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reprint from UpToDate www.uptodate.com ©2017 UpToDate ® Fever of unknown origin in children: Etiology Author: Debra

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 >38.3ºC (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 [3-14]. 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.

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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,

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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

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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

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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

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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.

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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 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 [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

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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".)

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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.)

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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

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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. 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.

41. Henter JI, Elinder G, Söder O, Ost A. Incidence in Sweden and clinical features of familial hemophagocytic lymphohistiocytosis. Acta Paediatr Scand 1991; 80:428.

42. Henter JI, Horne A, Aricó 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

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55. 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.

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

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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

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

Fever of unknown origin in children: Etiology - UpToDate

Sarcoidosis

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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.

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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, mosquitoes, sand flies)

Tularemia, Lyme disease, Rocky Mountain spotted fever, human ehrlichiosis or 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

Graphic 71081 Version 4.0

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Diagnostic criteria for Kawasaki disease

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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.

Graphic 67711 Version 5.0

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Conjunctivitis in Kawasaki disease

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Courtesy of Robert Sundel, MD. Graphic 78898 Version 2.0 17

Courtesy of Robert Sundel, MD.

Graphic 78898 Version 2.0

Fever of unknown origin in children: Etiology - UpToDate

Strawberry tongue

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Reproduced with permission from: www.visualdx.com .

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

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Cracked, red lips seen in Kawasaki disease

Cracked, red lips seen in Kawasaki disease Reproduced with permission from: www.visualdx.com .

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

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Indurated edema of the dorsum of the hands as seen in Kawasaki disease (acute phase)

of the hands as seen in Kawasaki disease (acute phase) The erythema overlying the metacarpophalangeal and

The erythema overlying the metacarpophalangeal and proximal interphalangeal joints is indicative of arthritis of the small joints of the hand.

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

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Characteristic periungual desquamation of the hands and feet seen in Kawasaki disease

desquamation of the hands and feet seen in Kawasaki disease Skin peeling usually begins under the

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.

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Select causes of fever of unknown origin in children

 

Associated clinical findings (which may not be present)

Condition

 

History

Examination

Laboratory, imaging, or other initial tests

Generalized infections

Brucellosis

Sustained feverBrucellosis Uveitis Mild elevation of

UveitisBrucellosis Sustained fever Mild elevation of

Mild elevation ofBrucellosis Sustained fever Uveitis

 

pattern

Hepatomegaly  pattern hepatic

hepatic

LethargySplenomegaly aminotransferases

SplenomegalyLethargy aminotransferases

aminotransferases

Osteoarticular painTesticular tenderness Lymphocytopenia

Testicular tendernessOsteoarticular pain Lymphocytopenia

LymphocytopeniaOsteoarticular pain Testicular tenderness

Positive blood culturepain Testicular tenderness Lymphocytopenia Exposures: Animals or animal products (eg, unpasteurized

Exposures: Animals or animal products (eg, unpasteurized milk/cheese, insufficiently cooked/raw meat)

Cat scratch disease

Cat scratch disease Gastrointestinal Localized Lymphocytosis

Gastrointestinal

LocalizedCat scratch disease Gastrointestinal Lymphocytosis

LymphocytosisCat scratch disease Gastrointestinal Localized

complaints

lymphadenopathy

 

Hepatomegaly 

Exposures: Cats/kittens

SplenomegalyExposures: Cats/kittens

Liver tendernessHepatomegaly Exposures: Cats/kittens Splenomegaly Papular lesion at entry site Leptospirosis Rigors

Papular lesion at entry siteExposures: Cats/kittens Splenomegaly Liver tenderness Leptospirosis Rigors Relative bradycardia*

Leptospirosis

RigorsLeptospirosis Relative bradycardia* Thrombocytopenia

Relative bradycardia*Leptospirosis Rigors Thrombocytopenia

ThrombocytopeniaLeptospirosis Rigors Relative bradycardia*

MyalgiaBulbar conjunctivitis Hyponatremia

Bulbar conjunctivitisMyalgia Hyponatremia

HyponatremiaMyalgia Bulbar conjunctivitis

HeadachePharyngeal hyperemia Proteinuria

Pharyngeal hyperemiaHeadache Proteinuria

ProteinuriaHeadache Pharyngeal hyperemia

CoughPyuria

PyuriaCough

GastrointestinalGranular casts

Granular castsGastrointestinal

 

complaints

Small nodular densities on CXR  complaints

Exposures: Animal urine, contaminated soil or water, infected animal tissue

Malaria

Malaria Relapsing fever Splenomegaly Anemia

Relapsing fever

SplenomegalyMalaria Relapsing fever Anemia

AnemiaMalaria Relapsing fever Splenomegaly

pattern

Lymphocytopeniapattern

Exposures: Travel to malaria-endemic area

Mycobacteria tuberculosis

Mycobacteria tuberculosis Intermittent fever Phlyctenular Positive TST or IGRA

Intermittent fever

PhlyctenularMycobacteria tuberculosis Intermittent fever Positive TST or IGRA

Positive TST or IGRAMycobacteria tuberculosis Intermittent fever Phlyctenular

pattern

conjunctivitis

Anemiapattern conjunctivitis

 

