Neuroinflammatory and immune responses in infants with enterovirus and parechovirus meningitis, and their association with CSF pleocytosis

ObjectivesEnterovirus (EV) and parechovirus (PeV) meningitis are significant causes of illness in febrile infants. The clinical significance of detecting EV/PeV in the CSF, particularly in the absence of pleocytosis and neurological symptoms, remains uncertain in this age group. We aimed to characterise the relationship between clinical features, systemic neuroinflammatory and immune responses, and CSF pleocytosis in infants with EV/PeV meningitis. MethodsProspective multicentre observational cohort study of febrile infants <90 days old undergoing CSF testing for infection. Infants were recruited as part of the Febrile Infant Diagnostic Assessment and Outcome (FIDO) Study from 35 Paediatric Emergency Research in the UK and Ireland (PERUKI) sites from 6th July 2022 to 31st August 2023 (NCT05259683). Plasma proteomic profiling of 724 inflammation and neurology-related proteins was performed using Olink technology and compared with clinical and laboratory data. Results603 febrile infants were included, with 21/603 (3{middle dot}5%) PeV, and 173/197 (28.7%) EV meningitis cases. Lymphopenia was significantly more common in infants without pleocytosis, 62/101 (63.9%), than those with pleocytosis 7/54 (16.7%). No significant differences in clinical symptoms or timing of presentation were observed with differing CSF WBC counts. Proteomic analysis (n=131) revealed that infants without pleocytosis exhibited elevated inflammatory cytokine responses and enrichment of pathways related to apoptosis and CNS involvement. In contrast, those with pleocytosis showed muted cytokine responses. ConclusionsThe absence of CSF pleocytosis in EV and PeV meningitis may result from systemic lymphocyte depletion, potentially mediated by cytokine-driven apoptosis. Our findings do not support the hypothesis that the lack of pleocytosis is primarily attributable to early presentation or to incidental detection of viral RNA due to viremia in infants.