DECEMBER 2015

Vol. 36 No. 12
www.pedsinreview.org

Meningitis
Swanson

Pain and Symptom

Management in
Pediatric Palliative Care
Komatz, Carter

Substance Abuse,
General Principles
Nackers, Kokotailo, Levy

ONLINE

Visual Diagnosis:
A 2-month-old Boy
With an Unusual Rash
Benza, Stankovic
HE DEPENDS
ON YOUR
EXPERTISE
“I took my boards last year
and it was the best study aid
+HQWPF+RCUUGFYKVJƃ[KPI
colors because NeoReviewsPlus
had so much information.”
—NeoReviewsPlus Subscriber

RT U U
PA U
NeoReviewsPlus is approved by the
C

UU

2
U MO

ABP for MOC Part 2: Lifelong Learning

UUUU
UU

UU UUU
U
U
and Self-Assessment Points.

COMPREHENSIVE NEONATOLOGY
REVIEW AND ONLINE JOURNAL
• Peer-reviewed Articles •/WNVKOGFKC6GCEJKPI(GCVWTGU
• NICU-team Case Studies • 24/7 Online Access
• Clinical Reviews • CE/CME Credit

Subscribe today at shop.aap.org/2015-NeoReviewsPlus

Supported, in part, through an educational
grant from Abbott Nutrition, a division of
Abbott Laboratories, Inc.

The American Academy of Pediatrics (AAP) is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians.
This activity has been approved for AMA PRA Category 1 Credit ™.
contents

Pediatrics in Review ®
Vol. 36 No. 12 December 2015

Editor-in-Chief: Joseph A. Zenel, Sioux Falls, SD

Deputy Editor: Hugh D. Allen, Houston, TX
Associate Editor: Philip R. Fischer, Rochester, MN
ARTICLES Associate Editor, Index of Suspicion: Deepak M. Kamat,
Detroit, MI
514 Meningitis Associate Editor, In Brief: Henry M. Adam, Bronx, NY
Douglas Swanson Associate Editor, In Brief: Janet Serwint, Baltimore, MD
Associate Editor, CME: Paula Algranati, Longmeadow, MA
527 Pain and Symptom Management in Pediatric Editorial Fellow: Mark F. Weems, Memphis, TN
Editor Emeritus: Lawrence F. Nazarian, Rochester, NY
Palliative Care Founding Editor: Robert J. Haggerty, Canandaigua, NY
Managing Editor: Luann Zanzola
Kelly Komatz, Brian Carter Editorial Associate: Sara Strand
Medical Copyediting: Deborah K. Kuhlman
535 Substance Abuse, General Principles
Kirstin A. M. Nackers, Patricia Kokotailo, Sharon J. L. Levy EDITORIAL BOARD
Robert D. Baker, Buffalo, NY
INDEX OF SUSPICION Peter F. Belamarich, Bronx, NY
Theresa Auld Bingemann, Rochester, NY
545 Case 1: Clavicular Pain of 2 Months’ Duration Stephen E. Dolgin, New Hyde Park, NY
in a 9-year-old Girl Lynn Garfunkel, Rochester, NY
Rani Gereige, Miami, FL
Rebecca C. Brady, Alvin H. Crawford Joseph Gigante, Nashville, TN
Nupur Gupta, Boston, MA
548 Case 2: Recurrent Anemia in a 10-year-old Girl Gregory A. Hale, St. Petersburg, FL
Uzma Rani, Aamer Imdad, Mirza Beg Thomas C. Havranek, Bronx, NY
Jacob Hen, Bridgeport, CT
551 Case 3: Abnormal Eye Movements and Jeffrey D. Hord, Akron, OH
Neal S. LeLeiko, Providence, RI
Congestion in a 3-month-old Boy Michael Macknin, Cleveland, OH
Joanna Wigfield, Aadil Kakajiwala, Michael L. Forbes, Susan Massengill, Charlotte, NC
Jennifer L. Miller, Gainesville, FL
Prasad Bodas Carrie A. Phillipi, Portland, OR
Peter Pizzutillo, Philadelphia, PA
553 Correction Mobeen Rathore, Jacksonville, FL
Jennifer S. Read, Rockville, MD
IN BRIEF E. Steve Roach, Columbus, OH
554 Upper Respiratory Tract Infections Sarah E. Shea, Halifax, Nova Scotia
Andrew Sirotnak, Denver, CO
Benjamin Weintraub Miriam Weinstein, Toronto, ON

557 Statement of Ownership PUBLISHER: American Academy of Pediatrics

Mark Grimes, Director, Department of Publishing
ONLINE Joseph Puskarz, Director, Division of Journal Publishing

e43 Visual Diagnosis: A 2-month-old Boy With an Pediatrics in Review offers 36 CME articles per year. A maximum
of one AMA PRA Category 1 Credit TM is earned after achieving a
Unusual Rash 60% score on each designated quiz.
Natalia Benza, Curt Stankovic CME STATEMENTS:
The American Academy of Pediatrics (AAP) is accredited by
the Accreditation Council for Continuing Medical Education
(ACCME) to provide continuing medical education for
physicians.
The AAP designates this journal-based CME activity for a
maximum of 1.00 AMA PRA Category 1 Credit TM. Physicians
should claim only the credit commensurate with the extent
of their participation in the activity.
Pediatrics in Review® (ISSN 0191-9601) is owned and controlled by the American Academy of Pediatrics. This activity is acceptable for a maximum of 1.00 AAP credit.
It is published monthly by the American Academy of Pediatrics, 141 Northwest Point Blvd., Elk Grove Village, IL 60007-1098. These credits can be applied toward the AAP CME/CPD*
Statements and opinions expressed in Pediatrics in Review® are those of the authors and not necessarily those of the American Award available to Fellows and Candidate Members of the
Academy of Pediatrics or its Committees. Recommendations included in this publication do not indicate an exclusive course of AAP.
treatment or serve as a standard of medical care.
Subscription price for 2015 for print and online/online only: AAP/CPS Member $199/$152; AAP National Affiliate Member $157/$107; The American Academy of Physician Assistants accepts
Nonmember $249/$193; Allied Health or In-training $185/$125. Institutions call for pricing (866-843-2271). For overseas delivery, add $120. certificates of participation for educational activities certified
Current single issue price is $10 domestic, $12 international. Replacement issues must be claimed within 6 months from the date of issue for AMA PRA Category 1 Credit TM from organizations accredited
and are limited to three per calendar year. Periodicals postage paid at ARLINGTON HEIGHTS, ILLINOIS and at additional mailing offices. by ACCME. Physician assistants may receive a maximum of 1.00
© AMERICAN ACADEMY OF PEDIATRICS, 2015. hour of Category 1 credit for completing this program.
All rights reserved. This program is accredited for 1.00 NAPNAP CE contact
Printed in USA. No part may be duplicated or reproduced without permission of the American Academy of Pediatrics. hour; pharmacology (Rx) and psychopharmacology contact
POSTMASTER: Send address changes to PEDIATRICS IN REVIEW®, American Academy of Pediatrics Customer Service Center, 141 hours to be determined per the National Association of
Northwest Point Blvd., Elk Grove Village, IL 60007-1098. Pediatric Nurse Practitioners (NAPNAP) Continuing Education
Pediatrics in Review® Print Issue Editorial Board Disclosures Guidelines.
The American Academy of Pediatrics (AAP) Policy on Disclosure of Financial Relationships and Resolution of Conflicts of Interest for
AAP CME Activities is designed to ensure quality, objective, balanced, and scientifically rigorous AAP CME activities by identifying It has been established that each CME activity will take the
and resolving all potential conflicts of interest before the confirmation of service of those in a position to influence and/or control learner approximately 1 hour to complete.
CME content. All individuals in a position to influence and/or control the content of AAP CME activities are required to disclose to the *Continuing Professional Development
AAP and subsequently to learners that the individual either has no relevant financial relationships or any financial relationships with
the manufacturer(s) of any commercial product(s) and/or provider(s) of commercial services discussed in CME activities. Commercial How to complete this activity:
interest is defined as any entity producing, marketing, reselling or distributing health-care goods or services consumed by, or used Pediatrics in Review can be accessed and reviewed in print or
on, patients. online at http://pedsinreview.aappublications.org. Learners
Each of the editorial board members, reviewers, question writers, PREP Coordinating Committee members and staff has disclosed, if can claim credit monthly online upon completion of each CME
applicable, that the CME content he/she edits/writes/reviews may include discussion/reference to generic pharmaceuticals, off-label article. The deadline for completing this activity is December
pharmaceutical use, investigational therapies, brand names, and manufacturers. None of the editors, board members, reviewers, 31, 2017. Credit will be recorded in the year in which it is
question writers, PREP Coordinating Committee members, or staff has any relevant financial relationships to disclose, unless noted submitted. It is estimated that it will take approximately 1 hour
below. The AAP has taken steps to resolve any potential conflicts of interest. to complete each CME article. This activity is not considered
Disclosures to have been completed until the learner documents
• Paula Algranati, MD, FAAP, has disclosed that her family member is on the AstraZeneca speaker bureau. participation in that activity to the provider via online
• Lynn Garfunkel, MD, FAAP, disclosed that her family member is an employee of Philips Healthcare. submission of answers. Course evaluations are online.
• Nupur Gupta, MD, MPH, disclosed she receives royalties from Springer US as co-editor for MassGeneral Hospital
for Children Handbook of Pediatric Global Health.
• Miriam Weinstein, MD, has disclosed she is a paid consultant and advisory board member for Johnson & Johnson,
Pierre Fabre, PediaPharm, Tribute, and Valeant; she is a paid consultant for La Roch Posay (funding to attend and support
a hospital-run eczema teaching center); and receives honoraria for lectures from Galderma and Pediapharm.
The journal extends special thanks to the following question writers and reviewers who contributed to this issue:
–Joseph Gigante, MD
–Melissa Held, MD
–Sydney Rice, MD
Answer Key appears on page 556.
 Meningitis
Douglas Swanson, MD*
*University of Missouri, Kansas City; Division of Infectious Diseases, Children’s Mercy Hospitals and Clinics, Kansas City, MO.

Educational Gaps
1. The epidemiology of bacterial meningitis in children is changing.
2. Routine neuroimaging is not necessary for the initial medical
evaluation of children with suspected bacterial meningitis who do not
have clinical signs of brain herniation.

Objectives After completing this article, the reader should be able to:

1. Describe the causes, clinical manifestations, and general approach to

the diagnosis, treatment, and prevention of the different types of
meningitis in children of various ages.
2. Understand the indications for neuroimaging, adjunctive
corticosteroids, and repeat lumbar puncture in children with bacterial
meningitis.
3. Recognize the complications and sequelae of bacterial meningitis in
children.

INTRODUCTION

Bacterial meningitis is a severe, life-threatening infection of the central nervous

system that requires immediate medical attention. Even with appropriate treat-
ment, morbidity and mortality can be substantial. It is essential for clinicians to
recognize the clinical signs and symptoms of meningitis and understand its
management and prevention. The focus of this review is acute bacterial meningitis
in children, including its causes in different age groups, epidemiology, clinical
features, diagnosis, treatment, and sequelae.

ETIOLOGY AND EPIDEMIOLOGY

Acute Bacterial Meningitis

Acute bacterial meningitis has a relatively rapid onset of symptoms, and routine
laboratory techniques can usually identify the pathogen. The most common
causes have been Streptococcus pneumoniae, Neisseria meningitidis, Haemophilus
influenzae type b (Hib), group B Streptococcus (GBS), and Listeria monocytogenes AUTHOR DISCLOSURE Dr Swanson has
disclosed that he has a research grant from
(Table 1). (1)(2)(3) These organisms caused more than 80% of acute bacterial
Pfizer. This commentary does not contain
meningitis in children during the 1970s and 1980s. In 1990, conjugate Hib a discussion of an unapproved/investigative
vaccine was introduced. It has almost eliminated Hib meningitis in countries use of a commercial product/device.

514 Pediatrics in Review

TABLE 1. Estimated Proportions of Organisms Causing Bacterial
Meningitis According to Age
BACTERIA <1 MONTH# 1–<3 MONTHSD
Streptococcus pneumoniae 1%–4% 14%
Neisseria meningitidis 1%–3% 12%
Group B Streptococcus* 50%–60% 39%
Listeria monocytogenes 2%–7% - -
Escherichia coli 20%–30% - -
$
Other bacteria 4%–12% 35%
*Streptococcus agalactiae.
#
Data from Gaschignard et al (1) and Heath et al (2).
þ
Data from Nigrovic et al (3).
$
For children ‡1 month of age, this includes L monocytogenes and E coli. In those 1 to <3 months of group, 32% of other bacteria are Gram-negative
bacilli.
where it has been implemented and decreased the overall
incidence of acute bacterial meningitis by 55%. Implemen-
tation of the heptavalent pneumococcal conjugate vaccine
(PCV7) in 2000 resulted in a 59% reduction in rates of
pneumococcal meningitis in children younger than 2 years of
age. (4) Through herd immunity, the vaccine also protected
nonimmunized children and adults. From 1998 to 2007, the
overall incidence of bacterial meningitis decreased by 31%
from 2.00 cases per 100,000 population to 1.38 cases per
100,000 population. (5) However, mortality from bacterial
meningitis remained substantial, and the case fatality rate did
not change. In addition, rates of pneumococcal meningitis
from non-PCV7–serotype strains began to increase, including
cases of meningitis due to drug-resistant strains, such as
serotype 19A. (6) In 2010, PCV13 was introduced to respond
to the emerging invasive strains of pneumococcus. Currently,
S pneumoniae remains the most common cause of acute
bacterial meningitis for children older than 1 month.
In developed countries, conjugated vaccines have decreased
the incidence of bacterial meningitis in all age groups except
children younger than 2 months. The success of the vaccines
has shifted the median age of meningitis disease from
younger than 5 years of age to 42 years. (5) Nonetheless,
the highest incidence of bacterial meningitis remains among
children younger than 2 months of age, primarily because the
pathogens responsible for meningitis in young infants differ
from those causing infection in older children (Table 1). GBS
causes 50% to 60% of bacterial meningitis cases among
neonates, Escherichia coli about 20% of cases, and other
Gram-negative bacilli another 10%. (1)(2) These organisms
are usually acquired from the maternal genitourinary tract.
AGE
>3–35 MONTHSD 3–9 YEARSD 10–18 YEARSD
45% 47% 21%
34% 32% 55%
11% 5% 8%
- -
- -
10% 16% 16%
Since 1996, the practice of maternal GBS screening and
use of intrapartum antimicrobials has become routine in
developed countries, resulting in an 86% reduction in
early-onset GBS disease in the United States. (7) However,
the incidence of late-onset disease has not fallen. Risk
factors for acute bacterial meningitis in neonates and older
children are highlighted in Table 2. (8)(9)(10)
Aseptic Meningitis
Aseptic meningitis is characterized by clinical signs and
symptoms of meningitis without evidence of a bacterial
cause by usual laboratory testing methods. Some bacteria
that do not grow in routine culture, such as Mycobacterium
tuberculosis and Borrelia burgdorferi, can cause aseptic men-
ingitis. Aseptic meningitis has many infectious and non-
infectious causes. The most common are listed in Table 3.
The incidence is uncertain because aseptic meningitis is
not a reportable disease. A birth cohort study from Finland
found the annual incidence to be 28 per 100,000 persons,
with the highest rates in children younger than 4 years of
age. (11) Enteroviruses and parechoviruses account for most
of all known cases. In temperate climates, infections with
these viruses typically occur in the summer and fall seasons.
Arboviruses encompass a vast number of viruses from
different biologic families that are transmitted by arthro-
pods, especially mosquitoes. The most commonly reported
arboviruses causing aseptic meningitis infections in the
United States are West Nile virus and La Crosse virus.
Noninfectious causes include medications, autoim-
mune and auto-inflammatory diseases, and neoplasms.
Herpes simplex virus (HSV) is a cause of life-threatening
Vol. 36 No. 12 DECEMBER 2015 515
 TABLE 2. Risk Factors for Meningitis (8)(9)(10) TABLE 3. Primary Causes of Aseptic Meningitis
RISK FACTORS IN NEONATES RISK FACTORS IN CHILDREN COMMON INFECTIOUS CAUSES
• Preterm birth • Asplenia (anatomic or • Enteroviruses and parechoviruses
functional)
• Arboviruses (especially West Nile virus and La Crosse virus)
• Low birthweight (<2,500 g) • Primary immunodeficiency
• Borrelia burgdorferi
• Chorioamnionitis • Human immunodeficiency
virus infection UNCOMMON INFECTIOUS CAUSES

• Endometritis • Sickle cell anemia • Herpes simplex virus 2

• Maternal Group B • Cochlear implant • Varicella-zoster virus

Streptococcus colonization
• Mumps virus
• Prolonged duration of • Cerebrospinal fluid leak
• Human immunodeficiency virus
intrauterine monitoring
(>12 hrs) • Mycobacterium tuberculosis
• Prolonged rupture of • Recent upper respiratory • Mycoplasma pneumoniae
membranes tract infection
• Fungi (especially Cryptococcus sp)
• Traumatic delivery • Day care attendance
NONINFECTIOUS CAUSES
• Fetal hypoxia • Lack of breastfeeding
• Medications (eg, nonsteroidal anti-inflammatory drugs,
• Galactosemia • Exposure to a case of trimethoprim-sulfamethoxazole, isoniazid, intravenous
meningococcal or immunoglobulin)
Haemophilus influenzae type
b meningitis • Autoimmune and auto-inflammatory diseases (eg, sarcoidosis,
systemic lupus erythematosus)
• Urinary tract abnormalities • Penetrating head trauma
• Neoplasm
• Dermal sinus tract of • Dermal sinus tract of the spine
the spine
• Travel to an area with
endemic meningococcal temperature instability is a common feature, with either
disease fever or hypothermia occurring in about 60% of newborns
• Lack of immunizations who have bacterial meningitis, normothermia is not un-
usual. (12) There is often a report of vomiting and poor
feeding. Parents frequently state that their infant is fussy,
inconsolable, sleepy, weak, or jittery. Seizures occur in 20%
meningoencephalitis in neonates. It is beyond the scope
to 50% of infants with the presentation of illness. Neck
of this review to discuss the clinical features and manage-
stiffness is uncommon in neonates. Parents may report that
ment of HSV meningoencephalitis.
the baby has a “knot on its head” to describe the presence of
Chronic Meningitis a bulging fontanelle. Important information to ascertain
Chronic meningitis involves ongoing signs and symptoms includes risk factors for meningitis (Table 2), the birth
of meningitis for 4 or more weeks without clinical improve- history, trauma, congenital anomalies, and maternal history
ment. It has many infectious and noninfectious causes of sexually transmitted infections (recognizing that there is
(Table 4), each with its own epidemiology. The overall in- often no history suggestive of maternal genital HSV in
cidence of chronic meningitis is unknown due to limitations infants with HSV disease).
in data collection. The epidemiology differs according to the Older Child. The clinical presentation of meningitis in
causative agent. older children often occurs over a few days and may include
a progressive history of fever, headache, lethargy, irritability,
confusion, photophobia, nausea, vomiting, back pain, and
CLINICAL MANIFESTATIONS
stiff neck. (13) Sometimes the presenting signs and symp-
History toms are severe and sudden, occurring within a period of
Neonate and Infant. The clinical manifestations of neonatal hours. About 20% of affected children have a seizure before
bacterial meningitis are generally nonspecific and usually diagnosis, and about 25% have a seizure during the first few
comprise a constellation of signs and symptoms. Although days of hospitalization. The seizures are frequently complex