Funduscopy: Choroid tubercles  Lymphocytopenia

Lymphocytopenia  Funduscopy: Choroid tubercles

Exposures: Travel to endemic area or contact with traveler to endemic area

HilarExposures: Travel to endemic area or contact with traveler to endemic area

Chronic nontenderlymphadenopathy

lymphadenopathy

lymphadenopathy

(pulmonary TB)

Sterile pyuria (in genitourinary TB)lymphadenopathy lymphadenopathy (pulmonary TB) Salmonellosis Gastrointestinal Weight loss  

Salmonellosis

GastrointestinalSalmonellosis Weight loss  

Weight lossSalmonellosis Gastrointestinal  

 
 

symptoms

Hepatomegaly  symptoms

FatigueSplenomegaly

SplenomegalyFatigue

MalaiseWeight loss     symptoms Hepatomegaly Fatigue Splenomegaly Headaches Urinary symptoms

HeadachesWeight loss     symptoms Hepatomegaly Fatigue Splenomegaly Malaise Urinary symptoms

Urinary symptomsGastrointestinal Weight loss     symptoms Hepatomegaly Fatigue Splenomegaly Malaise Headaches

Fever of unknown origin in children: Etiology - UpToDate

Respiratory symptomsFever of unknown origin in children: Etiology - UpToDate Exposures: Poultry, eggs, reptiles Toxoplasmosis Exposures:

Exposures: Poultry, eggs, reptiles

Toxoplasmosis

Exposures: Feline feces, pica (dirt), consumption of game meat

Tularemia

FeverTularemia

Chillspica (dirt), consumption of game meat Tularemia Fever Anorexia Malaise Headache Fatigue Muscle soreness

Anorexia(dirt), consumption of game meat Tularemia Fever Chills Malaise Headache Fatigue Muscle soreness Gastrointestinal

Malaiseconsumption of game meat Tularemia Fever Chills Anorexia Headache Fatigue Muscle soreness Gastrointestinal complaints

Headacheof game meat Tularemia Fever Chills Anorexia Malaise Fatigue Muscle soreness Gastrointestinal complaints

Fatiguemeat Tularemia Fever Chills Anorexia Malaise Headache Muscle soreness Gastrointestinal complaints Exposures: Dead

Muscle sorenessTularemia Fever Chills Anorexia Malaise Headache Fatigue Gastrointestinal complaints Exposures: Dead animal

GastrointestinalChills Anorexia Malaise Headache Fatigue Muscle soreness complaints Exposures: Dead animal carcasses (eg, rabbits),

complaints

Exposures: Dead animal carcasses (eg, rabbits), ingestion of rabbit or squirrel meat; ticks, mosquitoes, lice, fleas, flies

Typhoid fever

Abdominal painTyphoid fever

Localized infections

Osteomyelitis and septic arthritis

Infective endocarditis

Intraabdominal abscess (subphrenic, perinephric, pelvic)

Liver abscess/hepatic infection

perinephric, pelvic) Liver abscess/hepatic infection Chills Diarrhea or constipation Headache Exposures: Travel

Chills

Diarrhea orperinephric, pelvic) Liver abscess/hepatic infection Chills constipation Headache Exposures: Travel to endemic area

constipation

Headacheabscess/hepatic infection Chills Diarrhea or constipation Exposures: Travel to endemic area Bone pain Limp

Exposures: Travel to endemic area

Bone painor constipation Headache Exposures: Travel to endemic area Limp Pre-existing cardiac lesion Previous intraabdominal

LimpHeadache Exposures: Travel to endemic area Bone pain Pre-existing cardiac lesion Previous intraabdominal disease

Pre-existing cardiacHeadache Exposures: Travel to endemic area Bone pain Limp lesion Previous intraabdominal disease or surgery Vague

lesion

Previous intraabdominal disease or surgeryto endemic area Bone pain Limp Pre-existing cardiac lesion Vague abdominal pain Possible jaundice (jaundice is

Vague abdominal paincardiac lesion Previous intraabdominal disease or surgery Possible jaundice (jaundice is not common with a single

Possible jaundice (jaundice is not common with a singleintraabdominal disease or surgery Vague abdominal pain

https://www.uptodate.com/contents/fever-of-unknown-origin-in-childr

Lymphadenopathy(cervical or supraclavicular) Funduscopy: Chorioretinitis in

(cervical or

supraclavicular)

