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SPECIAL ISSUE ARTICLE

Evaluation of Prolonged and


Recurrent Unexplained Fevers
Victoria A. Statler, MD, MSc; and Gary S. Marshall, MD

ABSTRACT perature is affected by age, activity level,


Fever is a common symptom in children. Some children may present to their primary meals, and environmental conditions. Its
care physician with undifferentiated fever; that is, fever for which there is no obvious source measurement is also affected by anatom-
from the history or physical examination. Undifferentiated fevers may be prolonged or re- ic site, be it forehead, tympanic mem-
current. Distinguishing between the two is helpful for narrowing the differential diagnosis, brane, sublingual space, axilla, or rectum.
which can be broad and include infections and inflammatory diseases and, rarely, malig- The number of different temperature-
nancies and autoinflammatory disorders. The evaluation of such children requires a step- measuring devices (eg, glass-liquid,
wise approach. Taking a detailed history, performing a thorough physical examination, and digital, color-change) only complicates
reviewing a fever and symptom diary is crucial in recognizing clues that may ultimately matters. Contemporary authors and lay-
lead to a diagnosis. Some children who look good and whose fever disappears may never people cannot seem to agree on what
have a diagnosis, whereas referral to a specialist may be prudent for others. [Pediatr Ann. “normal” is—what number of degrees
2018;47(9):e347-e353.] is normal, how and where temperature
should be measured, and whether or not
to use a “correction factor” to approxi-

F
ever is one of the most common WHAT IS FEVER? mate core body temperature.
reasons that children visit a doctor. In 1992, Mackowiak et al.1 chal- If clinicians cannot agree on what
Most of the time fever is part of a lenged the concept—axiomatic since “normal” body temperature is, then it is
self-limited viral infection; however, it can 1869, when Wunderlich and Reeve2 said even more difficult to agree about what
be a sign of a serious illness such as a life- it was so—that 37°C (98.6°F) is the nor- body temperature constitutes “fever,”
threatening infection or malignancy. Rare- mal human body temperature. By mea- which is defined as the endogenous rise
ly, the fever is prolonged or recurrent and suring oral temperatures 3 times daily in of core body temperature above normal
the etiology is not readily apparent. The 148 healthy volunteers, they determined (there is no debate that fever is a warn-
differential diagnosis of these unexplained that the average body temperature is dif- ing sign that something is wrong).5,6 The
fevers is broad, and the evaluation of such ferent between people and fluctuates by only “official” definition of fever, to our
children requires a step-wise approach and the time of day within people. Other knowledge, comes from the Brighton
often the help of subspecialists. authors3,4 have shown that body tem- Collaboration, whose working groups
labor to create definitions of adverse
Victoria A. Statler, MD, MSc, is an Assistant Professor of Pediatrics. Gary S. Marshall, MD, is a Professor events after vaccination. Based on expert
of Pediatrics and the Division Chief. Both authors are affiliated with the Division of Pediatric Infectious opinion and literature review, Marcy et
Diseases, University of Louisville School of Medicine. al.6 (writing for the Brighton Collabora-
Address correspondence to Victoria A. Statler, MD, MSc, University of Louisville School of Medicine, tion) suggest that fever is the endogenous
571 S. Floyd Street, Suite 321, Louisville, KY 40202; email: victoria.statler@louisville.edu. elevation of at least one measured body
Disclosure: Gary S. Marshall discloses an honorarium received for service on an advisory board for temperature of ≥38°C (100.4°F), regard-
Novartis. The remaining author has no relevant financial relationships to disclose. less of the intrinsic and extrinsic fac-
doi:10.3928/19382359-20180806-01
tors mentioned above (in other words,

