Ask the Expert
Questions and Answers on Leukocyte Reduction
Question: Has the time come to leukoreduce the blood supply of Rhode Island?
Dr. Sweeney: There are several reasons for leukocyte reduction of blood products in Rhode Island and throughout the United States. Until recently, allogeneic white cells were considered a benign passenger when most patients were transfused with cellular blood components. Increasingly, it is recognized that this passenger is not quite as innocuous as previously thought and is an unwanted contaminant.
The conceptual reason to remove leukocytes from blood products is largely aimed at improving product purity i.e. the physician should be confident that he/she is getting what is prescribed for the patient and not unwanted leukocytes which are known to provoke adverse events. The practical reason for leukoreduction is to prevent known adverse events and perhaps, more importantly, suspected transfusion-related morbidity attributable to allogeneic leukocytes.
There has been an increasing awareness of the fact that the residual leukocytes in cellular blood products are responsible for many undesired adverse events in transfusion recipients. From a chronological perspective, the oldest observation from the 1950s is that the occurrence of nonhemolytic febrile transfusion reactions (NHFTR) could largely be prevented by a modest reduction in the leukocyte content of the red cell product transfused.
More recently, we have come to appreciate that primary alloimmunization to HLA antigens is largely brought about by the presence of a subpopulation of allogeneic leukocytes which express Class II HLA epitopes. Leukoreduction by filtration of cellular blood products has been shown in several studies to reduce the occurrence of primary alloimmunization to HLA antigens. The TRAP study (Trial to Reduce Alloimmunization to Platelets) published in the New England Journal of Medicine in December 1997 showed a significant beneficial effect of leukoreduction for transfusion recipients who receive multiple platelet transfusions. The management of patients who are refractory to platelet transfusions on the basis of alloimmunization greatly complicates transfusion support for these patients and drains the resources of transfusion services.
The third important adverse event of allogeneic leukocytes is caused by cell-associated viruses, which exist as a reservoir within leukocytes and may be transmitted by cellular blood products. The herpes family of viruses are key culprits, with cytomegalovirus (CMV), by far, the most significant. Numerous studies have shown that the transmission of primary CMV disease by blood transmission can be greatly reduced and probably eliminated by leukoreduction. Increasing attention is also being paid to Epstein-Barr virus and the retroviruses HTLV-1 and -2, which also are transmitted by white cells in cellular blood products.
Debate continues to surround the question of the role of leukocytes in transfusion-induced immunomodulation (TRIM). Many observational studies and several randomized controlled clinical trials have identified TRIM as a clinically significant adverse event and, in some studies, TRIM can be reduced or attenuated by leukoreduction. In two studies, analyses have shown that the reduction in patient morbidity justifies leukoreduction as a cost minimization strategy. Although this is not yet universally accepted, the evidence implicating allogeneic leukocytes as causal for TRIM is accumulating.
Also of great interest is the recent data gathered from several randomized controlled clinical studies, which show that leukoreduction of red cell products improves patient outcome and reduces morbidity in transfused surgical patients. Analyses of the economic data from these studies has shown that the cost savings with the use of leukoreduced red cells more than offsets the costs incurred due to the acquisition of the technology. This remains a very important area for further review and investigation.
Question: What steps has Rhode Island taken towards leukocyte reduction?
Dr. Sweeney: Over the course of 1999, three major hospitals in Rhode Island have adopted a policy of universal prestorage leukoreduction. Two hospitals (Roger Williams and The Miriam Hospital) were transfusing 100% prestorage leukocyte reduced cellular blood by June 1999. Rhode Island Hospital achieved 100% leukoreduction in the end of 1999. These three hospitals account for 60% of all red cells transfused and approximately 80% of all platelets transfused in the state of Rhode Island. Within Rhode Island, many of the smaller hospitals plan to introduce leukocyte reduction early in the year 2000. Thus, it is anticipated that by mid-year 2000, at least 90% of all blood products transfused in Rhode Island will be leukocyte reduced; with the vast majority through prestorage leukocyte reduction.
Question: Should there be universal leukoreduction?
Dr. Sweeney: The arguments for universal leukocyte reduction can be constructed along two lines. At the present time, approximately 20% of red cells and between 40-60% of platelet products are transfused as leukoreduced products, mostly post-storage at the bedside. The important question is what cost savings will immediately be achieved by universal leukocyte reduction. In this context, I strongly suggest that prestorage leukoreduction will be the preferred approach, using either inline filtration or some other form of process leukoreduction. The first cost savings to be quantitated is the savings associated with the acquisition cost of bedside filters. This would probably be a relatively small cost saving and will offset the cost of prestorage leukoreduction by 8-10%. There will be an important further cost savings if we accept that the universal use of prestorage leukoreduction will obviate the need for CMV testing. When the total acquisition cost of CMV negative products is calculated, particularly when whole blood derived (random donor) platelets are commonly transfused; this cost savings may be similar to the acquisition cost of bedside filters. The combination of these important economic benefits will decrease the acquisition cost about 15-20%.
