Transfusion Associated Infections

5 0 TH A N N I V E R S A R Y
Transfusion-associated infections: 50 years of relentless challenges and remarkable progress

_2851 2080..2099
Herbert A. Perkins and Michael P Busch .
he possibility of transfusion-transmitted infections has been a worry from the beginning of the modern era of blood banks. Beginning with the evidence that syphilis could be transmitted by blood transfusion and followed by increasing concerns about hepatitis, alarm peaked in the 1980s with the recognition of transfusion-associated AIDS and appreciation of the magnitude of transfusion transmission of hepatitis C virus (HCV). In more recent years the story has been one of remarkable successes in reducing transmission of known viral agents and rapid responses to emerging infectious diseases that are documented to be transmitted by blood transfusion. This review will address the response of the blood banking community to the major transfusion-transmitted infectious diseases (TTIDs) over the past 50 years, during which time the evolving appreciation of risk and progress in addressing TTIDs has been documented by more than 1000 publications in TRANSFUSION. Figure 1, which presents the annual number of publications in the journal focused on TTIDs relative to total publications, serves to demonstrate the increasing importance of TTIDs to the transfusion medicine community. It is evident that papers
on TTIDs grew from a handful of papers per year that represented a minor proportion of the journals publications to more than 50 papers per year representing 25% of articles appearing in TRANSFUSION in the 1980s and 1990s. The papers represented in the gure chronicle the remarkable contributions of several generations of scientists who not only aggressively addressed blood safety concerns but also advanced our understanding of methods of detection, natural history, and pathogenesis of TTIDs through studies of infected donors and recipients.
SYPHILIS
The evidence that syphilis can be transmitted by blood transfusion is unequivocal, with 138 cases published before 1941.1 Blood donors were tested for syphilis long before blood banks became common.2 In the early years of blood banking serologic tests for syphilis employed the nonspecic assay for antibodies to cardiolipin, usually using the VDRL or RPR versions of the original Wasserman test. In recent years automated assays have been developed that test for specic treponemal antibody, and almost all blood banks use that approach. In the initial switch from cardiolipin tests to tests with treponemal antibody, the rate of positive screening tests rose sharply,
ABBREVIATIONS: BSE = bovine spongiform encephalopathy; IFA = indirect immunouorescence assay; IND = investigational new drug; NANB = non-A, non-B; PRT(s) = pathogen reduction technology(-ies); PTH = posttransfusion hepatitis; PTLV(s) = primate T-lymphotropic virus(-es); TTID(s) = transfusiontransmitted infectious disease(s); TTV = transfusion-transmitted virus; vCJD = variant Creutzfeldt-Jacob disease; WNV = West Nile virus. From the Blood Systems Research Institute, Blood Centers of the Pacic, and University of California, San Francisco, California. Address reprint requests to: Michael P Busch, MD, PhD, . Blood Systems Research Institute, 270 Masonic Avenue, San Francisco, CA 94118; e-mail: MBusch@bloodsystems.org. Received for publication July 12, 2010; accepted July 12, 2010. doi: 10.1111/j.1537-2995.2010.02851.x TRANSFUSION 2010;50:2080-2099. 2080 TRANSFUSION Volume 50, October 2010
350 300 250 200 150 100 50 0 1960 1970 1980 1990 2000
Fig. 1. Number of publications in TRANSFUSION, by year, focused on TTIDs (solid bars) relative to total publications (open bars), demonstrating the increasing importance of TTIDs to the transfusion medicine community.
TRANSFUSION-ASSOCIATED INFECTIONS
reecting detection of low levels of treponemal antibodies in donors who had been infected decades earlier and had eradicated the infections. Reagin tests tend to become negative when a patient is treated successfully or spontaneously clears infection, while the treponemal tests are likely to remain positive for life even though the individual is no longer infectious.3 Despite more than 60 years of experience there is considerable disagreement as to whether testing blood donors for syphilis serves any useful purpose. Reports of transfusion-transmitted syphilis disappeared after blood storage at refrigerated temperatures became routine. In the past 50 years only one case has been reported from the United States.4 The reasons usually given for this marked reduction in incidence include the testing of donors for syphilis, the loss of viability of the syphilis spirochete in refrigerated blood and possibly also in the high oxygen content of platelet (PLT) concentrates, the common use of antibiotics among recipients, and failure to recognize the disease in recipients.5 AABB Standards no longer require syphilis testing of blood donors, but Food and Drug Administration (FDA) regulations still mandate them. Recent analyses by the American Red Cross indicate little if any value to syphilis screening as a surrogate for other infectious diseases in donors, which has been a major argument espoused by the FDA for retaining the screening test.6 Nonetheless testing is still required by the FDA as well as recommended by the World Health Organization as a required test for blood donations throughout the world.5,7
would get it anyway and with deliberate exposure he could monitor them closely and take good care of them. His studies conrmed unequivocally that there were at least two types of hepatitis, differing in incubation period, in laboratory ndings, and in failure to crossprotect against each other. Infectious hepatitis transmitted by the fecal-oral route became known as hepatitis A; serum hepatitis transmitted by injection was called hepatitis B. In terms of progress it is worth noting that neither Murrays nor Krugmans studies would meet current ethical standards.
Hepatitis A virus
Hepatitis A causes an acute infection that resolves without producing a chronic carrier state, so it is rarely a transfusion problem and blood banks do not test for its presence. They rely on the medical history to eliminate donors with a history of hepatitis. Nonetheless, transmissions of hepatitis A from donors in an asymptomatic viremic state have occurred. 10 Moreover, the hepatitis A virus does not have a lipid envelope and is not destroyed by some of the earlier processes used by plasma derivative manufacturers to inactivate viruses. There were some small epidemics among persons with hemophilia before viral inactivation processes performed during the manufacture of plasma derivatives were intensied.
Hepatitis B virus
Hepatitis B11 is highly contagious by parenteral injection (blood transfusion and injection drug abuse), by sexual contact especially among gay men, and by transmission from mother to child (the last especially common among Asians). Five percent of acutely infected adults become chronic carriers, but the rates of chronicity are much higher for immunosuppressed individuals and for newborns who acquire infection prenatally where up to 95% may become chronic carriers. Identication of the hepatitis B virus (HBV) began with the studies of Baruch Blumberg and colleagues,12 who were using gel diffusion techniques to identify plasma protein alloantigens. He discovered a unique antigen in the plasma of an Australian aborigine and labeled it the Australia antigen. It was several years before he realized that he was recognizing the protein coat of a hepatitis virus. The relation to hepatitis B was independently conrmed by Alfred Prince at the New York Blood Center.13 HBV has the unique propensity to produce a large excess of empty protein coats sufcient to form a visible precipitate when exposed to the appropriate antibody. The antigen detected on the protein coat is the hepatitis B surface antigen (HBsAg), which became the basis of the rst blood bank test for hepatitis.
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HEPATITIS
Although hepatitis has been recognized since Hippocrates, it was not until World War II that epidemics prompted intensive studies in this country. By that era it was clear that there were two forms of the disease: infectious hepatitis transmitted by contaminated food or water and serum hepatitis transmitted by injection.8 In the 1950s, Roderick Murray, Director of the National Institutes of Health Bureau of Biologic Standards (the regulator of blood banks before the FDA), performed studies with prison volunteers who were transfused with varying amounts of plasma from patients who had hepatitis. These studies used a lter to prove that a virus(s) was responsible. Samples from the research subjects were saved for decades and proved valuable in later studies evaluating the infectious doses of hepatitis viruses. In the 1960s, studies by Saul Krugman and colleagues at Willowbrook9 provided additional valuable information. Willowbrook was a state institution for children with a high incidence of hepatitis. Krugman deliberately exposed children to hepatitis, reasoning that they
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The original research studies idenAll volunteer donors 40 tied HBsAg by simple gel diffusion, a HBsAg technique too insensitive and slow for 30 routine blood bank use. Secondgeneration tests used counterelectrophoresis to speed and intensify 20 HCV Donor Screening for HIV Risk Factors precipitate formation. In 1972 the FDA rd Anti-HIV gen HBsAg 3 mandated use of this test on blood ALT/Anti-HBc donated for transfusion. The third10 Anti-HCV HCV RNA generation tests used a solid-phase HBV radioimmunoassay, ultimately replaced 0 by enzyme-labeled immunoassays and subsequently chemiluminescent signal 1964 1968 1972 1976 1980 1984 1988 1992 1996 2000 2010 amplication techniques now currently Year in use. Additional protection was provided in 1986 when the test for antibody Fig. 2. Declining incidence of transfusion-associated hepatitis in transfusion recipito the hepatitis B core antigen (anti- ents monitored prospectively at the NIH Clinical Center. Incidence of hepatitis, HBc) came into general use. traced from 1969 to 1998, demonstrated a decrease in risk from 33% to nearly zero. Nucleic acid testing (NAT) for HBV Arrows indicate main interventions in donor selection and screening that effected DNA was not employed in the United this change. Reproduced from Alter, with permission from the American Society of States until very recently. The delay, Hematology.154 relative to earlier implementation of HBV NAT in Europe and Asia, was because anti-HBc screening of US donors detects donors and HBV DNA is estimated at approximately 1 in 500,000 with longstanding low-level HBV infections (so-called per unit exposure.18 occult B infections), and the levels of viremia in the early ramp-up phases of HBV infection before HBsAg detecNon-A, non-B hepatitis and HCV tion are very low with little gain in sensitivity from minipool NAT based on studies of plasma donor panels Of the cases of PTH still occurring in the 1970s, only 10% and incidence-window period models.14-17 Moreover, the were caused by HBV. It was initially assumed that the remaining cases were caused by hepatitis A virus (HAV), widespread implementation of HBV vaccination was but Feinstone and coworkers22 found no evidence for antiexpected to dramatically reduce HBV incidence further diminishing the value of adding HBV NAT to HBsAg and body to HAV and concluded that one or more additional anti-HBc testing.18,19 However, recent FDA licensure of agents must be responsible. This observation led Dr Harvey Alter to designate a third type of hepatitis, which multiplexed NAT assays that include HBV DNA amplihe termed non-A, non-B (NANB) hepatitis. cation in addition to HIV and HCV RNA detection has led The diagnosis of NANB hepatitis was one of excluto general adoption of HBV DNA NAT in the United sion, primarily based on negative serologic markers of States. One surprising observation after implantation by HBV in transfusion recipients who developed elevated the American Red Cross was detection of HBV vaccine liver enzymes. In the 1970s two very important studies breakthrough infections; the rates of such breakthough began to shed light on NANB hepatitis. One was the infections in donors, the viral and host immunologic Transfusion Transmitted Virus (TTV) Study directed by mechanisms underlying these infections, and the infecJames Mosley;23 the other was a follow-up of heart tivity of transfusions of units from these donors are 20 current areas of active research. surgery patients at the National Institutes of Health (NIH) Clinical Center led by Paul Holland and Harvey After introduction of the test for HBsAg the inciAlter.24 Both studies observed blood recipients at fredence of posttransfusion hepatitis (PTH) dropped dramatically (Fig. 2). However, this was also the period quent intervals after transfusion, testing their blood for during which the National Blood Program was promoted abnormal levels of the liver enzyme alanine aminotransby the Nixon administration with a goal of minimizing ferase (ALT). The TTV study found that 12% of recipients PTH by eliminating prison donors and paid blood developed ALT levels in a range they considered indicadonors. In retrospect most experts believe that the tive of hepatitis, but so did 3% of nontransfused controls. majority of the decrease in PTH in the 1970s can be Ten percent of the PTH was caused by HBV, while the rest attributed to the change in the blood donor pool.21 The was diagnosed as NANB. Ninety percent of the NANB cases were asymptomatic. Results at the NIH were current risk of receiving potentially HBV-infectious blood similar. after donor screening and testing for HBsAg, anti-HBc,
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% of Recipients Infected
Both studies agreed that receipt of blood from a donor with an elevated ALT increased the chance of PTH and that elimination of donors with a high ALT might prevent 30% of PTH.23,24 Subsequently, based on the recognition that the epidemiology of NANB hepatitis appeared similar to that of HBV, the test for anti-HBc was evaluated as a surrogate test for NANB hepatitis, using samples from the TTV study repository.25 Again the results suggested that 30% of PTH could be prevented by using the test for anti-HBc to exclude donors. In addition, Jay Hoofnagle26 presented data suggesting that anti-HBc positive blood was associated with residual cases of posttransfusion HBV not detected by HBsAg screening. So, why did blood banks hesitate to adopt ALT and/or antiHBc as a screening test to prevent NANB hepatitis? During the 1970s it was generally accepted among those involved in transfusing patients that PTH was expected to occur in approximately 10% of recipients and was part of the risk-benet ratio to be considered. In general PTH was considered a relatively benign disease, especially for the 90% of patients with no clinical symptoms. The problems with use of the ALT test were summarized by Roger Dodd in 1982.27 The rst related to its very low predictive value. Seventy percent of recipients of high ALT blood do not develop hepatitis and 70% of patients who develop PTH receive blood with normal ALT levels; that is, the test has 70% false positives and 70% false negatives. The second problem related to difculties standardizing the test that would result in blood collected in one area being ineligible for transfusion in another. Third is the problem of what to tell the donor. No matter how one words it, the message the donor gets is that he or she is positive for a test that detects hepatitis, and that can have severe emotional and practical consequences. Finally, the test would eliminate as donors a very large number of individuals whose blood is probably perfectly safe, possibly putting patients at risk if blood is not available. Moreover, the NIH Clinical Center had been using ALT tests in its research without seeing any reduction in PTH, although this lack of efcacy was later attributed to continued use of paid PLT donors. In fact, both the TTV and the NIH studies were both conducted during the years when paid commercial donors were still in partial use, potentially confounding results. The anti-HBc test was equally problematic. It eliminated a different group of donors from the ALT test. It had no conrmatory test to prove specicity and it shared all of the other disadvantages of the ALT in terms of high rates of donor loss and poor positive predictive value. The situation changed dramatically, however, with the NIHs report on anti-HBc in 1986. They conrmed the results of the TTV study and argued for its implementation as a surrogate based on increasing evidence that NANB PTH was not as benign as we had thought. More than half of the
patients with NANB hepatitis continued to have intermittently elevated ALT levels, 20% of them developed cirrhosis, and some of these cases developed liver cancer. Both the ALT test and the anti-HBc test became routine in US blood banks in the late 1980s. After numerous false alarms, the cause of NANB hepatitis was discovered in 1989 by Michael Houghton and colleagues at Chiron, in collaboration with scientists at CDC and NIH.28 The virus was named hepatitis C and a test for HCV antibody was rapidly developed and licensed by FDA. Evidence was quickly generated that established that this new virus accounted for almost all NANB cases.29 On the other hand, most hepatitis C is not transfusion related (the virus is predominantly spread by injection drug use and other parenteral exposures). Most cases of HCV infection in transfusion recipients and other infected subpopulations do not result in clinically signicant disease.30 Leonard Seeff conducted two long term studies to determine the late fate of patients with hepatitis C.31,32 He studied TTV and NIH study recipients 18 years posttransfusion and found no increase in overall mortality compared with HCV-negative controls but a small increase in liver-related mortality. Similarly, veterans who were investigated 45 years after cryopreserved blood samples were obtained that were later tested and determined to be HCV seropositive were minimally affected by HCV infection in terms of overall and liver-related mortality. More recent follow-up studies of HCV-infected blood donors have conrmed relatively low rates of disease penetrance.33,34 Despite this relative benign course of HCV infection, the virus is so common that it remains the number one indication for liver transplantation. Of note, studies of specimens from HCV-infected blood donors and recipients have yielded important insights into the timing, determinants, and mechanisms of spontaneous viral clearance (which occurs in approximately 30% of infected persons) and of host and viral factors that correlate with control of viremia and pathogenesis of liver disease.35-38 The rst-generation test for HCV antibody was introduced into US blood banks in 1990 (Fig. 2). This rst test was quickly followed by second-generation tests in 1992, and we are now using third-generation tests that include multiple HCV antigens and employ chemiluminescent detection technologies on highly automated testing platforms. NAT for HCV began in 1999 in the United States and is now in widespread use throughout the world.39 Minipool NAT for HCV has a relatively high yield due to the lengthy (40- to 60-day) high-titer viremic phase that precedes antibody detection even by third-generation serologic assays.40 The current risk of receiving HCVpositive blood after donor risk factor screening and testing is approximately one in 2 million,41 a remarkable difference from the 1 in 10 risk of the 1970s. The serologic tests for HBV and HCV are relatively cost-effective due to the high prevalence of these viruses
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among donors, high rates of transmission by transfusion, and signicant, albeit modest, rates of disease progression in recipients. In contrast, the cost-effectiveness of NAT is low due to the high cost of molecular testing and the low yield of viremic window phase infections detected.42
AIDS, HUMAN IMMUNODEFICIENCY VIRUS, AND OTHER RETROVIRUSES

