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contents
Pediatrics in Review
COMMENTARY
378
Fever of Unknown Origin: Where Science Meets Art

Mobeen Rathore
ARTICLES
380
Pediatric Fever of Unknown Origin

James W. Antoon, Nicholas M. Potisek, Jacob A. Lohr
392
Constipation and Encopresis in Childhood

Jennifer M. Colombo, Matthew C. Wassom, John M. Rosen
403
Patient Safety and Quality Improvement:

Terminology
Lucy Pereira-Argenziano, Fiona H. Levy
INDEX OF SUSPICION
414
Case 1: Intractable Rash in a 7-month-old Boy

Priyanka Rao, Jennifer Stojan
417
Case 2: Cardiovascular Shock Following Acute

Gastroenteritis in a 17-year-old Boy
Lina Merjaneh, Lillian R. Meacham
420
Case 3: A Vascular-appearing Eyelid Mass in

a Neonate
Tiffany J. Herd, Hillary S. Lawrence, Michelle A. Manalang,
Laura S. Plummer, Lei Shao, Kimberly A Horii
422
423
Correction
Case 4: How Much Is Too Much? A Case of
Hypercalcemia in a 6-year-old Boy
Monica Liao, Philip Magcalas, Patricia Hopkins-Braddock
IN BRIEF
426
Head Growth
Mary Elizabeth Wroblewski, Joyce Bevington, Cathi Badik
ONLINE
e30
Visual Diagnosis: Newborn With a Facial Vascular

Birthmark
Brian M. Faux, Abraham W. Suhr, David T. Hsieh
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Vol. 36 No. 9 September 2015

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Commentary
Fever of Unknown Origin: Where
Science Meets Art
AUTHOR DISCLOSURE Dr Rathore has

disclosed no nancial relationships relevant to
this article. This commentary does not contain
a discussion of an unapproved/investigative
use of a commercial product/device.
378
Fever of unknown origin (FUO) is a relatively uncommon condition in United

States children. Nevertheless, FUO remains a challenging clinical problem
for even the most astute clinician that requires excellent history taking
and physical examination skills. In the more elusive cases, repeated history
and physical examination are the hallmarks of evaluation. Although diagnostic testing has been extremely valuable, a Sherlock Holmes-like attention
to clues and details is key (being that Sir Arthur Conan Doyle was also a
physician).
Infections remain the most common cause of fever in general and of
FUO in particular. In the past, infections obviously not only contributed to
conrmed causes of FUO but also perhaps to many cases in the unknown
cause categories. However, more advanced and rapid diagnostic techniques
now allow clinicians to diagnose more infectious causes sooner. Accordingly, compared to the past, infections now constitute the cause of a relatively smaller number of cases of FUO.
Even in todays high-tech era of medicine, FUO is one of those conditions in
which the art of medicine is critical. Good communication between the
clinician and the family and patient is often the key to success, and repeated
history taking and physical examination by the old-fashioned diagnostician
frequently triumph. Asking patients, even young patients, directed questions
may reveal the undeclared pet rat in the attic, the dead rabbit they found in
the back yard, or playing with grandmas neighborhood kittens that the parents
had specically instructed them to avoid. Parents may not report a visiting
uncle from India or grandaunt who babysits and has been coughing and was
told she has emphysema.
In this issue of Pediatrics in Review, Antoon et al present a succinct review of
outpatient FUO in childhood, which is distinct from evaluation of prolonged fever
in a hospitalized patient. Careful history and physical examination guide the
clinician to further evaluation, although sometimes the cause remains elusive,
and not infrequently laboratory and radiologic evaluations are necessary. Because
most cases of FUO can be diagnosed in an outpatient setting without resorting to
extensive laboratory evaluation, clinicians do well to follow a carefully considered
plan that looks initially for more common and treatable causes of FUO. We should
always be looking for horses, but sometimes these horses disguise themselves as
zebras.
Many experts, including the authors of the article in this issue, recommend
a tiered approach to diagnosing FUO. Clearly, no one algorithm can be provided
for diagnostic testing, but that shown in the Table is one approach. Rather than an
algorithm, it offers a framework for evaluating FUO, identifying the more
common causes, and if necessary, referring the patient to a specialist. Moving
TABLE.
Laboratory and Imaging Evaluation in Fever of Unknown Origin
BASIC TESTS
Complete white blood cell count with differential count on
a peripheral smear
Urinalysis
Erythrocyte sedimentation rate
Urine culture
C-reactive protein
Blood culture
Examination of peripheral smear
Complete metabolic panel

First-tier Tests
Serology*: Epstein-Barr virus, human immunodeciency
virus, Bartonella, hepatitis
Tuberculin skin test/Interferon gamma release assay

Chest radiograph
Blood culture
Second-tier Tests
Blood culture
Sinus computed tomography scan
Antinuclear antibody, rheumatoid factor, complement 3,

complement 4, 50% haemolytic complement (CH50)
Echocardiography
Stool culture and ova & parasites

Serology*: Rocky Mountain spotted fever, Histoplasma, Ehrlichia,
Anaplasma, Lyme disease, Cytomegalovirus, Toxocara gondii
Abdominal ultrasonography
Third-tier Tests
Upper gastrointestinal series with follow-through
Bone scan
Cerebrospinal uid
Bone marrow aspiration
*Additional serologic diagnostic tests should be specic for each individual situation.
from one tier to the next is not linear and varies with each case,
requiring some changes in the evaluative process, including
sometimes skipping a tier or two. Such a plan offers a more
strategic approach to FUO while making sure that any red ags
for more serious and especially treatable causes of FUO come
to light early in the course of evaluation.
Happy sleuthing!
Mobeen Rathore, MD, CPE*

*Editorial
Board member.
Professor and Director,

University of Florida Center for HIV/AIDS Research, Education and Service,
Jacksonville, FL.
Vol. 36 No. 9
SEPTEMBER 2015
379
Pediatric Fever of Unknown Origin

James W. Antoon, MD, PhD,* Nicholas M. Potisek, MD, Jacob A. Lohr, MD
*Department of Pediatrics, Division of General Pediatrics and Adolescent Medicine, University of Illinois at Chicago, Chicago, IL.
Department of Pediatrics, Division of Pediatric Hospital Medicine, Wake Forest School of Medicine, Winston-Salem, NC.
Department of Pediatrics, Division of General Pediatrics and Adolescent Medicine, University of North Carolina School of Medicine, Chapel Hill, NC.
Educational Gap
Pediatricians often confuse fever without a source and fever of unknown
origin.
Objective
After completing this article, readers should be able to:
1. Adopt a systematic approach to evaluation and management of fever

of unknown origin in patients of various ages.
CLINICAL PROBLEM
Fever is a common complaint in children. In most cases, fevers are due to selflimited viral infections and require no more than symptomatic treatment. Sometimes fever is due to common bacterial infections that are diagnosed by history and
physical examination and require antibiotic treatment without laboratory evaluation. In a few clinical situations, the cause of fever is not easily identied. Fever
without a source (FWS) may need further evaluation that includes laboratory tests or
imaging. Rarely, the fever is more prolonged, requires more intensive evaluation,
and falls in the category of fever of unknown origin (FUO).
There is often confusion about the terms FUO and FWS. Distinguishing
between FUO and FWS is important and is based on duration of fever. FWS can
progress to FUO if no cause is elicited after 1 week of fever.
The current incidence and prevalence of pediatric FUO remain unclear.
Several factors contribute to the difculty in determining the epidemiology,
including the lack of a standardized denition, clinical criteria, and coding using
the International Classication of Diseases-9 code for the condition. Furthermore, the causes of FUO often have an overlapping collection of symptoms and
insidious disease courses. The general direction of the evaluation varies based on
patient presentation, geographic location, associated symptoms, environmental
exposures, physician experience, and available testing techniques.
FEVER PHYSIOLOGY
Body temperature is primarily controlled by the hypothalamus via regulation of
pulmonary, skin, and metabolic systems. A basic understanding of the physiologic
factors regulating temperature can help distinguish between normal variance and
fever. The mean basal temperature varies according to age, gender, body habitus,
380
AUTHOR DISCLOSURE Drs Antoon, Potisek,

and Lohr have disclosed no nancial
relationships relevant to this article. This
commentary does not contain a discussion of
an unapproved/investigative use of
a commercial product/device.
time of day, activity level, menstrual cycle, and other factors.

(1)(2) Importantly, physiologic temperature exhibits a morning nadir and an early evening peak, which can vary by as
much as 1C. Furthermore, infants and young children
maintain higher temperatures than older children and
adults, primarily because of increased metabolic rate and
body surface-to-weight ratio. (1)(3) Of note, core body temperature is positively related to obesity, which should be
taken into account with the growing number of obese
children in the United States.
Fever generally is dened as a core temperature of at least
38.0C (100.4F) and is the result of a complex series of
signalling cascades initiated in response to specic biologic
stimuli. (2) Fever is believed to provide an evolutionary
advantage in ghting off infection. Bacteria and viruses are
heat sensitive and exhibit temperature-dependent toxin production, growth, and response to antibiotics. (4)(5) The bodys
mechanism of increasing core temperature in response to
infection functions to ward off the offending microbes.
Increased metabolic rate accelerates immune system mobilization, lymphocyte transformation, lysosome and neutrophil
activity, and phagocytosis. Increases in lipolysis and proteolysis diminish the amount of free glucose that can be used by
invading organisms. Similarly, the body transiently removes
iron, zinc, and copper, critical cofactors in viral and bacterial
replication, from the blood in response to the presence of
fever. (6) Taken together, the fever response provides a natural
defense mechanism against invading pathogens.
DEFINITION OF FEVER OF UNKNOWN ORIGIN

One of the challenges in investigating and reviewing FUO is
the lack of a standard denition. The number of fever days
before considering FUO historically ranged from 5 to 21 and
required some degree of medical evaluation. (7)(8) The
original literature included a lengthy time course of up to
3 weeks, but the advent of improved and rapid laboratory
techniques has led to a shortened number of fever days
before considering FUO diagnoses. With the availability of
rapid molecular diagnostic techniques for many infections,
most of the common causes of FUO from the past can now
be diagnosed or excluded rapidly, which has shortened the
time that is required to move from FWS to FUO.
FUO has more recently been dened as a temperature
higher than 38.0C (100.4F) that lasts longer than at least
8 days without a clear source. (9) Although most children
meeting the denition of FUO would have had some
laboratory assessment, it is not currently a prerequisite.
(10) However, any previous evaluation would help to
broaden or narrow the differential diagnosis.
CAUSES
FUO remains a diagnostic dilemma for many pediatricians
because it is frequently difcult to distinguish clinically
between benign and potentially life-threatening causes.
The spectrum of FUO causes is broad and includes infectious, autoimmune, oncologic, neurologic, genetic, factitious, and iatrogenic (Fig 1). Pediatricians face the
signicant challenge of not missing the diagnosis of a serious illness or an easily treatable condition that can result in
increased morbidity. Fortunately, FUO is usually an uncommon presentation of common diseases, most of which are
easily treatable without increased morbidity.
Relatively few studies document the cause of FUO in
developed countries; most of the current knowledge is
derived from three studies performed almost 4 decades
ago. (11)(12)(13) Low patient numbers and narrow patient
populations in more recent studies limit the value of conclusions. (14)(15)(16)(17) More recent studies conducted in
adult patients indicate a clear shift to noninfectious causes
of FUO, but few corresponding studies conrm this shift in
children. (10)(18)(19) Although numerous follow-up studies
in developing countries catalogue the underlying causes of
FUO, varying medical resources and endemic pathogens in
these countries make it unclear whether such ndings apply
to the United States. (20)(21)(22)(23)(24)
The sentinel studies on pediatric FUO in the United States
found that approximately 90% of cases had an identiable
cause: approximately 50% infectious, 10% to 20% collagenvascular, and 10% oncologic. (11)(12)(13) Smaller subsequent
studies from the 1990s had highly variable results: 20% to
44% infectious, 0% to 7% collagen-vascular, 2% to 3%
oncologic, and up to 67% undiagnosed. (14)(15) The reason
for this seemingly paradoxic increase in undiagnosed cases of
FUO in the setting of improved diagnostic techniques is
unclear. However, the shift from infectious to unidentiable
causes of FUO correlates with advances in diagnostic testing, including wider availability and rapid turnaround time.
The advent of polymerase chain reaction, improved culture
techniques, and better understanding of atypical viral and
bacterial pathogenesis and autoimmune processes likely
contribute to earlier diagnosis of the cause of FWS and fewer
children advancing to the category of FUO. This shift to
unidentiable causes due to laboratory advances is supported
by recent studies from developing countries with signicant
laboratory limitations, which show primarily infectious
causes of FUO, similar to those of older studies in developed
countries. (20)(21)(22)(23)(24)
Most cases of undiagnosed FUO appear to be benign,
with many resolving spontaneously without a conrmed
Vol. 36 No. 9
SEPTEMBER 2015
381
Figure 1. Causes of pediatric fever of unknown origin.
cause. These cases possibly consist of prolonged viral syndromes or difcult-to-conrm atypical bacterial infections.
Substantially more evidence in the adult population supports the dynamic etiology of FUO over time, with multiple
studies over several decades demonstrating an increasing
trend toward undiagnosed cases. Some studies suggest that
as many as 50% of adult FUO cases remain undiagnosed.
(18)(19) These investigations also show decreased infectious
and increased inammatory diagnoses in the adult population over the same period of time. A better understanding
of the current etiologic categories of FUO in children should
improve the ability of medical practitioners to generate
a differential diagnosis.
FEVER OF UNKNOWN ORIGIN IN DEVELOPING

COUNTRIES
Recent literature from developing countries indicates that
the causes of FUO remain primarily infectious. (20)(21)(22)
(23)(24)(25) Chow et al (20) reviewed FUO causes in several
382
developing countries from 1990 to 2008. In published

studies with greater than 49 patients, infection (36%
78%) was by far the most common cause compared to other
causes such as malignancy (2%12%), collagen-vascular
(2%21%), miscellaneous noninfectious (2%50%), and
unknown (12%29%). Most of these infections were of
bacterial or atypical bacterial origin in contrast to the more
common viral causes in developed countries. A more recent
report of FUO in Turkey revealed a similar composition,
with infection being most common, followed by malignancy
and collagen-vascular diseases. (23) A 2012 study of 95
pediatric patients in Iran demonstrated that collagenvascular diseases were more common causes than malignancy, but there was a high rate of undiagnosed cases. (26)
Interestingly, Chantada et al (25) reviewed 113 cases of
FUO in Argentina according to three age categories: 0 to
11 months, 12 to 59 months, and older than 60 months.
Infection was the most common cause across all age groups,
but infectious causes were less common in those ages 12 to
59 months compared to the other two age groups. Children
ages 12 to 59 months had a corresponding increase in

neoplastic and miscellaneous noninfectious causes of
FUO. These results differed from a study of 80 patients
in Turkey, which suggested a decreased likelihood of infectious causes with increasing age. (21) As with recent studies
in developed countries, small sample sizes and variation in
endemic infections limit generalization of these ndings.
Several contributing and complicating factors are associated with the higher infectious burden of FUO in developing countries. The prevalence of certain infections known
to cause FUO, such as human immunodeciency virus
(HIV), tuberculosis, leishmaniasis, and malaria, is higher
in developing countries. Similarly, the rate of vaccinepreventable diseases is higher in developing compared to
developed countries. Limited public health prevention programs and diminished access to health-care workers likely
contribute to an increased incidence of infectious diseases as
the cause for FUO, as does a decreased frequency of early
recognition of infectious causes. Furthermore, limited awareness and ability to test for newly recognized causes of FUO,
such as hemophagocytosis syndrome, may limit diagnosis of
certain noninfectious causes.
EVALUATION
Initially distinguishing among infectious, autoimmune,
malignancy, and miscellaneous causes of FUO may be
difcult, but a thorough history and physical examination
can often generate a directed differential diagnosis. We
highly recommend a tiered approach to FUO to decrease
overall costs and the use of invasive testing.
History and Physical Examination

Evaluation of FUO should be systematic and logically guided
by history and physical examination ndings. A detailed
history, a thorough physical examination, and a proper
interpretation of laboratory tests already performed are
critical. The speed with which the evaluation should proceed
and whether it should be outpatient or inpatient depends, in
large part, on how ill the patient appears.
The rst step in evaluating FUO is documentation that
fever is actually present. Parental perception of fever often
varies from the medical denition. It is useful to determine
what the parent denes as fever and whether this varies
from the medical denition of 38.0C (100.4F). In our
experience, parents frequently report tactile or subjective
fevers without actually measuring the patients temperature
with an instrument. Parents should be asked if the temperature was checked using a thermometer.
Pseudo-FUO has been dened as successive episodes of

benign, self-limited infections with fever that the parents
perceive as one prolonged fever episode. (27) This needs to
be carefully ruled out before undertaking an expensive and
unnecessary evaluation. Usually, pseudo-FUO starts with
a well-dened infection (most often viral) that resolves but is
followed by other febrile viral illnesses that may be less well
dened. Diagnosis of pseudo-FUO usually requires a careful
history, focusing on identifying afebrile periods between
febrile episodes. Differentiating pseudo-FUO from real
FUO can be challenging. If pseudo-FUO is suspected and
the patient does not appear ill, keeping a fever diary can be
helpful. In rare situations, a basic laboratory evaluation may
be necessary.
Any associated symptoms and the timing of antipyretic
administration is particularly important. A detailed description of the patients fever pattern as intermittent (eg, tuberculosis), recurrent (periodic fever disorders), relapsing (rat
bite fever), remittent (endocarditis, juvenile idiopathic
arthritis [JIA]), or sustained (pyogenic abscess) can sometimes narrow the differential diagnosis. (12)(13) Information
on the frequency and timing of fevers can be helpful in
determining the fever curve and ability to document the
fever in the medical setting. Periodicity of fever and the
presence of other symptoms at the time fever is present can
aid in making certain diagnoses, such as periodic fever,
aphthous stomatitis, pharyngitis, and adenopathy (PFAPA)
or other periodic fever disorders, without further expensive
evaluation. (28)
Fever can be the initial presentation of certain immunodeciency syndromes, but many affected patients have a history of repeated infections, diarrhea, or abnormal physical
ndings, such as a rash. A history of atopy or autoimmune
disease increases the likelihood of an autoimmune or rheumatologic cause. Furthermore, neutropenic fever in certain
situations can be a medical emergency, and the presence of
neutropenia may broaden the potential infectious sources of
fever while narrowing the diagnostic possibility (eg, cyclic
neutropenia). Determining the patients risk factors for neutropenic fever and any associated signs and symptoms is an
important step in an evaluation of FUO.
Information regarding the ethnicity, race, family history,
and genetic background of the patient can be helpful. Periodic
fever disorders often run in families and are more common
in certain ethnicities. For example, familial dysautonomia is
most common in the Ashkenazi Jewish population whereas
familial Mediterranean fever is seen in those of Arab, Jewish,
Armenian, and Turkish descent. (29)(30)
Geographic location and corresponding endemic pathogens known to cause FUO should be taken into consideration.
Vol. 36 No. 9
SEPTEMBER 2015
383
For example, coccidioidomycosis is more common in the

southwestern United States and 60% of the cases of Rocky
Mountain spotted fever are reported from North Carolina,
Oklahoma, Arkansas, Missouri, and Tennessee. Travel to or
residence in these areas is an important clue for making these
diagnoses. A thorough travel history is critical in the evaluation of FUO and should include exposure to animals,
unusual foods, insect bites, and sick contacts. Even if there
is no travel history, clinicians should determine the patients
overall exposure to any domestic or wild animals (eg, home,
school, woods, playground, friends or relatives house) rather
than simply asking Do you have any pets? when evaluating
for zoonoses (Table 1) (For a more extensive list of zoonoses,
see the table of diseases transmitted by animals in the Red
Book.) Similarly, a thorough history of any sick contacts or
high-risk exposures (eg, recent travel to foreign countries,
prisons, the homeless) can help narrow the differential diagnosis based on epidemiologic factors.
Many causes of FUO are accompanied by associated
symptoms. A detailed review of systems and their timing
TABLE 1.
384
in relation to fever can lead to a diagnosis. Because many

patients with FUO will have received a variety of treatments,
it is important to determine whether therapeutic interventions may have inuenced the disease or fever course. This
is particularly important because drug fever is one of the
causes of FUO and simply discontinuing a chronically
administered agent may lead to fever resolution.
The most important aspect of evaluation for FUO is
repeated history taking and encouraging the patient and
family to report any new, different, or unusual signs or
symptoms regardless of how trivial they may seem. Most
cases of FUO are diagnosed because important historical
information guides the direction of further evaluation.
A thorough physical examination should be performed
that documents vital signs and any reported weight loss.
Physical signs commonly provide evidence of the underlying diagnosis (Table 2). Serial physical examinations should
be performed, and observation in a controlled inpatient
setting may be benecial because up to 25% of signicant
physical ndings may be absent at the time of presentation.
Zoonoses and Fever of Unknown Origin
EXPOSURE
ZOONOSES
Birds
Psittacosis, cryptosporidiosis, histoplasmosis, West Nile virus
Cats
Bartonella henselae, tularemia, Pasteurella multocida, rabies, Capnocytophaga, Salmonella,

Campylobacter, Cryptosporidium, Giardia lamblia, Toxoplasma gondii, Toxocara cati,
Echinococcus, Ancylostoma braziliense, Dipylidium caninum, leptospirosis, Sporothrix schenckii,
Microsporum canis
Cows, Sheep, Goats
Escherichia coli, Campylobacter, Salmonella, Cryptosporidium, Coxiella, tularemia, Brucella
Dogs
Rabies, Brucella, Pasteurella multocida, Capnocytophaga, Salmonella, Campylobacter, Giardia

lamblia, Toxocara canis, Ancylostoma caninum, Echinococcus, Dipylidium caninum
Ferrets
Salmonella, Campylobacter, cryptosporidiosis, toxocariasis, tuberculosis, leptospirosis, listeriosis,

inuenza, Giardia, Mycobacterium microti, rabies
Water (Fish, Water Mammals, Oysters Clams)
Mycobacterium marinum, schistosomiasis, Vibrio parahaemolyticus, V vulnicus, Brucella

