The global epidemiology of clonorchiasis and its relation with cholangiocarcinoma

MISSING IMAGE

Material Information

Title:
The global epidemiology of clonorchiasis and its relation with cholangiocarcinoma
Physical Description:
Mixed Material
Language:
English
Creator:
Qian, Men-Bao
Chen, Ying-Dan
Liang, Song
Yang, Gu-Jing
Zhou, Xiao-Nong
Publisher:
BioMed Central (Infectious Diseases of Poverty)
Publication Date:

Notes

Abstract:
This paper reviews the epidemiological status and characteristics of clonorchiasis at global level and the etiological relationship between Clonorchis sinensis infection and cholangiocarcinoma (CCA). A conservative estimation was made that 15 million people were infected in the world in 2004, of which over 85% distributed in China. The epidemiology of clonorchiasis is characterized by rising trend in its prevalence, variability among sexes and age, as well as endemicity in different regions. More data indicate that C. sinensis infection is carcinogenic to human, and it is predicted that nearly 5 000 CCA cases attributed to C. sinensis infection may occur annually in the world decades later, with its overall odds ratio of 4.47. Clonorchiasis is becoming one major public health problem in east Asia, and it is worthwhile to carry out further epidemiological studies. Keywords: Clonorchiasis, Clonorchis sinensis, Epidemiology, Cholangiocarcinoma, Odds ratio
General Note:
Qian et al. Infectious Diseases of Poverty 2012, 1:4 http://www.idpjournal.com/content/1/1/4; Pages 1-11
General Note:
doi:10.1186/2049-9957-1-4 Cite this article as: Qian et al.: The global epidemiology of clonorchiasis and its relation with cholangiocarcinoma. Infectious Diseases of Poverty 2012 1:4.

Record Information

Source Institution:
University of Florida
Holding Location:
University of Florida
Rights Management:
© 2012 Qian et al.; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
System ID:
AA00024674:00001

Full Text

PAGE 1

Theglobalepidemiologyofclonorchiasisandits relationwithcholangiocarcinoma Qian etal. Qian etal.InfectiousDiseasesofPoverty 2012, 1 :4 http://www.idpjournal.com/content/1/1/4

PAGE 2

SCOPINGREVIEWOpenAccessTheglobalepidemiologyofclonorchiasisandits relationwithcholangiocarcinomaMen-BaoQian1,Ying-DanChen1,SongLiang2,Guo-JingYang3,4andXiao-NongZhou1*AbstractThispaperreviewstheepidemiologicalstatusandcharacteristicsofclonorchiasisatgloballevelandtheetiological relationshipbetween Clonorchissinensis infectionandcholangiocarcinoma(CCA).Aconservativeestimationwas madethat15millionpeoplewereinfectedintheworldin2004,ofwhichover85%distributedinChina.The epidemiologyofclonorchiasisischaracterizedbyrisingtrendinitsprevalence,variabilityamongsexesandage,as wellasendemicityindifferentregions.Moredataindicatethat C.sinensis infectioniscarcinogenictohuman,andit ispredictedthatnearly5000CCAcasesattributedto C.sinensis infectionmayoccurannuallyintheworlddecades later,withitsoveralloddsratioof4.47.ClonorchiasisisbecomingonemajorpublichealthproblemineastAsia, anditisworthwhiletocarryoutfurtherepidemiologicalstudies. Keywords: Clonorchiasis, Clonorchissinensis ,Epidemiology,Cholangiocarcinoma,OddsratioMultilingualabstractsPleaseseeAdditionalfile1fortranslationsoftheabstract intothesixofficialworkinglanguagesoftheUnited Nations.ReviewLiverflukesareapolyphyleticgroupoftrematodes (phylumPlatyhelminthes),including Clonorchissinensis Opisthorchisviverrini and Opisthorchisfelineus fromfamily opisthorchiidaeand Fasciola spp.fromfamilyfasciolidae [1-4].Here,opisthorchiidae,especially C.sinensis isfocused on,soliverflukesarespeciallytermedtothisfamily.Adults ofliverflukes,localizingintheliverofvariousmammals includinghumans,produceeggswhicharepassedintothe intestine.Mostoftheparasitesliveinbileducts,gallbladder andliverparenchyma,causingliverandbiliarydiseases. Humanbeingsareinfectedthroughingestionofrawor undercookedfishwhichcontainsthemetacercariaeofliver flukes(Figure1)[1-4]. Cholangiocarcinoma(CCA)isacancerofthebile ducts.RecentevidencessupportthefactthatCCAis themostseverecomplicationofliverflukeinfection, and C.sinensis and O.viverrini infectionsarebothclassifiedas “ carcinogenictohumans ” (Group1)bythe InternationalAgencyforResearchonCancer(IARC)in 2009[5,6]. Duetotheabsenceofdefiniteinformationongeographicaldistributionanddiseaseburden,theirpublic healthimpacthasbeenunderestimatedforalongtime [7].Herewereviewtheglobalepidemiologicalstatus andcharacteristicsofclonorchiasisandtheetiological relationshipbetween C.sinensis infectionandCCA.EpidemiologyofclonorchiasisDistributionClonorchiasisispredominantlyendemicineastAsia, butitmayalsooccurinotherregionswherethereare immigrantsfromendemicareas[8].Duetothegrowth andmovementofpopulationandtherapiddevelopment ofaquaculture,thefactofclonorchiasishinderingthe localeconomicdevelopmentisincreasinglynotified[2,7]. Threelarge-scalesurveysforclonorchiasishavebeen carriedoutinmainlandofChina.Theprevalenceofclonorchiasiswas0.37%accordingtothefirstnational parasitesurveyinvolvingin30Provinces/Municipalities/ AutonomousRegions(P/M/As)between1988and1992 (hereinafterreferringas1992)[9].Then,itincreasedto 0.58%inthesecondnationalparasitesurveyinvolvingin 31P/M/Asbetween2001and2004(hereinafterreferring *Correspondence: ipdzhouxn@sh163.net1NationalInstituteofParasiticDiseases,ChineseCenterforDiseaseControl andPrevention;WHOCollaborativeCenterforMalaria,Schistosomiasisand Filariasis;KeyLaboratoryofParasiteandVectorBiology,MinistryofHealth, Shanghai,People ’ sRepublicofChina Fulllistofauthorinformationisavailableattheendofthearticle 2012Qianetal.;licenseeBioMedCentralLtd.ThisisanOpenAccessarticledistributedunderthetermsoftheCreative CommonsAttributionLicense(http://creativecommons.org/licenses/by/2.0),whichpermitsunrestricteduse,distribution,and reproductioninanymedium,providedtheoriginalworkisproperlycited.Qian etal.InfectiousDiseasesofPoverty 2012, 1 :4 http://www.idpjournal.com/content/1/1/4

