- Email: [email protected]
Mad cows and monkey business: the end of vCJD?
Comment
Nevertheless, we agree with Dennis and colleagues’ clear message to clinicians: nasogastric feeding should be used for dysphagic patients early, and PEG feeding reserved for patients who do not tolerate nasogastric feeding and, possibly, as part of the long-term care of dysphagic patients. Further large studies investigating these questions are unlikely to proceed in the foreseeable future. Pragmatically then, we should reserve oral food supplements for undernourished patients, and feel confident that enteral feeding for those with dysphagia need not begin in the first few days after stroke and that nasogastric feeding is appropriate if enteral feeding is required. Perhaps even more importantly, the FOOD trials show the need to solve the problem of dysphagia in stroke patients. Although enteral feeding nicely sidesteps the
problem, research on early restoration of swallowing function is a priority. *Geoffrey A Donnan, Helen M Dewey National Stroke Research Institute, Austin Hospital, University of Melbourne, Heidelberg West, Victoria 3081, Australia [email protected] We declare that we have no conflict of interest. 1 2
3 4
5
Davalos A, Ricart W, Gonzalez-Huix F, et al. Effect of malnutrition after acute stroke on clinical outcome. Stroke 1996; 27: 1028–32. Gariballa SE, Parker SG, Taub N, Castleden CM. Influence of nutritional status on clinical outcome after acute stroke. Am J Clin Nutr 1998; 68: 275–81. Mann G, Hankey GJ, Cameron D. Swallowing function after stroke: prognosis and prognostic factors at 6 months. Stroke 1999; 30: 744–48. Toni D, Chamorro A, Kaste M, et al. Acute treatment for ischaemic stroke. European Stroke Initiative. Cerebrovasc Dis 2004; 17 (suppl 2): 30–46. National Stroke Foundation (Australia). National Clinical Guidelines for acute stroke management. 2003: http://www.strokefoundation.com.au (accessed Dec 17, 2004).
Mad cows and monkey business: the end of vCJD? Published online January 27, 2005. http://image.thelancet.com/ extras/05cmt17web.pdf See Research Letters page 781
730
In today’s Lancet, Corinne Lasmezas and colleagues report on the oral transmission of bovine spongiform encephalopathy (BSE) to macaques as a model for variant Creutzfeldt-Jakob disease (vCJD) in human beings. Two adult macaques were orally dosed with 5 g BSE-infected bovine brain. 5 years later, one animal developed a disease closely resembling vCJD in pathology, while the other shows no signs of infection. In an earlier study, a pair of macaques orally dosed with 5 g BSE-infected macaque brain both developed a similar disease with an incubation period of almost 4 years—ie, in the absence of a species barrier.1 Given the well-recognised link between BSE and vCJD2 and the epidemiological evidence that human exposure is most likely to be oral,3 why is this report noteworthy? We think the answer lies with some of the key uncertainties about BSE/vCJD. The amount of BSE material that constitutes an oral infectious dose for human beings and the incubation periods resulting from such exposure are unknown. Neither can be adequately studied in mouse models, “humanised” or otherwise. Lasmezas and colleagues’ report, in a primate model that might more closely replicate human pathophysiology and with a similar prionprotein genotype to that in vCJD patients, attempts to address some of these uncertainties. The results point
to a “protective” species barrier between bovines and primates and to the relative inefficiency of oral transmission, which involves an obligatory silent peripheral phase of infection before neuroinvasion (the incubation period) and subsequent clinical disease. We find the precise implications for vCJD difficult to assess, because Lasmezas and colleagues’ study is limited in terms of the numbers of animals used, and the level of infectivity in the inoculum was not titrated. Nevertheless, the investigators have estimated the magnitude of the species barrier between bovines and primates (ranging from a factor of 7–20), and extrapolate to human beings both the maximum incubation period for oral transmission of BSE (over 50 years) and the predicted oral dose of BSE-infected neural tissue that might now be required for transmission (in light of reinforced BSE controls)—a sizeable 150 g. These extrapolations are interesting, but necessarily limited by the factors mentioned above. In particular, the minimum infectious dose of BSE-infected neural tissue for primates is currently unknown, so 150 g may be an overestimate. There remain fundamental problems about comparing likely human exposure to BSE with experiments of this type, even in primates that mimic vCJD pathology after oral www.thelancet.com Vol 365 February 26, 2005
