Eliminating the Residual Risks of Transfusion Therapy: Pathogen Reduction

1. Eliminating the Residual Risks of Transfusion Therapy:Pathogen Reduction Paul M. Ness, M.D. Transfusion Medicine Division Department of Pathology Johns Hopkins Medical InstitutionsBaltimore, Maryland, USA

2. 消除输血治疗的残余风险：减少病原体 医学博士 输血医学部 病 理 科 美国约翰霍普金斯医学院美国马里兰州巴尔的摩，美国

3. Case I A 32 y/o patient with NHL received a pool of 4 platelet concentrates which had been stored for 5 days. She experienced a severe reaction of fever and chills leading to the onset of hypoxia and shock. Despite antibiotics and ICU management, she died within 12 hours of the transfusion.

4. 病 例 I • 32岁非霍奇金淋巴瘤患者，输注了已储存5天、由4人份汇集的浓缩血小板 • 她产生了严重的发烧和寒战反应，导致缺氧和休克发生。 • 尽管使用了抗生素和重症监护病房抢救措施，她还是在输血12小时后去世。

5. Case I (cont’d) • The event was reported to the Blood Bank as a transfusion reaction. • Gram stain of the bag revealed Gram + cocci and culture eventually grew Staph aureus. • The patient’s blood cultures also grew Staph aureus

6. 病 例 I（续） 该事件作为输血反应向血库报告。 血袋血革兰氏染色显示革兰氏阳性球菌，血培养最终长出金黄色葡萄球菌。 病人的血培养也长出了金黄色葡萄球菌

7. Septic Platelet TransfusionsJOHNS HOPKINS (1987-1990) • Incidence of 1:4200 transfusions in oncology patients • Septic reactions were more common with random donor platelet concentrates (RDP) • Reactions were more common with longer periods of storage • Source was skin contaminant in 4/7 cases; bacteremic donor in 3/7 cases

8. 败血症性血小板输血约翰霍普金斯大学（ 1987-1990 ） 肿瘤患者的发病率为每4200次输血发生1次 脓毒性反应在随机捐血者浓缩血小板（RDP）较常见。 随着储存时间的增加，反应更常见。 7例中的4例来自皮肤污染，3例来自菌血症的捐血者

9. Septic Platelet ReactionsOutcome

10. 败血症性血小板反应结果

12. 输血杂志

13. Bacterial Culturing Process: Transfusion 120 hr 96 hr 72 hr 48hr 24 hr Collection Outdate BacT bottle monitoring Inoculate • Efficacy monitored by:： MonthlyTP, FP, Ind. rates • Hemovigilance sepsis reports Release

14. 细菌培养的过程 输 血 120 hr 96 hr 72 hr 48hr 24 hr 采集 过期 细 菌 培 养 瓶 监 测 接 种 • 效能监测： 每月的TP, FP, Ind 率 • 血液预警败血症报告 发 报 告

15. Bacterial Screening Issues • Culture systems delay platelet release • False positive results result in platelet wastage and market withdrawals • Systems for WBDP have been inadequate • Anaerobic culture or increased sample size are now being suggested • Clinical reactions have been missed

16. 细 菌 筛 查 培养系统延迟血小板发放 假阳性结果导致血小板的浪费和召回 WBDP的系统是不够的 建议进行厌氧菌培养或增加样本大小 可避免临床反应

17. Hemovigilance Monitoring of Bacterial Culture Effectiveness: • Fang et al, Transfusion 2005

18. 血液预警监测细菌培养致病力 • Fang et al, Transfusion 2005

19. Case II • 54 y.o. WF with end-stage renal disease secondary to hypertensive and reflux • Underwent splenectomy and living related renal transplantation from ABO incompatible donor on 9/6/02 (recipient blood type O, donor A1) • Before transplantation underwent 5 plasmapheresis procedures to reduce anti-A isoagglutinin titer from 1:256 to <1:16 • Two additional plasmapheresis procedures were performed post-operatively

20. 病 例 II 54岁白种女人肾脏疾病晚期，继发高血压和回流肾病 脾切除和9/6/02进行过ABO血型不相容的肾移植，（受者为O型血，供者为A1型血） 移植前进行过5次血浆置换术，以减少同种凝集素抗A的滴度，从1: 16降到 1: 256 手术后又进行了两次血浆置换术

21. Case II (cont’d) • Discharged on post-operative day #8 with creatinine of 1.5 mg/dl • On post-op day #10 she was readmitted for presumed UTI with chills, elevated WBC of 21,800 and increased creatinine to 1.8 mg/dl • On post-op day #12 she developed a fever to 39.1C, dyplopia and nuchal rigidity • Subsequent deterioration in neurologic status with MRI suggestive of meningoencephalitis • West Nile Virus-specific IgM antibody positive on CSFExpired on POD#21

