Management of Fever of Unknown Origin

Definition and Classification

Fever of unknown origin (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, as defined by the European Journal of Nuclear Medicine and Molecular Imaging 1
FUO is classified into four subcategories: classical, nosocomial, neutropenic, and HIV-related, according to the European Journal of Nuclear Medicine and Molecular Imaging 1
The etiology of FUO includes infectious, inflammatory, malignant, and miscellaneous causes, as reported by the European Journal of Nuclear Medicine and Molecular Imaging 1

[18F]FDG PET/CT has a high diagnostic yield (56%) and should be performed if initial evaluation is unrevealing, as recommended by the European Journal of Nuclear Medicine and Molecular Imaging 1
[18F]FDG PET/CT has a sensitivity of 84-86% in identifying the cause of FUO, according to the European Journal of Nuclear Medicine and Molecular Imaging 1
PET/CT should ideally be performed within 3 days of initiation of oral glucocorticoid therapy, as suggested by the European Journal of Nuclear Medicine and Molecular Imaging 1
Consider CT or MR angiography if feeding vessel sign, reversed halo sign, or hemoptysis are observed in suspected fungal pneumonia, as recommended by the Annals of Oncology 2
In patients with lung infiltrates, bronchoalveolar lavage (BAL) should be performed at a segmental bronchus supplying an area of radiographic abnormalities, as recommended by the Annals of Oncology 2

Treatment should target the identified cause once diagnosis is established, as recommended by the Clinical Infectious Diseases 3
In severely neutropenic patients, broad-spectrum antibiotics should be initiated promptly, as recommended by the Annals of Oncology 4 and 5
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, as recommended by the Annals of Oncology 6
If fever persists despite broad-spectrum antibiotics in neutropenic patients, consider antifungal therapy with voriconazole or liposomal amphotericin B if lung infiltrates are not typical for Pneumocystis pneumonia (PcP) or lobar bacterial pneumonia, as recommended by the Annals of Oncology 6

Persisting fever without microbiological documentation is less concerning if the granulocyte count is increasing, as reported by the Annals of Oncology 4 and 5
In patients with severe and persistent neutropenia, FUO which persists despite broad-spectrum antimicrobial therapy may indicate fungal infection, as reported by the Annals of Oncology 4 and 5
Empiric antifungal treatment should only be considered in critically ill patients with fever of unknown origin and new pulmonary infiltrates, as recommended by the World Journal of Emergency Surgery 7