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.