A Guide to Clinical Management and Public Health Response for Hand, Foot and Mouth Disease (HFMD) doc

A Guide to Clinical Management
and Public Health Response
for Hand, Foot and Mouth
Disease (HFMD)
WHO Western Pacific Region
PUBLICATION
ISBN-13 978 92 9061 525 5

A Guide to Clinical Management
and Public Health Response
for Hand, Foot and Mouth
Disease (HFMD)
[ ii ]
A Guide to Clinical Management and Public Health Response
for Hand, Foot and Mouth Disease (HFMD)
WHO Library Cataloguing in Publication Data
A Guide to clinical management and public health response for hand, foot and mouth disease (HFMD)
 1.Hand,footandmouthdisease–epidemiology.2.Hand,footandmouthdisease–preventionandcontrol.
3.Diseaseoutbreaks.4.EnterovirusA,Human.I.RegionalEmergingDiseaseInterventionCenter.
ISBN9789290615255(NLMClassification:WC500)
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A Guide to Clinical Management and Public Health Response
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Contents
Acknowledgements v
Acronyms vi
Introduction 1
Developingtheguide 1
Section1:Epidemiology 3
1.1Overview 3
1.2Descriptiveepidemiology 4
1.3Seroepidemiologicalstudy 10
Section2:Virology 15
2.1Overview 15
2.2Virusreceptor 18
2.3Recombination 18
2.4ReservoirofEV71 18
Section3:LaboratoryDiagnosis 21
3.1Overview 21
3.2Laboratorysafety 21
3.3Clinicalsamples 21
3.4Laboratorydiagnosismethods 22

Section4:PathogenesisinEV71Infection 28
4.1Overview 28
4.2Virusneuro-virulencefactors 28
4.3Hostfactors 29
4.4Pathologicalfindings 30
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Section5:ClinicalFeaturesandCaseManagement 35
5.1Casedefinitions 35
5.2Differentialdiagnosis 39
5.3Clinicalassessmentandmanagement 39
Section6:PreventionandControlMeasures 46
6.1Overview 46
6.2PreventionMeasures:RecommendationsandRationale 47
6.3FutureConsiderations 51
Appendix1:SummaryofepidemiologicfindingsofHFMDfrom
surveillancedatainWesternPacificRegion(since1997) 54
Appendix2:Benefitsandlimitations
ofspecificpreventionandcontrolmeasures 62
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Acknowledgements
T
his document was jointly developed by the World Health Organization
Regional Office for the Western Pacific and the Regional Emerging Diseases
Intervention(REDI)Centre.
Its development was coordinated by Dr Satoko Otsu, (WHO Regional Office for the
Western Pacific) and Dr Zarifah Hussain Reed (REDI Centre) with support from

Dr Chin KeiLee(WHOChina),Dr Le VanTuan(WHOVietNam),DrHarpal Singh
(WHOMalaysia),andDrWeigongZhou(CentersforDiseaseControlandPrevention,
UnitedStatesofAmerica).
The following individuals contributed to chapters as lead writers, advisers or peer
reviewers:
Dr Jane Cardosa, Dr Jeremy Farrar, Dr Feng Zijian,  Dr Wakaba Fukushima,
Dr Gao Zifen, Dr Truong Huu Khanh, Ms Keiko Kumatani, Dr Raymond Lin
Tzer Pin, Dr Tzou-Yien Lin, Dr Ching-Chuan Liu, Dr Peter Charles McMinn,
Dr Lam Yen Minh, Dr Revathy Nallusamy, Dr Nguyen Thi Hien Thanh,
Dr Ooi  Mong How, Dr Hiroyuki Shimizu, Dr Tom Solomon, Ms Maria Takechi,
DrPhanVanTu,DrWongKumThong,DrDustinChen-FuYang.
ThanksarealsoduetoDrRuthFoxwellforprovidingtechnicalandeditorialoversight,
andMsRhiannonCookforprovidingeditorialadviceandcontributingtothefinalization
ofthepublication.
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Acronyms
ANS  Autonomicnervoussystem
BSL  Biosafetylevel
CA  CoxsackievirusA
CNS  Centralnervoussystem
CODEHOP Consensusdegeneratehybridoligonucleotideprimer
CPE  Cytopathiceffect
CSF  Cerebrospinalfluid
CT  Computedtomography
cAMP  cyclicadenosinemonophosphate
ECMO Extra-corporealmembraneoxygenation
EV  Enterovirus
HA  Herpangina

