输血传染病的残余风险

Residualriskfortransfusion

transmittedinfectionsChyangT.Fang,PhD Suzhou,ChinaOctober2021RogerY.Dodd,PhD ACBSA,Washington,DCJanuary20211整理课件输血传染病的剩余风险2整理课件OutlineCurrentinterventionsHowresidualriskisestimatedHowsafeissafe?

Whataretheneeds?Pathways3整理课件目录目前的干预手段如何评估剩余风险什么样的平安才是平安的有哪些需要途径4整理课件SettingthesceneBloodsafetyisanareaofconsiderablepublic,regulatoryandpoliticalconcern,eventhoughtransfusionappearstobeoneofthesafesttherapeuticmeasuresavailable.Surveillance,donorselection,testingandhemovigilance,alongwiththeuseofqualitysystemsanddeferralregistrieshaveledtoasituationwhereresidualriskforkeyinfectionsmaybelowerthanoneinfectionin2millionunitstransfused.Nevertheless,furthermeasuresareproposedandarevigorouslysupportedbysomethoughtleaders.

Isthereaframeworkforappropriatedecision-making,orisitappropriatetocontinuetoseekazero-riskbloodsupply?

Willthecurrentsystemofhealth-carefundingsupportsuchanapproach?

5整理课件场景设置血液平安是一个非常受公众、行政和政策关注的领域，即使输血似乎是最平安的治疗手段之一。监控、献血者的选择、检测、血液预警以及质量体系和推迟登记的应用，使关键感染的剩余风险低于1/200万单位输血。然而，一些思想倡导者仍建议和强烈支持采取进一步的措施。是否有一个适当的决策框架，或者继续寻求一个零风险的血液供给〔方案〕是否适当？现行的健康保健资金体系未来还能够支持这种做法？6整理课件AgentsforwhichtherearecurrentinterventionsQuestionsplustestingHBV,HCV,HIV,HTLV,syphilisTestingonlyWNV,T.cruzi,(CMV,bacteria)QuestionsonlyCJD,vCJD,HAV,malaria,babesia,leishmaniaQuestionsassumedtohaveimpactHHV-8,tropicalinfections,emergentsituations(e.g.,SARS)7整理课件目前干预的几个内容需要质疑和检测的内容乙型肝炎病毒，丙型肝炎病毒，艾滋病毒，人类嗜T细胞病毒，梅毒螺旋体只需要检测的内容西尼罗河病毒，克氏锥虫，〔巨细胞病毒，细菌〕只需要质疑的内容克雅氏病，变种克雅氏病，甲肝，疟疾，巴贝西虫，利什曼原虫需要质疑假设可产生影响的内容疱疹病毒-8，热带传染病，紧急情况〔如非典〕8整理课件RecentadditionsFormalapproachtohemovigilanceApprovalandlimiteduseofHBVDNAtestingChagas’testingadoptedbymajorityofbloodcollectorsBacterialtestingbyculture,approvalforPOUtest(withverylimitedclaims)WNVtesting,withIDT-NATifnecessary9整理课件最近新增血液预警的标准方法同意和限制使用乙肝病毒DNA检测被多数血液采集者接纳的南美锥虫检测利用培养进行细菌检测，认可使用POU检测〔有非常局限的要求〕西尼罗病毒检测，必要时对单个样本进行NAT检测10整理课件Whyisthererisk?FailureofselectionprocessAbsenceoftestsInsensitivetestsLaboratoryfailureMutantorvariantorganismsWindowperiodinfectionsPeriodinearlyinfectionwithcirculatingagent,butpriortotestpositivity11整理课件为什么有风险筛选过程失败没有检测不灵敏的检测

实验失败病原体突变或变异窗口期感染早期感染期，有循环抗体，但先于测试阳性12整理课件MeasuringriskbydirectobservationPosttransfusionstudiesTTV,NIH,FACTSMostinfectionstooinfrequentInfectiousdonationsBusch,Vyas:CultureofseronegativedonationsforHIVBusch,VyasSimilarissueBack-CalculationHistoricaldataonly13整理课件通过直接观察来检测风险输血后研究新型肝炎病毒，美国国立卫生研究院的数据大多数传染很少发生有传染性的献血的研究:艾滋病毒血清学阴性的血液的培养类似的问题追溯只有历史数据

