Two cases of sporadic Creutzfeldt-Jakob disease have recently been reported in teenagers in Britain,[i.ii] adding to only four cases previously reported in this age group. Four British dairy farmers have died from Creutzfeldt-Jakob disease in the past three years[iii - v] - an occupational association that is unlikely to have arisen by chance. In the light of these findings, we asked a range of professionals how likely they thought it was that the agent responsible for Creutzfeldt-Jakob disease could be transmitted to humans from cattle affected with bovine spongiform encephalopathy.
i. Britton TC, Al-Sarraj S, Shaw C, Campbell T, Collinge J. Sporadic Creutzfeldt-Jakob disease in a 16-year-old in the UK.Lancet 1995;346:1155.ii. Bateman D, Hilton D, Love S, Zeidler M, Beck J, Collinge J. Sporadic Creutzfeldt-Jakob disease in a 18-year-old in the UK. Lancet 1995,346:1155-6.
iii. Sawcer SJ, Yuill GM, Esmonde TFG, Estibeiro P, Ironside JW, Bell JE, et al Creutzfeldt-Jakob disease in an individual occupationally exposed to BSE. Lancet 1993;341:642.
iv. Davies PTG, Jahtar S, Ferguson IT, Windl 0. Creutzfeldt-Jakob disease in an individual occupationally exposed to BSE. Lancet 1993;342:680.
v. Smith PEM, Zeidler M, Ironside JW, Estibeiro P, Moss TH. Creutzfeldt-Jakob disease in a dairy farmer. Lancet 1995;346:898
Jeffrey W Almond
The possibility that bovine spongiform encephalopathy might transmit to humans has been acknowledged since the disease was first recognised in British cattle. Indeed, one of the control measures introduced in 1989 - that of removing certain offals from bovine carcasses - was designed to minimise the risk of transmission to humans. The proscribed offals were those which were known to contain high levels of infectivity in sheep infected with scrapie and in mouse models of transmissible spongiform encephalopathies, there being (at that time) no information about the tissue distribution and levels of infectivity of bovine spongiform encephalopathy in bovine tissues at the various stages of the disease. Reassurance was provided by the observation that transmissible spongiform encephalopathies from other animals showed no evidence of transmission to humans. This is in spite of the fact that, for sheep scrapie at least, there is widespread exposure to, and consumption of, infected animals. Nevertheless, transmissible spongiform encephalopathies can transmit from one species to another, and for any given donor species there is no way of predicting which recipient species will be susceptible.
How can the risk to humans be assessed in light of current knowledge? One question is whether bovine spongiform encephalopathy has a greater (or different) potential for cross species transmission than scrapie and other non-human transmissible spongiform encephalopathies. This is relevant irrespective of whether one accepts the proposition that bovine spongiform encephalopathy is derived from sheep scrapie, since passage through cattle may confer new transmission properties. Observations in experimental animals suggest that transmission of a transmissible spongiform encephalopathy to one foreign host can result in an infection that can then transmit to a second, initially insusceptible, foreign host.[i] Actually, a similar experiment may have been done serendipitously by exposing cats. Feline spongiform encephalopathy appeared in the 1980s, apparently as a new disease.[ii] The feline spongiform encephalopathy agent was examined by strain typing and found to have the same strain phenotype as bovine spongiform-encephalopathy.[iii] Assuming that cats have been equally exposed to sheep scrapie and to bovine spongiform encephalopathy, the observations suggest that bovine spongiform encephalopathy has a different, and possibly broader, host range than circulating scrapie strains. We do not yet know whether this apparently novel host range of bovine spongiform encephalopathy extends to humans.
