M.L. Green / Biol Blood Marrow Transplant 19 (2013) 1657e1660

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Prevention of Transfusion-Transmitted Cytomegalovirus Infection after Allogeneic HCT: The Debate Continues Margaret L. Green* Vaccines and Infectious Disease Division, Fred Hutchinson Cancer Research Center, Seattle, Washington Division of Allergy and Infectious Disease, Department of Medicine, University of Washington, Seattle, Washington

Article history: Received 3 October 2013 Accepted 7 October 2013

It has been well documented that leukoreduction of blood products results in fewer febrile nonhemolytic transfusion reactions, less HLA alloimmunization and platelet refractoriness, and less transmission of cytomegalovirus (CMV) to high-risk CMV-naïve patients [1-4]. This has led to widespread adoption of leukoreduction practices in most blood banks over the past 20 years. The debate that remains regarding transfusion-transmitted CMV (TT-CMV) is whether leukoreduced blood products are safe enough to discontinue the practice of screening blood donors for CMV seropositivity for patients at very high risk of developing CMV disease, such as seronegative recipients (R-) of allogeneic hematopoietic cell transplants (HCT) from seronegative donors (D-). The only randomized clinical trial directly comparing the use of leukocyte reduced blood products using bedside filtration versus CMV seronegative products for HCT recipients was published in 1995 and reported no difference in the incidence of CMV infection occurring after day 21 after transplantation [5]. However, when all infections were evaluated, including those occurring before day 21, the incidence of CMV disease was higher in the group receiving filtered blood. Of course, much has changed since this trial, including improvements in both filtration methods and CMV detection. A large prospective cohort study performed later at the same center found that each filtered RBC unit from a CMV seropositive blood donor was associated with a 32% increase in the odds of TT-CMV infection [6]. By this time, preemptive therapy with ganciclovir for CMV infection had already been established and so there was only 1 case of CMV disease among the 807 patients. Given concerns over a residual increased risk of TT-CMV in leukoreduced CMV positive blood products, many transplantation centers practicing universal leukoreduction continue to use preferentially CMV-negative products for these and other high-risk patient populations [7,8]. In this issue of Biology of Blood and Marrow Transplantation, Kekre at al. examined the question of whether, in the era of universal leukoreduction, a difference in TT-CMV incidence could be detected between D-/R- allogeneic HCT recipients who received leukoreduced blood products from CMV seronegative donors only versus leukoreduced blood products without knowledge of the CMV status [9]. In this

Financial disclosure: See Acknowledgments on page 1660. * Correspondence and reprint requests: Margaret L. Green, MD, MPH, Fred Hutchinson Cancer Research Center, 1100 Fairview Avenue N, Mail Stop E4-100, Seattle, WA 98109. E-mail address: [email protected] 1083-8791/$ e see front matter Ó 2013 American Society for Blood and Marrow Transplantation. http://dx.doi.org/10.1016/j.bbmt.2013.10.007

cohort, which spanned over a decade (1999 to 2012), 166 patients were evaluated. Importantly, patients were screened weekly with CMV PCR from engraftment until discontinuation of immune suppression. Patients in the 2 groups required similar numbers of red blood cell and single donor platelets, but patients in the leukoreduction only arm received significantly fewer random donor platelet transfusions. CMV infection was detected in 4 of 166 patients; 3 patients who received only CMV seronegative blood products and 1 patient who received leukoreduced only blood products. There were no confirmed cases of CMV disease, although 2 patients were suspected to have CMV pneumonia. Interestingly, CMV serology data for all of the transfused blood products was available from the Canadian Blood Services for 82% of the patients in the leukoreduced only arm. Only approximately one quarter of the transfused RBC units and one half of the platelet units were CMV positive, indicating that the CMV seroprevalence of Canadian blood donors is likely much lower than that of the general population. This has important implications for the applicability of these data to centers where the CMV seroprevalence of blood donors is much higher. An average incidence of TTCMV of 1.3% with an upper 95% confidence interval of 9.5% for high-risk patients receiving “only” leukoreduced blood products is less reassuring when the majority of those blood products were actually CMV negative. It is unknown what the incidence might be if 70% or 80% of the blood products were from seropositive donors. With a relatively small sample size, a comparison between 2 groups, both of whom received leukoreduced blood products, could not have adequate power to detect a moderate difference in TT-CMV between patients who received all CMV negative blood products and those who received mostly CMV negative blood products. In fact, a study designed to prove that the use of unscreened leukoreduced blood products was noninferior to using only CMV seronegative leukoreduced blood products for the prevention of TT-CMV after HCT would require several thousand patients. Clearly, this is beyond anything even the largest HCT centers can accomplish alone and might only be possible utilizing existing HCT trial networks or registries. What remains consistent and very reassuring, however, is the absence of significant morbidity or mortality from TTCMV in HCT patients who undergo routine surveillance and are treated pre-emptively when infection is detecteddas all of the patients were in this current study. However current guidelines do not include D-/R- allogeneic HCT recipients in patients considered at risk for post-transplantation CMV disease [10]. In an international survey of HCT centers reflecting infection prevention practices through 2003, 36% of centers were not routinely performing CMV surveillance on this patient group [7]. Any cost savings realized from discontinuation of testing blood donors for CMV may be balanced by the additional costs associated with monitoring

