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Leukodepletion, Pathogen Inactivation, Irradiation – For some, or everyone?

Leukodepletion, Pathogen Inactivation, Irradiation – For some, or everyone?. Aleksandar Mijovic King’s College Hospital/National Health Service Blood & Transplant London, UK. Zadar 2011. Immunologic effects. Alloimmunisation Febrile non-haemolytic reactions Platelet refractoriness

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Leukodepletion, Pathogen Inactivation, Irradiation – For some, or everyone?

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  1. Leukodepletion, Pathogen Inactivation, Irradiation – For some, or everyone? Aleksandar Mijovic King’s College Hospital/National Health Service Blood & Transplant London, UK Zadar 2011

  2. Immunologic effects Alloimmunisation Febrile non-haemolytic reactions Platelet refractoriness Rejection of transplanted organ Graft-vs-host disease Immune modulation Increased risk of bacterial infection (?) Increased recurrence of malignancy (?) Infectious disease transmission CMV HTLV-I Epstein-Barr virus vCJD? Adverse effects of leukocytes in blood components Modified from: McCullough 2005

  3. vCJD • 4 cases in UK due to transfusion of non-leukodepleted red cells from donors who later developed vCJD. • Incubation period 6-8.5 years

  4. Infectivity of experimental TSE’s in blood -intracerebral route(Brown et al, Transfusion 1998:38;810)

  5. vCJD - What’s been done to prevent transmission? • Universal Leukodepletion (1999) • Import of plasma from USA • Donor selection – ban of donors who received transfusions after 1980 • Donor testing not yet available • Prion-reduction filters (for children and patients with haemoglobinopathies) – 2012?

  6. Universal Leucocyte Depletion -specification (UK SACBC)

  7. Effect of Leukodepletion on NH-FTRYazer et al, 2004; Pruss et al, 2004 NH-FTR rate [%]

  8. Effects of Leukodepletion on Platelet Refractoriness • TRAP study, 1997 • Lymphocytotoxic antibodies • 45% controls • 17-21% in treated groups • Platelet Refractoriness • 13% controls • 3-5% if platelets filtered or UV light-treated • After leukoreduction in Canada: • Alloimmunisation reduced from 19% to 7% • Immune refractoriness reduced from 14% to 4% • Seftel et al 2004

  9. Leukodepletion for cardiac surgery • Randomised study of: a) Buffy-coat depleted RBC; b) filtered, fresh RBC; c) filtered RBC, post storage • Infection rates: • 23.0% : 16.9% : 17.9% • Mortality: • 7.8 % vs 3.6% vs 3.3% Van de Watering et al 1998

  10. Leukodepletion in hospitalised patientsDzik W et al, Transfusion 2002 • 2780 pts randomised to receive LD or non-LD blood products. • No difference in primary outcomes: 1) In-hospital mortality; 2) Length of hospital stay (LOS); 3) Hospital costs • Nor in secondary outcomes: 1) LOS in ICU; 2) post-operative LOS; 3) antibiotic usage; 4) re-admission rate

  11. Risk for CMV disease in BMT(Ljungman et al 1998)

  12. PREVENTION OF CMV INFECTION • Use of CMV Neg Blood Products • Incidence ofCMV Infection reduced to 0-7% (pneumonia ~ 0%) • Leukodepletion • Equally effective to donor screening(Bowden et al 1995) • Abandonment of CMV screening premature(Nichols et al 2003)

  13. Leukodepletion vs CMV serology to prevent CMV infection • Both are effective • Neither is perfect • Not possible to decide if one is better than the other • Benefit of using both is unknown Canadian Consensus Conference 2001

  14. Pathogen Inactivation:in search of Zero-risk?

  15. SHOT report 2010

  16. SHOT report 2010

  17. Estimated risk of viral transmission by transfusion in the UK [per million donations](2009) www.hpa.org.uk

  18. 414 blood donors in 2005 340 blood donors in 2006 1500 clinical cases with 9 deaths 2006

  19. PATHOGEN INACTIVATION/REDUCTIONkey issues • 1. Effective inactivation of a range of agents; no evidence of toxicity. Compare with current alternatives. • 2. Underlying residual risk in a given country. • 3. ?Threat from new (or newly identified) microbial agents. • ?How to measure safety increment from PI. • Logistics; process control. Separate PI steps needed for each blood component • 6. ?Cost-benefit.

