Leukocyte Reduction s Role in the Attenuation of Infection Risks among Transfusion Recipients

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1 REVIEW ARTICLE Leukocyte Reduction s Role in the Attenuation of Infection Risks among Transfusion Recipients Joseph S. Cervia, 1,2 Barry Wenz, 1 and Girolamo A. Ortolano 1 1 Pall Medical, East Hills, and 2 Albert Einstein College of Medicine, Bronx, New York (See the editorial commentary by Blumberg and Heal on pages ) Despite advances in the screening of donated blood for infectious agents, the risk of transmitting viral, bacterial, and protozoal infections, as well as newly emerging diseases, via transfusion persists. A complementary approach is leukocyte reduction (LR), the removal of leukocytes from donated blood by filtration. Published evidence, establishing the benefit of LR in reducing the risk of febrile nonhemolytic reactions, cytomegalovirus transmission, and human leukocyte antigen alloimmunization has led to its use for some time for the care of immunosuppressed and other individuals considered to be at high risk for such complications. Recent literature suggests that LR may be effective in reducing the risk of transmission of a number of additional transfusion-transmitted infectious agents, including herpesviruses, retroviruses, bacteria, protozoa, and prions. There is also evidence that LR may reduce the risk of transfusion-related immunomodulation, further contributing to protection against infections that would complicate treatment. With the mounting evidence of potential benefit, a number of countries, as well as many hospitals and blood centers in the United States, have adopted a policy of performing LR for all donated blood. Physicians who care for immunosuppressed patients and those who are responsible for institutional infection-control practices should remain informed of the growing body of literature on LR. Major advances in the testing of blood donations for the presence of infectious agents have been made. However, the risk of transfusion-transmitted viral, bacterial, protozoal, and prion-associated diseases via transfusion persists, albeit at a much reduced level for known pathogens, such as hepatitis viruses B and C and HIV. Removal of leukocytes from donor blood (i.e., leukocyte reduction [LR]) provides an additional approach to risk reduction. Federal guidelines define a blood component that has undergone LR as one that contains! residual donor leukocytes in the final product. This can be accomplished by filtration of whole blood, RBCs, and/or platelet concentrate. Platelet concentrate can also undergo LR by specialized apheresis procedures. Received 5 April 2007; accepted 4 June 2007; electronically published 6 September Reprints or correspondence: Dr. Joseph S. Cervia, Pall Medical, 2200 Northern Blvd., East Hills, NY (joe_cervia@pall.com). Clinical Infectious Diseases 2007; 45: by the Infectious Diseases Society of America. All rights reserved /2007/ $15.00 DOI: / LR removes 199.9% of the leukocytes in 1 U of blood in 30 min, with a!10% loss of blood volume. Nearly 80% of donated blood in the United States already undergoes LR; therefore, the incremental cost for subjecting all donated blood to LR is likely to be imperceptible. The benefits of LR in reducing the risk of febrile, nonhemolytic reactions [1], transmission of cytomegalovirus (CMV) [2], and HLA alloimmunization [3], leading to platelet refractoriness, have been reported in the literature. More-recent literature suggests that LR may also be effective in reducing the risk of a number of additional transfusion-transmitted infections, including infections due to herpesviruses (e.g., Epstein Barr virus [EBV] and human herpesvirus-8 [HHV-8]), retroviruses (e.g., human T cell lymphotropic virus type 1 [HTLV-1] and HIV), bacteria (e.g., Yersinia enterocolitica), protozoa (e.g., Leishmania species and Trypanosoma cruzi), and infectious prion. Additionally, LR may reduce the risk of transfusion-related immunomodulation (TRIM), which may predispose a recipient to postoperative infection. The mounting evidence of 1008 CID 2007:45 (15 October) Cervia et al.