What molecular factors influence cross species transmission? These remain incompletely defined, but the seminal experiments by Scott et al established that the genotype of the prion (PrP) gene is the major factor.[iv] Indeed, the species barrier to transmission between mouse and hamster was overcome by transferring the hamster PrP gene into a mouse by genetic engineering. Although recent reports have suggested the involvement of additional factors,[v,vi] homophilic interactions between PrP in the inoculum and PrP in the host seem necessary for transmission to occur,[vii] with amino acids 96-167 possibly being most important.[vi-viii] What inferences can be drawn by comparing the PrP sequences of humans and cattle? It would be comforting if the degree of homology between them was lower, or at least no greater, than that between humans and sheep. Unfortunately this is not the case. Overall, the bovine sequence is closer (albeit slightly) to the human sequence than is the sheep sequence, and the 96-167 region has only five differences rather than six. Reassuringly, however, a second important region of the molecule, the C-terminal,[vi] is equally diverged.[ix]
What conclusions can be drawn about the present cases of Creutzfeldt-Jakob disease? Obviously, any change in the pattern of presentation of Creutzfeldt-Jakob disease in Britain compared with countries free of bovine spongiform encephalopathy would be cause for concern. However, the incidence of Creutzfeldt-Jakob disease in Britain has shown no significant increase in recent years and is similar to that elsewhere. The cases in farmers do suggest a significantly elevated risk for this group versus the general population. However, an elevated risk is also observed for farmers in other countries where there is a zero or very low incidence of bovine spongiform encephalopathy.[x] The risk is therefore unlikely to be related to bovine spongiform encephalopathy. The cases in teenagers are possibly of greater concern since such cases are generally extremely rare. However, it is possible that in earlier times, when there was less awareness of the disease, cases in teenagers were misdiagnosed. We need to be sure that the present cases are more than simply coincidental before we conclude that they represent a real change in the presentation of Creutzfeldt-Jakob disease.
Where do we go from here? We need definitive experiments to establish whether bovine spongiform encephalopathy can transmit to humans and whether it has transmitted to humans. Experimental procedures that might provide answers are available. Collinge and others have recently published evidence that mice transgenic for the human PrP gene can be used as a model for human PrP related diseases." [xi,xii]Similar mice, on a mouse PrP' background (lacking their own PrP gene) are available[xiii] and should be tested for susceptibility to bovine spongiform encephalopathy by various routes. A positive outcome, particularly if the mice were relatively resistant to sheep scrapie, would be evidence that bovine spongiform encephalopathy can transmit to humans. Bruce et al have described "strain phenotypes" based on lesion profile and transmission characteristics for various isolates of scrapie and bovine spongiform encephalopathy.[iii] The bovine spongiform encephalopathy phenotype is distinct and, moreover, stable even on passage through another species such as cat or antelope. If the present cases of Creutzfeldt-Jakob disease have been caused by bovine spongiform encephalopathy it is likely that this will show up in strain typing tests. As a matter of urgency, therefore, necropsy material from all of the present cases should be strain typed. Any presence of the bovine spongiform encephalopathy phenotype should be regarded as strong evidence that bovine spongiform encephalopathy has transmitted to humans.
i. DeArmond SJ. Overview of the transmissible spongiform encephalopathies prion protein disorders. Br Med Bull 1993;49:725-37.ii. Wyatt JM, Pearson GR, Smerdon TN, Gruffydd Jones TJ, Wells GA, Wilesmith JW. Naturally occurring scrapie-like spongiform encephalopathy in five domestic cats. Vet Rec 1991;129:233-6.
iii. Bruce M, Chree A, McConnell I, Foster J, Pearson G, Fraser H. Transmission of bovine spongiform encephalopathy and scrapie to mice - strain variation and the species barrier. Philosophical Transactions of the Royal Society of London series B - Biological Sciences 1994-343:405-11.
iv. Scott M, Foster D, Mirenda C, Serban D, CoufaI F, Walchli M,et al. Transgenic mice expressing hamster prion protein produce species-specific scrapie infectivity and amyloid plaques. Cell 1989;59:847-57.
v. Telling GC, Scott M, Mastrianni L, Gabizon R, Torchia M, Cohen FE, et al. Prion propagation in mice expressing human and chimeric PrP transgenes implicates the interaction of cellular PrP with another protein. Cell 1995;83:79-90.