PAGE 3

as2004a)[10,11].Meanwhile,anotherspecialsurvey forclonorchiasisin27endemicP/M/Aswascarried outbetween2002and2004(hereinafterreferringas 2004b),whichshowedtheprevalencewas2.40%andthe populationinfectedwere12.49million[10,11].The2004b specialsurveyaimedatclonorchiasisandthreeKato-Katz smearswereexaminedforeachfecalsample,whilethenationalsurveysdidn ’ tfocuson C.sinensis butrather detectedanyparasitespeciesinasingleKato-Katzsmear. Hence,resultfromthespecialsurveywasmorereasonable.ClonorchiasiswasalsoendemicinTaiwan,mainly locatedinMiao-liinthenorth,Sun-moonLakeinthe middleandMei-nunginthesouth[12,13]andaprevalenceof0.4%-1.0%wasestimated[1].Thus,aconservative estimationwasmadethat89000peoplewereinfectedin 2004amongthetotalpopulationof22.28million[14]. Basedonthehospitalizedcasesintwohospitalsin HongKongbetween1990and1997,outofthe1782cases withintestinalparasiticdiseases,1162(65.21%)were infectedwith C.sinensis [15].Accordingtotheestimation byWHOin1995,thepopulationinfectedinHongKong was333000[8].From1958to1991,fivelocalsurveys wereimplementedinMacaoandtheprevalencevariedbetween1.40%and19.09%.Furthermore,itshowedthat 13.00%-18.87%peopleexaminedintheLaboratoryofPublicHealthinMacaowereinfectedwith C.sinensis between 1991and1997[16].Itwasestimatedthat21000persons wereinfectedwith C.sinensis inMacaoin1995[8].Consequently,aconservativeestimationofpopulationwith clonorchiasisinChinawas12.93millionin2004(Table1). Itwassimilartotheestimationof15millionbyLun etal. throughanalyzingtheliterature,butthedataextracted fromtheliteraturespannedquitealongtimeandwere discrepantfromthenationallysamplingsurveyinsome areas[1]. IntheRepublicofKorea,clonorchiasishasbeenbecomingapredominantparasiticdiseaserecently.Accordingto thenationallysamplingsurveyin2004,thetotalpopulation infectedwithhelminthiaseswas1.78million,ofwhich1.17 millionwaswithclonorchia sis[17].Inaddition,another largescalesurveyalongthe4majorriversinsouthern areasin2006showedtheprevalencereached17.1% inNakdong-gang,11.2%inSeomjin-gang,5.5%in Youngsan-gangand4.6%inGuem-gang[18]. Vietnamisanotherimportantendemicareaforliver flukes,whereclonorchiasisandopisthorchiasiscoexist [19].Itwasestimatedthat1millionpeopleinVietnam wereinfectedwithclonorchiasisin1995[8].According tothenewestreportbyDe etal. ,clonorchiasisisendemicin21northernprovinces,whileopisthorchiasis in11southernprovinces[20].Theprevalenceofclonorchiasisinnorthernareasvariedfrom0.2%to40.1%. Nevertheless,nonationallysamplingsurveyhasyetbeen implementedandmostofthesurveysweresmallscale andnon-sampled[19].Furthermore,itisarguedmany so-called C.sinensis infectedcasesareactuallyinfected withotherintestinaltrematodes[21].Thus,itis Figure1 Rawfreshwaterfishconsumedbyhumanbeings. The outerlayerisrawfleshwhichhasnotbeencookedanyway,while theinneroneisskinoffishwhichhasonlybeenblanchedinhot waterwithinafewseconds. Table1Theestimatedpopulationinfectedwith C.sinensis globallyin2004 Region1990s # 2004Note MaleFemaleBoth ChinaMainland 47010007870000462000012490000Reference[ 10 ]and[ 11 ].Theinfectedofthemaleandfemaleis deducedfromthesexrationof1.0674[ 14 ]andtherespective prevalenceof2.94%and1.84%[ 10 11 ]. Taiwan NK561553296589120Thetotalinfectedisdeducedfromaconservativeprevalenceof 0.40%[ 1 ]andthetotalpopulationof22.28million[ 14 ].The estimationfordifferentsexesreferstothatinmainlandofChina. HongKong 333000209825123175333000ThetotalinfectedadoptstheestimationbyWHOreportin1995 [ 8 ]andtheestimationfordifferentsexesreferstothatinmainland ofChina. Macao 2100013232776821000 theRepublicofKorea 9500007823833918411174224Reference[ 17 ]. Vietnam 10000006301043698961000000ThetotalinfectedadoptstheestimationbyWHOreportin1995 [ 8 ]andtheestimationfordifferentsexesreferstothatinmainland ofChina. Russia 3000189011103000 Total 70080009563589554675515110344 # AccordingtothefigureissuedbyWHOin1995[ 8 ].NK:Notknown. Qian etal.InfectiousDiseasesofPoverty 2012, 1 :4 Page2of11 http://www.idpjournal.com/content/1/1/4

PAGE 4

challengingtoarriveatanexactfigureofpopulation infectedwithclonorchiasisinVietnam.However,taking intoconsiderationofsuchfactorsasahugepopulationat risk(33million[22]),localhabitofeatingraworundercookedfish[21,23],andrapidgrowthoffreshwaterfish production[2],1millionpeopleestimatedtobeinfected withclonorchiasisshouldnotbeunreasonable. C.sinensis isalsoendemicinfareastareaofRussia andthepopulationinfectedestimatedbyWHOin1995 wereabout3000[8].Additionally,1.22millionpeople wereestimatedtobeinfectedwith O.felineus [8].However,thecurrentstatusinRussiaremainsunclear. Recently,eggsof C.sinensis weredetectedfromhumanfecesthroughPCR-basedmethodin O.viverrini endemicareaofThailand[24].Itwasfoundonly64% individualswereinfectedwith O.viverrini andadditional 23%with C.sinensis .Thisextendedthetraditionalknowledgeofclonorchiasis.Therefore,whether C.sinensis isalsoendemicinothertraditionalendemicareasof O.viverrini or O.felineus deservesmoreattentionand vice versa LittleisknownontheepidemiologicalsituationofclonorchiasisinDemocraticPeople ’ sRepublicofKorea (DPRK).Toourbestknowledge,onlyonearticlehas attemptedtoexplorethisproblem[25].Outof137patientsfromahospitalinCheongjin-shi,Hamgyeongbukdo,DPRK,27werepositiveforclonorchiasisusingELISA test.Furthermore,among133femaleimmigrantsfrom DPRKtotheRepublicofKorea,4werewithclonorchiasisbythesametest.Becauseclonorchiasiswas highlyendemicinthenortheastofChinaandtheRepublic ofKoreabothneighboringtoDPRK,andtheKorean nationalityintheformertwocountriesloveseating rawfish[10,11,17,18],itisprobablethatclonorchiasisis alsoanimportantparasiticdiseaseinDPRK.However,it isdifficulttopredicttheepidemiologicalsituation. Dozensofclonorchiasiscaseshavebeendocumentedin Malaysia[26-28].Inadditiontohumancases,infectionsin catsandfarmedfishwerealsoreported[29-31].However, twolocalsnailspecies-mostlikelytoactastheintermediatehost-werenotsusceptibletoinfection[29].Therefore, localtransmissionisremainingcontroversial.Nevertheless, suchdiseaseshouldnotbeneglectedduetohighpopularityofeatingrawfishintraditionalfestivals[27]. During1947 – 1950, C.sinensis occurredin19prefectures ofJapan.Owingtointegratedcontrolprogramme,clonorchiasishasbeensuccessfullycontrolled.In1991,no casewasfoundin1millionstoolsamplesexamined[8]. Nowadays,onlyoccasionalcaseswerereported[32,33]. Apparently,clonorchiasisisnolongerendemicinJapan. TherearealsocasereportsinotherpartsofAsia [34,35],Europe[36-46],NorthAmerica[47,48],South America[49-51],Australia[52]andevenAfrica[53]. Thosereportedcasesusuallyweresymptomatic,evenwith severecomplications.Duetothelackofknowledge amongpopulationandmedicalorganizationsandreports bias-tendencytoreportthosewithcomplications,theactualnumberofpersonsinfectedshouldbehigher.The reportedcasesweremainlyimmigrantsfromendemic countriesortravelerswhohadvisitedendemiccountries andeatenraworundercookedfish. Insummary,clonorchiasiswaspredominantlyendemic inChina,theRepublicofKorea,Vietnamandpartof Russia.ItisalsoprobablyendemicinDPRKandpossibly inMalaysia.Thesituationinothertraditional O.viverrini or O.felineus endemicareasisnotyetclear.Sporadic humancasesarealsoreportedfromothercountrieseither duetointernationaltravellingorowingtoimmigration. Theconservativeestimationofpopulationinfectedwith C.sinensis reached15millionin2004globally,ofwhich over85%wereinChina(Table1). However,thefigureofclonorchiasisintheglobemay becomplicatedbyseveralreasons.First,theeggsof C.sinensis O.viverrini and O.felineus aremorphologicallysimilaranddifficulttobedistinguishedundermicroscopicexamination[3,54,55].Basedonrecentlydeveloped PCRtest, C.sinensis wasalsodetectedintraditional O. viverrini endemicareas[24].Therefore, C.sinensis isprobablyoccurringintraditionalendemicareasof O.viverriniand O.felineus ,whichwasneglectedpreviouslyand vice versa .Inaddition,someminuteintestinalflukeswhose eggsassemblethatof C.sinensis alsocomplicatethe diagnosisofclonorchiasis[55].Second,examination techniquescontributetotheunderestimationofprevalenceofclonorchiasis.Currentdiagnosesaremainly basedonfecalexaminationwhichisthe “ gold ” standard, particularlyKato-Katztechniqueandformalinether technique.However,manystudiesshowedthereexisted falsenegativeresultusingthesetechniquesforschistosome,soil-transmittedhelminths,aswellas O.viverrini ,especiallyinlowinfectionintensity[56-61].Third, earlydatapertainingtoclonorchiasisinsomeareasmay alsocauseunderestimation.Duetotheusualresistanceto modifyingfoodhabitandthegrowingpopulationinendemicareas,itisreasonabletoassumethatthepopulation infectedisincreasing[7].However,theearlydatain1990s wereemployedtoestimatethestatusofclonorchiasisin HongKong,Macao,VietnamandRussia.Furthermore, thepotentialendemicityinDPRKandMalaysiais excludedfromtheestimation.IncreasingtrendinprevalenceComparedtotheestimationof7millionpopulationinfectedwithclonorchiasisin1990s[8],thenumberin 2004haddoubled.Drasticincreaseoccurredinmainland ofChina,from4.70millionto12.49million[8,10,11].The prevalenceintheRepublicofKoreafluctuated,which declinedfrom4.6%in1971to1.4%in1997andbouncedQian etal.InfectiousDiseasesofPoverty 2012, 1 :4 Page3of11 http://www.idpjournal.com/content/1/1/4

