輸血傳染病的殘余風(fēng)險(xiǎn)

Residualriskfortransfusion

transmittedinfectionsChyangT.Fang,PhD Suzhou,ChinaOctober2021RogerY.Dodd,PhD ACBSA,Washington,DCJanuary20211整理課件輸血傳染病的剩余風(fēng)險(xiǎn)2整理課件OutlineCurrentinterventionsHowresidualriskisestimatedHowsafeissafe?

Whataretheneeds?Pathways3整理課件目錄目前的干預(yù)手段如何評估剩余風(fēng)險(xiǎn)什么樣的平安才是平安的有哪些需要途徑4整理課件SettingthesceneBloodsafetyisanareaofconsiderablepublic,regulatoryandpoliticalconcern,eventhoughtransfusionappearstobeoneofthesafesttherapeuticmeasuresavailable.Surveillance,donorselection,testingandhemovigilance,alongwiththeuseofqualitysystemsanddeferralregistrieshaveledtoasituationwhereresidualriskforkeyinfectionsmaybelowerthanoneinfectionin2millionunitstransfused.Nevertheless,furthermeasuresareproposedandarevigorouslysupportedbysomethoughtleaders.

Isthereaframeworkforappropriatedecision-making,orisitappropriatetocontinuetoseekazero-riskbloodsupply?

Willthecurrentsystemofhealth-carefundingsupportsuchanapproach?

5整理課件場景設(shè)置血液平安是一個(gè)非常受公眾、行政和政策關(guān)注的領(lǐng)域，即使輸血似乎是最平安的治療手段之一。監(jiān)控、獻(xiàn)血者的選擇、檢測、血液預(yù)警以及質(zhì)量體系和推遲登記的應(yīng)用，使關(guān)鍵感染的剩余風(fēng)險(xiǎn)低于1/200萬單位輸血。然而，一些思想倡導(dǎo)者仍建議和強(qiáng)烈支持采取進(jìn)一步的措施。是否有一個(gè)適當(dāng)?shù)臎Q策框架，或者繼續(xù)尋求一個(gè)零風(fēng)險(xiǎn)的血液供給〔方案〕是否適當(dāng)？現(xiàn)行的健康保健資金體系未來還能夠支持這種做法？6整理課件AgentsforwhichtherearecurrentinterventionsQuestionsplustestingHBV,HCV,HIV,HTLV,syphilisTestingonlyWNV,T.cruzi,(CMV,bacteria)QuestionsonlyCJD,vCJD,HAV,malaria,babesia,leishmaniaQuestionsassumedtohaveimpactHHV-8,tropicalinfections,emergentsituations(e.g.,SARS)7整理課件目前干預(yù)的幾個(gè)內(nèi)容需要質(zhì)疑和檢測的內(nèi)容乙型肝炎病毒，丙型肝炎病毒，艾滋病毒，人類嗜T細(xì)胞病毒，梅毒螺旋體只需要檢測的內(nèi)容西尼羅河病毒，克氏錐蟲，〔巨細(xì)胞病毒，細(xì)菌〕只需要質(zhì)疑的內(nèi)容克雅氏病，變種克雅氏病，甲肝，瘧疾，巴貝西蟲，利什曼原蟲需要質(zhì)疑假設(shè)可產(chǎn)生影響的內(nèi)容皰疹病毒-8，熱帶傳染病，緊急情況〔如非典〕8整理課件RecentadditionsFormalapproachtohemovigilanceApprovalandlimiteduseofHBVDNAtestingChagas’testingadoptedbymajorityofbloodcollectorsBacterialtestingbyculture,approvalforPOUtest(withverylimitedclaims)WNVtesting,withIDT-NATifnecessary9整理課件最近新增血液預(yù)警的標(biāo)準(zhǔn)方法同意和限制使用乙肝病毒DNA檢測被多數(shù)血液采集者接納的南美錐蟲檢測利用培養(yǎng)進(jìn)行細(xì)菌檢測，認(rèn)可使用POU檢測〔有非常局限的要求〕西尼羅病毒檢測，必要時(shí)對單個(gè)樣本進(jìn)行NAT檢測10整理課件Whyisthererisk?FailureofselectionprocessAbsenceoftestsInsensitivetestsLaboratoryfailureMutantorvariantorganismsWindowperiodinfectionsPeriodinearlyinfectionwithcirculatingagent,butpriortotestpositivity11整理課件為什么有風(fēng)險(xiǎn)篩選過程失敗沒有檢測不靈敏的檢測

