; ventricular intensity sportsc recommended
proteins, eg, PKP2 widening; dysfunction High risk: aborted SCD,
(mostly AD) prolonged S-wave sustained VT, severe
Fatty fibrous upstroke; T-wave ventricular dysfunction
tissue replaces inversion in leads
heart muscle V1 through V3;
LBBB, PVCs, or VT
Channelopathies
LQTS Congenital: Normal QTc prolongation Normal Restrict to low- β-blockers Often incidental detection
mutations in Abnormal T-wave intensity sports if ICD if high risk on ECG; consider in
potassium or morphology symptomatic or patients with syncope
sodium channels prolonged QTcc or atypical seizures
(mostly AD) LQTS type 1 Risk of SCD is related
Acquired: genotype should to QTc duration,
medications, avoid competitive genotype, history of
electrolyte swimming symptoms, sex of
abnormalities, etc individual
Continued
 Table 2. Cardiovascular Conditions Associated with Sudden Cardiac Death (Continued)
PHYSICAL SPORTS GUIDELINES
CONDITION CAUSE EXAMINATION ECG/HOLTER ECHOCARDIOGRAM (USA)a MANAGEMENT NOTES
Brugada Mutations in sodium Normal Coved ST-segment Normal Restrict to low- Quinidine Highest risk of SCD with
syndrome channels, eg, elevation in leads intensity sportsbc Ablation type 1 Brugada pattern
SCN5A (mostly V1 and V2; If asymptomatic, ICD if high risk on ECG

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AD) abnormal T-wave participation can be Fevers increase risk;
morphology considered with treat with antipyretics

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precautionary
measures
CPVT Calcium Normal Normal Normal Restrict to low- Antiarrhythmic Exercise stress test may
dysregulation intensity sportsc medications (eg, reveal ectopy,
Mutation in nadolol, flecainide) polymorphic VT
ryanodine Left cardiac
receptor 2 (RyR2) sympathetic
(mostly AD) denervation
ICD if high risk
WPW Accessory pathway; Normal Slurred QRS upstroke Normal Asymptomatic: β-Blockers or ablation Return to competitive
syndrome unknown cause (“delta wave”), No restriction useful to prevent sports 4 wk after
short PR interval Symptomatic: SVT radiofrequency
EPS recommended ablation

AAOCA5anomalous aortic origin of a coronary artery, AC5arrhythmogenic cardiomyopathy, AD5autosomal dominant, CPVT5catecholaminergic polymorphic ventricular tachycardia, ECG5electrocardiogram,
EPS5electrophysiology study, HCM5hypertrophic cardiomyopathy, ICD5implantable cardioverter-defibrillator; LBBB5left bundle branch block, LQTS5long QT syndrome, LV5left ventricle, MRI5magnetic reso-
nance imaging, PVC5premature ventricular contraction, RV, right ventricle, SCD5sudden cardiac death, SVT5supraventricular tachycardia, VT5ventricular tachycardia, WPW5Wolff-Parkinson-White.
a
Sports restriction guidelines are from Maron BJ, Zipes DP, Kovacs RJ; on behalf of the American Heart Association Electrocardiography and Arrhythmias Committee of the Council on Clinical Car-
diology, Council on Cardiovascular Disease in the Young, Council on Cardiovascular and Stroke Nursing, Council on Functional Genomics and Translational Biology, and the American College of
Cardiology. Eligibility and disqualification recommendations for competitive athletes with cardiovascular abnormalities: preamble, principles, and general considerations: a scientific statement from
the American Heart Association and American College of Cardiology. Circulation. 2015;132:e256–e261.
b
Individuals who are genotype positive but phenotype negative can continue to participate in all competitive sports.
c
Low-intensity class 1A sports have low static (<20% of maximum voluntary contraction) and low dynamic (<40% of maximum oxygen uptake) components. These sports include billiards, bowl-
ing, cricket, curling, golf, and riflery.

Vol. 44 No. 12 D E C E M B E R 2 0 2 3
673

Figure 1. Echocardiograms showing left ventricular hypertrophy in a
teenager with hypertrophic cardiomyopathy.
impaired LV systolic or diastolic function. Although endo-
myocardial biopsy remains the gold standard, CMR has
emerged as a more sensitive and less invasive test to confirm
the diagnosis.
To promote the resolution of inflammation, athletes di-
agnosed as having myocarditis should be restricted from
exercise for 3 to 6 months, depending on the extent of car-
diac injury and inflammation on CMR. (15) Because SCD
in myocarditis is most likely due to development of ven-
tricular tachyarrhythmias resulting from myocardial scar-
ring, ambulatory ECG monitoring and/or exercise stress
testing are used in addition to CMR to evaluate for ar-
rhythmias before clearing patients for return to competi-
tive sports. (23)
Arrhythmogenic Cardiomyopathy
Arrhythmogenic cardiomyopathy (AC), previously known as
arrhythmogenic right ventricular cardiomyopathy, is an inher-
ited cardiomyopathy characterized by progressive replacement
of myocardium with fibrofatty tissue and a predisposition for
ventricular arrhythmias and SCD. Although structural abnor-
malities of the right ventricle predominate, LV involvement is
also possible. (24)
AC is usually inherited in an autosomal dominant
manner with incomplete penetrance and variable expres-
sivity. Most cases involve mutations in genes encoding
proteins in desmosomes, the membrane structures that
regulate intercellular adhesion and maintain structural
integrity of tissues during mechanical stress. Mutations
in the plakophilin-2 (PKP2) gene are the most frequent
cause. (25) AC predominantly affects men, whereas
women with an associated gene mutation have a lower
chance of expressing the disease and are more likely to be
asymptomatic carriers. (25)
The prevalence of AC is challenging to estimate because
it is often discovered postmortem. Its association with the
Mediterranean region explains why it is the most common
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cause of SCD in young athletes in Italy while accounting for
less than 5% in the United States. (24)(26)(27)
Clinical signs or symptoms of AC such as dizziness,
syncope, or palpitations are rarely recognized before pu-
berty, with onset typically ranging from the late 20s to
early 30s. (27) As a result, the condition is not likely to be
detected based on history and physical examination find-
ings unless there is a family history notable for SCD
or relatives diagnosed as having AC. Although ECG has
low sensitivity for this condition, it may show important
abnormalities, including a widened QRS, epsilon wave
(Fig 2A), and inverted T waves in the right precordial leads
(V1 through V3), the latter of which is abnormal after 14 years
of age. (25)(28) Although echocardiography is generally nor-
mal, especially in the early stages of the disease course, a
normal study does not exclude the diagnosis. If clinical sus-
picion is high, CMR should be performed to evaluate for
myocardial changes consistent with the disease.
There is no cure for AC. When the diagnosis is made,
the individual should be restricted from competitive sports
with the possible exception of low-intensity class 1A sports,
which include billiards, bowling, cricket, curling, golf, and
riflery. (15) Patients who meet specific high-risk criteria
usually undergo insertion of an implantable cardioverter-
defibrillator (ICD). (29)
Ion Channelopathies
Ion channelopathies are a group of hereditary defects in the
membrane channel proteins that can cause lethal arrhyth-
mias and SCD in individuals with structurally normal
hearts. These disorders are suspected to account for a sig-
nificant proportion of cases in which the autopsy reveals a
structurally normal heart with no identifiable cause of SCD.
(30) Long QT syndrome (LQTS), Brugada syndrome, and
Figure 2. Electrocardiographic findings associated with cardiac diseases.
A. Epsilon wave in arrhythmogenic right ventricular cardiomyopathy.
B. Prolonged QT interval in long QT syndrome. C. Coved-type ST-segment
elevation in Brugada syndrome. D. Delta wave in Wolff-Parkinson-White
syndrome.
 catecholaminergic polymorphic ventricular tachycardia
(CPVT) are the most common channelopathies associated
with SCD. Patients with these disorders may report palpita-
tions and syncope (particularly exertional or with auditory
stimulation) and a family history notable for early and/or
unexplained death. Although findings from physical exami-
nation and echocardiography are generally normal, each
channelopathy has a unique ECG fingerprint.
LQTS, which can be inherited or acquired (eg, QT-
prolonging drugs), is characterized by prolonged ventricu-
lar repolarization leading to ventricular arrhythmias, clas-
sically torsade de Pointes (“twisting of peaks” in French).
The risk of arrhythmias and SCD is directly related to the
duration of the QTc interval; each 10-millisecond increase
in QTc has been shown to increase the risk of malignant
arrhythmias. (31) QTc intervals are considered prolonged
when they are greater than 460 milliseconds in males or
greater than 470 milliseconds in females and highly ab-
normal regardless of sex when greater than or equal to
500 milliseconds (Fig 2B). Although QTc prolongation is
a hallmark of LQTS, 40% of patients with genetically con-
firmed LQTS have a normal QTc duration on baseline
ECG, with only subtle T-wave abnormalities. (32)(33) In
such cases of concealed LQTS, exercise stress testing can
unmask ECG abnormalities. On the opposite end of the
spectrum, LQTS is also frequently overdiagnosed, espe-
cially in patients with prolonged QTc secondary to vasova-
gal syncope. (34)
At least 17 different genes are associated with LQTS, of
which 90% are accounted for by 1 of 3 major genes:
KCNQ1 (LQTS1), KCNH2 (LQTS2), and SCN5A (LQTS3).
(35) SCD associated with mutations in each have signature
triggers: exercise, especially swimming, for LQTS1; arousal,
especially a sudden loud noise (along with one-third of
SCDs during exercise) for LQTS2; and during sleep (and
<5% of SCDs during exercise) with LQTS3. (35)
Current guidelines recommend restriction of individuals
with LQTS to class 1A sports if they have symptoms, ICDs,
or significant QTc prolongation (males: >470 milliseconds;
females: >480 milliseconds), although participation may be
considered after initiation of treatment and appropriate pre-
cautionary measures. (36) Genetically positive individuals
who have normal QT intervals can compete in sports with-
out restriction, except for individuals with symptomatic
LQTS1, who should be restricted from competitive swim-
ming. b-Blockers, particularly nadolol and propranolol, are
the first-line therapy for patients with LQTS and are most ef-
fective in LQTS1. Other therapeutic options reserved for
high-risk patients include ICD placement and left cardiac
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sympathetic denervation to reduce adrenergic stimulation of
the heart. (37)
Brugada syndrome commonly involves autosomal dom-
inant mutations in the cardiac sodium channel SCN5A
gene, although pathogenic variants in other genes have
been identified. (38) Patients with this condition may re-
port a history of palpitations or syncope triggered by fever
and a family history of Brugada syndrome or sudden
death. The cardiac examination is usually normal; how-
ever, the diagnosis is based on ECG abnormalities that
may occur spontaneously or be unmasked by a sodium
channel blocker (ie, provocative drug testing). ECG may
demonstrate pathognomonic abnormalities, including a
“coved-type” ST-segment elevation (Fig 2C) or “saddle-
back” ST-segment elevation in the right precordial leads,
V1 through V3, whereas Holter monitoring is useful to
evaluate for asymptomatic arrhythmias. Lethal arrhyth-
mias may be triggered by increased vagal tone (eg, during
exercise recovery or sleep) as opposed to during exercise.
(39) Despite the absence of a clear association between ex-
ercise and SCD in Brugada syndrome, previous US guide-
lines recommended restriction from competitive sports
with the potential exception of class 1A sports. (39)(40)
Current guidelines specify that participation in competitive
sports may be considered once appropriate precautionary
measures and treatments are in place provided that the ath-
lete has been asymptomatic for at least 3 months. (36) Treat-
ment has historically been limited to drugs and ICDs for
high-risk patients, although catheter ablation—a minimally
invasive procedure used to destroy abnormal tissue—has
also been suggested as a therapeutic option. (38)
CPVT results from genetic mutations—most commonly
autosomal dominant in the RyR2 gene encoding a ryano-
dine receptor in the sarcoplasmic reticulum—that cause ab-
normal calcium release in cardiomyocytes. The disease is
characterized by adrenergic-induced ventricular tachyar-
rhythmias, including bidirectional ventricular tachycardia, a
rare tachyarrhythmia in which dual QRS morphologies al-
ternate on a beat-to-beat basis. In this condition, syncope or
sudden death is usually triggered by acute emotional stress
or exercise. History and physical examination findings are
often normal, with a positive family history of exercise/
emotion syncope in approximately one-third of cases. (41)
Although resting ECG is usually normal, ventricular ectopy
and arrhythmias can be provoked by exercise (ie, exercise
stress testing) or epinephrine. With mortality in this condition
high if untreated (30%–50% by age 40 years), those diag-
nosed as having CPVT are generally restricted from compet-
itive sports and treated with antiarrhythmic medications,
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 including b-blockers (ie, nadolol) and sodium channel
blockers (ie, flecainide), left cardiac sympathetic denerva-
tion, and occasionally ICD implantation. (36)(41)(42)
Commotio Cordis
Commotio cordis (Latin etymology, “agitation of the heart”)
refers to a disruption of the normal heart rhythm due to a
direct blow to the chest and is particularly distressing be-
cause commotio cordis usually occurs in an otherwise
healthy athlete with no identifiable heart problem. Each
year in the United States, there are approximately 10 to 20
cases of this condition, which is primarily an electrical phe-
nomenon that does not result from structural damage to
the myocardium. (43) For ventricular fibrillation to be in-
duced, the blunt impact must involve a minimum pressure
of 250 mm Hg and must occur during a narrow window of
vulnerability during the cardiac cycle (ie, during the T-wave
upslope). (43)
Approximately 95% of cases occur in males, with a
mean age of 15 years. (43) Baseball has the highest inci-
dence of commotio cordis. Although commercial protec-
tive equipment may be helpful in preventing commotio
cordis, it can still occur when the victim is wearing a chest
guard. (44)(45)
During the past 2 decades, survival rates of patients
with commotio cordis have increased from 15% to 60%,
largely due to improved recognition of sudden cardiac ar-
rest (SCA), bystander-initiated CPR, and the widespread
availability of AEDs at sporting events. (46) In fact, the
survival rate drops to 3% when resuscitation is delayed be-
yond 3 minutes. (44) If no underlying cardiac abnormality
is identified, survivors of commotio cordis are allowed to
resume training and competition on full recovery. (46)
Other Causes
Several other conditions are associated with SCD, includ-
ing severe obstructive lesions such as aortic stenosis or
pulmonary stenosis, aortopathies such as Marfan syn-
drome (ie, due to aortic rupture or dissection), primary
pulmonary hypertension, sarcoidosis, and sickle cell trait.
Patients with complex congenital heart defects, including
those status post repair or palliative procedures, are at risk
for arrhythmias and SCD due to surgical scarring, hemo-
dynamic abnormalities, residual lesions, or ventricular dys-
function. (47) Wolff-Parkinson-White syndrome (Fig 2D) is
considered a rare cause of SCD, which likely occurs due to
the rapid conduction of atrial fibrillation to the ventricles via
the accessory pathway, resulting in ventricular fibrillation. (48)
Although mitral valve prolapse is typically considered a benign
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condition, it may pose an increased risk of SCD. (49) Fi-
nally, atherosclerotic cardiovascular disease is a major cause
of SCD in older athletes but rarely causes SCD in young
athletes, although the likelihood is higher if there are risk
factors such as a history of Kawasaki disease. (50) Although
performance-enhancing drugs can increase cardiac risk, evi-
dence has been inconclusive about their involvement in
SCD. (51)
NORMAL FINDINGS IN ATHLETES
The physiological and benign profile of an athlete’s heart
(so-called athlete’s heart) can be difficult to differentiate
from cardiovascular abnormalities. Because ECG changes
are observed in approximately 40% of trained athletes, in-
ternational consensus standards for normal, abnormal,
and borderline ECG findings in this population have been
established. (52)(53) Examples of findings that are consid-
ered normal for trained athletes include high QRS ampli-
tude (meeting voltage criteria for LV hypertrophy), early
repolarization, sinus bradycardia, sinus arrhythmia, and
first-degree atrioventricular block. Such findings are attrib-
uted to intense athletic conditioning resulting in structural
cardiac remodeling and increased vagal tone and do not
warrant further evaluation.
Morphologic remodeling associated with intense ath-
letic training, such as increased LV chamber dimensions
and wall thickness, can mimic features of genetic and ac-
quired heart disease such as cardiomyopathies. Certain
echocardiographic features are helpful in distinguishing
between benign adaptive remodeling and heart disease,
and a complete description is beyond the scope of this re-
view. However, a thorough evaluation of LV wall thickness
and morphology, diastolic LV cavity size, atrial size, sys-
tolic function, and diastolic function is required. For cases
in which echocardiographic findings are equivocal, re-
peated evaluation after a period of deconditioning (ie,
avoiding exercise) can be helpful because ECG and echo-
cardiographic changes associated with an athlete’s heart
should normalize during this time. (54) The distinction
between physiological and pathological changes in athletes
is important because an incorrect diagnosis can have sig-
nificant consequences, such as exclusion from competitive
sports or inappropriate reassurance and a missed opportu-
nity for therapeutic intervention.
SCREENING GUIDELINES
The primary goal of screening is to identify conditions
that predispose individuals to SCA or SCD. Personal his-
tory, family history, and physical examination findings are
 the core components of screening. The American Acad-
emy of Pediatrics (AAP) recommends that all children un-
dergo screening for the risk of SCD regardless of athletic
status. (55) Screening should occur during the PPE, a min-
imum of every 3 years, or on entry into middle or junior
high school and into high school. Four main screening
questions are recommended:
1. Have you ever fainted, passed out, or had an unexplained
seizure suddenly and without warning, especially during
exercise or in response to sudden loud noises, such as
doorbells, alarm clocks, and ringing telephones?
2. Have you ever had exercise-related chest pain or short-
ness of breath?
3. Has anyone in your immediate family (parents, grandpar-
ents, siblings) or other more distant relatives (aunts, uncles,
cousins) died of heart problems or had an unexpected sud-
den death before age 50 years? This would include unex-
pected drownings, unexplained car accidents in which the
relative was driving, or sudden infant death syndrome.
4. Are you related to anyone with HCM or hypertrophic ob-
structive cardiomyopathy, Marfan syndrome, AC, LQTS,
short QT syndrome, Brugada syndrome or CPVT, or a con-
dition requiring implantation of a pacemaker or ICD at
younger than 50 years?
The AAP’s recommended screening questions are based
on expert consensus and have not been scientifically validated
in a prospective study. These questions were designed to be
simple and easy to incorporate into a family questionnaire.
(55) The first question focuses on personal history of sudden
loss of consciousness, particularly events triggered by exertion
or sudden loud noises, which tend to occur in patients with
channelopathies such as LQTS. The second question focuses
on symptoms of chest pain or shortness of breath on exertion,
which can signal myocardial ischemia, congestive heart fail-
ure, arrhythmias, and valvar disease. The other 2 questions in-
quire about family members with heart conditions, potentially
pointing to a familial inheritance pattern. Steinberg et al (56)
previously showed that cardiac abnormalities can be identified
in nearly one-third of first-degree relatives of SCA survivors or
SCD victims.
Meanwhile, the American Heart Association (AHA) has
published guidelines for preparticipation screening of com-
petitive athletes, which consists of a 14-element (previously
12-point) history and physical examination (Table 3). Use of
this 14-element checklist for preparticipation screening is a
class I recommendation based on a scientific statement jointly
published by the AHA and American College of Cardiology.
(57)(58) As with the AAP’s screening questions, the AHA’s 14-
element screening tool was developed based on expert opinion
and over time has become the most commonly accepted
screening method for young athletes. (55)(57)(58) In addition,
it has also been incorporated into other screening guidelines,
such as a revised version with changes in language and word-
ing that has been incorporated into the PPE: Preparticipation

Table 3. The 14-Element American Heart Association Recommendations for Preparticipation Screening of
Competitive Athletes (57)

Personal history:
1. Chest pain/discomfort/tightness/pressure related to exertion
2. Unexplained syncope/near-syncopea
3. Excessive exertional and unexplained dyspnea/fatigue or palpitations, associated with exercise
4. Previous recognition of a heart murmur
5. Elevated systemic blood pressure
6. Previous restriction from participation in sports
7. Previous testing for the heart, ordered by a physician
Family history:
8. Premature death (sudden and unexpected, or otherwise) before age 50 y attributable to heart disease in $1 relative
9. Disability from heart disease in a close relative aged <50 y
10. Hypertrophic or dilated cardiomyopathy, long QT syndrome or other ion channelopathies, Marfan syndrome, or clinically significant
arrhythmias; specific knowledge of certain cardiac conditions in family members
Physical examination:
11. Heart murmurb
12. Femoral pulses to exclude aortic coarctation
13. Physical stigmata of Marfan syndrome
14. Brachial artery blood pressure (sitting position)c
a
Judged not to be of neurocardiogenic (vasovagal) origin; of particular concern when occurring during or after physical exertion.
b
Refers to heart murmurs judged likely to be organic and unlikely to be innocent; auscultation should be performed with the patient in
both the supine and standing positions (or with the Valsalva maneuver), specifically to identify murmurs of dynamic left ventricular outflow
tract obstruction.
c
Preferably taken in both arms.

