Universal Leukocyte Reduction

Substantial controversy exists as to whether the United States should require that all transfused red blood cells (RBCs) and platelets have 99.9+% of residual white blood cells (WBCs) removed by filtration (universal leukocyte reduction [ULR]), regardless of the intended recipient's medical history.1–9 Great Britain and Canada instituted ULR in 1999,6 in part for theoretical concerns about blood transmission of variant Creutzfeldt-Jakob disease. Not only is there no human evidence for such transmission, but there is no evidence that ULR filtration renders blood or fluids noninfectious for variant Creutzfeldt-Jakob disease. This article will outline the ULR medical debates, consider the appropriateness of such regulation, review the choices associated with this potential blood safety improvement, and discuss supply and economic implications. Under ULR, all platelets and RBCs available from blood centers will be leukoreduced (LR). This change results both from new Food and Drug Administration (FDA) quality control standards affecting bedside LR blood products and from the desire of blood centers to have only 1 type of inventory.The primary established advantage of LR blood products is reduced rates of alloimmunization to WBCs and platelets. Such reduction is desirable for patients undergoing repeated transfusions of platelets, particularly those with hematologic malignancies. Alloimmunization is a major cause of lower in vivo yield of platelet transfusions and reduces the success rate of allogeneic bone marrow transplants.Avoiding alloimmunization and WBC cytokines also should lower the frequency of febrile transfusion reactions. Again, the clear benefit is primarily for patients receiving repeated transfusions, including some with nonmalignant hematologic disorders, such as hemoglobinopathies, as well as those with malignancies. Unfortunately, while WBC cytokines induce fevers, many transfusion-associated fevers occur for other coincidental reasons, and findings for all patients are not clear cut. This problem is seen in 2 reports from large transfusion services comparing pre- and post-ULR febrile reactions. One brief note cited a more than 90% rate reduction with ULR,2 and the other, a full article, had a statistically insignificant change from 0.12% to 0.08% of transfusions.9White blood cell-reduced products also have lower risks of cytomegalovirus (CMV) transmission to susceptible patients (transplantation, chemotherapy, intrauterine, etc), roughly that of serologically negative products. Some centers already use LR products as CMV safe, but often only if precollection or laboratory filtration is used, with attendant quality control. Whether avoiding CMV-seropositive units in all patients is medically useful is a difficult question, given that 50% of adults are seropositive from generally unapparent CMV exposure sometime in their lives. However, transmission of as-yet-unknown viruses carried exclusively by WBCs would be potentially prevented.A more disputed matter focuses on a seemingly paradoxical effect of transfused alloleukocytes, that of immunosuppression or induction of immunotolerance. This effect is well established in transplantation, particularly of kidneys.10 Furthermore, this effect is posited as enhancing metastasis and also increasing the likelihood of postoperative infections and/or death for certain types of surgery.11,12 The issue has been extensively analyzed, most recently by Vamvakas and Blajchman.12 They concluded that many studies are inadequate, and that in positive reports, unrelated confounding factors cannot be excluded. Even if the positive results are valid, extension of study group conclusions to all patients may be incorrect, as illustrated by a report describing no adverse clinical or laboratory effects in patients with acquired immunodeficiency syndrome receiving non-LR products versus those receiving LR products.13 The opposing medical views of all these issues are presented in detail by Vamvakas and Blajchman,6,12 without agreement, including disagreement on ULR.The possible downsides of ULR are several, including supply. First, filtration reduces the red cell content of ULR units. Persons receiving large amounts of RBCs (trauma, chronic transfusions, etc) would average approximately 10% more units for the same clinical effect. Second, LR of sickle cell trait units is often technically unsuccessful. With ULR, will such donors be excluded? If so, approximately 0.5% to 1% of the total donor pool would be deferred. These donors are valuable sources of unusual antigen-negative units for sickle cell disease patients. Thus, from both medical and ethical standpoints, exclusion of healthy donors with sickle cell trait is a substantive concern. Another loss will be the 1% to 8% of units that fail LR quality control or are lost for technical reasons during filtration.14,15 The variable is whether quality control–failed units will still be transfused.In the aggregate, these negative impacts on blood supply are small, conservatively on the order of 2% to 3% of the total supply, but at certain times of the year 2% can be important. In the last few years, theoretical concerns relative to variant Creutzfeldt-Jakob Disease caused a similar donor loss. There have been major periodic supply shortages since then. Whether these shortages are worse than those hitherto experienced is difficult to determine. The qualitative conclusion is that the blood supply in the United States is marginal, with little current ability for sustained rapid increase. Other donor exclusions being considered will further decrease the donor base, such as a potential 8% to 10% decrease in donors resulting from broadening the Creutzfeldt-Jakob disease exclusion criteria.Cost estimates of ULR per unit range from $21 to $30, based on information from blood centers. Using a figure of $30 per RBC unit,16 and figuring that an additional 80% (9 600 000 units) of the blood supply will be filtered, the added cost will be $288 million per year. Other estimates range higher, reflecting the fact that added charges from blood centers are often greater than $30. Some question the cost/benefit of this use of health care dollars, based on the higher cost to hospitals and patients, as well as the medical disagreements cited earlier.17 Informally gathered data have yielded a difference in charges for LR versus non-LR RBCs ranging from $28 to $60. These numbers are from areas where the added charge for LR is identifiable. A full survey is not feasible, as many blood centers are making comprehensive charge changes that include LR plus nucleic acid testing and other local factors. However, mitigating savings might occur if ULR blood is accepted as CMV safe, eliminating serotesting costs. Conversely, sustained shortages will increase hospital charges due to increased costs of interregional blood importation.In the United States, the chief decision-making body for blood products is the FDA, which