Etiology - UpToDate

Fever of unknown origin in children: Etiology - UpToDate https://www.uptodate.com/contents/fever-of-unknown-origin-in-childr...
Official reprint from UpToDate

www.uptodate.com 2017 UpToDate
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: Jul 2017. | This topic last updated: May 26, 2017.
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 >38.3C (101F)
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 [3-14]. 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 disease. Clinical manifestations may include persistent fever and lethargy,
osteoarticular complaints and epididymo-orchitis, hepatosplenomegaly, mild elevation of liver enzymes,
and lymphocytopenia.
1 de 27 02/09/2017 14:15
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 [10,15]. 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 [16,17]. 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
[18,19]. 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 in endemic areas: 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 [20,21]. 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,
2 de 27 02/09/2017 14:15
which should be repeated if initially negative and fevers persist. Serologic testing is not recommended.
(See "Epidemiology, microbiology, clinical manifestations, and diagnosis of typhoid 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 "Acquired cytomegalovirus infection in children")
Epstein-Barr virus (see "Clinical manifestations and treatment of Epstein-Barr virus infection")
Adenovirus (see "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
3 de 27 02/09/2017 14:15
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 [22]. 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 [23], 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 [24,25]. (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
4 de 27 02/09/2017 14:15
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 [26]. (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 [27]. 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 [28,29]. 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 [30].
Epilepsy-induced fever also has been described in adults [31-34]. In another report, an adolescent had
cyclic episodes of fever accompanied by nausea, vomiting, and emotional disturbance, resulting from a
CNS lesion [35].
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
5 de 27 02/09/2017 14:15
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 [36]. The majority of affected children are of Ashkenazi Jewish parentage.
6 de 27 02/09/2017 14:15
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 [37]. 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 [38,39]. Other common findings include liver dysfunction, coagulopathy, hypertriglyceridemia,
or hypofibrinogenemia. Clinical presentations of patients with primary (familial) and secondary (reactive)
HLH are indistinguishable [40,41]. (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) [42]. 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 [39,42,43]. (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 40C (104F), 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 [44-46] 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
7 de 27 02/09/2017 14:15
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 [47,48]. 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 [49,50].
(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 [51]. (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 [52-54]. The elevated serum IgD is probably a
secondary effect, and some patients also have had elevated serum levels of IgA [55]. (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 [56]. (See
"Cyclic neutropenia".)
INFORMATION FOR PATIENTS UpToDate offers two types of patient education materials, "The
Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the
5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a
given condition. These articles are best for patients who want a general overview and who prefer short,
easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and
more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients
who want in-depth information and are comfortable with some medical jargon.
8 de 27 02/09/2017 14:15
Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail
these topics to your patients. (You can also locate patient education articles on a variety of subjects by
searching on "patient info" and the keyword(s) of interest.)
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.)
Use of UpToDate is subject to the Subscription and License Agreement.
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
9 de 27 02/09/2017 14:15
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. 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.
16. 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.
17. Jackson LA, Kaufmann AF, Adams WG, et al. Outbreak of leptospirosis associated with swimming.
Pediatr Infect Dis J 1993; 12:48.
18. 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.
19. Mace KE, Arguin PM. Malaria Surveillance - United States, 2014. MMWR Surveill Summ 2017; 66:1.
20. Tuberculin negative tuberculosis. Am Rev Respir Dis 1973; 107:882.
21. 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.
22. Kaplan SL, Feigin RD. Experience and reason--briefly recorded. Pediatrics 1976; 58:614.
23. Simon HB, Wolff SM. Granulomatous hepatitis and prolonged fever of unknown origin: a study of 13
patients. Medicine (Baltimore) 1973; 52:1.
24. Weinstein L. Bacterial hepatitis: a case report on an unrecognized cause of fever of unknown origin.
N Engl J Med 1978; 299:1052.
25. Wyllie R, Fitzgerald JF. Bacterial cholangitis in a 10-week-old infant with fever of undetermined
origin. Pediatrics 1980; 65:164.
26. 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.
27. Calabro JJ, Marchesano JM. Juvenile rheumatoid arthritis. N Engl J Med 1967; 277:746.
28. Lin KL, Wang HS. Reverse Shapiro's syndrome--an unusual cause of fever of unknown origin. Brain
Dev 2005; 27:455.
29. 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.
30. Berger H. Fever. An unusual manifestation of epilepsy. Postgrad Med 1966; 40:479.
31. Matsuda N, Akanuma J, Shimizu S, et al. [Recurrent episodes of fever of unknown origin as
10 de 27 02/09/2017 14:15
temporal lobe epilepsy]. Rinsho Shinkeigaku 2000; 40:999.

