Fever of unknown origin (FUO) is body temperature ≥ 38.3° C (≥ 101° F) rectally that does not result from transient and self-limited illness, rapidly fatal illness, or disorders with clear-cut localizing symptoms or signs or with abnormalities on common tests such as chest x-ray, urinalysis, or blood cultures.
FUO is currently classified into 4 distinct categories:
Classic FUO: Fever for > 3 weeks with no identified cause after 3 days of hospital evaluation or ≥ 3 outpatient visits
Health care–associated FUO: Fever in hospitalized patients receiving acute care and with no infection present or incubating at admission if the diagnosis remains uncertain after 3 days of appropriate evaluation
Immune-deficient FUO: Fever in patients with neutropenia and other immunodeficiency if the diagnosis remains uncertain after 3 days of appropriate evaluation, including negative cultures after 48 hours
HIV-related FUO: Fever for > 4 weeks in outpatients with confirmed HIV infection or > 3 days in inpatients with confirmed HIV infection if the diagnosis remains uncertain after appropriate evaluation
Etiology of FUO
Causes of FUO are usually divided into 4 categories ( see Table: Some Causes of Fever of Unknown Origin (FUO)):
Infections (25 to 50%)
Connective tissue disorders (10 to 20%)
Neoplasms (5 to 35%)
Miscellaneous (15 to 25%)
Infections are the most common cause of FUO. In patients with HIV infection, opportunistic infections (eg, tuberculosis; infection by atypical mycobacteria, disseminated fungi, or cytomegalovirus) should be sought.
Common connective tissue disorders include systemic lupus erythematosus, rheumatoid arthritis, giant cell arteritis, polymyalgia rheumatica, thyroiditis, vasculitis, and juvenile rheumatoid arthritis of adults (adult Still disease).
The most common neoplastic causes are lymphoma, leukemia, renal cell carcinoma, ovarian carcinoma, atrial myxoma, Castleman disease, hepatocellular carcinoma, and metastatic carcinomas. However, the incidence of neoplastic causes of FUO has been decreasing, probably because they are being detected by ultrasonography and CT, which are now widely used during initial evaluation of fever.
Important miscellaneous causes include drug reactions, deep venous thrombosis, recurrent pulmonary emboli, sarcoidosis, inflammatory bowel disease, and factitious fever.
No cause of FUO is identified in about 10% of adults.
Evaluation of FUO
In puzzling cases such as FUO, assuming that all information was gathered or was gathered accurately by previous clinicians is usually a mistake. Clinicians should be aware of what patients previously reported (to resolve discrepancies) but should not simply copy details of previously recorded history (eg, family history, social history). Initial errors of omission have been perpetuated through many clinicians over many days of hospitalization, causing much unnecessary testing. Even when initial evaluation was thorough, patients often remember new details when questioning is repeated.
Conversely, clinicians should not ignore previous test results and should not repeat tests without considering how likely results are to be different (eg, because the patient’s condition has changed, because a disorder develops slowly).
History
History aims to uncover focal symptoms and facts (eg, travel, occupation, family history, exposure to animal vectors, dietary history) that suggest a cause.
History of present illness should cover duration and pattern (eg, intermittent, constant) of fever. Fever patterns usually have little or no significance in the diagnosis of FUO, although a fever that occurs every other day (tertian) or every 3rd day (quartan) may suggest malaria in patients with risk factors. Focal pain often indicates the location (although not the cause) of the underlying disorder. Clinicians should ask generally, then specifically, about discomfort in each body part.
Review of systems should include nonspecific symptoms, such as weight loss, anorexia, fatigue, night sweats, and headaches. Also, symptoms of connective tissue disorders (eg, myalgias, arthralgias, rashes) and gastrointestinal disorders (eg, diarrhea, steatorrhea, abdominal discomfort) should be sought.
Past medical history should include disorders known to cause fever, such as cancer, tuberculosis, connective tissue disorders, alcoholic cirrhosis, inflammatory bowel disease, rheumatic fever, and hyperthyroidism. Clinicians should note disorders or factors that predispose to infection, such as immunocompromise (eg, due to disorders such as HIV infection, cancer, diabetes, or use of immunosuppressants), structural heart disorders, urinary tract abnormalities, operations, and insertion of devices (eg, IV lines, pacemakers, joint prostheses).
Drug history should include questions about specific drugs known to cause fever.
Social history should include questions about risk factors for infection such as injection drug use, high-risk sexual practices (eg, unprotected sex, multiple partners), infected contacts (eg, with tuberculosis), travel, and possible exposure to animal or insect and tick vectors. Social history should also include questions about history of illness in social contacts (eg, neighbors, coworkers, travel companions). Risk factors for cancer, including smoking, alcohol use, and occupational exposure to chemicals, should also be identified.
Family history should include questions about inherited causes of fever (eg, familial Mediterranean fever).
Medical records are checked for previous test results, particularly those that effectively rule out certain disorders.
Physical examination
The general appearance, particularly for cachexia, jaundice, and pallor, is noted.
The skin is thoroughly inspected for focal erythema (suggesting a site of infection) and rash (eg, malar rash of systemic lupus erythematosus); inspection should include the perineum and feet, particularly in diabetics, who are prone to occult infections in these areas. Clinicians should also check for cutaneous findings of endocarditis, including painful erythematous subcutaneous nodules on the tips of digits (Osler nodes), nontender hemorrhagic macules on the palms or soles (Janeway lesions), petechiae, and splinter hemorrhages under the nails.
The entire body (particularly over the spine, bones, joints, abdomen, and thyroid) is palpated for areas of tenderness, swelling, or organomegaly; digital rectal examination and pelvic examination are included. The teeth are percussed for tenderness (suggesting apical abscess). During palpation, any regional or systemic adenopathy is noted; eg, regional adenopathy is characteristic of cat-scratch disease in contrast to the diffuse adenopathy of lymphoma.