2 benefits derived from LR has caused many countries to subject the entire blood supply to LR. LR FOR PREVENTION OF VIRAL INFECTIONS CMV infection. The population harboring latent CMV infection ranges from 40% to 100% and is determined by geographic and socioeconomic factors [4]. Populations at risk of transfusion-induced CMV disease include CMV-seronegative patients in the following categories: pregnant women and their newborn babies, bone marrow transplant recipients of CMVnegative grafts, individuals with AIDS, and other profoundly immunosuppressed individuals. The virus is confined to leukocytes in latently infected blood donors and can be reactivated after transfusion, resulting in an infection rate of 0.9% 12% among adults, of 20% among neonates, and as high as 57% among bone marrow transplant recipients receiving random blood products [5, 6]. Infection can result in retinitis, pneumonitis, hepatitis, gastroenteritis, and death. Traditionally CMV-safe blood has been defined as blood screened for the presence of anti-cmv antibody. This procedure poses difficulties, including limited supply and a false-negative screening rate as high as 4% [7]. Larson et al. [8] reported a poor correlation between the detection of CMV DNA and an individual s serological status. Fifty-five percent of mononuclear cell samples from CMV-seronegative donors contained viral DNA. Lipson et al. [9] demonstrated that LR of blood containing an average 7.3 mean tissue culture infectious doses of CMV per milliliter eliminated the ability of CMV to infect tissue culture preparations. This finding is consistent with the results of experiments by Lau et al. [10] in which PCR could not detect CMV in blood specimens that had been spiked with to 2 10 transfected cells/u and subjected to LR. Visconti et al. [11] reported that LR reduces the CMV concentration in whole blood by 2.9 log and in platelet concentrate by 1.9 log. Bowden et al. [12] studied 502 bone marrow transplant recipients and confirmed that there were no differences in the rate of CMV infection among patients who received either screened products versus products that had undergone LR (1.3% vs. 2.4%) when primary analysis of data was restricted to days after transplantation. When analysis was broadened to days 0 100, 6 patients in the LR group developed CMV infection; however, the authors caution that infection that occurred during days 0 21 resulted from transfusion. Additional studies have found statistically equivalent rates of CMV infection among bone marrow transplant recipients [4, 13 17], leukemic patients [18], and neonates [19] who received either screened products or products that had undergone LR. Although the AABB considers the transfusion of LR-treated blood products to be an acceptable alternative to screened components [20], this view is not universally accepted. A metaanalysis performed by Vamvakas [21] concluded that there exists a small but significant bias favoring screened products over products that have undergone LR. One of the limitations of that study is that only 3 trials were accepted for comparative analysis by inclusion criteria. A Canadian Consensus Conference [22] concluded that patients would be needed to confirm a statistically significant difference in a decrease of the CMV infection rate from 2.5% to 1.5%, leading 7 of the 10 panelists to recommend the provision of blood that both was screened and had undergone LR for patients at highest risk of CMV infection and disease. Today, CMV-seronegative allogeneic transplant recipients are often regularly monitored for infection by nucleic acid testing, and early antiviral therapy is instituted if appropriate. For such patients, LR of the transfusions provides an added level of protection. EBV infection. EBV is the causative agent of infectious mononucleosis, Burkitt lymphoma, and nasopharyngeal carcinoma and is associated with diseases that included posttransplantation lymphoproliferative disease [23], Hodgkin lymphoma, postcardiopulmonary perfusion syndrome, and oral hairy leukoplakia [24]. The incidence of latent EBV infection in the general population is 90%. EBV-seronegative blood transfusion recipients who are immunocompromised or immunologically naive are at risk of acquiring EBV disease. Several cases of transfusion-associated EBV disease, including lymphoproliferative disease, have been reported [25 27]; however, the relatively rare rate of transmission via transfusion does not justify screening for virus-free donor blood. The concentration of EBV genome in the peripheral blood of infected individuals has been alternatively reported to be as low as 1 50 copies/ million B lymphocytes and as high as 968 copies/million B lymphocytes or ,630 copies/u of donated blood [28, 29]. In one study, LR eliminated the PCR signal in 15 of 16 U of EBV-contaminated blood, and none of 15 EBV-negative children who received the transfusions that had undergone LR experienced seroconversion during an 11-week follow-up period. The authors concluded that LR eliminates the need to screen blood for EBV for at-risk patients [24]. HHV-8 infection. In a study of 1295 women that compared women who used injection drugs daily with women who did not use injection drugs, the OR for HHV-8 infection was 3.2 in favor of injection drug use, strongly suggesting that HHV- 8 is transmissible through needle sharing [30]. This result is consistent with the findings of Hladik et al. [31], who observed a statistically significant excess risk of HHV-8 seroconversion (2.8%) among recipients of HHV-8 seropositive blood, compared with recipients of HHV-8 seronegative blood. The increase mainly occurred among patients in whom seroconversion occurred 3 10 weeks after transfusion, supporting the Leukocyte Reduction and Infection Risk CID 2007:45 (15 October) 1009