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 Physical Evaluation, 5th Edition, a monograph published by the
AAP in collaboration with 5 other medical societies. (59)
However, despite being endorsed by medical societies,
the 14-element screening tool remains heavily underused.
A recent study in Pediatrics found that a minority (27%) of
the 48 states providing PPE forms incorporate all 14 ele-
ments in their screening forms. (60) Moreover, a quality
review by Miliaresis et al (61) found that only one-third of
pediatricians are familiar with the AHA’s recommended
screening form and that, on average, only 3.5 of 14 ele-
ments are documented in visit notes. Barriers to PPE use
include lack of awareness of the 14-element screening
form, use of a different form, and time constraints. Of
note, the authors did increase use of the PPE through
standard quality improvement methods. (61)
Although the need for preparticipation screening of
young athletes is widely supported, the optimal approach has
long been debated. Studies have shown that the 14-element
screening has sensitivity and specificity of 20% and 68%,
respectively, for cardiac risk factors among high school ath-
letes. (62) The incorporation of ECG screening would
certainly increase screening sensitivity, as evidenced by a
meta-analysis published in 2015, based on screening of
47,137 athletes from several regions, that revealed a 5-fold
and 10-fold increase in sensitivity of ECG in detecting car-
diac conditions relative to history and physical examination,
respectively. (63) However, incorporating ECG screening
would also involve a substantial cost that medical societies
such as the AHA view as prohibitive. With nearly 10 mil-
lion student athletes in the United States annually, the
widespread implementation of ECG screening would cost
billions of dollars. One must also consider the additional
monetary, legal, and emotional cost of dealing with false-
positive and false-negative test results. Therefore, ECG is
usually reserved for patients at increased risk for SCD
based on routine screening with the PPE.
SECONDARY PREVENTION
Preparticipation screening is useful for identifying athletes
with high-risk cardiac conditions, but no screening strat-
egy can single-handedly prevent SCD. In addition, despite
improvements in survival rates after SCA, disparities in
outcomes based on race and socioeconomic status continue
to exist, with studies showing worse cardiac emergency pre-
paredness and lower survival rates in low-income neighbor-
hoods versus high-income neighborhoods. (64) To address
these disparities, it is essential to target these demographics
in the implementation of secondary prevention measures.
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CPR and AEDs
SCD can be prevented through prompt recognition, admin-
istration of high-quality CPR, and early defibrillation. This
“Chain of Survival” is highly dependent on public engage-
ment. Administration of bystander CPR is associated with
increased survival and improved neurologic outcome. (65)
Although previous CPR training increases bystanders’ will-
ingness to perform CPR, only a small percentage (<3%) of
the US population receives training each year. (66)(67)(68)
In recent years, self-directed online courses have emerged
as an acceptable alternative to in-person courses. Further-
more, statewide laws requiring CPR training in high
schools have also translated to more laypersons learning
this lifesaving skill, although the quality of such training is
inconsistent and has striking geographic disparities. (69)
Currently, the AHA recommends training students as early
as middle school on how to perform high-quality CPR.
Early defibrillation is another important intervention af-
fecting outcomes after SCA, and arguably the most impor-
tant determinant of survival. Despite the fact that most
cases of SCA involve a shockable rhythm (ie, ventricular fi-
brillation), the probability of surviving SCA caused by ven-
tricular fibrillation diminishes rapidly over time, declining
approximately 10% each minute defibrillation is delayed.
(70)(71) From 2000 to 2006, exercise-related SCA in the
young had an overall survival rate of 11%. (72) A more re-
cent study analyzing events from 2014 to 2018 reported a
higher overall survival rate of 68% among student athletes,
with a survival rate of 85% if an on-site AED is used. (73)
Emergency Preparedness
Schools have a responsibility to prepare for cardiac emer-
gencies that goes beyond the mere presence of an AED or
bystander with CPR training. The AHA recommends that
schools and/or school districts implement Cardiac Emer-
gency Response Plans (CERPs), which are associated with
a lower incidence of SCD. (74)(75) Core components of a
CERP include establishing a Cardiac Emergency Response
Team (a team of athletic trainers, teachers, and other staff
members with CRP/AED training), creating an emergency
activation system, ensuring AED equipment is easily acces-
sible and properly maintained, offering frequent CPR/AED
training, performing practice drills, and reviewing the plan
on an ongoing and annual basis. (76) Documents needed to
implement a CERP are available on the AHA’s website. (77)
The AHA also recommends that states enact legislation
that requires and funds the creation and maintenance of
CERPs in schools. (76) State legislation requiring schools
to have an AED has been shown to significantly increase
 AED availability across high schools, with public schools
being most affected by such legislation. (78) As of 2022,
according to data collected by the Sudden Cardiac Arrest
Foundation, only 20 states require AEDs. (79)
FUTURE DIRECTIONS
The absolute risk of SCD is low, even among athletes with
high-risk conditions, and the known detriments of lack of
physical activity have led to a recent focus on shared deci-
sion-making. Moreover, machine learning algorithms can
potentially help clinicians diagnose the conditions that
cause SCD and can already detect HCM and LQTS from
standard ECGs with excellent sensitivities and specificities,
and it is possible that artificial intelligence can similarly
be trained to facilitate more accurate risk stratification, re-
sulting in a lower burden of unnecessary sports disqualifi-
cation. (80)(81) Finally, gene therapy is an emerging area
of interest in SCD prevention, as investigators recently
published the first hybrid gene therapy for LQTS1, which
is now advancing to animal model studies. (82)
CONCLUSION
SCD is a rare but devastating event that is often prevent-
able. When SCD occurs in a young athlete, it is frequently
due to an underlying cardiac condition. Due to lack of dem-
onstrated efficacy as well as prohibitive costs and feasibility
of large-scale ECG and echocardiography screening, routine
PPE is limited to history and physical examination. Primary
care providers and pediatric cardiologists can prevent SCD
by identifying red flags associated with the most common
causes of SCD. Because the PPE is imperfect at identifying
athletes with high-risk conditions, secondary measures are
also essential to preventing SCD.
Summary
• Preparticipation screening for young athletes
is important because it can potentially reduce
the risk of sudden cardiac death (SCD). (Based on
research evidence and consensus) (55)(58)(59)(60)(83)
• Several cardiac conditions are associated with
SCD. Hypertrophic cardiomyopathy, coronary
artery anomalies, and myocarditis are the 3 most
common identifiable causes. Ion channelopathies
may account for a significant number of autopsy-
negative SCDs. (Based on research evidence and
consensus) (3)(30)
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• A focused history and physical examination is the
recommended preparticipation screening method,
although the American Heart Association’s 14-element
screening tool has low sensitivity. (Based on
research evidence and consensus) (58)(62)
• Universal electrocardiographic screening is not
recommended in the United States. This is partly due
to prohibitive cost and the potential for false-positives
resulting in additional unnecessary testing. (Based on
research evidence and consensus) (57)(58)(84)
• Providers should follow US guidelines for
determining the appropriate sports restriction
for individuals with high-risk cardiac conditions.
However, it is also important to recognize that
these conditions have a low risk of SCD and that
shared decision-making has emerged as an
important framework for the contemporary sports
eligibility discussion. (Based on research evidence
and consensus) (10)(15)(36)
• High-quality cardiopulmonary resuscitation and
prompt defibrillation are integral to preventing
SCD once sudden cardiac arrest (SCA) has occurred.
The probability of surviving SCA caused by ventricular
fibrillation is reduced by 10% each minute
defibrillation is delayed. (Based on research evidence
and consensus) (71)(75)
• Schools and/or school districts should implement
Cardiac Emergency Response Plans, which can help
schools prepare for SCAs and prevent SCDs. (Based on
some research evidence and consensus) (74)(75)(77)
• Machine learning could play an important role in
SCD prevention in the future. In addition, new
gene therapies may be available for individuals
diagnosed as having predisposing conditions. (Based
on some research evidence) (80)(81)(82)
ACKNOWLEDGMENTS
We dedicate this article to Frank J. Reali III, who lost his
life to sudden cardiac death, and we thank his family,
who, through the Protecting One Young Heart at a Time
Foundation, has generously supported local screenings for
high school athletes on Staten Island. We also thank Dr Philip
Roth for his insightful suggestions and comments.
References and teaching slides for this
article can be found at
https://doi.org/10.1542/pir.2023-005975.
Vol. 44 No. 12 D E C E M B E R 2 0 2 3 679
 PIR QUIZ

1. A 16-year-old male basketball player is brought to the pediatric outpatient

clinic by his parents for evaluation of chest pain and syncope with exertion.
The boy’s father and paternal uncle have been diagnosed as having
hypertrophic cardiomyopathy (HCM). On physical examination the patient
has a systolic murmur that becomes louder when he performs a Valsalva
maneuver. Of the following cardiac imaging findings, which one is
considered a distinctive feature of HCM diagnosis?
REQUIREMENTS: Learners can
A. Asymmetrical septal hypertrophy. take Pediatrics in Review quizzes
B. Early gadolinium enhancement on cardiac magnetic resonance imaging. and claim credit online only at:
C. Impaired left ventricular diastolic function. http://pedsinreview.org.

D. Impaired left ventricular systolic function. To successfully complete 2023

E. Left ventricular wall thickness greater than 30 mm. Pediatrics in Review articles for
AMA PRA Category 1 Credit™,
2. A 17-year-old female athlete is diagnosed as having HCM based on family
learners must demonstrate a
history and echocardiography findings. She is asymptomatic. She has minimum performance level of
undergone extensive evaluation and is found not to exhibit high-risk 60% or higher on this
features of HCM. The patient and her family have had a comprehensive assessment. If you score less
discussion about the risks and benefits of physical activity for individuals than 60% on the assessment,
you will be given additional
with HCM. They also ask whether the patient requires placement of an opportunities to answer
implantable cardioverter-defibrillator (ICD). Which one of the following questions until an overall 60%
management and physical activity recommendations is most appropriate to or greater score is achieved.
discuss with this patient and her parents?
This journal-based CME activity
A. Do not place an ICD, and clear her for participation in only low-intensity is available through Dec. 31,
physical activity. 2025, however, credit will be
B. Do not place an ICD, and clear her for participation in moderate- to recorded in the year in which
the learner completes the quiz.
high-intensity physical activity.
C. Place an ICD, and subsequently clear her for low-intensity physical activity.
D. Place an ICD, and subsequently clear her for moderate- to high-intensity
physical activity.
E. Place an ICD, and subsequently recommend that she not participate in
any physical activity. 2023 Pediatrics in Review is
3. A 17-year-old female athlete is brought to the outpatient clinic by her parents for approved for a total of 30
Maintenance of Certification
sports preparticipation clearance. She was diagnosed as having viral myocarditis
(MOC) Part 2 credits by the
3 months ago after she developed chest pain and dyspnea with exercise. American Board of Pediatrics
She recently completed follow-up testing; echocardiogram demonstrated (ABP) through the AAP MOC
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Review subscribers can claim up
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B. In 6 months without additional testing. learn how to claim MOC points,
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org/journals/pages/moc-credit.
D. She can now return to training and competition.
E. She should be restricted from high-intensity physical activity permanently.

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 4. An adolescent male athlete with a family history of sudden unexplained
death dies after collapsing while playing football. There is no history of
trauma to the chest. The autopsy does not reveal findings of any structural
heart or lung disease. Which one of the following is the most likely cause of
death in this patient?
A. Arrhythmogenic cardiomyopathy.
B. Commotio cordis.
C. Long QT syndrome.
D. Myocarditis.
E. Sarcoidosis.
5. An adolescent presents to the outpatient pediatric office for preparticipation
physical evaluation before the soccer season. The patient’s pediatrician
discusses the 14 elements of the American Heart Association’s (AHA)
screener for heart disease with the medical students attending the clinic.
The AHA screening criteria include which one of the following elements?
A. Blood pressure in supine and standing positions.
B. Echocardiogram.
C. Electrocardiogram.
D. Family history of ion channelopathies.
E. Radial and pedal pulses.

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 ARTICLE

Ensuring Emergency Readiness in the

Pediatric Primary Care Setting:
An Updated Guideline
Maria Milla, MD, MPH, FAAP,* Elisa Prebble, MD,* Gloria Riefkohl, MD, MPH, MSHSA, FAAP,*
Fernando Llopiz Martin, MD, FAAP,* Danielle Altares Sarik, PhD, APRN, CPNP-PC,*
Paola Garcia-Herreros, MSN, APRN, CPNP-PC*
*Nicklaus Children’s Hospital, Miami, FL

PRACTICE GAPS

In pediatric primary care, the misconception that emergencies rarely occur

can lead to a barrier in effectively preparing for and responding to life-
threatening situations. Often, practices may not be in close proximity to a
hospital, (1) and providers may not feel adequately prepared with pediatric
emergency skills. (2) Gaps in in-office protocols for emergencies may also
present challenges for adequate responses (3) as well as limitations in
available supplies and up-to-date emergency equipment and medications. (1)

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

1. Provide structured, evidence-based recommendations for the pediatric

primary care provider and practice regarding common urgent health
concerns and emergencies.
2. Review strategies for increasing the readiness of primary care office staff,
AUTHOR DISCLOSURE Drs Milla, Prebble,
including needed education, equipment, and training. Riefkohl, Llopiz Martin, and Sarik and Ms
Garcia-Herreros have disclosed no
3. Identify gaps and potential areas of improvement for effective emergency
financial relationships relevant to this
response in the pediatric primary care office. article. This commentary does not
contain discussion of an unapproved/
4. Identify the most common pediatric emergencies in the primary care investigative use of a commercial
setting. product/device.

5. Promote the implementation of proper protocols and training for

emergency response in the primary care setting. ABBREVIATIONS

AAP American Academy of Pediatrics

AHA American Heart Association
BLS basic life support
INTRODUCTION AND BACKGROUND ED emergency department
EMS emergency medical services
Pediatric primary care providers (PCPs) are highly competent, compassionate, IV intravenous
and trusted professionals. Many parents and caregivers rely on these providers ORT oral replacement therapy
PALS pediatric advanced life support
and their offices to support appropriate growth and development, provide acute PCP primary care provider
care, and serve as a source of advice for the journey through childhood. When SABA short-acting b-agonist

