01 Pediatrics in Review - January2010

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Editor-in-Chief: Lawrence F. Nazarian, Rochester, NY
Associate Editors: Tina L. Cheng, Baltimore, MD
Joseph A. Zenel, Sioux Falls, SD
Editor, In Brief: Henry M. Adam, Bronx, NY
Consulting Editor, In Brief: Janet Serwint, Baltimore, MD
contents
Editor, Index of Suspicion:
Deepak M. Kamat, Detroit, MI
Consulting Editor Online and Multimedia
PediatricsinReview姞 Vol.31 No.1 January 2010
Projects: Laura Ibsen, Portland, OR
Editor Emeritus and Founding Editor:
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Managing Editor: Luann Zanzola
Medical Copy Editor: Deborah K. Kuhlman Commentary
Editorial Assistant: Sydney Sutherland
Editorial Office: Department of Pediatrics
University of Rochester
School of Medicine & Dentistry
3 Expanding Our Horizons
Lawrence F. Nazarian
601 Elmwood Avenue, Box 777
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sydney_sutherland@urmc.rochester.edu
Editorial Board
Hugh D. Allen, Columbus, OH Mark Goldstein, Boston, MA
Articles
Margie Andreae, Ann Arbor, MI
Richard Antaya, New Haven, CT
Denise Bratcher, Kansas City, MO
George R. Buchanan, Dallas, TX
Brian Carter, Nashville, TN
Lindsey Grossman, Springfield, MA
Patricia Hamilton, London, United Kingdom
Hal B. Jenson, Springfield, MA
Donald Lewis, Norfolk, VA
Gregory Liptak, Syracuse, NY
4 Heart Failure in Infants and Children
Latha Chandran, Stony Brook, NY Blaise Nemeth, Madison, WI Erin Madriago, Michael Silberbach
David Cornfield, Stanford, CA John Pascoe, Dayton, OH
Joseph Croffie, Indianapolis, IN Thomas T. Sato, Milwaukee, WI
B. Anne Eberhard, New Hyde Park, NY
Leonard Feld, Charlotte, NC
Rani Gereige, Tampa, FL
Publisher: American Academy of Pediatrics
Sarah E. Shea, Halifax, Nova Scotia
Nancy Spector, Philadelphia, PA
Surendra K. Varma, Lubbock, TX 13 Pediatric Tuberculosis
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31 Index of Suspicion
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In Brief
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Disclosures
● Richard Antaya, MD, FAAP, disclosed that he has an Astellas Pharma, US, Inc,
38 Vaccines in Immunocompromised Patients
research grant and participates in its speaker bureau and advisory board; and that
he is a consultant for Novartis Pharmaceuticals.
● Joseph Croffie, MD, MPH, FAAP, disclosed that he has research grants and
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41 The Gifted Child
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Internet-Only Article
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e1 Chest Pain in Children and Adolescents
Surendranath R. Veeram Reddy, Harinder R. Singh
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Answer Key: 1. B; 2. E; 3. B; 4. B; 5. A; 6. B; 7. C; 8. E;
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Expanding Our Horizons
Pediatr. Rev. 2010;31;3
DOI: 10.1542/pir.31-1-3
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commentary
Commentary
healthy lifestyles. We like to think that cally, as with all subjects in the data-
Author Disclosure
participating in an ongoing program base. Each section has its own coordi-
Dr Nazarian has disclosed no
such as PREP The Curriculum姞 to main- nator, who works with experts in these
financial relationships relevant to tain one’s professional knowledge is realms.
this commentary. This commentary analogous to eating properly and exer- We started our coverage of these
does not contain a discussion of an cising regularly, with the emphasis on new topic areas in the latter half of
unapproved/investigative use of a the positive aspects of health. 2009 and expect to have all the content
The content of Pediatrics in Review姞 specifications covered by the end of
commercial product/device.
as well as the PREP Self-Assessment姞, 2011, at which point they will enter
the other component of PREP the Curric- the 5-year cycle used to address all of
As I interview candidates for admission ulum, is based on the 3,700 content our content. At the same time, we will
to medical school, I marvel at the ex- specifications of the American Board of continue to present topics that fall
periences they have had compared with Pediatrics (ABP). This database is valu- outside of the database but are of
my generation. International travel, vol- able to the reader because these knowl- interest and importance to our readers.
unteer experiences of kaleidoscopic di- edge statements form the basis for the Adding one or two articles each month
versity, exposure to research from the cognitive examinations that are part of in the online-only format allows us to
bench to the clinic, excursions into the ABP’s Maintenance of Certification go beyond the core content, which
disciplines far removed from medicine— program. However, they are even more almost fills our allocated printed pages.
these young people roam far beyond important because they constitute the Many people work to bring the jour-
the traditional track that I and most of core of general pediatric knowledge, nal to fruition. I would like to thank
my classmates followed. and most of our readers participate in my Associate Editors, Drs Tina Cheng
Similarly, the perspectives of medi- the program to stay current. Compiled and Joseph Zenel, and our Editorial
cine and of pediatrics have broadened and revised by experts in our field, the Assistant, Sydney Sutherland, as well as
constantly. Although good physicians content specifications define the body Luann Zanzola, Susan Piscoran,
always have realized that any aspect of knowledge critical to good pediatric Michael Held, and so many other staff
of the human condition is relevant to care. We are grateful to the ABP, which members of the AAP, and our Copy
the patient’s welfare, we now formally is the certifying organization, for shar- Editor, Deb Kuhlman. Our Editorial
study areas that were not part of the ing them with the American Academy Board comprises top educators in their
curriculum decades ago. One example is of Pediatrics (AAP), a major educator of fields, and they offer their services as
cultural effectiveness, which has had pediatricians. volunteers. Cadmus and HighWire pub-
more than one name but in essence In 2008, the ABP added three new lishers produce the final product. An
connotes sensitivity to and knowledge sections: Research and Statistics, Ethics unrestricted grant from Abbott Nutri-
of the elements of culture that affect for Primary Care Pediatricians, and Pa- tion provides significant support. And
a patient’s outlook and habits. The tient Safety and Quality Improvement. we are most grateful to you, our read-
spiritual aspect of a person’s life, al- All pediatricians will recognize these ers, for your feedback and your loyalty.
ways known to be important, has re- areas as important to their work, and
ceived specific focus. Finally, there is a the journal has addressed them to some
widespread emphasis in medicine and extent in the past. Now, however, we Lawrence F. Nazarian, MD
throughout society on wellness and are covering these topics systemati- Editor-in-Chief
Pediatrics in Review Vol.31 No.1 January 2010 3

DOI: 10.1542/pir.31-1-3
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Heart Failure in Infants and Children
Erin Madriago and Michael Silberbach
Pediatr. Rev. 2010;31;4-12
DOI: 10.1542/pir.31-1-4

Article cardiovascular

Erin Madriago, MD,*
Objectives After completing this article, readers should be able to:
Michael Silberbach, MD*
1. Define pediatric heart failure (HF) and review its pathophysiology.
2. Describe the clinical manifestations of pediatric HF.
Author Disclosure 3. Identify common pediatric HF syndromes.
Drs Madriago and 4. Recognize the differences between pediatric and adult HF.
Silberbach have 5. Discuss the treatment of pediatric HF.
disclosed no financial
relationships relevant
to this article. This
Introduction
Pediatric heart failure (HF) is an etiologically diverse disease manifesting a variety of
commentary does not
clinical presentations. Nevertheless, in all HF syndromes, whether adult or pediatric, a
contain a discussion unifying pathophysiologic mechanism is involved: A cardiac injury (either congenital or
of an unapproved/ acquired) activates both compensatory and deleterious pathways that cause a chronic and
investigative use of a progressive course that, if left untreated, ultimately hastens death. Indeed, pediatric HF is
commercial product/ the most common reason that infants and children who have heart disease receive medical
therapy and accounts for at least 50% of referrals for pediatric heart transplantation. (1)
device.
Definition
HF results when cardiac output is insufficient to meet the metabolic demands of the body.
Over time, decreased cardiac output leads to a cascade of compensatory responses that are
aimed directly or indirectly at restoring normal perfusion to the body’s organs and tissues.
For most adults, HF results from diminished myocardial contractility caused by ischemic
heart disease. In contrast, decreased contractile states account for a smaller percentage of
causes of pediatric HF. Instead, the various triggers of HF in children can be categorized
broadly as syndromes of excessive preload, excessive afterload, abnormal rhythm, or
decreased contractility, which all can lead to a final common HF pathway.
Prevalence
The overall incidence and prevalence of pediatric HF is unknown, largely because there is
no accepted universal classification applied to its many forms. The largest HF burden
comes from children born with congenital malformations. It has been estimated that 15%
to 25% of children who have structural heart disease develop HF. (2) Although cardiomy-
opathy is relatively rare, approximately 40% of patients who experience cardiomyopathy
develop heart failure of such severity that it leads to transplantation or death. (3)
Pathophysiology
Unmet tissue demands for cardiac output result in activation of the renin-aldosterone-
angiotensin system, the sympathetic nervous system,
cytokine-induced inflammation, and recently appreciated
“signaling” cascades that trigger cachexia. (4)
Abbreviations A vicious cycle begins when decreased cardiac output
ANP: atrial natriuretic peptide leads to increased metabolite production in downstream
BNP: brain natriuretic peptide organ systems. These metabolites, in turn, stimulate local
HF: heart failure vasodilation and decreased blood pressure. Falling blood
MVO2: myocardial oxygen consumption pressure stimulates angiotensin and mineralocorticoid re-
TNF-alpha: tumor necrosis factor-alpha lease further, inducing fluid-retaining mechanisms in the
kidney and stimulating increases in systemic vascular resis-
*Division of Pediatric Cardiology, Doernbecher Children’s Hospital, Oregon Health and Science University, Portland, Ore.
4 Pediatrics in Review Vol.31 No.1 January 2010

cardiovascular heart failure
tance. Stimulation of the sympathetic nervous system

and increased release of catecholamines cause tachycar-
dia, enhanced myocardial contractility, and maladaptive
forms of cardiac hypertrophy.
Initially, these effects help to improve cardiac output
and maintain blood pressure. The Pediatric Advanced
Life Support course offered by the American Heart
Association terms this stage of HF “compensated
shock.” However, HF occurs in diseases that are not
readily reversible. In these situations, longstanding in-
creases in myocardial work and myocardial oxygen con-
sumption (MVO2) ultimately worsen HF symptoms and
lead to a chronic phase that involves cardiac remodeling
(Fig. 1).
Cardiac remodeling is a structural transformation in
which the normally elliptical heart increases in mass and Figure 1. Heart failure results from an interaction of benefi-
becomes more spherical. This increase in cardiac mass cial and deleterious pathways that ultimately modulate car-
(maladaptive cardiac hypertrophy) involves an expansion diac output and remodeling. ANPⴝatrial natriuretic peptide,
of the myofibrillar components of individual myocytes BNPⴝbrain natriuretic peptide, GHⴝgrowth hormone,
IGF-1ⴝinsulin-like growth factor.
(new cells rarely form), an increase in the myocyte/
capillary ratio, and activation and proliferation of abun-
dant nonmyocyte cardiac cells, some of which produce Clinical Manifestations
cardiac scarring. Taken together, these processes pro- Because HF has multiple causes, it has a variety of age-
duce a poorly contractile and less compliant heart, result- dependent clinical presentations. In neonates, the earliest
ing in increased filling pressures, pulmonary or systemic clinical manifestations may be subtle. Most commonly,
edema, hypoxia, redistribution of blood flow away from infants have feeding difficulties due to dyspnea, increased
skeletal muscle and the splanchnic circulation, tissue fatigability, and secretion of anorexic hormones that
lactic acidosis, and loss of lean body mass (cachexia). limit the volume of feedings. Ultimately, affected babies
Cachexia is a state of catabolic/anabolic imbalance lead- fail to thrive. Physical findings in infants who have HF
ing to weight loss and disordered homeostasis and in- include mild-to-severe retractions, tachypnea or dyspnea
volves inflammatory cytokines such as tumor necrosis with grunting (a form of positive end-expiratory pres-
factor-alpha (TNF-alpha) and interleukins, as well as sure), tachycardia, a gallop rhythm (S3, S4), and hepato-
neurohormonal activation. Recent work suggests that megaly.
Older children manifest exercise intolerance, somno-
activation of cachexia pathways may drive worsening
lence, anorexia, or more “adultlike” symptoms such as
HF. (5)
cough, wheezing, or crackles (rales). As with younger
Although decreased cardiac output stimulates delete-
children, the physical examination may reveal a gallop
rious neuroendocrine mechanisms, endogenous mecha-
rhythm and hepatomegaly as well as peripheral edema
nisms defend the heart from progressive HF. These
and jugular venous distention.
mechanisms include stimulation of insulin-like growth
factor and growth hormone and secretion of atrial and Common Causes of HF
brain natriuretic peptides (ANP and BNP). For example, Heart failure can result from cardiac and noncardiac
growth hormone deficiency and low insulin-like growth causes. Cardiac causes include those associated with con-
factor concentrations have been associated with poor HF genital structural malformations (Table 1) and those
outcomes in adults, and increased concentrations appear involving no structural anomalies (Table 2).
to be protective. (6) ANP and BNP are hormones se-
creted by the heart in response to volume and pressure Cardiac Malformations Associated With
overload that increase vasodilation and diuresis acutely Excessive Preload (Volume Loading)
and chronically prevent inflammation, cardiac fibrosis, Among cardiac malformations, those that cause left-to-
and hypertrophy. (7) right systolic shunts at the ventricular level are associated

Cardiac Malformations
Table 1. Sources of Heart Failure
Table 2.
Leading to Heart Failure With a Structurally Normal

Shunt Lesions Heart
● Ventricular septal defect Primary Cardiac
● Patent ductus arteriosus
● Aortopulmonary window ● Cardiomyopathy
● Atrioventricular septal defect ● Myocarditis
● Single ventricle without pulmonary stenosis ● Myocardial infarction
● Atrial septal defect (rare) ● Acquired valve disorders
● Hypertension
Total/Partial Anomalous Pulmonary Venous Connection ● Kawasaki syndrome
● Arrhythmia (bradycardia or tachycardia)
Valvular Regurgitation
Noncardiac
● Mitral regurgitation
● Aortic regurgitation ● Anemia
● Sepsis
Inflow Obstruction ● Hypoglycemia
● Diabetic ketoacidosis
● Cor triatriatum
● Hypothyroidism
● Pulmonary vein stenosis
● Other endocrinopathies
● Mitral stenosis
● Arteriovenous fistula
Outflow Obstruction ● Renal failure
● Muscular dystrophies
● Aortic valve stenosis/subaortic stenosis/supravalvular
aortic stenosis
● Aortic coarctation
excessive volume leads to increased ventricular filling

pressure and, ultimately, to HF.
most commonly with HF. In this situation, a volume Valvular regurgitation lesions, either acquired or con-
load on the left side of the heart causes preload stress. genital, also volume load the heart. These most com-
The combined cardiac output is increased due to the monly are mitral or aortic regurgitation.
volume of “ineffective” pulmonary blood flow that recir- Rarely, right-sided volume loading due to longstand-
culates through the lungs. ing right ventricular preloading can lead to HF. Ex-
Ventricular-level shunts include ventricular septal de- amples include a large atrial septal defect or anomalous
fect and patent ductus arteriosus. The left heart volume pulmonary vein connections. Ventricular-level preload-
overload causes increased cardiac filling pressure and ing also can result from congenital or surgically acquired
pulmonary edema. Typically, affected patients present pulmonary valve regurgitation, especially if downstream
during the first 2 to 3 postnatal months, after the natural pulmonary arterial narrowing imposes an additional pres-
decrease in the pulmonary vascular resistance occurs. The sure load on the situation. Right-sided volume loading
lower pulmonary vascular resistance relative to the sys- rarely causes HF early in life. Compared with the left
temic vascular resistance leads to a significant increase in heart, the highly compliant right ventricle accepts signif-
the pulmonary blood flow relative to the systemic blood icant volume more readily without increasing filling pres-
flow. Ventricular-level shunts, accordingly, have been sure. Accordingly, it is only after years of volume loading
termed “dependent” shunts because they depend on the that maladaptive cardiac hypertrophy occurs and patients
pulmonary vascular resistance relative to the systemic vas- develop HF.
cular resistance. Excessive pulmonary venous return to the Constrictive pericarditis is one of the few cardiovascu-
left atrium volume loads the left heart, resulting in myofiber lar problems that can lead to HF in the setting of de-
stretching and decreased myocardial contractility. creased preload. Lower cardiac filling results in decreased
Arteriovenous malformations divert blood from the cardiac output. Constrictive pericarditis can result from a
relatively higher-resistance capillary beds of downstream pericardial bacterial infection (often staphylococcal) or
tissues to low-resistance venous circuits (including the chest irradiation during cancer treatment, which causes
atria). These are obligate shunts. Again, the returned fibrosis and constriction of the pericardium.

ductus arteriosus closes. In these

disorders, increased end-diastolic
filling pressures and a decreased
pressure gradient between the aorta
and ventricle at end-diastole pro-
duce subendocardial ischemia due
to inadequate coronary flow. In-
creased afterload and subendocar-
dial ischemia result in maladaptive
cardiac hypertrophy, ventricular re-
modeling, and the HF syndrome.
Disorders of Contractility
Cardiomyopathy (dilated, hyper-
trophic, constrictive, or restrictive)
is a genetically triggered or ac-
quired disease that occurs in ap-
proximately 1.13 in 100,000 chil-
dren. (8). HF (less commonly,
dysrhythmia) is the presenting fea-
ture. Different types of cardiomy-
opathy are illustrated in Figure 2.
Dilated cardiomyopathy is char-
Figure 2. Echocardiographic findings of cardiomyopathy subtypes. A. Normal. B. Hyper- acterized by enlarged ventricular
trophic: Concentric thickening of the left ventricular myocardium (other cases may have chambers and impaired systolic and
focal, subaortic, mid-cavity hypertrophy causing outflow obstruction). C. Restrictive: diastolic function. Usually, the cause
Dilated atria with compact ventricles giving “Mickey Mouse ear” appearance. D. Dilated: is unknown (idiopathic). Cardio-
Thin-walled, dilated ventricular cavities. myopathy may result from infec-
tion (myocarditis), operative injury,
High-output HF Associated With chemotherapy (most commonly due to anthracyclines),
Excessive Preload or as a consequence of degenerative or metabolic dis-
High-output HF seen in septic shock causes a volume eases (certain muscular dystrophies, mitochondriopathy,
load on both sides of the heart and increased stroke hyperthyroidism).
volume associated with hyperdynamic systolic function. Restrictive cardiomyopathy often is idiopathic but
During sepsis, the elaboration of vasoactive molecules can be caused by infiltrative or storage diseases (hemo-
such as endotoxin and cytokines such as TNF-alpha leads chromatosis, Pompe disease). The hallmark of restric-
to decreased systemic vascular resistance. Consequently, tive cardiomyopathy is abnormal diastolic function. The
cardiac output is increased. Precapillary shunting causes echocardiographic image shows enlarged atria and non-
decreased tissue perfusion and lactic acid production. dilated, mildly hypertrophied ventricles (a “Mickey
Increased vascular permeability leads to increased total Mouse” appearance of the heart) with abnormal tissue
body fluid volume. In addition, toxin or direct microbial Doppler indices.
actions have negative inotropic effects. Together, these Hypertrophic cardiomyopathy, such as idiopathic
stresses produce demands for cardiac output and MVO2. hypertrophic subaortic stenosis, seldom is associated
with pediatric HF.
Cardiac Malformations Associated With
Excessive Afterload Arrhythmias Associated With Pediatric HF
Left heart obstructive lesions such as mitral stenosis Arrhythmias cause HF when the heart rate is too fast or
(rare), aortic stenosis, and coarctation of the aorta too slow to meet tissue metabolic demands. During
(common) induce acute HF or lethal arrhythmias tachycardia-related diseases, diastolic filling time short-
when they cause severe afterload stress. Affected pa- ens to the point that cardiac output is decreased. This
tients often present in the first postnatal week, when the effect can occur after several hours of significant su-

praventricular tachycardia. With chronic bradycardias, Management

the left ventricle enlarges to accommodate larger stroke The first goal of HF care is to treat the specific cause.
volumes. However, HF ensues when chamber dilation Prompt treatment of noncardiac causes of HF such as
reaches a limit that cannot be compensated for by an anemia or endocrinopathies as well as timely referral for
increase in heart rate. Febrile states, in which metabolic surgical corrections of structural cardiac anomalies can
demands increase rapidly, are particularly stressful in the prevent or ameliorate HF. Examples include treating
setting of bradycardic heart diseases. hypothyroidism, stopping an episode of supraventricular
tachycardia, providing electronic pacing for a patient
who has heart block, closing a ventricular septal defect or
Laboratory Studies patent ductus arteriosus, repairing a coarctation, or re-
Because knowledge of the specific underlying disease is lieving a valve obstruction.
critical in the understanding of the pathophysiology, HF-causing cardiac malformations usually can be ap-
management, and response to therapy for HF, certain proached surgically. Accordingly, medical management
laboratory tests are essential. Pulse oximetry is helpful in of HF serves as a temporizing measure if surgery must be
identifying cyanosis in infants who have HF caused by delayed. Because there is no cure for primary childhood
increased pulmonary blood flow (left-to-right shunts) cardiomyopathies, the goal of medical management is to
because recognizing cyanosis in an infant is nearly im- delay or eliminate the need for cardiac transplantation.
possible by physical examination alone. Decreased per- Medical therapy in children has been guided by infor-
cutaneous oxygen saturation never is associated with mation derived largely from studies in adults. Given the
acyanotic heart disease unless poor tissue perfusion or many causes of pediatric HF, it is likely that infants and
intrapulmonary right-to-left shunting occurs. The 12- children will respond differently to therapies that have
lead electrocardiogram is essential to assess arrhythmia- been validated only in adult studies. Accordingly, it is
induced HF. The chest radiograph may demonstrate critical that pediatric-focused trials of “standard” HF
cardiac enlargement, increased pulmonary blood flow, treatments be performed. Because death is a relatively
venous congestion, or pulmonary edema. However, chest rare outcome in pediatric age groups, these studies
radiographs generally have a high specificity but low should take advantage of surrogate end points such as
sensitivity for detecting cardiac enlargement. (9) Al- rate of weight gain, lengths of hospital stays, and surgical
though not useful for the evaluation of HF, which is a morbidities.
clinical diagnosis, echocardiography is essential for iden- Medical management (Table 3) aims to maximize
tifying causes of HF such as structural heart disease, cardiac output and tissue perfusion while minimizing
ventricular dysfunction (both systolic and diastolic), stresses that increase MVO2. These goals are accom-
chamber dimensions, and effusions (both pericardial and plished by reducing the amount of force the heart needs
pleural). to generate to eject blood (reducing afterload stress) and
by reducing overfilling of the heart (preload). Thus,
treatments that “rest” the heart, such as vasodilators, are
HF Biomarkers preferred to inotropic agents that increase MVO2.
Recently, a number of HF biomarkers have been identi- Afterload reduction is accomplished by using drugs
fied that aid in assessing the severity of HF and predicting that decrease the systemic vascular resistance. These
the course of the disease. BNP measurement is a readily agents include angiotensin-converting enzyme inhibitors
available test that can distinguish between primary respi- and type 4 phosphodiesterase inhibitors (milrinone) or
ratory disease and cardiac-induced tachypnea. (10) Be- systemic nitrates (nitroprusside). Angiotensin-converting
cause this peptide is released primarily in response to enzyme inhibitors and angiotensin receptor blockers
atrial stretching, it is a sensitive marker of cardiac filling (losartan) also may help to inhibit cardiac fibrosis, as
pressure and diastolic dysfunction. C-reactive protein demonstrated in adult studies.
(11) and TNF-alpha (12) are both sensitive markers of Another approach to resting the failing heart is
systemic inflammation that correlate positively with a through inhibition of the sympathetic nervous system.
worse HF outcome in adult studies. C-reactive protein Beta-blocker therapy is a cornerstone of the medical
may augment interleukin-B, which can damage myocar- management of HF in adults. A recent large randomized,
dium directly. TNF-alpha depresses nitric oxide endo- controlled trial in children failed to show any significant
thelial relaxation acutely, an effect that can lead to ven- improvement in clinical severity from beta-blocker ther-
tricular remodeling and dysfunction over time. (12) apy compared with placebo. (13) However, in that study,

