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 Fever, Chronic (FUO): A Merck Manual of Patient Symptoms podcast
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:
Etiology
Causes of FUO are usually divided into 4 categories (see Table 2: Biology of Infectious Disease: Some Causes of FUO ):
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.
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Table 2
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| Some Causes of FUO |
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Cause
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Suggestive Findings
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Diagnostic Approach*
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Infectious
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Abscesses (abdominal, pelvic, dental)
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Abdominal or pelvic discomfort, usually tenderness
Sometimes history of surgery, trauma, diverticulosis, peritonitis, or gynecologic procedure
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CT or MRI
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Cat-scratch disease
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History of being scratched or licked by a cat
Regional adenopathy, Parinaud oculoglandular syndrome, headache
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Culture (sometimes of lymph node aspirate), antibody titers, PCR testing
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CMV infection
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History of blood transfusion from CMV-positive donor
Syndrome that resembles mononucleosis (fatigue, mild hepatitis, splenomegaly, adenopathy), chorioretinitis
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CMV IgM antibody titers
Possibly PCR testing
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EBV infection
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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
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Serologic testing
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HIV infection
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History of high-risk behaviors (eg, unprotected sex, sharing needles)
Weight loss, night sweats, fatigue, adenopathy, opportunistic infections
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Testing for HIV antibodies (ie, ELISA, Western blot)
Sometimes testing for HIV RNA (for acute HIV infection)
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Infective endocarditis
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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)
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Serial blood cultures, echocardiography
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Lyme disease
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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
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Serologic testing
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Osteomyelitis
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Localized pain, swelling, erythema
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X-rays
Sometimes MRI (most accurate test), radionuclide scanning with indium-111, bone scanning
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Sinusitis
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Prolonged congestion, headache, facial pain
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CT of sinuses
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TB (pulmonary and disseminated)
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History of high-risk exposure
Cough, weight loss, fatigue
Use of immunosuppressants
History of HIV infection
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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)
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Uncommon infections (eg, brucellosis, malaria, Q fever, toxoplasmosis, trichinosis, typhoid fever)
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History of travel to endemic areas
Exposure to or ingestion of certain animal products
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Serologic testing for individual causes
Peripheral blood smear for malaria
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Connective tissue
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Adult Still disease
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Evanescent salmon-pink rash, arthralgias, arthritis, myalgias, cervical adenopathy, sore throat, cough, chest pain
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ANA, RF, serum ferritin concentration, x-rays of affected joints
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Giant cell (temporal) arteritis
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Unilateral headache, visual disturbances
Often symptoms of polymyalgia rheumatica, sometimes jaw claudication
Tenderness of temporal artery when palpated
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ESR, temporal artery biopsy
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Polyarteritis nodosa
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Fever, weight loss, myalgias, arthralgias, purpura, hematuria, abdominal pain, testicular pain, angina, livedo reticularis, new-onset hypertension
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Biopsy of involved tissues or angiography
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Polymyalgia rheumatica
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History of morning stiffness in shoulders, hips, and neck
Malaise, fatigue, anorexia
Possibly synovitis, bursitis, pitting edema of extremities
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Creatinine kinase, ANA, RF, ESR
Possibly MRI of extremities
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Reactive arthritis
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Sometimes recent history of infection with Chlamydia, Salmonella, Yersinia, Campylobacter, or Shigella
Asymmetric oligoarthritis, urethritis, conjunctivitis, genital ulcerations
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ANA, RF, serologic testing for causative pathogens
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Rheumatoid arthritis
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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)
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ANA, RF, citrullinated peptide antibody (anti-CCP), x-rays (to identify bone erosions)
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SLE
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Fatigue, arthralgia, pleuritic chest pain, malar rash, tender swollen joints, mild peripheral edema, Raynaud syndrome, serositis, nephritis, alopecia
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Clinical criteria, ANA, antibodies to double-stranded DNA
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Neoplastic
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Colon carcinoma
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Abdominal pain, change in bowel habits, hematochezia, weakness, nausea, vomiting, weight loss, fatigue
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Colonoscopy, biopsy
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Hepatoma
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History of chronic liver disease, abdominal pain, weight loss, early satiety, palpable mass in right upper quadrant
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Abdominal ultrasonography and CT, liver biopsy
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Leukemia
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Sometimes history of myelodysplastic disorder
Fatigue, weight loss, bleeding, pallor, petechiae, ecchymoses, anorexia, splenomegaly, bone pain
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CBC, bone marrow examination
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Lymphoma
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Painless adenopathy, weight loss, malaise, night sweats, splenomegaly, hepatomegaly
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Lymph node biopsy
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Metastatic cancer
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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
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Biopsy of suspicious mass or node, imaging tests appropriate for area of concern
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Myeloproliferative disorders
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Frequently asymptomatic, abnormal indices incidentally detected during screening CBC
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Testing based on the suspected disorder
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Renal cell carcinoma
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Weight loss, night sweats, flank pain, hematuria, palpable flank mass, hypertension
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Serum Ca (to check for hypercalcemia), urinalysis, CT of kidneys
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Miscellaneous
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Alcoholic cirrhosis
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Long history of alcohol use
Sometimes ascites, jaundice, small or enlarged liver, gynecomastia, Dupuytren contracture, testicular atrophy
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PT/PTT, alkaline phosphatase, transaminases, albumin, bilirubin
Sometimes abdominal ultrasonography and CT
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Deep venous thrombosis
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Pain, swelling, sometimes redness of leg
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Ultrasonography
Sometimes D-dimer assay
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Drug fever
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Fever coincident with administration of a drug (usually within 7–10 days)
Sometimes a rash
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Withdrawal of drug
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Factitious fever
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Dramatic, atypical presentation, vague and inconsistent details, knowledge of textbook descriptions, compulsive or habitual lying (pseudologia fantastica)
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Diagnosis of exclusion
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Inflammatory bowel disease
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Abdominal pain, diarrhea (sometimes bloody), weight loss, guaiac-positive stools
Sometimes fistulas, perianal and oral ulcerations, arthralgias
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Upper GI 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; ANCA = antineutrophil cytoplasmic antibody; CMV = cytomegalovirus; EBV = Epstein-Barr virus; ELISA = enzyme-linked immunosorbent assay; RF = rheumatoid factor.
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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:
Interpretation of findings:
After a thorough history and physical examination, the following scenarios are typical:
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 2: Biology of Infectious Disease: 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:
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
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
Key Points
Last full review/revision October 2012 by Allan R. Tunkel, MD, PhD
Content last modified November 2012
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