1c Immunomodulation by blood transfusion: cancer recurrence and infection

lc I m m u n o m o d u l a t i o n by blood transfusion: cancer recurrence and infection ELEFTHERIOS C. V A M V A K A S Assistant Professor of Pathology

MD, PhD

Harvard Medical School

Assistant Director Blood Transfusion Service, Massachusetts General Hospital, GRJ 224, Gray Building, Boston, MA 02114, USA

The risks of cancer recurrence and post-operative bacterial infection which are attributed by some authors to an immunomodulatory effect of allogeneic transfusion have remained controversial for 15 years, as many observational studies and four randomized controlled trials have produced contradictory results. A review of these discrepant findings suggests that a deleterious immunomodulatory transfusion effect might exist, but it might operate only in specific surgical settings. The challenge is to identify those settings and to determine the magnitude of the adverse effect if it exists. This will require further randomized controlled trials designed to establish causal relationships and new observational studies designed to explain disagreements between published investigations. Lessons learned from the methodological limitations of the earlier reports can guide the design of future studies. It is hoped that the new studies will permit the formulation of rational guidelines for peri-operative transfusion practice which will prevent any deleterious effect(s) of transfusion-induced immunomodulation.

Key words: transfusion complications; transfusion-induced immunosuppression; postoperative infection; leukocyte reduction; leukodepletion. In the 1970s, the transfusion o f allogeneic blood was demonstrated to suppress the i m m u n e responses o f h u m a n hosts to renal allografts (Opelz et al, 1973). T h e possibility that peri-operative allogeneic transfusion m i g h t be associated with an increase in the recurrence rate o f resected malignancies, b y means o f a down-regulation o f the i m m u n e response o f a h u m a n host to a tumour, was raised by Gantt (1981). The formulation o f this hypothesis was f o l l o w e d by publication o f almost 100 observational clinical reports over the last 15 years (van Aken, 1989; Francis, 1991; Vamvakas, 1995). T h e related possibility o f an association o f perioperative transfusion with post-operative bacterial infections, secondary to suppression o f the i m m u n e response o f a host to bacterial invaders, Baillikre ~ Clinical Anaesthesiology--

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was also examined in over 310 observational studies (Tartter, 1989; Blumberg and Heal, 1994; Vamvakas and Moore, 1994). In addition, it was examined whether transfusion might reduce the post-operative recurrence rate of Crohn's disease (Peters et al, 1989), accelerate the progression of human immunodeficiency virus infection (Vamvakas and Kaplan, 1993; Busch et al, 1996) or prevent recurrent abortion (Unander, 1992). The observational studies produced discrepant results which ranged from no adverse transfusion effect to an up to 1000% increase in the risk of cancer recurrence or post-operative infection in association with perioperative transfusion. Neither of these deleterious effects of allogeneic blood was established (Houbiers et al, 1995; Klein, 1995; Nielsen, 1995; Vamvakas, 1996) by four recently completed randomized controlled trials (RCTs) investigating these two hypotheses (Busch et al, 1993; Heiss et al, 1993; Busch et al, 1994; Heiss et al, 1994; Houbiers et al, 1994; Jensen et al, 1996). Plausible biological mechanisms for the immunomodulatory effects of transfusion based on well-contr011ed laboratory experiments were advanced by several authors (Blajchman et al, 1993; Gianotti et al, 1993), and the reader is referred to the literature for a review of the proposed pathophysiological pathways (Brunson and Alexander, 1990; Blajchman and Bordin, 1994; Singal, 1994; Dzik et al, 1996). Different biological mechanisms may be involved in each of these several postulated adverse effects of allogeneic blood. Also, great caution should be exercised when immunomodulation results from animal models are extrapolated to humans (Goodarzi et al, 1995). The speculative immunosuppressive effects of allogeneic transfusion have been ascribed to donor leukocytes (Bordin et al, 1994) and/or donor plasma (Blumberg and Heal, 1994). These proposals raise the possibility that the related clinical consequences of transfusion-induced immunomodulation could be prevented by appropriate modifications of the transfused blood components. Jensen et al (1996) reported that leukodepletion of blood products through filtration prevents any post-operative septic complications that could allegedly be attributed to the transfusion of allogeneic blood. Another group ascribed a reduction in the observed incidence of post-operative bacterial infections to the use of autologous blood (Heiss et al, 1993). Autologous transfusion (as compared with transfusion of allogeneic blood) was found to be cost-effective in a population of patients undergoing hip replacement operations, specifically because it was assumed to reduce the frequency of post-operative bacterial infections (Healy et al, 1994). Similarly, leukodepletion of allogeneic blood was reported to lower the length and cost of hospital admissions by decreasing the incidence of septic complications of surgery (Jensen et al, 1995). Along these lines, allogeneic transfusion was estimated to cause at least 2150 deaths per year in the US by provoking cancer recurrence or infection (Dzik et al, 1996). On the basis of this figure, transfusion-induced immunomodulation is viewed by some authors as the leading cause of transfusion-associated mortality. This possibility would warrant major changes in peri-operative

