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Residual risk for transfusion transmitted infections

Residual risk for transfusion transmitted infections. Chyang T. Fang, PhD Suzhou, China October 2008 Roger Y. Dodd, PhD ACBSA, Washington, DC January 2008. 输血传染病的残余风险. 方强宗 博士 中国苏州 2008 年 10 月 Roger Y. Dodd 博士 华盛顿特区 2008 年 1 月. Outline. Current interventions

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Residual risk for transfusion transmitted infections

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  1. Residual risk for transfusion transmitted infections Chyang T. Fang, PhD Suzhou, China October 2008 Roger Y. Dodd, PhD ACBSA, Washington, DC January 2008

  2. 输血传染病的残余风险 方强宗 博士 中国苏州 2008年10月 Roger Y. Dodd 博士 华盛顿特区 2008年1月

  3. Outline • Current interventions • How residual risk is estimated • How safe is safe? • What are the needs? • Pathways

  4. 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

  5. Setting the scene Blood safety is an area of considerable public, regulatory and political concern, 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 infection 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 support such an approach?

  6. 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？

  7. Agents for which there are current interventions • Questions plus testing • HBV, HCV, HIV, HTLV, syphilis • Testing only • WNV, T. cruzi, (CMV, bacteria) • Questions only • CJD, vCJD, HAV, malaria, babesia, leishmania • Questions assumed to have impact • HHV-8, tropical infections, emergent situations (e.g., SARS)

  8. 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）

  9. Recent additions • Formal approach to hemovigilance • Approval and limited use of HBV DNA testing • Chagas’ testing adopted by majority of blood collectors • Bacterial testing by culture, approval for POU test (with very limited claims) • WNV testing, with IDT-NAT if necessary

  10. 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

  11. Why is there risk? • Failure of selection process • Absence of tests • Insensitive tests • Laboratory failure • Mutant or variant organisms • Window period infections • Period in early infection with circulating agent, but prior to test positivity

  12. 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

  13. Measuring risk by direct observation • Posttransfusion studies • TTV, NIH, FACTS • Most infections too infrequent • Infectious donations • Busch,Vyas: Culture of seronegative donations for HIV Busch,Vyas • Similar issue • Back-Calculation • Historical data only

  14. 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

  15. Declining risk of transfusion-associated hepatitis Adapted from HJ Alter

  16. 输血相关肝炎风险的减少 Adapted from HJ Alter

  17. Estimation of risk from donor datafor known infections with testing • With effective 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 incidence • Update by reference to test improvements

  18. 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 • 参考检测技术的改进而更新

  19. Measuring incidence rates • New infections per person, per time • Measured among repeat donors • With at least 2 donations within a two year study period • Numerator: number of seroconversions • Denominator: person-years of observation

  20. 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

  21. Incidence measures Dodd, Notari, Stramer. Transfusion 2002;42:975-979

  22. 发病率计算 Dodd, Notari, Stramer. Transfusion 2002;42:975-979

  23. 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 • Incidence can be measured among repeat donors by observation • Other methods are necessary to measure incidence in first-time donors: if the incidence differs, then overall risk estimates must be adjusted.

  24. 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。

  25. 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 known • Use of NAT data from routine HCV testing (Dodd) • NAT yield and the NAT window period can be used to calculate incidence • Both studies found that the incidence (and thus risk) among FT donors was ~ 2.4 X of repeat donors • Later data suggests that this approach may be susceptible to bias from test-seekers

  26. 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

  27. Individual rates and linear regression model of HIV RNA in early infection 9 N = 97 Samples from 44 Plasma donors DT: 21.5 hrs (95% CI: 19.2-24.6) 8 7 6 LOG HIV RNA [gEq/mL] 5 4 3 2 AIDS, 17:1871-9, 2003 1 -10 -5 0 day 5 10 15 20

  28. 早期感染中艾滋病毒RNA检测的各体率和线性回归模型早期感染中艾滋病毒RNA检测的各体率和线性回归模型 9 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 ） 8 7 6 艾滋病毒RNA的对数值 5 4 3 2 AIDS, 17:1871-9, 2003 1 -10 -5 0 day 5 10 15 20

  29. Window Periods in Days (Standard Error) for HIV and HCV S/LSEIA 1 copy/20 mls ID-NAT MP-NAT p24 Ag WB 5.6 (0.40) 3.4(0.22) 5.3 (1.02) HIV 9.0 (0.60) 6.0 (1.08) 170.0 (10.0) 1 copy/20 mls ID-NAT MP-NAT EIA 3.0 4.9 (0.45) 2.5 (0.22) HCV 7.4 (0.67) 50.9 (2.47) Busch et al. Transfusion, 2005; 45:254-64.

  30. 艾滋病毒和丙型肝炎病毒的窗口期天数（标准误）艾滋病毒和丙型肝炎病毒的窗口期天数（标准误） 酶免疫试验 1 拷贝/20 毫升 单人份-NAT 汇集-NAT p24 抗原 蛋白印记 5.6 (0.40) 3.4(0.22) 5.3 (1.02) HIV 9.0 (0.60) 6.0 (1.08) 170.0 (10.0) 1 copy/20 mls ID-NAT MP-NAT 第3代酶免疫测定 4.9 (0.45) 2.5 (0.22) HCV 7.4 (0.67) 50.9 (2.47) Busch et al. Transfusion, 2005; 45:254-64.

