What are the immediate diagnostic steps for a case of Fever of Unknown Origin (FUO)?

Immediate Diagnostic Steps for Fever of Unknown Origin

For patients with FUO, immediately obtain at least two sets of blood cultures from different anatomical sites, chest radiography, complete blood count with differential, inflammatory markers (CRP and ESR), comprehensive metabolic panel including liver enzymes, and urinalysis with culture as the mandatory first-line workup. 1, 2, 3, 4

Initial Laboratory Testing (Perform Immediately)

• Collect at least two sets of blood cultures (ideally 60 mL total) from different anatomical sites sequentially without time intervals, with proper skin preparation via peripheral venipuncture 1, 3
• Obtain complete blood count with differential to identify leucocytosis, neutrophilia, or left shift suggesting bacterial infection 2, 3, 5
• Measure inflammatory markers: C-reactive protein and erythrocyte sedimentation rate are essential baseline tests 1, 2, 5
• Order comprehensive metabolic panel including electrolytes, liver enzymes (transaminases, alkaline phosphatase, bilirubin) 1, 3, 5
• Perform urinalysis with culture, replacing urinary catheter if present before obtaining specimen 3, 5

Initial Imaging (Perform Immediately)

• Obtain chest radiography on all FUO patients as pneumonia is the most common infection causing fever in hospitalized patients 1, 2, 3
• Consider abdominal/pelvic CT in collaboration with surgical services for patients with recent thoracic, abdominal, or pelvic surgery if no alternative source is identified 1, 3
• Perform formal abdominal ultrasound only if abdominal symptoms, abnormal liver function tests, or recent abdominal surgery are present—do not use routinely 1, 3

Additional First-Line Testing

• Order three additional blood culture sets before initiating any antibiotics (total of at least 3 sets) 4
• Measure lactate dehydrogenase, creatine kinase, rheumatoid factor, and antinuclear antibodies as part of extended initial workup 5
• Obtain HIV testing and region-specific serologies (cytomegalovirus, Epstein-Barr virus, tuberculosis testing) based on epidemiologic risk factors 5, 6

Critical Timing Considerations

• Do not delay blood culture collection to start antimicrobials in septic patients, but cultures should be obtained within 45 minutes of presentation 1
• Avoid empiric antibiotics or steroids in stable FUO patients as they obscure diagnosis and may cause harm if malignancy or certain infections are present 4, 5
• If glucocorticoids are clinically necessary, plan advanced imaging (18F-FDG PET/CT) within 3 days of initiation, as steroids suppress inflammatory findings 1, 2, 4

When Initial Workup is Non-Diagnostic

• Proceed to 18F-FDG PET/CT if transport risk is acceptable, as this has 84-86% sensitivity and 56% diagnostic yield for identifying FUO etiology 1, 2, 4
• Consider myocardial suppression preparation for PET/CT when cardiac etiology is suspected 1, 2

Common Pitfalls to Avoid

• Never diagnose FUO prematurely—ensure the fever has persisted for at least 3 weeks with temperature >38.3°C (100.9°F) and remains undiagnosed despite appropriate investigation 1, 2, 4
• Do not use rapid molecular blood tests without concomitant conventional blood cultures, as cultures detect wider pathogen spectrum and provide isolates for susceptibility testing 1, 3
• Avoid routine abdominal imaging in patients without abdominal symptoms, signs, or liver function abnormalities, as yield is extremely low 1, 3
• Do not use empiric high-dose steroids, as they increase hospital-acquired infection risk, hyperglycemia, GI bleeding, delirium, and mask findings on subsequent imaging without mortality benefit 4

Special Population Considerations

• Neutropenic patients require immediate empiric antimicrobial therapy while diagnostic workup proceeds 2, 4
• Elderly patients warrant specific evaluation for temporal arteritis (16-17% prevalence in FUO) and deep vein thrombosis 7
• Recent surgical patients need lower threshold for cross-sectional imaging of the operative area 1, 3