Evolving evidence of transfusion AIDS
The rst cases of AIDS were reported in 1981. It was considered to be a disease limited to homosexually active males (gays) and was rst labeled gay-related immune deciency or GRID, but 1 year later, articles in the Centers for Disease Controls (CDCs) Morbidity and Mortality Report (MMWR) raised the possibility that the disease might be transmitted by blood transfusion. The condition now know as acquired immune deciency syndrome or AIDS was reported in injection drug users, and three persons with hemophilia had been diagnosed with Pneumocystis carinii pneumonia,43 an infection found only in immunosuppressed individuals and typical of AIDS. The MMWR report about the three persons with hemophilia led to a series of meetings among public health ofcials to consider the possibility that the plasma derivatives given to persons with hemophilia were transmitting AIDS and what, if anything, should be done about it. Early on, there was too little information for any consensus about what to do. The cause of AIDS was unknown. Intensive efforts for a year to discover a responsible new virus or other agent had been unsuccessful. Theories to explain the unusual immunosuppression in previously healthy young men included the possible immunosuppressive effect of sperm deposited in the rectum,44 the use of amyl nitrite poppers to increase sexual excitement,45 the effect of multiple infections with known agents, or immune exhaustion from exposure to innumerable foreign antigens.46 The need for more data was apparent. The level of alarm rose sharply in December 1982 after recognition in San Francisco of an immunosuppressed infant with a history of multiple transfusions at birth. One of the donors of the blood the baby received became ill 8 months after the donation and was diagnosed as having AIDS.47,48 The CDC convened a meeting on January 4, 1983, to which they invited representatives from the FDA, NIH, state health departments, New York City and San Francisco Health Departments, blood banks, plasma derivative manufacturers, gay community, and the press. At that time seven persons with hemophilia had been diagnosed with possible AIDS, and two more blood recipients were under investigation with no evidence that any of their donors had AIDS. San Francisco representatives reported that 13 additional patients did not have AIDS even though they had received blood from donors
who later developed AIDS. Clusters of gay males with AIDS suggested an infectious etiology. Evaluation of a large series of laboratory tests in search of a surrogate test for this disease of unknown origin identied ve tests (T-cell helper/suppressor ratio, absolute lymphocyte count, immune complexes, anti-HBc, and antibody to hepatitis B surface antigen [anti-HBs]), which were positive in a high proportion of patients with AIDS as well as gays volunteering to be in research studies or visiting sexually transmitted disease clinics, compared to relatively lower frequencies of reactivity in normal controls The debate that followed was complete chaos. There was not even universal agreement that AIDS was infectious. The fact that it could be transmitted by blood was considered possible but not conrmed. There was little support for rejecting all gay men as blood donors, and the usefulness of the suggested surrogate tests was hotly disputed. The meeting ended with no consensus, but the blood bank representatives there left knowing that they had to evaluate the suggested surrogate tests and modications to the donor questionnaire. The AABB Board of Directors had appointed a committee to advise them on an appropriate response to the possibility that AIDS was transmitted by blood transfusion. This committee met 2 days after the meeting at the CDC. Included were representatives from the American Red Cross, The Council of Community Blood Centers, National Hemophilia Foundation, plasma derivative manufacturers, the FDA, the NIH, the CDC, and representatives from the gay community. A statement from the committee was issued on January 13, 1983.49 The statement recommended that blood banks ask donors questions intended to detect signs or symptoms of AIDS and questions about exposures to patients with AIDS. They further recommended that blood banks stop recruiting donors from groups known at be at high risk for AIDS. They stated that questioning a donors sexual preferences would be inappropriate and ineffective and advised against any laboratory screening at that time. San Franciscos Irwin Memorial Blood Bank had been in constant discussions with the local gay community since early December 1982, eliminating blood drives to known gay groups and getting out the message that gays at risk should not be donating blood. All the evidence at that time said that the only gays at risk were the fast-lane gays, the ones with multiple anonymous partners. In early February 1983 a new donor questionnaire was initiated. A box on the form listed homosexually active males with multiple partners and injection drug users as risk groups as well as each of the known signs and symptoms of AIDS. A single yes or no answer to the box allowed a donor to exclude himself without actually confessing that he was gay (the beginning of condential unit exclusion). The New York Blood Center took a similar approach to condential unit exclusion. They used a separate piece of
paper, identied only by donor number, on which they listed the risk groups for AIDS as well as its signs and symptoms. The donor then had to check whether his blood was safe to transfuse or should be used for research. The rst published recommendations from Public Health Service (NIH, FDA, CDC) came on March 4, 1983,50 followed by similar recommendations from the FDA to blood banks on March 24. The PHS statement said that Members of groups at increased risk for AIDS should refrain from donating. . . . Among the dened risk groups were sexually active homosexual or bisexual men with multiple partners. They also said that screening procedures, including laboratory tests, needed to be evaluated. The incubation period from infection to clinical AIDS was estimated to be 2 years in this report, but the asymptomatic incubation period is now understood to be over a decade. As further experience accumulated the FDA recommended that male-to-male contact since 1977 should be grounds for rejection as blood donors. The effectiveness of these self-exclusion policies could be demonstrated in subsequent years by asking when did donors who later develop AIDS (or become positive in a test for anti-HIV) stop donating. Evidence from San Francisco51,52 showed that donations from those at risk began to fall off in December 1982, rapidly decreasing in 1983 and 1984 (Fig. 3). By March 1985, when the test for anti-HIV became available, 86% of the risk had been eliminated. The most startling fact in this San Francisco analysis was that more than 1% of the blood distributed by that blood bank was infected with AIDS by the end of Decem-
ber 1982.52 This rate of infected units was vastly different from the estimate of risk given out at the time: one in a million, an estimate that appeared in the PHS publication Facts about AIDS as late as April 1984. The huge underestimate of the risk at the time transfusion-associated AIDS became a possibility is the main reason the public lost condence in blood banks. At the beginning of 1983 there was a possibility that AIDS was transmitted by blood transfusions; by the end of 1983 the possibility had become a probability. In January 1984 CDC published details of its rst 18 investigations into cases of transfusion-associated AIDS,53 saying that These ndings strengthen the evidence that AIDS may be transmitted in blood. The probability became a certainty with the publication of four papers by Robert Gallos group in Science in May 1984. Not only did they have proof of the virus responsible, but they had an antibody test to detect carriers.54 The test for anti-HIV was licensed by the FDA and made available to blood banks in March 1985. Initially there was uncertainty whether a positive test for anti-HIV was synonymous with infection, or might represent immunity with recovery, and that made it very difcult to counsel blood donors with a positive test. As data accumulated, however, it became clear that antibody was synonymous with infectivity.55
The controversy over surrogate testing for AIDS
Before the discovery of the HIV and availability of the test for anti-HIV, blood banks had to wrestle with the question of surrogate tests. Would they work in a blood bank setting; that is, would they Risk of HIV per Unit (%) detect infected donors who were not the 2.0 First TA-AIDS cases reported; fast-lane visitors to sexual disease HIV discovered; High-risk donor deferral / selfclinics? Four blood banks published Progressive impact of highexclusion initiated. evaluations of the tests suggested by the risk donor education. 1.5 CDC, each of them concluding that the tests would not be useful and for differFirst AIDS cases reported ent reasons. Simon and Bankhurst56 1 from Albuquerque concluded that they Anti-HIV screening could not work because each test impmented rejected a different set of blood donors. 0.5 Kaplan and Kleinman57 from the Los Angeles Red Cross showed that the suggested tests would have a poor predictive value because the normal 0 population was so relatively large that 1978 1979 1980 1981 1982 1983 1984 1985 1990 its low level of positive tests would have Year of Transfusion a major impact on the results. They further recalled and reinterviewed conFig. 3. Risk of HIV transmission by blood transfusion, before the implementation of dentially and in depth 500 donors to HIV-1 antibody screening. The results of the risk projection demonstrate the drasee if they had hidden their history of matic decline in HIV risk coinciding with progressive implementation of high-risk male sexual contacts. Four acknowldonor qualication and deferral measures and preceding the availability of prospecedged that they had, and all four had tive antibody screening. TA = transfusion-associated. Reproduced from Busch et al.,52 negative tests for anti-HBc. Pindyck and with permission from the AABB.
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coworkers58 at the New York Blood Center took advantage of their condential unit exclusion procedure to compare surrogate test results between those donors who said that their blood was safe to use and those whose blood was to be reserved for research. They found no difference between the two groups for the T-cell helper/suppressor ratio or the absolute lymphocyte count. They did nd a higher frequency of positive tests for anti-HBc among the group who did not recommend their blood for transfusion (12% vs. 6%). When those data were reviewed in June 1983, the initial reaction was that we could not possibly use a test that missed 88% of those who did not feel that their blood was safe to transfuse. The gay community was begging us to implement a surrogate test that would allow them to continue to donatehad we done so in 1983 and high-risk gay men continued to donate there would likely have been many more transmissions than did occur. In San Francisco studies with anti-HBc among blood donors conrmed long-known facts: hepatitis B was more common among males than females, in cities compared with rural areas, and in non-Caucasian ethnic groups (especially Asians). None of that told us whether the test would be useful as a surrogate for AIDS. We reasoned that, if the test worked, we should obtain a higher frequency of positive tests among donors from areas where there was a high incidence of AIDS. Dr Selma Dritz from the San Francisco Health Department provided the blood bank with an estimate of the relative frequency of gays in different ZIP code areas of San Francisco, based on AIDS case reports. Unfortunately these did not correlate with positive tests for anti-HBc; the results correlated better with the frequency of Asians in the different ZIP code areas. The surrogate test debate continued throughout 1983 and in December of that year the FDA devoted a Blood Products Advisory Committee meeting to that topic. While conceding that the evidence for potential benet was scant, the increasing number of hemophiliacs with AIDS led the Committee to recommend that anti-HBc testing be considered for donors of plasma for derivative manufacture, but not for blood banks. A task force was established to recommend how this testing could be implemented. The task force eventually concluded that anti-HBc testing was not warranted (with a strong minority report favoring testing). The question was moot in any case, since by that time the Gallo reports had led to a prediction that a specic test would be available in 6 months. In May 1984 the Irwin Memorial Blood Bank in San Francisco began anti-HBc testing, pressured by the increasing number of cases of AIDS associated with transfusion of its blood. Other Bay Area blood banks followed suit, but the rest of the country did not. By May 1984 we had assumed that the modest benet of the anti-HBc test shown in the New York Blood Center studies would not be overcome by gays coming back to donatethe magnet effect.59
The beginning of lookback

