Definition of Pyrexia of Unknown Origin (PUO)
Pyrexia of unknown origin is defined as fever exceeding 38.3°C (100.9°F) that persists for at least 3 weeks without 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 higher than 38.3°C (100.9°F) 1, 2, 3
- Duration requirement: Fever must persist for a minimum of 3 weeks 1, 2, 3
- Investigation requirement: No diagnosis identified despite either 3 outpatient visits OR 3 in-patient days of evaluation 1, 2
Classification System
PUO should be classified into four distinct subcategories, as the etiology distribution varies significantly by category: 1, 2, 3
- Classical PUO: The traditional presentation in immunocompetent outpatients 1, 2, 3
- Nosocomial PUO: Fever developing in hospitalized patients 1, 2, 3
- Neutropenic PUO: Fever in patients with severe neutropenia 1, 2, 3
- HIV-related PUO: Fever in patients with HIV infection 1, 2, 3
This classification is critical because each subcategory requires different investigative strategies and has distinct likely etiologies. 2
Related Diagnostic Entity
- Inflammation of Unknown Origin (IUO) shares similar etiologies with PUO but is defined as unexplained and prolonged elevation of inflammatory markers without fever. 2
Etiologic Categories
The causes of PUO are broadly divided into four groups, with distribution varying by subcategory and geographic location: 3
Important Caveats
- This is fundamentally a diagnosis of exclusion that requires thorough evaluation before the label can be applied. 3
- In resource-limited settings, do not diagnose "fever of unknown origin" prematurely—always assume and treat infection when fever cannot be explained by other pathologies to prevent missing treatable infections. 1
- The definition excludes immunocompromised patients, those with HIV infection, and patients with hospital-acquired fever, as these represent distinct subgroups requiring different diagnostic and therapeutic approaches. 4