Central nervous system involvement, sequelae, and prognostic markers in children with severe hand-foot-and-mouth disease: A multicenter cohort study across four Chinese cities

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Approximately 10% of severe hand-foot-mouth disease (HFMD) cases develop post-recovery sequelae such as language and cognitive impairments, posing major social and family burdens. However, large-scale evidence on long-term outcomes is limited. This multicenter cohort study retrospectively analyzed hospitalized HFMD cases between January 1, 2015, and December 31, 2023, in four cities (Zhengzhou, Changchun, Xi'an, and Zhoukou). Among 25,536 medical records, all severe HFMD inpatients were identified, and mild HFMD inpatients from the same period were randomly selected as controls at a 1:1 ratio, resulting in 1,909 patients in each group. Sequelae were assessed through long-term follow-up, and potential prognostic markers were examined using Kaplan-Meier survival analysis and multivariable Cox proportional hazards models. The result showed that severe HFMD was associated with a significantly higher risk of long-term sequelae compared with mild cases, including motor disorders, epilepsy, attention-deficit/hyperactivity disorder, tic disorders, language disorders, developmental delays, psychiatric disorders, intellectual disabilities, and social impairments. Independent predictors of sequelae were peak fever, feeding mode, serum creatinine, serum sodium, and complement C3 levels, which together provided effective prediction of the 6-year cumulative risk. Abnormal magnetic resonance imaging (MRI) and electroencephalography (EEG) findings during the acute phase were strongly correlated with subsequent sequelae. Furthermore, learning disabilities were more common among patients with severe HFMD, further highlighting the potential long-term neurological and neurodevelopmental burden of the disease. Together, these findings underscore the importance of long-term follow-up and further research to improve early identification of children at risk and inform strategies to reduce the long-term effect of HFMD.