Transfusion-Associated Immunodulation in Cancer Recurrence and Postoperative Infection: Meta-Analyses of Randomised Controlled Clinical Trials

  • E. C. Vamvakas
Part of the Developments in Hematology and Immunology book series (DIHI, volume 34)


Allogeneic blood transfusion has been reported to cause immunomodulatory effects, which purportedly enhance the survival of renal allografts [1], increase the recurrence rate of resected malignancies [2–5], increase the frequency of postoperative bacterial infections [3,5,6–8], reduce the recurrence rate of Crohn’s disease [9], and/or accelerate the progression of human immunodeficiency virus (HIV) infection [10]. The specific constituent(s) of donor blood that mediate these immunomodulatory effects remain unknown, but both animal and human data suggest that these effects are mediated by allogeneic white cells (WBCs) [11]. Plausible mechanisms for these effects have been advanced by several authors [12,13], but experiments in laboratory animals may not directly extrapolate to humans [14]. Moreover, different pathophysiologic mechanisms may be involved in each of the reported immunosuppressive effects associated with allogeneic blood transfusion, and the clinical evidence supporting each of the aforementioned hypotheses should be examined on its own merits.


Blood Transfusion Cancer Recurrence Postoperative Infection Allogeneic Blood Allogeneic Blood Transfusion 