HEV  Humanenterovirus
H&E  Haematoxylinandeosinstain
HFMD Hand,footandmouthdisease
HLA  Humanleukocyteantigen
IgM  ImmunoglobulinM
IFA  Indirectimmunofluorescenceassay
IL  Interleukin
IVIG  Intravenousimmunoglobulin
MCP  Monocytechemoattractantprotein
MIG  Monokineinducedbyinterferongamma
PDE  Phosphodiesterase
PSGL  HumanP-selectinglycoproteinligand
RD  Humanrhabdomyosarcomacells
RNA  Ribonucleicacid
RT-LAMP Reversetranscriptionloop-mediatedisothermalamplification
RT-PCR Reversetranscriptionpolymerasechainreaction
SCARB HumanscavengerreceptorclassB
SD  Standarddeviation
UTR  Untranslatedregion
VTM  Virustransportationmedium
[ 1 ]
A Guide to Clinical Management and Public Health Response
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Introduction
H
and,footandmouthdisease(HFMD)isacommoninfectiousdiseasecaused
by a group of enteroviruses, including Coxsackievirus A16 (CA16) and
Enterovirus71(EV71).InfectionwithEV71 isofparticularconcernas it
cancauseseverediseaseinchildren,sometimesresultingindeath.
Overthelastdecade,manyoutbreaksofHFMDhavebeenreportedincountriesofthe

Western Pacific Region, including Japan, Malaysia and Singapore, and across China.
The incidence of HFMD, particularly that caused by EV71 infection, appears to be
increasingacrosstheRegion.Thishaspromptedconcernsthat,withoutintervention,
thepublichealthimpactandspreadofthediseasewillcontinuetointensify.
Thispublicationhasbeendevelopedtosupportthetreatment,preventionandcontrol
ofHFMD.Itisintended asaresourceforcliniciansworkingwithHFMDcasesona
regularbasis,aswellaspublichealthpersonnelwhoareresponsibleforpreventingand
respondingtooutbreaksofHFMD.Itdrawsonthemostrecentscientificliteratureand
capturesthecurrentunderstandingandexperiencesofinternationalexpertsworking
onHFMD.
Developing the guide
In2008and2009,epidemiological,diagnosticandclinicalissuesrelatingtoHFMDwere
reviewedanddiscussedatthreeinternationalmeetings.Thosemeetingsemphasized
the importance of establishing standardizedsurveillance systems that are supported
by laboratorydiagnosis, developing investigationandresponse strategiesforHFMD
outbreaks,andfurtheringresearchintothe bestclinical management forHFMD.In
particular, it was suggested that standardized case definitions and guidelines for
clinicalmanagementofseverecaseswereneededtoassistintheoverallcontroland
managementofEV71-associatedHFMD.
TheWorldHealthOrganization(WHO)WesternPacificRegionalOffice,incoordination
with the Regional Emergency Diseases Intervention (REDI) Centre, subsequently
organizedaninformalconsultativemeetingonHFMDinMarch2010inKualaLumpur,
Malaysia.Seventeenregionalandinternationalexpertsattendedthemeeting.Findings
were summarized and recommendations developed in the areas of: surveillance,
epidemiology and burden of disease; characterization of etiological agents and
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A Guide to Clinical Management and Public Health Response
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transmission; pathogenesis; laboratory diagnosis; clinical features and management;
andpreventionandcontrol.

In July 2010, the REDI Centre invited 10 clinical management experts to a further
meetingonHFMDinSingaporetoreviewthedraftguidancedocumentandconsolidate
up-to-dateknowledgeandexperiencesontheclinicalmanagementofHFMDcausedby
EV71.
Theresultingdocumentfromtheabovetwomeetingshasbeenreviewedbyexperts
withinandoutsidetheWesternPacificRegion,andconsensusreachedonthecontent
ofeachchapter.
The support of all those who contributed to development of this guide is gratefully
acknowledged.
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A Guide to Clinical Management and Public Health Response
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Section 1: Epidemiology
1.1 Overview
M
any small and large outbreaks associated with EV71 infection have been
reportedthroughouttheworldsincetheearly1970s(1,2).Childrenhave
beenmostcommonlyaffectedinthoseoutbreaks,andclinicalmanifestation
ofcaseshasbeenmostlytypicalofHFMD,withfever,skineruptionsonhandsandfeet,
andvesiclesinthemouth.However,casesinvolvingthecentralnervoussystem(CNS)
and/orpulmonaryoedemahavealsobeenobserved(3).
In the Western Pacific Region, widespread epidemics have been reported in many
countries, includingAustralia, BruneiDarussalam,China,Japan, Malaysia,Mongolia,
theRepublicofKorea,Singapore,andVietNam.Severalcountrieshavealsoreported
fatalcases,withsevereCNSdiseaseorpulmonaryoedema.In2009,forexample,an
outbreak in mainland China involved 1 155 525 cases, 13 810 severe cases and 353
deaths.
LessisknownregardingthedescriptiveepidemiologyofHFMDorEV71infectionin
countriesoutsidetheWesternPacificRegion.AlthoughdozensoffatalitieswithCNS
involvementwerereportedduringEV71outbreaksinBulgariain1975andHungaryin

