What is the initial workup for an adult patient with no significant past medical history presenting with fever of unknown origin (FUO)?

Fever of Unknown Origin Workup in Adults

For an adult with no significant past medical history presenting with fever of unknown origin, begin with mandatory first-line testing including at least two sets of blood cultures from different anatomical sites (before any antibiotics), complete blood count with differential, comprehensive metabolic panel, inflammatory markers (ESR and CRP), chest radiography, and urinalysis with culture. 1, 2, 3

Initial Mandatory Laboratory Testing

• Obtain at least two sets of blood cultures from different anatomical sites before initiating any antibiotics (ideally 60 mL total blood volume) 1, 3
• Complete blood count with differential to identify cytopenias, leukocytosis, or atypical cells 1, 2
• Comprehensive metabolic panel to identify hepatobiliary sources and electrolyte abnormalities 1, 2
• Erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) as inflammatory markers 4, 1, 3
• Urinalysis with culture to exclude urinary tract infection 5, 6

Initial Imaging

• Chest radiography is the only first-line imaging study recommended for all patients with FUO, particularly if pulmonary symptoms are present or concern exists for atypical bacterial infection, tuberculosis, or malignancy 4, 1, 2

Targeted History Elements (High-Yield)

• Travel history with specific countries visited to identify region-specific diseases (malaria in Central/Western Africa, dengue and schistosomiasis in Eastern/Western Africa) 3
• Immigration status or visiting friends/relatives abroad (higher malaria rates, less likely to seek pre-travel advice) 3
• Animal exposures and occupational risks 2
• Medication history, including recent antibiotic use 2
• Immunosuppression history 2

Targeted Physical Examination (High-Yield)

• Cardiac auscultation for new murmurs to evaluate for infective endocarditis 2
• Skin examination for rashes or lesions 2
• Oral cavity and conjunctival examination 2
• Lymph node examination 2

Second-Line Laboratory Testing (If Initial Workup Unrevealing)

• Lactate dehydrogenase, creatine kinase 5
• Rheumatoid factor and antinuclear antibodies 5
• HIV testing 5, 6
• Region-specific serologic testing (cytomegalovirus, Epstein-Barr virus, tuberculosis) 5

Advanced Imaging (If Initial Workup Non-Diagnostic)

[18F]FDG PET/CT is the highest-yield advanced imaging modality with 84-86% sensitivity and 56% diagnostic yield, and should be performed within 3 days of initiating oral glucocorticoid therapy to avoid false negatives. 4, 1, 2, 3

The most recent 2023 meta-analysis demonstrates diagnostic accuracy of 76% and helpfulness in 61% of cases 4. A negative PET/CT can predict favorable prognosis through spontaneous remission and potentially allows a watchful waiting approach 4, 1.

Alternative Advanced Imaging

• Abdominal/pelvic ultrasound or CT if abdominal symptoms, abnormal liver tests, or recent abdominal surgery are present 4, 1, 5
• CT chest with IV contrast identifies pulmonary sources in 72% of surgical ICU patients 1
• CT abdomen/pelvis with IV contrast has 81.82% positive predictive value for identifying septic foci 1

Invasive Testing (If Non-Invasive Tests Unrevealing)

Tissue biopsy is the invasive test of choice due to relatively high diagnostic yield 6. Consider:

• Liver biopsy 6
• Lymph node biopsy 6
• Temporal artery biopsy 6
• Bone marrow biopsy 6

Critical Management Principles

Avoid empiric antibiotics in non-neutropenic, stable patients with FUO, as up to 75% of cases resolve spontaneously without definitive diagnosis, and antibiotics obscure the underlying cause. 1, 3, 6

Do not use high-dose steroids empirically without specific indication, as they increase risk of hospital-acquired infection, hyperglycemia, gastrointestinal bleeding, and delirium, while also masking inflammatory findings on subsequent imaging 1, 2, 3.

Avoid NSAIDs as they impair renal and coagulation function and increase stress ulcer risk 2, 3.

Common Pitfalls to Avoid

• Most FUO cases result from uncommon presentations of common diseases, not rare diseases 2, 6
• Do not diagnose "FUO" prematurely—it is a diagnosis of exclusion requiring thorough evaluation 1, 3
• Always obtain blood cultures before initiating antibiotics to avoid masking the underlying cause 2, 3
• Do not systematically remove central venous catheters in clinically stable patients unless there is microbiological evidence of catheter-related infection 1

Temperature Measurement Considerations

Use central temperature monitoring (pulmonary artery catheter, bladder catheter, or esophageal balloon) or oral/rectal temperatures for accurate diagnosis 3. Avoid axillary, tympanic, temporal artery, or chemical dot thermometers due to unreliability 3.