Fever of unknown origin

Definition

Fever of unknown origin (FUO) is a body temperature of at least 38.3 °C (rectal) that does not result from a transient, self-limited illness, a rapidly fatal illness or a disorder with clear-cut localizing symptoms, and in which common tests such as chest X-ray, urinalysis and blood cultures show no cause.

Classification

• Classic FUO: fever for more than 3 weeks with no cause identified after 3 days of hospital evaluation or after at least 3 outpatient visits.
• Health care–associated FUO: fever in patients receiving acute hospital care with no infection present or incubating on arrival, if the cause remains unclear after 3 days of evaluation.
• Immunodeficiency-related FUO: fever in neutropenia or other immunodeficiency, if the cause remains unclear after 3 days of evaluation including cultures negative after 48 hours. In known HIV infection: fever for more than 4 weeks in outpatients or more than 3 days in inpatients without an identified cause.
• Travel-associated FUO: fever after travel; the priority is recognizing life-threatening or transmissible travel-related infections.

Occurrence & epidemiology

The frequency of the cause groups varies with age, region and underlying conditions. In adults, about 25–50 % are due to infections, 10–20 % to systemic rheumatic disorders, 2–25 % to neoplasms and 15–25 % to miscellaneous causes. In about 10 % of adults no cause is found. The proportion of neoplastic causes is decreasing, probably because ultrasonography and CT are now used early in the evaluation of fever.

Aetiopathogenesis

• Infections (most common group): abscesses (abdominal, pelvic, dental), infective endocarditis, tuberculosis (pulmonary and disseminated), osteomyelitis, sinusitis, EBV and CMV infection, HIV infection, Lyme disease, cat-scratch disease; less often brucellosis, malaria, Q fever, toxoplasmosis, trichinosis, typhoid fever. In HIV infection, opportunistic infections are added (tuberculosis, atypical mycobacteria, disseminated fungal infections, CMV).
• Systemic rheumatic disorders: systemic lupus erythematosus, rheumatoid arthritis, giant cell arteritis, polymyalgia rheumatica, vasculitides (e.g. polyarteritis nodosa), adult-onset Still disease, reactive arthritis.
• Neoplasms: lymphomas, leukemias, renal cell carcinoma, ovarian carcinoma, atrial myxoma, Castleman disease, hepatocellular carcinoma, metastases, myeloproliferative neoplasms.
• Miscellaneous causes: drug fever, deep venous thrombosis and recurrent pulmonary emboli, thyroiditis and hyperthyroidism, sarcoidosis, inflammatory bowel disease, alcoholic cirrhosis, hereditary fever syndromes (e.g. familial Mediterranean fever), factitious fever.

Clinical features

• Leading symptom: persistent or recurrent fever; the fever pattern usually has little diagnostic value. Fever every other or every third day may suggest malaria in patients at risk.
• Accompanying symptoms: nonspecific, such as weight loss, anorexia, fatigue, night sweats and headache; plus, depending on the cause, myalgias, arthralgias, rashes or abdominal discomfort.
• Suggestive findings: heart murmur, Osler nodes, Janeway lesions, petechiae and splinter hemorrhages (endocarditis); regional lymphadenopathy (e.g. cat-scratch disease) versus generalized lymphadenopathy (lymphoma); tender temporal artery (giant cell arteritis); evanescent salmon-pink rash (adult-onset Still disease); teeth tender to percussion (apical abscess).
• Important findings are often subtle and sometimes become apparent only on repeated examination.

Diagnosis

History and examination

• History: duration and course of fever, travel, occupation, contact with animals, insects and ticks, diet, medicines taken, drug use, sexual risks, illness among contacts, family history (hereditary fever syndromes), prior illnesses and foreign material (vascular access, pacemakers, joint prostheses).
• Physical examination: complete and repeated, including skin (also perineum and feet), lymph nodes, thyroid, spine, bones and joints, abdomen, cardiac auscultation, teeth, rectal and pelvic examination.

Laboratory tests

• Basic laboratory tests: complete blood count with differential, ESR, CRP, procalcitonin, LDH, ferritin, liver tests, urinalysis with microscopy.
• Microbiology: serial blood cultures; cultures of material from abnormal areas (bacteria, mycobacteria, fungi, viruses); organizm-specific PCR and serology (acute and convalescent titers) targeted by clinical suspicion.
• Further tests: HIV test (antibody/antigen, possibly HIV RNA), tuberculin skin test or interferon-gamma release assay, ANA and rheumatoid factor; blood smear if malaria is suspected.

Imaging and biopsy

• Targeted imaging guided by symptoms, e.g. contrast-enhanced MRI of the spine for back pain, contrast-enhanced CT of the abdomen for abdominal pain.
• CT of the chest, abdomen and pelvis even without localizing findings to look for lymphadenopathy and occult abscesses; MRI if a cause in the central nervous system is suspected.
• Echocardiography for positive blood cultures, heart murmur or peripheral signs of endocarditis; venous duplex ultrasonography if thrombosis is suspected.
• Nuclear medicine: PET shows areas of high metabolic activity in inflammation and infection; scintigraphy with labeled granulocytes.
• Biopsy of abnormal tissue (e.g. liver, bone marrow, skin, lymph nodes, muscle) with histology, culture and PCR; bilateral temporal artery biopsy in older adults with unexplained ESR elevation.

Keep learning in the app

Further reading (open access)

1. MSD Manual Professional: Fever of Unknown Origin (FUO)

Cross-references