Convergent Immunopathology in Influenza-Associated Encephalopathy: CD3+ CD4+ T Cell Depletion, IL-6-Mediated...

Background: Influenza-associated encephalopathy (IAE) is a severe neurological complication, yet immune biomarkers for its early prediction remain limited. This study aimed to elucidate the systemic immune signature defining IAE by integrating humoral and cellular immunity analyses. Methods: We conducted a retrospective cohort study of 623 pediatric influenza patients presenting with fever and convulsions (55 IAE, 568 febrile seizure (FS) group) at Wuhan Children's Hospital (2020-2025). Serum complement components (C3, C4), lymphocyte subsets (including CD3+ CD4+, CD3+ CD8+, CD19+ B cells, and NK cells), and cytokines (IL-2, IL-4, IL-6, IL-10, TNF-α) were quantified. Multivariable logistic regression was performed, rigorously adjusted for age, sex, influenza subtype, time from fever onset to sampling, prior use of intravenous immunoglobulin (IVIG) or glucocorticoids, and pre-diagnostic convulsive episodes. Sensitivity analysis via 5th-percentile Winsorization addressed floor effects in C3 measurements. Results: IAE was associated with distinct alterations in both humoral and cellular immunity. Patients with IAE had significantly lower serum C3 levels and higher IL-6 concentrations compared to controls. Multivariable regression revealed that IL-6 (adjusted OR = 1.002, 95% CI: 1.000-1.003, p = 0.037) and CD3+ CD4+ T cells (adjusted OR = 0.983, 95% CI: 0.979-0.988, p < 0.001) were independent predictors in the fully adjusted model. Lower serum C3 levels were associated with IAE across sequentially adjusted models (fully adjusted OR = 0.05, 95% CI: <0.001-0.138, p = 0.002). Sensitivity analysis using 5th-percentile Winsorization of C3 yielded a consistent direction of association (adjusted OR = 0.019, 95% CI: 0.002-0.226), supporting the robustness of the primary finding. Conclusions: These findings identify a convergent immunopathology involving CD3+ CD4+ T cell depletion, IL-6-dominated inflammation, and lower C3 levels in pediatric IAE. Monitoring this immune triad may facilitate early risk stratification. The causal relationships and therapeutic implications of these observations require validation in prospective and mechanistic studies.