The appearance of AIDS in previous blood donors, as well as the detection of donors with positive tests for anti-HIV, led to massive efforts (later termed lookback) to identify prior recipients of blood components from these donors, to inform them of the risk and to perform available tests to determine if they had been infected.60 The emotional turmoil created by these notications was intense. Identication of infected recipients, in turn, led to tests of their previous blood donors. In March 1987 Peterman and coworkers61 estimated that 29,000 transfusion recipients in the United States had been infected with HIV and that 12,000 of these were still alive and at risk of developing AIDS. Busch and colleagues52 estimated that 5000 recipients had received HIV-positive blood collected by the Irwin Memorial Blood Bank in San Francisco, a gure that makes Petermans national estimate possibly suspect. After these two reports the University of California Medical Center in San Francisco made the decision to notify all prior blood recipients from the year 1977 to March 1985 that there was a possibility they had been exposed to the AIDS virus and to recommend testing.62 UCSFs example was followed by all of the local hospitals.
Donor screening for HIV

Screening of donors for HIV antibodies using rstgeneration tests was implemented in March 1985. Since a reactive test for anti-HIV would be grounds for elimination of a blood donor, the remaining risk came almost entirely from donors so recently infected that they had not had time to produce detectable antibody (the window period). Lookback studies of recipients of previous donations from donors who tested positive for anti-HIV using the rst-generation assays yielded estimates of 56 days for the infectious preseroconversion window period.63 In an effort to reduce this window period second- and thirdgeneration antibody tests were developed in the late 1990s, and a test for HIV p24 antigen was introduced in 1995,64 which was ultimately supplanted by HIV NAT screening in 1999.39 The residual infectious window period with current NAT is less than 1 week, and the current risk of receiving blood infected with HIV that is nonreactive in all tests is approximately one in 2 million.41,65 Screening for HIV antibodies is highly cost-effective, with interdiction of approximately 500 infected donations annually. In contrast NAT detects only approximately 10 window phase units each year in the United States and consequently has a relatively high cost-effectiveness ratio (>$1 million quality-adjusted life-year).42 For additional safety the FDA still mandates that any male-to-male sexual contact since 1977 excludes a donor (a policy that is the focus of ongoing analysis and debate), whereas other risk groups for HIV can donate after 1 year free of risk.66
Human T-cell lymphotropic viruses

