Definition of Pyrexia of Unknown Origin
Pyrexia of unknown origin (PUO) is defined as fever ≥38.3°C (100.9°F) persisting for at least 3 weeks with no diagnosis despite 3 outpatient visits or 3 inpatient days of investigation. 1, 2, 3
Core Diagnostic Criteria
The three essential components that must all be present are:
- Temperature threshold: Fever must be ≥38.3°C (100.9°F) 1, 2, 3
- Duration requirement: Fever must persist for at least 3 weeks 1, 2
- Investigation requirement: No diagnosis despite 3 outpatient visits OR 3 inpatient days of investigation 1, 2, 3
Required Initial Work-Up
The mandatory first-line evaluation includes:
- Laboratory testing: Complete blood count with differential, inflammatory markers (CRP, ESR), at least 3 sets of blood cultures (obtained before any antibiotics), urinalysis, urine culture, and liver function tests 1, 3
- Basic imaging: Chest radiography as the minimum imaging standard 1
- Physical examination: Thorough examination including head/neck, rectal, pelvic, and breast examination 2
Classification Subcategories
PUO should be classified into four distinct subcategories, as each requires different investigative strategies and has different etiologic distributions:
- Classical PUO: Community-acquired fever meeting the standard definition 1, 3
- Nosocomial PUO: Fever developing in hospitalized patients 1, 3
- Neutropenic PUO: Fever in patients with absolute neutrophil count <0.5 × 10⁹/L, with a modified definition of either single oral temperature ≥38.3°C OR ≥38.0°C sustained over at least 1 hour (note the lower threshold and shorter duration) 3
- HIV-related PUO: Fever in patients with confirmed HIV infection 1, 3
Important Distinctions
- Inflammation of unknown origin (IUO): Shares similar etiologies with PUO but is defined as unexplained and prolonged elevation of inflammatory markers without fever 1
- Fever without source (FWS): An acute febrile episode with no apparent origin after initial evaluation—this differs from PUO in that it is acute rather than prolonged 1, 3
Temperature Measurement Considerations
For accurate diagnosis in inpatient settings:
- Preferred methods: Central temperature monitoring via pulmonary artery catheter thermistors, bladder catheters, or esophageal balloon thermistors 3
- Alternative reliable methods: Oral or rectal temperatures 3
- Avoid for diagnostic purposes: Axillary, tympanic membrane, temporal artery thermometers, or chemical dot thermometers due to unreliability 3
Critical Caveat
Not all infected patients manifest fever, and absence of fever in patients with infection is associated with worse outcomes, so the diagnostic approach may apply to suspected infection regardless of temperature elevation. 3