Volume 2: Science
4. The link between BSE and vCJD
Estimates of the size of the vCJD epidemic

4.16 In this Report we consider in depth the measures taken to address the possibility that BSE might be transmissible to humans. These measures were taken as precautions against a risk considered remote. Their importance can only be demonstrated with hindsight by reference to the extent to which BSE has in fact proved transmissible to humans. In the following sections we show that this is a matter on which it is too early to draw firm conclusions.

4.17 Attempts to estimate the possible size of a vCJD epidemic have been hampered by the many variables associated with the disease. Many important factors in determining the probability of BSE transmission to an individual, such as dose, route of exposure, incubation period, genetic susceptibility and scale of the species barrier between cattle and man, are unknown. Nevertheless, several groups of epidemiologists and statisticians have attempted to predict the possible number of cases, using complex mathematical models. Unsurprisingly, these groups have arrived at varying estimates, ranging from very few cases to many millions, as a result of the different methodologies adopted.

4.18 One of the first studies was published by Cousens and colleagues in 1997, and was based on the 14 cases of vCJD confirmed by the end of 1996. ¹ Their estimate was dependent on many variables and was highly sensitive to the distribution of average incubation periods. Thus, it was estimated that the incidence of vCJD could be anything between 75 and 80,000. However, the authors recognised the limitations of basing their calculations on so few cases. Further analysis carried out by Ghani and colleagues from the Wellcome Trust Centre for the Epidemiology of Infectious Disease in 1998, extended the work of Cousens and colleagues, determining that with the information that was currently available, the uncertainty over the future size of the epidemic was likely to remain for the following three to five years. ² However, they concluded that the current data could have been consistent with epidemics ranging from less than 100 to several million cases.

4.19 In a study published in 1999, Professors Philip Thomas and Martin Newby of City University, London, estimated that, if BSE is indeed the cause of vCJD, not more than a few hundred cases would be expected and that most likely, the actual number would be 100 or less. ³ The continued low incidence of vCJD since publication of their study was considered to be confirmation that the upper limit of their estimate was likely to be accurate.

4.20 However, the methodology adopted by Thomas and Newby has been criticised by Ferguson and colleagues from the Wellcome Trust Centre for the Epidemiology of Infectious Disease, who claim that they misused a test statistic and as a consequence arrived at an estimate for the upper bounds of disease incidence that was too low. ⁴ Using the same data as Thomas and Newby, Ferguson et al. determined that only very wide bounds could be placed on future vCJD incidence. Furthermore, they questioned the suitability of a model fitting to only four years of case data for a disease that may have an incubation period of several decades. Rather, Ferguson et al. proposed extensive scenario analysis as a more cautious and thorough approach to determining the range of potential future epidemic patterns consistent with current data.

4.21 The conclusions of Thomas and Newby were also examined by the Epidemiology Subcommittee of Spongiform Encephalopathy Advisory Committee (SEAC), whose remit is to assess any information about the epidemiology of vCJD and develop, as far as possible, advice on trends in the disease. ⁵ In a written statement to the Inquiry Professor Peter Smith, Chairman of the Subcommittee, emphasised the importance of knowing the future size of an epidemic in order to make policy decisions and to estimate the future burdens that might be put on the National Health Service (NHS). The Epidemiology Subcommittee felt that the analyses carried out by Thomas and Newby were flawed and therefore rejected their conclusions.

4.22 Following the discovery that abnormal PrP can be detected in certain tissues, such as tonsils and appendices, before the onset of clinical symptoms, two projects have recently been supported by the Department of Health (DH) and the Medical Research Council (MRC). The projects are based on the plan to test tonsil and appendix tissue anonymously for the prevalence of PrP^Sc. Information on the prevalence of incubating disease could then be used to reduce the current uncertainty about the future size of the epidemic. A recent study by Ghani and colleagues aimed to determine the age-group or groups that would provide the most information on the size of a potential epidemic from tissue samples. ⁶ Ghani et al. predicted that anonymous testing would be most informative if undertaken on samples from 25-29-year-olds, but random samples of appendix tissue removed recently from individuals of all age-groups would be almost as informative. Screening of this nature could only exclude a large epidemic if a small number of infections were detected and if the test was able to detect infection early in the incubation period. The usefulness of anonymous testing of stored tissues has, however, been questioned, since it is unknown if the presence of PrP^Sc is necessarily indicative that an individual is destined to develop clinical disease. ⁷

4.23 Interim results of this study, which have recently become available, show that of 3,000 tonsil/appendix samples tested, none was found to contain PrP^Sc. ⁸ This failure to detect a single positive test is consistent with previous estimates of an epidemic anywhere between 100 and a million cases, ie, the result neither increases the minimum number of cases expected nor reduces the maximum. However, this result is subject to a number of limitations. Firstly, the sample size was low. Modelling studies demonstrate that tests in tens of thousands of samples would be required to determine the future size of an epidemic. Indeed, these results are interim ones from a larger study examining around 18,000 samples, the results of which will be available by the end of 2000 and 2002. Secondly, the samples examined were all archived fixed material, which makes analysis more difficult. Studies examining fresh material are getting under way. Thirdly, the relationship between the presence of PrP^Sc in lymphoid tissue and the subsequent onset of clinical disease has not been proven, though it is highly probable. Moreover, the length of incubation period and the stage in the disease at which PrP^Sc is present in the lymphoid tissue are unknown. Thus the result of the analysis of any sample may only be indicative of the position at the time at which the sample was taken.

4.24 Thus the likely scale of an epidemic of vCJD is still uncertain and the subject of much debate. The emergence of vCJD cases to date has been consistent with both low and high estimates for future cases. It appears that the differences in opinion outlined above will not be resolved until such time as many more of the characteristics of vCJD are known and understood. In particular, the development of a robust blood test which could identify at least 75 per cent of those incubating the disease would allow more extensive screenings and more reliable estimates of the size of a future epidemic.