Fever of Unknown Origin in Children - Etiology - UpToDate

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Fever of unknown origin in children: Etiology
Author: Debra L Palazzi, MD, MEd

Section Editors: Morven S Edwards, MD, Robert Sundel, MD, Jan E Drutz, MD
Deputy Editor: Mary M Torchia, MD
All topics are updated as new evidence becomes available and our peer review process is complete.
Literature review current through: Feb 2018. | This topic last updated: Mar 02, 2018.
INTRODUCTION — Fever is a common presenting complaint in children, accounting for nearly one-third of
pediatric outpatient visits in the United States [1]. The specific entity of "fever of unknown origin" (FUO), as
opposed to a "fever without a source" (FWS), has occupied a special place within infectious diseases since the
first definition of and series about FUO by Petersdorf and Beeson in 1961 [2]. Although the original definition has
been modified, the assessment of broad categories of illness (including infections, connective tissue disease,
and malignancy) as a cause of FUO remains useful.
Common etiologies of FUO in children will be discussed below. The approach to the child with FUO, FWS, and
fever in unique host groups (eg, newborns, neutropenic children, or those with human immunodeficiency virus
[HIV] infection) are discussed separately. (See "Fever of unknown origin in children: Evaluation" and "Fever
without a source in children 3 to 36 months of age".)
DEFINITION — We apply the term fever of unknown origin (FUO) to children with fever >38.3ºC (101ºF) of at
least eight days' duration, in whom no diagnosis is apparent after initial outpatient or hospital evaluation that
includes a careful history and physical examination and initial laboratory assessment. (See "Fever of unknown
origin in children: Evaluation", section on 'Definitions'.)
OVERVIEW — The number of infectious and noninfectious etiologies of fever of unknown origin (FUO) in
children is extensive (table 1). FUO is usually caused by common disorders, often with an unusual presentation
[3-13].
The three most common etiologic categories of FUO in children in order of frequency are infectious diseases,
connective tissue diseases, and neoplasms [3-15]. In addition, there are causes of FUO, such as drug fever,
factitious fever, central nervous system dysfunction, and others, that do not fit into the above categories. In many
cases, a definitive diagnosis is never established and fever resolves.
In each category below, the conditions are discussed in alphabetical order, rather than by the frequency of
diagnosis.
GENERALIZED INFECTIONS — Generalized infections that cause fever of unknown origin (FUO) typically have
nonspecific presenting features. Obtaining a detailed history of exposures can be critical to making the diagnosis
of these infections. (See "Fever of unknown origin in children: Evaluation", section on 'Exposures'.)
Brucellosis — Brucellosis frequently is considered in the differential diagnosis of FUO because the infection is
indolent, causes nonspecific symptoms and signs, and persists if untreated. It is also often excluded as a
diagnostic possibility, particularly among clinicians who practice in urban areas and may forget to consider the
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disease. Clinical manifestations may include persistent fever and lethargy, osteoarticular complaints and
epididymo-orchitis, hepatosplenomegaly, mild elevation of liver enzymes, and lymphocytopenia.
When considering the possibility of brucellosis, it is important to ask about exposure to animals or animal
products, especially consumption of unpasteurized cheese and/or imported cheese (pasteurization is not
required for certification of imported cheeses). (See "Microbiology, epidemiology, and pathogenesis of Brucella"
and "Clinical manifestations, diagnosis, and treatment of brucellosis".)
Cat scratch disease — Cat scratch disease (CSD, Bartonella henselae infection) is one of the most common
causes of FUO in children [10,16]. While CSD frequently presents with isolated lymph node involvement,
hepatosplenic involvement is the hallmark of CSD associated with FUO. In one series from a single institution, B.
henselae infection accounted for 5 percent of all pediatric cases of FUO and 11 percent of the FUO cases
ultimately determined to be caused by infection [10]. High-resolution abdominal ultrasonography revealing the
multiple hepatic or splenic filling defects that are characteristic of granulomata can provide a provisional
diagnosis. Serology or biopsy of lesions in lymph nodes, liver, or bone marrow can lead to a definitive diagnosis
of B. henselae infection. (See "Microbiology, epidemiology, clinical manifestations, and diagnosis of cat scratch
disease".)
Leptospirosis — Leptospirosis is a common zoonotic infection with worldwide distribution; humans are
incidental hosts, and most infection occurs in tropical climates [17,18]. The clinical manifestations are nonspecific
and may include fever, rigors, myalgias, headache, cough, and gastrointestinal (GI) complaints. Leptospirosis
typically occurs after exposure to environmental sources, such as animal urine, contaminated soil or water
(particularly during swimming), or infected animal tissue. Portals of entry include cuts or abraded skin, mucous
membranes, or conjunctiva. The infection is rarely acquired by ingestion of food contaminated with urine or via
aerosols. (See "Epidemiology, microbiology, clinical manifestations, and diagnosis of leptospirosis" and
"Treatment and prevention of leptospirosis".)
Malaria — Malaria is an important consideration in a child with FUO. Splenomegaly usually accompanies fever.
Although the patient frequently has a history of travel to areas where malaria is endemic, this is not universal;
rare cases have been reported in individuals who have not traveled outside of the United States [19,20]. Malaria
infection can be delayed for months after travel and can arise in those who have taken malaria prophylaxis. The
diagnosis is made by examining appropriately stained thin or thick smears of blood. (See "Malaria: Epidemiology,
prevention, and control", section on 'Epidemiology' and "Clinical manifestations of malaria in nonpregnant adults
and children" and "Diagnosis of malaria".)
Mycobacterial — Tuberculosis (TB) is another important cause of FUO in children. Extrapulmonary TB