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M.L. Green / Biol Blood Marrow Transplant 19 (2013) 1657e1660

these patients for post-transplantation CMV infection in centers where this is not routinely done and the costs of treatment of CMV disease, which will predictably occur in approximately 1 in 200 patients with primary CMV infection. Although it may very well be safe to discontinue testing of blood product CMV serostatus for HCT patients if posttransplantation surveillance and pre-emptive therapy is performed, the study by Kekre et al. does not conclusively show this due to the small sample size. Additionally, blood centers would still likely be asked to maintain a CMVnegative blood supply for other high-risk groups where surveillance is not standard care, such as in fetal transfusion and transfusion to low-birth-weight infants. An observational clinical trial, which aims to determine the incidence of TT-CMV in 1300 low-birth-weight infants who receive CMV seronegative, leukoreduced blood products, is ongoing (NCT00907686). The investigators will also examine the individual blood products with nucleic acid testing (NAT); these data may provide important insight into CMV transmission from window-period blood donors and also about the feasibility of performing CMV NAT in donated blood products [11]. CMV NAT of blood products may eventually help us to identify CMV transmitters, both seropositive and seronegative, and to offer all of our high-risk patients a CMVsafer blood product. Because some portion of CMV infection in HCT patients will inevitably progress to CMV disease with its associated morbidity, mortality, and treatment expense, until we have data from adequately powered studies demonstrating that in the era of universal leukoreduction using CMVseropositive blood products does not increase the risk of TT-CMV over that of CMV-seronegative products, it would be premature to abandon CMV screening of our blood supply for these patients unless patients are undergoing post-transplantation CMV surveillance and preemptive therapy.

ACKNOWLEDGMENTS Conflict of interest statement: There are no conflicts of interest to report. Financial disclosure: The author has nothing to disclose. REFERENCES 1. Heddle NM, Blajchman MA, Meyer RM, et al. A randomized controlled trial comparing the frequency of acute reactions to plasma-removed platelets and prestorage WBC-reduced platelets. Transfusion. 2002;42:556-566. 2. King KE, Shirey RS, Thoman SK, et al. Universal leukoreduction decreases the incidence of febrile nonhemolytic transfusion reactions to RBCs. Transfusion. 2004;44:25-29. 3. Yazer MH, Podlosky L, Clarke G, Nahirniak SM. The effect of prestorage WBC reduction on the rates of febrile nonhemolytic transfusion reactions to platelet concentrates and RBC. Transfusion. 2004;44:10-15. 4. 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 cytomegalovirusunscreened blood-bank donors. Transplantation. 1990;50:964-968. 5. 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;86:3598-3603. 6. Nichols WG, Price TH, Gooley T, et al. Transfusion-transmitted cytomegalovirus infection after receipt of leukoreduced blood products. Blood. 2003;101:4195-4200. 7. Pollack M, Heugel J, Xie H, et al. An international comparison of current strategies to prevent herpesvirus and fungal infections in hematopoietic cell transplant recipients. Biol Blood Marrow Transplant. 2011;17: 664-673. 8. Smith D, Lu Q, Yuan S, et al. Survey of current practice for prevention of transfusion-transmitted cytomegalovirus in the United States: leucoreduction vs. cytomegalovirus-seronegative. Vox Sang. 2010;98:29-36. 9. Kekre N, Tokessy M, Mallick R, et al. Is CMV testing of blood products still needed for hematopoietic stem cell transplant recipients in the era of universal leukoreduction? Biol Blood Marrow Transplant. 2013;19: 1719-1724. 10. Tomblyn M, Chiller T, Einsele H, et al. Guidelines for preventing infectious complications among hematopoietic cell transplantation recipients: a global perspective. Biol Blood Marrow Transplant. 2009;15: 1143-1238. 11. Josephson CD, Castillejo M-I, Caliendo AM, et al. Prevention of transfusion-transmitted cytomegalovirus in low-birth weight infants ( 1500g) using cytomegalovirus-seronegative and leukoreduced transfusions. Transfus Med Rev. 2011;25:125-132.

Prevention of transfusion-transmitted cytomegalovirus infection after allogeneic HCT: the debate continues.

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