vi. Telling GC, Scott M, Mastrianni L, Gabizon R, Torchia M, Cohen FE, et al. Prion propagation in mice expressing human and chimeric PrP transgenes implicates the interaction of cellular PrP with another protein. Cell 1995;85:79-90.
vii. Scott M, Groth D, Foster D, Torchia M, Yang SL, De Armond SJ, et al Propagation of prions with artificial properties in transgenic mice expressing chimeric PrP genes. Cell 1993;73:979-88
viii. Schatzl HM, Dacosta M, Taylor L, Cohen FE, Prusiner SB. Prion protein gene variation among primates. J Mol Biol 1995;245:362-74.
ix. Goldmann W, Hunter N, Martin T, Dawson M, Hope J. Different forms of the bovine PrP gene have five or six copies of a short, G-C-rich element within the protein-Coding exon. J Gen Virol 1991;72:201-4.
x. Will RG. Creutzfeldt-Jakob disease surveillance in the United Kingdom. CJD Surveillance Unit Annual Report 1995;4(abstract)
xi. CoIlinge J, Palmer MS, Sidle KCL, Gowland I, Medori R, Ironside J, et al Transmission of fatal familial insomnia to laboratory-animals. Lancet 1995; 346 569-70.
xii. Telling GC, Scott M, Hsiao KR, Foster D, Yang SL, Torchia M, et al. Transmission of Creutzfeldt-Jakob disease from humans to transgenic mice expressing chimeric human-mouse prion protein. Proc Natl Acad Sci USA 1994-91:9936-40.
xiii. Whittington MA, Sidle KCL, Gowland I, Meads J, Hill AF, Palmer MS, et al Rescue of neurophysiological phenotype seen in PrP null mice by transgene encoding human prion protein. Nature Genetics 1995;9: 197-201
Paul Brown
Creutzfeldt-Jakob disease has now been identified in four farmers and two adolescents in Britain, where its bovine spongiform counterpart has been epidemic for the past several years. Is there a connection? This question is being discussed by many different groups according to pre-existing biases and professional goals as might be expected for so controversial and potentially explosive a topic. The media has in the main sounded alarm bells because its goal is to produce an exciting story; the government has taken a low key, cautious approach because its goal is to prevent unwarranted panic; and medical science has been somewhat unpredictably divided in its evaluation, depending at least in part on individuals' distaste or flair for publicity.
In fact, no one can yet say with any confidence whether these cases of Creutzfeldt-Jakob disease in adolescents and farmers are the result of infection with bovine spongiform encephalopathy. In favour of the idea is the fact that so called sporadic Creutzfeldt-Jakob disease is typically a disease of late middle age, with only a handful of cases in people aged under 25; the disease would, however, be expected to occur in a more uniform age distribution if the source of infection was ingestion of cattle products, which explains the concern about "back-to-back" cases in young people. With respect to the four farmers, it is also true that each had at least one infected cow in his herd, raising the possibility of contact infection from the cows or even inhalant infection from the contaminated meat and bone meal feed that caused their illness.
Against the idea is the fact that adolescent Creutzfeldt-Jakob disease has occurred at times and places that virtually exclude the possibility of infection with bovine spongiform encephalopathy and that farmers have died of Creutzfeldt-Jakob disease m countries where bovine spongiform encephalopathy does not occur. It is also notable that the type of illness experienced by all six of the patients was typical of sporadic disease, rather than the predominantly cerebellar illness seen in patients infected peripherally from an external source such as contaminated pituitary hormones.
