Appendix 1: Knowledge about the risk of transmission by blood transfusion of Creutzfeldt–Jakob disease in 1995 and 1999
There was limited scientific knowledge about the risk of transmission of classic Creutzfeldt–Jakob disease (CJD) by blood transfusion in 1995. Animal studies suggested that intracerebral inoculation of guinea pigs and hamsters with blood from human donors with CJD could produce disease, although no blood-to-blood transmission had been demonstrated at this time.35,36 In humans, transmission of the condition from cadaveric human growth hormone provided a model for acquisition of the condition via a peripheral route. Iatrogenic transmission had also been documented with human gonadotropin hormone, the reuse of neurosurgical equipment and stereotactic electroencephalogram electrodes, and from dura mater transplants. All of these involved transfer of material that had been in contact with the central nervous system of an individual with classic CJD to a previously unaffected individual.37 There was, however, no epidemiological evidence to support transmission of the condition via blood transfusion. One case report documented the development of classic CJD in an individual who had received a liver transplant. It was hypothesized that either the liver or a potentially infected albumin transfusion may have caused the development of the disease. However, the rapidity of onset of the condition following transplant made the causative association unlikely given the normally long latency period of CJD.38 Other case reports of CJD developing after blood transfusion also had important limitations such as the existence of CJD in the donor not having been documented.39 No controlled cohort studies to examine the question of blood transmission of CJD had been carried out by 1995. Three case–control studies had been carried out to identify the rates of blood transfusion in individuals with CJD and in controls. None of these studies demonstrated higher rates of transfusion among patients with CJD.40,41,42 CJD had also been shown not to have a higher incidence in those who received blood frequently, although this question had not been studied formally in 1995.43 Overall, most researchers who studied CJD considered the risk of transmission of the condition by blood transfusion to be theoretical.44
Between 1995 and 1999, further evidence accumulated that suggested that classic CJD was not transmitted through transfusion of blood products. In addition to 3 previous case–control studies, the results of which were available in 1995, 2 further large case–control studies did not show a higher rate of blood transfusion among individuals with CJD compared with controls.45,46 However, no long-term cohort studies were carried out to examine the question. Furthermore, several of the case–control studies had important methodological limitations related to the choice of control population, which could have biased their results. Look-back studies following recipients who had received blood products from individuals later diagnosed with CJD did not demonstrate development of the condition among the recipients.47,48 In addition, studies of hemophiliacs, a population exposed to large amounts of blood products, found that they were not predisposed to acquiring the condition.49
There was considerably less evidence regarding the question of whether variant CJD (vCJD) could be transmitted by blood. In 1999, there was no substantive epidemiological evidence, and the results of animal studies examining the question were not expected for another 2 years. Scientists considered the risk of transmission of the condition to be theoretical, although higher than for CJD. The primary reason for the increased risk was the higher concentration of the prion protein in the brains of individuals with vCJD, suggesting a higher "infectious" load, in addition to the presence of the prion protein in lymphoid tissue, which is intimately linked to blood. Furthermore, vCJD was believed to have crossed species barriers, presumably having been transmitted by the oral route. This demonstrated the potential for peripheral transmission of the condition. The fact that vCJD had only recently been described and had a potentially long latency period also suggested to scientists and decision-makers that a precautionary approach should be taken.50
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