Diagnostic Yield of [¹⁸F]FDG PET/CT in FUO: An Italian Multicenter Study of 929 Patients

Fever of unknown origin (FUO) presents a significant diagnostic challenge because of its wide range of potential causes. The role of [¹⁸F]FDG PET/CT in this complex clinical scenario is not yet fully understood. This multicenter retrospective observational study aimed to investigate the diagnostic value and clinical impact of [¹⁸F]FDG PET/CT in patients with FUO and to identify specific factors linked to a positive [¹⁸F]FDG PET/CT scan. Methods: We retrospectively included 929 patients from 12 centers who underwent [¹⁸F]FDG PET/CT for FUO. The final diagnosis for each patient was established on the basis of laboratory, imaging, histopathologic or pathologic examinations, and at least 6 mo of clinical follow-up data. Final diagnoses were classified into 4 categories: infectious diseases, noninfectious inflammatory diseases, malignancies, and unknown causes (no diagnosis). Moreover, the impact of [¹⁸F]FDG PET/CT on clinical management, as well as its association with clinical, epidemiologic, and biochemical parameters were analyzed. Results: The final diagnoses included infectious diseases in 332 patients (36%), noninfectious inflammatory diseases in 281 (30%), and malignancies in 103 (11%). The cause of FUO remained undiagnosed in 213 patients (23%). [¹⁸F]FDG PET/CT scans had positive results for 549 (59%) patients and negative for the remaining 380 patients. The overall [¹⁸F]FDG PET/CT sensitivity was 72% (95% CI, 69%-75%), specificity was 85% (95% CI, 79%-89%), positive predictive value was 94% (95% CI, 92%-96%), negative predictive value was 47% (95% CI, 44%-51%), and accuracy was 75% (95% CI, 72%-78%). Predictive markers for a positive PET/CT scan were high C-reactive protein, high erythrocyte sedimentation rate, high neutrophil-to-lymphocyte ratio, the presence of fever at the time of PET, and short duration of prior antibiotic therapy. Moreover, [¹⁸F]FDG PET/CT findings directly influenced the clinical management of approximately 75% of patients. Conclusion: [¹⁸F]FDG PET/CT is a high-yield diagnostic tool that directly influenced clinical management of approximately 75% of patients with FUO, with optimal performance in patients with elevated inflammatory markers, fever at the time of imaging, and limited prior antibiotic use.