Statistical analysis will not yet be helpful in our evaluation of these cases, even if the observed occurrence can be shown to exceed significantly the expected occurrence in adolescents and farmers, because the power of statistics when dealing with so few cases is not compelling. In due time, however, statistics will provide the most important evidence for or against an association between Creutzfeldt-Jakob disease and bovine spongiform encephalopathy, as it is most unlikely that infection with bovine spongiform encephalopathy will ever be proved to have caused any individual case of Creutzfeldt-Jakob disease (for example, in someone who ate brain from a cow shown to have died of bovine spongiform encephalopathy). It is therefore crucial that the ongoing surveillance programme of Creutzfeldt-Jakob disease in Britain, in cooperation with similar programmes in other European countries, is sustained for at least several more years if an association between Creutzfeldt-Jakob disease and bovine spongiform encephalopathy is ever to be properly assessed.
Finally, there does not seem to be any need for new governmental hearings, committee meetings, or parliamentary debates about what more might be done because the precautions taken some years ago to eliminate potentially infectious products from commercial distribution were both logical and thorough. We are left looking at possible present consequences of past events over which we now have no control, and we can only hope that the affair will be happily resolved. At least we do not have to face the spectre of reparative legal proceedings, which in this case would amount to a class action suit for anxiety brought by the entire British population against its own government.
Sheila M Gore
In 1986, four years after a change in the processing of offals - including those from sheep infected with scrapie - into cattle meal, the first British case of bovine spongiform encephalopathy was confirmed.
Median incubation period in cattle is around four to five years[i] By 14 April 1995, bovine spongiform encephalopathy had been confirmed in 53.3% of dairy herds, 14.7% of beef suckler herds, and 33.8% of all herds with adult breeding cattle; people who work on farms without confirmed cases of bovine spongiform encephalopathy may, however, have worked on farms with infected, but not affected, cattle. The aim of ongoing studies in cattle is to find evidence of direct transmission of bovine spongiform encephalopathy by the two suggested means of transmission of scrapie in sheep: from mother to offspring or between unrelated animals around parturition.
The incubation period of human spongiform encephalopathies - kuru and Creutzfeldt-Jakob disease - is poorly estimated from data[ii] but is apparently in the range 15-40 years, possibly shorter in people who were young at exposure. The potential for the agent responsible for bovine spongiform encephalopathy to cross species barriers after occupational or dietary exposure including exposure to cattle meal by ingestion or inhalation - has been a major concern for human health. Whether the agent is pathogenic to humans cannot be known by direct experimentation. Thus, surveillance of cases of sporadic Creutzfeldt-Jakob disease - in terms of occupational distribution, temporal changes in incidence, and dietary correlations - is the only way to get early warning of pathogenesis of bovine spongiform encephalopathy in humans. British surveillance of Creutzfeldt-Jakob disease was therefore reactivated in May 1990,[iii] and a grant from the European Community in 1993 enabled surveillance projects elsewhere in Europe to share common diagnostic criteria, methodologies, and case control questionnaires. Two observations from the other participating countries set the British data (see below) in wider context: the incidence of Creutzfeldt-Jakob disease was similar in France, Germany, Italy, the Netherlands, and Britain in 1993-4 (about 0 72 cases per million person years); and, across countries, the reported incidence in dairy farmers was consistently higher than in all farmers (pooled estimates: 6.31 v 0.74 cases per million person years).[iii]
Creutzfeldt-Jakob disease in British farmers
Based on the 1991 population and deaths from sporadic Creutzfeldt-Jakob disease in the United Kingdom from 1 May 1990 to 2 March 1995, the age specific incidence of the disease (per million person years) was estimated to be 0.05 (ages 40-44, 1 case), 0.42 (ages 45-49, 7 cases), 0.62 (ages 50-54, 9 cases), 1.80 (ages 55-59, 25 cases), 2.62 (ages 60-64, 36 cases), and 2.06 (ages 65 and over, 89 cases), with no cases for the age group 15-39 (R G Will, personal communication). These age specific incidences (irrespective of sex) were used in conjunction with the age distribution of farmers in England and Wales - available from the 1990 European Community structure survey (C Jennings, personal communication) - to derive the expected age appropriate incidence of sporadic Creutzfeldt-Jakob disease in farmers: 0.77 per million person years (male or female, full or part time employment, and including spouses and other family members). The structure survey gives the number of people employed in farming in England and Wales as 442,300, 136,440 of them in dairy farming. Corresponding numbers for the United Kingdom - including Scotland and Northern Ireland - have been arrived at on a population pro rata basis: that is, multiplying by 1.13 and rounding up to nearest thousand, to give 500,000 and 155,000 respectively. The number of people employed on farms with adult cattle is not easily available but is unlikely to exceed twice the number in dairy farming. An upper limit of 310,000 has been assumed (see table). An estimated 105,000 of these 310,000 (33.8%: rounded up to nearest thousand) work on farms with cattle affected with bovine spongiform encephalopathy.
