Emerging infectious agents and the nation's blood supply: responding to potential threats in the 21st century

In the early 1990s, the Department of Health and Human Services (DHHS) asked the Institute of Medicine (IOM) to assess how the government, the private sector, and other stakeholders had responded to the human immunodeficiency virus (HIV) epidemic and its impact on blood safety. In its executive summary published in TRANSFUSION,1 the IOM Committee to Study HIV Transmission Through Blood and Blood Products noted that although stakes were high, decisions had to be made under a cloud of uncertainty and that responses were slowed by imprecise and incomplete knowledge, personal and institutional biases, and ultimately by failures in leadership. Emphasizing that blood safety is a shared responsibility, the IOM Committee issued 14 recommendations related to structure and policy including the designation of a Blood Secretary Director by DHHS, the establishment of a Blood Safety Council by the US Public Health Service (PHS), and several recommendations to the Federal agencies involved in the evaluation of an infectious threat, in particular, the Food and Drug Administration (FDA). Since then, these recommendations have been implemented and the blood safety community (blood collectors, blood safety experts, and relevant Federal agencies) has responded to other emerging infectious disease (EID) threats, such as West Nile virus (WNV) and most recently the xenotropic murine leukemia virus–related virus (XMRV). Responding to any new threat entails assessing the risk to the blood supply and recipients' health; evaluating how best to manage and/or control each potential risk; and communicating this information to blood donors, recipients, physicians, and the general public. Although the FDA has the regulatory authority to develop guidance documents and new regulations in response to EID threats based on available data, the challenge of generating that data and responding to potential risks requires concerted and coordinated actions by the multiple PHS agencies (Centers for Disease Control and Prevention [CDC], FDA, National Institutes of Health [NIH]) and by the broader transfusion medicine community (AABB and blood providers). It is therefore incumbent upon the transfusion medicine professionals to collect and provide robust data in a timely manner to policymakers to inform their decision process, as well as take an active role in risk communication. All stakeholders must recognize what they can do and provide leadership and timely research and risk assessments. In so doing, they must take a hard look at their responses and learn lessons from history. Such a process does not involve a confirmation or criticism of what has been done in previous responses to potential threats to the blood supply, but an assessment of how responses can be improved for future threats. In the aftermath of the recent XMRV investigation and the inevitable occurrence of future infectious threats, the National Heart, Lung, and Blood Institute (NHLBI) convened an expert task force charged with evaluating how lessons from previous EID blood safety threat assessments could be used to optimize future response strategies. The task force was asked to review and discuss responses to past epidemics and recent EIDs and to consider: What worked? What could have worked better? What data are necessary to assess blood safety risk? Who needs to be engaged in the evaluation of risk; that is, who are the stakeholders? What methods and/or processes need to be in place and when? What resources, infrastructure, and capacity are needed? How best to train future experts? And how can a scientific culture be encouraged that encourages cooperation? In a first session, responses to earlier epidemics were examined, followed by a discussion on responses to recent agents of concern, including an in-depth look at the latest potential threat, XMRV. A general overview of other agents of potential concerns (the horizon) ensued followed by a general discussion on lessons learned and consideration of future strategies. This report summarizes the results of these discussions. Michael P. Busch, MD, PhD, Blood Systems Research Institute, University of California, San Francisco The possibility that AIDS could be transmitted through blood and blood products was first formally discussed in December 1982 in Morbidity and Mortality Weekly Report (MMWR),2 almost 6 months after the first reports of Pneumocystis carinii pneumonia in patients with hemophilia3 and almost 18 months after the first reports of P. carinii pneumonia in homosexual men.4 In January 1983 the CDC convened a workgroup to review existing information on transfusion- and factor concentrate–associated AIDS cases and to identify opportunities to prevent AIDS in blood recipients and persons with hemophilia. At that time persons with hemophilia accounted for only six of more than 800 reported AIDS cases, with five additional cases established as possibly transfusion related. A large lookback program had found that only 10 of 140 AIDS patients interviewed in San Francisco reported donating blood during previous years. In a statement issued later in January 1983, the CDC workgroup simply noted that “the possibility of blood borne transmission, still unproven, has been raised.” Furthermore, the cause of AIDS was still unknown in January 1983, but because existing data showed that the vast majority of homosexual men and intravenous (IV) drug users tested positive for surrogate markers such as antibodies against the hepatitis B virus (HBV; anti-HBc), the workgroup remarked that use of “non-specific markers” was under evaluation. No agency took responsibility for prevention of transfusion-transmitted AIDS. Although the workgroup considered several interventions to exclude risk groups from donating blood, there were concerns about adopting a confrontational approach toward potential higher-risk donors. Thus the 1983 statement noted that direct or indirect questions regarding donors' sexual preferences were inappropriate. Nonetheless, the blood bank in San Francisco developed a process whereby donors could discreetly exclude themselves by answering “yes” or “no” to a block of questions about known AIDS risk factors. By mid-1983 many blood collection organizations, particularly those in cities at high risk, had