實(shí)驗(yàn)失敗病原體突變或變異窗口期感染早期感染期，有循環(huán)抗體，但先于測試陽性12整理課件MeasuringriskbydirectobservationPosttransfusionstudiesTTV,NIH,FACTSMostinfectionstooinfrequentInfectiousdonationsBusch,Vyas:CultureofseronegativedonationsforHIVBusch,VyasSimilarissueBack-CalculationHistoricaldataonly13整理課件通過直接觀察來檢測風(fēng)險(xiǎn)輸血后研究新型肝炎病毒，美國國立衛(wèi)生研究院的數(shù)據(jù)大多數(shù)傳染很少發(fā)生有傳染性的獻(xiàn)血的研究:艾滋病毒血清學(xué)陰性的血液的培養(yǎng)類似的問題追溯只有歷史數(shù)據(jù)

14整理課件Decliningriskoftransfusion-associatedhepatitisAdaptedfromHJAlter15整理課件輸血相關(guān)肝炎風(fēng)險(xiǎn)的減少AdaptedfromHJAlter16整理課件Estimationofriskfromdonordata

forknowninfectionswithtestingWitheffectivetesting,thelargestcomponentofriskisfromwindowperiodRiskisafunctionofwindowperiodtimesincidenceofnewinfectionsNeedtodefinewindowperiodNeedtodefineincidenceUpdatebyreferencetotestimprovements17整理課件從獻(xiàn)血者感染的檢測數(shù)據(jù)中進(jìn)行風(fēng)險(xiǎn)評估通過有效的檢測，最大的風(fēng)險(xiǎn)因素來自窗口期風(fēng)險(xiǎn)是新感染窗口期的一個(gè)作用需要定義窗口期需要定義發(fā)病率參考檢測技術(shù)的改進(jìn)而更新18整理課件MeasuringincidenceratesNewinfectionsperperson,pertimeMeasuredamongrepeatdonorsWithatleast2donationswithinatwoyearstudyperiodNumerator:numberofseroconversions

Denominator:person-yearsofobservation19整理課件檢測發(fā)病率每人、每時(shí)間段的新發(fā)感染在重復(fù)獻(xiàn)血者中檢測兩年研究期間內(nèi)至少獻(xiàn)血2次分子：血清轉(zhuǎn)化的數(shù)量分母：觀察的人-年數(shù)20整理課件Incidencemeasures___________________________________________________________________________________________________

Number(incidencephtpy)ofnewinfectionsamongselectedrepeatdonors,bytime__________________________________________________Period______HTPY_______HBsAg___________HCV__________HIV__________HTLV____________98-9939.5178(1.974)95(2.404)63(1.595)55(1.392)99-0040.4749(1.186)81(2.001)59(1.458)15(0.371)00-0141.8253(1.267)79(1.889)65(1.554)10(0.239)___________________________________________________________________________________________________Dodd,Notari,Stramer.Transfusion2002;42:975-97921整理課件發(fā)病率計(jì)算___________________________________________________________________________________________________重復(fù)獻(xiàn)血者研究期間內(nèi)新發(fā)感染的發(fā)生數(shù)量（發(fā)病率）