14整理课件Decliningriskoftransfusion-associatedhepatitisAdaptedfromHJAlter15整理课件输血相关肝炎风险的减少AdaptedfromHJAlter16整理课件Estimationofriskfromdonordata

forknowninfectionswithtestingWitheffectivetesting,thelargestcomponentofriskisfromwindowperiodRiskisafunctionofwindowperiodtimesincidenceofnewinfectionsNeedtodefinewindowperiodNeedtodefineincidenceUpdatebyreferencetotestimprovements17整理课件从献血者感染的检测数据中进行风险评估通过有效的检测，最大的风险因素来自窗口期风险是新感染窗口期的一个作用需要定义窗口期需要定义发病率参考检测技术的改进而更新18整理课件MeasuringincidenceratesNewinfectionsperperson,pertimeMeasuredamongrepeatdonorsWithatleast2donationswithinatwoyearstudyperiodNumerator:numberofseroconversions

Denominator:person-yearsofobservation19整理课件检测发病率每人、每时间段的新发感染在重复献血者中检测两年研究期间内至少献血2次分子：血清转化的数量分母：观察的人-年数20整理课件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整理课件发病率计算___________________________________________________________________________________________________重复献血者研究期间内新发感染的发生数量（发病率）

__________________________________________________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整理课件Impactoffirst-timeblooddonorsonwindowperiodriskWindowperiodriskisafunctionofthelengthofthewindowperiodandthefrequencyofnewinfections(incidence)amongdonorsIncidencecanbemeasuredamongrepeatdonorsbyobservationOthermethodsarenecessarytomeasureincidenceinfirst-timedonors:iftheincidencediffers,thenoverallriskestimatesmustbeadjusted.23整理课件第一次献血者对窗口期风险的影响窗口期风险是献血者窗口期长度和新发感染频率〔发病率〕的作用可在重复献血者中通过观察计算发生率必须采用其他方法检测首次献血者中的发病率：如果发病率不同，那么对整体风险的估计必须加以调整。24整理课件Incidenceinfirst-timedonorsUseofaless-sensitive(LS)testforHIV(Busch)

TheproportionofsamplespositivebytheroutinetestandnegativebytheLStestcanbeusedtocalculateincidence,iftheLS‘window’periodisknownUseofNATdatafromroutineHCVtesting(Dodd)NATyieldandtheNATwindowperiodcanbeusedtocalculateincidenceBothstudiesfoundthattheincidence(andthusrisk)amongFTdonorswas~2.4XofrepeatdonorsLaterdatasuggeststhatthisapproachmaybesusceptibletobiasfromtest-seekers25整理课件第一次献血者的发病率使用低灵敏的方法检测HIV如果低灵敏方法的窗口期，常规方法检测阳性标本与低灵敏方法检测阴性标本的比例可用来计算发病率使用常规HCV的NAT检测数据检测结果和NAT窗口期可以用来计算发病率Both研究发现，第一次献血者的发病率〔和风险〕是重复献血者的2.4倍最新数据显示，这种方法可能会因受试者而易产生偏差26整理课件IndividualratesandlinearregressionmodelofHIVRNAinearlyinfectionLOGHIVRNA

[gEq/mL]123456789-10-50day5101520N=97Samplesfrom44PlasmadonorsDT:21.5hrs(95%CI:19.2-24.6)AIDS,17:1871-9,200327整理课件早期感染中艾滋病毒RNA检测的各体率和线性回归模型艾滋病毒RNA的对数值123456789-10-50day5101520N=97个样品来自44个供血浆者

DT：21.5小时〔95％的可信区间：19.2-24.6〕AIDS,17:1871-9,200328整理课件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整理课件HCV3.4(0.22)9.0(0.60)6.0(1.08)170.0(10.0)单人份-NAT聚集-NATp24抗原蛋白印记酶免疫试验ID-NATMP-NAT50.9(2.47)第3代酶免疫测定5.6(0.40)5.3(1.02)1拷贝/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数〔标准误〕Buschetal.Transfusion,2005;45:254-64.HIV30整理课件DayofInfection1copy/20mlsHBsAgdetectionbyAuszymeatS/COof1.0(6,800copies/mL)HBsAgdetectionbyPrismatS/COof1.0(1,664copies/mL)

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

31整理课件感染天数1拷贝/20毫升Auszyme报道的S/CO值为1.0时的HBsAg检测结果〔6800拷贝/毫升Prism报道的S/CO值为1.0时的HBsAg检测结果〔1664拷贝/毫升

10拷贝/20毫升潜伏期8.3days5.3days30days传染期38.3days乙肝病毒窗口期的时间线程KleinmanandBusch.AssessingtheImpactofHBVNATonWindowPeriodReductionandResidualRisk,JClinVirol2006