Funduscopy:Lymphadenopathy (cervical or supraclavicular) Chorioretinitis in nonvascular distribution Pharyngeal

Chorioretinitis in

nonvascular

distribution

Pharyngeal hyperemiaFunduscopy: Chorioretinitis in nonvascular distribution Vary depending upon the portal of entry; may include:

Vary depending uponin nonvascular distribution Pharyngeal hyperemia the portal of entry; may include: Pharyngeal hyperemia

the portal of entry;

may include:

PharyngealVary depending upon the portal of entry; may include: hyperemia Eschar at entry site Tender regional

hyperemia

Eschar at entry siteupon the portal of entry; may include: Pharyngeal hyperemia Tender regional lymphadenopathy Bulbar and palpebral

Tender regionalmay include: Pharyngeal hyperemia Eschar at entry site lymphadenopathy Bulbar and palpebral conjunctivitis Relative

lymphadenopathy

Bulbar andEschar at entry site Tender regional lymphadenopathy palpebral conjunctivitis Relative bradycardia* Rose spots

palpebral

conjunctivitis

Relative bradycardia*regional lymphadenopathy Bulbar and palpebral conjunctivitis Rose spots Bone tenderness or joint tenderness New onset

Bulbar and palpebral conjunctivitis Relative bradycardia* Rose spots Bone tenderness or joint tenderness New onset

Rose spots

Bone tenderness orpalpebral conjunctivitis Relative bradycardia* Rose spots joint tenderness New onset cardiac murmur Conjunctival

joint tenderness

New onset cardiac murmurbradycardia* Rose spots Bone tenderness or joint tenderness Conjunctival hemorrhage Hepatomegaly Splenomegaly Petechiae

ConjunctivalBone tenderness or joint tenderness New onset cardiac murmur hemorrhage Hepatomegaly Splenomegaly Petechiae Abdominal

hemorrhage

Hepatomegalytenderness New onset cardiac murmur Conjunctival hemorrhage Splenomegaly Petechiae Abdominal tenderness (may be absent)

Splenomegalyonset cardiac murmur Conjunctival hemorrhage Hepatomegaly Petechiae Abdominal tenderness (may be absent) Hepatomegaly

Petechiaemurmur Conjunctival hemorrhage Hepatomegaly Splenomegaly Abdominal tenderness (may be absent) Hepatomegaly Right

Abdominal tenderness (may be absent)Conjunctival hemorrhage Hepatomegaly Splenomegaly Petechiae Hepatomegaly Right upper quadrant pain Lymphocytosis

Splenomegaly Petechiae Abdominal tenderness (may be absent) Hepatomegaly Right upper quadrant pain Lymphocytosis

Hepatomegaly

Right upper quadrant painPetechiae Abdominal tenderness (may be absent) Hepatomegaly Lymphocytosis Thrombocytopenia Elevated hepatic

Lymphocytosis(may be absent) Hepatomegaly Right upper quadrant pain Thrombocytopenia Elevated hepatic aminotransferases Pyuria

Thrombocytopeniaabsent) Hepatomegaly Right upper quadrant pain Lymphocytosis Elevated hepatic aminotransferases Pyuria Anemia Leukopenia

Elevated hepaticRight upper quadrant pain Lymphocytosis Thrombocytopenia aminotransferases Pyuria Anemia Leukopenia or leukocytosis

aminotransferases

PyuriaThrombocytopenia Elevated hepatic aminotransferases Anemia Leukopenia or leukocytosis (especially in children

AnemiaThrombocytopenia Elevated hepatic aminotransferases Pyuria Leukopenia or leukocytosis (especially in children <5

Leukopenia or leukocytosis (especially in children <5 years of age)Elevated hepatic aminotransferases Pyuria Anemia Elevation of hepatic aminotransferases Positive blood

Elevation of hepatic aminotransferasesor leukocytosis (especially in children <5 years of age) Positive blood culture Elevated ESR/CRP Anemia Leukocytosis

Positive blood culture<5 years of age) Elevation of hepatic aminotransferases Elevated ESR/CRP Anemia Leukocytosis Elevated ESR/CRP

Elevated ESR/CRPof hepatic aminotransferases Positive blood culture Anemia Leukocytosis Elevated ESR/CRP Positive blood culture

Anemiaaminotransferases Positive blood culture Elevated ESR/CRP Leukocytosis Elevated ESR/CRP Positive blood culture

LeukocytosisPositive blood culture Elevated ESR/CRP Anemia Elevated ESR/CRP Positive blood culture Hematuria

Elevated ESR/CRPPositive blood culture Elevated ESR/CRP Anemia Leukocytosis Positive blood culture Hematuria Proteinuria Sterile pyuria

Positive blood cultureElevated ESR/CRP Anemia Leukocytosis Elevated ESR/CRP Hematuria Proteinuria Sterile pyuria Abnormal hepatic