22. 病 例 II （续） 术后第8天出院，肌酐为1.5毫克/分升 术后第10天，患者尿路感染伴寒战再次住院，白细胞升高到2.18万，肌酐为1.8毫克/分升 术后第12天，发烧到39.1C ，复视和颈部僵硬 继发神经系统损害，核磁共振成像提示脑炎 脑脊液中西尼罗河病毒特异性IgM阳性 术后第21天死亡

24. 输血杂志

25. New Test Implementation and Declining Risk of Viral Infections from Transfusion

26. 实施新的检测方法 降低输血后病毒感染的风险

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

28. 新 发 感 染 新的疾病 范围扩大 外来的 重新发生的 新确认的 病人改变 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

29. Pathogen Prioritization List from AABB AND ISBT Concern high, Action favored (HIV) WNV vCJD CJD T.cruzi HHV 8 Leishmania Ebola etc Babesia Bacteria B19 B19 HHV 6 HAV Lyme Malaria Ehrlichia HGV, etc Benefit High Action favored Chlamydia, JC, Leptospira Bartonella RMSF CTF idprio2001

30. AABB和ISBT的病原优先次序清单 关注度高结果满意 艾滋病 西尼罗病毒 变异的疯牛病 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 甲肝病毒 疟疾 病螺旋体 埃立克体 庚肝等 效益度高结果满意 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

31. MAJOR PATIENT CONCERNS • How safe are current transfusions with respect to AIDS and other complications? • Are there any alternatives that I can use to avoid blood transfusions or minimize their risks?

32. 患者的主要关切 鉴于艾滋病和其他并发症，当前输血的安全程度如何？ 是否有其他可以使用的替代治疗，以避免输血？或尽量减少输血的风险

33. PERIOPERATIVE RED CELL TRANSFUSION , 1988 • Transfusion trigger of 10 g/dl is NOT justified; 7 g/dl may be more appropriate. • Moderate perioperative anemia does not contribute to morbidity or delay wound healing. • Homologous transfusion should be minimized. • Alternatives to homologous transfusion should be encouraged.

34. 围手术期红细胞输血，1988 年 • 血红蛋白10克/分升的输血指针还不充分， 7克/分升可能更为恰当。 • 围手术期轻度贫血不会导致发病或延迟愈合。 • 同种异体输血应减少到最低限度。 • 应鼓励替代同种异体输血的方法

35. TRANSFUSION ALTERNATIVESReducing volunteer blood risks • Predeposit autologous transfusion • Hemodilution • Intraoperative autologous transfusion • Pharmacologic therapies • Blood substitutes • Apheresis to reduce donor exposure • Pathogen inactivation

36. 输血替代治疗减少献血者血液风险 • 预存的自体输血 • 血液稀释 • 术中自体输血 • 药物治疗 • 血液代用品 • 减少献血者暴露的机采 • 病原体灭活

37. PATHOGEN REDUCTIONCANDIDATE TECHNOLOGIES • Extensive leukodepletion • Solvent-detergent treatment • Psoralens and UV irradiation • Inactine • Riboflavin

38. 减少病原体的候选技术 广泛去除白细胞 可溶性去污剂处理 补骨脂和紫外线照射 乙撑亚胺衍生物 核黄素

40. S-59作用机制 插入 交联

42. 血小板减少污染处理过程 血小板和血浆 紫外线照射 处理过的血小板和血浆

43. Platelet Pathogen Inactivation Cerus • Photochemical treatment of platelets with psoralen S-59 inactivates high titers of virus, bacteria, and leukocytes • Excess psoralen is removed to limit toxicity • Although hemostasis is maintained when compared to control platelets, some platelet damage does occur as shown by reduced CCI and tx interval in phase III studies

44. Cerus公司的血小板病原体灭活 用补骨脂硫S- 59光化学处理血小板可灭活高滴度的病毒，细菌和白细胞 去除多余的补骨脂以限制毒性 在第三阶段的临床研究中，虽然与对照血小板相比，灭活血小板仍然有止血作用，但血小板计数增加校正指数和输血间隔降低表明一些血小板发生了损坏。

45. S- 59 SPRINT Trial, ASH 2001

46. 美国血液病学会2001年会

47. Problems with Cerus Approach Cerus • Patients will get smaller doses and need more frequent transfusions • Toxicity issues remain unresolved • Cost of treatment will be high; relative cost of the product will also increase because of smaller available dose • Blood centers will need to collect larger doses; splitting will be more difficult, again raising costs

48. 公司的灭活技术带来的问题 患者将获得较小的剂量，需要更频繁输血 毒性问题仍然没有得到解决 治疗费用将会很高;由于采集的剂量较少，产品的相对成本也将增加。 血液中心将需要采集较大的剂量;离心将更加困难，又提高成本。