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Fever of Unknown Origin in Children
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EDUCATIONAL OBJECTIVES
1. Review the history behind the di-
agnosis and purported outcomes
in fever of unknown (FUO) origin
in children.
2. State the importance of thorough
and serial history-taking and
physical examinations in the ap-
proach to the evaluation of FUO.
3. Describe the role of basic labora-
tory testing followed by special-
ized testing in the evaluation of a
child with FUO.
Carl J. Seashore, MD, is Assistant Profes-
sor of Pediatrics and Director, Pediatric Di-
agnostic Referral Service, Division of Gen-
eral Pediatrics and Adolescent Medicine,
University of North Carolina at Chapel Hill
School of Medicine, Chapel Hill, NC. Jacob
A. Lohr, MD, is the Jacob A. Lohr, MD, Dis-
tinguished Professor of General Pediatrics,
and Chief, Division of General Pediatrics
and Adolescent Medicine, Division of Gen-
eral Pediatrics and Adolescent Medicine,
University of North Carolina at Chapel Hill
School of Medicine.
Address correspondence to: Carl Sea-
shore, MD, Division of General Pediatrics
and Adolescent Medicine, Campus Box
7225, University of North Carolina, Cha-
pel Hill, NC, 27599; or e-mail: carl_sea-
shore@med.unc.edu.
Dr. Seashore and Dr. Lohr have disclosed
no relevant financial relationships.
doi: 10.3928/00904481-20101214-07
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4001Seashore.indd 26
F
ever of unknown origin (FUO)
in children remains one of the
most challenging clinical evalu-
ations for the pediatric clinician. Evalu-
ation of fever of unknown origin in chil-
dren benefits from an understanding of
the historical definition of this entity and
how its definition has changed over time.
Early literature from adults branded this
diagnosis with associations of illnesses
bearing high rates of morbidity and mor-
tality (see Sidebar, page 28).
THREE STUDIES
Three cardinal case series from the
1970s established the early definition of
FUO, specifically in children, as the pres-
ence of documented, persistent fever in a
child lasting 2 to 3 weeks without a clear
etiology based upon history, physical ex-
amination, and initial screening laboratory
studies.1-3 These case series, including 253
children total, found that roughly 30% to
50% of the patients had identifiable infec-
tious diseases; 10% to 20% had collagen
vascular disease; 10% had malignancy;
and 10% remained undiagnosed.
Rare diseases made up a small propor-
tion of diagnoses in all three series. Re-
ported long-term morbidity and mortality
were much lower than in similar series
of adult patients.1-3 An additional com-
Carl J. Seashore, MD; and Jacob A. Lohr, MD
mon feature from these early case series
was exposure to empiric antibiotics, often
causing a delay in diagnosis. All children
were admitted to the hospital for their de-
finitive evaluation.
Among the infectious causes of FUO
noted in these pediatric series, many fa-
miliar diagnoses populate the identified
causes, but none predominates. Urinary
tract infections, pneumonia, infectious
enteritis, and bacteremia were all identi-
fied by history, physical examination, or
simple laboratory studies. Tuberculosis
was common and often was found only af-
ter a positive skin test prompted more fo-
cused evaluation. One case of cat scratch
disease was identified, but numerous case
reports since the 1970s have highlighted
this disease as an important entity when
evaluating FUO in children.4-10
Second-most common were categori-
cally autoimmune diseases, such as juve-
nile inflammatory arthritis (JIA) or inflam-
matory bowel disease (IBD). Each series
also identified a relatively small number of
malignancies, most commonly leukemia
and lymphoma. All three papers concluded
that careful, serial history-taking and phys-
ical examinations, along with judicious,
focused laboratory tests (see Figure, page
28), were the most useful tools in evaluat-
ing children with FUO. Although newer
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diagnostic modalities have emerged since
the 1970s, leading to earlier diagnosis of
specific illnesses, these tenets remain the
foundation for evaluating children today.
In today’s practice, hospital admission
is less common for a pediatric patient with
a FUO unless a specific indication (eg, a
ruptured appendix or malignancy) exists,
so more evaluations are conducted in the
outpatient setting. Fever without a source
(FWS; see article, page 21) is a distinct
entity with special considerations in the
young infant and toddler populations and
is approached differently from a FUO.
However, children presenting initially
with FWS may progress to meet FUO cri-
teria if the cause is not identified early and
fever persists. Serial evaluation is critical
for these children as well. Children with
periodic fever syndromes (see article on
Periodic Fevers, page 48) often are referred
for a FUO evaluation. It is the characteris-
tic recurring nature of fever in these chil-
PEDIATRIC ANNALS 40:1 | JANUARY 2011
4001Seashore.indd 27
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dren along with specific findings in the his-
tory and physical examination (see Table 1,
page 29) that should prompt evaluation for
one of these syndromes.11-13
Most children presenting with fever
have either an identifiable entity at pre-
sentation that directs treatment or further
evaluation, or, more likely, have a self-lim-
ited viral illness that will “run its course,”
with attention to symptomatic care and a
watchful eye for secondary complications.
Children in whom fevers persist beyond 10
days, despite reassuring findings initially,
warrant more careful follow-up and are the
focus of the rest of this article.
THE MODERN OFFICE