__________________________________________________Period______HTPY_______HBsAg___________HCV__________HIV__________HTLV____________98-9939.5178(1.974)95(2.404)63(1.595)55(1.392)99-0040.4749(1.186)81(2.001)59(1.458)15(0.371)00-0141.8253(1.267)79(1.889)65(1.554)10(0.239)___________________________________________________________________________________________________Dodd,Notari,Stramer.Transfusion2002;42:975-97922整理課件Impactoffirst-timeblooddonorsonwindowperiodriskWindowperiodriskisafunctionofthelengthofthewindowperiodandthefrequencyofnewinfections(incidence)amongdonorsIncidencecanbemeasuredamongrepeatdonorsbyobservationOthermethodsarenecessarytomeasureincidenceinfirst-timedonors:iftheincidencediffers,thenoverallriskestimatesmustbeadjusted.23整理課件第一次獻(xiàn)血者對窗口期風(fēng)險(xiǎn)的影響窗口期風(fēng)險(xiǎn)是獻(xiàn)血者窗口期長度和新發(fā)感染頻率〔發(fā)病率〕的作用可在重復(fù)獻(xiàn)血者中通過觀察計(jì)算發(fā)生率必須采用其他方法檢測首次獻(xiàn)血者中的發(fā)病率：如果發(fā)病率不同，那么對整體風(fēng)險(xiǎn)的估計(jì)必須加以調(diào)整。24整理課件Incidenceinfirst-timedonorsUseofaless-sensitive(LS)testforHIV(Busch)

TheproportionofsamplespositivebytheroutinetestandnegativebytheLStestcanbeusedtocalculateincidence,iftheLS‘window’periodisknownUseofNATdatafromroutineHCVtesting(Dodd)NATyieldandtheNATwindowperiodcanbeusedtocalculateincidenceBothstudiesfoundthattheincidence(andthusrisk)amongFTdonorswas~2.4XofrepeatdonorsLaterdatasuggeststhatthisapproachmaybesusceptibletobiasfromtest-seekers25整理課件第一次獻(xiàn)血者的發(fā)病率使用低靈敏的方法檢測HIV如果低靈敏方法的窗口期，常規(guī)方法檢測陽性標(biāo)本與低靈敏方法檢測陰性標(biāo)本的比例可用來計(jì)算發(fā)病率使用常規(guī)HCV的NAT檢測數(shù)據(jù)檢測結(jié)果和NAT窗口期可以用來計(jì)算發(fā)病率Both研究發(fā)現(xiàn)，第一次獻(xiàn)血者的發(fā)病率〔和風(fēng)險(xiǎn)〕是重復(fù)獻(xiàn)血者的2.4倍最新數(shù)據(jù)顯示，這種方法可能會因受試者而易產(chǎn)生偏差26整理課件IndividualratesandlinearregressionmodelofHIVRNAinearlyinfectionLOGHIVRNA

[gEq/mL]123456789-10-50day5101520N=97Samplesfrom44PlasmadonorsDT:21.5hrs(95%CI:19.2-24.6)AIDS,17:1871-9,200327整理課件早期感染中艾滋病毒RNA檢測的各體率和線性回歸模型艾滋病毒RNA的對數(shù)值123456789-10-50day5101520N=97個(gè)樣品來自44個(gè)供血漿者

DT：21.5小時(shí)〔95％的可信區(qū)間：19.2-24.6〕AIDS,17:1871-9,200328整理課件HCV3.4(0.22)9.0(0.60)6.0(1.08)170.0(10.0)ID-NATMP-NATp24AgWBS/LSEIA

ID-NATMP-NAT50.9(2.47)EIA3.05.6(0.40)5.3(1.02)1copy/20mls1copy/20mls4.9(0.45)2.5(0.22)7.4(0.67)WindowPeriodsinDays(StandardError)forHIVandHCVBuschetal.Transfusion,2005;45:254-64.HIV29整理課件HCV3.4(0.22)9.0(0.60)6.0(1.08)170.0(10.0)單人份-NAT聚集-NATp24抗原蛋白印記酶免疫試驗(yàn)ID-NATMP-NAT50.9(2.47)第3代酶免疫測定5.6(0.40)5.3(1.02)1拷貝/20毫升1copy/20mls4.9(0.45)2.5(0.22)7.4(0.67)艾滋病毒和丙型肝炎病毒的窗口期天數(shù)〔標(biāo)準(zhǔn)誤〕Buschetal.Transfusion,2005;45:254-64.HIV30整理課件DayofInfection1copy/20mlsHBsAgdetectionbyAuszymeatS/COof1.0(6,800copies/mL)HBsAgdetectionbyPrismatS/COof1.0(1,664copies/mL)

