What is the approach to diagnosing and managing a patient with fever of unknown origin (FUO), considering their demographic information, medical history, and laboratory results, including complete blood counts, blood cultures, and inflammatory markers?

Fever of Unknown Origin: Definition and Diagnostic Approach

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. 1, 2, 3

FUO must be classified into one of four subcategories, as etiology and management differ significantly: 1, 2

• Classical FUO (community-acquired in immunocompetent patients)
• Nosocomial FUO (hospital-acquired)
• Neutropenic FUO (in patients with absolute neutrophil count <500 cells/mm³, defined as single oral temperature ≥38.3°C OR ≥38.0°C sustained over 1 hour) 1
• HIV-related FUO

Temperature Measurement Standards

Use central temperature monitoring (pulmonary artery catheter, bladder catheter, or esophageal balloon) as the preferred method in inpatient settings, or alternatively oral/rectal temperatures. 1 Never use axillary, tympanic, temporal artery, or chemical dot thermometers for diagnostic purposes due to unreliability. 1

Initial Diagnostic Workup

Mandatory History Elements

Target these specific high-yield historical features: 1

• Travel history with specific countries visited (malaria in Central/Western Africa, dengue and schistosomiasis in Eastern/Western Africa) 1
• Immigration status or visiting friends/relatives abroad (higher malaria rates, less pre-travel counseling) 1
• Recent surgery (thoracic, abdominal, or pelvic within days to weeks) 3
• Central venous catheter presence 3
• Neutropenia status and chemotherapy history 1, 3

Mandatory First-Line Laboratory Tests

Obtain these tests before initiating any antibiotics: 1, 2, 3

• Complete blood count with differential 1, 2
• Inflammatory markers (C-reactive protein, erythrocyte sedimentation rate) 2, 3
• At least 3 sets of blood cultures from different anatomical sites (ideally 60 mL total blood volume) 1, 3
• Comprehensive metabolic panel (to identify hepatobiliary sources) 3
• Chest radiography 2, 3

For patients with central venous catheters, obtain simultaneous central and peripheral blood cultures to calculate differential time to positivity. 3

Conditional Initial Testing

Based on clinical presentation: 3

• Formal diagnostic ultrasound of abdomen only if abdominal symptoms, abnormal liver tests, or recent abdominal surgery present 3
• CT of operative area if fever occurs several days after thoracic, abdominal, or pelvic surgery 3
• Avoid routine abdominal imaging without localizing signs 3

Advanced Diagnostic Approach When Initial Workup Non-Diagnostic

[18F]FDG PET/CT is the highest-yield advanced diagnostic tool with 84-86% sensitivity and 56% diagnostic yield. 1, 2, 3

Critical timing considerations: 1, 2

• Perform PET/CT within 3 days of initiating oral glucocorticoid therapy to avoid false negatives 1, 2
• Consider myocardial suppression preparation when cardiac etiology is possible 2
• A negative PET/CT predicts favorable prognosis and may allow watchful waiting 3

Additional advanced imaging based on clinical context: 3

• CT chest with IV contrast (72% sensitivity for pulmonary sources in surgical ICU patients) 3
• CT abdomen/pelvis with IV contrast (81.82% positive predictive value for septic foci) 3
• Avoid routine sinus CT in prolonged febrile neutropenia without localizing symptoms 3

Treatment Approach: The Critical Decision Point

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. 1, 2

When to Withhold Empiric Therapy

In stable, non-neutropenic patients: 1, 3

• Allow self-limiting viral illnesses to resolve without treatment 1
• Up to 75% of cases resolve spontaneously without definitive diagnosis 3
• Continue diagnostic workup systematically 1

Exceptions Requiring Empiric Therapy

Initiate empiric treatment in these specific scenarios: 1, 2, 3

Neutropenic patients (high-risk with neutrophils <100 cells/mm³ expected >7 days): 3

• Start monotherapy with β-lactam antibiotic (piperacillin-tazobactam as first-line) 3
• Broad-spectrum antibiotics with antipseudomonal activity 3
• Consider antifungal therapy only in critically ill patients with persistent fever and new pulmonary infiltrates 3

Suspected tickborne rickettsial diseases: 1, 2

• Initiate doxycycline empirically 2

Critically ill patients: 1, 2

• Broad-spectrum antibiotics may be necessary while awaiting diagnostic results 2

Confirmed diagnoses: 1

• Treat malaria, adult-onset Still's disease, or bacterial meningitis according to established guidelines 1

Re-evaluation Protocol for Patients on Empiric Antibiotics

For neutropenic patients receiving empiric therapy: 3

• Daily surveillance including physical examination and review of systems 3
• Formal re-evaluation after 2-4 days of treatment 3
• Persistent fever alone rarely justifies antibiotic modification without microbiological documentation 3
• Avoid empirical addition of vancomycin without microbiological evidence 3
• Do not switch from one empirical monotherapy to another without clinical or microbiological justification 3

Critical Pitfalls to Avoid

Never diagnose "fever of unknown origin" prematurely in resource-limited settings—always assume and treat infection when fever cannot be explained by other pathologies. 1, 3

Do not use high-dose steroids empirically, as they: 1, 3

• Increase hospital-acquired infection risk 1, 3
• Cause hyperglycemia, gastrointestinal bleeding, and delirium 1, 3
• Do not improve mortality 1
• Mask inflammatory findings on subsequent imaging 1, 2

Additional pitfalls: 3

• Avoid non-steroidal anti-inflammatory drugs (impair renal/coagulation function, increase stress ulcer risk) 3
• Do not systematically remove central venous catheters in stable patients without microbiological evidence of catheter-related infection 3
• Avoid routine sinus imaging in neutropenic patients without localizing symptoms 3

Special Population Considerations

Critically ill ICU patients: Single temperature ≥38.3°C without 3-week duration requirement. 1 Note that absence of fever in infected patients is associated with worse outcomes. 1

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. 1 Appropriate imaging includes chest radiography, whole body MRI, and FDG-PET/CT. 2