Allogeneic transfusion risks in the surgical patient

Allogeneic

Transfusion Risks in the Surgical Patient

Harvey

G.

Klein, MD,

The risk of blood transfusion-associated complieations has been reduced in the past 10 years through technical advances in testing of blood, viral inactivation of noncellular blood components, enforcement of stringent donor selection criteria, and the use of alternatives to allogeneic transfusion. Even so, a zero-risk blood supply is unfeasible. The general public perceives infectious complications to be the most significant risk: although the greatest fear is associated with transmission of human immunodeficiency virus (HIV), at least three hepatitis viruses are transmissible by all blood components. Human imnmnodeficiency virus accounts for <20 cases per year of transfusion-related acquired immunodeficiency syndrome in the United States. The three important noninfectious complications are alloinmmnization, which is common but clinically insignificant; imnmnosuppression, the clinical significance of which is controversial; and graft-versus-host disease, a lethal complication most likely to affect patients who are immunosuppressed, have cancer, or are recipients of bone marrow transplants.

From the Department of Transfusion Medicine, Warren Grant Magnuson Clinical Center, National Institutes of Health, Bethesda, Maryland. Requests for reprints should be addressed to Harvey G. Klein, MD, Department of Transfusion Medicine, Clinical Center, National Institutes of Health, Building 10, Room lC-711, Bethesda, Maryland 20892.

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M

odern surgical techniques, careful attention to blood loss, and preoperative autologous donation (PAD) have reduced the need for allogeneic transfusion; nevertheless, few surgeons would undertake an operation if sufficient, safe blood components were not readily available. “Safe” is a relative term, however. Just a few years ago, many experienced physicians wnsidered compatible blood transfusion innocuous, or at least far less risky than almost any surgical procedure, but allogeneic blood transfusions are associated with a number of potential infectious and noninfectious complications. Transfusion-transmitted infection remains the most common serious risk of blood transfusion; patients receiving blood transfusions face an approximate 3 in 10,000 risk of contracting a serious or fatal transfusiontransmitted disease [I]. The risk of transfusion-related mortality is extremely small, however-probably substantially less than the risk associated with general anesthesia. During the past 10 years, transfusion-associated risks have been reduced through technical advances in laboratory testing of blood, increased use of viral inactivation of noncellular blood components, and enforcement of more stringent donor-selection criteria. Physicians have further reduced the risk of transfusion-associated complications for patients with chronic anemia by limiting the frequency of allogeneic red blood cell (RBC) transfusions and by using alternatives to allogeneic blood, primarily recombinant human erythropoietin (Epoetin alfa). Epoetin alfa has been shown to reduce the need for blood transfusions in patients with end-stage renal disease by approximately 75% and is used in the anemia related to cancer chemotherapy, in selected patients taking zidovudine therapy for human immunodeficiency virus (HIV) infection, and in orher instances of the anemia of chronic disease. Administration of Epoetin alfa in the perioperative setting has been shown to enhance RBC mass. In the surgical setting, strategies to maximize autologous blood use and drugs that decrease blood loss have gained prominence. Each year in the United States, approximately 14 million units of blood are collected and screened, yielding 11-12 million units of RBCs for transfusion [2]. Several million units of platelets and plasma are transfused as well. While screening and testing have reduced the number of infected units, ensuring a zero-risk blood supply is unfeasible. It is therefore not surprising, in view of the concern about “tainted blood,” that both the collection and transfusion of allogeneic blood have decreased. Between 1989 and 1992, the collection of allogeneic RBCs dropped by about 7% and is now at 1979-1980 collection levels. The use of allogeneic transfusions dropped by about 9%. During the same interval,

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TABLE I Estimated Risks of Transfusion per Unit in the United States (1995) 1:lOO

Minor allergic reactions Bacterial infection (platelets) Viral hepatitis

1:5,000

Hemolytic transfusion

reaction

HTLV l/II infection

1:6,000 1:200,000

HIV infection

1:420.000

Acute lung injury

1:500,000

Anaphylactic

1:500,000

shock

Fatal hemolytic reaction Graft-vs-host disease

= human

T-cell

1:600,000 Rare

lmmunosuppression HTLV

1:2,500

Unknown

leukemia-lymphoma

virus; HIV = human

immunodefi-

ciency virus. Source: Harvey G. Klein, MD.