3 likelihood that HHV-8 infection was transmitted via transfusion. In an editorial accompanying this study, Blajchman and Vamvakas [32] asserted, As for CMV, leukocyte-reduced blood components may prevent transmission of HHV-8 by transfusion, but their efficacy in this regard has not been established (p ). Nevertheless, Lefrere et al. [33] detected no HHV-8 DNA by PCR in 19 multiple-transfusion recipients who had each received a mean of U of packed RBCs that had undergone LR. The study concluded that the failure to detect HHV-8 DNA sequences in these patients suggests that HHV-8 is not transmitted with a high frequency among individuals receiving WBC-reduced components and, thus, that LR seems to be a prudent preventive measure. HTLV-1 infection. When HTLV-1 infected blood was processed with LR filters, the infected cell concentration was reduced by 1 3 log, leading Al et al. [34] to conclude that leukocyte filtration of HTLV-1 infected blood potentially contributes to reducing the rate of transfusion-transmitted viral infection. Moreover, Zucker-Franklin and Pancake [35] found that PCR could not detect HTLV-1 Tax sequences in residual mononuclear cells that had undergone LR. Cesaire et al. [36] demonstrated a marked reduction ( log) in proviral HTLV-1 copies in the mononuclear cells of cell components that had undergone LR. This reduction correlated with the efficiency of the LR process, causing the authors to conclude that the main determinant for optimal reduction in the risk of HTLV-1 infection during the production of blood components remains the avoidance of suboptimal LR. Thus, there has come to be general agreement that LR reduces the risk of transmission of HTLV-1 via transfusion, although this reduction does not equate to zero risk [37, 38]. HIV infection. Two studies have addressed the reduction in HIV-infected cells from donor blood by LR. A National Heart Lung and Blood Institute funded study by Rawal et al. [39] demonstrated that filtration LR of HIV-inoculated RBCs resulted in a 5.9-log mean reduction in tissue culture infectious doses. Filtration of RBCs obtained from HIV-infected patients reduced infectivity by 12 log, as determined by coculture and PCR techniques. In addition, Bruisten et al. [40] demonstrated an average 2.5-log reduction of infected cells by LR, as measured by ID 50 titration and PCR. Although these studies do not suggest that LR eliminates or reduces the potential for HIV transmission by transfusion, they do demonstrate the ability of the process to reduce the viral burden in blood products. LR FOR PREVENTION OF BACTERIAL INFECTIONS One unit in every 3000 U of donated blood is contaminated with bacteria [41]. Although refrigerated storage of RBCs reduces the potential for bacterial growth, clinically significant sepsis results from 1 of every 250,000 RBC units transfused. Platelet concentrate stored at 22 C has been reported to cause sepsis at a rate of 1 case per 25,000 transfusions [42]. Recently adopted practices that screen platelet concentrate for bacteria should reduce this potential; however, because of the timing and sensitivity of the monitoring procedures, these practices will not eliminate the threat. Infection with Y. enterocolitica, a cryogenic, gram-negative organism that produces endotoxin, has periodically resulted in sepsis and death for patients receiving RBC transfusions. Prompted by an outbreak of transfusion-induced sepsis due to Y. enterocolitica, multiple studies demonstrated the ability of LR filters to eliminate or markedly reduce the growth of the bacterium in processed blood [43 50]. Although different in design, the studies shared a number of features in common, including the in vitro inoculation of Yersinia concentrations that exceeded those likely to be encountered clinically (range of inoculations studied, colony-forming units/ml) and the use of prestorage LR filters. All confirmed a dramatic effect in bacterial elimination or reduction through 42 weeks of storage. Aubuchon et al. [49] confirmed the ability of LR to remove low concentrations of Escherichia coli, Pseudomonas putida, and Klebsiella pneumoniae in both platelet concentrate and RBCs. Waters et al. [51], using a combination of LR filters and cell washing, were able to reduce the biological burden of surgically shed blood by 97.6% 100% when spiked with Staphylococcus aureus, E. coli, and Pseudomonas aeruginosa at concentrations ranging from 2000 to 4000 colony-forming units/ml. It must be emphasized that, although encouraging, no clinical evidence of this benefit currently exists. Dzik [52] proposed a number of mechanisms that could explain the salutary effect of filters, including the removal of phagocytozed bacteria, bacterial adherence to filter media, and the activation of bactericidal substances, such as complement. LR FOR PREVENTION OF PROTOZOAL INFECTIONS Leishmania infection. Performance of LR immediately after blood collection or after storage for 2 weeks has been proven to reduce the Leishmania concentration by 3 4 log [53]. This results in a substantial reduction in the number of both free and intracellular organisms. Because there is currently no donor screening for Leishmania infection, the use of LR filters could improve the safety of transfused blood in this regard. Trypanosoma infection. Using electron microscopy, Cardo et al. [54] observed that T. cruzi trypomastigotes are effectively removed from blood by filtration. The predominant mechanism appears to be the adherence of trypomastigotes to filter fibers CID 2007:45 (15 October) Cervia et al.

