Optimal prevention of transfusion‐transmitted cytomegalovirus (TTCMV) infection by modern leukocyte reduction alone: CMV sero/antibody‐negative donors needed only for leukocyte products

C ytomegalovirus (CMV) is a ubiquitous DNA virus of the human herpesvirus group that infects most individuals at some time during life by a variety of routes, including blood transfusions. Children and young adults are infected most commonly via exposure to respiratory secretions from other individuals with primary infections. When CMV infection occurs during infancy, an important route of primary infection is from mother to infant via breast milk. It is well known by the transfusion community that another route of primary infection can be via transfusion transmission. Primary infection with CMV begins as an acute upper respiratory infection that, despite the presence of viremia, is often subclinical with few overt signs/symptoms. As with other herpes viruses, primary infection and viremia resolve as antibodies emerge. As is true for all human herpesvirus infections, CMV then progresses to a “latent” phase of chronic infection or carrier state, during which the patient is asymptomatic, but the CMV virus resides within blood leukocytes. If activation of the latent infection occurs—which can happen with many perturbations of the immune system, including normal pregnancy, cancer, chemotherapy/radiotherapy, and solid organ or stem cell transplantation—the virus proliferates and can reappear in body fluids and/or tissues as a reactivation/secondary infection. In healthy individuals, primary and reactivation CMV infections are of little consequence; however, in patients with immunodeficiency, these infections can produce severe, even fatal, disseminated disease. Patients at risk of severe infections include children with congenital immunodeficiency disorders, patients with human immunodeficiency virus/acquired immunodeficiency syndrome (HIV/AIDS), recipients of organ allografts and/or stem cells, patients with cancer who are undergoing chemotherapy/radiotherapy, fetuses who receive intrauterine transfusions, and preterm neonates. During the latent or carrier stage of CMV infection, previously infected individuals are asymptomatic and fulfill all requirements to donate blood. However, in the bloodstream of individuals who have latent infection, CMV is associated almost exclusively with mononuclear leukocytes, and the transfusion of blood containing these leukocytes can infect the recipient with CMV. Although there has been debate about the subpopulation(s) of leukocytes carrying the virus, it has been consistently demonstrated that effective leukocyte reduction (i.e., that done in the blood center/bank with quality control to document satisfactory leukocyte removal, not filtration at the bedside) profoundly reduces—and, in some reports, actually eliminates—the risk of CMV transmission by transfusion. Despite the resounding success/efficacy of modern leukocyte reduction and the fact that this technology has never been found to be inferior to any other method of preventing transfusion-transmitted CMV (TTCMV), a potential problem does exist during the onset of primary infection: namely that, before antiCMV antibodies form, CMV virions are “free” and are present in plasma. Clearance of these plasma “free” CMV virions shortly follows the emergence of CMV antibodies, and the virus becomes partitioned within leukocytes, where it can be removed along with the carrier leukocytes by effective leukocyte reduction to prevent the transmission of CMV by transfusion. In contrast, leukocyte reduction cannot remove plasma “free” virions. Accordingly, leukocyte-reduced blood components that are collected from donors who are in the earliest stage of primary infection and are still both asymptomatic and CMV sero/antibody-negative (i.e., in the “window phase” of primary CMV infection) theoretically could transmit CMV—findings that initially gave rise to the unsettling possibility that neither leukocyte reduction nor the selection of CMV sero/antibody-negative donors could prevent occasional TTCMV infections. In this regard, it is important to note that later longitudinal studies of seroconverting donors in the early stages of primary CMV infections largely dispelled this concern by several interrelated findings. Those studies found that the number of plasma “free” CMV virions was very low at the time CMV infection began—when CMV antibody test results were still negative. As infection progressed, the number of CMV virions increased doi:10.1111/trf.13683