A scoping review on potential of novel developments in fever of unknown origin and inflammation of unknown origin: long-axial-field-of-view positron emission tomography/computed tomography and novel radiotracers.

Introduction: Fever of unknown origin (FUO) and inflammation of unknown origin (IUO) are among the most challenging diagnoses in clinical routine. [¹⁸F]FDG positron emission tomography/computed tomography (PET/CT) is a valuable diagnostic tool, particularly when conventional imaging and laboratory investigations fail to identify the root cause. While its diagnostic accuracy in FUO/IUO settings is high, several issues still remain to be addressed. Long axial field of view PET/CT and the availability of novel radiopharmaceuticals for molecular imaging may significantly advance the field of nuclear medicine and molecular imaging in FUO/IUO.

Evidence acquisition: This scoping review conforms to the "Preferred Reporting Items for Systematic reviews and Meta-Analyses extension for Scoping Reviews Checklist". An extensive literature search of PubMed/MEDLINE database was performed to find relevant published articles on the use of LAFOV PET/CT and novel radiotracers in FUO/IUO settings.

Evidence synthesis: LAFOV PET/CT provides faster whole-body imaging, improved sensitivity, and the ability to perform ultra-low-dose scans. These benefits are particularly valuable for special populations, such as pediatric patients, ICU patients, and pregnant women, where motion artifacts, radiation exposure, and procedural complexity are major concerns. Additionally, novel radiotracers, including FAPI and CXCR4-targeted agents, offer promising specificity for inflammatory or infectious etiologies beyond FDG, potentially improving diagnostic accuracy and reducing false positives.

Conclusions: LAFOV PET/CT and emerging radiopharmaceuticals represent major advancements in the diagnostic workup of FUO/IUO. They enhance lesion detection, reduce scan burden, and may improve outcomes, particularly in vulnerable populations. Further clinical studies are needed to standardize protocols and validate these tools in broader clinical practice.