Virus-virus interactions of enteroviruses and impact of the coronavirus disease 2019 interventions on the incidence of hand, foot and mouth disease in Nanchang, China

Pathogen spectrum of Hand, foot and mouth disease (HFMD) has substantially changed in the past decade. How do the co-circulating pathogens interact and the coronavirus disease 2019 (COVID-19) intervene the incidence of HFMD remain unclear. Here, we evaluated the virus-virus interaction (VVI) of EVs using Spearman’s Correlation in Nanchang, China. And the impact of COVID-19 intervention on HFMD incidence was estimated using seasonal autoregressive integrated moving average (ARIMA) models. Enterovirus (EV) serotypes were determined by RT-PCR. From 2019 to 2022, 1321 (57.5%) out of 2296 HFMD cases were EV-positive, in which coxsackievirus A6 (CVA6) and CVA16 were the major pathogens, accounting for 34.0%-59.6% and 14.9%-31.4%, respectively. Our analyses provide strong statistical support for the existence of VVIs among enteroviruses, in which CVA6 negatively interacted with CVA16 and EV-A71, and positive VVI between CVA16 and EV-A71 was observed. While CVA6 has a (albeit inconsistent) seasonal pattern in Nanchang, typically peaking in fall-winter months before COVID-19 epidemic, CVA16 and EV-A71 contemporaneously peaks around May, supporting the epidemiological VVIs among these strains. During the COVID-19 epidemic, the seasonal HFMD epidemic peak was restrained, indicating the COVID-19 intervention had mitigated EV transmission. Moreover, we first figured out the serotypes from other enteroviruses, among them CVA4, CVA2, CVA5 and CVB3 were the major agents accounting for 34.8%, 23.9%, 23.9% and 10.9%, respectively. Taken together, CVA6 and CVA16 were currently the most predominant pathogens negatively interacted with each other in Nanchang, while NPIs of COVID-19 outbreaks interfered the interactions by mitigating their incidence and transmission.