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 patients and families encounter challenging situations, it is
often the PCP who guides them to the correct resources. (4)
Emergencies are no different; emergencies happen sud-
denly, leading parents to seek care at their PCP’s office. In
this situation, the question arises as to whether the PCP
and the primary care office are well-equipped and prepared
to handle emergencies. Offices may often be situated geo-
graphically near a hospital or emergency department (ED),
facilitating a quick transfer of a patient in an emergency.
However, for practices in rural areas, or for critical emergen-
cies when immediate stabilization is required, PCPs must
be prepared.
In 2020, unintentional injuries caused 33% of infant
deaths, of which 10.7% were caused by respiratory dis-
tress. (5) Other leading causes of accidental injury deaths
in this population included suffocation, motor vehicle acci-
dents, drowning, poisoning, falls, and burns. Leading
causes of nonfatal ED visits for children vary slightly, with
unintentional falls, foreign body aspiration, being struck
by or against an object, unintentional inhalation or suffo-
cation, unintentional cuts, dog bites, unintentional poison-
ing, and unintentional overexertion topping the list. (5)
Although some patients and families may opt to pursue
care in the ED setting, others will visit their trusted PCP
office for assessment and treatment for these common
conditions. In addition to accidental injury, acute illness
PCP visits may be scheduled due to other common condi-
tions, such as asthma, dehydration, and croup. Patients
who present to the PCP office with these conditions can
experience rapid deterioration or changes in acuity. To be
prepared to address these situations, PCP offices should
create policies and train staff, as well as have clear and ac-
cessible protocols and procedures in place to handle emer-
gencies. From a structural perspective, confirming that
proper equipment and medications are available and ac-
cessible is a necessary step in ensuring preparedness.
EPIDEMIOLOGY
The pediatric primary care office contributes significantly to
the pediatric emergency care system. The outpatient office
serves as the primary care entry point across various geo-
graphic settings. Although some suburban pediatric practices
report an annual median of 24 emergency incidents, (4)
studies show that pediatric offices are unprepared to manage
emergencies in the office setting owing to documented lack
of preparedness in equipment and training. (6) Management
of pediatric emergencies is challenging in ambulatory set-
tings because it requires ongoing, realistic preparedness and
planning aimed at addressing specific medical situations.
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Considering that pediatric patients present to the pri-
mary care office with an emergency/urgent complaint be-
fore their first birthday, and that a patient’s first office visit
is likely to occur before 8 weeks of age, it is imperative
that clinicians are ready and able to confront emergency
challenges for children of any age.
Reports on presentation to the office setting indicate
that the most common illnesses experienced by children,
in order from most to least frequent, are respiratory dis-
tress, seizures, severe infections in young children, dehy-
dration, anaphylaxis, choking, and head trauma. (7)
When faced with a new and infrequent emergency inci-
dent in the office, such as the evaluation and treatment of
a critically ill child, a PCP faces the challenge of crafting
rapid clinical decisions and actions while avoiding poten-
tially common errors. As in any medical emergency, hav-
ing a standard algorithm enhances reliability.
PARENT AND PATIENT EDUCATION
The research (4) suggests that by using effective patient and
parent education, emergencies that present to the office can
be prevented. Cardiopulmonary resuscitation and first aid
training along with anticipatory guidance can be lifesaving.
Parents should be able to recognize an emergency, respond
appropriately to an emergency, and know how to prevent inju-
ries before they happen. Education should include knowing
where to go for help in the case of a non–life-threatening
emergency. PCPs should educate families about when to use
the office, urgent care, ED, or subspecialty office. During
health supervision visits, anticipatory guidance should include
when and how to access emergency medical services (EMS)
such as 9-1-1, the Poison Control Center (1-800-222-1222),
and after-hours advice. Furthermore, it is important to discuss
the need for treatment consent for minors, any limitations to
emergency care and referrals dictated by the family’s insur-
ance plan, and which facilities to access in a true medical
emergency. Family education materials, such as The Injury
Prevention Program (8)(9) and the emergency information
card, (10) both available through the American Academy of
Pediatrics (AAP), could be offered as a resource in the office
or practice website. Before the development of an emergency,
PCPs should discuss advance directives and limitations of life-
saving treatments with caregivers. Although this may be an
uncomfortable conversation, it is of critical importance to dis-
cuss advance directives and limitations of lifesaving treat-
ments for children with special medical needs or at increased
risk for experiencing a life-threatening emergency. One option
is to have this conversation with parents as part of the annual
care plan and health assessment. In some states, the law does
Vol. 44 No. 12 D E C E M B E R 2 0 2 3 683
 not allow for EMS personnel to respect pediatric advance di-
rectives. (4) Any out-of-hospital do not resuscitate or “accept
natural death” orders should be discussed ahead of time with
local EMS medical directors. This helps ensure that when
EMS personnel are asked to administer comfort measures
only, the EMS personnel are acting from a preapproved posi-
tion and remain clear of any liability. (4)
In addition, children with special health-care needs should
have a comprehensive summary of important information
available to share with hospital and EMS providers. Use of
the emergency information card and medical alert jewelry
can be helpful during an emergency. (4)(11)(12)
TRAINING THE STAFF
Frontline staff (clinical and administrative) in the pediatric of-
fice require training on how to recognize emergencies, acti-
vate the emergency response system, and understand EMS
roles and capabilities. Clinical staff should be provided with
the chance and the incentive to reinforce knowledge and
skills related to pediatric office-based emergencies. Providers
and office staff should be strongly encouraged to keep their
certification in basic lifesaving or pediatric advanced lifesaving
courses current. Staff can also engage in mock codes and on-
line case studies. Preparation and practice for primary care of-
fice emergencies can be achieved through mock codes, in
which all members of the office staff regularly take part in
mock codes and practice as a team. Such exercises can in-
crease staff and practitioner confidence and reduce anxiety
about having to perform lifesaving care. Resources are avail-
able to help guide practices in developing and implementing
these trainings/tasks. (13)(14) The role of staff and providers
during code situations should be defined and documented.
After a simulated experience, the use of debriefing can help
the team identify gaps in the care process as well as opportu-
nities for improvement. Videotaping the mock code provides
valuable feedback, education, and improvement opportunities.
When possible, including local EMS and disaster prepared-
ness teams can be a useful strategy. (7)(11)
EQUIPPING THE OFFICE
In an emergency, office staff as well as providers need to
have access to the right equipment and medications. (15)
Knowing the exact location of supplies is key to ensuring ef-
ficiency during an emergency. All office staff needs to be
trained to know where to locate resuscitation equipment. In
an office located in or near a hospital, basic airway equip-
ment may be the only thing necessary to initiate rescue.
However, if the office is located in a remote setting with
prolonged emergency response times, efforts to stabilize the
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patient may last 30 minutes or more. In this scenario, the
office needs to be equipped with an automated external defi-
brillator and the right tools to maintain an airway. (4)(7) Es-
sential and nonessential medication, equipment, and fluid
recommendations can be found in Appendix A.
POLICIES, PROTOCOLS, AND PROCEDURES
Emergencies in the primary care setting require unique re-
sources and training. Common emergencies are reviewed in
this article. Despite the wide variety of emergencies that
may present at the primary care office, at a minimum, basic
life support (BLS) and reference materials on full arrest
should be readily available. These references can be found
on the American Heart Association’s (AHA) website (www.
heart.org) under “Pediatric Algorithms.”
HEALTH-CARE PROFESSIONAL SKILLS AND
DOCUMENTATION
Provider Skills
Most health-care systems have a well-delineated list of re-
quired courses and certifications necessary to practice.
However, such requirements may not exist for providers
in private practice or community settings or for those not
affiliated or on staff with a local hospital. It is best practice
for all pediatric providers to be certified in BLS and to be
prepared to administer these services in cases of emer-
gency. PCPs should be able to provide BLS in the office
setting. The AHA’s certification for health-care providers
is titled “BLS for Healthcare Providers.”
Other courses beneficial for pediatric PCPs include the
following:
• The pediatric advanced life support (PALS) course is of-
fered by the AHA for health-care providers who care for
children and infants. The course teaches health-care pro-
viders how to assess, identify, and treat respiratory dis-
tress/failure, cardiac arrest, shock, and arrhythmias.
• The neonatal resuscitation program was developed and
is maintained by the AAP. The focus of this program is
basic resuscitation skills for newborns and infants.
• The Advanced Pediatric Life Support course is similar in
content to the PALS course, but the former is certified
by the AAP.
Education and recertification need to be periodically re-
viewed and renewed to ensure that providers maintain
their skills and knowledge.
 Documentation
Proper documentation is a key component of all patient en-
counters, which include office emergencies. Not only will ED
providers depend on these notes to determine further man-
agement of the patient, but proper documentation is key to
reducing the risk of litigation. Proper documentation helps
determine whether the care provided during an office emer-
gency meets the current standard of care. Documentation
can also help identify the learning needs of the office staff.
It is best practice that all staff are trained in proper docu-
mentation before an office emergency. During an office
emergency, stress levels are elevated. Therefore, training the
staff before an emergency occurs and using mock codes can
increase staff confidence, reduce stress, and improve the
management of emergencies. It is important to keep medi-
cation and fluid logs as well as a resuscitation log when
needed. Noting the exact timing of emergency events as
well as the elapsed time during an emergency intervention
is another critical element of proper documentation.
CONDITION-SPECIFIC MANAGEMENT OF
COMMON PEDIATRIC EMERGENCIES
In the following subsections, common conditions that chil-
dren experience in the primary care setting are reviewed.
Management of these conditions is subject to changes in
best practices, and as such, it is critical that PCPs remain
current on diagnosis and treatment.
Asthma
Asthma is a common disease in children, although its pre-
sentation can be quite variable. When treating a child with
an acute asthma exacerbation in the office, it is crucial
that the pediatrician be able to recognize not only the dis-
ease itself but also the severity of the exacerbation. Asthma
should be distinguished from other causes of respiratory
distress in children, including bronchiolitis, croup, pneu-
monia, and asphyxiation, because their treatments differ.
Signs of severe asthma exacerbation in the child in-
clude dyspnea at rest (the child may speak in single words
rather than in complete sentences), agitation, preference
to sit upright, use of accessory muscles, inspiratory and
expiratory wheezing, tachypnea, tachycardia (with normal
rates dependent on the child’s age), and pulsus paradoxus
with a fall of blood pressure between 20 and 40 mm Hg
with inspiration. (16) Infants with severe asthma exacerba-
tion will have difficulty feeding and will produce a weaker,
shorter cry. Infants and children with severe exacerbations
may often have only partial relief from frequently inhaled
short-acting b-agonists (SABAs). (16)
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Children with immediate life-threatening asthma exacer-
bations may have dyspnea that prevents them from speak-
ing, drowsiness or lethargy, bradycardia based on the child’s
age, paradoxical thoracoabdominal movements, and/or ab-
sence of wheezing and pulsus paradoxus, both of which
suggest respiratory muscle fatigue. (16) Infants with imme-
diately life-threatening exacerbations may not cry at all.
These infants and children may have minimal to no relief
with SABAs. (16)
Treatment should be started immediately while await-
ing transfer to an acute care setting. The main goals of
treatment are to rapidly reverse airflow obstruction and
correct hypoxemia, based on pulse oximetry reading.
A SABA, typically albuterol, should be administered im-
mediately, and supplemental oxygen should be started.
(16) Although the onset of action for SABAs is typically
less than 5 minutes in children with severe exacerbations,
note that the duration of action is typically significantly
shorter than that seen in more stable children. Therefore,
multiple doses of a SABA can and should be given be-
cause this will result in incremental bronchodilation.
However, be aware that because of ventilation-perfusion
mismatch, pulse oximetry O2 may decrease after SABA
therapy. A SABA can be given continuously, and there is
evidence that in patients with severe asthma, continuous
rather than intermittent administration of a SABA is the
most effective way to reverse airflow obstruction. (17) Fi-
nally, if available, the initial 3 doses of a SABA should be
given in combination with ipratropium or another anticho-
linergic agent because multiple doses of this combination
may decrease hospitalization rates when given on initial
presentation. (18)
There is no single assessment tool used to monitor re-
sponse to treatment, although it is recommended that the
PCP assess multiple signs, including shortness of breath,
vital signs including pulse oximetry, alertness, use of ac-
cessory muscles, chest tightness, and timing and quality
of wheezing. (16)
Status Epilepticus
Although relatively rare, affecting 0.5% to 1% of children,
(19)(20) epilepsy remains a disease commonly encoun-
tered in both the outpatient and inpatient pediatric set-
tings. Therefore, it is crucial that the PCP be able to
recognize and appropriately manage seizure activity in the
outpatient setting. There are several forms of seizures that
can be seen in a child with status epilepticus that the PCP
must be able to recognize, including convulsive seizures,
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 nonconvulsive seizures, and repetitive focal seizures with-
out altered consciousness. (21)
A seizure is classified as brief if it lasts less than 5 minutes,
whereas a prolonged seizure lasts between 5 and 30 minutes.
(21) A child is in status epilepticus when the child has 30 minutes
or more of continuous seizure activity or when the child experien-
ces 2 or more consecutive seizures without an intermittent return
to neurologic baseline. However, it is typically recommended that
treatment of the seizure be initiated after 5 minutes of epileptic
activity because children having a seizure for this duration are
highly likely to continue having a seizure without medical inter-
vention. (21)
The main goal of therapy in the child with status epilepti-
cus is to rapidly terminate both clinical and electrical epilep-
tic activity because prolonged seizure activity can lead to
permanent brain injury. Additional and equally important
goals are to support respiration, maintain blood pressure,
and identify and treat the underlying cause of the seizure.
The first 5 minutes of treating seizure activity can be
thought of as the stabilization phase. During this time, the
goals of the PCP should be to stabilize the patient’s airway,
breathing, and circulation. Supplemental oxygen should be
administered by either nasal cannula or mask. If possible,
electrocardiographic monitoring is recommended, although
the necessary equipment may not be available in the outpa-
tient setting. Neurologic examinations should be performed
intermittently while the child is having a seizure. During this
time, the blood glucose level should be assessed. If the glu-
cose level is less than 60 mg/dL (<3.33 mmol/L), then the
blood glucose level should be corrected. (21) The intravenous
(IV) route is preferred; however, in a suspected hypoglycemic
patient who is unable to swallow or is unconscious, intramus-
cular or intranasal glucagon may be administered. (22)
After 5 minutes of seizure activity, children should, accord-
ing to current recommendations, be given either IV loraze-
pam or IV diazepam. However, a child initially presenting to
the pediatric PCP office is highly unlikely to have an IV in
place, and rapid proper placement of an IV may not be feasi-
ble. In this case, either rectal diazepam or midazolam, given
in intranasal, intramuscular, or buccal formulations, can be
given. (21) These medications should be administered as a
full single dose rather than divided into multiple small doses.
In the event that the child is nonresponsive to initial treat-
ment, first-line therapies should typically not be repeated, ex-
cept in the case of IV lorazepam or diazepam, which are
rescue medications that have been shown to be safe and ef-
fective. (21) Second-line therapies, including fosphenytoin,
valproic acid, and levetiracetam, are all recommended in the
IV formulation and are typically given once the child has
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been having a seizure for 20 minutes, (21) at which point the
child should be transferred to an acute care setting, where IV
placement can be secured and recommended medications
can be administered.
Dehydration
Dehydration is a common worldwide cause of pediatric
death. Dehydration can be associated with a multitude of pe-
diatric illnesses as a result of excessive fluid loss and poor
fluid intake. Therefore, the PCP must be comfortable with
recognizing dehydration in children, assessing the severity of
the dehydration, and recognizing associated complications
such as metabolic acidosis and electrolyte disturbances.
A child with mild to moderate dehydration has typically
lost 3% to 9% of their body weight. (23) These children
can present with normal mental status, but they can also
be fatigued, irritable, or restless. (23) Unlike children with
severe dehydration, these children are often thirsty. On
physical examination these children will be noted to have
normal to decreased pulses and normal to elevated heart
rates. Their eyes are often sunken in, mucus membranes
are dry, and capillary refill is prolonged. Abnormal skin
turgor is often noted, with skin return to normal more
than 2 seconds after being pinched. Extremities are often
cool, and urine output and tear production are decreased.
(23)
Children with severe dehydration have lost greater than
9% of their body weight. On presentation they are lethar-
gic and unable to drink. On physical examination they will
be noted to have an elevated heart rate, although in the
most severe of cases they can present with bradycardia.
(19) Pulses are typically weak or nonpalpable, and children
will often be noted to be breathing deeply. Extremities are
often cold and mottled and may be cyanotic. Skinfold re-
coil is greater than 2 seconds. Urine output is minimal,
and these children do not make tears. (23)
It is important to note that diminished or absent
bowel sounds can be an indication of hypokalemia, and
deep respirations can be seen with metabolic acidosis.
Hypokalemia and metabolic acidosis often accompany
dehydration. (23)(24)(25)
The main goal of treatment is to rapidly replace the child’s
fluid deficit. Although in the United States this is typically ac-
complished with IV fluid replacement in the hospital setting,
oral replacement therapy (ORT) has been shown to be equally
effective in children with mild to moderate dehydration sec-
ondary to acute gastroenteritis, a common cause of dehydra-
tion worldwide. (26) Therefore, because IV placement is
often not feasible in the outpatient facility, it is reasonable to
 begin ORT when the child with acute gastroenteritis is mildly
to moderately dehydrated. ORT can be effective even with
children who are vomiting, although they must be observed
closely. One dose of ondansetron may be given before start-
ing ORT in children with acute diarrhea and vomiting (age
$6 months as approved by the Food and Drug Administra-
tion [FDA]) (27) because use of ondansetron has been shown
to result in improved hydration. (28) If the children do not re-
spond to ORT, they will require IV placement for IV fluid
therapy.
ORT should not be started in the child with paralytic il-
eus or glucose malabsorption. (23) ORT should not be
given as replacement of IV therapy in children with shock
or severe dehydration because IV fluid resuscitation re-
mains first-line treatment for these conditions. (23) In the
situations mentioned previously herein, an IV should be
placed as soon as possible, even before transfer to the
acute care setting if possible. Once an IV is placed, a nor-
mal saline bolus can be given to replace the fluid deficit.
Special care must be taken in caring for the severely
malnourished child with dehydration given the risks of
heart failure and pulmonary edema. Also, if glucose is
given with fluid replacement, the refeeding syndrome and
hypophosphatemia may occur. Apart from cases of shock,
these children should not receive emergency IV rehydra-
tion because they may be hypokalemic and hypernatremic.
(29)(30)
Croup
Laryngotracheobronchitis, generally known as croup, is a
common cause of upper airway obstruction in children. Pre-
sentation varies, with signs and symptoms ranging from
mild to severe. Croup should be expected when a child is
noted to have a barky cough, inspiratory stridor, hoarseness,
or respiratory distress. (31) Typically, children will have 1 to
2 days of nonspecific upper respiratory tract infection signs
and symptoms preceding the abrupt onset of a barky cough
and respiratory distress. (32) Mild disease courses are char-
acterized by a barky cough without stridor or respiratory
distress. These children can be given oral dexamethasone
0.6 mg/kg and discharged home with anticipatory guidance.
(31) Children who present with moderate disease, character-
ized by frequent coughing, retractions at rest, and normal
mental status along with stridor, can be given dexametha-
sone (31) 0.6 mg/kg as a 1-time dose. In this case, the intra-
muscular route is preferred over oral. After dexamethasone
administration, children should be observed for improve-
ment for approximately 4 hours. Severe disease presents
with stridor at rest that is mostly inspiratory but may be
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expiratory, with severe retractions and lethargy. (31) These
children should be given dexamethasone, which if given in
oral form may be given once more if the child vomits, as
well as nebulized racemic epinephrine, which is often not
available in the outpatient setting. Therefore, any child pre-
senting in the outpatient setting requiring racemic epineph-
rine should be transferred to the ED. There, children will be
observed for recurrence of respiratory distress after adminis-
tration of racemic epinephrine.
Although croup is the most common cause of upper air-
way obstruction, the differential diagnosis includes other
less frequent conditions requiring emergency treatment.
These conditions include epiglottitis, bacterial tracheitis, and
foreign body aspiration. Epiglottitis typically lacks the barky
cough of croup, and affected children will appear anxious,
may be drooling, and will prefer sitting in an upright posi-
tion. (32) These children should be left undisturbed, kept
calm, and sent immediately to the ED. Bacterial tracheitis
can also present with stridor and respiratory distress and,
similar to croup, also presents after upper respiratory tract
infection symptoms. Bacterial tracheitis should be consid-
ered in children who show little improvement after nebu-
lized epinephrine, and given the complications associated
with bacterial tracheitis, these children should be transferred
to the ED. (32)
Foreign Body Aspiration and Ingestion
Young children are at high risk for choking given both
common exploratory behaviors and the smaller diameter
of their airways. Because air flow is inversely related to the
radius of the airway to the fourth power, any decrease in
the cross-section of the airway can lead to respiratory dis-
tress. Respiratory distress worsens as mucus and secre-
tions accumulate around the foreign body, reducing the
airway’s radius even further. (33) Similar to croup, foreign
body aspiration can also present with stridor. The onset of
stridor is sudden and, unlike croup, does not typically pre-
sent with prodromal viral-like signs and symptoms unless
the retained object has caused an associated secondary
bacterial infection. (32) There is typically no barky cough
or hoarseness, but there is often respiratory distress. (34)
Children will require radiographic evaluation. Children
with a highly suspected tracheobronchial foreign body
must undergo bronchoscopy and, therefore, should be
transferred to the nearest medical center. Pending trans-
fer, the airway should be acutely managed per BLS guide-
lines. (35)
Children who have ingested foreign objects are often
asymptomatic, but they may present with drooling, coughing,
Vol. 44 No. 12 D E C E M B E R 2 0 2 3 687
 gagging, vomiting, hematemesis, pain, food refusal, and fussi-
ness, among other signs and symptoms. (34) Physical exami-
nation findings are often normal, but when examining the
child, the PCP should assess for crepitus or swelling of the
neck, findings that are concerning for esophageal perforation,
inspiratory stridor, or expiratory wheezing, which are concern-
ing for airway obstruction, or abdominal tenderness, which is
concerning for intestinal obstruction or perforation. (34) Coins
are the most commonly ingested foreign body but must be
distinguished from button batteries, which appear to have a
double ring on radiographs with a step-off on lateral views.
(34) Children with highly suspected foreign body ingestion re-
quire radiographic evaluation so that high-risk foreign bodies,
such as button batteries, which require urgent management,
are not misdiagnosed. Therefore, it is recommended that the
child with suspected foreign body ingestion be transferred to
a medical center for further evaluation and treatment.
DISCUSSION
Although this article provides general guidance and best
practices for the pediatric provider and the clinical facility,
each primary care setting is unique. As such, the capability
to diagnose and treat an emergency in the office setting
must be evaluated and determined before such an emer-
gency. For offices close to a tertiary care site, stabilization
and transfer of care is often the safest approach. However,
practices in rural settings or practices without adequate ac-
cess to tertiary care facilities for whatever reason must be
trained and equipped to handle immediate stabilization, pro-
viding supplemental oxygen if available, and delivering sub-
sequent life support until such time as a safe transfer can
be made. Maintaining emergency readiness requires time
and effort from a dedicated staff member or team, recom-
mended training for staff, maintaining staff competency,
and having a fully functional emergency cart with appropri-
ate medical supplies that have not expired. Without ade-
quate resources dedicated to these ongoing efforts, office
readiness will be very difficult to achieve.
CONCLUSION
Pediatric emergencies can present in primary care offices
frequently and without warning. It is imperative that the
pediatric PCP and office staff have proper training, not
only in triaging patients and redirecting care of such
emergencies but also in effectively handling the initial
phase of the emergency situation to improve patient
outcome. It is crucial that pediatric PCPs invest in
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certifications, equipment, and medications as well as in
training office staff and parents to identify emergency situa-
tions and react appropriately in such instances.
Summary
1. Increasing readiness of the primary care office
and staff, including necessary education, equip-
ment, and training, has been shown to improve
patient outcomes. (Based primarily on consensus
due to lack of relevant clinical studies) (4)
2. The most common emergencies in the pri-
mary care setting have been identified and
ranked in order of most to least common. (Based
primarily on consensus due to lack of relevant
clinical studies) (7)
3. Implementation of mock codes has been shown
to increase staff and practitioner confidence and
reduce anxiety of having to perform lifesaving
care. Resources exist to help guide practices in
developing and implementing these trainings/
tasks. (Based primarily on consensus due to lack
of relevant clinical studies) (10)(12)
KEY PRACTICE POINTS
• Recent studies reveal the positive effects of pediatric of-
fice readiness on ensuring good outcomes for children
treated in emergency situations. (4)
• Investigators have examined the effect of improved of-
fice readiness on the quality of pediatric emergency
care. Findings suggest a direct link between office readi-
ness and superior outcomes. (4)
SUGGESTED QI PROJECT TOPICS COULD
INCLUDE
1. Improving the emergency training of staff.
2. Improving adherence to protocol.
3. A process improvement for keeping supplies up to date.
Acknowledgments
Thank you to Dr Rani S. Gereige for his review of the man-
uscript and to Tatiana Consuegra from Nicklaus Children’s
Hospital for her support throughout the process.
References and teaching slides for this
article can be found at
https://doi.org/10.1542/pir.2021-005076.
 APPENDIX A (12)(13)
Recommended Office
Emergency Drugs
Essentials
Albuterol (solution for inhalation:
1.25 mg/3 mL; 2.5 mg/3 mL; 5 mg/mL
or MDI 90 lg per puff)
Epinephrine (1:1,000, IM autoinjector:
0.1, 0.15, 0.3 mg)
Oxygen
Nonessentials
Activated charcoal
Antibiotics
Anticonvulsant agents (diazepam,
lorazepam)
Atropine sulfate (0.1 mg/mL)
Corticosteroids (parenteral/oral)
Diazepam (IV) (injection: 5 mg/mL) or
(rectal) (rectal gel: 2.5, 5.0, 7.5, 10.0,
12.5, 15.0, 17.5, or 20.0 mg)
Diphenhydramine (parenteral:
50 mg/mL)
Epinephrine (1:10,000)
Glucagon (injection: 1 mg/mL)
Insulin (injection: 100 U/mL) plus
dextrose (10%; injection: 100 mg/mL)
Ipratropium (nebulized solution:
0.25 mg/mL or MDI 18 lg per puff)
Naloxone (0.4 mg/mL)
Ondansetron (injection: 2 mg/mL; ODT:
4 mg; solution: 0.8 mg/mL)
Ranitidine (injection: 25 mg/mL; syrup:
15 mg/mL)
Sodium bicarbonate (4.2%)
Fluids (nonessentials)
Dextrose (glucose) (injection: D10W,
D25W, D50W)
0.9% sodium chloride, Ringer lactate
solution (250, 500, 1,000 mL)
D10W/D25W/D50W 5 10%/25%/50% dextrose in water, IM 5 intramuscular, IV 5 intravenous, LMA 5 laryngeal
mask airway, MDI 5 metered-dose inhaler, ODT 5 orally disintegrating tablet.
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Recommended Equipment
for Pediatric Office Essentials
Airway management
Bag-valve-mask (450 and 1,000 mL)
Clear oxygen masks, breather and
nonrebreather, with reservoirs (infant,
child, adult)
Nebulizer (or MDI with spacer/mask)
Oropharyngeal airways (sizes 00–5)
Oxygen delivery system
Pulse oximeter
Suction device, tonsil tip, bulb syringe
Miscellaneous equipment and supplies
Cardiac arrest board/backboard
Color-coded tape or preprinted drug
doses
Sphygmomanometer (infant, child, adult,
thigh cuffs)
Splints
Sterile dressings
Recommended Equipment
for Pediatric Office Nonessentials
Airway management
Endotracheal tubes (uncuffed 2.5–5.5;
cuffed 6.0–8.0) or supraglottic devices
(LMA, Combitube)
Esophageal intubation detector or end-
tidal carbon dioxide detector
Laryngoscope blades (0–2 straight and
2–3 curved)
Laryngoscope handle (pediatric, adult)
with extra batteries, bulbs
Nasogastric tubes (sizes 6–14F)
Nasopharyngeal airways (sizes 12–30F)
Magill forceps (pediatric, adult)
Stylets (pediatric, adult)
Suction catheters (sizes 5–16F) and
Yankauer suction tip
Miscellaneous equipment and supplies
Automated external defibrillator with
pediatric capabilities
Heating source (overhead warmer/
infrared lamp)
Spot glucose test
Stiff neck collars (small/large)
Vascular access and fluid management
Arm boards, tape, tourniquet
Butterfly needles (19–25 gauge)
Catheter-over-needle device
(14–24 gauge)
Intraosseous needles (16 and 18 gauge)
Intravenous tubing, microdrip
Vol. 44 No. 12 D E C E M B E R 2 0 2 3 689
 PIR QUIZ

1. A pediatric resident is working in your clinic during their Community

Pediatrics rotation. You explain that the clinic’s emergency supply cart is
very different from the hospital’s emergency department cart based on
expected office presentations. Which one of the following is the most
common type of childhood illness presenting to the primary care pediatric
office setting?
A. Anaphylaxis.
B. Dehydration.
C. Head trauma.
D. Respiratory distress.
E. Seizures.
REQUIREMENTS: Learners can
2. A 3-year-old boy is brought to the clinic by his parents because of concern take Pediatrics in Review quizzes
that the child is having another “asthma attack.” The clinician assesses the and claim credit online only at:
child to determine the severity of this asthma exacerbation episode. The http://pedsinreview.org.

patient is placed on supplemental oxygen because of low oxygen saturation To successfully complete 2023
and is administered the first dose of a short-acting b-agonist. Of the Pediatrics in Review articles for
following signs or symptoms, which one is the least likely to be seen in a AMA PRA Category 1 Credit™,
severe asthma exacerbation in this patient? learners must demonstrate a
minimum performance level of
A. Difficulty speaking in full sentences. 60% or higher on this
B. Dyspnea at rest. assessment. If you score less
C. Preference to lay flat on the examination table. than 60% on the assessment,
you will be given additional
D. Rapid respiratory rate for age.
opportunities to answer
E. Use of accessory respiratory muscles. questions until an overall 60%
3. A 9-year-old with hemiplegic cerebral palsy and a known seizure disorder or greater score is achieved.

begins having a seizure during a health supervision visit in your office. The
This journal-based CME activity
parent realizes that the child did not get yesterday’s and this morning’s is available through Dec. 31,
doses of levetiracetam. Despite successfully stabilizing the child and giving 2025, however, credit will be
supplemental oxygen, the seizure has persisted for more than 5 minutes. recorded in the year in which
Administration of which one of the following therapies is the most the learner completes the quiz.

appropriate immediate next step in the management of this patient?

A. Fosphenytoin.
B. Intramuscular glucagon.
C. Rapid-onset benzodiazepine.
D. The morning levetiracetam dose. 2023 Pediatrics in Review is
E. Valproic acid. approved for a total of 30
Maintenance of Certification
4. The parents of a high school football player bring him to your office after he (MOC) Part 2 credits by the
collapsed at school. As part of the football team’s summer conditioning American Board of Pediatrics
program, there are extended periods of exercise but no body contact drills. (ABP) through the AAP MOC
The patient has no recollection of the event and is frustrated with being in Portfolio Program. Pediatrics in
Review subscribers can claim up
the office. His weight is down approximately 7% from the weight recently
to 30 ABP MOC Part 2 points
recorded as part of his preparticipation physical. During today’s physical upon passing 30 quizzes (and
examination, which one of the following clinical signs and symptoms are claiming full credit for each
most likely to be observed in this patient? quiz) per year. Subscribers can
start claiming MOC credits as
A. Bradycardia. early as November 2023. To
B. Decreased bowel sounds. learn how to claim MOC points,
C. Deep respirations. go to: https://publications.aap.
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D. Lethargy.
E. Prolonged capillary refill time.

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 5. A 2-year-old is brought to the office by his parents because of worsening
“noisy breathing.” The patient seems to have had progressive stridor during
the past 2 hours. There were no preceding respiratory symptoms or
associated fever. He has started to drool and cough more since their arrival
in the office. Which one of the following is most likely to represent your
working diagnosis in this case?
A. Asthma exacerbation.
B. Bacterial tracheitis.
C. Croup.
D. Epiglottitis.
E. Foreign body aspiration.

Vol. 44 No. 12 D E C E M B E R 2 0 2 3 691

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 CME: THREE PATIENT CASES

Fever: Three Patient Cases

Presented here are three patients who have a common chief complaint. All three cases have discussions on presentation,
the differential diagnosis, and management that collectively serve as a Review article. Following the three cases, an expert
weighs in in a short commentary with 5 questions for CME credit.

Case 1: Fever in a 40-day-old Infant

Stelios Kasikis, MD,* Maame Hayfron, MD,* Despoina Galetaki, MD,* Risa Bochner, MD*
*Department of Pediatrics, State University of New York Downstate Health Sciences University and New York City Health and Hospitals/Kings County,
Brooklyn, NY

PRESENTATION
A previously healthy, 40-day-old girl presents with 1 day of fever (100.8 F
[38.2 C]). She is sleeping more than usual and having more frequent bowel
movements but normal consistency. She has no cough, congestion, eye redness,
respiratory distress, emesis, rash, or change in appetite or urine output. She was
born at term via normal spontaneous vaginal delivery to a mother of Japanese
descent and a father of Western European descent. Maternal prenatal infection
screening was negative, including group B Streptococcus. She had a routine post-
natal course, is formula fed and breastfed, and is growing well.
On presentation she is febrile (temperature, 100.5 F [38.1 C]). Her heart rate
is 176 beats/min, respiratory rate is 48 breaths/min, and blood pressure is
93/53 mm Hg. She is well-appearing, with no dysmorphic features. The anterior
fontanelle is open and flat. There is no conjunctivitis or nasal congestion. Oral
mucosa appears pink and moist, without lesions. There is no rash or lymphade-
nopathy. Her neurologic examination findings are normal. The remainder of the
examination findings are normal.
Initial laboratory results are as follows: white blood cell count, 13,640/mL
(13.64 × 109/L) with a normal differential count; hemoglobin level, 13.3 g/dL
(133 g/L); platelet count, 349 × 103/mL (349 × 109/L); C-reactive protein level,
1.1 mg/dL (11 mg/L); procalcitonin level, 18 ng/dL (0.18 mg/L) (reference range,
0–50 ng/dL [0–0.5 mg/L]); cerebrospinal fluid (CSF) white blood cell count, 5/mL
(0.05 × 109/L); glucose level, 54 mg/dL (3 mmol/L); protein level, 0.051 g/dL
(0.51 g/L); and Gram-stain negative. Comprehensive metabolic panel and urinalysis
findings are normal. The respiratory viral panel, including severe acute respiratory
syndrome coronavirus 2, adenovirus, and enterovirus, is negative. Chest radiography is
normal. She is admitted to the hospital and started on empirical antibiotics pending AUTHOR DISCLOSURE FOR CASE 1
Drs Kasikis, Hayfron, Galetaki, and
blood, urine, and CSF culture results. Interval development of additional physical exami- Bochner have disclosed no financial
nation findings and increasing inflammatory markers support her ultimate diagnosis. relationships relevant to this article. This
After being admitted, she continued to spike high-grade fevers (maximum tempera- commentary does not contain a
discussion of an unapproved/
ture of 103.8 F [39.2 C]). On hospital day 2 she developed a diffuse, polymorphous mac- investigative use of a commercial
ulopapular rash (Fig 1) that started on her torso and eventually expanded to the product/device.