516 Pediatrics in Review


TABLE 4. Primary Causes of Chronic Meningitis
COMMON INFECTIOUS CAUSES
• Mycobacterium tuberculosis
• Treponema pallidum
• Borrelia burgdorferi
• Cryptococcus sp
• Human immunodeficiency virus
UNCOMMON INFECTIOUS CAUSES
• Brucella sp
• Nocardia sp
• Coccidioides immitis
• Histoplasma capsulatum
• Toxoplasma gondii
• Lymphocytic choriomeningitis virus
NONINFECTIOUS CAUSES
• Medications (eg, nonsteroidal anti-inflammatory drugs,
trimethoprim-sulfamethoxazole, isoniazid)
• Autoimmune and auto-inflammatory diseases (eg, sarcoidosis,
systemic lupus erythematosus)
• Neoplasm
and more common with meningitis due to Hib or S pneumo-
niae than N meningitidis. Important historical information to
obtain includes risk factors for meningitis (Table 2) and
recent medications, including use of antibiotics that might
interfere with the ability to isolate a pathogen from blood or
cerebrospinal fluid (CSF) culture.
Physical Examination
Neonate and Infant. Vital signs and general appearance
should be assessed. Affected infants usually do not like
to be moved or examined. Neurologic features of menin-
gitis in infants include inconsolable irritability, lethargy,
poor tone, and seizures. (12) Nuchal rigidity is uncommon.
The anterior fontanelle is usually full but not often bulging.
Poor capillary refill and respiratory difficulty with grunt-
ing, tachypnea, and nasal flaring are frequent findings. The
infant is less active and often seems apathetic and disin-
terested in its surroundings. Head circumference should
be measured daily to monitor for increased intracranial
pressure.
Older Child. The child with meningitis is usually irritable
or lethargic on physical examination. Vital signs, including
pulse oximetry, should be obtained promptly to help evaluate
for hypovolemia, shock, and increased intracranial pressure
(ICP). Cushing triad (hypertension, bradycardia, and respi-
ratory depression) is a late finding of increased ICP.
Although the following signs of ICP are uncommon, pa-
tients should screened for papilledema, diplopia, and cranial
nerve paralysis. (13) The pediatric Glasgow Coma Scale can
be a useful tool to monitor the patient’s level of conscious-
ness. Children who are obtunded or comatose upon admis-
sion have worse outcomes than those who are not.
Nuchal rigidity, a sign of meningeal inflammation, is de-
monstrated when the child is unable to flex the neck so that
it touches the chest, and by the presence of a Kernig or
Brudzinski sign. With the child in the supine position, the
Kernig sign is present when the hip and knee are flexed at
90 degrees and the leg cannot be passively extended more
than 135 degrees or the patient flexes the opposite knee. The
Brudzinski sign occurs when the child is in the supine
position and passive flexion of the neck causes the legs to
bend at the hip and knee.
DIAGNOSTIC EVALUATION
Blood Tests
Two separate blood cultures and a complete blood cell (CBC)
count with differential count should be obtained. If not
pretreated with antibiotics, 80% to 90% of children with
bacterial meningitis have positive blood cultures. The
peripheral white blood cell (WBC) count might be high
in bacterial meningitis, but it is frequently within normal
limits and may be low in neonates. If the CBC count reveals
thrombocytopenia or if petechiae or purpura are present on
examination, tests for disseminated intravascular coagula-
tion should be obtained. Serum electrolytes, blood urea
nitrogen, creatinine, and glucose should be monitored to
assess for syndrome of inappropriate antidiuretic hormone
(SIADH), manage fluid administration, adjust antimicro-
bial doses, and compare the CSF-to-blood glucose ratio.
Elevated serum procalcitonin and C-reactive protein values
are suggestive of bacterial meningitis but cannot reliably
discriminate between bacterial and viral meningitis. (14)
However, serial C-reactive protein measurements can be an
adjunctive tool to monitor the patient’s clinical response and
screen for potential complications.
Lumbar Puncture
CSF Evaluation. Unless otherwise contraindicated, a lumbar
puncture (LP) should be performed on any child suspected of
having bacterial meningitis (Figure). (9)(15) Contraindica-
tions to LP include increased ICP, coagulopathy, hemody-
namic or respiratory instability, or skin infection over the LP
site. If contraindications to LP exist, antimicrobial therapy
Vol. 36 No. 12 DECEMBER 2015 517

should not be delayed; blood cultures should be obtained and
empiric antibiotics started promptly. When obtained, CSF
should be evaluated for CBC count with differential count,
glucose and protein concentrations, Gram stain, and bacterial
culture. If the patient has not been pretreated with antibiotics,
the typical CSF findings in bacterial meningitis include
a neutrophilic pleocytosis (often >1,000 WBCs/mL), elevated
protein, low glucose, and a positive culture for a pathogenic
bacterium. However, in rare instances, no or few CSF WBCs
may be seen very early in the course of infection. Because of
possible misinterpretation of CSF Gram stains, antimicrobial
therapy should not be narrowed based on the Gram stain
result; empiric broad-spectrum antibiotics should be continued
until culture results are known. Table 5 provides the normal
518 Pediatrics in Review
Figure. Algorithm for suspected meningitis.
*Do not delay antimicrobial therapy if the
lumbar puncture cannot be accomplished.
BUN¼blood urea nitrogen, CNS¼central
nervous system, CRP¼C-reactive protein,
CSF¼cerebrospinal fluid, CT¼computed
tomography, DIC¼disseminated
intravascular coagulation, ICP¼intracranial
pressure, LP¼lumbar puncture.
Adapted from Mann and Jackson (9) and
Tunkel et al (15).
CSF parameters based on age and usual CSF findings based
on selected microbial cause of meningitis.
Traumatic Lumbar Puncture. Bleeding into the CSF from
a traumatic LP can make it difficult to interpret the CSF cell
count. One formula estimates the expected number of CSF
WBCs from a traumatic LP by comparing the ratio of (ex-
pected CSF WBCs)/(actual CSF red blood cells [RBCs]) to
(blood WBCs)/(blood RBCs). The calculated number of ex-
pected CSF WBCs is then subtracted from the actual number
of CSF WBCs to determine if there is a CSF pleocytosis. A
simpler correction method is to subtract 1 to 2 CSF WBCs for
every 1,000 CSF RBCs/mm3. However, these formulas are
inexact, and clinicians must be cautious when interpreting
the results. Empiric antibiotics should be administered while
awaiting culture results for children with a traumatic LP.
Furthermore, if the CSF is grossly bloody, attempting a repeat
LP is a prudent course.
Antimicrobial Pretreatment. Children with suspected
meningitis sometimes receive oral or parenteral antibiotics
before a lumbar puncture is performed. CSF cultures re-
main the reference standard for diagnosing bacterial men-
ingitis, but antibiotic pretreatment decreases the likelihood
of obtaining a positive CSF culture. In one study of 128
cases of pediatric meningitis, CSF cultures were negative in
29% of children who were pretreated with oral antibiotics
and 44% of children who were pretreated with parenteral
antibiotics. (16) Within 1 hour of receiving a third-generation
parenteral cephalosporin, three of nine children with me-
ningococcal meningitis had sterile CSF cultures, and all
were sterile within 2 hours. With pneumococcal meningitis,
CSF cultures usually become sterile by 4 or more hours after
parenteral antibiotic pretreatment unless the organisms
have decreased susceptibility to beta-lactam antibiotics.
Antimicrobial pretreatment does not adversely affect the
CSF cell count and is associated with higher CSF glucose and
lower protein values than would be expected for untreated
bacterial meningitis. However, these changes are unlikely to
obscure the diagnosis of bacterial meningitis. (17)
Latex agglutination tests have been used for patients with
suspected bacterial meningitis and negative CSF Gram stain
and culture. However, these tests have limited benefit, rarely
change the treatment plan, and are no longer routinely re-
commended for patients pretreated with antibiotics. (14)
The overall diagnostic sensitivities for multiplex nucleic acid
amplification tests such as polymerase chain reaction (PCR)
range from 72% to 92% for Hib, 61% to 100% for S
pneumoniae, and 88% to 94% for N meningitidis. (14) The
lower sensitivity results are usually from patients who
received antimicrobial pretreatment. Further study is
needed to determine if CSF PCR will prove useful in the
management of patients with suspected bacterial meningi-
tis who have been pretreated. On the other hand, CSF
enteroviral PCR can be a useful tool to identify an alternative
diagnosis to bacterial meningitis.
Neuroimaging. Computed tomography (CT) scan of the
brain obtained to rule out increased ICP often unnecessarily
delays LP. However, abnormal CT scan findings are rare in
children without clinical findings of a focal neurologic de-
ficit, papilledema, or coma. (18)(19) In addition, a normal CT
scan does not completely confirm that an LP is safe. Clin-
ically stable children with suspected bacterial meningitis
and no clinical signs of brain herniation should undergo
prompt LP. If a head CT scan is indicated (Figure), blood
cultures should be obtained first and antibiotics adminis-
tered. LP should be performed promptly after CT scan if no
contraindication is identified. Although antibiotics are given
in advance, routine imaging studies can lead to unnecessary
delays in obtaining a diagnostic LP, potentially confounding

TABLE 5. Usual Cerebrospinal Fluid Findings in Healthy Children and

Those With Meningitis Caused by Selected Pathogens*
TYPE OF WHITE BLOOD POSITIVE
MENINGITIS GLUCOSE PROTEIN CELLS/MM3 NEUTROPHILS STAIN†

Healthy newborn 30–120 mg/dL 0.03–0.15 g/dL (0.3–1.5 g/L) <30 20%–60% NA
(1.7–6.7 mmol/L)
Healthy child 40–80 mg/dL 0.02–0.04 g/dL (0.2–0.4 g/L) <6 None NA
(2.2–4.4 mmol/L)
Bacterial <1/2 serum 0.1–0.15 g/dL (1–1.5 g/L) >1,000 >85%–90% 60%
Pretreated bacterial <1/2 serum to N 0.07–>0.1 g/dL (0.7–>1 g/L) 500–>1,000 >60% 60%
‡
Enteroviral >1/2 serum 0.04–<0.1 g/dL (0.4–<1 g/L) <1,000 20%–50% NA
Lyme >1/2 serum <0.1 g/dL (<1 g/L) <500 <10% NA
Fungal <1/2 serum >0.1–0.2 g/dL (>1–2 g/L) <500 <10%–20% <40%
Tuberculosis <1/2 serum >0.1–0.3 g/dL (>1–3 g/L) <300 <10%–20%þ <30%

N¼normal, NA¼not applicable

*Values should not be used in isolation because there can be significant overlap in each of the categories.
†
Gram, silver, or acid-fast bacilli staining for bacteria, fungi, and mycobacteria, respectively.
‡
Neutrophil predominance can be seen in the early stages of meningitis.
Adapted from Mann and Jackson (9).

Vol. 36 No. 12 DECEMBER 2015 519

 and complicating the patient’s management. Therefore, CT
scan should be used judiciously in children with suspected
bacterial meningitis.
DIFFERENTIAL DIAGNOSIS
The signs and symptoms of fever, irritability, lethargy, head-
ache, vomiting, and nuchal rigidity are strongly suggestive of
bacterial meningitis. However, other conditions should be
considered in the differential diagnosis. Viruses, fungi, my-
cobacteria, and parasites can sometimes cause meningitis
that mimics bacterial meningitis in presentation. Brain
abscesses, encephalitis, subdural or epidural abscesses, rick-
ettsial disease, leptospirosis, and neck or retropharyngeal
abscesses are other infectious diseases that may mimic acute
bacterial meningitis. Noninfectious conditions such as cen-
tral nervous system autoinflammatory vasculitis, Kawasaki
disease, brain tumors, and drug reactions are also consid-
erations in the differential diagnosis. A careful review of the
medical history, examination of the CSF, selective laboratory
tests, and judicious use of neuroimaging should help discern
the final diagnosis if bacterial meningitis is excluded.
MANAGEMENT
Supportive Care
Initial supportive care is usually best provided in an inten-
sive care unit to assure close cardiopulmonary monitoring
and management. Serious complications of bacterial men-
ingitis (hypotension, cerebral infarction, seizures, increased
ICP) often occur in the first 2 to 3 days of therapy. Fluid and
electrolyte resuscitation must be administered to attain
appropriate blood pressure and cerebral perfusion. The
child’s weight, serum electrolytes, urine output, and urine
specific gravity should be monitored closely in the first 24 to
36 hours of hospitalization. If the patient does not have
hypovolemia or shock upon admission, there may be a role
for modest fluid restriction until SIADH can be ruled out,
especially if the serum sodium is less than 130 mEq/L (130
mmol/L). SIADH can cause hyponatremia and hypo-osmo-
lality, which could lead to mental confusion, lethargy, seiz-
ures, and increased ICP. (20) If SIADH is suspected, serum
and urine osmolalities should also be monitored. Fluid
restriction can be gradually removed when the sodium
concentration reaches 135 mEq/L (135 mmol/L), often within
24 to 48 hours after hospitalization.
Patients should receive a thorough neurologic examina-
tion daily and brief directed neurologic examinations several
times a day during the first few days of care. Children younger
than 18 months of age should have daily head circumference
520 Pediatrics in Review
measurements. Mild early signs of increased ICP can be
managed by elevating the head of the bed. However, severe
signs of increased ICP (apnea, bradycardia, hypertension,
sluggish or dilated pupils) require more aggressive therapy
with mannitol and hyperventilation. Generalized seizures
occur early in the disease course in 20% to 25% of meningitis
cases and can usually be controlled with standard seizure
medications, such as fosphenytoin or phenobarbital. Focal
seizures, difficult-to-control seizures, or seizures occurring
more than 48 hours after admission should prompt a neu-
rology consultation.
Up to one third of children with bacterial meningitis
develop a subdural effusion. In most cases, subdural effu-
sions cause minimal symptoms or are asymptomatic and do
not require specific treatment. Clinical manifestations of
subdural effusions are often subtle or absent. If a subdural
empyema develops, drainage is usually necessary. Subdural
empyema can present as persistent fever, headache, and
nuchal rigidity or new onset of neurologic features, such as
seizures, in the setting of appropriate antibiotic treatment.
Antimicrobial Therapy
Antimicrobial agents should be started promptly after LP to
decrease the risk of adverse outcomes. As mentioned pre-
viously, if a head CT scan is needed before the LP, blood
cultures should be obtained first and antibiotics quickly
administered (Figure). It is important to determine that the
antibiotics administered can achieve good concentrations in
the CSF and are bactericidal against the targeted bacterial
pathogens.
Neonatal Bacterial Meningitis. Empiric antimicrobial
therapy of suspected bacterial meningitis in the neonate
has often consisted of ampicillin and gentamicin. (2) How-
ever, with increasing resistance of E coli and other Gram-
negative enteric organisms to ampicillin, some clinicians
replace gentamicin with cefotaxime when bacterial menin-
gitis is strongly suspected. Although the use of cefotaxime
has been linked to the emergence of cephalosporin-resistant
Gram-negative bacilli, this risk must be weighed against the
risk of inadequately treating ampicillin-resistant Gram-neg-
ative meningitis in the face of suboptimal CSF penetration
by gentamicin. When the causative organism and its anti-
biotic susceptibilities are determined, specific targeted ther-
apy can be provided (Table 6). (8)(15)(20) For uncomplicated
meningitis caused by GBS, L monocytogenes, or S pneumo-
niae, 14 days of antibiotics is sufficient. Twenty-one days of
antibiotics is often considered the minimum length of
therapy for uncomplicated neonatal meningitis caused by
Gram-negative bacilli. Longer antimicrobial treatment courses
are necessary for complicated meningitis, such as subdural
empyema, ventriculitis, brain abscess, and suppurative venous
sinus thrombosis.
Postneonatal Bacterial Meningitis. Empiric antimicrobial
therapy of suspected bacterial meningitis for children 1
month of age and older involves vancomycin plus either
cefotaxime or ceftriaxone. (8)(15)(20) Vancomycin is used
because of the emergence of cephalosporin-resistant
pneumococci. It does not need to be continued if the
organism is susceptible to penicillin or cephalosporins.
When the causative organism and its antibiotic suscepti-
bilities are determined, specific targeted therapy can be
provided (Table 6).
For pneumococcal meningitis, clinicians should con-
sider adding rifampin if: 1) the child’s condition has wors-
ened after 24 to 48 hours of vancomycin and cephalosporin
therapy, 2) a repeat LP reveals the presence of bacteria, 3) the
organism has a high cephalosporin minimum inhibitory
concentration (‡4 mg/mL), or 4) dexamethasone has been
administered. (21) Care must be taken when treating pneu-
mococcal meningitis to ensure that antimicrobial suscepti-
bility is being interpreted for meningitis and not for
nonmeningitic infections.
Vancomycin plus rifampin or vancomycin plus merope-
nem are possible treatment options for children with seri-
ous allergic reactions to penicillins and cephalosporins.
Vancomycin should not be administered alone because it
has limited CSF penetration and clinical experience using it
as monotherapy for meningitis is limited. Rifampin should
not be administered alone because resistance can develop
during treatment.
For uncomplicated meningitis, the usual duration of
antimicrobial therapy is 10 to 14 days for S pneumoniae, 7
to 10 days for Hib, 5 to 7 days for N meningitidis, 14 to 21 days
for L monocytogenes, and a minimum of 3 weeks for Gram-
negative bacilli. A pediatric infectious diseases consultation
should always be considered, especially for complicated cases,
including drug resistance, persistent infection, immuno-
deficiency, CSF leak, penetrating head trauma, or recent
neurosurgery.
Culture-negative CSF. Antibiotics are discontinued for
patients with an unremarkable CSF profile and negative
blood and CSF cultures. If the child has a positive blood
culture, CSF pleocytosis, and negative CSF culture, treat-
ment is usually provided for meningitis as if the CSF culture
had been positive. In this circumstance, some experts treat
Gram-negative bacteremia and uncomplicated suspected
meningitis for only 14 days instead of 21 days. For patients
with unconfirmed, uncomplicated, but clinically suspected
bacterial meningitis (eg, pretreated with antibiotics), treat-
ment is often 14 days or more of ampicillin and cefotaxime

TABLE 6. Specific Antibiotics for Selected Pathogens (8)(9)(15)

PATHOGEN STANDARD ANTIBIOTIC(S) ALTERNATIVE ANTIBIOTIC(S)

Group B Streptococcus Penicillin G or ampicillin – gentamicin Cefotaxime or ceftriaxone

Escherichia coli*
Listeria monocytogenes
Neisseria meningitidis
Penicillin-susceptible
Penicillin-tolerant
Haemophilus influenzae type b
Beta-lactamase-negative
Beta-lactamase-positive
Streptococcus pneumoniae
Penicillin-susceptible
Penicillin-nonsusceptible
Cephalosporin-susceptible
Penicillin-nonsusceptible
Cephalosporin-nonsusceptible
Cefotaxime or ceftriaxone – gentamicin Cefepime or meropenem
Penicillin G or ampicillin – gentamicin Trimethoprim-sulfamethoxazole or meropenem
Penicillin G or ampicillin Cefotaxime or ceftriaxone
Cefotaxime or ceftriaxone Cefepime or meropenem
Ampicillin Cefotaxime or ceftriaxone
Cefotaxime or ceftriaxone Cefepime or meropenem
Penicillin G or ampicillin Cefotaxime or ceftriaxone
Cefotaxime or ceftriaxone Cefepime or meropenem
Vancomycin þ cefotaxime or ceftriaxone – rifampin Vancomycin þ meropenem – rifampin

*Or other Gram-negative enteric bacilli. Choice of antibiotic is directed by the results of susceptibility testing.

