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M.A. Blajchman, MD, FRCP(C) McMaster University Canadian Blood Services

PROTECTING THE BLOOD SUPPLY FROM EMERGING PATHOGENS: THE ROLE OF PATHOGEN INACTIVATION (PI). M.A. Blajchman, MD, FRCP(C) McMaster University Canadian Blood Services. WHAT IS PATHOGEN INACTIVATION?. ● A process of killing micro-organisms in biological fluids including: - Viruses

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M.A. Blajchman, MD, FRCP(C) McMaster University Canadian Blood Services

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  1. PROTECTING THE BLOOD SUPPLY FROM EMERGING PATHOGENS: THE ROLE OF PATHOGEN INACTIVATION (PI) M.A. Blajchman, MD, FRCP(C) McMaster University Canadian Blood Services

  2. WHAT IS PATHOGEN INACTIVATION? ● A process of killing micro-organisms in biological fluids including: - Viruses - Bacteria - Parasites ● PI is a well-established approach to treat fractionated blood products (proteins) during manufacture. ● PI is thus currently being explored to increase the safety of plasma, platelets and blood components including RBCs.

  3. REDUCING THE RISK OF TRANSFUSION-TRANSMITTED INFECTIONS • Donor history • Donor examination • Donor testing • Diversion of initial aliquot • Leukoreduction • Post donation information • Donor deferral registries • Limit donor exposure

  4. NEW TEST IMPLEMENTATION AND DECLINING RISK OF TA-VIRAL INFECTIONS IN THE U.S. Culture +

  5. Vamvakas EC, Blajchman MA. Blood 2009; 113: 3406-3417

  6. Vamvakas EC, Blajchman MA. Blood 2009; 113: 3406-3417

  7. CURRENT DONOR TESTING FOR INFECTIOUS DISEASE • Syphilis (1938) ● HBsAg • Anti-HIV ● Anti-CMV • Anti-HTLV ● Anti-HCV • HIV p24 Antigen ● HIV and HCV NAT • WNV NAT ● Bacteria (2004) • Anti-HBc ● Chagas Disease (2009)

  8. Chagas DONOR TESTING FOR INFECTIOUS DISEASE IN THE U.S. HBV NAT WNV HIV HCV NAT HIV Ag Anti-HCV Anti-HTLV ALT Malaria HHV8 Babesia Leishmania Foamy viruses HEV Anti-HBc Anti-CMV Anti-HIV HBsAg Syphilis 1938 1970 2010 1975 1980 1985 1990 1995 2000 2005

  9. ONGOING AND UNTESTEDRISKS TO THE BLOOD SUPPLY • Any agent known to cause disease in man and that has a viremic or bacteremic phase during its clinical course. • Agents for which there are no routine screening tests in place include (partial list): • vCJD HAV Foamy viruses • Malaria HPV HEV • HHV-8 Dengue Leishmania • Parvovirus Rickettsia SARS • Babesia Chikungunya etc.

  10. RISKS OF TRANSFUSION-TRANSMITTED INFECTIONS IN THE UNITED STATES(1984-2005) Blajchman MA, Vamvakas EC. NEJM 2006; 355: 1303-1305.

  11. RISK OF TA-BACTERIAL SEPSIS • Data from 2001 • Canadian data published in 2007 • ARC data published in 2007 • Passport data reported in 2008 • Murphy W et al. data published in 2008

  12. Bacterial-Related Septic Transfusion Reactions*(reported rates per million platelet units transfused) StudyAPWB PlateletsRBCs Perez (2001) 31.8 71.8 5.8 Kuehnert (2001) 9.8 10.6 0.2 Ness (2001) 74.5 67.0 ND AP = apheresis platelets “It is likely that only the most severe forms of transfusion reactions are reported and under-reporting undoubtedly occurs”. *From McDonald CP and Blajchman MA Transfusion Microbiology 2008.

  13. Bacterial Testing Apheresis Platelets at CBS & HQ* • 82,004 units tested, BacT/alert, aerobic only • 70 units initially positive • 6 confirmed positive • 2 false negative PC resulted in TA-bacterial sepsis • Salmonella sepsis in 61 yr. old man, with AML and neutropenia. • Serratia marcesens cultured at autopsy in a 3 year old girl with leukemia who died of multisystem organ failure 21 hours after transfusion with contaminated apheresis platelets. *Ramirez-Arcos et al, Transfusion 2007

  14. American Red Cross Bacterial Screening of Apheresis Platelets* Single bottle culture of 1,004,206 AP donations (2004-06) 186 True Positives (1:5,399) False negative cultures resulted in 20 reported septic reactions, including 3 fatalities (passive reporting) ●Partially associated with the use of 2-arm AP procedures ● 13 of 20 reactions occurred with day 5 APs *Eder AF et al. Transfusion 2007; 47: 1134-42.