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Figure 1. A maculopapular rash over the trunk, face, and extremities.
extremities, face, and inguinal area. Her palms and soles became
erythematous, and she developed bilateral, nonpurulent, limbic-
sparing conjunctival injection. Her lips became erythematous
and cracked. Repeated laboratory studies revealed increasing in-
flammatory marker values, with a maximum C-reactive protein
level of 14.5 mg/dL (145 mg/L) and a maximum procalcitonin
level of 207 ng/dL (2.07 mg/L).
DISCUSSION
Differential Diagnosis
Diagnostic considerations include infectious diseases (staphy-
lococcal or streptococcal toxin-mediated disease, measles,
adenovirus, Epstein-Barr virus, cytomegalovirus, parvovirus
B19, enterovirus, rickettsial infections, leptospirosis), inflamma-
tory disorders (systemic juvenile idiopathic arthritis, reactive
arthritis), and dermatologic conditions (drug reactions such
as Stevens-Johnson syndrome). (1) After initial blood, urine,
and CSF cultures were negative, further investigation included
human herpesvirus 6, parvovirus B19, Epstein-Barr virus,
cytomegalovirus, human immunodeficiency virus, a CSF
meningitis encephalitis panel, and a stool gastrointestinal
pathogen panel, which were all negative. Measles was less
likely given maternal immunity with passive immunity to
the infant. Multisystem inflammatory syndrome in chil-
dren was considered but thought unlikely with negative se-
vere acute respiratory syndrome coronavirus 2 polymerase
chain reaction and nucleoprotein antibody. Drug reactions,
including Stevens-Johnson syndrome, were also consid-
ered but thought unlikely given no medication exposure
before symptom onset and that mucus membrane was
limited to only cracked lips.
Actual Diagnosis
The presence of high-grade fever for 5 days with 4 of 5 clinical
criteria for Kawasaki disease (KD) (rash, bilateral nonpurulent
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conjunctivitis, cracked erythematous lips, and erythema of the
palms and soles), in the absence of an alternative source and
failure to improve with antibiotic drug therapy, led to the diag-
nosis of complete KD. (2)
The Condition
KD is a rare systemic inflammatory disease of unknown
etiology. The leading theory involves an immune-mediated
inflammatory response initiated by an unknown, likely in-
fectious, trigger in a genetically susceptible child. (3) The
highest annual incidence rates are reported in Japan, with
359 per 100,000 children younger than 5 years affected in
2018. (4) The annual number of hospitalizations for KD
in the United States ranged from 1,652 to 1,796 in 2016
to 2019 and decreased to 1,382 in 2020 amid the COVID-19
pandemic. (5) In the United States, children of all racial and
ethnic backgrounds are impacted. (5) Children younger than
5 years and males are predominantly affected. (3) KD in chil-
dren younger than 12 months is quite rare. (6)(7)(8)(9)(10)
One study of 443 patients diagnosed as having KD found
that 13% were younger than 12 months and just 3% were
younger than 6 months. (4)(8) A hurdle in the diagnosis of
KD in young infants is that 75% present as incomplete KD
with few or no classic symptoms. (8) KD should be considered
in infants with prolonged fever even if there are no accompa-
nying symptoms. (1)(2)
Treatment/Management
Infants younger than 6 months with KD are at particularly
high risk for coronary artery aneurysms (CAAs) and giant
CAAs, with poor outcomes. (2)(4)(8) This is in part attrib-
uted to late diagnosis given atypical presentations of KD
in infants with subtle or transient clinical findings aside
from fever. (2)(4)(8) Timely therapy with intravenous immu-
noglobulin (IVIg) is recommended by illness day 10 or as
soon as possible after diagnosis and improves outcomes.
(2)(8) IVIg significantly decreases the risk of CAA in chil-
dren with KD. (11) KD treatment also includes acetylsalicylic
acid (ASA) at moderate (30–50 mg/kg per day) to high
(80–100 mg/kg per day) doses for anti-inflammatory activity
and at low doses (3–5 mg/kg per day) for antiplatelet activity.
(2) Practices vary across institutions regarding ASA dosing
and duration of treatment. (2) In addition, there is no evi-
dence that treatment with ASA reduces CAAs. (2) Some cen-
ters treat patients with moderate- to high-dose ASA until
they have been afebrile for 48 to 72 hours before transition-
ing to a low dose. (2) Treatment is typically continued for
6 to 8 weeks until follow-up echocardiography is performed
to evaluate for CAAs. (2) If no CAAs are identified, ASA is
Vol. 44 No. 12 D E C E M B E R 2 0 2 3 693
 typically discontinued, but ASA may be continued indefi-
nitely if a CAA is identified. (2) Patients at high risk for
CAAs may benefit from adjuvant therapies in addition to
IVIg and ASA. (2) Options for adjuvant therapies include
corticosteroids, infliximab (anti–tumor necrosis factor a
monoclonal antibody), and etanercept (soluble tumor ne-
crosis factor receptor). (2) A 2017 meta-analysis including
7 trials and 922 children with KD found that corticosteroid
use during the acute phase of illness was associated with a
decreased incidence of CAAs. (12) The benefits of cortico-
steroids were greatest for children with high risk scores
and prolonged corticosteroid courses. (12) In addition, high-
risk patients with CAAs seen on baseline echocardiograms
had less CAA progression with treatment of corticosteroids
or infliximab in addition to IVIg. (13) Patients who have
persistent or recrudescent fevers at least 36 hours and less
than 7 days after completion of the first IVIg infusion are
considered IVIg resistant. (2) Treatment options for IVIg-
resistant KD include a second IVIg infusion, IVIg plus
prednisolone, infliximab, cyclosporin, anakinra, cyclophos-
phamide, and plasma exchange. (2)
Patient Course
Our patient was treated with a single dose of 2 g/kg IVIg,
after which she defervesced and was started on low-dose
oral ASA. Although the American Heart Association KD
scientific statement suggests moderate- to high-dose ASA
until fever resolution, followed by low-dose ASA, moderate-
to high-dose ASA was not used in this case due to the
rapid improvement in clinical symptoms and resolution
of fever after IVIg treatment. A baseline echocardiogram
was obtained before initiating treatment and did not reveal
any abnormal findings other than a small patent foramen
ovale. Her inflammatory markers returned to normal lev-
els during the following days. She was eventually dis-
charged on ASA treatment until cardiology follow-up and
was later noted to have peeling of her hands and feet. Re-
peated echocardiography at 2 and 6 weeks revealed no
abnormalities.
Lessons for the Clinicians
• Pediatricians should have a high index of suspicion for
Kawasaki disease when evaluating infants with unex-
plained fever for more than 5 days. (1)
• Kawasaki disease is a diagnosis of exclusion. It is impor-
tant to evaluate for the infectious, inflammatory, and
dermatologic etiologies that compose the differential di-
agnoses for Kawasaki disease. (1)
References for this article can be found at
https://doi.org/10.1542/pir.2021-005397.

Case 2: Ankle Pain 2 Days after a Febrile Illness in a

9-year-old Girl
Maya Heled Akiva, MD, MSc,*† Christos Karatzios, MD,*† Marina I. Salvadori, MD*†
*Montreal Children’s Hospital, Montreal, Quebec, Canada
†McGill University, Montreal, Quebec, Canada

PRESENTATION
A previously healthy 9-year-old girl presents to the emergency department with a 1-
day history of ankle pain and inability to bear weight. Four days before presentation,
she had fever, sore throat, vomiting, and a light cough that lasted for 2 days. As she
defervesced, she developed a diffuse rash over her trunk and arms described by the
mother as slightly raised, 2-mm nonpruritic papules. A throat culture, performed as
an outpatient, was negative for b-hemolytic streptococci. As the rash began to fade,
AUTHOR DISCLOSURE FOR CASE 2
approximately 24 hours after its appearance, she started complaining of right ankle Drs Akiva, Karatzios, and Salvadori have
pain and was reluctant to walk. There was no history of trauma. She lives in a Lyme disclosed no financial relationships
disease–endemic region and acknowledges having 2 dogs at home. When presenting relevant to this article. This commentary
does not contain a discussion of an
to the emergency department due to increasing ankle pain, she is afebrile (99.1 F unapproved/investigative use of a
[37.3 C]). On examination she is calm and cooperative; there is no rash, oral lesions, commercial product/device.

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 tonsillar erythema, or exudates. The right ankle is swollen,
tender, and warm, with mild erythema and limited range of
motion on extension and flexion. The remainder of the physi-
cal examination findings are normal.
Laboratory findings reveal a white blood cell (WBC)
count of 8,500/mL (8.5 × 109/L) (reference range [RR],
4,500–13,000/mL [4.5–13.0 × 109/L]), a hemoglobin level
of 11.7 g/dL (117 g/L) (RR, 11.5–15.5 g/dL [115–155 g/L]),
and a platelet count of 288 × 103/mL (288 × 109/L) (RR,
150–450 × 103/mL [150–450 × 109/L]). Her C-reactive protein
level is 7.5 mg/dL (75 mg/L) (RR, 0–0.5 mg/dL [0–5 mg/L]),
erythrocyte sedimentation rate is 48 mm/h, C3 level is ele-
vated (197 mg/dL [1.97 g/L] [RR, 79–152 mg/dL (0.79–1.52
g/L)]), C4 level is normal (34 mg/dL [0.34 g/L] [RR, 17–47
mg/dL (0.17–0.47 g/L)]), and antistreptolysin O level is 136
IU/mL (RR, #200 IU/mL). Radiography of the right tibia/
fibula, ankle, and foot shows no fracture or bony abnormality,
with moderate perimalleolar soft tissue swelling over the lateral
malleolus and a small to moderate tibiotalar joint effusion. Mag-
netic resonance imaging with contrast of the right ankle shows
no evidence of osteomyelitis, small tibiotalar and subtalar joint
effusions, mild signs of acute synovitis, and focal tenosynovitis
of the flexor tendons. From a bedside aspiration and irrigation
of the right ankle, 10 mL of turbid, reddish synovial fluid is ex-
tracted and sent for bacterial culture and cell count, revealing a
WBC count of 9,790/mL (9.79 × 109/L), with 93% neutrophils,
and a red blood cell count of 0.40 × 106/mL (0.40 × 1012/L). On
initial synovial Gram-stain, no organisms are noted.
Although the patient was afebrile and had a normal WBC
count, her physical examination findings and high inflamma-
tory markers suggest an infectious etiology. She is, therefore,
admitted for concern of septic arthritis and started on intrave-
nous (IV) cefazolin. After 48 hours of IV cefazolin, she starts
to bear weight; she is switched to oral cephalexin 1,000 mg/
dose 3 times a day for a planned duration of 3 weeks. She was
afebrile in the hospital, and her C-reactive protein level de-
creased to 1.63 mg/dL (16.3 mg/L) at discharge. After approxi-
mately 80 hours of incubation, a preliminary growth from
the synovial fluid was reported as gram-negative bacilli. The
synovial multiplex polymerase chain reaction was negative;
this assay detects the following bacteria: Staphylococcus au-
reus, Streptococcus pyogenes, Streptococcus group B, Streptococ-
cus pneumoniae, and Kingella kingae.
DISCUSSION
Differential Diagnosis
When assessing a child with arthritis subsequent to a fe-
brile illness, the main differential diagnosis includes
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septic and postinfectious arthritis with the consideration
of Lyme arthritis according to the local epidemiology.
Other less common etiologies would include rheumato-
logic diseases such as IgA vasculitis (Henoch-Sch€ onlein
purpura), juvenile idiopathic arthritis, and lupus. The
most common bacterial causes for septic arthritis in this
age group are Staphylococcus aureus and Streptococcus pyo-
genes. (1) In younger children (ages 6 months to 4 years)
with septic arthritis, K kingae is a common pathogen that
is frequently associated with a preceding upper respiratory
illness. (1)(2) Lyme arthritis can also present similarly;
however, in this case, serologic test results were negative.
Postinfectious arthritis can be divided into 3 categories:
postviral arthritis (described with parvovirus B19, rubella,
and hepatitis B infections), poststreptococcal arthritis as
part of or independent of rheumatic fever, and reactive
arthritis, commonly seen in patients with genetic predis-
position (HLA-B567). (3) In this case, clinical improve-
ment was noted after aspiration and irrigation of the
joint and initiation of antibiotics, suggesting a septic ar-
thritis. This was validated by the growth of a gram-nega-
tive bacillus from the synovial fluid.
K kingae is a gram-negative bacillus but is uncommon
in this age group. Other gram-negative bacilli are much
less common as pathogens causing septic arthritis in im-
munocompetent hosts (Table 1). These often are linked to
animal exposures. Identification of the organism isolated
was unsuccessful by means of mass spectrometry, a phe-
notypic approach to bacterial identification. Therefore, the
sample is then sent for nucleic acid 16S ribosomal RNA
sequencing for genomic identification. In this process, the
16S subunit gene of the well-conserved bacterial ribosome
is first amplified and sequenced, then matched through
databases of available sequences, revealing the identifica-
tion of the bacterium. This technique allows for recogni-
tion of bacteria that may not be able to be identified by
phenotypic methods. (4)
Actual Diagnosis
Two weeks after discharge she still had a minimal limp.
When pressed on possible exposures, the family disclo-
ses that the girl has 2 pet rats not mentioned during the
hospitalization. Septic arthritis in the context of rat expo-
sure is suspicious for a zoonotic etiology, and the differ-
ential diagnosis in these cases should include rat-bite
fever (caused by either Streptobacillus moniliformis or Spi-
rillum minus), leptospirosis, and Pasteurella spp infec-
tions. (5)
Vol. 44 No. 12 D E C E M B E R 2 0 2 3 695
 Table 1. Gram-Negative Bacilli That Cause Septic Arthritis in Children
RECOMMENDED FIRST-LINE
BACILLUS GRAM-STAIN AGE GROUP EXPOSURES/RISK FACTORS ANTIBIOTIC TREATMENT
Kingella kingae Gram-negative <5 y Preceding upper respiratory Cefazolin
(most coccobacillus tract infection and/or oral
common) ulcers
Salmonella spp Gram-negative All ages Sickle cell anemia Ceftriaxone
bacillus Connective tissue disease
Reptile exposures
Haemophilus Gram-negative <5 y Unimmunized Ceftriaxone or cefuroxime or
influenzae spp coccobacillus amoxicillin-clavulanic acid
Pasteurella spp Gram-negative All ages Animal exposure (especially Frequently polymicrobial and
coccobacillus after adjacent dog and cat should include
bites or scratches) antistaphylococcal and
antistreptococcal coverage
Amoxicillin-clavulanic acid or
cefuroxime
Pseudomonas Gram-negative All ages Intravenous drug use Antipseudomonal b-lactam ±
aeruginosa bacillus aminoglycoside
Brucella spp Gram-negative All ages Livestock exposure Doxycycline or trimethoprim-
coccobacillus Unpasteurized dairy products sulfamethoxazole 1 gentamicin ±
rifampin
Bartonella Gram-negative All ages (more Cat exposure Doxycycline or azithromycin ±
henselae coccobacillus common in children) rifampin
Streptobacillus Gram-negative More common in Rat exposure (bites) Penicillin G
moniliformis bacillus children Contaminated oral ingestion

A few days after her follow-up, the results from the 16s
ribosomal RNA sequencing identified the isolated bacte-
rium from the synovial fluid as S moniliformis, giving the
diagnosis of rat-bite fever septic arthritis.
The Condition
There are 2 pathogens that cause rat-bite fever: S monilifor-
mis (a gram-negative rod common in North America) and
S minus (a spirochete seen predominantly in Asia). Trans-
mission of S moniliformis is usually by a rat bite. Contami-
nated food and water outbreaks are also described, but
this mode of transmission is less common. Historically,
people living in poverty were the population at risk, with
children accounting for approximately 50% of the cases in
the United States. Recently, adoption of rats as pets has
become popular, causing a shift in the epidemiology to in-
clude pet owners (also usually children), pet store workers,
and laboratory workers. (6) The typical presentation in-
cludes fever, rash, chills, and polyarthralgia. (7)(8) Polyar-
thralgia and migratory polyarthritis may last for months to
years even after adequate treatment and is believed to be
reactive or immune-mediated. (8) Complications of rat-
bite fever can vary and include pneumonia, meningitis,
myocarditis, pericarditis, endocarditis, vasculitis, and sep-
tic arthritis, which may involve multiple joints. Although
joint involvement is a prominent feature of the clinical syn-
drome, septic arthritis is rare. Microbiological confirmation
is essential for a rat-bite fever septic arthritis diagnosis,
which may affect the choice and duration of antibiotics. (8)
The recommended treatment for rat-bite fever is IV penicil-
lin G for 5 to 7 days with a switch to oral for a total 2- to-4-
week course. (6) Ceftriaxone has also shown good results
and can be considered as an alternative. There are limited
data about the use of other cephalosporins. (6)(8) S monili-
formis septic arthritis is rare, there are no clear guidelines
for its management, and regimens described in the litera-
ture are variable. The expected prognosis for streptobacillus
septic arthritis is excellent; all published cases, regardless
the regimen chosen, had successful outcomes with resolu-
tion of symptoms. (5)(8)
Patient Course
Once diagnosed as having confirmed rat-bite fever septic ar-
thritis, treatment was changed to amoxicillin for an additional
4 weeks. At the end of therapy, she had no sign of infection or
residual pain and was back to doing her regular activities. The
pet rats were removed from the household because reinfection
and infection of other household members are possible.
Lessons for the Clinician
1. Exotic pets such as rats, other rodents, and reptiles are
increasing in popularity. Such exposure may give
important clues to disease etiology, and clinicians

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 should be aware that patients may not offer this
information without specific questioning.
2. An index of suspicion for less common causes of
arthritis should be considered in cases of patients with
animal exposures causing zoonotic arthritis.
3. In cases of suspected septic arthritis, synovial sampling
has unequivocal diagnostic importance. In complicated
or atypical culture-negative cases, one should consider
the use of molecular techniques such as synovial
multiplex polymerase chain reactions or 16s ribosomal
RNA sequencing. Molecular testing should also be
considered if identification of an isolated bacterium is
not readily identified.
References for this article can be found at
https://doi.org/10.1542/pir.2022-005593.

Case 3: Acute Right Lower Quadrant Abdominal Pain in a

2-year-old
Sagar D. Mehta, MD,*† Carrie Ng, MD*†
*Division of Pediatric Emergency Medicine, Emory University School of Medicine, Atlanta, GA
†Children's Healthcare of Atlanta, Atlanta, GA

PRESENTATION
A previously healthy 2-year-old girl presents to the pediatric emergency depart-
ment (ED) with 4 days of right lower quadrant abdominal pain. Three days ago,
she had presented to an outside adult ED where she was diagnosed as having
constipation despite having regular soft stools and was sent home with a poly-
ethylene glycol prescription. The day before our present presentation she devel-
oped a fever to 102.5 F (39.2 C) and was referred to the local children’s ED by
her pediatrician. The family denies any vomiting, and she has had 1 episode of
nonbloody diarrhea since starting the polyethylene glycol. She has a slightly de-
creased appetite but continues to snack on foods and is making her normal
number of wet diapers. Her twin sister recently recovered from a likely mild vi-
ral gastrointestinal illness. There is no history of abdominal trauma, and the pa-
tient had been growing and developing well before this illness.
Her vital signs are notable for a temperature of 101.3 F (38.5 C), heart rate of
154 beats/min, blood pressure of 121/85 mm Hg, respiratory rate of 38 breaths/min,
and oxygen saturation of 100% on room air. On physical examination she is alert
and interactive but appears uncomfortable. She has equal and reactive pupils,
clear tympanic membranes, and clear nares and oropharynx with moist mucous
membranes. Her lungs sound clear bilaterally, and her cardiac examination is no-
table for regular rate and rhythm without any murmurs. Her abdominal examina-
tion is notable for normoactive bowel sounds, focal right lower quadrant
tenderness with guarding and mild distention, without any appreciated masses or
hepatosplenomegaly, although examination was limited by patient guarding. She
AUTHOR DISCLOSURE FOR CASE 3
has pain with coughing, and a negative Rovsing sign. Her genitourinary examina- Drs Mehta and Ng have disclosed no
tion findings are normal, and she has a sexual maturity rating of 1. She has no financial relationships relevant to this
rashes or bruises. She is alert and appropriately oriented for age, and the remainder article. This commentary does not
contain a discussion of an unapproved/
of her neurologic examination is nonfocal. Point-of-care ultrasonography (POCUS) investigative use of a commercial
of the right lower quadrant point of maximal tenderness could not visualize the ap- product/device.

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 Figure 2. Right lower quadrant abdominal point-of-care ultrasonography demonstrating echogenic free fluid (star). The bowel (triangle), psoas muscle
(square), and iliac vessel (circle) are indicated.

pendix but shows a large area of echogenic free fluid (Fig 2).
Laboratory data are notable for a white blood cell count of
13,640/mL (13.6 × 109/L) (reference range, 5,000–15,500/mL
[5.0–15.5 × 109/L]) with 56.7% neutrophils, a hemoglobin
level of 9.5 g/dL (95 g/L) (reference range, 11.5–13.5 g/dL
[115–135 g/L]), a mean corpuscular volume of 84 mm3 (84
fL) (reference range, 75–87 mm3 [75–87 fL]), a C-reactive
protein level of 6.0 mg/dL (60 mg/L) (reference range,
<1.0 mg/dL [<10 mg/L]), and negative urinalysis results.
Given a high concern for perforated appendicitis with de-
veloping phlegmon and abscess, she is sent for radiology ap-
pendix ultrasonography, which is unable to visualize the
appendix but shows fluid and debris in the right lower quad-
rant. While scanning the area they note an abnormal appear-
ance adjacent to the kidney and so extend the imaging study
to the right upper quadrant and find a lobular vascular het-
erogeneous mass measuring 6.8 cm superior to the right
kidney (Fig 3). An abdominal computed tomographic (CT)
scan with contrast is ordered and is notable for a vascular bi-
lobed mass between the liver and the right kidney (anterior
to the kidney) with hypodense and hyperdense components,
some of which appear hemorrhagic. The mass appears to in-
vade the right abdominal wall and appears separate from the
liver. The right adrenal gland is normal in appearance, and

–5width.
Figure 3. Radiology abdominal ultrasonography demonstrating the size of the mass. 15height, X5length, X