PAD collection rose by about 70%. Apparently, both physicians and patients have chosen to improve transfusion safety by avoiding allogeneic blood. However, overuse of the avoidance strategy in the operative setting carries its own risk of morbidity and mortality [3]. INFECTIOUS COMPLICATIONS OF BLOOD TRANSFUSIONS Transfusion-transmitted infectious diseases, especially HIV, clearly overshadow all perceived complications of RBC transfusion. Ironically, allogeneic RBC transfusion is safer than ever before, and transfusion-transmitted HIV is not the most significant risk (Table I).

Most transfusion-transmitted infections are caused by viruses that may be difficult to detect because of their prolonged incubation periods and variable clinical presentations. At least three hepatitis viruses can be transmitted by all blood components and most plasma fractionation products other than albumin. No recent prospective studies have documented the frequency of post-transfusion hepatitis in the United States, but 1992 estimates place the risk at approximately one case for every 3,000 units of RBCs transfused [I]. Recent introduction of second- and third-generation hepatitis C screening tests will likely lower that risk further. More than 90% of posttransfusion hepatitis cases are now attributed to the hepatitis C virus (HCV), and about 2% to the hepatitis B virus (HBV). The remainder are caused by a variety of agents, including cytomegalovirus (CMV), Epstein-Barr virus (EBV), hepatitis A virus, and several recently identified hepatitis viruses [4]. Because posttransfusion hepatitis in its initial stages is usually mild or asymptomatic, physicians in the past have questioned the importance of posttransfusion hepatitis as a health hazard. However, as many as one third of these cases progress to chronic liver disease, and a significant number, perhaps as many as 20%, eventually develop cirrhosis. Further, both HBV and HCV have strong associations with hepatocellular carcinoma [5]. 22s

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Retroviruses remain the most feared transfusiontransmitted infectious agents, although HIV type 1 (HIV-l) accounts for < 20 transfusion-related acquired immunodeficiency syndrome (AIDS) cases per year in the United States [6]. A related agent, HIV type 2, can also cause AIDS, but it is rare in the United States. Although current screening tests for HIV have excellent sensitivity and specificity, the virus mutates rapidly. HIV-like variants and other similar agents may appear in the future, making the task of prevention by laboratory testing increasingly difficult. Such a variant, subtype 0, has recently been reported in Europe [7l. The human T-cell leukemia/lymphoma virus types I and II (HTLV-I and -II), endemic in southwest Japan and in the Caribbean basin, also have been transmitted by transfusion of cellular blood components [8]. The HTLV-I and T-cell leukemia association is easily overlooked, since the incubation time for HTLV-1 is measured in years. To date, no documented cases of leukemia related to transfusion have been reported, but a myelopathy known as tropical spastic paraparesis can develop after HTLV-I infection, and a small number of these cases has been traced to infected blood components. Currently, all cellular blood components in the United States are tested for the HTLV-I/II antibodies; units that test positive are discarded, and positive donors are counseled and deferred from further donations. Patients and physicians in the United States worry most about the risks of retroviruses and hepatitis viruses in transfusions, but in many parts of the world other infectious agents present a far greater danger. Malarial parasites are the major risk of RBC transfusions in most tropical developing countries; > 15% of the donor pool is infected in some areas of Africa [9]. Donor screening has effectively limited the risk of malaria from blood transfusion in the United States to 0.25 cases/million units transfused. Chagas’ disease, which is caused by the blood-transmitted parasite Tqpanosoma cruzi, is responsible for substantial morbidity and mortality in South and Central America. Chagas’ disease has been recognized as an emerging problem in the United States and Canada because of emigration from those countries [IO]. Screening methods and sensitive, specific tests are now in the pilot study phase to detect donors infected with this parasite. Bacterial contamination of blood components has not caused great anxiety since the development of interconnected sterile plastic container systems. CompIacency may have been premature, however. An apparent increase in the number of infections with such unusual organisms as the enteric pathogen, Yersinia enterocolitica, have once again raised concerns [II]. This organism grows well at 4” C in the anticoagulant preservative solutions designed for RBCs. Furthermore, platelet concentrates stored at room temperature may present an even greater risk of bacterial growth. The incidence of positive bacterial cultures from RBC and platelet units in Canada has consistently approximated 0.3% for 170