In the context of the growing appreciation of the magnitude of transfusion-transmitted HIV/AIDS in the late 1980s, the decision was made in 1988 to implement antibody testing for the previously discovered human T-cell lymphotropic viruses (HTLV-I/-II), retroviruses that are associated with development of acute T-cell leukemia/ lymphoma and several neurologic diseases.67-69 The subsequent rates of detection of infected donors were signicant, with risk factors primarily related to birth in endemic countries (for HTLV-I) or past injection drug use (for HTLV-II).70,71 Donor screening for anti-HTLV-I/-II remains an important component of donor screening in most countries. The residual risk of these viruses is extremely low given very low incidence of HTLV-I/II in the United States.72 In addition to HIV and HTLV, several other retroviruses have required extensive study to determine if they represent signicant threats to the blood supply. These potential pathogens include variant primate T-lymphotropic viruses (PTLVs),73 simian foamy viruses,74 and, most recently, xenotropic murine leukemia virusrelated virus, which has been implicated in prostate cancer and chronic fatigue syndrome.75,76 For PTLVs and simian foamy viruses, the evidence has indicated these are not signicant human pathogens in terms of prevalence or disease association, and there is no or limited evidence that they are transmissible by transfusion. For xenotropic murine leukemia virusrelated virus, donor prevalence and transmission studies are currently in progress, but based on epidemiologic data that have failed to demonstrate any associations between previous transfusions and prostate cancer or chronic fatigue syndrome, the likelihood this agent is a signicant threat to blood safety seems remote.
many donors, almost all of whom are probably safe. Endemic areas are dened by the CDC and do not take into account the marked differences in risk from different endemic areas.79 Approximately 50,000 prospective donors are excluded each year in the United States because of potential malaria risk. Unfortunately the medical history approach has low reliability. In one report 62% of donors who should have been excluded by criteria then in place were accepted.78 Donors either fail to remember or falsely deny that they were at risk. Medical history questions have been repeatedly modied in an effort to ensure more accurate donor responses. Recent analyses have suggested that it may be possible to dramatically increase the specicity of travel historybased screening without signicantly increasing risk of malaria transmission by revision of the regions in Mexico that are subject to the travel deferral;79 it is expected that FDA will concur with this revision in the near future. In Europe and some other areas more aggressive approaches to dene the donors at risk have been introduced using laboratory tests.77 The traditional blood smear approach to detect malaria is too insensitive and time-consuming for blood donor screening. Polymerase chain reaction (PCR) misses low-level infectious donors because the infecting organisms can be too infrequent to be detected in the small sample employed for the test. Antibody remains the only practical approach to identifying infected donors, recognizing that it will not yet be present very early in the infection and will persist for months after the donor infection has resolved, but with all these defects, a negative antibody test at an appropriate interval after the last possible exposure can be used to restore a person who has been in an endemic area to the eligible donor ranks. No donor test for malaria screening has been licensed by the FDA.
PARASITIC INFECTIONS
Malaria
Malaria may have been the rst infectious disease recognized to be transmitted by blood transfusion,77 but there have been relatively few changes in dealing with it in the United States over the past 50 years. Transfusion transmission is rare in nonendemic countriesless than one per million collected units in the United States. Nonetheless there were 93 cases reported in the United States between 1963 and 1999, 11% of whom died.78 The proportion of cases caused by Plasmodium falciparum, which results in the most dangerous form of the disease, is rising. FDA regulations and AABB Standards have relied on the medical history questionnaire to detect donors at risk for transmitting malaria, including immigrants from endemic countries as well as travelers to those areas. Deferral intervals are a compromise between ensuring safety of the blood supply and avoiding deferral of too
Chagas disease
Chagas disease is caused by the protozoan Trypanosoma cruzi. It is widespread in the poorer rural areas of Central and South America, where it is transmitted by triatomine bugs. Infection is usually unrecognized early on, but, if untreated, up to 30% to 40% of infected individuals develop cardiac disease and other serious problems as a late complication. Transmission by blood transfusion has long been recognized in these endemic areas where tests to exclude infected donors are in widespread use.80 In recent years concern has arisen in the United States based on the large number of immigrants from endemic areas. Nontransfusion cases have occurred in the United States81 but are extremely rare because the insect responsible for transmission is seldom found north of Mexico. However, at least seven transfusion transmissions have been reported in the United States and Canada, six associated with transfusion of PLT concentrates.82
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Studies to determine the frequency of blood donors in the United States with a history of living under conditions at risk for Chagas disease suggested that large numbers were at risk. In a Los Angeles study, Shulman and coworkers83 found that 39.5% of their donors were at risk for Chagas disease based on answers to a questionnaire. Eighteen California blood donor centers found that one in every 340 donors had a risk factor.84 In a study of more than 1 million donors 7.3% in Los Angeles and 14.3% in Miami had lived in endemic countries.85 Laboratory tests to detect Chagas infection have been unsatisfactory in the past. Pirard and coworkers86 concluded that no single test gave acceptable results and that the use of two tests was mandatory, which was the practice in endemic Latin American countries until quite recently. However, a recent comparison of tests concluded that enzyme-linked immunosorbent assay (ELISA) tests performed quite well in detection of T. cruzi antibodies and could be employed as single screening assays, while radioimmunoprecipitation assay was the best conrmatory test.87 A multicenter study of the Ortho ELISA test gave it high marks for sensitivity and specicity.88 The tests were performed on random volunteer blood donor samples from Minnesota, Oklahoma, Texas, and Northern California and resulted in a very low rate (0.002%) of repeat-reactive donations. The FDA licensed the test in December 2006, and it was widely although not universally implemented in the United States in 2007. Over the rst 3 years of screening, well over 1000 seropositive donors have been identied, the vast majority of whom had been born in endemic countries where they were infected before immigration to the United States. The rate of transmission of T. cruzi by seropositive blood transfusions is controversial. Studies from Latin America conducted before antibody screening indicated relatively high rates of transmission (>25%), but these typically implicated transfusions of whole blood derived from donors who had relatively recently acquired infection. In an early study of recipients of blood transfusions from antibody-positive donors in Los Angeles and Miami, none of 18 was reactive.85 On the other hand, in a lookback study performed at ve Mexican blood banks, four of nine recipients of blood from reactive donors were infected.89 Since the introduction of widespread testing in the United States, lookback has been performed to determine the rate of transmission by prior donations from radioimmunoprecipitation assay conrmed donors; only 2 of 242 tested recipients were infected, both of whom received apheresis PLT transfusions from the same donor, who was born in Argentina and was highly parasitemic. Based on the low rate of transmission documented from lookback and absence of observed seroconversions, the value of routine testing of subsequent donations from donors who have previously tested nonreactive has been questioned, and many blood
banks have converted to a selective testing strategy that involves one-time testing of donors.90 Filtration to remove white blood cells (WBCs) reduces the levels of protozoa but does not eliminate risk, while pathogen reduction techniques are capable of efcient inactivation,91 but unfortunately are not yet approved for use in the United States and at present are only developed for PLTs and plasma components.
Babesiosis
Babesiosis is a disease caused by an intraerythrocyte parasite with some similarities to malaria. The reservoir for Babesia is in animals and it is transmitted to humans by tick bite. Transmission from one human to another by transfusion has been documented in over 70 cases from 1979 to 2008.92 Twelve of these cases were fatal. Most reports of babesiosis come from the United States where the rst report occurred in 1968, but there are very marked differences in regional prevalence.93 The vast majority of cases can be traced to the New England States or the upper Midwest. Most of the cases are caused by the Babesia microti species, but rare cases involving other species have been reported especially in the West.94 This species distinction is important, since tests designed for one are not likely to work on another. Since patients can be infected with Babesia and remain totally asymptomatic, the true prevalence of the infection is not known. Even when symptoms appear, they are generally nonspecic. Infections are self-limited with or without treatment, but persistent low-level or intermittent parasitemia can persist for many months in an asymptomatic carrier. There is no evidence for lifetime carriers, but Tonnetti and colleagues95 found intermittent parasitemia in some cases for up to 3 years. Infected patients develop immunoglobulin (Ig)M and then IgG antibodies, which eventually disappear as the infection is controlled, but the time sequence of these antibodies and their relation to infectivity has not been well established. Patient susceptibility plays a major role, with the very young, the elderly, and immunocompromised and splenectomized (including functionally splenectomized sickle cell disease) patients accounting for almost all cases.93 The increasingly frequent reports of transfusion transmission and the signicant fatality rate calls for action to protect the blood supply, but it has been difcult to formulate reasonable recommendations.93 Babesiosis has been transmitted by red blood cells (RBCs) stored as long as 35 days96 and by previously frozen RBCs.97 PLTs were implicated in one case.98 The current strategy of excluding donors with a history of babesiosis is clearly not sufciently effective. Although babesiosis has been reported primarily from New England and the upper Midwest, geographical exclusion of blood donors is not a