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 Figure 4. Abdominal axial computed tomographic scan of the mid-abdomen. The heterogenous mass (star), mildly distended bowel loops (square), and
normal kidneys (triangles) are visualized.
the mass does not involve the right kidney. Complex fluid is
noted in the right and left lower quadrants (Fig 4). She is ad-
mitted for further evaluation, including a comprehensive
metabolic panel and tumor markers, and underwent subse-
quent biopsy of the mass, with pathologic analysis confirm-
ing the diagnosis.
DISCUSSION
Differential Diagnosis
The differential diagnosis of acute right lower quadrant abdom-
inal pain in a 2-year-old is very broad, with common causes in-
cluding gastroenteritis, constipation, intussusception, urinary
tract infection, appendicitis, and mesenteric adenitis. Less com-
mon etiologies include ovarian cysts or torsion, testicular tor-
sion, acute bowel obstruction, inflammatory bowel disease,
and abdominal tumors. (1) The patient’s history with acute-on-
set abdominal pain and recent fever raised suspicion in the dif-
ferential diagnosis to possible infectious or inflammatory
etiologies such as urinary tract infection, appendicitis, mesen-
teric adenitis, and gastroenteritis. The right lower quadrant PO-
CUS finding of echogenic free fluid along with the elevated
white blood cell count and C-reactive protein level raised con-
cern for perforated appendicitis with developing phlegmon and
abscess.
Because some abdominal tumors present with fever,
anorexia, vomiting, and/or diarrhea mimicking acute
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appendicitis or gastroenteritis, (2)(3) it is crucial to deter-
mine which patients require additional imaging after a
POCUS or a limited radiology ultrasonography. In this
case, the finding of echogenic free fluid in the pelvis
should prompt concern for possible hemoperitoneum and
consideration of full abdominal imaging such as complete
abdominal ultrasonography or cross-sectional imaging such
as magnetic resonance imaging or CT.
The peak incidence of pediatric malignant abdominal tu-
mors is between 1 and 5 years of age. Neuroblastoma and
Wilms tumor are the most common intra-abdominal tumors
in the pediatric population, composing 6% and 5% of all
childhood cancers, respectively, (4) with less common causes
including leukemia/lymphoma, hepatic tumors, ovarian tu-
mors, germ cell tumors, and soft tissue sarcomas. Wilms tu-
mor and neuroblastoma are found more commonly in
infants and toddlers, and leukemia or lymphomas of the liver,
spleen, or retroperitoneal lymph nodes occur more commonly
in older children. (5) Wilms tumor may present after sponta-
neous rupture or rupture after blunt abdominal trauma caus-
ing intra-abdominal bleeding and abdominal pain. (6)
Actual Diagnosis
The patient’s subsequent laboratory values were notable for
a normal b–human chorionic gonadotropic tumor marker
and an elevated a-fetoprotein (AFP) level of 34,184 ng/mL
(34,184 mg/L) (reference range, 1–11 ng/mL [1–11 mg/L]).
Vol. 44 No. 12 D E C E M B E R 2 0 2 3 699
 Pathologic analysis of the peritoneal fluid and abdominal
mass biopsy both showed a diagnosis of yolk sac tumor.
There was suspicion that a hemorrhage of the tumor led to
the patient’s fever and imaging findings of complex fluid in
the lower abdominal quadrants.
The Condition
Yolk sac tumor falls under a classification of germ cell tu-
mors, which originate from the primordial germ cell and
encompasses teratomas, germinomas, yolk sac tumors, em-
bryonal carcinomas, and choriocarcinomas. (7) Germ cell tu-
mors compose approximately 3.5% of childhood cancers for
children younger than 15 years. (8) Malignant germ cell tu-
mors in especially young children (<4 years) are primarily
all yolk sac tumors and may arise from a preexisting tera-
toma. They have a bimodal frequency of distribution, with
the first peak observed in the first 4 years after birth and a
second peak observed after 12 years, coinciding with the on-
set of puberty. (9) Their clinical presentation can be variable,
with a tendency to grow rapidly over weeks to months, and
may lead to development of abdominal enlargement and
acute abdominal pain. (10)(11)
Diagnostic evaluation should include a complete blood
cell count with differential count, serum electrolytes, blood
urea nitrogen, creatinine, urinalysis, and tumor markers
such as human chorionic gonadotropic, AFP, and lactate
dehydrogenase. The AFP level is commonly elevated in
yolk sac tumors and indicates the presence of malignant
components; however, it is not tumor specific. Ultrasonog-
raphy is often chosen as the initial imaging modality, fol-
lowed by advanced imaging such as CT or magnetic
resonance imaging as clinically indicated. (7)
Management
Management depends on the stage of the tumor and may
involve surgical resection and chemotherapy with bleomy-
cin, etoposide, and cisplatin. The survival rate is higher
for prepubertal pediatric yolk sac tumors at each stage,
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namely, localized, regional, and distant disease, compared with
postpubertal tumors of the same stage. (7)(9) Posttreatment
monitoring is conducted with AFP monitoring and repeated
imaging as indicated. (7)(12)
Patient Course
The patient was formally diagnosed as having a stage III
abdominal yolk sac tumor and received 4 cycles of chemo-
therapy with bleomycin, etoposide, and cisplatin. She had
residual mass resection 2 months later, with repeated
pathologic analysis showing no viable residual tumor. A
repeated scan 6 months later did not show residual or re-
current disease, and her repeated AFP levels were within
normal limits. She continues to do well and follows up in
the hematology/oncology clinic for routine monitoring.
LESSONS FOR CLINICIANS
• Oncologic abdominal presentations can mimic other
acute abdominal etiologies, such as appendicitis.
• Echogenic free fluid in the pelvis of a young child is ab-
normal and needs to be investigated further with com-
plete abdominal ultrasonography and/or further cross-
sectional imaging.
• The peak incidence of malignant abdominal tumors in
pediatrics is between ages 1 and 5 years.
• Neuroblastoma and Wilms tumor are the most common
intra-abdominal tumors in pediatrics, and yolk sac tu-
mor, a type of germ cell tumor, occurs more rarely.
• Abdominal mass evaluation should include a com-
plete blood cell count, a comprehensive metabolic
panel, a urinalysis, tumor markers (human chorionic
gonadotropic, a-fetoprotein, lactate dehydrogenase),
ultrasonography, and consideration of cross-sectional
imaging.
References for this article can be found at
https://doi.org/10.1542/pir.2023-005993.
 COMMENTARY

Commentary: Fever Is Your Friend

Henry M. Adam, MD
Pediatrics in Review Associate Editor

Fever, the theme of our 3 patient cases, is often looked on as a disease in itself, a misconception we have helped foster
by the language we use: scarlet and yellow fevers, typhoid and Rocky Mountain spotted fevers, also rheumatic, hay, den-
gue, cat-scratch, and rat-bite fevers. Reinforcing this impression of fever as a disease, rather than as a symptom or sign
of an underlying illness, contributes to parents’ fear of fever and their frequent compulsion to treat it.
An element of the human inflammatory response, fever in contrast to hyperthermia rarely threatens a child’s well-
being. Given that it is an energy-consuming process, metabolically costly, fever almost certainly has a protective effect or
it would not have persisted through its long evolutionary history. A controlled rise in the body’s temperature mediated
by the anterior hypothalamus, fever is a reaction to any insult that sets off the body’s inflammatory response. Akin to a
thermostat, the hypothalamic set point regulates body temperature. Some inciting factor, a viral infection most often in
children, stimulates the release of cytokines that act as pyrogens, which increase levels of prostaglandin E2 at the ante-
rior hypothalamus, causing a rise in the set point. With actual body temperature lower than the new set point, the pa-
tient at the onset of fever feels chilled and the body’s response is to shiver, generating more internal heat, and to
vasoconstrict at the skin and close down sweat glands, reducing heat loss: in effect, a controlled turning up the furnace
and shutting the windows.
Hyperthermia is fundamentally different from fever. An unregulated rise in temperature above the set point, it can
result from the body producing too much heat (thyroid storm), from the inability to disperse heat (an overbundled
baby), or from a combination of both (inappropriate exertion on a hot, humid day). Instead of the chill accompanying
the onset of fever, the body experiences intense flushing as blood vessels dilate and sweat glands go into overdrive to
shed heat to the environment: the opposite of fever, the furnace is heating out of control and the windows are thrown
wide open.
Evidenced by the epidemic of heat stroke during this past summer’s heat waves, hyperthermia can send body temper-
ature dangerously high. But fever, a homeostatic process, is kept within physiologic limits, rarely rising above 106 F
(41.1 C): a counter-acting element of the febrile response is the release of cryogens that check the effect of pyrogens as
fever rises. In fact, only approximately 0.05% of pediatric emergency patients present with a temperature higher than
106 F (>41 C). And although it seems intuitive that the higher a child’s fever the more likely is a serious bacterial infec-
tion, even at high temperatures a viral source is far more common. Temperature itself becomes dangerous only when it
reaches 107 F or higher ($41.7 C), in which case the underlying fever is likely to be exacerbated by a component of hy-
perthermia, often dehydration.
Fever, it turns out, has a long history widespread among animals as a protective response. When they become in-
fected, some fish and lizards, which are cold-blooded, seek out a warmer environment where their body temperatures
rise, in effect an induced fever. This behavior has been shown to confer a survival benefit that can be reversed by the ad-
ministration of antipyretic agents. Fever inhibits the growth of many viruses and bacteria, and hinders the absorption of
iron, without which many pathogenic bacteria cannot survive. It promotes the activity of neutrophils and the production
of superoxides, and it enhances the proliferation of T cells and the action of interferon. As a metabolically costly phe-
nomenon that increases the expenditure of energy by 7% to 10% for each rise in temperature of approximately 2 F
(–16.7 C), fever’s long and widespread endurance argues for it as a protective process with survival benefit.
Why then are we, both parents and pediatricians, so adamant about treating fever? Barton Schmitt coined the term
fever phobia in his study reporting parents’ overwhelming confusion about fever, their pervasive beliefs that it is harmful,

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 can cause brain damage, and can rise to 110 F (43.3 C) or
higher if not treated. Not surprising, then, that most pa-
rents worried “lots” about fever, considered it high even at
less than 102 F (<39 C), and treated even temperatures in
the normal range with antipyretic agents. Frequently, pa-
rents cited doctors and nurses as their primary source of
knowledge about fever, an assertion made credible by a
survey of AAP members in Massachusetts, two-thirds of
whom regularly suggested treating fevers less than 102 F
(<39 C) because they can themselves be dangerous, and one-
quarter of whom believed that a fever of 104 F (40 C) could
cause brain damage and even death (Pediatrics. 1992;90:
851–854).
A temperature of 100.4 F (38 C) or greater is usually
cited as signifying a fever. But as with any physiologic
measure, the limit of normal is not defined by a single
temperature but by a range of values that account for indi-
vidual variations, fluctuations by time of day, and differ-
ences related to age as well as to how and where the
temperature is taken. Body temperature varies throughout
the day, being higher late in the afternoon and early in the
evening than in the morning or at night. Infants have
higher body temperature than older children and adults.
Rectal temperature is the closest to core temperature, de-
fined as blood’s temperature in the pulmonary artery, but
aside from the discomfort that limits its use in many chil-
dren it can be inaccurate because of improper technique
or the presence of stool. As a rule, oral temperature is ap-
proximately 1 F (–17.2 C) less than rectal temperature, but
this difference varies from person to person, and its preci-
sion relies on the cooperation of the patient; recent intake
of cold or hot liquids or foods can also affect its accuracy,
as can tachypnea in an anxious child. Axillary tempera-
ture, although easy and convenient to take, does not have
a reliable correlation with rectal temperature so can be dif-
ficult to interpret. Infrared thermometers, despite their
convenience, do have limitations. Faulty placement in the
ear canal and the presence of ear wax can limit the reli-
ability of tympanic thermometers, and forehead thermom-
eter readings can be affected by ambient conditions such
as direct sunlight, cold room temperature, or sweaty skin.
Least dependable are so-called fever strips and pacifier
thermometers.
The management of fever should begin before the child
is febrile. In giving anticipatory advice, we pediatricians
should acknowledge our role in generating fever phobia.
When we recommend the routine use of antipyretics for
any rise in temperature, we undermine our reassurance to
parents that they need not worry about the fever itself.
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And that reassurance is less likely to be accepted when
their child is febrile than as part of routine counseling: fe-
ver is actually a protective process, not in itself a threat
that without treatment can climb to frightening heights;
sensible care means simple measures such as adequate
hydration, attention to ambient room temperature, and
avoiding overbundling. Our message should be that it is
the underlying illness, not the fever, that may put their
child in jeopardy, and we need to teach about the symp-
toms and behaviors that should trigger concern and signal
the need for professional involvement.
When the illness underlying a fever puts a child at risk,
clearly it must be treated; but how to deal with the fever,
beyond attention to hydration and ambient conditions, is a
question of judgment. Intervening to make a child more
comfortable is certainly appropriate, and the decision to
give an antipyretic should not be based on a specific tem-
perature but rather on how the child looks and behaves:
for many children, a fever of 104 F (40 C) or even higher
is tolerated without ill effect, whereas others become
droopy and upset when their temperature barely reaches
the threshold of fever. Another reason often given for treat-
ing a fever is that lowering the temperature helps separate
children with trivial illness from those with serious infections.
In reality, how a febrile child responds to a dose of antipyretic
drug does not reliably distinguish dangerous from nonthreat-
ening disease. A healthy child with a transitory viral illness is
not endangered by a fever, but a child with an underlying
chronic illness or a serious acute infection may not deal well
with the metabolic stress that fever can impose: tachycardia
and tachypnea, as well as higher oxygen consumption and
greater insensible water losses, can compromise a child who
is anemic, septic, or in shock, or who is at special risk from a
disease that strains homeostasis.
Aside from antipyretic medication, another common
approach to treating fever is physical cooling. Acetamino-
phen and nonsteroidal anti-inflammatory drugs are effec-
tive antipyretics because they inhibit the production of
prostaglandin E2, which then lowers the hypothalamic set
point back toward normal, turning off the stimulus for the
body to generate heat. In contrast, physical measures such
as cool baths or sponging do not affect the set point,
which remains high. Instead, they draw heat from the
body: rather than turning the furnace off, these measures
open the windows wide. The hypothalamus detects a widen-
ing gap between its high set point and the body’s lowering
temperature, with the paradoxical effect that it responds by
raising the set point still higher. Once the bath or sponging is
done, the stimulus remains to produce more heat by raising
 the metabolic rate and causing muscles to shiver, which may
cause the child discomfort and lead to a rebound in the fever.
Physical cooling can have an appropriate role in the man-
agement of fever when the triggering illness makes the
child dangerously vulnerable to the metabolic stress result-
ing from the rise in temperature. In such a case, the combi-
nation of cooling with an antipyretic brings the fever down
quickly while also lowering the set point to prevent a re-
bound rise in temperature.
A difficult issue is the role of antipyretic drugs in pre-
venting febrile seizures, which are most common in chil-
dren 6 months to 6 years of age, the same age group to
most often have benign viral infections. Advising parents
routinely to treat the fever of these self-limited illnesses to
prevent a febrile seizure contributes both to the fear of fe-
ver and to their anxiety about the risk a febrile seizure
poses to their child. Granted, a febrile seizure is certainly
alarming, but very rarely is it dangerous. Furthermore, no
convincing evidence establishes that this intervention is ef-
fective: the seizure can precede the fever, putting causality
into question so that preventing the fever may not abort
the seizure. Once a child has had a febrile seizure, the
urge to prevent a recurrence becomes more intense. The risk
of a recurrent seizure increases the lower the temperature
with the first seizure. But low-grade fevers can be difficult
to detect, so that parents have less sense of control and risk
becoming more aggressive about taking temperatures and
resorting to an antipyretic medication—neither is healthy to
a young, developing child. And again, without supporting
evidence, it is questionable that even 24-hour ongoing an-
tipyretic treatment can prevent another seizure. What pa-
rents clearly deserve from us is reassurance that neither
fever nor a febrile seizure is a fault in their care or likely to
threaten their child’s well-being.

With this last commentary, Dr Henry Adam concludes his 28 years of contributions as Associate Editor for the Pediatrics
in Review feature “In Brief.” We are indebted to Dr Adam for his thoughtful guidance and for his wit and wise insight at
the end of In Brief articles over the years, especially his focus on parental concerns, from his first In Brief comment in
July 1995: “ … parents are likely to need help overcoming the almost predictable revulsion of the thought of their child
having ‘worms’; counseling may be at least as important as mebendazole,” to his last on fever: “What parents clearly
deserve from us is reassurance that neither fever nor a febrile seizure is a fault in their care or likely to threaten their
child’s well-being.” Thank you, Henry, for a job well done.

Joseph A. Zenel, MD, Editor in Chief

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 PIR QUIZ

PIR QUIZ (for IOS Cases plus commentary)

1. A 6-week-old male infant with prolonged fever is brought to the emergency
department (ED) by his parents. Following an extensive work-up, the infant is
diagnosed with Kawasaki Disease (KD) and is admitted to the hospital for further
management. The treating clinician explains to the family the importance of the
timeliness of certain interventions on patient outcomes and disease
complications. Which of the following is the most appropriate immediate next
step in management of this patient with the highest impact on outcomes?
A. High dose acetylsalicylic acid (ASA).
B. Intravenous fluids. REQUIREMENTS: Learners can
take Pediatrics in Review quizzes
C. Intravenous immunoglobulins (IVIG). and claim credit online only at:
D. Low dose ASA. http://pedsinreview.org.
E. Watchful waiting.
To successfully complete 2023
2. The patient in the vignette in question #1 received IVIG and was placed on Pediatrics in Review articles for
high-dose ASA. A baseline echocardiogram showed no evidence of coronary AMA PRA Category 1 Credit™,
artery aneurysms. On day 4 after completing the IVIG infusion, the patient learners must demonstrate a
continued with daily spiking fevers. Which of the following is the most likely minimum performance level of
60% or higher on this
cause of the persistent fevers in this patient?
assessment. If you score less
A. Drug fever. than 60% on the assessment,
B. IVIG-resistance. you will be given additional
opportunities to answer
C. Superimposed bacterial infection.
questions until an overall 60%
D. Superimposed fungal infection. or greater score is achieved.
E. Superimposed viral infection.
This journal-based CME activity
3. A 6-year-old girl is brought to the clinic by her parents because of one-day
is available through Dec. 31,
history of fever, chills, and generalized joint pains. On the day of 2025, however, credit will be
presentation, she was noted to have a diffuse rash over her trunk, arms, and recorded in the year in which
legs. She also started complaining of right knee pain and limping. On the learner completes the quiz.
physical examination she is afebrile and is alert, non-toxic, and in no acute
distress. There is a diffuse blanching rash over her trunk and extremities. The
right knee is swollen, erythematous, warm, and tender to touch with
limitation of flexion due to pain and swelling. Small puncture wounds are
noted slightly above the right knee. The parents report that the child just
received a pet rat for her birthday a few weeks prior and that the wounds 2023 Pediatrics in Review is
approved for a total of 30
are due to a bite by the pet rat. The clinician suspects rat-bite fever as the
Maintenance of Certification
diagnosis. Which of the following pathogens is the most likely cause of the (MOC) Part 2 credits by the
right septic knee in this patient? American Board of Pediatrics
(ABP) through the AAP MOC
A. Group A beta-hemolytic Streptococcus.
Portfolio Program. Pediatrics in
B. Salmonella typhi. Review subscribers can claim up
C. Staphylococcus aureus. to 30 ABP MOC Part 2 points
D. Streptobacillus moniliformis. upon passing 30 quizzes (and
E. Streptococcus pneumoniae. claiming full credit for each
quiz) per year. Subscribers can
start claiming MOC credits as
early as November 2023. To learn
how to claim MOC points, go to:
https://publications.aap.org/
journals/pages/moc-credit.

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 4. The mother of a 15-month-old boy noted a “fullness” on the left side of the
abdomen while bathing him. The child has had normal growth and
development with no diarrhea or constipation and normal appetite. She is
worried about a malignancy and brings him to the clinic today for further
investigation. Among the following causes of intra-abdominal tumors, which
one is most likely to be the cause in a child of this patient’s age?
A. Hepatoblastoma.
B. Leukemia.
C. Lymphoma.
D. Rhabdomyosarcoma.
E. Wilms Tumor.
5. In a child who presents with an intra-abdominal mass and is diagnosed with
a yolk sac tumor, which of the following is the most accurate statement
about yolk sac tumors in children?
A. Elevated alpha-fetoprotein is a specific tumor marker.
B. Peak incidence is in children younger than 2 years of age.
C. Radiation therapy is the mainstay of treatment.
D. Survival of prepubertal is higher than postpubertal pediatric yolk sac
tumors of the same stage.
E. They are slow growing tumors.

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 INDEX OF SUSPICION

New-Onset Jaundice in an 11-month-old Boy

Sean E. Healton, MS,* Devon G. Lawrence, MD,† Noah J. Elkins, MD,† Leya Schwartz, MD,† Patricia A. Hametz, MD†
*Albert Einstein College of Medicine, Bronx, NY
†
The Children’s Hospital at Montefiore, Bronx, NY

PRESENTATION
A previously healthy 11-month-old boy presents to the emergency department
with new-onset jaundice. One day before admission the patient was picked up
from an extended stay with his grandparents. At that time, the parents noted yel-
lowing of the skin, fussiness, and abdominal pain relieved by 1 dose of acet-
aminophen (exact dose unknown). The patient is otherwise well, without
vomiting, diarrhea, change in color of stool or urine, fatigue, pruritus, changes
in activity, or decreased oral intake or urine output. He has no history of jaun-
dice during the neonatal period or infancy, no recent sick contacts or illnesses,
no recent travel, and according to his mother, no new known exposures. He
takes formula prepared with tap water and eats some table foods, such as soup.
The infant’s mother is unaware of any new introductions to his diet or different
water consumption while at his grandparents. The patient’s medical history,
birth history, and development are noncontributory. His immunizations are up
to date, and he has not yet received his hepatitis A vaccination. He lives at home
with his mother and father, who are originally from Ecuador but have lived in
the United States for the past 6 years. There is a family history of unspecified
liver disease in the patient’s father, maternal grandfather, and paternal aunt.
There is no known family history of splenectomy or early gallbladder diseases.
Physical examination reveals a well-appearing, well-developed infant in no
acute distress. Vital signs are within normal limits for his age. There is scleral
icterus and jaundice from head to abdomen, in addition to hepatomegaly. The
remainder of the examination findings are normal, without abdominal tenderness
or masses. Right upper quadrant ultrasonography demonstrates a borderline en-
larged, hyperechoic liver. Laboratory findings are significant for anemia (hemoglo-
bin level, 8.4 g/dL [84 g/L] [reference range, 11.3–12.5 g/dL (113–125 g/L)]) and
indirect hyperbilirubinemia (total bilirubin level, 9.7 mg/dL [165.91 mmol/L]
[reference range, <1.2 mg/dL (<20.52 mmol/L)]; direct bilirubin level, 0.3 mg/dL
[5.13 mmol/L] [reference range, <0.5 mg/dL (<8.55 mmol/L)]). Transaminase and
albumin levels are within normal limits.

DISCUSSION
AUTHOR DISCLOSURE: Drs Healton,
Differential Diagnosis Lawrence, Elkins, Schwartz, and Hametz
The differential diagnosis for jaundice, specifically secondary to indirect hyperbi- have disclosed no financial relationships
relevant to this article. This commentary
lirubinemia, includes etiologies related to increased production of bilirubin,
does not contain a discussion of an
reduced uptake by hepatocytes, and decreased conjugation; an appreciation of unapproved/investigative use of a
bilirubin metabolism (Fig 1) offers a systematic approach to the evaluation. commercial product/device.

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 RBCs
Increased production

Hemolytic anemias
Extrinsic - RBC destruction
1
- Immune mediated or microangiopathic
- Infection Bilirubin
- Toxins Reduced uptake
2
Heme - Reduced hepatic blood flow
Intrinsic - RBC fragility - Drugs
proteins
- Enzyme deficiencies
- RBC membrane defects
- Hemoglobinopathies
1 Production
Decreased conjugation Bilirubin
- Genetic disorders 3 2 Uptake
- Drugs Conjugated
bilirubin 3 Conjugation

Enterohepatic
recirculation
Conjugated
bilirubin

Unconjugated
bilirubin

Excretion
(urobilinogen,
sercobilinogen)

Figure 1. Overview of bilirubin metabolism. Critical steps where derangement results in indirect hyperbilirubinemia are numbered 1, 2, and 3; common
etiologies underlying each are highlighted in red. See the text and Table 1 for more details. RBC 5 red blood cell. Figure created using BioRender.com.

