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:
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Classic FUO: Fever for > 3 weeks with no identified cause after 3 days of hospital evaluation or ≥ 3 outpatient visits
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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
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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
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HIV-related FUO: Fever for > 3 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 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, vasculitis, and juvenile rheumatoid arthritis of adults (adult Still disease).
The most common neoplastic causes are lymphoma, leukemia, renal cell carcinoma, 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.
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.
Some Causes of Fever of Unknown Origin (FUO)
Cause |
Suggestive Findings |
Diagnostic Approach* |
Infectious |
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Abdominal or pelvic discomfort, usually tenderness Sometimes history of surgery, trauma, diverticulosis, peritonitis, or gynecologic procedure |
CT or MRI |
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History of being scratched or licked by a cat Regional adenopathy, Parinaud oculoglandular syndrome, headache |
Culture (sometimes of lymph node aspirate), antibody titers, polymerase chain reaction testing |
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History of blood transfusion from CMV-positive donor Syndrome that resembles mononucleosis (fatigue, mild hepatitis, splenomegaly, adenopathy), chorioretinitis |
CMV IgM antibody titers Possibly polymerase chain reaction testing |
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Sore throat, adenopathy, right upper quadrant tenderness, splenomegaly, fatigue Usually occurring in adolescents and young adults In older patients, typical findings possibly absent |
Serologic testing |
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History of high-risk behaviors (eg, unprotected sex, sharing needles) Weight loss, night sweats, fatigue, adenopathy, opportunistic infections |
4th-generation combination immunoassay Sometimes testing for HIV RNA (for acute HIV infection) |
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Often history of risk factors (eg, structural heart disease, prosthetic heart valve, periodontal disease, IV catheter, injection drug use) Usually a heart murmur, sometimes extracardiac manifestations (eg, splinter hemorrhages, petechiae, Roth spots, Osler nodes, Janeway lesions, joint pain or effusion, splenomegaly) |
Serial blood cultures, echocardiography |
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Visiting or living in an endemic area Erythema migrans rash, headache, fatigue, Bell palsy, meningitis, radiculopathy, heart block, joint pain and swelling |
Serologic testing |
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Localized pain, swelling, erythema |
X-rays Sometimes MRI (most accurate test), radionuclide scanning with indium-111, bone scanning |
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Prolonged congestion, headache, facial pain |
CT of sinuses |
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Tuberculosis (pulmonary and disseminated) |
History of high-risk exposure Cough, weight loss, fatigue Use of immunosuppressants History of HIV infection |
Chest x-ray, tuberculin skin test (PPD), interferon-gamma release assay Sputum smear for acid-fast bacilli, nucleic acid amplification testing (NAAT), culture of body fluids (eg, gastric aspirates, sputum, cerebrospinal fluid) |
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Uncommon infections (eg, brucellosis, malaria, Q fever, toxoplasmosis, trichinosis, typhoid fever) |
History of travel to endemic areas Exposure to or ingestion of certain animal products |
Serologic testing for individual causes Peripheral blood smear for malaria |
Connective tissue |
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Adult Still disease |
Evanescent salmon-pink rash, arthralgias, arthritis, myalgias, cervical adenopathy, sore throat, cough, chest pain |
ANA, RF, serum ferritin concentration, x-rays of affected joints |
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Unilateral headache, visual disturbances Often symptoms of polymyalgia rheumatica, sometimes jaw claudication Tenderness of temporal artery when palpated |
Erythrocyte sedimentation rate, temporal artery biopsy |
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Fever, weight loss, myalgias, arthralgias, purpura, hematuria, abdominal pain, testicular pain, angina, livedo reticularis, new-onset hypertension |
Biopsy of involved tissues or angiography |
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History of morning stiffness in shoulders, hips, and neck Malaise, fatigue, anorexia Possibly synovitis, bursitis, pitting edema of extremities |
Creatinine kinase, ANA, RF, erythrocyte sedimentation rate Possibly MRI of extremities |
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Sometimes recent history of infection with Chlamydia, Salmonella, Yersinia, Campylobacter, or Shigella Asymmetric oligoarthritis, urethritis, conjunctivitis, genital ulcerations |
ANA, RF, serologic testing for causative pathogens |