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at any anatomic site, using any device, “low,” and that anything above “normal” median duration of 30 days.12 In 71% of
at any age, and under all environmental constitutes a fever. Kleiman11 described these children with unexplained fever,
conditions).6 By the group’s own admis- children like this as having “pseudo- the fever had occurred on consecutive
sion, this definition is arbitrary; perhaps fever of unknown origin.” The parents’ days without interruption. The remain-
less arbitrarily, one could see the logic belief that something is wrong is real, ing 69% of children in the study had re-
of adjusting the reading of an axillary but manifestations of real disease are not current fevers.12
temperature upward to more closely ap- found. Family stress, recent illness or
proximate core body temperature.7 death of a loved one, behavior problems, PROLONGED UNEXPLAINED FEVER
and school absences may be clues to the Prolonged unexplained fever (PUF)
FEVER AS CHIEF COMPLAINT diagnosis. refers to sequential daily fevers that last
Fever is one of the most common beyond the typical (viral) illness; in this
presenting complaints in children, repre- UNDIFFERENTIATED FEVER regard, it is useful to remember that the
senting about 35% of unscheduled visits One has to be careful not to label fe- fever from nearly all viral illnesses will
to pediatric offices.8 Most children who brile illnesses as “undifferentiated” if resolve within 1 week. Most children
present with fever have additional signs there are clues in the history, physical will likely have seen their doctor before
and symptoms that lead to a specific diag- examination, or simple laboratory tests a fever becomes prolonged, and they
nosis. In this review, undifferentiated fe- that suggest a specific diagnosis at the may have been given the diagnosis of vi-
ver is present when a previously healthy index visit. Some children present with ral syndrome (not otherwise specified).
child presents as an outpatient with fever common manifestations of uncommon PUF does not become an issue until the
as the chief complaint without signs, diseases. For example, fever, rash, and second or third visit for a given illness.
symptoms, or physical findings of a spe- headache in the summertime could be PUF used to be called fever of un-
cific clinical illness.9 Not included, for caused by Rocky Mountain spotted fe- known origin (FUO) (PUF makes more
example, would be the febrile 6-month- ver, whereas fever, cough, and lymph- sense, as the term FUO does not convey
old infant with otitis media, or the 3-year- adenopathy could be histoplasmosis; the fact that the problem is the length
old toddler with an upper respiratory in- one can appreciate how geography in- of time the fevers have persisted). The
fection. Undifferentiated fever should not fluences the likelihood of each of these FUO concept in adults was introduced
be confused with fever without source, diagnoses. Fever and an erythematous by Petersdorf and Beeson in 196113 but
which refers to the febrile 3- to 36-month papule over a healed scratch could be was not addressed in children until the
old child who is at risk for occult bacte- clues to the diagnosis of cat scratch dis- 1970s. Between 1972 and 1998, five
rial infection.10 ease; one can appreciate how pet expo- major articles about FUO were pub-
Self-limited undifferentiated febrile sure affects the prior probability here. lished. Each was a retrospective case
illnesses are common in a primary pe- A detailed history may give it away— series from an academic medical center,
diatric practice despite the paucity of typhoid fever, for example, suspected and each used a different definition of
literature on the topic. Pediatricians are in the patient who has recently returned fever.14-18 These articles established the
experienced in testing and treating, or from traveling. Other patients may pres- four etiologic categories for FUO that
waiting out, these incidents. The chal- ent with uncommon manifestations of have been taught in pediatric training
lenge comes in undifferentiated fevers common diseases. For example, bacte- ever since: infectious diseases, inflam-
that are recurrent or prolonged. What rial pneumonia and pyelonephritis can matory conditions, neoplasms, and mis-
testing should be done in the office? present with fever alone. Providers must cellaneous causes (Figure 1).
What is the natural history? What is the follow all leads and think of all possible In the earlier studies about FUO,14-16
risk of a serious condition? What patient causes before deciding that a child truly infectious causes made up 29% to 52%
should be referred, and to whom? has undifferentiated fever.9 of cases. Final diagnoses included viral
Ironically, some children with “un- Undifferentiated fevers may be pro- syndrome, urinary tract infection, and
differentiated fever” are not experienc- longed or recurrent (Figure 1). In one osteomyelitis, as well as more specific
ing a fever at all. Parents may be con- recent study, 31% of 221 children re- infections like tuberculosis, typhoid fe-
cerned that their child’s temperature of ferred to an ambulatory pediatric infec- ver, and malaria. However, fever as a
99.0°F is a fever because of their belief tious diseases practice for unexplained presenting and predominant symptom
that the child’s temperature usually runs fever had a prolonged pattern, with a occurs commonly in diseases other than