1978,therehavebeenfewfatalcasesreportedoverthelastthreedecades.Arecent
longitudinal study from Norway suggested asymptomatic circulation of EV71 in the
community.
Information regarding the recent seroepidemiology of EV71 in the Western Pacific
Region is limited. A cross-sectional study in Singapore indicated that, following the
declineofmaternalantibodies,theseroprevalenceforEV71increasedatanaveragerate
of12%peryearinchildrenfromtwotofiveyearsofage,andreachedasteadystateof
approximately50%inthoseagedfiveyearsorolder.Similarresultsusingthreegroups
ofstoredserawerefoundinacross-sectionalstudyperformedinTaiwan(China).Two
otherseroepidemiologicalstudiesinTaiwan(China)indicatedthat,followingadecrease
in the circulation of EV71 in the community, an accumulation of susceptible young
childrenmayhavecontributedtothelarge-scaleepidemicthatoccurredtherein1998.
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A Guide to Clinical Management and Public Health Response
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1.2 Descriptive epidemiology
DiseaseassociatedwithEV71infectionwasfirstdescribedbySchmidtandcolleaguesin
1974,whoreportedon20patientswithCNSdisease,includingonefatalityinCalifornia,
UnitedStatesofAmerica,between1969and1972(1).Subsequentoutbreaksassociated
withEV71infectionwerereportedinNewYork,UnitedStatesofAmerica,in1972and
1977(4-6),Australiain1972-1973and1986(7,8),Swedenin1973(9),Japanin1973and
1978(10-13),Bulgariain1975(14,15),Hungaryin1978(16,17),Francein1979(18),
HongKong(China)in1985(19),andPhiladelphia,UnitedStatesofAmericain1987
(20).  During those outbreaks, EV71 caused a wide spectrum of diseases, including
HFMD, aseptic meningitis, encephalitis, paralysis, acute respiratory symptoms and
myocarditis.
Thoseoutbreaksreportedbetween1974andthemid-1990smaybeclassifiedaseither
“benign”or“severe”innature(21).Fortheformer,typicalexamplesincludethelarge
outbreaksinJapanin1973and1978, involving3296and36301cases,respectively.
Although cases involving CNS were observed during those outbreaks, including a

numberoffatalities,clinicalmanifestationofcaseswasmostlytypicalofHFMD(10-
13).ThatwasalsothecasefortheoutbreakinAustraliain1986,althoughnofatalities
were reported (8).  Reports of other outbreaks, however, have contained significant
componentsofCNSdisease.AlargeepidemicinBulgariain1975,involving705cases
andincludingalargenumberoffatalities,wasinitiallythoughttorepresentpoliomyelitis
orencephalitisandwasnotcharacterizedasHFMD(14).Asimilarepidemicofacute
CNSdiseaseinHungaryin1978showedthatonlyfourcaseswereclassifiedasHFMD
among323caseswithEV71infection(17)
Inthelate1990s,twowidespreadcommunityoutbreaksassociatedwithEV71infection
occurred;thefirstinSarawak,Malaysia,in1997,andthesecondinTaiwan(China)in
1998,with2628and129106casesreported,respectively(22,23).Althoughclinical
manifestations during those outbreaks were mostly typical of HFMD, a cluster of
deathsamongyoungchildrenwasidentified.Caseswithrapidlyprogressiveandfatal
pulmonaryoedema/haemorrhagewerealsoobservedforthefirsttime
Numerous Member States in the Western Pacific Region have since experienced
large HFMD epidemics associated with EV71 infection. Several countries have also
reportedsubstantialnumbersofdeaths.Thefollowingsectionpresentsthedescriptive
epidemiologyofanumberofthoseepidemics.Inaddition,findingsfromthesurveillance
dataofselectedcountriesintheWesternPacificRegionsince1997aresummarizedin
Annex1.
Australia
Between February and September 1999, 14 cases of EV71-associated neurological
diseasewere identifiedatahospitalduring acommunity-wideoutbreak of HFMD in
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A Guide to Clinical Management and Public Health Response
for Hand, Foot and Mouth Disease (HFMD)
Perth,WesternAustralia.Twelve(86%)ofthe14childrenwerelessthanfouryearsof
age(24).
AnoutbreakofHFMDduetoEV71occurredinSydneyinthesummerof2000–2001.
Approximately 200 children presented to hospital, including nine patients with CNS

