Epidemiology Of Severe Cases Of Hand,foot And Mouth Disease From 2013 To 2015 And Genetic Characteristics Of CV-A2 In China

Background:An outbreak of hand,foot and mouth disease(HFMD)took place in Fuyang,Anhui Province,which also led to 22 fatal cases up to May 9,2008.Since then,HFMD was incorporated in the class C infectious diseases.It is reported that the number of cases and deaths caused by HFMD ranked in the first place among the infectious diseases of class C from 2009 to 2015.Infection caused by non-enterovirus A71(EV-A71)and non-coxsackievirus A16(CV-A16)was known as the other enterovirus(other EV).In recent years,other EV has become increasingly common in the provincial HFMD surveillance,which has been gradually being attentioned.Purpose:This study aimed to elucidate the epidemiological characteristics and pathogen composition of severe HFMD,to provide scientific data for the development of severe HFMD prevention and control policy and to provide basic data for the policy of EV-A71 vaccine to prevent severe HFMD.At the same time,being one of the pathogens of HFMD,the molecuLar epidemiology and genetic evolution of CV-A2 was analyzed in this study in order to provide virological basis for control and prevention of the diseases caused by CV-A2.Materials and methods:According to the infectious disease reporting system from 2013 to 2015,the epidemiological characteristics and pathogen composition of severe HFMD in the seven regions were aunnally and geographically analyzed.In addition,we filtered the HFMD three-level laboratory network data and chose the representative strains of CV-A2,then identified the serotypes by gene sequencing of the target gene of VP1 coding region.Homology analysis was performed by using BioEdit,and the phylogenetic tree was constructed by MEGA software.Results:1.44754 severe HFMD cases were reported in mainland China from 2013 to 2015.The severe HFMD mainly consisted of 0-3-year-old children(91.35%)and the children in the 1～age group(40.70%)had the highest incidence.The incidence of severe HFMD was 1.72 times higher in boys than in girls.Incidence was highest in children that lived scatterly(87.02%).The epidemic intensity and the peak of onset were diverse in 7 regions,the results revealed that the epidemic intensity of South China,East China,Southwest and Central China remained high in three years and the peak of onset was in March.However,the epidemic intensity of North China,northwest was medium,and the peak of onset started in April.The epidemic intensity of Northeast wasthe lowest,and its peak time started in May.2.The pathogenic agents of 21425 cases were confirmed by laboratory from 44754 severe cases.And EV-A71 predominated in laboratory-confirmed cases,accounting for 70.94～51.45%during 2013～2015.However,we found that other EV has replaced EVy～A71/CV-A16 and became the most detected pathogen in several months of some regions.Other EV accounted for 63.37%and 51.52%in Northeast and South China,respectively in 2013 and Northeast(65.96%),South China(54.60%),North China(59.74%),northwest(50.69%)in 2015.Other EV had surpassed EV-A71 as the main pathogenic agent of severe HFMD locally.3.The VP1 sequences of 54 CV-A2 representative strains obtained from this study which isolated from 2011 to 2015 were analyzed by homology analysis with 51 Chinese CV-A2 VP1 coding region sequences from 2008 to 2015 downloaded in GenBank.Homologous analysis was performed based on 105 Chinese CV-A2 sequences.The nucleotide homology of 105 Chinese strains was 79.6～100%.The nucleotide homology of sequences from different years was analyzed respectively,which indicated that the nucleotide homology of the sequences from 2008 to 2009 and nucleotide homology of the sequences from 2011 to 2015 was 87.5%to 88.4%.And between 2011 and 2015,it was 94.4 to 97.0%.4.The phylogenetic tree was constructed based on the full-length VP1 coding region of CV-A2.CV-A2 strains isolated from China belonged to genotype B and D,agreeing with the previous study.The homology of the VP 1 coding region of the 54 strains sequenced in this study was 91.7～100%,which all belonged to genotype D.And the average evolutionary divergence over sequence pairs among 4 genotypes was greater than 0.171.In this study,genotype D was further divided into 2 lineages,1 and 2.And the evolutionary distance between the 2 lineages was 0.06.Lineage 1 was composed of the strains collected from 9 provinces or municipalitis and isolated mainly between 2008 and 2012 and a few strains were isolated from 2013.Lineage 2 consisted of the strains collected from 15 provinces or municipalitis,most of the strains were isolated in 2013～2015.Conclusions:1.Severe HFMD mainly infected 0～3-year-old children.The incidence of males was higher than females,and mainly happened to the children that lived scatterly during 2013～2015.EV-A71 still was the predominat pathogen in mainland China.However,with the proportion of cases infected by EV-A71 falling,infection proportion caused by other EV increased.2.The intensity and time of onset in different regions were analyzed by dividing the Chinese mainland into seven regions.The epidemic intensity of Central China,East China,Southwest,and South China were high,and the onset peak began early.The epidemic intensity in the Northeastern region was the smallest and the peak of onset started late in 2013～2015.3.EV-A71 was most detected pathogenic agent in 7 regions.But in the Northeast,South China,North China,Northwest regions,severe HFMD caused by other EV can be mainly detected in 2013 or 2015 or both 2 years,which suggested that the four regions should be concerned by the infection of other EV.4.Through the genetic homology and evolution analysis of CV-A2 VP1 coding region in mainland China,it was found that the CV-A2 strains collected from mainland China belonged to genotype B and D,and D genotype was the predominant genotype,and there were B genotype co-circulation in 2008～2009.During the 8-year circulation cycle,the virus has evolved and we should be concerned about the disease caused by CV-A2.