adopted a donor qualification process known as self-deferral by which presenting donors were provided with information about AIDS risk factors and where those with such risk factors were asked not to donate. There was also outreach to homosexual community organizations to discourage donation from at-risk men. In New York City, and later elsewhere, the “confidential unit exclusion” procedures were introduced that allowed individuals to give blood but then inform the blood bank of their nondisclosed risk behaviors so the blood units would be discarded or used for research. Blood banks in the San Francisco bay area also began to implement “surrogate” tests such as T-cell helper/suppressor ratios (Stanford University Blood Bank) or anti-HBc testing of blood donors (Irwin Memorial Blood Bank). Of note, flow cytometry equipment for performing T-cell ratios was not available outside of limited research labs and anti-HBc testing yielded many false positives, and no confirmatory tests were available. Moreover, there were concerns that positive surrogate tests would be concerning to donors, that homosexual men would donate blood simply to get the test, and that elimination of homosexual donors would negatively affect the blood supply. Once the homosexual community learned of the potential risks, many in the community stopped donating blood. By 1984, great concerns had arisen in the patient community, and there was a general fear of blood originating from San Francisco. Additionally, the performance characteristics of the anti-HBc test remained of concern. A larger study5 of transfusion-transmitted AIDS was published in January 1984, and by December 1984 the number of transfusion-related AIDS cases had risen to more than 100. HIV was discovered in the spring of 1984, with high rates of virus isolation and antibody detection in homosexual men, and several studies pointed to this virus as the causative agent of AIDS. Questioning of potential donors was not further optimized because blood banks expected that HIV tests would soon be available. Yet HIV antibody tests were not available until 1985. Lookback studies found that more than 30% of donors testing positive for HIV were also reactive for anti-HBc and that approximately 90% of recipients transfused with blood from HIV-infected or suspected cases acquired infection. An analysis of donation histories of HIV-infected donors in San Francisco, HIV infection prevalence among homosexual men in San Francisco, and HIV donation rates by subsequently identified infected donors estimated that the incidence of transfusion-transmitted HIV infection rose rapidly, from the first occurrence in 1978 to a peak in 1982 of approximately 1% per unit transfused and that more than 2000 recipients in San Francisco alone had been infected with HIV through transfusions.6 The analysis also showed that donor selection and education efforts had been effective in curbing the number of donations by infected individuals. Donations by individuals who later tested positive for HIV or developed clinical AIDS had declined by 75% by the time anti-HBc testing was implemented and by 90% by the time HIV-specific testing was available. It was hoped that the implementation of HIV antibody testing would eliminate transfusion-transmitted AIDS, but breakthrough cases were detected shortly after introduction of HIV testing, indicating that antibody screening had not eliminated the risk.7 These cases were related primarily to homosexual men who had initially tested negative for anti-HIV but later seroconverted after donating blood, which led to improvements in donor eligibility criteria including the exclusion of all males who had had sex with another male since 1977. A further study found an infectious window period of 56 days from infection to detectable antibody conversion by the first-generation screening assays.8 Later improvements in the sensitivity of antibody assays reduced this preseroconversion infectious window period to approximately 3 weeks, and the subsequent additions of p24 antigen and its replacement with nucleic acid testing (NAT) virtually eliminated this window, resulting in current risk estimates of approximately 1 infectious unit per 1.5 million transfused units. In fact, six transmissions have been reported in the United States since 1999, when NAT was implemented, during which time from 13 to 17 million whole blood (WB) donations per year were processed and distributed. Even more impressive, the implementation of viral inactivation steps, in addition to donor selection and HIV testing has eliminated transmission of HIV by plasma derivatives, with no cases reported in more than 20 years. The experience with transfusion-transmitted AIDS showed that infection with an agent having a long asymptomatic incubation period can spread in the blood supply for years before recognition, resulting in fatal infection of transfusion recipients. Blood bankers had been slow to recognize the magnitude of the problem and to implement additional safety procedures such as enhanced donor selection, surrogate testing, and plasma treatment measures that might have reduced HIV transmission. Even after HIV screening was implemented, it took several years to address the persistent risk of window-phase HIV infection. Yet these failures led to the transformation of the blood safety field into a highly regulated, science-based field that proactively addresses potential transfusion-related EIDs. Responses to HIV/AIDS were slowed because this virus was different from any that had been seen previously. Until the etiologic agent was identified and serology deployed, the epidemiology of HIV infection was unclear. The long latency from infection to symptoms and high disease risk in infected persons only became clear once serology was possible. Responding to the initial uncertainty surrounding HIV required a new paradigm of precaution that was foreign to the blood community who preferred to wait for more certain information before intervening aggressively and uniformly. Starting in March 1985, three HIV tests were (quickly) licensed. The ability to respond to future threats and move tests through the approval process may also take a long time, emphasizing the importance of having all stakeholders including manufacturers, the blood community, and the FDA involved as soon as possible. Roger Y. Dodd, PhD, American