disease and five with pulmonary oedema. EV71 was identified in all patients with
pulmonaryoedema(25).
Brunei Darussalam
Brunei Darussalam experienced its first major reported outbreak of EV71 between
February and August 2006. More than 1681 children were reportedly affected, with
threedeathsresultingfromsevereneurologicaldisease.EV71wasisolatedinsamples
from34ofatleast100patientsdiagnosedwithHFMDorherpangina(HA),including
twopatientswhodiedasaresultofsevereneurologicalcomplications(26).
China
Between March and May 2007, an outbreak of HFMD occurred in Linyi City,
ShandongProvince,China.By22May2007,1149caseshadbeenreportedthrougha
countrywide disease-reporting system in mainland China. The majority of those
patients(84.4%)wereyoungerthanfiveyearsofage.Eleven(0.9%)oftheHFMDcases
wereclassifiedas severe,presenting withneurologicalcomplications.Three (0.3%)
children(agedthreeyearsoryounger)diedduringtheoutbreak.Atotalof233clinical
specimens were collected from 105 hospitalized patients, including 11 patients with
severeHFMD.Amongthose,55(52.4%),includingsixseverecases,wereconfirmed
tobeEV71infections(27).
Between1Januaryand9May2008,61459HFMDcasesand36deathswerereported
through China’s disease reporting system.  However, prior to 2 May 2008, HFMD
wasnotcategorizedasanotifiablediseaseandreportingofHFMDreliedonvoluntary
reportssubmittedbyclinicians.Thenumberofreportedcasesincreasedsharplyafter
thediseasewasdesignatedasaclass“C”notifiabledisease,withcasesbeingreported
from nearly all provinces. The five provinces with the highest numbers of reported
caseswereGuangdong(11374),Anhui(9235),Zhejiang(6134),Shandong(4566)and
Henan(3230).Childrenyoungerthanfiveyearsofageaccountedfor92%ofreported
HFMDcases.Among582samplestested,EV71accountedfor54.5%ofcases(28).
More detailed studies of the 2008 outbreak were reported from Fuyang City, Anhui
Province, where6049 cases were reported between 1 March  and 9 May2008.  Of
those,353(5.8%)weresevereand22werefatal(casefatalityrate:0.4%).Amongthe

reportedcases,themale-to-femaleratiowas1.9:1andtheagerangedfrom28daysto
18years,with78%ofthecasesbeingthreeyearsofageoryounger.Epidemiological
investigation revealed no contact between the 22 fatal cases, but environmental
investigationofthehouseholdsofthefatalcasesrevealedpoorhygieneandsanitary
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A Guide to Clinical Management and Public Health Response
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conditions.Theinitially highcase-fatality rate(2.9% (18/610)between1Marchand
23April2008)wasattributedto:rapiddiseaseprogression;lateclinicalpresentation;
and limited local medical capacity. The case-fatality rate decreased considerably (to
0.07% (4/5439) for the period between 24 April and 9 May 2008) once the etiology
ofthediseasewasknownandearlytreatmentwasprovidedtoseverepatients.That
wasattributedtoenhancedsurveillanceandimplementationofpreventionandcontrol
measures(28).Itshouldbenotedthat,duringtheoutbreak(asof2May2008),HFMD
wasdesignatedasaclass“C”notifiabledisease.
In2009,thenumberofHFMDcasesnotifiedinmainlandChinaamountedto1155525,
including13810(1.2%)severecasesand353(0.03%)deaths.Themale-to-femaleratio
was1.8:1.Ofthosecases,93%werefiveyearsofageoryounger,and75%werethree
yearsofageoryounger.ThecaseswerewidelydistributedacrossChinaandincluded
bothclinicallydiagnosedandlaboratory-confirmedcases.Forthelaboratory-confirmed
cases,EV71wasresponsiblefor41%ofthecases,81%oftheseverecasesand93%of
thedeaths.
Taiwan (China)
In Taiwan (China), HFMD/HA has been included in the national sentinel-physician
reporting system since 3 March 1998 due to the prevalence of HFMD/HA cases. In
1998, 129 106HFMD/HA caseswerereportedintwowaves between 29March and
theendoftheyear.Theyincluded405(0.3%)patientswithseveredisease,mostof
whomwerefiveyearsofageoryounger.Seventy-eight(19.6%)patientswithsevere
diseasedied,71(91%)ofthemfiveyearsofageoryounger.Ofthepatientswhodied,65
(83%)hadpulmonaryoedemaorpulmonaryhaemorrhage.EV71wasfoundin44of59

(75%)isolatesfrompatientswithsevereinfectionswhosurvived,while34of37(92%)
isolatesfrompatientswhodiedwerepositiveforEV71(23).Furthersmalleroutbreaks
occurredin2000and2001,involving291and389severecasesand41and55fatalities,
respectively (41).  Sentinel physician surveillance data for 2000 and 2001 indicated
similar levels of disease were caused by CA16 and EV71 (17.1% and 18.2% versus
15.5%and15%,respectively).EV71wasassociatedwith47.3%(26/545)ofcasesin
2000andwasthedominantstrainassociatedwithfatalitiesin2001(25/41,61%).
Between1998and2005,thenumberofsevereHFMD/HAcasesperyearrangedfrom
35to405.Ofthe1548severecasesidentifiedduringtheeight-yearperiod,93%were
fouryearsofageoryounger,and75%weretwoyearsofageoryounger.Themale-to-
femaleratiowas1.5:1.Atotalof245fatalcaseswerereportedduringthesameperiod.
EV71positivityratesamongthefatalcasesrangedfrom11%to100%ineachyear(42-
44).Thenumberofseverecasesanddeaths,respectively,were:11and0in2006;12
and2in2007;373and14in2008;and29and2in2009.
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A Guide to Clinical Management and Public Health Response
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Japan
Approximately2400paediatricclinicsparticipatedinthesentinelsurveillancesystem
in Japan between 1993 and 1998, with an average of 36.5 cases of HFMD reported
per sentinel site annually (29). Since 1999, approximately 3000 paediatric clinics
haveparticipatedinthesentinelsurveillancenetwork,withanaverageof42.7cases
of HFMD reported per sentinel site between 1999 and 2005. Large-scale outbreaks
occurredin2000and2003,withthenumbersofreportedcases(casespersentinelsite)
205365(68.96)and172659(56.78),respectively.Approximately90%oftheHFMD
caseswereagedfiveyearsofageoryounger(30).
HFMD is also included in the Infectious Agents Surveillance system in Japan.  The
Infectious Agents Surveillance reports are derived from approximately 10% of the
sentinelclinicsandallthesentinelhospitalsinthenetwork.EV71wasfoundtobethe
primary causative agent of HFMD epidemics in both 2000 and 2003 (30).  Although

