Background: Overt immune activation by viral infections can lead to cytokine storm syndromes, such as hemophagocytic lymphohistiocytosis (HLH) and macrophage activation syndrome (MAS).
Objective: We aim to compare the immune response to different viral pathogens to understand the connection between infections and cytokine storm syndromes.
Methods: We 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).
Results: We 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.
Conclusion: This work broadens our understanding of common viral infections in children and provides an immunologic basis for the link between EBV infection and HLH / MAS.
Keywords: Epstein-Barr virus; cytokine storm; hemophagocytic lymphohistiocytosis; macrophage activation syndrome; mononucleosis.
Copyright © 2024. Published by Elsevier Inc.