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Neil Blumberg MD University of Rochester Medical Center, Rochester, NY

Blood and Immunomodulation-- Can we improve clinical outcomes by leukoreduction, washing and shorter red cell storage?. Neil Blumberg MD University of Rochester Medical Center, Rochester, NY Department of Pathology & Laboratory Medicine SABM September 21, 2012. Outline of Lecture.

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Neil Blumberg MD University of Rochester Medical Center, Rochester, NY

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  1. Blood and Immunomodulation--Can we improve clinical outcomes by leukoreduction, washing and shorter red cell storage? Neil Blumberg MD University of Rochester Medical Center, Rochester, NY Department of Pathology & Laboratory Medicine SABM September 21, 2012

  2. Outline of Lecture • Transfusion immunomodulation background, including • leukoreduction • Biologic mediators accumulate in the supernatant of blood • components • Washing may improve clinical outcomes in acute leukemia • and reduce post-transfusion inflammation in pediatric • cardiac surgery • • Shorter red cell storage (<15 days) is associated with dramatically fewer post-operative infections in pediatric cardiac surgery

  3. n=1,436 n=2,652 n=2,391 p<0.001 for all curves

  4. (Transplantation35: 320 (1983)

  5. Lancet 1982 Sep 18;2(8299):662

  6. Meta-Analysis: Association of Cancer Recurrence & Transfusion Vamvakas, Transfusion 1995; 35:760-768

  7. ≥ Surgery. 1986 Oct;100(4):796-803.

  8. Leukoreduction decreases post-operative mortality in cardiac surgery • Death rate reduced from 7.8% to 3.5% (van de Watering 1998), and 10.1% to 5.5% (Bilgin 2001) in randomized trials of leukoreduced transfusions • Death rate reduced from 5.3% to 3.2% in our implementation trial with LR blood (p= NS) • Post-operative infection has a mortality of 8-15% and is the leading cause of multiorgan failure syndromes

  9. Misapplication of the intention to treat principle in meta-analyses of LR • The published meta-analyses arbitrarily assigned hundreds of non-transfused patients and their infections, in equal numbers, to each arm of the study. • These patients had been excluded by the original authors. • This rendered the results non-significant in some cases • Evidence based medicine cannot consist of adding back to the analysis patients for whom you have no data whatever. • Fictional data cannot be used to draw scientific conclusions

  10. Transfusion 47: 573-581(2007)

  11. Limitations of the Existing Trial of ULR--Transfusion 42:1114 (2002) • More than one in eight patients in the LR arm received some non-LR blood (12.6%) • Patients in the LR arm were significantly more likely to receive non-LR blood than patients in the non-LR were to receive LR blood (p=0.0055)

  12. Transfusion 50: 2738 (December 2010)

  13. Transfusion 50: 2738 (December 2010)

  14. Proven Benefits of Leukoreduction • Reduced febrile transfusion reactions • Reduced HLA alloimmunization/reduced platelet refractoriness • Reduced CMV transmission • Reduced post-operative infections • Reduced cardiac surgery mortality

  15. Cost Savings with Leukoreduction • Cardiac surgery implementation trial (Am J Clin Path 118: 376-381, 2002) • Leukoreduction: cost per hospitalization DECREASED $1,700 • Non-transfused patients: cost per hospitalization INCREASED $4,000 • 750,000 cases nationwide x $1,700 = $1.3 billion/year • Enough to pay for universal leukoreduction 2-3 times over

  16. Estimated deaths potentially averted in surgical patients by leukoreduced transfusions • 2 million surgeries with transfusion • 10% fewer infections = 200,000 fewer infections • 8-15% of infections lead to death • 16,000 to 30,000 fewer deaths per year • Cardiac Surgery: 750,000 cases per year • 2-4% fewer deaths • 15,000 to 30,000 fewer deaths per year

  17. Number to treat to save one life (NNT) • Nucleic Acid Testing (NAT) for HIV/HCV • 500,000 to 1,000,000 • Cost per life saved = $2.5-5,000,000 • Leukoreduction of allogeneic transfusions in cardiac surgery • 20 • Cost per life saved = $400-600

  18. Immunomodulation and Leukoreduction • Surgery for Colorectal Ca & GI Diseases Reduced: post-op infection, Hospital costs • Cardiac Surgery Reduced:post-operative mortality, MOF • Acute leukemia Reduced: blood use, infections, hospital costs, mortality • BMT for Lymphoma Reduced: blood use, infections, costs

  19. Evidence that immunologic mechanisms underlie the clinical evidence • In patients with Crohn’s disease, perioperative allogeneic transfusion is associated with increases in post-operative infection, but decreases in inflammatory bowel disease recurrence • In patients undergoing solid organ transplants, perioperative allogeneic transfusion is associated with increases in post-operative infection, but decreases in allograft rejection • The suggestion that transfusion is merely a measure of unfavorable pre-existing morbidity is thus implausible