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Figure 1. Undifferentiated fever schematic. Asterisk indicates that consideration of a primary immune deficiency should be given to children with severe,
unusual, or recurrent infections. ALL, acute lymphocytic leukemia; ARF, acute rheumatic fever; EBV, Epstein-Barr virus; FMF, familial Mediterranean fever; HIDS,
hyper-immunoglobulin D syndrome; IBD, inflammatory bowel disease; JIA, juvenile idiopathic arthritis; PFAPA, periodic fever, aphthous stomatis, pharyngitis,
adenitis; SLE, systemic lupus erythematosus; TRAPS, tumor necrosis receptor-associated periodic syndrome.

infections. The early series found in- panels with rapid turnaround times, high malaria (Table 1). The review of sys-
flammatory disorders in 10% to 20% sensitivity and specificity, and the abil- tems may uncover clues to inflammato-
of children and malignancies in 4% to ity to test for several etiologies at once ry syndromes: weight loss and diarrhea
13%. In these early case series, 12% to have replaced less sensitive and labori- may indicate inflammatory bowel dis-
20% of children never received a spe- ous culture methods. Not surprisingly, ease, whereas fleeting, salmon-colored
cific diagnosis made.14-16 then, diagnoses of infectious diseases rash may indicate systemic-onset juve-
The etiologies of PUF have changed have become less common, and “no di- nile idiopathic arthritis (JIA). Physical
over time. In more recent case series, agnosis” more common among children examination may reveal important find-
specific infectious diseases like cat with PUF referred to academic medical ings: firm, rubbery, matted supracla-
scratch disease, tularemia, and Epstein- centers.17,18 vicular lymph node may indicate malig-
Barr virus infection were more com- The primary challenge represented nancy; whereas exudative tonsillitis and
monly reported. This does not mean that by patients with PUF is differentiating splenomegaly may indicate infectious
these diseases were necessarily emer- life-threatening infections or malignan- mononucleosis. Table 1 is a list of pos-
gent, but rather that the diagnoses were cies from prolonged viral syndromes sible infectious, inflammatory, and ma-
being made more often because of read- and other conditions that may not re- lignant etiologies, clues that should be
ily available specific diagnostic tests. quire treatment. The first step is to de- sought, and targeted diagnostic studies
These same diagnostic modalities have termine the fever pattern and catalog the that could confirm the diagnosis.
become more accessible, so more chil- diagnostic studies performed to date. Often there may be no clues to the
dren with PUF are probably being di- Next comes a detailed history, which diagnosis at the outset. In these cases, a
agnosed in the primary care setting and may lead the clinician down a specific good starting point would be to obtain
not being referred. Studies using mag- diagnostic path. Certain exposures serial standard laboratory studies that
netic resonance imaging or even lymph should trigger consideration of “expo- might eventually point you in the right
node biopsy are now performed in an sure-disease pairs,” such as kittens and direction. Inflammatory markers that
ambulatory setting prior to subspecialty cat scratch disease, unpasteurized milk remain normal or are down-trending
consultation. Polymerase chain reaction and brucellosis, and travel to Africa and are less worrisome than those that con-

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TABLE 1.

Targeted Studies for Fever of Unknown Origin

Test Diagnosis Reason for Suspicion


Infections
Bartonella serology Cat scratch disease Exposure to kittens, cat scratch with papule, regional adenopathy
EBV serology EBV infection Fatigue, lymphadenopathy, cytopenias, elevated LFTs
H
 istoplasma complement fixation and Histoplasmosis Residence in Ohio or Mississippi River Valleys, bird exposures
immunodiffusion
B
 lastomyces complement fixation and Blastomycosis Skin lesion, exposure to beavers, creeks
immunodiffusion
Brucella serology Brucellosis Consumption of unpasteurized milk products
Toxoplasma serology Toxoplasmosis Exposure to cats or litter boxes, consumption of poorly cooked meat
Francisella serology Tularemia Tick bite with eschar, rabbit hunting
Tuberculin skin test, IGRA Tuberculosis Exposure to active case, homeless shelter, travel
HIV Ab/Ag or PCR HIV infection Sexually active, IVDU, mononucleosis-like syndrome, cytopenias
Blood culture for Salmonella Typhoid fever Travel, hepatosplenomegaly, rose spots
Thick and thin smears Malaria Travel, anemia
C
 hlamydophila psittaci complement Psittacosis Exposure to domestic and wild birds
fixation or microimmunofluorescence
Coxiella burnetii serology Q fever Participation in animal births
Leptospira serology Leptospirosis Adventure travel, participating in sporting events that involve swimming in
rivers or lakes
Inflammatory disorders
Stool calprotectin, fecal occult blood Inflammatory bowel Anemia, fatigue, blood in stool, diarrhea, abdominal pain, weight loss
test disease
ASO titer, anti-DNAse B titer Rheumatic fever Heart murmur, migratory polyarthritis, erythema marginatum
ANA, RF, C3, C4 Various rheumatologic Arthritis, anemia, proteinuria, rash
disorders
Malignancy
Bone marrow aspirate, lymph node Leukemia, lymphoma Cytopenias, weight loss, bleeding, bruising, lymphadenopathy, night sweats
biopsy, peripheral smear
Miscellaneous
Free T4, TSH Hyperthyriodism Weight loss, hair loss, nervousness, tremors
Abdominal CT or U/S Abdominal abscess Abdominal pain, distension, history of surgery or IBD
Sinus CT Sinusitis Headache, congestion