thereisnosurveillancesystemforsevereorfatalcasesofHFMDinJapan,suchcases
havebeenidentifiedthroughcase-seriesfromhospitalsduringepidemicperiodsinthe
community.  In1997, threedeaths of youngchildren from HFMD or EV71 infection
wereidentifiedinOsakaprefecture(30).Inthesummerof1997,12patients,agedtwo
weeks to six years, with serologically confirmed EV71 infections, were hospitalized
in Otsu city as a result of CNS involvement (31). Between June and August 2000,
30 cases with HFMD complicated by CNS involvement were hospitalized in Hyogo
prefecture.Onepatientagedtwoyearsdiedasaresultofpulmonaryoedemacaused
by brainstem encephalitis. EV71 was isolated from nine (69%) of 13 faecal samples,
includingasamplefromthefatalcase(32).Anationwidequestionnairesurveyfound
272complicatedcaseswithHFMDduringtheperiod2000-2002.Ofthese,226cases
occurredin2000,32in2001,and14in2002.Therewerefourcasesinvolvingsequelae
andonefatalcasereportedin2000(52).
Malaysia
InSarawak,Malaysia,awidespreadcommunityoutbreakofHFMD,primarilycaused
byEV71infection,beganinearlyApril1997.From1Juneto30August1997,atotal
of2628caseswerereportedtotheSarawakStateDepartmentofHealth.Duringthe
outbreak,889childrenwerehospitalized,including39patientswithasepticmeningitis
oracuteflaccidparalysis.Atotalof29previouslyhealthychildrenyoungerthansix
yearsofage(median,1.5years;range,0.5–5.9years;male-to-femaleratioof1.9:1)died
ofrapidlyprogressivecardiorespiratoryfailure.EV71wasisolatedinsamplesfromsix
ofthefatalcases(22).Laterin1997,anoutbreakinvolving4625hospitaladmissions
occurredinpeninsularMalaysia,resultingin11fatalcases(35).
AsentinelsurveillanceprogrammeforHFMDwassubsequentlyestablishedinSarawak
inMarch1998.BetweenMarch1998andJune2005,4290specimenswerecollected
from 2950 children, with a male-to-female ratio of 1.4:1.  During that period, two
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largeoutbreakswereidentifiedinSarawak,in2000and2003.EV71wasthedominant

enterovirus serotype of the isolates in both years (36).  The sentinel surveillance
programmeinSarawakisongoing,withtwomoreoutbreaksidentified:thefirstin2006
andthesecondin2008/2009.
Mongolia
OfficialreportingofHFMDinMongoliabeganin2008,with3210casesreportedduring
thatyear.Caseswereequallydistributedbetweenthecapital cityand theprovinces.
Amongthe245samplesinvestigated,102(41.6%)werepositiveforEV71(37).
Republic of Korea
TheincidenceofHFMD/HAincreasedintheRepublicofKoreaduring2000,withan
outbreakofHFMD/HAinChejuProvince.WhiletheactualnumberofcasesofHFMD/
HAisunknown,nofatalitywasassociatedwiththeoutbreak(33).
AsentinelsurveillancesystemforEVinfectionwasinitiatedin2005.BetweenJanuary
2008and30October2009,719suspectedcasesofHFMDorHA(200casesin2008
and519casesin2009)wereidentified,includingonefatalcaseresultingfromsevere
neurological complications and two cases resulting in a comatose state. Enterovirus
wasdetectedin447(62.2%)cases.Ofthose,enteroviralgenotypewasidentifiedin218
cases(53casesin2008and165casesin2009).In2008,themostcommonpathogen
detected was CA10 (18 cases; 34.0%), while, in 2009, EV71 was the most common
pathogendetected(91cases;55.2%)(34).
Singapore
AlargeepidemicofHFMDcausedbyEV71infectionoccurredinSingaporebetween
SeptemberandOctober2000,with3790casesreportedandthreedeaths.Ofthe104
patientswhowereclinicallydiagnosedwithHFMDandwhosesamplesyieldedatleast
onevirus,EV71wasthemostcommonlyisolatedvirus(73%)(38).
ReportingHFMDsubsequentlybecamemandatoryinOctober2000.Intheseven-year
periodfrom2001through2007,nationwideepidemicsofHFMDwereobservedin2002
(16228reportedcases),2005(15256reportedcases),2006(15282reportedcases)
and2007(20003reportedcases).Theage-specificannualincidenceratewashighest
in those aged 0–4 years, ranging from 1640.5 to 5975.5 per 100 000 population and
accountingfor62.2%to74.5%ofreportedcases.DuringtheEV71-associatedHFMD