Legionella, Pseudomonas, Parachlamydia, Giardia, Mycobacterium leprae, M avium, M
marinum, M ulcerans, M simiae, Burkholderiaceae, Coxiella burnetii, Francisella tularensis,
Enterobacteriaceae, Vibrionaceae, Listeria monocytogenes, Helicobacter pylori, Cryptococcus
neoformans
Squirrels
Toxoplasma gondii, Rickettsia prowazekii
Horses
Salmonella, Campylobacter, Cryptosporidium, Giardia lamblia, Clostridium difcile, Brucella,

Rhodococcus equi, Coxiella burnetii
Insect Bites (Mosquitoes, Ticks, Fleas)
Malaria, Trypanosoma cruzi, equine encephalitis, West Nile virus, Lyme disease, ehrlichiosis,
babesiosis, Yersinia pestis, tularemia, Dirolaria immitis, leishmania, coltiviruses (Colorado tick
fever), Lyme disease, Rocky Mountain spotted fever, ehrlichiosis, babesiosis, Toscana virus
Rabbits
Salmonella, tularemia, Yersinia, Cryptosporidium, Trichophyton, Pasteurella multocida, rabies,

babesiosis
Reptiles
Salmonella, Edwardsiella tarda, Plesiomonas, pentastomiasis
Rodents
Tularemia, leptospirosis, rat bite fever (Streptobacillus moniliformis and Spirillum minus), rabies,
Salmonella, lymphocytic choriomeningitis virus, Trichophyton, hantavirus, Pasteurella
(11) On the other hand, completely normal physical examination ndings at the time of the initial FUO evaluation are
highly indicative of a benign underlying cause. (13)
During the evaluation, as the clinician expands the extent
of laboratory and imaging assessment, repeated history
taking and physical examinations are essential. They may
reveal new information that could aid in determining
appropriate laboratory and imaging studies.
Laboratory Studies and Imaging

A number of basic laboratory studies may be used to determine the source of FUO. A complete blood cell count (CBC)
with differential count and smear can suggest an infectious or
oncologic cause. Blood and urine cultures are recommended,
with the understanding that repeat cultures may be needed. If
the patient has neurologic symptoms, cerebrospinal uid
(CSF) studies are also indicated. Whenever possible, cultures
should be obtained before initiating antibiotics to avoid
ambiguity and contamination of results. Abnormalities in
serum electrolytes or liver enzymes may indicate viral, atypical bacterial, or hematologic causes. Specic molecular
testing for HIV, tuberculosis, or atypical bacterial pathogens
and viral serologies is expensive and nal results can be
delayed days to weeks. These tests should be performed based
on specic risk factors or suggestive physical ndings.
Testing for acute-phase reactants, such as C-reactive
protein (CRP), erythrocyte sedimentation rate (ESR), and
ferritin, is common in the evaluation of FUO. These tests
results are nonspecic and not diagnostic of any particular
disorder. On the other hand, elevated acute-phase reactants
should encourage the physician to proceed with further
appropriate evaluation. Of note, normal acute-phase reactant results do not exclude serious causes of FUO.
The CRP is a ring-shaped protein, consisting of ve
subunits, that is synthesized by the liver in response to
inammation. Detectable elevation of serum CRP occurs
within 6 hours of the trigger, heightens to a peak, and
resolves quickly following resolution of the stimulus. (32)
Physiologic levels of CRP vary based on age, gender, obesity,
exercise tolerance, sleep deprivation, and stress levels.
Therefore, clinicians should note the relative elevation of
CRP from baseline in the patient rather than rely on a single
initial value. CRP can be pathologically elevated in a wide
variety of disease processes, including inammatory, infectious, and autoimmune. There has been much interest in
CRP as a predictor of serious bacterial infection, and current
evidence suggests that a markedly elevated CRP is required
for specicity for bacterial infection. (33)(34)(35)(36) When
evaluating FUO, particularly in the hospital setting, mildly
elevated CRP values should not be used to rule in or out
a particular disease process. Trending CRP values are a more

valuable diagnostic tool and can be used to evaluate treatment response and direct treatment modalities. (37)
ESR responds to stimuli similar to those inuencing CRP
synthesis but is slower to elevate and has a longer half-life. ESR is
an indirect measurement of serum acute-phase protein concentrations, and physiologic values vary based on age, gender, and
other factors. Serum ESR may be altered in cases of abnormal
serum protein concentrations, including brinogen, albumin,
and immunoglobulin. In addition, ESR is subject to hemoglobin
concentration and size, shape, and number of red blood cells.
ESR is useful in determining chronic inammation or infection,
but for the previously stated reasons, it should be used with
caution as a diagnostic tool, particularly in the setting of possible
alterations in serum protein concentrations.
Ferritin is another acute-phase reactant. Elevated ferritin
(in the absence of increased iron) may indicate an infectious,
autoimmune, oncologic, or inammatory process. (38) Some
investigators have suggested that serum ferritin may
be helpful in evaluation of FUO to distinguish between
infectious and noninfectious causes. (39)(40) We have
found that serum ferritin can be particularly helpful in
diagnosing hemophagocytic lymphohistiocytosis (HLH), an
increasingly recognized cause of pediatric FUO. (41) Recent
guidelines have aided in the diagnosis of disease, and a serum
ferritin value greater than 10,000 mg/mL is 90% sensitive
and 96% specic for HLH. (42)(43)
Radiographs and imaging may play a role in the evaluation of FUO, but research suggests that empiric imaging
has limited utility. (15) Chest radiographs should be performed if pulmonary symptoms are present or if there is
concern for atypical bacterial infection, HIV, tuberculosis, or
oncologic processes. Additional imaging techniques, particularly computed tomography (CT) scan and magnetic resonance imaging (MRI), are associated with various risks and
should be performed discriminately. CT scans are known to
increase the risk of leukemia and brain tumors, particularly
in the pediatric population, and MRI is time-consuming and
often requires sedation in young children. (44) Therefore,
we recommend judicious imaging with specic diagnoses
in mind. For example, in a patient with gastrointestinal
symptoms, weight loss, and elevated CRP/ESR, an abdominal CTscan may aid in the diagnosis of inammatory bowel
disease, abscess, or cancer. Of note, all patients with a potential malignancy should receive a chest radiograph to evaluate
for a mediastinal mass before CT scan or MRI to avoid
airway complications while lying supine for imaging.
Other imaging modalities, such as white blood cell (galliumor indium-111-labeled) scans, positron emission tomography,
and immunoscintigraphy scanning, have not been well
Vol. 36 No. 9
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385
TABLE 2.
Physical Findings and Associated Fever of Unknown Origin

Diagnoses (31)
SYSTEM
FINDING
ASSOCIATED ILLNESS
Hepatomegaly
Lymphoma, metastatic carcinoma, relapsing fever, granulomatous hepatitis,

hemophagocytic lymphohistiocytosis, Q fever, typhoid fever, viral infections,
salmonellosis, brucellosis, bartonellosis, endocarditis, malaria, leukemia
Liver edge tenderness
Bartonellosis, liver abscess
Splenic abscess
Infective endocarditis, brucellosis, enteric fever
Splenomegaly
Leukemia, lymphoma, tuberculosis, brucellosis, infective endocarditis,

cytomegalovirus, hemophagocytic lymphohistiocytosis, Epstein-Barr virus,
psittacosis, relapsing fever, typhoid fever, Rocky Mountain spotted fever,
Kikuchi-Fuijmoto disease
Murmur
Infective endocarditis, atrial myxoma
Relative bradycardia
Typhoid fever, malaria, leptospirosis, psittacosis, central fever, drug fever
Abnormal funduscopic
examination ndings
Miliary tuberculosis, toxoplasmosis, vasculitis
Conjunctival suffusion
Leptospirosis, relapsing fever, Rocky Mountain spotted fever
Conjunctivitis
Epstein-Barr virus, Newcastle disease, leptospirosis, Kawasaki disease (limbic

sparing), tuberculosis, systemic lupus erythematosus, bartonellosis,
chlamydial infection, histoplasmosis, tumor necrosis factor receptorassociated periodic syndrome, familial cold autoinammatory syndrome
Decreased pupillary constriction
Hypothalamic or autonomic dysfunction
Dry eyes
Familial dysautonomia, systemic lupus erythematosus, polyarteritis nodosa,

Sjgren syndrome
Ischemic retinopathy
Polyarteritis nodosa
Periorbital edema
Tumor necrosis factor receptor-associated periodic syndrome
Subconjunctival hemorrhage
Endocarditis, trichinosis
Uveal tract involvement
Tuberculosis, juvenile idiopathic arthritis, toxoplasmosis, sarcoidosis, systemic

lupus erythematosus
Lymphadenopathy
Lymphoma, bartonellosis, tuberculosis, lymphogranuloma venereum,

cytomegalovirus, Epstein-Barr virus, human immunodeciency virus,
toxoplasmosis, juvenile idiopathic arthritis, brucellosis, Kikuchi-Fuijmoto
disease, tularemia, viral infections, mycobacterial infection, leukemia,
hyperimmunoglobulin D syndrome, familial cold autoinammatory
syndrome
Epididymo-orchitis
Tuberculosis, lymphoma, brucellosis, leptospirosis, Epstein-Barr virus,

blastomycosis, carcinoma
Bone tenderness
Osteomyelitis, malignancy, infantile cortical hyperostosis
Costovertebral tenderness
Chronic pyelonephritis, perinephric abscess
Hyperactive reexes
Hyperthyroidism
Abdomen
Chest
Eyes
Lymph Nodes
Genitourinary
Musculoskeletal
Continued
386
TABLE 2. (Continued )
SYSTEM
FINDING
ASSOCIATED ILLNESS
Hypoactive reexes
Familial dysautonomia
Joint tenderness
Familial Mediterranean fever, rat-bite fever, systemic lupus erythematosus, Lyme

disease, lymphogranuloma venereum, brucellosis,
hyperimmunoglobulinemia D syndrome, tumor necrosis factor receptorassociated periodic syndrome
Muscle tenderness
Brucellosis, trichinellosis, arboviral infection, dermatomyositis, polyarteritis,

subdiaphragmatic abscess (trapezius tenderness)
Spinal tenderness
Subacute vertebral osteomyelitis, infective endocarditis, brucellosis,

typhoid fever
Anomalous dentition
Anhidrotic ectodermal dysplasia
Dental or fascial abscess
Sinusitis, brain abscess, mediastinal abscess
Epistaxis
Relapsing fever, leukemia, psittacosis, rheumatic fever
Gingival hypertrophy
Leukemia, Langerhans cell histiocytosis
Pharyngeal hyperemia
Cytomegalovirus, Epstein-Barr virus, toxoplasmosis, tularemia, leptospirosis
Smooth tongue
Ulcerations
Behet disease; periodic fever, aphthous stomatitis, pharyngitis, and adenitis

(PFAPA); hyperimmunoglobulin D syndrome
Blotchy skin
Decreased body hair, hypohidrosis
Anhidrotic ectodermal dysplasia
Dehydration
Diabetes insipidus, ectodermal dysplasia, familial dysautonomia
Erythema nodosum
Infection, juvenile idiopathic arthritis, systemic lupus erythematosus,

malignancy, inammatory bowel disease
Erythema migrans
Lyme disease, southern tick-associated rash illness (STARI)
Eschar
Tularemia
Macular salmon-pink rash
Juvenile idiopathic arthritis
Malar erythema
Systemic lupus erythematosus
Palpable purpuric lesions
Polyarteritis nodosa
Oropharynx
Skin (limited review)
Petechiae
Endocarditis, bacteremia, viral infection, rickettsia
Seborrheic rash
Histiocytosis
Urticarial macular rash
Serum sickness, familial cold autoinammatory syndrome, Muckle-Wells

syndrome, neonatal-onset multisystem inammatory disease
studied in the diagnosis of pediatric FUO. Limited evidence

in children and additional studies in adults suggest that these
techniques have low sensitivity and specicity in the evaluation of FUO and should be used only if traditional imaging
fails to reveal a diagnosis. (45)(46)(47)(48)
If fever persists and laboratory studies and imaging fail to
reveal the underlying cause, invasive procedures may be
necessary. Bone marrow biopsy can be performed to evaluate
for oncologic or hematologic etiologies. Lumbar puncture,

thoracentesis, joint aspiration, or biopsies may also be indicated to obtain uid or tissue for analysis. These should be
performed as a last resort in the non-acute patient.
Initial Diagnostic Approach

We recommend that the initial laboratory evaluation of
pediatric FUO consist of a CBC, basic metabolic panel,
Vol. 36 No. 9
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387
Figure 2. Focused approach to fever of unknown origin based on suspected disease category.
388
liver function tests, urinalyses, and blood and urine cultures. If the patient has neurologic symptoms, CSF studies
may be considered. These tests should be performed
before initiating treatment to prevent contamination of
results.
The evaluation of FUO should be targeted if any ndings on history, physical examination, or laboratory and
imaging evaluation direct suspicion toward an organ
system or diagnosis. A patient with known tick exposure,
rash, and hyponatremia should receive serologic evaluation for Rocky Mountain spotted fever, Lyme disease,
ehrlichiosis, anaplasmosis, or babesiosis, depending on
the endemic region or travel history. (49) When deciding
which laboratory tests to order, it is important to note that
uncommon presentations of common diseases are more
likely to cause FUO than uncommon or rare diseases.
A well-appearing child with fever, rash, lymphadenopathy,
and transaminitis is more likely to have Epstein-Barr virus or
cytomegalovirus infection rather than HLH or systemic lupus
erythematosus. In a nonacute patient, ruling out common
causes of FUO before testing for uncommon causes or
performing invasive testing can minimize the likelihood of
dealing with false-positive, false-negative, or equivocal results
for rare diseases.
We have established an initial diagnostic algorithm based
on the broad etiologic categories of FUO that may be performed if a practitioner is suspicious for a particular disease
process (Fig 2). The recommended evaluation provides diagnostic rst steps in the evaluation of these categories that
may be performed before referral for specialized or invasive
TABLE 3.
testing. This tiered approach to FUO can decrease overall

costs and the use of invasive testing.
MANAGEMENT AND EMPIRIC TREATMENT

The initial management of FUO remains an area of debate.
Pediatric FUO is often overtreated because most cases are
caused by benign or nonacute disease. Physician concern
for serious illness or parental pressure can lead to empiric
treatment before sufcient evaluation. Physicians may be
inclined to start antipyretics, corticosteroids, or antibiotics
for an unknown disease process, which can affect future
laboratory data, imaging, or treatment. Many cases of FUO
resolve without a diagnosis and empiric treatment may mask
the diagnosis of life-threatening oncologic, infectious, and
autoimmune diseases. Empiric treatment should be initiated
with caution and in conjunction with judicious testing.
The rst step in the management of FUO is to discontinue all nonessential pharmacologic agents, including antipyretic medications. Drug fever can manifest at any time
after starting a medication, with an overall incidence of up to
5%. (50) Drug fever is a common source of FUO and can be
caused by any agent, including antibiotics, ibuprofen, and
acetaminophen (Table 3). Once the drug is discontinued,
fever usually abates within 24 hours or two half-lives of the
drug, typically resolving within 72 to 96 hours. (51) If drug
fever is suspected and the patient is taking multiple medications, eliminating one drug at a time may be helpful in
identifying the offending agent. However, other causes of
fever should be explored, based on history and physical
Common Causes of Drug Fever
CLASS
DRUGS
Antimicrobial agents
Acyclovir, carbapenems, cephalosporins, tetracyclines, mebendazole, nitrofurantoin, penicillins,

rifampin, sulfonamides, vancomycin
Anticonvulsants
Barbiturates, carbamazepine, phenytoin
Antidepressants
Doxepin, nomifensine
Antineoplastic agents
6-mercaptupurine, bleomycin, chlorambucil, cisplatin, cytosine arabinoside, daunorubicin,

hydroxyurea, interferon, L-asparaginase, procarbazine, streptozocin, vincristine
Cardiovascular drugs
Clobrate, diltiazem, dobutamine, furosemide, heparin, hydralazine, hydrochlorothiazide,

methyldopa, oxprenolol, procainamide, quinidine, triamterene
Histamine-2 blockers
Cimetidine, ranitidine
Immunosuppressants
Azathioprine, everolimus, mycophenolate mofetil, sirolimus
Nonsteroidal anti-inammatory drugs
Ibuprofen, sulindac, phenothiazines, salicylates
Other
Allopurinol, antihistamines, folate, herbal remedies, iodide, metoclopramide, piperazine,

propylthiouracil, prostaglandin E2, ritodrine, sulfasalazine, sympathomimetics, theophylline,
thyroxine
Vol. 36 No. 9
SEPTEMBER 2015
389
examination ndings, when discontinuing the medication

to ensure that fever resolution is due to drug fever rather
than resolution of another cause.
In an otherwise healthy, well-appearing child with FUO,
we do not recommend routine use of empiric antibiotics or
anti-inammatory agents. Empiric antibiotics can delay the
diagnosis of common infectious causes of FUO, such as
endocarditis, osteomyelitis, central nervous system infection, or abscesses. Pediatricians commonly prescribe tetracyclines (namely, doxycycline) or macrolides for presumed
atypical bacterial infections in the absence of risk factors
or clinical criteria for these diseases. These agents have
activity against some typical bacteria and have limited antiinammatory effects, which can delay the manifestation
or natural disease process of alternative causes of FUO.
(52)(53)(54) We recommend the use of these agents when
there is high clinical suspicion and only after the diagnostic tests for the pathogen are obtained.
The decision to use empiric anti-inammatory agents is
challenging. Corticosteroids can play a signicant role in
treating certain causes of FUO, such as autoimmune disease. There is no urgency for empiric treatment in most
autoimmune diseases, and treatment should be started after
the diagnosis is conrmed. On one hand, corticosteroids
affect a broad range of physiologic processes, including the
immune system; can potentially increase the risk of acquiring an infection or worsen an underlying infection; and can
impair the diagnostic usefulness of blood and tissue samples in oncologic testing and staging. On the other hand,
immune suppression should not be a contraindication for
specically indicated short-term corticosteroids. Clinical
immune suppression associated with corticosteroid use
manifests after 14 to 21 days of daily administration. (55)
(56)(57)(58) We recommend the use of corticosteroids if
there is high suspicion for serious autoimmune and inammatory conditions, such as systemic lupus erythematosus or
JIA, but not until oncologic etiologies have been excluded.
PROGNOSIS AND OUTCOME

A major difference between adult and pediatric FUO is
outcome. The prognosis of pediatric FUO is likely favorable
compared to FUO in the adult population due to differences
in causes. (59)(60) The original studies on pediatric FUO
from the 1970s demonstrated a mortality rate of 6% to 9%.

(12)(13) However, with the shifting causes of pediatric FUO,
further study is needed to dene outcomes in both adult and
pediatric cases.
The increasing percentage of undiagnosed causes of
FUO has inuenced the previously documented pediatric
mortality rates. Recent evidence suggests reassuring outcomes for undiagnosed pediatric FUO. Talano and Katz (17)
followed 19 children with undiagnosed FUO for a median of
3.5 years. Sixteen of 19 (82%) children with initially undiagnosed FUO were afebrile and clinically healthy at longterm follow-up. Of the three children who remained febrile
or were not clinically well, two were subsequently diagnosed
with JIA and the other with intussusception. Similarly, Miller
et al (16) studied 40 children referred to a rheumatology
clinic for evaluation of FUO. Of the 40 children, 37 were
available at long-term follow-up (median 60.5 months); 34
had complete resolution of fevers and 2 (5%) developed
evidence of inammatory bowel disease during follow-up.
Of note, neither of these studies was powered for morbidity
or mortality analysis. Whether the mortality rate of 6% to
9% found in previous studies applies to current cases of
FUO is currently unknown, particularly given the evolving
changes in underlying etiology over time. Further study is
needed to determine the mortality and overall outcomes
associated with pediatric FUO.
Summary
On the basis of strong clinical evidence, the causes of FUO are broad
and include both benign and life-threatening medical conditions. (12)
On the basis of observational studies, most cases of FUO have shifted
to noninfectious etiologies over the past several decades. (10)
On the basis of observational studies, completely normal physical
examination ndings at the time of the initial FUO evaluation
suggest a benign underlying cause. (13)
On the basis of consensus and expert opinion, a stepwise, tiered
approach to FUO should be implemented to decrease cost and
time to diagnosis. (13)
References for this article are at http://pedsinreview.aappublications.org/content/36/7/380.full.
Parent Resources from the AAP at HealthyChildren.org

https://www.healthychildren.org/English/health-issues/conditions/fever/Pages/When-to-Call-the-Pediatrician.aspx
Spanish: https://www.healthychildren.org/spanish/health-issues/conditions/fever/Paginas/When-to-Call-the-Pediatrician.aspx
390
PIR Quiz
1. A 5-year-old female has had a fever to 39.7C (103.6F) once or twice daily for 8 days. Her
pediatrician notes on history complaints of body aches and fatigue. Other than fever, there
are no abnormal ndings on physical exam. Which of the following is the most likely
diagnosis at this time?
A.
B.
C.
D.
E.
Bacteremia.
Fever of unknown origin (FUO).
Fever without a source.
Inuenza.
Rheumatoid arthritis.
2. Which of the following best describes usual etiologies of FUO?

