Variant CJD transmission through blood: risks to predictors and “predictees”

W hen it became evident in the mid-1990s that a significant proportion of plasma pools used in the production of therapeutic protein derivatives were “contaminated” by donations from individuals who later died of sporadic CJD, regulatory agencies responded with guidance about quarantine and/or destruction of implicated component lots. These precautions were based on laboratory evidence that low levels of infectivity were present in blood during both the incubation and the clinical phases of disease in experimental rodent models; however, it was also appreciated that there was a serious discrepancy between the experimental data and epidemiologic observations that, although mostly anecdotal, failed to identify any instance of a human case of CJD that could be traced to blood or blood components. With the passage of time, systematically collected epidemiologic data substantiated the absence of CJD transmissions in blood recipients and began to weigh more heavily on the perception of risk to humans. It was finally decided that any such risk was negligible, and plasma pools were no longer discarded upon knowledge of a contributing CJD donor (although deferrals designed to eliminate “high-risk” donor categories, such as growth hormone and dura mater recipients, remained in force). Similar concerns about the possibility that blood from individuals with variant CJD (vCJD) might pose a significant risk have led to an array of donor deferral policies aimed at minimizing the chances of accepting a blood donor who might be incubating this new form of disease. vCJD results from the consumption of meat products from cattle infected with bovine spongiform encephalopathy (BSE), and its national incidence roughly corresponds to the national incidence of BSE, which began in the UK and was subsequently exported to other mostly European countries. Since 1996, over 130 cases of cVJD have occurred in the UK, 6 in France, and 1 each in Ireland and Italy. Individual cases have also been diagnosed in the US, Canada, and Hong Kong in patients who resided for many years in the UK during the height of the BSE epidemic. Donor deferral policies related to vCJD are based on three considerations: The unknown number of individuals who might be infected with BSE, which could possibly be much larger than the 1 per million incidence of sporadic CJD and thereby increase the odds of accepting one or more asymptomatic but infected donors to plasma pools. The greatest risk would be from UK donors, with much diminished risk from other European nationals, and from visitors to the UK and continental Europe. The laboratory demonstration that, unlike sporadic CJD, pathologic “prion” protein can be detected in many peripheral tissues from patients dying of vCJD; also, that infectivity can be detected in blood-interactive organs such as tonsil and spleen. The experimental transmission of disease from the blood of rodents experimentally infected with vCJD and of sheep experimentally infected with BSE. These are all legitimate causes for concern, but they are only one side of the story. The other side can be summarized as follows: While it is true that the number of vCJD “carriers” remains unknown, early estimates of as many as 100,000 cases have in recent years shriveled to a maximum of just a few hundred cases, assuming the entirely reasonable estimate of 15 to 20 years as the average incubation period.1,2 The increasing time period during which the evolution of cases has been observed continues to improve the precision of mathematical modeling and to alleviate concern about the extent of infection of the exposed UK population. Although the concentration of prion protein is indisputably higher in the organs of patients with vCJD than sporadic CJD, and probably does indicate a correspondingly higher concentration of infectivity, infectivity is demonstrable in tissues of patients with both diseases,3,4 and no studies directly comparing infectivity levels have been performed. Furthermore, the presence of infectivity in blood-interactive organs is not equivalent to infectivity in the blood, as is well demonstrated in studies of circulating and splenic lymphocytes in an experimental mouse model of scrapie.5 Transmission of disease in experimental models via blood and blood components should not be considered in isolation. The only meaningful approach comes from a consideration of data that compare infectivity in vCJD and BSE experimental models to other experimental disease models or that compare epidemiologic observations in humans. These data are summarized in Table 1 (references 6-9 and unpublished data) and lead to the conclusion that, at the very least, the risk associated with vCJD and BSE is not yet demonstrably worse than the risk from non-vCJD forms of disease, which has been shown to be negligible. The argument presented here will not be popular with the media, for which stories about preventable misfortunes and consequent blame are more interesting, nor with the government, which tends to try to avoid censure by leaning toward the most conservative precautionary approach. It will not even be popular with research laboratories that because of public concern receive funds to study the issue. Moreover, the public is quicker to forget the prediction of bad things that never happen than to forgive a failure to predict (and prevent) bad things that do happen, an ancient human trait that has influenced forecasters at least as far back as the Delphic oracle. With such a “predictor risk” in mind, we wish to emphasize that our intent is not to minimize the continuing need to evaluate the possibility of disease transmission via blood or blood components from patients who are incubating vCJD. A number of important laboratory studies are still incomplete, and epidemiologic observations are limited to small numbers and a comparatively short period of time. We merely wish to urge regulatory agencies and the general public to take a balanced view of the risk, based on the facts as we presently know them, and appreciate that just as accumulating data extenuated the risk of blood transmission from patients with sporadic disease, so also should similarly accumulating data influence the perception of risk associated with vCJD.

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