PAGE 5

to2.4%in2004[17].ThepatterninVietnamandother areasisunclear.Intheendemicareas,ontheonehandit isdifficultfortheelderpreferringeatingrawfishtomodifydiethabit,andontheotherhandtheyoungergradually getaccustomedtothishabit.Furthermore,thegrowthof populationandfreshwaterfishaquacultureareotherimportantcontributors.Therewasagrowthof102million populationinthethreemajorendemicareas,namely China,theRepublicofKoreaandVietnamfrom1995to 2004[62].Meanwhile,theproductionoffreshwaterfish hasincreasedby55%,116%and91%intheaforementionedcountries[63]. Variabilityamongsexesandage Theprevalenceinthemaleisgenerallyhigherthanthat inthefemale.Accordingtothespecialsurveyin2004b inendemicareasofmainlandofChina,theprevalence was2.94%inthemale,whileitwas1.84%inthefemale (Figure2)[10,11].Theprevalencewas3.21%and1.62% inthemaleandfemalerespectivelyintheRepublicof Korea ’ snationalsurveyin2004[17],and13.60%and 8.90%along4majorriversin2006[18].Similarly,itwas foundthattheprevalenceinthemalewas2 – 3timesor morethanthatinthefemaleinlocalsurveysinVietnam [19].Accordingly,among15millionpopulationinfected, 9.6millionaremaleand5.5millionarefemale(Table1). Theinfectionintensityisalsohigherinthemalethan thatinthefemale.Takingthespecialsurveyinmainland ofChinain2004bforexample,thosewithmoderateand heavyintensity(eggspergramoffeces 1000)accountedfor28%inthemale,whileitwasonly15%in thefemale[10,11]. Theprevalenceincreaseswithageandreachesthe highestintheagegroupof50 – 59(Figure3)[10,11,17,18] or40 – 49(inlocalsurveysinVietnam)[19].Similarly,the infectionintensityalsoreachesthepeakintheagegroup of50 – 59[10,11]. Thedistributioncharacteristicsamongsexesandage aremainlyrelatedtosocialcustoms,inotherwords, humanraw-fish-eatingbehavior,andnoyetevidenceof concomitantimmunityhasbeenfoundtoplayimportant roles[64].Rawfishisoftenconsumedatrestaurantsor socialparties,whichthemalehavemorechancetoparticipatein[11,23,64,65].Moreover,rawfishareoftenenjoyed overalcohol,whichismorecommonamongthemale thanthefemaleandexcludeschildren[7,64].Furthermore,adultwormscansurviveinthebodyfordecades [52,64].Consequently,theexposureoftheadultmaleis higherandsodoesthewormload,whichleadstohigher prevalenceandinfectionintensity.However,insomelocal highendemicareas(prevalenceover60%),thereisnosignificantdifferenceinprevalencebysexes[66,67].Thedeclineofprevalenceinthoseolderthan60(50inlocal surveysofVietnam)isprobablyduetotheearlydeath causedbyclonorchiasis-relatedcomplications[68].We alsoarguethatelderliesseekformedicalservicesmore frequentlyduetoclonorchiasis-relatedcomplicationsor unrelateddiseases,andthenacceptdiagnosisandtreatment.It ’ snotsurprisingthatthepeakof O.viverrini infectionalsooccursintheagegroupof50 – 59inThailand-the mostendemicareaof O.viverrini withanoverallprevalenceof8.7%andover6millioninfected[22,69,70].Althoughatlowlevel,somechildrenisalsoinfected.In someareasofChina,childrenliketoingestincompletely roastedsmallfishandgetinfected[10].IntheRepublicof Korea,sometimeschildrenaregivenrawfishbytheir motherswhothinkrawfishcanmaketheirchildren strongintraditionalideas[64,71].However,inotherareas, childrenareusuallynotallowedtoeatrawfish[23]. Endemicity Duetodifferentdistributionofintermediatehostand foodhabit,thedistributionofclonorchiasisalsovariesin differentareas,measuredbyendemicity.Inaglobalview, itmainlydistributesinChina,theRepublicofKorea Figure2 Thevarianceofprevalenceofclonorchiasisbysexes inmainlandofChinaandtheRepublicofKorea. Figure3 Thevarianceofprevalenceofclonorchiasisbyagein mainlandofChinaandtheRepublicofKorea. Qian etal.InfectiousDiseasesofPoverty 2012, 1 :4 Page4of11 http://www.idpjournal.com/content/1/1/4

PAGE 6

andVietnam.However,theprevalenceisvariouseven inthesamecountry.Therearetwomajorendemic regionsinChina,i.e.thesoutheastincludingGuangdong andGuangxi,andthenortheastincludingHeilongjiang, JilinandLiaoning,withtheprevalenceof16.42%, 9.76%,4.73%,2.90%and0.80%,respectively(Figure4) [10,11].ThetopfourendemicareasintheRepublic ofKoreaareGyeongsangnam-do(11.3%),Daejeon(6.9%), Chungcheongnam-do(6.8%)andJeollanam-do(6.2%), whilethereisnoinfectioninJeju-do(Figure4)[17].To currentknowledge,clonorchiasisisendemicin21northernprovincesofVietnam(Figure4)[20]. Thus,thedistributionrangeof C.sinensis ismainly consistedoftwoepidemiczones.Thefirstzoneincludes thesoutheastofChinaandthenorthernareaof Vietnam,andthesecondonecoversthenortheastof China,theRepublicofKorea,partofRussiaandprobably DPRK(Figure4).Thefirstzoneneighborstotheendemic areaof O.viverrini (mainlyinThailand,Laos,Cambodia andthesouthernpartofVietnam[2,4,8,19,20,22,69,70]), whilethesecondoneisadjacenttothatof O.felineus (mainlyinRussia[2,4,8,72]). Associationof C.sinensis infectionwithCCA CCA,usuallywithpoorprognosis,isaprimaryhepatic malignancyarisingfrombileductepitheliumandranks thesecondmostcommonprimaryhepaticmalignancy [73-75].TheincidenceofCCAvariesgreatlyamongdifferentareasoftheworldandsodoestheconstituent ratioofCCAinhepaticmalignancy,whichisrelatedto thedistributionofriskfactors[76,77].Liverflukeinfectionisjustoneimportantfactor[74,76-78].In1994, C.sinensis and O.viverrini wereclassifiedas “ probably carcinogenictohumans ” (Group2A)and “ carcinogenic tohumans ” (Group1)byIARC,respectively[79].Based Figure4 Theglobaldistributionofthreemajorspeciesofliverflukes,i.e. C.sinensis O.viverrini and O.felineus Thismapfocusesonthe endemicityof C.sinensis inChina,theRepublicofKoreaandthenorthernpartofVietnam. Qian etal.InfectiousDiseasesofPoverty 2012, 1 :4 Page5of11 http://www.idpjournal.com/content/1/1/4

