Fever of Unknown Origin (FUO)

Key Features

Essentials of Diagnosis

• At least 3 weeks of illness with fever > 38.3°C on several occasions, and no diagnosis after three outpatient visits or 3 days of hospitalization

• Hospital-associated FUO

  • Occurs in a hospitalized patient with fever of ≥ 38.3°C on several occasions, due to a process not present or incubating at admission, in whom initial cultures are negative

  • Diagnosis remains unknown after 3 days of investigation

• Neutropenic FUO

  • Fever of ≥ 38.3°C in a patient on several occasions with < 500 neutrophils per microliter in whom initial cultures are negative

  • Diagnosis remains uncertain after 3 days

• HIV-associated FUO

  • Occurs in HIV-positive patients with fever of ≥ 38.3°C who have been febrile for 4 weeks or more as an outpatient or 3 days as an inpatient

  • Diagnosis remains uncertain after 3 days of investigation with at least 2 days for cultures to incubate

• Although not usually considered separately, FUO in solid organ transplant recipients is a common scenario with a unique differential diagnosis (see below)

General Considerations

Common causes

• Most cases represent unusual manifestations of common diseases and not rare or exotic diseases—eg, tuberculosis, endocarditis, gallbladder disease, and HIV (primary infection or opportunistic infection) are more common causes than Whipple disease or familial Mediterranean fever

• Infections (25–40% of cases) and cancer (25–40% of cases) account for the majority of FUOs

• Obtain thorough history, including

  • Family

  • Occupational

  • Social (sexual practices, use of injection drugs)

  • Dietary (unpasteurized products, raw meat), exposures (animals, chemicals)

  • Travel

Age of patient

• In patients > 65 years of age, 25–30% of all FUOs are due to multisystem immune-mediated diseases such as

  • Temporal arteritis

  • Polymyalgia rheumatica

  • Sarcoidosis

  • Rheumatoid arthritis

  • Granulomatosis with polyangiitis

Duration of fever

• Granulomatous diseases (granulomatous hepatitis, Crohn disease, ulcerative colitis) and factitious fever are more likely than infection, cancer, and autoimmune disorders if fever has been present for ≥ 6 months

• One-fourth of patients who report being febrile for ≥ 6 months have no true fever or underlying disease. Instead, the usual normal circadian variation in temperature (temperature 0.5–1.0°C higher in the afternoon than in the morning) is interpreted as abnormal

• Episodic or recurrent fever patients who meet the criteria for FUO but have fever-free periods of 2 weeks or longer are similar to those with prolonged fever

  • Infection, malignancy, and autoimmune disorders account for 20–25% of such fevers, whereas other diseases (Crohn disease, familial Mediterranean fever, allergic alveolitis) account for another 25%

  • ~50% remain undiagnosed but have a benign course with eventual resolution of symptoms

Immunologic status

• In neutropenia, fungal infections and occult bacterial infection are important causes of FUO

• In organ transplant patients or others taking immunosuppressive medications, ...