Version May 2024
INTRODUCTION — Fever is a common presenting complaint in children, accounting for nearly one-third of pediatric outpatient visits in the United States [1].
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) are discussed separately.
●(See "Fever of unknown origin in children: Evaluation".)
●(See "Fever without a source in children 3 to 36 months of age: Evaluation and management".)
●(See "Fever in children with chemotherapy-induced neutropenia".)
●(See "Management of children with non-chemotherapy-induced neutropenia and fever".)
DEFINITION — Although there is no universally accepted definition [2], we apply the term fever of unknown origin (FUO) to children with fever >38.3°C (101°F) 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. We use a duration of eight days because caregivers often seek medical care when fever persists for longer than one week; other experts may require a longer duration of fever. (See "Fever of unknown origin in children: Evaluation", section on 'Definitions'.)
OVERVIEW — The number of infectious and noninfectious etiologies of FUO in children is extensive (table 1). FUO is usually caused by common disorders, often with an unusual presentation (table 2) [3-13].
The three most common etiologic categories of FUO in children in order of frequency are infectious diseases, connective tissue diseases, and neoplasms [3-15]. In addition, there are causes of FUO, such as drug fever, factitious fever, central nervous system dysfunction, and others, that do not fit into the above categories. In many cases, a definitive diagnosis is never established and fever resolves.
In each category below, the conditions are discussed in alphabetical order, rather than by the frequency of diagnosis. In systematic reviews of studies in adult patients, the types of diagnoses and proportions of cases in various etiologic categories (eg, infectious, rheumatologic) varied geographically [16,17].
GENERALIZED INFECTIONS — Generalized infections that cause 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.
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 "Brucellosis: Epidemiology, microbiology, clinical manifestations, and diagnosis".)
Cat scratch disease — Cat scratch disease (CSD, Bartonella henselae infection) is one of the most common causes of FUO in children [10,18]. 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 [19,20]. 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 "Leptospirosis: Epidemiology, microbiology, clinical manifestations, and diagnosis" and "Leptospirosis: Treatment and prevention".)
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 [21,22]. Malaria infection can be delayed for months after travel and can arise in those who have taken malaria prophylaxis. The diagnosis is made by examining appropriately stained thin or thick smears of blood. (See "Malaria: Epidemiology, prevention, and control", section on 'Epidemiology' and "Malaria: Clinical manifestations and diagnosis in nonpregnant adults and children" and "Laboratory tools for 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 disease (table 3) can occur in children with negative chest radiography and tuberculin skin tests [23,24]. 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 "Tuberculosis infection (latent tuberculosis) in children" and "Tuberculosis disease in children: Epidemiology, clinical manifestations, and diagnosis" 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) or other T cell immunodeficiencies. (See "Overview of nontuberculous mycobacterial infections" and "Mycobacterium avium complex (MAC) infections in persons with HIV" and "Overview of nontuberculous mycobacteria (excluding MAC) in patients with HIV".)
Salmonellosis — Salmonella species contaminate a number of food products, especially poultry and eggs, and can be transmitted through contact with reptiles or animal feces. Salmonella species can cause typhoidal as well as localized GI illness. Patients with typhoid frequently have normal pulses or even bradycardia in association with high fevers. The diagnosis can be made with blood and stool cultures, which should be repeated if initially negative and fevers persist. Serologic testing is not recommended. (See "Enteric (typhoid and paratyphoid) fever: Epidemiology, clinical manifestations, and diagnosis" 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 (Ig)G antibodies to Toxoplasma gondii are prevalent, and IgM antibodies can persist for months. (See "Toxoplasmosis: Acute systemic disease".)
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 4). 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 "Tularemia: Clinical manifestations, diagnosis, treatment, and prevention".)
Viral infections — Most viruses cause self-limited infections of brief duration. However, cytomegalovirus (CMV), Epstein-Barr virus (EBV), 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:
●CMV (see "Overview of cytomegalovirus infections in children")
●EBV (see "Clinical manifestations and treatment of Epstein-Barr virus infection")
●Adenovirus (see "Pathogenesis, epidemiology, and clinical manifestations of adenovirus infection" and "Diagnosis, treatment, and prevention of adenovirus infection")
●Hepatitis viruses (see "Overview of hepatitis A virus infection in children" and "Clinical manifestations and diagnosis of hepatitis B virus infection in children and adolescents")
●Enteroviruses (see "Enterovirus and parechovirus infections: Clinical features, laboratory diagnosis, treatment, and prevention")
●Arboviruses (see "St. Louis encephalitis" and "Clinical manifestations and diagnosis of West Nile virus infection" and "Arthropod-borne encephalitides")
LOCALIZED INFECTIONS — When common localized infections cause fever of unknown origin (FUO), they may have an unusual presentation. Careful and repeated history and physical examination and careful review and interpretation of laboratory tests can help to diagnose these infections. All findings, even those that may seem trivial, must be taken seriously. (See "Fever of unknown origin in children: Evaluation", section on 'Overview of evaluation'.)
