What laboratory tests should be ordered for the initial workup of fever of unknown origin?

Laboratory Tests for Initial Workup of Fever of Unknown Origin

The initial laboratory workup for fever of unknown origin should include blood cultures, complete blood count with differential, comprehensive metabolic panel, erythrocyte sedimentation rate, C-reactive protein, procalcitonin, urinalysis with culture, and chest radiography. 1, 2, 3

Core Laboratory Tests

First-line Tests

• Blood cultures: At least two sets (ideally 60 mL total) from different anatomical sites 1

  • Should be collected before initiating antimicrobial therapy
  • For patients with central venous catheters, obtain simultaneous central and peripheral cultures to calculate differential time to positivity 1
  • If central line present, sample at least two lumens 1

• Complete blood count with differential

  • Pay special attention to:
    • Leukocytosis (>14,000 cells/mm³)
    • Elevated band count (>1,500/mm³)
    • Increased percentage of neutrophils (>90%)
    • Left shift (>16% band neutrophils) 1
  • These findings have high likelihood ratios for bacterial infection even without fever 1

• Inflammatory markers

  • Erythrocyte sedimentation rate (ESR)
  • C-reactive protein (CRP)
  • Procalcitonin (PCT) - particularly useful when probability of bacterial infection is low to intermediate 1

• Comprehensive metabolic panel

  • Liver function tests (ALT, AST, alkaline phosphatase, bilirubin)
  • Renal function (BUN, creatinine)
  • Electrolytes

• Urinalysis and urine culture

  • If urinary catheter present and UTI suspected, replace catheter and obtain culture from newly placed catheter 1

Second-line Tests

• Serologic and specialized testing based on epidemiology:

  • HIV testing
  • Viral studies (particularly if respiratory symptoms present) 1
    • SARS-CoV-2 PCR based on community transmission levels
    • Viral nucleic acid amplification test panels for respiratory pathogens
  • Region-specific serologic testing (e.g., cytomegalovirus, Epstein-Barr virus, tuberculosis) 2

• Additional biomarkers:

  • Ferritin (levels >1,000 ng/mL suggest inflammatory conditions; >5,000 ng/mL highly specific for adult-onset Still's disease) 1
  • Lactate dehydrogenase (LDH)
  • Creatine kinase

• Autoimmune workup:

  • Rheumatoid factor
  • Antinuclear antibodies

Imaging Studies

• Chest radiography - recommended for all patients with fever 1

• Abdominal and pelvic imaging:

  • For patients with abdominal symptoms, abnormal liver function tests, or recent abdominal surgery, obtain formal ultrasound 1
  • Consider CT abdomen/pelvis if no clear source identified after initial workup 2

• Advanced imaging if diagnosis remains elusive:

  • 18F-fluorodeoxyglucose positron emission tomography/CT (FDG-PET/CT) - particularly useful when ESR or CRP remain elevated without clear diagnosis 3, 4

Diagnostic Algorithm

1. Initial evaluation:

   • Obtain core laboratory tests (CBC with differential, blood cultures, CMP, ESR, CRP)
   • Perform chest radiography
   • Collect urinalysis and urine culture

2. If no clear source identified:

   • Add procalcitonin if bacterial infection probability is low to intermediate
   • Obtain appropriate serologic testing based on epidemiology
   • Consider autoimmune markers (RF, ANA)

3. If fever persists without diagnosis:

   • Proceed to cross-sectional imaging (CT abdomen/pelvis)
   • Consider FDG-PET/CT if inflammatory markers remain elevated
   • Consider tissue biopsy (lymph node, liver, bone marrow) based on clinical findings 3

Important Considerations

• Fever of unknown origin is more often an atypical presentation of a common disease rather than an unusual disease 2
• The most common categories in the differential are infection (32.7%), malignancy, noninfectious inflammatory diseases, and miscellaneous causes 1, 2
• Avoid empiric antibiotics unless the patient is neutropenic, immunocompromised, or critically ill 3
• Up to 17.8% of cases remain undiagnosed despite thorough evaluation 1

Remember that the diagnostic yield is highest when laboratory testing is guided by potential diagnostic clues from the history and physical examination rather than performing a battery of non-directed tests.