10copy/20mlsECLIPSEPHASE8.3days5.3days30daysINFECTIOUSPHASE38.3daysHBVwindowperiodtime-lineKleinmanandBusch.AssessingtheImpactofHBVNATonWindowPeriodReductionandResidualRisk,JClinVirol2006

31整理課件感染天數(shù)1拷貝/20毫升Auszyme報(bào)道的S/CO值為1.0時(shí)的HBsAg檢測結(jié)果〔6800拷貝/毫升Prism報(bào)道的S/CO值為1.0時(shí)的HBsAg檢測結(jié)果〔1664拷貝/毫升

10拷貝/20毫升潛伏期8.3days5.3days30days傳染期38.3days乙肝病毒窗口期的時(shí)間線程KleinmanandBusch.AssessingtheImpactofHBVNATonWindowPeriodReductionandResidualRisk,JClinVirol2006

32整理課件Residualrisk,alldonors(US)InfectionResidualriskfrom:RepeatdonorsAlldonorsHBV1:205,0001:144,000HCV(withoutNAT)1:276,0001:199,000HCV(withNAT)1:1,935,0001:1,390,000HIV(withoutNAT)1:1,468,0001:1,048,000HIV(withNAT)1:2,135,0001;1,525,000HTLV1:2,993,0001:2,230,00033整理課件美國獻(xiàn)血者的剩余風(fēng)險(xiǎn)感染殘余風(fēng)險(xiǎn)來自重復(fù)獻(xiàn)血者所有獻(xiàn)血者HBV1:205,0001:144,000HCV(無NAT)1:276,0001:199,000HCV(有NAT)1:1,935,0001:1,390,000HIV(無NAT)1:1,468,0001:1,048,000HIV(有NAT)1:2,135,0001;1,525,000HTLV1:2,993,0001:2,230,00034整理課件OthervirusesWNV 23casesin2002,9casessinceinitiation oftesting,3sinceuseofselectiveIDTB19 Definitelytransmissible,butfewreported clinicalcasesHHV-8 TransmissibilityestablishedoutsideUS,2 potentialtransmissionsreportedinUS,no clinicaloutcomereportedCMV Unknown,butmaystillbeanoccasional risk,evenwithLRandtestingDengue,HAV,HEV Occasionalcasesreported(not necessarilyintheUS)35整理課件其他病毒西尼羅病毒 2002年23例，其中9例是剛開始進(jìn)行西尼羅病毒檢測的結(jié)果，3例是使用選擇性的單個(gè)樣本NAT的檢測結(jié)果B19 明確可傳染，但僅有少數(shù)臨床病例報(bào)告HHV-8 美國之外已確定傳染性，美國國內(nèi)有2例潛在傳染的報(bào)道，沒有報(bào)告任何臨床結(jié)果CMV 不詳，但仍可能是一個(gè)時(shí)機(jī)性的風(fēng)險(xiǎn)，即使有去白和檢測登革熱，甲肝，戊肝病毒

不定期例報(bào)告〔在美國不是必須的〕36整理課件BacteriaBacterialtestingofapheresisproductsinitiatedin2004Assessmentofriskbaseduponreporting(ARC)

Pretesting:Septicreactions1:40,000Fatalities1:240,000PosttestingSepticreactions1:75,000Fatalities:1:500,000FurtherreductionsattributabletosamplediversionEderetal.TRANSFUSION2007;47:1134-1142.37整理課件細(xì)菌單采產(chǎn)品的細(xì)菌檢測始于2004年風(fēng)險(xiǎn)評估建立在報(bào)告的根底上〔美國紅十字會〕檢測前膿毒反響1:40,000死亡率1:240,000檢測后膿毒反響1:75,000死亡率1:500,000細(xì)菌的進(jìn)一步減少歸因于樣品的轉(zhuǎn)移Ederetal.TRANSFUSION2007;47:1134-1142.38整理課件DirectinfectivityfrombacteriaSyphilisNorecentcasesreportedTest-positiveunitsdonothavedetectableT.pallidumDNA/RNA(n=169)Anaplasma

