Use of Blood‐Donor and Transfusion‐Recipient Biospecimen Repositories to Address Emerging Blood‐Safety Concerns and Advance Infectious Disease Research: The National Heart, Lung, and Blood Institute Biologic Specimen Repository

In this issue of the Journal a seminal article by Cannon et al. [1] addresses the long-standing debate over the transmissibility of human herpesvirus (HHV)–8, the etiological agent of Kaposi sarcoma (KS), via blood transfusion. Although concern over transmission via transfusion was raised shortly after the discovery of HHV-8 nearly 2 decades ago, this issue has been difficult to resolve because of problems with the sensitivity, reliability, and throughput capacity of HHV-8 screening assays, particularly for healthy donors with latent infections, in whom antibody titers are low and viremia is generally undetectable [2]. Identifying appropriate populations in which to conduct large-scale linked donor-recipient transmission studies has also been a challenge The issue of HHV-8 in the blood supply is important, because it guides decisions as to whether donor screening is warranted and because it may affect the heated debate over relaxing (to either 1 or 5 years) the current “since 1977” donor deferral of men who have sex with men (MSM) [3, 4]. For all practical purposes, this deferral policy is now tantamount to permanently deferring men who have had sex with men once in their lifetime. MSM are known to have relatively high rates of HHV-8 infection, and, if HHV-8 is transmitted via transfusion and the prevalence of HHV-8 (or other potential transfusion-transmissible agents for which screening is not currently performed) among prospective donors with remote MSM exposure is high, then relaxing the current MSM deferral criterion could facilitate transmission of those infections to transfusion recipients, many of whom are immunocompromised and, hence, at risk for serious sequelae. Criticism over retention of the current policy has been intense, with many colleges and even cities canceling blood drives because of what they consider to be a discriminatory policy. The putative transmissibility of HHV-8 has been a major question in need of resolution before the US Food and Drug Administration (FDA) gives serious consideration to relaxing this deferral criterion Several elements in the study by Cannon et al. warrant emphasis. The investigators used a sensitive and extensively validated HHV-8 antibody assay as well as a rigorous testing algorithm. The study evaluated coded specimens from surgical patients who did not receive transfusions and from patients with KS, which were tested in parallel with linked donor-recipient specimens. Those demonstrating possible seroconversion, on the basis of initial testing of preenrollment and 6-month postenrollment specimens, were subjected to further investigation by testing multiple serial samples per individual to exclude specimen-labeling errors, persistent low-level seroreactivity, and very late seroconversions that likely resulted from community-acquired, rather than transfusion-transmitted, HHV-8 infections The study was based on donor and recipient specimens collected >30 years ago by the National Heart, Lung, and Blood Institute (NHLBI) Transfusion-Transmitted Viruses Study (TTVS). The TTVS was established in the late 1970s to investigate the cause of and approaches to the prevention of what was then termed “non-A, non-B hepatitis” (later established as infection with hepatitis C virus [HCV]). By focusing on the archived specimens in the TTVS repository, Cannon et al. were able to establish the prevalence of HHV-8 antibodies among donors and among patients who had and had not received transfusions in the late 1970s and compare the estimates with those observed among contemporary donors and recipients. HHV-8 seroprevalence was similar among TTVS donors (2.8%) and current donors (∼3.5%), indicating that HHV-8 has probably been endemic in the US donor population for decades [2]. This is reassuring with respect to blood safety, given the absence of any documented associations between KS and receipt of blood products or plasma derivatives over this prolonged period HHV-8 antibody prevalence 6 months after surgery was similar among the 1350 TTVS transfusion recipients (7.1%) and the 599 surgical control patients who did not receive transfusions (7.7%), as were the seroconversion rates in these groups (1.6 and 3.6 per 1000 person-years, respectively). Most importantly, transfusion of HHV-8–seropositive units into 128 susceptible recipients did not result in a single case of HHV-8 infection. The TTVS repository presented a unique opportunity to investigate HHV-8 transmission in a worst-case setting. In the late 1970s—in sharp contrast to today’s blood-banking and transfusion practices—transfusion of fresh whole blood or of red blood cell components that had been stored short term was common, and leukoreduction was not yet implemented. Thus, infectious HHV-8, a leukocyte-associated herpesvirus that is highly susceptible to inactivation by cold storage, would have been much more likely to be present in blood components transfused to TTVS recipients than in components currently transfused. Additional studies may still be warranted to exclude an exceedingly low risk of HHV-8 transmission in the United States, given that transmission