reasonable possibility. Even within endemic regions, prevalence varies immensely. Donors from nonendemic regions get infected when they travel. The number of donors lost would be impossible to replace. Although Babesia transmission occurs primarily between Memorial Day and Labor Day, transmissions frequently extend beyond that period. More important, the asymptomatic carriers ensure year-round potential for transfusiontransmission. There are no FDA-licensed laboratory tests to exclude donors at risk for transmitting babesiosis. Of tests in experimental use, indirect immunouorescence assay (IFA) using Babesia organisms as a target is the gold standard. As already noted, tests for B. microti are not likely to detect other species.93 Sensitive but less specic ELISA tests can be used for initial screening, using IFA for conrmation. A positive antibody test may, of course, exclude a donor whose disease has completely resolved, but there is no likelihood of a reentry protocol based on current assay availability. Blood smears to detect the parasite provide useful conrmation, but are too insensitive, timeconsuming, and subjective for donor screening. PCR or other NAT methods have been adapted for Babesia DNA detection in RBCs, but it appears that parasite loads are so low that the small sample of blood processed for NAT may not contain any detectable DNA yet the blood component can still be infectious (the minimum infectious dose has not been established). In the earliest stage of acute infection before antibody has had time to form, PCR will be more sensitive than ELISA or IFA. In the subsequent asymptomatic carrier phase, ELISA or IFA will be more sensitive than NAT, but would result in detection of donors with resolved infections but persistent seroreactivity. Pathogen reduction technologies (PRTs) have recently been reported to be highly effective at inactivation of Babesia, but PRT remains a distant hope since the techniques that are currently available and have been proven to destroy Babesia are designed for treatment of PLTs and plasma and cannot be used for RBCs.93 We are therefore left with an unsatisfying situation where the likely approach will be to employ laboratory tests (antibody and/or DNA detection) under an FDA investigational new drug (IND) in high-prevalence areas under restricted conditions, for example, to provide RBCs for the most susceptible populations. This scenario would be difcult for both blood centers and transfusion services to implement.
BACTERIAL CONTAMINATION
Although bacterial contamination of blood was recognized to be a potentially serious problem as early as the 1950s,99 it did not cause the type of alarm that hepatitis and AIDS did. As the risk of those viral illnesses became reduced to very low levels, it became obvious that bacterial infection of transfused blood was causing more mor-
bidity and mortality. The steady growth in transfusion of PLT concentrates (with room temperature storage facilitating bacterial growth) added to the concerns. The frequency of reported bacterial contamination of RBCs has varied widely between 0.002 and 1.0%; for PLTs results vary between 0.04 and 10%.100 Fortunately, most of the contaminated units do not result in recognizable infection of the recipient. Bacteria can be destroyed in blood components during storage through the effect of antibody plus complement and through phagocytosis by WBCs, which may kill the bacteria or be removed by subsequent ltration provided that sufcient time was permitted for the WBCs to engulf the bacteria.101 In addition many recipients are already receiving antibiotics. The frequency of clinical effects was estimated in the BaCon study.100 Recognized transfusion-transmitted bacteremia occurred with one in 100,000 PLT components and one in 5 million RBCs. The frequency of death was one in 500,000 for PLTs and one in 8 million for RBCs. Other studies of PLTs by single institutions or national biovigilance efforts suggest a higher incidence of septic reactions to PLTs. Bacterial contamination is generally believed to be a greater risk with pooled random-donor PLTs than with single-donor apheresis PLTs. Benjamin and colleagues102 found that the risk of contamination per original unit was the same as for apheresis PLTs. With 5 units pooled, the risk was ve times as great. The usual causes of bacterial contamination of blood components have long been recognized. Bacteria on or in the skin can be picked up by the phlebotomy needle despite increasing emphasis on optimal techniques for sterilizing the skin. Bacteria can remain deep in skin sweat glands, but in recent years blood banks have reduced this risk by diverting the rst blood to ow through the needle into an integral pouch separate from the collection bag.103 A more difcult problem is bacteremia in a healthy donor. Bacteremia may not be surprising after extraction of a tooth but also occurs after brushing the teeth, straining at stool, etc. Usually such incidents are too transient to persist until blood donation,104 but there are donors with persistent or intermittent bacteremia, sometimes with an obvious source105 but often with none. The most common responsible organism for whole blood and RBCs has been Yersinia enterocolitica.106 PLTs can be contaminated by a variety of Gram-positive and -negative bacteria. Since PLTs are far more likely than RBCs to cause clinical problems, PLT concentrates but not RBCs are generally tested by blood banks using semiautomated culture techniques.107,108 Both the BacT/ALERT and the Pall systems identied one in 5000 units as infected. Culturing individual PLT concentrates is not practical on a routine basis, but a procedure to test pooled PLT concentrates prepared from whole blood collections is now available.
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Despite this screening, persisting transfusion septic events suggest that up to 50% of contaminated units escape detection,109 presumably because bacterial growth occurred subsequent to the early sampling for culture. The use of anaerobic culture in addition to aerobic is controversial. Although it may detect more positives, this could be a result of the larger total sampling volume. Current efforts are devoted to developing methods to detect bacteria quickly and sensitively immediately before transfusion. Measuring pH, using reagent strips, and Gram stain of slides are not sufciently sensitive. Pathogen inactivation may prove to be the only effective way to improve results.110
CREUTZFELDT-JACOB DISEASE
The various forms of classical Creutzfeldt-Jacob disease (CJD) which have been recognized for many decades do not appear to be transmitted by transfusion,111 but variant Creutzfeldt-Jacob disease (vCJD, which is now accepted to be transfusion transmissible) was not reported in humans before 1996, so everything we know about vCJD is quite recent. Humans develop vCJD after ingestion of beef contaminated with the bovine spongiform encephalopathy (BSE) protein. The disease occurs in younger individuals than other forms of CJD. Also, unlike other forms, the responsible agent can be found in lymphoid tissue. The infectious agent appears to be a protein (prion), which is an isomer of a normal cellular constituent (PrPc), found in highest concentrations in the brain. The infectious isomer (PrPSc) has a different conformation with extended beta sheets and can induce neighboring normal isomers to adopt the infectious conformation. Reports of vCJD increased rapidly but peaked in 1999 or 2000 subsequent to cessation of feeding cattle with discarded animal scraps believed to be the source of BSE. The vast majority of cases of vCJD occurred in the United Kingdom. France had the second highest incidence, with a few cases scattered in other countries. All of the clinical transfusion recipient cases to date had the prion homozygous MM PRNP genotype, which is present in 40% of the random population. vCJD is clearly transmissible from human to human through blood transfusion with four infected recipients having received blood from donors subsequently diagnosed with vCJD.112,113 All received nonleukoreduced blood between 1996 and 1999. Three of these recipients developed clinical disease; one was identied without clinical evidence by nding PrPSc in lymphoid tissue. The three clinically evident cases had the MM genotype. The subclinical case had the heterozygous MV genotype. There is also evidence from studies of random lymphoid tissues that persons with the MV genotype and even with the VV genotype can have PrPSc in their tissues. Thus, while it is apparent that persons with the MM genotype are more
susceptible to developing clinical vCJD, there is concern that other genotypes may result in delayed onset of disease. If so, we can expect many more vCJD cases in the future than are now projected. The United Kingdom responded to the threat of transfusion transmission of vCJD with a number of precautions. Given evidence that the infectious agent in blood is approximately 50% in the WBCs and 50% in plasma (with little in RBCs or PLTs),114 universal leukoreduction of blood products was instituted. Plasma from UK sources was eliminated where possible. Plasma derivatives have never been implicated in vCJD transmission, and steps involved in their preparation are believed to remove prions,115 but the UK nonetheless discontinued production of therapeutic derivatives from plasma derived from their donor pool. In countries such as the United States where vCJD appears to have occurred only in previous UK residents, emphasis has been on deferring donors who have spent signicant time in countries at risk. Residence in the UK for 3 months or elsewhere in Europe for 5 years since 1980 is grounds for exclusion, as is a history of transfusion in those countries since 1980. Two further approaches to protecting transfusion recipients are under intensive investigation: tests to screen blood donors and lters to remove prions from blood. Unlike other infectious agents, prions are normal body constituents and infected individuals do not make antibodies against them. The abnormal prions themselves must be detected, a difcult process because the level of infectious prions in donors in the preclinical state is almost certainly very low and is accompanied by much larger amounts of normal PrPc. In all probability a successful technique may have to include amplication steps.116,117 Meanwhile, as the number of reported cases of vCJD declines, manufacturers are losing interest in developing tests. Several lters have been developed that do remove prions along with WBCs, but thus far they appear be only moderately effective (1-2 logs of reduction) and result in signicant loss of RBC and changes to the resulting component.118 There are no available techniques to inactivate prions in blood components.
WEST NILE VIRUS AND OTHER ARBOVIRUSES