HematuriaAnemia Leukocytosis Elevated ESR/CRP Positive blood culture Proteinuria Sterile pyuria Abnormal hepatic

ProteinuriaElevated ESR/CRP Positive blood culture Hematuria Sterile pyuria Abnormal hepatic aminotransferases (not

Sterile pyuriaESR/CRP Positive blood culture Hematuria Proteinuria Abnormal hepatic aminotransferases (not always present; 23

Positive blood culture Hematuria Proteinuria Sterile pyuria Abnormal hepatic aminotransferases (not always present; 23

Abnormal hepatic

aminotransferases (not always present;

Fever of unknown origin in children: Etiology - UpToDate

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Urinary tract infection

Rheumatologic diseases

Juvenile idiopathic arthritis

Systemic lupus

erythematosus

Vasculitis (eg, polyarteritis nodosa)

pyogenic liver

abscess)

Most often in immunocompromised patients(eg, polyarteritis nodosa) pyogenic liver abscess) Dysuria Urgency Frequency Incontinence Abdominal pain

liver abscess) Most often in immunocompromised patients Dysuria Urgency Frequency Incontinence Abdominal pain

liver abscess) Most often in immunocompromised patients Dysuria Urgency Frequency Incontinence Abdominal pain

Dysuria

Urgency

Most often in immunocompromised patients Dysuria Urgency Frequency Incontinence Abdominal pain Intermittent fever

Frequency

Incontinencein immunocompromised patients Dysuria Urgency Frequency Abdominal pain Intermittent fever pattern (≥1 fever spike

Abdominal painpatients Dysuria Urgency Frequency Incontinence Intermittent fever pattern (≥1 fever spike per day with

Intermittent fever pattern (≥1 fever spike per day with return to normal temperature between fevers)Dysuria Urgency Frequency Incontinence Abdominal pain Arthralgias Ill-appearing with fever Malaise Headache

Arthralgiasper day with return to normal temperature between fevers) Ill-appearing with fever Malaise Headache Anterior chest

Ill-appearing withreturn to normal temperature between fevers) Arthralgias fever Malaise Headache Anterior chest pain Dyspnea

temperature between fevers) Arthralgias Ill-appearing with fever Malaise Headache Anterior chest pain Dyspnea

temperature between fevers) Arthralgias Ill-appearing with fever Malaise Headache Anterior chest pain Dyspnea

fever

Malaise

Headache

Anterior chest painArthralgias Ill-appearing with fever Malaise Headache Dyspnea Neuropsychiatric complaints (eg, depression,

with fever Malaise Headache Anterior chest pain Dyspnea Neuropsychiatric complaints (eg, depression,

Dyspnea

Neuropsychiatric complaints (eg, depression, decreased academic performance)with fever Malaise Headache Anterior chest pain Dyspnea Malaise Abdominal pain Myalgia Muscle weakness Suprapubic

complaints (eg, depression, decreased academic performance) Malaise Abdominal pain Myalgia Muscle weakness Suprapubic

complaints (eg, depression, decreased academic performance) Malaise Abdominal pain Myalgia Muscle weakness Suprapubic

complaints (eg, depression, decreased academic performance) Malaise Abdominal pain Myalgia Muscle weakness Suprapubic

complaints (eg, depression, decreased academic performance) Malaise Abdominal pain Myalgia Muscle weakness Suprapubic

Malaise

Abdominal pain

Myalgia

Muscle weakness

performance) Malaise Abdominal pain Myalgia Muscle weakness Suprapubic tenderness Costovertebral angle tenderness

performance) Malaise Abdominal pain Myalgia Muscle weakness Suprapubic tenderness Costovertebral angle tenderness

performance) Malaise Abdominal pain Myalgia Muscle weakness Suprapubic tenderness Costovertebral angle tenderness

Suprapubic

tenderness

Costovertebral angle

tenderness

Salmon-pink rash

with fever

Erythema nodosumCostovertebral angle tenderness Salmon-pink rash with fever Lymphadenopathy Hepatomegaly Splenomegaly Arthritis

Lymphadenopathytenderness Salmon-pink rash with fever Erythema nodosum Hepatomegaly Splenomegaly Arthritis Tachycardia Tachypnea

HepatomegalySalmon-pink rash with fever Erythema nodosum Lymphadenopathy Splenomegaly Arthritis Tachycardia Tachypnea Weight loss

with fever Erythema nodosum Lymphadenopathy Hepatomegaly Splenomegaly Arthritis Tachycardia Tachypnea Weight loss

Splenomegaly

ArthritisErythema nodosum Lymphadenopathy Hepatomegaly Splenomegaly Tachycardia Tachypnea Weight loss Oral ulcers Malar rash

nodosum Lymphadenopathy Hepatomegaly Splenomegaly Arthritis Tachycardia Tachypnea Weight loss Oral ulcers Malar rash