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  1. 1.
    Opelz G, Sengar DP, Mickey MR, et al. Effect of blood transfusions on subsequent kidney transplants. Transplant Proc 1973;5:253–59.PubMedGoogle Scholar
  2. 2.
    Francis DM. Relationship between blood transfusion and tumor behavior. Br J Surg 1991;78:1420–28.PubMedCrossRefGoogle Scholar
  3. 3.
    Blumberg N, Heal JM. Effects of transfusion on immune function: cancer recurrence and infection. Arch Pathol Lab Med 1994;118:371–79.PubMedGoogle Scholar
  4. 4.
    Vamvakas E. Perioperative blood transfusion and cancer recurrence: meta-analysis for explanation. Transfusion 1995;35:760–68.PubMedCrossRefGoogle Scholar
  5. 5.
    Vamvakas E. Transfusion-associated cancer recurrence and infection: meta-analysis of the randomized controlled clinical trials. Transfusion 1996;36:175–86.PubMedCrossRefGoogle Scholar
  6. 6.
    Tartter PL Blood transfusion and bacterial infections: clinical studies. In: Singal DP, ed. Immunological Effects of Blood Transfusion. Boca Raton, FL: CRC Press, 1994, pp 111–26.Google Scholar
  7. 7.
    Vamvakas E, Moore SB. Blood transfusions and postoperative septic complications. Transfusion 1994;34:714–27.PubMedCrossRefGoogle Scholar
  8. 8.
    Duffy G, Neal KR. Differences in postoperative infection rates between patients receiving autologous and allogeneic blood transfusion: a meta-analysis of published randomized and nonrandomized studies. Transfusion Medicine 1996;6:325–28.PubMedCrossRefGoogle Scholar
  9. 9.
    Peters WR, Fry RD, Fleshman JW, et al. Multiple blood transfusions reduce the recurrence rate of Crohn’s disease. Dis Colon Rectum 1989;32:749–53.PubMedCrossRefGoogle Scholar
  10. 10.
    Busch MP, Collier A, Gernsheimer T, et al. The Viral Activation Transfusion Study (VATS): rationale, objectives, and design overview. Transfusion 1996;36:854–59.PubMedCrossRefGoogle Scholar
  11. 11.
    Bordin JO, Heddle NM, Blajchman MA. Biologic effects of leukocytes present in transfused cellular blood products. Blood 1994;84:1705–21.Google Scholar
  12. 12.
    Branson ME, Alexander JW. Mechanisms of transfusion-induced immunosuppression. Transfusion 1990;30:651–58.CrossRefGoogle Scholar
  13. 13.
    Blajchman MA, Bordin JO. Mechanisms of transfusion-related immunosuppression. Curr Opin Hematol 1994; 1:457–61.PubMedGoogle Scholar
  14. 14.
    Goodarzi MO, Lee TH, Pallavicini MG, Donegan EA, Busch MP. Unusual kinetics of white cell clearance in transfused mice. Transfusion 1995;35:145–49.PubMedCrossRefGoogle Scholar
  15. 15.
    Gantt CL. Red blood cells for cancer patients. Lancet 1981;ii:363.CrossRefGoogle Scholar
  16. 16.
    Busch ORC, Hop WCJ, Hoynek van Papendrecht MAW, Marquet RL, Jeekel J. Blood transfusions and prognosis in colorectal cancer. N Engl J Med 1993;328:1372–76.PubMedCrossRefGoogle Scholar
  17. 17.
    Houbiers JGA, Brand A, van de Watering LMG, et al. Randomized controlled trial comparing transfusion of leukocyte-depleted or buffy-coat-depleted blood in surgery for colorectal cancer. Lancet 1994;344:573–78.PubMedCrossRefGoogle Scholar
  18. 18.
    Heiss MN, Mempel W, Delanoff C, et al. Blood transfusion-modulated tumor recurrence: first results of a randomized study of autologous versus allogeneic blood transfusion in colorectal cancer surgery. J Clin Oncol 1994;12:1859–67.PubMedGoogle Scholar
  19. 19.
    Jensen LS, Andersen AJ, Christiansen PM, et al. Postoperative infection and natural killer cell function following blood transfusion inpatients undergoing elective colorectal surgery. Br J Surg 1992;79:513–16.PubMedCrossRefGoogle Scholar
  20. 20.
    Heiss MM, Mempel W, Jauch KW, et al. Beneficial effect of autologous blood transfusion on infectious complications after colorectal surgery. Lancet 1993; 342:1328–33.PubMedCrossRefGoogle Scholar
  21. 21.
    Busch ORC, Hop WCJ, Marquet RL, et al. Autologous blood and infections after colorectal surgery. Lancet 1994;343:668–69.PubMedCrossRefGoogle Scholar
  22. 22.
    Jensen LS, Kissmeyer-Nielsen P, Wolff B, Qvist N. Randomized comparisons of leukocyte-depleted versus buffy-coat-poor blood transfusion and complications after colorectal surgery. Lancet 1996;348:841–45.PubMedCrossRefGoogle Scholar
  23. 23.
    van de Watering LMG, Herman J, Houbiers JGA, et al. Beneficial effects of leukocyte depletion of transfused blood on postoperative complications in patients undergoing cardiac surgery: a randomized clinical trial. Circulation 1998;97:562–68.PubMedCrossRefGoogle Scholar
