Clinical Definition of Fever of Unknown Origin
Fever of Unknown Origin (FUO) is defined as fever higher than 38.3°C (100.9°F) persisting for at least 3 weeks, with no diagnosis despite 3 outpatient visits or in-patient days. 1, 2, 3
Core Diagnostic Criteria
The definition requires three essential elements to be met simultaneously:
- Temperature threshold: Documented fever exceeding 38.3°C (100.9°F) on multiple occasions 1, 4
- Duration requirement: Fever must persist for a minimum of 3 weeks 1, 2, 3
- Diagnostic evaluation: No diagnosis established despite either 3 outpatient visits OR 3 days of inpatient investigation 1, 3, 4
Classification into Four Subcategories
FUO must be classified into one of four distinct subcategories, as etiology distribution varies significantly by category and geographic location 1, 2, 3:
- Classical FUO: Community-acquired fever in immunocompetent patients 1, 3
- Nosocomial FUO: Fever developing in hospitalized patients 1, 3
- Neutropenic FUO: Fever in patients with neutropenia (typically <500 cells/mm³) 1, 3
- HIV-related FUO: Fever in patients with confirmed HIV infection 1, 3
Related Entity: Inflammation of Unknown Origin
Inflammation of Unknown Origin (IUO) shares similar etiologies with FUO but is defined as unexplained and prolonged elevation of inflammatory markers (C-reactive protein, erythrocyte sedimentation rate) without fever. 1, 3
Evolution of the Definition
The original 1961 Petersdorf and Beeson definition required one week of inpatient investigation, but this has been modernized to reflect current outpatient diagnostic capabilities 5, 6. The contemporary definition recognizes that a "reasonable diagnostic evaluation" can occur in the outpatient setting, making the diagnosis more practical for modern healthcare delivery 6.
Common Etiologic Categories
The underlying causes fall into four major groups, with distribution varying by FUO subcategory 1, 4:
- Infectious diseases: Most common overall etiology 1, 4
- Inflammatory/rheumatic disorders: Including adult-onset Still's disease and vasculitis 1, 4
- Malignancies: Particularly lymphomas and leukemias 1, 4
- Miscellaneous causes: Drug fever, factitious fever, and other rare entities 1, 4
Critical Diagnostic Pitfall
Do not diagnose FUO prematurely—it is a diagnosis of exclusion requiring thorough evaluation, and in resource-limited settings, always assume and treat infection when fever cannot be explained by other pathologies. 2, 4