| Background:Hand,foot and mouth disease(HMFD)is a common infectious disease,caused by human enterovirus,that mainly affects young children.HFMD is a self-limiting illness in most cases.However,a small proportion of HFMD cases could develop severely neurological complication and cardiorespiratory failure.EV-A71 and CV-A16 were previously believed to be the main causative enteroviruses for HFMD.However,an increase of CV-A6 and CV-A10 infections had been found among HFMD cases.Severe complications and deaths associated with other non-EV-A71 and non-CV-A16 enteroviruses have also been reported.In addition,the predominant serotypes of enteroviruses for HFMD vary among different regions and shift between years.Since 1997,HFMD has widely spread across Western Pacific region,particularly in China,causing a serious disease burden.Systematic and comprehensive understanding for spectrum of enterovirus serotypes associated with HFMD is limited,and the disease burden of HFMD has not been thoroughly studied in a well-defined population,particularly in rural area,although these data are valuable in informing healthcare systems,vaccine strategies and other intervention policies.Objectives:To explore the distribution of enterovirus serotypes for HFMD by clinical severity and by region worldwide,through systematic review and meta-analysis;to investigate the spectrum of enterovirus serotypes associated with HFMD,and estimate serotype and age-specific hospitalization burden of HFMD in a well-defined catchment population in a rural area(Anhua County,Hunan Province)of China.Methods:1.We extracted serotype-specific HFMD cases through systematic review until December 31,2018.We explored the spectrum of enterovirus serotypes for HMFD by complications and clinical outcomes,and by region.Random-effects model was used to summarize the pooled proportion of predominant serotypes associated with HFMD and severe HFMD.2.Virological surveillance of HFMD was conducted among three county-level hospitals and three township-level hospitals between October 2013 and September 2016 in Anhua County,Hunan Province.The strategy of multi-sample combination was used to identify the serotype of enterovirus by Real time RT-PCR and/or nested RT-PCR.Descrnptive analysis was conducted to present the characteristics for spectrum of enterovirus serotypes associated with HFMD.3.Information on the eligible patients who were not enrolled in the virological surveillance,were retrospectively collected from the six surveillance hospitals through the Hospital Information System and the paper-based medical charts.In addition,we collected the age-specific number of total hospitalizations,and the records of New Rural Cooperative reimbursement associated with HFMD hospitalization from each of the 23 township-level hospitals.The multiplier model was used to estimate the hospitalization burden of HFMD by serotype and age,in combination with the results of virological surveillance.Results:1.The systematic review included 173,701 cases of serotype-specific HFMD,15,208 cases of severe HFMD,659 cases complicated with cardiorespiratory failure,and 437 deaths,covering 36 countries in 6 continents.A total of 61 enterovirus serotypes were identified in HFMD cases.EV-A71(82,783,48%),CV-A16(45,919,26%),CV-A6(32,013,18%)and CV-A10(5,216,3%)infections were the most commonly detected.Severe HFMD(77%),cases complicated with cardiorespiratory failure(93%),and deaths(96%)were mainly associated with EV-A71 infection.From 2008 through 2016,the proportions of EV-A71,CV-A16,CV-A6,CV-A10 and other enterovirus infections were 34%,21%,22%,3%,and 12%among lab-confirmed HFMD in China mainland,respectively.From 2008 through 2016,the proportion of HFMD associated with EV-A71 infection decreased with time,while the proportion of CV-A6 infection was on the rise in China mainland.After altering cycles of EV-A71 and/or CV-A16 in Asia,CV-A6 gradually became the predominant enterovirus serotype of HFMD.From 2008 through 2015,HFMD was mainly caused by CV-A6 infection in Europe(37%-90%).With the widespread prevalence of CV-A6 infection worldwide,the number of severe HFMD associated with CV-A6 infection increased.2.Between October 2013 and September 2016,2,836 hospitalized patients associated with HFMD were enrolled into the virological surveillance.Enterovirus was detected among 2,517(89%)patients,and 19 serotypes of enteroviruses were identified in 2,513(99.8%)patients.The most commonly detected were CV-A16(819,33%),CV-A6(785,31%),EV-A71(514,20%)and CV-A10(149,6%).HFMD associated with CV-A6 and CV-A10 infection were younger than EV-A71 and CV-A16(p<0.05).Annual peaks of HFMD hospitalization occurred between April and June.The predominant enterovirus serotype shifted among EV-A71,CV-A16 and CV-A6.3.During the three-year virological surveillance,an estimated 3,642 and 3,273 pediatric patients were hospitalized for probable HFMD and lab-confirmed HFMD in Anhua County,respectively.The mean hospitalization rates of probable HFMD and lab-confirmed HFMD were 743 per 100,000 person-years and 660 per 100,000 person years,respectively.Hospitalization rates of HFMD with CV-A16(213/100,000)and CV-A6(209/100,000)infection were higher than EV-A71(134/100,000),CV-A10(39/100,000)and other enteroviruses(66/100,000)(p<0.001).Hospitalization rates of HFMD peaked among children aged 12-23 months(3,594/100,000),and decreased with age.Conclusions:1.HFMD was associated with multiple serotypes of enteroviruses infection,but mainly caused by EV-A71,CV-A16,CV-A6 and CV-A10 infection.After altering cycles of EV-A71 and/or CV-A16 in Asian region,CV-A6 infection gradually became the predominant serotype of HFMD.2.Severe HFMD,cases complicated with cardiorespiratory failure,and deaths were mainly associated with EV-A71 infection.However,with the widespread prevalence of CV-A6 in China and other regions,the number of severe HFMD associated with CV-A6 increased.Therefore,continuous and comprehensive virological surveillance of HFMD is essential to monitor serotype replacement,especially after implementation of the monovalent EV-A71 vaccine.3.Our study indicates a substantial hospitalization burden associated with non-severe HFMD,which mainly caused by CV-A16,CV-A6,EV-A71 and CV-A10 infection,in a rural county in China.Future mitigation policies should take into account the enterovirus serotype sepctrum and disease burden identified,and optimize intervemtions for HFMD. |
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