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1、Copyright 2016 Wolters Kluwer Health,Inc.Unauthorized reproduction of this article is prohibited.The Pediatric Infectious Disease Journal Volume35,Number10,October2016 |e285Original StudieSContext:Hand,foot and mouth disease(HFMD)is a widespread pediatric disease caused primarily by human enteroviru
2、s 71(EV-A71)and Coxsacki-evirus A16(CV-A16).Objective:This study reports a systematic review of the epidemiology of HFMD in Asia.Data Sources:PubMed,Web of Science and Google Scholar were searched up to December 2014.Study Selection:Two reviewers independently assessed studies for epi-demiologic and
3、 serologic information about prevalence and incidence of HFMD against predetermined inclusion/exclusion criteria.Data Extraction:Two reviewers extracted answers for 8 specific research questions on HFMD epidemiology.The results are checked by 3 others.Results:HFMD is found to be seasonal in temperat
4、e Asia with a summer peak and in subtropical Asia with spring and fall peaks,but not in tropi-cal Asia;evidence of a climatic role was identified for temperate Japan.Risk factors for HFMD include hygiene,age,gender and social contacts,but most studies were underpowered to adjust rigorously for confo
5、unding variables.Both community-level and school-level transmission have been implicated,but their relative importance for HFMD is inconclusive.Epi-demiologic indices are poorly understood:No supporting quantitative evi-dence was found for the incubation period of EV-A71;the symptomatic rate of EV-A
6、71/Coxsackievirus A16 infection was from 10%to 71%in 4 stud-ies;while the basic reproduction number was between 1.1 and 5.5 in 3 stud-ies.The uncertainty in these estimates inhibits their use for further analysis.Limitations:Diversity of study designs complicates attempts to identify features of HFM
7、D epidemiology.Conclusions:Knowledge on HFMD remains insufficient to guide interven-tions such as the incorporation of an EV-A71 vaccine in pediatric vaccina-tion schedules.Research is urgently needed to fill these gaps.Key Words:hand,foot and mouth disease,EV-A71,CV-A16,epidemiology(Pediatr Infect
8、Dis J 2016;35:e285e300)Hand,foot and mouth disease(HFMD)has become an endemic childhood disease in East and Southeast Asia.Its main etio-logic agents are human enterovirus 71(EV-A71)and Coxsackievi-rus 16(CV-A16).Although usually mildwith symptoms limited to 38C fever,malaise,rashes on the volar reg
9、ions of the hands and feet,herpangina and difficulty eating and drinkingmore rarely,infection can lead to complications of the nervous or car-diopulmonary systems.Such cases can result in long-term sequelae such as cognitive and motor disorders1,2 or death,usually from pul-monary edema or brainstem
10、encephalitis.3 Although complications are rare,the number of children being infected in high-incidence countries such as China(2.7 M cases in 20143)means the death toll can be substantial(384 deaths in China in 20143).The EV-A71 virus seems to be responsible for more severe outcomes,while CV-A16 and
11、 other Coxsackieviruses,such as CV-A2,CV-A6 and CV-A10,usually present milder symptoms that resolve within a few weeks.46There are nearly 25 years of literature from Asia that describes the epidemiology of HFMD,drawing on pediatric cohorts,national surveillance systems,outbreak investigations and cl
12、inical data,and from disparate countries that span stages of eco-nomic development and with climates that range from tropical to temperate.This diversity complicates attempts to identify general features of HFMD epidemiology and conceals gaps in the body of knowledge of this important pediatric dise
13、ase.The objective of this paper is to provide a robust systematic review of the epidemiology of HFMD that informs public health policy making about HFMD epidemics.The review covers 3 major areas:(1)history and seasonality of HFMD,and the efforts in pre-dictive modeling;(2)risk factors for infection,
14、to guide control and(3)global epidemiologic parameters,such as the incubation period and basic reproduction number,which may determine the effective-ness of control policies.METHODSSearch Strategy and Selection CriteriaUsing a combination of search terms,including“Hand foot and mouth disease,”“Hand
15、foot and mouth,”“HFMD,”“Entero-virus,”“Enterovirus 71,”“EV-A71,”“Coxsackie A16,”“CV-A16,”“CVA16,”we searched PubMed,Thomson Reuters Web of Science and Google Scholar to identify 1305,1255 and 100 articles,respec-tively.Eligibility criteria were articles that:(1)were published in peer-reviewed journa
16、ls from January 1957 to December 2014;(2)were studies with epidemiologic and/or serologic informa-tion(quantitative/qualitative)about incidence and prevalence of Copyright 2016 Wolters Kluwer Health,Inc.All rights reserved.This is an open-access article distributed under the terms of the Creative Co
17、mmons Attribution-Non Commercial-No Derivatives License 4.0(CCBY-NC-ND),where it is permissible to download and share the work provided it is prop-erly cited.The work cannot be changed in any way or used commercially.ISSN:0891-3668/16/3510-e285DOI:10.1097/INF.0000000000001242TheEpidemiologyofHand,Fo