Digoxin is derived from the common flowering plant

Principles of Managing
Table 3. foxglove (Digitalis purpura). Years ago, it was used to
treat “dropsy,” renal failure, and edema. Digoxin is the
Heart Failure only commonly used oral inotropic agent. However, its
Recognition and Treatment of Underlying Systemic most important mechanism of action may be its ability to
Disease blunt the sympathetic nervous system, slow the heart
rate, and increase cardiac filling time. Despite its wide
Timely Surgical Repair of Structural Anomalies usage in treating pediatric HF, no studies have demon-
strated its efficacy. Because digoxin not only has an
Afterload Reduction
inotropic effect but also a chronotropic effect of slowing
● Angiotensin-converting enzyme inhibitors atrial conduction and because it is largely excreted by the
● Angiotensin receptor blockers
● Milrinone kidney, its close therapeutic/toxic ratio demands close
● Nitrates surveillance, especially if the patient is in renal failure.
● Brain natriuretic peptide (BNP) Some patients who experience acute and severe unre-
Preload Reduction sponsive HF are treated with extracorporeal membrane
oxygenation or left ventricular assist devices. These mea-
● Diuretics
● BNP sures serve largely as bridges to transplantation but often
are used to tide over the postoperative patient or the
Sympathetic Inhibition patient recovering from myocarditis, thereby obviating
● Beta blockers the need for transplantation.
● BNP The ultimate therapy for HF that is unresponsive to
● Digoxin
treatment is cardiac transplantation. The decision to
Cardiac Remodeling Prevention proceed with heart transplantation is based on the likeli-
● Mineralocorticoid inhibitors hood of successful medical therapy, quality of life, donor
availability, and institutional preference. Assessing dis-
Inotropy
ease severity is particularly problematic because of the
● Digoxin
lack of a validated, pediatric-focused HF classification
system.
the subgroup that had primarily left ventricular dysfunc- Prognosis

tion had improved fraction shortening and tended to The outcome for patients experiencing HF depends
decrease their end-systolic volume in response to treat- largely on its cause. When noncardiac disorders are re-
ment. sponsible, the improvement in HF is related to successful
Diuretics reduce preload, thereby improving Frank- treatment of the systemic disease. For many cardiac mal-
Starling relationships in the heart. Decreased preload formations (preloading and afterloading conditions),
helps to prevent pulmonary edema-producing high car- surgical correction can be curative. Unfortunately, sur-
diac filling pressures. Besides loop diuretics such as furo- gery for many congenital heart lesions only palliates the
semide, other classes of diuretics are used, including underlying disease.
thiazides and mineralocorticoid inhibitors (spironolac- For example, the “unnatural” history of children who
tone). Recent data suggest that aldosterone inhibition have undergone the Fontan sequence of surgical repair is
also helps to prevent maladaptive cardiac remodeling and development of HF for a variety of reasons. HF may
interstitial fibrosis. occur in patients who have cardiac malformations in
Nesiritide, a recombinant form of BNP, promotes whom the geometrically unsuitable morphologic right
both diuresis and vasodilation. Nesiritide is an attractive ventricle generates the systemic cardiac output. One
therapy because of its multiple effects. The drug reduces example is congenitally corrected transposition of the
both preload and afterload; directly inhibits the sympa- great vessels with ventricular inversion. In other cases,
thetic nervous system, mineralocorticoid expression, and longstanding cyanosis prior to the Fontan operation may
cardiac fibroblast activation; and promotes myocyte sur- result in cardiac remodeling and maladaptive hypertro-
vival. Nesiritide is gaining some attention as a third-line phy. In these situations, surgical management of HF is
therapy, but studies in the pediatric age group are lack- essentially palliative.
ing. Similarly, there is no good medical approach to the

Heart Failure Staging in

Table 4.
Pediatric Heart Disease Summary

• Based on strong research evidence, pediatric HF is a
Stage Interpretation Clinical Examples clinical syndrome that occurs when cardiac output is
A At risk for developing Congenital heart defects not sufficient to meet the metabolic demands of the
HF Family history of body.
cardiomyopathy • Strong research evidence suggests that although
Anthracycline exposure there are many specific causes of HF, only a few
B Abnormal cardiac Univentricular hearts primary mechanisms operate in all patients
structure or function Asymptomatic cardio- regardless of age (volume loading, afterload stress,
No symptoms of HF myopathy disorders of rhythm, and impaired myocardial
Repaired congenital contractility). (2)
heart disease • Based on some research evidence and consensus,
C Abnormal cardiac Repaired and un- pediatric HF results from a less well understood set
structure or function repaired congenital of signaling pathways that involves the sympathetic
Past or present heart defects nervous system, inflammation, so-called
symptoms of HF Cardiomyopathies neuroendocrine hormones, (10)(11)(12)(18)(19) and
D Abnormal cardiac Same as stage C cachexia. (4)(5)(20) These pathways represent a
structure or function complex interaction between maladaptive and
Continuous infusion of beneficial actions.
intravenous inotropes • Based on some research evidence and consensus, the
or prostaglandin E1 clinical presentation of HF is multifaceted and
to maintain patency unique in children. Current medical management
of a ductus arteriosus addresses noncardiac systemic disease and treats
Mechanical ventilatory primary cardiac problems by surgery or medical
and/or mechanical strategies aimed at reducing preload and afterload.
circulatory support (21)
• The medical therapies for managing HF, including
HF⫽heart failure. Reprinted with permission from Rosenthal et al blockade of the sympathetic nervous system,
(17). afterload reduction with vasodilators, and treatment
of cachexogenic pathways, were pioneered in adults
and have not been well studied in children.
various forms of genetically triggered cardiomyopathies. Presently, most pediatric HF treatments depend on
Dilated cardiomyopathy commonly is treated with heart experience and reason rather than on evidence-based
studies in infants and children.
transplantation. (14) One study demonstrated that • The validation of a pediatric system of HF
nearly 13% of patients who received new diagnoses of classification and the acceptance of surrogate
dilated cardiomyopathy underwent heart transplantation endpoints for HF studies are essential for the field
within 2 years of diagnosis. (8) Unfortunately, the out- to move toward reducing morbidity and mortality in
comes for infants and children who have cardiomyopathy children who experience HF.
have not improved in the last 3 decades, despite techno-
logic advances in medical management and transplanta-
tion. (8) Cardiomyopathies due to metabolic or storage permits clinicians to discriminate between stable and
diseases have the worst prognoses. decompensated disease. (17)
In general, too little is known about HF risk assess-
ment in children to permit confident statements about
prognosis and response to treatment. The New York References
Heart Association Classifications, routinely used in adult 1. Boucek MM, Edwards LB, Keck BM, Trulock EP, Taylor DO,
Hertz MI. Registry for the International Society for Heart and
studies, fail in pediatric applications because of the Lung Transplantation: seventh official pediatric report–2004.
unique presentations of HF in children. Alternatives, J Heart Lung Transplant. 2004;23:933–947
such as the Ross classification (15) or the New York 2. Kay JD, Colan SD, Graham TP Jr. Congestive heart failure in
University Pediatric HF Index (16) also have not gained pediatric patients. Am Heart J. 2001;142:923–928
wide acceptance. A recently proposed staging system 3. Lipshultz SE. Ventricular dysfunction clinical research in infants,
children and adolescents. Prog Pediatr Cardiol. 2000;12:1–28
(Table 4) categorizes patients based on cause and symp- 4. Anker SD, Steinborn W, Strassburg S. Cardiac cachexia. Ann
toms. This system stratifies infants and children by their Med. 2004;36:518 –529
extent of risk at the earliest stages of heart failure and 5. von Haehling S, Doehner W, Anker SD. Nutrition, metabolism,

and the complex pathophysiology of cachexia in chronic heart Disease in the Young; the Councils on Clinical Cardiology, Cardio-
failure. Cardiovasc Res. 2007;73:298 –309 vascular Nursing, and Cardiovascular Surgery and Anesthesia; and
6. Colao A. The GH-IGF-I axis and the cardiovascular system: the Quality of Care and Outcomes Research Interdisciplinary
clinical implications. Clin Endocrinol (Oxf). 2008;69:347–358 Working Group. Circulation. 2007;115:658 – 676
7. Silberbach M, Roberts CT Jr. Natriuretic peptide signalling: 15. Ross RD, Bollinger RO, Pinsky WW. Grading the severity of
molecular and cellular pathways to growth regulation. Cellular congestive heart failure in infants. Pediatr Cardiol. 1992;13:72–75
Signalling. 2001;13:221–231 16. Connolly D, Rutkowski M, Auslender M, Artman M. The New
8. Lipshultz SE, Sleeper LA, Towbin JA, et al. The incidence of York University Pediatric Heart Failure Index: a new method of
pediatric cardiomyopathy in two regions of the United States. quantifying chronic heart failure severity in children. J Pediatr.
N Engl J Med. 2003;348:1647–1655
2001;138:644 – 648
9. Satou GM, Lacro RV, Chung T, Gauvreau K, Jenkins KJ. Heart
17. Rosenthal D, Chrisant MR, Edens E, et al. International
size on chest x-ray as a predictor of cardiac enlargement by echo-
Society for Heart and Lung Transplantation: practice guidelines for
cardiography in children. Pediatr Cardiol. 2001;22:218 –222
management of heart failure in children. J Heart Lung Transplant.
10. Law YM, Hoyer AW, Reller MD, Silberbach M. Accuracy of
plasma B-type natriuretic peptide to diagnose significant cardiovas- 2004;23:1313–1333
cular disease in children: the Better Not Pout Children! study. J Am 18. Colao A, Terzolo M, Bondanelli M, et al. GH and IGF-I excess
Coll Cardiol. 2009;54:1467–1475. control contributes to blood pressure control: results of an obser-
11. Kaneko K, Kanda T, Yamauchi Y, et al. C-reactive protein in vational, retrospective, multicentre study in 105 hypertensive acro-
dilated cardiomyopathy. Cardiology. 1999;91:215–219 megalic patients on hypertensive treatment. Clin Endocrinol (Oxf).
12. Ratnasamy C, Kinnamon DD, Lipshultz SE, Rusconi P. Asso- 2008;69:613– 620
ciations between neurohormonal and inflammatory activation and 19. Lainscak M, von Haehling S, Springer J, Anker SD. Biomarkers
heart failure in children. Am Heart J. 2008;155:527–533 for chronic heart failure. Heart Fail Monit. 2007;5:77– 82
13. Shaddy RE, Boucek MM, Hsu DT, et al. Carvedilol for chil- 20. Akashi YJ, Springer J, Anker SD. Cachexia in chronic heart
dren and adolescents with heart failure: a randomized controlled failure: prognostic implications and novel therapeutic approaches.
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14. Canter CE, Shaddy RE, Bernstein D, et al. Indications for 21. Moffett BS, Chang AC. Future pharmacologic agents for
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from the American Heart Association Council on Cardiovascular 533–551

PIR Quiz
Quiz also available online at pedsinreview.aappublications.org.
1. The endogenous substance that best protects infants and children who have myocardial dysfunction against
progressive heart failure is:
A. Angiotensin II.
B. Brain natriuretic peptide.
C. Epinephrine.
D. Interleukin-B.
E. Tumor necrosis factor-alpha.
2. The symptom most suggestive of early heart failure in a 2-month-old infant is:
A. Apnea.
B. Cough.
C. Pedal edema.
D. Seizure.
E. Slow feeding.
3. The primary mechanism by which an isolated ventricular septal defect produces heart failure is:
A. Excessive afterload.
B. Excessive preload.
C. Impaired contractility.
D. Impaired coronary blood flow.
E. Induced bradydysrhythmia.
4. Which of the following assertions applies to heart failure in pediatric patients?

A. Heart failure in most patients results from ischemic heart disease.
B. Future improvements in treatment require a valid system for classifying the risk of heart failure.
C. Lower concentrations of tumor necrosis factor-alpha reliably predict poorer outcomes.
D. Recombinant brain natriuretic peptide is well established as first-line therapy.
E. The benefits of beta-blocker therapy have been clearly demonstrated.
5. Angiotensin-converting enzyme inhibitors benefit patients who have heart failure primarily through:
A. Afterload reduction.
B. Inotropic effect.
C. Preload reduction.
D. Prevention of cardiac remodeling.
E. Sympathetic inhibition.

Erin Madriago and Michael Silberbach
Pediatr. Rev. 2010;31;4-12
DOI: 10.1542/pir.31-1-4

Subspecialty Collections This article, along with others on similar topics, appears in the
following collection(s):
Cardiovascular Disorders
http://pedsinreview.aappublications.org/cgi/collection/cardiovas
cular_disorders

Pediatric Tuberculosis
Andrea T. Cruz and Jeffrey R. Starke
Pediatr. Rev. 2010;31;13-26
DOI: 10.1542/pir.31-1-13

Article infectious diseases
Andrea T. Cruz, MD,*
Jeffrey R. Starke, MD*
1. Discuss how the risk of disease, clinical presentation, and morbidity of tuberculosis (TB)
vary by age and immune status.
Author Disclosure 2. Delineate the epidemiologic risk factors for the acquisition of TB infection, the subse-
Drs Cruz and Starke quent development of TB disease in a minority of children, and the risk of multidrug-
have disclosed no resistant TB.
financial relationships 3. Describe the presenting signs and symptoms of TB in children.
relevant to this 4. Recognize the extrapulmonary manifestations of TB and which children are at risk for
article. This these forms of disease.
commentary does not 5. Explain the utility of the tuberculin skin test, potential false-positive and false-
contain a discussion negative results, and the effect of the bacillus Calmette-Guérin vaccine on the ability
of an unapproved/ to interpret the test.
investigative use of a 6. Discuss interferon-gamma release assays and their limitations.
commercial product/ 7. List the primary findings seen on chest radiography in the child who has pulmonary
device. TB.
8. Plan a therapeutic course for children who experience TB exposure, infection, and
disease.
9. Describe the measures that can be taken to prevent the development of disease and to
limit spread of TB within the community and the health-care setting.
Introduction
Tuberculosis (TB) is an ancient disease, with evidence of skeletal TB found in mummies in
both the Old and New World. The causative agent is Mycobacterium tuberculosis, a
fastidious, aerobic, acid-fast bacillus. In the wake of human
immunodeficiency virus (HIV) infection, the number of
children and adults afflicted with TB has escalated tremen-
Abbreviations dously worldwide in the past 25 years. Control of TB in
AFB: acid-fast bacilli children often has been neglected because children are inef-
BCG: bacillus Camille-Guérin fective transmitters of the bacillus and frequently escape the
CNS: central nervous system attention of TB control programs. However, much of the
CSF: cerebrospinal fluid morbidity and mortality of TB occurs in childhood, and
CT: computed tomography acquisition of TB infection during childhood contributes to
DOT: directly observed therapy the future reservoir of cases. Risk factor-based screening of
DR: drug-resistant children for TB infection, appropriate implementation of
HCW: health-care worker chemoprophylaxis, and a high degree of suspicion for TB
HIV: human immunodeficiency virus disease on the part of clinicians can decrease the disease
IGRA: interferon-gamma release assay burden in children.
INH: isoniazid
LTBI: latent tuberculosis infection Definitions
MDR: multidrug-resistant Individuals who have been in contact with a source case of
PZA: pyrazinamide TB generally are classified into one of three groups (Table 1).
TB: tuberculosis The first group includes persons exposed to someone who
TST: tuberculin skin testing has TB but whose status is not yet clear, often because
insufficient time has passed to rely on results of tuberculin
*Department of Pediatrics, Section of Infectious Diseases, Baylor College of Medicine, Houston, Tex.

infectious diseases tuberculosis
Table 1. Tuberculosis (TB) Disease Classification and Initial Treatment

Classification Initial Treatment* Duration of Therapy Other
TB exposure, >4 years old None N/A Repeat TST 2 to 3 months after contact
and immunocompetent with source case is broken; if second
TST result is positive, see section on
TB infection
TB exposure, <4 years old INH 2 to 3 months Repeat TST 2 to 3 months after contact
or immunocompromised Second-line: with source case is broken; if second
Rifampin TST result is positive, see section on
TB infection
TB exposure, infant INH At least 2 to 3 months Because TSTs are less reliable in infants
Second-line: compared with older children, the
Rifampin TST results of other children in the
family should be considered when
making decisions about terminating
chemoprophylaxis; expert opinion
should be sought
TB infection INH 9 months Biweekly therapy should be
administered only via DOT
Second-line: 6 months
Rifampin
TB disease Multiple drugs 6 months for Medications should be administered
(Table 6) pulmonary and most only via DOT
extrapulmonary
forms
9 to 12 months for See section in text on indications for
patients who have steroids
meningitis,
disseminated
disease, or persistent
smear-positive
sputum on adequate
therapy
*Therapy should be modified based on source case susceptibility patterns or known resistance patterns within a given community. DOT⫽directly observed
therapy, INH⫽isoniazid, N/A⫽not applicable, TST⫽tuberculin skin test
skin testing (TST), otherwise known as the Mantoux contagious at all. Of persons who have untreated LTBI,
test. The treatment of children exposed to TB depends 5% to 10% ultimately develop TB disease; rates are higher
on age and immune status. The second class is termed in children and in immunocompromised hosts (Table 2).
latent TB infection (LTBI). Individuals who have LTBI Approximately one third of the global population has
have positive TST results but have no symptoms, physical LTBI, and at least 9 million new cases of TB disease and
findings, or radiographic anomalies consistent with TB. 2 million deaths from the disease occur annually. More
It is recommended that most children who have LTBI than 90% of the burden of TB disease is in the developing
receive a course of therapy to prevent the development world.
of TB disease in the future. The final group includes In the United States, about 13,000 new cases of TB
those persons who have clinical or radiographic manifes- disease were diagnosed in 2007, including approximately
tations of TB disease. These patients are treated with 820 in children younger than 15 years of age. Mandatory
multiple drugs. reporting exists for patients who have TB disease but not
for persons who have been exposed to TB or have LTBI.
Epidemiology Seven states (California, Florida, Georgia, Illinois, New
On average, each adult who has pulmonary TB infects Jersey, New York, and Texas) accounted for 60% of all
8 to 15 individuals prior to having TB diagnosed. How- cases in 2007. Foreign-born individuals in the United
ever, some patients are very contagious and some are not States have TB rates 9.5 times higher than those in

Table 2. Risk of Progression from Tuberculosis (TB) Infection to Disease

Age at Primary Pulmonary Miliary or Central
Infection (yr) No Disease (%) Disease (%) Nervous System TB (%)
<1 50 30 to 40 10 to 20
1 to 2 75 to 80 10 to 20 2.5
2 to 5 95 5 0.5
5 to 10 98 2 <0.5
>10 80 to 90 10 to 20 <0.5
Adapted from Marais, et al. Childhood pulmonary tuberculosis: old wisdom and new challenges. Am J Resp Crit Care Med. 2006;173:1078 –1090.
United States-born persons, with most cases occurring in regional lymph nodes. Following this stage, the infection
immigrants from Mexico, the Philippines, Vietnam, can be contained, spread rapidly, or reactivate at a later
China, and India. point in life. Different clinical manifestations of TB in
Other risk factors for development of TB disease in children have varying incubation periods. Miliary or dis-
the United States include untreated HIV infection (10% seminated disease usually occurs 2 to 6 months after
annual risk of progressing from LTBI to disease) and infection, renal TB manifests in 5 years, skeletal TB
other immunocompromising conditions, recent LTBI, occurs 1 to 2 years after infection, and pulmonary and
intravenous drug use, and certain medical conditions lymphatic TB occur within 4 to 12 months. Most clinical
such as diabetes and renal failure. Approximately 9% of manifestations in children occur within 1 to 2 years of
adult TB patients in the United States are coinfected with initial infection.
HIV.
Drug-resistant (DR) TB should be suspected if certain Clinical Manifestations
epidemiologic risk factors are present, including known Only 5% to 10% of children older than 3 years of age who
DR-TB in a potential source case, a history of treatment have untreated LTBI progress to disease, and most do so
failure or relapse in the patient or the source case, travel within 1 to 2 years of initial infection. The most common
to an area that has a high prevalence of endemic DR-TB, site of infection is the lung, which accounts for up to 80%
and positive sputum smears after 2 months of the usual of all cases of disease. The most common extrapulmonary
combination chemotherapy. Drug resistance shows wide manifestation is tuberculous lymphadenopathy (67%),
geographic variation. Multidrug-resistant (MDR) TB is followed by meningitis (13%, occurring most often in
defined as resistance to at least two of the first-line TB infants and toddlers), pleural TB (6%), miliary TB (5%),
medications, isoniazid (INH) and rifampin. Fewer than and skeletal TB (4%). Commonly involved areas in the
1% of TB cases in the United States are MDR-TB com- teenager are the lymph nodes, pleural spaces, and bones.
pared with rates of up to 15% in Kazakhstan. It is esti- The risk of extrapulmonary disease is highest in immu-
mated that 500,000 new cases of MDR-TB occurred in nocompromised children, infants, and adolescents. The
the world in 2007. Extensively drug-resistant TB has best-studied group of immunocompromised patients is
been described more recently and is defined as resistance HIV-infected patients, but children who have other
to INH, rifampin, any fluoroquinolone, and any second- T-cell dysfunction and malnourished children also have a
line injectable agent (excluding streptomycin). Exten- higher risk of progressing from LTBI to TB.
sively drug-resistant TB remains exceedingly rare in the
United States. Pulmonary Disease
Pulmonary TB includes both intrathoracic lymphade-
Pathogenesis nopathy and parenchymal disease. The three time frames
TB is transmitted most commonly via airborne spread. for pulmonary involvement with TB are primary paren-
Lymph nodes frequently become infected with M tuber- chymal, progressive primary, and reactivation disease.
culosis. Such infection causes enlargement of the nodes Primary parenchymal disease is one of the most common
with or without significant inflammation. Inhalation of manifestations of disease. Infants and adolescents are
the bacillus into a terminal airway can result in formation more likely to be symptomatic than are 5- to 10-year-old
of a Ghon complex, which includes the initial focus of children (Table 3). A variety of radiographic features may
infection, the draining lymphatic vessels, and enlarged be seen, the most common being hilar or mediastinal

