The abandoned controversy surrounding universal white blood cell reduction.

Proven benefits from white blood cell (WBC) reduction can be secured through selective removal of leucocytes from cellular blood components destined for transfusion to specific categories of patients, that is, patients with a history of febrile, non-haemolytic transfusion reactions (FNHTRs), patients at risk of platelet refractoriness because of receipt of multiple platelet transfusions, and patients at risk of cytomegalovirus disease1. In the absence of considerations of cost, universal leucoreduction of all transfused cellular blood components could extend to all patients these three proven benefits of WBC reduction. Although patients who have not suffered from a FNHTR, are not receiving long-term platelet transfusions, and are not at risk of developing cytomegalovirus disease may derive no immediate benefit from WBC reduction, it is possible that these patients may accrue some tangible benefit in the future. As regards specifically FNHTRs, patients may also accrue some tangible benefit from universal WBC reduction also in the present, because any patient receiving a non-leucoreduced cellular blood component is at risk of developing a FNHTR. It is for this reason that Tsantes et al.2, in this issue of Blood Transfusion, report on the cost-effectiveness of universal WBC reduction for preventing FNHTRs. Among patients transfused with 86,032 units of red blood cells, 0.411% of the recipients of non-WBC-reduced units, compared with 0.047% of the recipients of WBC-reduced units, developed a FNHTR. In Greece, where the study was conducted, the cost of preventing one FNHTR (i.e., the incremental cost-effectiveness ratio [ICER] of € 6,916 or US$ 9,438) was deemed not to be cost-effective by the authors. Nonetheless, the risk of developing FNHTRs was indeed reduced by WBC reduction. Moreover, the calculated ICER and the judgment about whether universal WBC reduction is cost-effective depend, respectively, on the setting in which costs are estimated and the ratio of the calculated ICER to the average cost of a hospitalisation during which a red blood cell transfusion is administered. An ICER of US$ 9,438 might be deemed by some to be cost-effective for the prevention of FNHTRs in at least some US settings, although the cost estimates that resulted in the calculation of this particular ICER in Greece are not directly transferrable to the USA. Notwithstanding the uncertainty about what the USA ICER might be, the study by Tsantes et al.2 raises the question of whether the policy of implementing universal WBC reduction needs to be reconsidered. In 1999, the United Kingdom, Ireland, and Portugal implemented universal WBC reduction of all transfused cellular blood components based on the hypothesis that this intervention might prevent transmission of the agent of variant Creutzfeldt-Jakob disease (vCJD). In North America, there was considerable debate about the appropriateness of introducing universal WBC reduction to prevent the purported adverse effects of allogeneic blood transfusion-related immunomodulation (TRIM)3. In the end, Canada implemented universal WBC reduction but the USA did not, and the proportion of WBC-reduced components transfused by hospitals in the USA today reflects local availability more than clinical preference. More specifically, hospitals in the USA use WBC-reduced components either universally or selectively, depending primarily on their location and the practice of the local blood provider (which may manufacture only leucoreduced or both leucoreduced and non-leucoreduced cellular blood components). Allogeneic blood transfusion results in numerous immunological alterations which may represent mere laboratory curiosities or may reflect some clinically relevant aberration in the recipient’s immune function —the so-called “immunomodulatory” effect— of the allogeneic transfusion. The acronym TRIM was initially introduced to designate the constellation of allogeneic blood transfusion-associated laboratory alterations as well as clinical effects (enhanced survival of renal allografts, increased recurrence rate of resected malignancies, increased incidence of post-operative bacterial infections, and activation of endogenous cytomegalovirus and human immunodeficiency virus infection) that could be attributed to allogeneic blood transfusion by immunological mechanisms. More recently, the term has been used more broadly, to encompass additional effects that could be related to allogeneic blood transfusion by means of both immunomodulatory as well as pro-inflammatory mechanisms. Pro-inflammatory, and other poorly-understood, effects of allogeneic blood transfusion have been invoked to explain, for example, the association between allogeneic blood transfusion and increased short-term (up to 3 month post-transfusion) mortality. Twelve randomised controlled trials4–15 comparing subjects randomised to receive non-WBC-reduced vs WBC-reduced allogeneic red blood cells or whole blood and investigating the development of bacterial infection were reported between 1992 and 2005. Eleven randomised controlled trials5,7–13,15–17 reported on short-term (up to 3-month post-transfusion) mortality from all causes. With regard to bacterial infection, estimates of the TRIM effect have varied from a 7.3-fold increase in the risk of post-operative infection in association with the receipt of non-WBC-reduced (vs WBC-reduced) allogeneic blood transfusion4 to no effect from the transfusion8–15. With the sole exception of the randomised controlled trial by Bilgin et al.7 in the context of cardiac surgery, all randomised controlled trials conducted in the 21st century9–13,15 have consistently produced negative findings. With respect to all-cause, short-term mortality, all studies produced negative findings with the exception of two randomised controlled trials in cardiac surgery8,13. Across all cardiac-surgery studies7,8,11,13,15, there was a 72% increase in mortality in association with non-leucoreduced (compared with leucoreduced) products in the context of allogeneic blood transfusion18. This result conforms with what would have been expected from the immunomodulation theory (that there would be more of a TRIM effect in cardiac surgery, in which the pro-inflammatory effect of the extracorporeal circuit acts as a co-factor, than in other settings19); and it is the only statistically valid and clinically meaningful adverse TRIM effect detected from the 14 available randomised controlled trials4–17. Thus, the comprehensive study of the purported adverse TRIM effects by means of randomised controlled trials added a fourth indication to the three established indications for WBC reduction: namely, the WBC reduction of all cellular blood components transfused in cardiac surgery. Perhaps the best argument for continuing the practice of universal WBC reduction in North America (in regions where it has been implemented) is the —real or perceived— difficulty in identifying, in real time, all the “targeted” patients who will benefit from WBC reduction; whereas the best argument for continuing the practice of universal WBC reduction in Western Europe (in the manner that it is currently employed) is that no case of vCJD has yet been documented in a recipient of a WBC-reduced cellular blood component collected from a donor who later developed vCJD20. Should universal WBC reduction be introduced in regions and/or countries in which it has not yet been implemented? No data from randomised controlled trials have been recently reported that would warrant resurrecting the debate over the appropriateness of introducing universal WBC reduction. Doing so would divert attention from our efforts to reduce other, proven risks of allogeneic blood transfusion. Transfusion-related acute lung injury21, mistransfusion, and bacterial contamination of platelets22 likely remain among the top proven, but not yet fully addressed, risks of blood transfusion23. Since all residual risks of blood transfusion cannot be dealt with simultaneously, policy-makers must carefully select which risk to confront next, so as to accrue the greatest possible societal gain in terms of improved transfusion safety. The greatest “competing risk” when a new safety measure is implemented is what other possible safety improvement(s) is/are left behind, because public resources and attention have been directed to the measure that has been selected for focused debate and/or implementation24. Given the competing risks of TRALI, mistransfusion, and bacterial contamination of platelets, and as also indicated by the cost-effectiveness study of Tsantes et al.2, the most effective way of expending public resources to improve transfusion safety would not be the implementation of universal WBC reduction in regions or countries in which universal WBC reduction has not yet been introduced.

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