The modern pediatric office is striving
to resemble a primary care medical home
and is often well equipped to begin the
evaluation of a child with FUO. In many
offices, sick children are seen by the first
available provider rather than an identi-
© iStockphoto.com
fied primary care provider (PCP). Children
with FUO ideally should be evaluated seri-
ally by the same provider, but modern re-
cord systems should optimize information
sharing among partners and with outside
providers when they are consulted.
Subtle changes in the history or physi-
cal examination or different ways of phras-
ing the same basic questions often help
elucidate subtleties that might otherwise be
overlooked. Consulting a colleague to lend
a fresh pair of eyes can be beneficial and
is preferable to the child simply seeing a
different provider on serial visits when
FUO is the chief complaint. Method of
temperature assessment at home should
be reviewed with the parent and its accu-
racy verified. It is sometimes helpful to
plot the occurrence of fever over time and
its diurnal variation.
Offices using mid-level providers
should promote a culture of collegiality in
which a physician can be readily consulted
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SIDEBAR.
Lessons Learned from the
Early Literature of FUO
1. Serial histories and physical examina-
tions are crucial in establishing a diagnosis.
2. A carefully performed and unremark-
able physical examination is predictive of a
benign outcome.
3. A diagnosis is most often reached us-
ing routine laboratory studies.
4. Early empiric antibiotics can obscure or
delay making a specific diagnosis in children
with FUO.
Source: Seashore CJ
for assistance in guiding evaluation when
needed. Reflex referral of a child with
FUO before beginning a thoughtful evalu-
ation may lead to a delay in diagnosis, de-
pending on the availability of specialists in
different areas and the range of expertise
these colleagues possess.
LAB STUDIES
After a careful history and physical
examination (see Table 2, page 29), ini-
tial screening laboratory studies should
be obtained.
As in the early case series, a com-
plete blood count (CBC), with manual
differential, erythrocyte sedimentation
rate (ESR), blood culture, urinalysis,
and urine culture, universally should be
obtained. Serum chemistries, including
liver enzymes, protein and albumin, lac-
tate dehydrogenase (LDH) and uric acid,
should be considered. C-reactive pro-
tein, a marker of acute inflammation, is
helpful to delineate acute versus chronic
inflammation when obtained with the
ESR. A tuberculin skin test is indicated
for most patients. A chest radiograph can
be helpful if pneumonia or lymphoma is
considered, and more directed studies
should be obtained based upon the his-
tory and physical examination.
Extensive serologic testing should be
reserved for those patients whose history
supports the diagnosis: A recent summer
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4001Seashore.indd 28
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Periodic?1 Fever FWS?2
FUO?
Fevers
H+P normal? H+P abnormal? Unstable?
documented?
Box 1: Box 1 plus: Consider hospital Box 1 plus: Hospital
Screening labs: CBC Additional labs as admission versus admission for
with diff.; blood Cx; indicated by H+P. home fever log stabilization and
ESR, CRP; serum Consider imaging based on degree of ongoing diagnostic
chemistries; or referral based on illness and caregiver workup.
urinalysis and Cx findings. reliability.
1. See article page 48; 2. see article page 21.
FWS: fever without source. FUO: fever of unknown origin. ESR: erythrocyte
sedimentation rate. CRP: C reactive protein. Cx: Culture. Diff: differential cell count.
H+P: history and physical examination.
Figure. Serial history-taking and physical examinations, along with judicious, focused laboratory tests
were the most useful tools in evaluating children with FUO. The flowchart gives recommendations on
which screening is appropriate for which patients. Source: Seashore CJ.
vacation in Connecticut makes Lyme for Still’s disease (systemic-onset JIA).
disease much more likely, whereas a The classic evanescent rash would fur-
newly acquired kitten should prompt ther support this diagnosis but is not al-
consideration of Bartonella infection. ways observed when the child is being
Imaging of the abdomen for occult in- seen in the office.
fection or malignancy, useful at times In adolescents, IBD is more likely to
in adults with FUO, has not been shown be found and can often present in an in-
to be of benefit in children with FUO. A dolent fashion. Anemia, decreased height
series of 109 patients in whom diagnos- velocity, or delayed sexual maturation and
tic imaging was performed concluded elevated inflammatory markers should
that without localizing clinical findings, draw attention to and necessitate a more
these tests were generally not useful.14 focused evaluation of the intestines.
Admission to the hospital for expedited Review of complete growth charts
evaluation should be considered for chil- should be part of the physical examina-
dren with localizing findings, progres- tion. The growth charts should always be
sive symptoms, clinical deterioration, or included when patients are referred for
concern for maltreatment (eg, Munchau- specialty evaluation or a second opinion,
sen’s syndrome, by proxy). along with relevant office notes, laborato-
ry results, and other clinical information.
WHAT TO SUSPECT In certain circumstances, evaluation
In the young child with fever alone of fever and FUO warrants a more care-
without localizing findings, the clinician ful eye. Children with chronic diseases,
should have a high index of suspicion such as cystic fibrosis and sickle cell
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TABLE 1.