Table 3. Signs and Symptoms of Pulmonary Tuberculosis

Clinical Feature or Disease Type Infants Children Adolescents
Symptom
Fever Common Uncommon Common
Night sweats Rare Rare Uncommon
Cough Common Common Common
Productive cough Rare Rare Common
Hemoptysis Never Rare Rare
Dyspnea Common Rare Rare
Sign
Rales Common Uncommon Rare
Wheezing Common Uncommon Uncommon
Decreased breath sounds Common Rare Uncommon
Location of Disease
Pulmonary Common Common Common
Pulmonary ⴙ Extrapulmonary Common Uncommon Uncommon
adenopathy (Fig. 1). Children become symptomatic Pediatric tuberculous cavitary disease develops in three
when enlarging lymph nodes compress adjacent struc- circumstances: a young infant or immunocompromised
tures; collapse of a terminal bronchus from extrinsic child as the host, lymph node erosion into airways lead-
compression leads to the collapse-consolidation pattern ing to aspiration of bacilli (preschool-age child), and the
seen in the younger child. The most common symptoms development of adult-type cavitary disease (generally in
are cough, low-grade fever, and rarely, weight loss. children older than 10 years). Direct extension of disease
Progressive primary disease results from poor contain- into surrounding structures can result in invasion of the
ment of the initial infection and can be associated with pericardium or pleural space or the creation of broncho-
lung tissue destruction and cavity formation (Fig. 2). pleural fistulas. Affected children usually appear more ill,
having severe cough, fevers, occasional night sweats, and
weight loss.
Reactivation disease is more common in adolescents,
particularly in geographic areas that have high rates of
coinfection with HIV. Patients complain of constitu-
Figure 1. Right hilar tuberculous lymphadenopathy in a

2-year-old boy who has hepatoblastoma. This child’s TB
disease was diagnosed during his chemotherapeutic course. Figure 2. Right upper lobe cavity seen in the father of a
A medication catheter and port are present in the left chest patient who has TB meningitis. This adult has no hilar or
wall. mediastinal adenopathy.

tional symptoms such as fever, weight loss, night sweats, Tuberculomas, occurring in 5% of children who have
and malaise, although physical findings may be unre- CNS TB, appear as single rim-enhancing lesions ranging
markable. Cough is common, and hemoptysis may oc- from 1 to 5 cm (Fig. 3). In TB meningitis, cerebrospinal
cur. Reactivation disease in adults is somewhat more fluid (CSF) analysis typically demonstrates lymphocytes,
common in the apices of the lungs and primary disease in a low glucose concentration, and a high protein value.
the basilar regions, but this pattern does not hold true for TST results are positive in only 33% of children. Chest
children, and the radiographic findings in reactivation radiographs are abnormal in almost 90% of patients, and
disease overlap considerably with primary parenchymal a miliary pattern may be seen. Acid-fast bacilli (AFB)
and progressive pulmonary TB. culture of the CSF is unlikely to be positive unless a large
volume of CSF is cultured. Gastric aspirates are positive
Lymphatic Disease in a minority of children. Children who have CNS TB are
Superficial lymphadenopathy is the most common ex- treated for a minimum of 9 months. Placement of a
trapulmonary form of TB. The most common route of ventriculoperitoneal shunt to relieve intracranial pressure
transmission is hematogenous spread. Children who and prevent herniation may be needed. This form of TB
have TB lymphadenopathy tend to be older than those has the highest morbidity and mortality rates.
who have nontuberculous mycobacterial lymphadenop-
athy. The lymph nodes involved most commonly are Pleural Disease
anterior cervical, followed by posterior triangle, subman- Pleural TB usually is a disease of the older child and
dibular, and supraclavicular. Tuberculous lymph nodes adolescent and can occur in isolation from or concomi-
usually measure 2 to 4 cm and lack the classic inflamma- tantly with pulmonary parenchymal disease (Fig. 4).
tory findings of pyogenic nodes. There may be overlying Symptoms include chest pain, fever, cough, dyspnea, and
violaceous skin discoloration. Systemic symptoms occur anorexia. Ausculatory findings mimic those of bacterial
in 50% of children, abnormal chest radiographs are seen pneumonia. Most children have positive TST results.
in approximately 33% of patients, and most have positive Effusions are more common on the right and rarely are
TST results. Untreated lymph nodes may caseate, spread bilateral. The pleural fluid is exudative and lymphocytic,
to contiguous structures, and lead to formation of un- with high protein, low glucose, and elevated adenosine
sightly sinus tracts. Surgical node excision is not curative deaminase values. AFB cultures of pleural fluid are posi-
but may be necessary to establish the diagnosis. Most
children respond well to a 6-month course of multidrug
therapy, but occasionally therapy must be extended to 9
months, based on clinical response.
Central Nervous System (CNS) Disease

CNS involvement is rare, developing in fewer than 2% of
all cases of TB. CNS TB usually occurs within months
after infection with the organism; 50% of all patients are
younger than 2 years of age. In many parts of the devel-
oping world, TB is the primary cause of subacute men-
ingitis, and tuberculomas are common causes of mass-
occupying CNS lesions.
Three clinical stages of CNS TB have been described.
Nonspecific constitutional symptoms and headache are
the initial symptoms in stage I, followed by cranial nerve
palsies and evidence of meningeal inflammation in stage
II. In the final stage, children have profoundly altered
mentation due to increased intracranial pressure and
vasculitis. The most common findings on CNS imaging
are hydrocephalus and basilar enhancement. Vascular Figure 3. Central nervous system tuberculoma in the right
lesions involving the basal ganglia and midbrain also are thalamus and basal ganglia in a 7-month-old child who has TB
common, and TB should be considered in cases of child- meningitis and miliary TB. This child’s chest radiograph is
hood stroke. shown in Fig. 5.

Figure 5. Miliary TB in a 7-month-old male who also has TB

meningitis with left upper lobe infiltrate and air bron-
chograms. Hilar or mediastinal adenopathy is difficult to
discern in this infant, whose thymus is not yet atrophied.
Skeletal Disease
Figure 4. Pleural TB in a 17-year-old male who has bilateral Skeletal TB is a disease of the older child, and most
(right > left) pleural effusions and bibasilar and left lingular patients are in the second decade of life, with the excep-
airspace disease. He also has TB peritonitis.
tion of spinal involvement (Pott disease), which can
affect even young children (Fig. 6). Skeletal lesions can
develop more than 10 years after initial infection. Solitary
tive in approximately 33% of patients; biopsy of pleural
lesions in the axial skeleton typically are seen in the
tissue has a higher culture yield, and histologic examina-
otherwise healthy host, whereas multiple lesions with
tion often shows caseating granulomatous inflammation
systemic symptoms are more common in the immuno-
of the pleura. A 6-month course of therapy is recom-
compromised child. Local signs of inflammation pre-
mended.
dominate, and systemic symptoms occur in only 33% of
children.
Miliary Disease The most common manifestations of skeletal disease
Miliary tuberculosis due to lymphohematogenous spread are spondylitis, arthritis, and osteomyelitis. Spondylitis is
is a disease of the younger or immunocompromised child seen most frequently, affecting the thoracic and lumbar
(Fig. 5). Miliary disease can present shortly after primary spines preferentially (Pott disease). Dactylitis is most
infection, and multiorgan involvement is common. Most common in the infant and young child. Magnetic reso-
affected children have fever and other constitutional nance imaging is the preferred imaging choice because it
symptoms, and pyrexia, hepatomegaly, and splenomeg- can demonstrate lesions months before plain radio-
aly commonly are seen on physical examination. CNS graphs. Chest radiographs are positive in 50% of children
involvement occurs in up to 20% of children, and a young who have skeletal TB, and TST results are positive in
child who has miliary TB always should be evaluated for most. AFB cultures of bone are positive in up to 75% of
meningitis. The TST is insensitive in these patients be- cases, and histopathology often is diagnostic.
cause disseminated disease can produce TST anergy.
AFB culture from gastric aspirates can have a yield as high Congenital Disease
as 50%. A prolonged course of therapy (9 to 12 months) Congenital TB is encountered infrequently in the United
should be administered to patients who have dissemi- States. It occurs in infants born to mothers who have
nated disease. endometrial or disseminated TB and presents with con-

more common in HIV-infected children and is difficult

to diagnose without performing tissue examination and
culture.
Diagnosis
TB disease often is diagnosed by a positive TST result,
epidemiologic information (exposure to a known source
case), and a compatible clinical and radiographic presen-
tation. In children, symptoms frequently are due to a
vigorous immune response to a relatively small number
of organisms, which greatly limits the feasibility of using
culture alone as the diagnostic test for TB disease. Only
30% to 40% of children who have clinically suspected
pulmonary TB have positive cultures. Cultures can be
obtained by sequential sputum sampling or by gastric
aspiration of early morning secretions in the younger
child. Culture yield is highest in neonates (up to 70%),
adolescents who have cavitary disease, and children who
Figure 6. Pott disease involving near-complete destruction of have tuberculous lymphadenopathy and undergo biopsy
the L4 vertebral body, with posterior displacement of the L3 or fine-needle aspiration. The bacillus grows slowly, of-
vertebral body and resultant kyphosis.
ten taking up to 6 to 8 weeks to grow on Lowenstein-
Jensen media and 2 to 3 weeks to grow in liquid media.
stitutional symptoms, difficulty breathing, and failure to AFB stains include Kinyoun, auramine-rhodamine
thrive in the first 3 months after birth. Physical findings (Truant), and Ziehl-Neelsen; Truant stains are the most
can include hepatomegaly, evidence of respiratory dis- sensitive. Microscopic observation drug susceptibility as-
tress, and peripheral lymphadenopathy. CNS involve- says were developed recently to identify resistant isolates
ment occurs in up to 20% of children. TST results rarely rapidly and to permit direct drug susceptibility testing
are positive in this age group. Chest radiography yields concomitant with detecting bacterial growth in liquid
abnormal results in almost all children. Gastric or tra- media, but these assays are not yet widely available.
cheal aspirates and hepatic biopsy cultures are positive in The TST comprises antigens (purified protein deriva-
most infants. tive) that are not all specific to M tuberculosis. The
antigens trigger a delayed hypersensitivity reaction in
Other Forms persons who have come in contact with TB bacilli. The
Less commonly encountered forms of TB include ab- size of the TST is measured in millimeters of induration
dominal, renal, and cutaneous disease. These forms often (not erythema) approximately 48 to 72 hours after place-
are difficult to diagnose because they frequently are late ment, but if a child returns for TST interpretation after
manifestations, epidemiologic links are more difficult to 72 hours and has induration meeting the criteria for
establish, the yield of AFB cultures can be lower than for positivity (Table 4), the skin test still should be inter-
children who have extensive pulmonary disease, and preted. The TST usually becomes positive 3 weeks to 3
clinical findings can overlap with those of numerous months after infection occurs and should remain positive
other disease processes. Diagnosis may be facilitated by for life or until immune system dysfunction or senescence
obtaining a chest radiograph and placing a TST. occurs. Sensitivity and specificity of the test are estimated
Children coinfected with HIV and TB present with to be 95%. Once a TST yields a positive result, a patient
symptoms similar to those of HIV-uninfected children should be counseled to avoid any additional TSTs be-
who have TB. However, in the former group, the differ- cause the test no longer is a useful tool and subsequent
ential diagnosis is much broader, and clinical presenta- skin tests can cause scarring. The determination of a TST
tion can overlap with many opportunistic infections. as positive depends on several variables (Table 4), includ-
HIV-infected children are more likely to have abnormal ing patient age and immune status, clinical probability of
chest radiography results compared with HIV-uninfected having TB disease, and risk factors for exposure. The use
children and to have either parenchymal infiltrates or of control skin tests (Candida, tetanus toxoid) is not
cavitary lesions. Extrapulmonary disease appears to be recommended when TSTs are placed.

Table 4. Reaction Size of Tuberculin Skin Test Considered Positive

Reaction Size Risk Factors
>5 mm Human immunodeficiency virus infection or other immunocompromising conditions
Abnormal chest radiograph consistent with tuberculosis
Contact with an infectious case
>10 mm Age <4 years
Birth or residence in high-prevalence country
Residence in a correctional or long-term care facility
Certain medical conditions (eg, diabetes, renal failure, silicosis)
Health-care workers exposed to patients who have tuberculosis
Any child who is a close contact of an adult who has any of the previously noted high-risk factors
>15 mm No risk factors
Both false-negative and false-positive results plague diagnose LTBI. More recently, new tests for LTBI have
the TST. A negative result never eliminates the possibility been introduced: whole blood interferon-gamma release
of TB disease because many disseminated forms of TB, assays (IGRAs). These tests measure the patient’s ability
including miliary and meningitis, can induce anergy to to produce interferon-gamma after their lymphocytes are
the skin test. Up to 15% of children who have clinical TB stimulated by two or three antigens found on M tuber-
have negative TST results. A false-negative TST result culosis. One of the available tests measures whole blood
also can be seen in association with recent measles infec- interferon-gamma and the other measures the number of
tion, high-dose corticosteroid treatment, irradiation, lymphocytes that produce interferon-gamma.
other immunosuppressive therapy, or immunocompro- These assays have several potential advantages. Only
mising medical conditions. False-positive results occur one office visit is required (versus two to have the TST
primarily in children exposed to nontuberculous (envi- placed and read); there is no risk of the boosting phe-
ronmental) mycobacteria or in those who have recently nomenon; and they have more specificity for LTBI be-
received a bacillus Calmette-Guérin (BCG) vaccine. cause the antigens in the IGRAs are shared less com-
A boosting phenomenon has been noted in some sensi- monly with nontuberculous mycobacteria and are not
tized persons who receive multiple sequential TSTs and found on BCG, which is derived from M bovis. Like the
only then develop a positive result, which usually repre- TST, they cannot distinguish LTBI from TB disease. The
sents a false-positive result in children. However, there is primary drawback is that the tests have been studied
no way to distinguish these positives from true positives. primarily in adults, and fewer data are available on the
Therefore, it is recommended that children be screened
for risks of exposure to TB by history initially, with a TST
used only for those who have epidemiologic risk factors
(Tables 4 and 5). Risk Factor-based
Table 5.
There are common misconceptions about the utility Questionnaire for Exposure
of the TST in children who have received the BCG
vaccine. Several well-designed studies have implied that a
to Tuberculosis
TST can be interpreted normally in a child who received ● Has the child received a bacillus Camille-Guérin
a single dose of the BCG vaccine as a young child. vaccination?
Having received a BCG as an infant may not explain a ● Was the child born outside of the United States?
positive skin test result later in life. The assumption that ● Has the child lived outside of the United States?
● Is there a household member who has a history of
BCG receipt is the cause of a positive TST result over-
tuberculosis?
looks that BCG is, for the most part, used in parts of the ● Is the child Hispanic or Asian?
world that have high rates of TB. Consequently, this
Answering yes to one question had a sensitivity for latent tuberculosis
assumption could lead to a lack of treatment for high- infection of 83%, with a specificity of 48%. With increasing responses of
risk children who potentially could benefit from LTBI “yes” to the questions, specificity increased, but sensitivity decreased.
From Froehlich et al. Targeted testing of children for tuberculosis:
therapy. validation of a risk assessment questionnaire. Pediatrics. 2001;107:e54.
For decades, the TST was the only test available to

performance characteristics in young children. The gression later in life. The mainstay of therapy for LTBI
greatest usefulness of IGRAs may be in determining if a is INH administered for a 9-month course. An alter-
positive TST result in a child who received a BCG vaccine native for patients intolerant of INH is rifampin, which is
is from the BCG (negative IGRA) or from LTBI (posi- administered for 6 months. Therapy for LTBI can be
tive IGRA). daily and self-administered or intermittent (biweekly or
Chest radiography should be obtained routinely in thrice-weekly) and supervised through directly observed
children being evaluated for TB disease or in any child therapy (DOT). Patients never should receive self-
who has a positive TST or IGRA result. Children who administered intermittent therapy because missed doses
have LTBI usually have normal-appearing chest radio- in this regimen increase the likelihood of failure. Chil-
graphs. An isolated calcified lesion in a child who has a dren whose source cases have isolates resistant to INH
positive TST result can be treated as LTBI. The most but susceptible to rifampin can be treated with rifampin
common abnormal radiographic finding is hilar or medi- alone. Children exposed to or infected by contacts in-
astinal adenopathy; other findings can include infiltrates, fected with DR-TB should be managed in coordination
atelectasis, pleural effusions, cavities, or miliary disease. with a TB expert, usually by attempting to find one or
Chest radiographs often indicate more severe disease more oral agents to which the organism has documented
than would be suspected based on physical examination. susceptibility.
Most studies of the radiographic diagnosis of TB have
used chest radiography as the reference standard. Com- TB Disease
puted tomography (CT) scan is much more sensitive in Children who have TB disease have a higher organism
detecting atelectatic regions and adenopathy, but the burden, and the mathematical likelihood of their having
clinical significance of CT scan findings that are not also resistant organisms is higher. Consequently, any child
seen on chest radiography is unclear. CT scan is not suspected of having TB disease should be started on
recommended routinely for the evaluation of the child combination therapy. All cases of TB disease should have
who has a positive TST result or suspected disease. medication administered via DOT, whereby a public
health worker supervises medication administration.
Treatment DOT has been shown to increase medication compliance
Deciding which medications to prescribe for a child and decreases the emergence of resistant isolates.
suspected of having TB disease or infection depends on The standard initial regimen should be the four most
several factors: disease classification (exposure versus commonly used agents in the treatment of TB disease:
LTBI versus disease), anatomic location of disease, route INH, rifampin, pyrazinamide (PZA), and ethambutol.
of administration, medication adverse effect profiles and INH, rifampin, and ethambutol are administered for 6
potential medication interactions, and data on isolate months and PZA is stopped after the first 2 months. If
susceptibility, when available. the source case’s isolate is known to be susceptible to the
other three drugs, ethambutol need not be given. These
TB Exposure medications are efficacious, available in oral formulation,
TB exposure is a category used to describe asymptomatic and well-tolerated by children. The doses, drug interac-
children who have had contact with a person suspected of tions, adverse effect profiles, and monitoring parameters
having TB disease and in whom the TST result and chest for these medications, as well as for second-line medica-
radiograph are normal. Children younger than 4 years of tions, are listed in Table 6. Other drugs are considered
age and immunocompromised children should be second-line medications for reasons that may include
started on medication, usually INH, pending results of route of administration (parenteral), toxicities, cost,
repeated skin testing, because they are at higher risk of availability, or limited experience in children.
rapid progression to clinical disease. If the second skin Medications usually are administered daily for the first
test result is negative, medication can be discontinued. 2 to 4 weeks and then can be changed to biweekly. For
Children experiencing TB exposure who are older than infants and toddlers, the increased medication volume
age 3 years and immunocompetent can be observed off required when changing from daily to biweekly or thrice-
of medications pending the second skin test result. weekly therapy can result in medication intolerance and
vomiting. Therefore, it may be reasonable to continue
TB Infection (LTBI) young children on daily therapy for a longer time. An-
The child demonstrating a positive skin test result should other concern for the young child is that INH suspension
be treated for LTBI to decrease the risk of disease pro- is sorbitol-based and can cause gastrointestinal distress.