Red Cross Viral hepatitis has long been recognized as a major adverse outcome of transfusion and, indeed, in the 1960s and early 1970s, prospective studies suggested that 10% or more of blood recipients were affected. Hepatitis A and B had been differentiated on epidemiologic and clinical grounds before the discovery of hepatitis B surface antigen (HBsAg) in 1968. At that time, posttransfusion hepatitis (PTH) was thought to be entirely due to HBV. Insensitive tests for HBsAg were implemented as a blood safety measure, starting in 1970 to 1971 and had some very limited impact on PTH, although a much greater impact was attributed to careful donor selection methods and the avoidance of paid donations. Even the introduction of highly sensitive radioimmunoassays in 1973 further reduced the incidence of PTH only by 20%. The recognition of hepatitis A virus (HAV) and the development of diagnostic tests revealed that the vast majority of residual PTH was not due to HAV or HBV, and the term non-A, non B hepatitis (NANBH) was coined. Efforts to identify the causative agent started, but did not succeed until 1989. In the meantime, large, multicenter prospective studies of PTH were executed.9 These studies revealed epidemiologic relationships between surrogate markers (elevated alanine aminotransferase [ALT] levels and the presence of anti-HBc) in donors and PTH in recipients.10, 11 In 1982, the introduction of donor testing for surrogate markers was predicted to reduce NANBH transmission by 30% to 60%; such testing was not widely implemented until 1986. This delay was attributable to a number of factors including concern about loss of donors, uncertainty about the true severity of NANBH, and the need to manage the HIV/AIDS epidemic. The recognition and characterization of NANBH involved studies in several disciplines including epidemiology, pathology, and prospective clinical posttransfusion studies. New solutions were needed to overcome the unique challenges presented by NANBH. Because hepatitis viruses could not be grown in tissue culture, investigations relied on inoculation of nonhuman primates. In addition, unlike HBV, it had not proven possible to detect antibodies to any putative causative agent. Further, today's more rapid pathogen discovery techniques were not available and hepatitis C virus (HCV) was cloned through an incredibly painstaking manual process. As a result of arduous cloning experiments using plasma blindly passaged in chimpanzees infected with NANBH, with the belief that the agent was an enveloped togavirus, HCV was eventually identified in 1989 and specific tests for antibodies to HCV were developed.12, 13 It became clear that essentially all NANBH was due to transmission of HCV and routine testing for this antibody by first-generation assays was implemented in 1990, followed by implementation of antibody tests with increased sensitivity starting in 1992. NAT for HCV was additionally implemented in 1999 and, currently, it is estimated that the residual risk of transfusion-transmitted HCV in the United States is 1 per 1.5 million blood components.14 The experience with NANBH illustrates the power of persistence and teaches us some lessons about the benefits and risks of surrogate testing. Although these tests were useful in eliminating potentially infected donors, many donors were excluded even though they were not carriers of HCV. In addition, lessons from the NANBH and/or HCV story might not apply to the 21st century. For example, the virus associated with severe acute respiratory syndrome (SARS) was identified within 24 hours after samples were received. On the other hand, we should recognize that it is likely that the increased use of molecular genetics and genomic methods to identify viruses will lead to the discovery of many viruses without associated diseases. Examining emerging threats does not mean ignoring existing threats. The response to NANBH was prolonged, in part, because the scientific community was focused on HIV. The majority of discussions regarding NANBH and surrogate testing focused not on the need to protect patients but on the potential impact of donor deferral on blood availability. The AIDS epidemic caused a massive shift in focus to blood safety. In the current era of molecular virology, many viruses will be identified without associated diseases. A baseline estimate of viral sequences in humans has not yet been established, but the human microbiome is under active investigation. Two NIH grants are specifically addressing plasma viral discovery programs. Viruses such as HCV and HIV remain significant public health problems in the developing world, in the face of the constraints against implementation of the resource-intensive solutions used in the developed world. At the NIH blood bank, evaluation of ALT testing after it was implemented indicated that it did not appear to be effective in reducing NANBH cases, and a cost–benefit analysis was unable to define a precise financial estimate for the benefits of ALT testing. Surrogate testing for other agents remains controversial although strict interpretations of the precautionary principle would encourage use of such a testing approach. Louis M. Katz, MD, Mississippi Valley Regional Blood Center WNV, a mosquito-borne flavivirus, was first recognized in the United States in New York City in 1999 and spread across North America by 2002.15, 16 Absent documented transfusion transmission, the transfusion medicine community took a wait-and-see approach during the first four transmission seasons. Familiarity with models developed at CDC to estimate the risk associated with WNV-viremic donors (and the lessons from recent experiences with HIV and NANBH and/or HCV) facilitated a rapid response by the blood community, public health, regulators, and the medical device industry after transmission by transfusion (and organ transplantation) was documented during the 2002 summer epidemic.16, 17 A series of interventions were implemented to mitigate the WNV risk starting in the fall of 2002,18 including a nonspecific deferral for symptoms consistent with WNV fever, quarantine of plasma for transfusion collected during periods of high WNV and the development and implementation of WNV NAT in in of than 1 year after of the first transfusion-transmitted infection. 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