Bovine spongiform encephalopathy, variant CJD, and blood transfusion: beefer madness?

Until recently, the population of North America has largely been spared from concerns about bovine spongiform encephalopathy (BSE) and variant CJD (vCJD). The absence of indigenous cases of either disease, and the presence of measures to protect the food chain and to defer blood donors judged to be at risk of exposure to BSE, have contributed to this sense of relative ease. Over the past 12 months or so, however, two cases of BSE have been diagnosed in cattle born in North America, and in the UK, there has been a suspicious case of epidemiologic linkage of a vCJD-affected blood recipient with the same disease in an implicated blood donor.1 The detection of the case of BSE in a cow in Washington State led to front-page press coverage for about 2 weeks and immediate regulatory action was taken with respect to the management of downer cattle destined for slaughter for consumption. Nevertheless, the apparent transmission of vCJD by transfusion attracted very little attention in North America, although it had profound impact in the UK. In a curious reversal of perspective, the New York Times reported on January 28, 2004, that a new FDA policy banning the use of bovine blood to feed calves2 was partly based upon the apparent transfusion-transmitted case of vCJD.3 Although neither the appearance of BSE in North America nor the apparent transfusion transmission of vCJD was entirely unexpected, these events do provide impetus for further consideration of means to safeguard the blood supply in North America from the risk of transmission of infectious prions or at least to raise public confidence in its perceived safety. Certainly, denial is not an option, but neither is panic. Although many feel that the existing measures to deal with this risk are excessive, they were at least developed with some deference to the need to balance their potential efficacy against the availability of lifesaving blood components. Three articles in this issue of TRANSFUSION clearly raise the need for careful discourse and the development (to the extent possible) of evidence-based decisions. Murphy and colleagues4 compare the predicted impact of a travel deferral for BSE exposure with the actual number of deferrals that occurred once the policy was put in place. In doing so, they directly support the perception that the number of deferrals predicted by survey significantly exceeded those documented by blood centers after implementation. A very welcome feature of this study is the actual use in the survey of the wording of the deferral questions to be implemented. Nevertheless, I do not believe that there is a great deal of good news in this study. In particular, I feel that it would be unwise to implement new questions without prior evaluation of their possible impact on donor and blood availability. Neither do I feel it smart to assume that the donation loss because of a deferral question will be less than that predicted by survey. A well-publicized deferral policy is quite likely to lead to self-deferral, which cannot be readily measured. Indeed, in other instances, such as deferrals for severe acute re-spiratory syndrome (SARS) exposure or for a history of symptoms associated with West Nile virus (WNV) infection, blood establishments appropriately encouraged self-deferral to reduce the administrative overhead of registering, and then rejecting, donors. Another issue is that donor loss has a reverberating impact on blood availability as each future donation is lost.5 There is also another side to the equation: it may indeed be true that donors fail to answer questions in the same way in the contrasting circumstances of completing a questionnaire at leisure and during the stressful completion of the donor interview. Careful cognitive assessment of any proposed donor question should be mandatory, or we are shooting if not in the dark, at least in the shadows. We must also be aware that the accessible donor population seems to be limited and that a succession of small slivers cut from the resource pretty soon add up to a big slice. A loss of 1 percent of our donors involves approximately 80,000 individuals in the first year, plus all of their potential future donations. Schreiber and coworkers6 pose the question of whether donors should be further screened to eliminate those at potentially increased risk of exposure to prions. Again, a questionnaire-based study is reported, specifically collecting information on the proportion of blood donors who recollect having eaten the brains of selected mammals. The survey-predicted impact of such deferrals would be as much as 6.4 percent and there are no data about exposure to deer and elk, which are known to have high frequencies of chronic wasting disease (CWD) in some areas and logically should be included if such a deferral were to be implemented. As the authors point out, there are no definitive data implicating direct consumption of brain as a risk factor for vCJD, although this is a plausible hypothesis. Unfortunately, there may have been far more exposure through inadvertent consumption of neural tissue by the use of mechanically separated meat products, improperly butchered carcasses, brain tissue embolism at slaughter, and the use of brains as an adjunct in culinary practice. Thus, movement toward a policy of this type might be a step presaging more and more deferral criteria and fewer and fewer donors. Preemptive strategies may appear attractive, but should be based on sound intelligence. Some countries have moved toward, or have adopted, a policy of permanently prohibiting the collection of blood from donors who themselves have received transfusion. Again, this appears to be an attractive and preemptive measure, but it does not take much reflection to realize that, if transfusion (of whole blood and components) were the only route of transmission of a disease, it would soon disappear. Thus, this policy relates to prevention of individual cases, rather than to control of an epidemic. This is not an argument for cavalier treatment of blood recipients, but rather a plea for careful consideration of expected benefits of any given policy. Broad deferral of persons who previously received transfusions would result in the loss of around 5 percent of currently active donors who would have to be replaced by newly recruited first-time donors. Such a policy might also decrease public confidence in the safety of the blood supply itself. In fact, when measured against some of these broad deferral policies, the seemingly aggressive actions suggested by Bird7 in her editorial addressing management of British donors at risk of vCJD are quite reasonable. There is a continuing discussion about the value of donor questioning: a process that is clearly neither sensitive nor specific. Those whose concern is focused only on safety would like to improve the sensitivity of the questioning process and their case is boosted by post-donation surveys showing that about 2 percent of successful donors failed to acknowledge risk factors or behaviors that would have resulted in their deferral.8 Those who are concerned about blood availability cite the current safety of the blood supply and lament the loss of numerous safe donors or donations. These issues should be of lesser concern in the face of effective means to test donations for infectivity. As a consequence, there is a perhaps misguided sense that a blood test for infectious prions is extremely desirable for blood safety. Such a solution is easy to think about, but hard to achieve. It now seems likely that the level of infectious BSE and/or vCJD prions in blood does not differ from the very low levels of the prions of classical CJD9—two to three orders of magnitude below currently achievable laboratory detection levels. Also, such an “easy” solution comes with a significant price of its own—that of the impact of such a test on those subjected to it.10,11 McCullough and associates12 report on a Canadian consensus conference, held in early 2003, to discuss the concerns and issues to be managed were a donor screening test for infectious prions to become available. This meeting was a wonderful example of establishing a process for defining and analyzing required data and specifying conditions around, and impacts of, a prion infectivity test. It provides a well-ordered set of factors that should be present before considering testing and numerous issues that would have to be resolved if testing is initiated. Perhaps most important are the ethical concerns associated with the use of a test with unknown performance characteristics and prognostic significance relating to a dreadful and deadly disease. It may be argued that these issues were effectively managed when testing for anti-HIV was introduced. Nevertheless, at the time, much more was known about the significance of a positive test and only a limited fraction of the population had an established risk factor. Another recent report provides an excellent and detailed overview of the current state of prion science and lays out a portfolio of needed research in the field.13 Interestingly, there is preliminary information to suggest that an alternate approach to safety may be on the horizon—that is, the use of affinity adsorption to remove prions from blood components. Two companies have released early data suggesting that this approach may be feasible. There is clearly a long way to go before this becomes reality, but it is certainly encouraging that only a relatively low titer of infectivity may need to be removed. In addition, it is to be hoped that this approach can be achieved with no, or minimal, damage to components and minimal loss of their therapeutic content. Such technology, were it to be effective and safe, would certainly eliminate the problems discussed in this commentary, were further action found to be necessary.

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