PAGE 7

onmoreevidences, C.sinensis isreassessedas “ carcinogenictohumans ” (Group1)in2009[5,6].TheepidemiologicalstudiesManyreportson C.sinensis infection-relatedCCAhave beendocumented.Citedhereare8cross-sectionalor case – controlstudiesandrelevantimportantinformation isextractedandlistedinAdditionalfile2[80-87]. During1960sand1970s,threecross-sectionalstudies werecarriedoutinHongKongandtheRepublicof Korea,whichpreliminarilyshowedtheprobablecarcinogenesisof C.sinensis infectiontohuman(Group2A) [80-82].Threecase – controlstudiesintheRepublicof Koreawerethenpublishe dbetween1996and2008, whichpromotedthereassessmentofitas “ carcinogenicto humans ” (Group1)in2009[83-85].Recently,anothertwo case – controlstudieshavealsobeenreportedinmainland ofChina,whichfurtherdemonstratedtheetiologicalrelationship[86,87]. Someaspectsdeservebeingemphasized.Firstly,ideally, thecaseandcontrolrepresentthesourcepopulation, otherwisethereexistsbias. C.sinensis infectionmainly causesliverandbiliarydiseases,ofwhichgallstoneisvery frequent[88,89].Thus,thecriteriaforinclusionandexclusionofsubjectsareimportant.However,inonecrosssectionalstudy,thecontrolconsistedofthosewithliver disease,whichbiasedtoincludethosewith C.sinensis infection[81].Inanothercase – controlstudy,personswith stonesinthebileductswereexcludedfromthecase, whichbiasedtoexcludethoseinfectedwith C.sinensis [84].Furthermore,inthesamecase – controlstudy,many patientswithalcoholinducedpancreatitiswereincludedascontrolsalthoughtheydidn ’ thavehepatobiliarydiseases.However,itmayalsobiastoincludethose with C.sinensis infectioninthecontrol.Ontheonehand, C.sinensis infectioncaninducepancreatitis[3,90-95].On theotherhand,raw-fish-eatinghabitisassociatedwithalcoholdrinking[7,64].Therefore,therelationshipintensity (oddsratio,OR)maybeunderestimatedinabovetwo studies.Secondly,thedeterminationofexposureisanotherimportantproblem,whichmaycausemisclassificationbias.Whenstoolexaminationisadopted,the misclassificationispronetooccurinthecase,becausebile obstructionusuallyoccursinCCAcases.Forexample,bile obstructionoccurredinmorethanhalfofcasesinone study,whichledtocontraryresultswhenstoolexaminationandpathologicalexaminationwereadopted,respectively[84].Additionally,thedevelopmentofcancers ischronicwithalongprocessandpastexposuremayalso beriskfactor.Therefore,serologictestandradiologic examinationmaybemoresensitive,aspastinfectioncan alsobedetected[84].Itisregrettingthatnodefinite methodfordeterminingexposurewasmentionedforthe twostudiesinmainlandofChina[86,87]. InadditiontothestudieslistedinAdditionalfile2,one ecologicalstudycarriedoutintheRepublicofKoreaalso showedthepositiverelationship[96].Theprevalenceof clonorchiasisinChuncheon,ChungjuandHamanwas 2.1%,7.8%and31.3%,respectively,whiletheincidenceof CCAwas0.3/100000,1.8/100000and5.5/100000,the proportionofCCAinlivercancerwas1.4%,8.9%and 13.2%,respectively.Furthermore,anothercase – control studywasreportedinmainlandofChina,but C.sinensis infectionhadonlybeentestedincasesratherthan controls[97].EstimationofCCAcasesattributableto C.sinensis infectionTheestimationofCCAcasesattributedto C.sinensis infectioncanbebasedoneitherformulabelow:[98,99] CCAsattributedto C : sinensis populationinfected CCAincidenceofuninfected oddsratio 1 1 CCAsattributedto C : sin ensis totalCCAs C : sinensis prevalencerate oddsratio Š 1 C : sinensis prevalencerate oddsratio Š 1 1 100 % 2 Althoughdifferentparametersarenecessaryin formula(1)andformula(2),theprevalenceof C. sinensis andthepopulationinfectedcouldbeconvertedmutually.Obviously,nomatterwhichformula isapplied,therelationshipintensity,namelyOR,isof crucialimportance. BasedonthestudiesshowninAdditionalfile2,the comprehensiveORcanbededucedthroughmeta-analysis. OriginalORratherthanadjustedoneineachstudyis applied,becausethosestudieshaddifferentobjectivesand designsandtookintoconsiderationofdifferentaspects.TheoverallORis4.47(95%CI:2.61-7.66)(RevMan software,http://ims.cochrane. org/revman)(Figure5).Other researchershavedonesimilaranalysis.Itwas4.65(95%CI: 2.21-9.79)throughmeta-analysisoftherelatedstudies intheRepublicofKorea[99],whileitwas4.84(95% CI:2.79-8.41)afterincludingthosestudiespertaining to O.viverrini infectionandCCA[77,100-103]. Shin etal. havemanagedtoestimateclonorchiasisinducedCCAintheRepublicofKorea[99].Duetolack ofCCAdatainother C.sinensis endemicareas,thatin theRepublicofKoreawillbeextrapolated(Table2). Firstly,basedonformula(2),thenumberofCCAcasesin theRepublicofKorea(2166maleand1440femalein 2005[99]), C.sinensis prevalence(3.7%inthemaleand 1.6%inthefemalein1981[17])andtheoverallOR(4.47),Qian etal.InfectiousDiseasesofPoverty 2012, 1 :4 Page6of11 http://www.idpjournal.com/content/1/1/4