Vol. 36 No. 12 DECEMBER 2015 521

 for neonates and 10 days of ceftriaxone for older infants and
children. (22) However, the specific management of patients
with a CSF pleocytosis and negative blood and CSF cultures
needs to be decided on an individual clinical basis; consul-
tation with a pediatric infectious diseases expert is recom-
mended. Sterile CSF pleocytosis sometimes occurs in young
febrile infants with urinary tract infections who have not
been pretreated with antibiotics. These infants are often not
treated for bacterial meningitis and are at very low risk for
adverse events. (23)
Adjunctive Therapy
Dexamethasone has been used as adjunctive therapy to
modulate the host inflammatory response and prevent
neurologic complications of bacterial meningitis, especially
hearing loss. However, its use in children with bacterial
meningitis has been controversial. A recent subgroup anal-
ysis of 2,511 children from a large meta-analysis found that
use of dexamethasone significantly reduced hearing loss
associated with meningitis caused by Hib, but not menin-
gitis caused by other bacteria. (24) Nonetheless, children in
this study from high-income countries who had non-Hib
meningitis and received corticosteroids experienced some
reduction in severe hearing loss. Therefore, the authors
suggested that these children might benefit from cortico-
steroids because there was no evidence of adverse effects
from the treatment. However, the results are inconclusive,
and the use of adjunctive dexamethasone for non-Hib
meningitis remains controversial. Because Hib meningitis
has become rare in developed countries, empiric dexameth-
asone therapy is harder to justify. In addition, vancomycin
was not part of the treatment regimen for most of the studies
using adjunctive corticosteroids. Vancomycin has subopti-
mal CSF penetration, and there is some concern that cortico-
steroids may further reduce its penetration into the CSF by
reducing meningeal inflammation.
The American Academy of Pediatrics (AAP) Committee
on Infectious Diseases identifies a potential benefit of de-
xamethasone for patients with Hib meningitis and indicates
that empiric use might be considered for suspected bacterial
meningitis in infants and children 6 weeks of age and older
after considering the possible risks versus potential benefits.
(25) The AAP recognizes that data are insufficient to rec-
ommend routine adjunctive corticosteroid therapy for pedi-
atric pneumococcal meningitis. (21) If dexamethasone is
used, it should be administered before or at the same time as
the first dose of antibiotics. Dexamethasone has no demon-
strable benefit if initiated more than 1 hour after antibiotics.
The usual dose is 0.15 mg/kg per dose intravenously every 6
hours for 2 days.
522 Pediatrics in Review
Repeat Lumbar Puncture
The AAP Committee on Infectious Diseases recommends
a repeat LP after 24 to 48 hours of therapy for all infants with
Gram-negative bacilli meningitis to ensure sterility of the
CSF. (26) If the CSF culture remains positive, the antimi-
crobial regimen should be re-evaluated and another LP
performed. Some experts recommend a repeat LP after
24 to 48 hours of therapy for all cases of neonatal meningitis
to confirm CSF sterilization. (2) In contrast, the United
Kingdom National Institute for Health and Clinical Excel-
lence Clinical Guideline 102 recommends against repeat LP
in neonates if they are receiving appropriate antibiotic
treatment for the causative organism and are making a good
clinical recovery. They recommend a repeat LP in neonates
with: 1) persistent or re-emergent fever, 2) deterioration in
clinical condition, 3) new clinical findings (especially neu-
rologic findings), or 4) persistently abnormal inflammatory
markers. (22)
For cases of pneumococcal meningitis, some experts
suggest repeating an LP after 48 hours of therapy if: 1)
the organism is penicillin-nonsusceptible and cephalospo-
rin susceptibility testing is not yet available, 2) the child’s
condition is not improved or is worsening, or 3) the patient
has received dexamethasone because it can obscure clinical
features such as fever, headache, and nuchal rigidity. (21) If
the organism is cephalosporin-nonsusceptible, repeat LP at
48 to 72 hours should be considered to verify CSF clearance
of the bacteria.
Obtaining an end-of-therapy LP for bacterial meningitis
is no longer common practice. (2) However, if one is
obtained, the duration of antimicrobial therapy might need
to be extended if the CSF has more than 30% neutrophils,
the glucose is less than 20 mg/dL (1.1 mmol/L), or the CSF-
to-blood glucose ratio is less than 20%.
Prolonged or Returned Fever
Fever usually lasts 4 to 6 days after initiation of appropriate
therapy. Return of fever or continued fever for more than 8
days should activate an evaluation for the cause. (8)(20) The
discontinuation of adjunctive dexamethasone often results
in a return of fever for several days. Suppurative compli-
cations, such as subdural empyema, pleural empyema,
arthritis, pericarditis, ventriculitis, or brain abscess should
be considered and appropriate evaluations performed when
indicated. The decision to repeat an LP for CSF analysis and
culture should be made on a case-by-case basis. Fever from
a hospital-acquired viral infection is not uncommon. A
treatment complication (eg, phlebitis from a peripheral
intravenous line, catheter-associated urinary tract infec-
tion, central line-associated bloodstream infection) is also
a consideration. Drug fever is uncommon and a diagnosis of
exclusion. A specific cause for fever is often not found.
Neuroimaging
Neonatal Meningitis. Cranial ultrasonography is often per-
formed early in the course of disease to identify possible
hydrocephalus, intraventricular hemorrhage, ventriculitis,
extra-axial fluid collections, or other problems. In addition,
some experts routinely obtain a head CT scan or magnetic
resonance imaging (MRI) with contrast 1 to 3 days before the
expected end of therapy, even in apparently uncomplicated
cases. (2) Such imaging is designed to identify any potential
complications, such as cerebritis or parenchymal abscesses,
that would require prolonged antimicrobial therapy. In
addition, it might provide prognostic information and indi-
cate the need for early interventional services. Contrast-
enhanced neuroimaging with CT scan or MRI is important
for infections from Citrobacter sp, Serratia marcescens, Pro-
teus mirabilis, and Cronobacter (formerly Enterobacter) saka-
zakii because of their tendency to cause brain abscesses.
Postneonatal Meningitis. As noted previously, radiologic
studies are used in conjunction with LP in the diagnostic
evaluation of bacterial meningitis. Routine neuroimaging
with CT scan or MRI is usually not necessary during the
management of bacterial meningitis in the older infant and
child. However, head CT scan or MRI with contrast is in-
dicated in certain circumstances, including focal neurologic
signs, prolonged obtundation, increasing head circumfer-
ence, seizures after 72 hours of antimicrobial therapy,
persistently positive CSF cultures, recurrent meningitis,
and infection with Gram-negative bacilli, especially Citro-
bacter sp or C sakazakii. (18)(20)
PROGNOSIS AND SEQUELAE
Bacterial meningitis can be a devastating disease. Mortality
rates across all pediatric ages range from less than 5% to
15%, depending on the pathogen and when the surveillance
was conducted. The patient’s prognosis and outcome are
affected by many factors, including age, infecting organism,
bacterial burden, and clinical status when antibiotics are
started. (8)(20) Younger age, greater bacterial burden, and
delayed CSF sterilization are all associated with worse
prognosis. A decreased level of consciousness at presenta-
tion is associated with increased risk for death or neurologic
sequelae. The development of seizures more than 72 hours
after starting antibiotics has been associated with learning
difficulties. Compared to Hib or N meningitidis, infection
caused by S pneumoniae is associated with a poorer outcome.
Hearing loss occurs in 20% to 30% of children with
pneumococcal meningitis, approximately 10% with menin-
gococcal meningitis, and approximately 5% with Hib men-
ingitis. Hearing impairment is also associated with CSF
glucose less than 20 mg/dL (1.1 mmol/L) at the time of
diagnosis. Vestibular injury can result in ataxia and difficulty
with balance. Other neurologic sequelae include cognitive
and developmental disability, hemiparesis, quadriparesis,
cranial nerve palsies, epilepsy, cortical blindness, hy-
drocephalus, diabetes insipidus, and hypothalamic dysfunc-
tion. Paresis generally improves over time and may resolve
months or years after the infection.
DISCHARGE CRITERIA
Patients can be considered for discharge to home when they
are clinically and neurologically stable, able to tolerate
enteral fluids, and have been afebrile for 24 to 48 hours.
In selected circumstances, completion of intravenous anti-
microbial therapy may be safely managed at home. Candi-
dates for home infusion therapy should meet the previously
stated discharge criteria, have received 5 to 7 days of inpa-
tient therapy, and have reliable caretakers with immediate
access to transportation and telephone. Advantages of home
therapy include avoidance of hospital-acquired infection,
return to a normal environment, and decreased treatment
costs.
FOLLOW-UP EVALUATIONS
Hearing evaluation should be performed before hospital
discharge or soon thereafter. Repeat testing is indicated if
the initial evaluation yields abnormal results, and audiology
services should be used as needed. Children with recog-
nized neurologic sequelae should be provided appropriate
referrals for physical, occupational, and other therapies so
they have the opportunity to reach their greatest recovery
potential. Even infants and children who appear well upon
completion of therapy are at risk for cognitive and develop-
mental delay. Regular routine follow-up evaluations with
their primary care clinician are recommended to monitor
their behavior, development, and academic progress. Further-
more, infants and young children may be eligible for state-
sponsored early intervention services. Children completing
antimicrobial therapy at home need close follow-up, preferably
from the clinician who was managing their inpatient care.
PREVENTION AND CONTROL
Timely childhood vaccination against Hib, S pneumoniae, and
N meningitidis is the best preventive approach for meningitis
Vol. 36 No. 12 DECEMBER 2015 523
 from these organisms. Use of the Hib conjugate vaccines in
infants has resulted in a dramatic decrease in the incidence
of Hib meningitis. The conjugated vaccines for pneumo-
coccus and meningococcus have been relatively effective in
preventing disease from vaccine-related serotypes. Unfor-
tunately, nonvaccine-related serotypes for both pneumococ-
cus and meningococcus continue to cause life-threatening
meningitis.
Patients with invasive Hib or meningococcal disease
should be placed in droplet precautions until they have
received 24 hours of therapy with a third-generation ceph-
alosporin or 4 days of rifampin chemoprophylaxis. In
addition, close contacts of patients with Hib and menin-
gococcal disease should be provided antimicrobial pro-
phylaxis. (25) Rifampin is indicated for all household
contacts of a patient with invasive Hib infection if at least
one of them is younger than age 4 years and is unim-
Finally, daily penicillin prophylaxis is recommended
for patients with functional and anatomic asplenia to pre-
vent invasive pneumococcal disease.
Summary
• Based on strong evidence, blood cultures usually recover the
causative organism of bacterial meningitis in children not
pretreated with antibiotics.
• Based on moderate evidence, pretreatment does not adversely
affect the cerebrospinal fluid cell count, but it decreases the
positive test result for cerebrospinal fluid culture, especially for
meningococcal meningitis. (16)(17)
• Based on some research evidence as well as consensus, children
with suspected bacterial meningitis and no clinical signs of brain
herniation do not need neuroimaging as part of their initial
clinical evaluation. (18)(19)(22)

munized or incompletely immunized. Rifampin ad- • Dexamethasone adjunctive therapy in children with
pneumococcal meningitis is controversial. (21)
ministration is 20 mg/kg (maximum dose 600 mg)
once daily by mouth for 4 days. If two or more cases • Some experts recommend neuroimaging toward the end of
therapy for all neonates with bacterial meningitis. (2)
of invasive Hib disease occur within 60 days at a child
• Based on some research evidence as well as consensus, home
care facility or preschool and unimmunized or incom-
intravenous antimicrobial therapy may be an option in selected
pletely immunized children attend, rifampin is recom-
cases of pediatric bacterial meningitis. (15)
mended for all attendees, regardless of age or vaccine
status. All close contacts of patients with meningococcal
infection, regardless of vaccine status, should receive
chemoprophylaxis with rifampin, ceftriaxone, ciprofloxa-
cin, or azithromycin. The choice of antimicrobial agent CME quiz and references for this article are at http://pedsinreview.
depends on the appropriateness for the individual contact. aappublications.org/content/36/12/514.full.

Parent Resources from the AAP at HealthyChildren.org

• https://www.healthychildren.org/English/health-issues/conditions/head-neck-nervous-system/Pages/Meningitis.aspx

524 Pediatrics in Review

PIR Quiz
There are two ways to access the journal CME quizzes:
1. Individual CME quizzes are available via a handy blue CME link in the Table of Contents of any issue.
2. To access all CME articles, click “Journal CME” from Gateway’s orange main menu. Use the publications filter at right to refine
results to a specific journal.

1. A 1-year-old girl presents to the emergency department with the acute onset of fever, REQUIREMENTS: Learners
irritability, photophobia, and vomiting. The child has no significant past medical history and the can take Pediatrics in
parents report that she is up-to-date with all immunizations, including varicella and the Review quizzes and claim
measles, mumps, and rubella vaccines. In the waiting room, the child has a 1-minute credit online only at: http://
generalized tonic-clonic seizure. You are concerned about bacterial meningitis and perform pedsinreview.org.
a lumbar puncture (LP). You send the cerebrospinal fluid (CSF) to the laboratory for analysis of
glucose, protein, cell count, Gram stain, and bacterial culture. One hour later, the microbiology
To successfully complete
laboratory technician reports that Gram-positive bacteria have been noted on the CSF Gram
2015 Pediatrics in Review
stain. Of the following, the most likely organism causing this child’s bacterial meningitis is:
articles for AMA PRA
A. Haemophilus influenzae type b. Category 1 CreditTM,
B. Listeria monocytogenes. learners must demonstrate
C. Neisseria meningitidis. a minimum performance
D. Streptococcus pneumoniae. level of 60% or higher on
E. Streptococcus pyogenes. this assessment, which
2. A 2-week-old male infant presents with a 1-day history of a temperature to 38.9°C (102°F), measures achievement of
irritability, and poor feeding. A complete blood cell count, blood culture, urinalysis, and urine the educational purpose
culture are obtained. LP is attempted five times without success. Of the following, the next best and/or objectives of this
step in management is: activity. If you score less
than 60% on the
A. Administration of parenteral antibiotics. assessment, you will be
B. Computed tomography scan of the brain. given additional
C. Cranial ultrasonography. opportunities to answer
D. Repeat attempt at LP the following day. questions until an overall
E. Measurement of serum electrolytes. 60% or greater score is
3. You are discussing a case of bacterial meningitis with a group of medical students. A 2-year-old achieved.
boy with fever, headache, irritability, and some emesis was seen by a physician in a walk-in
clinic. The child was diagnosed with acute bacterial sinusitis for which he was prescribed This journal-based CME
amoxicillin. Forty-eight hours later, the child continued to have fevers, headache, and emesis, activity is available through
and his parents took him to the emergency department. You discuss with the students whether Dec. 31, 2017, however,
LP would be indicated for this child when he is evaluated in the emergency department. One credit will be recorded in
student comments that because the child was already receiving antibiotics, the cerebrospinal the year in which the
fluid (CSF) culture would likely be sterile. Of the following, the most accurate response is that: learner completes the quiz.
A. Although antibiotic pretreatment decreases the likelihood of obtaining a positive
CSF culture, it does not adversely affect the CSF cell count.
B. Antibiotic pretreatment does not decrease the likelihood of obtaining a positive
CSF culture.
C. Antibiotic pretreatment decreases both the likelihood of obtaining a positive CSF
culture and the ability to interpret the CSF cell count.
D. Antibiotic pretreatment only decreases the likelihood of a positive CSF culture if the
etiology of the meningitis is Streptococcus pneumoniae.
E. Antibiotic pretreatment only decreases the likelihood of a positive CSF culture if the
lumbar puncture is traumatic.
4. A 2-month-old infant is admitted to the hospital because of fever and new-onset focal seizure
activity. A complete blood cell count, blood culture, urinalysis, and urine culture are obtained.
LP is also performed and the CSF is sent to the laboratory for glucose, protein, cell count,
Gram stain, and bacterial culture. The Gram stain performed on the CSF fluid is suspicious for
Gram-positive bacteria. Empiric antimicrobial therapy for suspected bacterial meningitis is
initiated. Of the following, which is the best choice for antimicrobial therapy?
A. Ampicillin plus gentamicin.
B. Ceftriaxone (or cefotaxime) monotherapy.
C. Gentamicin plus rifampin.

Vol. 36 No. 12 DECEMBER 2015 525

 D. Vancomycin monotherapy.
E. Vancomycin plus ceftriaxone (or cefotaxime).
5. A 2-week-old male infant in the neonatal intensive care unit, who had been born at 35 weeks’
gestation, is evaluated for possible meningitis. Analysis of the CSF reveals a glucose of
17 mg/dL (0.94 mmol/L) and protein of 0.2 g/dL (2 g/L). The CSF Gram stain shows Gram-
negative bacilli and within 12 hours, the CSF culture grows Escherichia coli. Appropriate
parenteral antibiotic therapy is initiated with a plan to complete 2 weeks of intravenous
antibiotics. Of the following, which is the best management plan for this child’s Gram-negative
bacilli meningitis with regard to follow-up LP?
A. An end-of-therapy LP should be performed for all infants with Gram-negative bacilli
meningitis to ensure sterility of the CSF.
B. A repeat LP after 24 to 48 hours of therapy should be performed for all infants with
Gram-negative bacilli meningitis to ensure sterility of the CSF.
C. A repeat LP is indicated in neonates only if they received dexamethasone before or
at the same time as the first dose of antibiotics.
D. A repeat LP should be performed in Gram-negative bacilli meningitis only if the
blood culture grew Escherichia coli.
E. Weekly LPs should be performed for neonates with Gram-negative bacilli men-
ingitis to ensure there are no complications.

