Immune Biomarker Signature in the Diagnostic Workup of Fever Without Source: A Pilot Study

Fevers without an identified source (FWS) are frequent in all-aged patients, even in children, with subjects being often labeled as affected with ‘fever of unknown origin’ if fever lasts for more than one week.1 This definition was formally created by Petersdorf and Beeson in the early ‘60s through the evaluation of a case series of subjects displaying unexplained rise of temperature over 38.3°C on several occasions for more than 3 weeks.2 It is well-known that FWS might include infectious, non-infectious inflammatory, tumoral diseases, but also further complex types of disorders in which fever is a predominant feature.3 Furthermore, among undiagnosed cases of FWS, the mortality rate may be relevant, varying from 6.9 to 18.6% in some reported series.4 In particular, investigating children with FWS may be may be frustrating because of multiple protean causes of fever, and autoinflammatory disorders.5 Infectious diseases are still a substantial etiology of FWS, while non-infectious conditions may elude many common diagnostic approaches, requiring imaging studies and more specific immunological or genetic tests.6