(disseminated TB, or TB of the liver, peritoneum, pericardium, or genitourinary tract), is more likely to cause FUO
than pulmonary TB, which is usually evident on chest radiography. Active disseminated TB can occur in children
with negative chest radiography and tuberculin skin tests [21,22]. A high index of suspicion for the disease must
be maintained and a careful history of possible contacts obtained. The diagnosis of TB can be made by culturing
the organism from sputum, gastric aspirates, liver, or bone marrow. Funduscopic examination occasionally can
reveal choroid tubercles. (See "Latent tuberculosis infection in children" and "Tuberculosis disease in children"
and "Clinical manifestations, diagnosis, and treatment of miliary tuberculosis".)
Nontuberculous mycobacterial infection also can cause disseminated infection and FUO, although this is more
common in children infected with the human immunodeficiency virus (HIV). (See "Overview of nontuberculous
mycobacterial infections in HIV-negative patients" and "Mycobacterium avium complex (MAC) infections in HIV-
infected patients" and "Overview of nontuberculous mycobacteria (excluding MAC) in HIV-infected patients".)
Salmonellosis — Salmonella species contaminate a number of food products, especially poultry and eggs, and
can be transmitted through contact with reptiles or animal feces. Salmonella species can cause typhoidal as well
as localized GI illness. Patients with typhoid frequently have normal pulses or even bradycardia in association
with high fevers. The diagnosis can be made with blood and stool cultures, which should be repeated if initially
negative and fevers persist. Serologic testing is not recommended. (See "Epidemiology, microbiology, clinical
manifestations, and diagnosis of enteric (typhoid and paratyphoid) fever" and "Nontyphoidal Salmonella:
Microbiology and epidemiology".)
Toxoplasmosis — Toxoplasmosis is another infection that can cause FUO in children. It should be considered in
children with exposure to soil contaminated with feline feces or consumption of game meat. Fevers are most
often accompanied by cervical or supraclavicular lymphadenopathy, but fever may occasionally be the sole
manifestation. A rise in antibody titer can establish the diagnosis; however, a single high antibody titer is not
sufficient to make a diagnosis of acute infection since immunoglobulin G antibodies to Toxoplasma gondii are
prevalent, and immunoglobulin M antibodies can persist for months. (See "Toxoplasmosis in immunocompetent
hosts".)
Tularemia — FUO resulting from tularemia is more common with the pneumonic or typhoidal forms of the
infection than with the glandular forms. Francisella tularensis can be carried by a variety of animals and insects
(ticks, mosquitoes, lice, fleas, flies) and can be acquired by a bite, ingestion, or inhalation (table 2). Tularemia
should be considered in children with a history of contact with animals, exposure to dead wild carcasses (eg,
rabbits) or ingestion of rabbit or squirrel meat. (See "Clinical manifestations, diagnosis, and treatment of
tularemia".)
Viral infections — Most viruses cause self-limited infections of brief duration. However, cytomegalovirus,
Epstein-Barr virus, adenovirus, hepatitis viruses, enteroviruses, and certain arboviruses can cause FUO.
Symptoms and signs of these infections can be nonspecific and variable. Liver enzymes may be elevated. Viral
cultures, serologic studies, and molecular techniques such as polymerase chain reaction can be used to facilitate
the diagnosis. Additional clinical features and diagnosis of these viruses are discussed separately:
● Cytomegalovirus (see "Overview of cytomegalovirus infections in children")
● Epstein-Barr virus (see "Clinical manifestations and treatment of Epstein-Barr virus infection")
● Adenovirus (see "Pathogenesis, epidemiology, and clinical manifestations of adenovirus infection" and
"Diagnosis, treatment, and prevention of adenovirus infection")
● Hepatitis viruses (see "Overview of hepatitis A virus infection in children" and "Overview of hepatitis B virus
infection in children and adolescents")
● Enteroviruses (see "Enterovirus and parechovirus infections: Clinical features, laboratory diagnosis,
treatment, and prevention")
● Arboviruses (see "St. Louis encephalitis" and "Clinical manifestations and diagnosis of West Nile virus
infection" and "Arthropod-borne encephalitides")
LOCALIZED INFECTIONS — When common localized infections cause fever of unknown origin (FUO), they
may have an unusual presentation. Careful and repeated history and physical examination and careful review
and interpretation of laboratory tests can help to diagnose these infections. All findings, even those that may
seem trivial, must be taken seriously. (See "Fever of unknown origin in children: Evaluation", section on
'Overview of evaluation'.)
Bone and joint — Infections involving the bones and joints usually present with recognizable symptoms.
However, occasionally FUO can be the only manifestation, especially in young children who cannot vocalize their
symptoms. This occurs more commonly with osteomyelitis than with septic arthritis. When FUO is the presenting
complaint, the pelvic bones, small bones, and flat bones are more frequently involved than long bones.
The diagnosis of osteomyelitis or septic arthritis can be suggested by imaging studies, including computed
tomography (CT), magnetic resonance imaging, and radioisotopic bone scanning. All of these modalities are
more sensitive than plain bone radiography. (See "Bacterial arthritis: Clinical features and diagnosis in infants
and children", section on 'Imaging' and "Hematogenous osteomyelitis in children: Evaluation and diagnosis",
section on 'Advanced imaging'.)
Infective endocarditis — Infective endocarditis (IE) is an infrequent but important cause of FUO in children. IE
is rare in normal, term infants but increases in frequency as children age and usually occurs in the setting of a
pre-existing cardiac lesion. Acute bacterial endocarditis generally is fulminant in onset, whereas subacute
infection is more indolent. (See "Infective endocarditis in children".)
The diagnosis of IE can be difficult to establish since patients do not always have positive blood cultures or a
cardiac murmur, especially if the infection is confined to the right side of the heart. Associated nonspecific
laboratory findings can include anemia, leukocytosis, and an elevated erythrocyte sedimentation rate.
Viridans streptococci, enterococci, and staphylococci (including S. aureus and coagulase-negative