epidemicinMarchandApril2006,1.8%ofthecaseswerehospitalized.Thatratewas
morethantwiceashighasinthoseepidemicscausedbyCA16(betweenMarchand
April2005,0.8%ofcaseswerehospitalized,andbetweenAprilandMay2007,0.7%of
caseswerehospitalized).
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InasmalleroutbreakinJanuaryandFebruary2001,5187caseswerereported,including
threeHFMD-associateddeaths.Ofthefatalcases,onewasagedfouryears,whilethe
othertwowereboth11monthsofage(39).
BetweenlateMarchandMay2008,anationwideepidemicofEV71-associatedHFMD
occurred.Inthefirst24weeksof2008,thenumberofreportedHFMDcaseswas15
030,atwo-foldincreasecomparedwiththesameperiodin2006(themostrecentEV71-
associatedepidemicpriorto2008).Fortheepidemicperiodfromweek8toweek24in
2008,EV71constituted33.2%ofthesamplestested.EV71positivitywassignificantly
higherduringthe2008epidemicperiodthanin2006(40).
Viet Nam
In southern VietNam,anoutbreakofacuteencephalitisassociatedwithHFMD was
reportedinHoChiMinhCityin2003.In2005,764childrenwerediagnosedwithHFMD
inHoChiMinhCitythroughsentinelsurveillanceatthelargestpaediatrichospital,with
mostcases(96.2%)beingfiveyearsofageoryounger.Allpatientsprovidedspecimens
and HEV was isolated from 411 patients.  Of those, 173 (42.1%) were identified as
EV71, and214(52.1%)asCA16.OfthosepatientswithEV71infections, 51(29.3%)
werecomplicatedbyacuteneurologicaldiseaseandthree(1.7%)werefatal(45).
In2006–2007,sentinelsurveillanceatthesamehospitalreported305casesdiagnosed
as neurological disease, of which 36 cases (11%), and three deaths (0.01%), were
associatedwithEV71.
In 2007,2008and2009, thenumbersof reportedand fatalcaseswere:5719 and23,
10958and25,and10632and23,respectively.Themajorityofthecaseswereinthe
southernpartofthecountry.

In northern Viet Nam, EV71/C4 has only been identified in one patient with acute
encephalitis since 2003. Between 2005 and 2007, EV71/C5 was identified in seven
patientswithacuteflaccidparalysis.Allcaseswereunderfiveyearsofage.During2008,
88casesofHFMDwerereportedfrom13provinces.Theresultsofvirusisolationfrom
the88cases confirmedthat33 (37.5%) isolateswere enterovirus-positive, including
nine(27.3%)withEV71,23(69.7%)withCA16,andonewithCA10.Nosevereorfatal
caseswerereported.Themajorityofcaseswereunderfiveyearsofage.
Countries outside the Western Pacic Region
Less is known regarding the descriptive epidemiology of HFMD or EV71 infection
in countries outside the Western Pacific Region.  In The Netherlands, only severe,
hospitalizedcasesofEV71infectionarereportedaspartofthenationalsurveillance
system.Whilebetween1963and2008therewasnoindicationofEV71-relatedfatalities,
58casesofEV71infectionrequiringhospitalizationwerereportedin2007aftera21-
yearperiodoflowendemicity(46).
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In the United Kingdom, there is evidence of continuous circulation of EV71, with
EV71isolatedeachyearfrom1998to2006,exceptfor2003.Of32patientswithEV71
infectionaccompaniedbyneurologicalcomplicationsand/orcutaneousmanifestations
duringthateight-yearperiod,onehadfatalencephalitis(47).
AlongitudinalstudyfromNorway,conductedbetweenSeptember2001andNovember
2003,indicatedasymptomaticcirculationofEV71.Atotalof113healthyinfantsfrom
theageofthreemonthswererecruitedtoprovidemonthlystoolsamplesandclinical
dataupuntiltheageof28months.PrevalenceofEV71instoolsamplesshowedthat
EV71wascirculatingwidelybetweenOctober2002andOctober2003.However,data
fromasurveillance/registersystemshowednocorrespondingincreaseinthenumber
ofhospitalizedpatientswithencephalitis,HFMDorHAwithintheagegroupduringthe
sameperiod(48).
1.3 Seroepidemiological study