Abbreviations: Ab, antibody; Ag, antigen; ANA, antinuclear antibody; ASO, anti-streptolysin O; C3, complement component 3; C4, complement component 4; CT, computed tomography; EBV, Epstein-Barr
virus; HIV, human immunodeficiency virus; IBD, inflammatory bowel disease; IGRA, interferon gamma release assay; IVDU, intravenous drug use; LDH, lactate dehydrogenase; LFTs, liver function tests;
PCR, polymerase chain reaction; RF, rheumatoid factor; T4, thyroxine; TSH, thyroid stimulating hormone; U/S, ultrasound.
Adapted from Marshall.9

tinue to rise, potentially signifying a given a fever/symptom diary and asked ness determines the cadence of testing.
more serious condition. Clinically ill to return for follow-up at weekly in- Patients who are sicker or becoming
children may warrant hospitalization tervals for repeated examinations and sicker at a rapid pace require more ex-
or more extensive evaluation at the first other diagnostic studies. To paraphrase tensive testing early on, whereas those
visit. Well-appearing children may be Long and Edward,19 the pace of the ill- who are clinically well and able to at-

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tend school or play with siblings may deficiency is shown in Table 2, but test- TABLE 2.
be evaluated in a step-wise fashion. ing should be tailored to the particular
After the third or fourth visit to the pri- infectious disease history. Immunology Tests Based
mary care provider without a diagnosis, A fever diary helps determine if the on Type of Immune
an infectious disease consultation may fever episodes are distinct or are part of Deficit
be requested. Referral to oncology, a more threatening process. It is rare for Humoral
rheumatology, or gastroenterology may a single infection to cause prolonged (as IgG, IgA, IgM, IgE levels
also be warranted depending on the test opposed to continuous) intermittent fe- A
 ntibody response to vaccine antigens
(eg, diphtheria toxoid, pneumococcal
results and symptoms. vers, although an intermittent fever pat-
polysaccharide)
tern may be seen with subacute bacte-
Immunophenotype (flow cytometry)
RECURRENT UNEXPLAINED FEVER rial endocarditis, deep-seated abdominal
Cellular
Recurrent unexplained fever abscess, or osteomyelitis, especially if
H
 IV Ag/Ab (4th generation EIA) or HIV
(RUF) may be intermittent or periodic antibiotics, which could suppress the in- DNA PCR
(Figure 1). In the case series alluded fection, were received during the illness. L ymphocyte proliferative response to
to above,12 61% of children referred Cases of relapsing fever in the United mitogens
for RUF had an intermittent fever pat- States are usually caused by Borrelia Phagocytic
tern and 39% had a periodic pattern. hermseii or Borrelia recurrentis, which Absolute neutrophil count
The majority of children with RUF will are transmitted by the bites of ticks or D
 ihydrorhodamine (DHR) oxidative burst
have intermittent fevers. Intermittent lice, respectively. Relapsing fever is assay
fevers are common in children and are characterized by sudden onset of high Complement system
usually due to sequential self-limited vi- fever and chills that end spontaneously CH50
ral infections. In fact, children younger after a few days, followed by an afebrile Abbreviations: Ag, antigen; Ab, antibody; EIA, enzyme
than age 2 years normally have five or period of days to weeks, then by one or immunoassay; Ig, immunoglobulin; PCR, polymerase
chain reaction.
six (or up to 12 for a child in daycare or more relapses, which are generally mild-
with siblings in school or daycare) acute er than the first episode. Malaria may
respiratory illnesses per year.20 So it is cause paroxysms of fever that occur ev-
not unusual (albeit, a bit unlucky) for a ery other day (Plasmodium falciparum, toms include rash, serositis (abdominal
child to have a febrile illness about every Plasmodium vivax, and Plasmodium pain, pericarditis, pleuritis), arthritis,
