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IJE vol.34 no.1 © International Epidemiological Association 2005; all rights reserved. International Journal of Epidemiology 2005;34:46–52 Advance Access publication 13 January 2005 doi:10.1093/ije/dyh374 Risk of variant Creutzfeldt–Jakob disease in France Marc Chadeau-Hyam* and Annick Alpérovitch Accepted 6 October 2004 Background France has the second highest number of variant Creutzfeldt–Jakob disease (vCJD) cases worldwide. Imports of bovine carcasses from the UK probably constituted the main source of exposure of the French population to the bovine spongiform encephalopathy (BSE) agent. Meat products consumed whilst visiting the UK have also been considered as a possible source of exposure. Methods We estimated the number of future vCJD cases in France using a simulation approach. Both the distribution of the vCJD incubation period and the agedependent susceptibility to the BSE agent were estimated from UK data. The French epidemic was simulated by gender and birth-cohort from data on the infectivity of UK bovine tissues and simulations of the French consumption of infected beef products. We also used data on travel to the UK between 1980 and 1995. Results We predicted 33 future cases of vCJD: 12 in the 1940–69 birth-cohort and 21 in the post-1969 birth-cohort. No case was predicted in the pre-1940 cohort. Based on our model, simulated vCJD cases occurred later in the older (1940–69) than in the younger cohort (post-1969). Age at onset was stable in the post-1969 cohort and increased in the older cohort. The model predicted a small excess of male patients. No case was attributed to travels in the UK. Conclusions This modelling confirms that a large vCJD epidemic in France is very unlikely. Since France (where 60% of the total British exports of bovine carcasses were exported) has been highly exposed to the BSE agent, our results are reassuring for most countries worldwide. Keywords Epidemiology, vCJD, France, predictions, simulation, exposure to BSE agent, birth-cohort 46 The data available indicate that the French population has been highly exposed to the bovine spongiform encephalopathy (BSE) agent from the early 1980s to the embargo on British beef, in 1996. France has the second highest incidence of variant Creutzfeldt–Jakob disease (vCJD) worldwide. The number of vCJD cases are, however, much lower in France than in the UK: 6 and 146, respectively at the time of this study (since, two new cases occurred in France and five in the UK). Several predictions of the vCJD epidemics in the UK have already been published. While early studies predicted very large epidemics, most recent studies predict that the number of future vCJD cases in the UK should not be greater than a few hundreds.1–6 To date, models that were used to estimate the risk of vCJD in the UK have not been applied to French data. Fitting models on only 6 cases, key parameters such as the incubation period distribution and the susceptibility to vCJD cannot be accurately estimated. But recent studies on the epidemics in the UK provided consistent estimates for these parameters.1–3 They can be used to assess the risk of vCJD in France, assuming factors that modulate these parameters to be similar in France and the UK. vCJD cases have two remarkable characteristics. First, they all are homozygous for methionine at the codon 129 of the prion protein (PRNP) gene.3,4 Therefore, predictions of vCJD incidence only apply to this genotype which accounts for 40% of both French and British populations. Second, about twothirds of the vCJD cases are aged between 15 and 35 years; only 3 cases were older than 60 years. This age distribution raises the issue of an age-dependant pattern in exposure, susceptibility and/or incubation period. Modelling approaches require those relations to be assessed and defined. INSERM U 360, Hôpital La Salpêtrière, 75651 Paris Cedex 13, France. * Corresponding author. E-mail: marc.chadeau@chups.jussieu.fr RISK OF vCJD IN FRANCE 47 Dietary exposure to the BSE agent is the most likely cause of vCJD. Products containing beef as mechanically recovered meat (MRM) (burgers, sausages, etc.) are generally considered as the major source of exposure as they could have been contaminated with infectious nervous tissues. There were three potential sources of BSE exposure in the French population: (i) the consumption of contaminated French meat, (ii) the consumption of contaminated British meat imported to France and (iii) the consumption of contaminated British meat in the UK whilst French travellers visited the UK. Previous studies indicated that the exposure due to indigenous BSE was low.7–10 The aim of this study is to forecast the number of vCJD cases in France based on exposure to BSE through British infected meat and meat products which were imported to France or consumed by French travellers during stays in the UK. Assessment of the exposure of the French population to BSE was based on previous studies by our group and others. We had already estimated the French consumption of beef MRM contained in burgers and other beef products. To investigate the