4 LR FOR PREVENTION OF PRION DISEASE Recently published data suggest that LR may reduce the risk of transfusion-associated transmission of variant Creutzfeldt- Jakob disease by preventing the passage of WBC-associated prions [55, 56]. LR FOR PREVENTION OF TRIM TRIM is known to occur unequivocally, but its clinical significance remains controversial [57, 58], and the contribution of WBCs as a causal agent of TRIM is also debated. The idea that transfusion is an immunosuppressive event derives from the work of Opelz and Terasaki and colleagues [59, 60], who reported that kidney transplant recipients had increased rates of successful engraftment when they received allogeneic blood [61]. This immunosuppressive effect of transfusion can occur with a single transfused unit of blood [62]. Even with the advent of immunosuppressive drugs, TRIM s effects have been shown to be additive in increasing the likelihood of successful engraftment [61], but not all studies are in agreement [63]. Studies show that infectious complications increase with the duration of storage of component blood products that have not undergone LR, suggesting that the agents accumulated during storage may be immunosuppressive [64, 65]. Potential mediators of the TRIM effect are the accumulated immunosuppressive products of WBCs in blood that has not undergone LR; these include fas ligand, TNF, and soluble HLA (both class I and class II) [66, 67]. Both fas ligand and TNF mediate programmed cell death or apoptosis by stimulating the caspase system. Both TNF and soluble fas ligand accumulate in leukocyte-containing blood products upon storage but not in blood products that are subjected to LR before storage [68]. Soluble HLA molecules, which also accumulate in stored blood products that have not been subjected to LR but not in blood products that have been subjected to LR, may interfere with the interaction of cell-associated HLA and cognate receptors, preventing normal immune responses. Among patients who underwent transfusion, there was significant reduction in the risk of infectious complications among those who received blood products that had been subjected to LR, compared with recipients of blood that had not been subjected to LR [69]. Recent clinical findings support the view that LR-subjected blood products impact clinical practice by reducing the rate of catheter-related infection [70]. Data are available to indicate that LR lowers the duration of hospital stay and the cost of care [71]. Although a published meta-analysis does not indicate a benefit for LR in attenuating the rate of infectious complications after surgery [72, 73], methodological flaws in the approach have been raised, suggesting that this conclusion was not warranted and that, when properly conducted, there is a benefit of LR with regard to the reduction of infectious complications [74, 75]. Although one study failed to demonstrate a statistically significant benefit of LR in reducing infectious complications following injury [76], recipients of blood transfusions that had not undergone LR were associated with a rate of infectious complications of 36%, compared with 30% for the LR group. The sample size was powered to show a much greater hypothesized effect, yet few clinicians would argue that a relative reduction in infectious complications by 16.7% (6 of 36) is not clinically relevant. In an additional study, patients were provided with LR-subjected RBCs, but the transfusion of leukocytes via receipt of platelet concentrates was not controlled. Although the study failed to demonstrate any value of LR in terms of infectious complications, the use of random donor platelets, leukoreduced by filtration, and transfused to patients in the non-lr group was paired with apheresis-derived platelets given to patients in the LR group [77]. This study suffered from a relatively high (112%) rate of protocol violation in the LR arm, suggesting that randomization had failed as a result of issues related to supply adequacy. Unwittingly, provision of these 2 products may have biased the results against LR, because products subjected to apheresis are known to contain higher levels of immunosuppressive complement protein fragments that could have mitigated any beneficial