Fever and inflammation of unknown origin in the 21st century.

Fever and inflammation of unknown origin (FUO/IUO) remain challenging clinical syndromes today, in which the internists play a central role in orchestrating the diagnostic process and interpreting key findings. FUO and IUO share similar diagnostic evaluations and overlapping etiologies, although the relative frequencies of their causes may differ. The established five-category classification includes infectious diseases (INF), non-infectious inflammatory diseases (NIID), malignancies (MAL), miscellaneous (MISC) and undiagnosed illnesses (UI). The relative distribution of these categories varies depending on the FUO diagnostic criteria applied, as well as geographical region and socioeconomic factors. Although infectious diseases were historically the predominant cause of FUO, in recent years there has been a shift toward UI and NIID, especially in high-income settings. IUO is typically associated with a lower likelihood of infections compared to FUO, while the most common causes are mainly NIID. Meticulous medical history and clinical examination, aimed at identifying potential diagnostic clues (PDCs), remain pivotal to FUO/IUO diagnostics. Modern technologies such as PET/CT and next-generation sequencing (NGS) have advanced the diagnostic workup of FUO/IUO. However, they should be employed selectively, guided by PDCs, and with consideration of their limitations and cost-effectiveness. Emerging techniques, including metagenomic NGS and cytokine-based assays (e.g. IL-1β/DNA complex detection), show promising results in distinguishing sterile from infectious inflammation. Despite advancements in diagnostics and considering that UI now represent a leading cause of FUO in the European region, there remains an urgent need to deepen our understanding of underlying disease mechanisms and to develop novel, pathophysiology-based diagnostic tools.