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the last 15 years. Routine bacterial monitoring has been recommended by some, but it is not yet standard practice [II]. NONINFECTIOUS COMPLICATIONS OF BLOOD TRANSFUSIONS In addition to infectious complications, patients receiving blood transfusions are at risk for several noninfectious complications. The three most common are alloimmunization, immunosuppression, and graftversus-host disease (GVHD). Allergic reactions, including urticaria, chills, and fever, although very common, are more an inconvenience for the patient [JO] and physician than a threat to health. These reactions are observed most often in patients repeatedly transfused or in multiparous women. Febrile nonhemolytic reactions are caused primarily by leukocytes and cytokines in the cellular blood component [12]. Alloimmunization: Alloimmunization after RBC transfusion is common but usually clinically inconsequential. Development of RBC alloantibodies occurs in approximately 1% of units transfused, but many of these antibodies are clinically insignificant [13]. Rarely do transfusion services fail to identify compatible RBCs for a patient with multiple alloantibodies; however, the time required for the crossmatching may delay treatment or surgical procedures. Alloantibodies may cause delayed hemolytic transfusion reactions in approximately 1 case for every 6,000 units transfused. Fatal hemolytic reactions, occurring in approximately 1 case for every 600,000 units transfused, are almost always related to incompatibility in the blood group system resulting from clerical errors, such as transfusing the wrong unit to a misidentified patient. A variety of systems for donor-patient identification are commercially available, but none has effectively eliminated all clerical errors. Fortunately, fatalities related to hemolytic transfusion reactions are rare [14]. In contrast, up to 30% of patients who receive chronic platelet transfusion therapy become refractory to further platelet transfusion because of alloimmunization to platelet-related antigens. This complication is potentially lethal for thrombocytopenic patients; in the United States, however, the actual number of thrombocytopenic patients who die from hemorrhage each year is small. Prevention of platelet alloimmunization is an area of intense research but, as yet, with little success [15]. Alloimmunization from plasma proteins can cause fatal anaphylaxis, but with the exception of antiimmunoglobulin A, these alloantibodies rarely account for severe RBC transfusion reactions. Immunoeuppression: Controversy surrounds the question of whether allogeneic transfusion is associated with clinically important immunosuppression in the recipient. The issue was raised in 1973 by Opelz et al [16], who provided evidence that blood transfusion prior to renal allograft surgery improved renal allograft survival. Furthermore, the effect appeared to be dose dependent. The results were subsequently supported by similar findings for patients who received renal grafts THE AMERICAN

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from living relatives and for cardiac transplant patients [17-191. Recent data suggest that potent immunosuppressive drug therapies that include cyclosporine have eliminated the importance of the transfusion effect, but a careful study of the human leukocyte antigen D-related (HI-A-DR) status of donor and recipient indicated that transfusions matched for at least one HLA-DR antigen were associated with improved survival of both cardiac and renal allografts [29]. Blood transfusions initiate a number of immunologic responses that can be measured in the laboratory [20]. Investigators have reported the development of Fcreceptor-blocking factors, lymphocyte activation, lymphocyte subpopulation changes, and downregulation of antigen-presenting cells after blood transfusion. Further, reduced numbers of B lymphocytes and alterations in natural killer cell function may persist for years. The mechanisms for such changes, whether related to a component of the transfusion or to a special characteristic of the recipient, are unclear. Neonates who received washed and irradiated RBCs, for example, failed to exhibit many of the immunosuppressive changes reported in adult transfusion recipients [21]. Furthermore, these laboratory findings do not correlate with known clinical abnormalities. Clinical evidence suggests that blood transfusions cause significant immunomodulatory effects. Among the postulated beneficial effects are improved tolerance of allografts, suppression of immune inflammatory disease, and prevention of recurrent abortion [22,23]. Among the suspected negative effects are recurrence of malignancy, increased frequency of postoperative infections, and reactivation of latent viruses [24,25]. The latter effect may play a role in the rapid progression of AIDS in heavily transfused patients. Another well-recognized adverse effect of RBC transfusion is GVHD, a lethal disorder mediated by transfused immunocompetent lymphocytes that engraft and reject the transfused host [26]. RECURRENCE OF MALIGNANCY: The role of RBC transfusion in the recurrence rate and survival of cancer patients has been disputed for more than a decade. More than 40 studies have examined the relationship between transfusion and cancer recurrence or survival in patients who underwent cancer surgery; the combined results are equivocal. In early retrospective studies [27-291 of patients with colon cancer matched for clinical stage, histologic characteristics, and various other factors, patients who received transfusions, particularly those who were heavily transfused, had poorer prognoses in terms of tumor recurrence, survival, and tumor-free survival than did the control groups. Although some retrospective studies confirmed that observation [30,31], other studies detected no relationship between RBC transfusion and patient outcome. A multicenter, randomized, controlled study of surgery for colorectal carcinoma reported by Busch et ~1 [32] found no relationship between allogeneic transfusion and prognosis. However, patients transfused with either allogeneic blood or autologous blood had a VOLUME