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transfusion practices to prevent any immunosuppressive transfusion effect(s) if the role of transfusion in either cancer recurrence or postoperative infection were to be corroborated by future research. The changes would probably include leukodepletion of most or all collected allogeneic blood and increased use of autologous transfusion. However, following review of the contradictory findings of the observational studies and the early RCTs, panels of experts advised against adoption of such measures at the present time (Danish Society of Clinical Immunology, 1996; Royal College of Physicians of Edinburgh, 1996). Also, two cost-effectiveness analyses of autologous transfusion did not consider transfusion-induced immunomodulation to be a risk of allogeneic transfusion (Birkmeyer et al, 1993; Etchason et al, 1995). The variance in the conclusions of all these groups underscores the magnitude of the controversy which surrounds the clinical effects of transfusion-induced immunomodulation. OBSERVATIONAL STUDIES In most observational studies of the association of transfusion and postoperative infection (and in several of the reports on transfusion and cancer recurrence) transfusion emerged as the best predictor of either adverse outcome, in both univariate and multivariate analyses. These studies compared the frequency of infection or cancer recurrence between patients who did or did not need peri-operative transfusion. Transfused and untransfused patients differed with respect to many baseline characteristics, which might be related to both the need for transfusion and the risk of post-operative infection or cancer recurrence. Most authors tried to separate the effect of transfusion from the effects of confounding factors by introducing the exposure of interest (transfusion) and the confounding variables into multivariate regression models. This statistical technique permits adjustment for the effects of all known and measurable confounders, provided that the analysis is conducted by the forced entry (as opposed to the stepwise) method. In a forced entry analysis, transfusion is tested for entry into a model that already includes all identified confounding factors. Entry of transfusion into this model indicates that an adverse transfusion effect exists, even after adjustment for all known confounders. In a stepwise analysis, transfusion and the other variables enter the model one at a time in the order of statistical significance. Factors enter the model only if they exercise a statistically significant effect following adjustment for the effects of the variables that are already included in the model. As a result, not all confounders are present in the final model, and the effects of variables which fail to enter the model are left uncontrolled. In this body of literature, most published analyses were conducted by the stepwise method, and the reported 'adjusted' transfusion effect was often still confounded by some factors which had been identified as potentially confounding by the authors (Vamvakas and Moore, 1994). More importantly, some systematic differences between transfused and untransfused patients with regard to known risk factors for the outcome of

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interest were not evaluated as potential confounders of the association under study, in investigations of transfusion and post-operative infection, these variables included risk factors for infection at specific sites, for example the following: the number of days with indwelling urinary or vascular catheters, which predispose a patient to urinary tract infection (UTI) and bloodstream infection, respectively; endotracheal intubation leading to pneumonia; gastric acid neutralization therapy and the number of days of nasogastric tube use, which may increase the risk of pneumonia and nosocomial diarrhoea; intervals of impaired consciousness, which may predispose to aspiration and pneumonia; malnutrition and chronic systemic illness, which predispose to UTI, bloodstream infection, pneumonia and wound infection. We recently calculated, in 492 patients undergoing colorectal cancer surgery, the probability of post-operative infection in association with transfusion, with and without adjustment for the effects of chronic systemic illness, number of days with urinary catheter, endotracheal intubation, impaired consciousness and specific risk factors for wound infection. Postoperative infection at any site and infections at specific sites were analysed as separate outcomes. To our knowledge, this is the first observational study to present adjustment for the effects of all these factors (Vamvakas et al, 1996). Transfusion was the most highly significant predictor of infection at any site in an analysis adjusting for the effects of 18 confounders examined by earlier authors (P < 0.001). However, when the analysis also included the additional risk factors for infection listed here, transfusion was no longer associated with post-operative infection (P=0.407). Significant (P < 0.05) predictors of infection at any site included the number of days with indwelling urinary catheter (preceding a diagnosis of UTI), chronic systemic illness, impaired consciousness (preceding a diagnosis of pneumonia) and duration of surgery. Allogeneic transfusion was not associated with UTI (P=0.498) or pneumonia (P=0.261), but it was related to wound infection (P = 0.012). A third consideration pertains to the inherent limitations of observational studies. Even if a forced entry analysis controls for the effects of all known and measurable confounders, these studies cannot adjust for the effects of unknown and/or poorly quantifiable risk factors for cancer recurrence or post-operative infection. For example, the extent of tumour resection, the difficulty of the operation, the skill of the surgeon and the nutritional and overall health status of the patient can be reasonably expected to be related both to a patient's transfusion needs and to the likelihood of tumour recurrence and post-operative infection. However, these variables cannot be precisely quantified and are thus difficult to control by statistical techniques. It is unclear whether adjustment for their effects can be achieved through the use of measurable 'surrogate' variables, such as the duration of surgery, the amount of peri-operative blood loss, the qualifications of the surgeon and the patient's American Society of Anesthesiologists class. A related problem is the high degree of correlation between perioperative transfusion and some of these confounding factors. A difficult and long operation, a peri-operative haemorrhage and a patient's poor physical

