Features of hyperinflammation link the biology of Epstein-Barr virus infection and cytokine storm syndromes.

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 aimed to compare the immune response to different viral pathogens to understand the connection between infections and cytokine storm syndromes.

Methods: We recruited children who sought care at the emergency department 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 of confirmed common viral infections. We found that Epstein-Barr virus (EBV) uniquely triggered high levels of multiple cytokines (IL-18, IL-27, TNF, 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 are 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.