  24. 24.
    Blumberg N, Heal JM. Blood transfusion immunomodulation: the silent epidemic. Arch Pathol Lab Med 1998;122:117–19.PubMedGoogle Scholar
  25. 25.
    Blajchman MA. Allogeneic blood transfusions, immunomodulation and postoperative bacterial infection: Do we have the answers yet? Transfusion 1997;37:121–25.PubMedCrossRefGoogle Scholar
  26. 26.
    Vamvakas EC, Blajchman MA. A proposal for an individual patient data based metaanalysis of randomized controlled trials of allogeneic transfusion and postoperative bacterial infection. Transf Med Rev 1997,11:180–94.CrossRefGoogle Scholar
  27. 27.
    McAlister FA, Clark HD, Wells PS, Laupacis A. Perioperative allogeneic blood transfusion does not cause adverse sequelae in patients with cancer: a meta-analysis of unconfounded studies. Br J Surg 1998;85:171–78.PubMedCrossRefGoogle Scholar
  28. 28.
    Jenicek M. Meta-analysis in medicine: where we are and where we want to go. J Clin Epidemiol 1989;42:35–44.PubMedCrossRefGoogle Scholar
  29. 29.
    L’Abbe KA, Detsky AS, O’Rourke K. Meta-analysis in clinical research. Ann Intern Med 1987;107:224–33.PubMedCrossRefGoogle Scholar
  30. 30.
    Vamvakas EC. Meta-analysis in transfusion medicine. Transfusion 1997;37:329–45.PubMedCrossRefGoogle Scholar
  31. 31.
    Cooper H, Hedges LV, eds. The handbook of research synthesis. New York, NY: Russell Sage Foundation, 1994.Google Scholar
  32. 32.
    Elwood P. Causal relationships in medicine. New York, NY: Oxford University Press, 1988.Google Scholar
  33. 33.
    Sackett DL. Bias in analytic research. J Chron Dis 1979;32:51–63.PubMedCrossRefGoogle Scholar
  34. 34.
    Kleinbaum DG, Kupper LL, Morgenstern H. Epidemiologic research: principles and quantitative methods. New York, NY: van Nostrand Reinhold Company, 1982:194–240.Google Scholar
  35. 35.
    Friedman LM, Furberg CD, DeMets DL. Fundamentals of clinical trials, 3rd ed. St Louis, MO: Mosby, 1995.Google Scholar
  36. 36.
    Waymack JP, Robb E, Alexander JW. Effect of transfusion on immune function in a traumatized animal model: II. Effect on mortality rate following septic challenge. Arch Surg 1987;122:935–39.PubMedCrossRefGoogle Scholar
  37. 37.
    Waymack JP, Chance WT. Effect of blood transfusions on immune function: IV. Effect on tumor growth. J Surg Oncol 1988;39:159–64.PubMedCrossRefGoogle Scholar
  38. 38.
    Persijn GG, Cohen B, Lansbergen Q, van Rood JJ. Retrospective and prospective studies on the effect of blood transfusion in renal transplantation in the Netherlands. Transplantation 1979;28:396–401.PubMedCrossRefGoogle Scholar
  39. 39.
    Passamani E. Clinical trials: are they ethical? N Engl J Med 1991;324:1589–91.PubMedCrossRefGoogle Scholar
  40. 40.
    Hennekens CH, Buring JE. Epidemiology in Medicine. Boston: Little, Brown, and Co., 1987:30–53.Google Scholar
  41. 41.
    Yusuf S, Peto R, Lewis J, Collins R, Sleight P. Beta blockade during and after myocardial infarction: an overview of the randomized trials. Prog Cardiovasc Dis 1985;27:335–71.PubMedCrossRefGoogle Scholar
  42. 42.
    DerSimonian R, Laird N. Meta-analysis in clinical trials. Control Clin Trials 1986; 7:177–88.PubMedCrossRefGoogle Scholar
  43. 43.
    Goodman SN. Have you ever meta-analysis you didn’t like? Ann Intern Med 1991; 114:244–46.PubMedCrossRefGoogle Scholar
  44. 44.
    Moher D, Jadad AR, Nichol G, Penman M, Tugwell P, Walsh S. Assessing the quality of randomized controlled trials: an amiotated bibliography of scales and checklists. Control Clin Trials 1995;16:62–73.PubMedCrossRefGoogle Scholar
  45. 45.
    Moher D, Jadad AR, Tugwell P. Assessing the quality of randomized controlled trials. Int J Technol Assess Health Care 1996;12:195–208.PubMedCrossRefGoogle Scholar
  46. 46.
    Chalmers TC, Smith H Jr, Blackburn B, et al. A method for assessing the quality of a randomized controlled trial. Control Clin Trials 1981;2:31–49.PubMedCrossRefGoogle Scholar
  47. 47.
    Schultz KF, Chalmer I, Hayes RJ, Altman DG. Empirical evidence of bias: dimensions of methodological quality associated with estimates of treatment effects in controlled trials. JAMA 1995;273:408–12.CrossRefGoogle Scholar
  48. 48.
    Moher D, Jones BA, Cook DJ, et al. Does quality of reports of randomized trials affect estimates of intervention efficacy reported in meta-analyses? Lancet 1998; 352:609–13.PubMedCrossRefGoogle Scholar