| Probability of occurrence of Creutzfeldt-Jakob disease in British farm workers and their families | |||||
| Farms with adult cattle | |||||
| All farms | Dairy farms | All | Affected by bovine spongiform encephalopathy | Not affected by bovine spongiform encephalopathy | |
| Population size* | 500,000 | 155,000 | 310,000** | 105,000 | 205,000 |
| Expected No of cases in six years | 2.31 | 0.7161 | 1.4322 | 0.4851 | 0.9471 |
| Probability of cases: | |||||
| At least 1 | 0.90 | 0.51 | 0.76 | 0.38 | 0.61*** |
| At least 2 | 0.67 | 0.16 | 0.42 | 0.09 | 0.24 |
| At least 3 | 0.41 | 0.036 | 0.17 | 0.013 | 0.07 |
| At least 4 | 0.20 | 0.006*** | 0.06 | 0.0016*** | 0.016 |
| At least 5 | 0.085*** | 0.00087 | 0.016*** | 0.00015 | 0.0029 |
| At least 6 | 0.031 | 0.00010 | 0.0036 | 0.000012 | 0.00045 |
| At least 7 | 0.010 | 0.00001 | 0.0007 | 0.000001 | 0.00006 |
| *Rounded up to nearest thousand. **Upper limit ***Confirmed cases. | |||||
EXPECTED INCIDENCE OF CREUTZFELDT-JAKOB DISEASE
The expected number of cases of sporadic Creutzfeldt-Jakob disease during the six years from 1 May 1990 to 30 April 1996 in people who work on British farms at time of diagnosis is thus: 0.77 (expected age appropriate incidence per million person years)x0.5 million x6 years=2.31. Based on this Poisson expectation,[iv] the table shows the probability of observing n or more actual cases for n= 1, 2, . . . 7. The probability of five or more cases in farm workers is 0.085.
If we restrict attention to people who work on British dairy farms the expected number of cases of sporadic Creutzfeldt-Jakob disease during six years is 0.72, and the probability of observing four of more confirmed cases is 0.006.
For people who work on British farms with adult cattle, the expected number of cases in six years is 1.43, and the probability of observing five or more confirmed cases is 0.016. Subdivision of farms with adult cattle according to whether cattle are affected with bovine spongiform encephalopathy suggests that the probability of observing four or more cases from affected farms and one or more from unaffected farms is 0 0016x0.61, or 1 in 1,000.
All four confirmed cases of Creutzfeldt-Jakob disease in people who worked on farms affected by bovine spongiform encephalopathy were male, lifelong, full time farm workers. The 1990 European Community structure survey reports that 44% of all farm labour is performed by men working full time. I estimate that 46,000 men work full time on British farms with cattle affected by bovine spongiform encephalopathy: on the basis of 0.2134 cases of sporadic Creutzfeldt-Jakob disease expected in six years, the probability of observing four or more confirmed cases in such men is less than 1 in 10,000.