Bone and joint — Infections involving the bones and joints usually present with recognizable symptoms. However, occasionally FUO can be the only manifestation, especially in young children who cannot vocalize their symptoms. This occurs more commonly with osteomyelitis than with septic arthritis. When FUO is the presenting complaint, the pelvic bones, small bones, and flat bones are more frequently involved than long bones.
The diagnosis of osteomyelitis or septic arthritis can be suggested by imaging studies, including computed tomography (CT), magnetic resonance imaging, and radioisotopic bone scanning. All of these modalities are more sensitive than plain bone radiography. (See "Bacterial arthritis: Clinical features and diagnosis in infants and children", section on 'Imaging' and "Hematogenous osteomyelitis in children: Evaluation and diagnosis", section on 'Advanced imaging'.)
Infective endocarditis — Infective endocarditis (IE) is an infrequent but important cause of FUO in children. IE is rare in normal, term infants but increases in frequency as children age and usually occurs in the setting of a pre-existing cardiac lesion. Acute bacterial endocarditis generally is fulminant in onset, whereas subacute infection is more indolent. (See "Infective endocarditis in children".)
The diagnosis of IE can be difficult to establish since patients do not always have positive blood cultures or a cardiac murmur, especially if the infection is confined to the right side of the heart. Associated nonspecific laboratory findings can include anemia, leukocytosis, and an elevated erythrocyte sedimentation rate.
Viridans streptococci, enterococci, and staphylococci (including Staphylococcus 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.
Intra-abdominal abscess — Intra-abdominal 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 [25]. 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 [26], 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 "Evaluation of the adult patient with hepatic granuloma".)
Bacterial cholangitis can occasionally cause FUO in the absence of jaundice and other liver function abnormalities [27,28]. (See "Acute cholangitis: Clinical manifestations, diagnosis, and management".)
Upper respiratory tract infection — It is surprising how frequently upper respiratory tract infections (URTI) 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 URTI have been reported as causes of FUO in children. One would expect these infections to be associated with localized symptoms, but it appears that complaints may be ignored as trivial.
Urinary tract infection — Urinary tract infection is among the most common causes of FUO in children [8-10]. In one series, the two most frequent laboratory errors were failure to perform a urinalysis and failure to adequately pursue the finding of pyuria [4]. (See "Urinary tract infections in infants and children older than one month: Clinical features and diagnosis", section on 'Clinical presentation'.)
RHEUMATOLOGIC DISEASES — Rheumatologic disease is the second most common etiologic category of FUO in children. A positive antinuclear antibody test can suggest the presence of an underlying connective tissue disorder, particularly systemic lupus erythematosus (SLE) [29]. (See "Measurement and clinical significance of antinuclear antibodies".)
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 [30]. 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 SLE. (See "Vasculitis in children: Incidence and classification", section on 'Polyarteritis nodosa' and "Childhood-onset systemic lupus erythematosus (SLE): Clinical manifestations and diagnosis".)
NEOPLASMS — Leukemia and lymphoma are the most common malignancies that cause FUO in children. Other less common tumors include neuroblastoma, hepatoma, sarcoma, and atrial myxoma. (See "Overview of the clinical presentation and diagnosis of acute lymphoblastic leukemia/lymphoma in children" and "Overview of Hodgkin lymphoma in children and adolescents" and "Clinical presentation, diagnosis, and staging evaluation of neuroblastoma" and "Overview of common presenting signs and symptoms of childhood cancer".)
OTHER CAUSES — The other noninfectious causes of 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 [31,32]. 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 [33]. Epilepsy-induced fever also has been described in adults [34-37]. In another report, an adolescent had cyclic episodes of fever accompanied by nausea, vomiting, and emotional disturbance, resulting from a CNS lesion [38].