Comment
Number of vCJD cases
30 25 20 15 10 5 0 1994 1995 1996 1997 1998 1999 2000 2001 2002 2003 2004 Year
infection or carrier state in some individuals (perhaps the majority) exposed orally to BSE.5,9 Although not manifesting clinical disease, subclinical carriers could be a source of iatrogenic infection, for example by blood transfusion10,11 or by contamination of surgical instruments that are used on tissues that harbour vCJD infectivity. Other host genes are also likely to influence the incubation period of BSE in mice12 and primates, although tantalisingly little is known of their nature and function. These factors seem to indicate that the declining numbers of clinical cases might instead represent the end of the beginning of vCJD, and that continued surveillance will be required for a considerable time before any firm conclusions can be drawn on the likely demise of this tragic condition. Mark W Head, *James W Ironside National Creutzfeldt-Jakob Disease Surveillance Unit, University of Edinburgh, Western General Hospital, Edinburgh EH4 2XU, UK [email protected]
Figure: Current dilemma in vCJD Upper=declining incidence of new clinical cases of vCJD by date of disease onset.3 Lower=positive staining for prion protein in germinal centre within wall of appendix surgically removed from anonymous asymptomatic individual.7
BSE exposure. Multiple oral-exposure events over a period of years seem likely in the UK, and vCJD occurs predominantly in young adults, raising the possibilities of age-related susceptibility or exposure.4,5 More data will be forthcoming on some of these points from a larger primate study funded by the European Union,6 but it will be several years before they are likely to emerge. In view of the declining incidence of new clinical cases of variant CJD (figure, upper),3,5 one interpretation of these results would be that it is premature to conclude that this is the beginning of the end of vCJD. Such caution is supported by the findings of a retrospective study to detect accumulation of the abnormal prion protein in UK tonsil and appendix specimens,7 which found a prevalence rate of 237 cases per million for prion infection (figure, lower), far higher than current clinical cases of vCJD would indicate. Other influences on the interpretation of these results include the effects of the codon 129 polymorphism in the human prion-protein gene on incubation periods,8 and the possibility of a subclinical www.thelancet.com Vol 365 February 26, 2005
JWI has a consultancy with Millennium Pharmaceuticals Inc. MWH declares that he has no conflict of interest. 1
Herzog C, Sales N, Etchegary N, et al. Tissue distribution of bovine spongiform encephalopathy agent in primates after intravenous or oral infection. Lancet 2004; 363: 411–12. 2 Bruce ME, Will RG, Ironside JW, et al. Transmissions to mice indicate that “new variant” CJD is caused by the BSE agent. Nature 1997; 389: 498–501. 3 The National Creutzfeldt-Jakob Disease Surveillance Unit. Creutzfeldt-Jakob disease surveillance in the UK: twelfth annual report 2003. Oct 18, 2004: http://www.cjd.ed.ac.uk (accessed Jan 20, 2005). 4 Cooper JD, Bird SM. Predicting incidence of variant Creutzfeldt-Jakob disease from UK dietary exposure to bovine spongiform encephalopathy for the 1940 to 1969 and post-1969 birth cohort. Int J Epidemiol 2003; 32: 784–91. 5 Clarke P, Ghani AC. Projections of the future course of the primary vCJD epidemic in the UK: inclusion of subclinical infection and the possibility of wider genetic susceptibility. J R Soc Interface 2005: DOI: 10.1098/ rsif.2004. 0017. http://www.pubs.royalsoc.ac.uk/interface_ homelink2.shtml (accessed Jan 26, 2005). 6 Working group “prion diease: risk assessment”. BSE transmission through food and blood products: a study in primates to assess the risk for humans. http://www.dpz.gwdg.de/virol/web-viro/WG_Moz. htm (accessed Jan 24, 2005). 7 Hilton DA, Ghani A, Conyers L, et al. Prevalence of lymphoreticular prion protein accumulation in UK tissue samples. J Pathol 2004; 203: 733–39. 8 Goldfarb LG, Cervenakova L, Gajdusek DC. Genetic studies in relation to kuru: an overview. Curr Mol Med 2004; 4: 375–84. 9 Carrell RW. Biomedicine: prion dormancy and disease. Science 2004; 306: 1692-93. 10 Llewelyn CA, Hewitt PE, Knight RSG, et al. Possible transmission of variant Creutzfeldt-Jakob disease by blood transfusion. Lancet 2004; 363: 417–21. 11 Peden AH, Head MW, Ritchie DL, Bell JE, Ironside JW. Preclincal vCJD after blood transfusion in a PRNP codon 129 heterozygous patient. Lancet 2004; 364: 527–29. 12 Manolakou K, Beaton J, McConnell I, et al. Genetic and environmental factors modify bovine spongiform encephalopathy incubation period in mice. Proc Natl Acad Sci USA 2001; 98: 7402–77.