FURTHER STUDIES
Possible occupational exposure to the agent responsible for bovine spongiform encephalopathy (or other spongiform encephalopathy) agent must be rigorously researched therefore. If the bovine spongiform encephalopathy agent is implicated it is likely that any such exposure first occurred in the early 1980s when cattle were also first exposed. Have there been changes in farm practices, including changes in farm workers' diet, that have limited possible occupational exposures since the first cases of bovine spongiform encephalopathy were confirmed? Do historical or current farm practices differ between lifelong farm workers and others, between full time and part time farm workers, between dairy and other cattle farmers, or between farming families in which Creutzfeldt-Jakob disease has occurred and other farming families? The European data warn that aspects of dairy farming other than working with herds affected by bovine spongiform encephalopathy could be implicated in higher incidences of Creutzfeldt-Jakob disease in dairy farmers.[iii]
The potential for bias in case-control comparison of recalled diet when the item of interest is public knowledge[v,vi] has been underlined elsewhere.[iii] Transmission experiments in mice have begun with brain tissue from farmers who have died from Creutzfeldt-Jakob disease and whose herds were affected by bovine spongiform encephalopathy, but these will require two to three years for completion.
Creutzfeldt-Jakob disease in young adults
Three cases of sporadic Creutzfeldt-Jakob disease in people aged under 40 have been reported in the United Kingdom since May 1990,[vii-ix] two of them in people aged under 20. About 21 million persons in the United Kingdom are aged 15-39, and the incidence of Creutzfeldt-Jakob disease increases with age (see above). The Poisson probability of observing n or more cases of sporadic Creutzfeldt-Jakob disease during six years in the age group 15-39 - if the sporadic incidence is taken as 0 01 or as 0 001 per million person years (a fifth or a fiftieth of that for the age group 40-44) - can easily be computed based on 1.26 or 0.126 expected cases. If the higher of the two postulated incidences is the more reasonable, three or more cases in people aged under 40 in six years are not untoward (P=0.13) but four or more begins to be (P=0.04). Even three or more cases are highly improbable if the alternative postulate applies (P=0.0003).
A clear epidemiological priority is to pool data from comparable European surveillance studies of Creutzfeldt-Jakob disease to derive a best estimate of incidence for people aged 15-39. A new environmental or dietary exposure to a spongiform encephalopathy pathogenic to humans is likely to be first evident in young adults because background sporadic cases are rare and the incubation period may be shorter in young people. Transmission experiments with brain tissue from young adults who have died from Creutzfeldt-Jakob disease will be needed.
Taken together, cases of Creutzfeldt-Jakob disease in farmers and young adults are more than happenstance.[x] They signal an epidemiological alert to investigate intensively possible exposures - farm related and dairy - and to devise means of doing so that are minimally compromised by pre-existing publicity.
i. Spongiform encephalopathy Advisory Committee. Transmissible spongiform encephalopathies: a summary of present knowledge and research. London: HMSO, 1994.ii. Woolridge M. A study of the incubation periods or age at onset of the transmissible spongiform encephalopathies/prion diseases [PhD thesis] London: University of London, 1995.
iii. National CJD Surveillance Unit and Department of Epidemiology and Population Sciences, London School of Hygiene and Tropical Medicine. Creutzfeldt-Jakob disease surveillance in the United Kingdom. Edinburgh: National CJD Surveillance Unit, 1995
iv. Gore SM, Altman DG. Statistics in practice. London: BMA, 1982:95.
v. Watkins A Mad cow disease: now fifth farmer is suspect. Today 1995 October 25:1-2
vi. Sinclair K Scot sues over death from CJD. Herald 1995 October 25:11.
vii. Watkins A. Now CJD kills dad aged 30. Today 1995 November 10:8.
viii. Britton TC, Al-Sarraj S, Shaw C, Campbell T, Collinge J. Sporadic Creutzfeldt-Jakob disease in a 16-year-old in the UK.Lancet 1995;346:1155.
ix. Bateman D, Hilton D, Loce S, Zeidler M, Beck J, Collinge J. Sporadic Creutzfeldt-Jakob disease in an 18-year-old in the UK. Lancet 1995;346: 1155-6.
x. Bibby J. Quotes, damned quotes, and... Milton Keynes: Open University, 1983:45.
