Safety of the Blood Supply in the United States: Opportunities and Controversies

The blood supply in the United States has never been safer, and the risk for infection with transfusion-transmitted viruses has never been lower. However, this success poses new dilemmas, and uncertainty remains about how safe the blood supply in the United States can or should be and how much of our limited resources should be spent on making it safer. Expansion of blood donor screening and improvements to laboratory markers have reduced the risk for HIV infection from as high as 1 in 100 units in some U.S. cities in the early 1980s [1] to approximately 1 in 680 000 units [2, 3] (Figure 1). Transfusion-related hepatitis has also almost been vanquished: Transmission rates for hepatitis C virus (HCV) has decreased from 1 in 200 units in the early 1980s to approximately 1 in 100 000 units today, and the risk for hepatitis B virus (HBV) infection has been reduced from 1 in 2100 units to 1 in 63 000 units [3, 5, 6]. Figure 1. Decrease in per-unit risk for transmission of hepatitis B virus (broken line), hepatitis C virus (dotted line), and HIV (solid line) by blood transfusion in the United States. Despite these improvements, a zero-risk blood supply remains a popular goal. However, being on the flat part of the transfusion safety curve poses new problems. Do future improvements have unanticipated side effects that could offset their benefits? Can we improve transfusion safety while responding to demands to control health care costs? We considered ongoing efforts to improve transfusion safety and some of their potential consequences. Established and Developmental Blood Safety Initiatives Selection of Lower-Risk Donors More attention to behavioral, medical, and demographic factors in donor selection improved transfusion safety even before specific laboratory screening tests were available [7, 8]. For example, increasingly specific questioning of donors about HIV risk led to a substantial decrease in transmission by transfusion before HIV antibody testing became available [1], and the rate of HIV seropositivity and seroconversion among volunteer blood donors today is 1% of the rate in the general U.S. population [3]. Detection of Blood-Borne Pathogens Because not all infectious exposures are recognized or acknowledged, laboratory testing remains important and is becoming increasingly sensitive. Although surrogate markers for some infections (such as non-A, non-B hepatitis and AIDS) with limited efficacy were implemented or proposed in the mid-1980s, quantum reductions in transfusion-related risk accompanied implementation of virus-specific antibody tests for HIV (1985) and HCV (1990). Virus-specific antigen assays promise further improvements. For example, an assay for HIV p24 antigen, approved by the U.S. Food and Drug Administration in 1996, is projected to reduce HIV transmission by an additional 25% [9]. New tests based on polymerase chain reaction techniques are currently being developed and may reduce the infectious window even further [10]. Inactivation of Blood-Borne Pathogens Because donor history and testing cannot eliminate all risk for transfusion-related infectious disease, viral inactivation techniques continue to be attractive. Solvent-detergent inactivation of lipid-enveloped viruses (including HIV, HBV, and HCV), which was developed to treat coagulation factor derivatives, has been adapted for liquid plasma and is used in Europe [11, 12]. Adding methylene blue to plasma is another successful viral inactivation technique used in Germany and Switzerland [13]. Techniques for cellular components remain in development as researchers seek ways to inactivate contaminating microbes while leaving intact the metabolic processes of blood cells. Minimizing the Need for Allogeneic Transfusion Avoiding allogeneic exposure is key to reducing transfusion risk. More conservative transfusion practices have developed in recognition of the fact that transfusion decisions must be tailored to an individual patient's clinical condition and not determined solely by laboratory data [14]. Autologous transfusions have also become more widely practiced. Preoperative autologous donation now accounts for approximately 5% of all red blood cell units transfused in the United States [15], and instruments for intraoperative red blood cell recovery are used more frequently. Potential Side Effects of Blood Safety Measures As the risk for transfusion-related infection approaches zero, the risks of blood safety measures themselves, once dismissed as trivial, become more important. The negative consequences of some measures may even outweigh the benefits. Donor Selection About 5% of prospective donors are turned down because of their answers to questions about medical history, demographic factors, or risk-related behaviors in the remote past. This loss is problematic given the marginal adequacy of the blood supply and the psychological effect of the deferrals on these (usually