With the experience of HIV, HBV, and HCV behind us and many nonviral threats addressed, there was a general sense in the blood banking community that the major threats from transfusions had been identied and addressed. The period of complacency was short-lived, however, with the entry of West Nile virus (WNV) into the United States in 1999 and its remarkable spread through the country over the past decade. WNV was predicted to be a potential threat to blood safety by modeling studies conducted by Lyle Petersen
and his colleagues at CDC in a seminal publication in TRANSFUSION in August 2002, the same month as the rst case of probable transplant and transfusion transmission was identied.119 Proving transfusion transmission of WNV relied on a surveillance system capable of rapid identication of WNV cases with recent transfusion history and subsequent epidemiologic and virologic investigation to document transfusion of a viremic blood product. During 2002, retrospective studies were conducted on retained samples, usually fresh-frozen plasma or retention tubing segments, from more than 600 donors that documented 26 transmissions from 16 viremic donors.120 Many other likely transmissions remained undocumented because virus titers in the retained samples fell below detection limits of contemporary nucleic acid detection tests. The following year, newly implemented nationwide WNV RNA screening of blood donors yielded more than 500 likely infectious, RNApositive, IgM antibodynegative donors.121-123 Because the 2002 and 2003 outbreaks were of similar magnitude,124 a comparison of the 2 years suggested that the monumental effort to identify transfusion transmission cases in 2002 yielded less than 5% of the actual number that occurred that year. Excluding donors based on symptoms had marginal yield as most WNV infections were asymptomatic or produced mild symptoms not prohibiting donation.120,125 IgM antibody testing was ineffective since all but one of the 32 transfusion transmissions documented through 2009 resulted from donations lacking IgM antibody.120,126 Therefore, national blood donor screening using WNV NAT was initiated in 2003 to ensure transfusion safety. Follow-up of NAT-positive donors has detailed the timing of viremia and antibody development.127 NAT sensitivity decreases when samples are tested in minipools and increases when samples are tested individually, particularly when subjected to replicate testing. Low-titered samples that only test positive when tested individually occur during a relatively short period at the initial phase of viremia when donations are likely highly infectious (resulting in breakthrough transmissions), as well as during a relatively long period past the peak of viremia, when IgM antibody is present and donations are rarely infectious. During the rst 7 years of WNV NAT screening, approximately one-third to one-half of RNA-positive donations were missed by minipool screening, yet only about 5% of these donations lacked IgM antibody and were likely infectious.121,122,124,128 To minimize breakthrough transmissions, blood centers adopted screening strategies to switch to individual donation testing during times of increased transfusion transmission risk as indicated by detection of minipool-positive donations and/or other evidence of increased transmission of WNV in the community. The criteria for turning on or off individual unit testing have been debated and enhanced over time.128-131
The estimated overall cost-benet of WNV screening of the United States blood supply was $483,000 per quality-adjusted life-year in 2003.132 However, this gure depends on screening yields, which vary greatly by season, year, location, and algorithms for switching to individualdonation testing. In the Old World, WNV outbreaks tend to be highly localized and in any given location, separated by decades. However, the large outbreaks that occurred annually since 2002 in North America highlight the difculties in predicting the impact of newly imported arboviruses.133 The WNV outbreaks in the United States have gradually decreased in magnitude in recent years, but it is unclear whether this decline represents a long-term trend. Thus, even 10 years after the introduction of WNV in North America, the long-term cost-effectiveness of blood donor screening cannot be predicted. In addition to WNV, there are published reports of transfusion transmission of a number of other arthropodborne virus (arboviruses) present in the United States, including Colorado tick fever,134 dengue,135,136 and tickborne encephalitis.137-139 Given the fact that at least 50 million dengue infections occur annually throughout the world,140 it is remarkable that only two instances of dengue transfusion transmission have been identied. Recent studies, published in TRANSFUSION, have documented high rates of viremia in asymptomatic donors in several Latin American countries as well as Puerto Rico.141-143 The American Red Cross has recently launched dengue screening in Puerto Rico under an FDA IND study protocol. The future impact of other arboviruses on transfusion medicine is difcult to assess, in part because arboviral disease incidence is often sporadic and unpredictable and arbovirus importations are chance events with uncertain long-term consequences. The WNV experience demonstrates the utility of arbovirus transfusion transmission models in predicting risk, and the difculties in proving actual transmission even under ideal circumstances where there is a high index of suspicion and substantial resources and systems in place to detect transfusion cases. Similar to WNV, screening for other arboviruses will likely require very sensitive viral nucleic acid detection assays that may not identify all infectious donors in a minipool format. In addition, NAT positivity may not be synonymous with infectivity. For the other arboviruses, it is unknown whether the presence of IgM and IgG antibodies in low-level viremic donations will similarly signify low transmission risk.
OTHER ESTABLISHED TRANSFUSION-TRANSMITTED INFECTIONS