731
Nevertheless, we agree with Dennis and colleagues’ clear message to clinicians: nasogastric feeding should be used for dysphagic patients early, and PEG feeding reserved for patients who do not tolerate nasogastric feeding and, possibly, as part of the long-term care of dysphagic patients. Further large studies investigating these questions are unlikely to proceed in the foreseeable future. Pragmatically then, we should reserve oral food supplements for undernourished patients, and feel confident that enteral feeding for those with dysphagia need not begin in the first few days after stroke and that nasogastric feeding is appropriate if enteral feeding is required. Perhaps even more importantly, the FOOD trials show the need to solve the problem of dysphagia in stroke patients. Although enteral feeding nicely sidesteps the
problem, research on early restoration of swallowing function is a priority. *Geoffrey A Donnan, Helen M Dewey National Stroke Research Institute, Austin Hospital, University of Melbourne, Heidelberg West, Victoria 3081, Australia [email protected] We declare that we have no conflict of interest. 1 2
3 4
5
Davalos A, Ricart W, Gonzalez-Huix F, et al. Effect of malnutrition after acute stroke on clinical outcome. Stroke 1996; 27: 1028–32. Gariballa SE, Parker SG, Taub N, Castleden CM. Influence of nutritional status on clinical outcome after acute stroke. Am J Clin Nutr 1998; 68: 275–81. Mann G, Hankey GJ, Cameron D. Swallowing function after stroke: prognosis and prognostic factors at 6 months. Stroke 1999; 30: 744–48. Toni D, Chamorro A, Kaste M, et al. Acute treatment for ischaemic stroke. European Stroke Initiative. Cerebrovasc Dis 2004; 17 (suppl 2): 30–46. National Stroke Foundation (Australia). National Clinical Guidelines for acute stroke management. 2003: http://www.strokefoundation.com.au (accessed Dec 17, 2004).
Mad cows and monkey business: the end of vCJD? Published online January 27, 2005. http://image.thelancet.com/ extras/05cmt17web.pdf See Research Letters page 781
730
In today’s Lancet, Corinne Lasmezas and colleagues report on the oral transmission of bovine spongiform encephalopathy (BSE) to macaques as a model for variant Creutzfeldt-Jakob disease (vCJD) in human beings. Two adult macaques were orally dosed with 5 g BSE-infected bovine brain. 5 years later, one animal developed a disease closely resembling vCJD in pathology, while the other shows no signs of infection. In an earlier study, a pair of macaques orally dosed with 5 g BSE-infected macaque brain both developed a similar disease with an incubation period of almost 4 years—ie, in the absence of a species barrier.1 Given the well-recognised link between BSE and vCJD2 and the epidemiological evidence that human exposure is most likely to be oral,3 why is this report noteworthy? We think the answer lies with some of the key uncertainties about BSE/vCJD. The amount of BSE material that constitutes an oral infectious dose for human beings and the incubation periods resulting from such exposure are unknown. Neither can be adequately studied in mouse models, “humanised” or otherwise. Lasmezas and colleagues’ report, in a primate model that might more closely replicate human pathophysiology and with a similar prionprotein genotype to that in vCJD patients, attempts to address some of these uncertainties. The results point
to a “protective” species barrier between bovines and primates and to the relative inefficiency of oral transmission, which involves an obligatory silent peripheral phase of infection before neuroinvasion (the incubation period) and subsequent clinical disease. We find the precise implications for vCJD difficult to assess, because Lasmezas and colleagues’ study is limited in terms of the numbers of animals used, and the level of infectivity in the inoculum was not titrated. Nevertheless, the investigators have estimated the magnitude of the species barrier between bovines and primates (ranging from a factor of 7–20), and extrapolate to human beings both the maximum incubation period for oral transmission of BSE (over 50 years) and the predicted oral dose of BSE-infected neural tissue that might now be required for transmission (in light of reinforced BSE controls)—a sizeable 150 g. These extrapolations are interesting, but necessarily limited by the factors mentioned above. In particular, the minimum infectious dose of BSE-infected neural tissue for primates is currently unknown, so 150 g may be an overestimate. There remain fundamental problems about comparing likely human exposure to BSE with experiments of this type, even in primates that mimic vCJD pathology after oral www.thelancet.com Vol 365 February 26, 2005
Comment
Number of vCJD cases