6 weeks, especially in the winter; there- ovale) or every third day (Plasmodium aphthous ulcers, and elevated inflam-
fore, one need not always have to con- malariae). matory markers. Whereas autoimmune
sider an underlying medical condition. Intermittent fever can be a sign of disorders will worsen over time without
When does the number of febrile ill- an autoimmune disorder, like inflam- treatment, autoinflammatory disorders,
nesses merit additional evaluations? Pri- matory bowel disease or JIA. Although because the innate immune system does
mary immunodeficiencies are rare in the clinicians may think of these diseases not exhibit memory, will continue to
United States, with a prevalence of 1 per as presenting with organ-specific com- have distinct stereotypical episodes that
20,000.21 Conceivably, a child with an plaints, fever alone can be the prominent are usually no different in magnitude
immune deficiency could present with symptom, as it was in 83% of children than the previous episodes, although
intermittent fevers in the absence of de- diagnosed with Crohn’s disease in one some of these disorders will lead to amy-
fined specific infections. Several sets of case series24 and in 98% to 100% of loidosis over time.26 Fever is a predomi-
criteria have been proposed for suspect- children with systemic onset JIA.25 Au- nant symptom in familial Mediterranean
ing a primary immunodeficiency; the toinflammatory disorders are rare but fever, tumor necrosis factor receptor-as-
most publicly acknowledged are those should be considered once infections, sociated periodic syndrome, and hyper-
from the Jeffrey Modell Foundation.22 immune deficiencies, malignancies, and immunoglobulin D syndrome.
Children with primary immune deficien- autoimmune disorders have been ruled Periodic fevers occur with clockwork
cies are likely to have some combina- out. These conditions are characterized predictability, but cyclic neutropenia
tion of a positive family history, failure by stereotypical episodes of inflamma- and PFAPA (periodic fever, aphthous
to thrive, and unusual or severe infec- tion caused by dysregulation of the in- stomatitis, pharyngitis, and adenitis)
tions.23 A reasonable screen for immune nate immune system. Common symp- syndrome are the only causes. Cyclic

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SPECIAL ISSUE ARTICLE

neutropenia is characterized by fever, these tests may not be that helpful in dif- 8. McGowan JE, Bratton L, Klein JO,
Finland M. Bacteremia in children seen in
aphthous ulcers, malaise, and occasional ferentiating PFAPA from other etiolo-
a “walk-in” pediatric clinic. N Engl J Med.
bacterial infections every 21 days, coin- gies. Episodes can be aborted with oral 1973;288:1309-1312.
cident with a drop in blood neutrophil steroids, and tonsillectomy appears to be 9. Marshall G. Prolonged and recurrent fe-
count. It is caused by a mutation in the curative in most patients.31 vers in children. J Infect. 2014;68:S83-S93.
doi:10.1016/j.jinf.2013.09.017.
neutrophil elastase gene, resulting in cy- 10. Baraff LJ. Management of infants and young
clical decreased production of myeloid CONCLUSION children with fever without source. Pediatr
progenitor cells in the bone marrow. The Children with PUF and RUF will Ann. 2008;37:673-679.
11. Kleiman MB. The complaint of persistent
diagnosis can be made by obtaining se- continue to present to outpatient prac- fever. Pediatr Clin North Am. 1982;29:201-
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weekly, looking for those nadirs that oc- may help narrow the differential diagno- 12. Statler VA, Marshall GS. Characteristics
of patients referred to a pediatric infectious
cur every 21 days.27 sis. Taking a detailed history, perform-
diseases clinic with unexplained fever. J
PFAPA syndrome is the most com- ing a thorough physical examination, Pediatric Infect Dis Soc. 2016;5:249-256.
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