  15. THE PASSPORT STUDY FDA mandated post-marketing surveillance of 7-day apheresis platelets (AP) Participation of 51 US Blood Centers Assessed the risk of bacterial contamination in 7-day AP compared to 5-day AP Cultures (BacT/ALERT, 2 bottles, 5 ml each) Release: 100% at 24-36 h post-collection Surveillance: PC inventory on day 7 Passive reporting of clinical outcomes

  16. PASSPORT Surveillance Cultures 4369 PC initially culture negative Re-tested after day 7 3 true positives: S. aureus , S. epidermidis, S. veridans Residual risk: 686 per million PC (1 in ~1500) L. Dumont, BPAC, May 2008

  17. ARC 4 / 6039 7 / 8282 6 / 6438

  18. Contaminated Platelet Units Often Escape Bacterial Culture Detection* • 100% bacterial screening of platelet concentrates (PC) introduced by Irish Blood Transfusion Service in 2005 • Overall Sensitivity of Screening: 29.2% (CI: 19.4-39.1%) • All PCs tested prior to release on day after manufacture • 0.08% (35/43,220) positive • PCs false negative at release • Expired PCs retested, 0.22% (18/8282) positive • Repeat test of PCs in stock on day 4 of storage to re-qualify, 0.12% (4/3320) positive *W.G. Murphy et al, Vox Sanguinis 2008 (e-pub)

  19. ●“It is unthinkable that a manufacturer of other intravenous medications could eschew reasonable methods to eradicate possible contamination on the basis that only organisms of questionable clinical significance persisted in the preparations infused.” ● “It is also unthinkable that end users of intravenous agents would be asked to check sterility before use, …….” ● “It is apparent to us that bacterial testing, whether early or late, lacks sufficient robustness …… as the method of choice once a method of eradication of adequate proven safety and utility is available.” W.G. Murphy et al Vox Sanguinis 2008 95:13-19

  20. TAS RISK - SUMMARY • Current methods for the bacterial screening of platelets are clearly inadequate. • Considerable TAS risk remains, particularly for recipients of platelets, as ~1 in 1500 PC units may not be identified as containing bacteria. • PI has shown efficacy in killing bacteria that may be present in PCs.

  21. FRACTIONATED PLASMA PROTEINS It is particularly relevant that there has been no reported transmissions of HIV, HBV or HCV by a pathogen inactivated plasma derivative since 1987. Should we not apply PI technology to all blood products, including platelets, RBCs and plasma?

  22. BIOPHARMACEUTICAL PATHOGEN REDUCTION/CLEARANCE TECHNOLOGY Product NAT Product NAT Nanofiltration Affinity Purification Solvent-Detergent AHF Heat Low pH UV/Propiolactone Fractionation Pasteurization 2000 1985

  23. LESSONS LEARNED FROM PI OF PLASMA PROTEINS • Efficacy of biological products is maintained. • Toxicity not usually encountered. • Immunogenicity seldom encountered. • Viral safety clearly can be achieved.

  24. PATHOGEN-INACTIVATED BLOODCOMPONENTS • Goal: Eliminate transmission of viruses, bacteria and parasites (known and unknown) • Secondary Specific Drivers: - Bacteria - Parasites - CMV - GvHD

  25. ADDITIONAL CONSIDERATIONS APPLICABLE TO BLOOD COMPONENTS • Eliminating infectivity from components is more difficult than eliminating infectivity from derivatives: • Higher viral concentration • More proteins to consider • Cells (platelets, RBCs) more fragile • Some microbes not sensitive to PI (i.e. prions). • Validation studies need to examine a wider range of variables than encountered in the protein setting. • GMP requirements are yet to be enunciated.

  26. PATHOGEN INACTIVATION METHODOLOGY • Solvent-detergent (SD plasma) • Methylene blue (MB, for plasma) • Psoralens (S-59, Amotosalen) • Riboflavin (vitamin B2) • S-303 (for RBCs, Amustaline) • Other dyes • UVC (under investigation for platelets)

  27. Disrupting Nucleic Acid

  28. REASONS FOR SLOW ACCEPTANCE OF PI • Perceived current safety of the volunteer blood supply. • No single method to treat all components. • Success of surveillance and screening in dealing with emerging pathogens, even if delayed. • Inability of current technologies to inactivate all agents (small, non-encapsulated viruses, spores, high-titer viremia, and prions). • Risks from the residual unknown agents? • Cost/Benefit ratio acceptable?

