Fever of unknown origin

Background

Typically defined as a persistent fever that remains undiagnosed despite an extensive initial workup
Causes have changed over the decades as diagnostic tools have improved

Type	Definition
Classic	Temperatures >38.3ºC without diagnosis despite 3 weeks of outpatient investigations over 3 visits, or 1 week of intensive outpatient investigation, or 3 days of inpatient investigation
Nosocomial	Temperatures >38.3ºC without diagnosis in a hospitalized acute-care patient, where infection was not community-acquired, despite 3 days of investigations including preliminary results of blood cultures at 48 hours
Neutropenic	Temperatures >38.3ºC without diagnosis in patients with neutrophils <500/μL or expected to fall to that level in 1-2 days, despite initial investigations including preliminary results of blood cultures at 48 hours
HIV-associated	Temperatures >38.3ºC without diagnosis over 4 weeks (outpatient) or 3 days (inpatient) in patients with HIV, despite initial investigations including preliminary results of blood cultures at 48 hours

Infectious (16 to 52%)
- More common: tuberculosis (especially extrapulmonary disease), culture-negative endocarditis, Epstein-Barr virus, cytomegalovirus
- More common, in recent travelers: malaria and dengue
- Less common: bartonellosis, brucellosis, occult abscess, salmonellosis, urinary tract infection, acute HIV, hepatitis A, hepatitis B, hepatitis E, roseolavirus, HHV-7, osteomyelitis, septic arthritis
- Less common, in recent travelers: rickettsioses, leptospirosis, schistosomiasis, gnathostomiasis, cysticercosis, enteric fever
Neoplastic (7 to 35%)
- More common: lymphoma, leukemia, solid organ tumour (especially renal cell carcinoma and melanoma)
- Less common: myelodysplastic syndrome, colonic adenocarcinoma, multiple myeloma, gastric carcinoma, mesothelioma, Castleman disease
Inflammatory (11 to 34%)
- More common: adult-onset Still disease, systemic lupus erythematosus, polymyalgia rheumatica, temporal arteritis, inflammatory bowel disease
- Less common: rheumatoid arthritis, polyarteritis nodosa, sarcoidosis, granulomatosis with polyangiitis, Kawasaki syndrome
Other (2 to 20%)
- More common: drug fever, chronic pulmonary embolism, hyperthyroidism, hematoma
- Less common: subacute thyroiditis, hypoadrenalism, necrotizing lymphadenitis, periodic fever syndromes, hemophagocytic lymphohistiocytosis, factitious fever
Undiagnosed (7 to 32%)