The heart is auscultated for murmurs (suggesting bacterial endocarditis) and rubs (suggesting pericarditis due to a rheumatologic or infectious disorder).
Sometimes key physical abnormalities in patients with FUO are or seem so subtle that repeated physical examinations may be necessary to suggest causes (eg, by detecting new adenopathy, heart murmurs, rash, or nodularity and weak pulsations in the temporal artery).
Red flags
The following are of particular concern:
Immunocompromise
Heart murmur
Presence of inserted devices (eg, IV lines, pacemakers, joint prostheses)
Recent travel to endemic areas
Interpretation of findings
After a thorough history and physical examination, the following scenarios are typical:
Localizing symptoms or signs that were not present, not detected, or not managed during previous examinations are discovered. These findings are interpreted and investigated as indicated ( see Table: Some Causes of Fever of Unknown Origin (FUO)).
More commonly, evaluation detects only nonspecific findings that occur in many different causes of FUO, but it identifies risk factors that can help guide testing (eg, travel to an endemic area, exposure to animal, insect, or tick vectors). Sometimes risk factors are less specific but may suggest a class of illness; eg, weight loss without anorexia is more consistent with infection than cancer, which usually causes anorexia. Possible causes should be investigated further.
In the most difficult scenario, patients have only nonspecific findings and no or multiple risk factors, making a logical, sequential approach to testing essential. Initial testing is used to narrow the diagnostic possibilities and guide subsequent testing.
Testing
Previous test results, particularly for cultures, are reviewed. Cultures for some organisms may require a long time to become positive and special techniques may be required. A microbiology laboratory should be consulted about culture conditions (eg, duration of incubation, special media, temperature, gaseous environment) that may be needed.
As much as possible, clinical information is used to focus testing ( see Table: Some Causes of Fever of Unknown Origin (FUO)). For example, housebound older patients with headache would not be tested for tick-borne infections or malaria, but those disorders should be very seriously considered in younger travelers who have hiked, explored caves, or engaged in water sports in an endemic area. Older patients require evaluation for giant cell arteritis; younger patients do not.
In addition to specific testing, the following should usually be done:
Complete blood count with differential
Erythrocyte sedimentation rate
Liver tests
Serial blood cultures (ideally before antimicrobial therapy)
HIV antibody test, RNA concentration assays, and polymerase chain reaction assay
Tuberculin skin test or interferon-gamma release assay
Even if done earlier, these tests may suggest a helpful trend.
Urinalysis, urine culture, and chest x-ray, usually already done, are repeated only if findings indicate that they should be.
Any available fluid or material from abnormal areas identified during the evaluation is cultured (eg, for bacteria, mycobacteria, fungi, viruses, or specific fastidious bacteria as indicated). Organism-specific tests, such as polymerase chain reaction assay and serologic titers (acute and convalescent), are helpful mainly when guided by clinical suspicion, not done in a shotgun approach.
Serologic tests, such as antinuclear antibody (ANA) and rheumatoid factor (RF), are done to screen for rheumatologic disorders.
Imaging tests are guided by symptoms and signs. Typically, areas of discomfort should be imaged—eg, in patients with back pain, MRI of the spine (to check for infection or tumor); in patients with abdominal pain, CT of the abdomen. However, CT of the chest, abdomen, and pelvis should be considered to check for adenopathy and occult abscesses even when patients do not have localizing symptoms or signs.
If blood cultures are positive or heart murmurs or peripheral signs suggest endocarditis, echocardiography is done.
In general, CT is useful for delineating abnormalities localized to the abdomen, pelvis, or chest.
MRI is more sensitive than CT for detecting most causes of FUO involving the central nervous system (CNS) and should be done if a CNS cause is being considered.
Venous duplex imaging may be useful for identifying cases of deep venous thrombosis.
Radionuclide scanning with indium-111–labeled granulocytes may help localize some infectious or inflammatory processes. This technique has generally fallen out of favor because it is thought to contribute very little to diagnosis, but some reports suggest that it provides a higher diagnostic yield than CT (1).
Positron emission tomography (PET) may also be useful in detecting the focus of fever. PET scans show areas of high metabolic activity that are areas of inflammation and infection.
Biopsy may be required if an abnormality is suspected in tissue that can be biopsied (eg, liver, bone marrow, skin, pleura, lymph nodes, intestine, muscle). Biopsy specimens should be evaluated by histopathologic examination and cultured for bacteria, fungi, viruses, and mycobacteria or sent for molecular (polymerase chain reaction) diagnostic testing. Muscle biopsy or skin biopsy of rashes may confirm vasculitis. Bilateral temporal artery biopsy may confirm giant cell arteritis in older patients with unexplained erythrocyte sedimentation rate elevation.
Testing reference
1. Fisher RE, Drews AL, Palmer EL: Lack of clinical utility of labeled white blood cell scintigraphy in patients with fever of unknown origin. Open Forum Infect Dis 9(3):ofac015, 2022. doi: 10.1093/ofid/ofac015
Treatment of FUO
Treatment of FUO is focused on the causative disorder. Antipyretics should be used judiciously, considering the duration of fever.
Geriatrics Essentials: FUO
Causes of FUO in older patients are usually similar to those in the general population, but connective tissue disorders are identified more often. The most common causes are
Key Points
Classic FUO is body temperature ≥ 38.0° C rectally for > 3 weeks with no identified cause after 3 days of hospital investigation or ≥ 3 outpatient visits.
Identified causes can be categorized as infectious, connective tissue, neoplastic, or miscellaneous.
Evaluation should be based on synthesis of history and physical examination, with particular consideration of risk factors and likely causes based on individual circumstances.
