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Fever of Unknown Origin (FUO)

by Allan R. Tunkel, MD, PhD

FUO is body temperature 38.0° C 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 wk 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 immunodeficiencies if the diagnosis remains uncertain after 3 days of appropriate evaluation, including negative cultures after 48 h

  • HIV-related FUO: Fever for > 3 wk in outpatients with confirmed HIV infection or > 3 days in inpatients with confirmed HIV infection if the diagnosis remains uncertain after appropriate evaluation

Etiology

Causes of FUO are usually divided into 4 categories (see Some Causes of 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, TB; infection by atypical mycobacteria, disseminated fungi, or cytomegalovirus) should be sought.

Common connective tissue disorders include SLE, RA, giant cell arteritis, vasculitis, and juvenile RA 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 FUO

Cause

Suggestive Findings

Diagnostic Approach*

Infectious

Abscesses (abdominal, pelvic, dental)

Abdominal or pelvic discomfort, usually tenderness

Sometimes history of surgery, trauma, diverticulosis, peritonitis, or gynecologic procedure

CT or MRI

Cat-scratch disease

History of being scratched or licked by a cat

Regional adenopathy, Parinaud oculoglandular syndrome, headache

Culture (sometimes of lymph node aspirate), antibody titers, PCR testing

CMV infection

History of blood transfusion from CMV-positive donor

Syndrome that resembles mononucleosis (fatigue, mild hepatitis, splenomegaly, adenopathy), chorioretinitis

CMV IgM antibody titers

Possibly PCR testing

EBV infection

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

HIV infection

History of high-risk behaviors (eg, unprotected sex, sharing needles)

Weight loss, night sweats, fatigue, adenopathy, opportunistic infections

Testing for HIV antibodies (ie, ELISA, Western blot)

Sometimes testing for HIV RNA (for acute HIV infection)

Infective endocarditis

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

Lyme disease

Visiting or living in an endemic area

Erythema migrans rash, headache, fatigue, Bell palsy, meningitis, radiculopathy, heart block, joint pain and swelling

Serologic testing

Osteomyelitis

Localized pain, swelling, erythema

X-rays

Sometimes MRI (most accurate test), radionuclide scanning with indium-111, bone scanning

Sinusitis

Prolonged congestion, headache, facial pain

CT of sinuses

TB (pulmonary and disseminated)

History of high-risk exposure

Cough, weight loss, fatigue

Use of immunosuppressants

History of HIV infection

Chest x-ray, PPD, interferon-gamma release assay

Sputum smear for acid-fast bacilli, nucleic acid amplification testing (NAAT), culture of body fluids (eg, gastric aspirates, sputum, CSF)

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

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

Giant cell (temporal) arteritis

Unilateral headache, visual disturbances

Often symptoms of polymyalgia rheumatica, sometimes jaw claudication

Tenderness of temporal artery when palpated

ESR, temporal artery biopsy

Polyarteritis nodosa

Fever, weight loss, myalgias, arthralgias, purpura, hematuria, abdominal pain, testicular pain, angina, livedo reticularis, new-onset hypertension

Biopsy of involved tissues or angiography

Polymyalgia rheumatica

History of morning stiffness in shoulders, hips, and neck

Malaise, fatigue, anorexia

Possibly synovitis, bursitis, pitting edema of extremities

Creatinine kinase, ANA, RF, ESR

Possibly MRI of extremities

Reactive arthritis

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

Rheumatoid arthritis

Symmetric peripheral polyarthritis, prolonged morning stiffness, subcutaneous rheumatoid nodules in pressure sites (extensor surface of ulna, sacrum, back of head, Achilles tendon)

ANA, RF, citrullinated peptide antibody (anti-CCP), x-rays (to identify bone erosions)

SLE

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

Neoplastic

Colon carcinoma

Abdominal pain, change in bowel habits, hematochezia, weakness, nausea, vomiting, weight loss, fatigue