  29. CAUTIONS REGARDING PATHOGEN INACTIVATION TECHNOLOGY • Each technology is different: • Chemical/biological characteristics; • Spectrum of pathogen reduction; • Activity for specific pathogens -“log reduction;” • Activity in specific components; • Adducts and metabolites; • Lack of knowledge of the profile of adverse reactions (toxicity).

  30. FUTURE SCREENING TEST DEVELOPMENT • Babesia testing? • Chagas’ disease testing ? • Dengue (DFV) virus testing? • Malaria testing? • Point-of-use bacterial testing? • Chikungunya virus?

  31. U.S.TRANSFUSION-ASSOCIATED BABESIA MORTALITY • Human babesiosis is a protozoal zoonotic illness that is transmitted by Ixodes scapularis ticks. • Various babesia species can infect vertebrate hosts. • 70 Babesia TTIs have been reported in North America since 1979, most in the last decade. • Ten TTI babesia deaths since 1997, nine within the last 3 years. • Babesia would be readily killed by PI. Gubernot DM et al. Clin Infect Dis 2009; 48: 25-30.

  32. MALARIA RISK MANAGEMENT • The parasites are readily killed by PI. • Would avoid malaria donor deferrals. • Travel deferrals for malaria avoided. • Testing strategy implementation will be avoided altogether.

  33. AVOIDANCE OF BACTERIAL TESTING • Current PI strategy would do nothing to prevent TAS due to contaminated RBCs. • PI impact on platelet viability is minimal. • Could result in significant cost savings. • Increased safety of platelets. • Platelet inventory could be released earlier.

  34. AVOIDANCE OF NEW MICROBIOLOGICAL THREATS • Good likelihood of killing most emerging agents. • Fewer donor deferrals will be required. • Test avoidance (WNV, Syphilis, anti-HBc). • No impact on prions! • Would eliminate the need for Chagas’ Disease testing. • N.B. This would apply only if RBC or whole blood PI also becomes available.

  35. IMPACT ON CONTINUED NEED FOR UNIVERSAL LEUKOREDUCTION • With implementation of PI, there would be no need to γ-irradiate blood components. • Thus there would be no need for blood irradiators in Blood Centres. • May however not address the HLA-alloimmunization risk of non-LR platelets.

  36. IMPACT OF PI ON CMV TESTING • Current CMV TTI risk ~2%. • Reduced risk of CMV transmission to susceptible patients. • When PI becomes universal, CMV testing would no longer be required. • Avoids a special inventory for “CMV-safe” products.

  37. IMPACT ON DONOR TESTING • Simplified donor questionnaire. • MSM would no longer be an issue. • Less time would be needed to screen donors.

  38. WHAT PI WILL PROBABLY NOT DO • Will not reduce TRALI risk.* • Will not reduce prion risk or associated vCJD travel deferrals. • Will not prevent the occurrence of transfusion errors. *The use of SD-plasma will likely reduce the TRALI risk with its use (Prowse C. Transfus Med Rev 2009; 23: 124-133).

  39. __________Pathogen Inactivation Making Decisions About New Technologies CONSENSUS CONFERENCE ON PATHOGEN INACTIVATION Sponsors: Canadian Blood Services Héma Québec (BEST Collaborative) March 29-30, 2007

  40. STEERING COMMITTEE Morris Blajchman, MD, FRCPC (Chair) Canadian Blood Services Gilles Delage MD Héma-Québec Jaroslav Vostal, MD, PhD CBER, FDA Dana Devine, PhD Canadian Blood Services Stephen Wagner, PhD American Red Cross Kathryn Webert, MD, FRCPC McMaster University Sunny (Walter) Dzik, MD Massachusetts General Hospital Lorna Williamson, MD, FRCP University of Cambridge NHS UK Blood and Transplant BEST Collaborative, Chair Heather Hume, MD Canadian Blood Services Harvey G. Klein, MD NIH (Panel Chair)

  41. CONSENSUS CONFERENCE PROCESS March 29 – 30, 2007 • Topic Identified. • Steering Committee crafts questions, identifies speakers, and appoints panel. • Speakers outline key issues (day 1). • Panel deliberates and produces statement. • Draft Statement presented (day 2). • Panel refines Consensus Statement.