Albert Hofman, Dorothee P W M Wientjens
The occurrence of Creutzfeldt-Jakob disease in British dairy farmers possibly exposed to cattle with bovine spongiform encephalopathy has focused attention on the possibility of a causal link between the two diseases. We briefly review the currently available epidemiological evidence.
The table shows the incidence of Creutzfeldt-Jakob disease in France, Germany, Italy, the Netherlands, and Britain. The data are based on registries in the countries, which have used similar methods of surveillance and criteria for diagnosis since the start of a European collaborative study in 1992. The incidence in Britain, with a much higher risk of exposure to bovine spongiform encephalopathy, was similar to that in the other European countries.
The epidemiological evidence concerning occupational exposure derives from two sources- a meta analysis of three case-control studies, conducted in Japan, Britain, and the United States[iv]; and an ongoing European case-control study based on the registries of Creutzfeldt-Jakob disease that were started in 1992.[v] The meta-analysis included data on 178 cases of Creutzfeldt-Jakob disease and 333 controls. In 95 cases information on occupational exposure to cattle was available, and 26 subjects had been exposed. The corresponding figures for the controls were 26 out of 145. The resulting relative risk for exposure (adjusted for age and sex) was 1-7 (95% confidence interval 0 9 to 31).
| lncidence of Creutzfeldt-Jakob disease per million person years in European countries in 1993 and 1994[i,ii] | |||||
| France | Germany | Italy | Netherlands | Britain | |
| 1993: | |||||
| No of cases* | 28 | 19 | 31 | 10 | 32 |
| Incidence | 0.50 | 0.47** | 0.54 | 0.68 | 0.56 |
| 1994: | |||||
| No of cases* | 47 | 58 | 30 | 16 | 54 |
| Incidence | 0.81 | 0.73 | 0.53 | 1.04 | 0.93 |
| *Includes
probable and definite cases according to criteria adapted from Masters et al **Extrapolated from figures for June to December 1993. | |||||
A preliminary analysis from the ongoing European case-control study included 234 cases of people with the disease, of whom 24 had ever been occupationally exposed to cows, and 237 controls, of whom 19 had ever been exposed. The relative risk amounted to 13 (95% confidence interval 0 7 to 2 5) (personal communications from A Alperovitch and N Delasnerie-Laupretre, France; S Poser and T Weber, Germany; C Masullo and M Pocchiari, Italy; A Hofman and D P W M Wientjens, Netherlands; and R G Will, Britain).
Although the occurrence of Creutzfeldt-Jakob disease in four dairy farmers in Britain is clearly a matter of concern, the current evidence from the European surveillance study suggests that there is no higher risk of the disease in British dairy farmers than in farmers in other European countries. Furthermore, the overall incidence of Creutzfeldt-Jakob disease is similar in the five European countries, while there is a substantial difference in the incidence of bovine spongiform encephalopathy. Taken together, the epidemiological evidence to date does not point to a causal link between bovine spongiform encephalopathy and Creutzfeldt-Jakob disease but, unfortunately, does not strongly reject that possibility either.
i. Alperovitch A, Brown P, Weber T, Pocchiari M, Hofman A, Will R. Incidence of Creutzfeldt-Jakob disease in Europe in 1993. Lancet 1994,343:918.ii. Delasnerie-Laupretre N, Poser S, Pocchiari M, Wientjens DPWM, Will R. Creutzfeldt-Jakob disease in Europe. Lancet 1995;346:898.
iii. Masters CL, Harris JO, Gajdusek DC, Gibbs CJ Jr, Bernoulli C, Asher DM. Creutzfeldt-Jakob disease: patterns of worldwide occurrence and the significance of familial and sporadic clustering. Ann Neurol 1979;5:177-88.
iv. Wientjens DPWM, Davanipour Z, Hofman A, Kondo K, Matthews WB, Will RG, et al Risk factors for Creutzfeldt-Jakob disease: a reanalysis of case control studies. Neurology (in press)
v. Hofman A. Risk of Creutzfeldt-Jakob disease in relation to animal spongiform encephalopathies: a collaborative study in Europe. Eur J Epidemiol 1991;7:466-8.