observed age-dependent risk of vCJD, consumptions were computed by birth-cohorts (pre-1940, 1940–69, post-1969) and gender.11 The present analysis also required estimates of the infectivity in UK beef MRM by calendar year, which were provided by Cooper and Bird.12 Methods Exposure to the BSE agent through consumption of UK beef MRM Dietary exposure intensities to the BSE agent were expressed as bovine oral ID50 (Bo-ID50), the oral dose required to cause an infection in 50% of an exposed bovine population. Two infectivity options were considered.12 Assuming an exponential increase in infectivity in the last year of incubation with a doubling time of 6 months (optimistic option), infected bovines slaughtered 12 months before their onset were approximately half (54%) as infectious as bovines with clinical signs. The pessimistic option assumed that pre-clinical and clinical bovines were equally infectious. The Monte Carlo simulation process providing estimates of the infectivity titre per tonne of UK beef MRM, for each calendar year from 1980 to 1995, has been detailed by Cooper and Bird.12 Their study showed that the infectivity titre of UK beef MRM increased exponentially between 1980 and 1992, and then fell; in 1995, MRM infectivity was approximately at the 1987–1988 level. In 1989, a sharp but transitory drop in MRM infectivity was observed when specified bovine offal (SBO) legislation was introduced in the UK. These measures prevented potentially infectious products from entering the human food chain. Exposure to BSE agent through bovine carcasses imported from the UK In a previous study, we estimated by calendar year the total quantity of beef MRM produced for human consumption in France and the proportion of MRM produced from imported bovine carcasses.11 To estimate the annual number of Bo-ID50 consumed due to imports, we simulated the infectivity titre distribution in French MRM due to British imported bovines, using the methodology developed by Cooper and Bird.12 Combining estimated individual consumption of products containing MRM by age group and gender with the simulated infectivity titre of French MRM, we first got the simulated distribution of the individual exposure and then the total population exposure to BSE by birth-cohort, calendar year and gender. Exposure to BSE whilst visiting the UK This part of our study is detailed elsewhere.13 Briefly, to know the proportion of blood donors who had travelled to the UK from 1980 to 1996, the French Blood Transfusion Service conducted a nationwide survey in 1999. Donors (n 16 191) answered questions about dates and durations of their visits to the UK during the critical years. About one-third of the French donors had spent at least one day in the UK during the surveyed period. Only 1.2% had spent more than six months in the UK. Data from blood donors were extrapolated to the general population, with adjustments which were necessary to take into account the specific age and gender characteristics of the donors. Based on these data, we simulated the distribution of the number of weeks spent in the UK by French travellers and we estimated exposure to BSE during those trips by birthcohort and gender. Estimation of the vCJD incidence in France The approach we used is derived from the one described by Cooper and Bird.3 The evolution of the health status of each infected individual was simulated. Individuals were all attributed a calendar year of infection and an incubation period. Consequently, the size and the temporal pattern of French vCJD epidemic could be described. To get distributions, 5000 independent epidemics were simulated. The required number of infected individuals was not fixed but set along the simulation runs. A run stopped once as many cases as really observed in each birth-cohort by the end of 2003 were simulated. The year in which infection took place (y) was randomly attributed according to the probability of being infected at year y. That probability was assumed to be proportional to the density of the exposure that year. Exposure itself depended on gender g, birth-cohort c and on how the individual was exposed (during trips to the UK or not): the source of exposure s. Therefore, y was sampled simultaneously with the three other parameters from their joint distribution { ˆPy,g,c,s}(y,g,c,s). Let (Ey,g,c,s)(i) denote the exposure intensity simulated for iteration i, for given y, g, c and s, and (Py,g,c,s)(i) the corresponding probability of getting infected. (Py,g,c,s)(i) was estimated for given y, g, c, s with the exposure density: Each infected individual was then randomly attributed a combination of modalities for those four variables describing how and when their infection occurred. Incubation periods were sampled from a log-normal distribution whose parameters were dependent on the birth-cohort c.3 Values were the ones which provided the best fitting epidemic in the UK according to a 2 criterion, namely a mean of 11 years (SD 1.5) for the youngest cohort, and a mean of 26 years (SD 16.5) for the two older cohorts. Finally, to know whether each onset was observed or censored, the year of death from other reasons