526 Pediatrics in Review

 Pain and Symptom Management in Pediatric
Palliative Care
*Division of Community & Societal Pediatrics, University of Florida College of Medicine, Jacksonville, FL.
†
Division of Neonatology & Bioethics Center, University of Missouri-Kansas City & Children’s Mercy Hospital, Kansas City, MO.
AUTHOR DISCLOSURE Drs Komatz and
Carter have disclosed no financial
relationships relevant to this article. This
commentary does not contain a discussion of
an unapproved/investigative use of
a commercial product/device.
Kelly Komatz, MD, MPH,* Brian Carter, MD†
Practice Gap
Chronic pain in childhood is underrecognized, and clinicians are
unfamiliar with treatment options and symptom management in children
with chronic medical conditions.
Objectives After completing this article, the reader should be able to:
1. Discuss the features of a detailed pain history leading to the origins of pain.
2. Identify the first lines of treatment for a pediatric patient experiencing pain.
3. Define different symptoms associated with chronic medical conditions.
4. Identify treatment options to control symptoms for pediatric patients.
Abstract
Pain and symptom management is considered one of the cornerstones of
palliative and hospice medicine. However, general clinicians and
specialists are not usually comfortable addressing the most common
forms of pain seen in the pediatric population. In addition, non-pain
symptom management, especially when related to underlying chronic
medical conditions, can be managed by the general clinician and
specialists. The goal of this article is to educate clinicians about pain
categories, taking a detailed pain history, and developing a plan for
treatment, including nonpharmacologic methods. Finally, we discuss
common symptoms in patients with chronic medical conditions,
including first-line treatment options.
“The concepts of pain and suffering go well beyond that of a simple
sensory experience. It has emotional, cognitive, and behavioral
components as well as developmental, environmental and socio-
cultural aspects” – American Academy of Pediatrics and American Pain
Society policy statement
September, 2001
Vol. 36 No. 12 DECEMBER 2015 527
 PAIN HISTORY
A patient’s pain history is often obtained as part of the
routine history during medical encounters. Pain is usually
easy to assess in an adult, but how does one assess pain in
a pediatric patient from infancy to adolescence? Pain man-
agement continues to be an area of uncertainty for clini-
cians. Common concerns include, “If I treat the pain with an
opioid, I might make the patient a drug addict.” or “If I
undertreat the pain, it might result in my patient missing school,
having behavioral issues, or being depressed.” Multiple modal-
ities, including nonpharmacologic interventions, are avail-
able to help control a patients’ pain.
As with most diagnoses in medicine, the answer to
treating a patient’s pain lies in the details of the history.
It is essential to obtain a thorough pain history from the
patient, if possible, and collaborate with the caregivers. Of
note, it is the patient’s history that matters. Even patients as
young as 2 years can answer very basic questions related to
their pain. Research has demonstrated that parents may
underestimate their child’s postoperative pain, but they can
reliably offer observations and judgments about a young
child’s pain behaviors, responses, and factors that may
exacerbate or ameliorate pain when presented in a struc-
tured format (Table 1). (1)
The details of a thorough pain history include asking
questions related to when the pain first started, what makes
it worse, and what makes it better. The quality of the pain
should be defined: sharp, dull, feels like pressure or pulling,
cramping, stabbing, needlelike, or burning. Does the pain
radiate and if so, to where? Is the pain constant or inter-
mittent; does it come on suddenly or start slowly; and does it
interrupt particular daily functions, activities, or sleep?
What does the patient do to make the pain go away? What
interventions, including medications, physical therapy, or
other modalities, have been tried and what was the
response? The history and answers to these questions can
guide the differential diagnosis of the type of pain: somatic,
TABLE 1. Pain Assessment Questions
PROVOKES QUALITY
Aggravating and/or alleviating factors: What does it feel like?
What causes the pain? Sharp?
What makes it better? Dull?
What makes it worse? Stabbing?
Burning?
528 Pediatrics in Review
visceral or neuropathic (Table 2). Treatment options differ
for each type of pain.
PAIN SCALES
Validated pain scores or rating scales should be used to
measure and assess the severity of pain consistently. The
effectiveness of the treatment plan can be evaluated using
the same rating scale. Pain rating scales are available for
infants, nonverbal patients, and patients who are able to
verbalize a response. The scales are multimodal and incor-
porate behavioral and physiologic components, including
facial expression (grimace), extremity position and move-
ment (flexion), body habitus (stillness or inability to get
comfortable), heart rate, blood pressure, and oxygen satu-
ration. Examples include:
• Neonatal Infant Pain Scale (NIPS) (2), a behavioral
assessment tool for preterm and term neonates up to 6
weeks after birth
• Pediatric FACES, used for patients from ages 3 to 7 years (3)
• FLACC (Face, Legs, Activity, Cry, Consolability) Scale for
nonverbal patients (4)(5)
A numeric scale from 0 to 10 is commonly used for
children who are older and can self-report a number. Clini-
cians must remember to ask the patient, unless he or she is
unable to communicate, about the level of pain. Parents
might over- or underreport their child’s degree of pain. Also,
asking the patient begins to nurture a therapeutic relation-
ship that continues with pain treatment.
TYPES OF PAIN
The diagnostic groups of pain are defined by their mech-
anistic causes. Nociceptive pain is usually due to tissue
damage (mechanical or traumatic) or inflammation and
can be classified as somatic or visceral. Visceral pain affects
the internal organs and the soft tissue of the body. It
is commonly described as being sore, gnawing, achy,
RADIATES SEVERITY
Does the pain radiate? Using the pain scale:
If yes, where does it start? What is the worse pain?
Where does it move to? What is the least pain?
What is the level now?
What is your acceptable level of pain?
TABLE 2. Types of Pain and Descriptive Terms
SOMATIC VISCERAL
• Throbbing • Not well-localized
• Aching • Involves abdominal area
• Sometimes sharp • Gnawing
• Well-localized • Cramping
• Intermittent
• Nausea
• Vomiting
• Pressure-like
pressure, or cramping. Somatic type pain is described more
often as constant, worsening with movement, sharp, throb-
bing, and is usually localized to a specific body area such as
an extremity or the back. Neuropathic pain is usually due to
nerve fiber damage (pressure, trauma, swelling, inflamma-
tion) or entrapment of nerves. Neuropathic pain is best
described as burning, shooting, and stinging and can be
associated with skin color changes (autonomic vasomotor
changes) or an inability to tolerate even light touch without
experiencing pain.
Distinguishing between acute and chronic pain is also
important. Acute pain is experienced when there is an
injury to a body tissue. As healing occurs, the pain resolves.
The goal of managing acute pain is to relieve the pain
during the body’s healing process. However, there is a pro-
pensity to develop hyperalgesia in areas of repetitive tissue
damage (eg, repeated heel lancing in an infant) where the
“field” of receptors becomes hypersensitive to less invasive
sensation. Chronic pain persists after the initial insult has
“healed.” The causative agent cannot be removed. The
overall treatment goal for a patient with chronic pain is
functional improvement; total pain relief is rarely achiev-
able. Chronic pain has been demonstrated to cause central
nervous system changes affecting feelings and complex
thoughts. (6)(7)(8)
PAIN MANAGEMENT
Management depends on the category or type of pain. Noci-
ceptive pain is treated with nonsteroidal anti-inflammatory
drugs for mild pain, with the addition of opioids for moderate-
to-severe nociceptive pain. An important point is that many
orally administered opioid medications contain acetamin-
ophen. Therefore, the patient and parents/caregivers should
be specifically counseled about the potential cumulative effect
NEUROPATHIC
• Pins and needles
• Hot or burning
• Numbness
• Aggravated by touch – even clothes
of acetaminophen and reminded not to take other medi-
cations containing acetaminophen so as to minimize the
potential for liver toxicity. Also, codeine is no longer rec-
ommended for children due to the potential for acute
overdose in those who have hypermetabolism, a genetic
predisposition that is generally unknown to the patient or
clinician. (9) Affected children rapidly metabolize codeine
into morphine and are more prone to respiratory depres-
sant effects. Therefore, only hydrocodone or oxycodone
should be used if an opioid is necessary.
Clinicians must recognize the different potencies of
opioids, especially when they are changing a prescription
between intravenous and enteral formulations. For exam-
ple, intravenous morphine is three times more potent than
oral morphine. Also, oxycodone is more potent than mor-
phine and hydrocodone in enteral formulation. Therefore,
clinicians should work with a pharmacist, palliative care
clinician, or pain/anesthesia specialist when treating a
patient with any opioid or use references that assist in
determining equivalent intravenous and enteral dosing.
Neuropathic pain is treated with gabapentinoids. The
theory behind using the gabapentinoids is their inhibition
of excitation within the central nervous system. The two
common medications used are gabapentin and pregabalin.
Other medications that affect the central nervous system can
also be used, including tricyclic antidepressants, serotonin
norepinephrine reuptake inhibitors, and anticonvulsants.
Chronic opioid therapy has no role in the treatment of
neuropathic pain.
Other, nonpharmaceutical treatment modalities for pain man-
agement often prove more effective for patients experiencing
pain or other symptoms related to an underlying condition or
adverse effects from treatments. Such interventions include
biofeedback, guided imagery, meditation, hypnosis, and
acupuncture. Among the physical measures that can prove
Vol. 36 No. 12 DECEMBER 2015 529
 effective are therapeutic massage, the application of heat
or cold, healing touch or Reiki, and physical/occupational
therapies. Activities that provide distraction, such as music,
art, or other expressive therapies, have been proven to be
beneficial in patients with chronic pain. Clinicians should
be familiar with the resources available in their own areas
and encourage the patient and family to consider these other
modalities of treatment.
SYMPTOM MANAGEMENT
Symptom management in children requires astute attention
to clinical assessment tools and scales. It is important for the
child to contribute to this assessment by answering specific
questions after being presented age-appropriate cues. (10)
Admittedly, this approach may pose a challenge with a child
who has a chronic complex medical condition, but the
results can be worthwhile. Generally, an otherwise healthy
pediatric patient has acute symptoms related to one or two
organ systems. The child who has a chronic complex medical
condition usually has more than two organ systems affected,
which can lead to multiple symptoms that require concom-
itant management. The most common symptoms in chil-
dren with chronic complex medical conditions are pain,
nausea and vomiting, dyspnea, fatigue, anorexia and weight
loss, depression, anxiety, and sleep disturbances. Table 3
lists common medications used to relieve pain and other
systemic signs and symptoms.
Nausea, with or without vomiting, is the most common
symptom other than pain in children with chronic medical
conditions. Several physiologic mechanisms contribute to
nausea and vomiting. Nausea is mediated through the
autonomic nervous system. Distension of an organ within
the abdominal cavity triggers the gastric mechanorecep-
tors that stimulate the vagal afferent fibers. Also, stimu-
lation of receptors in the medulla by toxins or increased
intracranial pressure can induce nausea. The vestibular
system can also cause nausea with or without vomiting,
but this is less commonly seen in the pediatric patient.
Although nausea may be perceived as a problem, it also can
serve to indicate the nature or locus of certain conditions
that require assessment, such as increased intracranial
pressure, adverse drug effects or exposure to toxic agents,
or bowel distention that deters eating so as to mitigate
ongoing gastrointestinal distress. If nausea accompanies
chemotherapy or other medications that are necessary in
a patient’s care, its treatment may be essential to improve
the patient’s quality of life. Treatment may also make living
with certain vestibular dysfunctions more bearable and
facilitate eating.
530 Pediatrics in Review
Vomiting is coordinated by the vomiting center. Several
afferent pathways lead to the vomiting center, including the
chemoreceptor trigger zone, the cerebral cortex and limbic
system, the vestibular system of the inner ear, and peripheral
stimuli. The neural receptors involved in both the peripheral
and central nervous system are mediated by dopamine
receptor type 2, serotonin receptor type 3, histamine receptor
type 1, and muscarinic cholinergic receptors. Like nausea,
vomiting may indicate an underlying problem requiring
identification and correction or be an adverse effect of
necessary medical management (eg, medications) for which
treatment of the vomiting may be useful.
The choice of pharmaceutical agent for treatment of nau-
sea and vomiting is based on the likely pathway affected in
the vomiting center. For example, most chemotherapeutic
agents affect the chemoreceptor trigger zone, which is the
reason for frequently using promethazine before chemo-
therapy administration.
Metoclopramide can be used if gastric distension is
suspected as the underlying cause of nausea. Scopolamine
or glycopyrrolate may be appropriate if nausea is attributed
to the vestibular system. If increased intracranial pressure is
suspected, dexamethasone is indicated. Ondansetron, a sero-
tonin 5-HT3 receptor antagonist, may be used in children
older than 4 years to prevent postoperative nausea and
vomiting, or that associated with chemotherapy.
Constipation is a common adverse effect of opioid pain
medication, dehydration, decreased ambulation, or diet. A
bowel regimen that mitigates constipation should be sim-
ultaneously prescribed for any patient receiving long-term
opioids. Constipation often leads to nausea and, at times,
vomiting. Laxatives and stool softeners are the mainstay of
treatment for constipation. It is important to use the most
effective combinations to maintain regular bowel move-
ments while not causing more gastrointestinal distress.
Dyspnea is defined as feeling short of breath, which may
be due to actual difficulty in breathing or to chest wall or
pleural pain associated with breathing. Results of the tra-
ditional respiratory assessment, including respiratory rate,
oxygen saturation, and blood gases, do not always correlate
with the patient’s report of breathlessness. Dyspnea scales
used in some adult populations, such as those with chronic
obstructive pulmonary disease, are not applicable to chil-
dren. The best studied dyspnea scale in pediatrics is the
Dalhousie Dyspnea Scale (Figure) which has been used in
children with asthma or cystic fibrosis. (11)
Causes of dyspnea include an underlying pulmonary
disease, anemia, airway obstruction, and heart failure.
A trial of supplemental oxygen, a fan blowing on the patient’s
face, repositioning, and relaxation techniques are suggested
TABLE 3. Commonly Used Medications for Pain and Symptom
Management
MECHANISM OF ROUTES OF ADVERSE EFFECTS/
SYMPTOM ACTION DOSE RANGES ADMINISTRATION COMMENTS

Nausea/Vomiting
Promethazine Chemoreceptor >2 years of age PO, PR Sedating
trigger zone 0.25–0.5 mg/kg per dose every Extrapyramidal effects
4 to 6 hours as needed;
maximum initial dose 12.5 mg
Metoclopramide Gastric stasis 0.1–0.2 mg/kg per dose 3 PO, PR Sedating
times a day before meals as Extrapyramidal effects
needed;
maximum dose not to
exceed 0.8 mg/kg in any
24-hr period
Lorazepam Central nervous 0.03–0.05 mg/kg per dose PO, SL, PR, IV
system - anxiety every 6 hours as needed;
maximum initial dose not to
exceed 2 mg
Dexamethasone Central nervous 0.1 mg/kg per dose 3 times per PO, PR, SL, IV Typically used for
system – increased day; maximum initial dose nausea/vomiting related
intracranial pressure 5 mg to chemotherapy
Ondansetron 0.15 mg/kg per dose every PO, IV Limited data on children
8 hours as needed; < 2 years old
maximum dose not to
exceed 8 mg

Constipation
Polyethylene glycol 3350 Osmotic laxative 20–40 mL/kg/hour until rectal PO Cramping, bloating, and
effluent is clear; or 1 to nausea
1.5 L/hour up to a 4-L Administer with adequate
maximum free water
Senna syrup Gastrointestinal tract Age 6–24 months: 1.25–2.5 mL PO Cramping
(218 mg/5 mL) stimulant every night
Age 2–6 years: 2.5–3.75 mL
every night
Age ‡6 years: 5–7.5 mL every
night
Glycerin Local action for stool in Based on patient age PR Can use slivers or full
vault suppository, depending
on patient’s age
Dyspnea
Morphine immediate Central nervous 0.1 mg/kg PO every hour PO, SL, SC, PR, IV Maximum dose determined by
release system suppression and titrate as necessary adverse effects (eg, respiratory
depression) more so than mg
dose; especially in patients
who have been receiving
opioid therapy; titrate to
effect
Lorazepam Benzodiazepine Depends on route of delivery; PO, SL, PR, IV Appropriate if patient has
Central nervous 0.1 mg/kg enteral forms a component of agitation
system - anxiety
Continued

Vol. 36 No. 12 DECEMBER 2015 531

 TABLE 3. (Continued )

MECHANISM OF ROUTES OF ADVERSE EFFECTS/

SYMPTOM ACTION DOSE RANGES ADMINISTRATION COMMENTS

Neuropathic Pain
Gabapentin Antiepileptic 5 mg/kg every night for PO Must titrate up to maximum
3 nights effective dose due to sedation
5 mg/kg BID for 1 days Attempt to use BID dosing,
especially in school-age patients
5 mg/kg per dose TID Use higher doses at bedtime
OR
5 mg/kg per dose AM and
10 mg/kg per dose every night
Nortriptyline Tricyclic 0.2 mg/kg every night for 3 PO Urinary retention
antidepressant nights
0.4 mg/kg every night

PO¼oral, PR¼rectal, IV¼intravenous, SC¼subcutaneous, SL¼sublingual.

Adapted from: Storey P, Knight CF, and Schonwetter RS. American Academy of Hospice & Palliative Medicine’s Pocket Guide to Hospice/Palliative
Medicine, 2003. AAHPM, 4700 W. Lake Avenue, Glenview, IL

treatments. Anxiolytics, such as lorazepam, are used to con-
trol anxiety that may contribute to the sensation of shortness
of breath, especially in end-of-life situations. Morphine
sulfate is commonly used by palliative care practitioners to
control dyspnea but in lower doses than used for pain
management, such as 0.05 mg/kg administered intrave-
nously or subcutaneously.
Fatigue is often experienced by patients as they enter the
last months of life, and this becomes an area of focus and
concern for both the patient and caregivers. Anemia, infec-
tion, uncontrolled pain, deconditioning, poor dietary intake,
sleep disturbances, depression, anxiety, and adverse effects
of medications all may contribute to fatigue. The treatment
should focus initially on treatment of underlying causes
such as depression, anxiety, or sleep disturbances. The
patient also should be encouraged to take frequent naps
or modify activities. At times, methylphenidate can be used
to increase the patient’s wakefulness, especially for impor-
tant events that the patient and family desire.
CONCLUSION
Although not exhaustive, this review is intended to assist the
clinician in taking a thoughtful approach to pain and symptom

Figure. Dalhousie Dyspnea Scales. (11)

 2005 McGrath et al; licensee BioMed
Central Ltd.
This is an Open Access article distributed
under the terms of the Creative Commons
Attribution License (http://creativecommons.
org/licenses/by/2.0), which permits unrestricted
use, distribution, and reproduction in any
medium, provided the original work is properly
cited.

532 Pediatrics in Review

assessment and management in children with complex and
chronic medical conditions. Symptoms may wax and wane
over the course of the child’s life, at key times in development
or with certain activities, or during hospitalizations for acute
decompensations from a primary life-limiting disease. When
causes of symptoms are understood, they can be anticipated
and addressed, even before the child’s end of life. In so
addressing them, clinicians contribute to improved comfort
and an enhanced quality of life for the patient and his or her
family. Pediatric palliative care is a growing specialty, as
evidenced by Accreditation Council for Graduate Medical
Education-approved fellowship programs and the growth
of inpatient and outpatient palliative care services associated
with children’s hospitals worldwide. Palliative care physicians
are trained in recognizing and treating pain and symptoms in
children with chronic medical conditions. By gaining knowl-
edge about the common symptoms and initial treatments for
such pain, treating clinicians can begin therapy while await-
ing a referral to the appropriate subspecialist.
Parent Resources from the AAP at HealthyChildren.org
• https://www.healthychildren.org/English/family-life/health-management/pediatric-specialists/Pages/What-is-a-Hospice-and-Palliative-
Medicine-Pediatrician.aspx
Based on consensus, the earlier a patient’s pain and
symptoms are addressed and managed, the sooner he or
she can return to a previous level of function. The keys to
the treatment plan can be found in the history and details
related to the characteristics of the pain. Evaluation should
encompass current medications or treatments that could
be causing the pain, prompting clinicians occasionally to
discontinue or change treatment. Appropriate early treat-
ment can enhance the patient-clinician relationship and
bring satisfaction to the treating clinician who is providing
relief to the patient.
NOTE: The authors have made every effort to attempt to
check specific medication dosing for accuracy. Due to incomplete
pediatric dosing information on some drugs, we recommend the
reader check current specific product information and published
literature, or consult your pharmacist, for questions.
CME quiz and references for this article are at http://pedsinreview.
aappublications.org/content/36/12/527.full.
Vol. 36 No. 12 DECEMBER 2015 533
 PIR Quiz
There are two ways to access the journal CME quizzes:
1. Individual CME quizzes are available via a handy blue CME link in the Table of Contents of any issue.
2. To access all CME articles, click “Journal CME” from Gateway’s orange main menu. Use the publications filter at right to refine
results to a specific journal.

1. You see a 3-year-old girl with autism who was in a motor vehicle collision with her family. REQUIREMENTS: Learners
She has a nondisplaced fracture of the right forearm. You want to assess her pain level can take Pediatrics in
before sending her home with pain medication. She is nonverbal and inconsistent with Review quizzes and claim
communicating using gestures. Her mother is at the bedside and also sustained several credit online only at:
minor orthopedic injuries. Which of the following methods is most appropriate to assess http://pedsinreview.org.
this child’s pain?
A. FACES scale. To successfully complete
B. FLACC scale. 2015 Pediatrics in Review
C. Maternal perception of girl’s pain. articles for AMA PRA
D. NIPS scale. Category 1 CreditTM,
E. Numeric 1–10 scale. learners must
2. A 17-year-old adolescent had spinal fusion to treat severe scoliosis associated with demonstrate a minimum
muscular dystrophy. Since his surgery, he has had shooting and burning pains down his performance level of 60%
left leg. He is being treated with physical therapy and massage. His parents ask if there is or higher on this
a medication that would help manage his pain. Of the following, the best recommendation assessment, which
for pain management in this patient is: measures achievement of
A. Acetaminophen. the educational purpose
B. Gabapentin. and/or objectives of this
C. Hydrocodone. activity. If you score less
D. Lorazepam. than 60% on the
E. Music therapy. assessment, you will be
given additional
3. A 13-year-old girl was treated surgically for a large ovarian cyst approximately 1 year ago.
opportunities to answer
During the past 9 months, she has had recurrent abdominal pain for which she has
questions until an overall
undergone multiple evaluations that yielded normal examination and study findings. You
60% or greater score is
speak with the girl and her family about treatment for her pain. Of the following, the most
achieved.
appropriate recommendation for treating this patient’s recurrent abdominal pain is:
A. Anxiolytic medication for 1 month.
B. Guided imagery and meditation. This journal-based CME
C. High-dose anti-inflammatory medication. activity is available
D. Intense aerobic exercise daily. through Dec. 31, 2017,
E. Low-dose opioid medication. however, credit will be
recorded in the year in
4. A 6-year-old boy is hospitalized for bowel obstruction. He has severe nausea. Which of the
which the learner
following medications is the best choice for this boy’s pain?
completes the quiz.
A. Dexamethasone.
B. Metoclopramide.
C. Ondansetron.
D. Promethazine.
E. Scopolamine.
5. A 17-year-old young man is hospitalized with severe dyspnea related to cystic fibrosis. The
most accurate method of assessing his dyspnea is:
A. Arterial blood gas.
B. Dalhousie Dyspnea Scale.
C. Oxygen saturation.
D. Respiratory rate.
E. Pulmonary function tests.