PAGE 8

itisestimatedthat246maleand76femaleCCAcasesattributedto C.sinensis infectionoccurredinthe RepublicofKoreain2005.Secondly,accordingtothe clonorchiasis-relatedCCAcasesoccurringintheRepublic ofKoreain2005andthepopulationinfectedwith C. sinensis in1981,theincidenceofCCAamong C.sinensis infectedpopulationisdeduced,namely35/100000and 25/100000inthemaleandfemale,respectively.Thirdly, aftermultiplyingtheglobalpopulationinfected,theglobal CCAcasesattributedto C.sinensis infectionarecaptured, namely4726,ofwhich3345aremaleand1381are female(Table2).Itmustbecautiousthatthemorbidityof cancerisachronicprogressspanningseveraldecades. Thus,theprevalenceof C.sinensis in1981wasadopted, whileCCAcasesin2005wereapplied[99].Likewise,the deducedglobalclonorchiasis-relatedCCAcasesmay occurseveraldecadeslatertheoretically. OneobviouslimitationisthatnoindividualORhas beenavailableforthemaleandfemale,respectively.Inthe studyfocusingontherelationshipbetween O.viverrini infectionandCCA,itwasfoundthehighertheinfectionintensity,thehighertheOR[102].Furthermore,compared tothefemale,themaleinfectedhavehigherinfection intensityaswasdepictedabove[10,11].Thus,itisreasonabletoassumedifferentORsshouldbeofferedfordifferentsexes.However,duetolackofsuchdata,onlythe sameORisadoptedhere. Conclusion Aconservativeestimationwasmadethat15millionpeoplewereinfectedwith C.sinensis in2004ineastAsia,especiallyinChina,theRepublicofKoreaandVietnam, whichmaycausenearly5000CCAcasesannuallyin thefuture.Althoughthepopulationinfectedisrelatively smallercomparedtoschistosomiasisandsoil-transmitted helminthiases,thedistributionishighlyconcentratedin severalAsiancountries,wherethepublichealthisbeing threatenedseverely.Furthermore,theimpactisincreasing andexpandingtonon-endemicareasduetothegrowth andmovementofpopulationandtherapiddevelopment ofaquaculture.Thus,itislistedamongthemostneglected tropicaldiseases[7,104].Fortunately,theevaluationon theburdenoffood-bornediseaseswaslaunchedbyWHO in2006andclonorchiasisandotherliverflukediseases wereincluded[105].Theassessmentofdiseaseburden promotestheawarenessofharm,adoptionofintervention andevaluationofcost-effectiveness.Epidemiologicaldata arethebasisofassessmentofdiseaseburden.Onlywhen thedataareavailable,candiseaseburdenbecalculated objectively.CCAisthemostsevereandfataloutcome causedby C.sinensis infection,whichpredominantlyconstitutesthemortalitylostofdiseaseburdenintermof disability-adjustedlifeyears[106].Therefore,theepidemiologicaldataonCCAisalsocrucial.Itisexpected thededuceddataonpopulationinfectedandCCAcases herewillbenefittheevaluationofdiseaseburdenofclonorchiasis,whichwillpromotethecontrolandprevention ultimately. However,furtherresearchesonepidemiologyofclonorchiasisandCCAshouldbecarriedout.Although nation-widesurveyshavebeencarriedoutinChinaand theRepublicofKorea,theepidemiologicalstatusin Vietnamisnotyetclearandthusnationallysampling surveywouldbeexpected.Whetherthereexistlocal transmissionandevenepidemicityinDPRKandMalaysia alsoneedstobesolved.Anotherimportantissueisthe speciesdiscrimination,whichmayturntothemolecular biologytechniques.NowthatKato-Katztechniqueisstill themajordiagnosismethodasitispathogen-oriented, convenientandatlowcost,howtoreducetheunderestimationespeciallyinlowinfectionlevelisimportant.The accurateevaluationofprevalencewillpromotetheadoptionofsuitableinterventionandobjectiveevaluationof diseaseburden.Newtechniquessuchasmodelsimulation maydeservebeingintroduced.Furtherstudiesontherelationshipbetween C.sinensis infectionandCCAarealso expected,especiallytheseparateORfordifferentsexes. Thedeterminationofexposureshouldalsobefurther Figure5 Meta-analysisofrelationshipintensity(OR)between C.sinensis infectionandCCA. Eventsdenote C.sinensis infection. Qian etal.InfectiousDiseasesofPoverty 2012, 1 :4 Page7of11 http://www.idpjournal.com/content/1/1/4

PAGE 9

Table2TheestimatedincidenceofCCAamongpopulationinfectedwith C.sinensis andCCAcasesattributableto C.sinensis infectiongloballySexTotalCCAcases intheRepublic ofKoreain2005#C.sinensis prevalencein theRepublic ofKoreain 1981*OR(95%CI)CCAcases attributableto C.sinensis infection intheRepublicof Korea(95%CI) Populationin theRepublicof Koreain1981Populationinfected intheRepublicof Koreain1981 CCAincidence ininfected (per100000) (95%CI) Globalpopulation infectedin2004 CCAcases attributableto C.sinensis infection Globally(95%CI) Male 21663.70%4.47(2.61-7.66)246(122 – 428)1904120370452535(17 – 61)95635893345(1653 – 5813) Female 14401.60%4.47(2.61-7.66)76(36 – 139)1901340030421425(12 – 46)55467551381(659 – 2528) Total --------4726(2312 – 8341)#Reference[ 99 ];*Reference[ 17 ];Reference[ 62 ].Qian etal.InfectiousDiseasesofPoverty 2012, 1 :4 Page8of11 http://www.idpjournal.com/content/1/1/4

PAGE 10

approached.TheprogressofCCAischronicandcomplicatedinwhichvariousfactorsareinvolved.Consequently, thepublichealthimpactofclonorchiasisisremarkably indicatedbytheabovementionedresultthatthededuced CCAcasesaresignificantlyattributedto C.sinensis infectionwithanoverallORof4.47,althoughtheresulthere maynotbehighlyaccurate.Asitshouldbe,newmethods areexpectedtobeappliedandmoreaccuratedatatobe captured.AdditionalfileAdditionalfile1: Multilingualabstractsinthesixofficialworking languagesoftheUnitedNations. Additionalfile2: Epidemiologicalstudiesontherelationship between C.sinensis infectionandCCA. Competinginterests Theauthorsdeclarethattheyhavenocompetinginterests. Authors ’ contributions M-BQandX-NZdesignedthestudy.M-BQandY-DCcollectedthedata. M-BQ,SLandG-JYanalyzedthedata.M-BQandX-NZwrotethepaper. Allauthorsreadandapprovedthemanuscript. Acknowledgments WearegratefultoCarlosA.M.LimadosSantosinBrazilforhiskindly presentationofsomepapersontheepidemiologyof Clonorchissinensis in Malaysia.Thisprojectisfundedthroughacapacitybuildinginitiativefor EcohealthResearchonEmergingInfectiousDiseaseinSoutheastAsia supportedbytheInternationalDevelopmentResearchCentre(IDRC),the CanadianInternationalDevelopmentAgency(CIDA),andtheAustralian AgencyforInternationalDevelopment(AusAID)inpartnershipwiththe GlobalHealthResearchInitiative(grantNo.105509-00001002-023),aswellas supportedbytheNationalS&TMajorProgram(grantNo.2008ZX10004011),andbytheNationalS&TSupportingProject(grantNo. 