Table 6. Drugs Used for the Treatment of Tuberculosis in Children and Adults
Daily Dose Biweekly dose
Hepatic or
Children Maximum Children Maximum Drug Monitoring Renal Dosing
Agent (mg/kg per day) Dose (mg/kg per day) Dose Interactions1 Toxicities CNS Penetrance 2
Parameters Necessary
First-line Agents
Isoniazid3 10 to 15 300 mg 20 to 30 900 mg ⴙ Hepatitis, 100% †
*
peripheral
neuropathy
Rifampin 10 to 20 600 mg 10 to 20 600 mg ⴙⴙ Hepatitis 10% to 20% †
*
Pyrazinamide 30 to 40 2g 50 2g ⴚ Gout, rash 100% †
*Renal
Ethambutol 20 2.5 g 50 2.5 g ⴚ Optic neuritis Minimal‡ †
*Renal
Agents for Drug-resistant TB
Amikacin 15 to 30 1g Few data available ⴚ Nephrotoxicity, Low Baseline and Renal
on the efficacy ototoxicity monthly
of biweekly creatinine, drug
dosing of concentrations,
second-line and hearing
agents in screen
children
Capreomycin 15 to 30 1g ⴚ Nephrotoxicity, Minimal‡ Baseline and Renal
ototoxicity monthly
creatinine and
hearing screen
Kanamycin 15 to 30 1g ⴚ Nephrotoxicity, Low Baseline and Renal
ototoxicity monthly
creatinine and
hearing screen
Streptomycin 20 to 40 1g ⴚ Ototoxicity, Minimal Baseline and Renal
nephrotoxicity monthly
creatinine and
hearing screen
Ethionamide 15 to 20 1g ⴚ Hepatotoxicity, 100% Consider baseline *Renal
GI distress, ALT and TSH
hypersensitivity
reactions,
hypothyroidism,
peripheral
neuropathy,
optic neuritis
Levofloxacin 7.5 to 10† 1 g† ⴙⴙ Arthropathy, CNS 16% to 20% Renal
stimulation
Ciprofloxacin 20 to 30 †
1.5 g †
ⴙⴙ Arthropathy, CNS 10% Renal
stimulation
Cycloserine 10 to 20 1g ⴚ Rash, seizures, 100% Monthly neuro- Renal
psychosis psychiatric
evaluation;
serum
concentrations
available
Para-aminosalicylic 200 to 300 10 g ⴙ Hepatotoxicity, 10% to Baseline ALT, TSH; Renal
acid GI distress, 50%‡ check monthly
hypersensitivity if used >3
reactions, months
hypothyroidism
1
For drug interactions: ⫺⫽minimal interactions, ⫹⫽few interactions, ⫹⫹⫽multiple interactions
2
Percentage of serum concentrations reached in cerebrospinal fluid.
3
Isoniazid metabolism can vary by how rapidly a child acetylates the medication, but specific testing or dosage modifications are not indicated based on
whether a child is a slow or fast acetylator.
†
Routine baseline laboratory evaluation not necessary except in children who have known underlying hepatic disease.
*Can be used, but with more frequent monitoring, in patients who have underlying hepatic disease.
‡
Only marginally efficacious for tuberculous meningitis.
ALT⫽alanine aminotransferase, CNS⫽central nervous system, GI⫽gastrointestinal, TSH⫽thyroid-stimulating hormone
Once a child is taking soft foods, consideration should be cific treatments in adults or children, and in most circum-
given to changing to INH tablets, which can be crushed stances, therapy needs to be individualized based on the
and mixed with semisolid foods. exact drug resistance pattern. Consultation with a TB
MDR-TB, defined as resistance to at least INH and expert always should be sought.
rifampin, presents many challenges to the clinician. No The usual treatment duration for pulmonary and most
large-scale studies have investigated the efficacy of spe- extrapulmonary forms of TB is 6 months for isolates that

are susceptible to all first-line TB drugs. Exceptions are negative and the child is immunocompetent, INH can
treating children who have disseminated or CNS TB, be discontinued. If the TST result is positive or the child
where treatment courses of 9 to 12 months often are is immunocompromised, INH should be continued for
used; children infected with MDR-TB, who often are 9 months.
treated for 12 to 18 months; and patients who have Management of the infant whose mother has TB is
cavitary disease and persistently positive sputum cultures more difficult because infants are more likely to pro-
on appropriate therapy, when it is recommended that gress rapidly to pulmonary or extrapulmonary disease
therapy be extended to 9 months. If therapy is inter- and the TST is helpful only if the result is positive, which
rupted for more than 14 days, the treatment course is very rare. If the mother has a positive TST result and
should be restarted in its entirety. Chest radiographs negative chest radiograph (LTBI), the child needs no
obtained at the end of therapy continue to appear abnor- evaluation. If the mother has a positive skin test result
mal, but improved, in most children who have adenopa- and an abnormal radiograph but one that is not consis-
thy. This finding is not an indication to continue therapy tent with TB, sputum smears should be obtained from
until resolution of radiographic disease. the mother. If the mother is AFB sputum smear-
Children coinfected with TB and HIV pose a number negative, the infant does not need to be isolated from the
of treatment challenges. These in-
clude higher mortality rates; in-
creased likelihood of malabsorption
of TB medications; drug-drug in-
teractions between rifampin and “Management of the infant whose mother
many antiretrovirals (protease in- has TB is more difficult because infants are
hibitors and non-nucleoside reverse
transcriptase inhibitors); and para-
more likely to progress rapidly to
doxic worsening of TB symptoms
after initiation of antimycobacterial
pulmonary or extrapulmonary disease. . . .”
therapy, the immune reconstitu-
tion inflammatory syndrome. These challenges have mother or started on INH; the mother should be treated
led the Centers for Disease Control and Prevention to for LTBI. In contrast, if the mother has radiographic
recommend 9 months of treatment for HIV-infected features consistent with TB, the neonate requires evalu-
United States children who have TB. Initial therapy ation for congenital TB. If the infant does not have
should include four drugs, if possible. Treatment of congenital TB (normal chest radiograph and physical
an HIV-infected child who also has TB should be di- examination findings), he or she should be separated
rected by subspecialists well versed in the care of both from the mother until the infant is receiving INH (and
diseases. pyridoxine if the mother is breastfeeding) and the
Corticosteroids have been used as adjunctive therapy mother is receiving appropriate multidrug therapy. Once
in certain forms of TB to try to decrease the damage the infant is receiving INH, separation is unnecessary and
caused by a profound inflammatory response. Indica- breastfeeding should be encouraged unless INH resis-
tions for corticosteroid use include CNS involvement, tance is suspected.
pericarditis, pleural or severe miliary disease, endobron- Health-care workers (HCWs) who have positive TST
chial TB, and abdominal TB. The usual dose is 2 mg/kg results should receive chest radiographs. If the chest
per day (maximum, 60 mg/day) of prednisone or pred- radiograph is negative, the HCW may be offered therapy
nisolone for 4 to 6 weeks, followed by a slow taper. for LTBI after weighing the risks and benefits of INH in
Clinical scenarios that can challenge the pediatrician adults. If the chest radiograph is positive, the HCW
include the family in which an adult has TB and the in- needs to be evaluated further. Contact investigations are
fant whose mother has active TB. The scenario en- performed by the health department in a concentric
countered most commonly is one in which an adult in circle pattern; that is, the first group (circle) evaluated is
the household has infectious TB. All children in the the HCW’s closest contacts, such as family and friends.
household should have chest radiographs and TSTs The concentric circles are used to evaluate individuals of
performed. Children younger than 4 years of age different levels of exposure to the source case, and
should be started empirically on INH until the TST is screening is stopped once a given group has no evidence
repeated in 2 to 3 months. If the second TST result is of TST conversion.

Follow-up children continually exposed to adults who have infec-

Children who have TB disease should be seen monthly tious TB and who cannot be removed from that setting
while receiving therapy to document medication toler- or who receive long-term chemoprophylaxis.
ance and adherence, weight gain, and achievement of
appropriate milestones (especially with TB meningitis) Prognosis
and to assure that the disease is not spreading. Children LTBI therapy is close to 100% effective in children for
who have pulmonary TB should have repeat chest radio- preventing future disease if adherence is excellent. Treat-
graphs after 1 to 2 months of therapy; subsequent radio- ment of drug-susceptible TB disease in children results in
graphs usually are unnecessary except for the child who cure rates of approximately 95% to 100%. In contrast,
has extensive pulmonary involvement. Children who clinical cure is achieved in only 50% to 70% of adult
have TB meningitis often require sequential CNS imag- patients infected with MDR-TB. The overall mortality
ing by CT scan or magnetic resonance imaging. rate from TB in childhood is low. The highest rates of
worldwide mortality and long-term sequelae in children
Prevention occur in those who have TB meningitis; of these chil-
Prevention of TB disease can be conceptualized in at least dren, as many as 33% die and almost 50% of survivors
three ways. First, prevention can occur via chemoprophy- have residual neurologic deficits. However, effective
laxis of children who have been exposed or who have treatment of LTBI and prompt recognition of TB disease
LTBI to prevent future disease cases, as has been dis- can decrease both the morbidity and mortality of child-
cussed. Second, infection control and contact investiga- hood TB.
tions can serve to limit the spread of TB in a variety of
settings. Finally, the BCG vaccine can be used to prevent
disease in babies and, in select circumstances, in the older
child. Summary
Isolation in the hospital is unnecessary for many chil-
dren who have TB disease because the younger child • Childhood TB is, in large part, a preventable and
treatable disease.
rarely has a sufficiently forceful cough or a high enough
• The risk of acquiring TB infection is not evenly
organism burden in the airways to be infectious. How- distributed across the population, with higher risk
ever, the same individuals who brought the children to seen in immigrants and members of minority groups.
medical attention often have disease and have infected The risk of a child progressing from TB infection to
the children. Consequently, obtaining chest radiographs disease and the clinical manifestations of disease
depend on the child’s age and immune status.
on caregivers is one method of identifying potential
• The most common forms of TB disease in childhood
source cases (in whom culture yield is higher) rapidly and are pulmonary disease infection, lymphadenopathy,
limiting health-care-associated transmission. Negative- and meningitis.
pressure isolation rooms and HCW use of N95 respira- • Because culture yield in children is low, TB often is
tors should be implemented in the care of children diagnosed by the combination of a positive TST or
IGRA, consistent radiographic information,
hospitalized because of cavitary or extensive pulmonary
appropriate epidemiologic links, and exclusion of
involvement, AFB smear-positive TB, or laryngeal TB or other possible diagnoses. However, the TST produces
during procedures in which the risk of aerosolization of a number of false-positive and false-negative results
the bacteria is high (eg, bronchoscopy). Such children for a variety of reasons, and knowledge of how to
should remain isolated until effective therapy has been use the TST is important for clinicians.
• Prompt diagnosis and appropriate implementation of
initiated, cough has diminished, and sputum AFB smears
therapy are facilitated by maintaining suspicion for
convert to negative. TB, using public health resources, and knowing the
The BCG vaccine is administered routinely in most epidemiologic face of TB in a community.
countries, with the exceptions of the United States and
the Netherlands. Vaccination has been shown to de-
crease the risk of life-threatening forms of TB, primarily
meningitis and miliary disease, in infants. The BCG Suggested Reading
vaccine has no proven efficacy outside this age group. American Academy of Pediatrics. Tuberculosis. In: Pickering LJ,
Baker CJ, Kimberlin DW, Long SS, eds. Red Book: 2009
The two groups who should receive BCG vaccine in the Report of the Committee on Infectious Diseases. 28th ed. Elk
United States are HIV-negative and TST-negative in- Grove Village, Ill: American Academy of Pediatrics; 2009:
fants and children continually exposed to MDR-TB and 680 –701

American Thoracic Society. Targeted tuberculin testing and treat- Dye C. Global epidemiology of tuberculosis. Lancet. 2006;367:
ment of latent tuberculosis infection. Am J Respir Crit Care 938 –940
Med. 2000;161:1376 –1395 Froehlich H, Ackerson LM, Morozumi PA. Targeted testing of
Aziz MA, Wright A, Laszlo A, et al. Epidemiology of antitubercu- children for tuberculosis: validation of a risk assessment ques-
losis drug resistance (the Global Project on Anti-tuberculosis tionnaire. Pediatrics. 2001;107:e54
Drug Resistance Surveillance): an updated analysis. Lancet. 2006; Marais BJ, Gie RP, Schaaf HS, et al. Childhood pulmonary tuber-
368:2142–2154 culosis: old wisdom and new challenges. Am J Resp Crit Care
Centers for Disease Control and Prevention. Treatment of tuber- Med. 2006;173:1078 –1090
culosis, American Thoracic Society, CDC, and Infectious Dis- Starke JR. Interferon-gamma release assays for diagnosis of tuber-
eases Society of America. MMWR Morbid Mortal Wkly Rep. culosis infection in children. Pediatr Infect Dis J. 2006;25:
2003;52:RR-11 941–942
PIR Quiz
Quiz also available online at pedsinreview.aappublications.org.
6. An 8-month-old boy who had acquired human immunodeficiency virus infection perinatally presents with fever
and cough. A chest radiograph reveals lesions consistent with tuberculosis (TB), and a gastric aspirate is positive
for Mycobacterium tuberculosis. The most likely site of extrapulmonary disease in this infant is the:
A. Lymph nodes.
B. Meninges.
C. Miliary.
D. Pleura.
E. Skeleton.
7. An 8-year-old boy is brought to you for a health supervision visit. The family returned from a visit to their
family in India 2 months ago. The mother was just told that the child’s paternal grandfather, whom they all
visited in India, has cavitary TB. The child has been well and has normal physical examination findings. The
tuberculin skin test (TST) result is positive. Of the following, the most appropriate next investigation is:
A. Bone scan.
B. Chest computed tomography scan.
C. Chest radiography.
D. Sputum acid-fast bacilli (AFB) stain.
E. Sputum culture for AFB.
8. Which of the following best describes the use of the TST in the treatment of children?
A. It becomes positive within 2 weeks of exposure to TB.
B. It should be used routinely to screen all children.
C. Prior bacillus Camille-Guérin vaccination routinely causes a false-positive result.
D. The TST is the only appropriate screening test for TB.
E. Up to 15% of children who have clinical TB have a negative TST result.

9. During a health supervision visit, you learn that a 10-year-old girl returned from a 3-week trip to Kenya
to visit her family 3 months ago. You perform a TST and identify 14 mm of induration 72 hours later. The
child otherwise is well and has normal findings on physical examination. Chest radiograph reveals hilar
adenopathy. The most appropriate agent(s) to be prescribed with direct observation is (are):
A. Isoniazid monotherapy for 9 months.
B. Isoniazid, pyrazinamide, and ethambutol for 9 months.
C. Isoniazid, rifampin, and ethambutol for 6 months and pyrazinamide for 2 months.
D. Isoniazid, rifampin, and ethambutol for 9 months.
E. Rifampin monotherapy for 6 months.
10. You are called to the nursery to evaluate a 1-day-old girl whose mother had no prenatal care. On
admission to the hospital, the mother reported that she had several weeks of low-grade fever and cough.
A maternal TST placed yesterday has a 7-mm induration, chest radiography reveals a cavitary lesion, and
sputum for AFB is negative. The baby has normal findings on physical examination and chest radiograph.
The most appropriate treatment for this infant is to:
A. Begin isoniazid and rifampin therapy.
B. Begin isoniazid, but isolation is not necessary.
C. Begin isoniazid, pyrazinamide, and ethambutol therapy.
D. Isolate the infant from the mother until isoniazid is started for the infant and the mother is receiving
appropriate therapy.
E. Wait to see if the maternal TST induration becomes >10 mm.

Andrea T. Cruz and Jeffrey R. Starke
Pediatr. Rev. 2010;31;13-26
DOI: 10.1542/pir.31-1-13

Infectious Diseases
http://pedsinreview.aappublications.org/cgi/collection/infectious
_diseases Respiratory Disorders
http://pedsinreview.aappublications.org/cgi/collection/respirator
y_disorders Neurologic Disorders
http://pedsinreview.aappublications.org/cgi/collection/neurologi
c_disorders Musculoskeletal Disorders
http://pedsinreview.aappublications.org/cgi/collection/musculos
keletal_disorders Disorders of Blood/Neoplasms
http://pedsinreview.aappublications.org/cgi/collection/disorders_
of_blood_neoplasms

Research and Statistics: Validity Hierarchy for Study Design and Study Type
Carisa Perry-Parrish and Rachel Dodge
Pediatr. Rev. 2010;31;27-29
DOI: 10.1542/pir.31-1-27

research and statistics
Validity Hierarchy for Study Design

and Study Type
Carisa Perry-Parrish, PhD,* Rachel Dodge, MD, MPH†
Case Studies Validity Hierarchy

Validity hierarchy is based on the
● The parents of a child in whom you
internal validity of the study design
have diagnosed attention-deficit/
and type (Table). Internal validity
hyperactivity disorder (ADHD) are
reflects the accuracy of the study’s
concerned about starting the boy on
conclusions and is needed to deter-
stimulant medicine. They want to
mine causal relations among vari-
know if behavioral interventions
ables; external validity reflects how
can be as effective as stimulant
well a study represents the “real
medicine.
world.” Different study designs (eg,
● At a 1-year health supervision visit,
experimental versus nonexperimen-
Author Disclosure a first-time mother expresses concern
tal) and study types (eg, cohort,
Drs Perry-Parrish and Dodge have about giving her child the measles,
cross-sectional, and case studies) of-
disclosed no financial relationships mumps, and rubella (MMR) vac-
fer varying advantages and disadvan-
cine. She read several websites that
relevant to this article. This tages for answering research ques-
recommended not allowing a child
commentary does not contain a tions. Feasibility, cost, and ethical
to receive the vaccine because of pos-
discussion of an unapproved/ considerations also influence which
sible links to autism.
study designs and types can be used
investigative use of a commercial
to answer the research question.
product/device. Introduction
Identifying and implementing effec-
tive, evidenced-based care is consid- Experimental Studies
ered best practice in pediatrics. An Randomized, controlled trials
evidence-based clinician reviews the (RCTs) are considered the gold stan-
current literature to understand the dard of research designs. RCTs have
evidence before addressing the con- high internal validity because several
cerns of parents such as those in the aspects of study design are con-
case studies, but it is important to trolled. For example, study partici-
determine what counts as good evi- pants are assigned randomly to treat-
dence. Engaging in evidence-based ment or comparison groups to
practice requires the clinician to in- reduce the chance of differences be-
terpret the evidence from research tween the two groups at baseline.
studies. Research study design and Thus, RCTs should allow a re-
type are important considerations searcher to conclude that the inter-
when determining if the conclusions vention causes or is responsible for
of the study are valid and to provide different outcomes between the
sufficient evidence to guide clinical groups, rather than other baseline
decisions. Both study design and differences (eg, the use of stimulant
type influence the validity of the re- medications was the reason for the
search study. difference between two groups of
children who have ADHD). In other
*Division of General Pediatrics and Adolescent study designs, these baseline differ-
Medicine, Johns Hopkins University School of ences may result in confounding,
Medicine, Baltimore, Md. which occurs when another variable
†
Medical Director for Foster Care, The MATCH
Program, Baltimore HealthCare Access, Inc, may explain the different outcomes
Baltimore, Md. between groups. For example, the

Table. Validity Hierarchy

Study Design Strengths Weaknesses
Randomized controlled trials ● High internal validity ● Reduced external validity
● Reduced risk of confounding ● Expensive, time-consuming
variables
Cohort studies ● Useful for sequential events ● Requires large sample size
● Can study multiple outcomes ● Risk of confounding variables
● ●
Internal Validity
Retrospective: less expensive Difficult to study rare outcomes

● Prospective: Expensive
Case-control studies ● Useful for rare outcomes ● Risk of confounding variables
● Can study several exposures
● Inexpensive
Cross-sectional studies ● Can study multiple outcomes and ● Cannot infer causality
exposures ● Risk of confounding variables
● Less useful for rare exposures or
outcomes
Case studies ● Useful for rare outcomes ● Risk of confounding variables
● Convenient, inexpensive ● Lack of a comparison group
● Cannot infer causality
Adapted from Ho, et al. Circulation. 2008;118:1675–1684.
differences in symptom control be- Nonexperimental Studies cause the researcher can match cases
tween children who received stimu- In cohort studies, a sample of people and controls according to age, sex, or
lant medication and those who did (or cohort) can be followed over other relevant factors. However, the
not may not be a result of the expo- time to evaluate risks for a future case-control design has lower inter-
sure to the stimulant medication, but outcome (prospective cohort study) nal validity because the researcher
rather due to the children who re- or traced back to investigate poten- frequently must rely on recall of his-
ceived the stimulant medication be- tial historic risks for a current out- torical facts (eg, maternal recall of
ing older or having fewer ADHD come or diagnosis (retrospective co- first emergence of autistic symptoms
symptoms at baseline. A major hort study). The major strength of and timing of MMR vaccine).
strength of RCTs is the reduced in- the cohort design is that researchers Case studies also can be used to
fluence of confounding variables by can examine the risk of a particular
explore rare events and to identify clin-
making the groups equivalent at exposure (eg, receiving MMR vac-
ical questions that need more study. It
baseline. cine) for a certain outcome (eg, de-
is important to remember that a case
In addition, RCTs often use velopment of autism). However, co-
study only provides evidence for the
“blinding” of both the researcher hort studies require a large sample
one or few cases studied.
and participants to eliminate bias in size, and it often is not possible to
interpreting the outcomes. How- control for exposure to other vari- Another nonexperimental design
ever, RCTs can be expensive and ables that could influence the out- is the cross-sectional study, in which
time-consuming to conduct. More- comes (ie, confounding variables). the researcher collects data about
over, some research questions do not An approach that can be used with factors of interest at one point in
lend themselves to an RCT design. smaller sample sizes and rare out- time. The convenience of cross-
For example, consider the challenges comes is the case-control design, in sectional studies makes them more
in designing an RCT to investigate which the researcher can compare practical to implement than designs
the potential links between the cases (eg, children who have autism) higher on the validity hierarchy.
MMR vaccine and autism. Given the with controls (eg, children who do Cross-sectional studies allow a re-
known risks of infection with mea- not have autism) regarding exposure searcher to examine potential associ-
sles, mumps, and rubella, it would to a risk factor (eg, MMR vaccina- ations between two measured factors
be unethical to withhold the MMR tion). Case-control studies have the at one point in time. Because the
vaccine from children as part of benefit of controlling for differences factors are measured at the same
randomization. between the cases and controls be- time, one limitation of this design is

that it cannot provide evidence of lidity and, therefore, provides robust ethically to the intervention (eg,
causality. evidence to make an appropriate withholding vaccines). When RCTs
Nonexperimental designs are vul- clinical decision regarding ADHD are not available, other studies that
nerable to the effects of confounding treatments. In contrast, the hypoth- have sufficiently large samples of
variables. Thus, the inability to infer esized causal link between the MMR participants and consistent results
causality is a prominent disadvantage. vaccine and autism has not been eval- among multiple studies can provide
However, as noted previously, re- uated by using an RCT design. How- compelling evidence for making
searchers often must rely on nonex- ever, many retrospective and pro- good clinical decisions.
perimental designs due to ethical and spective cohort and case-control
logistical concerns. Such studies can studies repeatedly have failed to link
yield important and beneficial infor- the MMR vaccine to the develop- Suggested Reading
mation and frequently lay the foun- ment of autism. Thus, the available American Academy of Pediatrics. Vaccine
Studies: Examine the Evidence. Accessed
dation for later RCTs. evidence that refutes the hypothe- April 2009 at: www.cispimmunize.org/
sized association between MMR vac- Vaccine%20Studies.pdf
Considering the Case Studies cines and autism can guide clinical Concato J, Shah N, Horwitz RI. Random-
Considering the case studies in light decisions. ized, controlled trials, observational stud-
of the validity hierarchy can aid in ies, and the hierarchy of research designs.
N Engl J Med. 2000;342:1887–1892
providing answers to the parents. Re- Conclusion Ho PM, Peterson PN, Masoudi FA. Evaluat-
garding ADHD treatments, a large- The validity hierarchy provides a ing the evidence: is there a rigid hierarchy?
scale, multisite RCT showed that guide to interpreting the level of ev- Circulation. 2008;118:1675–1684
stimulants alone or in combination idence that a study can provide for a Jensen P, Hinshaw S, Swanson J, et al. Find-
with behavioral interventions are particular research question. RCTs ings from the NIMH Multimodal Treat-
ment Study of ADHD (MTA): implica-
more effective than behavioral inter- may not address all clinical questions tions and applications for primary care
ventions alone or usual community due to risk of harm in the treatment providers. J Dev Behav Pediatr. 2001;
care. This RCT has high internal va- or inability to randomize patients 22:60 –73