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TABLE II Blood Transfusion and Cancer Recurrence: Prospective Studies Control

Subjects

Design

study Ness et al [34]

Prospective nonrandomized

315 consecutive

Heiss et al [33)

Prospective randomized

120/ 150 colorectal cancer patients

prostate cancer patients

Busch et a/ [32]

Prospective randomized

475 colorectal cancer patients

Houbiers eta/ [35]

Prospective randomized

871 I1

,108colorectal

cancer patients

Results

PAD

NS

PAD

P < 0.05

PAD

NS

Leukodepletion

NS

PAD = preoperative autologous donation. Source: Harvey G. Klein, MD.

TABLE III Blood Transfusion and Postoperatlve Infection: Prospective Studies Subjects

Design

Study

Prospective nonrandomized

Braga et al [39]

285 consecutive gastric, colon, pancreas cancer patients

Control

Results

None

P < 0.05 P < 0.05

Heiss et al [38]

Prospective randomized

120/l 50 colorectal cancer patients

Autologous

Busch et a/ [32]

Prospective randomized

475 colorectal cancer patients

Autologous

Houbiers eta/ [35]

Prospective randomized

871 /l ,108 colorectal cancer patients

Leukodepletion

P < 0.001

Jensen et a/ [40]

Prospective randomized

197 colorectal cancer patients

Leukodepletion

P < 0.01

NS

NS = difference not significant. Source: Harvey G. Klein, MD.

significantly increased risk of recurrence compared with the nontransfused patients. A second prospective study, using a similar design, arrived at the opposite conclusion [33]. Both studies are limited by an intent-to-treat analysis that included, in the allogeneic transfusion arm, substantial numbers of patients who required no transfusion, and in the PAD control arm, a significant percentage of patients who required allogeneic blood in addition to their own autologous collection. Retrospective studies of patients with renal cell and lung cancer most often report a transfusion effect, although patients with soft-tissue sarcoma, or cancer of the breast, head and neck, or prostate, have shown similar results. A prospective but nonrandomized study of radical retropubic prostatectomy for patients with prostatic malignancy did not demonstrate a relationship between transfusion and cancer recurrence or patient survival [34]. It is not yet possible to reconcile these findings. The controlled, prospective studies of transfusion in cancer surgery are summarized in Table II [32-351. Any comprehensive analysis must account for variables such as study design, tumor type and stage, transfusion dose, blood component preparation, patient selection, surgical technique, and publication bias. Although the data are inconclusive, the combined experience points to some effect of blood transfusion on tumor recurrence; nevertheless, it is premature to alter transfusion practice solely because of fear of cancer recurrence. POSTOPEHATIVE INFECTION: Similar controversy surrounds the relationship between perioperative RBC transfusion and the risk of postoperative infection. A

