Universal Leukoreduction Research Articles

Transfusion reaction patterns by blood component

Abstract Introduction/Objective Blood transfusion is becoming safer by continuous improvement of donor screening, patient identification, blood management, and infectious disease screening. This study was conducted to examine the rate and characteristics of transfusion reactions in the setting of universal leukoreduction of cellular products as well as pathogen reduction and/or irradiation of apheresis platelets. Methods/Case Report Data from the blood bank database for a 5-year period from 1/1/2019 to 12/31/2023 was collected. Transfusion reaction data as reported to National Healthcare Safety Network (NHSN) was analyzed. Results (if a Case Study enter NA) A total of 134,552 transfusions and 491 transfusion reactions were reported over the study period, resulting in the overall transfusion reaction rate of 0.36%. Allergic reaction was the most common reaction (38%), followed by febrile non-hemolytic transfusion reaction (FNHTR, 30%), delayed serologic transfusion reaction (DSTR, 14%), transfusion-associated circulatory overload (TACO, 10%), and transfusion-associated dyspnea (TAD, 4%). Platelets had the highest rate of transfusion reaction at 0.61% (n=167 of 27,180), red blood cells (RBC) at 0.35% (n=289 of 82,963), plasma at 0.13% (n=24 of 19,114), and cryoprecipitate at 0.06% (n=3 of 5295). The most common reaction associated with platelet transfusion was allergic reaction (64%, n=107), while FNHTR was the most common reaction associated with RBC transfusion (37%, n=106). By severity, 9 (2%) reactions were life-threatening, 21 (4%) were severe, 374 (75%) were non-severe, and 87 (18%) were not determined. Of life-threatening reactions, allergic reactions were the most common (5 of 9), while TACO was the most common severe reaction (9 of 21). Platelets were the most commonly implicated component in life- threatening reactions (4 allergic and 2 TACO), and RBCs were more commonly implicated in severe reactions. Conclusion Platelet transfusions were associated with a higher rate of transfusion reactions and life-threatening allergic reactions compared to other blood components.

Seroprevalence of Human T-cell Lymphotropic Virus Types I/II Among Blood Donors in a Tertiary Hospital in Oman.

Routine blood donor screening of human T-cell lymphotropic virus (HTLV) has been practiced in Oman since 2017. Limited data exists on HTLV seroprevalence among Omanis. This study aims to determine the seroprevalence of HTLV-I/II among blood donors attending a hospital-based blood bank to assess the need for a universal versus targeted screening. We conducted a retrospective review of blood donors' results attending a hospital blood bank between January 2017 and February 2020. Blood samples were screened for HTLV-I/II antibodies using ARCHITECT i2000SR. Reactive samples underwent further testing by immunoblot assay (MP Diagnostics HTLV Blot 2.4). Age, gender, and nationality were assessed. All components manufactured at the blood bank undergo leukoreduction before storage. A total of 24 469 first-time blood donors were screened for HTLV antibodies. Most participants were male (n = 22 186, 90.7%), and the majority were Omani (n = 22 711, 92.8%). The age range was 18 to 64 years, with a median of 32 years. The seroreactivity rate was 0.2% (43; 95% CI: 0.12-0.23). Confirmatory testing by immunoblot revealed three indeterminate results (7.9%), of which two were Omani and one non-Omani donor, and the remaining 40 seroreactive donors tested negative. Our study revealed zero seroprevalence of confirmed HTLV among blood donors. The continuation of universal screening for first-time donors is a standard of care. With universal leukoreduction at Sultan Qaboos University Hospital and a very low risk of HTLV in Oman's population, the need for screening regular donors can be reconsidered if these findings are confirmed on a larger scale involving other blood banks in Oman.

How do we forecast tomorrow's transfusion? - Next generation transfusion practices to improve recipient safety.

Recipient safety measures play a key role in overall transfusion efficacy. The key advances in safety over the first century of transfusion medicine have been the development of techniques to prevent hemolytic transfusion reactions, hemolytic disease of the newborn and transmission of viral pathogens. While these risks remain important, they affect many fewer patients than previously. We propose that some of the most important current safety issues relate to toxicities broadly encompassed by the immunomodulatory effects of allogeneic transfusion. These include (1) universal leukoreduction to mitigate nosocomial infections, inflammation and organ injury, (2) removal of stored supernatant and its attendant toxic contents that cause dysfunctional immunity and organ injury, (3) avoiding infusing ABO incompatible antigen and antibody that can lead to bleeding, platelet refractoriness and inflammation, (3) minimizing prophylactic transfusions (particularly of plasma and platelets) except where benefit is proven, and (4) avoiding use of normal saline which is linked to renal failure and possibly hemolysis. Accompanying these safety measures will be the continued growth of one of the most important safety measures, patient blood management, which has as one benefit the avoidance of unnecessary and harmful transfusions. Reducing the toxicity of transfusions will enhance the improved clinical outcomes seen with patient blood management.