effect of LR [78]. CONCLUSIONS Despite the controversy over the merits of LR in abrogating infectious complications in surgical patients, there is a clear global commitment to the concept of subjecting all component blood products to LR, a program known as universal LR. The reasons are substantial and include a well-accepted value in reducing febrile, nonhemolytic transfusion reactions, alloimmunization, and consequent platelet refractoriness. Included also is the proven value in reducing the risk of transfusiontransmitted CMV infections and other infections due to WBCassociated pathogens. At least 15 European nations have adopted universal LR [79]. Reporting at the recent US Food and Drug Administration Workshop on universal LR, the American Red Cross and America s Blood Centers, who provide the United States with 190% of all transfused blood products, presented data indicating that 80% of all donated blood in the United States undergoes LR. There is speculation by some that subjecting all donated blood to LR will become a universal standard of practice [80]. Given the high percentage of blood products transfused in the United States that have undergone LR at this time, one might argue that such a standard has already emerged. The current review does not suggest that serological screening procedures currently in place be replaced by the use of LR- Leukocyte Reduction and Infection Risk CID 2007:45 (15 October) 1011

5 subjected blood. Rather, it recognizes that no assay has a sensitivity of 100% or can absolutely eliminate the risk of infection with the screened agent. It also accepts the fact that not all transmissible infectious agents are screened in donor blood and that yet-unrecognized, emerging pathogens cannot be detected. The safety of blood transfusion has consistently been addressed by a redundancy of procedures; in this light, subjecting blood components to LR provides an additional and justified measure of caution. Acknowledgments Potential conflicts of interest. The authors are employed by Pall Medical, a manufacturer of LR filters. References 1. Sirchia G, Wenz B, Rebulla P, et al. Removal of white cells from red cells by transfusion through a new filter. Transfusion 1990; 30: Bowden RA, Slichter SJ, Sayers M, et al. A comparison of filtered leukocyte-reduced and cytomegalovirus (CMV) seronegative blood products for the prevention of transfusion-associated CMV infection after marrow transplant. Blood 1995; 86: The Trial to Reduce Alloimmunization to Platelets Study Group. Leukocyte reduction and ultraviolet B irradiation of platelets to prevent alloimmunization and refractoriness to platelet transfusions. N Engl J Med 1997; 337: Pamphilon DH, Rider JR, Barbara JA, Williamson LM. Prevention of transfusion-transmitted cytomegalovirus infection. Transfus Med 1999; 9: Kuhn JE. Transfusion-associated infections with cytomegalovirus and other human herpesviruses. Infusionsther Transfusionsmed 2000; 27: Ronghe MD, Foot AB, Cornish JM, et al. The impact of transfusion of leucodepleted platelet concentrates on CMV disease after allogeneic stem cell transplant. Br J Haematol 2002; 118: Strauss RG. Leukocyte-reduction to prevent transfusion-transmitted cytomegalovirus infections. Pediatr Transplant 1999; 3(Suppl 1): Larsson S, Soderberg-Naucler C, Wang FZ, Moller E. Cytomegalovirus DNA can be detected in peripheral blood mononuclear cells from all seropositive and most seronegative healthy blood donors over time. Transfusion 1998; 38: Lipson SM, Shepp DH, Match ME, et al. CMV infectivity in whole blood following leukocyte reduction by filtration.am J Clin Pathol 2001; 116: Lau W, Onizuka R, Krajden M. PCR-based assessment of leukoreduction efficacy using a CMV DNA transfected human T-cell line. J Clin Virol 1998; 11: Visconti MR, Pennington J, Garner SF, Allain JP, Williamson LM. Assessment of removal of human cytomegalovirus from blood components by leukocyte depletion filters using real-time quantitative PCR. Blood 2004; 103: Bowden RA, Slichter SJ, Sayers MH, Mori M, Cays MJ, Meyers JD. Use of leukocyte-depleted platelets and cytomegalovirus-seronegative red blood cells for prevention of primary cytomegalovirus infection after marrow transplant. Blood 1991; 78: Van Prooijen HC, Visser