phagocytophilum1potentialtransmissionreported(inanabstract)Otherbacteria-(includingBorrelia

burgdorferi)NonereportedintheUSinrecentyears39整理課件由細(xì)菌引起的直接感染梅毒沒有新近報(bào)告的病例檢測陽性血液沒有可撿出的蒼白螺旋體DNA/RNA嗜吞噬細(xì)胞無漿體報(bào)告1例潛在傳播〔在一篇摘要里〕？〔少翻一句〕40整理課件ParasitesMalariaCurrently,fewerthan1caseperyearintheUSAtacostof~100,000deferralsChagas’disease7knowncasesinUSandCanadaSeroprevalence1:30,000Pre-testriskprobably<1:300,000TestingimplementedJanuary2007Babesia~60casesreportedinpast20yearsRiskmaybeupto1:1,000inareasofhighendemicity

Noeffectiveinterventionatthistime41整理課件寄生蟲瘧疾目前，美國每年少于1例，代價(jià)是約10萬延期南美錐蟲病在美國和加拿大7例病例血清感染率1:30,000檢測前風(fēng)險(xiǎn)可能<1:300,0002007年1月實(shí)施檢測巴貝西蟲過去20年內(nèi)約報(bào)道60例在高流行性的地方，風(fēng)險(xiǎn)可達(dá)1:1000目前無有效的干預(yù)手段42整理課件Howdoesthissquarewithreality?HIV Notransmissionreportedsince2002HCV Notransmissionreportedsince1999HBV Fewerthan10transmissionsinthepast4years, noneafterimplementaitonofhighlysensitive HBsAgtestingHTLV Notransmissionreportedsince????WNV 9casessince2003(6ofwhichwerein2003– incompleteIDT)Malaria Fewerthan1caseperyearforthepasttenyearsBabesia Morethan60knowncasesCJD NocasesofCJD. 3cases,1transmissionofvCJDinUK43整理課件現(xiàn)實(shí)情況是怎樣？HIV 自2002年以來沒有傳染報(bào)道HCV 自1999年以來沒有傳染報(bào)道HBV 過去4年中傳染不到10例，實(shí)施高度敏感的乙型肝炎外表抗原檢測后，無1例傳染HTLV自？？？？年以來沒有傳染報(bào)道WNV自2003年以來有9例西尼羅病毒〔其中6例是在2003年傳染-不完全的單個(gè)樣本NAT〕Malaria在過去10年里每年少于1例傳染Babesia超過60例病例CJD 沒有任何克雅氏病病例。

有3例變異病例，1例在英國感染44整理課件EmergingInfectionsNewAgentExpandingRangeImportedReemergentNewlyrecognizedPatientchangesHIV,BSE/vCJD,SARSBabesia,EhrlichiaChagas’,WNVMalariaHHV-6,8,TTV….CMV,B19?45整理課件新發(fā)感染新的疾病范圍擴(kuò)大的疾病I外來的疾病重新發(fā)生的疾病新確認(rèn)的疾病病人的改變艾滋病，瘋牛病/變異的瘋牛病巴貝西蟲病/埃立克體病南美錐蟲感染，西尼羅病毒感染瘧疾皰疹病毒-和8型的感染，輸血傳染病毒的感染巨細(xì)胞病毒的感染，B19病毒？的感染46整理課件ElementsofanemerginginfectionsprogramSurveillance/IntelligenceAssessmentforrelevancePublichealthPublicconcernMeasuresofriskInvestigationofintervention(s)RecommendationsImplementationEvaluation47整理課件一個(gè)新發(fā)感染報(bào)告程序的組成監(jiān)控/智能化意義評估公眾健康公眾關(guān)心控制風(fēng)險(xiǎn)的措施干預(yù)調(diào)查建議執(zhí)行評估48整理課件Concernhigh,ActionfavoredBenefitHighActionfavoredvCJDCJDLymeHGV,etcRMSFHAVEhrlichiaB19BabesiaT.cruziBacteriaHHV8HHV6HIVHBVHCVidprio2001Chlamydia,Leptospira,Bartonella,HPV,etc.EbolaetcLeishmaniaMalariaWNV49整理課件關(guān)注度高