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condition almost predictably generate requests for transfusion. The calculations involved in multivariate statistical techniques cannot tolerate such a high degree of interdependence between the exposure (peri: operative transfusion) and the other factors that are introduced into the statistical model. For all these reasons, a substantial portion of the effects of some fairly obvious confounders may have persisted even after the undertaking of multivariate analyses in the published observational reports; different degrees of stringency in adjusting for the effect of confounding might explain, at least in part, the disagreements between the studies, and a causal relationship between allogeneic transfusion and cancer recurrence or postoperative infection cannot be established by the completed observational investigations. R A N D O M I Z E D C O N T R O L L E D TRIALS RCTs are prospective clinical experiments in which the treatment (perioperative allogeneic transfusion) is allocated by the investigators to a subset of the study subjects (the treatment group) via randomization. Patients randomly assigned to the control group receive either autologous or leukodepleted allogeneic blood, in the event that they need perioperative transfusion. Both of these are presumed to have no immunosuppressive potential. The purpose of random assignment of subjects to groups is to distribute all confounding factors equally between the two comparison groups. When a very large number of subjects is involved in the process, the groups will be equal with regard to all baseline characteristics, including all unknown or poorly quantifiable risk factors for cancer recurrence or post-operative infection. Therefore, a higher frequency of cancer recurrence or infection in patients receiving unmodified allogeneic blood (than in recipients of autologous or filtered allogeneic blood) could suggest a causal relationship between transfusion and these adverse outcomes. In contrast to the findings of the observational studies, the hitherto reported RCTs have not supported the hypothesis that transfusion of buffycoat-poor allogeneic red cells (as compared with autologous or leukodepleted red cells) increases the risk of cancer recurrence (Table 1). When all three studies were considered together in a meta-analysis (Vamvakas, 1996), the summary (or 'average') relative risk of cancer recurrence across the studies in the treatment (as compared with the control) group was 1.03 (95% confidence interval, 0.79-1.33, P >>0.05). However, these combined RCTs did not attain an adequate sample size to rule out the possibility of a smaller than a 33% increase in the risk of cancer recurrence in the treatment group, as compared with the control group. Also, RCTs transfusing buffycoat-rich red cells to the treatment group (as is standard practice in the United States) have not yet been reported, and the possibility of an adverse transfusion effect which might become manifest only after a certain threshold number of donor leukocytes has been transfused remains open.

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Table 1. Randomized controlled trials investigating an association between peri-operative transfusion and colorectal cancer reculTence. Study

Red cell product given to the control group

Busch et al (1993) Heiss et al (1994) Houbiers et al (1994)

Autologous Autologous Leukodepleted allogeneic

Sample size

Overall recurrence rate (%)*

Relative risk]

P value~:

423 100 697

24.8 23.0 25.5

1.01 1.73 0.98

0.93 0.11 0.79

* For all patients enrolled in the study. t- Incidence of adverse outcome in treatment versus control group. 5; Based on an intention-to-treat analysis.