32整理课件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整理课件美国献血者的剩余风险感染残余风险来自重复献血者所有献血者HBV1:205,0001:144,000HCV(无NAT)1:276,0001:199,000HCV(有NAT)1:1,935,0001:1,390,000HIV(无NAT)1:1,468,0001:1,048,000HIV(有NAT)1:2,135,0001;1,525,000HTLV1:2,993,0001:2,230,00034整理课件OthervirusesWNV 23casesin2002,9casessinceinitiation oftesting,3sinceuseofselectiveIDTB19 Definitelytransmissible,butfewreported clinicalcasesHHV-8 TransmissibilityestablishedoutsideUS,2 potentialtransmissionsreportedinUS,no clinicaloutcomereportedCMV Unknown,butmaystillbeanoccasional risk,evenwithLRandtestingDengue,HAV,HEV Occasionalcasesreported(not necessarilyintheUS)35整理课件其他病毒西尼罗病毒 2002年23例，其中9例是刚开始进行西尼罗病毒检测的结果，3例是使用选择性的单个样本NAT的检测结果B19 明确可传染，但仅有少数临床病例报告HHV-8 美国之外已确定传染性，美国国内有2例潜在传染的报道，没有报告任何临床结果CMV 不详，但仍可能是一个时机性的风险，即使有去白和检测登革热，甲肝，戊肝病毒

不定期例报告〔在美国不是必须的〕36整理课件BacteriaBacterialtestingofapheresisproductsinitiatedin2004Assessmentofriskbaseduponreporting(ARC)

Pretesting:Septicreactions1:40,000Fatalities1:240,000PosttestingSepticreactions1:75,000Fatalities:1:500,000FurtherreductionsattributabletosamplediversionEderetal.TRANSFUSION2007;47:1134-1142.37整理课件细菌单采产品的细菌检测始于2004年风险评估建立在报告的根底上〔美国红十字会〕检测前脓毒反响1:40,000死亡率1:240,000检测后脓毒反响1:75,000死亡率1:500,000细菌的进一步减少归因于样品的转移Ederetal.TRANSFUSION2007;47:1134-1142.38整理课件DirectinfectivityfrombacteriaSyphilisNorecentcasesreportedTest-positiveunitsdonothavedetectableT.pallidumDNA/RNA(n=169)Anaplasma

phagocytophilum1potentialtransmissionreported(inanabstract)Otherbacteria-(includingBorrelia

burgdorferi)NonereportedintheUSinrecentyears39整理课件由细菌引起的直接感染梅毒没有新近报告的病例检测阳性血液没有可捡出的苍白螺旋体DNA/RNA嗜吞噬细胞无浆体报告1例潜在传播〔在一篇摘要里〕？〔少翻一句〕40整理课件ParasitesMalariaCurrently,fewerthan1caseperyearintheUSAtacostof~100,000deferralsChagas’disease7knowncasesinUSandCanadaSeroprevalence1:30,000Pre-testriskprobably<1:300,000TestingimplementedJanuary2007Babesia~60casesreportedinpast20yearsRiskmaybeupto1:1,000inareasofhighendemicity

Noeffectiveinterventionatthistime41整理课件寄生虫疟疾目前，美国每年少于1例，代价是约10万延期南美锥虫病在美国和加拿大7例病例血清感染率1:30,000检测前风险可能<1:300,0002007年1月实施检测巴贝西虫过去20年内约报道60例在高流行性的地方，风险可达1:1000目前无有效的干预手段42整理课件Howdoesthissquarewithreality?HIV Notransmissionreportedsince2002HCV Notransmissionreportedsince1999HBV Fewerthan10transmissionsinthepast4years, noneafterimplementaitonofhighlysensitive HBsAgtestingHTLV Notransmissionreportedsince????WNV 9casessince2003(6ofwhichwerein2003– incompleteIDT)Malaria Fewerthan1caseperyearforthepasttenyearsBabesia Morethan60knowncasesCJD NocasesofCJD. 3cases,1transmissionofvCJDinUK43整理课件现实情况是怎样？HIV 自2002年以来没有传染报道HCV 自1999年以来没有传染报道HBV 过去4年中传染不到10例，实施高度敏感的乙型肝炎外表抗原检测后，无1例传染HTLV自？？？？年以来没有传染报道WNV自2003年以来有9例西尼罗病毒〔其中6例是在2003年传染-不完全的单个样本NAT〕Malaria在过去10年里每年少于1例传染Babesia超过60例病例CJD 没有任何克雅氏病病例。

