Differential Cytokine Signature Profiles in Neonates, Infants, and Children with Enterovirus Meningitis

Hélène Chabrolles; Léa Gaume; Bruno Pereira; Jérémy Lafolie; Pascale Gueirard; Anne Sophie L'Honneur; Marie Noelle Adam; Sylvie Nathanson; Stéphanie Marque-Juillet; Fouad Madhi; Matthieu Verdan; Marie Aline Guitteny; Gisele Lagathu; Jean-Luc Bailly; Cécile Henquell; Christine Archimbaud;

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ABSTRACT

Enteroviruses (EVs) are the most frequent cause of pediatric aseptic meningitis, and cause neurological complications, such as encephalitis and flaccid paralysis. Our aim was to characterize the age-specific cytokine and chemokine response profiles in the cerebrospinal fluid (CSF) and blood of neonates, infants, and children with enterovirus meningitis. We performed an ancillary study to the French multicenter BLEDI study. We selected 163 patients with confirmed EV or suspected meningitis. Demographic, clinical, and laboratory data were analyzed. Twenty-seven cytokine/chemokines were simultaneously quantified in the CSF and plasma of the patients, using a bio-plex multiplex immunoassay. Cytokine-chemokine expression increased in the CSF with the age of EV patients compared with controls: CSF IP-10, IL-6, and IL-1ra increased 13-, 11-, 5-fold, respectively, in neonates, 41-, 53-, and 20-fold in infants, and 52-, 168-, and 69-fold in children. In plasma, cytokine/chemokines were overexpressed in neonates and downregulated in children, compared with their respective controls: plasma MCP-1, IP-10, and IL-1ra increased 10-fold in neonates, and decreased threefold in children. The expression of cytokine/chemokines varied with CSF pleocytosis but not with EV types and viral load. These findings show that cytokine and chemokine responses during EV meningitis are strongly age-dependent and should be interpreted according to patient age, with neonates, infants, and children being considered separately. Our results also indicate that age stratification is essential in future studies aiming to evaluate cytokines and chemokines as biomarkers of disease severity in EV-associated neurological infections.IMPORTANCEAlthough enteroviruses (EVs) are the main cause of pediatric viral meningitis, the age-specific immune response to infection remains poorly understood. Our work is novel in combining the study of paired biological compartments (cerebrospinal fluid [CSF] and plasma), age stratification, pleocytosis status, viral load, and EV genotype, which allows a comprehensive assessment of how age shapes both local and systemic immune responses during EV meningitis. This study shows that the immunological response to EV meningitis in CSF and plasma evolves with the age of the patients. The expression of cytokines/chemokines varied with CSF pleocytosis but not with EV types and viral load. Our findings highlight that neonatal EV meningitis is associated with distinct immunopathogenic features that reflect age-dependent immune responses. These results indicate that age stratification is essential in future studies aiming to evaluate cytokines and chemokines as biomarkers of disease severity in EV-associated neurological infections.

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