  20. “Bad” Th1 processes antagonized by allogeneic transfusion • Allograft rejection • Rejection of the fetus as an allograft • Inflammatory diseases such as Crohn’s, Rheumatoid Arthritis, Type I Diabetes

  21. “Good” Th1 processes antagonized by allogeneic transfusion • Antibacterial immunity • Antitumor immunity • Antiviral immunity

  22. So what about the supernatant of stored blood components? • During 14 years the incidence of TACO and TRALI due to leukoreduced PLTS and RBC was 11 of 319,161 • During that same period, the incidence of TACO and TRALI due to washed leukoreduced PLTS and RBC was ZERO of 97,445(p = 0.049) • Transfusion 50: 2738 (December 2010)

  23. Reactions versus mediator levels Transfusion 46: 1813-21 (2006)

  24. sCD40L in Platelet Concentrates Implicated in TRALI p<0.0001 N=62 N=57 Blood 108: 2455-62 (2006)

  25. p = 0.037 BMC Blood Disorders 4: 6 (2004)

  26. Modeling of Survival in Adult Acute Leukemia Patients <50 years old (n=41) Employing the Cox Proportional Hazard Technique

  27. Leukemia 22: 631-635 (2008)

  28. Washed, LR, ABO Identical ABO Identical LR, ABO Identical ABO Unmatched Type of Transfusion and Survival in Acute Leukemia in Adults Survival Months Leukemia 22: 631-635 (2008)

  29. Washing dramatically reduces reaction rates in patients with a history of reactions to platelet transfusions Transfus Med 2001 Feb;11(1):45-7

  30. A Randomized Trial of Washed Transfusions Pediatr Crit Care Med 3:290-9 (2012) To compare the cytokine response in children undergoing open heart surgery with cardiopulmonary bypass randomized to either: • Unwashed group: irradiated, pre-storage leukoreduced RBC and platelet transfusions • Washed group: washed, irradiated, pre-storage leukoreduced RBC and platelet transfusions

  31. IL-6 levels (pg/ml) Pre-, Post-, 6 and 12 Hours Post-operatively p=0.03

  32. Distribution of IL-6 levels (pg/ml) at 6 hours post-op

  33. Histogram of day 1 C-reactive protein levels (mg/L) in the washed group None in Washed Group >90 mg/L (0/61) p=0.006 by Fisher’s exact vs. Unwashed Group

  34. Histogram of day 1 C-reactive protein levels (mg/L) in the unwashed group Eight in Unwashed Group >90 mg/L (8/61)

  35. Table 4. Clinical Outcome data Data expressed as median [range], mean ± SD, or number (%). No statistically significant between group differences Washed v. Unwashed

  36. Storage and Patient Parameters • Mean storage duration of oldest red cell transfused = 20 ± 2 days (95% C.I.) • Median storage duration of oldest red cell transfused = 21 days (range 7-38) • <5% received FFP or platelet transfusions • Mean dose = 86 ± 18 ml/kg • Median Dose = 56 ml/kg (range 4-800)

  37. Hours of Intubation n = 33, 30, 30, 33 (Quartiles); p = 0.029

  38. Proportion of Patients with Infection Includes all patients; p = 0.004 by Chi square

  39. Proportion of Patients with Infection Restricted to maximum of 1-2 transfusions, given only on the day of surgery; p = 0.01 by Chi square

  40. Effect of washing when the oldest red cell transfused is ≤15 days of storage • Washed is superior to unwashed when ≤15 day storage blood is transfused

  41. Effect of washing when the oldest red cell transfused is ≥28 days of storage • Washed is inferior to unwashed when ≥28 day storage blood is transfused

  42. Summary • Older stored red cells at doses equivalent to massive transfusion in adults dramatically predispose to post-operative infection in infants • In pediatric cardiac surgery, washed red cells should be selected to be <21 and ideally <15 days of storage • Washed red cells of shorter storage duration (<15-21 days) may reduce morbidity and perhaps mortality in pediatric cardiac surgery • Older red cells (>15 days) are associated with increases in infection quantitatively similar to those seen with steroid use

  43. Conclusions • Transfusions strikingly predispose to infection, cancer recurrence, lung injury, inflammation, multi-organ failure and possibly thrombosis • Leukoreduction strikingly reduces the risks of post-operative infection, multi-organ failure and death in cardiac surgery, and may reduce the risk of lung injury, inflammation, and thrombosis • Leukoreduction also reduces CMV transmission, febrile reactions, HLA alloimmunization

  44. Conclusions • Washing may reduce the risk of death in younger patients with acute leukemia and reduces inflammatory markers in pediatric cardiac surgery • Reduces allergic & febrile reactions to leukoreduced platelets • Washing may increase the post-operative infection rate in pediatric cardiac surgery when units >27 days of storage are transfused, yet decrease morbidity and mortality when units <15 days of storage are transfused • Receipt of an oldest unit >27 days of storage is associated with a ten fold increase in post-operative infections in pediatric cardiac surgery

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