A.
B.
C.
D.
E.
A common presentation of an uncommon disease.

An uncommon presentation of a common disease.
An untreatable disease with increased morbidity.
A relatively serious disease that is usually treatable.
A relatively uncommon disease requiring minor or no treatment.
3. Based on sentinel studies, which of the following are the most common identiable
etiologies of FUO in the United States?
A.
B.
C.
D.
E.
Allergic diseases.
Autoimmune diseases.
Collagen vascular diseases.
Infectious diseases.
Oncologic diseases.
4. A 10-year-old male presents with a 14-day history of FUO. His elevated temperature to
40.1C (104.2F) has been relatively sustained throughout this time period. Which of the
following etiologies based on this fever pattern most likely underlies this childs problem?
A.
B.
C.
D.
E.
Endocarditis.
Juvenile idiopathic arthritis.
Pyogenic abscess.
Rat bite fever.
Tuberculosis.
5. Periodic fever disorders often run in families and are more common in certain ethnicities.
Among which of the following ethnic groups is familial dysautonomia most common?
A.
B.
C.
D.
E.
Arab population.
Armenian population.
Ashkenazi Jewish population.
Sephardic Jewish population.
Turkish population.
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Vol. 36 No. 9
SEPTEMBER 2015
391
Constipation and Encopresis in Childhood

Jennifer M. Colombo, MD,* Matthew C. Wassom, PhD, John M. Rosen, MD*
*Division of Gastroenterology, Childrens Mercy Kansas City, University of Missouri at Kansas City School of Medicine, Kansas City, MO.
Division of Developmental & Behavioral Sciences, Childrens Mercy Kansas City, University of Missouri at Kansas City School of Medicine, Kansas City, MO.
Educational Gap
A recent study in Pediatrics concluded that 25% of children with functional
constipation continued to experience symptoms at adult age, suggesting
that referral to specialized clinics at an early stage for children who are
unresponsive to rst-line treatment may help improve outcomes. (1)
Objectives
After completing the article, the reader should be
able to:
1. Know that constipation is a common problem in childhood with
a diverse clinical presentation.
2. Understand that functional constipation is a symptom-based diagnosis
that does not require extensive testing.
3. Recognize that most children who present with fecal incontinence or
encopresis have associated constipation.
4. Describe the treatment of constipation and encopresis, which should
include a medical-behavioral approach that focuses on maintaining
soft and regular bowel movements and improving toileting behavior.
INTRODUCTION
What do the following children have in common?
A 12-month-old girl with hard pellet-like stools.
A 3-year-old girl with frequent complaints of dysuria and hard stools.
An 8-year-old boy with a weekly stool that is large enough to clog a toilet.
A 12-year-old boy with daily loose stools in his underpants.
Answer: They share a familiar diagnosis: functional constipation.
Constipation is a common pediatric problem and parental concern. In general,
a complaint of constipation accounts for 5% of general pediatric ofce visits and
25% of all referrals to pediatric gastroenterologists. The estimated worldwide
prevalence is 0.7% to 29.6%. (2) Constipation rarely signies a serious disease,
but it has an unfavorable impact on patient quality of life, parental satisfaction,
and health-care costs. Children with constipation often complain of abdominal
pain, decreased appetite, and painful stooling, which can be distressing to both
the child and the parents. Common transient problems with defecation, if unrecognized and untreated, can develop into disruption of toilet training and
392
AUTHOR DISCLOSURE Drs Colombo,

Wassom, and Rosen have disclosed no
nancial relationships relevant to this article.
This commentary does not contain
interference with achieving and maintaining bowel continence. The chronic nature of constipation and common
misconceptions about the symptoms and pathophysiology
of constipation can lead to frustrating experiences for patients and families. Multiple ofce visits, emergency department visits, and unnecessary diagnostic testing contribute
to the rising cost of health-care.
DEFINITION
Dening constipation remains a challenge because stooling
patterns are highly variable in childhood. Generally, infants
have an average of three to four stools per day and a toddler
may have two to three stools per day. (3) By the age of 4 years,
children have a pattern and frequency of bowel movements
that are similar to those of adults. (4) A consistent, reliable
method for diagnosis allows for better understanding of and
communication about the disorder. Constipation can be
roughly dened as infrequent passage of hard, uncomfortable stools that are distressing to the child.
Encopresis is the repeated passage of feces into inappropriate places (usually the underpants). Some have suggested
replacing the term fecal incontinence with the term encopresis in the literature to clarify that most children treated
for this problem have either current or intermittent constipation. However, we continue to reference the term
encopresis along with fecal incontinence due to the prevalence of this term in the literature. Fecal incontinence/
encopresis is often the result of liquid/soft stool leaking
around a large mass of stool in the rectum, which clinicians
should describe as constipation with overow.
Encopresis differs from delayed bowel training in that
children with encopresis pass liquid/soft stool in their underpants unknowingly because of constipation with overow and
difculty feeling the indication to stool. Children with encopresis also generally do not have accidents of formed stool
whereas children with delayed bowel training simply refuse
to use the toilet and have regular bowel movements in their
diapers or underpants. Children with encopresis often also
use the toilet to pass formed or semiformed stool.
Children with delayed bowel training may refuse to use
the toilet because of fear, anxiety, oppositional behavior, skill
decits, or lack of interest or motivation. Bowel continence
is expected to occur by the age of 4 years. Encopresis is not
a developmental variation after the age of 4 to 5 years.
PATHOGENESIS
Causes for the development of constipation include inadequate hydration, low-ber diet, slow intestinal transit, minimal
activity level or inactivity, and behavioral factors. Because some

or all components may play a role in the development of
constipation and encopresis, these conditions should be
conceptualized in the biopsychosocial framework. Constipation can manifest at any age and most commonly presents
during a period of transition in the childs life. In infancy,
constipation may present when the breastfed infant is
transitioned to formula or whole milk or when transitioning
from pureed to solid foods. In toddlers, constipation may
arise when toilet training begins. In childhood, constipation
is more likely when a child enters school and is using a toilet
away from home.
Normal Anatomy and Physiology

The internal anal sphincter, external anal sphincter,
puborectalis muscle, and rectum must work together for a
productive bowel movement. The internal anal sphincter and
the rectum are composed of circular smooth muscle. The
external anal sphincter and puborectalis muscle are made up
of skeletal muscle. When the rectum is empty and collapsed,
the internal and external anal sphincters are tonically contracted, maintaining continence. The puborectalis muscle
forms a sling around the rectum, pulling the rectum forward
when it is contracted and increasing the angle acuity between
the rectum and the anus.
When a bolus of stool reaches the rectum, distension of
the rectal wall signals the urge to defecate. The internal anal
sphincter reexively relaxes and the external anal sphincter
contracts. There are two options at this time: 1) squatting
or sitting on the toilet, relaxing the puborectalis muscle,
straightening the anorectal angle, relaxing the external anal
sphincter, and increasing intra-abdominal pressure to evacuate stool or 2) maintaining and increasing contraction of
the external anal sphincter and gluteal muscles to force stool
back into the rectum. When the stool is pushed back into the
rectum, the sensation or urge to have a bowel movement
disappears.
Constipation and Withholding

When children do not recognize or respond to the urge to
defecate, stool is retained in the rectum, the urge to defecate
subsides, and the rectal wall stretches to accommodate the
fecal load. Repeated withholding or avoidance of defecation
leads to larger stool load in the rectum, causing further
stretching and potential thinning of the rectal wall. The
retained stool becomes larger, harder, drier, and more difcult
to pass the next time the urge arises.
Prolonged and repetitive stool withholding and avoidance of defecation leads to large amounts of retained stool in
the rectum. The large fecal mass becomes impacted and
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393
extremely difcult to evacuate. Peristaltic movement of the

colon pushes semiformed and liquid stool lower in the
colon, resulting in leakage around the large mass of stool
into the childs underpants. This is especially true if the
impacted fecal mass is putting downward pressure on the
anosphincteric complex, distending a normally tonically
contracted outow barrier and making voluntary closure
of the external anal sphincter more difcult. Therefore,
a common complication of unrecognized and untreated or
undertreated chronic constipation is encopresis or fecal
incontinence.
If chronic constipation and encopresis are untreated,
they can lead to other signicant clinical issues, such as
enuresis, frequent urinary tract infections, rectal prolapse, or
pelvic dyssynergia. The hard fecal mass in the rectum puts
pressure on the urethra and bladder, causing incomplete
evacuation of the bladder. Incomplete bladder evacuation can
predispose children to urinary stasis and sensations of urgency followed by hesitancy. Chronic fecal soiling exposes the
urethra to bacterial pathogens that can ascend into the
bladder, causing infection. In addition, the enlarged dilated
rectum may result in decreased tone and contractility. Thus,
increasing intra-abdominal pressure (necessary for defecation) may ultimately result in rectal prolapse during a defecation attempt. Finally, chronic constipation and encopresis
can contribute to the development of pelvic dyssynergia, or
pelvic oor dysfunction, in which pelvic oor muscles contract instead of relax with attempted defecation, continuing
the cycle of incomplete rectal evacuation.
There are many reasons why a child may start to withhold
stool or avoid defecation. Stool withholding may be an intentional behavior to avoid unpleasant sensations or associations
with defecation. It may be a response to a painful bowel
movement that is caused by a stool that was larger or harder
than normal, an anal ssure, or a perianal infection. The child
may not want to use the toilet at school due to limited time,
lack of privacy, or concern about restroom cleanliness, choosing instead to withhold stool until arriving home. A child may
not want to interrupt an enjoyable activity to have a bowel
movement. Finally, stool withholding may be a learned avoidance behavior that is less intentional or even unconscious due
to repeated painful bowel movements.
Early recognition of stool withholding can prevent chronic
constipation and long-term defecation problems. Certain
behaviors, such as extending and crossing legs, clenching
gluteal muscles and the external anal sphincter, and avoiding the squatting position, are compatible with active stool
withholding. These behaviors can be confusing for parents
who may interpret them as strenuous efforts to have a bowel
movement.
394
DIFFERENTIAL DIAGNOSIS
Some of the multiple causes for constipation (Table 1) are
reviewed in this article. Most of the diagnoses discussed are
exceedingly rare. Functional constipation is most common
in childhood.
Functional
Infant dyschezia describes healthy infants younger than
6 months of age who strain excessively with bowel movements. They appear to be in signicant discomfort, often
crying or screaming, turning red in the face, and bringing
their knees up to their abdomens, before eventually passing
soft stools. Symptoms abate following the stool passage.
Infants of this age have not yet coordinated increasing intraabdominal pressure with relaxation of pelvic oor muscles
to have a bowel movement. Infant dyschezia often spontaneously resolves around 6 months of age.
Functional constipation and functional fecal retention
are synonymous and the terms are often used interchangeably. Functional constipation refers to hard or infrequent
TABLE 1.
Differential Diagnosis of Constipation

and Defecation Disorders
FUNCTIONAL
NEUROLOGIC
Infant dyschezia
Hirschsprung disease
Functional constipation
Neuronal dysplasia
Nonretentive fecal soiling
Anal achalasia
Disorders of the spinal cord
Obstructive
Endocrine/Metabolic
Anal stenosis
Hypothyroidism
Anterior displacement
of the anus
Celiac disease
Small left colon syndrome
Diabetes
Meconium ileus
Cystic brosis
Colonic stricture
Medications
Dietary/Allergy
Opioid narcotics
Cow milk protein allergy
Anticholinergic agents
Low-ber diet
Tricyclic antidepressants
Decreased uid intake for

age
Other
Sexual abuse
Chronic intestinal pseudoobstruction
stools in the absence of any other disorders, including neurologic, obstructive, endocrine, or metabolic, and is discussed in
more detail throughout this review.
Neurologic
Hirschsprung disease (HD) is a congenital form of constipation in which the infant or child cannot evacuate stool
due to a lack of ganglion cells in the myenteric and submucosal plexus of the intestinal wall. Without ganglion cells
and nerve bers to innervate the intestinal musculature, the
affected colonic segment remains in a chronic contracted
state.
HD should be considered in any newborn who has delayed passage of meconium (ie, beyond 48 hours after birth).
Age at presentation may depend on the length of the affected
intestine. Infants with long-segment HD develop signs of
distal intestinal obstruction, which may include abdominal
distention, vomiting, irritability, lethargy, and failure to pass
meconium or stool. Enterocolitis with or without bowel
perforation must be considered if the infants develop fever,
bloody diarrhea, and continued abdominal distention. One
of the most serious and possibly fatal complications of
Hirschsprung enterocolitis is progression to toxic megacolon and overwhelming sepsis.
Infants with shorter segments of HD may not be diagnosed until childhood. They may experience intermittent
abdominal distention and severe constipation that is refractory to standard treatment. They may also have poor growth
or failure to thrive due to decreased caloric intake. Only
rarely do children who have HD experience encopresis or
inadvertent leakage of stool.
Anal achalasia is the failure of the internal anal sphincter
to relax despite the presence of ganglion cells on biopsy. It is
unclear if anal achalasia is a variant or mild form of HD.
Neuronal dysplasia and hypoganglionosis are rare disorders involving inadequate or inappropriate numbers of
ganglion cells. These conditions are infrequent and incompletely understood. They can be associated with neurobromatosis, multiple endocrine neoplasia type IIb, or Chagas
disease.
Obstructive
Anal stenosis presents with painful and difcult defecation
in infancy. This is due to the presence of a tight anal opening
or ring.
Anterior displacement of the anus is a congenital variation in the placement of the anus. External anal inspection
can reassure the clinician that anterior displacement is not
present. Theoretically, the anogenital index can be calculated
after careful examination and measurement of the perineum
by dividing the distance (in centimeters) from the vagina or

scrotum to the anus by the distance (in centimeters) from the
vagina or scrotum to the coccyx. The normal anogenital index
in females is 0.30 0.09 and in males is 0.56 0.2. Affected
children have difculty with defecation because they are not
able to straighten the anorectal canal completely due to malposition of the anal sphincter complex in relation to the
anus.
Meconium ileus causes delayed passage of meconium in
children with cystic brosis. It is one of the earliest signs of
cystic brosis and is almost always associated with pancreatic insufciency. The meconium in infants with cystic
brosis is much thicker than the meconium in unaffected
children, which is attributed to an altered ratio of albumin
and water concentrations. The viscous meconium and increased mucus production can lead to partial or total bowel
obstruction. This is often recognized at birth or within the
rst few days of birth.
Strictures can occur anywhere in the intestinal tract. If
they occur more distally, children often have symptoms of
distal obstruction, including lower abdominal pain, abdominal distention, and infrequent or total lack of bowel movements. Strictures can be congenital or acquired due to
necrotizing enterocolitis in infants or inammatory bowel
disease in children and adolescents.
Small left colon syndrome is a rare diagnosis that is most
closely associated with infants born to women who have
diabetes. Infants with signs of distal intestinal obstruction
and a small left colon noted on barium enema should be
screened for HD and cystic brosis because a small-caliber
left colon is a common nding on barium enema due to the
aganglionic segment in HD or as a result of meconium ileus
in cystic brosis.
Other
Hypothyroidism may slow the motility of the gastrointestinal tract, leading to constipation. Other symptoms of hypothyroidism include fatigue; weight gain; shortness of breath;
and changes in the skin, hair, or nails. This constellation of
ndings can help direct appropriate testing.
Celiac disease is an autoimmune sensitivity to gluten and
gluten-containing products in genetically susceptible individuals. The clinical presentation of this disease is so variable that the atypical or nonclassic presentation of celiac
disease is becoming more commonplace. Children may
present with diarrhea, constipation, bloating, abdominal
pain, poor weight gain, short stature, skin rash, or iron
deciency anemia. Evaluation for celiac disease should be
considered in children who have constipation that does not
respond to laxative therapy.
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Chronic intestinal pseudo-obstruction manifests as severe altered motility of the intestinal tract. This rare disorder
can be congenital or acquired. Children with this disorder
experience recurrent signs and symptoms of bowel obstruction, such as vomiting, abdominal pain and distention, and
constipation or diarrhea without an anatomic obstruction.
CLINICAL ASPECTS
Diagnosis of constipation relies foremost on an appropriate
denition, including the symptom-based Rome III criteria
for functional constipation. (5) Rome III denes functional
constipation as two or more of the following (fullled at least
weekly for 2 months) in a child older than 4 years who does
not have irritable bowel syndrome:
1. Two or fewer defecations in the toilet per week.
2. At least one episode of fecal incontinence per week.
3. History of retentive posturing or excessive volitional
stool retention.
4. History of painful or hard bowel movements.
5. Presence of a large fecal mass in the rectum.
6. History of large-diameter stools that may obstruct the
toilet.
Similar age-appropriate criteria are also available for children younger than 4 years. A variety of supplemental tests
should be applied only in the presence of warning signs
or symptoms or with failure of constipation to respond to
typical therapy. Test results should be interpreted in the
context of the patients history and physical examination
ndings, which are sufcient for diagnosis in most
cases.
The clinical history should include a description of stool
frequency and quality, associated symptoms such as abdominal pain and rectal bleeding, growth pattern, continence
and toilet training, presence or absence of withholding
behavior, and symptom onset and duration. Delayed passage of meconium should raise suspicion for HD. Thin,
ribbonlike stools also may suggest HD compared to the
large bulky stools that often are found with functional constipation. Fecal incontinence should be directly assessed in
terms of frequency and quality because it may be concurrent
with constipation due to leakage of liquid stool around a rm
rectal stool mass. Symptoms of overow incontinence typically are small-volume liquid stools, often passed in the
afternoon or during activities and sometimes unrecognized
or ignored by the child. Specic questions, including family
history, should be directed toward exclusion of diagnoses
other than functional constipation.
Standardized measures such as the modied Bristol stool
form scale (6) or Amsterdam infant stool scale (7) allow for
396
a common language and description of stools. These measures can be used in combination with age-appropriate
questions that engage the patient and caregiver in an effort
to overcome barriers of symptom anxiety, embarrassment,
or denial (eg, Does it take you a long time to push poop out of
your body? Does the poop hurt your bottom when it comes
out?). Physically exemplifying withholding behavior during
the interview sometimes provides a moment of clarity for
caregivers who thought such behavior indicated an attempt
at defecation.
Physical examination should explore both the severity of
constipation and potential causes. Ideally, a growth curve
contains data spanning the onset of constipation to determine current parameters as well as past growth velocity.
Observation of the patient should not be underestimated in
its ability to elicit information; interaction between the
patient and caregiver, willingness of the patient to engage
in toileting discussion, and ability to sit and climb on or off
the examination table can provide important diagnostic
clues and sometimes direct treatment strategies. Abdominal
distension, tenderness to palpation, and presence of fecal
mass as well as perianal examination for skin tags, ssures,
and anal appearance and location are important for all new
patients in whom constipation is suspected. External anal
inspection can assess for anal atresia and displacement and
may identify anal ssures, skin tags, or external hemorrhoids. It may also be useful to assess sphincter tone visually
or identify fecal material around the anus or in the underwear. In addition, examining the back for sacral dimples or
spinal deformities and assessing lower extremity motor
tone, strength, and deep-tendon reexes can indicate
whether additional assessment for neurologic pathology is
indicated.
Digital rectal examination (DRE) is important in specic
circumstances but is not always necessary to diagnose functional constipation. Palpation of a rm or large rectal stool
mass on rectal examination often conrms clinical suspicions, abnormalities in sphincteric tone may indicate anal
stenosis, and an empty rectal vault with expulsion of stool on
nger withdrawal is a classic but infrequently seen nding
in HD. Performing a DRE should be left to the discretion of
the clinician. DRE may provoke anxiety or fear in children
who have had past experiences with painful stool passage. It
is important to avoid reinforcing this negative association
when possible and limiting frightening or painful interventions, which can aid in building a therapeutic alliance
between the patient and caregiver.
Laboratory evaluation is not warranted for constipation
unless warning signs are present (Table 2) or other aspects
of the history or physical examination suggest systemic
TABLE 2.
Red Flag Symptoms
Delayed passage of meconium
Failure to thrive
Bloody stools
Severe abdominal distention
Perianal stula
Absent anal wink
Sacral dimple
disease. Constipation rarely is the sole presenting symptom

of hypothyroidism, electrolyte abnormalities, lead toxicity,
or celiac disease, and routine screening for these diseases is
not recommended. Routine allergy testing is also not recommended in evaluation of constipation, and cow milk
protein restriction in young children for a limited time to
assess the clinical response remains controversial.
History and physical examination generally precludes the
need for radiography to diagnose functional constipation.
Although the presence or absence of a fecal mass and
determination of stool burden are important to direct therapy, abdominal radiography is usually not necessary. An
abdominal radiograph may help parents visualize the
amount of retained stool, allowing for a better understanding of constipation (with or without overow) and the proposed treatment plan. A single abdominal radiograph is an
inexpensive, low-risk test, but even when using standardized scales to determine stool burden, it is not clearly
reliable, sensitive, or specic.
The indications for barium enema are extremely limited.
Barium or other contrast enema is suggested but not required when constipation is accompanied by red ag
symptoms (Table 2). It provides information about the
caliber of the rectum and colon and may be useful if obstruction in the colon is suspected. It does not require any
specic preparation and does not subject the patient to risk
aside from radiation exposure. Gastrogran enemas in the
setting of suspected meconium ileus may be diagnostic as
well as therapeutic.
Further diagnostic tests when the clinician suspects HD
depend on patient characteristics (age, health status) and
test availability. Full-thickness rectal biopsy remains the gold
standard for diagnosis and is performed under anesthesia,
but rectal suction biopsy can be performed at the bedside
without adjunct medication and is recommended in lieu of
surgical biopsy as initial evaluation. Although rectal suction
biopsy traditionally is performed in infants, it may also be
sufcient in older children and teenagers. Aganglionosis or

