Antoniadou Christina, Gavriilidis Efstratios, Chatzopoulos Petros, Gkouliavera Maria, Skendros Panagiotis
First Department of Internal Medicine and Laboratory of Molecular Hematology, University Hospital of Alexandroupolis, Democritus University of Thrace, Alexandroupolis, Greece.
First Department of Internal Medicine and Laboratory of Molecular Hematology, University Hospital of Alexandroupolis, Democritus University of Thrace, Alexandroupolis, Greece.
Eur J Intern Med. 2025 Aug 20:106443. doi: 10.1016/j.ejim.2025.106443.
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.
不明原因发热和炎症（FUO/IUO）如今仍是具有挑战性的临床综合征，在内科医生在协调诊断过程和解读关键发现方面发挥着核心作用。FUO和IUO具有相似的诊断评估和重叠的病因，尽管它们病因的相对频率可能有所不同。既定的五类分类包括传染病（INF）、非感染性炎症性疾病（NIID）、恶性肿瘤（MAL）、杂项（MISC）和未确诊疾病（UI）。这些类别的相对分布因所应用的FUO诊断标准以及地理区域和社会经济因素而异。尽管传染病在历史上是FUO的主要原因，但近年来已转向UI和NIID，尤其是在高收入地区。与FUO相比，IUO通常感染的可能性较低，而最常见的原因主要是NIID。旨在识别潜在诊断线索（PDC）的细致病史和临床检查，对于FUO/IUO诊断仍然至关重要。PET/CT和下一代测序（NGS）等现代技术推动了FUO/IUO的诊断检查。然而，应在PDC的指导下有选择地使用它们，并考虑其局限性和成本效益。包括宏基因组NGS和基于细胞因子的检测（例如IL-1β/DNA复合物检测）在内的新兴技术，在区分无菌性炎症和感染性炎症方面显示出有希望的结果。尽管诊断取得了进展，并且考虑到UI现在是欧洲地区FUO的主要原因，但仍迫切需要加深我们对潜在疾病机制的理解，并开发基于病理生理学的新型诊断工具。
