Definition and Classification of Fever of Unknown Origin
Current Definition
Fever of unknown origin (FUO) is defined as fever exceeding 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
The temperature threshold of 38.3°C represents a single measurement for diagnostic purposes, though some definitions specify documentation on multiple occasions. 1, 3 This standardized definition allows for consistent clinical application across different healthcare settings.
Evolution of the Definition
The original 1961 Petersdorf and Beeson criteria required one week of inpatient investigation, but this has evolved to accommodate modern outpatient diagnostic capabilities. 4 The current definition recognizes that extensive workup can now occur in the outpatient setting through 3 visits, reflecting advances in ambulatory diagnostic testing and imaging availability. 1, 2
The definition remains a "moving target" as diagnostic technology advances—what constitutes adequate investigation continues to evolve with improved imaging modalities and biomarker analysis. 4 This creates ongoing challenges in determining true "unknown origin" versus simply unresolved etiology despite available testing.
Four Subcategories of FUO
FUO is classified into four distinct subcategories, each with different etiologic distributions and requiring tailored diagnostic approaches: 1, 2, 5
1. Classical FUO
- Fever in immunocompetent patients without hospitalization or healthcare exposure
- Most common etiologies include infections, inflammatory/autoimmune diseases, malignancies, and miscellaneous causes 1, 6
- Distribution of causes varies significantly by geographic location 1
- Up to 75% of classical FUO cases resolve spontaneously without definitive diagnosis 6, 7
2. Nosocomial FUO
- Fever developing in hospitalized patients receiving acute care
- Does not require the 3-week duration criterion used in classical FUO 1
- Defined as new fever in ICU patients, with single temperature ≥38.3°C sufficient for diagnosis 2
- Associated with healthcare-associated infections, drug reactions, and postoperative complications 1
3. Neutropenic FUO
- Occurs in patients with absolute neutrophil count <500 cells/μL or expected to fall below this threshold
- Lower fever threshold: either single oral temperature ≥38.3°C OR ≥38.0°C sustained over at least 1 hour 2
- Requires prompt empiric broad-spectrum antibiotics with antipseudomonal activity before completing full diagnostic workup 6
- Most commonly caused by bacterial infections, associated with severe illness and high mortality 1
4. HIV-Associated FUO
- Fever in patients with confirmed HIV infection
- Requires assessment of immune function through CD4+ T-cell counts and HIV viral load 6
- Differential includes opportunistic infections (Mycobacterium tuberculosis, cytomegalovirus, Pneumocystis jirovecii), malignancies, and drug reactions 6
- Etiology distribution differs substantially from classical FUO based on degree of immunosuppression 1
Importance of the 3-Week Duration Criterion
The 3-week duration requirement serves as a critical filter to exclude self-limiting viral illnesses and common infections that typically resolve within days to weeks. 2, 7
Key Rationale for Duration Threshold:
Eliminates transient febrile illnesses: Most acute viral infections and common bacterial infections resolve or declare themselves within 1-2 weeks, making prolonged fever inherently more concerning 7
Allows time for natural disease evolution: Many conditions develop localizing signs or symptoms over time that guide diagnosis, and the 3-week window permits this clinical evolution 4, 3
Prevents premature extensive workup: Without a duration requirement, every acute fever would trigger expensive and invasive investigations for rare diseases 2
Focuses resources on truly puzzling cases: The duration criterion identifies patients who genuinely require advanced diagnostic approaches like FDG-PET/CT rather than routine evaluation 1, 5
Reflects uncommon presentations of common diseases: Most FUO cases result from atypical manifestations of familiar conditions rather than rare diseases, and time allows these patterns to emerge 6, 7
Important Caveats:
The 3-week requirement does not apply to neutropenic or critically ill patients, where diagnostic urgency supersedes the need for prolonged observation. 2, 6 In these populations, fever warrants immediate investigation and empiric treatment due to high mortality risk.
Additionally, absence of fever does not exclude serious infection—some infected patients never manifest fever, and this is associated with worse outcomes. 2 The diagnostic approach may apply to suspected infection regardless of meeting strict temperature criteria in high-risk populations.