Overproduction of bilirubin is most commonly secondary to
hemolysis and release of heme, which is converted to biliru-
bin. The differential diagnosis for hemolytic anemia (Table 1)
includes autoimmune etiologies, hemoglobinopathies, heredi-
tary enzyme deficiencies, and erythrocyte membrane defects.
Uptake of bilirubin by hepatocytes can be impaired by reduc-
tion in hepatic blood flow (eg, cirrhosis, hepatic congestion
due to right-sided heart failure, Budd-Chiari syndrome) (1)
and certain drugs (rifampin, probenecid). (2) Decreased or
absent bilirubin conjugation occurs secondary to genetic
disorders that affect uridine diphosphoglucuronate glucur-
onosyltransferase activity, including Crigler-Najjar (types I
and II) and Gilbert syndromes, or certain drugs (some
viral protease inhibitors used in human immunodeficiency

Table 1. Overview of Common Etiologies of Hemolytic Anemia

CATEGORY EXAMPLES
Intrinsic to RBCs
Enzymatic defects G6PD deficiency
Glycolytic enzyme deficiencies: pyruvate kinase deficiency, phosphofructokinase deficiency, etc
RBC membrane defects Hereditary spherocytosis
Hereditary elliptocytosis
Hereditary pyropoikilocytosis
Hemoglobinopathies HgbSS, HgbSC, HgbSβ thalassemia
a- and β-thalassemias
Other Paroxysmal nocturnal hemoglobinuria (rare in children)
Extrinsic to RBCs
Microangiopathic hemolytic Hemolytic uremic syndrome, thrombotic thrombocytopenic purpura, ADAMTS13 deficiency
anemia Artificial heart valves
Disseminated intravascular coagulation; HELLP (hemolysis, elevated liver enzymes, low platelets) syndrome
Immune-mediated Autoimmune hemolytic anemia (eg, in systemic lupus erythematosus)
Delayed hemolytic transfusion reactions
Mycoplasma and Epstein-Barr virus (both due to cold agglutinin)
Infectious Sepsis, malaria, babesiosis
Systemic disease Liver disease, uremia, extensive burn injuries
Toxins and venoms Clostridia infections, snake bites, spider bites inducing spherolytic hemolysisa

G6PD 5 glucose-6-phosphate dehydrogenase, HgbSS/SC/Sβ 5 hemoglobin SS/SC/Sβ, RBC 5 red blood cell.
a
Mechanism not fully understood, thought to be complement-mediated.

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Figure 2. Peripheral blood smear. Light microscopy of peripheral blood
from the patient demonstrating bite cells (white arrows) and schistocytes
(red arrow).
virus treatment—indavinir and atazanavir; some chemothera-
peutic agents, tyrosine kinase inhibitors—erlotinib, nilotinib).
(3)(4) Physical examination findings are often nonspecific,
and, thus, laboratory findings guide diagnosis.
Diagnosis
Subsequent laboratory findings were consistent with a hemo-
lytic anemia (haptoglobin level, <10 mg/dL [<100 mg/L]
[reference range, 30–200 mg/dL (300–2,000 mg/L)]; reticu-
locyte count, 4.3% [reference range, 1.0%–3.1%]). The reticu-
locyte index was calculated to be 2.07 based on a normal
hematocrit level of 34% for an 11-month-old boy and a matu-
ration factor of 1.5, which is appropriate proliferation in the
setting of hemolysis. Hemoglobin electrophoresis results
were normal; evaluation for infectious etiologies, including
Epstein-Barr virus, was negative; and direct antiglobulin
(Coombs) test results were negative. Peripheral blood smear
demonstrated schistocytes and bite cells (Fig 2), consistent
with hemolytic anemia secondary to glucose-6-phosphate de-
hydrogenase (G6PD) deficiency. The G6PD screen was noted
to be deficient, which was confirmed by quantitative G6PD
testing (4.8 U/L [reference range, 7.0–20.5 U/L]), supporting
this diagnosis. On further questioning, the parents discovered
that the grandparents had fed the patient a new food before
G6P NADP
Glutathione
G6PD
D e
6-phosphogluconate NADPH
Figure 3. The role of glucose-6-phosphate dehydrogenase (G6PD) in intracellular nicotinamide adenine dinucleotide phosphate (NADPH) production.
G6PD is necessary to convert NADP to NADPH in red blood cells (RBCs), a key step in the pathway for reduction of oxidants; without G6PD, RBCs are sub-
jected to oxidative damage. NADPH is then required to convert glutathione disulfide (GSSG) to glutathione (GSH), which finally reduces oxidants to water
(H20) via glutathione peroxidase. H202 5 hydrogen peroxide.
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the onset of jaundice—habas, Spanish for fava beans, a popular
snack in Ecuador. Fava beans contain the compounds vicine
and convicine, which, when metabolized to divicine and iso-
uramil, cause significant oxidative stress to RBCs in G6PD
deficiency. Further genetic testing showed 2 hemizygous
G6PD mutations resulting in the G6PD A– variant.
The Condition
G6PD deficiency is the most common erythrocyte enzyme
disorder. (5) A link between the ingestion of fava beans
and disease (“favism”) was known in the time of Pythagoras,
but the modern origins of the discovery of G6PD deficiency
lie in the observation, made in the early 20th century, that
certain patients developed hemolytic anemia while being
treated for malaria. (6) The genetic basis of the disorder
was elucidated in the 1950s as an X-linked recessive disor-
der; most of those affected are male.
Nicotinamide adenine dinucleotide phosphate (NADPH)
is involved in multiple enzymatic reactions that mitigate the
physiologic oxidative burden in the red blood cell (RBC) and
is, therefore, crucial for protection from these free oxygen
radicals. NADPH formation occurs only via reduction of the
glucose-6-phosphate by G6PD, which is normally activated
by oxidative stress. The RBC is devoid of DNA, RNA, and
protein synthesis, and, therefore, the G6PD is consumed as
the lifespan of an RBC passes, thus making older erythro-
cytes particularly sensitive to oxidative stress in the setting of
reduced G6PD activity. Acute hemolysis can occur in pa-
tients with G6PD deficiency variants when oxidizing free
radicals are generated, such as after ingesting certain drugs,
eating fava beans, or during an acute infection, (7) and are
unopposed in the absence of NADPH formation (Fig 3).
Common causative agents are listed in Table 2. Infection
is the primary precipitant of hemolytic episodes in those
with an established diagnosis. Although common and long-
studied, the nonhematopoietic effects of G6PD deficiency
remain underexplored; a recent review suggests the possible
involvement of this enzyme deficiency in neurodegenerative
disorders. (8)
GSH Oxidants (H2O2)
e
e
Glutathione
reductase peroxidasee
GSSG H2O
 Table 2. Common Triggers to Avoid in Glucose-6-phosphate dehydrogenase Deficiency
CATEGORY
Antibiotics
Antimalarials
Analgesics
Other drugs
Foods
Chemicals
a
Agents that usually do not cause clinically significant hemolysis in A– variant.
Of note, diagnosis of G6PD deficiency during an acute
episode of hemolysis may rely on clinical suspicion alone.
Enzymatic activity of G6PD is higher in reticulocytes than
in mature erythrocytes. Therefore, during hemolysis—
when mature erythrocytes are hemolyzing and reticulo-
cytes are high—G6PD levels may be falsely normal. In situa-
tions with high clinical suspicion for G6PD deficiency and a
negative screen, it is recommended that testing is repeated
when hemolysis resolves. (5)
Treatment/Management
Treatment of G6PD deficiency relies primarily on avoid-
ance of triggering agents (Table 2) and management of he-
molytic episodes. Breastfeeding mothers of an infant with
G6PD deficiency should also avoid these triggers. There
are several variants, which differ in severity. The precipitated
anemia may be mild to severe depending on the precise mu-
tation involved. The notable forms of G6PD include the
G6PD Mediterranean variant (563C>T), which is associated
with severe hemolysis. This form is contrasted to the G6PD
A– variant (biallelic mutation: 202G>A and 376A>G) found
in the present patient, which is most often associated
with a mild to moderate degree of hemolysis. (6) The G6PD
A– variant tends to preferentially affect only mature eryth-
rocytes and results in a mild-moderate anemia. Acute
management for anemia in G6PD deficiency does not differ
significantly from anemia due to other etiologies. Aggressive
hydration and transfusion when indicated are the mainstays
of treatment. Despite several studies in the 1980s suggesting
improved outcomes with administration of vitamin E or sele-
nium, (9)(10) these treatments have not been incorporated
into standard practice.
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NAME
Dapsone
Trimethoprim-sulfamethoxazolea
Nitrofurantoin
Fluoroquinolones (ciprofloxacin, moxifloxacin, ofloxacin, norfloxacin)
Primaquine, pamaquine, chloroquine
Aspirina
Methylene blue
Dimercaprol
Probenecid
Rasburicase
Fava beans (also called broad beans)
Naphthalene (moth balls)
Henna dyes
Patient Course
The patient was admitted to the hospital and developed
worsening anemia during admission, with a nadir hemo-
globin level of 6.4 mg/dL (0.064 g/L) on hospital day 3.
Transfusion was not required, however, because he re-
mained clinically stable with steadily decreasing serum in-
direct bilirubin levels. Anemia improved on hospital day 4
to a hemoglobin level of 6.8 mg/dL (0.068 mg/L). Given
his stable and rising hemoglobin level, established diagno-
sis, and family education for avoidance of triggers, the pa-
tient was discharged with hematology-oncology follow-up.
Lessons for the Clinician
• Indirect hyperbilirubinemia and anemia in an infant or
neonate should prompt evaluation for hemolytic anemia.
• Glucose-6-phosphate dehydrogenase (G6PD) deficiency
should be suspected in a child with hemolytic anemia
and possible new food exposures. There is a higher preva-
lence in males, those with a positive family history, and
those from particular geographic areas correlated with pre-
vious endemic malaria (Africa, the Mediterranean region,
the Middle East, and southern Asia).
• Currently, newborn screening for G6PD deficiency occurs
only in Washington, DC, and Pennsylvania. (See the Baby’s
First Test website [https://www.babysfirsttest.org/] for a full
state-by-state list of conditions on newborn screens.)
• Screening for G6PD during acute episodes may be falsely
negative. A high index of suspicion should prompt repeated
screening after resolution of hemolysis.
References for this article can be found at
https://doi.org/10.1542/pir.2021-005158.
Vol. 44 No. 12 D E C E M B E R 2 0 2 3 709
 INDEX OF SUSPICION

Early Satiety and Nausea in a 12-year-old Girl

Alexandra S. Hudson, MD, FRCPC,* Amira Balbaa, MD,† Bryan J. Dicken, MSc, MD, FRCSC, FAAP,‡
Matthew Carroll, BMed (Hons), MHSc (Clin Epi), FRACP*
*Division of Pediatric Gastroenterology and Nutrition, Department of Pediatrics; †Department of Pediatrics; and ‡Division of Pediatric Surgery, Department
of Surgery, University of Alberta, Edmonton, Alberta, Canada

PRESENTATION
A 12-year-old girl with a history of attention-deficit/hyperactivity disorder pre-
sents to the emergency department with persistent nausea, fatigue, and mild
bloating. She has rare nonbloody and nonbilious vomiting, which consists of re-
cently ingested food. She has no dietary restrictions. She is experiencing early
satiety and has had an 18-lb (8.2-kg) weight loss (from 78.9 lb [35.8 kg] [16th per-
centile] to 60.9 lb [27.6 kg] [0.24 percentile]) during the past 3 months. This cor-
responded to a drop in BMI from 14 (0.96 percentile) to 12 (<0.01 percentile).
She has no diarrhea, hematochezia, or melena. Two weeks earlier she was
started on a proton pump inhibitor (PPI). With no symptom change after a
week, she discontinued its use 1 week before presentation. There is no family
history of inflammatory bowel disease or other gastrointestinal disorders. Recent
outpatient blood work shows a normal complete blood cell count with differential
count, electrolytes, thyrotropin, creatinine, urea, albumin, and urinalysis. Magnetic
resonance imaging performed to rule out increased intracranial pressure as an etiology
of her persistent nighttime and early-morning nausea was normal.
She is admitted to the hospital to establish the etiology of her significant
weight loss, in addition to monitoring her for refeeding syndrome when enteral
nutrition is initiated. A full physical examination is normal aside from a thin
body habitus. Baseline blood work, including a celiac screen, complete blood cell
count with differential count, electrolytes, calcium, magnesium, phosphate, lipase,
albumin, liver enzymes, and C-reactive protein, is unremarkable. An upper gastro-
intestinal contrast study finds a distended gastric bubble but no obstructive lesion,
with contrast freely flowing into the duodenum (Fig 1). Pediatric gastroenterology is
consulted. Upper endoscopy reveals a dilated stomach, residual gastric contents,
and a significantly narrowed pylorus of unclear etiology (Fig 2). There is no stom-
ach nodularity. General surgery is consulted intraprocedure and decides to take her
for a pyloroplasty the following day.

DISCUSSION
Differential Diagnosis
AUTHOR DISCLOSURE: Drs Hudson,
Gastric outlet obstruction of any etiology can occur in up to 5 per 1,000 pediatric Balbaa, Dicken, and Carroll have disclosed
patients. (1) Hypertrophic pyloric stenosis, most often affecting infants aged 2 to no financial relationships relevant to this
article. This commentary does not
12 weeks, is the most common of all pediatric etiologies. Other, rarer anatomic
contain a discussion of an unapproved/
causes, such as gastric webs, malrotation, polyps, or pyloric duplication cysts, investigative use of a commercial
should also be considered. External compression from a malignancy is an product/device.

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 Figure 1. Upper gastrointestinal contrast study showing a dilated stomach with contrast movement into the intestine.
important diagnosis to rule out, particularly with rapidly
progressive symptoms, which may parallel a rapidly grow-
ing mass (eg, Burkitt lymphoma). Foreign body ingestions
and bezoars can present at any age. Trichotillomania lead-
ing to a hair bezoar should be considered in older children
and teenagers. Caustic ingestions can also lead to scarring
and obstruction. Stricturing Crohn disease may be present
at initial inflammatory bowel disease diagnosis.
Gastroparesis is an important consideration in any pediat-
ric patient presenting with early satiety, nausea, and reduced
oral intake leading to weight loss. (2) Recurrent vomiting is
the most common symptom. Its diagnosis requires the ex-
clusion of a mechanical outlet obstruction. The gold standard
for diagnosis is a gastric emptying study using a solid-phase
meal. Up to three-quarters of pediatric cases are idiopathic,
with the next most common causes being medication-
related, postsurgical, and diabetic. This diagnosis was cer-
tainly a consideration in our patient; however, she very rarely
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had vomiting and was ultimately found to have a mechanical
outlet obstruction instead.
Diagnosis
Intraoperatively, the pylorus is noted to be scarred and has
a thick fibrotic band coursing over it. There is a small lu-
minal ulcer, identifying peptic ulcer disease (PUD) as the
etiology of her partial gastric outlet obstruction. Endoscopic
culture is negative for Helicobacter (Helicobacter pylori).
Pathology identifies chronic gastric inflammation with acute
patchy duodenal inflammation. There are no granulomas
that suggest Crohn disease.
The Condition and Treatment
PUD is rarer in pediatric patients than in adults; however,
it remains a clinically significant disease with potential for
serious complications. It occurs when inflammation dam-
ages the gastric or duodenal mucosa down to its third
Vol. 44 No. 12 D E C E M B E R 2 0 2 3 711

Figure 2. Endoscopic image showing narrowing, friability, and bleeding
at the pyloric opening (solid arrow). White patches (dashed arrow) are re-
sidual contrast from the upper gastrointestinal contrast study completed
2 days earlier and are visible throughout the stomach.
layer (muscularis mucosa). In a review of several interna-
tional studies of children undergoing endoscopy for any
reason, the incidence of PUD has been found to be 2% to
8%. (3) Risk factors include persistent gastroesophageal re-
flux disease, nonsteroidal anti-inflammatory drug (NSAID)
use, corticosteroid use, H pylori infection, immunosuppres-
sion, and severe illness. The most common presenting
symptom in the pediatric patient is abdominal pain, partic-
ularly postprandial epigastric pain. Our patient did not pre-
sent with this classic symptom and instead presented with
symptoms secondary to PUD complications. In her case,
the inflammation had led to obstruction, which explained
her main presenting symptoms of nausea and early satiety.
Gastric outlet obstruction results in incomplete gastric emp-
tying. Residual food and liquid leads to gastric distention,
which can trigger nausea. Other potential complications of
PUD that can be the primary presenting symptom or sign
include gastrointestinal bleeding, hemodynamic instability
secondary to gastric or intestinal perforation, and anemia.
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Treatment includes treating the underlying etiology if appli-
cable (eg, stopping NSAIDs, treating an H pylori infection)
and using a PPI for a minimum of 4 to 8 weeks continu-
ously for acid suppression.
Patient Course
Given the significant peptic stricture that had developed,
our patient needed surgical correction instead of sole medi-
cal management. After the surgery, our patient feels imme-
diate symptomatic relief of her nausea and bloating. She
progresses to a full diet with no issues and is discharged
from the hospital 1 week later. She is kept on a PPI contin-
uously for an 8-week course and fully recovers. Ultimately,
her diagnosis is classified as idiopathic PUD because no
cause (eg, infection, medication, endocrine disorder, inflam-
matory bowel disease, corrosive ingestion, stress [3]) was
identified.
Lessons for the Clinician
• In a patient with nausea and weight loss, the absence of
vomiting does not preclude gastric outlet obstruction.
• Peptic ulcer disease may not present with classic upper
abdominal pain and may instead present with symptoms
secondary to ulcer complications.
• Upper gastrointestinal contrast studies may not always
identify a partial gastric outlet obstruction; further inves-
tigations such as upper endoscopy should be sought if
the clinical suspicion remains high.
Consent
Informed consent was obtained from the patient and the
patient’s family for publication of this case.
References for this article can be found at
https://doi.org/10.1542/pir.2021-005495.
 INDEX OF SUSPICION

Intermittent Fussiness in a Well-Appearing

5-week-old Girl
Elizabeth Wikle, MD,*‡ Amani Sanchez, DO,*†‡ Arianna Nassiri, MD,*†‡ Francis Onyebuchi, MD*‡
*Department of Pediatrics and †Department of Pediatric Emergency Medicine, Dell Children’s Medical Center, Austin, TX
‡
University of Texas at Austin-Dell Medical School, Austin, TX

PRESENTATION
A 5-week-old term infant with a normal perinatal course and born via an uncompli-
cated vaginal delivery to a gravida 2 para 1 mother with good prenatal care presents
to the emergency department with 3 days of fussiness. Mother reports that the in-
fant has had intermittent episodes of crying as if she is in pain and that nothing
consoles her. The crying episodes last up to an hour and are associated with breath-
holding and facial redness. She has not had fever, emesis, or hematochezia. The in-
fant is tolerating direct breastfeeding well, with appropriate urine output and nor-
mal stool frequency and consistency. Mother was supplementing with formula but
stopped a day before admission.
In the emergency department, her temperature is 97.6 F (36.4 C), with a
heart rate of 134 beats/min, a respiratory rate of 40 breaths/min, and oxygen sat-
uration of 98% on room air. She weighs 3.63 kg and demonstrates adequate
weight gain from birth. Examination is significant for intermittent crying and
fussiness; otherwise, the infant is in no acute distress. She has a flat and open
anterior fontanelle. Her eyes, ears, and nose are normal. Oral examination dem-
onstrates normal suck without ulcer or abrasion but with a small erythematous
macule on her hard palate. Her cardiopulmonary examination findings are nor-
mal. Her abdomen is soft, nontender, and without organomegaly or masses.
She has no gross deformities or bony tenderness of limbs, rash, visible bruising,
or joint swelling. She has full passive range of motion of upper and lower
extremities. Her capillary refill is less than 2 seconds, and she appears well
hydrated. No hair tourniquet is present. Her neurologic examination findings are
normal.
Initial laboratory findings demonstrate a normal complete blood cell
Dr Wikle’s current affiliation is the
count and a normal complete metabolic panel aside from an elevated total bili- general pediatrics department, University
rubin level of 2.6 mg/dL (44.5 mmol/L) (reference range, 0.05–0.68 mg/dL of Iowa, Iowa City, IA. Dr Nassiri’s current
affiliation is Department of Pediatric
[0.86–11.63 mmol/L]). Total bilirubin level on day of life 3 was 9.8 mg/dL
Emergency Medicine, Children’s Hospital
(167.6 mmol/L). Urinalysis results are within normal limits, including the ab- of New Orleans, New Orleans, LA.
sence of red and white blood cells. A flat and upright abdominal radiograph
AUTHOR DISCLOSURE: Drs Wikle,
demonstrates a normal gas pattern without free air or bowel dilation. No ileocolic Sanchez, Nassiri, and Onyebuchi have
intussusception is identified on focused ultrasonography, but it does demonstrate disclosed no financial relationships
a small volume of complex free fluid in the lower pelvis. The patient is admitted relevant to this article. This commentary
does not contain a discussion of an
to the hospital for observation, serial abdominal examinations, and continued unapproved/investigative use of a
evaluation. commercial product/device.

