IJE Advance Access originally published online on January 13, 2005
International Journal of Epidemiology 2005 34(1):52-53; doi:10.1093/ije/dyh393
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IJE vol.34 no.1 © International Epidemiological Association 2005; all rights reserved.
Commentary |
Commentary: The risk of variant Creutzfeldt–Jakob Disease: reassurance and uncertainty
University of Edinburgh Teviot Place, Edinburgh EH8 9AG, Scotland, UK. E-mail: r.g.will{at}ed.ac.uk
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 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.
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Notes |
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The possibility of life-long infection without the development of disease cannot be excluded. 
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References |
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1 Andrews NJ, Farrington CP, Ward HJT et al. Deaths from variant Creutzfeldt-Jakob disease in the UK. Lancet 2003;361:751–52.[CrossRef][Web of Science][Medline]
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.[CrossRef][Medline]
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.[CrossRef][Web of Science][Medline]
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.[CrossRef][Web of Science][Medline]
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.[CrossRef][Web of Science][Medline]
8 World 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.[CrossRef][Web of Science][Medline]
11 Stephenson DA, Chotti K, Ebeling C et al. Quantitative trait loci affecting prion incubation time in mice. Genomics 2000;69:47–53.[CrossRef][Web of Science][Medline]
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