Definition of Pyrexia of Unknown Origin
Pyrexia of unknown origin (PUO) is defined as fever exceeding 38.3°C (100.9°F) that persists for at least 3 weeks, with no diagnosis established despite 3 outpatient visits or 3 days of inpatient investigation. 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) on multiple occasions 1, 4, 5
- Duration requirement: Fever must persist for a minimum of 3 weeks 1, 2, 3
- Investigation threshold: No diagnosis despite either 3 outpatient visits OR 3 days of inpatient evaluation 1, 4, 5
This definition was originally proposed by Petersdorf and Beeson in 1961 and later revised to reflect modern outpatient diagnostic capabilities. 5
Clinical Subcategories
PUO is classified into four distinct subcategories, each with different etiologic distributions and requiring tailored diagnostic approaches:
- Classical PUO: Occurs in immunocompetent patients without specific risk factors 1, 2, 3
- Nosocomial PUO: Develops in hospitalized patients after admission for other reasons 1, 3
- Neutropenic PUO: Occurs in patients with absolute neutrophil count <500 cells/μL 1, 2
- HIV-related PUO: Develops in patients with confirmed HIV infection 1, 3
The etiology varies significantly according to subcategory and geographic location. 1, 2
Related Entity: Inflammation of Unknown Origin
Inflammation of unknown origin (IUO) represents a parallel syndrome defined as unexplained and prolonged elevation of inflammatory markers (C-reactive protein, erythrocyte sedimentation rate) without documented fever, sharing similar etiologic categories with PUO. 1, 3, 4
Etiologic Categories
The causes of PUO are broadly divided into four major groups:
- Infectious causes: Including bacterial, viral, fungal, and parasitic infections 1, 6
- Inflammatory/autoimmune causes: Including vasculitis, connective tissue diseases, and Adult-onset Still's disease 1, 6
- Malignant causes: Including lymphomas, leukemias, and solid tumors 1, 6, 7
- Miscellaneous causes: Including drug fever, factitious fever, and other rare entities 1, 6
Despite extensive investigation, up to 50% of PUO cases remain undiagnosed, though this cohort generally has favorable prognosis. 6
Important Distinction from Simple Fever
The key distinction is that PUO specifically refers to prolonged febrile illness that remains unexplained despite reasonable initial evaluation and diagnostic testing, not merely any fever without immediate obvious cause. 5 The 3-week duration requirement excludes self-limiting viral illnesses and ensures that only truly persistent, diagnostically challenging cases meet criteria. 5, 6