  31. HBV window period time-line ECLIPSE PHASE INFECTIOUS PHASE 38.3 days 8.3 days 30 days 5.3 days HBsAg detection by Prism at S/CO of 1.0 (1,664 copies / mL) Day of Infection 1 copy/20 mls 10 copy/20 mls HBsAg detection by Auszyme at S/CO of 1.0 (6,800 copies / mL) Kleinman and Busch. Assessing the Impact of HBV NAT on Window Period Reduction and Residual Risk, J Clin Virol 2006

  32. 乙肝病毒窗口期的时间线程 潜伏期 传染期 38.3 days 8.3 days 30 days 5.3 days 感染天数 1 拷贝/20 毫升 10 拷贝/20 毫升 Prism报道的 S/CO值为1.0时的 HBsAg检测结果（ 1664拷贝/毫升 Auszyme报道的 S/CO值为1.0时的 HBsAg检测结果（ 6800拷贝/毫升 Kleinman and Busch. Assessing the Impact of HBV NAT on Window Period Reduction and Residual Risk, J Clin Virol 2006

  33. Residual risk, all donors (US)

  34. 美国献血者的残余风险

  35. Other viruses • WNV 23 cases in 2002, 9 cases since initiation of testing, 3 since use of selective IDT • B19 Definitely transmissible, but few reported clinical cases • HHV-8 Transmissibility established outside US, 2 potential transmissions reported in US, no clinical outcome reported • CMV Unknown, but may still be an occasional risk, even with LR and testing • Dengue, HAV, HEV Occasional cases reported (not necessarily in the US)

  36. 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）

  37. Bacteria • Bacterial testing of apheresis products initiated in 2004 • Assessment of risk based upon reporting (ARC) • Pre testing: • Septic reactions 1:40,000 • Fatalities 1:240,000 • Post testing • Septic reactions 1:75,000 • Fatalities: 1:500,000 • Further reductions attributable to sample diversion Eder et al. TRANSFUSION 2007;47:1134-1142.

  38. 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1:500,000 • 细菌的进一步减少归因于样品的转移 Eder et al. TRANSFUSION 2007;47:1134-1142.

  39. Direct infectivity from bacteria • Syphilis • No recent cases reported • Test-positive units do not have detectable T. pallidum DNA/RNA (n=169) • Anaplasma phagocytophilum • 1 potential transmission reported (in an abstract) • Other bacteria - (including Borrelia burgdorferi) • None reported in the US in recent years

  40. 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）

  41. Parasites • Malaria • Currently, fewer than 1 case per year in the US • At a cost of ~100,000 deferrals • Chagas’ disease • 7 known cases in US and Canada • Seroprevalence 1:30,000 • Pre-test risk probably <1:300,000 • Testing implemented January 2007 • Babesia • ~60 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

  42. 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 • 在高流行性的地方，风险可达1:1000 • 目前无有效的干预手段

  43. How does this square with reality? • HIV No transmission reported since 2002 • HCV No transmission reported since 1999 • HBV Fewer than 10 transmissions in the past 4 years, none after implementaiton of highly sensitive HBsAg testing • HTLV No transmission reported since ???? • WNV 9 cases since 2003 (6 of which were in 2003 – incomplete IDT) • Malaria Fewer than 1 case per year for the past ten years • Babesia More than 60 known cases • CJD No cases of CJD. 3 cases, 1 transmission of vCJD in UK

  44. 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

  45. New Agent Expanding Range Imported Reemergent Newly recognized Patient changes HIV, BSE/vCJD, SARS Babesia, Ehrlichia Chagas’, WNV Malaria HHV-6, 8, TTV…. CMV, B19? Emerging Infections

  46. 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

  47. Elements of an emerging infections program • Surveillance/Intelligence • Assessment for relevance • Public health • Public concern • Measures of risk • Investigation of intervention(s) • Recommendations • Implementation • Evaluation

  48. 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

  49. Concern high, Action favored HIV HBV HCV vCJD WNV CJD T. cruzi Babesia Ebola etc HHV 8 Bacteria Leishmania B19 HHV 6 HAV Lyme Malaria Ehrlichia HGV, etc Benefit High Action favored Chlamydia, Leptospira, Bartonella, HPV, etc. RMSF idprio2001

  50. 关注度高结果满意 艾滋病 变异的疯牛病 西尼罗病毒 疯牛病 枯氏锥虫 疱疹病毒-8 巴贝西虫 细菌 埃博拉病毒等 Leishmania B19病毒 疱疹病毒-6 HAV甲肝病毒 病螺旋体 Malaria疟疾 埃立克体 庚肝等 效益高结果满意 衣原体 痉挛性假硬化 钩端螺旋体 巴尔通体，等 落矶山斑疹热 科罗拉多蜱热 idprio2001

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