National Blood Foundation 2021 Research and Development summit: Discovery, innovation, and challenges in advancing blood and biotherapies.

National Blood Foundation 2021 Research and Development summit: Discovery, innovation, and challenges in advancing blood and biotherapies.

Monkeypox and the safety of the blood supply.

Monkeypox and the safety of the blood supply.

Universal or selective irradiation: a comparison of approaches

Pathological mechanisms proposed for transfusion-associated graft-versus-host diseases (TA-GVHD) include HLA homozygosity in donor cells of the transfusion unit that is shared by the recipient (one-way HLA match) and immunosuppression in the transfusion recipient. Which of these factors is indispensable or to what degree each factor contributes to the development of TA-GVHD has been the issue of debate. In countries like Japan with higher HLA homogeneity, TA-GVHD occurrence was thought to be primarily dependent on the one-way HLA match mechanism regardless of immunosuppression. Accordingly, universal irradiation of blood components has been conducted with no further TA-GVHD cases. In other developed countries, in contrast, TA-GVHD was thought to be a sort of extrapolation of GVHD observed among heavily immunosuppressed patients. Guidelines with the detailed list of diseases with the indication for irradiated components have been established in those countries. Although TA-GVHD occurrence decreased markedly after the introduction of universal leukoreduction, a considerable number of TA-GVHD cases have occurred among immunocompetent patients mostly by the one-way HLA match mechanism. Because one-way HLA matching with donor homozygosity is thought to be a ubiquitous and independent mechanism for TA-GVHD, it could occur in any transfusion setting regardless of immunosuppression. It would be thoughtful to select an area-specific strategy considering the drawbacks of irradiation and the frequency of TA-GVHD in that area. However, if complete abolition of TA-GVHD is required from the perspective of the high fatality of the disorder, universal irradiation of cellular components will be necessary.

Changes in the incidence of transfusion reactions in hematological patients over the past 30 years.

Patients with hematological diseases are polytransfused and often immunocompromised, therefore susceptible to transfusion reactions (TR). This study aims to document the incidence of TRs in adult hematological patients and assess the effect of changes in the production of blood components and transfusion practice on their occurrence. Retrospective observational analysis of TRs reported from 1993 to 2019 was performed. For the analysis of the effect of changes on the incidence of TRs, the evaluated time was divided into two periods: the 1st period before the introduction of changes in production, when leukoreduced blood components were used only selectively, and the 2nd period, when semi-automated method of production and universal leukoreduction was introduced. The decrease in the incidence of TRs was observed for both red blood cell (RBC) and platelet concentrate (PC) transfusions in the 2nd period. Since platelet additive solution has been used, a further decrease in the incidence was reported. The decrease in incidence was also observed for delayed hemolytic/serological transfusion reactions and for transfusion-transmitted bacterial infections. Four cases of incorrect blood transfusions were uniquely related to the hematological patients, caused by antigen loss and transfusion ordering after ABO-incompatible hematopoietic stem cell transplantation. Our results provided evidence that the introduction of tools offered by modern transfusion medicine: universal leukodepletion, plasma replacement with additive solutions, sensitive laboratory techniques, prophylactic antigen matching policy, informatization, and automatization, decreased the incidence of TRs and improved transfusion safety.

The Role of Platelets in the Induction of Alloimmunization after Platelet Transfusion