has 2 advisory bodies. Both committees have recommended ULR in decisions that are in part science and in part opinions based on admittedly fragmentary data. The first advisory body, the Blood Products Advisory Committee, is structurally traditional, and the second is a special group, resulting from the Institute of Medicine's report, which had concluded decision-making errors occurred during the 1980s and 1990s in response to acquired immunodeficiency syndrome transmission by blood. This special group is the Advisory Committee on Blood Safety and Availability. In 1998, the Blood Products Advisory Committee voted in favor of ULR, albeit noting the need for additional data.18 In 2001, the Advisory Committee on Blood Safety and Availability recommended ULR, recognizing the uncertain data regarding the benefit for all patients. They expressed fear that without ULR, mixed inventories would lead to errors,1 whereby some patients clearly needing LR products would not receive them. This approach, while rational and protective, attacks the problem on the surface, rather than at the root. By the same reasoning or beliefs, all cellular blood products for all patients should be irradiated to prevent graft versus host disease in the minority of patients who are susceptible because of congenital immunodeficiency or other reason. (Ness and Lipton19 recently noted hazards of mistakenly not giving irradiated blood.) More broadly, if misordering or misrelease of blood is a problem, then such issues should be addressed primarily, since errors concerning wrong ABO type, nonirradiation, HLA mismatch, etc, can occur from other errors, not just the immunological sequelae of non-LR blood products.While not emphasized, reduced usage, such as occurred in the late 1980s, might have a variety of gains.11,20 In the 1980s, I noted data suggesting public fears, not transfusion education, had been causal in reduced usage.21 Whether we can be more effective now with our peers is unknown.A possibly simpler initial ULR approach, ignoring cost, would add a clearer safety device, total reliance on apheresis, rather than random donor platelets. This approach would cut infectious and immunologic exposure by 80% to >90%, and apheresis platelets are easily LR with current equipment. Hospital costs would go up, and blood center net revenues might decrease. Similar to ULR, this tactic would remove individual physician decision making, in this instance just for platelets.Many physicians believe that until more substantive data emerge, the decision for LR product use should be made for individual patients by individual physicians, or for types of patients by individual hospital medical staffs, rather than by outside agencies. They view this question in the same way they view decisions about other pharmaceuticals, that is, this issue is a matter of the practice of medicine, not a regulatory one. The College of American Pathologists (CAP) endorses this concept and believes the current data for LR for all patients are not compelling.22 Other organizations, including the American Medical Association (AMA), also favor this position.23In part because of the aforementioned advisory committee recommendations, it is likely ULR will occur in the United States. On its own, the American Red Cross plans to implement ULR by the end of 2001, and has already done so in many cities. The CAP has formally expressed concerns about implementation of ULR and its potential impact on the blood supply.21 The CAP believes implementation will require constant monitoring, with follow-up studies to determine whether ULR will truly be beneficial.21 Whether ULR or current practice is present, pathologists are key for medical staff education, ensuring that transfusion procedures guard against patients receiving unsuitable products. Errors arising from “selective protocols“ were recently stressed,18 and simpler is better. The issues are similar for all products, special and routine, and conservatism in transfusion can be a virtue.11,20The financial impact of ULR on hospitals does not have immediate relief, under Medicare or other capitation. Blood center charge increases of 30% to 40% are cited for ULR and other reasons. Some believe blood products should be on a cost reimbursement under Medicare. Regardless of reimbursement, if ULR is established, the CAP believes no patient should be denied ULR for financial reasons.21Universal leukocyte reduction will benefit those patients universally recognized as needing LR products by avoiding potential errors of release of non-LR products. There may be actual benefits to some, but not all, of the other transfused patients. These possible benefits include reduced febrile reactions, reduced CMV risk, and largely unknown or debated clinical sequelae of immunosuppression.In an ideal world, any medical advantage, even if slight or hypothetical and costly, should be seized. Transfusion of wrong or inappropriate blood products does occur. We can argue that if transfusion professionals do not push for advances, then no one will. By this criteria, some in the CAP, including myself, agree with ULR advocates. However, as noted, it is not clear that ULR is the best use of finite medical resources, even just within blood transfusion, and ULR may exacerbate serious supply shortages. Additionally, the decision process is troubling for those who believe choice of therapy should be decided by individual physicians and medical staffs. This concern is voiced by both the CAP and AMA, in addition to questions concerning the inconclusive data about benefit for all patients. There is a poorly defined gray area between those items we regard as the purview of federal agencies and those reserved for states and practitioners. The schism in opinions, in part, indicates ULR is in this area. Similar policy and ethical questions apply to whether largely local monopoly blood centers should effectively decide therapy by providing only 1 type of product. Lastly, the topic of ULR has generated heated rhetoric, to the point that larger health policy and ethical issues are not considered. Both sides can, and do, consider themselves to be medically and morally correct, and regard their opponents as not serving the best interests of patients. In this regard, the ULR debate is an ugly paradigm for our current fractured manner of solving health care priority and delivery questions.Note.—Since submission of this manuscript, the tragic events of September 11 resulted in a spontaneous flood of blood donations. I hope that an increase in donations will be sustained and the above pessimistic comments about supply will be incorrect. Past disasters did not do so, but we are in a new era. Additionally, scientific reports at the AABB meeting (Transfusion. 2001;41(suppl):1S, 111S–112S) yielded conflicting data on the degree of reduction of transfusion reactions by ULR and the impact on short-term mortality and morbidity.

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