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The expected generally occurs. Thus, the low transfusion risks reported in this issue of TRANSFUSION by Pillonel and colleagues1 in France for human immunodeficiency virus (HIV; 1 in 3.35 million) and by Hourfar and colleagues2 in Germany for HIV-1 (1 in 4.30 million), hepatitis C virus (HCV; 1 in 10.88 million), and hepatitis B virus (HBV; 1 in 0.36 million) should not come as a surprise. In the resource-rich countries of the world, the introduction of stringent donor deferral criteria combined with the implementation of more sensitive screening assays such as nucleic acid amplification testing (NAT) has rendered the probability of an HIV-1 or hepatitis infectious blood donation being released into the blood supply very small, so small that risks need to be estimated using mathematical models. Our statistical arsenal to model transfusion-transmitted risks has expanded in the past decade. While still based on the incidence window-period model originally developed by investigators in the National Heart, Lung, and Blood Institute (NHLBI) Retrovirus Epidemiology Donor Study (REDS),3, 4 Centers for Disease Control and Prevention (CDC), and the American National Red Cross (ARC),5 novel strategies for estimating incidence have recently been developed by Busch and coworkers6 in the United States and are now being implemented in the international setting by large national blood programs, as elegantly illustrated by the work of Pillonel and colleagues1 and Houfar and colleagues.2 (It is worth noting that all approaches are based on accurate estimates of the duration of the window periods.2, 4, 6) Incidence can be modeled using either the classic method, which evaluates the number of incident infections among repeat donors and makes an adjustment for the usually higher first-time donor risks, or the “new strategy” cross-sectional method.6 The latter allows for derivation of incidence from the prevalence of NAT only–positive donations or from the prevalence of early infected donations based on novel HIV-1 assays, which can reasonably differentiate between recently and remotely acquired infections such as the S/LS-EIA assay6, 7 or the EIA-RI immunoassay developed by the French National Reference Center for HIV.1 Kourfar and colleagues2 observed a NAT-only prevalence of 1 in 1.4 million for HCV, 1 in 4.5 million for HIV-1, and 1 in 0.7 million for HBV among 31.5 million blood donations collected in Germany between 1997 and 2005 that were screened by minipool NAT. These findings underscore the need for NAT screening data from a large number of donations to perform these calculations accurately in countries with low HIV-1 incidence. In France, incidence estimates based on HIV-1 EIA-RI results decreased between 1992 through 1994 and 2004 through 2006.1 This report demonstrates the usefulness of being able to differentiate incident from prevalent infections using these new assays because this approach does not necessitate the compilation of large donation databases or the accurate ascertainment of first-time versus repeat donor status, which in many developing countries is not possible. Thus, further development and/or refinement of such assays should be encouraged and extended to other viral agents such as HCV.8 These assays will permit the determination of incidence and residual risks and, thus, ascertainment of blood safety in developing countries where NAT is usually not available. More importantly, research aimed at identifying donors who recently became infected, such as is currently being conducted for HIV-1 by the REDS-II Domestic and International Programs, allows for evaluation of risk factors and characterization of the evolving epidemiology of the infection in blood donors, which is often reflective of population trends.9-13 Thus, understanding behavioral risk factors among recently infected donors may allow not only implementation of appropriate deferral criteria and testing strategies to improve blood safety but may have also broader public health implications for the country as a whole. The ability to study the temporal evolution of genotypes and their global distribution is also key to safeguarding the blood supply in the United States and abroad because such a surveillance program permits proactive identification of subtype and drug resistance patterns. This type of evaluation was conducted by Pillonel and colleagues1 who found an association between HIV-1 non-B subtypes and recent infection, an observation that will warrant further investigation. An active molecular surveillance effort is also underway in the United States through the REDS-II program where biospecimens from HIV-1, HCV, and HBV incident and prevalent donations from the ARC, United Blood Services, New York Blood Center, and non-ARC REDS-II centers (representing about 70% of the US blood supply) have undergone genotyping and drug resistance characterization since 2006.9 This program is also being conducted in parallel at the REDS-II International sites in Brazil and China. As we go forward, it will be important to establish temporal trends and compare incident and prevalent genotypic distributions. It is also critical that we attempt to expand our surveillance efforts to additional developing countries struggling with the HIV epidemic. It is envisioned that support of research efforts in these settings will result in the development of “centers of excellence” with the necessary infrastructure, capacity, and expertise to assure the continued evaluation of issues facing their country's/region's blood supply(-ies), even beyond the life of the original research program. It would be premature and counterproductive to terminate support until such programs are well established and self-sustaining. While support of international research programs is key to NHLBI's efforts to promote global blood safety and availability, we also need to enhance the safety of transfusions in the United States. The success of the past three decades in controlling the transfusion transmission risks of HIV-1 and hepatitis viruses and, more recently, West Nile virus, should not lull us to a false sense of security. Rather, we should use the lessons learned from the past to proactively address the challenges of the future. New emerging infectious agents will periodically threaten our blood supply. Although not demonstrated to be risks to the US blood supply, recent outbreaks of Dengue fever virus and the emerging Chikungunya virus threat are a cause for concern. To meet these challenges effectively, we need to have a research program infrastructure in place