Recent data regarding the seroepidemiology of EV71 in the Western Pacific Region
arelimited.InSingapore,aserologicalsurveywasconductedatapaediatricclinicat
theNationalUniversityHospitalthatincludedallchildrenbornatthehospitalorthose
aged12yearsoryoungerbroughtforroutinevisitsandvaccinationsbetweenJuly1996
andDecember1997,givingatotalof856children.Antibodyprevalenceincordblood
suggestedthat44%ofmothershadantibodiestoEV71.Noneofthechildrentested
hadmaternalantibodiestoEV71afteronemonth,andantibodieswerefoundinonly
oneofthe124samplesfromchildrenaged1-23months.Inchildrenagedfromtwoto
fiveyears,theseropositiverateincreasedatanaverageof12%peryear.Insamples
fromchildrenfiveyearsofageandolder,theage-specificseroprevalencesteadiedat
approximately50%(49).
Anothercross-sectionalstudycarriedoutinTaiwan(China)examinedseroprevalence
ratesforEV71byusingamicro-neutralizingassaytotestthreegroupsofstoredsera
collectedin1994,1997and1999.Regardlessoftheperiodfromwhichthespecimens
weretaken,theseropositiverateswererelativelyhigh(38%-44%)ininfantsyounger
than six months of age.  The rates declined to 0%-15% in infants age 7-11 months,
increasedgraduallythereafteruntiltheageofsix,andreachedaplateauatabout50%
inchildrenolderthansixyearsofage(50).
Two seroepidemiological studies have contributed to the understanding of factors
underlyingtheHFMDoutbreakinTaiwan(China)in1998.Inacross-sectionalstudy,
neutralizing antibodies to EV71 were assayed for 539 subjects who provided serum
samples for vaccine trials or health examinations in two hospitals between July and
December 1997.  Age-specific EV71-seropositive rates before the outbreak were
inverselyrelatedtoage-specificmortalityratesandsevere-caseratesinthecommunity
duringtheoutbreak(r=-0.82and-0.93,respectively)(51).Alongitudinalstudywas
alsoconductedusingserumsamplesfromabirthcohortstudyof81healthychildren
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whoprovidedyearlybloodsamplesbetween1988and1998.Thestudyfoundthatthe

yearly incidence of EV71 seroconversion was 3%-11% between 1989 and 1997, and
that 68% of children had serological evidence of EV71 infection by 1997.  However,
compared with previous years, the seroconversion rate for EV71 was relatively low
between1994and1997.TherarityofEV71infectionbetween1994and1997suggests
decreasedcirculationofEV71inthecommunity.Anaccumulationofsusceptibleyoung
childrenmaythereforehavecontributedtothelarge-scaleepidemicthatoccurredin
1998(44,50).
References
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Section 2: Virology
2.1 Overview
ThemajoretiologicalagentsthatcauseHFMDarethehumanenterovirusesspeciesA
(HEV-A),particularlycoxsackievirusA16(CA16)andenterovirus71(EV71).These
belong to the genus Enterovirus within the family Picornaviridae.  Other HEV-A
serotypes,suchasCoxsackievirusA6andCoxsackievirusA10,arealsoassociatedwith
HFMD and herpangina.  While all these viruses can cause mild disease in children,
EV71hasbeenassociatedwithneurologicaldiseaseandmortalityinlargeoutbreaksin
theAsiaPacificregionoverthelastdecade(1–4).
Enteroviruses are small viruses with virions that are about 30 nm in diameter and
composedoffourstructuralproteinscalledVP1,VP2,VP3andVP4.VP1isthemajor
capsidproteinonthesurfaceofthevirion,whileVP4isnotexposedonthesurface.
Serotypingofhumanenteroviruseshastraditionallybeenbasedonneutralizationtests

using specific antiserum pools: as such they are directed particularly at serological
responsestotheVP1protein.Morerecently,dueinparttolimitedaccesstoserotyping
antisera and improved accessibility to molecular technology, there has been a move
towardsusingmoleculartypingmethods.ThegeneencodingVP1isthetargetgene
mostoftenusedinmoleculartypingmethodsforenteroviruses.Itisforthisreason
that a wealth of genetic sequence data on EV71 is available, enabling the genetic
classificationofvirusstrainsincommoncirculation(5–7).
Ribonucleic acid (RNA) viruses, such as the enteroviruses, generate evolutionary
changesfairlyrapidly.Labels(genogroups)canbeappliedtoclustersofepidemiologically
relatedEV71strains,generallythosewithuptoa5%nucleotidedifferenceintheVP1
region.  These genogroup divisions have no known significance for any enterovirus
otherthanbeingaconvenientlabeltoreflectviralsequenceclusteringwithinaseaof
geneticdiversity.Itisimportanttonotethatthereisnotyetevidenceofanyassociation
betweenvirulenceandparticulargenogroupsorsubgenogroupsofEV71.
Figure 1 on the succeeding page shows a phylogenetic tree containing the three
genogroupsofEV71:genogroupsA,BandC.TheprototypeEV71virusisBrCr,isolated
inCaliforniain1969.ThisistheonlysampledvirusofgenogroupA(8).
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Figure 1: Circulating genotypes of HEV71 between 1970 and 2010
HEV71 - circulating genotypes, 1970 - present
White Dendrograms:
Worldwide, 1970-1995
*C1 has continued to circulate
in the Asia-Pacific region to
the present
Coloured Dendrograms:
Asia-Pacific, 1997-present
A