Tachycardia

Tachypnea

Weight lossHepatomegaly Splenomegaly Arthritis Tachycardia Tachypnea Oral ulcers Malar rash Erythema nodosum Pericardial rub

Splenomegaly Arthritis Tachycardia Tachypnea Weight loss Oral ulcers Malar rash Erythema nodosum Pericardial rub

Splenomegaly Arthritis Tachycardia Tachypnea Weight loss Oral ulcers Malar rash Erythema nodosum Pericardial rub

Splenomegaly Arthritis Tachycardia Tachypnea Weight loss Oral ulcers Malar rash Erythema nodosum Pericardial rub

Oral ulcers

Malar rash

Erythema nodosumTachycardia Tachypnea Weight loss Oral ulcers Malar rash Pericardial rub Small joint arthritis Weight loss

Pericardial rubWeight loss Oral ulcers Malar rash Erythema nodosum Small joint arthritis Weight loss Hypertension Palpable

Small joint arthritisloss Oral ulcers Malar rash Erythema nodosum Pericardial rub Weight loss Hypertension Palpable purpura Subcutaneous

rash Erythema nodosum Pericardial rub Small joint arthritis Weight loss Hypertension Palpable purpura Subcutaneous

rash Erythema nodosum Pericardial rub Small joint arthritis Weight loss Hypertension Palpable purpura Subcutaneous

rash Erythema nodosum Pericardial rub Small joint arthritis Weight loss Hypertension Palpable purpura Subcutaneous

rash Erythema nodosum Pericardial rub Small joint arthritis Weight loss Hypertension Palpable purpura Subcutaneous

Weight loss

Hypertension

Palpable purpura

Subcutaneous

nodules

Asymmetricloss Hypertension Palpable purpura Subcutaneous nodules neuropathy Testicular tenderness Funduscopic examination:

neuropathy

Testicular tendernessPalpable purpura Subcutaneous nodules Asymmetric neuropathy Funduscopic examination: Perivascular sheathing Neoplasms

Funduscopicnodules Asymmetric neuropathy Testicular tenderness examination: Perivascular sheathing Neoplasms Leukemia

examination:

Perivascular

sheathing

Neoplasms

Leukemia

Limb or bone painLeukemia Gingival hypertrophy

Gingival hypertrophyLeukemia Limb or bone pain

 

Hepatosplenomegaly

Lymphadenopathybone pain Gingival hypertrophy   Hepatosplenomegaly Testicular enlargement Lymphoma Intermittent, Weight

TesticularGingival hypertrophy   Hepatosplenomegaly Lymphadenopathy enlargement Lymphoma Intermittent, Weight loss

enlargement

Lymphoma

Intermittent,Lymphoma Weight loss

Weight lossLymphoma Intermittent,

remittent, or

relapsing fever

pattern

FatigueWeight loss remittent, or relapsing fever pattern Night sweats Lymphadenopathy Hepatosplenomegaly more likely

Night sweatsWeight loss remittent, or relapsing fever pattern Fatigue Lymphadenopathy Hepatosplenomegaly more likely with multiple

remittent, or relapsing fever pattern Fatigue Night sweats Lymphadenopathy Hepatosplenomegaly more likely with multiple

Lymphadenopathy

Hepatosplenomegaly

more likely with multiple abscesses or hepatic infection)

more likely with multiple abscesses or hepatic infection) Pyuria Bacteriuria Hematuria Positive urine culture

more likely with multiple abscesses or hepatic infection) Pyuria Bacteriuria Hematuria Positive urine culture

more likely with multiple abscesses or hepatic infection) Pyuria Bacteriuria Hematuria Positive urine culture

Pyuria

Bacteriuria

Hematuria

Positive urine cultureabscesses or hepatic infection) Pyuria Bacteriuria Hematuria Leukocytosis Thrombocytosis Anemia Elevated ESR Mild

Pyuria Bacteriuria Hematuria Positive urine culture Leukocytosis Thrombocytosis Anemia Elevated ESR Mild

Leukocytosis

ThrombocytosisBacteriuria Hematuria Positive urine culture Leukocytosis Anemia Elevated ESR Mild elevation of aminotransferases

AnemiaHematuria Positive urine culture Leukocytosis Thrombocytosis Elevated ESR Mild elevation of aminotransferases Anemia

Elevated ESRPositive urine culture Leukocytosis Thrombocytosis Anemia Mild elevation of aminotransferases Anemia Neutropenia

Mild elevation ofculture Leukocytosis Thrombocytosis Anemia Elevated ESR aminotransferases Anemia Neutropenia Thrombocytopenia

aminotransferases

Anemia Elevated ESR Mild elevation of aminotransferases Anemia Neutropenia Thrombocytopenia Hematuria Proteinuria