staphylococci) are the organisms most commonly isolated. Blood cultures may be negative if patients have
received a trial of empirical antibiotics, have right-sided cardiac involvement, or have infection caused by unusual
or fastidious organisms (eg, Brucella, Coxiella burnetii, Bartonella spp, anaerobes, fungi).
Children with suspected IE as the cause of FUO should have several blood cultures (aerobic and anaerobic)
drawn over a 24-hour period before initiation of antimicrobial therapy. Echocardiography is frequently performed
to assess damage to the heart valves and look for valvular vegetations. However, the absence of these findings
does not exclude the diagnosis of IE.
Intraabdominal abscess — Intraabdominal abscesses, including liver, subphrenic, perinephric, and pelvic
abscesses, can cause FUO. Patients may not have abdominal complaints at presentation. However, the index of
suspicion for an abscess should increase if the patient has a history of prior intra-abdominal disease, abdominal
surgery, or vague abdominal pain.
Pyogenic liver abscesses typically occur in immunocompromised children but can arise in an immunocompetent
child [23]. Many children with liver abscess have hepatomegaly and right upper quadrant tenderness, but some
only have fever. Liver enzymes are usually normal in these patients, and detectable bacteremia is uncommon.
Depending upon the source of the abscess, common pathogens include S. aureus, streptococci, Escherichia
coli, and anaerobes. Imaging of the abdomen, typically with ultrasonography or CT, generally demonstrates the
collection. If imaging is negative, but clinical suspicion of intra-abdominal abscess is high, radioisotope or gallium
scanning may be warranted.
Hepatic infection — Granulomatous hepatitis, which can be caused by a number of organisms, is another
cause of FUO in children. It occurs more commonly in adults, but cases have been reported in children [24],
especially in association with Bartonella. The diagnosis of granulomatous hepatitis can be suggested by
ultrasonography or other diagnostic imaging. However, confirmation requires a biopsy. (See "Hepatic
granulomas".)
Bacterial cholangitis can occasionally cause FUO in the absence of jaundice and other liver function
abnormalities [25,26]. (See "Acute cholangitis".)
Upper respiratory tract infection — It is surprising how frequently upper respiratory tract infections (URI) and
infections of related organs, such as mastoids or sinuses, present as FUO in children [3-5]. Mastoiditis, sinusitis,
chronic or recurrent otitis media, chronic or recurrent pharyngitis, tonsillitis, peritonsillar abscess, and nonspecific
URI have been reported as causes of FUO in children. One would expect these infections to be associated with
localized symptoms, but it appears that complaints may be ignored as trivial.
Urinary tract infection — Urinary tract infection is among the most common causes of FUO in children [8-10]. In
one series, the two most frequent laboratory errors were failure to perform a urinalysis and failure to adequately
pursue the finding of pyuria [4]. (See "Urinary tract infections in infants and children older than one month:
Clinical features and diagnosis", section on 'Clinical presentation'.)
RHEUMATOLOGIC DISEASES — Rheumatologic disease is the second most common etiologic category of
fever of unknown origin (FUO) in children. A positive antinuclear antibody test can suggest the presence of an
underlying connective tissue disorder, particularly systemic lupus erythematosus [27]. (See "Measurement and
clinical significance of antinuclear antibodies", section on 'The significance of a positive test for ANA in the as-yet
undiagnosed patient with musculoskeletal symptoms'.)
Juvenile idiopathic arthritis — Juvenile idiopathic arthritis (JIA, formerly juvenile rheumatoid arthritis, JRA) is a
chronic inflammatory disorder with three distinct forms:
● A systemic presentation with high, spiking fevers, evanescent rash, and lymphadenopathy
● Polyarticular involvement
● Monoarticular involvement, the so-called oligoarticular form
Fever can be observed with all of the three presentations but is nearly universal in the systemic form, which is
the type of JIA most likely to present as FUO [28]. Arthritis may follow the development of fevers by months to
years. Serologic tests are usually negative, and thus, JIA initially may be a diagnosis of exclusion. (See
"Systemic juvenile idiopathic arthritis: Clinical manifestations and diagnosis" and "Polyarticular juvenile idiopathic
arthritis: Clinical manifestations, diagnosis, and complications" and "Oligoarticular juvenile idiopathic arthritis".)
Others — Other collagen connective tissue diseases to consider in the evaluation of FUO include vasculitis (eg,
polyarteritis nodosa) and systemic lupus erythematosus. (See "Vasculitis in children: Classification and
incidence", section on 'Polyarteritis nodosa' and "Systemic lupus erythematosus (SLE) in children: Clinical
manifestations and diagnosis".)
NEOPLASMS — Leukemia and lymphoma are the most common malignancies that cause fever of unknown
origin (FUO) in children. Other less common tumors include neuroblastoma, hepatoma, sarcoma, and atrial
myxoma. (See "Overview of the presentation and diagnosis of acute lymphoblastic leukemia in children and
adolescents" and "Overview of Hodgkin lymphoma in children and adolescents" and "Clinical presentation,
diagnosis, and staging evaluation of neuroblastoma" and "Clinical assessment of the child with suspected
cancer".)
OTHER CAUSES — The other noninfectious causes of fever of unknown origin (FUO) are varied but can be
summarized by the categories and examples below.
Central nervous system dysfunction — Children with severe brain damage or other central nervous system
(CNS) dysfunction can have altered thermoregulation and present with intermittent or recurrent elevated body
temperatures [29,30]. One case was reported of an adolescent with episodes of fever who responded to
phenytoin therapy, suggesting that a form of epilepsy was responsible for the fevers [31]. Epilepsy-induced fever
also has been described in adults [32-35]. In another report, an adolescent had cyclic episodes of fever
accompanied by nausea, vomiting, and emotional disturbance, resulting from a CNS lesion [36].
Diabetes insipidus — FUO in infants and young children can be due to either central or nephrogenic diabetes
insipidus (DI). Since polyuria and polydipsia can be difficult to appreciate during infancy, dehydration or
hypernatremia may be unrecognized until hyperthermia, weight loss, and decreased peripheral perfusion ensue.
The diagnosis of DI can be established by evaluating electrolytes and osmolality simultaneously in serum and
urine for periods of normal hydration and careful water restriction. Serum levels of antidiuretic hormone can also
be determined by radioimmunoassay. (See "Diagnosis of polyuria and diabetes insipidus", section on 'Infants and
children'.)
Drug fever — Fever is a common allergic reaction to drugs, and virtually any drug can cause a drug fever. When
taking a medication history, it is important to include prescription, over-the-counter, and illicit drugs, as well as
complementary and alternative therapies. Topical preparations, such as atropine, can also cause fever. The
duration of use does not help in determining whether the agent is responsible for the FUO.
In addition, some drugs impair thermoregulation or thermoregulatory control mechanisms and cause fever on this
basis rather than as an allergic phenomenon. Examples include phenothiazines, anticholinergic drugs, and
epinephrine and related compounds.
Neither the height of the fevers nor their pattern is helpful in judging whether drugs are the cause. Drugs can
cause low-grade or high and spiking fevers; the pattern can be continuous or intermittent. Fevers resulting from
medications typically disappear within 48 to 72 hours of discontinuation of the drug but can take as long as five to
seven days to resolve and, occasionally, fever can persist for weeks.
Factitious fever — Factitious fever, whether a false report by a parent or patient or related to manipulation of
body temperature by rinsing the mouth with or dipping the thermometer bulb into hot liquid, can be difficult to
establish as the etiology of FUO. However, a number of clues should raise the possibility of factitious fever.
These include:
● Absence of tachycardia and nonspecific symptoms, such as malaise or discomfort, in a patient with a high
fever
● Rapid defervescence without diaphoresis
● Failure of the temperature curve to show normal diurnal variation (see "Fever in infants and children:
Pathophysiology and management", section on 'Normal body temperature')
● Extreme hyperpyrexia
● Discrepancies between temperatures recorded by the patient or by providers not in attendance and those
obtained rectally or when someone is observing in the room
Measuring the temperature of a freshly voided urine specimen, which reflects core body temperature, is one way
to verify or exclude the presence of fever. The temperature of freshly voided urine closely parallels the
temperature obtained orally. Electronic or one-time use thermometers that measure temperature rapidly reduce
the likelihood that a recorded fever is factitious since a provider is usually in attendance to make these
measurements.
A more unusual cause of factitious fever is Munchausen syndrome or Munchausen syndrome by proxy
(caregiver-fabricated illness) in which one person, usually a parent, fabricates symptoms and signs of illness on
behalf of the child. In some of these cases, fevers are actually induced by the injection of infective or foreign
materials, either by the usually older patient or by a parent. (See "Medical child abuse (Munchausen syndrome
by proxy)" and "Factitious disorder imposed on self (Munchausen syndrome)".)
Familial dysautonomia — Familial dysautonomia (also called the Riley-Day syndrome and hereditary sensory
autonomic neuropathy type 3 [HSAN3]), is an autosomal recessive disorder in which autonomic and peripheral
sensory nerve dysfunction results in defective temperature regulation. Hyperthermia or hypothermia may be
observed [37]. The majority of affected children are of Ashkenazi Jewish parentage.
A number of features in the history and physical examination can suggest familial dysautonomia, including a
history of recurrent aspiration or vomiting because of poor coordination of swallowing, excessive salivation,
diminished tearing, excessive or diminished sweating, labile blood pressure, and erythema or blotchiness of the
skin. Fungiform papillae of the tongue may be sparse or absent, and the sense of taste is diminished [38].
Absence of peripheral pain sensation can lead to multiple sites of skin trauma. Deep tendon reflexes and corneal
reflexes usually are impaired, and dysarthria is common. Patients with this syndrome also demonstrate mental
deficiencies and emotional lability. (See "Hereditary sensory and autonomic neuropathies", section on 'HSAN3
(Familial dysautonomia)'.)
Hemophagocytic lymphohistiocytosis — Hemophagocytic lymphohistiocytosis (HLH) is a nonmalignant but