than (Pˆ y,g,c,s)(i) y,g,c,s(Ey,g,c,s)(i) 48 INTERNATIONAL JOURNAL OF EPIDEMIOLOGY vCJD was simulated according to French mortality rate by age, gender, and calendar year (http://www.ined.fr). Simulated individuals were only considered if (i) their onset led to an epidemic which was compatible with observations and (ii) they were susceptible, according to an age-related susceptibility function s(a). We considered individuals aged 15 years old to be totally susceptible [s(a) 1], thereafter, the susceptibility exponentially decreased, with 6% decrease per year of age.2 Results French exposure to BSE through imports and travels to the UK Figure 1 shows the total exposure of the French population by birth-cohort and calendar year, assuming that pre-clinical bovines were 54% as infectious as clinical BSE bovines (optimistic option). In all cohorts, exposure peaked in 1993. The pre-1940 birth-cohort was far less exposed than the two younger cohorts. The exposure patterns of the 1940–69 and post-1969 cohorts were similar, the 1940–69 cohort being, however, more exposed. A direct interpretation of these figures can be misleading because sizes of the cohorts were very different and varied differently with time: while the population in the oldest cohort decreased, it increased in the post-1969 cohort. In order to get size-independent results, exposure was simulated for virtual birth-cohorts whose size was fixed to 105 individuals. That simulation indicated that individuals born before 1940 had been as exposed to BSE as the younger ones (Figure 2). Under the optimistic infectivity option, the French population was exposed to 36 142 Bo-ID50 (Table 1). During the same period, the exposure of the UK population was equal to 710 350 Bo-ID50 12,13 (ratio UK/France: 20). As expected, the exposure was roughly multiplied by two under the pessimistic option, but the UK/France ratio remained unchanged. Travels to the UK accounted for only 2% of the French total exposure to BSE. Number of future vCJD cases in France Under the optimistic infectivity option (Table 2), a total of 33 vCJD cases are expected:12 cases in the 1940–69 cohort and 21 cases in the post-1969 cohort. Only three cases were expected to occur after 2020. No case was predicted in the pre-1940 cohort. Almost all simulated onsets, except three in the 1940–69 cohort, occurred in individuals infected between 1990 and 1995. The temporal distribution of onsets differed between the two cohorts: while all expected vCJD onsets occurred before 2010 in the youngest cohort, 7 out of 12 onsets in the 1940–69 cohort were predicted to occur after 2010. We also found that no onset was censored in the youngest cohort while three onsets were censored in the 1940–69 cohort. According to our simulation, the age at onset of the simulated vCJD cases in the post-1969 cohort remained stable along time, whereas it increased in the 1940–69 cohort. As a consequence of gender differences in exposure to BSE, we predicted an excess of male patients in both cohorts (around 60%). That proportion was constant over time and consistent with French and British data, which did not suggest any gender-related susceptibility function. Simulations did not predict any case that could be attributed to travels in the UK. We also computed a crude estimate of the bovine-to-human transmission barrier (T-barrier) in the genetically susceptible population. As a consequence of the assumed age-dependent susceptibility, an individual in the 1940–69 birth-cohort required more (1.5) infectious units to be infected than an individual from the post-1969 cohort. Indeed, the mean estimated number of infectious units required to cause one infection was around 280 for the youngest cohort and 420 for the 1940–69 cohort. Confidence intervals were very large: [167–1382] and [106–972] for the 1940–69 and post-1969 cohorts respectively. Under the pessimistic infectivity option, the mean T-barrier roughly doubled. Comments Our model predicted a low vCJD incidence in the French genetically susceptible population (methionine homozygous), with a median estimate of 33 future clinical cases between 2004 and 2020. We found that two-thirds of the simulated vCJD cases were expected in the post-1969 birth-cohort and the remaining one-third in the 1940–69 cohort. As six cases were not sufficient enough to get reliable estimates for the key parameters of our model, their values were fixed to the ones obtained by the modelling of the vCJD epidemics in the UK. First, the incubation period was sampled from an agedependent log-normal distribution whose parameters best fitted Cooper’s model.3 Second, as proposed by others,1,2 we used an age-dependent susceptibility function exponentially decreasing after the age of 15 years. Previous modelling studies showed that these assumptions and parameters were accurate enough to predict the vCJD epidemics in the UK. As incubation period and susceptibility are mainly related to biological mechanisms, UK estimates are valid in other populations as well. However, a sensitivity analysis (results not shown) indicated that our conclusions remained stable while considering