Anemia Elevated ESR Mild elevation of aminotransferases Anemia Neutropenia Thrombocytopenia Hematuria Proteinuria

Anemia

Neutropenia

ThrombocytopeniaESR Mild elevation of aminotransferases Anemia Neutropenia Hematuria Proteinuria Positive stool guaiac Cytopenia in

of aminotransferases Anemia Neutropenia Thrombocytopenia Hematuria Proteinuria Positive stool guaiac Cytopenia in

of aminotransferases Anemia Neutropenia Thrombocytopenia Hematuria Proteinuria Positive stool guaiac Cytopenia in

Hematuria

Proteinuria

Positive stool guaiacAnemia Neutropenia Thrombocytopenia Hematuria Proteinuria Cytopenia in ≥1 cell line Bizarre/immature WBCs

Cytopenia in ≥1 cell lineThrombocytopenia Hematuria Proteinuria Positive stool guaiac Bizarre/immature WBCs Neutropenia Mediastinal mass

Bizarre/immaturePositive stool guaiac Cytopenia in ≥1 cell line WBCs Neutropenia Mediastinal mass Mediastinal mass or

WBCs

Neutropeniaguaiac Cytopenia in ≥1 cell line Bizarre/immature WBCs Mediastinal mass Mediastinal mass or lymphadenopathy 24 de

Mediastinal massin ≥1 cell line Bizarre/immature WBCs Neutropenia Mediastinal mass or lymphadenopathy 24 de 27 02/09/2017

Mediastinal mass orCytopenia in ≥1 cell line Bizarre/immature WBCs Neutropenia Mediastinal mass lymphadenopathy 24 de 27 02/09/2017 14:15

lymphadenopathy

Fever of unknown origin in children: Etiology - UpToDate

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Other causes

Altered thermoregulation

Diabetes insipidus (central or nephrogenic)

thermoregulation Diabetes insipidus (central or nephrogenic) History of brain damage or CNS dysfunction Polyuria

thermoregulation Diabetes insipidus (central or nephrogenic) History of brain damage or CNS dysfunction Polyuria

thermoregulation Diabetes insipidus (central or nephrogenic) History of brain damage or CNS dysfunction Polyuria

History of brain damage or CNS dysfunction

Polyuria

Polydipsia

More common in Ulster Scots (nephrogenic)of brain damage or CNS dysfunction Polyuria Polydipsia Weight loss Lack of sweat with fever Decreased

Polydipsia More common in Ulster Scots (nephrogenic) Weight loss Lack of sweat with fever Decreased peripheral

Polydipsia More common in Ulster Scots (nephrogenic) Weight loss Lack of sweat with fever Decreased peripheral

Weight loss

Lack of sweat with

fever

Decreased peripheral perfusionScots (nephrogenic) Weight loss Lack of sweat with fever Drug fever Resolution with Rash discontinuation

Drug fever

Resolution withDrug fever Rash

RashDrug fever Resolution with

discontinuation of

offending drug

Exposures: Virtually any drug or complementary and alternative agent

Factitious fever

Absence of nonspecific symptoms (malaise, discomfort) during feverFactitious fever Rapid defervescence without diaphoresis

Rapid defervescence without diaphoresisFactitious fever Absence of nonspecific symptoms (malaise, discomfort) during fever

Familial dysautonomia

Hemophagocytic

lymphohistiocytosis

Infantile cortical

hyperostosis

Inflammatory bowel disease

Discrepancy between temperatures recorded or reported by the patient or caregiver and those obtained rectally under direct observationInfantile cortical hyperostosis Inflammatory bowel disease Lack of sweat during fever More common in patients of

Lack of sweat during feverand those obtained rectally under direct observation More common in patients of Ashkenazi Jewish descent May

More common in patients of Ashkenazi Jewish descentrectally under direct observation Lack of sweat during fever May have positive family history Exposures: Infection,

fever More common in patients of Ashkenazi Jewish descent May have positive family history Exposures: Infection,

May have positive family history

Exposures: Infection, immunologic disorder, malignancy, drugs

Infection, immunologic disorder, malignancy, drugs Limb or bone pain Gastrointestinal complaints Delayed sexual

Infection, immunologic disorder, malignancy, drugs Limb or bone pain Gastrointestinal complaints Delayed sexual

Infection, immunologic disorder, malignancy, drugs Limb or bone pain Gastrointestinal complaints Delayed sexual

Infection, immunologic disorder, malignancy, drugs Limb or bone pain Gastrointestinal complaints Delayed sexual

Limb or bone pain

Gastrointestinal

complaints

Delayed sexual

maturation

More common in

Labile blood pressurecomplaints Delayed sexual maturation More common in Decreased/absent tears Absent corneal reflex Hypodontia,