  42. QUESTIONS POSED TO THE PANEL ─ 1 1. Implementation criteria: Is the current risk of transfusion-transmitted diseases acceptable in relation to other risks of transfusions? a) If so, under what new circumstances should pathogen inactivation be implemented? b) Should the criteria be the same for RBCs, platelets, and FFP? c) Should different criteria be used for certain patient populations? 2. Licensing requirements: What minimum acceptable safety and efficacy criteria should be put into place for the pre-approval assessment of pathogen inactivated products? Specifically: a) What criteria should govern acceptable toxicology standards and how should they be assessed? b) What type of post-marketing surveillance should be required (if any) with the implementation of pathogen inactivated blood components. 3. Blood Service and Clinical issues:For pathogen inactivation technologies that have been approved by the regulatory authorities, what implications should be considered prior to their widespread adoption? Also, if pathogen inactivated components differ in function from non-pathogen inactivated equivalent products, how should this information be disseminated?

  43. QUESTIONS POSED TO THE PANEL ─ 2 4. Risk management issues: If pathogen inactivation were to be implemented for all components; in principle, what criteria would allow: a) The relaxation of any current donor deferral/exclusion policies? b) The cessation of any currently undertaken screening tests? c) A decision not to implement new screening tests for agents susceptible to pathogen inactivation? Should multiple inventories be considered for each component and if yes how should allocation be decided? 5. Cost-benefit impact: How should the costs/benefits of pathogen inactivation be assessed? Should these be aligned with other blood safety interventions and/or other health care interventions? 6. Research requirements: What other information, considerations, and research-related questions would need to be answered in order to decide whether/when a particular pathogen inactivation procedure should be implemented?

  44. CONSENSUS PANEL Harvey G. Klein - Panel Chair National Institutes of Health David Anderson (Hematologist) QE II Health Sciences Centre Halifax, NS Jeffrey S. Hoch (Health Economist) St. Michael’s Hospital Toronto, ON Marie-Josée Bernard (Ethicist) CRIR Montreal, QC Nancy Robitaille (Hematologist–Paeds) CHU St. Justine Montreal, QC Ritchard Cable (Transfusionist) American Red Cross Blood Services Farmington, CT Marco L.A. Sivilotti (Toxicologist) Queen’s University Kingston, ON William Carey (Blood Recipient) Owen Sound, ON Fiona Smaill (Infectious Disease Expert) McMaster University Health Sciences Hamilton, ON

  45. CONSENSUS CONFERENCE SPEAKERS TOPICSPEAKER 1. Microbiological reasons for considering Dr. H. Alter PI in Transfusion Medicine. 2. Biochemical and biological mechanisms Dr. R. Dodd of PI methodology. 3. Toxicology issues relating to the PI Dr. J. Chapman of blood products: Impact on recipients.

  46. CONSENSUS CONFERENCE SPEAKERS TOPICSPEAKER 4. Efficacy of PI FFP. Dr. C. Prowse 5. Efficacy of PI platelets. Dr. S. Slichter 6. Clinical experience with PI Dr. J-P Cazenave platelets. 7. Efficacy of PI RBCs. Dr. J. AuBuchon 8. Immunogenic issues with the use of Dr. G. Garratty PI RBCs.

  47. CONSENSUS CONFERENCE SPEAKERS TOPICSPEAKER 9. The place of PI in the Transfusion Medicine Dr. W. Dzik overall risk-benefit ratio. 10. Regulatory issues: FDA perspective. Dr. J. Vostal 11. Regulatory Issues: Dr. M. Heiden European community perspective. 12. Regulatory Issues: Dr. P. Ganz Canadian perspective.

  48. CONSENSUS CONFERENCE SPEAKERS TOPICSPEAKER 13. Public health aspect of residual risks Dr. M. Kuehnert relating to transfusions. 14. Economic issues. Cost benefits of Dr. B. Custer PI in relation to other aspects of transfusion medicine. 15. Overview of newer PI technologies. Dr. S. Wagner

  49. PRIMARY PUBLICATIONS • Preliminary Panel Report: Klein HG et al. Vox Sanguinis 2007; 93: 179-182. • Final Panel Report: Klein HG et al. Transfusion2007; 47: 2338-2347. • Proceedings: Webert KE et al. Transfusion Medicine Reviews 2008; 22: 1-34.

  50. SECONDARY PUBLICATIONS 4. Editorial: McCullough J. Pathogen inactivation: A new paradigm for blood safety. Transfusion 2007; 47: 2180-2184. • Editorial: Sher GD, Devine DV. The consensus development process in transfusion medicine: Does it add value? Transfusion 2007; 47: 2176-2179. 6. Alter HJ. Pathogen reduction: A precautionary principle paradigm. Transfusion Medicine Reviews 2008; 22: 97-102

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