alternative values. Assuming that vCJD was a consequence of eating BSE-infected beef, we estimated dietary exposure intensities to BSE by combining two categories of data: estimated distributions of the French consumption of products containing beef MRM, by birth-cohort and gender, and infectivity titre in MRM produced from British bovines, expressed as number of units of Bo-ID50. This methodology had been proposed to predict vCJD incidence in the UK.3 Others used estimates of the number of BSE-infected animals entering the human food chain to quantify human exposure to BSE.1,2,4,5 Both approaches resulted in comparable predictions. The advantage of the latter methodology is that it required neither any assumption about which types of beef products are infective nor any data on the consumption of meat products which induced serious uncertainties that have already been discussed.11,15 On the another hand, our methodology, derived from Cooper and Bird’s study, facilitates the discussion about age-dependent exposure and/or incubation period. To get an estimate of the French exposure to BSE during stays in the UK, we extrapolated data from blood donors to the general population. We adjusted for age distribution and sex ratio differences between donors and the general population. It is established that, on the average, French blood donors have lower socioeconomic level than the general population. Since the proportion of travellers increases with the RISK OF vCJD IN FRANCE 49 Figure 1 Evolution of the French total dietary exposure to BSE in beef MRM produced from British carcasses, expressed in Bo-ID50 units, for pre-1940 (a), 1940–69 (b), post-1969 (c) birth-cohorts, assuming preclinical bovines being 0.54 times less infectious than clinical bovines (optimistic infectivity option) (a) (b) (c) socioeconomic level, this could have resulted in underestimating the proportion of travellers in the general population. Consequently, the number of vCJD cases due to infections whilst travelling in the UK may be slightly higher than expected in our analysis. But probably, no more than one French vCJD case might be due to infections contracted in the UK. Based on a previous analysis,10 the exposure due to BSEinfected cattle in France was neglected in our model. This major 50 INTERNATIONAL JOURNAL OF EPIDEMIOLOGY Figure 2 Evolution of the French total dietary exposure to BSE in beef MRM produced from British carcasses (in Bo-ID50 units), for the three birth-cohorts whose size is fixed to 105 individuals. Figures are based on 5000 simulation runs, under the optimistic infectivity option Table 1 Total infectivity (in Bo-ID50 units) consumed in France and in the UK between 1980 and 1995, by birth-cohorts. Figures are based on 5000 simulation runs. Median values are reported Optimistic infectivity option Pessimistic infectivity option French British Ratio French British Ratio Birth-cohorts exposure Exposure UK/France exposure Exposure UK/France Pre-1940 5379 86 500 16.08 9456 138 000 14.59 1940–1969 16 412 352 500 21.48 28 948 560 500 19.36 Post-1970 14 351 271 350 18.91 25 612 457 700 17.87 Total 36 142 710 350 19.65 64 016 1 156 200 18.06 Table 2 Estimated incidence of vCJD linked to the importation of British bovines in France by birth-cohort. Figures are based on 5000 simulation runs, under the optimistic infectivity option. Mean values, (bold), median values, and [5th, 95th] percentiles are presented Before 2003 2004–2005 2006–2010 2011–2020 After 2020 Birth-cohort No.of period onsets Observed Simulated Simulated Simulated Simulated Simulated Pre-1940 0 0.00 0 [0,0] 0.05 0 [0,1] 0.09 0 [0,1] 0.09 0 [0,1] 0.01 0 [0,0] 1940–69 3 3.00 3 [3,3] 1.17 1 [0,4] 3.08 3 [0,9] 4.49 4 [0,12] 3.14 3 [0,9] Post-1969 3 3.00 3 [3,3] 12.57 11 [2,32] 8.82 8 [1,23] 0.04 0 [0,1] 0.00 0 [0,0] assumption must be carefully discussed. Although available estimates of the BSE epidemics in France were not perfectly consistent, they indicated that exposure due to infected French meat had probably been small.7–9 For the period 1987–2000/2001, estimates of the number of infected animals varied from 7000 to 70 000 according to the assumptions considered. The number of infected animals entering the food chain comprised between 100 and 7600 in France, compared with 3.3 million in the UK16 during the same period of time. On the other hand, the data indicated that exports of British bovine carcasses to France represented about 10% of the beef meat consumption in the UK. Based on these figures, French infected bovines could have been responsible for a very small percentage of the total BSE exposure of the French population between 1987 and the early 2000s. A study suggested that the number of BSE infections in France could have been much higher before 1987 than after.9 If confirmed, this result could lead to revisiting some models of the BSE and vCJD epidemics. Another argument which supports our assumption is the comparison between estimated exposure and observed vCJD incidence: the ratio between the exposure in the UK computed by Cooper and Bird and that provided by our model (20:1) is consistent with the current vCJD incidence ratio (21:1) between these countries. However, if it was necessary to consider indigenous French exposure to BSE in modelling, the temporal and age-sex distributions of the predicted vCJD cases might be affected, but not (or only very slightly) the predicted number of vCJD cases. Indeed, while the key parameter defining epidemic size is RISK OF vCJD IN FRANCE 51 the observed numbers of cases, estimates of the French exposure are only involved in the description by gender, age, and calendar year of simulated vCJD cases. We set the end of the exposure period in 1995 as the embargo on British beef was ordered at the beginning of 1996. Afterwards, indigenous BSE constituted the unique source of infection of the French population. A total of 1500 French bovine carcasses were estimated to have entered the human food chain after 1995.9 If all those carcasses had been used to produce MRM, French exposure between 1996 and 2001 would have represented less than 2% of the French total exposure. Other limitations of these predictive models have been already pointed out. Other genotypes at the PRNP gene codon 129 could be susceptible to the BSE agent with longer incubation period. Indeed, in both iatrogenic CJD due to human growth hormone treatment17 and Kuru,18,19 individuals with the methionine-valine heterozygous genotype, which represents about 50% of the French population, have longer incubation periods than the methionine-methionine homozygotes. As heterozygotes also have a lower susceptibility to prion diseases, they should not contribute much to the vCJD epidemics. Moreover, possible transmission of vCJD by blood transfusion was suggested by recent case reports in the UK20,21 and iatrogenic transmission of vCJD through medical or surgical procedures cannot be excluded. But, a series of effective measures to reduce the risk of transmission of vCJD by infected material and blood products were taken in France. In addition, transfused individuals were banned from blood donation. Predictions of the vCJD epidemics in the UK, France, and the Republic of Ireland6 are consistent and reassuring. To date, the best estimates of the number of future clinical cases were between 200 and 400 cases in the UK, approximately 30 in France and between one and two in the Republic of Ireland. The Republic of Ireland had the second highest incidence of BSE worldwide. Harney et al. estimated that exposure due to the BSE epidemic in Ireland and exposure due to Irish imports from the UK were equivalent.6 Our study suggests that, in France, imports from the UK have represented the main source of infection by the BSE agent and that exposure due to BSE in French cattle plays a negligible role in the vCJD epidemic. Data from Customs and Excise in the UK indicated that, over the period 1980–1995, about 60% of the total exports of UK bovine carcasses to the European Community (EC) countries (about 2 million tonnes equivalent of carcasses) were exported to France. Therefore, very few vCJD cases due to the past BSE epidemics are expected in other EC countries, and worldwide. Nevertheless, as long as BSE and other forms of animal transmissible spongiform encephalopathies are not eliminated, surveillance of human prion diseases at both the national and international levels remains necessary. Acknowledgements This study was funded by a grant from the Groupement d’Intérêt Scientifique (GIS) ‘Maladies à prions’. M.C.-H. participated in the study during his PhD which was funded by the French Ministry of Education. We would also like to thank Sheila Bird and Jason Copper for having provided the British data required for our study. KEY MESSAGES • The French population may have been mainly exposed to the BSE agent through the consumption of BSE-infected bovines which were imported from the UK. • Thirty-three future vCJD cases are expected in the French population, with the upper bound at lower than 100 cases. • Expected cases of vCJD are young: two-thirds of the simulated vCJD cases are expected in the post-1969 birth-cohort and the remaining one-third in the 1940–69 cohort. Cases in people born before 1939 are very unlikely to occur. • No gender-related susceptibility to the BSE agent can be outlined. References 1 Huillard d’Aignaux JN, Cousens SN, Smith PG. Predictability of the UK variant Creutzfeldt-Jakob disease epidemic. Science 2001;294: 1729–31. 2 Valleron AJ, Boelle PY, Will RG, Cesbron JY. Estimation of epidemic size and incubation time based on age characteristics of vCJD in the United Kingdom. Science 2001;294:1726–28. 3 Cooper JD, Bird SM. Predicting incidence of variant Creutzfeldt-Jakob disease from UK dietary exposure to bovine spongiform encephalopathy for the 1940–1969 and post-1969 birth cohorts. Int J Epidemiol 2003;32:784–91. 4 Ghani AC, Ferguson NM, Donnelly CA, Anderson RM. Short-term projections for variant Creutzfeldt-Jakob disease onsets. Stat Methods Med Res 2003;12:191–201. 5 Ghani AC, Donnelly CA, Ferguson NM, Anderson RM. Updated projections of future vCJD deaths in the UK. BMC Infect Dis 2003;3:4. 6 Harney MS, Ghani AC, Donnelly C et al. vCJD risk in the Republic of Ireland. BMC Infect Dis 2003;3:28. 