What is the initial workup for a patient presenting with Fever of Unknown Origin (FUO)?

Workup for Fever of Unknown Origin

Initial Mandatory Evaluation

Begin with chest radiography and obtain at least two sets of blood cultures from different anatomical sites BEFORE initiating any antibiotics, along with complete blood count with differential, C-reactive protein, erythrocyte sedimentation rate, and comprehensive metabolic panel. 1, 2

Essential History Components

• Recent travel history, animal exposures, and occupational risks 1
• Medication history including recent antibiotic use 1
• Immunosuppression history and HIV risk factors 1
• Symptoms suggesting specific organ involvement 1
• Recent surgical procedures (thoracic, abdominal, or pelvic) 2

Physical Examination Focus

• Skin examination for rashes or lesions 1
• Oral cavity and conjunctival examination 1
• Comprehensive lymph node examination 1
• Temporal artery palpation (consider giant cell arteritis in older patients) 3

Mandatory Initial Laboratory Tests

• At least two sets of blood cultures (ideally 60 mL total blood volume) from different anatomical sites 1, 2
• Complete blood count with differential 1, 3
• C-reactive protein and erythrocyte sedimentation rate 1, 2
• Comprehensive metabolic panel including liver enzymes 1, 2
• Urinalysis and urine culture 3

Second-Line Testing

If initial workup is unrevealing, proceed with additional serologic testing and cross-sectional imaging based on clinical context. 1, 3

Additional Laboratory Studies

• Lactate dehydrogenase and creatine kinase 3
• Rheumatoid factor and antinuclear antibodies 3
• HIV testing with CD4+ T-cell counts and viral load if positive 1
• Region-specific serologic testing (tuberculosis, cytomegalovirus, Epstein-Barr virus) 3

Cross-Sectional Imaging

• CT chest with IV contrast identifies pulmonary sources in 72% of cases and changes management in 45% of patients 4, 1
• CT abdomen/pelvis with IV contrast has 81.82% positive predictive value for identifying septic foci, most commonly in abdomen and pelvis 2
• For post-surgical patients, CT of the operative area if fever occurs several days postoperatively 1, 2
• Formal diagnostic ultrasound of abdomen only if abdominal symptoms or abnormal liver tests present 1, 2

Advanced Imaging

FDG-PET/CT is the highest-yield advanced imaging modality with 56% diagnostic yield and 84-86% sensitivity, and should be performed if initial evaluation remains unrevealing. 1, 2, 5

FDG-PET/CT Indications and Timing

• Perform when initial workup including chest radiography and basic labs are unrevealing 4, 1
• Should ideally be performed within 3 days of starting oral glucocorticoid therapy 1, 2
• Identifies new infectious focus in 52% of positive scans, leading to treatment modifications 4
• Has 100% negative predictive value in some studies 4
• Negative PET/CT predicts favorable prognosis through spontaneous remission 2

PET/CT Performance Characteristics

• Sensitivity: 84-86% 1, 5
• Specificity: 87.5% 4
• Positive predictive value: 95.2% 4
• Most common sites identified: musculoskeletal (38%), chest (25%) 4

Special Population Considerations

Post-Surgical Patients

• CT of operative area (chest, abdomen, or pelvis) based on surgical site 1, 2
• Consider anastomotic leak, abscess formation, or infected collections 2

Neutropenic Patients

• Initiate broad-spectrum antibiotics with antipseudomonal activity BEFORE completing full workup 1, 2
• Imaging includes chest radiography, CT paranasal sinuses, CT chest, CT abdomen/pelvis 1
• Avoid routine sinus CT without localizing symptoms 2

HIV-Positive Patients

• Test CD4+ T-cell counts and HIV viral load 1
• Consider opportunistic infections: Mycobacterium tuberculosis, cytomegalovirus, Pneumocystis jirovecii 1

Critical Management Principles

Avoid empiric antibiotics in non-neutropenic patients unless critically ill, as up to 75% of cases resolve spontaneously. 1, 2, 6

What NOT to Do

• Do not start antibiotics before obtaining blood cultures 1, 2
• Do not use high-dose steroids without specific indication - increases risk of hospital-acquired infection, hyperglycemia, gastrointestinal bleeding, and delirium 1, 2
• Do not use NSAIDs - impair renal and coagulation function, increase stress ulcer risk 1, 2
• Do not routinely remove central venous catheters in clinically stable patients without microbiological evidence of catheter-related infection 2
• Do not perform routine abdominal ultrasound without abdominal signs, symptoms, or liver function abnormalities 2

Key Clinical Pearls

• Most FUO cases result from uncommon presentations of common diseases, not rare diseases 1, 3, 6
• Fever alone rarely constitutes indication to modify antibiotic regimen in patients already on antibiotics 2
• In immunocompromised patients, imaging findings may represent non-malignant lesions or opportunistic infections 1
• Liver cirrhosis is significantly associated with negative PET/CT findings 4

Invasive Procedures

If noninvasive testing remains unrevealing, tissue biopsy has relatively high diagnostic yield and should be directed by imaging findings or clinical suspicion. 6

Biopsy Options Based on Clinical Context

• Liver biopsy 6
• Lymph node biopsy 6
• Temporal artery biopsy (if age >50 and elevated ESR) 6
• Skin or skin-muscle biopsy 6
• Bone marrow biopsy 6