What are the initial diagnostic steps for a patient with Fever of Unknown Origin (FUO), including baseline investigations, imaging, inflammatory markers, blood cultures, and tissue biopsy?

Baseline Investigations in FUO

All FUO patients require at minimum: complete blood count with differential, inflammatory markers (CRP and ESR), comprehensive metabolic panel, at least 2-3 sets of blood cultures from different anatomical sites (ideally 60 mL total blood volume) before any antibiotics, chest radiography, and urinalysis with culture. 1, 2, 3

Mandatory First-Line Laboratory Testing

• Obtain at least 2-3 sets of blood cultures from different anatomical sites before initiating any antibiotic therapy, with no required interval between collection 1, 2
• Collect ideally 60 mL of total blood volume across all culture sets to maximize diagnostic yield 1
• In patients with central venous catheters, obtain simultaneous central and peripheral blood cultures to calculate differential time to positivity for catheter-related infection 1
• Measure inflammatory markers including C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR) as these guide subsequent imaging decisions 4, 1, 3
• Complete blood count with differential is essential, as WBC count <4,000/μL significantly increases malignancy likelihood (p=0.015) 5
• Comprehensive metabolic panel to identify hepatobiliary sources 1
• Additional testing should include lactate dehydrogenase, creatine kinase, rheumatoid factor, and antinuclear antibodies 3

Critical Baseline Imaging

• Chest radiography is mandatory in all FUO patients as initial imaging 1, 3
• Perform formal diagnostic ultrasound of the abdomen only for patients with abdominal symptoms, abnormal liver tests, or recent abdominal surgery 1
• Avoid routine abdominal ultrasound or point-of-care ultrasound in patients without abdominal signs, symptoms, or liver function abnormalities 1

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Escalation to PET-CT Imaging

PET-CT should be performed when initial standard workup (blood cultures, inflammatory markers, chest X-ray, basic CT imaging) fails to identify a diagnosis, as it has 84-86% sensitivity and 56% diagnostic yield in FUO. 4, 1, 6, 7

Timing and Indications for PET-CT

• Escalate to [18F]FDG PET/CT after standard workup is unrevealing, as it represents the highest-yield advanced diagnostic tool 4, 1, 2
• PET-CT should ideally be performed within 3 days of initiating oral glucocorticoid therapy to avoid false negatives from suppressed inflammatory activity 4, 1, 6
• Early implementation of PET/CT is cost-effective and prevents missed diagnoses due to extended antibiotic therapy 4
• The diagnostic accuracy is 76% with helpfulness in 61% of cases 4

Predictive Factors for Diagnostic PET-CT

• Age over 50 years significantly predicts diagnostic PET-CT yield (p=0.019) 7
• CRP level over 30 mg/L increases likelihood of diagnostic PET-CT (p=0.002) 7
• Absence of intermittent fever paradoxically increases PET-CT diagnostic yield (p=0.001) 7
• PET/CT has insufficient evidence for patients with FUO and normal inflammatory markers (normal CRP and ESR) 4

Standard CT Before PET-CT

• For patients with recent thoracic, abdominal, or pelvic surgery, perform CT of the operative area if etiology is not readily identified 1
• CT chest with IV contrast identifies pulmonary sources in 72% of surgical ICU patients with suspected infection 1
• CT abdomen/pelvis with IV contrast has 81.82% positive predictive value for identifying septic foci, resulting in management changes in 45% of patients 1

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Role of Inflammatory Markers

Inflammatory markers guide the diagnostic pathway: elevated CRP >30 mg/L and ESR >40 mm/h increase PET-CT yield, while normal ESR essentially excludes malignancy as a cause of FUO. 7, 5

CRP and ESR as Diagnostic Guides

• All FUO patients with malignancy showed ESR >40 mm/h, making normal ESR powerful evidence for excluding malignancy 5
• CRP >30 mg/L significantly predicts diagnostic PET-CT yield (p=0.002) 7
• Elevated inflammatory markers (CRP/ESR) are required for accurate PET-CT results, as certain inflammatory activity is necessary for FDG uptake 4, 7
• CRP and procalcitonin concentrations appear unrelated to specific causative disease categories 5

WBC Count Patterns

• WBC count <4,000/μL significantly increases malignancy rate compared to WBC 4,000-8,000/μL (p=0.015) 5
• Higher WBC counts correlate with increased rates of non-infectious inflammatory disease and fewer unknown cases 5

Limitations and Caveats

• PET/CT has insufficient evidence for diagnostic utility in FUO patients with normal inflammatory markers 4
• Extended antibiotic therapy suppresses inflammatory activity and may cause false-negative PET scans, even when active infection persists 4

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Blood Culture Strategy

Obtain at least 2-3 sets of blood cultures (60 mL total blood volume) from different anatomical sites before any antibiotics, with simultaneous central and peripheral draws if a central line is present. 1, 2

Optimal Collection Technique

• Collect at least two sets of blood cultures from different anatomical sites before initiating any antibiotic therapy 1
• Ideally obtain 60 mL of total blood volume across all culture sets to maximize pathogen detection 1
• No interval is required between blood culture sets 1
• Use rapid molecular tests on blood in conjunction with conventional blood cultures, never as replacement 2

Central Venous Catheter Considerations

• In patients with central venous catheters, obtain simultaneous central and peripheral blood cultures to calculate differential time to positivity 1
• Do not systematically remove central venous catheters in clinically stable patients with FUO unless there is microbiological evidence of catheter-related infection 2

Adequacy Assessment

• Three sets of blood cultures are recommended in the comprehensive workup 2, 3
• Multiple blood and urine cultures may be necessary when initial sets are negative, as demonstrated in case reports requiring repeated sampling 8

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Tissue Biopsy vs. Further Laboratory Testing

Tissue biopsy becomes more valuable than further laboratory testing when PET-CT or other imaging identifies a focal lesion, when there is unexplained lymphadenopathy or hepatosplenomegaly, or when all non-invasive testing remains unrevealing after comprehensive workup. 4, 9, 3

When to Prioritize Tissue Biopsy

• PET-CT should guide tissue biopsy site selection when it identifies focal areas of increased FDG uptake 4, 3
• Lymph node biopsy is critical when imaging suggests lymphoproliferative disease, as demonstrated in cases where it ultimately diagnosed peripheral T-cell lymphoma after months of unrevealing tests 9
• Liver lesion biopsy should be performed when MRI identifies atypical tumors without characteristic features of benign lesions, as inflammatory myofibroblastic tumors can cause FUO 8
• Bronchoalveolar lavage should be performed at segmental bronchus supplying radiographic abnormalities in patients with lung infiltrates 6

Algorithmic Approach to Biopsy Decision

• If PET-CT is positive and identifies a focal lesion, proceed directly to biopsy of the most accessible site with highest uptake 4
• If all imaging and laboratory testing remain negative after comprehensive workup, consider bone marrow examination to evaluate for occult hematologic malignancy 8
• Biopsy is more valuable than additional laboratory testing when there is progressive clinical deterioration despite negative workup 9

Common Pitfalls to Avoid

• Do not delay biopsy of accessible lesions in favor of additional serologic testing when imaging identifies a target 9, 3
• Avoid empiric steroids before tissue diagnosis, as they increase infection risk, mask inflammatory findings on subsequent imaging, and may obscure histopathologic diagnosis 4, 2
• Do not prematurely diagnose "fever of unknown origin" without thorough evaluation, as it is a diagnosis of exclusion requiring comprehensive workup 1, 2
• Recognize that atypical presentations of common diseases are more frequent than rare diseases in FUO 3