Fever of unknown origin remains one of internal medicine's most vexing diagnostic puzzles — patients can languish for months through invasive workups without answers. A large multicenter analysis now provides the most statistically robust picture yet of where whole-body metabolic imaging fits in that workup, and the numbers are both encouraging and sobering.
Drawing on 929 patients across 12 centers, this retrospective study found that [18F]FDG PET/CT returned positive scans in 59% of cases, with an overall sensitivity of 72% (95% CI 69–75%) and specificity of 85% (95% CI 79–89%). Among patients who eventually received a diagnosis, infectious diseases accounted for 36%, noninfectious inflammatory conditions for 30%, and malignancies for 11%. Notably, 23% of the cohort remained undiagnosed despite full workup and at least six months of clinical follow-up — a reminder that a substantial fraction of FUO cases simply resist classification. The study also examined which clinical, epidemiologic, and biochemical parameters predicted a positive scan, findings that could help clinicians triage who benefits most from this costly and radiation-bearing test.
PET/CT's diagnostic role in FUO has been debated for over a decade, with smaller single-center series showing wide sensitivity ranges (50–90%). This 929-patient multicenter dataset substantially narrows that uncertainty and aligns with a 2016 meta-analysis that estimated sensitivity around 70%. The 85% specificity is clinically meaningful — false positives in FUO can trigger unnecessary biopsies or immunosuppression — yet it also means roughly one in seven negative diagnoses could still harbor significant pathology detectable only through other means. The study's retrospective design and multicenter heterogeneity in imaging protocols are real limitations; prospective randomized data on whether PET/CT-guided management actually improves outcomes over conventional workup remain sparse. Still, this is confirmatory, high-confidence evidence placing FDG PET/CT as a useful second-line tool in FUO — particularly valuable for directing biopsy sites in cases where inflammatory or malignant disease is suspected.