Clinical Definition of Fever of Unknown Origin (IDSA)
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
Core Diagnostic Criteria
The IDSA definition requires three essential elements to be met:
- Temperature threshold: Single measurement ≥38.3°C (100.9°F) 1, 2
- Duration requirement: Fever must persist for at least 3 weeks 1, 2
- Diagnostic evaluation: No diagnosis established despite either 3 outpatient visits OR 3 in-patient days of investigation 1
Four Distinct Subcategories
FUO must be classified into one of four subcategories, as etiology and management differ substantially: 1, 2
- Classical FUO: Community-acquired fever in immunocompetent patients meeting the above criteria 1
- Nosocomial FUO: Fever developing in hospitalized patients receiving acute care 1
- Neutropenic FUO: Fever in patients with absolute neutrophil count <0.5 × 10⁹ cells/L 1
- HIV-related FUO: Fever in patients with confirmed HIV infection 1
Important Context-Specific Variations
While the classical IDSA definition uses 38.3°C, fever thresholds vary by clinical context and should be adjusted accordingly:
- Neutropenic patients: Single oral temperature ≥38.3°C OR ≥38.0°C sustained over 1 hour 1
- ICU patients: Single temperature measurement ≥38.3°C 1
- Elderly in long-term care: Single oral temperature >37.8°C, repeated measurements >37.2°C (oral) or >37.5°C (rectal), OR increase from baseline >1.1°C 1
Etiologic Categories
The differential diagnosis spans four major categories, with distribution varying by FUO subcategory and geographic location: 1, 2
- Infectious diseases 1, 2
- Malignancies 1, 2
- Noninfectious inflammatory diseases (autoimmune/rheumatologic) 1, 2
- Miscellaneous causes 1, 2
Critical Diagnostic Pitfall
The original 1961 Petersdorf and Beeson definition required "one week of inpatient investigation," but this has been modernized to "3 outpatient visits or in-patient days" to reflect contemporary diagnostic capabilities and healthcare delivery patterns. 1, 3 The updated definition recognizes that advanced imaging (PET/CT) and biomarker analysis now allow more rapid evaluation without prolonged hospitalization 1, 3.
Related Entity: Inflammation of Unknown Origin
Inflammation of Unknown Origin (IUO) is defined as unexplained and prolonged elevation of inflammatory markers (CRP, ESR) without fever, sharing similar etiologies with FUO. 1 This entity should be evaluated using the same diagnostic algorithm as classical FUO 1.