Background Platelet (PLT) transfusion can elicit alloimmune responses leading to alloantibody formation. These alloantibodies can opsonize PLTs which causes rapid clearance of transfused PLTs and thereby render the transfusion ineffective. Contaminating WBCs in PLT concentrates are important for the induction of this alloimmunization which is evident from the fact that leukoreduction of platelet concentrates significantly reduced the frequency of alloimmunization. Despite universal leukoreduction, however, a residual risk remains. Currently, it is unknown if this is due to the residual WBCs (<1*106 / transfusion) in PLT concentrates or if PLTs themselves can also induce primary HLA-alloimmunization. Furthermore, it is not known which factors increase or reduce the likelihood of alloimmunization. Therefore, the aim of our study was, first, to determine the involvement of PLTs in the induction of alloimmunization, and second, to investigate whether storage of PLT concentrates might be a risk factor for alloimmunization.Methods To determine if PLTs are phagocytosed and presented by antigen presenting cells, monocyte derived dendritic cells (moDCs) were incubated at 37°C with allogeneic PLTs. After incubation, moDCs were either fixed and analysed for phagocytosis of PLTs using z-stacks obtained with confocal microscopy, or moDCs were lysed and HLA-DR was immunoprecipitated from this lysate. Thereafter, HLA-DR presented peptides were eluted and measured using mass spectrometry. Furthermore, HLADRB3*01:01+ moDCs were incubated with either HPA1a+ or HPA1b+ PLTs and later exposed for 24 hours to HPA1a-specific HLADRB3*01:01+ CD4 T cells after which production of IFNy by T cells was determined using ELISA. To investigate if storage may be a potential risk factor for alloimmunization, moDCs were incubated with freshly isolated PLTs or PLTs stored 7 days under blood bank conditions. Finally, in some experiments, freshly isolated PLTs were activated using thrombin-receptor agonistic peptide, treated with calcimycin A23187 to induce apoptosis, or incubated with either purified phosphatidylserine (PS) or phosphatidylcholine (PC). Subsequently, phagocytosis of these PLTs by moDCs was quantified using imaging flow cytometry.Results Confocal microscopy clearly showed that PLTs are phagocytosed by moDCs. Mass spectrometry analyses showed presentation of peptides derived from proteins exclusively expressed in PLT by HLA class II of moDCs. In addition, moDCs induced a significant HPA1a+ specific CD4 T cells response (measured as IFNy production) after incubation with HPA1a+ PLTs, which was not observed after incubation with HPA1b+ PLTs. PLTs obtained from stored PLT concentrates were significantly more phagocytosed compared to fresh PLTs. This might be caused by increased presence of apoptotic platelets in stored PLT concentrate, as phagocytosis of apoptotic platelets was significantly increased compared to activated or unstimulated PLTs. This increased phagocytosis was partially caused by PLT surface expression of PS. Furthermore, apoptotic PLTs also induced a stronger CD4 T cell response.Discussion Our studies clearly show that peptides of phagocytosed PLTs are presented by DCs, resulting in a platelet-specific CD4 T cell response. This implicates that not only WBCs, but also PLTs themselves can induce alloimmunization after PLT transfusion. As a result, factors that increase phagocytosis of PLTs could also increase the risk of alloimmunization after PLT transfusion. In this respect, PLTs stored for 7 days showed increased phagocytosis as compared to fresh PLTs. This increase is at least partly due surface expressed PS caused by storage-induced apoptosis and resulted in a stronger platelet-specific CD4 T cell responses compared to DCs incubated with untreated fresh PLTs. Although these in vitro experiments only partly represent the complex processes that are involved in an immune response in vivo , these data suggest that storage of PLT concentrates may be associated with increased alloimmunization. DisclosuresNo relevant conflicts of interest to declare.

Leucorreducción Universal en Costa Rica: ¿Es realmente urgente?

La transfusión sanguínea confiere beneficios clínicos evidentes; sin embargo, posee algunos riesgos y resultados adversos si no se realiza bajo los controles estrictos que garanticen la seguridad de la donación, almacenamiento y transfusión adecuados. La leucorreducción es el proceso mediante el cual los leucocitos se eliminan de la sangre donada, y los estándares actuales de la Asociación Americana de Bancos de Sangre establece un valor residual de glóbulos blancos &lt;5 × 106 por unidad. El beneficio clínico de la aplicación selectiva se traduce en pacientes sometidos a múltiples transfusiones, inmunocomprometidos e internados en las Unidades de Cuidados Intensivos. La leucorreducción universal consiste en realizar este procedimiento en todas las transfusiones a cualquier tipo de paciente y los beneficios comprobados van dirigidos a disminuir las reacciones febriles no hemolíticas, las aloinmunizaciones HLA y las transmisiones virales. Desde el punto de vista médico, la leucorreducción universal parece estar justificada, pero el costo de implementación es significativo. Al estimar los costos en Costa Rica con base en las unidades colectadas en el 2017, la implementación universal sobrepasaría los $2 millones, una inversión significativa para un país de ingresos medios.

