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1、Residual risk for transfusion transmitted infections,输血传染病的残余风险,Outline,Current interventionsHow residual risk is estimatedHow safe is safe?What are the needs?Pathways,目 录,目前的干预手段如何评估残余风险什么样的安全才是安全的有哪些需要途径,Setting the scene,Blood safety is an area of considerable public,regulatory and political conc
2、ern,even though transfusion appears to be one of the safest therapeutic measures available.Surveillance,donor selection,testing and hemovigilance,along with the use of quality systems and deferral registries have led to a situation where residual risk for key infections may be lower than one infecti
3、on in 2 million units transfused.Nevertheless,further measures are proposed and are vigorously supported by some thought leaders.Is there a framework for appropriate decision-making,or is it appropriate to continue to seek a zero-risk blood supply?Will the current system of health-care funding suppo
4、rt such an approach?,场景设置,血液安全是一个非常受公众、行政和政策关注的领域，即使输血似乎是最安全的治疗手段之一。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，使关键感染的残余风险低于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应（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？,Agents for which there are current interventions,Questions plus testingHBV,HCV,HIV,HTLV,
5、syphilisTesting onlyWNV,T.cruzi,(CMV,bacteria)Questions onlyCJD,vCJD,HAV,malaria,babesia,leishmaniaQuestions assumed to have impactHHV-8,tropical infections,emergent situations(e.g.,SARS),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
6、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）,Recent additions,Formal approach to hemovigilanceApproval and limited use of HBV DNA testingChagas testing adopted by majority of blood collectorsBacterial testing by culture,approval for POU test(with very limited claims)WNV testing,with IDT-NAT if necess
7、ary,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,Why is there risk?,Failure of selection processAbsence of tests Insensitive testsLaboratory failureMutant or variant organismsWindow period infectionsPeriod in early infection with circulating ag
8、ent,but prior to test positivity,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,Measuring risk by direct observation,Posttransfusion studiesTTV,NIH,FACTSMost infections too infrequent Infectious donationsBusch,Vyas:Culture of seronegative donations for HIV Busch,VyasSimilar issueBack-C
9、alculationHistorical data only,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,Declining risk of transfusion-associated hepatitis,Adapted from HJ Alter,输血相关肝炎风险的减少,Adapted from HJ Alter,Estimation of risk from donor datafor known infections with testing,With effe
10、ctive testing,the largest component of risk is from window period Risk is a function of window period times incidence of new infections Need to define window period Need to define incidenceUpdate by reference to test improvements,从献血者已知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
11、考检测技术的改进而更新,Measuring incidence rates,New infections per person,per time Measured among repeat donors With at least 2 donations within a two year study periodNumerator:number of seroconversions Denominator:person-years of observation,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,Incid
12、ence measures,Dodd,Notari,Stramer.Transfusion 2002;42:975-979,发病率计算,Dodd,Notari,Stramer.Transfusion 2002;42:975-979,Impact of first-time blood donors on window period risk,Window period risk is a function of the length of the window period and the frequency of new infections(incidence)among donors I
13、ncidence can be measured among repeat donors by observationOther methods are necessary to measure incidence in first-time donors:if the incidence differs,then overall risk estimates must be adjusted.,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
14、计必须加以调整。,Incidence in first-time donors,Use of a less-sensitive(LS)test for HIV(Busch)The proportion of samples positive by the routine test and negative by the LS test can be used to calculate incidence,if the LS window period is knownUse of NAT data from routine HCV testing(Dodd)NAT yield and the