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retrospective analysis of orthopedic, open heart, and colorectal surgery patients suggests that perioperative RBC allogeneic transfusion is associated with increased numbers of wound infections and numbers of distant infections, including pneumonitis and urinary tract infection [36,37]. The effect may be dose dependent. Unfortunately, this variable is difficult to control with matched PAD recipients because of the limited amount of autologous blood that can be predeposited [36]. More than 20 retrospective studies of transfusion and postoperative infection have reported that RBC transfusion is a significant predictor of postoperative infection. In most reports, transfusion was the single best predictor of infection [371. Other factors that correlate with transfusion, such as hematocrit level, blood loss, and duration of surgery, were generally insignificant predictors in multivariate analysis models. Patients who receive autologous blood appear to have fewer infections than patients who receive similar amounts of allogeneic blood. However, one large, multicenter, prospective, randomized study of colorectal surgery failed to detect an association between postoperative infection and perioperative transfusion [32]. Two other studies found a small but significant increase in postoperative infection in the recipients of allogeneic blood [35,38]. The prospective studies are summarized in Table III [32,35,3840]. REACTIVATION OF LATENT VIKUSES:Another aspect of the relationship between allogeneic transfusion and infection involves patients with AIDS. Several reports suggest that patients with AIDS who receive transfusions may suffer more rapid disease progression, de170

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creased survival, and increased frequency of CMV infection, bacterial infection, and cachexia [41-43]. An attractive explanation for these findings, and one that may have broader implications, is the observation by Busch et al [25] that allogeneic peripheral blood leukocytes stimulate the replication and spread of HIV-l in lymphocytes and monocytes in vitro. Other transfusiontransmitted lymphotropic viruses, such as CMV and EBV, may play a role in HIV activation as well. It is likely that transfusion-related lymphocyte stimulation affects other latent viral infections as well [44,45]. Activation of latent viral infection may be one mechanism by which allogeneic transfusions suppress host immune defenses. A controlled trial has been undertaken to determine whether allogeneic lymphocytes reactivate latent HIV infection in vivo and to what extent, if any, such activation alters the clinical course of the disease. If allogeneic blood has an immunomodulatory effect, the mechanism is poorly understood. Murphy et al [37J suggest that plasma contained in whole blood may be related to immunosuppression and to recurrence of colorectal, cervical, and prostate cancer. Conversely, studies of latent virus activation and suppression of recurrent abortion suggest that leukocytes may be implicated. Other hypotheses implicate viruses transmitted by allogeneic blood, cytokines produced by the cells during storage, or chemical contaminants, such as the plasticizer from the blood container (i.e., diethylhexylphthalate). Possibly, combinations of factors in the appropriate host may have differing effects on immune response. GRAFT-VERSUS-HOST DISEASE: Transfused patients are at a small but finite risk of developing GVHD, a lethal disorder mediated by transfused immunocompetent lymphocytes that engraft and reject the transfused host. Most blood components that have not been frozen contain enough viable lymphocytes to cause GVHD. Patients most susceptible are those who are immunosuppressed, such as premature infants; those who have a congenital immune deficiency; those who have cancer, especially lymphoproliferative disorders; or those who are recipients of bone marrow transplants. The complication has also been reported in patients with no apparent immunocompromise. Although GVHD is rare, its frequency is increasing as more tissue-compatible family members direct their blood donations to firstdegree relatives. Low-dose irradiation of blood components is an effective, although often logistically cumbersome, preventive measure for components intended for susceptible patients [15]. SUMMARY Although donor screening and laboratory testing have lowered the risk of allogeneic RBC-transmitted infections, neither technique will eliminate the risk. Major infectious agents still elude the most sensitive assays, while less-common infectious agents, such as parvoviruses, spirochetes, parasites, bacteria, and, possiTHE AMERICAN