Diabetes insipidus — FUO in infants and young children can be due to either arginine vasopressin deficiency (AVP-D, previously called central diabetes insipidus) or arginine vasopressin resistance (AVP-R, previously called nephrogenic diabetes insipidus) [7]. Since polyuria and polydipsia can be difficult to appreciate during infancy, dehydration or hypernatremia may be unrecognized until hyperthermia, weight loss, and decreased peripheral perfusion ensue. The diagnosis of AVP-D or AVP-R 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 "Evaluation of patients with polyuria", section on 'Protocol in infants and children'.)
Drug fever — Fever is a common adverse 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 [39]. 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, regardless of the mechanism. 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. (See "Drug fever".)
Factitious fever — Factitious fever, whether a false report by a caregiver 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, collected in a plastic cup and measured immediately after voiding, closely parallels the temperature obtained orally [40]. 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 or caregiver, 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/caregiver. (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 [41]. The majority of affected children are of Ashkenazi Jewish parentage.
A number of features in the history and physical examination can suggest familial dysautonomia, including a history of recurrent aspiration or vomiting because of poor coordination of swallowing, excessive salivation, diminished tearing, excessive or diminished sweating, labile blood pressure, and erythema or blotchiness of the skin. Fungiform papillae of the tongue may be sparse or absent, and the sense of taste is diminished [42]. 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.
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. Typical manifestations of HLH are prolonged fever, hepatosplenomegaly, hyperferritinemia, and cytopenias [43,44]. Other common findings include liver dysfunction, coagulopathy, hypertriglyceridemia, or hypofibrinogenemia. Clinical presentations of patients with primary (familial) and secondary (reactive) HLH are indistinguishable. (See "Clinical features and diagnosis of hemophagocytic lymphohistiocytosis", section on 'Clinical features'.)
The diagnosis and treatment of HLH are discussed separately. (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 40°C (104°F), subperiosteal bone hyperplasia, and swelling of overlying tissues. Patients with this disease can exhibit irritability and tenderness over the affected regions in addition to fever. Leukocytosis and an elevated erythrocyte sedimentation rate (ESR) are common laboratory findings. These clinical features, in conjunction with radiologic demonstration of periosteal involvement, establish the diagnosis. (See "Differential diagnosis of the orthopedic manifestations of child abuse", section on 'Infantile cortical hyperostosis (Caffey disease)'.)
Inflammatory bowel disease — Fever is a prominent component of inflammatory bowel disease (IBD) in many children [45-47] and may be more common than abdominal symptoms, especially in children with Crohn disease. Ulcerative colitis is a less common cause of FUO in children than Crohn disease; patients with ulcerative colitis typically have accompanying gastrointestinal (GI) symptoms. (See "Clinical manifestations and complications of inflammatory bowel disease in children and adolescents" and "Management of mild to moderate ulcerative colitis in children and adolescents".)
Abdominal CT can be suggestive of IBD in children with prolonged FUO, even in the absence of GI symptoms, but contrast studies of the bowel with special attention to the terminal ileum should be performed, especially in patients with an elevated ESR accompanied by anemia, weight loss, failure of linear growth, or occult blood in the stool. (See "Clinical presentation and diagnosis of inflammatory bowel disease in children".)
Kawasaki disease — Kawasaki disease is a multisystem vasculitis of unknown, but possibly 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 5): 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".)
Multisystem inflammatory syndrome in children — Multisystem inflammatory syndrome in children (MIS-C) is an uncommon complication of coronavirus disease 2019 (COVID-19) that often presents with persistent fever. It is characterized by prominent cardiovascular, gastrointestinal, and mucocutaneous signs and symptoms (table 6). MIS-C is discussed separately. (See "COVID-19: Multisystem inflammatory syndrome in children (MIS-C) clinical features, evaluation, 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 [48]. Fatigue, hepatosplenomegaly, nausea, vomiting, diarrhea, joint pain, arthritis, and rash also may occur. Lymph node biopsy demonstrating paracortical foci with necrosis and histiocytic cellular infiltrate confirms the diagnosis. Kikuchi disease is discussed in detail separately. (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 "The 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.
Here are the patient education articles that are relevant to this topic. We encourage you to print or email these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient education" 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
●Causes – 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 – Generalized infections that cause FUO typically have nonspecific presenting features (table 2). 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.)
•Localized infections – When common localized infections cause FUO, they may have an unusual presentation (table 2). 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 – Noninfectious causes of FUO include collagen vascular diseases (eg, juvenile idiopathic arthritis) and neoplasms, among others (table 2). (See 'Rheumatologic diseases' above and 'Neoplasms' above and 'Other causes' above.)
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