life-threatening disorder in which uncontrolled proliferation of activated lymphocytes and histiocytes leads to
hemophagocytosis and dysregulation and hypersecretion of inflammatory cytokines. HLH encompasses both
familial and reactive disease triggered by infection, immunologic disorder, malignancy, or drugs. Typical
manifestations of HLH are prolonged fever, hepatosplenomegaly, hyperferritinemia, and cytopenias [39,40].
Other common findings include liver dysfunction, coagulopathy, hypertriglyceridemia, or hypofibrinogenemia.
Clinical presentations of patients with primary (familial) and secondary (reactive) HLH are indistinguishable
[41,42]. (See "Clinical features and diagnosis of hemophagocytic lymphohistiocytosis", section on 'Clinical
features'.)
The diagnosis of HLH is based on a patient fulfilling at least five of eight criteria (fever, splenomegaly,
bicytopenia, hypertriglyceridemia and/or hypofibrinogenemia, hemophagocytosis, low/absent natural killer cell
activity, hyperferritinemia, and high soluble interleukin-2-receptor levels) [43]. HLH can manifest initially as FUO
but can rapidly progress to resemble overwhelming sepsis and result in death; therefore, a high index of
suspicion is required to establish the diagnosis. Therapy includes treating the underlying infection or trigger, if
possible, and aggressive immune modulation therapies. Even with prompt and appropriate chemotherapy,
mortality due to HLH is high [40,43,44]. (See "Clinical features and diagnosis of hemophagocytic
lymphohistiocytosis", section on 'Diagnosis' and "Treatment and prognosis of hemophagocytic
lymphohistiocytosis".)
Immunodeficiency — FUO also can be caused by a number of congenital and acquired immunodeficiency
states (eg, HIV). Some children with immunoglobulin deficiencies (eg, Bruton agammaglobulinemia) have a
history of recurrent fevers with or without focal infections. Others with lymphocyte function abnormalities are
more likely to have persistent viral or parasitic infections in association with prolonged fevers. (See "Primary
humoral immunodeficiencies: An overview".)
Infantile cortical hyperostosis — Infantile cortical hyperostosis (Caffey disease) is an inherited disease
characterized by persistent fevers, sometimes as high as 40ºC (104ºF), subperiosteal bone hyperplasia, and
swelling of overlying tissues. Patients with this disease can exhibit irritability and tenderness over the affected
regions in addition to fever. Leukocytosis and an elevated erythrocyte sedimentation rate (ESR) are common
laboratory findings. These clinical features, in conjunction with radiologic demonstration of periosteal
involvement, establish the diagnosis. (See "Differential diagnosis of the orthopedic manifestations of child
abuse", section on 'Infantile cortical hyperostosis (Caffey disease)'.)
Inflammatory bowel disease — Fever is a prominent component of inflammatory bowel disease (IBD) in many
children [45-47] and may be more common than abdominal symptoms, especially in children with Crohn disease.
Ulcerative colitis is a less common cause of FUO in children than Crohn disease; patients with ulcerative colitis
typically have accompanying gastrointestinal (GI) symptoms. (See "Clinical manifestations of Crohn disease in
children and adolescents" and "Management of mild to moderate ulcerative colitis in children and adolescents".)
Abdominal CT can be suggestive of IBD in children with prolonged FUO, even in the absence of GI symptoms,
but contrast studies of the bowel with special attention to the terminal ileum should be performed, especially in
patients with an elevated ESR accompanied by anemia, weight loss, failure of linear growth, or occult blood in
the stool. (See "Clinical presentation and diagnosis of inflammatory bowel disease in children".)
Kawasaki disease — Kawasaki disease is a multisystem vasculitis of unknown, but possible infectious, etiology.
It is an important cause of prolonged fever in childhood. The diagnosis is established primarily on the basis of the
clinical findings (table 3): bulbar conjunctivitis (picture 1), oral changes (picture 2 and picture 3), rash, changes in
the hands and feet (picture 4 and picture 5), and cervical adenopathy. These manifestations may not appear until
the second week of fever or may have occurred and resolved by the time the patient is examined. (See
"Kawasaki disease: Clinical features and diagnosis".)
Kikuchi disease — Kikuchi disease (also known as Kikuchi-Fujimoto disease, Kikuchi histiocytic necrotizing
lymphadenitis) is a benign, unusual disorder characterized by fever and cervical lymphadenopathy that may last
for one to four months [48,49]. Fatigue, hepatosplenomegaly, nausea, vomiting, diarrhea, joint pain, arthritis, and
rash also may occur. Kikuchi disease is more common in females and patients younger than 40 years of age.
The pathogenesis is unknown but thought to be related to a T cell and histiocytic response to an infectious agent.
Lymph node biopsy demonstrating paracortical foci with necrosis and histiocytic cellular infiltrate confirms the
diagnosis. Treatment is supportive. Kikuchi disease may precede or occur in association with an autoimmune
condition. (See "Kikuchi disease".)
Periodic fevers — Several different periodic fever disorders have been described. Some have been classified
as autoinflammatory, referring to episodes of "unprovoked" inflammatory events and are often but not always
accompanied by fever. At least eight such hereditary disorders have been reported [50,51]. (See "Periodic fever
syndromes and other autoinflammatory diseases: An overview".)
The two most common heritable periodic fever disorders in children are familial Mediterranean fever (FMF) and
hyperimmunoglobulin D syndrome (hyper-IgD syndrome or HIDS). The febrile episodes in these disorders
usually recur at irregular intervals. Specific defective genes have been identified for both FMF and HIDS.
● FMF is an autosomal recessive disease found in individuals of Mediterranean descent. It is characterized by

