Host-derived immune signatures as biomarkers to differentiate arboviral acute febrile illness from other causes of acute fever

Introduction Arbovirus infections are emerging or re-emerging global health threats due to their raised incidence and geographical spread in endemic regions, as well as the increased risk of local transmission in non-endemic areas. When symptomatic, arboviral infections usually manifest as acute febrile illnesses (AFI) accompanied by mild, often non-specific symptoms. This non-specific clinical presentation contributes to their misdiagnosis, leading to adverse effects at both the patient and public health levels. Leveraging the potential of host biomarkers as fever triage tools, we assessed their utility for the early identification of arbovirus-associated AFI. Methods We retrospectively compared the serum concentrations of 16 immune mediators and 4 haematological parameters (haemoglobin—Hgb, and leukocyte, erythrocyte and platelet counts) in a population of febrile or symptomatic patients with arboviral infections (Arbo-AFI, n  = 89) or with fever caused by other infectious conditions, including respiratory viral infections (Other-AFI, n  = 51). Results Arbo-AFI was accompanied by increased mediators of the anti-viral response (IFNα, CXCL10, TRAIL and CCL2) and decreased acute phase reactants (CRP, PCT and PTX3) and acute innate cytokines (IL-6 and IL-8) when compared to other causes of AFI. Importantly, some of the best performing markers—including CXCL10, TRAIL, CRP and PCT—showed distinct profiles in Arbo-AFI versus AFI due to respiratory viruses. CRP was the best individual marker (Area Under the ROC Curve—AUC = 0.822), and its diagnostic potential was significantly improved when combined with PCT, CXCL10, IL-6 or Hgb, reaching an AUC > 0.90. Discussion We identified novel host-derived immune signatures capable of discriminating acute fever caused by arboviral infections from other infectious aetiologies. Our findings pave the way for prospective validation studies to establish the clinical utility of these markers as triage tools for arboviral fevers.