JJ, van Oostendorp WR, et al. Prevention of primary transfusion-associated CMV infection in bone marrow transplant recipients by the removal of white blood cells from blood components by high-affinity filters. Br J Haematol 1994; 87: Verdonck LF, de Graan-Hentzen YC, Dekker AW, et al. CMV seronegative platelets and leukocyte-poor red blood cells from random donors can prevent primary CMV infection after bone marrow transplant. Bone Marrow Transplant 1987; 2: Ljungman P, Larsson K, Kumlien G, et al. Leukocyte-depleted unscreened blood products give a low risk for CMV infection and disease in CMV seronegative allogeneic stem cell transplant recipients with seronegative stem cell donors. Scand J Infect Dis 2002; 34: Narvios AD, Delima M, Shah H, et al. Transfusion of leukoreduced cellular blood components from CMV-unscreened donors in allogeneic hematopoetic transplant recipients: analysis of 72 recipients. Bone Marrow Transplant 2005; 36: De Witte T, Schattenberg A, Van Dijk BA, et al. Prevention of primary cytomegalovirus infection after allogeneic bone marrow transplantation by using leukocyte-poor random blood products from cytomegalovirus-unscreened blood-bank donors. Transplantation 1990; 50: Murphy MF, Grint PC, Hardman AE, et al. Use of leukocyte-poor blood components to prevent primary CMV infection in patients with acute leukemia. Br J Haematol 1988; 70: Gilbert GL, Hayes K, Hudson IL, James J. Prevention of transfusionacquired cytomegalovirus infection in infants by blood filtration to remove leucocytes. Neonatal Cytomegalovirus Infection Study Group. Lancet 1989; 1: AABB technical manual. Bethesda, MD: AABB, Vamvakas EC. Is white blood cell reduction equivalent to antibody screening in preventing transmission of cytomegalovirus by transfusion? A review of the literature and a meta-analysis. Transfus Med Rev 2005; 19: Blajchman MA, Goldman M, Freedman JJ, Sher GD. Proceedings of a consensus conference: prevention of post-transfusion CMV in the era of universal leukoreduction. Transfus Med Rev 2001; 15: van Esser JW, van der Holt B, Meijer E, et al. Epstein-Barr virus (EBV) reactivation is a frequent event after allogeneic stem cell transplantation (SCT) and quantitatively predicts EBV-lymphoproliferative disease following T-cell depleted SCT. Blood 2001; 98: Wagner HJ, Kluter H, Kruse A, Kirchner H. Relevance of transmission of Epstein-Barr virus through blood transfusion. Beitr Infusionsther Transfusionsmed 1994; 32: Alfieri C, Tanner J, Carpentier L, et al. Epstein-Barr virus transmission from a blood donor to an organ transplant recipient with recovery of the same virus strain from the recipient s blood and oropharynx. Blood 1996; 87: Solem JH, Jorgensen W. Accidentally transmitted infectious mononucleosis: report of a case. Acta Med Scand 1969; 186: Turner AR, MacDonald RN, Cooper BA. Transmission of infectious mononucleosis by transfusion of pre-illness plasma. Ann Intern Med 1972; 77: Wagner HJ, Kluter H, Kruse A, et al. Determination of the number of EBV genomes in whole blood and red cell concentrates. Transfus Med 1995; 5: Qu L, Xu S, Rowe D, et al. Efficacy of EBV removal by leukoreduction of red blood cells. Transfusion 2005; 45: Cannon MJ, Dollard SC, Smith DK, et al. Blood-borne and sexual transmission of human herpesvirus 8 in women with or at risk for human immunodeficiency virus infection. N Engl J Med 2001; 344: Hladik W, Dollard SC, Mermin J, et al. Transmission of human herpesvirus 8 by blood transfusion. N Engl J Med 2006; 355: Blajchman MA, Vamvakas EC. The continuing risk of transfusiontransmitted infections. N Engl J Med 2006; 355: Lefrere JJ, Mariotti M, Girot R, et al. Transfusional risk of HHV-8 infection. Lancet 1997; 350: Al E, Visser S, Broersen S, et al. Reduction of HTLV-I-infected cells in blood by leukocyte filtration. Ann Hematol 1993; 67: Zucker-Franklin D, Pancake B. White cell reduction by filtration may significantly decrease human T-lymphotropic virus type I tax sequences and tax-encoded proteins in blood used for transfusion. Transfusion 1998; 38: Cesaire R, Kerob-Bauchet B, Bourdonne O, et al. Evaluation of HTLV- I removal by filtration of blood cell components in a routine setting. Transfusion 2004; 44: CID 2007:45 (15 October) Cervia et al.