534 Pediatrics in Review

 Substance Abuse, General Principles
Kirstin A. M. Nackers, MD,* Patricia Kokotailo, MD, MPH,* Sharon J. L. Levy, MD†
*Department of Pediatrics, University of Wisconsin School of Medicine and Public Health, Madison, WI.
AUTHOR DISCLOSURE Drs Nackers,
Kokotailo, and Levy have disclosed no
financial relationships relevant to this article.
This commentary does not contain
a discussion of an unapproved/investigative
use of a commercial product/device.
†
Division of Developmental Medicine, Boston Children’s Hospital, Boston, MA.
Educational Gap
The American Academy of Pediatrics recommends screening for alcohol
and other drug use at adolescent health supervision visits and appropriate
acute-care visits, (1) yet many clinicians find addressing substance use
with youth to be a challenge.
Objectives After completing this article, the reader should be able to:
1. Describe the use trends for alcohol and common other drugs by youth
in the United States.
2. Explain the primary care clinician’s role in screening and management
of alcohol and substance use.
3. Using motivational interviewing techniques, adopt an in-office brief
intervention across the spectrum of adolescent substance use.
4. Analyze the utility of urine drug testing in various clinical situations,
such as random screening in a low-risk patient/population, testing an
adolescent who self-reports ongoing substance use, monitoring
adherence to treatment for a substance use disorder, and evaluating
a patient with signs/symptoms of acute toxicity.
NATURE OF THE PROBLEM
Adolescent drug and alcohol use remains a major issue in the United States.
The American Academy of Pediatrics (AAP) recommends screening for use of
these substances at adolescent health supervision visits and appropriate acute-
care visits. (1) Primary care clinicians (PCCs) serve an important role in both
the identification and management of alcohol and substance use disorders
(SUDs). This role comes with many challenges, including managing the
dynamics of families that may be in crisis, issues of adolescent confidentiality,
and high variability of local resources to support patients in need of treatment
for SUDs. In this article, we review the epidemiology of alcohol and substance
use, the approach to screening and treatment, the issue of adolescent confi-
dentiality, and the role of urine drug testing.
Epidemiology
The epidemiology of adolescent substance use must be considered differently
than for many other diseases. Epidemiologic measures traditionally focus simply
Vol. 36 No. 12 DECEMBER 2015 535
 on substance use, although use of alcohol and other drugs
(AOD) among adolescents ranges from experimentation to
SUD. The incidences of health consequences related to use,
such as SUD, endocarditis related to intravenous drug use, or
alcohol-related liver disease, are other traditional epidemio-
logic measures. However, these late-stage manifestations are
less common in pediatric populations and could underesti-
mate problematic AOD use. Because of this, including de-
scriptions of the patterns of use provides a more robust
understanding of the epidemiology of adolescent substance
use.
Many groups have studied patterns of adolescent AOD
use. The epidemiologic data provided here are from the
national 2014 Monitoring the Future (MTF) report. (2) Use
rates have varied over the course of the study, which began in
1975. Use at different ages are tracked by the study (8th, 10th,
and 12th graders) in parallel (Fig 1).
Alcohol, tobacco, and marijuana are among the substances
most frequently used by adolescents. Although nonmedical use
of prescription medications is reported at lower rates, such use
continues to be problematic. Overall rates of use by youth for
many substances have declined, although use levels still remain
relatively high and substance use continues to be a substantial
public health problem for this age group.
In earlier years of the MTF study, alcohol use ran parallel
to use of any illicit substance. In the past 15 years, alcohol use
has steadily declined to record lows at 66% of 12th graders
reporting any use and 49.8% reporting having been drunk
before completing high school. Approximately 50% of high
Figure 1. Trends in lifetime prevalence of illicit drug use among 8th-, 10th-,
and 12th-grade students. Reproduced from Monitoring the Future. (2)
536 Pediatrics in Review
school students have used alcohol by 10th grade. Tobacco
use has similarly declined, with 34.4% of 12th graders
reporting having ever tried cigarettes and 6.7% reporting
daily use in 2014 compared with the most recent peaks of
65.4% and 24.6% in 1997, respectively. Statistics from
2014 show cigarette smoking and alcohol use at their
lowest levels in the history of the survey. The new product
of e-cigarettes has made rapid inroads among adolescents,
however, and its reported prevalence is now higher than
that of tobacco cigarette smoking. (2)
The most recently reported marijuana use is stable at
44.4% for 12th graders in 2014. This comes after substantial
declines in the early 1990s, followed by increased use in the
mid-1990s to 2000s. Increases in use have been associated
with declines in perceived risk of use that have paralleled the
national conversation regarding changes in marijuana pol-
icy. Nonmedical use of prescription medications increased
significantly in the 1990s and then slowly declined from
2005 to 2008 to 19.9% lifetime prevalence among 12th
graders surveyed in 2014. Prescription drugs taken without
medical supervision include narcotics, sedatives, tranquil-
izers, and stimulants, such as amphetamines used in the
treatment of attention-deficit disorder. Narcotics other than
heroin, including the analgesic oxycodone, are among the
most dangerous of prescription drugs. Use of these drugs
declined since peaks in about 2009, with some reports from
students that they are increasingly difficult to obtain. (2)
Abused over-the-counter drugs are often cold and cough
medications containing dextromethorphan that, when taken
in large quantities to get “high,” can be dangerous. Abuse of
these over-the-counter drugs has fallen since 2006, with an
annual prevalence of less than 4.0% for 8th, 10th, and 12th
graders combined. (2)
Correlates of Use
Multiple risk factors are associated with adolescent sub-
stance use; social, biological, and genetic/epigenetic factors
likely all play a role. Socially, academic failure predisposes to
multiple types of adolescent dysfunction, including use of
AOD. Parental tolerance of adolescent substance use and
use by close contacts, such as the adolescent’s friends or even
parents, are predictive of adolescent substance use. Other
social factors, such as child abuse or family disruption, are also
associated. In contrast, a sense of connectedness, either to
school, family, or community, is protective against substance
use in youth. (3)
On a neurodevelopmental level, adolescence is a critical
time with respect to substance use. The sequential matu-
ration of the typically developing brain leaves adolescents in
an “imbalanced” state. During adolescence, the incentive
and reward neuronal pathways are very active. In contrast,
the prefrontal cortex, involved in executive function, is one
of the last areas to mature in the early to mid-third decade of
life. This later maturation partially explains the increased
risk-taking behavior seen among adolescents. As a result
of active incentive and reward pathways and still developing
executive function, substance exposure is more likely and
results in activation and reinforcement of those incentive and
reward pathways in response to the substance used. This
leaves youth uniquely vulnerable to the development of
problematic substance use, and early drug use is associated
with a higher probability of SUDs. Differences in brain
architecture and neurocognitive function have also been
noted in adolescents using alcohol and marijuana compared
to nonusing controls. Genetic predisposition is believed to be
contributory; this and epigenetic contributors (the impact of
environmental and social factors on gene expression) are
areas of active study. (3)
All of these correlates of use inform areas for ongoing
study and intervention. There are opportunities for inter-
vention at the level of the individual and community or more
broadly through public policy. Within the local community,
involvement of clinicians in substance use education in
schools and communities is one important opportunity for
primary prevention of substance use.
Diagnosis
Diagnostic criteria for specific SUDs were redefined in the
fifth edition of the American Psychiatric Association’s Diag-
nostic and Statistical Manual of Mental Disorders (DSM-V), (4)
combining prior diagnoses that distinguished between addic-
tion and dependence. A representative example for cannabis
use disorder is shown in Table 1.
SCREENING, BRIEF INTERVENTION, AND REFERRAL TO
TREATMENT (SBIRT)
Pediatricians and other PCCs have a well-recognized role in
the prevention, detection, and management of many risk
behaviors, including substance use. The AAP recommends
universal screening of adolescents for tobacco, alcohol, and
other drug use with a formal validated screening tool at every
health supervision visit and appropriate acute-care visits. (1)
In some instances, substance use is the reason for medical
evaluation, either directly or indirectly. A caregiver may bring
the patient in for suspected/observed use or because of other
concerning behavior that is less specific for substance use.
Adolescent dysfunction, such as decreased school perfor-
mance, delinquency, multiple sexual partners, family conflict,
running away from home, depression, or suicide attempts,
may be concomitant with substance use/abuse. Psychiatric
symptoms are common among adolescents with SUDs.
Many adolescents present with chief complaints that may
not appear to pertain to substance use. They also may benefit
from screening for use of AOD because substance use varies
from experimentation to SUD. Even adolescents who are
abstaining from substance use may benefit from discussions
that follow screening and positive reinforcement of healthy
lifestyle choices. The US Preventive Services Task Force
recently concluded that evidence is insufficient to support
brief interventions for adolescent AOD use. However, the
AAP and US Substance Abuse and Mental Health Services
Administration still recommend SBIRT, based on the very
low cost and low risk of the intervention, with the caveat that
further research studies are needed. The AAP will provide
further guidance on evidence-based approaches to screening
and appropriate interventions for problematic substance use
in their upcoming policy statement on SBIRT, updated from
the initial 2011 statement.
Screening
A variety of methods are available to screen for adolescent
substance use and are often incorporated into health super-
vision visits as part of broader adolescent screens. Recently,
the US National Institute on Drug Abuse funded the devel-
opment of brief adolescent substance abuse screening tools
that are self- or interviewer-administered and compatible with
electronic health records. The Screening to Brief Intervention
tool (S2BI) uses a comprehensive stem question and forced
response items to assess the frequency (none, once or twice,
monthly, weekly or more) of past-year use for tobacco, alcohol,
marijuana, and five other classes of substances commonly
used by adolescents. In the initial validation study, this tool had
high sensitivity and specificity for discriminating among clin-
ically relevant risk categories of adolescent substance use: no
use, substance use without a SUD (correlated to a response of
use “once or twice”), mild or moderate SUD (correlated to
a response of “monthly”), and severe SUD (correlated to
a response of “weekly or more”). Although these results require
validation in studies with larger samples, the excellent psycho-
metric properties of the screen, the ability for both self and
interviewer administration, and the fact that the process takes
less than 1 minute to complete are very promising. Figure 2 is
a clinical SBIRT algorithm based on the S2BI tool. (5)
Motivational intervention is recommended as a next step
following monthly or weekly use reported for eight types of
drugs in the past year on the S2BI screen. The CRAFFT
questions can be used for brief assessment of problems
associated with substance abuse and as well as facilitation of
a plan: (6)
Vol. 36 No. 12 DECEMBER 2015 537
 TABLE 1. Diagnostic and Statistical Manual of Mental Disorders (5th Edition)
Diagnostic Criteria for Cannabis Use Disorder
Note: specific substance use disorders are defined for each major drug class, for example, alcohol use disorder, phencyclidine use disorder, and so
on. Cannabis use disorder is presented here as a representative sample.
A pattern of cannabis use leading to clinically significant impairment or distress, as manifested by at least two of the following, occurring within
a 12 month period:
1. Cannabis is often taken in larger amounts or over a longer period than was intended.
2. There is a persistent desire or unsuccessful efforts to cut down or control cannabis use.
3. A great deal of time is spent in activities necessary to obtain cannabis, use cannabis, or recover from its effects.
4. Craving, or a strong desire or urge to use cannabis.
5. Recurrent cannabis use resulting in a failure to fulfill major role obligations at work, school, or home.
6. Continued cannabis use despite having persistent or recurrent social or interpersonal problems caused or exacerbated by the effects of
cannabis.
7. Important social, occupational, or recreational activities are given up or reduced because of cannabis use.
8. Recurrent cannabis use in situations in which it is physically hazardous.
9. Cannabis use is continued despite knowledge of having a persistent or recurrent physical or psychological problem that is likely to have been
caused or exacerbated by cannabis.
10. Tolerance, as defined by either of the following:
a. A need for markedly increased amounts of cannabis to achieve intoxication or desired effect.
b. A markedly diminished effect with continued use of the same amount of cannabis.
11. Withdrawal, as manifested by either of the following:
a. The characteristic withdrawal syndrome for cannabis (refer to Criteria A and B of the criteria set for cannabis withdrawal).
b. Cannabis (or a closely related substance) is taken to relieve or avoid withdrawal symptoms.
Specify if:
• In early remission: After full criteria for cannabis use disorder were previously met, none of the criteria for cannabis use disorder have been
met for at least 3 months but for less than 12 months (with the exception that Criterion A4, “Craving, or a strong desire or urge to use
cannabis,” may be met).
• In sustained remission: After full criteria for cannabis use disorder were previously met, none of the criteria for cannabis use disorder have
been met at any time during a period of 12 months or longer (with the exception that Criterion A4, “Craving, or a strong desire or urge to use
cannabis,” may be met).
Specify if:
• In a controlled environment: This additional specifier is used if the individual is in an environment where access to the cannabis is restricted.

Specify current severity:

Mild: Presence of 2–3 symptoms.
Moderate: Presence of 4–5 symptoms.
Severe: Presence of 6 or more symptoms.

Reproduced from the DSM-V. (4)

C Have you even ridden in a CAR driven by someone (including
yourself) who was “high” or had been using alcohol or drugs?
R Do you ever use alcohol or drugs to RELAX, feel better
about yourself, or fit in?
A Do you ever use alcohol or drugs while you are by yourself
or ALONE?
F Do you ever FORGET things you did while using alcohol
or drugs?
F Do your family or FRIENDS ever tell you that you should
cut down on your drinking or drug use?
T Have you ever gotten into TROUBLE while you were using
alcohol or drugs?

538 Pediatrics in Review

Figure 2. S2BI algorithm.  Boston Children’s Hospital 2014. All rights reserved. This work is licensed under a Creative Commons Attribution-
NonCommercial 4.0 International License. Reprinted with permission.

The National Institute on Alcohol Abuse and Alcoholism friends’ use patterns, then asking about individual use. The
(NIAAA) has an alternate alcohol use screen that can be order of questions should be reversed for older adolescents.
adapted to younger patients. They recommend screening (Fig 3). In addition to assessing current use, this approach
middle school-age and younger patients by asking first about helps identify patients who may be abstaining currently but

Figure 3. National Institute on Alcohol Abuse and Alcoholism (NIAAA) two-step alcohol screen by patient age. (7)

Vol. 36 No. 12 DECEMBER 2015 539

 TABLE 2. Substance Use Spectrum and Goals for Office Intervention
STAGE DESCRIPTION
Abstinence The time before an individual has ever used drugs or
alcohol (more than a few sips)
Experimentation The first 1-2 times that a substance is used and the
adolescent wants to know how intoxication from
using a certain drug(s) feels
Limited use Use together with ‡ 1 friend(s) in relatively low-risk situations
and without related problems; typically, use occurs at
predictable times such as on weekends
Problematic use Use in a high-risk situation, such as when driving or
babysitting; use associated with a problem such as
a fight, arrest, or school suspension; or use for emotional
regulation such as to relieve stress or depression
Substance use Drug use associated with recurrent problems or that
disorder interferes with functioning, as defined in the DSM-V
DSM-V¼Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition.
Adapted from: Committee on Substance Abuse, Levy SJ, Kokotailo PK. Substance use screening, brief intervention, and referral to treatment for
pediatricians. Pediatrics. 2011;128(5):e1330–1340. Available at: http://pediatrics.aappublications.org/content/128/5/e1330.full.
are at risk for future use. Follow-up questions and manage-
ment algorithms are described in the NIAAA’s Alcohol Screen-
ing and Brief Intervention For Youth: A Practitioner’s Guide. (7)
The CRAFFT questions begin to assess the patterns of
use and associated problems. Determining the specific
substances used as well as the frequency and amount of
use is critical to understand specific risks. Understanding
the circumstances of use can identify other risks associated
with use and inform intervention strategies. This informa-
tion can also help a clinician place a patient on the spectrum
from abstinence to SUD (Table 2).
The caregiver may provide important historical informa-
tion that is critical for determining further management. The
caregiver who has concerns about his or her child’s suspected
or known substance use can give additional insight into the
symptoms he or she has observed and may share school or law
enforcement records that pertain to the patient’s substance
use. Parental opinions about drug/alcohol use and even their
own personal substance use may also affect adolescent behav-
ior. In addition to the caregiver’s contributions to the history of
present illness, a detailed family and social history should be
obtained.
Brief Intervention in the Primary Care Office
Management varies, depending upon level of use and asso-
ciated risk factors, as shown in the S2BI algorithm (Fig 2). The
540 Pediatrics in Review
OFFICE INTERVENTION GOALS
Prevent or delay initiation of substance use through
positive reinforcement and patient/parent education
Promote patient strengths; encourage abstinence and
cessation through brief, clear medical advice and
educational counseling
Promote patient strengths; further encourage cessation
through brief, clear medical advice and educational
counseling
As stated above, plus initiate office visits or referral for brief
intervention to enhance motivation to make behavioral
changes; provide close patient follow-up; consider
breaking confidentiality
Continue as stated above, plus enhance motivation to
make behavioral changes by exploring ambivalence
and triggering preparation for action; refer for
comprehensive assessment and treatment; consider
breaking confidentiality; encourage parental
involvement whenever possible
first steps in management of adolescent substance use and
SUDs is a brief intervention based on motivational interview-
ing techniques, followed by referral to treatment as appropri-
ate. The goal of motivational interviewing is to assess the
patient’s readiness to make a change, help him/her to identify
reasons for change, and support his/her autonomy to do so.
The desired change may be discontinuation of substance use
or may focus on risk reduction, depending upon the patient’s
level and risks of use. Although the quality of research on the
effectiveness of motivational interviewing techniques for
reducing substance use and related problems has varied, it
is believed to have substantial effects for intervention in
adolescents and young adults. (8) Examples of motivational
interviewing are reviewed here briefly; the seminal work by
Miller and Rollnick provides more detailed information. (9)
During the brief intervention, the interviewer should
partner with the patient. The conversation may include
exploration of life goals, reasons for substance use, and
disadvantages or consequences of use. Reflective listening
and repeating back this information can help highlight how
substance use and its consequences may interfere with aspi-
rations and may help inspire the patient to make a healthy
change. For example, “It sounds like you and your friends
smoke marijuana as a way to relax on the weekends. On the
other hand, you’ve found this is an expensive habit and noticed
you feel more depressed as you’ve started smoking more. You
were also kicked off the soccer team because you got caught.
What do you make of this?” A long pause, waiting for the
patient to consider this representation of his or her statements
before responding, can be revealing.
All patients and their families can benefit from anticipa-
tory guidance about the dangers of AOD use. This may include
problem-solving to minimize the risks, such as avoidance of
drinking and driving, and advice to parents about appropriate
monitoring. Local resources through organizations such as
Safe Rides or Students/Mothers/Dads Against Drunk Driving
may help patients develop a safety plan to mitigate risks of use.
For patients who report no substance use, positive rein-
forcement and brief advice “not to use” can help to maintain
abstinence in the future and encourage patients to plan how
they might succeed in continuing to abstain. Anticipatory
guidance should also be provided as noted previously. Some
teens may be at low risk in that they abstain from substance use
but still be at risk for morbidity and mortality due to riding in
a vehicle operated by a driver who is under the influence of
alcohol or drugs. For these patients, it is important to help them
recognize this as a risk and develop a safety plan to avoid it in
the future. Consider breaking confidentiality if the patient
cannot or will not commit to safety.
Adolescents who report using a substance “once or twice” in
the past year are unlikely to have a SUD or related problems. A
brief explanation of health risks and advice to not use sub-
stances is appropriate. For adolescents with mild-to-moderate
SUD, a brief motivational intervention starting with the pre-
viously noted CRAFFT questions is recommended. Motiva-
tional interviewing techniques can be used to identify
consequences of use or the potential for use to interfere with
perceived strengths and future plans. The core activity of the
brief intervention involves comparing the benefits of continued
substance abuse with the benefits of behavioral change. The goal
TABLE 3. Signs of Acute Danger(1)
• Drug-related hospital visits
• Intravenous drug use
• Combining sedatives (alcohol, benzodiazepines, barbiturates, opioids)
• Consuming a potentially lethal volume of alcohol
• Driving or engaging in other potentially dangerous activities after alcohol
or drug use
Follow-up:
✓ If signs of acute danger are present, refer for detailed evaluation and subspecialty treatment.
✓ Whenever signs of acute danger are present, safety planning must occur. A safety contract and close follow-up to ensure safety and
compliance may be helpful. Consider breaking confidentiality if adolescents are unwilling or unable to commit to safety.
✓ If not present, proceed with an in-office brief intervention.
of discussion is to help adolescents commit to discontinuing or
decreasing use.
Adolescents with severe SUDs need referral for treatment.
Additional information about patterns of use is necessary to
assess for acute danger or SUD (Table 3); focused questions can
help diagnose SUDs according to the DSM-V criteria (Table 1).
Referral to Subspecialty Treatment
Local resources for adolescent SUD treatment may vary and
extend beyond the medical realm into school and community
resources. PCCs should familiarize themselves with local
resources, which may include school counseling services,
mental health facilities, or drug and alcohol treatment centers.
Referral to addiction medicine, adolescent medicine, or
mental health specialists may be appropriate for subsequent
evaluation, counseling, and possible pharmacotherapy. The
subspecialty clinician can help determine the appropriate level
of therapy (Table 4).
The PCC plays an important role in this process as well.
First, he/she must engage the patient and family in a con-
versation at the time of referral to prepare them for the next
steps in evaluation and treatment. Frequent PCC follow-up
throughout the ongoing subspecialty management can
sometimes prevent or at least help with early identification
of relapse. Unlike many medical conditions where cure is
more easily attainable, relapse is common and expected
with SUDs. Patients remain at risk for relapse years after
attaining sobriety, and relapse can serve as a learning oppor-
tunity during recovery.
CONFIDENTIALITY
Substance use falls within the bounds of adolescent confiden-
tiality (along with mental health, sexuality, and reproductive
Vol. 36 No. 12 DECEMBER 2015 541
 TABLE 4. Substance Use Treatment
OUTPATIENT