episodic fever and serosal inflammation [52]. (See "Clinical manifestations and diagnosis of familial
Mediterranean fever" and "Familial Mediterranean fever: Epidemiology, genetics, and pathogenesis".)
● HIDS is also an autosomal recessive disease. Clinical manifestations include episodes of fever, skin
eruptions, abdominal complaints, and joint involvement [53-55]. The elevated serum IgD is probably a
secondary effect, and some patients also have had elevated serum levels of IgA [56]. (See
"Hyperimmunoglobulin D syndrome: Clinical manifestations and diagnosis".)
Cyclic neutropenia, also known as cyclic hematopoiesis, is another heritable cause of recurrent fevers. Children
with this disorder are prone to fever during periods of severe neutropenia. Neutropenic cycles usually occur at
regular intervals of 15 to 35 days, with 21 days being the most frequent pattern [57]. (See "Cyclic neutropenia".)
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● Basics topic (see "Patient education: Fever in children (The Basics)")
● Beyond the Basics topic (see "Patient education: Fever in children (Beyond the Basics)")
SUMMARY
● Fever of unknown origin (FUO) has a number of infectious and noninfectious causes (table 1). FUO is
usually caused by common disorders, often with an unusual presentation. (See 'Overview' above.)
● The three most common etiologic categories of FUO in children in order of frequency are infectious
diseases, connective tissue diseases, and neoplasms. In many cases, a definitive diagnosis is never
established and fever resolves. (See 'Overview' above.)
● Generalized infections that cause FUO typically have nonspecific presenting features (table 4). Obtaining a
detailed history of exposures can be critical to making the diagnosis of these disorders. (See "Fever of
unknown origin in children: Evaluation", section on 'Exposures' and 'Generalized infections' above.)
● When common localized infections cause FUO, they may have an unusual presentation (table 4). Careful
and repeated history and physical examination and careful review and interpretation of laboratory tests can
help to diagnose these infections. All findings, even those that may seem trivial, must be taken seriously.
(See 'Localized infections' above and "Fever of unknown origin in children: Evaluation", section on 'Overview
of evaluation'.)
● Noninfectious causes of FUO include collagen vascular diseases (eg, juvenile idiopathic arthritis),
neoplasms, central nervous system dysfunction, diabetes insipidus, Kawasaki disease, drug fever, factitious
fever, inflammatory bowel disease, infantile cortical hyperostosis, and periodic fevers (table 4). (See 'Other
causes' above.)
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REFERENCES
1. Finkelstein JA, Christiansen CL, Platt R. Fever in pediatric primary care: occurrence, management, and
outcomes. Pediatrics 2000; 105:260.
2. PETERSDORF RG, BEESON PB. Fever of unexplained origin: report on 100 cases. Medicine (Baltimore)
1961; 40:1.
3. Lohr JA, Hendley JO. Prolonged fever of unknown origin: a record of experiences with 54 childhood
patients. Clin Pediatr (Phila) 1977; 16:768.
4. McClung HJ. Prolonged fever of unknown origin in children. Am J Dis Child 1972; 124:544.
5. Pizzo PA, Lovejoy FH Jr, Smith DH. Prolonged fever in children: review of 100 cases. Pediatrics 1975;
55:468.
6. Feigin RD, Shearer WT. Fever of unknown origin in children. Curr Probl Pediatr 1976; 6:3.
7. Cogulu O, Koturoglu G, Kurugol Z, et al. Evaluation of 80 children with prolonged fever. Pediatr Int 2003;
45:564.
8. Pasic S, Minic A, Djuric P, et al. Fever of unknown origin in 185 paediatric patients: a single-centre
experience. Acta Paediatr 2006; 95:463.
9. Bourrillon A. [Management of prolonged fever in infants]. Arch Pediatr 1999; 6:330.
10. Jacobs RF, Schutze GE. Bartonella henselae as a cause of prolonged fever and fever of unknown origin in
children. Clin Infect Dis 1998; 26:80.
11. Chantada G, Casak S, Plata JD, et al. Children with fever of unknown origin in Argentina: an analysis of
113 cases. Pediatr Infect Dis J 1994; 13:260.
12. Akpede GO, Akenzua GI. Management of children with prolonged fever of unknown origin and difficulties in
the management of fever of unknown origin in children in developing countries. Paediatr Drugs 2001;
3:247.
13. Schneider T, Loddenkemper C, Rudwaleit M, et al. [Fever of unknown origin in the 21st century: infectious
diseases]. Dtsch Med Wochenschr 2005; 130:2708.
14. Cho CY, Lai CC, Lee ML, et al. Clinical analysis of fever of unknown origin in children: A 10-year
experience in a northern Taiwan medical center. J Microbiol Immunol Infect 2017; 50:40.
15. Antoon JW, Peritz DC, Parsons MR, et al. Etiology and Resource Use of Fever of Unknown Origin in
Hospitalized Children. Hosp Pediatr 2018; 8:135.
16. Arisoy ES, Correa AG, Wagner ML, Kaplan SL. Hepatosplenic cat-scratch disease in children: selected
clinical features and treatment. Clin Infect Dis 1999; 28:778.
17. Van CT, Thuy NT, San NH, et al. Human leptospirosis in the Mekong delta, Viet Nam. Trans R Soc Trop
Med Hyg 1998; 92:625.
18. Jackson LA, Kaufmann AF, Adams WG, et al. Outbreak of leptospirosis associated with swimming. Pediatr
Infect Dis J 1993; 12:48.
19. Centers for Disease Control and Prevention (CDC). Local transmission of Plasmodium vivax malaria--Palm
Beach County, Florida, 2003. MMWR Morb Mortal Wkly Rep 2003; 52:908.
20. Mace KE, Arguin PM. Malaria Surveillance - United States, 2014. MMWR Surveill Summ 2017; 66:1.
21. Tuberculin negative tuberculosis. Am Rev Respir Dis 1973; 107:882.
22. Steiner P, Portugaleza C. Tuberculous meningitis in children. A review of 25 cases observed between the
years 1965 and 1970 at the Kings County Medical Center of Brooklyn with special reference to the problem
of infection with primary drug-resistant strains of M. tuberculosis. Am Rev Respir Dis 1973; 107:22.
23. Kaplan SL, Feigin RD. Experience and reason--briefly recorded. Pediatrics 1976; 58:614.
24. Simon HB, Wolff SM. Granulomatous hepatitis and prolonged fever of unknown origin: a study of 13
patients. Medicine (Baltimore) 1973; 52:1.
25. Weinstein L. Bacterial hepatitis: a case report on an unrecognized cause of fever of unknown origin. N Engl
J Med 1978; 299:1052.
26. Wyllie R, Fitzgerald JF. Bacterial cholangitis in a 10-week-old infant with fever of undetermined origin.
Pediatrics 1980; 65:164.
27. Steele RW, Jones SM, Lowe BA, Glasier CM. Usefulness of scanning procedures for diagnosis of fever of
unknown origin in children. J Pediatr 1991; 119:526.
28. Calabro JJ, Marchesano JM. Juvenile rheumatoid arthritis. N Engl J Med 1967; 277:746.
https://www-uptodate-com.ezproxy.uniandes.edu.co:8443/contents/fever-of-unknown-origin-in-children-etiology/print?search=fiebre%20prolongada&… 10/27
29. Lin KL, Wang HS. Reverse Shapiro's syndrome--an unusual cause of fever of unknown origin. Brain Dev
2005; 27:455.
30. Hirayama K, Hoshino Y, Kumashiro H, Yamamoto T. Reverse Shapiro's syndrome. A case of agenesis of
corpus callosum associated with periodic hyperthermia. Arch Neurol 1994; 51:494.
31. Berger H. Fever. An unusual manifestation of epilepsy. Postgrad Med 1966; 40:479.
32. Matsuda N, Akanuma J, Shimizu S, et al. [Recurrent episodes of fever of unknown origin as temporal lobe
epilepsy]. Rinsho Shinkeigaku 2000; 40:999.
33. Chan KM. Epilepsy--another cause of intermittent fever with confusion. Postgrad Med J 1992; 68:119.
34. el-Ad B, Neufeld MY. Periodic febrile confusion as a presentation of complex partial status epilepticus. Acta
Neurol Scand 1990; 82:350.
35. Semel JD. Complex partial status epilepticus presenting as fever of unknown origin. Arch Intern Med 1987;
147:1571.
36. WOLFF SM, ADLER RC, BUSKIRK ER, THOMPSON RH. A SYNDROME OF PERIODIC
HYPOTHALAMIC DISCHARGE. Am J Med 1964; 36:956.
37. Dancis J, Smith AA. Familial dysautonomia. N Engl J Med 1966; 274:207.
38. SMITH AA, FARBMAN A, DANCIS J. TONGUE IN FAMILIAL DYSAUTONOMIA, A DIAGNOSTIC SIGN.
Am J Dis Child 1965; 110:152.
39. Janka GE. Familial and acquired hemophagocytic lymphohistiocytosis. Eur J Pediatr 2007; 166:95.
40. Palazzi DL, McClain KL, Kaplan SL. Hemophagocytic syndrome in children: an important diagnostic
consideration in fever of unknown origin. Clin Infect Dis 2003; 36:306.
41. Aricò M, Janka G, Fischer A, et al. Hemophagocytic lymphohistiocytosis. Report of 122 children from the
International Registry. FHL Study Group of the Histiocyte Society. Leukemia 1996; 10:197.
42. Henter JI, Elinder G, Söder O, Ost A. Incidence in Sweden and clinical features of familial hemophagocytic
lymphohistiocytosis. Acta Paediatr Scand 1991; 80:428.
43. Henter JI, Horne A, Aricó M, et al. HLH-2004: Diagnostic and therapeutic guidelines for hemophagocytic
lymphohistiocytosis. Pediatr Blood Cancer 2007; 48:124.
44. Jordan MB, Allen CE, Weitzman S, et al. How I treat hemophagocytic lymphohistiocytosis. Blood 2011;
118:4041.
45. CROHN BB, YARNIS H. Continuous fever of intestinal origin. Ann Intern Med 1947; 26:858.
46. LEE FI, DAVIES DM. Crohn's disease presenting as pyrexia of unknown origin. Lancet 1961; 1:1205.
47. WALKER SH. Periodic fever in juvenile regional enteritis. J Pediatr 1962; 60:561.
48. Scagni P, Peisino MG, Bianchi M, et al. Kikuchi-Fujimoto disease is a rare cause of lymphadenopathy and
fever of unknown origin in children: report of two cases and review of the literature. J Pediatr Hematol
Oncol 2005; 27:337.
49. Lee KY, Yeon YH, Lee BC. Kikuchi-Fujimoto disease with prolonged fever in children. Pediatrics 2004;
114:e752.
50. Tunca M, Ozdogan H. Molecular and genetic characteristics of hereditary autoinflammatory diseases. Curr
Drug Targets Inflamm Allergy 2005; 4:77.
51. Hayem F. [Periodic fevers]. Arch Pediatr 2002; 9:638.
52. SHAPIRO TR, EHRENFELD EN. Recurrent polyserositis ("periodic disease," "familial Mediterranean
fever") in children. Pediatrics 1962; 30:443.
53. Drenth JP, Haagsma CJ, van der Meer JW. Hyperimmunoglobulinemia D and periodic fever syndrome. The
clinical spectrum in a series of 50 patients. International Hyper-IgD Study Group. Medicine (Baltimore)
1994; 73:133.
54. Grose C, Schnetzer JR, Ferrante A, Vladutiu AO. Children with hyperimmunoglobulinemia D and periodic
fever syndrome. Pediatr Infect Dis J 1996; 15:72.
55. Grose C. Periodic fever in children with hyperimmunoglobulinemia D and mevalonate kinase mutations.
Pediatr Infect Dis J 2005; 24:573.
56. Klasen IS, Göertz JH, van de Wiel GA, et al. Hyper-immunoglobulin A in the hyperimmunoglobulinemia D
syndrome. Clin Diagn Lab Immunol 2001; 8:58.
57. REIMANN HA. Periodic disease; periodic fever, periodic abdominalgia, cyclic neutropenia, intermittent
arthralgia, angioneurotic edema, anaphylactoid purpura and periodic paralysis. J Am Med Assoc 1949;
141:175.
Topic 5996 Version 21.0
GRAPHICS
Causes of fever of unknown origin in children
Infectious disease Rheumatologic diseases