6 37. Wenz B, Ortolano G. Leukocyte reduction and HTLV-I: is the glass half empty or half full? Blood 2003; 101: Allain J, Williamson L. Infectious dose of HTLV-I in transfusion recipients. Blood 2003; 101: Rawal BD, Busch MP, Endow R, et al. Reduction of human immunodeficiency virus infected cells from donor blood by leukocyte filtration. Transfusion 1989; 29: Bruisten SM, Tersmette MR, Wester MR, Vos AH, Koppelman MH, Huisman JG. Efficiency of white cell filtration and a freeze-thaw procedure for removal of HIV-infected cells from blood. Transfusion 1990; 30: Beckers EAM. Bacterial contamination of platelets. Blood Ther Med 2005; 5: Blajchman MA, Beckers EA, Dickmeiss E, Lin L, Moore G, Muylle L. Bacterial detection of platelets: current problems and possible resolutions. Transfus Med Rev 2005; 19: Kim DM, Brecher ME, Bland LA, et al. Prestorage removal of Yersinia enterocolitica from red cells with white cell-reduction filters. Transfusion 1992; 32: Pietersz RN, Reesink HW, Pauw W, Dekker WJ, Buisman L. Prevention of Yersinia enterocolitica growth in red-blood-cell concentrates. Lancet 1992; 340: Wenz B, Burns ER, Freundlich LF. Prevention of growth of Yersinia enterocolitica in blood by polyester fiber filtration. Transfusion 1992; 32: Buchholz DH, AuBuchon JP, Snyder EL, et al. Removal of Yersinia enterocolitica from AS-1 red cells. Transfusion 1992; 32: Siblini L, Lafeuillade B, Ros A, Le Petit JC, Pozzetto B. Reduction of Yersinia enterocolitica load in deliberately inoculated blood: the effects of blood prestorage temperature and WBC filtration. Transfusion 2002; 42: Wagner SJ, Robinette D, Dodd R. Factors affecting Yersinia enterocolitica (serotype O:8) viability in deliberately inoculated blood. Transfusion 1993; 33: AuBuchon JP, Pickard C. White cell reduction and bacterial proliferation. Transfusion 1993; 33:533; author reply Gong J, Rawal BD, Hogman CF, Vyas GN, Nilsson B, Gustafsson I. Complement killing of Yersinia enterocolitica and retention of the bacteria by leucocyte removal filters. Vox Sang 1994; 66: Waters JH, Tuohy MJ, Hobson DF, Procop G. Bacterial reduction by cell salvage washing and leukocyte depletion filtration. Anesthesiology 2003; 99: Dzik W. Use of leukodepletion filters for the removal of bacteria. Immunol Invest 1995; 24: Cardo L, Salata J, Harman R, et al. Leukodepletion filters reduce Leishmania in blood products when used at collection or at bedside. Transfusion 2006; 46: Cardo L, Asher L. Electron micrographic study of the removal of Trypanosoma cruzi from blood products by leukodepletion filters. Transfusion 2006; 46: Gregori L, McCombie N, Palmer D, et al. Effectiveness of leucoreduction for removal of infectivity of transmissible spongiform encephalopathies from blood. Lancet 2004; 364: Cervia JS, Sowemimo-Coker SO, Ortolano GA, Wilkins K, Schaffer J, Wortham ST. An overview of prion biology and the role of blood filtration in reducing the risk of transfusion-transmitted variant Creutzfeldt-Jakob disease. Transfus Med Rev 2006; 20: Blajchman MA. Transfusion immunomodulation or TRIM: what does it mean clinically? Hematology 2005; 10(Suppl 1): Blajchman MA. Immunomodulation and blood transfusion. Am J Ther 2002; 9: Opelz G, Sengar DP, Mickey MR, Terasaki PI. Effect of blood transfusions on subsequent kidney transplants. Transplant Proc 1973;5: Opelz G, Terasaki PI. Improvement of kidney-graft survival with increased numbers of blood transfusions. N Engl J Med 1978; 299: Opelz G, Vanrenterghem