There are several additional classes of infectious agents that have been determined to be transmissible by transfusion and for some of these selective donor screening or other interventions (e.g., leukoreduction) have been
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implemented to reduce risk of transmission for all or selected subgroups of recipients. These include three species of herpes viruses (cytomegalovirus [HHV-5], Epstein-Barr virus [HHV-4], and Kaposis sarcoma virus [HHV-8]), Parvovirus B19, and several additional vectorborne agents (Borrelia burgdorferi, the agent of Lyme disease; Ehrlichia chaffeensis and Anaplasma phagocytophilum, which cause human monocytic and granulocytic ehrlichosis, respectively; Toxoplasma gondi, the agent of toxoplasmosis, and Leishmania tropica and donovani, which cause leishmaniasis. Further discussion of these agents is beyond the scope of this brief review.
was the case with HIV. The new paradigm includes a wide array of agents that do not t the HIV or HCV model. The concept of a global village has emerged, which reects the fact that a potential blood-borne infectious agent present in any region of the world could trafc to the United States overnight. There are increasing examples of zoonotic transmissions of infectious agents, with the potential for rapid adaptation of new agents to humans and subsequent spread to blood donors and then
TABLE 1. Changing paradigm of signicant transfusion pathogens
RESPONSE TO NEW AND EMERGING PATHOGENS: THE CHANGING PARADIGM OF TRANSFUSION PATHOGENS
Despite the dramatic progress over the past ve decades in understanding and reducing risk from established TTIDs, emerging infectious threats continue to be identied and there continues to be pressure to further enhance the safety of transfusions (Fig. 4). Table 1 compares the features of established and emerging pathogens of concern for blood safety. The previous paradigm for an emerging transfusion-transmitted pathogen was that it would cause a prolonged, asymptomatic carrier state, as
Classic transfusion pathogens (HBV, HIV, HTLV, HCV) Asymptomatic, persistent infections in donors. Primarily attributable to sexual or IDU exposure in donors. Proven transmission by transfusion. Proven disease associations. New agents of concern Transient infections in donors (bacteria, HAV, B19, WNV). Zoonotic agents (T. cruzi, PTLV, ERV, BSE/CWD, WNV, SARS). Transfusion transmission not established (enteroviruses, SARS, inuenza). No established disease (GBV/HCV, TTVs, SEN-v, HERVs). BSE/CWD = bovine spongioform encephalopathy/chronic wasting disease; GBV = GB virus; HERV = human endogenous retrovirus; IDU = injection drug use; SARS = severe acute respiratory syndrome; SEN-v = SEN virus.
Risks of major TTVs linked to interventions, and accelerating rate of EIDs of concern to blood safety
Risk per Unit 1:100
Monkey Pox Leishmania HCV bacteria PTLVs T cruzi influenza DENV Babesia
Emerging Infectious Disease Threats
HBV
1:10,000
H IV
1:100,000
1:1,000,000
<1984 1984 1986 1988 1990 1992 1994 1996 1998 2000 2002 2004 2006 2008 2010
Revised Donor Deferral Criteria HBsAg Screening HIV Ab Screening HCV Ab Screening p24 Ag Testing HCV and HIV NAT WNV NAT T cruzi Ab Screening HBV NAT
NANB Hepatitis Surrogate Testing
vCJD Deferral Criteria
Adapted from TRANSFUSION 2006;46:1624-1640
Fig. 4. Evolution of the risks of transmission by blood transfusion for HIV, HBV, and HCV. Major interventions to reduce risks are indicated below the time line on the X axis. Emerging infectious disease threats over the past 20 years are indicated above in the top right quadrant of the gure. Ab = antibody; Ag = antigen; CHIKV = Chikungunya virus; DENV = dengue virus; ICL = idiopathic CD4+ T-lymphocytopenia; SARS = severe acute respiratory syndrome; SFV = simian foamy virus; XMRV = xenotropic murine leukemia virus-related virus. Reproduced from Busch,155 with permission from the AABB. 2092 TRANSFUSION Volume 50, October 2010
SFV
ICL
1:1000
CHIKV XMRV
vCJD
WNV
SARS
to blood recipients. Salient examples include probable origins of HIV-1 and -2 from chimpanzee and simian immunodeciency viruses, HTLV-I and -II from PTLV and vCJD from BSE. Proactive surveillance for such events is clearly important. There is intense research to identify new blood-borne infectious agents using novel molecular discovery strategies.144 Although recent examples of putative new agents have proven to be nonpathogenic (hepatitis G virus, TTV, and Sen-V)145 or not transmitted at signicant rates by transfusions (HHV-8),146,147 every newly discovered agent requires serious investigation to assess its relevance to transfusion safety. In an effort to proactively assess transfusion safety threats in the United States and Canada, the TransfusionTransmitted Diseases Committee of the AABB has systematically reviewed relevant data and prioritized the risks of individual emerging disease agents according to the scientic evidence and regulatory considerations, as well as public perception and concern regarding each disease agent. This process led to publication of an important supplement to TRANSFUSION in 2009 that includes an overview article and Fact Sheets for each agent.148 These Fact Sheets are updated on the AABB website as new information becomes available or new agents of concern are identied.
MODELS FOR INTRODUCING BLOOD DONOR SCREENING ASSAYS