7 Donnelly CA. Likely size of the French BSE epidemic. Nature 2000;408:787–88. 8 Donnelly CA. BSE in France: epidemiological analysis and predictions. C R Biol 2002;325:793–806. 9 Supervie V, Costagliola D. The unrecognised French BSE epidemic. Vet Res 2004;35:349–362. 10 Alperovitch A, Will RG. Predicting the size of the vCJD epidemic in France. C R Acad Sci III 2002;325:33–36. 52 INTERNATIONAL JOURNAL OF EPIDEMIOLOGY 11 Chadeau-Hyam M, Tard A, Alpérovitch A et al. Estimation of the exposure of the French population to the BSE agent: comparison of the 1980–1995 consumption of beef products containing mechanically recovered meat in France and the UK by birth cohort and gender. Statist Meth Med Res 2003;12:247–60. 12 Cooper JD, Bird SM. UK dietary exposure to BSE in beef mechanically recovered meat: by birth cohort and gender. J Cancer Epidemiol Prev 2002;7:59–70. 13 Chadeau-Hyam M, Alpérovitch A. [Variant Creutzfeld–Jakob disease in France: eliminating the number of cases related to travels to the UK between 1980 and 1995.] Rev Epidemiol Sante Publique 2004 (in press). 14 Cooper JD, Bird SM. UK dietary exposure to BSE in head meat: by birth cohort and gender. J Cancer Epidemiol Prev 2002;7:71–83. 15 Cooper JD, Bird SM. UK bovine carcass meat consumed as burgers, sausages and other meat products: by birth cohort and gender. J Cancer Epidemiol Prev 2002;7:49–57. 16 Ferguson NM, Donnelly CA. Assessment of the risk posed by bovine spongiform encephalopathy in cattle in Great Britain and the impact of potential changes to current control measures. Proc R Soc Lond B Biol Sci 2003: 270:1579–84. 17 Huillard d’Aignaux J, Alperovitch A, Maccario J. A statistical model to identify the contaminated lots implicated in iatrogenic transmission of Creutzfeldt-Jakob disease among French human growth hormone recipients. Am J Epidemiol 1998;147:597–604. 18 Lee HS, Brown P, Cervenakova L et al. Increased susceptibility to Kuru of carriers of the PRNP 129 methionine/methionine genotype. J Infect Dis 2001;183:192–96. 19 Cervenakova L, Goldfarb LG, Garruto R, Lee HS, Gajdusek DC, Brown P. Phenotype-genotype studies in kuru: implications for new variant Creutzfeldt–Jakob disease. Proc Natl Acad Sci USA 1998;95: 13239–41. 20 Llewelyn CA, Hewitt PE, Knight RS et al. Possible transmission of variant Creutzfeldt–Jakob disease by blood transfusion. Lancet 2004;363:417–21. 21 Ironside JW, Hilton DA, Ghani A et al. Retrospective study of prionprotein accumulation in tonsil and appendix tissues. Lancet 2000;355:1693–94. IJE vol.34 no.1 © International Epidemiological Association 2005; all rights reserved. International Journal of Epidemiology 2005;34:52–53 Advance Access publication 13 January 2005 doi:10.1093/ije/dyh393 Commentary: The risk of variant Creutzfeldt–Jakob Disease: reassurance and uncertainty RG Will The annual number of deaths from variant Creutzfeldt–Jakob Disease (vCJD) in the UK is currently on a decline.1 Epidemiological and laboratory evidence strongly supports the hypothesis that vCJD is caused by human infection with bovine spongiform encephalopathy (BSE) and the population risk of developing this condition is likely to be proportional to the extent of human exposure to BSE, presumptively through contaminated meat products. The risk of vCJD in countries other than the UK may be due to exposure to indigenous BSE, import of infected animals, animal feed, and food products from the UK, or exposure to BSE during travel to the UK in the risk period 1980–1996. The paper by Chadeau-Hyam and Alperovitch2 assesses these potential risks in France and concludes that overall there may be a limited number of future vCJD cases in the French population (33 cases from 2004–2020) and that the main risk was through consumption of infected bovines from the UK. Travel to the UK was assessed to account for only 2% of BSE exposure and exposure to French cases of BSE was not considered because this was judged to represent a low risk. This paper and a similar study in Ireland3 suggest that the number of future cases of vCJD may be very limited outside the UK. There are, however, a number of important caveats. To date all clinical cases of vCJD in which the prion protein gene (PRNP) has been examined have been methionine homozygotes, with no identified cases in the 68% of the Caucasian population with the alternative valine homozygotes or heterozygous genotypes. All predictive studies of vCJD to date have overtly assumed that only methionine homozygotes will be affected, but the possibility that infection with BSE can occur in the other genetic backgrounds has been supported by the recent publication of a presumed preclinical† case of vCJD in a PRNP heterozygous blood transfusion recipient.4 If heterozygotes can be infected with BSE it would be surprising if valine homozygotes could not also be infected, although Chadeau-Hyam and Alperovitch suggest that heterozygotes (and presumably valine homozygotes) may have a lower susceptibility to infection and may not add significantly to the vCJD epidemic. Cattle are uniformly methionine homozygotes and homology of prion protein types is thought to lead to University of Edinburgh