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bly, viruses with prolonged incubation periods, cannot be eliminated by practical screening tests [46]. Substantial progress has been made in decreasing the complications of RBC transfusion. Disposable equipment, improved screening and testing, and increasingly prudent use of RBCs have contributed to achieving this goal. A variety of blood sterilization methods are under investigation, but the success achieved in pasteurizing albumin and concentrates of fractionated clotting factor has not been matched by efforts to inactivate infectious agents in cellular blood components. Red blood cell substitutes have received much attention recently, but even those in early phase II trials are still several years from licensure. At present, the most effective way to improve transfusion safety is the judicious use of blood components and the use of alternatives to allogeneic transfusion. REFERENCES 1. Dodd RY. The risk of transfusion-transmitted infection. N Engl J Med 1992; 327: 419-21. 2. Wallace El, Surgenor DM, Hao SHS, et nl. Collection and transfusion of blood and blood components in the United States, 1989. Transfusion 1993; 33: 1394l. 3. Nelson AH, Fleisher LA, Rosenbaum SH. Relationship between postoperative anemia and cardiac morbidity in high-risk vascular patients in the intensive care unit. Crit Care Med 1993; 21: 860-6. 4. Zuckerman AJ. The new GB viruses. Lancet 1995; 345: 1453-4. 5. Gilliam JH III, Geisinger KR, Richter JE. Primary hepatocellular carcinoma after chronic non-A, non-B post-transfusion hepatitis. Ann Intern Med 19&1,101: 794-5. 6. Selik RM, Ward JW, Buehler JW. Trends in transfusionassociated acquired immune deficiency syndrome in the United States, 1982 through 1991. Transfusion 1993; 33: 890-3. 7. Loussert-Ajaka I, Ly TD, Chaix M, et al. HIV-l/HIV-2 seronegativity in HIV-l subtype 0 infected patients. Lancet 1994; 343: 1393-4. 8. Bove JR, Sandier SG. HTLV-1 and blood transfusion. Transfusion 1988; 28: 93-4. 9. Wells L, Ala FA. Malaria and blood transfusion. Lancet 1985; i: 1317-9. 10. Kirchhoff LV. Is Ttypatwsoma cnui a new threat to our blood supply? Ann Intern Med 1989; 111: 773-5. 11. Blajchman MA, Ah AM, Richardson HL. Bacteria1 contamination of cellular blood components. VOX Sang 1994, 67(suppl 3): 25-33. 12. Davenport RD, Kunkel SL. Cytokine roles in hemolytic and nonhemolytic transfusion reactions. Transfusion Med Rev 1994; 8: 157-63. 13. Lostumbo MM, Holland PV, Schmidt PJ. Isoimmunization after multiple transfusions. N Engl J Med 1966; 275: 1414. 14. Linden JV, Paul B, Dressler KP. A report of 104 transfusion errors in New York State. Transfusion 1992; 32: 601-6. 15. Aster RI-I. New approaches to an old problem. Refractoriness to platelet transfusions. Transfusion 1988; 28: 95-6. 16. Opelz G, Sengar DP, Mickey MR, Terasaki PI. Effect of blood transfusions on subsequent kidney transplants. Transplant Proc 1973; 5: 253-9. 17. Fabre JW, Morris PJ. The effect of donor strain blood pretreatment on renal allograft rejection in rats. Transplantation 1972; 14: 608-17. 18. Salvatierra 0 Jr, Vincenti F, Amend W, et al. Deliberate donor-specific blood transfusions prior to living related renal transplantation. Ann Surg 1980; 192: 543-52.