Storage-Induced Platelet Apoptosis Is a Potential Risk Factor for Alloimmunization Upon Platelet Transfusion.

Platelet transfusion can elicit alloimmune responses leading to alloantibody formation against donor-specific polymorphic residues, ultimately resulting in platelet transfusion refractoriness. Universal leukoreduction significantly reduced the frequency of alloimmunization after platelet transfusion, thereby showing the importance of white blood cells (WBCs) in inducing this alloresponse. It is, however, unknown if the residual risk for alloimmunization is caused by WBCs remaining after leukoreduction or if alloimmunization can be induced by platelets themselves. This study investigated the capacity of platelets to induce alloimmunization and identified potential product-related risk factors for alloimmunization. First, internalization of allogeneic platelets by dendritic cells (DCs) was demonstrated by confocal microscopy. Second, after internalization, presentation of platelet-derived peptides was shown by mass spectrometry analysis of human leukocytes antigen (HLA)-DR eluted peptides. Third, platelet-loaded DCs induced platelet-specific CD4 T cell responses. Altogether, this indicates a platelet-specific ability to induce alloimmunization. Therefore, factors enhancing platelet internalization may be identified as risk factor for alloimmunization by platelet concentrates. To investigate if storage of platelets is such a risk factor, internalization of stored platelets was compared with fresh platelets and showed enhanced internalization of stored platelets. Storage-induced apoptosis and accompanied phosphatidylserine exposure seemed to be instrumental for this. Indeed, DCs pre-incubated with apoptotic platelets induced the strongest IFN-γ production by CD4 T cells compared with pre-incubation with untreated or activated platelets. In conclusion, this study shows the capacity of platelets to induce platelet-specific alloimmune responses. Furthermore, storage-induced apoptosis of platelets is identified as potential risk factor for alloimmunization after platelet transfusions.

Survey on Transfusion-Transmitted Cytomegalovirus and Cytomegalovirus Disease Mitigation.

- Cytomegalovirus (CMV) can be transmitted by cellular blood products, leading to severe disease in immunosuppressed patients such as neonates and transplant recipients. To mitigate transfusion-transmitted CMV (TT-CMV), "CMV-safe" blood products (leukoreduced and/or CMV-seronegative) are transfused. Attempts to develop practice guidelines for TT-CMV mitigation have been limited by paucity of high-quality clinical trials. - To assess current TT-CMV mitigation strategies across medical institutions for specific at-risk populations. - Supplemental questions regarding TT-CMV and CMV disease mitigation were added to a College of American Pathologists Transfusion Medicine (Comprehensive) Participant Survey in 2015, addressing whether a given institution provided CMV-safe products for 6 at-risk patient populations. - Ninety percent (2712 of 3032) of institutions reported providing universally leukoreduced blood products. Among institutions without universal leukoreduction, 92% (295 of 320) provided leukoreduced products on the basis of clinical criteria. Eighty-three percent (2481 of 3004) of respondents reported having availability of CMV-seronegative products; however, wide variation in policies was reported governing CMV-seronegative product use. Among all respondents, less than 5% reported using CMV prophylaxis and monitoring in high-risk patient groups. Transplant centers reported higher rates of CMV prophylaxis (25% [97 of 394] solid organ) and monitoring (15% [59 of 394] solid organ) for CMV-negative transplant recipients. - Universal leukoreduction is the primary strategy for mitigating TT-CMV. While most institutions have both CMV-seronegative and leukoreduced blood products available, consensus is lacking on which patients should receive these products. High-quality studies are needed to determine if CMV-seronegative and leukoreduced blood products are needed in high-risk patient populations.

Human T-lymphotropic virus and transfusion safety: does one size fit all?

Human T-cell leukemia viruses (HTLV-1 and HTLV-2) are associated with a variety of human diseases, including some severe ones. Transfusion transmission of HTLV through cellular blood components is undeniable. HTLV screening of blood donations became mandatory in different countries to improve the safety of blood supplies. In Japan and Europe, most HTLV-infected donors are HTLV-1 positive, whereas in the United States a higher prevalence of HTLV-2 is reported. Many industrialized countries have also introduced universal leukoreduction of blood components, and pathogen inactivation technologies might be another effective preventive strategy, especially if and when generalized to all blood cellular products. Considering all measures available to minimize HTLV blood transmission, the question is what would be the most suitable and cost-effective strategy to ensure a high level of blood safety regarding these viruses, considering that there is no solution that can be deemed optimal for all countries.