Associations with Periodic Fever Syndromes11-13

Familial Mediterranean Fever
Mediterranean or Middle Eastern descent;
painful episodes with fever (abdominal pain,
arthritis, myalgia, general malaise); fever alone
if younger than 2 years old
Pediatric Fevers, Aphthous Stomatitis,
Hyper IgD Syndrome
Pharyngitis and Adenitis (PFAPA)
Age typically younger than 5 years;
Age typically younger than 1 year; abdomi-
aphthous stomatitis; pharyngitis; cervical
nal pain, vomiting, diarrhea; lymphadenop-
adenitis; abdominal pain, diarrhea; rash,
athy +/- splenomegaly; arthralgias; rash
arthralgia

Source: Seashore CJ

TABLE 2.

Cardinal Elements in the History and Physical Examination of Children with FUO
History Physical Examination
Growth parameters (including trends): HEENT: oral ulcers, thyroid
Symptoms at onset of fever; relevant travel history; pet or other animal
contour, conjunctiva, ears, lymph nodes, scalp; CVR: murmur, tachycar-
exposures; immunization history; current or recent medications; allergies
dia, tachypnea, rales, dullness, work of breathing; ABD: focal tender-
(drug or others); pattern of fever since onset; pattern of additional symp-
ness, guarding; EXT/SKIN: joint tenderness, chronic changes, effusions,
toms; accuracy of fever assessment; past medical, social, family history
rashes, bites, nails; GU: stool guaiac, urethral discharge, ulcers

HEENT: head eyes ears nose throat; CVR: cardiovascular respiratory; ABD: abdominal; EXT/SKIN: extremities skin; GU: genitourinary.