Colonoscopy, biopsy

Hepatoma

History of chronic liver disease, abdominal pain, weight loss, early satiety, palpable mass in right upper quadrant

Abdominal ultrasonography and CT, liver biopsy

Leukemia

Sometimes history of myelodysplastic disorder

Fatigue, weight loss, bleeding, pallor, petechiae, ecchymoses, anorexia, splenomegaly, bone pain

CBC, bone marrow examination

Lymphoma

Painless adenopathy, weight loss, malaise, night sweats, splenomegaly, hepatomegaly

Lymph node biopsy

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

Myeloproliferative disorders

Frequently asymptomatic, abnormal indices incidentally detected during screening CBC

Testing based on the suspected disorder

Renal cell carcinoma

Weight loss, night sweats, flank pain, hematuria, palpable flank mass, hypertension

Serum Ca (to check for hypercalcemia), urinalysis, CT of kidneys

Miscellaneous

Alcoholic cirrhosis

Long history of alcohol use

Sometimes ascites, jaundice, small or enlarged liver, gynecomastia, Dupuytren contracture, testicular atrophy

PT/PTT, alkaline phosphatase, transaminases, albumin, bilirubin

Sometimes abdominal ultrasonography and CT

Deep venous thrombosis

Pain, swelling, sometimes redness of leg

Ultrasonography

Sometimes D-dimer assay

Drug fever

Fever coincident with administration of a drug (usually within 7–10 days)

Sometimes a rash

Withdrawal of drug

Factitious fever

Dramatic, atypical presentation, vague and inconsistent details, knowledge of textbook descriptions, compulsive or habitual lying (pseudologia fantastica)

Diagnosis of exclusion

Inflammatory bowel disease

Abdominal pain, diarrhea (sometimes bloody), weight loss, guaiac-positive stools

Sometimes fistulas, perianal and oral ulcerations, arthralgias

Upper GI endoscopy with small-bowel follow-through or CT enterography (Crohn disease)

Colonoscopy (ulcerative colitis or Crohn colitis)

*Patients with FUO may lack typical findings, but such findings should be sought.

ANA = antinuclear antibodies; ANCA = antineutrophil cytoplasmic antibody; CMV = cytomegalovirus; EBV = Epstein-Barr virus; ELISA = enzyme-linked immunosorbent assay; RF = rheumatoid factor.

Evaluation

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 GI disorders (eg, diarrhea, steatorrhea, abdominal discomfort) should be sought.

Past medical history should include disorders known to cause fever, such as cancer, TB, 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 TB), travel, and possible exposure to animal or insect 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 SLE); 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

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 Some Causes of 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 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.

As much as possible, clinical information is used to focus testing (see Some Causes of FUO). For example, housebound elderly 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. Elderly patients require evaluation for giant cell arteritis; younger patients do not.

In addition to specific testing, the following should usually be done:

  • CBC with differential

  • ESR

  • Liver function tests

  • Serial blood cultures (ideally before antimicrobial therapy)

  • HIV antibody test, RNA concentration assays, and PCR 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 PCR 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, 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 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. PET 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 (PCR) diagnostic testing. Muscle biopsy or skin biopsy of rashes may confirm vasculitis. Bilateral temporal artery biopsy may confirm giant cell arteritis in elderly patients with unexplained ESR elevation.


Treatment

Treatment focuses on the causative disorder. Antipyretics should be used judiciously, considering the duration of fever.

Geriatrics Essentials: FUO

Causes of FUO in the elderly are usually similar to those in the general population, but connective tissue disorders are identified more often. The most common causes are

  • Giant cell arteritis

  • Leukemias

  • Lymphomas

  • Abscesses

  • TB

Key Points

  • Classic FUO is body temperature 38.0° C rectally for > 3 wk with no identified cause after 3 days of hospital investigation or 3 outpatient visits.

  • Identified causes can be categorized as infectious, rheumatologic, 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.

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