Group therapy Group therapy is a mainstay of substance abuse treatment for adolescents with substance use disorder.
It is a particularly attractive option because it is cost-effective and takes advantage of the developmental
preference for congregating with peers. However, group therapy has not been extensively
evaluated as a therapeutic modality in this age group, and existing research has produced mixed
results. (10)(11)
Family therapy Family-directed therapies are the best validated approach for treating adolescent substance abuse.
A number of modalities have been demonstrated effective. Family counseling typically targets domains
that figure prominently in the etiology of substance use disorder in adolescents: family conflict,
communication, parental monitoring, discipline, child abuse/neglect, and parental substance use
disorder. (10)
Intensive outpatient program Intensive outpatient programs serve as an intermediate level of care for patients who have needs that are
too complex for outpatient treatment but do not require inpatient services. These programs allow
people to continue with their daily routine and practice newly acquired recovery skills both at home and
at work.
Intensive outpatient programs generally comprise a combination of supportive group therapy, educational
groups, family therapy, individual therapy, relapse prevention and life skills, 12-step recovery, case
management, and aftercare planning. The programs range from 2–3 h/d for 2–5 d/wk and last
1–3 months. These programs are appealing because they provide a plethora of services in a relatively
short period of time.a (12)
Partial hospital program Partial hospitalization is a short-term, comprehensive outpatient program in affiliation with a hospital that is
designed to provide support and treatment for patients with substance use disorder. The services
offered at these programs are more concentrated and intensive than regular outpatient treatment; they
are structured throughout the entire day and offer medical monitoring in addition to individual and
group therapy. Participants typically attend sessions for 7 or 8 h/d, at least 5 d/wk, for 1–3 weeks. As
with intensive outpatient programs, patients return home in the evenings and have a chance to
practice newly acquired recovery skills.b (13)
INPATIENT/RESIDENTIAL
Detoxification Detoxification refers to the medical management of symptoms of withdrawal. Medically supervised
detoxification is indicated for any adolescent who is at risk of withdrawing from alcohol or
benzodiazepines and might also be helpful for adolescents withdrawing from opioids, cocaine, or other
substances. Detoxification may be an important first step but is not considered definitive treatment.
Patients who are discharged from a detoxification program should then begin either an outpatient or
residential substance abuse treatment program. (11)(14)
Acute residential treatment Acute residential treatment is a short-term (days to weeks) residential placement designed to stabilize
patients in crisis, often before entering a longer-term residential treatment program. (14) Acute
residential treatment programs typically target adolescents with co-occurring mental health disorders.
Residential treatment Residential treatment programs are highly structured live-in environments that provide therapy for those
with severe substance abuse, mental illness, or behavioral problems that require 24-hour care. The goal
of residential treatment is to promote the achievement and subsequent maintenance of long-term
abstinence and equip each patient with both the social and coping skills necessary for
a successful transition back into society. Residential programs are classified as short-term (<30 d)
or long-term (>30 d).
Residential programs generally comprise individual and group-therapy sessions plus medical,
psychological, clinical, nutritional, and educational components. Residential facilities aim to simulate real
living environments with added structure and routine to prepare patients with the framework necessary
for their lives to continue drug- and alcohol-free after completion of the program.c (15)
Therapeutic boarding school Therapeutic boarding schools are educational institutions that provide constant supervision for their
students by a professional staff. These schools offer a highly structured environment with set times for all
activities; smaller, more specialized classes; and social and emotional support. In addition to the regular
services offered at traditional boarding schools, therapeutic schools also provide individual and group
therapy for adolescents with mental health or substance use disorder.d (16)
a
See www.ncbi.nlm.nih.gov/books/NBK25875.
b
See http://www.cignabehavioral.com/web/basicsite/provider/providerOnlyPage.jsp.
c
See www.ncbi.nlm.nih.gov/books/NBK25881.
d
See www.ncbi.nlm.nih.gov/books/NBK24159.
Reproduced from Committee on Substance Abuse, Levy SJ, Kokotailo PK. Susbstance use screening, brief intervention, and referral to treatment for
pediatricians. Pediatrics. 2011;128(5):e1330–1340. Available at: http://pediatrics.aappublications.org/content/128/5/e1330.full.

542 Pediatrics in Review

health issues), as endorsed by the AAP and Society for
Adolescent Medicine. (17)(18) It is often helpful to review
with both the minor patient and his or her caregiver
examples of what can be kept confidential as well as the
limits of confidentiality (abuse, self-injury, plans to harm
others). Substance use screening subsequently may be
performed with the adolescent privately, although issues
may need to be addressed with patient and caregiver together,
depending upon the degree of danger present to self and
others.
There are some limits to confidentiality as well as times
when it is helpful to encourage adolescents to disclose their
substance use to their caregivers. Depending upon local
laws, many adolescents may be able to obtain confidential
treatment for alcohol or SUDs. Despite this, adolescents
tend to be more successful in treatment when well sup-
ported, and clinicians should encourage adolescents to
disclose AOD use to their parents. Clinicians can serve
an important role in facilitating this discussion. Consider
breaking confidentiality in situations where adolescents are
engaging in substance use behaviors that are high risk for
morbidity and mortality, especially if the adolescent states
that he/she cannot or will not make a change or disclose to
caregivers.
DRUG TESTING
Testing for evidence of drug use can be particularly helpful for
monitoring compliance with SUD treatment and in cases of
acute intoxication where identification of specific substances
guides acute medical management. It is not a routine part of
substance use screening and is not necessary to initiate
substance use treatment; a thorough history is most impor-
tant. Caregivers may request that a teen undergo drug
testing, sometimes without the teen’s consent or knowledge.
Testing without the patient’s consent undermines the ther-
apeutic relationship between physician and patient. The AAP
also opposes widespread implementation of school drug
testing programs because of the lack of solid evidence for
their effectiveness. (19)
A request for drug testing often can be addressed by
eliciting the caregiver’s concern and reasons for wanting
the test, sharing the limitations of testing, and facilitating
a discussion with patient and caregiver together. The
discussion should include consideration of how different
possible outcomes of the test may alter (or not alter) the
care plan. If the patient admits to substance use, testing
may not improve management. Alternatively, some pa-
tients may want to take a test to show their caregivers that
they are not using a substance. This conversation also can
elicit challenging family dynamics not related to substance
use and may support referral for individual or family
counseling.
The type of drug testing used depends upon local re-
sources. Urine drug testing is most common, is readily
available, and has been most rigorously studied. However, it
is also easy to adulterate or substitute a specimen if not
collected under direct observation. Tests have variable sen-
sitivity and specificity, with frequent false-positive or false-
negative results. False-positive results may be due to certain
food products or medications and vary somewhat, depend-
ing upon the specific assay used. Most urine drug tests are
screening immunoassays, and clinicians should consider
confirmatory testing of positive screening tests by gas chro-
matography/mass spectroscopy, depending upon the situa-
tion and ramifications of a positive result. False-negative
results may occur due to variation in hydration status and the
limitations of the test itself, such as the cutoff concentration
and window of detection. Even multitest panels cannot
detect every psychoactive substance. For example, syn-
thetic cannabinoids, dextromethorphan, and methylene-
dioxymethamphetamine (MDMA/Ecstasy/Molly) have all
recently had periods of popularity among teens but are
not typically included in test panels. Inhalants are not
excreted in the urine and cannot be detected by urine tests.
The specific substance, an individual’s metabolism, and the
frequency and amount of use all affect the window of
detection, which generally ranges from days to weeks.
For example, marijuana can be detected in the urine for up
to about 3 days after single use and up to 1 month with
chronic heavy use. (20)
Summary
• On the basis of strong evidence, alcohol, tobacco, and marijuana
remain the most commonly abused substances by youth;
nonmedical use of prescription drugs is also of great concern.
• On the basis of strong research and substantiated experiential
evidence, screening, brief intervention, and referral to treatment
is a widely used approach to substance use screening and
management; additional study is needed to determine the
most effective screening tools and impact of in-office brief
intervention.
• On the basis of consensus, management of adolescent substance
use remains challenging, in part due to confidentiality issues;
clinicians must use their best judgment to determine when
significant risks may warrant breaking confidentiality.
• On the basis of consensus, family input and support with referrals
to treatment remain very important factors in recovery.
Vol. 36 No. 12 DECEMBER 2015 543
 CONCLUSION
Although use of some substances is on the decline, use of
alcohol and other drugs remains a substantial public health
problem for many youth in the United States. (2) Better
screening and brief interventions have been developed and
continue to be actively studied. (1)(5)(7) Coordination of contin-
ued management and referral to treatment remain an important
yet challenging role for clinicians dealing with adolescents.
Current recommendations are based on research evidence (5)
(7)(8) as well as consensus. Ongoing research in the neuro-
developmental aspects of substance use and abuse as well as
screening and interviewing strategies should aid in developing
better management strategies and improve evidence-based
practice in this area.
CME quiz and references for this article are at http://pedsinreview.
aappublications.org/content/36/12/535.full.

PIR Quiz
There are two ways to access the journal CME quizzes:
1. Individual CME quizzes are available via a handy blue CME link in the Table of Contents of any issue.
2. To access all CME articles, click “Journal CME” from Gateway’s orange main menu. Use the publications filter at right to refine
results to a specific journal.

1. You are asked to speak to parents and teachers about adolescent alcohol and other drug use at your REQUIREMENTS: Learners
local high school. Which of the following statements most accurately describes the rates of use of can take Pediatrics in Review
alcohol and other drugs in the United States? quizzes and claim credit
A. Nonmedical use of prescription drugs has increased over the past decade. online only at: http://
B. Use of alcohol has increased over the past 15 years. pedsinreview.org.
C. Use of marijuana is currently stable, having increased from the mid-1990s to 2000s.
D. Use of narcotics other than heroin has increased since 2009. To successfully complete
E. Use of tobacco has increased over the over the past 15 years. 2015 Pediatrics in Review
2. You are seeing an 18-year-old male high school senior in your office for a general health supervision articles for AMA PRA Category
visit. You ask the parents to leave the room and ask the teen about substance use. He denies smoking 1 CreditTM, learners must
any marijuana or using any other substances or drugs to get “high.” However, he does admit to demonstrate a minimum
drinking several beers a month, usually at parties. Which of the following would you do next in the performance level of 60% or
office? higher on this assessment,
A. Ask the parents to come back in the room and continue your history in their presence. which measures
B. Do nothing because most 12th graders report use of alcohol. achievement of the
C. Obtain further information to determine the extent and risk of alcohol use. educational purpose and/or
D. Obtain random urine drug screen. objectives of this activity. If
E. Refer the teen to an alcohol counselor for further evaluation. you score less than 60% on
the assessment, you will be
3. Which of the following statements regarding urine drug testing is most accurate?
given additional
A. A negative urine drug screen rules out substance use. opportunities to answer
B. It can be helpful to monitor compliance with a substance use disorder treatment. questions until an overall
C. It is a routine part of substance use screening. 60% or greater score is
D. It is necessary to initiate substance use treatment. achieved.
E. It should be obtained at parents’ request if the patient has falling grades.
4. A 17-year-old female whom you are screening for substance use during a general health supervision
This journal-based CME
visit admits to alcohol and marijuana use. You use the CRAFFT screening tool to further evaluate her
activity is available through
substance use and discover that she admits to driving under the influence of alcohol and sometime
Dec. 31, 2017, however,
using marijuana to relieve stress. Of the following, the substance use stage that best describes this
credit will be recorded in the
patient is:
year in which the learner
A. Addiction. completes the quiz.
B. Experimentation.
C. Limited use.
D. Problematic use.
E. Substance use disorder.
5. Which of the following is a red flag for a substance abuse disorder?
A. Alcohol-related blackouts.
B. CRAFFT score¼3.
C. Drinking alcohol when babysitting.
D. First use of alcohol at age 16 years.
E. Use of alcohol on weekends.

544 Pediatrics in Review


EDITORS NOTE
We invite readers to contribute Index of
Suspicion cases at: Submit and Track My
Manuscript.
AUTHOR DISCLOSURE Dr Brady has
disclosed that she has received research grant
funding from Pfizer for a quality improvement
project to improve vaccination receipt among
adolescents with high-risk and
immunocompromising conditions. Dr
Crawford has disclosed no financial
relationships relevant to this article. This
commentary does contain a discussion of an
unapproved/investigative use of
a commercial product/device.
Clavicular Pain of 2 Months’ Duration in a
1 9-year-old Girl
Rebecca C. Brady, MD,* Alvin H. Crawford, MD*
*Cincinnati Children’s Hospital Medical Center, Cincinnati, OH.
PRESENTATION
A 9-year-old girl presents with a 2-month history of left clavicle pain. She has no
history of trauma, fever, chills, or weight loss. She developed swelling of her left
lateral clavicle about 2 weeks ago, but there has been no redness or drainage. Her
past medical history is unremarkable. She lives with her family on a farm in
southern Kentucky.
On physical examination, her vital signs are within normal parameters. There
is tenderness and firm swelling over the lateral one-third of the left clavicle
without overlying warmth or skin changes. The range of motion of her left
shoulder is normal. No cervical, axillary, or supraclavicular adenopathy is present.
Her lungs are clear. The rest of the physical examination findings are normal.
A radiograph of the left clavicle reveals bony expansion and periosteal reaction
involving the inferior border of the left distal clavicle. Because this finding is
concerning for a bone tumor, additional laboratory and radiographic studies are
obtained. The white blood cell count is 7,900/mL (7.9  109/L) with a differential
count of 70% segmented neutrophils, 23% lymphocytes, and 7% monocytes.
Platelet count is 328  103/mL (328  109/L) and erythrocyte sedimentation rate is
31 mm/hr (reference range, 0–10 mm/hr). Serum uric acid and lactate dehydro-
genase values are normal. Radiographs of the chest and upper arm do not reveal
additional disease. The only finding on technetium bone scan is significantly
increased uptake in the lateral 40% of the left clavicle. An open biopsy of the
clavicle mass establishes the diagnosis.
DISCUSSION
Histopathologic examination of the clavicle revealed acute and chronic granulo-
matous inflammation with scattered multinucleated giant cells. Gram stain was
negative, but the Grocott-Gomori methenamine-silver nitrate (GMS) stain showed
scattered yeast of 8 to 10 mm. Empiric itraconazole (200 mg orally daily) was started
for suspected fungal osteomyelitis. Within 3 weeks, growth of Blastomyces dermatitidis
was detected and confirmed by chemiluminescent DNA probe. The girl received
itraconazole for 12 months, and her clavicle pain and swelling resolved.
The Condition
B dermatitidis is a dimorphic fungus that exists as a yeast form at 37°C in infected
tissues and as a mycelial form in soil and at room temperature. Conidia, produced
Vol. 36 No. 12 DECEMBER 2015 545
 from hyphae of the mycelial form, are infectious. B dermatitidis
inhabits soils throughout the midwestern, south central,
and southeastern United States. Infection is acquired most
commonly through inhalation of conidia from soil. Within
the lungs, the conidia transition to the yeast phase, and
individuals may either remain asymptomatic or develop an
acute illness resembling influenza or bacterial pneumonia.
From the lungs, the infection may disseminate hematoge-
nously to the skin and bones. In children, blastomycosis
most commonly disseminates to bones. The long bones,
ribs, and vertebrae are involved most frequently. Focal
osteolytic lesions of blastomycosis may be painful.
Differential Diagnosis
The differential diagnosis of chronic osteolytic lesions of the
clavicle includes aneurysmal bone cysts, infections (blasto-
mycosis and tuberculosis), malignant tumors such as Ewing
sarcoma, and inflammation associated with chronic recur-
rent multifocal osteomyelitis (CRMO).
Children with aneurysmal bone cysts present with pain,
swelling, or a pathologic fracture of the involved bone. The
mean age at onset is 13 to 18 years. Aneurysmal bone cysts
most commonly affect the long tubular bones, followed by
the spine and flat bones. They are benign osteolytic lesions
that may grow rapidly, leading to bone destruction.
Most tuberculosis infections do not produce symptoms
in children. When tuberculosis disease occurs, children
may present with fever, weight loss, night sweats, and
cough. Tuberculosis may disseminate to bones, especially
the vertebrae.
Ewing sarcoma in children is characterized by focal bone
pain and swelling that progressively worsens. The femur is
the most commonly involved bone, but virtually any bone may
be affected. Radiographs may demonstrate a poorly margin-
ated, lytic lesion with an onion skin periosteal reaction.
Osteolytic lesions of the clavicle are commonly reported
in children with CRMO, an inflammatory bone disease of
unknown cause. Children who have CRMO may present with
focal bone pain at one or more sites. The medial clavicle, tibia,
femur, and vertebral bodies are often affected. Radiographs
usually reveal lytic lesions with sclerosis and new bone for-
mation. Technetium bone scans may reveal clinically silent
lesions. Cultures are negative with CRMO, and biopsies
demonstrate nonspecific fibrosis and inflammation.
Diagnosis
The range of differential diagnoses for a child with a chronic
osteolytic lesion of the clavicle underscores the importance
of a thorough evaluation. The history should include ques-
tions about the child’s general health and travel. The
546 Pediatrics in Review
physical examination should initially focus on the shoulder,
upper arm, and chest. Sites of bone pain, swelling, and
limitation of movement should be carefully sought. A
general survey of the body is warranted because other
findings may provide important clues. The presence of
regional lymphadenopathy may suggest either infection
or malignancy. Radiographs should include the clavicle,
chest, and upper arm. Children with blastomycosis or
tuberculosis may have associated primary pulmonary dis-
ease. A bone scan may reveal additional sites of bone
involvement in CRMO. Prompt referral to an orthopedic
surgeon or interventional radiologist is required for biopsy
to establish a definitive diagnosis. Cultures for aerobic and
anaerobic bacteria, mycobacteria, and fungi should be ob-
tained. When granulomatous inflammation is present, acid-
fast stains for mycobacteria and GMS stain for fungi may aid
in diagnosis.
The definitive diagnosis of osteomyelitis due to B
dermatitidis requires isolation of the fungus from infected
bone. When specimens are cultured on Sabouraud dextrose
agar at 25°C to 30°C, B dermatitidis produces fluffy white
mycelial colonies within 1 to 3 weeks. Identification is
confirmed by either conversion to the yeast form, growth
at 37°C, or a positive test with a DNA probe. Often, as was
true in this case, the detection of thick-walled, broad-based,
single-budding yeast cells of 8 to 20 mm in diameter using
the GMS stain provides a presumptive diagnosis of blasto-
mycosis. Serologic tests lack both sensitivity and specificity
and, therefore, are not generally helpful in diagnosing
blastomycosis.
Management
Osteoarticular blastomycosis responds to curettage and
biopsy combined with antifungal therapy, usually either
an azole or amphotericin B. Itraconazole is indicated for
the treatment of nonmeningeal, non-life-threatening in-
fections in adults. Although the safety and efficacy of
itraconazole in children with blastomycosis has not been
established, it is recommended for use in children in this
setting. The recommended duration of treatment for
osteomyelitis is at least 1 year because bone disease is
difficult to treat and likely to relapse.
Lessons for the Clinician
• When a child presents with chronic clavicle pain, the
shoulder, upper arm, and chest require careful exami-
nation. Radiographs of the clavicle are recommended.
• The differential diagnosis of osteolytic lesions includes
aneurysmal bone cysts, infections, malignant bone tu-
mors, and inflammatory conditions.
• Prompt biopsy with special stains and cultures of
clavicle lesions aids in diagnosis and management
decisions.
• Residence and travel history may provide clues to fungal
infections.
• The most common clinical manifestation of blastomy-
cosis in children is pulmonary disease, but infection may
spread hematogenously to the skin and bones.
Suggested Readings for this article are at http://pedsinreview.
aappublications.org/content/36/12/545.full.
Vol. 36 No. 12 DECEMBER 2015 547