Research and Statistics: Validity Hierarchy for Study Design and Study Type
Carisa Perry-Parrish and Rachel Dodge
Pediatr. Rev. 2010;31;27-29
DOI: 10.1542/pir.31-1-27

Research and Statistics
http://pedsinreview.aappublications.org/cgi/collection/research_s
tatistics

Pediatrics in the Community: "Keep Smiling!" The Florida Fluoride Project
Valerie Ritter, Frank Catalanotto and Michele Lossius
DOI: 10.1542/pir.31-1-30

pediatrics in the community
“Keep Smiling!” The Florida

Fluoride Project
Meanwhile, together with the better oral health habits and result in
Florida Pediatrics Society and their dentition that is much improved com-
governmental affairs liaison Dr Rick pared with the parents’ teeth.”
Bucciarelli, the residents worked with The physicians working on this
Author Disclosure Frank Catalanotto, DMD, a profes- project learned about both oral
Drs Ritter, Catalanotto, Lossius, and sor in the Department of Commu- health and legislative advocacy. Dr
Aligne have disclosed no financial nity Dentistry at UF. He was leading Catalanotto’s advice is, “You just
relationships relevant to this article. the advocacy for Florida Medicaid to keep plugging until you meet the
This commentary does not contain a reimburse physicians for fluoride ap- right person.” He adds that the
plication. After 15 months of talking most important action is to keep talk-
discussion of an unapproved/
to as many people as he could with- ing: Share your story with anyone
investigative use of a commercial out any results, Dr Catalanotto gave who will listen. (Valerie Ritter, DO,
product/device. a presentation to the state’s dental Frank Catalanotto, DMD, Michele
society. In the audience was a staffer Lossius, MD, University of Florida-
from the Governor’s office, who ap- Gainesville)
During their third year of residency proached him and made arrange-
at the University of Florida- ments for him to come to Tallahassee SECTION EDITOR’S NOTE: I’m of-
Gainesville (UF), Michele Lossius to meet with key officials. On April 1, ten asked why pediatricians should
and Kristen Eisenman noted that 2008, Medicaid officially started re- engage in activities such as legislative
while the American Academy of Pe- imbursing physicians for oral health advocacy. “Isn’t it enough that we
diatrics (AAP) recommended that preventive procedures. The fluoride practice good medicine?” Yes, of
children see a dentist by 1 year of age, application program now has been course it is, but sometimes, as in this
(1) most of their patients were un- expanded and integrated into rou- story, a policy hole can impede the
able to do so because of poverty or tine practice at the UF clinic. In ad- path to best practices, and advocacy
because local dentists would not see dition, Dr Catalanotto has provided is necessary for filling that cavity.
free in-office training for private (C. Andrew Aligne, MD, MPH)
infants. The Oral Health American
pediatricians.
National Grading Project gave Flor-
The project opened the residents’
ida a D⫹ for prevention, including
eyes regarding the value to families
water fluoridation. Fluoride varnish
of a comprehensive medical home.
References
is an evidence-based practice (2) that
“Most of all, I have been surprised at 1. Rozier RG, Sutton BK, Bawden JW, et
could have helped, but the children how many parents are concerned al. Prevention of early childhood caries in
at highest risk for caries did not have about their child’s teeth when they ini- North Carolina medical practices: implica-
access to it. With a CATCH grant from tions for research and practice. J Dent Educ.
tially seemed only mildly interested in 2003;67:876 – 885
the AAP, Drs Lossius and Eisenman other aspects of their child’s health,” 2. Weintraub JA, Ramos-Gomez F, Jue B, et al.
and their clinic attendings estab- said Dr Ritter. “They are thrilled that Fluoride varnish efficacy in preventing early
lished a project to train residents to we are doing something extra to pro- childhood caries. J Dent Res. 2006;85:172–176
assess teeth; educate parents about tect their children’s teeth. Most par- 3. University of Minnesota. Dental Health
Screening and Fluoride Varnish Application
early childhood caries; and apply flu- ents are open to the strategies to pre- Course. Accessed October 2009 at: http://
oride varnish at 12-, 18- and 24- vent dental caries that we have www.meded.umn.edu/apps/pediatrics/
month health supervision visits. (3) targeted. I hope that this will set up FluorideVarnish/index.cfm

Pediatrics in the Community: "Keep Smiling!" The Florida Fluoride Project
Valerie Ritter, Frank Catalanotto and Michele Lossius
DOI: 10.1542/pir.31-1-30

Ear, Nose and Throat Disorders
http://pedsinreview.aappublications.org/cgi/collection/ear_nose_
throat_disorders Preventive Pediatrics
http://pedsinreview.aappublications.org/cgi/collection/preventive
_pediatrics

Index of Suspicion
Tashveen Kaur, Deborah Whitney, Zachary Repanshek, Raemma Pardes Luck, Harsh
Grewal, Mona Patel and Bethany Stafford
Pediatr. Rev. 2010;31;31-36
DOI: 10.1542/pir.31-1-31

index of suspicion
Case1 Presentation
A 10-month-old boy is referred to
the ED for fever, rash, and decreased
oral intake. He has asthma, eczema,
and a milk-protein allergy. One week
ago, he developed a mild cough and
rhinorrhea. Three days later, he de-
veloped temperatures to 39.9°C but
has been afebrile for the past 24
hours. Two days ago, erythematous
The reader is encouraged to write eczematous patches appeared on his
possible diagnoses for each case before feet. The rash subsequently became
turning to the discussion. We invite vesiculopustular and spread up his
readers to contribute case presentations legs and to his arms, chest, abdomen,
and discussions. Please inquire first by
contacting Dr. Deepak Kamat at back, and groin. His oral intake and
dkamat@med.wayne.edu. urine output have decreased over the
past 24 hours. He has had no diar-
Figure 2. Vesiculopustular lesions with
rhea or vomiting. He has a dog at surrounding erythema on hand.
home, attends child care, and has no
Author Disclosure travel history. His only medication is
Drs Kaur, Whitney, Repanshek, Pardes occasional levalbuterol. hands, toes, back, and groin. All the
On physical examination, the boy lesions have surrounding erythema
Luck, Grewal, Patel, and Stafford have
is afebrile and has normal vital signs. (Figs. 1 and 2). The rest of the physical
disclosed no financial relationships He has enlarged tonsils (2⫹) with examination findings are normal.
relevant to these cases. This commentary yellow ulcerations; clusters of crusted Polymerase chain reaction (PCR)
does not contain a discussion of an lesions on the dorsum of his feet and testing for herpes simplex virus (HSV)
unapproved/investigative use of a on all four extremities; and scattered and varicella-zoster virus (VZV) from
commercial product/device. vesiculopustules on the dorsum of his the base of a freshly unroofed vesicle
is ordered as well as bacterial cultures
of the pustular fluid and crusted le-
sions. The infant is admitted and
started on intravenous (IV) acyclovir
Frequently Used Abbreviations and clindamycin. An additional test
ALT: alanine aminotransferase reveals his diagnosis.
AST: aspartate aminotransferase
BUN: blood urea nitrogen
CBC: complete blood count Case 2 Presentation
CNS: central nervous system A 16-year-old girl is transferred from
CSF: cerebrospinal fluid an outlying hospital to the ED for
CT: computed tomography additional evaluation of severe ab-
ECG: electrocardiography dominal pain of sudden onset. The
ED: emergency department pain is constant and localized in
EEG: electroencephalography the periumbilical and right lower
ESR: erythrocyte sedimentation rate quadrant regions. She denies any fe-
GI: gastrointestinal ver, anorexia, vomiting, vaginal dis-
GU: genitourinary charge, or bleeding. She has had one
Hct: hematocrit bowel movement in the past 24
Hgb: hemoglobin hours and no history of constipa-
MRI: magnetic resonance imaging tion or diarrhea. She admits to be-
WBC: white blood cell Figure 1. Clusters of crusted lesions on coming sexually active recently with a
lower extremities. 16-year-old boy. There is no history

index of suspicion
of previous abdominal trauma, uri- 56 cm (40th percentile), and head The Condition
nary tract infection, or sexually trans- circumference is 35 cm (⬍5th per- KVE and eczema herpeticum (EH)
mitted infection (STI). Her last men- centile). He exhibits tachycardia and are terms often used interchange-
strual period was 2 weeks ago. tachypnea, but his blood pressure is ably. Both refer to a vesiculopustular
Physical examination reveals an normal. He does not have any dys- eruption in patients who have predis-
anxious adolescent girl in significant morphic features, but his conjuncti- posing skin conditions affecting the
pain. Her temperature is 36.3°C, vae are pale. He has a grade III/IV integrity of the stratum corneum.
heart rate is 120 beats/min, respira- systolic ejection murmur radiating EH refers specifically to HSV infec-
tory rate is 24 breaths/min, and throughout his hyperdynamic pre- tion in patients who have atopic der-
blood pressure is 109/47 mm Hg. cordium. His liver is palpable to 3 cm matitis. KVE is a more inclusive term
She has marked tenderness in the below the right costal margin and the referring to a viral infection (eg,
right lower quadrant and umbilical spleen to 2 cm below the left costal HSV-1 or -2, coxsackievirus A16, or
area of the abdomen with rebound margin. His extremities are warm vaccinia) in patients who have vari-
tenderness and guarding. The re- and well perfused, with brisk pulses. ous skin conditions, such as atopic
mainder of the physical examination Laboratory findings of note in- dermatitis, congenital ichthyosiform
findings are unremarkable. clude Hgb of 3.9 g/dL (39 g/L), erythroderma, seborrheic dermatitis,
Her initial laboratory results show Hct of 11.7% (0.117), mean corpus- Darier disease, pemphigus, Wiskott-
Hgb of 11 g/dL (110 g/L); WBC cular volume (MCV) of 110.4 fL, red Aldrich syndrome, pityriasis rubra
count of 16.3⫻103/mcL (16.3⫻ blood cell (RBC) distribution width pilaris, irritant contact dermatitis,
109/L) with 60% neutrophils, 10% of 15.9%, RBC count of 1.06⫻106/
psoriasis, and skin burns. The true
bands, and 20% lymphocytes; and incidence of KVE is unknown, but it
mcL (1.06⫻109/L), and reticulo-
platelet count of 235⫻103/mcL is more common in children than in
cyte count of 0.4% (0.004). Peripheral
(235⫻109/L). A urine pregnancy adults.
blood smear reveals slight hypo-
test is negative. Urinalysis reveals KVE can occur during a primary
chromasia, moderate macrocytosis,
moderate hematuria. CT scan of her viral infection or by autoinoculation
moderate tear-drop cells, and ovalo-
abdomen is read as normal, except following reactivation of HSV infec-
cytosis. His leukocyte, differential,
for a suspicion of free air under the tion. The disrupted skin barrier al-
and platelet counts are normal. His
diaphragm. She is given IV fluids and lows for easy entry of viral particles.
serum electrolyte and liver function
started on parenteral antibiotics. She Decreased cell-mediated immunity
tests, including bilirubin, yield nor-
gives consent for exploratory laparos- and decreased cytokine secretion in
copy. A finding on laparoscopy re- mal results. An additional test reveals affected skin play roles in disease
veals the underlying cause of the se- the diagnosis. pathogenesis. Patients who have
vere abdominal pain. atopic dermatitis have decreased ex-
pression of cathelicidins and beta-
defensins, endogenous antimicrobial
Case 3 Presentation Case 1 Discussion peptides that are first-line host de-
A 7-week-old boy is brought to the PCR testing for enterovirus from the fenses on the epithelium. Patients
ED because of 3 days of increased fluid and base of a freshly unroofed who have high serum immunoglob-
irritability, which his mother defines vesicle was positive, establishing the ulin E concentrations and those who
as “breathing fast” and “crying.” She diagnosis of Kaposi varicelliform have experienced the onset of atopic
also states that yesterday the baby eruption (KVE). The PCR test re- dermatitis at an early age are at in-
took a “little longer” to breastfeed sults for HSV and VZV were nega- creased risk for developing KVE.
but maintained normal urine output tive, and acyclovir was discontinued. KVE begins with clusters of dome-
and bowel movements. He has had The bacterial culture was positive for shaped vesicles that can progress to
no fever, weight loss, vomiting, or Staphylococcus aureus, and the patient pustules, hemorrhagic crusted le-
diarrhea. He does not have a cough, remained on IV clindamycin. Over sions, and punched-out erosions.
congestion, or rhinorrhea and has the course of several days, his lesions The lesions are predominantly in
had no illness contacts. crusted over and his oral intake im- areas affected by the predisposing
Physical examination reveals a proved; he was discharged from the skin condition and have a predilec-
crying, pale infant whose weight is hospital on a 7-day course of oral tion for the head and neck. Within
4.6 kg (30th percentile), length is clindamycin. 2 weeks, the blisters usually become

index of suspicion
crusted and by 2 to 6 weeks are dicative of viral infection but is not treating KVE is controversial. Due to
completely healed. The skin manifes- sensitive or specific for HSV. Direct a theoretical risk of immunosuppres-
tations may be accompanied by sys- fluorescent antibody (DFA) staining sion, oral and topical corticosteroids,
temic symptoms such as flulike ill- can be useful as a rapid screen for as well as topical calcineurin inhibi-
ness, fever, and malaise. Viremia can HSV-1 or -2. PCR testing for tors used for treating atopic dermati-
result in multiorgan involvement HSV-1, HSV-2, or enteroviruses tis, often are withheld until lesions
such as hepatitis or disseminated in- obtained by scraping the base of a are crusted.
travascular coagulation. previously intact vesicle are sensitive
and specific. The diagnosis of entero- Lessons for the Clinician
Differential Diagnosis virus infection also can be established ● Although HSV-1 and HSV-2 are
Other vesicular and pustular erup- by PCR testing on serum or urine
the most common causes of KVE,
tions should be considered in the early in the course of the illness when
other viruses must be considered,
diagnosis. Varicella presents with a the patient is more likely to be vire-
especially if DFA or PCR testing
similar vesicular rash along with mal- mic. Viral cultures are less useful be-
for HSV yields negative results.
aise and fever. Varicella typically pre- cause results are not available for ● PCR testing for enteroviruses can
sents on the scalp, face, or trunk, more than 48 hours and often are
detect coxsackievirus that, if posi-
subsequently spreading to the ex- negative if taken from a crusted le-
tive, allows discontinuation of acy-
tremities. The vesicular eruption of sion. CBC, serum electrolytes, and
clovir and perhaps can lead to fewer
herpes zoster could be confused with liver enzymes are recommended pro-
medication adverse effects and a
KVE but typically is limited to a der- cedures to evaluate for other organ
shorter hospital stay.
matomal distribution, and patients involvement. Affected skin is at risk
tend to be older and have a prior for bacterial superinfection, and bac- (Tashveen Kaur, MD, Deborah Whit-
history of varicella. Herpes zoster of- terial cultures should be obtained by ney, MD, The Children’s Hospital of
ten is preceded by burning pain prior swabbing the affected skin or obtain- Philadelphia, Philadelphia, Pa.)
to the appearance of skin lesions. ing fluid from a vesicle or pustule.
Contact dermatitis can have a blister-
ing component, but the condition is Treatment
limited to a localized area. Blistering Concern for KVE should prompt Case 2 Discussion
skin disorders such as pemphigus vul- consideration of initiating antiviral Exploratory laparoscopy revealed a
garis or bullous pemphigoid should medication. Acyclovir is effective hemoperitoneum. The source of the
be considered but typically produce against HSV-1 and HSV-2, espe- bleeding seemed to be primarily
large bullae, which are not character- cially when started within the first from the pelvis, although the uterus
istic of KVE. Bacterial superinfection 72 hours of the illness. Pediatric pa- and the ovaries appeared normal.
of atopic areas has a similar presenta- tients typically are admitted to the Following retraction of the uterus, a
tion to that of KVE, with pustules, hospital for IV acyclovir, pain con- perforation was found on the poste-
yellow crust, erythema, or induration trol, and monitoring for systemic rior vaginal wall at the pouch of
being the prominent findings. It is complications. If bacterial superin- Douglas. The vaginal laceration was
important to note that bacterial su- fection is suspected, antibiotic ther- repaired, and a postoperative vaginal
perinfection can occur concurrently apy against staphylococcal species examination confirmed a repaired
with KVE. as well as group A beta-hemolytic laceration at the posterior cervical
Streptococcus is warranted. Topical fornix.
Diagnosis antibiotic preparations such as silver The girl was referred to an adoles-
KVE can be diagnosed clinically by sulfadiazine are recommended as cent psychiatrist and a social worker
the appearance of the characteristic prophylaxis in the absence of active for evaluation. Initially, she denied
lesions in a patient who has a pre- bacterial infection. Periocular lesions any physical or sexual abuse, but
disposing skin condition, but several or the presence of ocular symptoms her mother expressed concern over
laboratory tests are useful and can should prompt an ophthalmologic her recent relationship with a 16-
guide treatment. A Tzanck smear evaluation for keratoconjunctivitis, year-old boy and the possibility of
obtained from vigorously swabbing which is an ophthalmologic emer- sexual assault. Speaking in private
the base of a freshly unroofed vesicle gency. The role of corticosteroids with the social worker, she eventually
shows multinucleated giant cells in- and topical immunosuppressants in admitted that her partner had forced

index of suspicion
sexual intercourse on her 2 days be- Perforation into the peritoneal cavity nurses as well as processes in place to
fore the ED visit. is a rare complication of vaginal lacera- preserve forensic evidence. Between
tion and is believed to occur in fewer 4 and 7 days after the event, forensic
than 1% of patients. Some cases of vag- examinations still may be useful, es-
Differential Diagnosis
inal perforation and intra-abdominal pecially with the availability of newer
Myriad conditions must be consid-
bleeding have been reported during DNA amplification techniques. After
ered in an adolescent girl who pre-
consensual sexual activity. 1 week, the patient can be seen expe-
sents with acute abdominal pain, in-
Other noncoital causes of vaginal ditiously by a child abuse specialist in
cluding appendicitis, urolithiasis,
lacerations include straddle injury, the clinic.
ectopic pregnancy, ovarian torsion,
pelvic fractures, and iatrogenic trauma, The American Academy of Pedi-
and pelvic inflammatory disease. The
which frequently are associated with atrics, the Centers for Disease Con-
radiographic finding of free air under
marked vaginal bleeding. However, trol and Prevention, and the Ameri-
the diaphragm suggests a perforation
studies have shown that vaginal lac- can College of Emergency Physicians
of a viscus and may be due to a perfo-
erations are most common in cases of have published guidelines for the
rated appendicitis, spontaneous bowel
sexual assault and rape. Therefore, evaluation of STIs in victims of sexual
perforation, or perforation caused by
the possibility of assault must be en- abuse or assault. Given the higher
abdominal or vaginal trauma. All of
tertained in any girl who presents prevalence of STIs in the adolescent
these conditions must be diagnosed
with a nonobstetric vaginal lacera- age group, testing for such infections
and treated urgently. However, be-
tion. Patients who lack prior sexual after an acute assault is controversial.
fore surgical intervention, a history and
experience also have been reported All STI screening, prophylaxis, and
physical examination are essential.
to be more susceptible to traumatic treatment, as well as postexposure
Pelvic examinations are not par-
vaginal laceration than those who prophylaxis for human immunodefi-
ticularly comfortable procedures to
have a history of sexual activity. In ciency virus infection, should be dis-
perform, either for an adolescent girl
addition, as in this patient, affected cussed with the adolescent.
or for the physician, but they still are
adolescent girls often give incom- A pregnancy test also should be
necessary to identify potential gyne-
plete and misleading histories. There- performed. Emergency contracep-
cologic causes of abdominal pain. In
fore, suspicion for assault must be tion is indicated for patients at risk
this case, the pelvic examination was
high for the adolescent girl who re- for pregnancy. In the United States,
omitted because of the absence of
cently has become sexually active and ED physicians should know the laws
vaginal complaints, the emergent
presents with vaginal laceration. of their state about reporting sexual
surgical nature of the girl’s condi-
assault and the mechanisms for ob-
tion, and the need for examination
Management taining forensic evidence and assuring
under sedation or anesthesia. Yet,
Most vaginal lacerations without ab- the appropriate chain of evidence. Fi-
such an examination may allow iden-
dominal perforation must be exam- nally, outpatient psychological coun-
tification of a perforated vaginal lac-
ined under anesthesia for better seling and social work referral for com-
eration prior to surgery.
viewing and repaired in the operating munity support groups should be set
suite. In the event of suspected per- up for the patient.
The Diagnosis foration, laparoscopy or exploratory
The most common cause of nonob- laparotomy should be performed to Lessons for the Clinician
stetric vaginal laceration is coitus- determine the extent of the lacera-
related trauma. Factors that may tion and involvement of other or- ● The diagnosis of vaginal lacerations
increase the risk of vaginal injury dur- gans. Patients also should receive ap- can be complicated by the sensitive
ing sexual intercourse include dis- propriate antibiotic treatment and nature of the sexual mechanism of
proportionate anatomy of the geni- tetanus prophylaxis. injury. Patients often are too em-
talia, rough or violent intercourse, Ideally, suspected victims of sex- barrassed to seek treatment or may
certain sexual positioning, and use of ual assault, especially if it occurred not provide an adequate history.
foreign objects. Some minor trauma within 4 days, should be transferred Adolescents may not want their
may result from normal sexual activ- to an ED that has the capability of parents to find out or may be afraid
ity. The posterior fornix is especially performing a forensic medical inter- of getting their partners into trou-
susceptible to injury due to its loca- view and examination. Such EDs ble. Adolescents should be inter-
tion and relatively weak structure. have specially trained physicians and viewed alone in a private setting