Teviot Place, Edinburgh EH8 9AG, Scotland, UK. E-mail: r.g.will@ed.ac.uk †The possibility of life-long infection without the development of disease cannot be excluded. http://ije.oxfordjournals.org/cgi/reprint/34/1/46?maxtoshow=&HITS=10&hits=10&RESULTFORMAT=&fulltext=creutzfeldt&searchid=1133791738792_657&stored_search=&FIRSTINDEX=0&journalcode=intjepid IJE vol.34 no.1 © International Epidemiological Association 2005; all rights reserved. International Journal of Epidemiology 2005;34:52–53 Advance Access publication 13 January 2005 doi:10.1093/ije/dyh393 Commentary: The risk of variant Creutzfeldt–Jakob Disease: reassurance and uncertainty RG Will The annual number of deaths from variant Creutzfeldt–Jakob Disease (vCJD) in the UK is currently on a decline.1 Epidemiological and laboratory evidence strongly supports the hypothesis that vCJD is caused by human infection with bovine spongiform encephalopathy (BSE) and the population risk of developing this condition is likely to be proportional to the extent of human exposure to BSE, presumptively through contaminated meat products. The risk of vCJD in countries other than the UK may be due to exposure to indigenous BSE, import of infected animals, animal feed, and food products from the UK, or exposure to BSE during travel to the UK in the risk period 1980–1996. The paper by Chadeau-Hyam and Alperovitch2 assesses these potential risks in France and concludes that overall there may be a limited number of future vCJD cases in the French population (33 cases from 2004–2020) and that the main risk was through consumption of infected bovines from the UK. Travel to the UK was assessed to account for only 2% of BSE exposure and exposure to French cases of BSE was not considered because this was judged to represent a low risk. This paper and a similar study in Ireland3 suggest that the number of future cases of vCJD may be very limited outside the UK. There are, however, a number of important caveats. To date all clinical cases of vCJD in which the prion protein gene (PRNP) has been examined have been methionine homozygotes, with no identified cases in the 68% of the Caucasian population with the alternative valine homozygotes or heterozygous genotypes. All predictive studies of vCJD to date have overtly assumed that only methionine homozygotes will be affected, but the possibility that infection with BSE can occur in the other genetic backgrounds has been supported by the recent publication of a presumed preclinical† case of vCJD in a PRNP heterozygous blood transfusion recipient.4 If heterozygotes can be infected with BSE it would be surprising if valine homozygotes could not also be infected, although Chadeau-Hyam and Alperovitch suggest that heterozygotes (and presumably valine homozygotes) may have a lower susceptibility to infection and may not add significantly to the vCJD epidemic. Cattle are uniformly methionine homozygotes and homology of prion protein types is thought to lead to University of Edinburgh Teviot Place, Edinburgh EH8 9AG, Scotland, UK. E-mail: r.g.will@ed.ac.uk †The possibility of life-long infection without the development of disease cannot be excluded. greater efficiency of prion protein conversion. However, studies in transgenic mice indicate that this phenomenon is not always predictable.5 The pathogenesis of vCJD is different from other forms of human prion disease with higher levels of disease associated prion protein and infectivity in peripheral lymphoreticular tissues,6 raising the possibility of secondary transmission of infection via blood transfusion, plasma products, or through contaminated surgical instruments. The identification of a case of possible transfusion transmitted vCJD7 and the case of presumed preclinical infection in a transfusion recipient indicate that secondary transmission of vCJD may already be a reality. Measures to minimize the risks of transmission of vCJD through this route, including deferral of transfusion recipients and donor deferral related to residence in the UK, have been introduced and should reduce the risk of recycling of infection. If these measures are fully implemented, the expectation is that the risk of future cases of secondary vCJD may be limited, on the assumption that geographical areas at risk of vCJD are aware of this risk. It is important to underline that the efficiency of transmission of an agent adapted to a species is usually greater than transmission of a prion between species. The paper by Chadeau-Hyam and Alperovitch suggests that risk of BSE exposure in France was largely related to imports from the UK, but this may not be true in other European countries. The numbers of cases of BSE in these countries are far less than the UK (numbered in hundreds of cases or less, rather than over 180 000 cases in the UK) indicating a significantly lower risk of exposure to indigenous BSE. The first cases of BSE were identified in some countries through the introduction of active abattoir testing in 2000/2001 and this also resulted in a significant increase in the number of identified cases (http://www.oie.int/eng/en_index.htm). Passive surveillance of BSE may have