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19. Lagaaij EL, Hennemann IP, Ruigrok M, et al. Effect of one-HLA-DR-antigen-matched and completely HLA-DR-mismatched blood transfusions on survival of heart and kidney allografts. N Engl J Med 1989; 321: 701-5. 20. Brunson ME, Alexander JW. Mechanisms of transfusioninduced immunosuppression. Transfusion 1990; 30: 651-8. 21. DePalma L, Duncan B, Chan MM, Luban NL. The neonatal response to washed and irradiated red cells: lack of evidence of lymphocyte activation. Transfusion 1991; 31: 737-42. 22. Williams JG, Hughes LE. Effect of perioperative blood transfusion on recurrence of Crohn’s disease. Lancet 1989; 2: 1524. 23. Mowbray JF, Gibbings CR, Sidgwick AS, et al. Effects of transfusion in women with recurrent spontaneous abortion. Transplant Proc 1983; 15: 896-9. 24. Blumberg N, Heal JM. Transfusion and host defenses against cancer recurrence and infection. Transfusion 1989,29: 236-45. 25. Busch MP, Lee TH, Heitman J. Allogeneic lymphocytes but not therapeutic blood elements induce reactivation and dissemination of latent human immunodeficiency virus type 1 infection: implications for transfusion support of infected patients. Blood 1992; 80: 2128-35. 26. Anderson KC, Weinstein I-D. Transfusion-associated graft-vs.host disease. N Engl J Med 1990,323: 315-21. 27. Burrows L, Tartter P. Effect of blood transfusion on colonic malignancy recurrent rate. Lancet 1982; ii: 662. 28. Blumberg N, Agarwal M, Chuang C. Relation between recurrence of cancer of the colon and blood transfusion. Br Med J 1985; 290: 1037-9. 29. Creasy TS, Veitch PS, Bell PR. A relationship between perioperative blood transfusion and recurrence of carcinoma of the sigmoid colon following potentially curative surgery. Ann R Co11 Surg Engl 1987; 69: 100-3. 30. Blair SD, Janvrin SB. Relation between cancer of the colon and blood transfusion. Br Med J 1985; 290: 1516-7. 31. Frankish PD, McNee RK, Alley PG, Woodfield DG. Relation between cancer of the colon and blood transfusion. (Letter.) Br Med J 1985; 290: 1827. 32. Busch OR, Hop WC, Hoynck van Papendrecht MA, et al. Blood transfusions and prognosis in colorectal cancer. N Engl J Med 1993; 328: 1372-6. 33. Heiss MM, Mempel W, Delanoff C, et al. Blood transfusionmodulated tumor recurrence: first results of a randomized study of autologous versus allogeneic blood transfusion in colorectal cancer surgery. J Clin Oncoll994; 12: 1859-67. 34. Ness PM, Walsh PC, Zahurak M, et al. Prostate cancer recurrence in radical surgery patients receiving autologous or homologous blood. Transfusion 1992; 32: 316.

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35. Houbiers JG, Brand A, van de Watering LM, et al. Randomized controlled trial comparing transfusion of leucocyte-depleted or huffy-coat depleted blood in surgery for colorectal cancer. Lancet 1994; 344: 573-8. 36. Ottino G, De Paulis R, Pansini S, et al. Major sternal wound infection after open heart surgery: a multivariate analysis of risk factors in 2,579 consecutive procedures. Ann Thorac Surg 1987; 44: 173-9. 37. Murphy P, Heal JM, Blumberg N. Infection or suspected infection after hip replacement surgery with autologous or homologous blood transfusions. Transfusion 1991; 31: 212-7. 38. Heiss MM, Mempel W, Jauch KW, et al. Beneficial effect of autologous blood transfusion on infectious complications after colorectal cancer surgery. Lancet 1993; 342: 1328-33. 39. Braga M, Vignali A, Radaelli G, et al. Association between perioperative blood transfusion and postoperative infection in patients having elective operations for gastrointestinal cancer. Eur J Surg 1992; 158: 5314. 40. Jensen LS, Andersen AJ, Christiansen PM, et al. Postoperative infection and natural killer cell function following blood transfusion in patients undergoing elective colorectal surgery. Br J Surg 1992; 79: 513-6. 41. Ward JW, Bush TJ, Perkins HA, et al. The natural history of transfusion-associated infection with human immunodeficency virus. Factors influencing the rate of progression to disease. N Engl J Med 1989; 321: 947-52. 42. Vamvakas E, Kaplan HS. Early transfusion and length of survival in acquired immune deficiency syndrome: experience with a population receiving medical care at a public hospital. Transfusion 1993; 33: 11l-8. 43. Sloand E, Kumar P, Klein HG, et al. Transfusion of blood components to persons infected with human immunodeficiency virus type 1: relationship to opportunistic infection. Transfusion 1994; 34: 48-53. 44. Margolick JB, Volkman DJ, Folks TM, Fauci AS. Amplification of HTLV-III/LAV infection by antigen-induced activation of T cells and direct suppression by virus of lymphocyte blastogenic responses. J Immunoll987; 138: 1719-23. 45. Kenney S, Kamine J, Markovitz D, et al. An Epstein-Barr virus immediate-early gene product trans-activates gene expression from the human immunodeficiency virus long terminal repeat. Proc Nat1 Acad Sci USA 1988; 85: 1652-6. 46. Prodouz KN, Fratantoni JC. Inactivation of virus in blood products. Transfusion 1988; 28: 2-3.

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