hypertrophied nerves on rectal biopsy hematoxylin and
eosin staining can indicate HD. Although the presence or
absence of these ndings is typically sufcient for determining or ruling out the diagnosis of HD, supplementary
analysis may demonstrate aganglionic intestine with altered
acetylcholinesterase morphology or absent calretinin expression. Anorectal manometry uses a small rectal balloon
and anorectal pressure sensors to determine the presence or
absence of the rectoanal inhibitory reex (relaxation of the
internal anal sphincter in response to rectal distension).
Although not used as an isolated test to diagnose HD, clear
demonstration of the rectoanal inhibitory reex is sufcient
to remove HD from diagnostic consideration.
Anorectal manometry may also have a role in determining rectal sensation threshold and the presence of anorectal
dyssynergia, potentially directing therapy, including the addition of physiotherapy or biofeedback. High-resolution
anorectal manometry with increased number of pressure
sensors and enhanced computer analysis may better delineate anorectal sensory and motor function, but this test is
not widely available in pediatrics.
Spinal imaging, including magnetic resonance imaging,
should be considered in the child with constipation and
other neurologic signs or symptoms, including lower motor
dysfunction, lower urinary tract symptoms, and lumbosacral spinal abnormalities. The neurologic examination may
yield normal results in constipated children with spinal cord
abnormalities, but routine spinal imaging of constipated
children is not recommended.
MANAGEMENT
Constipation and fecal incontinence are clinical issues that
require a thorough understanding of physiology, biology,
behavior, and psychology for effective management. Therefore, a combined treatment approach is recommended. Although no objective clinical trials and data support a single
treatment approach to constipation and fecal incontinence,
we discuss a general management protocol. The management protocol can be divided into four major treatment
components: 1) education about constipation and encopresis,
2) disimpaction or cleanout of stool, 3) maintenance laxative therapy and establishing regular bowel movements,
and 4) behavior modications to improve daily toileting
behaviors.
Education
Education and reassurance comprise the rst component in
the management of functional constipation and encopresis
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397
or fecal incontinence and should continue throughout all

stages of management. Education includes talking with the
parents and the child about constipation and its inuence on
lower gastrointestinal tract functioning and overow and
fecal incontinence. Developmentally appropriate discussion
of the anatomy and physiology of the lower gastrointestinal
tract and defecation is important and visual diagrams can
aid in this education. Many parents of children presenting
with encopresis incorrectly assume that the child is soiling
on purpose. Parents need to be educated that fecal incontinence is often involuntary and the result of overow from
constipation, deconditioning, or altered function of the rectum and pelvic oor as well as learned withholding behaviors in some children. Counseling can be provided to
parents to help them establish a positive and supportive
attitude toward their child during treatment. Counseling
can help remove blame from the child and encourage the
parents and child to join the clinician in addressing the
symptoms. Clinicians should recognize and empathize with
families about the stress and frustration surrounding constipation and fecal incontinence.
Disimpaction or Cleanout
The second component in the management of functional
constipation is removal of the fecal impaction. Such removal
decompresses the rectum, allows for the normal passage of
stool, and prevents liquid stool from leaking around the
fecal mass. If the fecal impaction is not removed, a child
with functional constipation cannot achieve a normal stooling pattern, and fecal soiling may be exacerbated, which is
highly frustrating to parents and children.
Among the approaches to disimpaction are high-dose
oral laxatives, enemas, manual disimpaction, or admission
to the hospital for nasogastric administration of a bowel
cleansing agent. High-dose oral laxatives and enemas are
equally efcacious, but the preferred method for evacuation
of fecal impaction is via the oral route. Minimizing attention
to the anus and rectum via oral laxatives can be important
because these children have a history of unpleasant and
painful experiences associated with defecation. Current recommendations (Table 3) suggest the use of polyethylene
glycol solution (PEG 3350) at doses of 1 to 1.5 g/kg per day for
3 consecutive days (up to 6 consecutive days if necessary) to
achieve disimpaction. If PEG 3350 is unavailable, once-daily
sodium phosphate, saline, or mineral oil enemas for 3
consecutive days are acceptable. Suppositories may be used
in combination with high-dose oral laxatives to help promote evacuation of the fecal impaction. Manual disimpaction is rarely necessary and generally not advised except
in cases of severe impaction and obstipation. If manual
398
TABLE 3.
Medical Therapy for Disimpaction
Oral (preferred)
n
Polyethylene glycol solution 11.5 g/kg/day x 36 consecutive

days
Magnesium citrate 4 mL/kg/day x 2 consecutive days
Rectal
n
Normal saline enema 10 mL/kg x 3 consecutive days
Sodium phosphate enema x 3 consecutive days

24 years: one-half contents of a 2.25-oz pediatric enema
511 years: 2.25-oz pediatric enema
>12 years: 4.5-oz enema
Mineral oil enema x 3 consecutive days

211 years: one-half contents of a 4.5-oz bottle
>12 years: 4.5-oz bottle
Nasogastric (requires hospital admission)

n
Polyethylene glycol solution 2540 mL/kg/hr until rectal

efuent is clear (2448 hr)
disimpaction is required, general anesthesia should be used

to decrease the trauma associated with this procedure.
Maintenance Therapy
The third component in the management of functional
constipation is maintenance laxative therapy to ensure regular passage of soft, appropriate-sized stools. Such maintenance can eliminate painful defecation and prevent the
recurrence of fecal impaction. This component of treatment
may last many months to years and requires ongoing close
follow-up evaluation. Having families use a bowel symptom
tracking form or calendar to monitor the childs response to
treatment may be helpful. Clinicians should emphasize the
need for close monitoring and long-term treatment with
parents because nonadherence to prescribed medications or
discontinuing medications too early can result in the development of hard stools and relapses of withholding, leading
to fecal impaction. The most common medication used for
maintenance therapy is PEG 3350 due to its ease of use,
titratability, low adverse effect prole, and efcacy.
When full evacuation of the rectum consistently occurs
with stooling for 1 to 2 months without any development of
hard stools or withholding behaviors, the laxative medication may gradually be reduced. Early recognition of relapse
by both parents and clinicians is vital to long-term treatment
of functional constipation. Increasing therapy and aggressively treating a relapse can avoid prolongation of the maintenance phase.
Laxatives used for maintenance therapy should be individualized for each patient. Dosing guidelines and recommendations are suggestions for starting therapy (Table 4). In
practice, laxative doses should be titrated to achieve at least
one soft bowel movement every day. Understanding the
mechanism of action of each laxative can aid clinicians in
customizing maintenance therapy because combination
therapy can be useful and necessary.
Osmotic laxatives increase the osmotic load within the
lumen of the intestine, allowing for uid retention. The
retained uid is incorporated into the stool and distends the
colon, promoting peristalsis. Children may experience bloating,
but these laxatives are generally safe; the most common
adverse effect is diarrhea. Examples of osmotic laxatives
include PEG 3350, lactulose, and magnesium products such
as magnesium hydroxide and magnesium citrate.
TABLE 4.
Maintenance Therapy for Chronic

Constipation
Osmotic laxatives
n
Polyethylene glycol 1 g/kg/day
Lactulose 13 mL/kg/day divided into 2 doses
Magnesium hydroxide
<2 years: 0.5 mL/kg/dose
25 years: 515 mL/day once before bedtime or in divided
doses
doses
doses
Stool Softeners/Lubricants
n
Docusate 5 mg/kg/day (up to 400 mg/day)
Mineral oil 13 mL/kg/day divided into 2 doses
Stimulant Laxatives (can be used for rescue therapy)

n
Senna
1 month-2 years: 2.24.4 mg/day at bedtime or in 2 divided
doses
26 years: 4.46.6 mg/day at bedtime or in 2 divided doses
612 years: 8.813.2 mg/day at bedtime or in 2 divided doses
Stimulant laxatives such as bisacodyl or senna irritate

smooth muscle of the colon and stimulate the myenteric
plexus to produce peristaltic activity within the colon. Children may experience abdominal cramping with the peristaltic activity. The abdominal cramping is self-limited and
can be reduced by decreasing the dose. Although stimulant
laxatives are safe, no studies have assessed dependency
with chronic daily use. Stimulant laxatives can generally be
reserved for intermittent use and rescue therapy.
Stool softeners decrease the surface tension of the stool,
which allows integration of more water into the stool, thereby
softening it. Docusate has a modest stool softening effect. It is
generally safe, with minimal adverse effects.
Mineral oil may ease the passage of stool by lubricating
the intestine and decreasing water absorption. A common
complaint with use of mineral oil is leaking of the oil from
the rectum, which can be unpleasant. Palatability of mineral
oil is also a challenge for many children. Oral mineral oil is
contraindicated in children younger than age 1 year or with
known or suspected aspiration.
Dietary modication is frequently considered for treatment, but increasing uid or ber intake has unclear
efcacy in constipated children. Maintaining adequate
hydration is important for a variety of physiologic functions
and, in most cases, is a safe recommendation. However,
solely increasing uid intake should not be expected to alter
stooling frequency or consistency. Fiber is often chosen as
rst-line therapy in constipated adults, but recent reviews of
evidence cast some doubt on its effectiveness. Dietary ber
intake may be reduced in constipated children compared to
those without constipation, but increasing ber does not
clearly improve symptoms and is not recommended as
therapy based on current evidence. Fiber also may be tolerated less well than other therapies for constipation in
children. Although complications related to ber therapy
are unusual, use of ber as monotherapy may delay implementation of effective treatment and prolong patient
symptoms. Growing evidence supports probiotic and prebiotic use as treatment in adult constipation. These agents
may reduce whole-gut transit time, increase stool frequency,
and reduce constipation-associated symptoms. However,
evidence in pediatrics demonstrates mixed efcacy and their
use is associated with additional patient expense, possibly to
the exclusion of other effective therapies.
>12 years: 17.626.4 mg/day at bedtime or in 2 divided doses
Behavior Modication
Bisacodyl
The fourth treatment component is behavior modication

to improve daily toileting habits and routines. This component should be started at the time of bowel disimpaction or
cleanout and continue throughout maintenance treatment.
312 years: 510 mg/day

>12 years: 515 mg/day
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Research regarding specic behavioral treatments for encopresis is disjointed and difcult to synthesize based on
recent reviews. However, the use of operant procedures
(incentive/reward programs and positive reinforcement)
for goals related to toileting and cleanliness have empiric
support. Incentive/reward systems can be used to target
various goals related to successful toileting. The targets of
intervention may vary with individual children. Rewarding the patient for cooperation with the components of
the treatment regimen and NOT just for proper elimination in the toilet is important. Children must achieve
important goals or behavioral skills on the way to successful toileting, such as gaining condence and compliance
with toilet sitting, responding appropriately and honestly
to soiling accidents, and learning effective pushing
techniques to produce complete and emptying bowel
movements.
An important part of the standard medical-behavioral
treatment of encopresis is improving toilet sitting behavior.
However, stool withholding and toileting refusal behaviors
may interfere with progress toward toilet sitting goals and
sometimes must be addressed before implementing a toilet
sitting plan. Stool withholding and toileting refusal are
believed to be related to the history of difcult-to-pass or
even painful bowel movements and are often conceptualized as an anxiety or phobia about passing bowel movements, especially into the toilet. The initial focus of stool
withholding management should be to ensure soft and easyto-pass bowel movements so that the child can gain comfort
in passing a bowel movement on a daily basis. In early stages
of treatment, bowel movements in a pull-up or diaper may
need to be reinforced for the child to gain condence and
voluntarily relax the pelvic oor to achieve a bowel movement. Toilet refusal behavior should also be treated with
interventions that gradually desensitize children toward
toileting. Desensitization to the toilet may include rewarded
trips to the bathroom to look at the toilet, stand by the toilet,
sit on a closed lid fully clothed, and eventually sit on the toilet
with open lid and pants down. Once the child is having
bowel movements comfortably in the diaper or a pull-up and
able to sit on the toilet without signicant anxiety, parents
can use a shaping procedure to encourage bowel movements closer to the toilet and eventually into the toilet.
Reward systems or incentives are used to encourage
children to take a next step toward successful toileting
behavior.
Once the child is comfortable and compliant with sitting
on the toilet, the overall goal is to improve daily toileting
habits and routines. Empiric evidence suggests that operant
procedures or reward systems should be an active part of
400
a toilet sitting schedule. Scheduled toilet sits can occur 20 to

30 minutes after meals to take advantage of the gastrocolic
reex. In addition, pairing toilet sitting with meals is easier
to build into the family routine and can create a behavioral
stimulus condition for bowel movement success. The time
on the toilet should be unrushed and positive. It may include
special activities that are only available while on the toilet
(special books, toys, or handheld electronics). Parents can
also be counseled to provide modeling and coaching during
toilet sitting, which includes the parents showing the child
when they sit on the toilet and that they are pushing to help
get bowel movements out in the toilet. Toilet sits should
generally last 5 minutes, but some children need to gradually work their way up to longer sits if there is initial
resistance. Scheduled, rewarded toilet sits should include
small stepstools to assist the children in getting on the
toilet and to use as leverage for their feet. We recommend
a wider stepstool or potty stool to allow the child to spread
out the feet and knees for better posture to allow successful
defecation and for them to feel more comfortable and
balanced on the toilet. Once children are having more
productive bowel movements in the toilet and soiling
has stopped for a 1 month, the number of daily toilet sits
can be reduced. Often parents can observe which toilet sits
during the day are most productive and begin focusing on
those sits. As treatment progresses, children can start to
earn incentives/rewards for independently going to the
toilet when they feel the urge to have a bowel movement
rather than strictly relying on the schedule and parental
prompt.
Involving the preschool, kindergarten, or school in scheduled and rewarded toilet sitting is important. Children who
are apprehensive about completing toilet sits at school benet from a more private restroom so that they can take their
time and be comfortable with toileting. It also is helpful to
allow an anytime bathroom pass for children when they
start school so that they do not withhold stool when they
need to have a bowel movement.
Due to the biopsychosocial nature of functional constipation and fecal incontinence, multidisciplinary or even
interdisciplinary care is becoming more common and is
highly recommended when available. The combination of
medical therapy, behavioral modication, and supportive
counseling has the greatest success in the treatment of
constipation and encopresis. When multidisciplinary or
interdisciplinary care is not readily available, clinicians
can still effectively treat this condition with a basic understanding of behavior modication techniques, such as the
use of incentives/rewards and gradual setting of goal related
to effective toileting.
PROGNOSIS
The overall prognosis for functional constipation has not been
completely established. However, a general message for families is that the treatment of constipation and encopresis often
requires many months of medication and behavior modication. In addition, relapse of symptoms is very common.
According to a recent systematic review, approximately 60%
of children with functional constipation are symptom-free
between 6 and 12 months after beginning treatment regardless of laxative use, with the remaining 40% of children still
experiencing symptoms. (8) In addition, a study in Pediatrics
concluded that 25% of children with functional constipation
continue to experience symptoms into adulthood. (9) Older
school-age children and adolescents who have ongoing constipation and encopresis are even more difcult to treat. All
these points highlight the need for aggressive treatment as
early as possible as well as close follow-up evaluation and
adjustments to the treatment plan. Nonetheless, most children with constipation and encopresis can be managed
effectively by the general pediatrician. Indications for referral
to a pediatric gastroenterologist include medical red ags,
trouble with disimpaction, trouble establishing maintenance therapy, and lack of improvement after 6 months
of therapy. Referral to a pediatric behavioral specialist
should be considered if signicant conditions are interfering
with treatment, such as attention-decit/hyperactivity disorder, oppositional behaviors, anxiety or mood disorders, family
conict or parent-child conict, or problems with adherence

to recommendations.
Summary
The following summary statements are based primarily on
consensus and expert opinion due to the lack of relevant clinical
studies. A recent comprehensive review of the literature by Tabbers
et al, in the Journal of Pediatric Gastroenterology and Nutrition,
identied no moderate- or high-quality evidence regarding
therapeutic interventions for the evaluation and treatment of
functional constipation in infants and children.
The presentation of constipation varies, but constipation should
be identied according to an appropriate denition, which
includes the symptom-based Rome III criteria.
Constipation is prevalent in children and infrequently a result of
underlying intestinal or systemic disease.
Based on limited evidence as well as consensus, history and
physical examination are sufcient to provide a diagnosis of
functional constipation; digital rectal examination, laboratory
tests, and abdominal radiography are generally not necessary.
Treatment of constipation requires four components: education,
disimpaction, maintenance therapy, and behavioral modication.
References for this article are at http://pedsinreview.aappublications.org/content/36/9/392.full.
Vol. 36 No. 9
SEPTEMBER 2015
401
PIR Quiz
1. By what age do children have a pattern and frequency of bowel movements similar to
those of adults?
A.
B.
C.
D.
E.
Three years.
Four years.
Five years.
Six years.
Seven years.
2. Which of the following is more characteristic of behavior by children with delayed bowel
training versus children with encopresis?
A.
B.
C.
D.
E.
Have difculty feeling the indication to stool.

Generally do not have accidents with formed stool.
Often use the toilet to pass formed or semiformed stool.
Usually have regular bowel movements in the diaper or underpants.
Pass liquid/soft stool in their underpants.
3. A 4-month-old girl presents with substantial straining with bowel movements. She cries
and turns red in the face just before she passes a soft stool, after which she relaxes. Which
of the following is the most likely diagnosis for this infants signs and symptoms?
A.
B.
C.
D.
E.
Anal achalasia.
Functional constipation.
Hirschsprung disease.
Infant dyschezia.
Neuronal dysplasia.
4. A 3-day-old term infant has had delayed passage of meconium. At 48 hours, he passed
a small, thick stool. Which of the following is the most likely diagnosis?
A.
B.
C.
D.
E.
Anterior displacement of the anus.

Celiac disease.
Cystic brosis.
Hirschsprung disease.
Hyperthyroidism.
5. An 8-year-old boy with chronic constipation and encopresis has been successfully treated
with education and disimpaction. Which of the following medications is most commonly
used for maintenance therapy due to its ease of use, titratability, low adverse effect prole,
and efcacy?
A.
B.
C.
D.
E.
402
Lactulose.
Magnesium hydroxide.
Mineral oil.
Polyethylene glycol solution.
Senna.
learners must
or higher on this
assessment, which
than 60% on the
given additional
achieved.
which the learner
completes the quiz.
Patient Safety and Quality Improvement:

Terminology
Lucy Pereira-Argenziano, MD,* Fiona H. Levy, MD*
*Department of Pediatrics, NYU School of Medicine, New York, New York.
Education Gap
Medical errors and unintended harm continue to occur, despite
preventive strategies. Understanding terminology and key attributes of
improving safety can lead to creation of systems to reduce medical errors
and preventable harm.
Objectives
After completing the article, the reader should be able to:
1. Understand and apply common terms used during discussions of

safety and quality.
2. Describe common types of error and harm in pediatrics.
3. Describe the pediatric response to Institute of Medicine
recommendations.
4. Understand attributes of high-reliability organizations and how their
principles can be used to improve patient safety.
BACKGROUND
AUTHOR DISCLOSURE Drs PereiraArgenziano and Levy have disclosed no

The patient safety movement was galvanized by publication of To Err is Human by the
Institute of Medicine (IOM) in 1999. (1) The report estimated that 44,000 to 98,000
people die in US hospitals each year as a result of medical errors. Equally interesting and perhaps as important to the magnitude of preventable injury occurring to
patients in the United States is the fact that much of the data used as the basis for
these estimates had been published and available in 1991. (2) The economic impact
of medical errors has equally alarming implications for both health systems and
consumers. Researchers analyzed clinical and billing data from a hospital database
containing information from 600 hospitals and ambulatory surgery centers within
the United States for visits in which injury occurred as a result of medical error. (3)
A cost analysis was performed for each injury visit. Extrapolation of the data to the
broader US population estimated the cost of medical errors to the US health-care
system to have been $1 billion in 2009. Because the study focused solely on inpatient
costs of medical errors and did not account for societal impacts such as time lost from
work, this is likely an underestimate of the true cost of medical errors.
With the publication of To Err is Human and resulting attention of both the
press and the public, the medical community was held accountable to address
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403
recommendations for improvement. The stated intent of the

IOM recommendations was to achieve a synergy between
the external pressures of regulatory, governmental, and
purchasing organizations and the internal motivations of
clinicians, organizations, and professional societies working to improve the safety of care at the point of delivery.
Three of the four key strategic recommendations to achieve
safer care can be broadly summarized as: (1)
1. Develop mandatory and voluntary reporting systems to
allow both the identication of and learning from
medical errors.
2. Encourage external oversight organizations, professional
groups, and group purchasers of health-care to raise
performance standards and set expectations of improved
patient safety.
3. Design and implement safety systems in health-care
organizations to ensure safe practices at the delivery
level.
TERMINOLOGY
Clarifying terminology is important because there is significant overlap and variation among medical errors, adverse
events, and preventability. Probably the best and most
widespread denitions come from the IOM.
Medical Error
A medical error has been dened by the IOM as a failure to
complete a planned action as intended or the use of a wrong
plan to achieve an aim. (1) A medical error does not always
lead to patient harm because it may not reach the patient and
it may not be such a critical aspect in the process of care as to
injure the patient (Figure). However, that statement does not
mean that clinicians should not track and seek to understand all medical errors. A near miss is a medical error that
has the potential to cause patient harm but has not. (4) The
knowledge that something kept the error from reaching the
patient provides an excellent opportunity to learn about
processes of care; understanding how we intentionally or
accidently prevent an error from reaching a patient allows
clinicians to improve safety systems. An adverse event is
a medical error in management or intervention that leads to
patient injury (1)(4) and results in prolonged hospitalization
or the presence of a disability at hospital discharge.
Sentinel Event
A sentinel event is a term coined and dened by the Joint
Commission as an unexpected occurrence involving death
or serious physical or psychological injury, or the risk
thereof. (5) Individual health-care organizations have the
404
responsibility of dening serious physical or psychological

injury, but the intent is to capture injuries of permanence and
signicance, such as loss of limb or function. The phrase or
the risk thereof can be thought of as a near miss, where the
risk and potential consequences of a recurrence may lead to
a serious adverse outcome. Of note, a sentinel event may or
may not be due to a medical error. Once a sentinel event has
been identied, the Joint Commission mandates that an
investigation be immediately undertaken to determine the
root causes that have led to the event as well as implementation of an action plan and monitoring to minimize future risk
that this event will recur. The information is reported to the
Joint Commission Sentinel Event Database. Aggregate sentinel event data are reviewed by the Joint Commission for
trends of root causes or risk-reduction strategies. Events that
demonstrate either frequency or high risk are shared with
hospitals and the public via Sentinel Event Alerts. Examples
of pediatric-specic Sentinel Event Alerts include: Preventing pediatric medication errors and Revised guidance to
prevent kernicterus. (6) Aggregate data from the Sentinel
Event Database are also used to guide development of
National Patient Safety Goals (NPSG). (5)
MEDICAL ERRORS IN PEDIATRICS