Source: Seashore CJ

anemia, are prone to specific infections
and other complications of their dis-
eases and treatments. Children receiving
medications must be considered for drug
fever, and adjustment of these medicines
should be made in consultation with the
person who is prescribing them.
Certain children, such as those with
tracheotomy tubes, gastric tubes, or co-
chlear implants, for example, have ad-
ditional diagnostic considerations, such
as infections of their sites or portals of
entry for systemic infection. Children
receiving or who have received chemo-
therapy abide by different rules. For the
most part, these patients are under the
care of a subspecialist, but such chronic
conditions are far more common today
than they were 40 years ago and should
not be overlooked when the child pres-
ents to the PCP.
Since the three cardinal articles on
FUO were published in the 1970s, there
have been only a small number of case
series on which to base a more modern
approach, and the lessons from history
suggest a new approach may not be
needed. Most modern references cite
at least 10 days of fever without a clear
diagnosis as the definition of FUO in
children.10,15-17 Talano and Katz reported
on 19 children with FUO followed after
more than 1 year had passed and only
included those in whom a diagnosis was
not made at initial presentation.18 Only
two of these children went on to have
chronic illness (JIA in both), while the
remaining children were well.
Miller et al. described long-term
follow-up of 40 children with FUO 5
years after an initial diagnosis was not
reached.19 In their series, this undiag-
nosed group had a high incidence of
periodic fever (29 of 40), predominantly
among younger patients, and 23 of these
children’s symptoms had resolved at
follow up. Of the 11 with initial daily
fevers, one patient had inflammatory
bowel disease, and another had uve-
itis, while the remainder had recovered.
They also noted that 29% of the children
having initial periodic fevers were noted
to have neurologic problems of varying
significance at 5-year follow up. Cogulu
et al.20 reported on 80 children in Turkey
identified between 1996 and 2001.
They found that 47 of 80 had identifi-
able infections while a smaller number
were diagnosed with collagen vascular
disease (5 of 80) or malignancy (2 of
80). These results suggest that these di-
agnoses currently might be made more
quickly than in previous decades be-
cause they have become better under-
stood. Importantly, this group also noted
lack of a diagnosis in 10 of 80 patients
despite the availability of more modern
diagnostic tools. Periodic fevers and
specific immune deficiencies were de-
scribed in several patients, highlighting
the success of newer diagnostic tools
and a better understanding of certain
disease entities.
More recent case series from Tuni-
sia,21 Kuwait,22 and another from Tur-
key23 all found similar incidences of
infectious diseases, collagen vascular
disease, and malignancy.21-23 The Ku-

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4001Seashore.indd 29 12/29/2010 1:22:42 PM


wait study had a higher overall rate of
infectious diseases, possibly reflect-
ing significant geographic variation in
disease patterns.
A CAVEAT
A caveat must be stated if the defi-
nition of FUO is altered to include pa-
tients with only 10 days of fever. A con-
cern is that this shortened period may
allow for inclusion of more potentially
life-threatening or debilitating acute or
subacute infectious or inflammatory
disorders (aggressive sinusitis compli-
cated by intracranial spread; prolonged
Rocky Mountain spotted fever or Eh-
rlichia infection; Kawasaki disease;
EBV-associated hemophagocytic syn-
drome; systemic lupus erythematosis
complicated by sepsis; and others) that
call for a prompt diagnostic approach.
On the other hand, these disorders are
likely to be accompanied by an abnor-
mal physical examination and/or suspi-
cious initial laboratory studies, which
should compel the diagnostician to
promptly pursue additional studies that
could lead to an accurate diagnosis.
CONCLUSION
FUO in children remains a puzzle
each time pediatricians are faced with
the challenge its evaluation presents.
Initially, children can be managed
competently by the generalist in the
outpatient setting, using time as a di-
agnostic tool with frequent re-evalu-
ation and simple laboratory testing.
Severity of presentation should direct
a faster evaluation or earlier referral
for admission or outpatient specialty
evaluation. A general pediatric refer-
ral service, if available, is often a good
starting point if a clear diagnosis, such
as malignancy, is not evident. Hospital
admission is also indicated when the
patient is unstable or there is concern
for maltreatment or factitious fever.24
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4001Seashore.indd 30
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In the 40 years since the first three
case series describing FUO in chil-
dren, this entity has remained one of
the more challenging diagnostic dilem-
mas for pediatric clinicians. Although
newer diagnostic modalities have likely
hastened the diagnosis of malignancy
and collagen vascular diseases, and a
better understanding of periodic fever
syndromes has allowed identification
of these patients, the challenge still re-
mains about how to approach the child
with an FUO when the child first pres-
ents. Once the child is identified as hav-
ing FUO, serial physical examinations,
careful reviews of the history, and a
basic workup should be started. Careful
attention should be paid to follow-up,
referral, and further evaluation.
Consistency in provider, commu-
nication within the medical home
among providers, and thoughtful fur-
ther workup and referral are all impor-
tant in optimizing the likelihood of a
prompt and accurate diagnosis.
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