  49. 49.
    Ioannidis JPA, Lau J. Can quality of clinical trials and meta-analyses be quantified? Lancet 1998;352:590–91.PubMedCrossRefGoogle Scholar
  50. 50.
    Huque MF. Experiences with meta-analysis in FDA submissions. Proc Biopharma-ceutical Section Am Stat Assoc 1988;2:28–33.Google Scholar
  51. 51.
    Dubey S. Regulatory considerations on meta-analysis and multicenter trials. Proc Biopharmaceutical Section Am Stat Assoc 1988;2:18–27.Google Scholar
  52. 52.
    Stein RA. Meta-analysis from one FDA reviewer’s perspective. Proc Biopharma-ceutical Section Am Stat Assoc 1988;2:34–38.Google Scholar
  53. 53.
    Ness PM, Walsh PC, Zahurak M, Baldwin ML, Piantadosi S. Prostate cancer recurrence in radical surgery patients receiving autologous or homologous blood. Transfusion 1992;32:31–36.PubMedCrossRefGoogle Scholar
  54. 54.
    Giurati G, Zanetta G, Caspani L, et al. Autologous blood transfusion in patients undergoing radical hysterectomy. Br J Obstet Gynecol 1995;102:64–65.CrossRefGoogle Scholar
  55. 55.
    Kajikawa M, Nonami T, Kurokawa T, et al. Autologous blood transfusion for hepa-tectomy in patients with cirrhosis and hepatocellular carcinoma: use of recombinant human erythropoietin. Surgery 1994;115:727–34.PubMedGoogle Scholar
  56. 56.
    Lachin JM. Statistical properties of randomization in clinical trials. Control Clin Trials 1988;9:289–311.PubMedCrossRefGoogle Scholar
  57. 57.
    Peto R. Why do we need systematic overviews of randomized trials? Stat Med 1987;6:233–44.PubMedCrossRefGoogle Scholar
  58. 58.
    Huskisson EC, Scott J. How blind is double blind? And does it matter? Br J Clin Pharmacol 1976;3:331–32.PubMedCrossRefGoogle Scholar
  59. 59.
    Jadad AR, Moore RA, Carroll D, et al. Assessing the quality of reports of randomized clinical trials: is blinding necessary? Control Clin Trials 1996;17:1–12.PubMedCrossRefGoogle Scholar
  60. 60.
    Borzak S, Ridker PM. Discordance between meta-analyses and large-scale randomized controlled trials: examples from the management of acute myocardial infarction. Ann Intern Med 1995;123:873–77.PubMedCrossRefGoogle Scholar
  61. 61.
    Bailar JC III. The promise and problems of meta-analysis. N Engl J Med 1997;337: 559–61.PubMedCrossRefGoogle Scholar
  62. 62.
    Editorial: Meta analysis under scrutiny. Lancet 1997:350:675.Google Scholar
  63. 63.
    Villar J, Carroli G, Belizan JM. Predictive ability of meta-analyses of randomized controlled trials. Lancet 1995;345:772–76.PubMedCrossRefGoogle Scholar
  64. 64.
    Cappelleri JC, Ioannidis JPA, Schmid CH, et al. Large trials vs meta-analyses of small trials: how do their results compare? JAMA 1996;276:1332–38.PubMedCrossRefGoogle Scholar
  65. 65.
    LeLorier J, Gregoire B, Benhaddad A, Lapierre J, Derderian F. Discrepancies between meta-analyses and subsequent large randomized, controlled trials. N Engl J Med 1997;337:536–42.PubMedCrossRefGoogle Scholar
  66. 66.
    Ioannidis JPA, Cappelleri JC, Lau J. Issues in comparisons between meta-analyses and large trials. JAMA 1998;279:1089–93.PubMedCrossRefGoogle Scholar
  67. 67.
    Videm V, Fosse E, Mollness TE, Garred P, Svennevig JL. Complement activation with bubble and membrane oxygenators in aortocoronary bypass grafting. Ann Tho-rac Surg 1990;50:387–91.CrossRefGoogle Scholar
  68. 68.
    Bilfinger TV, Kushnerik V, Bundz S, Liu Y, Stefano GB. Evidence for morphine downregulating immunocytes during cardiopulmonary bypass in a porcine model. Int J Cardiol 1996;53 (Suppl):39–46.CrossRefGoogle Scholar
  69. 69.
    Shau H, Golub SH. Modulation of natural killer-mediated lysis by red blood cells. Cell Immunol 1988;116:60–72.PubMedCrossRefGoogle Scholar
  70. 70.
    Nielsen HJ, Reimert M, Pedersen AN, et al. Time-dependent, spontaneous release of white cell- and platelet-derived bioactive substances from stored human blood. Transfusion 1996;36:960–65.PubMedCrossRefGoogle Scholar
  71. 71.
    Houbiers JG, van de Velde CJ, van de Watering LM, et al. Transfusion of red cells is associated with increased incidence of bacterial infection after colorectal surgery: a prospective study. Transfusion 1997;37:126–34.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media Dordrecht 1999

Authors and Affiliations

  • E. C. Vamvakas
    • 1
  1. 1.Pathology and Laboratory Medicine ServiceNew York VAMCNew YorkUSA

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