Medical errors can be categorized as diagnostic, treatment,
and preventive. (7) Errors can be further categorized as
preventable and nonpreventable.
Diagnostic Errors
Malpractice claims have been used to extrapolate the distribution of pediatric medical errors. According to analysis by
the Physician Insurers Association of America, diagnostic
errors in the form of missed or incorrect diagnosis account
for most pediatric malpractice cases. (8) Pneumonia, meningitis, appendicitis, and testicular torsion were among the
diagnoses most frequently associated with diagnostic errors
in medical malpractice claims. (9)(10) In an attempt to
elucidate pediatricians perceptions and experiences with
diagnostic errors, Singh et al (11) conducted a multicenter
survey. More than 50% of surveyed pediatricians reported
making a diagnostic error at least once per month, with
misdiagnosis of a viral illness as a bacterial illness as the
perceived most frequent diagnostic error. Misdiagnosis of
otitis media with effusion as acute otitis media is an example
of a viral illness diagnosed as a bacterial illness.
Treatment Errors
Medication errors are an example of treatment errors.
The National Coordinating Council for Medication Error
Figure. Medical errors.
Reporting was convened in 1995 with representation from

multiple interdisciplinary agencies in an attempt to encourage
reporting and prevention of medication errors. (12) The
Council developed an Index for Categorizing Medical Errors
to provide a standard method for categorizing and tracking
errors. The Index classies medical errors as A through I,
according to whether or not they reached the patient, and if
they reached the patient, the progressive degree of resultant
harm. Medication errors classied in categories E through H
are associated with increasing severity of patient harm, with
the ultimate outcome of death in category I. A chart review
from 12 childrens hospitals throughout the United States
found the incidence of medication errors resulting in patient
harm (category E or greater) to be 11.1 per 100 patients or 15.7
per 1,000 patient-days. (13) Analysis of the events revealed
ordering and monitoring as the stages of medication management that are most prone to preventable error.
Pediatric medication management is especially complex
because of calculations necessary for weight-based dosing,
off-label use of medications, compounding and dilution
needed for medication preparation, and limited ability of
young patients to communicate. (14)(15) Within pediatrics,
patients in the neonatal intensive care unit are particularly
vulnerable due to frequent changes in medication dosing
weights and altered pharmacokinetics leading to variation
in medication metabolism. (14)(16)
Preventive Errors
Preventive errors encompass failure to provide a prophylactic treatment. Examples of preventive errors have been seen
in perinatal hepatitis B prevention. Neonates born to women
infected with hepatitis B require immunoprophylaxis after
delivery. Without appropriate treatment, approximately
40% of exposed infants are estimated to develop chronic
hepatitis B infection. (17) The Immunization Action Coalition
reported approximately 500 cases of hepatitis B perinatal
prevention errors between July 1999 and October 2002. (18)

The errors reported included: infants born to [hepatitis B
surface antigen] HBsAg-positive mothers did not receive both
hepatitis B vaccine and [hepatitis B immune globulin] HBIG
within 12 hours, Infants born to mothers of unknown
HBsAg status were not properly prophylaxed, and screening test results were misordered, misinterpreted, mistranscribed, or miscommunicated. In response to the errors
reported, the Centers for Disease Control and Prevention
Advisory Committee on Immunization Practices updated
recommendations to prevent hepatitis B transmission,
including universal hepatitis B vaccination at birth. (19)
The Committee also provided strategies to aid in implementation of the recommendations, such as the inclusion of
hepatitis B vaccine as a standing order at birth.
Preventable and Nonpreventable Medical Errors

Medical errors of all types can be further classied as
preventable and nonpreventable. Making this distinction
allows targeted efforts to eradicate preventable errors and
any associated harm, with less focus on nonpreventable
errors. Equally important is the determination of whether
patient harm is preventable or nonpreventable.
An example of nonpreventable error may be an adverse
drug event (ADE), such as a patient without a history of
a medication allergy developing an allergic reaction after
administration of a medication. Although the patient may be
harmed by the event, the event was not preventable because
the allergy was previously unknown. In contrast, if a patient
has a known medication allergy and the medication is
administered, a preventable error has occurred.
Patient harm may also be designated as preventable or
nonpreventable. Nabhan et al (20) performed a literature
review to determine common themes used to designate
a harm event as preventable. According to these authors,
presence of an identiable modiable cause, reasonable
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405
adaption to a process will prevent future recurrence and lack

of adherence to guidelines implies preventability.
The concept of the preventability of patient harm has led
to a modied and enhanced approach to patient safety in
hospitals. In 2008, Nationwide Childrens Hospital set
a 5-year goal to eliminate preventable harm within their institution. The journey to elimination of preventable patient
harm included a cultural change based upon the principles
of high-reliability organizations (HROs). (21) HROs are typically found in the arenas of nuclear power, naval aircraft
carriers, and commercial aviation. (22) Many organizations
have begun to test and study how these cultural underpinnings of HROs might be brought to the world of healthcare and improve the safety of patient care. HROs are
governed by ve key principles: three of anticipation and
two of containment (Table 1). (23)
To achieve both the preoccupation with failure and the
sensitivity to operations, transparency of information about
the system in which people work is required. Deviations of
performance or errors are transparently shared with members of the HRO. To achieve this, Nationwide Childrens
Hospital developed and implemented a Preventable Harm
Index (PHI). (21) The PHI is composed of the number of
harm events that occur in eight different categories, including
hospital-acquired infections, ADEs, preventable non-intensive
care unit cardiac arrests, signicant postsurgical complications, serious falls, pressure ulcers, and miscellaneous
TABLE 1.
Principles of High-reliability
Organizations
Principles of Anticipation:
1. Preoccupation with failure: Identication of failures and signs
of system weakness are embraced.
2. Reluctance to simplify: Simplication of factors leading to
a failure may lead to missed identication of factors and
opportunities for improvement.
3. Sensitivity to operations: Attention is paid to what is
occurring in the system rather that what is supposed to occur
and recognition that accidents are the consequence of
multiple errors.
Principles of Containment:
1. Commitment to resilience: Ability of a system to recover after
an error has occurred.
2. Deference to expertise: Acknowledgement that knowledge
and decision support are needed and sought based on level of
expertise, not hierarchy.
Adapted from Weick K, Sutcliffe K. Managing the Unexpected. 2nd
edition. San Francisco, CA: Copyright (c) 2007 by John Wiley & Sons, Inc.
All rights reserved.
406
signicant harm and serious safety events. (21) In 2008,

teams were established to work on reducing each category of
patient harm. Through cultural transformation, the work of
quality improvement teams, and the measurement and sharing of the PHI, Nationwide Childrens Hospital experienced
a signicant decrease in preventable harm events and patient mortality. (21) Similar organization-wide initiatives to
decrease preventable harm in children also were successful at
institutions such as Cincinnati Childrens Hospital (24) and
Helen DeVos Childrens Hospital. (25)
Interestingly, the designation of harm as nonpreventable
may change over time. Events that are currently determined
to be nonpreventable may become preventable if additional
knowledge is acquired or new standards of care are established. (26) An example of preventable harm that previously
was believed to be the price of being sick and in an intensive
care unit and, therefore, nonpreventable is central lineassociated blood stream infections (CLABSI). Central line
insertion and maintenance bundles emerged from collaborative efforts and sharing of data. (A bundle is a structured
approach to improving processes of care and patient outcomes.) As the bundles were tested and the incidence of
CLABSI was signicantly decreased, (27) use of bundles as
well as certain components of the bundle have become the
standard of care. The presence of guidelines that have been
found to prevent the occurrence of CLABSI has led to the
designation of CLABSI as preventable harm.
MEDICAL ERRORS UNDERSTOOD THROUGH PROCESS

ANALYSIS
The occurrence of a medical error is often multifactorial and
requires multiple small deviations to occur in sequence,
leading to the larger event. The Swiss Cheese Model developed by James Reason can be used to illustrate how a medical
error occurs. (22) In the model, every step in a process (the
process of care in the case of medical errors) is represented
as a slice of Swiss cheese. Each step in the process can
prevent or facilitate an error reaching a patient and causing
harm. When the process works well, the cheese is intact and
blocks errors from reaching patients. When processes of
care are awed (represented by holes in the cheese), they
provide avenues for errors to reach the patient and cause
harm. When all of the steps are placed together, if some of
the holes align through the successive layers, the error
reaches the patient. The opportunity to study errors from
the perspective of processes and system analysis after real
and near-miss events allows for redesigning of systems of
care that can prevent the recurrence of adverse or sentinel
events in the future.
The importance of process analysis can be illustrated by

the example of a prescriber making an error when entering
a medication order into a computerized physician order
entry (CPOE) system. Normally the rst barrier to keep this
error from reaching the patient might be the CPOE system.
In this case, the CPOE system was not designed with
safeguards for this medication, so the error passes through
the rst barrier (it nds the hole in the Swiss cheese). The
next barrier could be a pharmacist who needs to verify all
orders. On this day, a covering pharmacist who is unfamiliar
with pediatrics approves the medication. The error has
moved through two intended barriers or safeguards. Finally,
the medication is picked up by the nurse, who normally
would have checked and rejected the medication. However,
on this day the patient care unit is very busy and loud and the
nurse is continually interrupted while checking this unusual
medication before administering it. Thus, a simple error
made by a prescriber passes through all of the safeguards
between the error and the patient.
The next step is to understand how the processes broke
down and allowed this medication error to happen. What is
wrong with the design of CPOE system and what needs to be
xed? What processes are in place to orient new pharmacists
to the pediatric pharmacy to prevent error? How is the
clinical unit designed to ensure that nurses have the uninterrupted time and space to check all medications thoroughly? Process analysis allows clinicians to determine
the real causes of error (latent failures) and focus on how
to x systems rather than punish individuals.
DEVELOP REPORTING SYSTEMS FOR MEDICAL ERRORS

The ability to detect and report medical errors is critical to
improving the safety of care. Error reporting via voluntary or
mandatory reporting systems allows for review of factors that
have contributed to an error (actual or near miss), and the
subsequent development of risk-reduction strategies can help
prevent the recurrence of a similar event. (28)(29) Understanding and implementing a plan to address barriers to error
reporting, including difculty with error detection, can enhance
the use of reporting systems and, therefore, learning potential.
Voluntary Error Reporting

Voluntary incident reporting systems are used in health-care
to report the occurrence of errors. Frequently, the errors
reported have resulted in little or no patient harm, but they
provide critical information necessary to drive performance
improvement and improve patient safety. (1) Voluntary
reporting systems, although useful, have limitations. In
2004, Tayor et al (30) surveyed 200 physicians and nurses
at a large childrens hospital. Fewer than 50% of the respondents indicated that they completed incident reports on
80% or more of the errors they committed. Approximately
one third of respondents indicated that they completed an
incident report for fewer than 20% of the errors they
committed. When evaluating per discipline, nurses were
more likely to report their errors than physicians.
To understand barriers to the use of voluntary incident
reporting systems, physicians and nurses have been surveyed regarding their practices of and beliefs about error
reporting. (31) The barriers encountered by each discipline
varied. Physicians most frequently identied lack of feedback, incident form takes too long to complete, and a belief
that an event was too trivial as barriers. Nurses identied
lack of feedback, a belief that there was no point in reporting
near misses, and forgetting to make a report when ward was
busy as the most common barriers to error reporting.
Concern about legal implications from the generation of
an error report, (32) lack of physician access to electronic
incident reporting systems, interruption of patient care to
complete incident report, and concern that reporting may
result in punitive action have been identied as additional
barriers to voluntary incident reporting systems. (33)
Physicians surveyed identied changes to voluntary reporting systems that may increase reporting of medical
errors. Recommendations include: education about which
errors should be reported, feedback on a regular basis about
errors reported and about individual events, evidence of
system changes because of reports of errors, and electronic
format for reports. (30) In addition, the Agency for Healthcare Quality (AHRQ) has recommended key components to
increase the effectiveness of an error reporting system. (34)
The components include: generation of error reports by
a wide range of employees, protecting the condentiality of
the author of the incident report, implementation of a system to review events, performing analysis, implementation
of risk-reduction strategies, and timely feedback to staff.
Enhanced Error Detection

The strength of a voluntary reporting system is dependent
on the ability to detect medical errors. The Institute for
Healthcare Improvement (IHI) developed trigger tools to
complement error detection. Triggers are occurrences that
may signify the presence of an error if present in a medical
record. Examples of triggers include the use of naloxone,
a rising creatinine value, hyperglycemia, and unexplained
return to surgery. (35) Identication of a trigger prompts
further evaluation of the medical record to determine
whether a medical error has occurred. Evaluation of trigger
tools may be manual or automated. Manual detection
Vol. 36 No. 9
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407
requires that a trained reviewer audit a sample of charts for

the presence of a trigger. If a trigger is identied, the chart
is reviewed in depth to determine if a medical error has
occurred. Currently available pediatric-specic trigger tools
through the IHI include the Pediatric Trigger Toolkit: Measuring Adverse Drug Events in the Childrens Hospitals (36)
and Trigger Tool for Measuring Adverse Events in the
Neonatal Intensive Care Unit. (37) Examples of triggers in
the Pediatric Trigger Toolkit include administration of
diphenhydramine, rash, and hyperkalemia. (36)
The Childrens Health Corporation of America developed and tested a pediatric-specic trigger tool for ADEs.
(13) A manual retrospective chart review was conducted to
identify the presence of triggers. Identied triggers, including administration of diphenhydramine, presence of rash,
and hyperkalemia, prompted an in-depth review for ADEs.
The study determined that the mean ADE rate was 11.1 per
100 patients and 15.7 per 1,000 patient-days. Only 3.7% of
the ADEs identied using the trigger tools were also identied by the voluntary reporting system. (13)
Although manual identication of triggers improves
error detection, it only samples a small number of charts
and is labor intensive. Automated adverse event detection
(AAED) uses algorithms to identify triggers in the electronic
health record on a continual basis, thereby enabling auditing of all charts. As with manual detection, once a trigger is
identied, a chart review is conducted for evaluation of
a potential medical error. Lemon and Stockwell (38) published results with use of AAED over a 4-year period. Of the
triggers identied, 34% identied adverse events. Only 3%
of the adverse events found using the AAED were also
identied by the voluntary reporting system.
Mandatory Error Reporting

State law may require reporting of sentinel events and
adverse events leading to signicant patient harm. The
New York Patient Occurrence Reporting and Tracking
System (NYPORTS) is an example of a state-led mandatory reporting system. (39) Requirements for reporting to
NYPORTS include: deaths not related to anticipated disease
progression, medical equipment malfunction or misuse
leading to serious patient harm or death, and discharge of
a patient incapable of making medical decisions to an unauthorized person. Trending of NYPORTS data allows for
identication of opportunities for quality improvement
within an institution and throughout the system. Successful
institution of preoperative protocols to decrease the incident
of wrong-site surgery, wrong-site procedure, and procedure
on the wrong patient is an example of an initiative driven by
NYPORTS data. (40)
408
Mandatory error and adverse event reporting is also used

by the US Food and Drug Administration (FDA). The FDA
is responsible for review of medical equipment to ensure its
safety and effectiveness before approval for use. After
approval, monitoring for device safety with the use of an
event reporting system continues. Mandatory Medical
Device Reporting mandates device user facilities, which
include hospitals and outpatient treatment facilities, to
report any serious injuries or deaths that may be attributed
to the use of medical equipment. (41)
Medical Error Reporting to Share Lessons Learned

Because the occurrence of medical errors at each institution
is relatively small, the knowledge gained through collaboration and sharing of information among institutions can
greatly enhance the speed of error prevention. In 2005,
Congress approved the Patient Safety and Quality Improvement Act. The Act provides condentiality protection to
members of Patient Safety Organizations (PSOs), allowing
for sharing of medical errors and safety events. Currently,
80 PSOs are listed with the AHRQ. Pediatric PSOs include
Safe Pediatric Health Care PSO, Child Health Patient Safety
Organization, and Wake Up Safe. (42)
Wake Up Safe is a quality improvement initiative of the
Society for Pediatric Anesthesia. The initiative contains
a registry of serious safety events that have occurred in
pediatric anesthesia. The knowledge gained in the analysis
of serious safety events is shared with members of the PSO
and used to drive learning and safety initiatives. (43)
The AHRQ has established common formats, which serve
as a standard for reporting and analyzing patient safety events.
PSOs use common formats for submission and reporting of
events. Common formats are available for falls, health-careacquired infections, blood or blood product events, medication
or other substance events, perinatal events, surgery or anesthesia events, and venous thromboembolic events. (44)
ENCOURAGE EXTERNAL OVERSIGHT ORGANIZATIONS,

PROFESSIONAL GROUPS, AND GROUP PURCHASERS
TO RAISE PERFORMANCE STANDARDS AND SET
EXPECTATIONS OF IMPROVED PATIENT SAFETY
Standards and expectations for patient safety may be set by
accrediting organizations such as the Joint Commission
through the development of the NPSG. More recently,
the work of pediatric networks, exemplied by the Childrens Hospitals Solutions for Patient Safety (CHSPS), have
applied standard bundles for hospital-acquired conditions
and complementary work on the culture of safety to improve
patient outcomes.
National Patient Safety Goals

In 2002, the Joint Commission established the NPSG program to enhance patient safety across all accredited healthcare organizations (Tables 2 and 3). (45) An advisory group
that includes nurses, physicians, pharmacists, risk managers, and clinical engineers identies patient safety concerns
throughout the health-care system and potential solutions.
Specic patient safety goals are established for ambulatory
health-care, behavioral health-care, critical access hospitals,
home care, and hospice. Every 2 years these goals are
reviewed and revised. Once a goal has become an accepted
standard of practice, it and its assigned goal number are
removed, so the goals are not numbered sequentially. Accredited health-care organizations are required to establish
NPSG as organizational priorities and develop policies and
procedures to ensure compliance.
Childrens Hospitals Solutions for Patient Safety

In 2009, the childrens hospitals in Ohio joined together to
create the Ohio Childrens Hospitals Solutions for Patient
Safety, a collaborative to improve patient safety. The initial
focus was to decrease surgical site infections and ADEs,
which subsequently expanded to the goal of eliminating
serious harm. The success of the collaborative, which demonstrated a 40% reduction in serious harm events and 55%
reduction in serious safety events, prompted the support of
the Centers for Medicare and Medicaid Services Innovation
Center in 2012, allowing collaboration to spread to hospitals
outside of Ohio. (46) Currently the network, renamed as
CHSPS, comprises more than 80 childrens hospitals
throughout the United States. (47) Current goals of the
network include: 40% reduction in hospital-acquired
TABLE 2.
2015 National Patient Safety Goals for

Hospitals
Goal 1: Improve the accuracy of patient identication

Goal 2: Improve the effectiveness of communication among
caregivers
Goal 3: Improve the safety of using medications
TABLE 3.
2015 National Patient Safety Goals for

Ambulatory Care
Goal 1: Improve the accuracy of patient identication

Goal 3: Improve the safety of using medications
Goal 7: Reduce the risk of health care associated infections
UP 01 Universal Protocol for Preventing Wrong Site, Wrong
Procedure, and Wrong Person Surgery
Adapted from The Joint Commission. Hospital: 2015 National Patient
Safety Goals. http://www.jointcommission.org/ahc_2015_npsgs/.
Accessed Aug. 6, 2015.
conditions, 20% reduction in readmissions, and a 25% reduction in serious safety events. (48) The hospital-acquired
conditions that form the current focus of CHSPS are: CLABSI,
catheter-associated urinary tract infections, ventilatorassociated pneumonias, ADEs, injuries from falls, pressure
ulcers, surgical site infections, preventable readmissions,
venous thromboembolism, and obstetric adverse events.
The shared belief in the principle All Teach, All Learn
allows hospital teams to share lessons learned with one
another to promote safety and improved outcomes for all.
IMPLEMENTING SAFETY SYSTEMS IN HEALTH-CARE

ORGANIZATIONS TO ENSURE SAFE PRACTICES AT THE
DELIVERY LEVEL
Health-care organizations strive to create a safe system and
environment for all patients and employees. Despite great
efforts and devotion by members of health-care teams, tools
to ensure safety of care must be developed and implemented. The military and aviation industries perform
incredibly difcult processes under stress yet have implemented processes and protocols to ensure the safety of their
employees and others. (22) Some of the tools that have been
adapted for use in health-care include: checklists, TeamSTEPPS, and CPOE. Fostering a culture of safety within an
organization is an integral component of preventing medical errors and reducing patient harm.
Goal 6: Reduce the harm associated with clinical alarm systems

Goal 7: Reduce the risk of health care associated infections
Goal 15: The hospital identies safety risks inherent in its population
UP 01: Universal Protocol for Preventing Wrong Site, Wrong
Procedure, and Wrong Person Surgery
Adapted from The Joint Commission. Hospital: 2015 National Patient
Safety Goals. http://www.jointcommission.org/hap_2015_npsgs.
Accessed Aug. 6, 2015.
Checklists
A checklist contains a listing of tasks that must be completed
to ensure accuracy and safety. Checklists have been used in
aviation since the 1960s. The aviation industry realized that
checklists play a vital role in ensuring safety by providing
a list of tasks that must be completed before engine starts,
takeoff, and landing as well as tasks for in-ight procedures
and emergencies. The checklist ensures that the same
Vol. 36 No. 9
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409
process is followed consistently each time without reliance

on human memory, allows for mutual checking, and enhances communication among crew members. (49)
The role and importance of checklists in ensuring safety
has been recognized by the health-care industry. In 2007,
The World Health Organization launched the Safe Surgery
Saves Lives Campaign in response to an estimated 7 million
surgical complications per year worldwide. The initial study
included hospital representation from Toronto, Canada;
New Delhi, India; Amman, Jordan; Auckland, New Zealand;
Manila, The Philippines; Ifakara, Tanzania; London, United
Kingdom; and Seattle, Washington. A surgical checklist was
developed for completion at transition points throughout
the surgical procedure, including before administration of
anesthesia, before skin incision, and at completion of procedure. Through consistent use of the surgical checklist, the
rate of major complications and mortality decreased by
more than one-third in each of the eight centers. (50)(51)
TeamSTEPPS
Complete, timely, and effective communication is critical to
ensuring patient safety. Unfortunately, communication is
frequently the root cause of sentinel events. (52) The US
Department of Defense and AHRQ have worked collaboratively to develop TeamSTEPPS, a system to enhance communication and teamwork. (53) Some critical times of
information exchange include handoff, change in clinical
status, and whenever a team member has a safety concern.
TeamSTEPPS provides health-care teams with tools and
common language to foster timely and effective communication as well as a culture of mutual respect and support. An
example of a tool to organize presentation of information
that requires immediate response is SBAR: Situation, Background, Assessment, and Recommendation/Response.
Computerized Provider Order Entry