  20. HIV >6.2 HBV >5.5 HCV >4.5 CMV >5.9 West Nile >6.0 HTLV I/II 4.7-5.1 ParvoB19 4.0-4.9 E.Coli >6.4 S.Aureus 6.6 P.Aeruginosa 4.5 B.Cereus >6.0 Yersinia E. >5.9 P.Falciparum 7.0 T.Cruzi >5.3 Inactivation of Pathogens in platelets by S-59 (Log)

  21. Photochemical Treatment of Platelets – euroSPRITE trial • Randomised study (52 v 51 pts) of Amotosalen(S-59) treated BC platelets. • Average dose: 3.9 vs 4.3 x 1011 (p<.001) • 1-h increment: 27.5 vs 35.8 x 109 /L. Difference 8.3 (95% CI, 0.9 – 15.8) (p=.03) • 1-h CCI: 13.1 vs 14.9 x 103 (p=.11) • Bleeding/adverse events not different Van Rhenen et al 2003

  22. Photochemical Treatment of Platelets – SPRINT trial • Randomised study (318 v 327 pts) of Amotosalen(S-59) treated apheresis platelets. • Average dose: 3.7 vs 4.0 x 1011 (p<.001) • Grade 2 bleeding: 58.5% vs 57.5% (NInf) • Grade ¾ bleeding: 4.1% vs 6.1% (Ninf) • 1-h CCI: 11.1 vs 16.0 x 103 (p<.001) • Units received: 8.4 vs 6.2 (p<.001) McCullough et al 2004

  23. MIRASOL randomised trialMirasol Clinical Evaluation Group 2010 • Mirasol: Riboflavin (vitamin B2) + UV light • RCT: 56 pts (303 transf.) received PR-platelets, 54 pts (238 transf.) received reference platelets. • Primary outcome: 1-hour CCI • PR-P vs REF-P: 11725 : 16939 (criteria for non-INF not met). • PLT/RC utilisation not significantly different; Safety profile similar.

  24. Plasma - Spoiled for Choice? • Fresh Frozen Plasma • Solvent/Detergent treated plasma • Methylene Blue/UV light treated plasma

  25. FFP vs S/D vs MB Plasma: risk of disease transmission

  26. A.S., 18 y, TTP 22 Plasma exchanges Pulmonary Embolism R Fem Vascath L Fem Vascath Prednisolone = SD/Cryopoor plasma exchange

  27. COMPARATIVE STUDY OF TWO TYPES OF PLASMA IN LIVER TRANSPLANTATION RETROSPECTIVE, SINGLE CENTRE STUDY OF ADULT ORTHOTOPIC LIVER TRANSPLANT PATIENTS: 200 S/D FFP OCTAPLAS (1998-2001) 199 SINGLE DONOR FFP (after March 2001) ENDPOINTS PRIMARY: AMOUNT OF BLOOD PRODUCTS USED ESTIMATED BLOOD LOSS USE OF OTHER HAEMOSTATIC PRODUCTS SECONDARY 48HRS MORTALITY

  28. RESULTS

  29. S/D plasma or FFP ? Viral safety Reduced risk of TRALI Reduced risk of vCJD? Increased blood usage in OLT Increased VTE risk Cost

  30. Conclusions Use S/D PLASMA in: • Below age 16 • Young patient with good immediate and long-term prognosis, anticipated to receive few blood products. • Thrombotic Thrombocytopenic Purpura

  31. Transfusion related onset 2-30 days pancytopenia/BM aplasia No response to Th Mortality >90% Post BMT/PBPCT onset 35-70 days rare BM aplasia Incidence 20-70% 80-90% respond to Th mortality 10-15% Acute GVHD

  32. Graft-versus-host disease of the skin

  33. Transfusion-associated Graft-vs-Host disease: Prevention Gamma/ X-ray Irradiation 25Gy Leukodepletion – does it prevent TA-GVHD? - No case since 2001 in UK Pathogen Inactivation for Cellular Components

  34. Indications for irradiation of blood components in the UK A. Indication by patient condition • Intrauterine transfusions • Neonatal exchange transfusions • Congenital immune deficiencies • Allogeneic HSC transplant patients • Autologous HSC patients • Hodgkin’s disease • Purine analogue treatment • Aplastic anaemia treated with ATG or Alemtuzumab B. Indication by component type • Granulocyte transfusions • HLA-matched blood components • Blood components from relatives

  35. Frequency of Homozygous HLA donors to recipients heterozygous for the same haplotype[1 : x]

  36. Survey of Blood Use in France (1997)175 Hospitals, 3206 Transfused Patients 57% of transfusion recipients were > 65 years Mathoulin-Pelissier et al, Transfusion 40:1140, 2000

  37. “Greying” of the Population • Life Expectancy in UK (2001) • 80 y for Women • 75 y for Men • In 2007, people ≥ 60 were 21.8% of UK population. • The same year, people aged 65+ outnumbered those under 16 y for the first time ever. UN Dept. of Economic & Social Affairs

  38. Who should we irradiate blood products for? • According to national guidelines • All recipients with malignant disease • Recipients > age 65 yr • Everyone

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