Effects of universal vs bedside leukoreductions on the alloimmunization to platelets and the platelet transfusion refractoriness

BackgroundMultiple platelet exposure induces anti-HLA and/or anti-HPA antibody production, which may cause platelet transfusion refractoriness (PTR). In Japan, the universal pre-storage leukocyte reduction (ULR) was fully implemented since 2006, but prior to ULR, in our institution, leukocyte reduction filters were routinely used at the bedside (bedside leukoreduction, BSLR) for all onco-hematological patients receiving multiple platelet transfusions. ObjectiveWe retrospectively compared patients receiving platelet transfusions in the era of ULR with those of BSLR era. Materials and methodsPatients of the BSLR group (409 cases) and the ULR group (586 cases) were compared in terms of alloimmunization and immunological PTR. The clinico-pathological features, including gender, history of pregnancy, number of exposed transfusion donors, periods of transfusion, and prior stem cell transplantation were compared, and the risk factors of alloimmunization were determined. ResultsThe antibody detection rate was significantly higher in the ULR compared to BSLR group (8.7% vs. 5.4%), as well as the immunological PTR rate (7.3% vs. 3.2%). By the multivariate analysis, female gender and the number of platelet donor exposure, but not universal leukoreduction or transfusion period, were found to be the risk factors strongly associated with alloantibody formation. ConclusionAlthough ULR may be superior to BSLR in terms of preventing non-hemolytic transfusion reactions, BSLR was found to be as effective as ULR in terms of preventing platelet alloimmunization and refractoriness. Thus, BSLR should be actively indicated as a realistic alternative in developing countries, before the universal leukoreduction is fully implemented.

Is there justification for universal leukoreduction?

The Associacao Brasileira de Hematologia, Hemoterapia e Terapia Celular (ABHH), the institution that represents the Associacao Medica Brasileira (AMB) in respect to hematology, transfusion therapy and cell therapy in Brazil hereby states: Prospective randomized studies have not demonstrated any positive clinical impact with the universal use of blood components in which the initial number of leukocytes has been reduced (universal leukoreduction). For this reason, universal leukoreduction remains a technically controversial topic. The current consensus is that leukoreduction has defined indications in the prevention of three blood transfusion complications only: (i) non-hemolytic febrile reactions when the patient has had this reaction previously; (ii) platelet refractoriness caused by alloimmunization against leukocyte antigens and (iii) the transmission of cytomegalovirus

Adverse events related to blood transfusion.

The acute blood transfusion reactions are responsible for causing most serious adverse events. Awareness about various clinical features of acute and delayed transfusion reactions with an ability to assess the serious reactions on time can lead to a better prognosis. Evidence-based medicine has changed today's scenario of clinical practice to decrease adverse transfusion reactions. New evidence-based algorithms of transfusion and improved haemovigilance lead to avoidance of unnecessary transfusions perioperatively. The recognition of adverse events under anaesthesia is always challenging. The unnecessary blood transfusions can be avoided with better blood conservation techniques during surgery and with anaesthesia techniques that reduce blood loss. Better and newer blood screening methods have decreased the infectious complications to almost negligible levels. With universal leukoreduction of red blood cells (RBCs), selection of potential donors such as use of male donors only plasma and restriction of RBC storage, most of the non-infectious complications can be avoided.

Is Cytomegalovirus Testing of Blood Products Still Needed for Hematopoietic Stem Cell Transplant Recipients in the Era of Universal Leukoreduction?