Medication prescription and administration pose a signicant risk to the pediatric population. Pediatric patients are at
increased risk for harm due to factors such as weight-based
dosing, use of off-label medications, large dosing range based
on indication for medications, and limited ability of the
patient to communicate. Most medication errors occur at
the time of prescription. (14)(15) CPOE systems used in
conjunction with clinical decisions improve medication
safety by eliminating illegibility of orders and transcription
errors, providing support for medication selection and adherence to guidelines, and delivering alerts for dosing outside of
the accepted range. A meta-analysis conducted to review the
effect of CPOE on prescription errors, ADEs, and mortality
showed that prescription errors were signicantly decreased
410
after the introduction of CPOE, but ADEs and mortality were

not. (54) Longhurst et al (55) published results from a quaternary care childrens hospital documenting that the monthly
adjusted mortality rate decreased by 20% with the introduction of a commercially available CPOE. With continued
evolution of commercially available pediatric-specic CPOE
systems and clinical decision support, the contribution of
these systems to medication safety should expand.
Culture of Safety
CHSPS maintains that the development of a culture of
safety is essential to reducing patient harm. A culture of
safety incorporates principles learned from HROs, such as
sensitivity to operations, preoccupation with failure, and
reluctance to simplify. By following these principles, the
organizational expectation becomes that all employees have
a personal responsibility to maintain the safety of all patients. (56)
MEDICAL ERROR DISCLOSURE

Despite many efforts, medical errors continue to occur within
pediatric practices. Once a medical error has been detected,
the medical team must face the difcult task of disclosure to
the patient and family. Patients desire disclosure of errors that
have caused them harm. They request information, including
why it happened, how the error can be corrected, and how the
error can be prevented in the future. In addition, patients
have stated that disclosure of medical errors by physicians
helps build their trust in the clinician. (57) A survey to
examine parental preferences for error disclosure and legal
action was conducted on a sample of parents who presented
to an emergency department with a child. The responses
revealed that 36% of parents were less likely to seek legal
action if a medical error was disclosed by a physician. (58)
Physician perceptions regarding medical error may differ from that of their patients. Although physicians agree
that medical errors resulting in harm should be disclosed to
their patients, they hesitate to do so because of fear of
litigation. Physicians may nd themselves choosing their
words carefully in an attempt to discuss the adverse event
without explicitly mentioning that an error has occurred.
The act of apologizing has also been an area of concern due
to the perception that an apology creates a legal liability and
may be damaging to the physicians reputation. (59)
The IHI provides recommendations for disclosure of
adverse events to ensure that the patient and family remain
at the center of communication. (60) Among the recommendations are: clear communication about the event that
includes how it happened and what will be done to prevent
this occurrence in the future, appointment of a staff member as the family support person who is available 24/7,
assurances that any new information obtained from investigation of the event is shared with the family in a timely
manner, and addressing all patient and family concerns as
soon as possible.
SECOND VICTIMS
The Hippocratic Oath states, I will prescribe regimens for
the good of my patients according to my ability and my
judgment and never do harm to anyone. The concept that
a physician will never do harm and, in essence, never
commit a medical error creates professional and societal
pressure. Unfortunately, when a medical error resulting in
patient harm does occur, the emotional and psychological
effects on the clinician can be profound. Anger, fear, guilt,
and self-doubt are common. The designation of second
victim recognizes medical professionals involved in medical
errors who experience difculty in coping with emotions. (61)
Providing appropriate support to second victims is critically important. Many institutions have readily available
employee assistance programs, but clinicians may be reluctant to seek resources. (59) Additional programs have been
developed specically to lend support to second victims.
Medically Induced Trauma Support Services is an organization established by a patient and a physician involved in
a medical error that had caused harm to the patient. The
organization provides A Toolkit for Building a Clinician and
Staff Support Program as well as support services to clinicians
involved in a medical error. (62)
Colleague support for second victims is also important,
although it can be challenging. Victims often need support
and understanding following an adverse event. Simply
asking how he or she feels and listening can be comforting
and alleviate concerns and feelings of being shunned. In
addition, exchanging personal experiences with errors can
be reassuring. (61)
Another program developed to lend support to clinicians
in deeply stressful situations is Code Lavender. (63) Code
Lavender is a hospital response team that is deployed to care
for patients, parents, and clinicians in times of emotional
stress and fatigue. The team may consist of nurses, chaplains, social workers, and other clinicians. The tools they use
may include imagery, Reiki (Japanese technique for stress
reduction and relaxation), meditation, and music therapy.
CONCLUSION
Quality improvement initiatives and implementation of
safety systems have resulted in a decrease in patient harm,
although harmful events continue to occur. (13)(14)(18)(21)
(38)(64) Improved detection and reporting of medical errors
allows review of factors that contribute to the error and
implementation of risk reduction strategies. (28)(29) The
development of pediatric networks and collaboratives enable
shared learning and can expedite the rate of change. (24)(27)
(46)(50)(51) In addition, the recognition of cultural transformation as a key component of a successful patient safety
program has further enhanced the work to prevent patient
harm. (21)(25)(26)(28)
Summary
Case study data continue to demonstrate instances of
unintended harm to pediatric patients. (13)(14)(18)(21)(38)(63)
On the basis of strong evidence, pediatric networks and
improvement collaborative mechanisms improve quality and
safety of care. (24)(27)(46)(50)(51)
Increasingly, case studies are demonstrating culture change as
a necessary component to improving pediatric patient safety. (21)
(25)(26)(28)
References for this article are at http://pedsinreview.aappublications.

org/content/36/9/403.full.
To view PowerPoint slides that accompany this article,

visit http://pedsinreview.aappublications.org
and click on the Data Supplement for this article.
Vol. 36 No. 9
SEPTEMBER 2015
411
PIR Quiz
1. As you prepare a lecture on patient safety for third-year medical students, you decide to
begin by dening the terminology used nationally by governmental agencies as well as by
the local hospital administration. The most accurate description of a medical error is that it:
A.
B.
C.
D.
E.
Always injures the patient.

Does not require investigation if patient harm has not occurred.
Is a mistake that always reaches and causes harm to the patient.
Is characterized by the use of a wrong plan to achieve a desired aim.
Offers little to learn if the error was intercepted and prevented from reaching
a patient.
2. A fourth-year medical student is completing a quality improvement project as part of his

graduation requirements. He is interested in a career in pediatrics and recently completed
a sub-internship on the general pediatric ward. He is interested in educating medical
students and residents on medical errors among pediatric patients. Which of the following
information is most correct in support of his research?
A. Although incorrectly interpreting viral as bacterial illness is common, pediatricians
rarely report this diagnostic error.
B. In a multicenter survey conducted by Singh et al, nearly 50% of surveyed
pediatricians reported making a diagnostic error at least once a year.
C. In a multicenter study conducted by Singh et al, the most frequent diagnostic error
was misinterpretation of complete blood cell count indices.
D. The most common diagnoses in pediatric medical malpractice claims are
intussusceptions and suspected child abuse.
E. Most pediatric malpractice claims result from missed or incorrect diagnoses.
3. You are conducting rounds on a 4-day-old preterm infant who was born at 26 weeks
gestation. The infant is maintained on mechanical ventilation and nothing by mouth.
You are preparing to write the medication order for a second course of indomethacin
for treatment of a patent ductus arteriosus. Which of the following is not a factor that
increases the difculty in pediatric medication management?
A.
B.
C.
D.
E.
Altered pharmacokinetics in preterm infants.

Calculations necessary for weight-based dosing.
Frequent changes in weight that require changes in dosing.
Limited ability of parents to communicate with physicians.
Off-label use of medications.
4. A pediatric nephrologist diagnoses nephrotic syndrome in an 11-year-old boy based on

clinical symptoms of gross edema, pleural effusions with dyspnea, proteinuria, and fatigue.
He admits the boy to the nephrology ward to begin a course of corticosteroid therapy. The
boy has no known drug allergies documented in his medical records. After the initial dose
of corticosteroid, he develops an allergic reaction. Which of the following most accurately
describes the type of error that occurred?
A.
B.
C.
D.
E.
A diagnostic error made by the pediatric nephrologist.

A nonpreventable medical error.
A preventable medical error.
Not a treatment error because it did not result in patient death.
Not a medical error.
5. During ward rounds last week, one of the general pediatricians wrote orders for
vancomycin and cefotaxime to treat orbital cellulitis in a 3-year-old girl. After
administration of the antibiotics, clinicians discovered that the child received an overdose
of vancomycin. Voluntary error reporting revealed that the medication had been ordered
incorrectly by the physician, and the error was overlooked by pharmacy and nursing.
Which of the following is a common reason cited by both physicians and nurses as a barrier
to voluntary error reporting?
412
learners must
or higher on this
assessment, which
than 60% on the
given additional
achieved.
which the learner
completes the quiz.
A.
B.
C.
D.
E.
Belief that the event was too trivial to make a formal report.
Forgetting to le a report.
Incident form takes excessive amount of time to complete.
Lack of feedback.
Not necessary to report near misses.
Vol. 36 No. 9
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413
Intractable Rash in a 7-month-old Boy

Priyanka Rao, MD,* Jennifer Stojan, MD*
*University of Michigan Mott Childrens Hospital, Ann Arbor, MI.
PRESENTATION
EDITORS NOTE
We invite readers to contribute case
presentations and discussions. Please use
the Submit and Track My Manuscript link
on the Pediatrics in Review homepage:
http://pedsinreview.aappublications.org.
AUTHOR DISCLOSURE Drs Rao and Stojan
have disclosed no nancial relationships
relevant to this article. This commentary does
not contain a discussion of an unapproved/
investigative use of a commercial product/
device.
A 7-month-old previously healthy boy presents with a diffuse rash. Three months
ago he developed an erythematous perioral rash that spread to his trunk and
extremities. The rash persisted despite treatment with numerous corticosteroid
creams, antibiotic courses, and antifungal treatments. The rash is not pruritic or
painful, and he has been afebrile. He has also had hair loss.
The boy has no history of diarrhea, viral respiratory tract infections, acute otitis
media, or other rashes. He is growing and developing appropriately and is up-todate on his immunizations. He breastfeeds without difculty and in the last
month has begun to eat a small amount of soft, age-appropriate foods. His general
skin care consists of three to four baths per week with lukewarm water. He is
moisturized with petroleum immediately following his baths. His family has been
trying tar shampoo and uses fragrance-free laundry detergent.
On physical examination, his vital signs are all within age-appropriate ranges,
and he appears well. His weight is 8.5 kg (31st percentile), length is 70 cm (41st
percentile), and head circumference 45 cm (51st percentile). The rash covers 70%
of his body surface and consists of orange-hued, aking, erythematous plaques
on his bilateral malar surfaces, neck creases, wrists, elbows, palms, bilateral groin
creases, and scrotum (Figs 1 and 2). Small erythematous papules cover his scalp
and upper trunk, but no there are blisters (Fig 3). He has areas of decreased hair
density. Other ndings on his physical examination are normal.
Dermatology is consulted and a punch biopsy performed. Laboratory tests are
obtained to evaluate for nutritional deciencies.
DISCUSSION
Initial laboratory results included: all electrolytes within appropriate range,
vitamin B12 308 pg/mL (227.2 pmol/L) (normal, 211911 pg/mL [115.7672.1
pmol/L]), and zinc less than 10 mg/dL (1.5 mmol/L) (normal, 55150 mg/dL [8.4
23.0 mmol/L]). A punch biopsy revealed numerous changes consistent with
a general nutritional deciency, including conuent parakeratosis with serum
crust and neutrophils in the stratum corneum, spongiosis and keratinocytes
with pale cytoplasm and clear vacuoles in the upper epidermis, and perivascular
lymphohistiocytic inltrate in the upper dermis. Histopathologic changes on
biopsy in combination with laboratory studies provided the basis for a diagnosis of
zinc deciency dermatitis. The infant was started on 5 mg/kg per day zinc sulfate
supplementation (equivalent to 1 mg/kg per day of elemental zinc) and skin care
414
Figures 3. Erythematous papules covering the scalp and upper trunk.
severe eczema, or an inltrative disorder such as Langerhans cell histiocytosis.
The Condition
Figure 1. Orange-hued, aking erythematous plaques on bilateral malar

surfaces and neck creases.
with triamcinolone cream 0.1% in water-washable base

(excluding groin, axillae, and intertriginous folds) covered
with a sauna suit to prevent further skin breakdown. He did
well and his rash resolved within 2 months of starting zinc
supplementation.
Differential Diagnosis
Although zinc deciency was apparent in this case, several
other diagnoses should be considered in the differential
diagnosis for the type of rash described for this infant. These
include other nutritional deciencies such as biotin, a blistering disorder such as linear immunoglobulin A disease,
Figure 2. Erythematous plaques on groin creases and scrotum.
Zinc deciency may have numerous clinical manifestations.

Patients typically present with cutaneous eruptions surrounding mucous membranes, often with an erythematous base
and a peeling supercial layer, as seen in this infant. However,
they may also present with nonspecic dermatitis, alopecia,
delayed wound healing, increased allergic sensitivity, diarrhea, slowing of growth, neurosensory changes, and impaired
concentration. The causes of zinc deciency may be divided
into four categories: inadequate intake, excessive losses,
malabsorption, and increased demand. Inadequate intake
is typically seen in infants ages 7 to 12 months who are
exclusively breastfed and may be a result of low zinc levels
in the breast milk due to zinc deciency in the mother or
a genetic mutation that results in sequestration of zinc in
the mammary tissue lysosomes. In older children, zinc deciency may result from inadequate intake in solid foods.
Excessive loss of zinc that can lead to deciency is seen with
digestive uid losses (severe diarrhea) or increased urinary
elimination (renal disease, diabetes mellitus, or diuretics).
Malabsorption is seen with acrodermatitis enteropathica,
a rare autosomal recessive disorder with a genetic mutation
that prevents zinc absorption. Increased demand is seen in
lactating and pregnant women as well as preterm infants.
Diagnosis is based on results of history, physical examination, and laboratory testing. A serum zinc concentration
is the gold standard laboratory test. Of note, serum must be
properly collected in acid-washed plastic tubes to prevent
contamination from glass. However, up to 60% of serum
zinc is bound to albumin and, therefore, serum values
should be corrected based on albumin values. Cutaneous
histopathology is also useful in solidifying a diagnosis.
Findings on skin biopsy include conuent parakeratosis,
focal spongiosis, and epidermal acanthosis. If more chronic
lesions are present, cytoplastic pallor, reticular degeneration, and necrosis of keratinocytes may be appreciated. This
patients source of zinc deciency was determined to be
Vol. 36 No. 9
SEPTEMBER 2015
415
zinc-decient breast milk; his mothers serum zinc concentration was less than 10 mg/dL (1.5 mmol/L).
Management
Zinc supplementation is the required treatment regardless
of the cause of the deciency. Approximately 70% of patients
respond within 6 months to supplementation. For children
with acquired zinc deciency, the recommended daily dose
of elemental zinc is 0.5 to 1 mg/kg to replenish stores, which
takes approximately 6 months. However, the child who has
acrodermatitis enteropathica may need as much as 3 mg/kg
per day of elemental zinc throughout his or her lifetime.
416
Lessons for the Clinician

Zinc deciency should be considered in the differential
diagnosis of a rash for breastfed infants, especially when
the rash is resistant to antibiotic or corticosteroid cream
treatments.
A rash that surrounds mucous membranes (mouth, anus)
should raise suspicion for zinc deciency.
Treatment for zinc deciency is supplementation. If zinc values increase, no further evaluation is
necessary.
Suggested Readings for this article are at http://pedsinreview.
aappublications.org/content/36/9/414.full.
Cardiovascular Shock Following Acute

Gastroenteritis in a 17-year-old Boy
Lina Merjaneh, MD,* Lillian R. Meacham, MD*
*Division of Endocrinology and Diabetes, Department of Pediatrics, Emory University
School of Medicine, Atlanta, GA.
PRESENTATION
AUTHOR DISCLOSURE Drs Merjaneh and

Meacham have disclosed no nancial
commentary does contain a discussion of an
unapproved/investigative use of
A 17-year-old boy presents to the emergency department with a 3-day history of

watery and explosive diarrhea, vomiting, abdominal pain, progressive weakness,
and light-headedness. Other family members had diarrhea a few days before and
all have recovered.
On physical examination, the lethargic and dehydrated teen has a blood
pressure of 85/45 mm Hg, heart rate of 120 beats/min, and respiratory rate
of 24 breaths/min. His height is 163 cm (4th percentile) and weight is 55 kg
(10th percentile). He has dry mucous membranes and sunken eyes with left
exotropia. His abdomen is soft and nontender with hyperactive bowels sounds.
His pubic hair and genitalia are at Sexual Maturity Rating 1. He has cold
extremities, with a capillary rell of 4 seconds. The rest of the physical ndings
are normal.
Initial laboratory evaluation shows metabolic acidosis with pH of 7.24,
bicarbonate of 15 mEq/L (15 mmol/L), sodium of 139 mEq/L (139 mmol/L),
potassium of 4.6 mEq/L (4.6 mmol/L), glucose of 83 mg/dL (4.6 mmol/L),
blood urea nitrogen of 31 mg/dL (11.1 mmol/L), and creatinine of 1.4 mg/dL
(123.8 mmol/L). He receives aggressive uid resuscitation with 4 L normal
saline without signicant improvement. He requires dopamine infusion for 2
days in the pediatric intensive care unit to maintain his blood pressure in the
normal range.
After stabilization and on further questioning, he reports having a longstanding history of a lazy left eye. He also reports poor growth since age 12 years.
Ophthalmologic examination reveals left eye exotropia with very low vision, right
hemi-eld defect in the left eye, and left optic nerve pallor with increased cupping.
Further laboratory evaluation and imaging reveal the diagnosis.
DISCUSSION
Endocrine evaluation, as outlined in the Table, revealed panhypopituitarism. The
diagnosis of central adrenal insufciency, the likely cause of the recalcitrant
presenting hypotension, was based on the low morning cortisol concentration and
poor response to the low- and high-dose adrenocorticotropin hormone stimulation. The boy also had hypogonadotropic hypogonadism with low gonadotropin
and testosterone values and central hypothyroidism with low thyroid hormone
Vol. 36 No. 9
SEPTEMBER 2015
417
concentrations despite the mild elevation in thyrotropin that

would be expected to be much higher in the case of primary
hypothyroidism. He was also suspected to have growth hormone deciency based on a low insulinlike growth factor 1,
insulinlike growth factor binding protein 3, and delayed
bone age. Brain magnetic resonance imaging showed
absence of the pituitary infundibulum, decreased volume
of the pituitary gland, ectopic neurohypophysis, and diminished volume of the left optic nerve, with severe thinning of
the optic chiasm most notable on the left (Figs 1 and 2).
These ndings were consistent with the diagnosis of septooptic dysplasia (SOD).
Viral gastroenteritis severe enough to result in hypotension that requires pressor support and admission to the
intensive care unit is unusual for a healthy adolescent. The
viral gastroenteritis did not appear exceptionally virulent
because other affected family members recovered quickly.
This unusual course combined with short stature and
absence of puberty raised suspicion for hypopituitarism.
The presence of optic nerve hypoplasia (ONH) made the
diagnosis of SOD likely.
Physiologic replacement of hydrocortisone (10 mg/m2
per day) was started. Thyroid replacement began with
a slowly advancing dose of thyroid hormone. The boy was
discharged home after clinical improvement in blood
TABLE.
pressure and diarrhea with instructions to triple his hydrocortisone dose in case of acute illness. He was provided with
injectable hydrocortisone to administer in case of vomiting
and severe illness and told to proceed to an emergency
department for administration of parenteral corticosteroids
if this occurred. Plans were made for growth hormone
testing and outpatient testosterone replacement.
The Condition
SOD is a rare congenital disorder with incidence of 1 in
10,000 live births and an equal prevalence in males and
females. The diagnosis can be made when two or more
features of the classic triad are present: ONH, pituitary
hormone abnormalities, and midline brain defects, including agenesis of the septum pellucidum or corpus callosum.
SOD is caused by mutations in genes involved in early
development and patterning of the forebrain and pituitary
that result in this association of neuroanatomic ndings.
SOD is a phenotypically variable disorder with a wide
spectrum of clinical presentations. Visual impairment is
present in 23% of patients. Developmental delay is seen in
57% of patients with bilateral ONH and 32% of those with
unilateral ONH. The primary ndings are hypopituitarism
(62%80%), with growth hormone deciency being the
most common abnormality, followed by adrenal, thyroid,
Hormonal Evaluation of Patient

TESTING
PATIENTS RESULTS
EXPECTED NORMAL VALUES FOR

A 17-YEAR-OLD MALE
Pituitary-Adrenal Axis
Screening tests
AM cortisol
< 0.8 mg/dL (22.1 nmol/L)
319 mg/dL (82.8524.2 nmol/L)
Stimulation test
Low-dose ACTH
High-dose ACTH
Peak cortisol 5.3 mg/dL (146.2 nmol/L)

Peak cortisol 7.9 mg/dL (218.0 nmol/L)
> 18 mg/dL (496.6 nmol/L)