18、otandMouthDiseaseinAsiaA Systematic Review and AnalysisWee Ming Koh,MSc,*Tiffany Bogich,PhD,Karen Siegel,MPH,*Jing Jin,MSc,*Elizabeth Y.Chong,PhD,Chong Yew Tan,BSc,Mark IC Chen,MBBS,PhD,*Peter Horby,MBBS,PhD,and Alex R.Cook,PhD*Accepted for publication March 22,2016.From the*Saw Swee Hock School of
19、Public Health,National University of Singapore and National University Health System,Singapore;Standard Analytics,New York,New York;Rollins School of Public Health,Emory University,Atlanta,Georgia;Duke-NUS Graduate Medical School,Singa-pore;Communicable Disease Centre,Tan Tock Seng Hospital,Singapor
20、e;Nuffield Department of Medicine,University of Oxford,United Kingdom;and*Yale-NUS College,National University of Singapore,Singapore.Supported by Singapores Ministry of Health Services Research(HSRG-12MAY023),Communicable Disease Public Health Research(CDPHRG12NOV021),the Centre for Infectious Dise
21、ase Epidemiology and Research,the Ministry of Education Tier 1 grant and the Presidents Gradu-ate Fellowship to W.M.K.The funders had no role in the decision to publish.T.B.is employed by commercial company,Standard Analytics.The remain-ing authors have no financial relationships relevant to this ar
22、ticle to disclose.The authors have no conflicts of interest to disclose.Address for correspondence:Alex R.Cook,PhD,Saw Swee Hock School of Public Health,Tahir Foundation Building,12 Science Drive 2,National University of Singapore,Singapore 117549.E-mail:.Copyright 2016 Wolters Kluwer Health,Inc.Una
23、uthorized reproduction of this article is prohibited.Koh et al The Pediatric Infectious Disease Journal Volume35,Number10,October2016e286| 2016 Wolters Kluwer Health,Inc.All rights reserved.HFMD;and/or(3)contained information about factors associ-ated with prevalence and incidence and/or(4)employed
24、statistical models to derive the above.Articles not in English,not related to HFMD,or HFMD articles that did not cover epidemiologic or clini-cal factors were excluded.Two independent readers examined each of the 407 abstracts to determine if specific research questions were answered.The 8 specific
25、research questions were as follows:(1)What time of the year do HFMD outbreaks occur,and with what seasonal factors are outbreaks associated?(2)How long have EV-A71 and CV-A16 been circulating in Asia?(3)What age groups are at higher risk of infection?(4)What risk factors are associated with infectio
26、n and severe outcomes?(5)Where do infections predominantly occur(home or school)?(6)What is the incubation period?(7)What pro-portion of infections are symptomatic?and(8)What is the basic reproduction number for HFMD by virus?An article was retained as long as both readers indicated that it answered
27、 at least 1 specific research question and was discarded if both readers agreed that no questions were answered.A third independent reader arbitrated when there was a disparity between the original readers.The 2 original readers each read the full text of half of the arti-cles to identify answers to
28、 the questions.A second pair of independ-ent readers read the articles again.Finally,the first author compiled all answers to the specific questions and compared the extracted answers to the original text.Relevant references from these papers were included in the analysis,in particular to identify n
29、on-English and early references.In total,information from 242 papers was compiled and 108 papers were used in data synthesis.Hourly weather data were downloaded from the Weather Underground and aggregated at a weekly scale.Incidence data from Tokyo,Hong Kong,Taiwan and Singapore were extracted from
30、routine surveillance data published by government agencies(the National Institute of Infectious Diseases,Japan7;the Depart-ment of Health,Hong Kong8;the Taiwan National Infectious Dis-ease Statistics System9 and the Ministry of Health,Singapore).Nontabular data were extracted from figures using Plot
31、 Digi-tizer.10 Data on weather and incidence were analyzed using a time series model.Symptomatic proportions were pooled by aggregat-ing denominators and numerators.Other analyses used standard statistical methods and were conducted using R.11RESULTSTiming and Seasonality of HFMD OutbreaksOutbreaks
32、of HFMD do not occur uniformly throughout the year across Asia.In Fukuoka,Japan,for example,weekly numbers of HFMD cases have been found to increase with average tem-perature and humidity,especially among younger children.12 By digitizing the incidence data from publications on Japan5,1214 and North
33、 China1520(Fig.1),we observe that May through July are the months with highest incidence in temperate regions of Asia.How-ever,this relationship is less clear for tropical and subtropical Asia.The extracted data on Southwest China,15,21 South China,2,15,22,23 Hong Kong24,25 and Taiwan2628 show that