32. Chan KM. Epilepsy--another cause of intermittent fever with confusion. Postgrad Med J 1992;
68:119.
33. el-Ad B, Neufeld MY. Periodic febrile confusion as a presentation of complex partial status
epilepticus. Acta Neurol Scand 1990; 82:350.
34. Semel JD. Complex partial status epilepticus presenting as fever of unknown origin. Arch Intern Med
1987; 147:1571.
35. WOLFF SM, ADLER RC, BUSKIRK ER, THOMPSON RH. A SYNDROME OF PERIODIC
HYPOTHALAMIC DISCHARGE. Am J Med 1964; 36:956.
36. Dancis J, Smith AA. Familial dysautonomia. N Engl J Med 1966; 274:207.
37. SMITH AA, FARBMAN A, DANCIS J. TONGUE IN FAMILIAL DYSAUTONOMIA, A DIAGNOSTIC
SIGN. Am J Dis Child 1965; 110:152.
38. Janka GE. Familial and acquired hemophagocytic lymphohistiocytosis. Eur J Pediatr 2007; 166:95.
39. 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.
40. Aric 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.
41. Henter JI, Elinder G, Sder O, Ost A. Incidence in Sweden and clinical features of familial
hemophagocytic lymphohistiocytosis. Acta Paediatr Scand 1991; 80:428.
42. Henter JI, Horne A, Aric M, et al. HLH-2004: Diagnostic and therapeutic guidelines for
hemophagocytic lymphohistiocytosis. Pediatr Blood Cancer 2007; 48:124.
43. Jordan MB, Allen CE, Weitzman S, et al. How I treat hemophagocytic lymphohistiocytosis. Blood
2011; 118:4041.
44. CROHN BB, YARNIS H. Continuous fever of intestinal origin. Ann Intern Med 1947; 26:858.
45. LEE FI, DAVIES DM. Crohn's disease presenting as pyrexia of unknown origin. Lancet 1961;
1:1205.
46. WALKER SH. Periodic fever in juvenile regional enteritis. J Pediatr 1962; 60:561.
47. 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.
48. Lee KY, Yeon YH, Lee BC. Kikuchi-Fujimoto disease with prolonged fever in children. Pediatrics
2004; 114:e752.
49. Tunca M, Ozdogan H. Molecular and genetic characteristics of hereditary autoinflammatory
diseases. Curr Drug Targets Inflamm Allergy 2005; 4:77.
50. Hayem F. [Periodic fevers]. Arch Pediatr 2002; 9:638.
51. SHAPIRO TR, EHRENFELD EN. Recurrent polyserositis ("periodic disease," "familial Mediterranean
fever") in children. Pediatrics 1962; 30:443.
52. 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.
53. Grose C, Schnetzer JR, Ferrante A, Vladutiu AO. Children with hyperimmunoglobulinemia D and
periodic fever syndrome. Pediatr Infect Dis J 1996; 15:72.
54. Grose C. Periodic fever in children with hyperimmunoglobulinemia D and mevalonate kinase
11 de 27 02/09/2017 14:15
mutations. Pediatr Infect Dis J 2005; 24:573.

55. Klasen IS, Gertz JH, van de Wiel GA, et al. Hyper-immunoglobulin A in the
hyperimmunoglobulinemia D syndrome. Clin Diagn Lab Immunol 2001; 8:58.
56. 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 20.0
12 de 27 02/09/2017 14:15
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
Periodic fever (eg, familial Mediterranean fever, PFAPA
mononucleosis)
syndrome)
Hepa s viruses
Serum sickness
Human immunodeciency 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
13 de 27 02/09/2017 14:15
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
14 de 27 02/09/2017 14:15
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
15 de 27 02/09/2017 14:15
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.
16 de 27 02/09/2017 14:15
Conjunctivitis in Kawasaki disease
Courtesy of Robert Sundel, MD.
17 de 27 02/09/2017 14:15
Strawberry tongue
Reproduced with permission from: www.visualdx.com. Copyright Logical Images, Inc.
18 de 27 02/09/2017 14:15
Cracked, red lips seen in Kawasaki disease
19 de 27 02/09/2017 14:15
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.
20 de 27 02/09/2017 14:15
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.
21 de 27 02/09/2017 14:15
Select causes of fever of unknown origin in children
Associated clinical findings (which may not be present)

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

pattern Hepatomegaly hepatic
Lethargy Splenomegaly aminotransferases
Osteoarticular pain Testicular tenderness Lymphocytopenia
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 Splenomegaly Anemia

pattern 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
endemic area or contact Chronic nontender lymphadenopathy
with traveler to endemic lymphadenopathy (pulmonary TB)
area
Sterile pyuria (in
genitourinary TB)
Salmonellosis Gastrointestinal Weight loss

symptoms Hepatomegaly
Fatigue Splenomegaly
Malaise
Headaches
Urinary symptoms
22 de 27 02/09/2017 14:15
Respiratory symptoms
Exposures: Poultry,
eggs, reptiles
Toxoplasmosis Exposures: Feline feces, Lymphadenopathy Lymphocytosis

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

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

arthritis Limp joint 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 Abdominal tenderness Sterile pyuria