> 18 mg/dL (496.6 nmol/L)
Pituitary-Gonadal Axis
Screening tests
LH
FSH
Testosterone
0.35 mIU/mL (0.35 IU/L)

0.72 mIU/mL (0.72 IU/L)
< 2 ng/dL (0.07 nmol/L)
0.5712.07 mIU/mL (0.5712.07 IU/L)

0.9511.95 mIU/mL (0.9511.95 IU/L)
1171,218 ng/dL (4.142.3 nmol/L)
Pituitary-Thyroid Axis
Screening tests
TSH
Free T4
6.36 mIU/mL
0.71 ng/dL (9.14 pmol/L)
0.603.60 mIU/mL
0.791.34 ng/dL (10.217.3 pmol/L)
Growth Hormone*
Screening tests
IGF1
IGFBP3
Bone age
< 10 ng/mL (1.3 nmol/L)

832 ng/mL (109 nmol/L)
13 years
SMR 1: 52391 ng/mL 6.851.2 nmol/L)

SMR 1:1,8786,190 ng/mL (246.0810.9 nmol/L)
17 years 15.4 months
ACTHadrenocorticotropin hormone, FSHfollicle-stimulating hormone, IGFinsulinlike growth factor, IGFBPinsulinlike growth factor binding protein,
LHluteinizing hormone, SMRSexual Maturity Rating, TSHthyrotropin, T4thyroxine.
*Growth hormone evaluation with stimulation testing is planned in the outpatient setting.
418
Figure 1. Brain magnetic resonance imaging sagittal T1-weighted

image demonstrates absence of pituitary infundibulum (bold arrow)
and severe thinning of the adenohypophysis (solid arrow) in addition to
ectopic neurohypophysis (dashed arrow).
and gonadotropin deciencies. The clinical features of

endocrinopathies are not always evident in early childhood
because hormone deciencies can evolve with time. Better
outcomes are associated with earlier diagnoses; untreated
hormonal deciencies may result in abnormalities of growth
and development. The presence of unrecognized adrenal
insufciency places the patient at risk of hypoglycemia,
adrenal crises, and subsequent death.
SOD should be suspected in the newborn period in
infants who have hypoglycemia, jaundice, microphallus,
and abnormal eye movements. A newborn screen that is
based on primary thyrotropin measurements might not
detect central hypothyroidism because thyrotropin values
are usually normal or only mildly elevated. SOD should be
suspected during childhood when a child who has visual
abnormalities presents with growth failure. ONH is the
third most common cause of vision impairment in children
younger than 3 years in the United States. Many children
with ONH do not actually have hypopituitarism, but consultation with a pediatric endocrinologist is warranted for
any child with ONH, especially if there is any associated
growth delay.
When SOD is suspected, evaluation for hormone deciencies can be performed as outlined in the Table and brain
magnetic resonance imaging (MRI) should be performed.
Findings on MRI consistent with SOD include: hypoplasia
of the optic nerves and optic chiasm, agenesis of the septum
pellucidum, and abnormalities of the corpus callosum and the
pituitary gland. MRI ndings vary considerably among patients.
Figure 2. Brain magnetic resonance imaging coronal T2-weighted

image demonstrates severe volume loss of the left optic nerve (arrow).
Management
Hormone replacement therapy is tailored for the specic
deciencies. Of note, cortisol must be replaced before
starting any other hormone therapy. Thyroid hormone
replacement in an adrenally insufcient child could precipitate an adrenal crisis by accelerating cortisol metabolism
and increasing the metabolic rate. Furthermore, growth
hormone replacement might worsen a preexisting thyroid
or adrenal insufciency by modulating thyroid hormone or
cortisol metabolism. Early diagnosis of SOD can facilitate
early interventions for hormone deciencies, visual impairment, and developmental delay and may favorably improve
health outcomes in patients by decreasing associated morbidity and mortality.

Septo-optic dysplasia is a phenotypically variable disorder
with a wide spectrum of clinical presentations. Hormone
deciencies might not be present at diagnosis but may
evolve with time.
Referral to endocrinology is required for any child with
abnormalities of vision and growth failure or delayed
puberty.
In the case of multiple pituitary hormone deciencies,
cortisol must be replaced before any other hormone.
Patients should receive clear instructions about stress
dosing during times of acute illness.
Vol. 36 No. 9
SEPTEMBER 2015
419
A Vascular-appearing Eyelid Mass in

a Neonate
Tiffany J. Herd, MD,* Hillary S. Lawrence, MD, Michelle A. Manalang, MD,

Laura S. Plummer, MD,x Lei Shao, MD,* Kimberly A Horii, MD*
*Department of Dermatology, Childrens Mercy Hospital & Clinics, Kansas City, MO.
Department of Dermatology, The University of Oklahoma College of Medicine, Oklahoma City, OK.
Departments of Dermatology and Hematology/Oncology, Childrens Mercy Hospital & Clinics, Kansas
City, MO.
x
Departments of Dermatology and Ophthalmology, Childrens Mercy Hospital & Clinics, Kansas City, MO.
PRESENTATION
AUTHOR DISCLOSURE Drs Herd, Lawrence,
Manalang, Plummer, Shao, and Horii have
disclosed no nancial relationships relevant to
this article. This commentary does not contain
A 12-day-old girl presents to the dermatology clinic with ptosis, edema, and purple
discoloration of the right upper eyelid. She was born at 38 weeks gestation via an
uncomplicated vaginal delivery. The ndings were noted at birth and initially
attributed to birth trauma. However, the lesion had slightly grown since birth and
was still present at 10 days of age, prompting a presumed diagnosis of infantile
hemangioma (IH) of the eyelid by the referring ophthalmologist.
Physical examination shows a well-appearing neonate. Growth parameters include
a weight of 3.4 kg (25th-50th percentile) and length of 51 cm (25th-50th percentile).
Her temperature is 36.6C (97.9F), heart rate is 168 beats/min, respiratory rate is 49
breaths/min, blood pressure is 80/46 mm Hg, and oxygen saturation is 100% in
room air. Examination of the eyelid shows a 6.0 5.5-cm rm, violaceous growth
involving the entire upper right eyelid with complete ptosis (Fig 1).
The neonate is hospitalized for further evaluation. Ultrasonography reveals
a hypervascular solid and cystic mass concerning for a sarcoma or vascular tumor.
Magnetic resonance imaging of the orbits shows an encapsulated mass conned to
the preseptal soft tissues of the right orbit, with focal areas of hemorrhage and
ndings suggestive of high cellularity (Fig 2A). Excisional biopsy reveals the
diagnosis.
DISCUSSION
The histology resembled a malignant, undifferentiated, small round cell tumor
composed of densely cellular sheets of primitive spindle cells with little pleomorphism and no tumor necrosis. Although the tumor was largely undifferentiated, immunohistochemistry revealed both epithelial and mesenchymal
markers, including cytokeratin, CAM5.2, and Vimentin. The tumor cells were
negative for Glut-1, synaptophysin, CD99, myogenin, CD31, CD34, CD45, EMA,
and WT-1 (C terminus). Fluorescence in situ hybridization studies were negative
for ETV6/NTRK3 gene rearrangement, seen in infantile brosarcoma. Histologic
and cytogenetic studies excluded rhabdomyosarcoma, Ewing sarcoma/primitive
neuroectodermal tumor (PNET), infantile brosarcoma, and neuroblastoma.
420
Figures 1. A violaceous growth involving the

entire upper right eyelid (A) with complete
ptosis (B).
Glut-1, a specic marker of IH, was also lacking, thereby

excluding IH as the diagnosis. The nal pathologic diagnosis, also reviewed by an outside consultant, was a malignant
undifferentiated soft-tissue tumor.
The differential diagnosis of soft-tissue masses of the orbit
is broad. Although IHs are the most common periocular
soft-tissue tumors, other soft-tissue sarcomas, including
rhabdomyosarcoma, Ewing sarcoma/PNET, and infantile
brosarcoma, should be considered. Further possible diagnoses include lacrimal gland lesions, neuroblastoma, leukemia, malignant rhabdoid tumor, Langerhans cell histiocytosis,
other vascular tumors, dacryocystoceles, and infection.
Described clinical features may distinguish IHs from
malignant lesions. Among the characteristics believed to be
concerning for malignant lesion are congenital lesions,
rapid growth, ulceration, xation to deep fascia, rm texture,
size greater than 3 cm, and mass immobility. Because some

of these features may be present in IH, making a denitive
diagnosis based solely on the clinical appearance is not
always possible. In 2006, Frieden et al suggested that a fully
formed congenital tumor should exclude IH as a diagnostic
possibility. Furthermore, lesions that grow beyond the expected period of proliferation for IHs should raise concern
for malignant soft-tissue tumors or other vascular tumors.
Imaging with ultrasonography or magnetic resonance imaging may be useful. If the diagnosis in an atypical case is
unclear, biopsy may be needed for histologic diagnosis.
Biopsy is often necessary for histologic and immunohistochemical evaluation of soft-tissue tumors to delineate a diagnosis. Molecular testing may also have diagnostic value.
The Condition
Malignant undifferentiated tumors are a heterogenous
group of neoplasms with little or no morphologic evidence
Figure 2. A. Multiplanar post-contrast

T1-weighted magnetic resonance imaging of the
orbits shows an enhancing, heterogenous mass
anterior to the right globe, with dense cellularity
and uid levels suggestive of hemorrhage or
cystic change. B. Clinical appearance at
2- months of age following excisional biopsy
and chemotherapy.
Vol. 36 No. 9
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421
of differentiation that cannot be further classied based on

histologic features. Malignant undifferentiated tumors
exhibit unpredictable clinical behavior. These may be
present at birth or develop over time. Size may remain
stable or tumors may undergo rapid proliferation beyond
the period of growth anticipated for IHs, which may serve
as a diagnostic clue. Atypical clinical characteristics or
growth patterns of a presumed IH may warrant further
investigation.
Similar cases of soft-tissue tumors mimicking IHs have
been reported. In 2006, three cases of congenital vascularappearing tumors diagnosed as ulcerated IH and treated
with systemic corticosteroids were described. After reevaluation of unusual characteristics, including congenital presence and ulceration present at birth, tissue was obtained for
pathology, leading to the diagnosis of a congenital infantile
brosarcoma in each instance. A recently reported case of
congenital infantile brosarcoma of the lip that underwent
rapid proliferation was treated as a presumed IH. Because
of the refractory response to therapy, biopsy was performed, conrming the diagnosis. To our knowledge, no
case has been reported describing a malignant undifferentiated soft-tissue tumor misdiagnosed as IH of the eyelid in
a neonate.
Management
Malignant undifferentiated tumors often require full excision and possibly chemotherapy and radiation. Treatment is
multidisciplinary and may include ophthalmology, dermatology, oncology, and pathology services to ensure optimal
therapy. The girl in this case underwent evaluation
for metastatic disease, which was negative. Treatment
was initiated with a sarcoma-based chemotherapy protocol
(ifosfamide, etoposide, vincristine, doxorubicin, and cyclophosphamide) and proton therapy. She had an excellent
clinical response to treatment by 2- months of age (Fig 2B).

Cutaneous malignant soft-tissue tumors can clinically
mimic infantile hemangiomas, which poses a diagnostic
dilemma because treatment and prognosis drastically
differ between the two conditions.
Clinicians should consider diagnostic possibilities other
than infantile hemangioma if the clinical history, behavior,
or appearance of the lesion is not typical; atypical growth
pattern or lack of response to treatment should raise
suspicion for a possible malignant soft-tissue tumor.
Correction
In the July 2015 article Dehydration: Isonatremic, Hyponatremic, and Hypernatremic Recognition and Management
(Powers KS. Pediatrics in Review. 2015;36(7): 274285, doi: 10.1542/pir.36-7-274), key phrases were deleted from the
Question 1 answer options, which should begin as follows:
A. In hypernatremic dehydration
B. In hypernatremic dehydration
C. In hyponatremic dehydration
D. In hyponatremic dehydration
E. In hyponatremic dehydration
The phrases have been restored in the online quizzes, a correction has been attached to the article online. The journal
regrets the copyediting error.
422
How Much Is Too Much? A Case of

Hypercalcemia in a 6-year-old Boy
Monica Liao, MD,* Philip Magcalas, MD,* Patricia Hopkins-Braddock, MD*

*Childrens Hospital at Albany Medical Center, Albany, NY.
PRESENTATION
EDITORS NOTE
This case was selected for publication from
the 10 nalists in the 2014 Clinical Case
Presentation program for residents held
by the Resident Section of the American
Academy of Pediatrics. Dr Liao, a resident
from Childrens Hospital at Albany
Medical Center, wrote this case report.
Choosing which case to publish involved
considerations of the teaching value and
excellence of writing but also the content
needs of the journal. Another case will
be chosen from the nalists presented at
this years AAP National Conference and
Exhibition and published in the September
2016 issue of Pediatrics in Review.
AUTHOR DISCLOSURE Drs Liao, Magcalas,
and Hopkins-Braddock have disclosed no
A 6-year-old Caucasian boy with a past medical history of eczema presents to the
pediatric emergency department with 12 days of worsening bilateral anterolateral
leg pain and edema that has resulted in refusal to ambulate. His mother noted an
atypical rash on the boys anterior shins, which has persisted despite application
of hydrocortisone cream. Other symptoms include low energy, low-grade fever,
nausea, poor oral intake, and persistently dry and bleeding lips. Immunizations
are up-to-date, and he has had no sick contacts. The only medication he has
received is ibuprofen for pain. Developmental milestones are appropriate for age,
and the boy has no dietary restrictions. The only nding of note in the family
is rheumatoid arthritis in the paternal great-grandmother. The boy has been
evaluated by his primary care physician, and laboratory results, including complete blood cell count, Lyme studies, antinuclear antibody, and C-reactive protein,
are within normal limits. He has a slightly elevated erythrocyte sedimentation rate
of 33 mm/hr (normal, 015 mm/hr). Bilateral lower extremity radiographs are
negative for any fractures or indications of trauma.
Physical examination reveals erythematous, cracked, and bleeding lips with mild
oropharyngeal erythema. Other positive ndings include nontender cervical lymphadenopathy as well as salmon-colored, erythematous, dry macules on the lateral
thighs and anterior shins. Bilateral lower extremities are diffusely tender to palpation,
with mild nonpitting edema. The child cries when attempting to stand and bear
weight. Initial laboratory results in the emergency department reveal a serum calcium
of 13.9 mg/dL (3.5 mmol/L) (normal 8.610.3 mg/dL [2.22.6 mmol/L]) and ionized
calcium of 6.6 mg/dL (1.65 mmol/L) (normal 4.65.3 mg/dL [1.141.33 mmol/L]).
DISCUSSION
Because of concern for a malignant process causing bone pain, urine metanephrines
were assessed and determined to be within normal limits. Imaging and procedures
performed to evaluate for malignancy included chest radiograph, bone marrow biopsy,
magnetic resonance imaging of the spine, computed tomography scan of the head, and
a technetium-99m bone scan. The bone scan (Figure) revealed increased uptake in the
bilateral forearms, proximal femurs, tibias, and kidneys, consistent with metabolic
bone disease. In investigating a possible endocrinologic cause for the patients
hypercalcemia, parathyroid hormone values were found to be low, while thyrotropin,
free thyroxine, and vitamin D values were within normal limits.
Vol. 36 No. 9
SEPTEMBER 2015
423
Figure. Technetium-99m bone scan shows increased uptake in both forearms, proximal femurs, tibias, and kidneys.
Hypercalcemia persisted despite hydration and treatment

with calcitonin, which reduces calcium concentrations by
inhibiting parathyroid hormone activity. The boy subsequently
received pamidronate, a bisphosphonate that reduces bone
resorption and turnover by inhibiting osteoclast activity. He
also underwent diuresis with furosemide. Potassium and
magnesium repletion were provided as necessary. With this
therapy, his symptoms, including cheilosis, bone pain, and
inability to bear weight, improved grossly. During the boys
hospital stay, the parents revealed that they had taken him to
a natural health practitioner 6 months ago for eczema, and he
had been taking nutritional supplements since. These supplements were not formulated for children, and many contained
vitamin A, with one containing 39,000 IU of vitamin A per pill.
With therapy, calcium values decreased gradually. At discharge, his ionized calcium value was 5.2 mg/dL (1.3 mmol/L).
The boy was sent home with magnesium oxide and a lowdairy diet. His electrolytes and calcium concentrations were
evaluated regularly. He resumed a regular diet 2 months after
his electrolyte values normalized, but he continued to have
persistent hypotonia and required outpatient physical therapy
for months before he fully regained his strength.
The differential diagnosis for a child with bone pain, refusal
to bear weight, peripheral edema, and rash is both broad and
challenging. Potential diagnoses include accidental and nonaccidental trauma, osteomyelitis, myositis, septic arthritis,
postinfectious myalgias, and chronic kidney disease. Given
the involvement of this patients bilateral lower extremities,
424
rheumatologic conditions such as juvenile dermatomyositis

and juvenile polymyositis were also considered. The concurrent hypercalcemia also raised concern for possible malignancy or derangements of parathyroid hormone activity.
The Condition
Vitamin A is an essential fat-soluble micronutrient that has
signicant effects on vision, cell proliferation, immunity,
growth, and reproduction. It is used in the treatment of skin
conditions such as acne and keratosis follicularis. Acute
vitamin A toxicity usually affects the central nervous system
and skin, with signs and symptoms of headaches, vomiting,
dry skin, and lip ssuring. Chronic toxicity may progress
to include ataxia, liver injury, and, particularly in children,
bone demineralization. The mechanisms behind the effects
of vitamin A toxicity are not well-understood but may involve
angiogenic factors, bone resorption, and competition with
vitamin D, leading to hypercalcemia. In addition to being
fat-soluble, vitamin A is subject to varying rates of excretion
and resorption. Therefore, serum concentrations do not
necessarily correlate with those in the tissues.
The recommended daily allowance of vitamin A is between
1,000 and 5,000 IU. However, acute toxicity can occur in
children with intakes as low as 1,500 IU/kg per day. This boy
was found to be taking more than 39,000 IU per day, which
is 1,860 IU/kg per day for more than 6 months.
Treatment and Prognosis

If toxicity is suspected, supplementation should be stopped
and vitamin A intake from the diet restricted. Much of the
symptomatology is strongly related to hypercalcemia, and this

boy was treated with hydration and calcitonin. When refractory
to these interventions, diuretics and bisphosphonates may also
be used. This boy responded well to therapy with both furosemide and pamidronate. Otherwise, pain and any other
concurrent electrolyte derangements are the focus of therapy.
Limiting intake of vitamin A and controlling hypercalcemia are generally believed to have a favorable outcome,
but the effects of toxicity are not quickly corrected. The
condition is rare enough that long-term effects have not
been extensively described. However, chronic ingestion of
excessive vitamin A can cause permanent damage, including liver cirrhosis or failure. Patients should be monitored
for stability on an outpatient basis.