2007BAC03A02).ZhouXNwassupportedbyShanghaiS&TCommittee (grantNo.11XD1405400). Authordetails1NationalInstituteofParasiticDiseases,ChineseCenterforDiseaseControl andPrevention;WHOCollaborativeCenterforMalaria,Schistosomiasisand Filariasis;KeyLaboratoryofParasiteandVectorBiology,MinistryofHealth, Shanghai,People ’ sRepublicofChina.2DepartmentofEnvironmentaland GlobalHealth,CollegeofPublicHealthandHealthProfessions,and EmergingPathogensInstitute,UniversityofFlorida,Gainesville,USA.3Jiangsu InstituteofParasiticDiseases,Wuxi,People ’ sRepublicofChina.4Schoolof PublicHealth,ChineseUniversityofHongKong,HongKong,People ’ s RepublicofChina. Received:23August2012Accepted:24September2012 Published:25October2012 References1.LunZR,GasserRB,LaiDH,LiAX,ZhuXQ,YuXB,FangYY: Clonorchiasis:a keyfoodbornezoonosisinChina. LancetInfectDis 2005, 5: 31 – 41. 2.KeiserJ,UtzingerJ: Emergingfoodbornetrematodiasis. EmergInfectDis 2005, 11: 1507 – 1514. 3.KeiserJ,UtzingerJ: Food-bornetrematodiases. ClinMicrobiolRev 2009, 22: 466 – 483. 4.SripaB,KaewkesS,IntapanPM,MaleewongW,BrindleyPJ: Food-borne trematodiasesinSoutheastAsia:epidemiology,pathology,clinical manifestationandcontrol. AdvParasitol 2010, 72: 305 – 350. 5.BouvardV,BaanR,StraifK,GrosseY,SecretanB,ElGhissassiF, Benbrahim-TallaaL,GuhaN,FreemanC,GalichetL,CoglianoV,WHO InternationalAgencyforResearchonCancerMonographWorkingGroup: A reviewofhumancarcinogens--PartB:biologicalagents. LancetOncol 2009, 10: 321 – 322. 6.InternationalAgencyforResearchonCancer: AReviewofHuman CarcinogensPartB:BiologicalAgents.IARCmonographsontheevaluationof carcinogenicriskstohumans .Lyon:IARC;2011. 7. FirstWHOreportonneglectedtropicaldiseases2010:workingtoovercomethe globalimpactofneglectedtropicaldiseases .;[http://www.who.int/ neglected_diseases/2010report/en/] 8.WHO: ControlofFoodborneTrematodeInfections ,WHOTechnicalReport Series,Volume849.Geneva;WorldHealthOrganization;1995. 9.YuSH,XuLQ,JiangZX,XuSH,HanJJ,ZhuYG,ChangJ,LinJX,XuFN: NationwidesurveyofhumanparasiteinChina. SoutheastAsianJTrop MedPublicHealth 1994, 25: 4 – 10. 10.TechnicalSteeringPanelforNationalSurveyofCurrentStatusofMajor HumanParasiticDiseases: ReportontheNationalSurveyofCurrentStatusof MajorHumanParasiticDiseasesinChina .Beijing:People'sMedicalPublishing House;2008. 11.FangYY,ChenYD,LiXM,WuJ,ZhangQM,RuanCW: Currentprevalence of Clonorchissinensis infectioninendemicareasofChina. ChinJParasitol ParasitDis 2008, 26: 99 – 103.inChinese. 12.ChenER: ClonorchiasisinTaiwan. SoutheastAsianJTropMedPublicHealth 1991, 22 (Suppl):184 – 185. 13.FanPC: RegionaldistributionofhumanparasiticinfectioninTaiwan province .In DistributionandpathogenicimpactofhumanparasitesinChina 1stedition.EditedbyXuLQ,YuSH,XuSH.Beijing:People ’sMedical PublishingHouse;2000:262 – 279.inChinese. 14. NationalBureauofStatisticsofthePeople ’ sRepublicofChina,Communiqu onMajorFiguresofthePopulationCensus .[http://www.stats.gov.cn/tjgb/ rkpcgb/] 15.ZhengXB,LingML: StatusofintestinalparasiticinfectionsinHongKong In DistributionandpathogenicimpactofhumanparasitesinChina .1st edition.EditedbyXuLQ,YuSH,XuSH.Beijing:People ’ sMedicalPublishing House;2000:279 – 282.inChinese. 16.QuGY: StatusofhumanparasiticinfectionsinMacao .In Distributionand pathogenicimpactofhumanparasitesinChina .1stedition.EditedbyXuLQ, YuSH,XuSH.Beijing:People ’ sMedicalPublishingHouse;2000:282 – 286.in Chinese. 17.KimTS,ChoSH,HuhS,KongY,SohnWM,HwangSS,ChaiJY,LeeSH,Park YK,OhDK,LeeJK,WorkingGroupsinNationalInstituteofHealth;Korea AssociationofHealthPromotion: Anationwidesurveyontheprevalence ofintestinalparasiticinfectionsintheRepublicofKorea,2004. KoreanJ Parasitol 2009, 47: 37 – 47. 18.ChoSH,LeeKY,LeeBC,ChoPY,CheunHI,HongST,SohnWM,KimTS: PrevalenceofclonorchiasisinsouthernendemicareasofKoreain2006. KoreanJParasitol 2008, 46: 133 – 137. 19.DeNV,MurrellKD,leCongD,CamPD,leChauV,ToanND,DalsgaardA: Thefood-bornetrematodezoonosesofVietnam. SoutheastAsianJTrop MedPublicHealth 2003, 34 (Suppl1):12 – 34. 20.DeNV,LeTH: CurrentstatusofopisthorchiasisinVietnam .In Proceedings &Abstracts:96YearsofOpisthorchiasis,InternationalCongressofLiverFlukes: 7 – 8,March2011 .Thailand:KhonKaen;2011:49 – 51. 21.TrungDungD,VanDeN,WaikagulJ,DalsgaardA,ChaiJY,SohnWM, MurrellKD: Fishbornezoonoticintestinaltrematodes,Vietnam. Emerg InfectDis 2007, 13: 1828 – 1833. 22.WHO: ReportoftheWHOExpertConsultationonFoodborneTrematodeInfections andTaeniasis/Cysticercosis .Vientiane:WorldHealthOrganization;2009. 23.PhanVT,ErsbllAK,DoDT,DalsgaardA: Raw-fish-eatingbehaviorand fishbornezoonotictrematodeinfectioninpeopleofnorthernVietnam. FoodbornePathogDis 2011, 8: 255 – 260. 24.TraubRJ,MacaranasJ,MungthinM,LeelayoovaS,CribbT,MurrellKD, ThompsonRC: AnewPCR-basedapproachindicatestherangeofClonorchissinensis nowextendstoCentralThailand. PLoSNeglTropDis 2009, 3: e367. 25.ShenC,LiS,ZhengS,ChoiMH,BaeYM,HongST: Tissueparasitic helminthiasesareprevalentatCheongjin,NorthKorea. KoreanJParasitol 2007, 45: 139 – 144. 26.ShekharKC,NazarinaAR,LeeSH,PathmanathanR: Clonorchiasis/ opisthorchiasisinMalaysianscasereportsandreview. MedJMalaysia 1995, 50: 182 – 186.Qian etal.InfectiousDiseasesofPoverty 2012, 1 :4 Page9of11 http://www.idpjournal.com/content/1/1/4