Decreased/absentsexual maturation More common in Labile blood pressure tears Absent corneal reflex Hypodontia, adontia, or conical

tears

Absent corneal reflexMore common in Labile blood pressure Decreased/absent tears Hypodontia, adontia, or conical teeth Smooth tongue

Hypodontia, adontia, or conical teethblood pressure Decreased/absent tears Absent corneal reflex Smooth tongue Erythematous or blotchy skin Decreased DTR

Smooth tongueAbsent corneal reflex Hypodontia, adontia, or conical teeth Erythematous or blotchy skin Decreased DTR Lymphadenopathy

Erythematous orreflex Hypodontia, adontia, or conical teeth Smooth tongue blotchy skin Decreased DTR Lymphadenopathy

blotchy skin

Decreased DTRor conical teeth Smooth tongue Erythematous or blotchy skin Lymphadenopathy Hepatosplenomegaly Skin lesions (generalized

LymphadenopathySmooth tongue Erythematous or blotchy skin Decreased DTR Hepatosplenomegaly Skin lesions (generalized rash,

Hepatosplenomegaly

Skin lesionsskin Decreased DTR Lymphadenopathy Hepatosplenomegaly (generalized rash, erythroderma, edema, petechiae, purpura)

(generalized rash,

erythroderma,

edema, petechiae,

purpura)

Neurologic symptoms(generalized rash, erythroderma, edema, petechiae, purpura) Bony tenderness Swelling of overlying tissues Weight loss

erythroderma, edema, petechiae, purpura) Neurologic symptoms Bony tenderness Swelling of overlying tissues Weight loss

Bony tenderness

Swelling of overlying tissuespetechiae, purpura) Neurologic symptoms Bony tenderness Weight loss Short stature or decreased height velocity Oral

symptoms Bony tenderness Swelling of overlying tissues Weight loss Short stature or decreased height velocity Oral

Weight loss

Short stature orBony tenderness Swelling of overlying tissues Weight loss decreased height velocity Oral ulcers Normal ESR/CRP

Swelling of overlying tissues Weight loss Short stature or decreased height velocity Oral ulcers Normal ESR/CRP

decreased height

velocity

Oral ulcers

loss Short stature or decreased height velocity Oral ulcers Normal ESR/CRP Hypernatremia Normal ESR/CRP Leukocytosis

loss Short stature or decreased height velocity Oral ulcers Normal ESR/CRP Hypernatremia Normal ESR/CRP Leukocytosis

loss Short stature or decreased height velocity Oral ulcers Normal ESR/CRP Hypernatremia Normal ESR/CRP Leukocytosis

Normal ESR/CRP

Hypernatremia

Normal ESR/CRP

LeukocytosisOral ulcers Normal ESR/CRP Hypernatremia Normal ESR/CRP Eosinophilia Elevated ESR Normal ESR/CRP Normal ESR/CRP

EosinophiliaNormal ESR/CRP Hypernatremia Normal ESR/CRP Leukocytosis Elevated ESR Normal ESR/CRP Normal ESR/CRP Cytopenias in

Elevated ESRHypernatremia Normal ESR/CRP Leukocytosis Eosinophilia Normal ESR/CRP Normal ESR/CRP Cytopenias in ≥1 cell line

Normal ESR/CRPNormal ESR/CRP Leukocytosis Eosinophilia Elevated ESR Normal ESR/CRP Cytopenias in ≥1 cell line (especially

Normal ESR/CRPLeukocytosis Eosinophilia Elevated ESR Normal ESR/CRP Cytopenias in ≥1 cell line (especially anemia and

Cytopenias in ≥1 cell line (especiallyEosinophilia Elevated ESR Normal ESR/CRP Normal ESR/CRP anemia and thrombocytopenia) Coagulopathy Liver dysfunction

anemia and thrombocytopenia)

Coagulopathyin ≥1 cell line (especially anemia and thrombocytopenia) Liver dysfunction Leukocytosis Elevated ESR Anemia Positive

line (especially anemia and thrombocytopenia) Coagulopathy Liver dysfunction Leukocytosis Elevated ESR Anemia Positive

line (especially anemia and thrombocytopenia) Coagulopathy Liver dysfunction Leukocytosis Elevated ESR Anemia Positive

Liver dysfunction

Leukocytosis

Elevated ESRCoagulopathy Liver dysfunction Leukocytosis Anemia Positive stool guaiac Elevated ESR/CRP 25 de 27

Coagulopathy Liver dysfunction Leukocytosis Elevated ESR Anemia Positive stool guaiac Elevated ESR/CRP 25 de 27

Anemia

Positive stool guaiacCoagulopathy Liver dysfunction Leukocytosis Elevated ESR Anemia Elevated ESR/CRP 25 de 27 02/09/2017 14:15

Elevated ESR/CRPCoagulopathy Liver dysfunction Leukocytosis Elevated ESR Anemia Positive stool guaiac 25 de 27 02/09/2017 14:15