Hematopoietic stem cell transplantation (HSCT) recipients are a high-risk, immunocompromised group of patients who receive frequent transfusions after transplantation. Transfusion of cytomegalovirus (CMV)-negative blood products has long been the standard of care to prevent transfusion-transmitted CMV in this patient population. Leukoreduction of blood products before transfusion has been shown to significantly reduce the risk of transfusion-transmitted CMV. In the era of universal leukoreduction in Canada, the need for CMV testing of blood products remains unclear. We sought to identify whether there is a difference in transfusion-transmitted CMV viremia in patients receiving only leukoreduced versus CMV-negative and leukoreduced blood products in HSCT recipients. Patients who were CMV negative and received an allogeneic HSCT from a CMV-negative donor between October 1, 1999 and June 30, 2012 were included in the analysis. Transfusion data were collected from The Ottawa Hospital Blood Bank and Canadian Blood Services. CMV viremia was defined as PCR positivity. One hundred sixty-six patients were identified who met the inclusion criteria. Of these, 89 patients received an HSCT before January 2007, during the time when patients received leukoreduced and CMV-negative blood products. Seventy-seven patients received an HSCT after this time, receiving only leukoreduced blood products. The 2 groups did not differ in terms of age, gender, diagnosis, graft type, graft source, conditioning regimen, or ABO compatibility (P > .05). CMV viremia was detected in 3 patients who received CMV-negative leukoreduced blood products (3.37%) and in 1 patient who received only leukoreduced blood products (1.30%, P = .6244). Of the patients who developed CMV viremia, 2 developed suspected CMV disease. Both of these patients were transfused with CMV-negative blood products. Secondary outcomes, including total length of stay in hospital, admission to the intensive care unit, acute and chronic graft versus host disease, and 100-day nonrelapse mortality, did not differ between the groups. In the era of universal leukoreduction of blood products, this study demonstrates that testing for CMV-negative blood products is not needed for HSCT recipients.

An association between decreased cardiopulmonary complications (transfusion-related acute lung injury and transfusion-associated circulatory overload) and implementation of universal leukoreduction of blood transfusions

An association between decreased cardiopulmonary complications (transfusion-related acute lung injury and transfusion-associated circulatory overload) and implementation of universal leukoreduction of blood transfusions

Reducing noninfectious risks of blood transfusion.

As screening for transfusion-associated infections has improved, noninfectious complications of transfusion now cause the majority of morbidity and mortality associated with transfusion in the United States. For example, transfusion-related acute lung injury, transfusion-associated circulatory overload, and hemolytic transfusion-reactions are the first, second, and third leading causes of death from transfusion, respectively. These complications and others are reviewed, and several controversial methods for prevention of noninfectious complications of transfusion are discussed, including universal leukoreduction of erythrocyte units, use of male-only plasma, and restriction of erythrocyte storage age.

The reintroduction of nonleukoreduced blood: would patients and clinicians agree?

With today’s economic uncertainty, hospitals continue to look for new ways to reduce costs in a safe fashion. Some hospitals currently providing only leukoreduced blood have considered providing nonleukoreduced blood components for their patients, presumably assuming that nonleukoreduced blood is less expensive than leukoreduced blood. This commentary examines the safety of the reintroduction of nonleukoreduced blood components in hospitals that previously implemented universal leukoreduction. Because universal leukoreduction has been in place in most hospitals for almost a decade, 1 many clinicians have never had to weigh the risks and benefits of leukoreduced and nonleukoreduced products, and currently they are not required to decide whether nonleukoreduced components would be seriously detrimental for their patients. In the past there was debate about whether universal leukoreduction was cost-effective, but the debate did not include a balancing of risks and benefits, because no true risks have been identified (aside from device failures). 2-7

Prevention of Transfusion-Transmitted Cytomegalovirus in Low–Birth Weight Infants (≤1500 g) Using Cytomegalovirus-Seronegative and Leukoreduced Transfusions

The transfusion-transmitted cytomegalovirus (TT-CMV) can cause serious morbidity and mortality in low-birth weight infants (LBWIs). Transfusion-transmitted cytomegalovirus can be minimized in LBWIs born to cytomegalovirus (CMV)-seronegative mothers with the use of CMV-seronegative blood components. Despite evidence that has independently shown that either leukoreduction or the use of CMV-seronegative components mitigates TT-CMV, the potential efficacy of combining these 2 strategies has not been substantiated in very LBWIs (<1500 g) born to either CMV-seronegative or CMV-seropositive mothers. Nonetheless, the serious risks of CMV infection posed by allogeneic transfusions and the broad implementation of universal leukoreduction have made this combination strategy the de facto clinical standard for transfusion of LBWIs. Although preferred, this combined approach has not been validated in clinical trials and, thus, warrants a large prospective study to determine whether this is the optimal transfusion tactic or if additional safety measures are necessary to prevent TT-CMV in LBWIs born to both CMV- seronegative and CMV-seropositive mothers. The aim of this prospective birth cohort study, therefore, is to estimate the incidence of TT-CMV in 1300 LBWIs (≤1500 g) who receive CMV-seronegative plus leuko-reduced blood products to evaluate the effectiveness of this coupled strategy. Conducted in Atlanta, GA, this study has been registered at the US National Institutes of Health (ClinicalTrials.gov no. NCT00907686).