What is the approach to diagnosing and treating fever of unknown origin?

Diagnostic and Treatment Approach to Fever of Unknown Origin

Definition and Initial 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 Classify FUO into four subcategories to guide your workup: classical, nosocomial, neutropenic, or HIV-related, as etiology distribution varies significantly by category and geographic location. 1, 2

Structured Diagnostic Algorithm

Phase 1: Initial Evaluation (Days 0-3)

Obtain a focused history targeting specific high-yield elements:

• Travel history with specific countries visited (malaria predominates in Central/Western Africa; dengue, schistosomiasis in Eastern/Western Africa) 1
• Medication exposure and timing relative to fever onset 3
• Occupational exposures and animal contacts 3
• Immigration status or visiting friends/relatives abroad (VFRs are less likely to seek pre-travel advice and have higher malaria rates) 1
• HIV risk factors and immunosuppression history 1

Perform targeted physical examination looking for:

• Lymphadenopathy, hepatosplenomegaly, and cardiac murmurs 3
• Skin rashes, joint inflammation, or temporal artery tenderness 3
• Fundoscopic examination for embolic phenomena 3

Order mandatory first-line laboratory tests:

• Complete blood count with differential 2, 3
• Inflammatory markers: C-reactive protein and erythrocyte sedimentation rate 1, 2, 3
• At least 3 sets of blood cultures (before any antibiotics) 4, 3
• Urinalysis and urine culture 2, 3
• Liver function tests 2, 3
• Chest radiography 2, 4

Phase 2: Secondary Evaluation (Days 3-7 if fever persists)

Add targeted testing based on Phase 1 clues:

• Lactate dehydrogenase, creatine kinase, rheumatoid factor, and antinuclear antibodies 3
• HIV testing 3
• Region-specific serologic testing: cytomegalovirus, Epstein-Barr virus, tuberculosis based on exposure history 3
• Up to three daily blood films to exclude malaria in patients with relevant travel history 4
• CT abdomen/pelvis with IV contrast if abdominal symptoms or abnormal liver enzymes 4

Consider highly elevated biomarkers for Still's disease if clinical picture fits:

• Serum IL-18 and S100 proteins (calprotectin, S100A12) show high sensitivity and specificity, though validated thresholds are not yet established 1

Phase 3: Advanced Imaging (After Day 7 if diagnosis remains elusive)

[18F]FDG PET/CT is your highest-yield advanced diagnostic tool, with 84-86% sensitivity and 56% diagnostic yield. 1, 2, 4 This should be your preferred second-line imaging modality when initial workup is non-diagnostic. 1, 2

Critical timing considerations for PET/CT:

• Perform within 3 days of initiating oral glucocorticoid therapy, as steroids suppress inflammatory activity and cause false negatives 1, 2
• Use myocardial suppression preparation protocol when cardiac etiology is suspected 1, 2

Alternative advanced imaging if PET/CT unavailable:

• Whole body MRI, particularly useful in pediatric patients 2, 4

Phase 4: Invasive Procedures (When imaging identifies targets)

Pursue tissue diagnosis through biopsy of suspicious lesions identified on PET/CT or other imaging. 4 This provides definitive diagnosis in many cases where non-invasive testing fails. 5

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. 1, 3 The pragmatic approach in most clinical settings is to rule out potentially severe causes while allowing self-limiting viral illnesses to resolve without treatment. 1

Exceptions requiring empiric therapy:

• Neutropenic patients require prompt empiric antimicrobial therapy 2, 4
• Suspected tickborne rickettsial diseases warrant doxycycline 2
• Critically ill patients may require broad-spectrum antibiotics while awaiting diagnostic results 2

For confirmed diagnoses:

• Malaria (most common in returning travelers): treat immediately as it can rapidly become fatal 1
• Adult-onset Still's disease: prioritize IL-1 and IL-6 inhibitors over prolonged glucocorticoid use 1
• Bacterial meningitis: dexamethasone 40 mg/day for 48 hours, optimally before first antibiotic dose 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. 1 This pragmatic approach prevents missing treatable infections. 1

Do not order non-clue-based imaging and testing early in the workup, as this is inefficient and potentially misleading. 5 FUO is more often an atypical presentation of a common disease rather than a rare condition. 3

Do not use high-dose steroids empirically, as they increase hospital-acquired infection risk, hyperglycemia, gastrointestinal bleeding, and delirium without improving mortality. 1 They also mask inflammatory findings on subsequent imaging. 1

Do not assume normal inflammatory markers rule out FUO—there is insufficient evidence for [18F]FDG PET/CT utility in FUO with normal CRP/ESR. 1

Expected Outcomes

Accept that 40-56% of FUO cases never receive a final diagnosis even in specialized tertiary centers. 1 Most unspecific fevers are self-limiting viruses that resolve without specific treatment once severe causes are excluded. 1 The wide variability in "fever of unknown origin" as a final diagnosis (0.7-45%) reflects this pragmatic clinical reality. 1