via transfusion has been documented at 3% per seropositive unit in Uganda, where HHV-8 is hyperendemic and fresh nonleukoreduced blood is routinely transfused [5]. However, Cannon et al.’s study should alleviate concerns over the need to screen donors for HHV-8 and to maintain MSM deferral to prevent transmission of the virus Our ability to respond to new and emerging infectious threats to blood safety has improved dramatically since HCV and human immunodeficiency virus (HIV) spread in the blood supply in the late 1970s and 1980s. We now have standing committees within both the blood industry (the American Association of Blood Banks Transfusion-Transmitted Diseases Committee) and the government (the FDA Blood Products Advisory Committee and the Health and Human Services Advisory Committee on Blood Safety and Availability) that scrutinize potential new infectious threats. When warranted, these groups aggressively respond by recommending (1) enhancements to donor selection and screening practices (e.g., deferral of donors at potential risk for variant Creutzfeldt-Jakob disease and severe acute respiratory disease); (2) improvements in blood-component processing (e.g., leukoreduction to reduce transmission of cell-associated viruses and immunologic responses in recipients and the use of “diversion pouches” that direct the initial 30 mL of collected blood, which contains skin bacteria, to testing, a practice that results in a 50% reduction in septic transfusion reactions); and (3) implementation of new screening tests (recent examples include implementation of sensitive and specific tests for West Nile virus RNA in 2003 and Trypanasoma cruzi antibodies in 2007) There also has been a marked expansion in our efforts to discover new viruses that may present transfusion risks. After discovery, systematic research is pursued to establish seroprevalence and rates of viremia in the donor pool, the transmissibility via blood components and plasma derivatives, and the disease penetrance in recipient populations. The capacity to implement new screening tests for new infectious agents has increased with the development of multiplexed assays for pathogen nucleic acids, antigens, and antibodies and of automated platforms for high-throughput serologic and nucleic acid amplification technology (NAT) screening. Emerging agents for which donor screening is currently under consideration include dengue and chikungunya viruses, parvovirus B19 and new human parvoviruses, and the agents that cause babesiosis and malaria This research and the resulting advances in blood safety have depended on sustained federal support. Since the 1970s, the NHLBI has supported systematic studies to establish etiologies and develop interventions to prevent infectious and noninfectious complications of transfusion. NHLBI supported the development and evaluation of NAT screening and of promising new methods for the inactivation of infectious agents and leukocytes in blood components. NHLBI-funded investigators have also developed novel approaches to assess the need for and impact of blood-safety interventions, either through direct measurement of risks or reduction in risks or through the development and application of models to estimate the safety gains achieved by expanded donor deferrals or enhanced testing One of the tools used in these National Institutes of Health–funded blood-safety programs has been the development and use of large-scale donor and recipient biospecimen repositories (table 1) [6, 7]. These collections, which now include >3 million cryopreserved serum, plasma, or whole-blood aliquots, were initially developed to investigate specific infectious risks that were of concern at the time the studies were launched. Each study collection was established over a specific time frame, generally ranging from several months to 5 years. The oldest collection (the TTVS repository) contains samples from the mid to the late 1970s, whereas the newest collections contain samples from early in this decade. The NHLBI Biologic Specimen Repository, which houses these collections, is a program that adheres to the institute’s desire to strongly endorse data sharing and facilitate access to resources for scientific research. The repository provides interested investigators with access to cryopreserved specimens and corresponding donor-recipient demographic and infectious disease testing data. As clearly illustrated in the article by Cannon et al., the NHLBI Biologic Specimen Repository has enabled future research to address blood-safety concerns that subsequently surfaced, particularly related to emerging infectious agents. The repository has also allowed for investigations into the viral and immune dynamics of acute infection and the natural history and pathogenesis of infections with bloodborne viruses, such as HIV and HCV [8, 9]. These repositories are available to qualified investigators who submit requests and protocols to the NHLBI. Additional details regarding these repositories as well as detailed citations documenting the breadth of research that has resulted from them can be found in several recent reviews [6–9] and at the NHLBI Biologic Specimen Repository’s Web site (http://www.nhlbi.nih.gov/resources/medres/reposit/reposit.htm) Donor, recipient, and linked donor-recipient repositories in the United States