Bacterial Juvenile idiopathic arthritis
Bacterial endocarditis Systemic lupus erythematosus
Bartonella henselae Vasculitis (eg, polyarteritis nodosa)
Brucellosis Malignancies
Leptospirosis Hodgkin disease
Liver abscess Leukemia/lymphoma
Mastoiditis (chronic) Neuroblastoma
Osteomyelitis
Miscellaneous
Pelvic abscess
Central diabetes insipidus
Perinephric abscess
Drug fever
Pyelonephritis
Ectodermal dysplasia
Salmonellosis
Factitious fever
Sinusitis
Familial dysautonomia
Subdiaphragmatic abscess
Granulomatous colitis
Tuberculosis
Hemophagocytic lymphohistiocytosis
Tularemia
Infantile cortical hyperostosis
Viral
Inflammatory bowel disease
Adenovirus
Kawasaki disease
Arboviruses
Kikuchi-Fujimoto disease
Cytomegalovirus
Nephrogenic diabetes insipidus
Enteroviruses
Pancreatitis
Epstein-Barr virus (infectious mononucleosis)
Periodic fever (eg, familial Mediterranean fever, PFAPA syndrome)
Hepa s viruses Serum sickness
Human immunodeﬁciency virus Thyrotoxicosis
Chlamydial
Lymphogranuloma venereum
Psittacosis
Rickettsial
Q fever
Rocky Mountain spotted fever
Fungal
Blastomycosis (nonpulmonary)
Histoplasmosis (disseminated)
Parasitic
Malaria
Toxoplasmosis
Visceral larva migrans
Unclassified
Sarcoidosis
PFAPA: periodic fever with aphthous stomatitis, pharyngitis, and adenitis.
Original table modified for this publication. Lorin MI, Feigin RD. Fever without localizing signs and fever of unknown origin. In:
Textbook of Pediatric Infectious Disease, 4th ed, Feigin RD, Cherry JD (Eds), WB Saunders, Philadelphia 1998. Table used with
the permission of Elsevier Inc. All rights reserved.
Graphic 69379 Version 6.0
Infections associated with animal exposure
Animal Infection
Cats
Saliva Bartonella henselae, tularemia, Pasteurella multocida, rabies, Capnocytophaga
Feces Salmonella, Campylobacter, Cryptosporidium, Giardia lamblia, Toxoplasma gondii,

Toxocara cati, Echinococcus, Ancylostoma braziliense, Dipylidium caninum
Urine Leptospirosis
Tick or flea bites Lyme disease, human ehrlichiosis or anaplasmosis, babesiosis, Yersinia pestis
Direct contact Sporothrix schenckii, Microsporum canis
Dogs
Saliva Rabies, Brucella, Pasteurella multocida, Capnocytophaga
Feces Salmonella, Campylobacter, Giardia lamblia, Toxocara canis, Ancylostoma caninum,

Echinococcus, Dipylidium caninum
Urine Leptospirosis
Insect bites (fleas, ticks, Tularemia, Lyme disease, Rocky Mountain spotted fever, human ehrlichiosis or
mosquitoes, sand flies) anaplasmosis, babesiosis, Yersinia pestis, Dirofilaria immitis, Leishmania
Direct contact Methicillin-resistant Staphylococcus aureus
Horses
Saliva Rabies
Feces Salmonella, Campylobacter, Cryptosporidium, Giardia lamblia, Clostridium difficile
Mosquito bites Equine encephalitis
Aerosol Brucella, Rhodococcus equi, Coxiella burnetii
Rabbits (domestic or wild) Salmonella, tularemia, Yersinia, Cryptosporidium, Trichophyton, Pasteurella multocida,
rabies, babesiosis
Pet rodents
Saliva Tularemia, rat bite fever, rabies
Feces Salmonellosis
Direct contact or aerosol Lymphocytic choriomeningitis virus, monkeypox, Trichophyton
Wild rodents Hantavirus, tularemia
Bird feces Psittacosis, Cryptococcus, Histoplasmosis
Wild and pet birds Avian influenza, West Nile virus, Chlamydia
Fish Mycobacterium marinum
Pet reptiles Salmonella, Edwardsiella tarda, Plesiomonas
Wild reptiles Pentastomiasis
Ferrets Salmonella, Campylobacter, cryptosporidiosis, toxocariasis, tuberculosis, leptospirosis,

listeriosis, influenza, Giardia, Mycobacterium microti, rabies
Flying squirrels Toxoplasma gondii, Staphylococci, Rickettsia prowazekii
Monkeys B-virus (Cercopithecine herpesvirus 1) infection
Cattle, sheep, goats Escherichia coli, Campylobacter, Salmonella, Cryptosporidium, Brucella, Coxiella burnetii,
tularemia
Diagnostic criteria for Kawasaki disease
The diagnosis of Kawasaki disease requires the presence of fever lasting at least five days* without any other
explanation combined with at least four of the five following criteria:
Bilateral bulbar conjunctival injection
Oral mucous membrane changes, including injected or fissured lips, injected pharynx, or strawberry tongue
Peripheral extremity changes, including erythema of palms or soles, edema of hands or feet (acute phase), and periungual
desquamation (convalescent phase)
Polymorphous rash
Cervical lymphadenopathy (at least one lymph node >1.5 cm in diameter)
* If ≥4 of the above criteria are present, Kawasaki disease can be made on day 4 of illness.
Conjunctivitis in Kawasaki disease
Courtesy of Robert Sundel, MD.
Strawberry tongue
Reproduced with permission from: www.visualdx.com. Copyright Logical Images, Inc.
Cracked, red lips seen in Kawasaki disease
Indurated edema of the dorsum of the hands as seen in