Finally, the presumptions that the autologous and/or leukodepleted allogeneic red cells are immunologically neutral have not been tested. It is possible that the transfusion of any blood component may exercise immunomodulatory effects, which would preclude the detection of those effects by RCTs comparing the frequency of adverse outcomes in recipients of standard versus specially prepared blood products. The findings of the hitherto published RCTs which reported on the association between transfusion of buffy-coat-poor allogeneic red cells and an increase in the risk of post-operative septic complications (Table 2) cannot be combined by the techniques of meta-analysis. The use of metaanalysis requires that the retrieved studies agree with each other and that they can be assumed to measure one and the same treatment effect. Of the four published RCTs, two reported a statistically significant, more than twofold increase in the risk of infection in the treatment (as compared with the control) group, and two observed no deleterious treatment effect (Table 2). When the four studies are considered together, the calculated value for the Q test statistic (Q = 22.2, P < 0.001) precludes a combination of all four trials with one another. (The Q test statistic assesses whether the differences between the findings of the retrieved studies could have arisen by chance. This hypothesis is rejected here, and the four trials cannot be assumed to measure the same treatment effect.) Accordingly, the four RCTs cannot be combined for calculation of a summary relative risk.

Table 2. Randomized controlled trials investigating an association between peri-operative transfusion and post-operative infection in colorectal cancer surgery.

Study

Red cell product given to the control group

Heiss et al (1993) Busch et al (1994) Houbiers et al (1994) Jensen et al (1996)

Autologous Autologous Leukodepleted allogeneie Leukodepleted allogeneic

Sample size

Overall infection rate (%)*

Relative risk]"

P values

120 470 697 589

20.0 26.0 33.4 17.5

2.27 0.91 0.91 2.64 §

0.0419 0.60 0.42 <0.0001§

* For all patients enrolled in the study. ]- Incidence of adverse outcome in treatment versus control group. $ Based on an intention-to-treat analysis. § Patients developing more than one infection are double-counted.

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Instead, the reasons for the disagreements between the studies need to be investigated. Differences in the criteria for diagnosing post-operative infections may account for some of the discrepancy, as investigators who reported a low overall infection rate observed a deleterious transfusion effect, whereas the two groups which more frequently recorded post-operative infections failed to detect an effect (Table 2). The frequency of wound infections observed by Jensen et al was 4.9% in 1992-1995 (Jensen et al, 1996), as compared with 8.1% in 1989-1990 when the same diagnostic criteria were used (Jensen et al, 1992). These investigators reported a statistically significant increase in the incidence of wound infection and pneumonia in the treatment group, but no difference in the frequency of UTI between the groups (Jensen et al, 1996). There was a trend toward a higher incidence of wound infections in the treatment group of Heiss et al (1993) although the difference did not attain statistical significance; the frequency of pneumonia or UTI did not differ between the comparison groups in that study (Heiss et al, 1993). Similar results were recently presented by van de Watering et al (1996) who randomized 915 cardiac surgery patients to receive buffy-coat-poor or leukodepleted red cells, and observed a higher incidence of post-operative infection and death from infection in the treatment (than in the control) group. Perhaps the greater number of transfusions administered to cardiac surgery patients and the use of an extracorporeal circuit in that setting (which might have induced complement activation) are responsible for the difference in the findings reported by those investigators in patients undergoing cardiac surgery versus patients admitted for colorectal cancer resection (Houbiers et al, 1994). It may be necessary that a certain threshold number of donor leukocytes be transfused before the adverse transfusion effect becomes manifest. Houbiers et al (1994), who did not observe a deleterious transfusion effect, administered 0.8 x 109 leukocytes per unit of buffy-coat-poor red cells. Jensen et al (1996) used 1.5 times that dose per unit of transfused red cells (i.e. 1.2 x 109 leukocytes per unit of buffy-coatpoor red cells), and reported an adverse transfusion effect in the treatment group. Those authors had used unmodified whole blood in their earlier report (Jensen et al, 1992), where they had observed an even higher frequency of wound infections in the treatment group. As is often the case (Miller et al, 1989), studies that did not conform to established methodological principles for the design and analysis of RCTs reported a substantially larger treatment effect (Table 2). The findings of Jensen et al are difficult to evaluate, because these investigators enrolled a heterogeneous patient population, consisting of all patients admitted for elective colorectal surgery, making it unlikely for randomization to distilbute all confounding factors equally between the comparison groups of subjects with the less common diagnoses. The majority of patients had colorectal cancer, but the authors did not present data on confounders (e.g. Dukes' stage of turnout) to show that a balance was achieved between their comparison groups. In addition, the authors did not present an intention-totreat analysis comparing the two prospectively formed arms of the study,

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but compared three groups with one another (i.e. transfused patients from the treatment group with transfused patients from the control group and with untransfused patients).