Historically, decisions to implement donor screening tests have been made based on perceived threats to the blood supply. The FDA and blood centers have encouraged diagnostic companies to develop and license tests to screen blood donors as potentially infectious agents were identied. These companies invested heavily in conducting the assay development work and clinical trial studies required by the FDA for approval with the expectation that when licensed, the FDA would require universal donor screening. Once licensed, companies would commercialize the test, selling it to blood centers to realize a return on their investment. In 1999, NAT technology was launched using an unconventional regulatory pathway and with seed funding from the National Heart, Lung, and Blood Institute. With a sense of urgency from the FDA to implement NAT for detection of HIV and HCV, universal donor screening was implemented as part of the national clinical trial using an IND exemption. Blood centers introduced donor screening as part of a study and paid the diagnostic companies cost recovery to use the test in the clinical trial. Blood centers in turn recovered the costs from the hospitals. Once the tests were licensed, the companies increased the price to the blood centers (commercial pricing) who passed the cost to the hospitals. This model was repeated for WNV NAT in 2003. In this model a
large part of the costs of the clinical trial studies was borne by the blood centers. In 2007, a test for T. cruzi antibody was introduced to the blood testing market using the rst model described above. However, the FDA did not issue guidance to blood centers to perform the test and the test was not universally accepted or adopted. After 3 years of testing, most of the blood centers have elected to move to selective testing, testing donors only once in their lifetime.90,149 The delayed adoption and continued lack of a nal FDA guidance requiring implementation of HBV NAT, despite both NAT vendors having developed and received FDA clearance of triplexed HIV/HCV/HBV assays, has further heighted manufacturer reluctance to invest in donor screening assay development. This problem is magnied in the United States where nancially onerous clinical trials and the BLA licensure process (can cost in excess of $20 million/test, compared to less than $5 million approval in the European Union. As infectious agents transmitted via blood products are identied going forward, new models are needed for development and implementation of donor screening and supplemental tests. The model used in the past is not realistic in the current environment. Test manufacturers are not willing to make the required investment to obtain an FDA license to commercialize potentially useful tests. Once approved, the costs of assays have become too onerous for the blood organizations to afford for some agents. The paradigm has already begun to change. As we learned from the NAT experience, it is acceptable to perform donor testing under an IND exemption. The T. cruzi experience illustrates the feasibility and acceptance of selective testing. The remaining challenge is to modify the way donor testing decisions are made. The purpose of the clinical trial should be to conduct a study, the results of which would be used to make a decision about the need for and optimal approach to implementation of testing. Initializing a clinical trial should not be based on anticipated universal implementation except in extremely rare circumstances when a bona de epidemic of a highly signicant new pathogen is occurring (e.g., HIV and perhaps WNV).
PRTs
There has been substantial progress over the past decade in development of PRTs that have the potential to transform the approach used to prevent (or at least signicantly reduce) transmission of infectious agents by labile blood components, similar to the dramatic impact of PRT on the infectious risks of plasma derivatives.150-153 PRT would eliminate the risk of transmission from window period and chronic occult infection donations that contain low titers of TTIDs; will likely allow for discontinuation of some donor screening assays (e.g., syphilis and anti-HBc) and donor deferral policies (e.g., malaria travel deferral);
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and, perhaps most important, would enable proactive (prophylactic) rather than reactive (delayed testing) responses to emerging infectious agents.110,149-153 Unfortunately, this hope is guarded by signicant concerns of regulators at FDA as well as some transfusion medicine experts, regarding the efcacy and safety of the PRTtreated plasma and PLT components that are currently available and utilized in some European countries. Moreover, there are no commercialized methods for PRT treatment of whole blood or RBC components, although methods are in development and clinical trials in the planning stages. When PRT becomes available for all components and is adopted by the transfusion medicine community, the blood supply may nally reach the goal of near zero risk that has been the mantra of blood safety experts since the onset of the HIV epidemic 30 years ago.
6. Zou S, Notari EP, Fang CT , Stramer SL, Dodd RY. Current value of serologic test for syphilis as a surrogate marker for blood-borne viral infections among blood donors in the United States. Transfusion 2009;49:655-61. 7. WHO. Recommendations. Screening donated blood for transfusion-transmissible infections. 2009. [cited 2010 August 16] Available from URL: http://www.who.int/ entity/bloodsafety/ScreeningDonatedBloodfor Transfusion.pdf 8. Havens WP Jr. Viral hepatitis. Yale J Biol Med 1961/1962; 34:314-28. 9. Krugman S, Giles JP, Hammond J. Infectious hepatitis. Evidence for two distinctive clinical, epidemiological, and immunological types of infection. JAMA 1967;200: 365-73. 10. Gowland P, Fontana S, Niederhauser C, Taleghani BM. Molecular and serologic tracing of a transfusiontransmitted hepatitis A virus. Transfusion 2004;44:155561. 11. Ganem D, Prince AM. Hepatitis B virus infectionnatural history and clinical consequences. N Engl J Med 2004;350: 1118-29. 12. Blumberg BS, Alter HJ, Visnich SA. New antigen in leukemia sera. JAMA 1965;191:541-6. 13. Prince AM. An antigen detected in the blood during the incubation period of serum hepatitis. Proc Natl Acad Sci U S A 1968;60:814-21. 14. Biswas R, Tabor E, Hsia CC ,Wright DJ, Laycock ME, Fiebig EW, Peddada L, Smith R, Schreiber GB, Epstein JS, Nemo GJ, Busch MP. Comparative sensitivity of HBV NATs and HBsAg assays for detection of acute HBV infection. Transfusion 2003;43:788-98. 15. Stramer SL. Pooled hepatitis B virus DNA testing by nucleic acid amplication: implementation or not. [Editorial].Transfusion 2005;45:1242-6. 16. Hollinger FB. Hepatitis B virus infection and transfusion medicine: science and the occult. Transfusion 2008;48: 1001-26. Kleinman SH, Busch MP. Assessing the impact of HBV NAT on window period reduction and residual risk. J Clin Virol 2006;36 Suppl 1:S23-9. Zou S, Stramer SL, Notari EP, Kuhns MC, Krysztof D, Musavi F, Fang CT, Dodd RY. Current incidence and residual risk of hepatitis B infection among blood donors in the United States. Transfusion 2009;49:1609-20. Kuhns MC, Busch MP. New strategies for blood donor screening for hepatitis B virus: nucleic acid testing versus immunoassay methods. Mol Diagn Ther 2006;10:77-91. Kleinman SH, Lelie N, Busch MP. Infectivity of human immunodeciency virus-1, hepatitis C virus, and hepatitis B virus and risk of transmission by transfusion. Transfusion 2009;49:2454-89. Cherubin CE, Prince AM. Serum hepatitis specic antigen (SH) in commercial and volunteer sources of blood. Transfusion 1971;11:25-7.
CONCLUSIONS
Our ability to identify, understand, measure, and reduce infectious risks from transfusions has evolved dramatically over the past 50 years. Progress in developing approaches for systematic assessment of emerging infectious risks and for implementing rational approaches to respond to new pathogens of concern are particularly noteworthy. Although there will undoubtedly continue to be new agents of concern and challenges to implementation of costly blood safety initiatives, we now have a foundation based on science and open policy discussion that should suit us well in the decades ahead.
CONFLICT OF INTEREST None.
REFERENCES
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125. Custer B, Kamel H, Kiely NE, Murphy EL, Busch MP. Associations between West Nile virus infection and symptoms reported by blood donors identied through nucleic acid test screening. Transfusion 2009;49:278-88. 126. Orton SL, Stramer SL, Dodd RY. Self-reported symptoms associated with West Nile virus infection in RNA-positive blood donors. Transfusion 2006;46:272-7. 127. Brown JA, Factor DL, Tkachenko N, Templeton SM, Crall ND, Pape WJ, Bauer MJ, Ambruso DR, Dickey WC, Marn AA. West Nile viremic blood donors and risk factors for subsequent West Nile fever. Vector Borne Zoonotic Dis 2007;7:479-88. 128. Kleinman SH, Williams JD, Robertson G, Caglioti S, Williams RC, Spizman R, Morgan L, Tomasulo P, Busch MP. West Nile virus testing experience in 2007: evaluation of different criteria for triggering individual-donation nucleic acid testing. Transfusion 2009;49:1160-70. 129. CDC. West Nile virus transmission through blood transfusionSouth Dakota, 2006. MMWR Morb Mortal Wkly Rep 2007;56:76-9. 130. Busch MP, Kleinman SH, Tobler LH, Kamel HT, Norris PJ, Walsh I, Matud JL, Prince HE, Lanciotti RS, Wright DJ, Linnen JM, Caglioti S. Virus and antibody dynamics in acute west nile virus infection. J Infect Dis 2008;198:98493. 131. Biggerstaff BJ, Petersen LR. A modeling framework for evaluation and comparison of trigger strategies for switching from minipool to individual-donation testing for West Nile virus. Transfusion 2009;49:1151-9. 132. Custer B, Busch MP, Marn AA, Petersen LR. The costeffectiveness of screening the U.S. blood supply for West Nile virus. Ann Intern Med 2005;143:486-92. 133. Petersen LR, Hayes EB. West Nile virus in the Americas. Med Clin North Am 2008;92:1307-22. ix. 134. CDC. Transmission of Colorado tick fever virus by blood transfusion. MMWR Morb Mortal Wkly Rep 1975;24:422-7. 135. Tambyah PA, Koay ES, Poon ML, Lin RV, Ong BK; Transfusion-Transmitted Dengue Infection Study Group. Dengue hemorrhagic fever transmitted by blood transfusion. N Engl J Med 2008;359:1526-7. Chuang VW, Wong TY, Leung YH, Ma ES, Law YL, Tsang OT, Chan KM, Tsang IH, Que TL, Yung RW, Liu SH. Review of dengue fever cases in Hong Kong during 1998 to 2005. Hong Kong Med J 2008;14:170-7. Lindquist L, Vapalahti O. Tick-borne encephalitis. Lancet 2008;371:1861-71. Kaiser R. Tick-borne encephalitis. Infect Dis Clin North Am 2008;22:561-75. x. Petersen LR, Busch MP. Transfusion-transmitted arboviruses. Vox Sang 2009;98:495-503. Gubler DJ. The global emergence/resurgence of arboviral diseases as public health problems. Arch Med Res 2002; 33:330-42. Linnen JM, Vinelli E, Sabino EC, Tobler LH, Hyland C, Lee TH, Kolk DP, Broulik AS, Collins CS, Lanciotti RS, Busch
MP. Dengue viremia in blood donors from Honduras, Brazil, and Australia. Transfusion 2008;48:1355-62. 142. Mohammed H, Linnen JM, Munoz-Jordan JL, Tomashek K, Foster G, Broulik AS, Petersen L, Stramer SL. Dengue virus in blood donations, Puerto Rico, 2005. Transfusion 2008;48:1348-54. 143. Bianco C. Dengue and Chikungunya viruses in blood donations: risks to the blood supply? Transfusion 2008;48: 1279-81. 144. Delwart EL. Viral metagenomics. Rev Med Virol 2007;17: 115-31. 145. Bernardin F, Operskalski E, Busch M, Delwart E. Transfusion transmission of highly prevalent commensal human viruses. Transfusion 2010 May 24;50:[Epub ahead of print]. 146. Cannon MJ, Operskalski EA, Mosley JW, Radford K, Dollard SC. Lack of evidence for human herpesvirus-8 transmission via blood transfusion in a historical US cohort. J Infect Dis 2009;199:1592-8. 147. Busch MP, Glynn SA. 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. J Infect Dis 2009; 199:1564-6. 148. Stramer SL, Hollinger FB, Katz LM, Kleinman S, Metzel PS, Gregory KR, Dodd RY. Emerging infectious disease agents and their potential threat to transfusion safety. Transfusion 2009;49 Suppl 2:1S-29S. 149. Custer B, Agapova M, Martinez RH. The cost-effectiveness of pathogen reduction technology as assessed using a multiple risk reduction model. Transfusion 2010 May 24;50:[Epub ahead of print]. 150. Bryant BJ, Klein HG. Pathogen inactivation: the denitive safeguard for the blood supply. Arch Pathol Lab Med 2007;131:719-33. 151. Klein HG, Anderson D, Bernardi MJ, Cable R, Carey W, Hoch JS, Robitaille N, Sivilotti ML, Smaill F. Pathogen inactivation: making decisions about new technologies. Report of a consensus conference. Transfusion 2007;47: 2338-47. Alter HJ. Pathogen reduction: a precautionary principle paradigm. Transfus Med Rev 2008;22:97-102. Klein HG, Glynn SA, Ness PM, Blajchman MA. Research opportunities for pathogen reduction/inactivation of blood components: summary of an NHLBI workshop. Transfusion 2009;49:1262-8. Alter HJ, Klein HG. The hazards of blood transfusion in historical perspective. Blood 2008;112:2617-26. Busch MP. Transfusion-transmitted viral infections: building bridges to transfusion medicine to reduce risks and understand epidemiology and pathogenesis. 2005 Emily Cooley Award Lecture. Transfusion 2006;46:1624-40.
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TRANSFUSION 2099

Transfusion Associated Infections

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Transfusion Associated Infections

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5 0 TH A N N I V E R S A R Y

Transfusion-associated infections: 50 years of relentless challenges and remarkable progress

Herbert A. Perkins and Michael P Busch .

PERKINS AND BUSCH

PERKINS AND BUSCH

AIDS, HUMAN IMMUNODEFICIENCY VIRUS, AND OTHER RETROVIRUSES

The controversy over surrogate testing for AIDS

PERKINS AND BUSCH

The beginning of lookback

Donor screening for HIV

Human T-cell lymphotropic viruses

PERKINS AND BUSCH

PERKINS AND BUSCH

WEST NILE VIRUS AND OTHER ARBOVIRUSES

OTHER ESTABLISHED TRANSFUSION-TRANSMITTED INFECTIONS

PERKINS AND BUSCH

TABLE 1. Changing paradigm of signicant transfusion pathogens

Emerging Infectious Disease Threats

NANB Hepatitis Surrogate Testing

vCJD Deferral Criteria

Adapted from TRANSFUSION 2006;46:1624-1640

MODELS FOR INTRODUCING BLOOD DONOR SCREENING ASSAYS

PERKINS AND BUSCH

Volume 50, October 2010

Volume 50, October 2010

PERKINS AND BUSCH

Volume 50, October 2010

Volume 50, October 2010

PERKINS AND BUSCH

Volume 50, October 2010

137. 138. 139. 140.

Volume 50, October 2010

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