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Symmetric peripheral polyarthritis, prolonged morning stiffness, subcutaneous rheumatoid nodules in pressure sites (extensor surface of ulna, sacrum, back of head, Achilles tendon) |
ANA, RF, anticyclic citrullinated peptide (anti-CCP) antibody, x-rays (to identify bone erosions) |
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Fatigue, arthralgia, pleuritic chest pain, malar rash, tender swollen joints, mild peripheral edema, Raynaud syndrome, serositis, nephritis, alopecia |
Clinical criteria, ANA, antibodies to double-stranded DNA |
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Neoplastic |
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Abdominal pain, change in bowel habits, hematochezia, weakness, nausea, vomiting, weight loss, fatigue |
Colonoscopy, biopsy |
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History of chronic liver disease, abdominal pain, weight loss, early satiety, palpable mass in right upper quadrant |
Abdominal ultrasonography and CT, liver biopsy |
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Sometimes history of myelodysplastic disorder Fatigue, weight loss, bleeding, pallor, petechiae, ecchymoses, anorexia, splenomegaly, bone pain |
Complete blood count, bone marrow examination |
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Painless adenopathy, weight loss, malaise, night sweats, splenomegaly, hepatomegaly |
Lymph node biopsy |
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Metastatic cancer |
Symptoms dependent on the site of metastasis (eg, cough and shortness of breath for lung metastasis, headache and dizziness for brain metastasis) Often asymptomatic, discovered during a routine medical evaluation |
Biopsy of suspicious mass or node, imaging tests appropriate for area of concern |
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Frequently asymptomatic, abnormal indices incidentally detected during screening complete blood count |
Testing based on the suspected disorder |
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Weight loss, night sweats, flank pain, hematuria, palpable flank mass, hypertension |
Serum calcium (to check for hypercalcemia), urinalysis, CT of kidneys |
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Miscellaneous |
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Long history of alcohol use Sometimes ascites, jaundice, small or enlarged liver, gynecomastia, Dupuytren contracture, testicular atrophy |
Prothrombin time/partial thromboplastin time, alkaline phosphatase, transaminases, albumin, bilirubin Sometimes abdominal ultrasonography and CT |
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Pain, swelling, sometimes redness of leg |
Ultrasonography Sometimes D-dimer assay |
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Drug fever |
Fever coincident with administration of a drug (usually within 7–10 days) Sometimes a rash |
Withdrawal of drug |
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Dramatic, atypical presentation, vague and inconsistent details, knowledge of textbook descriptions, compulsive or habitual lying (pseudologia fantastica) |
Diagnosis of exclusion |
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Abdominal pain, diarrhea (sometimes bloody), weight loss, guaiac-positive stools Sometimes fistulas, perianal and oral ulcerations, arthralgias |
Upper gastrointestinal endoscopy with small-bowel follow-through or CT enterography (Crohn disease) Colonoscopy (ulcerative colitis or Crohn colitis) |
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* Patients with FUO may lack typical findings, but such findings should be sought. |
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ANA = antinuclear antibodies; CMV = cytomegalovirus; RF = rheumatoid factor. |
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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. 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 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
Interpretation of findings
After a thorough history and physical examination, the following scenarios are typical:
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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)).
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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.
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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.
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 considered in younger travelers who have hiked 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:
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 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.
Positron emission tomography may also be useful in detecting the focus of fever.
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.
Treatment of FUO
Geriatrics Essentials: FUO
Key Points about FUO
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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.
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Identified causes can be categorized as infectious, connective tissue, neoplastic, or miscellaneous.
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Evaluation should be based on synthesis of history and physical examination, with particular consideration of risk factors and likely causes based on individual circumstances.
