What is the appropriate treatment for fevers of unknown origin (FUO)?

Management of Fever of Unknown Origin (FUO)

For fever of unknown origin (FUO), a systematic diagnostic approach should be followed with appropriate imaging studies including [18F]FDG PET/CT, and empiric antimicrobial therapy should be avoided except in neutropenic, immunocompromised, or critically ill patients. 1, 2

Definition and Classification

• FUO is defined as fever higher than 38.3°C (100.9°F) persisting for at least 3 weeks, with no diagnosis despite 3 outpatient visits or in-patient days 1
• FUO is classified into four subcategories: classical, nosocomial, neutropenic, and HIV-related 1
• The etiology includes infectious, inflammatory, malignant, and miscellaneous causes 1, 3

Diagnostic Approach

Initial Evaluation

• Perform thorough physical examination focusing on potential sources of infection, signs of malignancy, or inflammatory conditions 2
• Initial laboratory testing should include:
  • Complete blood count, liver enzymes, electrolyte panel 3
  • Erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) 3
  • Blood cultures, urinalysis and culture 3
  • Chest radiography 3

Advanced Imaging

• If initial evaluation is unrevealing, [18F]FDG PET/CT has a high diagnostic yield (56%) and should be performed 1
• [18F]FDG PET/CT has a sensitivity of 84-86% in identifying the cause of FUO 1
• PET/CT should ideally be performed within 3 days of initiation of oral glucocorticoid therapy 1
• Consider CT or MR angiography if feeding vessel sign, reversed halo sign, or hemoptysis are observed in suspected fungal pneumonia 1

Invasive Procedures

• If noninvasive tests are unrevealing, tissue biopsy may be necessary (liver, lymph node, temporal artery, skin, skin-muscle, or bone marrow) 2
• In patients with lung infiltrates, bronchoalveolar lavage (BAL) should be performed at a segmental bronchus supplying an area of radiographic abnormalities 1
• Bronchoscopy and BAL should be available within 24 hours after clinical indication has been established 1

Treatment Approach

General Principles

• Empiric antimicrobial therapy has not been shown to be effective in the treatment of FUO and should be avoided except in neutropenic, immunocompromised, or critically ill patients 2, 3
• Treatment should target the identified cause once diagnosis is established 1

Management of Neutropenic Patients with FUO

• In severely neutropenic patients, broad-spectrum antibiotics should be initiated promptly 1
• For patients with severe neutropenia due to chemotherapy for acute leukemia or other aggressive hematologic malignancy, use a broad-spectrum β-lactam with antipseudomonal activity 1
• If fever persists despite broad-spectrum antibiotics in neutropenic patients:
  • Re-evaluate with thoracic CT scan and possibly bronchoscopy and BAL after 7 days 1
  • Consider antifungal therapy with voriconazole or liposomal amphotericin B if lung infiltrates are not typical for Pneumocystis pneumonia (PcP) or lobar bacterial pneumonia 1

Duration of Therapy

• In patients with documented infections, continue appropriate antibiotics for at least the duration of neutropenia (until ANC > 500 cells/mm³) or longer if clinically necessary 1
• For unexplained fever, continue the initial regimen until there are clear signs of marrow recovery (ANC > 500 cells/mm³) 1
• If an appropriate treatment course has been completed and all symptoms of documented infection have resolved, neutropenic patients may resume oral fluoroquinolone prophylaxis until marrow recovery 1

Special Considerations

Persistent Fever Despite Treatment

• Persisting fever without microbiological documentation is less concerning if the granulocyte count is increasing 1
• In patients with severe and persistent neutropenia, FUO which persists despite broad-spectrum antimicrobial therapy may indicate fungal infection 1
• Consider empiric antifungal therapy with amphotericin B if a clinical focus of infection is present or if no oral antifungal prophylaxis has been given 1
• Continue broad-spectrum antibiotics as their discontinuation may be associated with fatal bacteremia in febrile neutropenic patients 1

Caution with Empiric Therapy

• Prolonged antimicrobial treatment has been associated with superinfections, particularly fungal infections 1
• Empiric antifungal treatment should only be considered in critically ill COVID-19 patients with fever of unknown origin and new pulmonary infiltrates 1

By following this systematic approach to diagnosis and treatment, clinicians can effectively manage patients with FUO while minimizing unnecessary antimicrobial use and focusing on identifying the underlying cause.