30 25 20 15 10 5 0 1994 1995 1996 1997 1998 1999 2000 2001 2002 2003 2004 Year
infection or carrier state in some individuals (perhaps the majority) exposed orally to BSE.5,9 Although not manifesting clinical disease, subclinical carriers could be a source of iatrogenic infection, for example by blood transfusion10,11 or by contamination of surgical instruments that are used on tissues that harbour vCJD infectivity. Other host genes are also likely to influence the incubation period of BSE in mice12 and primates, although tantalisingly little is known of their nature and function. These factors seem to indicate that the declining numbers of clinical cases might instead represent the end of the beginning of vCJD, and that continued surveillance will be required for a considerable time before any firm conclusions can be drawn on the likely demise of this tragic condition. Mark W Head, *James W Ironside National Creutzfeldt-Jakob Disease Surveillance Unit, University of Edinburgh, Western General Hospital, Edinburgh EH4 2XU, UK [email protected]
Figure: Current dilemma in vCJD Upper=declining incidence of new clinical cases of vCJD by date of disease onset.3 Lower=positive staining for prion protein in germinal centre within wall of appendix surgically removed from anonymous asymptomatic individual.7
BSE exposure. Multiple oral-exposure events over a period of years seem likely in the UK, and vCJD occurs predominantly in young adults, raising the possibilities of age-related susceptibility or exposure.4,5 More data will be forthcoming on some of these points from a larger primate study funded by the European Union,6 but it will be several years before they are likely to emerge. In view of the declining incidence of new clinical cases of variant CJD (figure, upper),3,5 one interpretation of these results would be that it is premature to conclude that this is the beginning of the end of vCJD. Such caution is supported by the findings of a retrospective study to detect accumulation of the abnormal prion protein in UK tonsil and appendix specimens,7 which found a prevalence rate of 237 cases per million for prion infection (figure, lower), far higher than current clinical cases of vCJD would indicate. Other influences on the interpretation of these results include the effects of the codon 129 polymorphism in the human prion-protein gene on incubation periods,8 and the possibility of a subclinical www.thelancet.com Vol 365 February 26, 2005
JWI has a consultancy with Millennium Pharmaceuticals Inc. MWH declares that he has no conflict of interest. 1
Herzog C, Sales N, Etchegary N, et al. Tissue distribution of bovine spongiform encephalopathy agent in primates after intravenous or oral infection. Lancet 2004; 363: 411–12. 2 Bruce ME, Will RG, Ironside JW, et al. Transmissions to mice indicate that “new variant” CJD is caused by the BSE agent. Nature 1997; 389: 498–501. 3 The National Creutzfeldt-Jakob Disease Surveillance Unit. Creutzfeldt-Jakob disease surveillance in the UK: twelfth annual report 2003. Oct 18, 2004: http://www.cjd.ed.ac.uk (accessed Jan 20, 2005). 4 Cooper JD, Bird SM. Predicting incidence of variant Creutzfeldt-Jakob disease from UK dietary exposure to bovine spongiform encephalopathy for the 1940 to 1969 and post-1969 birth cohort. Int J Epidemiol 2003; 32: 784–91. 5 Clarke P, Ghani AC. Projections of the future course of the primary vCJD epidemic in the UK: inclusion of subclinical infection and the possibility of wider genetic susceptibility. J R Soc Interface 2005: DOI: 10.1098/ rsif.2004. 0017. http://www.pubs.royalsoc.ac.uk/interface_ homelink2.shtml (accessed Jan 26, 2005). 6 Working group “prion diease: risk assessment”. BSE transmission through food and blood products: a study in primates to assess the risk for humans. http://www.dpz.gwdg.de/virol/web-viro/WG_Moz. htm (accessed Jan 24, 2005). 7 Hilton DA, Ghani A, Conyers L, et al. Prevalence of lymphoreticular prion protein accumulation in UK tissue samples. J Pathol 2004; 203: 733–39. 8 Goldfarb LG, Cervenakova L, Gajdusek DC. Genetic studies in relation to kuru: an overview. Curr Mol Med 2004; 4: 375–84. 9 Carrell RW. Biomedicine: prion dormancy and disease. Science 2004; 306: 1692-93. 10 Llewelyn CA, Hewitt PE, Knight RSG, et al. Possible transmission of variant Creutzfeldt-Jakob disease by blood transfusion. Lancet 2004; 363: 417–21. 11 Peden AH, Head MW, Ritchie DL, Bell JE, Ironside JW. Preclincal vCJD after blood transfusion in a PRNP codon 129 heterozygous patient. Lancet 2004; 364: 527–29. 12 Manolakou K, Beaton J, McConnell I, et al. Genetic and environmental factors modify bovine spongiform encephalopathy incubation period in mice. Proc Natl Acad Sci USA 2001; 98: 7402–77.
731