15、NAT window period can be used to calculate incidenceBoth studies found that the incidence(and thus risk)among FT donors was 2.4 X of repeat donorsLater data suggests that this approach may be susceptible to bias from test-seekers,第一次献血者的发病率,使用低灵敏的方法检测HIV如果已知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
16、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,Individual rates and linear regression model of HIV RNA in early infection,LOG HIV RNA gEq/mL,1,2,3,4,5,6,7,8,9,-10,-5,0 day,5,10,15,20,N=97 Samples from 44 Plasma donorsDT:21.5 hrs(95%CI:19.2-24.6),AIDS
17、,17:1871-9,2003,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,1,2,3,4,5,6,7,8,9,-10,-5,0 day,5,10,15,20,N=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,17:1871-9,2003,HCV,3.4(0.22),9.0(0.60),6.0(1.08),170.0(10.0),ID-NAT,MP-NAT,p24 Ag,WB,S/LSEIA,ID-NAT,MP-NAT,50.9(2.47),EIA 3.0,5.6(0.40),5.3(1.02),1 copy
18、/20 mls,1 copy/20 mls,4.9(0.45),2.5(0.22),7.4(0.67),Window Periods in Days(Standard Error)for HIV and HCV,Busch et al.Transfusion,2005;45:254-64.,HIV,HCV,3.4(0.22),9.0(0.60),6.0(1.08),170.0(10.0),单人份-NAT,汇集-NAT,p24 抗原,蛋白印记,酶免疫试验,ID-NAT,MP-NAT,50.9(2.47),第3代酶免疫测定,5.6(0.40),5.3(1.02),1 拷贝/20 毫升,1 copy
19、/20 mls,4.9(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）,Busch et al.Transfusion,2005;45:254-64.,HIV,Day of Infection,1 copy/20 mls,HBsAg detection by Auszyme at S/CO of 1.0(6,800 copies/mL),HBsAg detection by Prism at S/CO of 1.0(1,664 copies/mL),10 copy/20 mls,ECLIPSE PHASE,8.3 days,5.3 days,3
20、0 days,INFECTIOUS PHASE,38.3 days,HBV window period time-line,Kleinman and Busch.Assessing the Impact of HBV NAT on Window Period Reduction and Residual Risk,J Clin Virol 2006,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,8.3 days
21、,5.3 days,30 days,传染期,38.3 days,乙肝病毒窗口期的时间线程,Kleinman and Busch.Assessing the Impact of HBV NAT on Window Period Reduction and Residual Risk,J Clin Virol 2006,Residual risk,all donors(US),美国献血者的残余风险,Other viruses,WNV23 cases in 2002,9 cases since initiation of testing,3 since use of selective IDTB19
22、Definitely transmissible,but few reported clinical casesHHV-8Transmissibility established outside US,2 potential transmissions reported in US,no clinical outcome reportedCMVUnknown,but may still be an occasional risk,even with LR and testingDengue,HAV,HEVOccasional cases reported(not necessarily in
23、the US),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，但仍可能是一个机会性的风险，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）,Bacteria,Bacterial testing of apheresis products initiated in 2004Assessment of risk based upon reporting(ARC
24、)Pre testing:Septic reactions 1:40,000Fatalities 1:240,000Post testingSeptic reactions 1:75,000Fatalities:1:500,000 Further reductions attributable to sample diversion,Eder et al.TRANSFUSION 2007;47:1134-1142.,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基础上（美国红十字会）检测前脓毒反应1:40,000死亡率1:240,000检测后脓毒反应1:75,000死亡率1:50
25、0,000细菌的进一步减少归因于样品的转移,Eder et al.TRANSFUSION 2007;47:1134-1142.,Direct infectivity from bacteria,SyphilisNo recent cases reportedTest-positive units do not have detectable T.pallidum DNA/RNA(n=169)Anaplasma phagocytophilum1 potential transmission reported(in an abstract)Other bacteria-(including Bor
26、relia burgdorferi)None reported in the US in recent years,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）,Parasites,MalariaCurrently,fewer than 1 case per year in the US At a cost of 100,000 deferrals Chagas disease7 known cases in US and CanadaSeroprevalence 1:30,000Pr
27、e-test risk probably 1:300,000Testing implemented January 2007 Babesia60 cases reported in past 20 years Risk may be up to 1:1,000 in areas of high endemicity No effective intervention at this time,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已知7例病例血清感染率1:30,000检测前风险可能1:300,000 2007年1月实施检测巴贝西虫过去20年内约报道60例
28、在高流行性的地方，风险可达1:1000目前无有效的干预手段,How does this square with reality?,HIVNo transmission reported since 2002HCVNo transmission reported since 1999HBVFewer than 10 transmissions in the past 4 years,none after implementaiton of highly sensitive HBsAg testing HTLVNo transmission reported since?WNV9 cases si
29、nce 2003(6 of which were in 2003 incomplete IDT)MalariaFewer than 1 case per year for the past ten yearsBabesiaMore than 60 known casesCJDNo cases of CJD.3 cases,1 transmission of vCJD in UK,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 炎表面抗原检测后，无1例传染HTLV 自？年以来没有传染报道WNV 自2