Kawasaki disease (acute phase)
The erythema overlying the metacarpophalangeal and proximal interphalangeal joints is

indicative of arthritis of the small joints of the hand.
Characteristic periungual desquamation of the hands

and feet seen in Kawasaki disease
Skin peeling usually begins under the nails during the second week of illness.
Peeling of large sheets of skin progresses proximally over the next several days.
Select causes of fever of unknown origin in children
Associated clinical findings (which may not be present)

Condition Laboratory, imaging, or
History Examination
other initial tests
Generalized infections
Brucellosis Sustained fever pattern Uveitis Mild elevation of hepatic

Lethargy Hepatomegaly aminotransferases
Osteoarticular pain Splenomegaly Lymphocytopenia
Testicular tenderness Positive blood culture
Exposures: Animals or
animal products (eg,
unpasteurized milk/cheese,
insufficiently cooked/raw
meat)
Cat scratch disease Gastrointestinal Localized Lymphocytosis

complaints lymphadenopathy
Hepatomegaly
Exposures: Cats/kittens Splenomegaly
Liver tenderness
Papular lesion at entry
site
Leptospirosis Rigors Relative bradycardia* Thrombocytopenia

Myalgia Bulbar conjunctivitis Hyponatremia
Headache Pharyngeal hyperemia Proteinuria
Cough Pyuria
Gastrointestinal Granular casts
complaints Small nodular densities
on CXR
Exposures: Animal urine,
contaminated soil or water,
infected animal tissue
Malaria Relapsing fever pattern Splenomegaly Anemia

Lymphocytopenia
Exposures: Travel to
malaria-endemic area
Mycobacteria tuberculosis Intermittent fever Phlyctenular Positive TST or IGRA

pattern conjunctivitis Anemia
Funduscopy: Choroid Lymphocytopenia
Exposures: Travel to tubercles Hilar lymphadenopathy
endemic area or contact Chronic nontender (pulmonary TB)
with traveler to endemic lymphadenopathy Sterile pyuria (in
area
genitourinary TB)
Salmonellosis Gastrointestinal Weight loss

symptoms Hepatomegaly
Fatigue Splenomegaly
Malaise
Headaches
Urinary symptoms
Respiratory symptoms
Exposures: Poultry, eggs,

reptiles
Toxoplasmosis Exposures: Feline feces, Lymphadenopathy Lymphocytosis

pica (dirt), consumption of (cervical or
game meat supraclavicular)
Funduscopy:
Chorioretinitis in
nonvascular distribution
Pharyngeal hyperemia
Tularemia Fever Vary depending upon Thrombocytopenia

Chills the portal of entry; may Elevated hepatic
Anorexia include: aminotransferases
Malaise Pharyngeal Pyuria
hyperemia
Headache
Eschar at entry site
Fatigue
Tender regional
Muscle soreness
lymphadenopathy
Gastrointestinal
Bulbar and palpebral
complaints
conjunctivitis
Exposures: Dead animal

carcasses (eg, rabbits),
ingestion of rabbit or
squirrel meat; ticks,
mosquitoes, lice, fleas, flies
Typhoid fever Abdominal pain Relative bradycardia* Anemia

Chills Rose spots Leukopenia or
Diarrhea or constipation leukocytosis (especially
Headache in children <5 years of
age)
Exposures: Travel to Elevation of hepatic

endemic area aminotransferases
Positive blood culture
Localized infections
Osteomyelitis and septic Bone pain Bone tenderness or joint Elevated ESR/CRP
arthritis Limp tenderness
Infective endocarditis Pre-existing cardiac New onset cardiac Anemia

lesion murmur Leukocytosis
Conjunctival Elevated ESR/CRP
hemorrhage Positive blood culture
Hepatomegaly Hematuria
Splenomegaly Proteinuria
Petechiae
Intraabdominal abscess Previous intraabdominal Abdominal tenderness Sterile pyuria

(subphrenic, perinephric, disease or surgery (may be absent)
pelvic) Vague abdominal pain
Liver abscess/hepatic Possible jaundice Hepatomegaly Abnormal hepatic

infection (jaundice is not common Right upper quadrant aminotransferases (not
with a single pyogenic pain always present; more
liver abscess) likely with multiple
Most often in abscesses or hepatic
immunocompromised infection)
patients
Urinary tract infection Dysuria Suprapubic tenderness Pyuria

Urgency Costovertebral angle Bacteriuria
Frequency tenderness Hematuria
Incontinence Positive urine culture
Abdominal pain
Rheumatologic diseases
Juvenile idiopathic arthritis Intermittent fever Salmon-pink rash with Leukocytosis

pattern (≥1 fever spike fever Thrombocytosis
per day with return to Erythema nodosum Anemia
normal temperature Lymphadenopathy Elevated ESR
between fevers)
Hepatomegaly Mild elevation of
Arthralgias
Splenomegaly aminotransferases
Ill-appearing with fever
Arthritis
Systemic lupus Malaise Tachycardia Anemia

erythematosus Headache Tachypnea Neutropenia
Anterior chest pain Weight loss Thrombocytopenia
Dyspnea Oral ulcers Hematuria
Neuropsychiatric Malar rash Proteinuria
complaints (eg, Erythema nodosum
depression, decreased Pericardial rub
academic performance)
Small joint arthritis
Vasculitis (eg, polyarteritis Malaise Weight loss Positive stool guaiac

nodosa) Abdominal pain Hypertension
Myalgia Palpable purpura
Muscle weakness Subcutaneous nodules
Asymmetric neuropathy
Testicular tenderness
Funduscopic
examination:
Perivascular sheathing
Neoplasms
Leukemia Limb or bone pain Gingival hypertrophy Cytopenia in ≥1 cell line

Hepatosplenomegaly Bizarre/immature WBCs
Lymphadenopathy Neutropenia
Testicular enlargement Mediastinal mass
Lymphoma Intermittent, remittent, Weight loss Mediastinal mass or

or relapsing fever Lymphadenopathy lymphadenopathy
pattern Hepatosplenomegaly
Fatigue
Night sweats
Other causes
Altered thermoregulation History of brain damage Normal ESR/CRP

or CNS dysfunction
Diabetes insipidus (central Polyuria Weight loss Hypernatremia

or nephrogenic) Polydipsia Lack of sweat with fever Normal ESR/CRP
More common in Ulster Decreased peripheral
Scots (nephrogenic) perfusion
Drug fever Resolution with Rash Leukocytosis

discontinuation of Eosinophilia
offending drug Elevated ESR
Exposures: Virtually any

drug or complementary and
alternative agent
Factitious fever Absence of nonspecific Rapid defervescence Normal ESR/CRP

symptoms (malaise, without diaphoresis
discomfort) during fever
Discrepancy between
temperatures recorded
or reported by the
patient or caregiver and
those obtained rectally
under direct observation
Familial dysautonomia Lack of sweat during Labile blood pressure Normal ESR/CRP
fever Decreased/absent tears
More common in Absent corneal reflex
patients of Ashkenazi Hypodontia, adontia, or
Jewish descent conical teeth
Smooth tongue
Erythematous or blotchy
skin
Decreased DTR
Hemophagocytic May have positive family Lymphadenopathy Cytopenias in ≥1 cell

lymphohistiocytosis history Hepatosplenomegaly line (especially anemia
Skin lesions (generalized and thrombocytopenia)
Exposures: Infection, rash, erythroderma, Coagulopathy
immunologic disorder, edema, petechiae, Liver dysfunction
malignancy, drugs purpura)
Neurologic symptoms
Infantile cortical Limb or bone pain Bony tenderness Leukocytosis

hyperostosis Swelling of overlying Elevated ESR
tissues
Inflammatory bowel Gastrointestinal Weight loss Anemia

disease complaints Short stature or Positive stool guaiac
Delayed sexual decreased height Elevated ESR/CRP
maturation velocity
More common in Oral ulcers
adolescents Perianal fistulae, skin
tags, or fissures
Erythema nodosum
Kawasaki disease Bulbar conjunctivitis Thrombocytosis

