What is the initial approach to managing a patient with fever of unknown origin (FUO)?

Initial Management of Fever of Unknown Origin

Begin with a structured diagnostic evaluation including at least two sets of blood cultures from different anatomical sites, chest radiography, comprehensive metabolic panel, inflammatory markers (ESR and CRP), and urinalysis—all obtained before initiating any antibiotics—while avoiding empiric antimicrobial therapy in non-neutropenic patients unless they are critically ill. 1, 2

Definition and Patient Stratification

FUO is defined as fever >38.3°C (100.9°F) persisting for at least 3 weeks with no diagnosis despite 3 outpatient visits or in-patient days. 1, 2 The critical first step is determining whether the patient is neutropenic, immunocompromised, or critically ill, as this fundamentally changes management. 1, 3

Risk Stratification Categories:

• Classical FUO: Immunocompetent outpatients 1
• Neutropenic FUO: Absolute neutrophil count <500 cells/mm³ 2
• Nosocomial FUO: Hospitalized patients 1
• HIV-related FUO: Immunocompromised patients 1

Initial Diagnostic Workup

Mandatory First-Line Testing (Before Any Antibiotics):

Laboratory Studies:

• At least two sets of blood cultures from different anatomical sites (ideally 60 mL total blood volume) 2
• Complete blood count with differential 4
• Comprehensive metabolic panel (to identify hepatobiliary sources) 2
• Erythrocyte sedimentation rate and C-reactive protein 2, 4
• Urinalysis and urine culture 4
• Lactate dehydrogenase, creatine kinase 4
• Rheumatoid factor and antinuclear antibodies 4

Imaging:

• Chest radiography (mandatory initial imaging) 2
• Abdominal/pelvic ultrasound only if abdominal symptoms, abnormal liver tests, or recent abdominal surgery are present 2

Region-Specific Serologic Testing:

• HIV testing 4
• Tuberculosis screening (especially in endemic areas) 4, 5
• Cytomegalovirus and Epstein-Barr virus serology 4

Treatment Approach Based on Patient Category

Non-Neutropenic, Immunocompetent Patients:

Avoid empiric antibiotics. Up to 75% of FUO cases resolve spontaneously without definitive diagnosis, and empiric antimicrobial therapy has not been shown effective. 1, 2, 3 This is a critical pitfall—resist pressure to "do something" with antibiotics in stable patients.

Neutropenic or Critically Ill Patients:

Initiate immediate broad-spectrum antibiotics with an antipseudomonal β-lactam (piperacillin-tazobactam, cefepime, or carbapenem) as monotherapy. 1, 2 For high-risk neutropenic patients (ANC <100 cells/mm³ expected >7 days), this is first-line treatment. 2

Add vancomycin immediately only if the patient appears septic, has severe infection signs, or has documented gram-positive infection—not empirically. 2, 6

Advanced Diagnostic Strategy When Initial Workup is Unrevealing

Second-Line Imaging:

If ESR or CRP are elevated and initial evaluation is non-diagnostic, [18F]FDG PET/CT should be performed, which has 56% diagnostic yield and 84-86% sensitivity. 1, 2 This should ideally be done within 3 days of starting oral glucocorticoids if steroids are being considered. 1

For postoperative patients with fever several days after thoracic, abdominal, or pelvic surgery, obtain CT of the operative area. 2

Invasive Diagnostic Procedures:

When noninvasive tests are unrevealing, tissue biopsy is the invasive test of choice due to relatively high diagnostic yield. 3 Consider:

• Liver biopsy
• Lymph node biopsy
• Temporal artery biopsy (if giant cell arteritis suspected)
• Bone marrow biopsy
• Skin or skin-muscle biopsy 3

Surveillance and Re-evaluation

For neutropenic patients on antibiotics, perform daily surveillance including:

• Daily physical examination
• Review of systems for new symptoms
• Cultures of any suspect sites
• Assessment for adverse effects and secondary infections 2

Re-evaluate after 2-4 days of empirical treatment—this is when most modifications to the initial regimen should be made. 2

Critical Pitfalls to Avoid

• Do not remove central venous catheters in clinically stable patients without microbiological evidence of catheter-related infection 2
• Do not switch empirical monotherapy to another agent or add aminoglycosides without clinical or microbiological justification 2
• Do not add vancomycin empirically for persistent fever alone without documented gram-positive infection 2
• Avoid high-dose steroids without specific indication, as they increase risk of hospital-acquired infection, hyperglycemia, and GI bleeding 2
• Do not use NSAIDs as they impair renal/coagulation function and increase stress ulcer risk 2

Special Considerations for Persistent Fever

In neutropenic patients with persistent fever despite broad-spectrum antibiotics:

• Consider antifungal therapy (voriconazole or liposomal amphotericin B) only if new pulmonary infiltrates develop that are not typical for Pneumocystis pneumonia or lobar bacterial pneumonia 1
• Persisting fever is less concerning if granulocyte count is increasing 1
• Fever alone rarely constitutes indication to modify antibiotics 2

Geographic and Demographic Considerations

In developing countries, infectious diseases (particularly tuberculosis) remain the most important cause, so initial investigations should prioritize infectious workup. 5 In younger patients, consider hematological malignancy; in older patients, consider extrapulmonary tuberculosis and temporal arteritis. 5