(BrCr)
C1*
Singapore 2000, Sarawak
WA 2001 & 2005, Vietnam 2005
C2
Taiwan 1998 WA 1999
C3
Korea 2000
C4
China & Korea, 2004, Vietnam 2005
C5
Vietnam, 2005-06
B1
B2
B3
1997-99
B4
2000-01
B5
2003,2006
B6
2006
Southeast Asia
1997-2006
SubgenogroupB1wascirculatingintheUnitedStatesofAmerica,Europe,Japanand
Australiainthe1970s,whilesubgenogroupB2wassampledmainlyintheUnitedStates
inthe1980s.In1997,whenthefirstofseveralrecentandlargeAsiaPacificoutbreaks
ofEV71occurredinSarawak,Malaysia,themajorcirculatingviruswasaBgenogroup
virus that was clearly distinct from the genogroup B viruses that had been sampled
inthe1970sand1980s.ThiswasthennamedsubgenogroupB3.Theviruswasalso

foundintheMalaysianpeninsulaandinSingapore(1,2).
In 1998, anotherlargeoutbreak ofEV71 HFMD occurred in the Asia Pacific region,
thistimeinTaiwan(China).ThemajorcirculatingviruswasfromsubgenogroupC2.
ThissubgenogrouphadalsobeenfoundinJapanandwasassociatedwithanoutbreakin
Perth,WesternAustralia,in1999,wheregenogroupB3viruseswerealsocirculating.
InTaiwan(China)in1998,subgenogroupB4viruseswerealsosampledand,by2000,
thoseviruseshadbeenassociatedwithlargeoutbreaksthroughouttheregion,including
inJapan,MalaysiaandSingapore,aswellasinTaiwan(China),wheresubgenogroupB4
virusesreplacedtheC2viruses.InSarawak,Malaysia,subgenogroupB4wasreplaced
bysubgenogroupB5in2003,andthishassinceremainedthedominantsubgenogroup.
SubgenogroupB5virusesarealsoimportantcirculatingvirusesinJapan,Singaporeand
Taiwan(China)(1–3,9–21).
[ 17 ]
A Guide to Clinical Management and Public Health Response
for Hand, Foot and Mouth Disease (HFMD)
Subgenogroup C1 viruses were sampled in North America in the 1970s and 1980s.
Throughoutthe1990s,anduptothepresentday,theyhavebeenconsistentlyidentified
inmanypartsoftheworld,includinginAustralia,Japan,Malaysia,NewZealand,Norway,
ThailandandtheUnitedKingdom,Despitebeingfoundincirculationinmanycountries,
however,thesubgenogroupC1viruseshavenotcausedlargeoutbreaksduringthelast
twodecades.ThesubgenogroupC2virusesthatwerereplacedbyB4virusesinTaiwan
(China)by2000havecontinuedtobeidentifiedinJapan,SingaporeandThailandover
thelastfewyears.
Viet Nam began investigatingEV71 in 2005.It is interesting to note that, although
C1andC4virusesdocirculateinVietNam,thedominantsubgenogrouphasbeen,and
remains,C5(22).ThatsubgenogroupemergedinTaiwan(China)in2006.
AsimilarsituationexistsinChina,wherethesingledominantsubgenogroupC4caused
majoroutbreaksin2008and2009(23,24).ThatsubgenogroupwassampledinChina
andJapaninthelate1990sandearly2000sandwasdominantinTaiwan(China)in2004
and2005.ItiscurrentlycirculatinginJapan,theRepublicofKorea,Taiwan(China),

ThailandandVietNam.TheRepublicofKorearecordedasubgenogroupC3clusterof
casesin2000,whenB4virusesweredominantelsewhereintheregion(25).
Figure2illustratesthetemporaldistributionofthedifferentsubgenogroupsofEV71
circulating in various countries in the region.  The figure includes data generated
following the enhanced surveillance activities in operation in many countries since
1997.Itisthereforeimportanttonotethattherearegapsintheknowledgeregarding
circulatingstrainspriortothatperiod.
Figure 2: Recorded prevalence of EV71 subgenogroups in the Asia-Pacific
region
Area
Year
1970’s 1980 ’s 1990’s 2000 -2004 2005 -2009
Malaysia
Taiwan
Australia
Japan
Singapore
China
Vietnam
Korea
Mongolia
Thailand
New Zealand
Area
-
B1
C2
C4
B2
B3

B4
B5
C3
C5
C2
B4
C4
B5
C4
C1
C4
C2
C1
C2
B4
B3
B4
C1
B5
B3
B4
C4
B5
C1
C1
C2
C4
B5
C5
C5

C1
C1
C2
B1
B2
C2
C2