The symptoms of hypervitaminosis A are suggestive of
other serious illnesses, such as malignancies, rheumatologic disorders, or infection, necessitating extensive
evaluation and close outpatient follow-up evaluations.
Vitamin A is fat-soluble, and toxicity can occur even in the
absence of elevated blood concentrations.
Dietary and medication history should address all
nutritional supplements.
Patients should be educated on the potential adverse effects of supplements, ideally before initiating
treatment.
Vol. 36 No. 9
SEPTEMBER 2015
425
in
Brief
Head Growth
Mary Elizabeth Wroblewski, MD,* Joyce Bevington, MD, PhD,* Cathi Badik, MD*
*University of Toledo College of Medicine and Life Sciences, Toledo, OH.
AUTHOR DISCLOSURE Drs Wroblewski,

Bevington, and Badik have disclosed no
Microcephaly Syndromes. Abuelo D. Semin

Pediatr Neurol. 2007;14(3):118127.
Macrocephaly Syndromes. Haskins Olney A.
Semin Pediatr Neurol. 2007;14(3):128135.
Positional Plagiocephaly: An Analysis of the
Literature on the Effectiveness of Current
Guidelines. Shweikeh F, Nuno M, Daielpour
M, Kreiger MD, Drazin D. Neurosurg Focus.
2013;35(4):19.
Evidence-based Care of the Child with
Deformational Plagiocephaly, Part 1:
Assessment and Diagnosis. Looman WS,
Kack Flannery AB. J Pediatr Health Care.
2012;26(4):243250.
Evidence-based Medicine:
Craniosynostosis. Fearon JA. Plast Reconstr
Surg. 2014;133(5):12611275.
426
Evaluation of head size and shape is a routine part of the infant and toddler health
supervision visit. Maximal occipitofrontal circumference is the best correlate for
brain growth and is plotted on a Centers for Disease Control and Prevention
growth chart normalized for age and gender up to 36 months of age. Microcephaly
and macrocephaly are dened as a head circumference less than two standard
deviations and greater than two standard deviations from the norm, respectively.
For both micro- and macrocephaly, it is important to document parental head size
because the size may represent a trait that can be hereditary. If the childs head
size is not congruent with familial sizes, a full history (including prenatal, birth,
past medical, and family) in addition to a physical examination focused on
identifying dysmorphic features and a neurologic examination are warranted.
Microcephaly may be due to cessation of brain growth or abnormal brain
development. Considerations include intrauterine infections such as rubella,
cytomegalovirus, or toxoplasmosis as well as possible genetic or metabolic causes.
Among the causes of macrocephaly are increased intracranial pressure, hydrocephalus, intracranial hemorrhage, mass, or genetic causes.
Children who have abnormal head size, whether present at birth or acquired
over time, should be evaluated with neuroimaging. When an infants anterior
fontanelle is still open, brain ultrasonography may be sufcient, but if it is closed,
brain computed tomography (CT) scan or magnetic resonance imaging (MRI) is
indicated to detect any abnormalities in the brain parenchyma or ventricles or the
presence of a space-occupying lesion. Infants who have microcephaly at birth
should be tested for rubella, toxoplasmosis, and cytomegalovirus infections and
inborn errors of metabolism, if appropriate. A genetic panel is available to evaluate
the causes of microcephaly because some causes may have genetic markers. More
than 100 syndromes have been associated with increased head size, the most
common of which is Soto syndrome. If a cause of abnormal head size can be
determined, genetic counseling can be offered to the patients family.
Head shape also should be evaluated, whether it is associated with a normal or
abnormal head circumference. An abnormally shaped or attened, asymmetrically shaped head is referred to as plagiocephalic. Flattening or asymmetry can be
due to many causes, the most common of which is positioning that can cause
molding of the skull, often referred to as positional or deformational plagiocephaly. Because attening due to positional plagiocephaly can improve with
time, the prevalence is age-dependent.
Plagiocephaly due to premature closure of one or more suture lines is
termed craniosynostosis. The incidence of craniosynostosis is as high as 1 in
1,700 live births. When viewed from above, closures of the sutures have the
following appearances:
Sagittal suture closure results in an elongated skull
Metopic suture closure results in a triangular skull
Coronal suture closure results in a reduced anteriorposterior skull length on the side with the closed suture
Lambdoid suture closure results in attening of the
affected side, reduced posterior skull height, and contralateral parietal bossing
Differentiating craniosynostosis from abnormal head
shape due to external forces is important, especially in light
of the American Academy of Pediatrics (AAP) Back To
Sleep campaign, which has led to an increase in positional
molding and attening of the back of the skull. Factors that
may help to differentiate between the two are the normal
posterior skull height and lack of parietal bossing in positional plagiocephaly.
Both positional plagiocephaly and craniosynostosis can
be diagnosed clinically based on a history of head positioning and skull shape. The current reference standard for
diagnosis of craniosynostosis is head CT scan with threedimensional reconstruction of the skull. With concerns
about radiation dosing in pediatric patients, though, some
researchers have shown that physical examination by a specialist, such as a neurosurgeon or physical therapist, with
specic anthropomorphic skull measurements may be as
accurate as CT scan at diagnosing and classifying different
types of craniosynostoses.
Treatment of positional plagiocephaly depends on the
severity of the deformity and the age of the patient. Surgical
intervention is not recommended because the results are
merely cosmetic and the surgery is fraught with risk. If the
deformity is present after 6 months of age, use of a helmet
orthosis may be considered, but this has been shown to be
no more effective than no intervention in resolving deformities. Physical therapy may also be useful. In response to the
Back To Sleep campaign, the AAP recommends daily
tummy time as well, not only to improve development
of motor skills, but also to decrease the amount of time that

the occiput experiences molding forces. Unlike positional
plagiocephaly, craniosynostoses usually require surgical
intervention to allow the brain to continue to grow without
restriction.
All infants and toddlers with abnormal head size or shape
need to be monitored over time for changes in other growth
parameters, delays in developmental milestones, and evidence of syndromic features. Children with microcephaly
especially are at increased risk for epilepsy and cerebral
palsy.
COMMENTS: The longitudinal measurement of head
growth is an important component of primary care visits.
Accurate measurement is essential but can be challenging
in young infants who are moving frequently and have a full
head of hair or braided hair that can contribute to falsely
larger readings. Plotting the head circumference on a growth
curve is essential to determine changes that may not be
apparent by physical examination alone. An acute increase
in head circumference requires more urgent evaluation
because acute onset of hydrocephalus or intracranial hemorrhage may require more urgent assessment and intervention. When contemplating neuroimaging, it is important to
consider the best test balanced against radiation exposure.
If an infants anterior fontanelle is still open, head ultrasonography may be sufcient as a rst-line imaging study. If
the fontanelle is too small or closed, brain CT scan or MRI
may be needed. Brain MRI is preferable if it can be obtained
in an appropriate time frame because it is associated with
less radiation exposure than CT scan and offers more details
of parenchymal and anatomic changes.
Janet Serwint, MD
Associate Editor, In Brief
ANSWER KEY FOR SEPTEMBER 2015 PEDIATRICS IN REVIEW:

Pediatric Fever of Unknown Origin: 1. B; 2. B; 3. D; 4. C; 5. C.
Constipation and Encopresis in Childhood: 1. B; 2. D; 3. D; 4. C; 5. D.
Patient Safety and Quality Improvement: Terminology: 1. D; 2. E; 3. D; 4. B; 5. D.
Vol. 36 No. 9
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427
Newborn With a Facial Vascular

Birthmark
Brian M. Faux, MD,* Abraham W. Suhr, MD, David T. Hsieh, MD*
*Department of Pediatrics, Division of Pediatric Neurology, Department of Ophthalmology, San
Antonio Military Medical Center, Ft Sam Houston, TX.
PRESENTATION
After an unremarkable pregnancy, a term baby boy is delivered without complications. The newborn examination is notable only for a at facial vascular birthmark
involving nearly the entire distribution of the left trigeminal nerve, with some
patchy involvement of the left upper torso, as well as involvement of the right upper
eyelid (Fig 1). The patient otherwise acts well and has no abnormal movements. No
notable similar dermatologic ndings are reported within the family.
The clinician discusses the possibility of ophthalmologic and neurologic
complications with the family. They choose to defer neuroimaging. Ophthalmology consultation initially reveals suspicious ndings for glaucoma, with mildly
elevated intraocular pressure in both eyes and myopic cycloplegic refraction. The
infant initially is closely observed because both optic nerves appear healthy, but by
age 3 months, therapy for glaucoma is initiated.
At age 5 months, the boy presents in status epilepticus with generalized clonic
convulsions, which are aborted with intravenous lorazepam.
DIAGNOSIS
AUTHOR DISCLOSURE Drs Faux, Suhr, and

Hsieh have disclosed no nancial
commentary does not contain a discussion of
an unapproved/investigative use of
e30
Upon hospital admission, magnetic resonance imaging (MRI) of the brain reveals
diffuse leptomeningeal enhancement of the left temporal and parietal lobes and
prominence of the left choroid plexus (Fig 2), conrming the clinical diagnosis of
Sturge-Weber syndrome (SWS). After a hospital course of progressive mental
status improvement without recurrence of seizures, the boy is discharged on
phenobarbital and later transitioned to oxcarbazepine.
SWS is a sporadic congenital neurocutaneous syndrome that is characterized
by cutaneous capillary malformations in the distribution of the trigeminal nerve,
particularly in the V1 distribution, with associated ndings of glaucoma and
cerebral venous malformations. SWS is caused by an activating somatic mutation
of the GNAQ gene, whose gene product Gaq plays an important role in cell
proliferation, although much research is still needed to better understand the
developmental processes affected by GNAQ mutations. SWS occurs in approximately 1 in 20,000 of the population. Because SWS is due to a somatic mutation,
it is not inherited.
Clinical Features and Diagnosis

The skin ndings of SWS derive from aberrant ectatic dermal blood vessels
resulting in capillary malformations (port-wine stains). Most patients born with
Figure 1. A port-wine birthmark involved nearly the entire (V1, V2, V3)
distribution of the left trigeminal nerve, the upper eyelid, and partly the
V1 distribution of the right trigeminal nerve.
facial port-wine stains, however, do not have SWS. Of all

patients born with facial port-wine stains, approximately 8%
to 15% have SWS. Affected patients have skin ndings
involving the distribution of the rst trigeminal nerve
branch, at minimum, but often have extension into the
second or third branches. More recent literature emphasizes
that port-wine stain involvement of the embryologic vascular distribution of the forehead, rather than the trigeminal neural innervation, confers the highest risk of SWS,
although this proposal is still being investigated. In most
case series, bilaterality of facial port-wine stain lesions is
associated with a higher risk of neurologic involvement.
Rarely, patients who have SWS do not have skin lesions. The
birthmarks typically appear as pale-pink macular lesions at
birth and may evolve into a darker red-purple over time, with
both head and neck and sometimes truncal involvement
possible.
Eye ndings of SWS also derive from ectatic capillary
venous vascular malformations, resulting in glaucoma due
to impaired episcleral venous outow as well as a component
of primary trabecular meshwork maldevelopment. These
malformations cause increased intraocular pressure, which
contributes to glaucomatous optic neuropathy. A rapid rise
in intraocular pressure in children younger than age 2 years
can cause an abnormally large eye, termed buphthalmos,
clinically manifesting as enlarged corneal diameters, tears
in the posterior layer of the cornea, and axial myopia. The
eye ipsilateral to the port-wine stain is most commonly
affected, but bilateral glaucoma can also occur. Glaucoma
occurs in approximately 30% to 70% of those affected by
SWS, with up to 40% of patients developing glaucoma later
in childhood or adolescence.
Leptomeningeal venous angiomatosis, a cerebral venous
malformation, is one aspect of brain involvement that
typically, but not exclusively, occurs ipsilateral to the portwine stain. Most commonly, the parietal-occipital lobe is
involved, but frontal and temporal lobe involvement is also
possible. The sluggish ow through these redundant vessels
can result in a spectrum of disease ranging from seizures,
stroke, and headache to cognitive and behavioral problems.
Epilepsy presents in more than 85% of all patients who
have SWS, with most becoming symptomatic within the
Figure 2. T1-weighted axial brain magnetic

resonance imaging with gadolinium contrast
reveals diffuse left temporal and parietal
leptomeningeal enhancement (white arrow)
and prominence of the left choroid plexus
(black arrow).
Vol. 36 No. 9
SEPTEMBER 2015
e31
rst 2 years after birth. Earlier onset of epilepsy is associated

with a worse cognitive prognosis. The seizures tend to be
focal motor in origin but may also secondarily generalize
from a focal nidus. In many patients, the seizures tend to
cluster, with long seizure-free periods, particularly clustering around times of intercurrent illness. In addition to
seizures, headaches with migrainous features occur in about
one third of patients.
Strokelike episodes with hemianesthesia, hemiparesis,
and hemianopsia also occur in patients with SWS. These
episodes tend to cluster around times of minor head trauma
but may also be brought on by prolonged seizures, with
a hypothesized inability of the abnormal vasculature to
autoregulate to the increased metabolic demand at these
times.
Intellectual disability ranging from borderline to severe
is seen in more than 50% of patients with SWS. Behavioral
issues such as attention-decit/hyperactivity disorder are
also common.
Finally, endocrinologic disorders such as central hypothyroidism (2.4% of patients) and growth hormone deciency (0.54%) are possible.
The diagnosis of SWS is clinical, requiring two of three
criteria: facial port-wine birthmark, increased intraocular
pressure, and leptomeningeal angiomatosis. Routine ophthalmology assessments are needed to identify ocular manifestations. MRI is the most sensitive neuroimaging
modality. MRI can be used before symptom onset but is
sometimes delayed until after age 1 year due to possible
false-negative ndings in infancy, the need for sedation and
its intrinsic risks, and the large number of patients with
visible facial birthmarks who do not have SWS. If MRI is
undertaken, intravenous contrast is required to highlight
the abnormal vasculature. In addition, susceptibility-weighted
imaging sequences are recommended to supplement the
sensitivity of neuroimaging. Additional ndings can include
dilated deep-draining venous vessels, cortical and subcortical
calcications, white matter abnormalities consistent with
gliosis, and hemiatrophy of the brain.
Treatment
The port-wine stain in patients with SWS is primarily a cosmetic issue, but the possible signicant psychosocial effects
are a tangible concern. Thus, treatment with a tunable dye
laser should be offered to patients. Repeated treatments over
several months are often required.
All children who have SWS need initial and regular surveillance examinations by an ophthalmologist for evidence of
glaucoma, refractive error, or amblyopia. Symptoms such as
ocular pain or visual disturbance should prompt urgent
e32
referral to an ophthalmologist. When glaucoma is diagnosed, management can consist initially of medical treatment with topical eyedrops to reduce intraocular pressures.
Many patients may also require surgical techniques to lower
intraocular pressure. Patients also should be seen by a pediatric ophthalmologist for amblyopia monitoring, prevention, and or treatment.
The management of epilepsy in children with SWS starts
with behavioral adjustments, including good sleep hygiene,
fever control during illnesses, and avoidance of known
triggers. For example, pressure equalizer tubes for those
who have SWS and recurrent otitis media has been reported
to improve seizure control. However, seizure management
most often consists of standard anticonvulsant medications.
The choice of anticonvulsant medication often depends, in
part, upon the patients seizure type, comorbidities, and
family preferences in consultation with the treating neurologist. Although there is a theoretical concern of glaucoma
with the use of topiramate, this adverse effect is rarely
reported in SWS. In addition, the possibility of an association between oxcarbazepine and hypothyroidism in SWS
has been raised, but this relationship remains uncertain.
Because the benets of starting anticonvulsant medications
prophylactically, ie, before the onset of epilepsy, in SWS have
not been proven, most patients do not begin such treatment
unless epilepsy has been diagnosed.
Seizure control is especially important in patients with
SWS due to functional radiographic evidence of ictal hypoperfusion to affected cortical regions during seizures, which
has been hypothesized to contribute to cortical injury and
atrophy. Thus, a clear seizure action plan is imperative that
includes home-based abortive medications such as rectal
valium to minimize the occurrence and duration of status
epilepticus in patients who are susceptible to prolonged
seizures. For patients whose epilepsy is refractory to anticonvulsant medications, dietary treatments such as the
ketogenic diet, modied Atkins diet, or low-glycemic index
treatment should be considered. Finally, the possibility of
epilepsy surgery should be explored in medicationrefractory patients and can consist of either focal resections
or hemispherectomy. Although earlier surgery has been suggested to be associated with improved long-term outcome,
further evidence and study is needed.
Retrospective data suggest that daily low-dose aspirin
(35 mg/kg) appears to be safe and can prevent and reduce
the number of strokelike episodes in patients with SWS.
In addition, patients with SWS who are taking daily aspirin
therapy can receive the additional benet of improved
seizure control. The benet of starting aspirin therapy
before the onset of strokelike symptoms is uncertain. As
Figure 3. The child at age 4 years.
with all children receiving chronic aspirin therapy, patients

should be reminded to obtain all vaccinations, especially
inuenza, due to the theoretical risk of Reye syndrome.
Chronic migraine headaches can negatively affect quality
of life and should be treated with standard therapy. Such
therapy should include behavior modication (routine sleep
hygiene, good hydration), psychological techniques (relaxation therapies), and medications as needed. Medical therapy
for headaches can include standard pediatric daily prophylactic medications and the judicious use of abortive medications. The use of triptans to abort migraines is associated
with a theoretical vascular risk in SWS, although in the
published literature, some patients with SWS have reported
triptan use without self-reported adverse events.
Educational and social supports are as important to address
as medical treatments. Neuropsychological and educational
testing can identify areas of need for educational support.
Furthermore, families should be encouraged to join national
organizations such as the Sturge-Weber Foundation (www.
sturge-weber.org).
More recently, patients with SWS have been found to
have a higher risk than the general population for endocrine
abnormalities. Thus, those who have signs and symptoms of
hypothyroidism or growth hormone deciency should be
referred to an endocrinologist for consideration of therapy
with thyroxine or growth hormone replacement. Finally,
with the recent discovery of the somatic mutation GNAQ as
a known cause of SWS, there is hope that future therapies
based on the genes downstream protein products may possibly help prevent and treat SWS.
Patient Course
The boy is now 4 years old (Fig 3). He has received multiple
pulse-laser treatments of his facial port-wine stain that have
been successful in fading the lesion. He has developed bilateral
glaucoma that is treated with topical drops and surgically
implanted drains. Due to intermittent seizure clustering, he

has undergone slow titration of his oxcarbazepine doses until
the seizures stabilized clinically. After a prolonged episode of
right hemiparesis in the setting of a seizure cluster, daily
aspirin therapy was recently initiated. Although not clinically
symptomatic for hypothyroidism, the boy has had his serum
thyrotropin and free thyroxine routinely screened, with normal
results thus far. Possible migraine headaches have been
suspected due to occasional episodes of holding his head,
but these episodes do not occur often enough to initiate daily
medication prophylaxis at this time. Hyperactive and deant
behaviors have been managed with both behavioral therapy
and medications.
Summary
Sturge-Weber syndrome is characterized by facial port-wine

stains that involve either the V1 trigeminal distribution or the
forehead embryologic vascular distribution, glaucoma, and
cerebral vascular malformations.
Neurologic complications can include epilepsy, migraine
headaches, strokelike episodes, and learning and behavioral
difculties.
Identication and treatment of Sturge-Weber syndrome
complications are directed toward the goal of improved quality of
life.
The recently described associated somatic activating mutation in
GNAQ raises hope for potential novel treatments and a preventive
cure.
Note: The view(s) expressed herein are those of the author(s)

and do not reect the ofcial policy or position of Brooke Army
Medical Center, the U.S. Army Medical Department, the U.S.
Army Ofce of the Surgeon General, the Department of the
Army, the Department of the Air Force and Department of
Defense or the U.S. Government.
Vol. 36 No. 9
SEPTEMBER 2015
e33
Suggested Reading
Comi AM, Bellamkonda S, Ferenc LM, Cohen BA, Germain-Lee EL.
Central hypothyroidism and Sturge-Weber syndrome. Pediatr
Neurol. 2008;39(1):5862
Irving ND, Lim JH, Cohen B, Ferenc LM, Comi AM. Sturge-Weber
syndrome: ear, nose, and throat issues and neurologic status.
Pediatr Neurol. 2010;43(4):241244
Lo W, Marchuk DA, Ball KL, et al; Brain Vascular Malformation
Consortium National Sturge-Weber Syndrome Workgroup.
Updates and future horizons on the understanding, diagnosis, and
treatment of Sturge-Weber syndrome brain involvement. Dev Med
Child Neurol. 2012;54(3):214223
e34
Miller RS, Ball KL, Comi AM, Germain-Lee EL. Growth hormone
deciency in Sturge-Weber syndrome. Arch Dis Child. 2006;91
(4):340341
Shirley MD, Tang H, Gallione CJ, et al. Sturge-Weber syndrome and
port-wine stains caused by somatic mutation in GNAQ. N Engl J
Med. 2013;368(21):19711979
Tallman B, Tan OT, Morelli JG, et al. Location of port-wine stains and the
likelihood of ophthalmic and/or central nervous system
complications. Pediatrics. 1991;87(3):323327
Waelchli R, Aylett SE, Robinson K, Chong WK, Martinez AE, Kinsler VA.
New vascular classication of port-wine stains: improving
prediction of Sturge-Weber risk. Br J Dermatol. 2014;171
(4):861867

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EgyptianPediatrics

Fever of Unknown Origin: Where Science Meets Art

Pediatric Fever of Unknown Origin

Constipation and Encopresis in Childhood

Patient Safety and Quality Improvement:

Case 1: Intractable Rash in a 7-month-old Boy

Case 2: Cardiovascular Shock Following Acute

Case 3: A Vascular-appearing Eyelid Mass in

Visual Diagnosis: Newborn With a Facial Vascular

Vol. 36 No. 9 September 2015

Answer Key appears on page 427.

AUTHOR DISCLOSURE Dr Rathore has

Fever of unknown origin (FUO) is a relatively uncommon condition in United

Laboratory and Imaging Evaluation in Fever of Unknown Origin

Erythrocyte sedimentation rate

Examination of peripheral smear

Complete metabolic panel

Tuberculin skin test/Interferon gamma release assay

Sinus computed tomography scan

Antinuclear antibody, rheumatoid factor, complement 3,

Stool culture and ova & parasites

Bone marrow aspiration

Mobeen Rathore, MD, CPE*

Professor and Director,

Pediatric Fever of Unknown Origin

After completing this article, readers should be able to:

1. Adopt a systematic approach to evaluation and management of fever

AUTHOR DISCLOSURE Drs Antoon, Potisek,

time of day, activity level, menstrual cycle, and other factors.

DEFINITION OF FEVER OF UNKNOWN ORIGIN

Figure 1. Causes of pediatric fever of unknown origin.

FEVER OF UNKNOWN ORIGIN IN DEVELOPING

developing countries from 1990 to 2008. In published

ages 12 to 59 months had a corresponding increase in

History and Physical Examination

Pseudo-FUO has been dened as successive episodes of

For example, coccidioidomycosis is more common in the

in relation to fever can lead to a diagnosis. Because many

Zoonoses and Fever of Unknown Origin

Psittacosis, cryptosporidiosis, histoplasmosis, West Nile virus

Bartonella henselae, tularemia, Pasteurella multocida, rabies, Capnocytophaga, Salmonella,

Cows, Sheep, Goats

Escherichia coli, Campylobacter, Salmonella, Cryptosporidium, Coxiella, tularemia, Brucella

Rabies, Brucella, Pasteurella multocida, Capnocytophaga, Salmonella, Campylobacter, Giardia

Salmonella, Campylobacter, cryptosporidiosis, toxocariasis, tuberculosis, leptospirosis, listeriosis,

Water (Fish, Water Mammals, Oysters Clams)

Mycobacterium marinum, schistosomiasis, Vibrio parahaemolyticus, V vulnicus, Brucella

Toxoplasma gondii, Rickettsia prowazekii

Salmonella, Campylobacter, Cryptosporidium, Giardia lamblia, Clostridium difcile, Brucella,

Insect Bites (Mosquitoes, Ticks, Fleas)

Salmonella, tularemia, Yersinia, Cryptosporidium, Trichophyton, Pasteurella multocida, rabies,

Salmonella, Edwardsiella tarda, Plesiomonas, pentastomiasis

Laboratory Studies and Imaging

a particular disease process. Trending CRP values are a more

Physical Findings and Associated Fever of Unknown Origin

Lymphoma, metastatic carcinoma, relapsing fever, granulomatous hepatitis,

Liver edge tenderness

Bartonellosis, liver abscess

Infective endocarditis, brucellosis, enteric fever

Leukemia, lymphoma, tuberculosis, brucellosis, infective endocarditis,

Infective endocarditis, atrial myxoma

Typhoid fever, malaria, leptospirosis, psittacosis, central fever, drug fever

Miliary tuberculosis, toxoplasmosis, vasculitis

Leptospirosis, relapsing fever, Rocky Mountain spotted fever