Another potential benefit of universal leukocyte reduction is the possibility to discontinue routine testing for HTLV-1 and -2. This could result in real achievable cost savings. An alternative strategy would be to test first time donors for HTLV-1 and -2, but not repeat donors. Since most donations come from repeat donors, this would reduce the majority (70- 80%) of tests performed.
There are other important benefits associated with leukocyte reduction, which are not necessarily apparent to those unfamiliar with the day-to-day operations of a blood bank. Firstly, the management of patients requiring specialized blood products can absorb far greater amounts of time and resources than might be appreciated. For example, the amount of time spent requesting CMV negative products or juggling with different inventories of ABO compatible or identical blood for specific recipients because of the need for CMV testing. This can tax the transfusion service at a time when there is continuing pressure for reduction in full-time employees. The time spent to obtain these specialized products, inventory management, issues on product availability; dealing with physicians on the appropriateness of accepting different ABO types or rhesus types because of limited availability of CMV tested products and the potential delays incurred in transfusing patients, can also significantly drain resources. All of this would no longer be an issue with universal leukoreduction. Furthermore, since both leukoreduced and non-leuko-reduced blood is already transfused in day-to-day practice, there would be cost savings with the elimination of specialized manuals and training of nurses to transfuse both types of products (bedside filtered/nonfiltered). In the aggregate, these cost savings could be quite substantial. With prestorage leukoreduction, the problems associated with the maintenance of dual inventories would be eliminated, again resulting in a substantial cost savings. Economic analyses of the cost of universal prestorage leukoreduction must incorporate all these cost savings factors and quantify the impact throughout the nation.
So even before discussing cost savings associated with potential clinical benefits, such as a reduction in TRIM and improved patient outcome, prestorage universal leukocyte has already eliminated a sub-stantial portion (possibly 25-40%) of the increased costs of changing the technology. Even if we assume that only a small percentage of transfusion recipients (in the range of 1-5%) will actually benefit from prestorage leukoreduced blood products, it is highly likely the cost savings associated with the reduction in patient morbidity will more than offset any increase in costs. In fact, leukoreduction may even show a net cost savings. It is interesting to note that in the studies where an economic analysis has been confirmed, there is an overwhelming cost advantage with the use of leukoreduced blood.
Question: How do the advantages of leukocyate reduction measure up against the disadvantages?
Dr. Sweeney: Weighing the benefits versus the disadvantages associated with leukocyte reduction is a highly topical subject. A superficial analysis of the increased cost of implementing universal prestorage leukoreduction in the U.S. is estimated at $500-700 million. However, this estimate is unlikely to be accurate for a variety of reasons. First, there are cost savings that can be achieved in how transfusion services operate. Furthermore, application of universal leukocyte prestorage reduction may allow us to achieve cost avoidance with the elimination of CMV and HTLV testing. And, it is anticipated that unit acquisition cost of prestorage leukoreduced red cells will decrease as volume grows.
Additionally, benefits in patient outcome including reduced morbidity, even for a small percentage of patients, can result in potentially enormous cost savings. Therefore, with thorough economic analysis of universal leukocyte reduction, it is certainly possible that it will not only be cost neutral, but that it could actually result in very substantial cost savings. In this schema, universal leukocyte reduction is indeed a true cost minimization approach, and should be implemented as a cost savings intervention, regardless of any improved patient outcome, although the latter is what mostly motivates physicians!
A possible disadvantage of implementing universal prestorage leuko-eduction is that blood centers will need to change their procedures and processing practices. However, this is a temporary issue and once implementation is in place, will be eliminated. Leukoreduction also raises the question of potential technology- related effects, such as reduction in product potency. Prestorage leukocyte reduction generally causes much less red cell loss than bedside filtration. Thus, even if prestorage leukocyte reduction is more expensive than bedside filtration, part of the difference may be offset by the improved product potency. Prestorage leukoreduction improves red cells, but not platelet potency. I believe this will be a silent issue, because of the increase in whole blood draw from 450 mls to 500 mls, which will result in increased red cell mass and platelet yield per unit of red blood cells or platelets, respectively, and will not increase the overall need for units of red cells or platelets. Another disadvantage with filtration reported with both red blood cells and platelets is the potential for rare hypotensive reactions to occur. This has not been reported with prestorage leukocyte reduction and, therefore, is unlikely to continue as an area of concern.
Question: What additional improvements in blood quality and safety, beyond leukocyte reduction, lie ahead in the near future?
Dr. Sweeney: Although there remains some debate in the U.S. regarding the pros and cons of leukocyte reduction, many experts consider leukocyte reduction, specifically prestorage leukoreduction, for all practical purposes to be a done deal. The developments in Europe and Canada throughout 1998, and more recently in Switzerland (1999), have demonstrated that this is how the technology is moving. It is probable that some isolated regions in the U.S. and, perhaps, some European countries may delay universal leukocyte reduction for one or two years; but this is unlikely to be sustained. In the U.S., formal recommendations from the FDA, and within the European Union, directives to member countries may finally resolve the issue.
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