BackgroundOvert immune activation by viral infections can lead to cytokine storm syndromes, such as hemophagocytic lymphohistiocytosis (HLH) and macrophage activation syndrome (MAS). ObjectiveWe aim to compare the immune response to different viral pathogens to understand the connection between infections and cytokine storm syndromes. MethodsWe recruited children who presented to the emergency room with fever for ≥ 3 days. We performed immune profiling using Olink proximity extension assay and flow cytometry. We compared the findings with cases of HLH, MAS, Kawasaki disease (KD), and multisystem inflammatory syndrome in children (MIS-C). ResultsWe enrolled 352 febrile patients and studied 110 cases with confirmed common viral infections. We found that Epstein-Barr virus (EBV) uniquely triggered high levels of multiple cytokines (IL-18, IL-27, tumor necrosis factor, FLT3 ligand, and lymphotoxin alpha) and IFN-γ-induced chemokines (CXCL9/10/11 and CCL19). These patterns are similar to the hyperinflammatory response associated with HLH / MAS, but less consistent with the findings in KD and MIS-C. Flow cytometry analysis revealed that CD38+HLA-DR+ T lymphocytes, which are pathogenic cells responsible for IFN-γ production in HLH / MAS, are vastly expanded in patients with acute EBV infection. Cell sorting identified CD38+HLA-DR+ T cells as atypical lymphocytes that are classically associated with acute EBV infection. ConclusionThis work broadens our understanding of common viral infections in children and provides an immunologic basis for the link between EBV infection and HLH / MAS.
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