Fever of unknown origin
Also known as: FUO, PUO, Pyrexia of unknown origin
Fever of unknown origin is a prolonged fever with no diagnosis after a defined, structured initial evaluation. The classic definition requires a temperature of 38.3 degrees Celsius or more on at least two occasions, duration of 3 weeks or more, and no diagnosis after at least 3 outpatient visits, 3 days in hospital, or 1 week of intelligent ambulatory investigation. Most patients have an atypical presentation of a common disease rather than a rare disease.
Clinical relevance. Careful repetition of the history and examination, plus a targeted but wide first tier panel, finds a cause in about half to two thirds of patients. Patients who remain undiagnosed after full evaluation and are clinically stable usually do well, and many recover spontaneously. Empirical corticosteroids and antibiotics before a structured evaluation reduce diagnostic yield.
Categories.
- Classic: community onset, meeting the definition in the first paragraph.
- Nosocomial: fever of 38.3 degrees Celsius or more in a hospitalised patient who was not infected or incubating infection at admission, with no diagnosis after 3 days of appropriate investigation including 2 days of culture incubation.
- Neutropenic: neutrophil count under 0.5 x 10^9/L (or expected to fall under it within 1 to 2 days), with no diagnosis after 3 days including 2 days of culture incubation.
- HIV associated: HIV infection with fever over 4 weeks as an outpatient or over 3 days as an inpatient, with no diagnosis after 3 days of investigation including 2 days of culture incubation.
Causes by frequency. In high income settings, roughly a quarter are infective, around a quarter noninfectious inflammatory, 10% to 15% neoplastic, a small share miscellaneous, and a third or more remain undiagnosed. In resource limited and tropical settings, infection predominates, especially tuberculosis, brucellosis, enteric fever, malaria, visceral leishmaniasis, HIV related opportunistic infection and abscess.
Inflammation of unknown origin. Persistent elevation of inflammatory markers (C reactive protein, ESR) with or without fever and without a diagnosis follows a similar approach. Older patients carry a higher risk of giant cell arteritis, polymyalgia rheumatica and lymphoma.
Mechanisms. Infection, tumour necrosis, cytokine release (interleukin 1, interleukin 6, tumour necrosis factor), immune complex deposition, drug hypersensitivity and inflammasome activation raise the hypothalamic set point. Rare causes include central (hypothalamic) fever and factitious fever.