Vol. 44 No. 12 D E C E M B E R 2 0 2 3 713

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 DISCUSSION
Differential Diagnosis
The differential diagnosis for a fussy infant is broad and
encompasses many etiologies, including sepsis, meningitis,
gastroesophageal reflux disease, anatomic gastrointestinal
etiologies such as intussusception or malrotation, heart fail-
ure or arrhythmia, hair tourniquet, corneal abrasion, nonac-
cidental trauma, and colic. Although sepsis and colic seem
to be more prevalent conditions in this age group, the rest
are less commonly seen. Absence of history of arching move-
ments and emesis makes gastroesophageal reflux disease less
likely. Intussusception is most common between 3 and
9 months of age but can occur in younger infants. Our
patient’s examination findings are grossly normal, making
hair tourniquet less likely. Although corneal abrasion is on
the differential diagnosis, a fluorescein test is not com-
pleted. The erythematous papule on the hard palate raises
concern for nonaccidental trauma, herpes simplex virus, or
trauma (burn from a hot bottle). This finding is subtle and
quickly resolves. In addition, the laboratory assessment did
not demonstrate electrolyte abnormalities or other abnor-
malities such as leukocytosis or leukopenia that could be
concerning for infection. Although colic is a diagnosis of
exclusion, our initial investigation demonstrates complex
free fluid in the lower pelvis, which prompts further evalua-
tion. Further imaging reveals the diagnosis.
Actual Diagnosis
Complete abdominal ultrasonography reveals a 6.5-cm cys-
tic lesion with debris in the right lower quadrant with a
nonvisualized right ovary (Fig). Pediatric general surgery
is consulted to review the ultrasonographic image and pro-
vide recommendations regarding management. The infant
undergoes a diagnostic laparoscopy that day. Intraopera-
tively, a necrotic chocolate cyst is seen in the right upper
quadrant that is avulsed from the adnexa and twisted in
the omentum. The uterus and left ovary appear healthy.
She is diagnosed as having a hemorrhagic ovarian cyst
and right ovarian torsion with autoamputation of the right
adnexa.
The Condition
Ovarian torsion occurs when the adnexa rotates about its
ligamentous support, which results in occlusion of blood
flow to the ovary and can lead to edema, enlargement, and
eventual tissue necrosis. This also can lead to adnexal
avulsion, as seen in our patient. Ovarian torsion is rare in
the pediatric population, with an incidence of 0.5 to 2 per
10,000 patients. (1) Of the few studies of pediatric ovarian
714 Pediatrics in Review
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Figure. Long axis cross section of 6.6 × 4.1 × 4.6-cm complex cystic lesion
in the right lower quadrant extending into the subhepatic region. The
hypoechoic cystic fluid is contrasted with hyperechoic debris settling at the
base. Markers indicate measurement of the width of the cystic structure.
torsion, even fewer include patients younger than 1 year.
One such study demonstrated that the incidence of ovarian
torsion in pediatric patients is bimodal, with increases in in-
fancy (16%) and early adolescence (9–14 years of age; 52%).
(2)(3)
Risk of torsion increases with ovarian cysts, tumors,
and pregnancy. As the size of the ovary increases due to a
mass, the risk of torsion increases; the risk is highest
when the mass becomes 5 cm or greater in a pediatric pa-
tient. (1) The right ovary is more likely to torse compared
with the left, possibly due to the longer utero-ovarian liga-
ment and/or the presence of the colon on the left side of the
abdomen, which may help prevent ovarian torsion. (4) In
utero exogenous estrogen exposure is thought to be the etiol-
ogy of cystic lesions noted prenatally or in infancy, which
predisposes fetuses and neonates to ovarian torsion. Some
incidences of infantile ovarian torsion do not have evidence
of enlarged ovaries or cysts. The proposed mechanism of tor-
sion in these cases is congenitally elongated utero-ovarian
ligaments compared with the size of a premenarchal uterus,
prompting a higher risk for adnexal movement.
Abdominal pain is the only consistent symptom of
ovarian torsion in all pediatric age ranges and can often be
similar to acute appendicitis in the older child. (1) Other
findings in infants often also include the palpation of a
mass, feeding intolerance, and intermittent fussiness. The
most common factor in infantile ovarian torsion is prenatal
imaging demonstrating an enlarged ovary, predisposing the
infant to torsion. (2) Most symptoms are nonspecific and
lead to further evaluation for more common conditions
based on the patient’s age. In younger children, the differ-
ential diagnosis usually includes urinary tract infections,
intussusception, and nonaccidental trauma. In all patients,
nephrolithiasis, appendicitis, and mesenteric adenitis should
be considered. (3)
 Imaging is the cornerstone of evaluation for ovarian
torsion. The most common ultrasonography finding is an
enlarged heterogeneous mass with an inability to identify
the ipsilateral ovary, as seen in our patient. Doppler ultra-
sonography has a high false-negative rate and should not
exclude the diagnosis of ovarian torsion if the clinical sus-
picion is high. One study demonstrated flow in 62% of
torsed ovaries. (3) Doppler flow may be appreciated in a
torsed ovary without complete cessation of blood flow be-
cause the ovary has a dual blood supply from collateral
vessels (eg, utero-ovarian vessels, infundibulopelvic vessels).
More recently, assessments that evaluate laboratory value
ratios, such as lymphocyte-to–C-reactive protein ratio, have
been explored to assist in diagnosis, but they have not been
found useful in patients younger than 1 year. (5) The gold
standard for the diagnosis of ovarian torsion is intraopera-
tive visualization of a torsed ovary.
Note that this patient was evaluated in the emergency
department of a major regional children’s hospital. This
setting provides quick and easy access to diagnostic testing,
which may prompt further evaluation of the crying infant,
specifically laboratory assessment and imaging as described
previously herein. In this patient’s case, examination of the
infant did demonstrate clear periods of calmness within
episodes of inconsolable crying, which prompted further
evaluation rather than a more conservative approach.
Management
Preferred management is ovarian detorsion rather than
oophorectomy due to evidence of ovarian viability after de-
torsion. (6) Detorsion is often performed to assess viability
because ovarian necrosis is rare and is evident when the
ovary “falls apart” when manipulated. (7) In 1 large study,
younger patient age was associated with oophorectomy.
(8) One would suspect that infrequency of premenarchal
ovarian torsion would lead to delay in diagnosis, increased
tissue death, and increased need for oophorectomies in
younger patients. Unlike testicular torsion, which has a com-
monly understood window of tissue viability of 6 to 8 hours
after symptom initiation, ovarian necrosis does not have an
obvious correlation to duration of symptoms. (9) Pain may
originate from venous congestion before arterial compromise
and can be very severe. (10) Adequate pain management is
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important, but detorsion is the ultimate modality for pain
resolution. This further highlights the importance of keeping
ovarian torsion on the differential diagnosis for premenar-
chal children and infants with fussiness or abdominal pain
and potential use of diagnostic laparotomy in highly suspi-
cious clinical scenarios.
Patient Course
An oophorectomy is performed and the infant does well
postoperatively, with complete resolution of intermittent
crying episodes. Postoperatively, the infant’s pain is man-
aged with scheduled acetaminophen. She tolerates human
milk and has a bowel movement before discharge. The in-
fant is discharged on postoperative day 1 with instructions
to follow up with pediatric general surgery 2 weeks after
discharge. Two days after discharge, the infant presents
back to the emergency department with inconsolable fussi-
ness and decreased oral intake. A serious bacterial infec-
tion, potentially related to her recent surgery, is suspected,
and a full evaluation for sepsis is performed, which is unre-
markable. Of note, her laboratory assessment demonstrates
an improved total bilirubin level, which is now 0.8 mg/dL
(13.7 mmol/L). A normal left ovary and corresponding vessels
with no evidence of intussusception are seen on ultraso-
nography. The infant is admitted for observation. In the
morning, the fussiness resolves, she is drinking well, and
she is discharged home.
Lessons for the Clinician
• If an infant presents with increased fussiness and has
normal examination findings, intra-abdominal and pelvic
pathology should still be ruled out.
• Consider early surgical consultation if acute intra-
abdominal pathology is suspected.
• Ultrasonography is a cost-efficient, safe, and quick way
to assess intra-abdominal and pelvic pathology, but one
should not rule out ovarian torsion if Doppler findings
are normal and there is high clinical suspicion for ovarian
torsion.
References for this article can be found at
https://doi.org/10.1542/pir.2022-005671.
Vol. 44 No. 12 D E C E M B E R 2 0 2 3 715
 INDEX OF SUSPICION

Fatigue, Weight Loss, and Acute Chest Pain in a

15-year-old Boy
Madeline F.E. Parr, MD,* Katharine N. Clouser, MD, FAAP,* Meghan Tozzi, MD, FAAP,* Sejal M. Bhavsar, MD, FAAP*
*Joseph M. Sanzari Children’s Hospital, Hackensack, NJ

PRESENTATION
A 15-year-old boy with a history of membranous ventricular septal defect (VSD),
not surgically repaired, presents to the emergency department (ED) with a 1-month
history of fatigue, 5-lb (2.3-kg) weight loss, and productive cough, along with 3 days
of right-sided chest pain. The patient went to his pediatrician approximately a
month earlier due to cough, fatigue, and decreased activity and was presumed to
have Mycoplasma pneumoniae and was treated empirically with azithromycin. His
cough improved mildly, but he continued to have low energy. Two weeks before
presentation, he developed night sweats without documented fever. Three days be-
fore presentation, the patient went to a gun range and was struck on his right
chest by his rifle recoiling while he was shooting. After this event, he had constant
chest pain and was taken to an orthopedic surgeon, where a chest radiograph was
performed that, per verbal report, did not reveal evidence of fracture, and the
patient’s mother was not informed of any cardiopulmonary findings. His chest
pain worsened with deep inspiration and he began having shortness of breath,
which prompted his mother to bring him to the ED.
The patient denies any history of substance abuse or sexual activity, and he
lives with his mother, father, and siblings. The family has had their home cleaned
for the past 8 years by a housekeeper who had emigrated from El Salvador and
developed an undiagnosed chronic cough 4 months ago. Travel history includes a
trip to Florida 6 months ago, and he has traveled to Israel multiple times, with
his most recent trip 3 years before presentation. He had COVID-19 pneumonia
3 months before presentation and did not require hospitalization. He received
2 doses of the Pfizer-BioNTech COVID-19 vaccine 3 weeks apart, with his second
dose 2 months before presentation.
In the ED he appears fatigued but is afebrile and normotensive with normal
heart and respiratory rates and is saturating at 98% on room air. He has mild
right-sided chest wall tenderness overlying the T-4 level in the axillary line. He
has decreased air entry to his bilateral lung bases, but no adventitious sounds
are auscultated. He has a IV/VI harsh holosystolic murmur at Erb’s point and is
warm and well perfused, with peripheral pulses 21 in all extremities. On oral
AUTHOR DISCLOSURE: Drs Parr, Clouser,
examination he has braces on his upper and lower teeth and no evidence of car- Tozzi, and Bhavsar have disclosed no
ies or gingival inflammation. No lymphadenopathy, rash, abdominal tenderness, financial relationships relevant to this
or organomegaly are appreciated. No evidence of cutaneous septic or vascular article. This commentary does not
contain a discussion of an unapproved/
phenomena, such as Osler nodes, Janeway lesions, or nail bed hemorrhages, are investigative use of a commercial
appreciated. product/device.

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 Laboratory results are significant for a white blood cell count
of 9,900/mL (9.9 × 109/L [reference range, 4,500–13,000/mL
(4.5–13.0 × 109/L)]) with a differential count of 73% neutro-
phils (reference range, 40%–62%), 15% lymphocytes (refer-
ence range, 27%–40%), 10% monocytes (reference range,
2%–8%); C-reactive protein level, 12.3 mg/dL (123 mg/L
[reference range, <0.5 mg/dL (<5 mg/L)]); erythrocyte sedi-
mentation rate, 99 mm/h (reference range, 0–15 mm/h);
and hemoglobin level, 11.3 g/dL (113 g/L [reference range,
13.0–16.0 g/dL (130–160 g/L)]), with a mean corpuscular
volume of 79.1 fL (reference range, 78–98 fL). A complete
metabolic panel demonstrates normal serum levels of elec-
trolytes and transaminases. His COVID-19 polymerase chain Figure 1. Apical computed tomographic view of the chest with consolida-
tions in the left lower lung lobe and in the right middle lung lobe demon-
reaction, respiratory pathogen panel, rheumatoid factor, and strating central necrosis (red arrows).
antineutrophil cytoplasmic antibody panel are negative. His
electrocardiogram demonstrates sinus arrhythmia with nor-
(TTE) revealed a small, semimembranous VSD with minimal
mal axis and intervals and normal voltages and repolariza-
mitral regurgitation and no evidence of pedunculated vegeta-
tion. Two large-volume blood cultures at different peripheral
tions. A transesophageal echocardiogram (TEE) was recom-
sites are collected.
mended to evaluate for small sessile lesions, but the family
declined due to the more invasive nature of the study. After
DIFFERENTIAL DIAGNOSIS
72 hours of incubation, both initial blood cultures grew Strep-
The diagnostic possibilities included diverse infectious tococcus mutans, which is sensitive to ceftriaxone, penicillin G,
etiologies due to the patient’s history and risk factors, and vancomycin. All blood cultures obtained after starting cef-
including international and domestic travel, subacute triaxone treatment were negative. The patient was diagnosed
fatigue, weight loss, night sweats, and acute chest pain. as having S mutans endocarditis due to his positive blood cul-
Differential diagnoses at the time of admission included tures, historical cardiac defect, and evidence of septic emboli
pulmonary contusion, pneumothorax, pulmonary tuber- on chest imaging. He was treated with 6 weeks of ceftriaxone
culosis, multifocal pneumonia, sarcoidosis, endocardi- therapy. At his 4-week outpatient follow-up appointment, he
tis, distal infection with pulmonary septic emboli, and continued to be afebrile and reported no complaints of chest
sequelae from COVID-19 infection. A chest radiograph pain, cough, or fatigue. Repeated chest radiography showed
demonstrated right middle lobe parenchymal infiltrate interval improvement of bilateral opacities.
associated with right pleural effusion and possible left
lower lobe pneumonia versus parenchymal contusion. A
computed tomographic scan of the chest with contrast
revealed multifocal consolidations most significant in
the right middle lobe and left lower lobe. The consolida-
tion in the left lower lobe demonstrated central necrosis,
raising the suspicion for necrotizing pneumonia, pulmo-
nary tuberculosis, lung abscesses, and septic emboli (Figs 1
and 2). Thoracic adenopathy was appreciated, and this con-
stellation of findings suggested an infectious etiology rather
than trauma.
The patient was started on ceftriaxone and placed on air-
borne isolation precautions due to concern for pulmonary
tuberculosis. Early-morning sputum samples were collected
for acid-fast bacilli smear and culture, and 3 consecutive
morning samples had negative acid-fast bacilli smears.
Interferon-g release assay was negative, and the purified pro- Figure 2. Apical computed tomographic view of the chest with a consoli-
tein derivative was 0 mm. A transthoracic echocardiogram dation in the right middle lung lobe (red arrow). Motion artifact is present.

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 DISCUSSION
Infective endocarditis (IE) is a rare diagnosis among pediatric
patients in the United States, with an estimated incidence of
0.43 cases per 100,000 children compared with 15 cases per
100,000 adults. (1) Underlying cardiac malformations con-
tribute significantly to the risk of IE, as approximately 53%
of diagnosed cases are in children with congenital heart de-
fects. (1) Disruptions in cardiac architecture from malfor-
mations such as atrial septal defects or VSDs create areas
of increased flow in the heart chambers, which can damage
the endocardium and increase the risk of platelet thrombus
formation. (2) Platelet thrombi can subsequently be seeded
in a state of transient bacteremia, leading to infectious
thrombus formation. Due to bacteria hidden deep within a
platelet thrombus, the treatment of IE typically requires 4 to
8 weeks of antibiotics to eradicate an infection. (2)
Diagnosis of IE is based on the modified Duke criteria,
which has been adapted from the original Duke criteria.
IE is categorized as definite, possible, or rejected based on
pathologic, major, and minor clinical criteria. Definite di-
agnosis requires all subcriteria to be met within these cate-
gories, and possible diagnosis requires 2 major criteria,
1 major and 2 minor criteria, or 3 minor criteria. (3) The
pathologic criteria are histologic confirmation of a cardiac
or embolized vegetation or a cardiac lesion such as an ab-
scess. Major criteria include evidence of endocardial in-
volvement on imaging or a positive blood culture of an
organism with a propensity for IE. Minor criteria are fever,
predisposing cardiac lesion or drug use, immunologic
phenomena, vascular phenomena such as septic emboli,
or microbiological evidence of infection. Our patient’s di-
agnosis of endocarditis was categorized as “possible” and
relied on 3 minor criteria: his history of VSD, positive
blood cultures, and the presence of multifocal pulmonary
lesions that were attributed to septic emboli. Pulmonary
septic emboli typically result from the showering of small
bacterial thrombi from a central cardiac infectious thrombus.
A TEE was recommended to confirm the diagnosis and to
evaluate for sessile vegetations, but the family declined the
more invasive test.
TEE demonstrates a significantly superior ability to
diagnose endocarditis, with sensitivity of 94% compared
with 24% with TTE among adults. (4) Many families
can be hesitant to pursue TEE, but clinicians should
consider strong recommendations of TEE in the setting
of IE that may warrant additional intervention. Indications
for considering surgical intervention include electrocardio-
graphic conduction changes that would suggest abscess,
significant change in valvular flow, children with prosthetic
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valves, or abnormalities of the thoracic cage or chest wall
that make TTE less accurate. (2) Blood cultures are also
highly important in the evaluation of IE, and 3 large-volume
peripheral blood cultures drawn at different sites and under
aseptic technique are preferred. Smaller volumes can
be appropriate for smaller patients, such as 1 to 3 mL in
infants or 5 to 7 mL in young children. (2)
IE can arise from a variety of infectious organisms.
Staphylococcal IE continues to be the most frequently di-
agnosed subtype, but the incidence of streptococcal IE is
increasing. (1) Among streptococcal infections, the viri-
dans group of streptococci is most frequently identified.
S mutans is a rare cause of endocarditis, primarily giving a
subacute clinical picture, and can have significant morbidity
and mortality. (5) S mutans is a bacterial species that is most
frequently isolated in the oral cavity and can form biofilms
that increase virulence. (6) Dental caries and poor oral hy-
giene contribute to the formation of Streptococcus-containing
biofilms, which can predispose the host to transient bacter-
emia, as can routine dental brushing and flossing. (7) It is
proposed that transient bacteremia, in conjunction with en-
docardial malformations seen in congenital heart defects,
provides an environment for bacterial colonization, which
can precipitate the development of subacute IE. (2) In a
4-year-old patient with S mutans IE, poor oral hygiene
was determined to be the source of her bacteremia. (8)
Although our patient had appropriate oral hygiene, he
did have frequent orthodontic appointments for the manage-
ment of braces, and it is possible that gingival manipulation
during procedures or with daily oral care may have been the
source of his bacteremia. In addition, before presentation,
our patient was treated with a 5-day course of azithromycin,
which likely partially treated the infection, accounting for his
initial improvement of overall symptoms. Current guidelines
do not recommend antibacterial prophylaxis against endocar-
ditis for children with a VSD undergoing routine orthodontic
care, as in our patient. (2) However, prophylaxis should be
considered in high-risk children, such as those with cardiac
transplants, previous cases of IE, cyanotic heart disease, or
prosthetic valves.
Lessons for the Clinician
• Infective endocarditis (IE) is a rare but vital differential diag-
nosis in pediatric patients presenting with subacute illness.
Risk factors such as congenital heart malformation or poor
oral hygiene should raise a clinician’s suspicion for IE.
• The modified Duke criteria are favored in diagnosing IE
in children. Transesophageal echocardiography should
be performed when transthoracic echocardiography is
 inadequate and when additional findings, such as an ab-
scess, would change patient management.
• Staphylococcal species are most frequently implicated in
IE, although streptococcal infections are on the rise.
• Peripheral blood cultures should be collected whenever
IE is suspected, and 3 large-volume cultures at different
sites and under aseptic technique should be collected at
initial presentation. Blood cultures should be repeated
within 24 to 48 hours of starting therapy.
References for this article can be found at
https://doi.org/10.1542/pir.2022-005552.

ANSWER KEY FOR DECEMBER PEDIATRICS IN REVIEW

Athlete Screening and Sudden Cardiac Death: 1. A; 2. B; 3. D; 4. C; 5. D.
Ensuring Emergency Readiness in the Pediatric Primary Care Setting: An Updated Guideline: 1. D; 2. C; 3. C; 4. E; 5. E.
Fever: Three Patient Cases: 1. C; 2. B; 3. D; 4. E; 5. D.

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 IN BRIEF

Pneumocystis Pneumonia
Asif Noor, MD,* Leonard R. Krilov, MD*
*Division of Pediatric Infectious Diseases, Department of Pediatrics, NYU Long Island School of Medicine, Mineola, NY

Pneumocystis is an opportunistic pathogen that causes lower respiratory tract infection.

Over time, the terminology has changed from Pneumocystis carinii to Pneumocystis
jirovecii, and its placement in taxonomy has shifted from protozoa to fungi. During
the past 50 years, it has become an important cause of pneumonia in people with a
weakened immune system from the effects of human immunodeficiency virus
(HIV) or other immunosuppressive states. Pneumocystis pneumonia (PCP) remains
an important clinical entity as the number of children with altered immune sys-
tems, receiving chronic immunosuppressive therapy, or receiving bone marrow and
organ transplants is rapidly increasing.
Modern molecular mapping has established that the DNA sequence of
Pneumocystis differs markedly based on the host species. The former name, P carinii,
is now reserved for the Pneumocystis species that causes lung infection in rats.
Pneumocystis affecting human lungs is P jirovecii (pronounced “yee row vet zee”)
based on the nucleotide sequence of the organism. This new name is in honor of
the Czech parasitologist Otto Jerovic who first described this pathogen in humans.
P carinii can still be acceptable terminology, but only with the annotation forma
specialis or f. sp. to identify the host of origin: the organism infecting humans is
named as P carinii f. sp. homini. The term PCP is still used to refer to the clinical
syndrome Pneumocystis pneumonia.
Pneumocystis was reclassified as a fungus in 1988 based on molecular studies
of the organism demonstrating the presence of chitin and 1,3-ß-D-glucan, although AUTHOR DISCLOSURE: Drs Noor and
Krilov have not disclosed any financial
the organism also has protozoan features, including the presence of different relationships relevant to this article. This
stages: cysts, sporozoites, and trophozoite forms. commentary does not contain a discussion
Transmission is through the airborne route from human to human. Although of an unapproved/investigative use of a
commercial product/device.
the pathogen is found in the lungs of several animals other than humans (eg,
rats and mice), interspecies transmission has not been demonstrated. People A New Name (Pneumocystis jiroveci) for
with normal immune systems carry asymptomatic infection (colonization) and Pneumocystis from Humans. Stringer JR,
serve as a pool for transmission. Most healthy children acquire infection by Beard CB, Miller RF, Wakefield AE, et al.
Emerg Infect Dis. 2002;8(9):891–896
2 years of age: in a prospective cohort study in Chile, 85% of healthy infants had
seroconverted by 20 months of age. Although a few cases have been reported in Primary Infection by Pneumocystis carinii
immunocompetent infants, symptomatic disease occurs almost exclusively in in a Cohort of Normal, Healthy Infants.
immunocompromised children. Vargas SL, Hughes WT, Santolaya ME, et al.
Clin Infect Dis. 2001;32(6):855–861
The severity of infection depends on the degree of immunosuppression, with
the single most important factor being the compromise of cell-mediated immu- Pneumocystis jirovecii Infections. In: Red
nity. The risk of PCP in children with HIV depends on their CD4 count, which Book: 2018–2021 Report of the Committee
normally is highest at birth and falls through childhood. Infants younger than on Infectious Diseases. 31st ed. Kimberlin
DW, Brady MT, Jackson MA, Long SS, eds.
12 months are at risk with a CD4 count less than 1,500/mL; children 1 to 5 years Itasca, IL: American Academy of Pediatrics;
of age at less than 500/mL; and, similar to adults, less than 200/mL in children 2021:651–656