that allows us to evaluate a new agent quickly for its transfusion transmission potential and clinical relevance to the blood recipient population. The ability to conduct these investigations rapidly, combined with studies that assess potential risk reduction strategies (such as the introduction of a new screening assay or pathogen inactivation method), their impact on blood availability, and their cost-effectiveness, are absolutely essential in the United States and other developed countries. Additional strategies are also needed, however. Decisions to implement a new method must not only be based on this scientific input but must also include plans on how the effectiveness of the new strategy will be evaluated after implementation and the criteria that will determine whether such a strategy should be continued, modified, or discontinued. These criteria, which include stopping rules and time boundaries similar to those established in well-designed clinical trials, should be developed and approved by policy-making organizations before the implementation of a new strategy and monitored appropriately. This proactive approach minimizes the need to take action in the heat of the moment when subjective rather than objective evidence may influence decision making. Such an approach could clearly have benefited decisions surrounding the current 7-day versus 5-day platelet (PLT) storage controversy or inform the upcoming debate on the continued value of antibody screening for Chagas disease. Hopefully, a priori criteria and adequate surveillance for efficacy will be established before the introduction of strategies such as HLA antibody testing of alloexposed donors which are aimed at reducing the incidence of transfusion-related acute lung injury in PLT recipients. It is also time to seriously consider the implementation of new strategies that provide the “biggest bang for the buck,” that is, that maximize blood safety by reducing or eliminating major—rather than minor—risks or that simultaneously address multiple transfusion-associated risks, while minimizing impact on blood availability and costs. This action plan is in sharp contrast to the reactive, “piecemeal” approach to infectious disease risks that usually has been followed in the United States, with the addition of each new deferral criterion or screening test strategy in response to the concern du jour. This anachronistic approach will be difficult to maintain as new emerging agents are identified, considering the consequent additive (if not multiplicative) detrimental impact on cost and blood availability. Conversely, the introduction of safe pathogen inactivation/reduction techniques should virtually eliminate transfusion risks from new or emerging infections, address bacterial contamination risks that still exist even after implementation of apheresis PLT bacterial screening in 2004,14 and probably reduce transfusion-related immunomodulation, although this effect remains to be evaluated. Pathogen reduction methods are currently being applied successfully to plasma and PLT preparations in Europe. Additional research needs to be conducted to further the development of these methods for all blood components, assess their safety and efficacy vis-à-vis infectious disease and immune complication risks in clinical trials, and ensure active postmarketing surveillance for effectiveness and identification of adverse effects that may not have been observed in prelicensure clinical trials. This assessment brings us to a major area of concern. How can we evaluate such effects, whether positive or negative, when we do not clearly understand blood product utilization patterns and the effects of allogeneic transfusion in blood recipients? While our research efforts over the past three decades have justifiably been focused on reducing infectious disease risks, and while there is a need to retain the ability to rapidly evaluate new infectious disease threats, it is time to turn our attention to the noninfectious complications of blood transfusion. As clearly enunciated in their report in this issue of TRANSFUSION,15 a group of transfusion medicine experts convened by NHLBI in October of 2007 identified a critical need for the following investigations: 1) studies that characterize blood transfusion practices in various clinical settings (e.g., trauma, intensive care units) and in specific patient populations (e.g., racial/ethnic minorities, the young, the elderly) and their associated outcomes and costs; 2) studies that evaluate the benefits and risks (infectious and noninfectious) of allogeneic blood transfusion; 3) evaluations of the potential clinical benefit(s) of introducing a modified product or treatment strategy; and 4) characterization of the risks, benefits, and clinical outcomes of prophylactic versus therapeutic transfusion strategies, as well as alternatives to allogeneic transfusions. The need to further evaluate current practices and transfusion-associated clinical outcomes comes from recent observations that suggest that a liberal transfusion strategy may harm, rather than help, patients in the critical care setting who develop anemia,16, 17 and from studies that have reported an association between transfusions and increased morbidity such as postoperative infections.18 Other reports have also suggested that the “storage age” of the blood product may impact its therapeutic benefit, with transfusion of blood that has been stored for longer periods of time potentially less effective (and perhaps even detrimental) in terms of critical tissue oxygenation than transfusion of “younger” blood.19, 20“Older” blood may also induce more transfusion-related immunomodulatory effects, although this concern has not been well studied. All but a few reports linking transfusion to adverse outcomes, however, are difficult to interpret due to potential confounding by severity of illness. To improve transfusion guidelines and enhance personalized transfusion therapies, it is important to focus future research efforts on understanding the immunologic, inflammatory, and vasoactive properties of transfusions; how best to prepare and store blood products; and how to optimize and target transfusions and alternative therapeutics based on empirically defined characteristics of patients who will truly benefit. This research is critical to public health in the United States, since transfusion therapy is the most commonly employed21 and, arguably, one of the least understood medical procedures in the United States affecting approximately 5 million recipients annually.
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