missed cases identified through clinical signs alone and there is uncertainty about the true extent of human BSE exposure in the 1990s in some countries. Measures to minimize human exposure to BSE were introduced more than 10 years after the UK in some countries and there is a possibility that cases of vCJD related to exposure to indigenous BSE may appear later than in the UK or France. If the predictions in the paper by Chadeau-Hyam and Alperovitch are correct, the numbers of such cases are likely to be limited but the recent evidence suggesting secondary transmission of vCJD underlines the importance of maintaining surveillance for human prion disease. Data on the export of meat, cattle, and cattle feed from the UK are available from UK Customs and Excise for the period 1980–1995 and have been used as a component in the analysis of geographical BSE risk carried out by the European Commission for some countries. Although not verified by all importing countries, the data on UK exports suggests that in the 1980s and early 1990s cattle and cattle feed were exported to countries outside Europe, including South East Asia. Recycling of infection within the cattle population may have taken place in countries with a meat and bone meal industry and re-exporting may have taken place. The risk of BSE is not restricted to those countries in which BSE has already been identified and one recommendation of a joint meeting of the OIE/FAO/WHO in 2002 was that all countries should carry out a risk assessment for BSE.8 One remarkable finding in the paper by Chadeau-Hyam and Alperovitch is the extent of population exposure to BSE infection with an estimate, using pessimistic assumptions, of more than 64 000 bovine ID 50s in France and more than a million ID 50s in the UK. This contrasts with the limited number of predicted cases of vCJD in France and recent analyses in the UK, which forecast hundreds rather than thousands of future cases.9 This mismatch between exposure and disease is unexplained. A barrier to transmission between species is well recognised10 in prion disease and it is possible that transmission between bovines and humans is very inefficient, with the implication that the currently limited number of cases of vCJD may be related to a rare exposure to a very high infectious dose. This might also explain the fact that to date only one case has been identified in any affected family. There is also the possibility that there are genetic factors outside PRNP that influence the likelihood of infection11 and that the proportion of susceptible individuals in the population is restricted. There is also the possibility of a co-factor, which increases the likelihood of infection, e.g. concurrent bowel disease or dental procedures at the time of exposure, but there is, as yet, no evidence of this. If the mismatch between exposure to infection and the likelihood of developing disease is maintained, the reassurance from the paper by Chadeau-Hyam and Alperovitch may prove to be justified, provided appropriate measures are taken to protect public health in countries with BSE or vCJD. References 1 Andrews NJ, Farrington CP, Ward HJT et al. Deaths from variant Creutzfeldt-Jakob disease in the UK. Lancet 2003;361:751–52. 2 Chadeau-Hyam M, Alpérovitch A. Risk of variant Creutzfeldt–Jakob disease in France. Int J Epidemiol 2005;34:46–52. 3 Harney MS, Ghani AC, Donnelly CA, McConn Walsh R, Walsh M, Howley R, Brett F, Farrell M. vCJD risk in the Republic of Ireland. BMC Infect Dis 2003;3:28–37. 4 Peden AH, Head MW, Ritchie DL, Bell JE, Ironside JW. Preclinical vCJD after blood transfusion in a PRNP codon 129 heterozygous patient. Lancet 2004;364:527–29. 5 Barron RM, Thomson V, Jamieson E, et al. Changing a single amino acid in the N-terminus of murine PrP alters TSE incubation time across three species barriers. EMBO 2001;20:5070–78. 6 Hilton DA, Sutak J, Smith MEF et al. Specificity of lymphoreticular accumulation of prion protein for variant Creutzfeldt–Jakob disease. J Clin Pathol 2004;57:300–02. 7 Llewelyn CA, Hewitt PA, Knight RSG et al. Possible transmission of variant Creutzfeldt–Jakob disease by blood transfusion. Lancet 2004; 363:417–21. 8World Health Organisation, Food and Agricultural Organisation, Office International des Epizooties. Technical Consultation on BSE: public health, animal health and trade, 2002. 9 Boelle P-Y, Thomas G, Valleron A-J, Cesbron J-Y, Will R. Modelling the epidemic of variant Creutzfeldt-Jakob disease in the UK based on age characteristics: updated, detailed analysis. Stat Methods in Med Res 2003;12:221–33. 10 Prusiner SB, Scott M, Foster D et al. Transgenic studies implicate interactions between homologous PrP isoforms in scrapie prion replication. Cell 1990;63:673–86. 11 Stephenson DA, Chotti K, Ebeling C et al. Quantitative trait loci affecting prion incubation time in mice. Genomics 2000;69:47–53. RISK OF vCJD IN FRANCE 53 http://ije.oxfordjournals.org/cgi/reprint/34/1/52?maxtoshow=&HITS=10&hits=10&RESULTFORMAT=&fulltext=creutzfeldt&searchid=1133791855862_662&stored_search=&FIRSTINDEX=0&journalcode=intjepid TSS
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