Diagnostic Approach to Fever of Unknown Origin

Definition and Classification

Fever of unknown origin (FUO) is defined as fever exceeding 38.3°C (100.9°F) persisting for at least 3 weeks without diagnosis despite 3 outpatient visits or in-patient days, and should be classified into four subcategories to guide workup: classical, nosocomial, neutropenic, or HIV-related, as etiology distribution varies significantly by category and geographic location 1, 2

Obtain a focused history targeting specific high-yield elements, including travel history with specific countries visited, which can help identify region-specific diseases such as malaria in Central/Western Africa or dengue and schistosomiasis in Eastern/Western Africa 3
Consider immigration status or visiting friends/relatives abroad, as these individuals are less likely to seek pre-travel advice and have higher malaria rates 3
Perform targeted physical examination and order mandatory first-line laboratory tests, including complete blood count with differential, inflammatory markers, and at least 3 sets of blood cultures before any antibiotics 1, 2, 4
Use [18F]FDG PET/CT as the highest-yield advanced diagnostic tool, with 84-86% sensitivity and 56% diagnostic yield, and perform it within 3 days of initiating oral glucocorticoid therapy to avoid false negatives 1, 2, 4

Avoid empiric antibiotics or steroids in stable patients with FUO, as they obscure diagnosis and may be harmful if malignancy or certain infections are present, and instead rule out potentially severe causes while allowing self-limiting viral illnesses to resolve without treatment 3, 5
Consider empiric therapy in exceptions such as neutropenic patients, suspected tickborne rickettsial diseases, or critically ill patients, and treat confirmed diagnoses such as malaria, adult-onset Still's disease, or bacterial meningitis according to established guidelines 2, 3, 4, 5, 6

Do not diagnose "fever of unknown origin" prematurely in resource-limited settings, and always assume and treat infection when fever cannot be explained by other pathologies to prevent missing treatable infections 3, 6
Do not use high-dose steroids empirically, as they increase hospital-acquired infection risk, hyperglycemia, gastrointestinal bleeding, and delirium without improving mortality, and also mask inflammatory findings on subsequent imaging 1, 6

The Society of Critical Care Medicine defines fever as a single temperature ≥38.3°C (100.9°F) for diagnostic purposes in critically ill ICU patients, without the 3-week duration requirement 7, 8
Central temperature monitoring via pulmonary artery catheter thermistors, bladder catheters, or esophageal balloon thermistors is the preferred method for accurate diagnosis in the inpatient setting 7, 8
Oral or rectal temperatures are alternative reliable methods when central monitoring is unavailable 7, 8
Axillary, tympanic membrane, temporal artery thermometers, or chemical dot thermometers should not be used for diagnostic purposes due to their unreliability 7, 8

For neutropenic patients due to chemotherapy, fever is defined as either a single oral temperature ≥38.3°C OR ≥38.0°C sustained over at least 1 hour, which is a lower threshold than classical FUO 7, 8
In pediatric patients, fever without source (FWS) differs from FUO—FWS is acute illness with no apparent source after initial evaluation, while FUO requires prolonged fever >3 weeks with no identifiable source 9

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 7, 8