AUTHOR DISCLOSURE Drs Rani, Imdad, and
Beg have disclosed no financial relationships
relevant to this article. This commentary does
not contain a discussion of an unapproved/
investigative use of a commercial product/
device.
548 Pediatrics in Review
2 Recurrent Anemia in a 10-year-old Girl
Uzma Rani, MBBS,* Aamer Imdad, MBBS,* Mirza Beg, MD*
*SUNY Upstate Medical University, Syracuse, NY.
PRESENTATION
A 10-year-old premenarchal girl presents to the emergency department with an
episode of syncope. She has been feeling progressively more tired for the last
week, and her mother noticed that she was pale. The girl has had intermittent
headaches but no complaints of palpitations, weight loss, abdominal pain, or
rectal bleeding. Her diet consists of vegetables and meat. She is taking oral iron
supplements because she presented with similar symptoms 4 months ago and
was found to have severe anemia (hemoglobin of 4.9 g/dL [49.0 g/L]). The cause
of the anemia at that time was determined to be iron deficiency, based on
peripheral blood smear, iron studies, and bone marrow examination. A stool
guaiac test was negative and hemoglobin electrophoresis yielded normal results.
After packed red blood cell transfusion, she was started on ferrous sulfate supple-
ments. Her anemia responded to iron supplements; her hemoglobin 3 months later
measured 11 g/dL (110 g/L). Her maternal uncle has aplastic anemia.
Physical examination findings today include: heart rate of 116 beats/min,
respiratory rate of 28 breaths/min, blood pressure of 102/52 mm Hg, oxygen
saturation of 100%, and body mass index of 15.3. The only finding of note on
physical examination is conjunctival pallor.
Laboratory test results are:
• Hemoglobin 2 g/dL (20 g/L)
• Hematocrit 9% (0.9)
• Mean corpuscular volume 67.5 mm3 (67.5 fL)
• White blood cell count 4,200/mL (4.2  109/L)
• Platelet count 363  103/mL (363  109/L)
• Reticulocyte count 10.8% (0.11)
Peripheral smear shows hypochromic microcytosis. In addition, the girl has
decreased serum iron, normal iron binding capacity, and very low ferritin. Stool
guaiac test is positive. Meckel scan is negative. Packed red blood cell transfusion is
administered. Diagnosis is determined following additional studies.
DISCUSSION
A pediatric gastroenterology consultation was obtained and esophagoduodenoscopy
was performed that revealed a mass at the antropyloric area of the stomach with
central ulceration (Figure). Biopsies from the esophagus, stomach, and small
intestine yielded normal findings. Subsequent abdominal magnetic resonance
imaging revealed a 3-cm solid mass at the antrum that was circumferential and
intramural, with the largest portion located at the greater
curvature. There was no evidence of enlarged lymph nodes
or liver or spleen masses. Laparoscopic distal gastrectomy
with Billroth-II reconstruction was performed to excise the
mass. Histopathologic examination of the mass revealed
sections composed of short, spindle-shaped cells exhibiting
mild cytologic atypia. Some areas were hypocellular with
a fibrous stroma, and others showed increased cellularity
with myxoid-like stroma. Immunohistochemistry revealed
expression of smooth muscle actin, desmin, calponin,
vimentin, and nestin by tumor cells. Stains for CD34 and
CD117 were negative. The immunophenotype was consis-
tent with a mesenchymal tumor with smooth muscle dif-
ferentiation, called gastrointestinal stromal tumor (GIST).
After surgical intervention, the patient was continued on
iron therapy, and she has since been asymptomatic, with
stable hemoglobin values. A repeat upper gastrointestinal
(GI) endoscopy and computed tomography scan of the
abdomen showed no evidence of tumor recurrence.
Condition
GI stromal tumors are mesenchymal tumors, which
account for only 1% of all GI tumors across all ages. Such
tumors in children represent 1% to 2% of all GISTs. Young
girls have 2.7-fold higher incidence and higher-grade tumor
than boys. Histology of GIST varies from epithelioid cells
and spindle cells to pleomorphic cells. Epithelioid morphol-
ogy is most common overall in children. Usually GISTs are
part of syndromes such as Carney triad (a sporadic associ-
ation of GIST, paraganglionoma, and pulmonary chondroma),
Carney Stratakis syndrome, neurofibromatosis type 1, and
familial GISTs, but they rarely can exist as separate entity.
GISTs can occur in any part of GI tract. They are most
commonly located in the stomach (50%–60%), small intes-
tine (20%–30%), and large intestine (10%), with the remain-
der of the cases equally distributed between other locations
in the GI tract and extragastrointestinal sites. They may lead
to GI symptoms and are primarily diagnosed due to refrac-
tory anemia secondary to chronic, insidious GI bleeding.
The exact cause is not known, but there is evidence of a KIT
Figure. Endoscopic view of mass protruding from the antrum into the
body of the stomach, demonstrating a well-defined ulceration in the
center.
gene mutation. Fewer than 15% of pediatric GISTs have
mutations in c-KIT and PDGFRA in contrast to adult GISTs
in which 80% have a mutation in these genes.
Pediatric GISTs lacking KIT/PDGFRA mutation are
called wild-type GIST and are less responsive to medical
therapy. The hallmark of GIST is staining positive for CD34
and CD 117, smooth muscle antigen (SMA), S-100, and
desmin.
The differential diagnosis for GIST includes smooth
muscle tumors, desmoid tumors, fibrosarcoma, spindle cell
sarcoma, and GI schwannomas. Location in the GI tract
along with histopathologic and immunohistochemical
examination can differentiate GIST from other entities.
GIST is uniformly negative for glial fibrillary acidic pro-
tein (GFAP), which helps to differentiate GIST from GI
schwannomas, which are GFAP-positive.
Diagnostic investigations for suspected GIST include
complete blood cell count, iron studies, occult blood tests,
computed tomography scan, and magnetic resonance imag-
ing. However, endoscopy, upper GI contrast series, abdom-
inal ultrasonography, and more recently, fludeoxyglucose
positron emission tomography (FDG-PET) also may be
performed. FDG-PET measures tumor metabolism and,
thus, helps in diagnosing disease progression, recurrence,
and response to therapy.
Management and Prognosis
Standard treatment for localized GIST involves complete
surgical excision with microscopically free margins. If
complete surgical resection with negative margins is
not achieved initially, repeat surgery may be performed.
If tumor size is too large or disease is metastasized and
complete surgical resection is not possible, a perioperative
trial of tyrosine kinase inhibitors may be considered. In
pediatric patients, lymph node biopsy should be considered
because metastases to lymph nodes were reported in chil-
dren in a few case series. The most common route of tumor
metastasis is hematogenous, involving the liver and
omentum.
Medical therapy can be undertaken with selective tyro-
sine kinase inhibitors (imatinib), which bind KIT, Bcr-Abl,
and platelet-derived growth factor receptor-alpha (PDGFRA)
and prevent substrate phosphorylation, which inhibits
downstream signaling, cellular proliferation, and cell sur-
vival. Its role in pediatric GISTs is limited; administration is
only considered in advanced disease. Prognostic factors
include tumor size and mitotic activity. GIST has an indo-
lent course in children, but tumor recurrence has been
reported in some cases. Follow-up evaluation with complete
blood cell count, stool guaiac studies, GI endoscopy, and
Vol. 36 No. 12 DECEMBER 2015 549
 FDG-PET scan should be considered to diagnose recurrence
of tumor.
Lessons for the Clinician
• A gastrointestinal cause of blood loss should be consid-
ered in cases of recurrent severe anemia.
• Gastrointestinal stromal tumors are rare in children, but
they should be considered in the differential diagnosis of
Parent Resources from the AAP at HealthyChildren.org
• https://www.healthychildren.org/English/health-issues/conditions/chronic/Pages/Anemia-and-Your-Child.aspx
550 Pediatrics in Review
recurrent anemia in a patient with or without a history of
frank bleeding from the gastrointestinal tract.
• Early diagnosis and complete surgical resection of gas-
trointestinal stromal tumor (GIST) can be curative.
• Persistence or recurrence of anemia in a treated case of
GIST should raise suspicion for recurrence.
Suggested Readings for this article are at http://pedsinreview.
aappublications.org/content/36/12/548.full.

AUTHOR DISCLOSURE Drs Wigfield,
Kakajiwala, Forbes, and Bodas have disclosed
no financial relationships relevant to this
article. This commentary does not contain
a discussion of an unapproved/investigative
use of a commercial product/device.
Abnormal Eye Movements and Congestion in
3 a 3-month-old Boy
Joanna Wigfield, DO,* Aadil Kakajiwala, MD,* Michael L. Forbes, MD,*
Prasad Bodas, MD*
*Akron Children’s Hospital, Akron, OH.
PRESENTATION
A 3-month-old Amish boy presents to the emergency department with recurrent
nasal congestion since birth. He has had no fevers, cough, or difficulty
breathing. He was born at term without complications. His parents report that
his growth and development are overall appropriate, but his mother expresses
concern about abnormal eye movements. The father has moderate deficiency of
Factor IX.
Physical examination results include: temperature 98.4°F (36.9°C), heart
rate 140 beats/min, respiratory rate 40 breaths/min, and pulse oximetry 99%
in room air. His length is 59.7 cm (7th percentile), weight is 6.1 kg (22nd
percentile), and head circumference is 40.6 cm (15th percentile). He has
minimally reactive and dilated pupils, with consistent downward gaze and
disconjugate ocular movements. Anterior fontanelle is soft and flat. He has
prominent upper airway sounds. A nasal catheter cannot be passed through
the right nare. Lungs are clear to auscultation. He has symmetric reflexes
with good strength and tone. The remainder of the physical examination is
unremarkable.
Cranial/facial/sinus computed tomography scan shows stenosis of the nasal
cavity. Three days later, an adenoidectomy and repair of the choanal stenosis is
performed. Before surgery, the infant’s hemoglobin concentration is low-normal.
Postoperative complete blood cell count shows anemia and thrombocytopenia.
Further studies, including bone marrow biopsy, skeletal survey, and genetic
testing, confirm the diagnosis.
DISCUSSION
The bone marrow aspirate was hypocellular. Bone marrow biopsy was charac-
terized by abnormal epiphyses, thick trabeculae with apparent persistent
cartilage cores, and small marrow spaces containing many osteoclasts. Review
of the chest radiograph obtained in the emergency department showed an
increase in bone density. A skeletal survey showed diffuse sclerosis and
obliteration of the medullary cavity in several bones. The clinical manifesta-
tions, findings on bone marrow evaluation, and results of imaging studies were
suggestive of a sclerosing bone dysplasia, most consistent with osteopetrosis.
Vol. 36 No. 12 DECEMBER 2015 551
 Genetic testing detected a TCIRG1 mutation, consistent
with the diagnosis of malignant infantile osteopetrosis.
The patient underwent a matched unrelated donor bone
marrow transplant at the age of 6 months, which was
99 days after initial presentation.
The Condition
Osteopetrosis is a genetic disorder that causes bony sclerosis
due to failure of osteoclast differentiation or function
(Table). Osteoclasts are specialized cells that degrade bone
mineral and organic bone matrix. Abnormal osteoclast
function results in aberrant bone remodeling and increased
bone density. Malignant infantile osteopetrosis is a severe,
life-threatening, autosomal recessive form of osteopetrosis
that is often caused by mutations in the TCIRG1 gene.
Mutations in this gene account for approximately 50% of
cases of autosomal recessive osteopetrosis. In approximately
30% of cases, no genetic mutations are identified.
Affected children have a variety of symptoms related to
bony sclerosis. These symptoms can include growth retar-
dation; bone marrow failure with extramedullary hematopoi-
esis and hepatosplenomegaly; and narrowed nerve foramina
causing optic nerve compression, deafness, or facial palsy.
Patients may also have severe hypocalcemia leading to sei-
zures and hyperparathyroidism. Some patients have evi-
dence of neurodegeneration, including symptoms such as
seizures despite a normal calcium concentration or devel-
opmental delay. Those symptoms could indicate a more seri-
ous form of osteopetrosis that is not curable by hematopoietic
stem cell transplant. This patient had no evidence of
neurodegeneration.
Differential Diagnosis
Because the initial symptoms of an infant presenting with
osteopetrosis are nonspecific, a variety of conditions must
be considered before diagnosis. This infant’s initial symp-
toms of nasal congestion certainly did not raise the sug-
gestion of osteopetrosis. Because of the inability to place
a nasal catheter, this patient was initially believed to have
choanal atresia. This finding in conjunction with abnor-
mal eye movement should prompt consideration of con-
ditions involving bony sclerosis. Once he showed evidence
of bone marrow failure with anemia and thrombocytope-
nia, bony sclerosis was an even greater possibility. Review
of the chest radiograph confirmed a metabolic bone dis-
ease, with evidence of diffuse bony sclerosis and obliter-
ation of the medullary cavity. Osteopetrosis was diagnosed
based on myriad clinical manifestations related to bony
sclerosis and later confirmed by genetic testing. Other
sclerosing bone dysplasias, such as infantile cortical
hyperostosis or sclerosteosis, could be considered in this
case.
Treatment and Prognosis
The treatment of osteopetrosis varies according to clinical
manifestations and genetics of the condition. Appropriate
treatment of hypocalcemia, seizures, pathologic fractures,
anemia, and thrombocytopenia is required. Hematopoietic

TABLE. Classification of Osteopetrosis

GENETIC
CLASSIFICATION SUBTYPES MUTATION ONSET SEVERITY MANAGEMENT PROGNOSIS

Autosomal CLCN7 Infancy Mild to moderate, Supportive Normal life

dominant (ADO) occasionally severe expectancy
Autosomal Classic TCIRG1 Perinatal Severe Supportive; HSCT Poor; fatal in
recessive (ARO) infancy
Neuropathic OSTM1, CLCN7 Perinatal Severe Supportive Poor; fatal in
infancy
ARO with renal Carbonic Infancy Moderate Supportive; may Variable
tubular acidosis anhydrase II benefit from
HSCT*
Intermediate (IRO) PLEKHM, CLCN7 Childhood Mild to moderate Supportive Variable
X-linked IKBKG Late childhood Severe Supportive Poor; fatal in
to adolescence early childhood

HSCT¼hematopoietic stem cell transplant.

*Note that Autosomal Recessive, Classic type with TCIRG1 mutation is the only type that has definite benefit from hematopoietic stem cell transplant.
Adapted from Stark Z, Savarirayan R. Osteopetrosis. Orphanet J Rare Dis. 2009;4:5.

552 Pediatrics in Review

stem cell transplant is reserved for the severe form of
autosomal recessive osteopetrosis. Such transplant using
human leukocyte antigen (HLA)-identical donors can result
in a 73% 5-year disease-free survival. Transplantation before
3 months of age improves conservation of vision. Without
treatment, most children die from bone marrow suppres-
sion before 10 years of age.
Lessons for the Clinician
• When presented with a combination of symptoms that
can be attributed to bony sclerosis, ie, nasal congestion
concerning for choanal stenosis, abnormal eye movements,
pupillary dysfunction, deafness, facial palsy, anemia, or
hypocalcemia, osteopetrosis should be part of the dif-
ferential diagnosis.
• Because hematopoietic stem cell transplant is the only
known cure for malignant infantile osteopetrosis, pa-
tients should be tested for the TCIRG1 gene mutation, the
most common genotype, and referred to a hematopoietic
stem cell transplant center immediately.
• Early transplantation decreases morbidity and mortality
in patients with osteopetrosis.
Suggested Readings for this article are at http://pedsinreview.
aappublications.org/content/36/12/551.full.

Correction
In the October 2015 Index of Suspicion, Case 3, “Acute Onset of Headache, Fever, and Right Arm Weakness in a 12-year-
old Boy (Chamarthi VS, Chamarthi S, and Johansson BE. Pediatrics in Review. 2015;36(10):465, doi: 10.1542/pir.36-10-
465), the term Kernig sign was misspelled in the Presentation portion of the case, second paragraph, second sentence,
which should read, “Physical examination reveals neck stiffness and positive Kernig sign.” The online version of the
journal article has been corrected. The journal regrets the oversight.