PAGE 11

27.JamaiahI,RohelaM: Prevalenceofintestinalparasitesamongmembers ofthepublicinKualaLumpur,Malaysia. SoutheastAsianJTropMedPublic Health 2005, 36: 68 – 71. 28.RohelaM,JohariS,JamaiahI,InitI,LeeSH: Acutecholecystitiscausedby Clonorchissinensis SoutheastAsianJTropMedPublicHealth 2006, 37: 648 – 651. 29.BisseruB: Clonorchissinensis inWestMalaysia. TropGeogrMed 1970, 22: 352 – 356. 30.ShekharKC: Epidemiologicalaspectsofaquacultureinrelationtofish bornetrematodiasisinMalaysia. SoutheastAsianJTropMedPublicHealth 1997, 28 (Suppl1):54 – 57. 31.CarlosAM,LimadosSantos,HowgateP: Fishbornezoonoticparasitesand aquaculture:areview. Aquaculture 2011, 318: 253 – 261. 32.Nakamura-UchiyamaF,HiromatsuK,IshiwataK,SakamotoY,NawaY: The currentstatusofparasiticdiseasesinJapan. InternMed 2003, 42: 222 – 236. 33.OnoderaS,SaitoK,SaitoT,TogashiH,KawataS,UkaiK,ShinzawaH: Clonorchiasiscomplicatedwithduodenalpapillarycancerinavisitorfrom China. NipponShokakibyoGakkaiZasshi 2007, 104: 213 – 218.inJapanese. 34.MirdhaBR,GulatiS,SarkarT,SamantrayJC: Acuteclonorchiasisinachild. IndianJGastroenterol 1998, 17: 155. 35.TanWB,ShelatVG,DiddapurRK: Orientalliverflukeinfestationpresenting morethan50yearsafterimmigration. AnnAcadMedSingapore 2009, 38: 735 – 736. 36.KuzmickiR,DzieciolowskiZ,Borowska-KuzmickaJ: AcaseofClonorchis sinensisinfection. PolTygLek(Wars) 1959, 14: 819 – 821(inPolish). 37.Ku mickiR,GajdaE,Switalska-KowalewskaE: 2casesof Clonorchissinensis infectionwithassociatedinfestationwithotherparasites. WiadLek 1966, 19: 325 – 328(inPolish). 38.ZieglerK,OstenM,LafrenzM,MllerFW:Humaninfestationwithliver flukes. ZGesamteInnMed 1975, 30: 344 – 346(inGerman). 39.HartleyJP,DouglasAP: AcaseofclonorchiasisinEngland. BrMedJ 1975, 3: 575. 40.HollerA,BlanchonP,LapierreJ,HollerC: Letter:Distomatosiswith Clonorchissinensisdiagnosedbyhepaticpuncturebiopsy. NouvPresse Med 1976, 5: 39(inFrench). 41.TaatCW: Acutecholecystitisand clonorchissinensis infection. NedTijdschr Geneeskd 1981, 125: 2008 – 2012(inDutch). 42.WahlgrenM,WihlborgB,LiljeqvistL: Clonorchiasis – anunusualcauseof cholangitis. Lakartidningen 1983, 80: 153 – 154(inSwedish). 43.DennisMJ,DennisonAR,MorrisDL: Parasiticcausesofobstructive jaundice. AnnTropMedParasitol 1989, 83: 159 – 161. 44.PoinsignonY,MounierN,FritschS,SarfatiC,Farge-BancelD: Cholangitis dueto Clonorchissinensis detectedinEscherichiacolisepticshock. Med Trop(Mars) 1996, 56: 203(inFrench). 45.StunellH,BuckleyO,GeogheganT,TorreggianiWC: Recurrentpyogenic cholangitisduetochronicinfestationwith Clonorchissinensis (2006:8b). EurRadiol 2006, 16: 2612 – 2614. 46.CiprandiG,CavallucciE,CuccurulloF,DiGioacchinoM: Helminthic infectionasafactorinnew-onsetcoffeeallergyinafatherand daughter. JAllergyClinImmunol 2008, 121: 773 – 774. 47.DixonBR,FlohrRB: Fish-andshellfish – bornetrematodeinfectionsin Canada. SoutheastAsianJTropMedPublicHealth 1997, 28 (Suppl1):58 – 64. 48.FriedB,AbruzziA: Food-bornetrematodeinfectionsofhumansinthe UnitedStatesofAmerica. ParasitolRes 2010, 106: 1263– 1280. 49.CaleroC: ClonorchiasisinChineseresidentsofPanama. JParasitol 1967, 53: 1150. 50.OostburgBF,SmithSJ: ClonorchiasisinSurinam. TropGeogrMed 1981, 33: 287 – 289. 51.GmezN,UrreaI,AstudillioR: Primaryepidermoidcarcinomaofthe gallbladder. ActaGastroenterolLatinoam 1990, 20: 169 – 173. 52.AttwoodHD,ChouST: Thelongevityof Clonorchissinensis Pathology 1978, 10: 153 – 156. 53.MorsyAT,Al-MathalEM: Clonorchissinensis anewreportinEgyptian employeesreturningbackfromSaudiArabia. JEgyptSocParasitol 2011, 41: 221 – 225. 54.KaewkesS: Taxonomyandbiologyofliverflukes. ActaTrop 2003, 88: 177 – 186. 55.JohansenMV,SithithawornP,BergquistR,UtzingerJ: Towardsimproved diagnosisofzoonotictrematodeinfectionsinSoutheastAsia. Adv Parasitol 2010, 73: 171 – 195. 56.SithithawornP,TesanaS,PipitgoolV,KaewkesS,PairojkulC,SripaB, PaupairojA,ThaiklarK: Relationshipbetweenfaecaleggcountandworm burdenof Opisthorchisviverrini inhumanautopsycases. Parasitology 1991, 102 (Pt2):277 – 281. 57.UtzingerJ,RinaldiL,LohourignonLK,RohnerF,ZimmermannMB, TschannenAB,N'goranEK,CringoliG: FLOTAC:anewsensitivetechnique forthediagnosisofhookworminfectionsinhumans. TransRSocTrop MedHyg 2008, 102: 84 – 90. 58.LinDD,LiuJX,LiuYM,HuF,ZhangYY,XuJM,LiJY,JiMJ,BergquistR,Wu GL,WuHW: RoutineKato-Katztechniqueunderestimatestheprevalence of Schistosomajaponicum :acasestudyinanendemicareaofthe People'sRepublicofChina. ParasitolInt 2008, 57: 281 – 286. 59.KnoppS,RinaldiL,KhamisIS,StothardJR,RollinsonD,MaurelliMP,Steinmann P,MartiH,CringoliG,UtzingerJ:AsingleFLOTACismoresensitivethan triplicateKato-Katzforthediagnosisoflow-intensitysoil-transmitted helminthinfections. TransRSocTropMedHyg 2009, 103: 347 – 354. 60.KnoppS,GlinzD,RinaldiL,MohammedKA,N'GoranEK,StothardJR,Marti H,CringoliG,RollinsonD,UtzingerJ: FLOTAC:apromisingtechniquefor detectinghelmintheggsinhumanfaeces. TransRSocTropMedHyg 2009, 103: 1190 – 1194. 61.GlinzD,SiluKD,KnoppS,LohourignonLK,YaoKP,SteinmannP, RinaldiL,CringoliG,N'GoranEK,UtzingerJ: Comparingdiagnostic accuracyofKato-Katz,Kogaagarplate,ether-concentration,and FLOTACfor Schistosomamansoni andsoil-transmittedhelminths. PLoSNeglTropDis 2010, 4: e754. 62.UnitedNations,PopulationDivision,DepartmentofEconomicandSocial Affairs,WorldPopulationProspects: The2010Revision [http://esa.un.org/ unpd/wpp/Excel-Data/population.htm] 63.FoodandAgricultureOrganizationoftheUnitedNations,Fisheriesand AquacultureDepartment: FisheryStatisticalCollections:ConsumptionofFish andFisheryProducts [http://www.fao.org/fishery/statistics/globalconsumption/en] 64.ChenMG,LuY,HuaXJ,MottKE: Progressinassessmentofmorbiditydue to clonorchissinensis infection:areviewofrecentliterature. TropDisBull 1994, 91: R7 – R65. 65.NontasutP,ThongTV,WaikagulJ,AnantaphrutiMT,FungladdaW,Imamee N,DeNV: Socialandbehavioralfactorsassociatedwith Clonorchis infection inonecommunelocatedintheRedRiverDeltaofVietnam. SoutheastAsianJTropMedPublicHealth 2003, 34: 269 – 273. 66.DuanJH,TangXY,WangQZ,TangY,ZhangZS,LiZX,LiuAH,WuYJ,Chen WH,HuangQR: EpidemiologicalSurveyon Clonorchiasissinensis inan EndemicAreaofSouthHunanProvince. ChinJParasitolParasitDis 2009, 27: 467 – 471(inChinese). 67.DiseaseControlBureauofMinistryofHealthofthePeople ’ sRepublicof ChinaandChineseCenterforDiseaseControlandPrevention: Assessing reportofthecomprehensivedemonstratingzonesforcontrollingandtreating ofparasiticdiseasesbetween2006and2009 .Beijing;People ’ sMedical PublishingHouse;2010. 68.ChoiBI,HanJK,HongST,LeeKH: Clonorchiasisandcholangiocarcinoma: etiologicrelationshipandimagingdiagnosis. ClinMicrobiolRev 2004, 17: 540 – 552. 69.WattanayingcharoenchaiS: Nationalsurveyof Opisthorchisviverrini in Thailand:currentsituationandcontrol .In Proceedings&Abstracts:96YearsofOpisthorchiasis,InternationalCongressofLiverFlukes:7 – 8,March2011 Thailand:KhonKaen;2011:35. 70.SithithawornP,AndrewsRH,VanDeN,WongsarojT,SinuonM, OdermattP,NawaY,LiangS,BrindleyPJ,SripaB: Thecurrentstatus ofopisthorchiasisandclonorchiasisintheMekongBasin. ParasitolInt 2012, 61 (1):10 – 16. 71.ChoiDW: Clonorchissinensis :lifecycle,intermediatehosts,transmission tomanandgeographicaldistributioninKorea. Arzneimittelforschung 1984, 34 (9B):1145 – 1151. 72.MordvinovVA,YurlovaNI,OgorodovaLM,KatokhinAV: Opisthorchis felineus and Metorchisbilis arethemainagentsofliverflukeinfectionof humansinRussia. ParasitolInt 2012, 61 (1):25 – 31. 73.BlechaczBR,GoresGJ: Cholangiocarcinoma. ClinLiverDis 2008, 12: 131 – 150.ix. 74.KhanSA,ToledanoMB,Taylor-RobinsonSD: Epidemiology,riskfactors,and pathogenesisofcholangiocarcinoma. HPB(Oxford) 2008, 10: 77 – 82. 75.MosconiS,BerettaGD,LabiancaR,ZampinoMG,GattaG,HeinemannV: Cholangiocarcinoma. CritRevOncolHematol 2009, 69: 259 – 270.Qian etal.InfectiousDiseasesofPoverty 2012, 1 :4 Page10of11 http://www.idpjournal.com/content/1/1/4