CONCLUSIONS A deleterious effect of an impressively large magnitude, linking allogeneic transfusion to cancer recurrence or post-operative infection, was reported over the last 15 years by many observational studies comparing transfused and untransfused patients. Other observational studies failed to detect this adverse effect. The contradictory findings, and some important methodological limitations of the published observational reports, detracted from the credibility of the two hypotheses, despite the publication of an extensive body of basic research which proposed plausible biological mechanisms for transfusion-induced immunomodulation. Recent RCTs comparing recipients of buffy-coat-poor red cells with recipients of autologous or leukodepleted red cells focused the analysis on the kind of blood product received, as opposed to the factors which determine the need for peri-operative transfusion. These studies did not support a link between transfusion of buffy-coat-poor red ceils and cancer recurrence, although the possibilities of a 'small' adverse effect or an effect limited to the transfusion of buffy-coat-rich red cells cannot be addressed with the currently available data. RCTs generated contradictory findings with regard to the presumed link between transfusion and post-operative infection. The discrepancies could be potentially attributed to differences in the number of donor leukocytes administered per patient, differences in the diagnostic criteria for infection and/or methodological limitations of the published studies. No adequate explanation for the disagreements has yet been offered. Based on the hitherto published results from RCTs, any radical alteration in peri-operative transfusion practice is unwarranted. A lot more research is needed to identify the kind(s) of blood product(s) associated with any adverse transfusion effect(s) and the conditions required for these effects to become manifest if or when they exist. Because some data indicate that transfusion-induced immunomodulation might be responsible for a substantial number of transfusion-related deaths, valid results from welldesigned studies addressing these questions are urgently needed. Transfusion-induced immunomodulation should be an area of intense scrutiny in transfusion medicine research, and rational guidelines for peroperative transfusion practice should be based on the results of future experimental and observational clinical studies.

REFERENCES van Aken WG (1989) Does perioperative blood transfusion promote tumor growth? Transfusion Medicine Reviews 3: 243-252.