index of suspicion
and the limits of confidentiality in a hemodynamically stable state at this age unless the mother also has
discussed. with close follow-up monitoring. a history of such anemias or a defi-
● An adolescent who admits to being cient diet.
sexually assaulted should receive Transient erythroblastopenia of
The Condition
appropriate medical and mental childhood (TEC) is the most com-
Diamond-Blackfan anemia (DBA),
health care, including collection of mon RBC aplasia of childhood and
also known as congenital hypoplastic
evidence if indicated, STI evalua- must be differentiated from DBA.
anemia, typically presents during the
tion and treatment, emergency TEC is a profound anemia occurring
first 3 months of infancy with a nor-
contraception, and psychological in previously healthy children from
mochromic, macrocytic anemia asso-
counseling. the age of 6 months to 3 years. The
ciated with reticulocytopenia and an
● Any adolescent girl complaining of anemia is transient and commonly
absence of erythroid precursors in
abdominal pain deserves a com- caused by a virally induced immuno-
otherwise normal bone marrow. The
plete physical examination, includ- logic suppression of erythropoiesis.
condition is due to a mutation of
ing a pelvic examination. If radio- Differentiation from DBA is made
a gene responsible for encoding one
graphic findings include free air by the age of onset and laboratory
or more ribosomal proteins, most
under the diaphragm, it is impor- results.
commonly RPS19. The mechanism
tant to consider vaginal laceration
through which a mutation in ribo-
as a source.
somal proteins causes hypoplastic
anemia is still being elucidated, but it Clinical and
(Zachary Repanshek, MD, Raemma Diagnostic Features
is hypothesized that the transloca-
Pardes Luck, MD, Harsh Grewal,
tion causes an intrinsic defect in the The clinical presentation of DBA
MD, Temple University School of Med-
40S subunit of the ribosome, result- can be diverse. Anemia typically is
icine, Philadelphia, Pa.)
ing in failure of erythroid progenitor detected at 2 to 6 months of age.
cells to differentiate properly, ulti- Approximately 50% of patients have
mately leading to apoptosis. associated congenital anomalies be-
lieved to be due to the abnormal
Case 3 Discussion
ribosomal proteins causing dys-
Of paramount importance was treat- Differential Diagnosis
functional translation at the cellular
ment of this infant’s high-output car- Hypoplastic anemia in the newborn
level. Congenital anomalies include
diac failure, as indicated by his vital must be differentiated from other
short stature and craniofacial dys-
signs and findings on physical exam- anemias that also present with reticu-
ination. After obtaining IV access, locytopenia. Hemolytic disease of morphisms such as a snub nose,
four blood transfusions were pro- the newborn can present with de- wide-set eyes, and a thickened upper
vided at 5 mL/kg to raise his Hgb to creased erythropoiesis but would be lip. Defects of the upper extremity,
a desired level of 12 g/dL (120 g/ expected to resolve spontaneously especially the thumbs, include a flat-
L). He showed immediate clinical by the second postnatal month. tened thenar eminence and tripha-
improvement, with decreased pallor, Infection-associated RBC aplasia with langeal, bifid, subluxed, absent, or
a diminished systolic ejection mur- chronic hemolysis also can present in supernumerary thumbs that can be
mur, and less prominent hepato- this manner but most commonly is bilateral or unilateral in presentation.
splenomegaly. The clinical presenta- associated with a fetal viral infection Laboratory values reveal low Hgb
tion and laboratory test results are with parvovirus B19 that is cytotoxic concentrations with an elevated MCV
consistent with a normochromic to erythroid progenitor cells in the for age and a low corresponding
macrocytic anemia with an inappro- marrow. Moreover, this is a transient reticulocyte count. Bone marrow
priate reticulocyte response. Given infection that is expected to resolve aspiration shows isolated erythroid
the normal leukocyte and platelet by the second week after birth. Fan- hypoplasia in an otherwise normo-
counts, a form of pure RBC aplasia coni anemia is a consideration as a cellular marrow. Fetal Hgb, erythro-
was the likely cause. Because of his macrocytic anemia presenting in the poietin, and adenosine deaminase
age, a genetic test for Diamond- first postnatal year, but it is associated activity all are elevated in DBA but
Blackfan syndrome was ordered and with chromosomal breaks and reduc- not in TEC. Diagnosis can be con-
found to be positive for mutation in tion in several cell lines. Folate and firmed by detection of mutations in
the RPS19 gene. He was discharged vitamin B12 deficiencies are less likely the RPS19 gene.

index of suspicion
Management resents the only chance for cure and ● When considering the differential
Corticosteroid therapy is the treat- is being used increasingly in patients diagnosis for anemia in an infant,
ment of choice for DBA and is effec- who do not respond to corticoste- many clues are provided through
tive as monotherapy for nearly 75% roid therapy and have undergone the history and physical examina-
of patients. It increases sensitivity to several years of transfusion therapy. tion of the infant and diet history of
erythropoietin that, in turn, pro- the mother.
motes erythroid differentiation. RBC Prognosis ● Fifty percent of patients who have
recovery can be seen in the first 1 According to the information at the DBA may have physical dysmorph-
to 3 weeks of therapy, as determined DBA Registry, life expectancy for an isms.
by serial reticulocyte counts. The tar- affected patient is 40 years of age. ● The treatment of choice for chil-
get Hgb value is about 9 g/dL Those who are long-term responders
dren who have DBA is corticoste-
(90 g/L) and can be expected in to corticosteroid therapy have better
roids. If patients do not respond,
approximately 4 to 6 weeks. Those prognoses. Nearly 20% experience
chronic transfusion of blood and
who do not respond to corticoste- spontaneous remission in the first
later stem cell transplant may be
roid therapy should receive transfu- postnatal year. DBA is a premalig-
necessary.
sions every 4 to 8 weeks, as deter- nant syndrome that has been linked
mined by Hgb values. Patients who to acute myeloid leukemia, myelo-
dysplasia, and solid tumors such as (Mona Patel, MD, Bethany Stafford,
become transfusion-dependent are at MD, Children’s Hospital of Los Angeles,
increased risk for hemosiderosis and osteosarcoma, which is an important
association of which to be aware Los Angeles, Calif.)
must be treated with iron chelation
when treating a patient who has DBA.
therapy to prevent organ damage,
especially to the heart and liver. He-
Lessons for the Clinician To view Suggested Reading lists
matopoietic stem cell transplanta-
tion, usually from bone marrow, ● It is important to recognize the signs for these cases, visit pedsinreview.
peripheral blood, or cord blood from of high-output cardiac failure early in aappublications.org and click on
a related histocompatible donor, rep- children and treat it cautiously. Index of Suspicion.

Index of Suspicion
Tashveen Kaur, Deborah Whitney, Zachary Repanshek, Raemma Pardes Luck, Harsh
Grewal, Mona Patel and Bethany Stafford
Pediatr. Rev. 2010;31;31-36
DOI: 10.1542/pir.31-1-31

Supplementary Material Supplementary material can be found at:
http://pedsinreview.aappublications.org/cgi/content/full/31/1/31/
DC1
Skin Disorders
http://pedsinreview.aappublications.org/cgi/collection/skin_disor
ders Infectious Diseases
_diseases Allergy and Related Disorders
http://pedsinreview.aappublications.org/cgi/collection/allergy_re
lated_disorders Adolescent Medicine/Gynecology
http://pedsinreview.aappublications.org/cgi/collection/adolescent
_medicine_gynecology Genital System Disorders
http://pedsinreview.aappublications.org/cgi/collection/genital_sy
stem_disorders Emergency Care
http://pedsinreview.aappublications.org/cgi/collection/emergenc
y_care Disorders of Blood/Neoplasms
of_blood_neoplasms

Vaccines in Immunocompromised Patients
Pediatr. Rev. 2010;31;38-40
DOI: 10.1542/pir.31-1-38

in brief
In Brief
Pranita Tamma, MD nodeficiency virus (HIV) infections, the plantation. Inactivated influenza vacci-
Johns Hopkins University School of population of immunocompromised nation, however, can be given as soon
Medicine children who have special vaccination as 6 months after HSCT. Some experts
Baltimore, Md. needs is burgeoning. Understanding the elect to reimmunize all children after
degree of immune recovery of these HSCT; others base the decision on in-
children is important in guiding vaccine adequate serologic titers obtained 1
Author Disclosure administration. Inactivated vaccines year posttransplantation.
Drs Tamma and Serwint have can be administered safely to persons Children being considered for solid
disclosed no financial relationships who have altered immunocompetence, organ transplantation should receive
relevant to this In Brief. This but the effectiveness of such vaccines age-recommended immunizations prior
may be suboptimal. Inactivated influ- to transplantation. Vaccines generally
commentary does not contain a
enza immunization should be adminis- are more immunogenic at this time be-
tered annually to immunosuppressed cause posttransplant immunosuppres-
investigative use of a commercial children 6 months of age and older sive medications often interfere with
product/device. before each influenza season. In gen- T- and B-lymphocyte activity. Live virus
eral, severely immunocompromised vaccines should be administered at
children should not receive live vac- least 4 weeks before organ transplan-
Immunization in Special Clinical Cir- cines, either viral or bacterial, because tation to minimize the potential for
cumstances. Pickering LK, Baker CJ, of the risk of disease caused by vaccine posttransplant vaccine-related illness.
Kimberlin DW, Long SS, eds. Red strains. Oral polio virus vaccine and live It is reasonable to evaluate serum con-
Book: 2009 Report of the Committee bacterial vaccines, such as bacillus centrations of antibodies to measles,
on Infectious Diseases. 28th ed. Elk Calmette-Guérin (BCG) and Salmonella mumps, rubella, and varicella to deter-
Grove Village, Ill: American Academy typhi Ty21, are contraindicated for im- mine if these vaccines are needed.
of Pediatrics; 2009:72– 86 munocompromised patients as well as Monovalent measles vaccination or
General Recommendations on Immuni-
their household contacts. Household if not available, MMR, may be admin-
zation: Recommendations of the
Advisory Committee on Immuniza-
contacts and other close contacts of istered before transplantation in chil-
tion Practices (ACIP). Centers for persons who have altered immunocom- dren as young as 6 months of age if the
Disease Control and Prevention. petence, however, should receive all transplantation is anticipated before
MMWR Morbid Mortal Wkly Rep. other age-appropriate vaccines, includ- the child reaches 1 year of age. Because
2006;55(No.RR-15):24 –29 ing the live oral rotavirus vaccines. of the increased mortality associated
Immunizations in HIV-infected Adults. Although many children who un- with hepatitis A infection in liver trans-
Rivas P, Herrero MD, Puente S, et al. dergo HSCT acquire the immunity of plant recipients, hepatitis A vaccination
AIDS Rev. 2007;9:173–187 the donor, some lose serologic evidence should be considered in this population.
Immunization of Pediatric Solid-organ of immunity. Studies indicate that ad- Similarly, liver transplant recipients ex-
Transplantation Candidates: Immu- ministration of diphtheria and tetanus perience a more rapid and severe course
nizations in Transplant Candidates.
toxoids to the donor before organ har- compared with immunocompetent indi-
Campbell AL, Herold BC. Pediatr
Transplant. 2005;9:652– 661
vest and to the recipient after trans- viduals if infected with hepatitis B.
plantation can facilitate response to Therefore, all liver transplant candidates
these antigens. Similar results are ex- should receive hepatitis B vaccination if
With improving survival rates after pected with other inactivated vaccine adequate protective antibodies are not
treatment of childhood malignancy, an antigens. Healthy survivors can be im- present. Most experts recommend
increase in hematopoietic stem cell munized with inactivated vaccines 1 waiting at least 6 months after trans-
(HSCT) and solid organ transplantation, year after HSCT and can receive mea- plantation for the resumption of immu-
and the use of highly active antiretro- sles, mumps, and rubella (MMR) and nization schedules.
viral therapy (HAART) for human immu- varicella vaccines 2 years after trans- For children who will be receiving

in brief
chemotherapy, the administration of all and are recommended according to the plenic older children who did not re-
routinely recommended vaccinations routine schedules. Accumulating data ceive the childhood Hib vaccine series.
prior to initiation of chemotherapy is suggest that measles and varicella vac- Of note, children who have all of the
optimal, and revaccination with these cinations also are safe for HIV-infected aforementioned immunosuppressive con-
agents is not necessary. During active children who have mild clinical disease ditions are at increased risk of invasive
chemotherapy and shortly thereafter, and adequate CD4 counts (CD4 per- pneumococcal disease and are candi-
antibody responses to vaccines are im- centage, ⱖ15%). Measles immuniza- dates for the 23-valent pneumococcal
paired. However, improvement in anti- tion is especially important because polysaccharide vaccine.
body production occurs rapidly, and wild-type measles can result in severe As the number of children who have
immunization as early as 3 months disease in HIV-infected children. altered immunity continues to grow,
after cessation of chemotherapy, in- Live vaccines are contraindicated for understanding which immunizations
cluding with live virus vaccines, is all patients who have T-lymphocyte- should be administered and when they
reasonable. mediated disorders. Measles and vari- can be provided safely with maximal
A dosage equivalent to at least cella vaccines should be considered for benefit is increasingly important to
2 mg/kg per day of prednisone or equiv- children who have B-lymphocyte disor- protect some of the most vulnerable
alent to a total of at least 20 mg/day ders, but other live viral vaccines are children against significant but pre-
for children who weigh more than 10 kg, contraindicated, except in immuno- ventable illnesses.
when administered for more than 14 globulin A deficiency. Many experts
days, is considered sufficient to raise believe that live-virus vaccines are safe Comment: Understanding immuni-
concern about the safety of immuniza- to administer to children who have zation principles and strategies for chil-
tion with live virus vaccine. Therefore, disorders of phagocyte or complement dren who are immunocompromised is
vaccine schedules should be postponed function. critically important to maximize pro-
until corticosteroids have been discon- Children who have deficiencies in tection against preventable diseases.
tinued for at least 3 months. The safety antibody-synthesizing capacity may be Dr Tamma reviews important concepts
and efficacy of live-attenuated vaccines incapable of developing an antibody and principles. One strategy worth em-
administered concurrently with recombi- response to vaccines and should receive phasizing is the immunization of house-
nant human immune mediators and anti- regular doses of gamma globulin as hold contacts, particularly other chil-
B-lymphocyte monoclonal antibodies is passive protection. Children receiving dren and adolescents in the family.
unknown. Until additional information gamma globulin may not respond to This procedure is essential to try to
becomes available, avoidance of live vac- live virus vaccines due to the continued minimize exposure of the immuno-
cines while receiving immunomodulators presence of neutralizing antibody. De- compromised patient to household
generally is recommended. pending on the dose of gamma globulin contacts who might contract vaccine-
Studies suggest that antibody re- administered, measles and varicella vac- preventable illnesses. Pediatric health-
sponses, although frequently improved cinations need to be delayed for several care clinicians need to update and re-
in the presence of HAART, still are lower months. If gamma globulin must be view the vaccine status of all siblings
than in HIV-uninfected populations, given within 14 days of measles or and pediatric-age household members.
suggesting that immune reconstitution varicella vaccination, readministration Annual influenza vaccination of all
with HAART varies among people and of these vaccines should be considered. family members with inactivated influ-
may be incomplete. An inverse relation- (See Table 3.34 of the 2009 Red Book enza vaccine is recommended in addi-
ship between vaccine response and HIV for additional details.) tion to ensuring routine immunization
viral load has been found for a number Children and adolescents who have of all other recommended vaccines.
of vaccines. This information suggests anatomic or functional asplenia are at MMR, varicella, and rotavirus vac-
that vaccinations optimally should be an increased risk of invasive infections cines, although live viral vaccines, are
administered when patients are on sta- with encapsulated bacteria and should recommended for immunocompetent
ble HAART, have good CD4 response, receive protection with the 7-heptavalent household contacts because transmis-
and have maximally suppressed vire- conjugate pneumococcal vaccine and, af- sion of the virus is rare. The lack of viral
mia. It may be reasonable to delay ter 2 years of age, the 23-valent pneu- shedding with MMR eliminates con-
vaccination until these endpoints are mococcal polysaccharide vaccine as well cern regarding transmission. Because
reached or to consider reimmunization. meningococcal vaccination. A single dose the varicella virus rarely can be shed
Inactivated vaccines generally pose of Haemophilus influenzae type B (Hib) through a postimmunization vesicular
no harm to the HIV-infected patient vaccine also can be considered for as- rash that may develop, recommenda-

in brief
tions include avoiding contact until the after vaccination should be implemented. questions, and clinicians may want to
rash resolves. For the rotavirus vaccine, Note, however, that oral polio vaccine, review guidelines in special circum-
avoidance of contact with the stools by BCG, and typhoid vaccine Ty21 are con- stances.
the immunocompromised patient and traindicated for household contacts.
good hand hygiene measures by all The resources that Dr Tamma pro- Janet R. Serwint, MD
family members for at least 1 week vides are helpful for answering specific Consulting Editor
Find it in January NeoReviews™

The American Academy of Pediatrics online neonatology journal at http://
neoreviews.aappublications.org
Commentary: NeoReviews 10th Anniversary Issue—Philip
International Perspectives: Teaching in Underresourced Hospitals: Experi-
ence From South Africa—Woods/Greenfield
Special Article: Neonatal Health-care Policy: Promise and Perils of Reform—
Wise
NICU Nursing for the 21st Century— McCann/Kenner/Boykova
Neonatal Nurse Practitioners in Interdisciplinary Care of High-risk Infants—
Parker
Index of Suspicion in the Nursery: Prolonged Jaundice in Twins—
Vachharajani
Visual Diagnosis: Lower Lumbosacral Cutaneous Lesion in a Newborn

Pediatr. Rev. 2010;31;38-40
DOI: 10.1542/pir.31-1-38

Allergy and Related Disorders
http://pedsinreview.aappublications.org/cgi/collection/allergy_re
lated_disorders Infectious Diseases
_diseases Disorders of Blood/Neoplasms
of_blood_neoplasms

The Gifted Child
Pediatr. Rev. 2010;31;41-43
DOI: 10.1542/pir.31-1-41

in brief
In Brief
The Gifted Child
Maris D. Rosenberg, MD National Association for Gifted Children tics of these children include, but are
Dimitra Robokos, PhD from 2001 to 2004 revealed that ap- not limited to, alertness during infancy,
Rose F. Kennedy UCEDD proximately 50% of all inquiries in- early language development, advanced
Children’s Evaluation and volved children 5 years of age or vocabulary, abstract thinking, the abil-
Rehabilitation Center younger. Most of the questions dealt ity to generate original ideas, excep-
Albert Einstein College of Medicine with the recognition of giftedness and tional problem-solving skills, and ex-
Bronx, NY how to develop a child’s exceptional cellent memory skills. Gifted young
abilities. Other frequent questions in- children usually ask provocative and
volved information about resources, penetrating questions and demonstrate
Author Disclosure such as the type of school program that exceptional curiosity and a heightened
Drs Rosenberg, Robokos, and Adam is best for a gifted child. Next most sense of wonder.
have disclosed no financial common were questions about achieve- Some of the social and emotional
relationships relevant to this In Brief. ment issues, social and emotional characteristics of young gifted children
needs, and resources for specific talent consist of the early development of
This commentary does not contain a
areas. empathy, concern with truth and fair-
Research on giftedness remains lim- ness in play, a mature sense of humor,
investigative use of a commercial ited in its generalizability for many leadership in cooperative play, and per-
product/device. reasons, most fundamentally, the lack fectionism. Young children, like older
of a universally accepted definition. gifted children, show asynchronous de-
Different school districts, for example, velopmental patterns. For example,
Gifted and Talented Children: Issues for have different criteria based on demo- cognitive and academic skills often ex-
Pediatricians. Robinson NM, Olszewski- graphics and available resources. Gen- ceed social-emotional and motor skills,
Kubilius PM. Pediatr Rev. 1996;17: eral giftedness, as measured by superior and such discrepancies become more
427– 434 intelligence quotient (IQ) (top 3%), is apparent the younger the child is. It is
The Gifted Child. Jaffe AC. Pediatr Rev. only one subtype, but superior IQ alone important to note that the early iden-
2000;21:240 –242 does not predict academic success be- tification (first 2 years after birth) of
Early Childhood. Robinson NM. In: cause of the coexistence of emotional giftedness in young children based on
Plucker JA, Callahan CM, eds. Critical
and behavioral as well as cultural and developmental assessments tends to be
Issues and Practices in Gifted Educa-
tion: What the Research Says. Waco,
learning differences. Academic gifted- an unstable predictor of later intelli-
Tex: Prufrock Press; 2007:179 –194 ness tends to be given the greatest gence. Generally, IQs obtained before
Homeschooling. Kunzman R. In: Plucker emphasis yet varies among population the age of 5 years must be interpreted
JA, Callahan CM, eds. Critical Issues groups. General giftedness must be dis- with caution.
and Practices in Gifted Education: tinguished from specific talents or do- Decisions regarding educational
What the Research Says. Waco, Tex: mains of excellence. Most often there is placement should focus on an optimal
Prufrock Press; 2007:253–260 asynchrony in different areas of devel- match, taking into account the child’s
Parenting. Schader RM. In: Plucker JA, opment, and children who have isolated levels and patterns of giftedness, emo-
Callahan CM, eds. Critical Issues and abilities may be missed by some school tional maturity, and social skills. Early
Practices in Gifted Education: What criteria. school entry can provide appropriate
the Research Says. Waco, Tex: Pru-
Giftedness in young children consti- and stimulating developmental chal-
frock Press; 2007:479 – 492
tutes significantly advanced skills and lenges for precocious learners and is
abilities in any domain. The research on the least disruptive approach to accel-
Parents suspecting that their young early childhood characteristics of young erating academically advanced chil-
child may be “gifted” often seek the gifted children tends to lack coherence, dren. However, the decision often is
advice of their pediatricians. An analy- but several general characteristics have challenging for parents, and placement
sis of parent email received by the been identified. Cognitive characteris- on a trial basis is a reasonable recom-