Y, Kirste G, et al. Prospective evaluation of pretransplant blood transfusions in cadaver kidney recipients. Transplantation 1997; 63: Cecka JM. The transfusion effect. Clin Transpl 1987; Sanfilippo FP, Bollinger RR, MacQueen JM, Brooks BJ, Koepke JA. A randomized study comparing leukocyte-depleted versus packed red cell transfusions in prospective cadaver renal allograft recipients. Transfusion 1985; 25: Mynster T, Nielsen HJ. The impact of storage time of transfused blood on postoperative infectious complications in rectal cancer surgery. Danish RANX05 Colorectal Cancer Study Group. Scand J Gastroenterol 2000; 35: Offner PJ, Moore EE, Biffl WL, Johnson JL, Silliman CC. Increased rate of infection associated with transfusion of old blood after severe injury. Arch Surg 2002; 137: Ghio M, Contini P, Mazzei C, et al. Soluble HLA class I and fas ligand molecules in blood components and their role in the immunomodulatory effects of blood transfusion. Leuk Lymphoma 2000; 39: Ghio M, Contini P, Mazzei C, et al. In vitro immunosuppressive activity of soluble HLA class I and fas ligand molecules: do they play a role in autologous blood transfusions? Transfusion 2001; 41: Hodge GL, Hodge SJ, Nairn J, Tippett E, Holmes M, Reynolds PN. Poststorage leuko-depleted plasma inhibits T-cell proliferation and Th1 response in vitro: characterization of TGFb-1 as an important immunomodulatory component in stored blood. Transplantation 2005; 80: Fergusson D, Khanna MP, Tinmouth A, Hebert PC. Transfusion of leukoreduced red blood cells may decrease postoperative infections: two meta-analyses of randomized controlled trials. Can J Anaesth 2004; 51: Blumberg N, Fine L, Gettings KF, Heal JM. Decreased sepsis related to indwelling venous access devices coincident with implementation of universal leukoreduction of blood transfusions. Transfusion 2005; 45: Tartter PI, Mohandas K, Azar P, Endres J, Kaplan J, Spivack M. Randomized trial comparing packed red cell blood transfusion with and without leukocyte depletion for gastrointestinal surgery. Am J Surg 1998; 176: Vamvakas EC. White-blood-cell-containing allogeneic blood transfusion, postoperative infection and mortality: a meta-analysis of observational before-and-after studies. Vox Sang 2004; 86: Vamvakas EC. White-blood-cell-containing allogeneic blood transfusion and postoperative infection or mortality: an updated meta-analysis. Vox Sang 2007; 92: Kunz R, Guyatt G. Which patients to include in the analysis? Transfusion 2006; 46: Blumberg N, Zhao H, Wang H, Messing S, Heal JM, Lyman GH. The intention-to-treat principle in clinical trials and meta-analyses of leukoreduced blood transfusions in surgical patients. Transfusion 2007; 47: Nathens AB, Nester TA, Rubenfeld GD, Nirula R, Gernsheimer TB. The effects of leukoreduced blood transfusion on infection risk following injury: a randomized controlled trial. Shock 2006; 26: Dzik WH, Anderson JK, O Neill EM, Assmann SF, Kalish LA, Stowell CP. A prospective, randomized clinical trial of universal WBC reduction. Transfusion 2002; 42: Wenz B, Ortolano GA. Effect of universal WBC reduction. Transfusion 2003; 43:831 3; author reply Wortham ST, Ortolano GA, Wenz W. A brief history of blood filtration: clot screens, microaggregate removal, and leukocyte reduction. Transfus Med Rev 2003; 17: Shapiro MJ. To filter blood or universal leukoreduction: what is the answer? Crit Care 2004; 8(Suppl 2):S Leukocyte Reduction and Infection Risk CID 2007:45 (15 October) 1013