PAGE 12

76.ShaibY,El-SeragHB: Theepidemiologyofcholangiocarcinoma. Semin LiverDis 2004, 24: 115 – 125. 77.ShinHR,OhJK,MasuyerE,CuradoMP,BouvardV,FangYY,WiangnonS, SripaB,HongST: Epidemiologyofcholangiocarcinoma:anupdate focusingonriskfactors. CancerSci 2010, 101: 579 – 585. 78.SripaB,KaewkesS,SithithawornP,MairiangE,LahaT,SmoutM, PairojkulC,BhudhisawasdiV,TesanaS,ThinkamropB,BethonyJM, LoukasA,BrindleyPJ: Liverflukeinducescholangiocarcinoma. PLoS Med 2007, 4: e201. 79.InternationalAgencyforResearchonCancer: Schistosomes,liverflukesand Helicobacterpylori.IARCmonographsontheevaluationofcarcinogenicrisks tohumans .Lyon;IARC;1994. 80.GibsonJB: Parasites,LiverDiseaseandLiverCancer .Lyon:IARC;1971. 81.KimYI,YangDH,ChangKR: Relationshipbetween Clonorchissinensis infestationandcholangiocarcinomaoftheliverinKorea. SeoulJMed 1974, 15: 247 – 253(inKorean). 82.ChungCS,LeeSK: Anepidemiologicalstudyofprimarylivercarcinomas inBusanareawithspecialreferencetoclonorchis. KoreanJPathol 1976, 10: 33 – 46(inKorean). 83.ShinHR,LeeCU,ParkHJ,SeolSY,ChungJM,ChoiHC,AhnYO,Shigemastu T: HepatitisBandCvirus, Clonorchissinensis fortheriskoflivercancer:a case – controlstudyinPusan,Korea. IntJEpidemiol 1996, 25: 933 – 940. 84.ChoiD,LimJH,LeeKT,LeeJK,ChoiSH,HeoJS,JangKT,LeeNY,KimS, HongST: Cholangiocarcinomaand Clonorchissinensis infection:a case – controlstudyinKorea. JHepatol 2006, 44: 1066 – 1073. 85.LeeTY,LeeSS,JungSW,JeonSH,YunSC,OhHC,KwonS,LeeSK,SeoDW, KimMH,SuhDJ: HepatitisBvirusinfectionandintrahepatic cholangiocarcinomainKorea:acase – controlstudy. AmJGastroenterol 2008, 103: 1716 – 1720. 86.CaiWK,SimaH,ChenBD,YangGS: Riskfactorsforhilar cholangiocarcinoma:Acase – controlstudyinChina. WorldJGastroenterol 2011,17: 249 – 253. 87.PengNF,LiLQ,QinX,GuoY,PengT,XiaoKY,ChenXG,YangYF,SuZX, ChenB,SuM,QiLN: Evaluationofriskfactorsandclinicopathologic featuresforintrahepaticcholangiocarcinomainSouthernChina:a possibleroleofhepatitisBvirus. AnnSurgOncol 2011, 18: 1258 – 1266. 88.RimHJ: Clonorchiasis:anupdate. JHelminthol 2005, 79: 269 – 281. 89.ChoiD,LimJH,LeeKT,LeeJK,ChoiSH,HeoJS,ChoiDW,JangKT,LeeNY, KimS,HongST: Gallstonesand Clonorchissinensis infection:ahospitalbasedcase – controlstudyinKorea. JGastroenterolHepatol 2008, 23 (8Pt2):e399 – e404. 90.McFadzeanAJ,YeungRT: Acutepancreatitisdueto Clonorchissinensis TransRSocTropMedHyg 1966, 60: 466 – 470. 91.ChoiTK,WongJ: Severeacutepancreatitiscausedbyparasitesinthe commonbileduct. JTropMedHyg 1984, 87: 211 – 214. 92.BalthazarEJ,LambT: CTof ClonorchisSinensis pancreatitis. IntJPancreatol 1993, 14: 189 – 194. 93.KimYH: Pancreatitisinassociationwith Clonorchissinensis infestation:CT evaluation. AJRAmJRoentgenol 1999, 172: 1293 – 1296. 94.YangLC,HuangBY,XueGF,LiXL,MoDL: Relationshipbetweeninfection of Clonorchissinensis andhepatobiliaryandpancreaticdiseases. ChinJ HepatobiliarySurg 2004, 10: 165 – 166(inChinese). 95.HuangH,JiaLP,XieCS,GuYP,WangHX: Analysisonetiologyofacute pancreatitisinNanhairegionofGuangdongprovince. ChinJIntegrTrad WestMedDig 2005, 13: 43 – 44(inChinese). 96.LimMK,JuYH,FranceschiS,OhJK,KongHJ,HwangSS,ParkSK,ChoSI, SohnWM,KimDI,YooKY,HongST,ShinHR:Clonorchissinensis infection andincreasingriskofcholangiocarcinomaintheRepublicofKorea. AmJ TropMedHyg 2006, 75: 93 – 96. 97.ZhouYM,YinZF,YangJM,LiB,ShaoWY,XuF,WangYL,LiDQ: Risk factorsforintrahepaticcholangiocarcinoma:acase – controlstudyin China. WorldJGastroenterol 2008, 14: 632 – 635. 98.ParkinDM: Theglobalhealthburdenofinfection-associatedcancersin theyear2002. IntJCancer 2006, 118: 3030 – 3044. 99.ShinHR,OhJK,LimMK,ShinA,KongHJ,JungKW,WonYJ,ParkS,ParkSJ, HongST: Descriptiveepidemiologyofcholangiocarcinomaand clonorchiasisinKorea. JKoreanMedSci 2010, 25: 1011 – 1016. 100.KurathongS,LerdverasirikulP,WongpaitoonV,PramoolsinsapC, KanjanapitakA,VaravithyaW,PhuapraditP,BunyaratvejS,UpathamES, BrockelmanWY: Opisthorchisviverriniinfectionandcholangiocarcinoma. Aprospective,case-controlledstudy. Gastroenterology 1985, 89: 151 – 156. 101.ParkinDM,SrivatanakulP,KhlatM,ChenvidhyaD,ChotiwanP,InsiripongS, L'AbbKA,WildCP: LivercancerinThailand.I.Acase – controlstudyof cholangiocarcinoma. IntJCancer 1991, 8: 323 – 328. 102.Haswell-ElkinsMR,MairiangE,MairiangP,ChaiyakumJ,ChamadolN, LoapaiboonV,SithithawornP,ElkinsDB: Cross-sectionalstudyof Opisthorchisviverrini infectionandcholangiocarcinomaincommunities withinahigh-riskareainnortheastThailand. IntJCancer 1994, 59: 505 – 509. 103.HonjoS,SrivatanakulP,SriplungH,KikukawaH,HanaiS,UchidaK,Todoroki T,JedpiyawongseA,KittiwatanachotP,SripaB,DeerasameeS,MiwaM: Geneticandenvironmentaldeterminantsofriskforcholangiocarcinoma via Opisthorchisviverrini inadenselyinfestedareainNakhonPhanom, northeastThailand. IntJCancer 2005, 117: 854 – 860. 104.SripaB: Concertedactionisneededtotackleliverflukeinfectionsin Asia. PLoSNeglTropDis 2008, 2: e232. 105. WHOInitiativetoestimatetheGlobalBurdenofFoodborneDiseases [http:// www.who.int/foodsafety/foodborne_disease/ferg/en/index.html] 106.QianMB,ChenYD,FangYY,XuLQ,ZhuTJ,TanT,ZhouCH,WangGF,Jia TW,YangGJ,ZhouXN:DisabilityWeightof Clonorchissinensis Infection: CapturedfromCommunityStudyandModelSimulation. PLoSNeglTrop Dis 2011, 5: e1377.doi:10.1186/2049-9957-1-4 Citethisarticleas: Qian etal. : Theglobalepidemiologyofclonorchiasis anditsrelationwithcholangiocarcinoma. InfectiousDiseasesofPoverty 2012 1 :4. Submit your next manuscript to BioMed Central and take full advantage of: € Convenient online submission € Thorough peer review € No space constraints or color “gure charges € Immediate publication on acceptance € Inclusion in PubMed, CAS, Scopus and Google Scholar € Research which is freely available for redistribution Submit your manuscript at www.biomedcentral.com/submit Qian etal.InfectiousDiseasesofPoverty 2012, 1 :4 Page11of11 http://www.idpjournal.com/content/1/1/4