Introduction
Hand, foot and mouth disease (HFMD) is a highly contagious disease in children caused by several human enteroviruses (EV), particularly enterovirus A71 (EV-A71) and coxsackievirus A16 (CVA16) and CVA6 (1-3). Enteroviruses belong to the family Picornaviridae , genus Enterovirus . Their positive single-strand RNA genome is about 7,500 nucleotides, and is composed of a large open reading frame (ORF) flanked by 5’ and 3’ untranslated regions (UTRs). The 5’ part of the ORF encodes the structural proteins that form the capsid, while the 3’ part of the ORF encodes the non-structural proteins (4). HFMD primarily affects children younger than 5 but can infect teenagers and adults (1, 2). Clinical manifestations of HFMD include mild to severe rash, herpangina, pulmonary edema, circulatory disturbances, meningitis, aseptic encephalitis, and even death (5, 6). Since 2012, outbreaks associated with Coxsackievirus A6 (CVA6) have been frequently reported in Europe, Japan and some developed regions of China (7-11). From then on, CVA6 has been gradually predominant in most areas of China since 2013 (9, 12). Our former study found D3 sub-genotype CVA6 (D3-CVA6) increasingly predominated in local HFMD cases, and EV-A71 was no longer detected from HFMD surveillance after 2-year EV-A71 vaccine promotion and implementation(12).
In early 2020, non-pharmaceutical interventions (NPIs) were implemented in China to reduce and contain the coronavirus disease 2019 (COVID-19) transmission. A national-scale investigation found that these NPIs have substantially reduced the incidence of HFMD in the first wave of COVID-19 (13). Since the first outbreak in most cities of China, NPIs, vaccines and dynamic Zero-Covid policy were implemented to combat SARS-CoV-2 around mainland China till the end of 2022 (14). However, the impact of these measures on epidemiological and etiologic characteristics of HFMD has not been well studied. In this study, we retrospectively analyzed the epidemiological and etiological characteristics of HFMD in the southeastern capital city of Nanchang before and during the COVID-19 pandemic. And for the first time, the virus-virus interactions among the major serotypes CVA6, CVA16, EV-A71 were systematically analyzed in Nanchang, China. Our analyses provide strong statistical support for the existence of interactions among enteroviruses. Furthermore, we clarified the serotypes of other un-serotyped EVs using a reverse transcription-nested PCR targeting 5’UTR, facilitating to see the whole picture of the dynamics of pathogen spectrum. These findings will help improve disease forecasting and evaluation of HFMD control interventions in the future.