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 6 years and older. In children with non-HIV conditions,
the risk of PCP is proportional to the extent of immuno-
suppression. For example, in children receiving 3 or more
chemotherapeutic agents, the risk is 22% vs 2% to 5% in
children who are taking fewer than 3 chemotherapeutic
agents. Similarly, the addition of radiation to chemothera-
peutic agents increases the risk by 35%. The use of anti–
tumor necrosis factor–modulating agents in children with in-
flammatory bowel disease also increases the risk of PCP.
Lungs are primarily affected, and hypoxia is the hallmark
clinical finding. The clinical course varies greatly depending
on the underlying T-cell defect and individual host factors.
Disease onset may be either fulminant or indolent, and dura-
tion is variable. An abrupt onset is typically seen in children
with non-HIV causes of T-cell suppression. Often, the onset
of PCP in patients without HIV precedes discontinuation or
tapering of corticosteroids. The course in patients without
HIV is rapidly progressive over a few days. To the contrary,
an indolent onset is observed in children with HIV infection,
and the clinical course may span 3 weeks or more. Due to its
slow progression, PCP in children with HIV often presents
only later in its course, with worsening fevers and hypoxia.
Signs and symptoms in children and adolescents can
include fever, cough, tachypnea, and dyspnea, but fever is
not universal with PCP. On auscultation, there is a startling
absence of adventitious lung sounds disproportionate to the
degree of tachypnea (60–80 breaths/min). The alveolar-
arterial gradient, which measures the difference in oxygen-
ation between alveolar and arteriolar blood, is often greater
than 30 mm Hg (reference range, 5–10 mm Hg) in HIV-
associated PCP.
The classic chest radiograph with PCP demonstrates
symmetrical bilateral interstitial infiltrates. Early in the dis-
ease course, the infiltrates are perihilar, which progress to
involve the peripheral lung fields (Fig 1). The apical lung
areas are spared. Uncommon chest radiography findings
may include asymmetrical distribution, unilateral lobar con-
solidation, pneumothorax, pneumomediastinum, and pleural
effusion. In cases of PCP with a normal chest radiograph, a
high-resolution computed tomographic scan may reveal
bilateral ground glass opacification or cystic lesions.
Clinical features of PCP overlap with other causes of
pneumonia. Definitive testing through polymerase chain
reaction (PCR) assay or stains should be considered in a
suspected case. Confirmation of PCP requires demonstration
of P jirovecii in the pulmonary parenchyma or bronchoalveo-
lar fluid. The likelihood of detection is higher in children
with HIV versus those with non-HIV conditions, reflecting
the high burden of infection in children with AIDS.
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Figure 1. Bilateral perihilar infiltrates due to Pneumocystis jirovecii. Courtesy
of AAP Red Book.
Specimen retrieval to identify P jirovecii can be done
through several methods. The least invasive method is induced
sputum. Limitations include low sensitivity of 20% to 40%
and the need for cooperation from the child in obtaining the
specimen. A tracheal aspirate can be obtained from an intu-
bated patient and has sensitivity of 50% to 60%. A specimen
obtained by bronchoalveolar lavage is the preferred method for
detecting P jirovecii. When performed through a flexible
fiberoptic bronchoscope, the sensitivity is 75% to 95%. A
transbronchial lung biopsy (small sample, close to 20 alveoli)
in conjunction with bronchoalveolar lavage increases the yield.
An open lung biopsy provides a larger specimen and allows
for histopathologic analysis, and sensitivity is 90% to 100%;
however, the disadvantage is the requirement for general anes-
thesia and complications such as pneumothorax and bleeding.
Several diagnostic tests are used to identify P jirovecii.
PCR assay on respiratory fluid, especially from bronchoal-
veolar lavage, is widely used but has the drawback that
PCR does not distinguish colonization from infection. In
addition, there is currently no Food and Drug Administra-
tion (FDA)–approved PCR test for this organism. Immuno-
fluorescence stain using fluorescent monoclonal antibodies
and stains such as Gomori methenamine silver and Giemsa
are commonly used (Fig 2).
Other nonspecific laboratory tests, such as lactate dehy-
drogenase levels, eosinophil count, and albumin levels,
may support the diagnosis of PCP. However, abnormalities
seen on these tests can also be reflect the child’s underlying
disease, as in a child with malignancy whose baseline lactate
dehydrogenase levels might be elevated from increased cell
turnover.
Vol. 44 No. 12 D E C E M B E R 2 0 2 3 721
 Figure 2. A. Giemsa stain of trophozoites of Pneumocystis jiroveci. B. Cysts of P jirovecii stained with methenamine silver and hematoxylin and eosin. C. Direct
immunofluorescence antibody stain. Courtesy of the Centers for Disease Control and Prevention.
Empirical treatment should be initiated when there is a
high clinical suspicion for PCP in children with known
risk factors who are acutely ill. Management has 3 funda-
mentals: supportive care, antibiotic treatment, and anti-
inflammatory therapy. The basis of supportive care is to
maintain the partial pressure of oxygen at 70% or greater
with supplemental oxygen and, if necessary, ventilatory
support. Trimethoprim-sulfamethoxazole (TMP-SMZ) is
the antibiotic of choice, and it can be administered either
intravenously or orally. Adverse effects are more common
with HIV than with non-HIV underlying conditions. The
most common adverse effect is a maculopapular rash,
which is usually transient. In a child unable to tolerate
TMP-SMZ, intravenous pentamidine isethionate is used.
The treatment duration is 21 days. In a child with partial
pressure of oxygen less than 70% and/or alveolar-arterial
oxygen gradient greater than 35%, an anti-inflammatory
agent, such as methylprednisolone, should be considered.
PCP is highly preventable with appropriate antibiotic
prophylaxis. Children at risk for PCP with malignancy
undergoing intensive chemotherapy, with a cell-mediated
immune deficiency such as severe combined immunode-
ficiency, transplant recipients, and patients with HIV infec-
tion and an abnormally low CD4 count, should be placed on
PCP prophylaxis. The agent of choice is TMP-SMZ, taken
3 times a week. Dapsone, which is both effective and inex-
pensive, is an option in children who cannot tolerate TMP-
SMZ. The dose is 2 mg/kg per day, or 4 mg/kg per week.
Both TMP-SMZ and dapsone should be avoided in children
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with a history of a severe reaction to a sulfonamide: anaphy-
laxis, Steven-Johnsons syndrome, toxic epidermal necrolysis.
Atovaquone, although expensive, is safe and as effective as
dapsone. Aerosolized pentamidine is reserved for children
who cannot tolerate the other 3 agents but is less effective
and requires patient cooperation. Its dose is 300 mg once
monthly in children 5 years and older and adolescents. The
rate of breakthrough PCP infection is up to 6% in children
receiving TMP-SMZ as opposed to 12% in children receiving
alternative prophylaxis.
Comments: This In Brief strikes a personal note for
me. Just out of fellowship, I began my career in the Bronx
in 1983, just as the AIDS epidemic was exploding. New
York State’s newborn screening program in the 1980s
showed that 2% to 5% of women delivering babies in the
Bronx were infected with HIV, and given a transmission
rate of 25% to 35%, 1 in 200 to 1 in 50 babies born in the
Bronx were likewise infected—an astonishing number not
very different from that of sub-Saharan Africa. With no
HIV-specific treatment available beyond supportive care,
the prognosis for those babies was dire, and a frequent
cause of their deaths was PCP. Long before zidovudine
was approved as the first antiretroviral agent for use
against HIV for adults in 1997 and for children in
2000, the single most effective intervention we had was
reliable prophylaxis against PCP with TMP-SMZ—truly
a lifesaver.
Henry M. Adam, MD
Associate Editor, In Brief
 IN BRIEF

Implications of Food and Drug Administration

Approval of Respiratory Syncytial Virus Prophylactic
Medication
Ashley L. Saint-Fleur, MD,* Catherine Kier, MD†
*Division of Pulmonary Medicine, Boston Children’s Hospital, Boston, MA
†Division of Pulmonary Medicine, Department of Pediatrics, Stony Brook Children’s Hospital, Stony Brook, NY

Therapies for prevention of respiratory syncytial virus (RSV), a major cause of

lower respiratory tract infections (LRTIs) among infants and toddlers, are ex-
panding. The Food and Drug Administration (FDA) recently approved adminis-
tration of nirsevimab, a monoclonal antibody aimed at preventing medically
attended RSV LRTIs, for all infants and especially those at high risk.
RSV is the most common cause of LRTI and hospitalization for respiratory AUTHOR DISCLOSURE: Drs Saint-Fleur
and Kier have disclosed no financial
illness among infants and young children. RSV is a highly contagious pathogen
relationships relevant to this article. This
belonging to the Pneumoviridae family of negative-strand RNA viruses that oc- commentary does not contain a
curs in a somewhat predictable seasonal epidemic. Although most infants ex- discussion of an unapproved/
perience mild, coldlike symptoms, some infants, particularly with a primary investigative use of a commercial
product/device.
infection in the first year after birth, can experience more severe symptoms
that often require urgent medical attention. Infants with chronic lung disease Single-Dose Nirsevimab for Prevention of
(CLD), prematurity, or congenital heart disease are at particularly high risk for RSV in Preterm Infants. Griffin MP, Yuan Y,
Takas T, et al. N Engl J Med.
severe disease. Nonetheless, the most hospitalizations due to RSV occur in
2020;383(5):415–425
healthy term infants. Therefore, preventing RSV illness in all infants is a ma-
jor public health priority. New Strategies for the Prevention of
The FDA approved nirsevimab in July 2023 for the prevention of RSV LRTI Respiratory Syncytial Virus (RSV). Messina
A, Germano C, Avellis V, et al. Early Hum
in neonates and infants born during or entering their first RSV season and in
Dev. 2022;174:105666
children up to 24 months of age who remain vulnerable to severe RSV disease
through their second RSV season. Nirsevimab is a recombinant human immu- FDA Approves New Drug to Prevent RSV
noglobulin G1 kappa monoclonal antibody. Nirsevimab binds the F1 and F2 sub- in Babies and Toddlers. FDA news release.
Available at: https://www.fda.gov/news-
units of the RSV fusion (F) protein. The F protein is necessary for cell infection events/press-announcements/fda-approves-
and remains a main target for vaccines and monoclonal antibodies, as the F pro- new-drug-prevent-rsv-babies-and-toddlers.
tein mediates the virus entry process by binding to the cell and enabling fusion Published July 17, 2023. Accessed August 21,
2023
of the virus envelope with the host cell plasma membrane. By binding the F1
and F2 subunits of the F protein at a highly conserved epitope, nirsevimab locks Nirsevimab: First Approval. Keam SJ.
the RSV F protein in the prefusion conformation to block viral entry into the Drugs. 2023;83(2):181–187
host cell. The enhanced neutralizing activity of nirsevimab and a modification of
Use of Nirsevimab for the Prevention of
the Fc region of this monoclonal antibody to promote extension of the half-life
Respiratory Syncytial Virus Disease
support a vaccinelike strategy to protect infants from RSV with a single intramuscular Among Infants and Young Children:
dose administered once per RSV season, which typically spans 5 months. Recommendations of the Advisory
Griffin et al demonstrated that nirsevimab provided healthy newborns of at Committee on Immunization Practices—
United States, 2023. Jones JM, Fleming-
least 35 weeks’ gestational age a stark reduction of RSV-associated LRTI that re- Dutra KE, Prill MM, et al. MMWR Morb
quired medical attention with an efficacy of 74.5% (95% confidence interval [CI], Mortal Wkly Rep. 2023;72(34):920–925

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 49.6% to 87.1%; P < .001) and a reduction of hospitaliza-
tions for RSV-associated LRTI with an efficacy of 62.1%
(95% CI, 8.6% to 86.8%; P 5 .07) from the start of the
RSV season, including those born out of the RSV season.
This single intramuscular injection provides this extended
benefit over 5 months without the need for serial, monthly
injections.
The safety and efficacy of nirsevimab has been evalu-
ated through 3 clinical trials (Trials 03, 04, and 05). The
primary outcome measure was the number of participants
with medically attended RSV LRTI evaluated during the
150 days after nirsevimab administration. Medically at-
tended RSV LRTI included all health-care provider visits
(physician’s office, urgent care, and emergency depart-
ment visits and hospitalizations) for LRTI with worsening
clinical severity and a positive RSV test result. These ran-
domized, double-blind, placebo-controlled (Trials 03 and 04)
and active (palivizumab)-controlled (Trial 05) multicenter
clinical trials provided evidence for the use of nirsevimab to
prevent medically attended RSV LRTI in preterm, late pre-
term, and term infants who were entering their first RSV
season at the time of screening along with high-risk infants
eligible to receive palivizumab entering their first or second
RSV season.
Noted possible adverse effects of nirsevimab include
rash and injection site reactions. Nirsevimab comes with
precautions about serious hypersensitivity reactions, in-
cluding anaphylaxis, that have been observed with other
human IgG1 monoclonal antibodies. Nirsevimab should
be given with caution to infants and children with clini-
cally significant bleeding disorders. In clinical trials, there
was no increased incidence of serious adverse events
among infants randomized to taking nirsevimab com-
pared with control patients.
Nirsevimab is recommended by the American Academy
of Pediatrics (AAP) and approved by the FDA and the Ad-
visory Committee on Immunization Practices (ACIP). The
ACIP to the Centers for Disease Control and Prevention
(CDC), which includes representatives from the AAP and
the American Academy of Family Physicians, recom-
mends that all infants younger than 8 months born dur-
ing or entering their first RSV season receive nirsevimab
to protect them from RSV. Nirsevimab is also recom-
mended for children 8 months through 19 months who
are at increased risk for severe RSV disease and are enter-
ing their second RSV season. This includes children with
CLD of prematurity who require medical support during
the 6 months before the start of the second RSV season,
children who are severely immunocompromised, children
724 Pediatrics in Review
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with cystic fibrosis who have manifestations of severe lung
disease or weight-for-length below the 10th percentile,
American Indian children, and Alaskan native children.
Infants born shortly before or during the RSV season
should receive nirsevimab in their first week of life either in
the hospital or in an outpatient setting. Newborns with a pro-
longed hospital stay should receive nirsevimab shortly before
or after discharge. For other infants and eligible toddlers, nir-
sevimab should be administered shortly before the beginning
of RSV season. Standard-risk children who did not receive a
dose at the start of the season can receive a dose at any time
during the season. High-risk children should get a dose in
both their first and second seasons, even if they are younger
than 8 months when entering their second season. Children
who received palivizumab in their first season can get nirsevi-
mab in their second season if they meet eligibility. Children
who receive nirsevimab should not receive palivizumab later
that season. Although the typical RSV season is October
through March, in tropical climates and Alaska, where the
RSV season may be different than the rest of the United
States, clinicians should consult state, local, or territorial guid-
ance on timing.
Nirsevimab has been compared with palivizumab, a spe-
cific RSV immunoglobulin G administered in 5 monthly in-
jections with license limited to infants who are at highest risk
for severe disease, namely, infants who are born at 35 weeks
or less of gestational age or children younger than 2 years
with CLD or hemodynamically significant congenital heart
disease. Nirsevimab has greater neutralizing activity and a lon-
ger serum half-life (63- to 73-day half-life of nirsevimab com-
pared with 19- to 27-day half-life of palivizumab) without the
need for monthly injections. In addition, nirsevimab has been
evaluated in healthy late-preterm and term infants, with fewer
limitations on eligible cohorts. Furthermore, additional targets
for RSV prevention are under investigation, including vac-
cines, oral RSV F protein fusion inhibitors, and other fusion
antibodies, that if successful, may provide additional preven-
tive options and potentially lower costs.
The AAP has stated that equitable access to nirsevimab is of
the highest priority, particularly because nirsevimab can be
offered to otherwise healthy infants rather than to only those
affected by potential risk factors. As with all new preventive treat-
ments administered to healthy children, caregivers may require
additional counseling to understand nirsevimab’s indications
and to gain confidence in its benefits to infants. Clinicians
should be prepared with handouts and links to reputable web-
sites, such as from the AAP and the CDC, to aid caregivers
in their decision-making.
 VISUAL DIAGNOSIS

Exfoliative Erythematous Rash in an 11-day-old

Preterm Infant
Janani Rajkumar, MBBS,* Jamie B. Warren, MD, MPH,† Jina Park, MD†
*Department of Pediatrics and †Division of Neonatal-Perinatal Medicine, Department of Pediatrics, Oregon Health & Science University, Portland, OR

PRESENTATION
A male neonate is born prematurely via cesarean delivery at 30 weeks and 2 days of
gestation to a 29-year-old gravida 2 para 1 woman. The mother was diagnosed
as having esophageal cancer during the pregnancy, and the premature delivery
was elective so that she could begin chemotherapy. Routine prenatal fetal sonograms
were normal, and prenatal laboratory tests were remarkable only for unknown
gonorrhea and chlamydia status.
The neonate required intubation at birth for respiratory distress syndrome
and need for surfactant. He was extubated to continuous positive airway pressure
(CPAP) the following day. The following day, he developed emesis and increased
work of breathing. Abdominal and chest radiographs were notable for bowel loop
dilation and diffuse moderate ground glass opacity and findings of pulmonary inter-
stitial emphysema. A blood culture was obtained, and he was started on ampicillin
and gentamicin. He completed 36 hours of antibiotic therapy; the blood culture
remained negative, and emesis improved. At 4 days of age, the neonate was rein-
tubated for ongoing increased respiratory distress, then extubated again to CPAP
on day 6. At 11 days of age, he is noted to have skin breakdown around the nasal
CPAP prongs and cannula adhesive. On physical examination he is noted to have
superficial peeling skin erosions with erythematous base and irregular borders
over the nasal bridge, malar cheeks, and left upper eyelid (Fig 1). He also has a
similar-appearing 1-cm erosion in the right axilla with a yellow-tinged exudate at
the base (Fig 2). The rest of his examination findings and vital signs are normal.
During the next 12 hours, additional skin lesions appear around the umbilicus,
gluteal cleft, left hand (Fig 3), chest (Fig 4), and scrotum. Nasal polymerase
Dr Rajkumar’s current affiliation is
chain reaction for methicillin-sensitive (MSSA) and methicillin-resistant (MRSA) Department of Neonatal and Pulmonary
Staphylococcus aureus and superficial swabs for bacterial culture from facial lesions Medicine, Cincinnati Children’s Hospital,
and oral, umbilical, and anal regions are obtained. A new blood culture is also Cincinnati, OH.

obtained. The clinical pattern confirms the diagnosis. Dr Park’s current affiliation is Division of
Neonatology, Department of Pediatrics,
Kaiser Permanente Northern California,
DIAGNOSIS Walnut Creek, CA.
The differential diagnosis for exfoliative skin lesions includes bullous impetigo, epi-
AUTHOR DISCLOSURE: Drs Rajkumar,
dermolysis bullosa, bullous mastocytosis, neonatal pemphigus, contact dermatitis, Peterson, and Park have disclosed no
chemical skin burns, and toxic epidermal necrolysis/Stevens-Johnsons syndrome. financial relationships relevant to this
The infant in this case was diagnosed as having staphylococcal scalded skin syn- article. This commentary does not
contain a discussion of an unapproved/
drome (SSSS) based on the clinical appearance of the lesions. In particular, the ery- investigative use of a commercial
thematous blanching macular rash followed by the classic exfoliative erythematous product/device.

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Figure 1 Superficial peeling skin erosions with erythematous base and ir-
regular borders over nasal bridge, malar cheeks, and left upper eyelid.
rash with skin peeling is consistent with SSSS. In addition,
SSSS usually involves the face (mouth and nose) first and
then spreads to the axilla, groin, abdomen, umbilicus, and
trunk, sparing the mucous membranes. The rash in this case
evolved in this pattern.
DISCUSSION
The characteristic finding of SSSS is an exfoliative erythem-
atous rash with desquamation. It is caused by exotoxins
released by S aureus, a gram-positive bacterial organism.
Figure 2 Right axillary skin erosion 1 cm in size with a yellow-tinged exu-
date at the base.
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Figure 3 Superficial peeling skin erosion with erythematous base on left
hand.
Certain strains of S aureus release epidermolytic exotoxins A
and B. (1). These toxins spread systemically and function as
proteases that target desmoglein 1, an intercellular attachment
protein found in the zona glomerulosa of the epidermis. (2).
Approximately 5% of S aureus strains produce epidermolytic
exfoliative exotoxins. Exotoxin A makes up approximately 80%
of exotoxins produced. (3)(4).
SSSS primarily affects children and neonates. This is
thought to be due to the immature immune system and a
lower renal clearance capacity of exfoliative toxins in these
age groups. (5). In addition, the composition of the skin is
variable and the proportion of desmoglein-1 in keratinocytes
Figure 4 Superficial peeling skin erosion with erythematous base located
on the chest and abdomen.
 decreases with increasing age, which results in a greater
number of intercellular attachment protein targets for the
exfoliative exotoxins in younger individuals. (6).
The initial finding is usually an erythematous blanching
macular rash. This is followed by the classic exfoliative ery-
thematous rash with skin peeling. (3). In some cases, friction
with the skin results in flaccid bullae, which break to form
exfoliated erythematous areas when rubbed (Nikolsky sign).
(2)(7). Lesions usually start in the face (mouth and nose) and
then spread to the axillae, groin, abdomen, umbilicus, and
trunk. Mucous membranes are characteristically spared.
A complete blood cell count may show elevated or
normal white blood cell counts. Erythrocyte sedimenta-
tion rate and C-reactive protein level may be elevated.
Electrolytes may show fluid/electrolyte imbalances due
to increased insensible losses through the damaged skin
barrier. (6). Skin cultures from the lesions and blood
cultures may be positive for growth of S aureus. The sub-
typing of S aureus and determining exotoxin production is
usually not necessary. (8)
The diagnosis of SSSS is based on the clinical appear-
ance of the rash. Bullous impetigo, epidermolysis bullosa,
bullous mastocytosis, neonatal pemphigus, contact derma-
titis, chemical skin burns, and toxic epidermal necrolysis/
Stevens-Johnson syndrome may present with similar skin
lesions, but there are important differences. Lesions in
epidermolysis bullosa form at sites of friction against the
skin and can also involve the oral cavity and eye. (9) Neona-
tal pemphigoid is an autoimmune dermatologic condition
and is differentiated from SSSS by a negative Nikolsky sign.
(10) Chemical skin burns and contact dermatitis are differ-
entiated based on exposure history. The lesions in bullous
mastocytosis are recurrent, (11) but the recurrence of SSSS
is rare. (12) In toxic epidermal necrolysis, there is involve-
ment of mucous membranes, but SSSS rarely involves
the mucous membranes. In addition, toxic epidermal nec-
rolysis can be differentiated from epidermolysis bullosa by
widespread involvement of the skin, with no clear topical
trigger. In SSSS, the culture of fluid may or may not have
bacterial growth. (13) However, bacteria or toxins are usually
found in the bullous lesions, and S aureus can be cultured
from the bullous fluid of bullous impetigo. Early initiation
of therapy with empirical antistaphylococcal antibiotics
such as nafcillin or oxacillin is essential until cultures with
sensitivity are available to narrow the therapy. If a patient
has an allergy to penicillins, clarithromycin or cefuroxime
may be used. Vancomycin should be considered in patients
with extensive skin involvement, critical illness, lack of
clinical improvement despite antibiotics, or when there is
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a high prevalence of MRSA. (2)(3)(4)(5) The lesions are
dressed with emollients and nonstick dressings to assist
with healing and reduce fluid losses. Other components of
care include pain management, adequate nutrition, and
monitoring and management of fluid and electrolyte imbal-
ances. (5) There are typically no long-term sequelae, and re-
covery occurs over 2 to 3 weeks without significant scarring
or disfigurement. Occasionally, it is associated with postin-
flammatory hypopigmentation. Complications of extensive
skin involvement include sepsis and fluid and electrolyte imbal-
ances. Mortality varies from 3% to 11% in children. (3)
SSSS has been associated with outbreaks in nurseries and
NICUs. These outbreaks are usually spread by asymptomatic
carriers to susceptible individuals. Contact isolation precau-
tions are a key factor in containing outbreaks. (13)(14)(15)
PATIENT COURSE
Initially, the patient was placed under contact and droplet
isolation precautions. Treatment was initiated with nafcillin.
Dermatology and pediatric infectious diseases were consulted.
To avoid further irritation from nasal CPAP prongs, the in-
fant was transitioned to high-flow nasal cannula for respira-
tory support. Pain was managed with as-needed enteral
acetaminophen, intravenous morphine, and enteral gaba-
pentin. Within 12 hours of skin lesion onset, the skin le-
sions spread to the perineum, scrotum, lip, and left foot.
Given the progression of the skin lesions, enteral clindamy-
cin was added to the antibiotic regimen to cover for MRSA.
The nasal swab MSSA/MRSA polymerase chain reac-
tion was positive for MSSA. There was no growth in the
cultures from the blood or the oral cavity, but the cultures
from the facial lesions were positive for S aureus resistant to
clindamycin and erythromycin. Therefore, clindamycin was
discontinued. After receiving a 2-day course of nafcillin,
antibiotics were narrowed to cefazolin. After receiving cefa-
zolin for 48 hours, the infant was transitioned to enteral
cephalexin to complete a total 12-day course of antibiotics.
Figure 5 Resolving skin lesions.
Vol. 44 No. 12 D E C E M B E R 2 0 2 3 e35
 Emollients were applied generously to the lesions and covered
• The characteristic finding of SSSS is an exfoliative
by nonadherent dressings.
erythematous rash with desquamation. The initial
Forty-eight hours after the initiation of antibiotics, the le-
finding is usually an erythematous blanching macular
sions began to improve and stabilize. Lesions healed completely
rash. This is followed by the classic exfoliative
(Fig 5) within 7 days of onset (18 days of age). He did not
have recurrence of the skin lesions throughout the rest of his erythematous rash with skin peeling.
hospitalization (1 month). The infant’s initial symptoms (vom- • SSSS is caused by exotoxins released by Staphylococcus
iting, respiratory distress) are not traditionally associated with aureus, a gram-positive bacterial organism.
SSSS. In addition, there were no other known risk factors for
• Early initiation of therapy with empirical anti-
SSSS in this case. There were no other infants in the unit
staphylococcal antibiotics such as nafcillin or oxacillin
with similar infections, and no source was identified.
is essential until cultures with sensitivity are available
to narrow the therapy.
Summary
• Staphylococcal scalded skin syndrome (SSSS)
primarily affects children and neonates.
References for this article can be found at
https://doi.org/10.1542/pir.2022-005739.

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