Profiling of circulating immune factors and host-derived extracellular vesicles in response to bacterial or malaria acute fever

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The misdiagnosis of acute febrile illness (AFI) aetiology is associated with antibiotic overuse and improper patient management. To develop novel strategies, a more comprehensive understanding of the pathophysiological mechanisms underlying the early response to different causes of fever is essential. Here we examined the host response to AFI, through the retrospective investigation of serum samples from febrile patients with bacterial infection ( n = 52) or malaria ( n = 73). The systemic levels of CXCL10, IFNγ, IL-2, IL-4, IL-6, IL-8, procalcitonin (PCT), TRAIL, ICAM-1, VCAM-1, osteopontin, TNFα, MMP-2 and MMP-9 were measured by multiplex immunoassays, while the relative abundance of 37 different surface markers of circulating extracellular vesicles (EVs) was determined using the MACSplex kit (Miltenyi Biotec). Markers of endothelial activation (CD29 + , CD62P + , CD9 + EVs) and immune cell migration (MMP-2 and MMP-9) appeared elevated in bacterial AFI (q-value < 0.05). Mediators associated with antigen recognition (CD8 + , CD81 + , HLA-DR/DP/DQ + EVs) and cytokine storm (IFNγ, CXCL10, TNFα) were instead prominent in malaria infection (q-value < 0.005). Interestingly, HLA-DR/DP/DQ + EVs distinguished between bacterial and malaria AFI with area under the ROC curve (AUC) of 0.87, not significantly different from platelets’ AUC (0.92), which was the best individual discriminator. Our results showed different biological processes as associated with bacterial and malaria AFI, paving the way for the identification of novel potential markers for a timely and reliable AFI diagnosis. The study also provides novel insights on the potential role of EVs as mediators of pro-inflammatory signalling during acute fever, which should be investigated more comprehensively in vitro.

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