in brief
mendation. When a child is to be placed and enjoy supportive and flexible learn- mental and behavioral issues in young
in school early, his or her development ing together. children, parents often consult their
across most domains should be com- Once a young child has been recog- pediatricians for guidance about how
mensurate with the mean of the class nized or is suspected of possessing to maximize their child’s potential. In
being entered. Some studies have indi- exceptional abilities or talents, issues response, pediatricians must be pre-
cated that boys may face greater be- emerge that significantly affect family pared to discuss the current evidence
havioral risks than girls when they en- functioning. Parents may feel increas- about gifted and talented children, in-
ter school earlier. ing pressure to define and develop their cluding the relative lack of research and
In planning for the education of child’s talents by taking on the role of the disagreement about issues as fun-
young gifted and talented children, teacher but not have the expertise or damental as the precise definition of
parents may consider home schooling. confidence to do so. They may feel the giftedness. They must be ready to point
It is estimated that more than 2 million need to become active advocates, out the common phenomenon of “un-
children are home-schooled in the “fighting the system” to gain additional evenness” in the profiles of children in
United States. Although the number of services for their child. These pursuits their cognitive, social, and emotional
children home-schooled over the past are time-consuming and can cause sig- development and should be aware that
decade has increased, few empiric data nificant strain on family resources, time giftedness can be associated with
are available on gifted children who are devoted to other children, or time de- attention-deficit/hyperactivity disorder,
schooled at home. Advocates claim that voted to the marital relationship. Par- Asperger syndrome, oppositional defi-
home schooling allows for the type of ents may differ in their acknowledg- ant disorder, and learning disabilities.
ment of the child’s abilities or their A multidisciplinary team is optimal to
pedagogy that is ideal for children en-
priorities for devoting family resources arrive at diagnoses and to develop com-
dowed with exceptional abilities: The
to the child’s special gift. One parent, prehensive treatments to determine
children can have individual mentoring,
therefore, may foster feelings of closer which combinations of strategies (ie,
they can focus in-depth on particular
alignment to the child, straining the behavioral, medical, educational) might
subjects or projects, and they can have
relationship between the child and the be most effective for the individual
tailored accelerated programs to meet
“less involved” parent. child.
their academic needs and address their
Close attention also must be paid to It is incumbent on the pediatrician
asynchronous skill areas. However, with
the effect on the child’s social and to become knowledgeable about re-
most reports depending on anecdote, it
emotional development. Given the fo- sources in the community that provide
is impossible to assess the academic
cus, time, and energy devoted to devel- diagnostic, educational, and behavioral
outcomes associated with home oping the child’s exceptional abilities, interventions and to be able to discuss
schooling. parents may communicate a sense of educational decisions such as early
One concern about home schooling expectation that places undue pressure school entrance, home schooling, and
is whether parents are capable of pro- on the child, a situation compounded enrichment programs. Most impor-
viding the most appropriate instruction. by the sensitivity and intense personal- tantly, an open dialogue on issues re-
Home-school consultants, some of ity styles often described in gifted and garding the social and emotional ef-
whom are experienced teachers, can talented children. Another potential fects on the child, family functioning,
help families design curricula and as- problem is the inability to identify with and family dynamics must be main-
sure that they are meeting state stan- peers, either because of the absence of tained and continuously revisited as the
dards. The increase in online home- peers who have similar interests or child progresses through the school
school options raises concerns about because of the lack of time for informal years.
quality control as well as the lack of socialization due to “overprogram-
interpersonal experiences and social- ming.” Children may become overly de- RESOURCES
ization for the children. One response pendent on their parents, who may • National Association for Gifted
to the concern about socialization is manage everyday activities excessively, Children: www.nagc.org
the creation of community groups, so preempting ordinary responsibilities, • Center for Talented Youth–Johns
education is not received entirely such as household chores, and retard- Hopkins University: www.jhu.edu/gifted
within the home. Such home-school ing the development of organizational • Talent Identification Program–
groups should consist of children of skills that are critical to a child’s devel- Duke University: www.tip.duke.edu
various ages, allowing for children of opment over the school years. • Center for Gifted Education Pol-
varying interests and abilities to gather As is the case with many develop- icy: www.apa.org/ed/cgep.html

in brief
• Neag Center for Gifted Education about our educational system. The Or- those who are not. Not surprisingly,
and Talent Development–University of ganization for Economic Cooperation & children living in poverty, especially if
Connecticut: www.gifted.uconn.edu Development, for example, has ranked they are from minority families, the
secondary education in our country same who are least likely to have ac-
Comment: The debate about health 18th among 36 industrialized nations cess to high-quality health care, are
care in the United States has widely worldwide. If growth and develop- most likely to suffer from inadequate
publicized the reality that, by many ment are the fundamental outcomes schooling.
measures, although we spend the most, of childhood, we are fundamentally
we do not deliver the best. Unfortu- failing too many of our children, both Henry M. Adam, MD
nately, much the same can be said those who are specially gifted and Editor, In Brief

The Gifted Child
Pediatr. Rev. 2010;31;41-43
DOI: 10.1542/pir.31-1-41

Disorders of Cognition, Language, Learning, and Attention
http://pedsinreview.aappublications.org/cgi/collection/cognition
_language_learning_attention_disorders Growth and
Development
http://pedsinreview.aappublications.org/cgi/collection/growth_d
evelopment Psychosocial Issues and Problems
http://pedsinreview.aappublications.org/cgi/collection/psychosoc
ial_issues_problems

Chest Pain in Children and Adolescents
Surendranath R. Veeram Reddy and Harinder R. Singh
Pediatr. Rev. 2010;31;e1-e9
DOI: 10.1542/pir.31-1-e1
http://pedsinreview.aappublications.org/cgi/content/full/31/1/e1

Article cardiology

Surendranath R. Veeram
Reddy, MD,* Harinder R.
Singh, MD* 1. Enumerate the most common causes of chest pain in pediatric patients.
2. Differentiate cardiac chest pain from that of noncardiac cause.
3. Describe the detailed evaluation of a pediatric patient who has chest pain.
Author Disclosure 4. Screen and identify patients who require a referral to a pediatric cardiologist or other
Drs Veeram Reddy specialist.
and Singh have 5. Explain the management of the common causes of pediatric chest pain.
disclosed no financial
relationships relevant
to this article. This
Case Studies
Case 1
commentary does not
During an annual physical examination, a 12-year-old girl complains of intermittent chest
contain a discussion pain for the past 5 days that localizes to the left upper sternal border. The pain is sharp and
of an unapproved/ stabbing, is 5/10 in intensity, increases with deep breathing, and lasts for less than 1 minute.
investigative use of a The patient has no history of fever, cough, exercise intolerance, palpitations, dizziness, or
commercial product/ syncope. On physical examination, the young girl is in no pain or distress and has normal vital
signs for her age. Examination of her chest reveals no signs of inflammation over the sternum
device.
or rib cage. Palpation elicits mild-to-moderate tenderness over the left second and third
costochondral junctions. The patient reports that the pain during the physical examination is
similar to the chest pain she has experienced for the past 5 days. A detailed cardiovascular and
other organ system examination yields normal results. What is the most likely cause of this
patient’s chest pain? What will you recommend for this patient? Does she need to see a pediatric
cardiologist?
Case 2
A 17-year-old boy is playing soccer on a Saturday afternoon and has a syncopal event on the
field. He regains consciousness within a few seconds, does not require resuscitation, and is taken
to the emergency department. The patient informs the physician that he developed sudden
midsternal chest pain and lightheadedness prior to passing out. His vital signs are normal for
age, and he is alert, oriented, and in no apparent pain or distress. Physical examination
reveals an ejection click and a harsh, grade 3/6 systolic ejection murmur at the base of his heart
and right upper sternal border with radiation to both carotid arteries. The rest of the physical
examination findings are normal, except for minor abrasions on his elbows and knees caused
by the fall. Twelve-lead electrocardiography (ECG) reveals left ventricular hypertrophy with
ST segment depression in leads V5 and V6. What is the diagnosis? What would you recommend
for this patient? Does he need a referral to a pediatric cardiologist?
Introduction
Chest pain in children is one of the most common reasons for
Abbreviations an unscheduled visit to the primary care physician’s office
AAP: American Academy of Pediatrics and the emergency department, accounting for more than
d-TGA: d-transposition of great arteries 650,000 physician visits per year in patients 10 to 21 years of
ECG: electrocardiography age. (1) Although alarming to parents, chest pain in children
GERD: gastroesophageal reflux disease usually is not caused by a serious disease, in contrast to chest
NSAID: nonsteroidal anti-inflammatory drug pain in adults, which raises concern for coronary ischemia.
Chest pain is second only to heart murmur for referral to a
*Division of Cardiology, The Carman and Ann Adams Department of Pediatrics, Children’s Hospital of Michigan, Wayne State
University School of Medicine, Detroit, Mich.
Pediatrics in Review Vol.31 No.1 January 2010 e1

cardiology chest pain
pediatric cardiologist. (2) Pediatric chest pain can be

classified broadly into cardiac chest pain or noncardiac Noncardiac Causes of
Table 1.
chest pain. Noncardiac chest pain is, by far, the most
common cause of chest pain in children and adolescents.
Chest Pain in Children (4 – 6)
This article reviews most causes of chest pain in children Musculoskeletal
and adolescents, emphasizing cardiac causes, and pro-
● Costochondritis/costosternal syndrome
vides a guideline for evaluating a child or adolescent who ● Tietze syndrome
has chest pain. ● Nonspecific or idiopathic chest-wall pain
● Slipping rib syndrome
Noncardiac Chest Pain ● Trauma and muscle strain–overuse injury
● Xiphoid pain (xiphoidalgia)
Chest pain is noncardiac in origin in more than 98% of
● Sickle cell vaso-occlusive crisis
children and adolescents who complain of it. (3) Non-
cardiac causes of chest pain can be classified into muscu- Pulmonary or Airway-related
loskeletal, pulmonary, gastrointestinal, and miscella- ● Bronchial asthma
neous (Table 1). ● Exercise-induced or cough variant asthma
● Bronchitis
● Pleurisy
Musculoskeletal or Chest-wall Pain ● Pneumonia
The most common cause of chest pain in children and ● Pneumothorax
adolescents is musculoskeletal or chest-wall pain. The ● Pulmonary embolism
prevalence of musculoskeletal chest pain is between 15% ● Acute chest syndrome
and 31%. (6)(7) There are various types of musculoskel- Gastrointestinal
etal pain. ● Gastroesophageal reflux disease
● Esophageal spasm
COSTOCHONDRITIS. Costochondritis, or costosternal ● Peptic ulcer disease
syndrome, is characterized by unilateral sharp, stabbing ● Drug-induced esophagitis/gastritis
● Cholecystitis
pain along the upper two or more contiguous costo-
chondral joints. The pain usually is exacerbated by deep Miscellaneous
breathing and lasts from a few seconds to a few minutes. ● Panic disorder
There is no sign of inflammation, although chest-wall ● Hyperventilation
tenderness can be reproduced by manual palpation over ● Breast-related conditions
● Herpes zoster
the affected area. In most patients, pain due to costo-
● Spinal cord or nerve root compression
chondritis is self-limited, with intermittent exacerbations
occurring during adolescence.
bated by deep breathing or by manual pressure on the
TIETZE SYNDROME. Tietze syndrome is a localized sternum or rib cage. Signs of inflammation are absent.
nonsuppurative inflammation of the costochondral, cos-
tosternal, or sternoclavicular joint seen in adolescents SLIPPING-RIB SYNDROME. Also known as the lower
and young adults. The cause is unknown, but recent rib pain syndrome, slipping-rib syndrome occurs infre-
upper respiratory tract infection with excessive coughing quently in children, and the exact prevalence is unknown.
has been implicated. (8) Tietze syndrome usually in- Slipping-rib syndrome is characterized by intense pain in
volves a single joint, commonly at the second or third rib. the lower chest or upper abdominal area caused by
Unlike the more diffuse costochondritis, Tietze syn- trauma or dislocation of the 8th, 9th, and 10th ribs.
drome is distinguished by localized involvement of a Because these ribs do not attach to the sternum directly
single joint along with signs of inflammation in the form but rather are attached to each other via a cartilaginous
of warmth, swelling, and tenderness. cap or fibrous band, they can be hypermobile and prone
to trauma. Slipping-rib syndrome pain can be repro-
IDIOPATHIC CHEST-WALL PAIN. Also known as non- duced by the “hooking maneuver,” in which the exam-
specific chest-wall pain, this disorder is one of the com- iner places his or her fingers under the inferior rib margin
mon causes of chest pain in children. The pain is sharp, and pulls the rib edge outward and upward. (9) Occa-
lasts for a few seconds to minutes, localizes to the middle sionally, a clicking sound accompanies the pain during
of the sternum or the inframammary area, and is exacer- this maneuver.
e2 Pediatrics in Review Vol.31 No.1 January 2010

TRAUMA AND MUSCLE STRAIN. Teenagers active in approximately 73% had laboratory evidence of asthma,
gymnastics and most other sports are prone to chest-wall suggesting that the incidence of exercise-induced asthma
trauma. In one series, skeletal trauma was the cause of is greater than previously reported. Patients who have
chest pain in 2% of children. (6) Chest-wall injury can chest pain due to reactive airway disease should be
produce localized pain and tenderness and usually is treated with inhaled bronchodilators.
associated with swelling or erythema at the site of injury. Infections of the bronchial tree or lung, including
Teenagers who experience chest muscle strain usually bronchitis, pleurisy, pleural effusion, pneumonia, empy-
give a history of weightlifting. For patients who have a ema, bronchiectasis, and lung abscess, can cause acute
history of significant trauma to the chest, the findings of chest pain. Intense chest pain with hypoxia is the mani-
severe chest pain, arrhythmia, and shortness of breath festing feature of pulmonary embolism. Patients who
may indicate myocardial contusion and hemopericar- have sickle cell disease may present with chest pain due to
dium. acute chest syndrome or pulmonary infarctions.
PRECORDIAL CATCH. The pain of precordial catch,

Gastrointestinal Causes
also known as “Texidor twinge,” usually is sudden and
Evangelista and colleagues (14) found the prevalence of
sharp, lasts for a few seconds, and localizes to one inter-
chest pain due to gastrointestinal causes to be about 8%.
costal space along the left lower sternal border or to the
Common gastrointestinal causes of chest pain in children
cardiac apex. (10) The origin of the pain is unknown, but
are gastroesophageal reflux disease (GERD), peptic ulcer
precordial catch has been associated with poor posture
disease, esophageal spasm or inflammation, and chole-
and may be caused by a pinched nerve. The pain occurs
cystitis. Rare gastrointestinal causes include esophageal
either at rest or during mild activity and is exacerbated
strictures, foreign body, and ingestion of caustic sub-
with inspiration, often leading to shallow breathing in an
stances. Chest pain caused by GERD typically is de-
effort to alleviate pain.
scribed as a burning pain in the epigastric area that
frequently has a temporal relationship to food intake.
XIPHOID PAIN OR XIPHODYNIA. Also known as hyper-
Histamine-2 blockers or proton pump inhibitors are the
sensitive xiphoid syndrome, xiphodynia is localized pain
mainstay of treatment for GERD. If symptoms suggest
or discomfort over the xiphoid process of the sternum
cholecystitis, prompt referral to a specialist and treatment
that can be exacerbated by eating a heavy meal, cough-
with antibiotics are indicated.
ing, and bending or rotating movements. (11) The cause
of pain is unknown. Digital compression of the xiphoid
elicits dull pain. Miscellaneous
Psychogenic chest pain in older children occasionally can
TREATMENT. Reassurance, rest, and analgesia are the result from anxiety or a conversion disorder triggered by
primary treatments for musculoskeletal chest pain. In recent stressors in personal or family life. Pantell and
most circumstances, allaying the fears of the patient and Goodman (6) reported that approximately one third of
parents by counseling them about the benign nature of adolescents who presented to the outpatient clinic com-
the condition helps to relieve concern for and reduce the plaining of chest pain had a history of stressful events
degree of chest pain. For patients who have severe pain, either in the family or at school. Psychogenic chest pain
applying warm compresses and administering nonsteroi- often is associated with other somatic complaints as well
dal anti-inflammatory drugs (NSAIDs) for 1 week may as with sleep disturbances.
be helpful. Hyperventilation, either due to anxiety or a panic
disorder, can cause chest pain that is accompanied by
Pulmonary and Airway-related Causes complaints of difficulty in breathing, dizziness, or pares-
The prevalence of chest pain due to respiratory causes is thesias. Spasm of the diaphragm, gastric distension
approximately 2% to 11%. (12) Bronchial asthma is the caused by aerophagia, and coronary vasoconstriction due
most common pulmonary cause of chest pain. Exercise- to hypocapnic alkalosis are postulated explanations for
induced asthma frequently causes chest pain, even in chest pain during hyperventilation.
patients who have no audible wheezing. Weins and asso- Chest pain due to breast-related causes has a preva-
ciates (13) analyzed pulmonary function during tread- lence of 1% to 5%. (6) Postmenarchal girls may complain
mill testing in a group of 88 otherwise healthy children of throbbing or burning chest pain caused by mastitis,
and adolescents who had chest pain and found that fibrocystic disease, or pregnancy. Teenage males who

have gynecomastia occasionally complain of unilateral or

bilateral chest pain. Cardiac Causes of
Table 2.
Herpes zoster infection of the chest wall might
present with burning pain or paresthesia in a dermatomal
Pediatric Chest Pain
pattern, sometimes preceding the rash by a few days. Inflammatory: Pericarditis, Myocarditis
Children who have scoliosis or other deformities that
● Infective: viruses, bacteria
lead to spinal cord or nerve root compression also may ● Noninfective: SLE, Crohn disease, postpericardiotomy
complain of chest pain as their initial presentation and syndrome
should be referred to an orthopedist for additional eval-
Increased Myocardial Demand or Decreased Supply
uation and treatment.
● Cardiomyopathy: dilated or hypertrophic
● LVOT obstruction: aortic stenosis, subaortic stenosis,
Cardiac Chest Pain supravalvar aortic stenosis
Chest pain due to a cardiac condition is rare in children ● Arrhythmias
and adolescents, with a prevalence of less than 6%. (2)(5)
Coronary Artery Abnormalities
Table 2 lists the common causes of cardiac chest pain.
● Congenital: ALCAPA, ALCA from right coronary
sinus, coronary fistula
Inflammatory Causes ● Acquired: Kawasaki disease, postsurgical (after
Pericarditis with or without pericardial effusion usually is arterial switch operation, after Ross procedure),
infectious in origin. Pericarditis presents as a sharp retro- posttransplant coronary vasculopathy, familial
sternal chest pain that often radiates to the left shoulder, hypercholesterolemia
is aggravated when the patient lies supine or takes a deep Miscellaneous
breath, and is relieved by bending forward. Myocarditis ● Aortic dissection
or endocarditis also can present with chest pain. ● Rupture of aortic aneurysm
● Pulmonary hypertension
Increased Myocardial Demand or Decreased ● Mitral valve prolapse
● Atrial myxomas
Oxygen Supply
● Cardiac device/stent complications
Chest pain may be the first complaint that points to an
unsuspected anatomic heart defect. Pain associated with Drugs
palpitations, dizziness, and panic attacks may be the ● Cocaine
presenting symptoms in some patients who have mitral ● Sympathomimetic overdose
valve prolapse (Barlow syndrome). Mitral valve prolapse ALCA⫽anomalous left coronary artery, ALCAPA⫽anomalous origin
usually is associated with a midsystolic click and, occa- of the left coronary artery from pulmonary artery, LVOT⫽left ventric-
ular outflow tract, SLE⫽systemic lupus erythematosus
sionally, an apical mid-to-late systolic honking murmur.
Bisset and colleagues (15) reported that only 18% of
patients in a group of 119 children who had mitral valve
prolapse complained of atypical chest pain. including congenital anomalies of the coronary artery,
Patients who have left ventricular outflow tract ob- coronary artery fistulas, and stenosis or atresia of the
struction in the form of stenosis of the aortic valve, coronary artery ostium. Coronary artery abnormalities
subaortic valve area, or supra-aortic valve area or who are second only to hypertrophic cardiomyopathy in caus-
have coarctation of the aorta may present with chest pain ing sudden cardiac deaths in adolescents. Unfortunately,
associated with dizziness and fatigue. In aortic valve sudden death may be the first and only presentation of
stenosis, a harsh ejection systolic murmur with radiation coronary artery abnormalities. However, a significant
to the neck is heard on auscultation. An ejection click number of patients who have abnormal coronary artery
from a stenosed bicuspid aortic valve may be heard. connections present initially with anginal chest pain,
Chest pain in association with exercise intolerance and usually associated with exertion.
fatigue may be the initial presenting complaint of pa- Patients describe ischemic chest pain as a squeezing
tients who have hypertrophic or dilated cardiomyopathy. sensation, tightness, pressure, constriction, burning, or
fullness in the chest. One example of chest pain due to
Coronary Artery Abnormalities myocardial ischemia is a condition in which the left main
Chest pain due to myocardial ischemia can occur in coronary artery or left anterior descending coronary ar-
patients who have abnormal coronary artery anatomy, tery arises from the right sinus of Valsalva or right coro-