34、outbreaks typically hap-pen in late spring and fall.No distinct pattern is obvious for tropical regions as seen from data in Thailand,2931 Vietnam,32,33 Malaysia34 and Singapore,3538 where outbreaks occur sporadically through-out the year,although models have been developed for Singapore (1 north)th
35、at show a positive statistical relationship between maximum daily temperature above 32C with HFMD incidence in the subsequent 12 weeks.37To assess how general the relationship between climate and transmissibility of HFMD was,we took incidence data from Tokyo,Hong Kong,Taiwan and Singapore(Fig.2,Appe
36、ndix 1),that is,spanning temperate,subtropical and tropical latitudes,and fitted time series models to them.After controlling for contagion via autoregression terms,the effect of meteorologic factors was weak:a small positive increase in transmissibility with rising abso-lute humidity/temperature du
37、ring the current week in Tokyo and Singapore.There was no evidence for temperature and humidity in having the same effect in Hong Kong or Taiwan,although rising relative humidity seems to decrease transmissibility in Singapore.The earliest recorded cases of HFMD in Asia are from Japan(1967),30 Singa
38、pore(1970),31 Taiwan(1980)32 and Shanghai,China(1981).33 Since then,outbreaks have been reported in many parts of Asia,including mainland China,1214,3352 Korea,5355 Japan,5670 Taiwan,6,69,7174 Hong Kong,17,18,75 India,7681 Thailand,21,23,82 Viet-nam,24 Malaysia,26,69,8387 Singapore4,88 and Brunei,89
39、 as summa-rized in Figure 3.These reported outbreaks are unlikely to reflect the true first outbreaks of HFMD,as serologic studies provide evidence that by the time surveillance systems were established,EV-A71 and CV-A16 were already endemic in many of these coun-tries.Early serologic tests conducte
40、d in Japan in 1970 show evi-dence of EV-A71 and CV-A16 circulation.90 Serum taken in the late 1990s in Singapore,before the start of surveillance in 2000,shows that around 50%children and 44%cord blood,indicating maternal infection,had already seroconverted to EV-A71.91 Blood samples from Taiwan(198
41、91997)show 3%11%EV-A71 inci-dence per year,and up to 68%of children92 had serologic evidence of EV-A71 infection before the large HFMD outbreak of 1997.Similarly,although China has reported millions of HFMD cases since the beginning of the HFMD surveillance program in 2008,evidence from Anhui47 show
42、s high seroprevalence of up to 74.6%in older children before the 2008 outbreaks.Retrospective seroepi-demiologic tests from blood serum collected in 200593 also show that China had positive rates of 32.0%to EV-A71 and 43.4%to CV-A16,indicating that outbreaks happened earlier but were sim-ply not rep
43、orted in the literature.Risk FactorsRisk factors for infection are depicted in Figure 4(Appen-dix 2)and summarized below.HygieneEvidence from Qiaosi,China,94 indicates the importance of hygiene for protection against HFMD infection.Children who always wash their hands before meals are about 50 times
44、 less likely to contract HFMD,while those whose caregivers wash their hands before feeding are about 25 times less likely.Additional protective habits include washing of hands after play,washing of hands more than 4 times per day,using soap,and not sucking fingers.A study in Korea95 revealed that dr
45、inking unboiled water odds ratio(OR):3.34(1.596.99),a change in water quality such as color,taste,smell,presence of precipitation or floating materials OR:6.93(2.1722.15),using communal toilets/toilets outside the house OR:2.77(1.146.74)and eating outside the home OR:37.0(5.1269.5)were risk factors
46、for HFMD.Rural Versus Urban AreasAll papers51,9698 that compared urban with rural areas agreed that the latter conferred a higher risk for HFMD.However,this might be confounded by socioeconomic status and hygiene prac-tices.SexAlthough most papers show that being male is a risk factor for both mild4
47、,14,16,23,27,34,37,51,82,98101 and severe52,97,102,103 HFMD(OR ranges between 1.2 and 2),surprisingly,serologic evidence does not support this finding:A study from Singapore104 shows marginal Copyright 2016 Wolters Kluwer Health,Inc.Unauthorized reproduction of this article is prohibited.The Pediatr
48、ic Infectious Disease Journal Volume35,Number10,October2016 Epidemiology of HFMD in Asia 2016 Wolters Kluwer Health,Inc.All rights |e287FIGURE 1.TemporalpatternsofHFMDoutbreaksinAsia,bylatitude.Left:PlotDigitizerisusedtoconvertchartsintonumbers.WhiteboxesarethemonthswhereHFMDcasesfallbelowtheyearsme
49、dian.Theremainingcellsarethenshadedinto4darkershadesbyoctiles.TheregionsofChinawerebasedonWangetalsclassification101(Cstandingforcentral).Theregionsarearrangedbylatitude.SouthChina,HongKongandTaiwanhavesubtropicalclimates.Areasfurthernortharetemperate,whiletheSoutheastAsianregionsaretropical.Right:T
50、hecoefficientofvariationistheratioofthestandarddeviationtoitsmean,andtheproportionofcasesintop3monthsistheproportionofcasesofthe3monthswithhighestincidencetotheannualincidence.Pointsrepresent1yearperregion.Thelinesareobtainedfromordinaryleastsquaresregressionwithlatitudeastheindependentvariableandsh