30、003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例已知病例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,Emerging Infections,New AgentExpanding RangeImportedReemergentNewly recognizedPatient changes,HIV,BSE/vCJD,SARSBabesia,EhrlichiaChagas,WNVMalariaHHV-6,8,TTV.CMV,B19?,新 发 感 染,新的疾病范围扩大的疾病I外
31、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,Elements of an emerging infections program,Surveillance/IntelligenceAssessment for relevancePublic health Public concern Measures of risk Investigation of intervention(s)RecommendationsImplementa
32、tionEvaluation,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,Concern high,Action favored,Benefit HighAction favored,vCJD,CJD,Lyme,HGV,etc,RMSF,HAV,Ehrlichia,B19,Babesia,T.cruzi,Bacteria,HHV 8,HHV 6,HIVHBVHCV,idprio2001,Chlamydia,Leptospira,Bartonella,HPV,etc.,Ebola etc,Leishmania,Malaria,WNV,关注度
33、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,Leishmania,Malaria疟疾,西尼罗病毒,Emerging infections,Inherently difficult to define risk May show very rapid progression/expansion(WNV,SARS)Not always predictable(chiku
34、ngunya virus)“Precautionary principle”often invoked(but often without benefit of moderating commentaries)Unique solutions may be neededNo unifying epidemiologic pattern,新 发 感 染,本来难以确定的风险可表现出非常迅速的发展/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“预防原则”(but often without benefit of moderating commentaries)需要唯一的解决方案没
35、有统一的流行病学模式,How safe is safe?,Perception of risk is not straightforward Low risk values are hard to conceptualize or visualizeVoluntary risk cannot be equated with imposed riskFear and dread have a major impact on perceptionDiffuse risk(e.g.,drug reaction)seems to be more palatable than focused risk,
36、什么样的安全才是安全的,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心和恐惧对感觉产生重大影响散播性风险（例如，药物反应）似乎比焦距式风险更容易接受。,How safe is safe?,Reported deaths from transfusion amount to fewer than 50 reported cases per year(with a minor proportion from viral infections)Risk of death from hospital errors estimated to be on the o
37、rder of 100,000 per yearYet transfusion medicine represents about 2%of health-care expenditures,什么样的安全才是安全的,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）由医院差错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,Drivers of safety,Ethical imperativesAdvocacyAccreditationPublic and political pressuresCompetitionExamples from other cou
38、ntriesAvailable technologies(Fear of)litigationRegulation,安全的驱动力,道德义务宣传认可公众和政治压力竞争其他国家的榜样可用的技术（恐惧）诉讼管理,What are the needs?,Zero risk?All the safety we can afford?Who makes that decision?Acceptable risk?What does that mean?An arbitrary value?Risk that is as low as reasonably achievable?What is“reason
39、ably”?Continuous improvement with no specific target?Are there different standards for different agents?HIV,vCJD compared with HTLV,babesiaModerate the escalation of current interventions?Deferrals,testing,有 那 些 需 求？,零风险？我们能够负担得起所有的安全吗？谁作出决定？可接受的风险？这意味着什么？一个任意的价值呢？风险应在可以合理达到最低水平吗？什么是“合理”？没有具体目标的持续改进
40、？不同的病原有不同的标准？艾滋病病毒、变异的疯牛病病毒与人t细胞淋巴瘤病毒和贝西虫进行比较控制目前干预的扩大？延期，检测,Pathways,Education and advocacyWhat is“reasonable”Rational public health decision structureExplicit balance of costs and benefits across health careAlternative funding mechanismsHow to pay for enhanced safety?More testsBetter testsLess tra
41、ditional bloodInactivation/removal,途 径,教育和宣传什么是“合理的”理性的公共健康决策构架明确保健成本和效益的平衡替代的筹资机制如何支付加强的安全？更多的检测更好的检测少一点传统的血液灭活/去除,Advantages of pathogen reduction,Blood safety reduction of infectivityReduction of bacterial contaminationReduction of immunologic effectsElimination of many new testing requirementsIn
42、creased public confidence,病原体减少的优点,血液安全-减少感染减少细菌污染减少免疫效应减少许多新的检测要求 增强公众信心,Potential disadvantages of pathogen reduction,Added cost,complexityStaff safety Reduced therapeutic doseUncertainty about product safety(despite data)Neoantigenicity of treated productReduction,not true inactivationNot approvable for non-validated conditionsMarket uncertainty(cf SD plasma,LR)No single method for all components,病原体去除的潜在缺点,增加成本和复杂性工作人员的安全减少治疗剂量有关产品安全的不确定性（尽管数据）治疗产品新抗原性减少，而不是真正的失活不批准非确认情况市场的不确定性（SD血浆，去白）对于所有成分，没有简单的方法,Thank you for your attentionQuestions?,谢谢您的关注 有问题吗？,