結(jié)果滿意效益高

結(jié)果滿意變異的瘋牛病瘋牛病病螺旋體庚肝等落磯山斑疹熱科羅拉多蜱熱HAV甲肝病毒埃立克體

B19病毒巴貝西蟲枯氏錐蟲細(xì)菌皰疹病毒-8皰疹病毒-6艾滋病idprio2001衣原體痙攣性假硬化鉤端螺旋體巴爾通體，等埃博拉病毒等LeishmaniaMalaria瘧疾

西尼羅病毒50整理課件EmerginginfectionsInherentlydifficulttodefineriskMayshowveryrapidprogression/expansion(WNV,SARS)Notalwayspredictable(chikungunyavirus)“Precautionaryprinciple〞ofteninvoked(butoftenwithoutbenefitofmoderatingcommentaries)UniquesolutionsmaybeneededNounifyingepidemiologicpattern51整理課件新發(fā)感染本來難以確定的風(fēng)險(xiǎn)可表現(xiàn)出非常迅速的開展/擴(kuò)張〔西尼羅病毒，非典〕不總是可預(yù)測的〔基孔肯亞病病毒〕經(jīng)常呼吁“預(yù)防原那么〞(butoftenwithoutbenefitofmoderatingcommentaries)需要唯一的解決方案沒有統(tǒng)一的流行病學(xué)模式52整理課件Howsafeissafe?PerceptionofriskisnotstraightforwardLowriskvaluesarehardtoconceptualizeorvisualizeVoluntaryriskcannotbeequatedwithimposedriskFearanddreadhaveamajorimpactonperceptionDiffuserisk(e.g.,drugreaction)seemstobemorepalatablethanfocusedrisk53整理課件什么樣的平安才是平安的風(fēng)險(xiǎn)的感知不是簡單的低風(fēng)險(xiǎn)的價(jià)值是難以概念化或形象化的自愿的風(fēng)險(xiǎn)不能等同于強(qiáng)制風(fēng)險(xiǎn)擔(dān)憂和恐懼對感覺產(chǎn)生重大影響散播性風(fēng)險(xiǎn)〔例如，藥物反響〕似乎比焦距式風(fēng)險(xiǎn)更容易接受。54整理課件55整理課件56整理課件Howsafeissafe?Reporteddeathsfromtransfusionamounttofewerthan50reportedcasesperyear(withaminorproportionfromviralinfections)

Riskofdeathfromhospitalerrorsestimatedtobeontheorderof100,000peryearYettransfusionmedicinerepresentsabout2%ofhealth-careexpenditures57整理課件什么樣的平安才是平安的輸血死亡報(bào)告數(shù)每年少于50例〔其中病毒感染占的比例非常小〕由醫(yī)院過失導(dǎo)致的死亡風(fēng)險(xiǎn)為每年1/100000然而，輸血醫(yī)學(xué)占醫(yī)療保健支出的約2％58整理課件DriversofsafetyEthicalimperativesAdvocacyAccreditationPublicandpoliticalpressuresCompetitionExamplesfromothercountriesAvailabletechnologies(Fearof)litigationRegulation59整理課件平安的驅(qū)動力道德義務(wù)宣傳認(rèn)可公眾和政治壓力競爭其他國家的典范可用的技術(shù)〔恐懼〕訴訟管理60整理課件Whataretheneeds?Zerorisk?Allthesafetywecanafford?Whomakesthatdecision?Acceptablerisk?Whatdoesthatmean?Anarbitraryvalue?Riskthatisaslowasreasonablyachievable?Whatis“reasonably〞?Continuousimprov