Strawberry tongue, Sterile pyuria
cracked lips
Rash
Edema and periungual
desquamation of hands
and feet
Cervical
lymphadenopathy
Kikuchi-Fujimoto disease Fatigue Cervical Leukopenia

Gastrointestinal lymphadenopathy Atypical lymphocytes
complaints Hepatosplenomegaly Thrombocytopenia
Joint pain Arthritis Pancytopenia

More common in Rash Elevated ESR
females and patients Mildly elevated hepatic
<40 years of age transferases
Periodic fever disorders: Recurrent fever pattern Refer to UpToDate Elevated ESR/CRP
Cyclic neutropenia content on periodic fever during episodes
Hyperimmunoglobulin syndromes
D syndrome
PFAPA syndrome
Deficiency of IL-1 or
IL-36 receptor
antagonist
FUO: fever of unknown origin; CXR: chest radiography; TST: tuberculin skin test; IGRA: interferon gamma release assay; TB:
tuberculosis; ESR: erythrocyte sedimentation rate; CRP: C-reactive protein; WBC: white blood cell; CNS: central nervous
system; DTR: deep tendon reflexes; PFAPA: periodic fever with aphthous stomatitis, pharyngitis, and adenitis; IL: interleukin.
* Relative bradycardia: For patients ≥13 years with temperature ≥38.9°C (102°F), failure of the pulse to increase as expected
with fever (approximately 10 beats per minute for each 0.6°C [1°F]).
Contributor Disclosures
Debra L Palazzi, MD, MEd Grant/Research/Clinical Trial Support: Merck [Invasive fungal infections
(Caspofungin, posaconazole)]; Durata [Antibiotic safety and PK (Dalbavancin)]; Cempra [Antibiotic safety and PK
(Solithromycin)]. Consultant/Advisory Boards: Pfizer [Antifungal trial data safety monitoring board (Voriconazole,
Anidulafungin)]. Other Financial Interest: JAMA Peds Associate Editor [pediatrics (journal articles)]; AAP PREP
ID Editorial board [PREP ID educational products and course]. Morven S Edwards, MD Grant/Research/Clinical
Trial Support: Pfizer [Group B Streptococcus]. Robert Sundel, MD Grant/Research/Clinical Trial Support: Pfizer
[Juvenile idiopathic arthritis (Tofacitinib)]. Other Financial Interest: Expert consultant in patent case involving
application for biosimilar status of an anti-TNF agent. Jan E Drutz, MD Nothing to disclose Mary M Torchia,
MD Nothing to disclose
Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are
addressed by vetting through a multi-level review process, and through requirements for references to be
provided to support the content. Appropriately referenced content is required of all authors and must conform to
UpToDate standards of evidence.
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Official reprint from UpToDate®

Fever of unknown origin in children: Etiology

Author: Debra L Palazzi, MD, MEd

Mycobacterial — Tuberculosis (TB) is another important cause of FUO in children. Extrapulmonary TB

● Cytomegalovirus (see "Overview of cytomegalovirus infections in children")

Viridans streptococci, enterococci, and staphylococci (including S. aureus and coagulase-negative

● Monoarticular involvement, the so-called oligoarticular form

● Rapid defervescence without diaphoresis

Hemophagocytic lymphohistiocytosis — Hemophagocytic lymphohistiocytosis (HLH) is a nonmalignant but

● FMF is an autosomal recessive disease found in individuals of Mediterranean descent. It is characterized by

● Basics topic (see "Patient education: Fever in children (The Basics)")

Use of UpToDate is subject to the Subscription and License Agreement.

Topic 5996 Version 21.0

Causes of fever of unknown origin in children

Infectious disease Rheumatologic diseases

Bacterial endocarditis Systemic lupus erythematosus

Bartonella henselae Vasculitis (eg, polyarteritis nodosa)

Rocky Mountain spotted fever

Visceral larva migrans

PFAPA: periodic fever with aphthous stomatitis, pharyngitis, and adenitis.

Graphic 69379 Version 6.0

Infections associated with animal exposure

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

Feces Salmonella, Campylobacter, Cryptosporidium, Giardia lamblia, Toxoplasma gondii,

Direct contact Sporothrix schenckii, Microsporum canis

Saliva Rabies, Brucella, Pasteurella multocida, Capnocytophaga

Feces Salmonella, Campylobacter, Giardia lamblia, Toxocara canis, Ancylostoma caninum,

Direct contact Methicillin-resistant Staphylococcus aureus

Feces Salmonella, Campylobacter, Cryptosporidium, Giardia lamblia, Clostridium difficile

Mosquito bites Equine encephalitis

Aerosol Brucella, Rhodococcus equi, Coxiella burnetii

Saliva Tularemia, rat bite fever, rabies

Direct contact or aerosol Lymphocytic choriomeningitis virus, monkeypox, Trichophyton

Wild rodents Hantavirus, tularemia

Bird feces Psittacosis, Cryptococcus, Histoplasmosis

Fish Mycobacterium marinum

Pet reptiles Salmonella, Edwardsiella tarda, Plesiomonas

Wild reptiles Pentastomiasis

Ferrets Salmonella, Campylobacter, cryptosporidiosis, toxocariasis, tuberculosis, leptospirosis,

Flying squirrels Toxoplasma gondii, Staphylococci, Rickettsia prowazekii

Monkeys B-virus (Cercopithecine herpesvirus 1) infection

Graphic 71081 Version 4.0

Diagnostic criteria for Kawasaki disease

Graphic 67711 Version 6.0

Conjunctivitis in Kawasaki disease

Courtesy of Robert Sundel, MD.

Graphic 78898 Version 2.0

Reproduced with permission from: www.visualdx.com. Copyright Logical Images, Inc.

Graphic 68321 Version 3.0

Cracked, red lips seen in Kawasaki disease

Reproduced with permission from: www.visualdx.com. Copyright Logical Images, Inc.

Graphic 59319 Version 3.0

Indurated edema of the dorsum of the hands as seen in

The erythema overlying the metacarpophalangeal and proximal interphalangeal joints is

Reproduced with permission from: www.visualdx.com. Copyright Logical Images, Inc.

Graphic 72040 Version 5.0

Characteristic periungual desquamation of the hands

Graphic 53452 Version 1.0

Select causes of fever of unknown origin in children

Associated clinical findings (which may not be present)

Brucellosis Sustained fever pattern Uveitis Mild elevation of hepatic

Cat scratch disease Gastrointestinal Localized Lymphocytosis