有3例变异病例，1例在英国感染44整理课件EmergingInfectionsNewAgentExpandingRangeImportedReemergentNewlyrecognizedPatientchangesHIV,BSE/vCJD,SARSBabesia,EhrlichiaChagas’,WNVMalariaHHV-6,8,TTV….CMV,B19?45整理课件新发感染新的疾病范围扩大的疾病I外来的疾病重新发生的疾病新确认的疾病病人的改变艾滋病，疯牛病/变异的疯牛病巴贝西虫病/埃立克体病南美锥虫感染，西尼罗病毒感染疟疾疱疹病毒-和8型的感染，输血传染病毒的感染巨细胞病毒的感染，B19病毒？的感染46整理课件ElementsofanemerginginfectionsprogramSurveillance/IntelligenceAssessmentforrelevancePublichealthPublicconcernMeasuresofriskInvestigationofintervention(s)RecommendationsImplementationEvaluation47整理课件一个新发感染报告程序的组成监控/智能化意义评估公众健康公众关心控制风险的措施干预调查建议执行评估48整理课件Concernhigh,ActionfavoredBenefitHighActionfavoredvCJDCJDLymeHGV,etcRMSFHAVEhrlichiaB19BabesiaT.cruziBacteriaHHV8HHV6HIVHBVHCVidprio2001Chlamydia,Leptospira,Bartonella,HPV,etc.EbolaetcLeishmaniaMalariaWNV49整理课件关注度高

结果满意效益高

结果满意变异的疯牛病疯牛病病螺旋体庚肝等落矶山斑疹热科罗拉多蜱热HAV甲肝病毒埃立克体

B19病毒巴贝西虫枯氏锥虫细菌疱疹病毒-8疱疹病毒-6艾滋病idprio2001衣原体痉挛性假硬化钩端螺旋体巴尔通体，等埃博拉病毒等LeishmaniaMalaria疟疾

西尼罗病毒50整理课件EmerginginfectionsInherentlydifficulttodefineriskMayshowveryrapidprogression/expansion(WNV,SARS)Notalwayspredictable(chikungunyavirus)“Precautionaryprinciple〞ofteninvoked(butoftenwithoutbenefitofmoderatingcommentaries)UniquesolutionsmaybeneededNounifyingepidemiologicpattern51整理课件新发感染本来难以确定的风险可表现出非常迅速的开展/扩张〔西尼罗病毒，非典〕不总是可预测的〔基孔肯亚病病毒〕经常呼吁“预防原那么〞(butoftenwithoutbenefitofmoderatingcommentaries)需要唯一的解决方案没有统一的流行病学模式52整理课件Howsafeissafe?PerceptionofriskisnotstraightforwardLowriskvaluesarehardtoconceptualizeorvisualizeVoluntaryriskcannotbeequatedwithimposedriskFearanddreadhaveamajorimpactonperceptionDiffuserisk(e.g.,drugreaction)seemstobemorepalatablethanfocusedrisk53整理课件什么样的平安才是平安的风险的感知不是简单的低风险的价值是难以概念化或形象化的自愿的风险不能等同于强制风险担忧和恐惧对感觉产生重大影响散播性风险〔例如，药物反响〕似乎比焦距式风险更容易接受。54整理课件55整理课件56整理课件Howsafeissafe?Reporteddeathsfromtransfusionamounttofewerthan50reportedcasesperyear(withaminorproportionfromviralinfections)

Riskofdeathfromhospitalerrorsestimatedtobeontheorderof100,000peryearYettransfusionmedicinerepresentsabout2%ofhealth-careexpenditures57整理课件什么样的平安才是平安的输血死亡报告数每年少于50例〔其中病毒感染占的比例非常小〕由医院过失导致的死亡风险为每年1/100000然而，输血医学占医疗保健支出的约2％58整理课件DriversofsafetyEthicalimperativesAdvocacyAccreditationPublicandpoliticalpressuresCompetitionExamplesfromothercountriesAvailabletechnologies(Fearof)litigationRegulation59整理课件平安的驱动力道德义务宣传认可公众和政治压力竞争其他国家的典范可用的技术〔恐惧〕诉讼管理60整理课件Whataretheneeds?Zerorisk?Allthesafetywecanafford?Whomakesthatdecision?Acceptablerisk?Whatdoesthatmean?Anarbitraryvalue?Riskthatisaslowasreasonablyachievable?Whatis“reasonably〞?Continuousimprov