Fever of Unknown Origin: Definition and Diagnostic Approach
Definition
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 either 3 outpatient visits or 3 inpatient days of investigation. 1, 2, 3
Classification into Four Subcategories
FUO must be classified into one of four distinct categories, as etiology distribution varies significantly by type 1, 2:
- Classical FUO: Community-acquired fever in immunocompetent patients 2, 3
- Nosocomial FUO: Fever developing in hospitalized patients 2, 3
- Neutropenic FUO: Fever in patients with absolute neutrophil count <500 cells/μL, defined as either single oral temperature ≥38.3°C OR ≥38.0°C sustained over 1 hour 1
- HIV-related FUO: Fever in patients with confirmed HIV infection 2, 3
Temperature Measurement Standards
- Use central temperature monitoring (pulmonary artery catheter, bladder catheter, or esophageal balloon) as the preferred method for accurate diagnosis 1
- Oral or rectal temperatures are acceptable alternatives when central monitoring is unavailable 1
- Never use axillary, tympanic, temporal artery, or chemical dot thermometers for diagnostic purposes due to unreliability 1
Diagnostic Approach for Adults with Travel History
Initial History: High-Yield Elements
Obtain a focused travel history targeting specific countries visited, as geographic location predicts disease patterns—Central/Western Africa suggests malaria, while Eastern/Western Africa suggests dengue and schistosomiasis. 1
Key historical elements to elicit 1, 4:
- Specific countries and regions visited (not just continents) 1
- Immigration status or visiting friends/relatives abroad: These individuals have 72.8% inadequate prophylaxis rates and higher malaria risk 4, 1
- Duration of travel: Trips >30 days account for 36.6% of cases 4
- Time between return and symptom onset: Median is 7 days (range 0-360 days) 4
- Pre-travel medical advice received: Only 51.7% sought advice 4
Mandatory First-Line Laboratory Testing
Perform targeted physical examination and order the following mandatory tests before any antibiotics 1, 2, 3:
- Complete blood count with differential 1, 2, 3
- Inflammatory markers (C-reactive protein, erythrocyte sedimentation rate) 2, 3
- At least 3 sets of blood cultures (before any antibiotics) 1, 3
- Liver function tests 3
- Urinalysis and urine culture 3
- Chest radiography 2, 3
Disease-Specific Testing for Travelers
For all febrile travelers from malaria-endemic regions, perform rapid malaria testing immediately, as malaria accounts for 70% of tropical diseases and 22.2% of all febrile illness in returning travelers. 4
If malaria testing is negative, perform dengue rapid diagnostic testing (combined NS1 antigen and IgG), as dengue accounts for 5.2% of cases and has high positive likelihood ratios. 4
Additional region-specific testing 4:
- Up to three daily blood films to exclude malaria if initial testing is negative but suspicion remains 3
- Enteric (typhoid) fever testing: Accounts for 2.3% of tropical diseases 4
- Rickettsioses testing: Accounts for 1.7% of tropical diseases 4
- Schistosomiasis, chikungunya, and viral hemorrhagic fever assessment based on exposure 4
Non-Tropical Infections in Travelers
Do not assume all fever in travelers is tropical disease—38.6% of diagnoses are non-tropical infections 4:
- Acute diarrheal disease: 13.6% of cases 4
- Respiratory tract infections: 13.5% of cases (including pneumonia 2.7%, influenza 2.5%, upper respiratory 6.0%) 4
- Genitourinary tract infections: 2.7% of cases 4
- Acute hepatitis (A/B/C/E): 1.1% of cases 4
- Tuberculosis: 0.6% of cases 4
Advanced Diagnostic Approach When Initial Workup is Non-Diagnostic
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, 3
Timing and Preparation for PET/CT
- Perform within 3 days of starting oral glucocorticoids if steroids are necessary 1, 2
- Consider myocardial suppression preparation when cardiac etiology is suspected 2
- Use PET/CT to guide tissue biopsy of suspicious lesions 3
Alternative Advanced Imaging
If PET/CT is unavailable 2, 3:
- CT abdomen and pelvis with IV contrast as second-line investigation 3
- Whole body MRI, particularly in pediatric patients 2, 3
Treatment Approach
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—instead rule out potentially severe causes while allowing self-limiting viral illnesses to resolve without treatment. 1, 5
Exceptions Requiring Empiric Therapy
Consider empiric treatment only in these specific scenarios 1:
- Neutropenic patients: Require prompt broad-spectrum antimicrobial therapy 1, 2, 3
- Suspected tickborne rickettsial diseases: Start doxycycline empirically 1, 2
- Critically ill patients: May require broad-spectrum antibiotics while awaiting diagnostic results 1, 2
Treatment of Confirmed Diagnoses
Once diagnosis is established, treat according to disease-specific guidelines 1:
- Malaria: Follow established antimalarial protocols 1
- Adult-onset Still's disease: NSAIDs, corticosteroids, or immunosuppressive drugs 2
- Bacterial meningitis: Appropriate antimicrobial therapy 1
Critical Pitfalls to Avoid
Do not diagnose "fever of unknown origin" prematurely in resource-limited settings—always assume and treat infection when fever cannot be explained by other pathologies to prevent missing treatable infections. 1
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
Additional Pitfalls
- Do not start antibiotics before obtaining blood cultures, as this obscures microbiologic diagnosis 1, 3
- Do not assume absence of fever excludes infection: Non-febrile infected patients have worse outcomes 1
- Recognize that 17.8% of febrile travelers remain undiagnosed despite thorough evaluation 4