nary artery and courses between the aorta and pulmonary lesterolemia, the AAP recommends measurement of a
artery. (16)(17) During exertion, the aorta and pulmo- nonfasting serum total cholesterol concentration as the
nary artery squeeze the left main coronary artery or initial screening test, followed by a fasting lipid profile if
left anterior descending artery, leading to myocardial the total cholesterol value is abnormal. (21)
ischemia and, occasionally, sudden death in adolescents.
Infants who have coronary insufficiency due to anoma- Miscellaneous Causes
lous origin of the left coronary artery from the pulmonary When a patient complains of an extremely severe and
artery usually present with irritability, drawing of their tearing midsternal chest pain radiating to the back, aortic
knees up to their abdomens after feeding, pallor, dia- dissection should be considered. Pediatric patients who
phoresis, and circulatory shock. These babies often are have Marfan syndrome are at risk for a dissecting aortic
misdiagnosed as having colic. aneurysm that may present with the sudden onset of
Children who have a history of cardiac surgery and severe chest pain. Aortic root dissection also can be seen
heart transplantation also are susceptible to myocardial in patients who have Turner syndrome, type IV Ehlers-
ischemia and may present with chest pain as the initial Danlos syndrome, and homocystinuria.
complaint. Beyond the first year after transplantation, Young children who are unable to describe palpita-
secondary malignancy and transplant coronary vascu- tions caused by arrhythmias may complain of chest pain
lopathy are the most common causes of mortality. (18) and point to the sternum. Chest pain in children or
Among patients who have had orthotopic heart trans- adolescents who have congenital heart disease and un-
plantation, chest pain may be a sign of rejection or dergo Fontan palliation or Mustard or Senning palliation
accelerated coronary artery vasculopathy with myocardial for d-TGA may have intra-atrial re-entry arrhythmias
ischemia. Patients who have had an arterial switch oper- (slow atrial flutter).
ation for d-transposition of the great arteries (d-TGA) Primary or secondary pulmonary hypertension may
are at risk of developing coronary artery ostial stenoses. present with chest pain in association with fatigue and
A long-term complication of Kawasaki disease is cor- exertional dyspnea or syncope.
onary artery stenosis. Giant coronary artery aneurysms in
Kawasaki disease have a high risk for rupture, occlusion Toxic Drug-induced Chest Pain
due to thrombosis, or stenosis causing myocardial isch- Toxic exposure to cocaine, marijuana, methamphet-
emia or infarction. (19) Kato and associates, (20) in a 10- amines, and sympathomimetic decongestants may be
to 21-year follow-up study, reported that 46% of patients the cause of chest pain due to myocardial ischemia or
who had Kawasaki disease and a history of giant coronary arrhythmias.
aneurysms developed stenosis or complete obstruction
and 67% experienced myocardial infarction, with a 50% Management of Chest Pain in Children and
mortality rate. Risk factors for developing coronary ar- Adolescents
tery aneurysms, thrombosis, and stenosis are male sex, Although cardiac disease rarely presents as chest pain,
early age (⬍6 months), or older age (⬎5 years) at the primary care physicians should evaluate every patient
time of diagnosis. (19) complaining of chest pain to rule out any significant
Coronary artery disease also may be seen in patients underlying disease. The history and physical examination
who have a family history of hypercholesterolemia, but are the first steps in diagnosing the cause of such pain in
children and adolescents seldom have enough obstruc- most pediatric patients (Table 3).
tion to cause chest pain from ischemia. Coronary artery
disease may present within the first 2 decades in patients History
born with homozygous familial hypercholesterolemia, in The history should include a description of the pain;
contrast to those who have heterozygous familial hyper- associated complaints; and precipitating, aggravating,
cholesterolemia, in whom coronary artery disease com- and relieving factors. Acute chest pain can be caused by
monly occurs after the fifth decade of life. According to trauma, pulmonary embolism, asthma, and cardiac
the preventive health-care guidelines from the American causes, including aortic dissection or ischemic pain due
Academy of Pediatrics (AAP), every child should un- to coronary artery anomalies. Chronic chest pain usually
dergo a dyslipidemia risk assessment beginning at 2 years is noncardiac, and causes can be musculoskeletal, gastro-
of age, and assessment should be repeated every 2 years intestinal, psychogenic, or idiopathic.
until 10 years of age and then annually. (21) For children Location of pain sometimes may aid in differentiating
and adolescents who have a family history of hypercho- the cause. Localized or pinpoint pain usually is chest-wall

pain, or extremity pain could be psychogenic. Chest pain

History and Physical
Table 3. with lightheadedness and paresthesias is associated with
hyperventilation. Arrhythmias may present as chest pain
Examination of a Pediatric with palpitations.
Patient Who Has Chest Pain A history of asthma should alert the physician to
bronchospasm as the cause of chest pain. Exercise-
History induced asthma should be considered if the patient com-
1. Description of chest pain: duration, onset, location, plains of cough, chest pain, and difficulty in breathing
quality, severity, radiation, precipitating and after physical activity.
relieving factors
2. Past medical history: asthma, sickle cell disease, Adolescents who have chest pain may give a recent
Kawasaki disease, cardiac disease, history of having trauma, lifting heavy weights, or pulling
hypercholesterolemia a muscle during sports or exercise. History of any recent
3. Surgical history: any previous surgeries of the chest use of tobacco or of recreational drugs should be sought.
or abdomen Bronchitis is a common cause of chest pain in tobacco
4. Family history: early/sudden cardiac deaths of
unknown cause, arrhythmias, cardiomyopathy, smokers. Cocaine and other sympathomimetic drugs are
hypercholesterolemia potent vasoconstrictors, and their use may lead to myo-
5. Genetic disorders: Marfan syndrome, Turner cardial ischemia.
syndrome, type IV Ehlers-Danlos syndrome A past history of Kawasaki disease or arterial switch
6. History of trauma, drug abuse (eg, cocaine), operation for d-TGA should alert the physician to the
psychological stressors
possibility of coronary ostial stenosis causing myocardial
Physical Examination ischemia. Patients who have undergone transcatheter
stent placements or device closure of atrial or ventricular
Vital signs, dysmorphic features, peripheral pulses, chest
inspection, reproducible chest pain, hyperdynamic septal defects may complain of chest pain related to
precordium, irregular heart beats, distant heart sounds, device embolization or impingement on adjacent struc-
abnormal loud second heart sound, systolic clicks or tures. Anginal chest pain may be the presenting symptom
murmurs, gallops, absent femoral pulses in patients born with anomalies of the coronary artery,
coronary vasculopathy in heart transplant patients, and
coronary artery narrowing due to familial hypercholes-
terolemia. Acute chest syndrome in patients who have
or pleural; diffuse chest pain usually is due to underlying sickle cell disease may be the cause of chest pain. A past
visceral disease of the lung or heart. Radiation of chest history of Crohn disease, systemic lupus erythematosus,
pain to a certain area may suggest a specific cause. Chest or other autoimmune disease should alert the physician
pain due to myocardial ischemia may radiate to the neck, to pericarditis as the cause of chest pain.
throat, lower jaw, teeth, upper extremity, or shoulder. In A family history of certain genetic or connective tissue
acute cholecystitis, chest pain radiates to the right shoul- disorders, such as Marfan syndrome, should prompt
der. Patients who have pericarditis complain of chest pain evaluation for specific disease-related features.
radiating to the left shoulder. Chest pain from aortic
dissection frequently radiates to the interscapular space Physical Examination
in the back. The physical examination of a child complaining of chest
Certain precipitating and aggravating factors might pain always should begin with vital signs and anthropo-
help identify the cause of chest pain. Musculoskeletal metric measurements. Tall stature might point toward
chest pain may worsen with certain body positions, certain genetic causes (Marfan syndrome). Fever and
movement, and deep breathing. Chest pain aggravated tachypnea might help to confirm an infectious disorder,
by eating or associated with vomiting, regurgitation, or usually of the lung and rarely the heart, especially if the
swallowing suggests a gastrointestinal cause. Chest pain pain is associated with tachycardia and worsens with lying
precipitated by exertion and associated with dyspnea down (pericarditis with or without effusion). Elevated
could be due to cardiac or respiratory disease. A recent jugular venous pressure or hypotension should point
history of upper respiratory tract infection with fever and toward systolic or diastolic dysfunction of the heart
current symptoms of chest pain should raise suspicion of (myocarditis or cardiomyopathy). Any facial dysmor-
pericarditis. Chest pain associated with recurrent multi- phism or abnormality of the lens (Marfan syndrome)
ple somatic complaints such as headaches, abdominal should be noted. Visual inspection of the chest wall is

important to look for any bony abnormalities such as ECG is useful for evaluation of rate and rhythm and signs
pectus excavatum or carinatum, scoliosis, or surgical of ischemia, pericarditis, or chamber hypertrophy. Addi-
scars. Thelarche in girls or gynecomastia in adolescent tional testing should be left to the discretion of the
boys can cause chest pain. Warmth, redness, and tender- pediatric cardiologist. When baseline ECG readings are
ness around the nipple and of the breast occur with normal, an exercise stress test may be necessary to assess
mastitis. Particular attention should be paid to eliciting the development of arrhythmia or ischemia during exer-
any reproducible tenderness, similar to the experienced tion. Exercise stress testing along with pulmonary func-
chest pain, on palpation of the chest wall. Cough, crack- tion testing may be warranted in patients who experience
les, or wheezes might suggest a hyperreactive bronchial exertional chest pain and other cardiovascular symptoms.
airway (asthma or exercise-induced asthma) or a pneu- Echocardiography, performed in a pediatric center
monic process of the lung. and supervised by a pediatric cardiologist, is a very
A detailed cardiovascular examination should include valuable tool for delineating cardiac anatomy. (22)
palpation of the precordium for heaves (right ventricular The diagnosis of pericardial effusion, aortic root dissec-
heave in pulmonary hypertension) or thrills (obstructive tion, left-sided obstructive lesions, cardiomyopathy,
valvular lesions). Particular attention should be paid to pulmonary hypertension, and ventricular dysfunction
heart sounds. When the heart sounds are distant or may be established by two-dimensional echocardiogra-
not strongly audible, a diagnosis of pericardial effusion phy. Echocardiography also can help to identify coronary
should be entertained. A loud second heart sound along abnormalities, including abnormal origin and course of
the left upper sternal border suggests pulmonary hy- the coronary arteries, coronary aneurysms, and coronary
pertension. Pericardial rub may be heard in mild-to- artery fistulas. Historically, coronary angiography has
moderate pericardial effusions. been the gold standard for evaluation of the origin and
Patients who have myocarditis may present with course of the coronary arteries. However, newer non-
tachycardia, muffled heart sounds, a gallop rhythm, and a invasive techniques such as 64-slice computed tomogra-
mitral regurgitation murmur. An ejection systolic click is phy scan or magnetic resonance angiography are being
heard in aortic stenosis and a midsystolic click in mitral used increasingly to define abnormal coronary artery
valve prolapse. A harsh, medium-pitched midsystolic anatomy. Occasionally, electrophysiologic studies may
murmur is heard in patients who have a fixed aortic help diagnose underlying arrhythmias.
obstruction due to valvular, subvalvular, or supravalvular
stenosis or hypertrophic cardiomyopathy. In patients Treatment of Chest Pain
who have mitral valve prolapse, a midsystolic click may be Reassurance, analgesia, rest, or any combination of
accompanied by an apical mid- to late-systolic honking these three measures is the best treatment for patients
murmur. A continuous murmur is heard in patients who experiencing noncardiac chest pain. NSAIDs adminis-
have coronary artery fistulas or ruptured sinus of Valsalva. tered for 1 week often decrease inflammation and pain.
Weak or absent femoral pulses with upper limb hyperten- Patients who have pericarditis and pericardial effusion
sion and a continuous flow murmur at the left lower should be treated with ibuprofen. Administration of
scapular margin should prompt evaluation for coarcta- steroids may be considered in refractory cases of peri-
tion of the aorta. Hepatomegaly, ascites, and peripheral carditis and pericardial effusions. (23) The appropriate
edema should alert the physician to look for causes of specialist should treat specific cardiac, pulmonary, gas-
congestive heart failure. trointestinal, and psychogenic causes of chest pain. Most,
but not all, patients who experience chest pain and are
Investigations awaiting a cardiology consultation should have their
Patients who have the clinical features of musculoskeletal physical activity restricted pending their final cardiology
chest pain and no other noteworthy findings do not evaluation.
require additional evaluation or referral. Those who have
a significant history or abnormal findings on physical Referring a Patient to a
examination should have additional diagnostic evalua- Pediatric Cardiologist
tion and a referral to a pediatric cardiologist if cardiac Consultation with a pediatric cardiologist is highly rec-
disease is suspected. Evaluation is individualized, based ommended for any child or adolescent patient who has
on associated symptoms and findings. A chest radiograph chest pain associated with exertion, palpitations, sudden
should be performed to look for bony lesions, cardio- syncope (especially during exercise) or abnormal findings
megaly, airways, and lung parenchymal or pleural lesions. on cardiac examination or ECG; a history of past cardiac

Case Discussion
Reasons to Refer Children
Table 4. Case 1
The 12-year-old child described in this case has a classic
Who Have Chest Pain to a history for costochondritis, a benign condition that is a very
Cardiologist common cause of chest pain in the pediatric population. On
physical examination, most affected patients have repro-
1. Abnormal cardiac findings
2. Exertional chest pain ducible tenderness on palpation of the chest. The absence of
3. Exertional syncope signs of inflammation differentiates costochondritis from
4. Chest pain with palpitations Tietze syndrome. This patient does not need any additional
5. Electrocardiographic abnormalities
investigations or referral to a pediatric cardiologist. Reas-
6. Significant family history of arrhythmias, sudden
death, or genetic disorders suring her and her family about the benign nature of the
7. History of cardiac surgery or interventions condition is sufficient. For patients experiencing severe
8. Orthotopic heart transplant pain, NSAID therapy and warm compresses applied for a
9. History of Kawasaki disease
few days may be beneficial.
10. First-degree relatives have familial
hypercholesterolemia
Case 2
The 17-year-old boy described in this case has exertional
surgery or intervention; or a family history of genetic chest pain followed by a syncopal event. Any patient expe-
syndrome, arrhythmias, sudden cardiac death, or high riencing exertional chest pain and syncope should be re-
risk for coronary artery disease (Table 4). Patients who stricted from all strenuous physical activities and referred
have a past history of Kawasaki disease, congenital heart to a pediatric cardiologist immediately for additional eval-
disease, cardiac surgery, or heart transplantation are at uation and treatment. In this patient, 12-lead ECG re-
risk for coronary artery disease. Heart transplant patients vealed left ventricular hypertrophy and ST segment depres-
who experience myocardial ischemia may not complain sions in the left-sided precordial leads, suggesting a strain
of chest pain because of sympathetic denervation of pattern caused by transient left ventricular subendocar-
the transplanted heart but may present with nonspecific dial ischemia. Echocardiography performed the next day
symptoms such as nausea, vomiting, and an elevated demonstrated a bicuspid aortic valve with moderate-to-
resting heart rate. Patients who have had a Mustard severe aortic stenosis and left ventricular hypertrophy. The
or Senning procedure for d-TGA or who have had Fon- patient was taken to the cardiac catheterization laboratory
tan palliation for a single ventricle are at high risk for for balloon aortic valvuloplasty.
intra-atrial re-entry tachycardias (also called slow atrial
flutters) and should be referred promptly to a pediatric
cardiologist.
Children or adolescents who have had a recent trans- Summary
catheter cardiac intervention, including device closure
or stent placements, should be evaluated by a cardiolo- • Every patient who has chest pain warrants a
thorough evaluation. Usually, the history and
gist for device embolization or compression of adjacent
physical examination are sufficient to diagnose the
structures. Complaints of chest pain in patients who cause of the pain.
recently had congenital heart disease correction should • Based on strong research evidence, musculoskeletal
be taken seriously. The chest should be inspected to rule chest pain is the most common cause of chest pain
out any infection of the sternotomy incision and chest in the pediatric population. (3) Educating and
reassuring both the patient and the family about the
tube sites. History of fever, chest pain worsening when
benign nature of chest pain is of utmost importance.
supine, and distant heart sounds on auscultation should • Based on some research evidence as well as on
raise the suspicion of postpericardiotomy syndrome. consensus, a cardiac cause for chest pain is more
Patients who have had arterial switch operation for likely if the pain occurs during exertion. (3) Any
d-TGA and those having a history of Kawasaki disease are coexisting symptoms suggestive of myocardial
ischemia or an abnormal cardiac finding should
at risk for coronary artery stenosis or atresia and subse-
prompt immediate referral to a pediatric
quent myocardial ischemia or infarction. Obtaining ECG cardiologist.
is a good starting point to look for signs of ischemia.

References 15. Bisset GS 3rd, Schwartz DC, Meyer RA, James FW, Kaplan S.
1. Feinstein RA, Daniel WA Jr. Chronic chest pain in children and Clinical spectrum and long-term follow-up of isolated mitral valve
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2. Fyfe DA. Chest pain in pediatric patients presenting to a cardiac 16. Barth CW 3rd, Roberts WC. Left main coronary artery origi-
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3. Driscoll DJ. Chest pain in children and adolescents. In: Allen aorta and pulmonary trunk. J Am Coll Cardiol. 1986;7:366 –373
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Heart Disease in Infants, Children, and Adolescents. 6th ed. Phila- a complication of anomalous left coronary origin from the anterior
delphia, Pa: Lippincott Williams & Wilkins; 2001:1379 –1382 sinus of Valsalva, a not-so-minor congenital anomaly. Circulation.
4. Selbst SM, Ruddy R, Clark BJ. Chest pain in children. 1974;50:780 –787
Follow-up of patients previously reported. Clin Pediatr. 1990;29: 18. Hosenpud JD, Shipley GD, Wagner CR. Cardiac allograft
374 –377 vasculopathy: current concepts, recent developments and future
5. Selbst SM. Chest pain in children. Pediatrics. 1985;75:1068 –1070 directions. J Heart Lung Transplant. 1992;11:9
6. Pantell RH, Goodman BW Jr. Adolescent chest pain: a prospec- 19. Reddy SV, Forbes TJ, Chintala K. Cardiovascular involvement
tive study. Pediatrics. 1983;71:881– 887
in Kawasaki disease. Images Paediatr Cardiol. 2005;23:1–19
7. Selbst SM, Ruddy RM, Clark BJ, Henretig FM, Santulli T Jr.
20. Kato H, Sugimura T, Akagi T, et al. Long-term consequences
Pediatric chest pain: a prospective study. Pediatrics. 1988;82:
of Kawasaki disease. A 10- to 21-year follow-up study of 594
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8. Aeschimann AKM. Tietze’s syndrome: a critical review. Clin patients. Circulation. 1996;94:1379 –1385
Exp Rheumatol. 1990;8:407 21. American Academy of Pediatrics, Committee on Practice and
9. Heinz GJ, Zavala DC. Slipping rib syndrome. JAMA. 1977; Ambulatory Medicine. Recommendations for preventive pediatric
237:794 –795 health care. Pediatrics. 2007;120:1376
10. Pickering D. Precordial catch syndrome. Arch Dis Child. 1981; 22. Cheitlin MD, Armstrong WF, Aurigemma GP, et al. ACC/
56:401– 403 AHA/ASE 2003 Guideline update for the clinical application of
11. Howell J. Xiphoidynia: a report of three cases. J Emerg Med. echocardiography: summary article. A report of the American Col-
1992;10:435 lege of Cardiology/American Heart Association Task Force on
12. Driscoll D, Glicklich LB, Gallen WJ. Chest pain in children: a Practice Guidelines (ACC/AHA/ASE Committee to Update the
prospective study. Pediatrics. 1976;57:648 1997 Guidelines for the Clinical Application of Echocardiography).
13. Wiens L, Sabath R, Ewing L, et al. Chest pain in otherwise J Am Soc Echocardiogr. 2003;16:1091–1110
healthy children and adolescents is frequently caused by exercise- 23. Maisch B, Seferovic PM, Ristic AD, et al. Guidelines on the
induced asthma. Pediatrics. 1992;90:350 –353 diagnosis and management of pericardial diseases executive sum-
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Surendranath R. Veeram Reddy and Harinder R. Singh
Pediatr. Rev. 2010;31;e1-e9
DOI: 10.1542/pir.31-1-e1

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The composition and production of Pediatrics in Review威

Cover: The artwork on the cover of this month’s issue

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Pediatrics in Review Vol.31 No.1 January 2010 3

Updated Information including high-resolution figures, can be found at:

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Heart Failure in Infants and Children

4 Pediatrics in Review Vol.31 No.1 January 2010

tance. Stimulation of the sympathetic nervous system

Pediatrics in Review Vol.31 No.1 January 2010 5

Leading to Heart Failure With a Structurally Normal

excessive volume leads to increased ventricular filling

6 Pediatrics in Review Vol.31 No.1 January 2010

ductus arteriosus closes. In these

Pediatrics in Review Vol.31 No.1 January 2010 7

praventricular tachycardia. With chronic bradycardias, Management

8 Pediatrics in Review Vol.31 No.1 January 2010

Digoxin is derived from the common flowering plant

the subgroup that had primarily left ventricular dysfunc- Prognosis

Pediatrics in Review Vol.31 No.1 January 2010 9

Heart Failure Staging in

Pediatric Heart Disease Summary

10 Pediatrics in Review Vol.31 No.1 January 2010

Pediatrics in Review Vol.31 No.1 January 2010 11

4. Which of the following assertions applies to heart failure in pediatric patients?

12 Pediatrics in Review Vol.31 No.1 January 2010

Updated Information including high-resolution figures, can be found at:

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Pediatrics in Review Vol.31 No.1 January 2010 13

Table 1. Tuberculosis (TB) Disease Classification and Initial Treatment

14 Pediatrics in Review Vol.31 No.1 January 2010

Table 2. Risk of Progression from Tuberculosis (TB) Infection to Disease

Pediatrics in Review Vol.31 No.1 January 2010 15

Table 3. Signs and Symptoms of Pulmonary Tuberculosis

Figure 1. Right hilar tuberculous lymphadenopathy in a

16 Pediatrics in Review Vol.31 No.1 January 2010

Central Nervous System (CNS) Disease

Pediatrics in Review Vol.31 No.1 January 2010 17

Figure 5. Miliary TB in a 7-month-old male who also has TB

18 Pediatrics in Review Vol.31 No.1 January 2010

more common in HIV-infected children and is difficult

Pediatrics in Review Vol.31 No.1 January 2010 19

Table 4. Reaction Size of Tuberculin Skin Test Considered Positive

20 Pediatrics in Review Vol.31 No.1 January 2010

Pediatrics in Review Vol.31 No.1 January 2010 21

22 Pediatrics in Review Vol.31 No.1 January 2010

Pediatrics in Review Vol.31 No.1 January 2010 23

Follow-up children continually exposed to adults who have infec-

24 Pediatrics in Review Vol.31 No.1 January 2010

Pediatrics in Review Vol.31 No.1 January 2010 25

26 Pediatrics in Review Vol.31 No.1 January 2010

Updated Information including high-resolution figures, can be found at:

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Validity Hierarchy for Study Design

Case Studies Validity Hierarchy

Pediatrics in Review Vol.31 No.1 January 2010 27

Table. Validity Hierarchy

Retrospective: less expensive Difficult to study rare outcomes