Vol. 36 No. 12 DECEMBER 2015 553

 Brief
in
Upper Respiratory Tract Infections
Benjamin Weintraub, MD*
*Marblehead Pediatrics, Marblehead, MA.
AUTHOR DISCLOSURE Dr Weintraub has
disclosed no financial relationships relevant to
this article. This commentary does not contain
a discussion of an unapproved/investigative
use of a commercial product/device.
Incidence of Acute Otitis Media and
Sinusitis Complicating Upper Respiratory
Tract Infections: The Effect of Age. Revai K,
Dobbs LA. Pediatrics. 2007;119e:1408–1412
Principles of Judicious Antibiotic
Prescribing for Upper Respiratory Tract
Infections in Pediatrics. Hersh AL, Jackson
MA. Pediatrics. 2013;132:1146–1152
Upper Respiratory Tract Infections in Young
Children: Duration of and Frequency of
Complications. Wald ER, Guerra N. Pediatrics.
1991;87:129–133
Red Book: 2012 Report of the Committee on
Infectious Diseases. Pickering LK, Baker CJ,
Kimberlin DW, et al, eds. Elk Grove Village,
IL: American Academy of Pediatrics;
2012:220–222; 533–535; 609–618; 619–620
554 Pediatrics in Review
Every day worried parents bring their children to clinicians for evaluation of
coughs, runny noses, and sore throats. Most of these children have a simple cold
and only require reassurance. However, clinicians must remain vigilant to not
overlook a more severe possibility, such as secondary bacterial infection, an
asthma exacerbation, or perhaps a foreign body. After ruling out a more severe
issue, the most likely possibility is an everyday viral infection. These upper
respiratory tract infections (URIs) and pharyngeal infections have many causes,
but their presentations tend to follow similar patterns, which allow clinicians to
reassure and advise worried parents.
On average, children are infected with two to eight URIs annually in the first
2 years after birth; those who attend day care may have as many as 14 annually.
Even older children and adults may experience three to six URIs a year. In the
United States, infants in the first year after birth experience an estimated 12 to
32 million URIs annually, and older children as many as 200 million. These viral
illnesses result in millions of office visits and more than 10 million antibiotic
prescriptions every year. The risk of secondary bacterial infections with URIs has
been estimated at 0.5% up to as high as 5% to 10% for acute bacterial sinusitis. For
acute otitis media, the estimated risk is up to 36% in infants younger than 1 year of
age, decreasing to 15% for children 2 to 3 years old.
Unfortunately, for the more than 2 million cases of acute bronchitis diagnosed
annually in children, approximately 70% result in a prescription for an antibiotic,
despite the lack of any evidence to support such use for these viral infections. The
unwarranted use of antibiotics increases the risk of children becoming colonized
with resistant Streptococcus pneumoniae, Haemophilus influenzae, and other bac-
teria; helps promote bacterial resistance in the community; and is the cause of
countless unnecessary allergic reactions and other medication adverse effects. It
is important for clinicians to understand the general presentation of viral URIs
and pharyngitis, to be diligent in diagnosing secondary bacterial complications,
and to be judicious in antibiotic prescribing so as to eliminate unnecessary use.
Generally, viral URIs present similarly, often beginning with a sore throat,
especially if caused by a rhinovirus, then progressing to congestion, rhinorrhea,
and a cough. As many as 50% may have an associated fever that usually resolves by
the third day but may linger a few days longer. The average duration of a simple
URI is 7 to 9 days, although as many as 13% may last as long as 15 days. The
symptoms for most of these illnesses tend to peak on or around the third day,
subsequently slowly resolving over the following 1 to 3 weeks. Frequently, the
cough from these illnesses lingers longer than other symptoms. According to
current guidelines, the diagnosis of acute bacterial sinusitis requires that symp-
toms be present for more than 10 days without improving, worsen with new onset
of fever or cough, or be associated with temperatures greater than 102.2°F (39.0°C)
along with purulent nasal discharge for more than 3 days.
 With the potential overlap in duration of symptoms
between a long-lasting cold and the diagnostic criteria for
a bacterial sinusitis, waiting at least 2 weeks before starting
antibiotics may be appropriate when the issue is simply
duration of symptoms. Most cases resolve with a bit more
time. It is also important to tease out whether the symptoms
have really lasted 2 to 3 weeks or whether the patient had been
improving or was even better for 1 or 2 days when a new set of
cold symptoms began. This is a common scenario more
consistent with back-to-back URIs than with acute sinusitis.
In contradiction to previous hypotheses about the color of
nasal discharge indicating bacterial infections, clinicians now
understand that rhinorrhea from even a simple rhinovirus
can become mucopurulent after a few days and last for 10 to
14 days or longer.
The usual causes of URIs are rhinoviruses, adenoviruses,
parainfluenza viruses, respiratory syncytial virus (RSV),
influenza viruses, human metapneumoviruses, and human
bocaviruses. Of these, rhinoviruses are the most common.
In addition to common cold symptoms, rhinoviruses may
result in pharyngitis, acute otitis media, bronchiolitis, and
pneumonia and may cause up to 50% of all asthma exac-
erbations. They are spread through self-inoculation from
secretions on surfaces, fomites, and via aerosol droplets.
Rhinoviruses are most contagious in the first 3 days of
illness; viral shedding is generally finished by day 7 but
may continue for up to 3 weeks. Although occurring through-
out the year, rhinovirus infections peak in the spring and fall.
The predominant symptoms are runny nose and cough. Sore
throat, fever, and headache may occur as well. Treatment for
rhinoviruses is supportive: increased fluids, rest, perhaps
a cool mist humidifier, and nasal saline spray for younger
children, and drops with bulb suction for infants. Honey may
be used for cough in children older than 1 year. The U.S. Food
and Drug Administration has stated that over-the-counter
(OTC) cough and cold preparations should not be used in
children younger than 4 years and should be used only with
extreme caution in those younger than 6 years. Studies have
shown that OTC dextromethorphan is no better than placebo
for control of nighttime cough, although honey offers some
improvement compared to placebo.
Parainfluenza type 1 and 2 viruses are the primary cause
of croup or laryngotracheitis, although they also cause
standard cold symptoms, bronchiolitis, or even the rare
case of aseptic meningitis. Infections with parainfluenza
virus type 1 peak every other autumn, while type 2 infections
have annual peaks and frequently include conjunctivitis in
association with other URI symptoms. Parainfluenza is
spread through direct contact, secretions, droplets, and fomites.
Infected individuals are contagious for up to 1 week before
symptoms appear and continue to shed virus for 1 to 3 weeks
after symptoms begin. The incubation period for parainfluenza
virus is 2 to 6 days. Croup is differentiated from other
routine URIs by its characteristic “barking,” dry, harsh-sounding
cough and stridor that is predominantly inspiratory,
although occasionally biphasic. Treatment for croup includes
dexamethasone orally or intramuscularly at a dose of 0.6 mg/kg
when stridor is present at rest. Having children with croup
sit in a steamed-up bathroom or taking them outside to breathe
cool night air sometimes can alleviate symptoms. Other-
wise, care for croup and other presentations of parainfluenza
virus is supportive, just as for rhinoviruses.
Adenoviruses are another common cause of cough, con-
gestion, and runny nose, along with pharyngitis, tonsillitis,
otitis media, and pharyngoconjunctival fever. These viruses
spread via direct contact, droplets, and fomites. They are most
contagious the first few days of illness and have an incubation
period of 2 to 14 days. Treatment is simply supportive care.
RSV is an extraordinarily contagious virus that infects
nearly all children at least once by 2 years of age. Although
20% to 30% of RSV infections present as classic bronchiolitis
that may progress to pneumonia in some children, the rest of
the cases manifest as a routine URI with cough, congestion,
and runny nose and sometimes with fever and sore throat.
Children with RSV infection often have copious, thick, tena-
cious rhinorrhea. If a child is wheezing, a single trial of
albuterol may be considered, but if significant improvement
is not seen, care for RSV infections should simply be sup-
portive. Viral shedding is greatest in the first few days but may
continue for 8 or more days after an incubation of 2 to 8 days.
Sore throat is a frequent accompanying symptom of URIs.
It may also present as its own entity. By far, most cases of
pharyngitis are viral and resolve with time, requiring neither
testing nor treatment. Agents causing pharyngitis include all
the viruses discussed previously as well as Epstein-Barr virus,
herpes simplex virus, and Coxsackievirus. Factors that suggest
a viral rather than a bacterial cause include hoarse voice or
laryngitis, ulcerative lesions in the mouth or pharynx, or the
presence of rhinorrhea or cough. Pharyngitis with an exuda-
tive tonsillitis and fever, tender and swollen anterior cervical
adenopathy, and lack of a cough are suggestive of group A beta-
hemolytic streptococcal (GABHS) infection. However, many
other viral causes, including infectious mononucleosis, ade-
novirus, and herpesvirus, can be clinically indistinguishable
Vol. 36 No. 12 DECEMBER 2015 555
 from GABHS. With a strong clinical suspicion for GABHS
pharyngitis, confirmatory testing with rapid antigen detection
or culture is appropriate. Treatment with a penicillin or a macro-
lide for patients allergic to penicillin should be initiated within
the first 9 days of GABHS illness to prevent rheumatic heart
disease. Other bacteria causing pharyngitis, such as group C
and G streptococci, generally do not require treatment.
Although a secondary bacterial infection may necessitate
treatment, care for URIs is generally supportive. The most
important treatments that clinicians can offer are reassurance
about the benign and self-limited nature of these illnesses and
reminders for parents and patients to be vigilant about hand-
washing. Clinicians should intervene medically only when
truly needed.
COMMENT: “Above all, do no harm” has been validated
over and again as a basic tenet of good medicine. From
thalidomide to diethylstilbestrol, from bleeding for fevers to
radiation treatment for tonsillitis, we have examples aplenty
to document that, even with the best of intentions, acting in
the absence of evidence is too often a mistake. Millions of
courses of antibiotics for viral infections and bronchodila-
tors and corticosteroids for bronchiolitis are evidence that
we feel a compelling need to do something! As hard as it
may be in the face of a sick child and anxious parents, when
we do not have a soundly supported intervention to offer, we
need to remind ourselves that a better strategy is: “Don’t just
do something, stand there!” And, yes, while standing there,
we do no harm by offering an explanation and reassurance,
neither of which has harmful adverse effects.
– Henry M. Adam, MD
Associate Editor, In Brief

Parent Resources from the AAP at HealthyChildren.org

• https://www.healthychildren.org/English/safety-prevention/at-home/medication-safety/Pages/Antibiotics-for-a-Sore-Throat-Cough-or-
Runny-Nose.aspx
• https://www.healthychildren.org/English/health-issues/conditions/chest-lungs/Pages/Respiratory-Syncytial-Virus-RSV.aspx
• https://www.healthychildren.org/English/health-issues/conditions/chest-lungs/Pages/Protecting-Your-Baby-from-RSV.aspx

ANSWER KEY FOR DECEMBER 2015 PEDIATRICS IN REVIEW:

Meningitis: 1. D; 2. A; 3. A; 4. E; 5. B.
Pain and Symptom Management in Pediatric Palliative Care: 1. B; 2. B; 3. B; 4. B; 5. B.
Substance Abuse, General Principles: 1. C; 2. C; 3. B; 4. D; 5. A.

556 Pediatrics in Review

 Statement of Ownership

Vol. 36 No. 12 December 2015 557

Statement of Ownership

558 Vol. 36 No. 12 December 2015


AUTHOR DISCLOSURE Drs Benza and
Stankovic have disclosed no financial
relationships relevant to this article. This
commentary does not contain a discussion of
an unapproved/investigative use of
a commercial product/device.
A 2-month-old Boy With an Unusual
Rash
Natalia Benza, MD,* Curt Stankovic, MD†
*Department of Pediatrics, Children’s Hospital of Michigan, Detroit, MI.
†
Pediatric Emergency Department, Children’s Hospital of Michigan, Detroit, MI.
PRESENTATION
A 2-month-old boy presents to the pediatric emergency department (ED) for
evaluation of a rash that has been present for 2 weeks. His mother states that the
rash appeared on his head and trunk; is circular with a white center; and is not
associated with pain, itching, or discharge. The boy has no history of fever or
behavior or feeding changes and he has had no contact with anyone who has a
rash. The infant has no other complaints or symptoms.
The boy was born to a 25-year-old G3 P2012 mother at 38 weeks and 4 days of
gestation via scheduled cesarean section. The delivery was uncomplicated, with
Apgar scores of 8 at 1 minute and 9 at 5 minutes. His birthweight was 3.765 kg.
The mother started receiving prenatal care at 21 weeks of gestation. She tested
positive for human immunodeficiency virus (HIV) via enzyme-linked immuno-
sorbent assay, but her Western blot test result was negative. Other prenatal
laboratory tests yielded unremarkable results.
Upon presentation to the emergency department, the baby appears well and in
no distress. His rectal temperature is 98.2°F (36.8°C), heart rate is 136 beats/min,
respiratory rate is 32 breaths/min, blood pressure is 112/51 mm Hg, and oxygen
saturation is 99% in room air. His weight is 5.57 kg. The only finding of note on
physical examination is a dry, scaly, maculopapular rash on his head and trunk.
Some of the lesions have a hypopigmented central area. The largest lesions are
0.5 cm in diameter. He also has a nonpalpable, hyperpigmented, red rash on his
palms (Fig 1) and soles (Fig 2), which the mother states that she has never seen
before on her child. The physician makes a clinical diagnosis.
DIAGNOSIS
Upon further questioning, the mother recalls that both she and the boy’s father
recently tested positive for syphilis. The infant undergoes comprehensive evaluation
of the blood, urine, and cerebrospinal fluid (CSF). Laboratory tests reveal:
• White blood cell (WBC) count 20,500/mL (20.5  109/L), with 27% neutrophils,
2% bands, 61% lymphocytes, and 10% monocytes
• Hemoglobin 8.1 g/dL (81 g/L)
• Platelet count 151  103/mL (151  109/L)
CSF results are:
• Clear color
• 1 red blood cell/mm3
Vol. 36 No. 12 DECEMBER 2015 e43

Figure 1. Nonpalpable, hyperpigmented, red rash on palm.
• WBC count 50 cells/mm3 with 6% neutrophils and 42%
lymphocytes
• Glucose 58 mg/dL (3.22 mmol/L)
• Protein 22 mg/dL
Syphilis enzyme immunoassay screen is positive at 28.70.
The CSF Venereal Disease Research Laboratory (VDRL) test is
reactive and the HIV antibody is negative. Chest radio-
graph and long bone films show no evidence of syphilis.
Discussion
Congenital syphilis occurs when Treponema pallidum is
transmitted from a pregnant woman with syphilis to her
fetus by maternal bloodstream or direct contact with infec-
tious lesions. Transmission to the fetus can cause stillbirth,
hydrops fetalis, or preterm birth. The World Health Organi-
zation estimates that 1 million pregnancies are affected by
syphilis worldwide every year. In 2009, 432 cases of congen-
ital syphilis were identified in the United States, translating
into 10 cases/100,000 live births. The Centers for Dis-
ease Control and Prevention recommends routine serologic
Figure 2. Nonpalpable, hyperpigmented, red rash on sole.
e44 Pediatrics in Review
syphilis screening in the first trimester for all pregnant women
and repeat screening for high-risk women at 28 weeks’
gestation and again at delivery. Transplacental transmission
of syphilis can be prevented if the pregnant mother is treated
by the 16th week of pregnancy. If the mother has secondary
syphilis, fetal transmission can be reduced to 2% if anti-
biotics are administered to the mother before the last week
of pregnancy.
Clinical Presentation
Congenital syphilis can be classified as early (Table 1) if
manifestations are seen in the first 2 years after birth or
as late congenital syphilis (Table 2), which manifests after
2 years of age. Approximately 60% of infected infants are
asymptomatic at the time of birth. Infants with early disease
can present with vague complaints, such as poor feeding,
rhinorrhea, rash, and fever. More specific findings include
hepatosplenomegaly, lymphadenopathy, pneumonia, skele-
tal abnormalities, and skin lesions. The typical skin man-
ifestations are a maculopapular rash on the hands and feet
and syphilitic pemphigus, which involves vesiculobullous
lesions that may be preceded by red papules turning to
desquamative lesions and crust over 1 to 3 weeks. Neuro-
syphilis is often asymptomatic, and the CSF typically shows
a WBC count of greater than 25 cells/mm3 and protein of
more than 150 mg/dL. Sixty-three percent of infants with
late disease present with the Hutchinson triad (keratitis,
deafness, and Hutchinson teeth). Antibiotics must be ad-
ministered before the development of late symptoms be-
cause once present, these findings may be permanent.
Pathophysiology
Congenital syphilis arises from transplacental transmission
during maternal spirochetemia or during birth by contact
with infectious lesions. Of note, syphilis is not transmitted
via breastfeeding unless an infectious lesion is present on
the breast. Most infants born with congenital syphilis are
exposed in utero after the fourth month of pregnancy. Once
infected, the spirochete infiltrates the bloodstream and
lymphatics, resulting in both polymorphonuclear leukocytes
and antibody responses.
Infection is divided into five stages: primary, secondary,
early latent, late latent, and tertiary. The primary, secondary,
and early latent phases are the most infectious stages.
Laboratory Examination
Two types of serologic tests are used routinely to diagnose
syphilis. The nontreponemal tests that are used as primary
screens measure antibody directed against antigens that
result from the interaction of host tissues with T pallidum.
 required. All patients who test positive for syphilis need HIV
TABLE 1. Clinical Findings in Early Congenital testing. If the initial HIV test result is negative, they should
Syphilis (<2 Years) be retested 3 months later.
Complicating the diagnosis of syphilis is the transpla-
• Rash
cental transfer of treponemal and nontreponemal antibod-
• Hepatosplenomegaly
ies to the fetus, making the interpretation of syphilis serologic
• Jaundice tests difficult. Treatment often is based upon a combination of
• Edema factors:
• Snuffles/Rhinorrhea 1. Identification of syphilis in the mother
• Pseudoparalysis (decreased movement of extremity due to painful 2. Prenatal care
syphilitic periostitis) 3. Evidence of infection in the infant (clinical, laboratory,
• Anemia/Thrombocytopenia radiographic)
• Nontender adenopathy 4. Comparison of maternal (delivery) nontreponemal serologic
titers to infant

The Centers for Disease Control and Prevention has

These screens include the VDRL test and rapid plasma
reagin (RPR) test. Treponemal tests, such as the fluorescent
treponemal antibody absorption test (FTA-ABS), T pallidum
immobilization (TPI) test, and microhemagglutination assay
for antibodies to T pallidum (MHA-TP), detect specific anti-
bodies to T pallidum. These tests are used as confirmatory
assessments after a positive nontreponemal screen. The titers
become positive almost immediately after initial infection
and remain positive for life.
All infants born to mothers with positive treponemal or
nontreponemal titers should undergo serum RPR or VDRL
testing. Infants require nontreponemal and treponemal testing
at birth, 2, 4, 6, and 12 months of age. If testing continues to
be reactive at 6 months, repeat testing at 12 and 18 months is
developed the following case classification for syphilis:
Probable: An infant whose mother has untreated or in-
adequately treated syphilis at delivery regardless of infant
symptoms or an infant with a reactive treponemal test and
one of the following:
1. Any evidence of syphilis on examination
2. Any evidence of congenital syphilis on radiologic
examination
3. A reactive CSF VDRL
4. Elevated CSF cell count or protein (without another
cause)
5. A reactive fluorescent treponemal antibody absorbed—
19S-IgM antibody test or IgM enzyme-linked immuno-
sorbent assay

Confirmed: A case that is laboratory-confirmed

TABLE 2. Clinical Findings in Late Congenital
Syphilis (‡2 Years) Differential Diagnosis
• Interstitial keratitis The differential diagnosis of congenital syphilis includes in-
fections such as toxoplasmosis, rubella, cytomegalovirus, and
• Frontal bossing
herpes. Neonatal sepsis, hepatitis, and osteomyelitis can cause
• Bowing of shins
similar findings. More common newborn rashes such as with
• Sensorineural hearing loss staphylococcal or streptococcal infection, epidermolysis bullosa,
• Mulberry molars scabies, and cutaneous mastocytosis are in the differential
• Hutchinson teeth diagnosis. Intentional trauma is also part of the differential
diagnosis due to associated skin, neurologic, and bone findings.
• Saddle nose
• Rhagades (fissures, cracks, or linear scars of the skin, usually in areas Management
of frequent motion)
Management consists of aqueous crystalline penicillin G
• Clutton joints (symmetric joint swelling)
50,000 units/kg per dose intravenously (IV) every 12 hours
• Nontender adenopathy during the first 7 postnatal days and every 8 hours there-
• Developmental delay after for a total of 10 to 14 days. Such treatment should
• Seizures
be undertaken in consultation with a pediatric infectious
disease specialist.

Vol. 36 No. 12 DECEMBER 2015 e45

 Prognosis
The prognosis for patients with congenital syphilis varies.
Infants who are promptly treated may not develop any sequelae.
However, those who develop symptoms may be permanently
affected.
Patient Course
This patient was admitted to the infectious disease floor and
completed treatment with penicillin G 50,000 units/kg per
dose IV every 12 hours for 10 days. Additional laboratory
tests were obtained, including enterovirus CSF, HIV DNA
polymerase chain reaction, and hepatitis C antibody, and all
results were negative.
Serial complete blood cell counts were followed due
to the prolonged antibiotic course. The infant developed
hemolytic anemia that slowly improved with supportive
care, and he was discharged from the hospital with a
follow-up appointment with infectious disease and hematology.
At the time of discharge, the parents had also received three
doses of penicillin.
The infant returned 20 days later with “jerking move-
ments of the right arm and eyes rolling back.” He was
readmitted because of a suspected seizure. He was observed
for 24 hours, and electroencephalography showed no seizure
activity. He continues to be followed by the infectious disease
team.
Summary
Congenital syphilis should be considered in the differential
diagnosis of common newborn rashes, especially if the palms and
soles are involved. As soon as the diagnosis is confirmed, a lumbar
puncture should be performed to rule out neurosyphilis and
intravenous antibiotics started pending confirmatory testing.
Suggested Reading
Woods CR. Congenital syphilis-persisting pestilence. Pediatr Infect
Dis J. 2009;28(6):536–537

Parent Resources from the AAP at HealthyChildren.org

• https://www.healthychildren.org/English/health-issues/conditions/sexually-transmitted/Pages/Syphilis.aspx

e46 Pediatrics in Review

http://www.aap.org/mocinfo

the
Pathway
to MOC
Powerful ID problem-solvers
you won’t find anywhere else!
RED BOOK®
2015 Report of the Committee on Infectious Diseases,
30th Edition
Editor
David W. Kimberlin, MD, FAAP
Associate editors
Michael T. Brady, MD, FAAP
Mary Anne Jackson, MD, FAAP
Sarah S. Long, MD, FAAP
New
3d0ititohn!
E
“Considered by many
the quintessential resource
and reference for clinical practice.”
—Emerging Infectious Diseases

®
The Red Book , your trusted
source for more than 75 years
for pediatric infectious disease
solutions, now brings you the
state of the art in digital design,
giving you point-of-care access
to lifesaving diagnosis and
treatment answers wherever and
whenever you need them.

AAP members receive

Red Book® Online as a
valuable member benefit.

Order today! Online at shop.aap.org ‡ Phone at 888/227-1770 toll-free from 7:30 am to 5:00 pm CT
The Official Journal of the American Academy of Pediatrics

Your print issue of

Pediatrics just got ®

easier to read.

Coming January 2016!

The print edition will feature a
1-page abstract article format.

All research abstracts now appear in print.

AAP Policy and Clinical Practice Guidelines full text in print.
t.
Daily publishing of latest research in full text online at
AAP Gateway gateway.aap.org.
Easy-to-read when you’re on the move.
Quick summaries of the latest research published monthly..
Online Journal is the “Journal of Record.”
 ASAP!
Every article. Any device.
Anytime. Anywhere.

Desktop. Tablet. Mobile.

It’s powerful and it’s here, now! It’s a smart new benefit, free
A single, integrated network of journals and periodicals — AAP News,
to all AAP members. Log on
Pediatrics, Pediatrics in Review, Hospital Pediatrics, NeoReviews and
AAP Grand Rounds — all available in one intuitive interface that using your AAP ID and visit
works on all of your devices. gateway.aap.org.
It’s tailored to your interests.
AAP Gateway will help you manage AAP journals and periodicals,
news, updates and clinical research that’s most relevant and
important to you, based on your specialty and interests.

It’s simple, intuitive and accessible.

Take full advantage of AAP Gateway and easily find, filter and sort
over 50,000 articles with the all new search platform — now
including PubMed.