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

infection (jaundice is not Right upper quadrant aminotransferases
common with a single pain (not always present;
23 de 27 02/09/2017 14:15
pyogenic liver more likely with

abscess) multiple abscesses or
Most often in hepatic infection)
immunocompromised
patients
Urinary tract infection Dysuria Suprapubic Pyuria

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

pattern (1 fever with fever Thrombocytosis
spike per day with Erythema nodosum Anemia
return to normal Lymphadenopathy Elevated ESR
temperature between
Hepatomegaly Mild elevation of
fevers)
Splenomegaly aminotransferases
Arthralgias
Arthritis
Ill-appearing with
fever
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
Small joint arthritis
performance)
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

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

remittent, or Lymphadenopathy lymphadenopathy
relapsing fever Hepatosplenomegaly
pattern
Fatigue
Night sweats
24 de 27 02/09/2017 14:15
Other causes
Altered thermoregulation History of brain Normal ESR/CRP

damage or CNS
dysfunction
Diabetes insipidus (central Polyuria Weight loss Hypernatremia

or nephrogenic) Polydipsia Lack of sweat with Normal ESR/CRP
More common in fever
Ulster Scots Decreased peripheral
(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 Rapid defervescence Normal ESR/CRP

nonspecific symptoms without diaphoresis
(malaise, 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
More common in tears
patients of Ashkenazi Absent corneal reflex
Jewish descent Hypodontia, adontia,
or conical teeth
Smooth tongue
Erythematous or
blotchy skin
Decreased DTR
Hemophagocytic May have positive Lymphadenopathy Cytopenias in 1 cell

lymphohistiocytosis family history Hepatosplenomegaly line (especially
Skin lesions anemia and
Exposures: Infection, (generalized rash, thrombocytopenia)
immunologic disorder, erythroderma, Coagulopathy
malignancy, drugs edema, petechiae, Liver dysfunction
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
25 de 27 02/09/2017 14:15
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
<40 years of age hepatic transferases
Periodic fever disorders: Recurrent fever Refer to UpToDate Elevated ESR/CRP

Cyclic neutropenia pattern content on periodic during episodes
Hyperimmunoglobulin fever 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 38.9C (102F), failure of the pulse to increase as
expected with fever (approximately 10 beats per minute for each 0.6C [1F]).
26 de 27 02/09/2017 14:15
Contributor Disclosures
Debra L Palazzi, MD, MEd Grant/Research/Clinical Trial Support: Astellas [Antifungal safety and PK
(Micafungin)]; 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 Inc. [Group B Streptococcus]. Robert Sundel, MD Nothing to disclose 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.
Conflict of interest policy
27 de 27 02/09/2017 14:15

Etiology - UpToDate

Uploaded by

Document Information

Copyright

Available Formats

Share this document

Share or Embed Document

Sharing Options

Did you find this document useful?

Is this content inappropriate?

Copyright:

Available Formats

Etiology - UpToDate

Uploaded by

Copyright:

Available Formats

Fever of unknown origin in children: Etiology - UpToDate https://www.uptodate.com/contents/fever-of-unknown-origin-in-childr...

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 "Acquired cytomegalovirus infection in children")

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

Intraabdominal abscess Intraabdominal abscesses, including liver, subphrenic, perinephric, and

Hepatic infection Granulomatous hepatitis, which can be caused by a number of organisms, is

Rapid defervescence without diaphoresis

Hemophagocytic lymphohistiocytosis Hemophagocytic lymphohistiocytosis (HLH) is a nonmalignant

Immunodeficiency FUO also can be caused by a number of congenital and acquired

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

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

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

experience. Acta Paediatr 2006; 95:463.

temporal lobe epilepsy]. Rinsho Shinkeigaku 2000; 40:999.

mutations. Pediatr Infect Dis J 2005; 24:573.

Topic 5996 Version 20.0

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)

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

Direct contact Sporothrix schenckii, Microsporum canis

Saliva Rabies, Brucella, Pasteurella multocida, Capnocytophaga

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

Direct contact Methicillin-resistant Staphylococcus aureus

Feces Salmonella, Campylobacter, Cryptosporidium, Giardia lamblia, Clostridium

Mosquito bites Equine encephalitis

Aerosol Brucella, Rhodococcus equi, Coxiella burnetii

Rabbits (domestic or wild) Salmonella, tularemia, Yersinia, Cryptosporidium, Trichophyton, Pasteurella

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,

Flying squirrels Toxoplasma gondii, Staphylococci, Rickettsia prowazekii

Monkeys B-virus (Cercopithecine herpesvirus 1) infection

Cattle, sheep, goats Escherichia coli, Campylobacter, Salmonella, Cryptosporidium, Brucella,

Graphic 71081 Version 4.0

Diagnostic criteria for Kawasaki disease

Bilateral bulbar conjunctival injection

Cervical lymphadenopathy (at least one lymph node >1.5 cm in diameter)

Graphic 67711 Version 5.0

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