Fever of unknown origin in children: Etiology - UpToDate

Kawasaki disease

Kikuchi-Fujimoto disease

Periodic fever disorders:

Cyclic neutropeniadisease Kikuchi-Fujimoto disease Periodic fever disorders: Hyperimmunoglobulin D syndrome PFAPA syndrome Deficiency of

Hyperimmunoglobulin D syndrome

PFAPA syndromedisorders: Cyclic neutropenia Hyperimmunoglobulin D syndrome Deficiency of IL-1 or IL-36 receptor antagonist adolescents

Deficiency of IL-1 or IL-36 receptor antagonistneutropenia Hyperimmunoglobulin D syndrome PFAPA syndrome adolescents Fatigue Gastrointestinal complaints Joint pain

adolescents

Deficiency of IL-1 or IL-36 receptor antagonist adolescents Fatigue Gastrointestinal complaints Joint pain More common

Fatigue

Gastrointestinalof IL-1 or IL-36 receptor antagonist adolescents Fatigue complaints Joint pain More common in females and

receptor antagonist adolescents Fatigue Gastrointestinal complaints Joint pain More common in females and patients

complaints

Joint pain

More common in females and patients <40 years of ageadolescents Fatigue Gastrointestinal complaints Joint pain Recurrent fever pattern

Recurrent feverMore common in females and patients <40 years of age pattern

pattern

https://www.uptodate.com/contents/fever-of-unknown-origin-in-childr

Perianal fistulae, skin tags, or fissuresErythema nodosum Bulbar conjunctivitis Strawberry tongue,

Erythema nodosumPerianal fistulae, skin tags, or fissures Bulbar conjunctivitis Strawberry tongue, cracked lips Rash

Perianal fistulae, skin tags, or fissures Erythema nodosum Bulbar conjunctivitis Strawberry tongue, cracked lips Rash

Bulbar conjunctivitis

Strawberry tongue,tags, or fissures Erythema nodosum Bulbar conjunctivitis cracked lips Rash Edema and periungual desquamation of hands

cracked lips

RashBulbar conjunctivitis Strawberry tongue, cracked lips Edema and periungual desquamation of hands and feet Cervical

Edema and periungual desquamation of hands and feetBulbar conjunctivitis Strawberry tongue, cracked lips Rash Cervical lymphadenopathy Cervical lymphadenopathy

CervicalRash Edema and periungual desquamation of hands and feet lymphadenopathy Cervical lymphadenopathy Hepatosplenomegaly

lymphadenopathy

desquamation of hands and feet Cervical lymphadenopathy Cervical lymphadenopathy Hepatosplenomegaly Arthritis Rash

desquamation of hands and feet Cervical lymphadenopathy Cervical lymphadenopathy Hepatosplenomegaly Arthritis Rash

Cervical

lymphadenopathy

Hepatosplenomegaly

Arthritis

RashCervical lymphadenopathy Hepatosplenomegaly Arthritis Refer to UpToDate content on periodic fever syndromes

Refer to UpToDate content on periodic fever syndromesCervical lymphadenopathy Hepatosplenomegaly Arthritis Rash Thrombocytosis Sterile pyuria Leukopenia Atypical

Rash Refer to UpToDate content on periodic fever syndromes Thrombocytosis Sterile pyuria Leukopenia Atypical

Thrombocytosis

Sterile pyuriaUpToDate content on periodic fever syndromes Thrombocytosis Leukopenia Atypical lymphocytes Thrombocytopenia

on periodic fever syndromes Thrombocytosis Sterile pyuria Leukopenia Atypical lymphocytes Thrombocytopenia

Leukopenia

Atypical lymphocytesfever syndromes Thrombocytosis Sterile pyuria Leukopenia Thrombocytopenia Pancytopenia Elevated ESR Mildly elevated

ThrombocytopeniaSterile pyuria Leukopenia Atypical lymphocytes Pancytopenia Elevated ESR Mildly elevated hepatic

Pancytopeniapyuria Leukopenia Atypical lymphocytes Thrombocytopenia Elevated ESR Mildly elevated hepatic transferases Elevated

Elevated ESRAtypical lymphocytes Thrombocytopenia Pancytopenia Mildly elevated hepatic transferases Elevated ESR/CRP during

Mildly elevated hepatic transferaseslymphocytes Thrombocytopenia Pancytopenia Elevated ESR Elevated ESR/CRP during episodes FUO: fever of unknown

Elevated ESR/CRPElevated ESR Mildly elevated hepatic transferases during episodes FUO: fever of unknown origin; CXR: chest

during episodes

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]).

Graphic 111282 Version 2.0

Fever of unknown origin in children: Etiology - UpToDate

https://www.uptodate.com/contents/fever-of-unknown-origin-in-childr

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