healthy) persons. Furthermore, characteristics that are associated with reduced risk for one infectious agent may be associated with increased risk for another. Concerns about the theoretical risk for transfusion-related transmission of the agent that causes Creutzfeldt-Jakob disease are illustrative. Because Creutzfeldt-Jakob disease usually presents in older persons, several blood collectors have proposed turning down older donors or diverting plasma from persons older than 50 years of age from derivative manufacture. However, older donors are the safest group with respect to recent infection with a blood-borne virus. Exclusion of older donors is projected to cause increases of 10% to 20% in the risk for infection with HIV, HCV, and HBV and to remove 20% of donated units from available inventories [16]. Thus, turning down older donors out of concern for a theoretical, unproven risk could adversely affect blood safety and availability. Testing More sensitive methods for viral detection also pose potential and real risks. Availability of more accurate blood tests for infections (especially HIV infection) may lead some high-risk persons to donate just to obtain this testing in a free, socially acceptable setting. This magnet effect could increase the frequency of infectious disease in blood donors [17]. Because residual risks in tested allogeneic units are a function of the incidence and prevalence of disease in donors and the accuracy of screening tests, the magnet effect of new tests for infectious disease could paradoxically result in a blood supply that is less safe. Furthermore, even small problems with the specificity of new donor-screening tests, particularly tests with very low yields and therefore low positive predictive values, can result in substantial losses of safe, repeat donors who will be replaced by relatively less safe first-time donors. Finally, consideration must be given to the multiple implications of the presence of an infectious disease marker. For example, the presence of viral antibody may indicate previous exposure and thus risk for infection, but it may also indicate the presence of neutralizing antibody. Testing donated blood for antibody to HCV dramatically reduced transmission of HCV by transfusion, but removal of plasma containing this antibody from pools used for the production of gammaglobulin products led to transmission of HCV to recipients of intravenous gammaglobulin for the first time [18, 19]. Viral Inactivation Viral inactivation methods also carry potential risks. For example, the solvent-detergent process does not inactivate nonenveloped viruses, such as hepatitis A and parvovirus B19 [20, 21]. The clinical importance of nonenveloped viruses in blood donors is currently unknown. However, the risk for transmitting these types of viruses is amplified substantially by the solvent-detergent process, in which thousands of plasma units are pooled. According to one analysis, a nonenveloped virus that causes an AIDS-like syndrome would have to be present in the population only at an undetectably low level (1 in 71 000 000 donors) before all of the benefits of avoiding lipid-enveloped viruses were entirely negated [22]. Reductions in the projected pool size have been proposed but are unlikely to substantially increase safety [23]. Furthermore, any chemical inactivation method must be scrutinized for the toxic potential of residual decontaminants that may exceed the risk associated with viruses that are being inactivated. Transfusion Alternatives Blood donation by a healthy person is considered innocuous, but is this true for a patient whose coronary artery disease is so severe that bypass surgery has been planned? By using higher risks for infection than those currently present in allogeneic transfusion, one model [24] concluded that the risk for death from a donation reaction of only 1 in 101 000 for a patient awaiting bypass surgery negated all of the benefits of having autologous blood available. No study to date has been large enough to fully document the risks of preoperative autologous donation, but the risk for a reaction is so serious that hospitalization is required is 1 in 17 000 [25]. Using allogeneic blood may be the least risky approach for some patients. Even the drive to alter transfusion thresholds has come under scrutiny because of concern that failure to give a transfusion when indicated may result in morbidity or mortality [26]. Cost-Effectiveness of Safety Initiatives Improvements in safety generally add new costs to the blood supply system. Because transfusion medicine faces the same economic pressures felt in other areas of medicine, interest in applying cost-effectiveness analysis to decisions about blood safety has increased. Cost-effectiveness analysis can be used as part of an effort to optimize the health benefit to a population by comparing the net costs of an intervention with its net benefits. By defining the aggregate or average health benefits achieved from competing interventions in terms of common