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Birkmeyer JD, Goodnough LT, AuBuchon JP et al (1993) The cost-effectiveness of preoperative autologous blood donation for total hip and total knee replacement. Transfitsion 33:544-551. Blajchman MA & Bordin JO (1994) Mechanisms of transfusion-related immunosuppression. Current Opinion in Hematology 1: 457-461. Blajchman MA, Bardossy L, Carmen R et al (1993) Allogeneic blood transfusion-induced enhancement of tumor growth: two animal models showing amelioration by leukodepletion and passive transfer using spleen cells. Blood 81: 1880-1882. Blumberg N & Heal JM (1994) Effects of transfusion on immune function. Cancer recurrence and infection. Archives of Pathology and Laboratory Medicine 118: 371-379. * Bordin JO, Heddle NM & Blajchman MA (1994) Biologic effects of leukocytes present in transfused cellular blood products. Blood 84: 1703-1721. *Brunson ME & Alexander JW (1990) Mechanisms of transfusion-induced immunosuppression. Transfitsion 30:651-658. Busch OR, Hop WC, Marquet RL & Jeekel J (1994) Autologous blood and infections after colorectal surgery. Lancet 343: 668-669. *Busch OR, Hop WC. Hoynck van Papendrecht MA et al (1993) Blood transfusions and prognosis in colorectal cancer. New England Journal of Medicine 328: 1372-1376. Busch MR Collier A, Gernsheimer T et al (1996) The Viral Activation Transfusion Study (VATS): rationale, objectives, and design overview. Transfitsion 36: 854-859. Danish Society of Clinical Immunology (1996) Danish recommendations for the transfusion of leukocyte-depleted blood components. Vox Sanguinis 70:185-186. Dzik S, Blajchman MA, Blumberg N e t al (1996) Current research on the immunomodulatory effect of allogeneic blood transfusion. Vox Sanguinis 70: 187-194. Etchason J, Petz L, Keeler E et al (1995) The cost-effectiveness of preoperative autologous blood donations. New England Journal of Medicine 332: 719-724. Francis DM (1991 ) Relationship between blood transfusion and tumour behaviour. British Journal of Surgery 78: 1420-1428. Gantt CL (1981) Red blood cells for cancer patients. Lancet ii: 363. Gianotti L, Pyles T, Alexander JW et al (1993) Identification of the blood component responsible for increased susceptibility to gut-derived infection. Transfusion 33: 458-465. Goodarzi MO, Lee TH, Pallavicini MG et al (1995) Unusual kinetics of white cell clearance in transfused mice. Transfusion 35: 145-149. Healy JC, Frankforter SA, Graves BK et al (1994) Preoperative autologous blood donation in total hip arthroplasty. A cost-effectiveness analysis. Alrhives of Pathology and Laboratory Medicine 118: 465-470. * Heiss MN, Mempel W, Jauch KW et al (1993) Beneficial effect of autologous blood transfusion on infectious complications after colorectal cancer sm'gery. Lancet 342: 1328-1333. Heiss MM, Mempel W, Delanoff C et al (1994) Blood transfusion-modulated tumor recurrence: first results of a randomized study of autologous versus allogeneic blood transfusion in colorectal cancer surgery. Journal of Clinical Oncology 12:1859-1867. * Houbiers JGA, Brand A, van de Watering LMG et al (1994) Randomized controlled trial comparing transfusion of leukocyte-depleted or buffy-coat-depleted blood in surgery for colorectal cancer. Lancet 344: 573-578. Houbiers JGA, Busch ORC, van de Watering LMG et al (1995) Blood transfusion in cancer surgery: a consensus statement. European Journal of Surgery 161: 301-314. Jensen LS, Grunnet N, Hamberg-Sorensen F & Jorgensen J (1995) Cost-effectiveness of blood transfusion and white cell reduction in elective colorectal surgery. Tran,sfusion 35:719-722. * Jensen LS, Kissmeyer-Nielsen P, Wolff B & Qvist N (1996) Randomized comparison of leukocytedepleted versus buffy-coat-poor blood transfusion and complications after colorectal surgery. Lancet 348:841-845. Jensen LS, Andersen A J, Christiansen PM et al (1992) Postoperative infection and natural killer cell function following blood transfusion in patients undergoing elective colorectal surgery. British Journal ~" Surgery 79:513-516. Klein HG (1995) Allogeneic transfusion risks in the surgical patient. American Journal (?f Surgery 170:$21-$26. Miller JN, Colditz GA & Mosteller F (1989) How study design affects outcomes in comparisons of therapy: II. Surgical. Statistics in Medicine 8: 455-466. Nielsen HJ (1995) Detrimental effects of perioperative blood transfusion. British Journal of Surgery 82: 582-587.

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* Opelz G, Sengar DP, Mickey MR & Terasaki P1 (1973) Effect of blood transfusions on subsequent kidney transplants, Transplantation Proceedings 5: 253-259. Peters WR, Fry RD, Fleshman JW & Kodner IJ (1989) Multiple blood transfusions reduce the recurrence rate of Crohn's disease. Diseases of Colon and Rectum 32: 749-753. Royal College of Physicians of Edinburgh (1996) Consensus Development Conference on Autologous Transfusion. Transfusion 36: 626-667. Singal DP (1994) Mechanisms of the blood transfusion effect. In Singal DP (ed.) Immunological Effects of Blood Transfusion, pp 155-185. Boca Raton, FL: CRC Press. Tartter PI (1989) Blood transfusion and postoperative infections. Transfusion 29: 456459. Unander MA (1992) The role of immunization treatment in preventing recurrent abortion. Transfusion Medicine Reviews 6: 1-16. *Vamvakas EC (1995) Perioperative blood transfusion and cancer recurrence: meta-analysis for explanation. Transfusion 35: 760-768. *Vamvakas EC (1996) Transfusion-associated cancer recurrence and infection: meta-analysis of randomized, controlled clinical trials. Transfusion 36:175-186. Vamvakas EC & Kaplan HS (1993) Early transfusion and length of survival in acquired immune deficiency syndrome. Transfusion 33:111-118, Vamvakas EC & Moore SB (1994) Blood transfusion and postoperative septic complications. Transfusion 34:714-727. *Vamvakas EC, Carven JH & Hibberd PL (1996) Blood transfusion and infection after colorectal cancer surgery. TransJ~tsion36: 1000-1008. van de Watering LMG, Houbiers JGA, Hermans J e t al (1996) Leukocyte depletion reduces postoperative mortality in patients undergoing cardiac surgery. In Proceedings of the 24th Cangress of the International SocieryJor Blood Transfusion, Makuhari, Japan, abstract SY3 DI-06.