R M Ridley, H F Baker
Whenever an unusual case of Creutzfeldt-Jakob disease is reported in Britain someone asks: "Is this the beginning of the end - are we all going to die of BSE?" It is a commonly held view that the incubation period for spongiform encephalopathy in humans is at least one to two decades. This is a misconception. For kuru, when the dose of infectivity by the oral route was high the minimum incubation period was less than four years and the median ranged from less than five years to nine years (judged by the minimum ages at onset at the height of the epidemic)[i] However, the incubation period can be as long as 30 years (judged by the ages of the most recent cases).[ii]
While experimental transmission of spongiform encephalopathy across species generally results in increased incubation times, this is because the "species barrier" increases the dose required, so that fewer individuals are affected. It is now six to nine years since the general public was at greatest risk of consuming meat products containing brain tissue from cattle incubating bovine spongiform encephalopathy (that is, between the emergence of this disease in 1986 and the Specified Offals Ban of 1989), so it is already clear that a substantial proportion of the population will not be affected. Nonetheless, the occurrence of only a handful of cases of human spongiform encephalopathy resulting from exposure to bovine spongiform encephalopathy would be a tragedy, and any possible case warrants close examination. It is, however, another misconception to suppose that every case of Creutzfeldt-Jakob disease must have been caught from somewhere. About 15% of cases are wholly genetic in origin, and in nearly all of the remaining cases persistent and extensive epidemiological investigation has failed to find a contamination event, leading to the proposition that these cases are idiopathic. It is against this background that the occurrence of Creutzfeldt-Jakob disease in four farmers and two teenagers should be considered.
The four farmers had ages at onset and clinical pictures consistent with idiopathic Creutzfeldt-Jakob disease.[iii-v] During a similar period the number of farming employees with Creutzfeldt-Jakob disease in France was five, in Germany two, and in Italy three.[vi] Bovine spongiform encephalopathy has not been reported in these countries. This suggests that the number of cases in farmers in Britain is not surprising and need not be related to bovine spongiform encephalopathy. The only known cases of acquired spongiform encephalopathy in humans have involved ingestion, injection, or other internal contamination with material associated with human brain, and brain is the only tissue consistently infectious in bovine spongiform encephalopathy. If these farmers had been at risk from handling cattle feed one would expect feed producers to have been at greater risk, and if the farmers had been at risk from handling affected cattle one would expect abattoir workers to have been at greater risk. There is no evidence that these occupational groups are at higher risk of contracting Creutzfeldt-Jakob disease.
Four cases of apparently idiopathic Creutzfeldt-Jakob disease have been reported in teenagers in continental Europe and the United States.[vii-x] Since these cases cannot be related to bovine spongiform encephalopathy, the occurrence of Creutzfeldt-Jakob disease in two teenagers in Britain[xi,xii] does not make a link with bovine spongiform encephalopathy obligatory. However, these two cases are extremely unusual both in the ages at onset and in the reported neuropathology. A greater appreciation of the variety of clinical presentations, neuropathology, and age at onset of Creutzfeldt-Jakob disease in recent years - together with the heroic attempts of the National CJD Surveillance Unit to identify all cases - should lead to greater ascertainment, particularly of those cases which are unusual. We hope that this explains the detection of these two cases in young people.
i. Alpers MP. Kuru - implications of its transmissibility for the interpretation of its changing pattern. In: Bailey OT, Smith DE, eds. The central nervous system - some experimental models of neurological disease. Baltimore, MD: Williams and Wilkins, 1968:234-51 . ii. Scrimgeour EM, Masters CL, Alpers MP, Kavan J, Gajdusek DC. A clinico-pathological study of a case of kuru. J Neurol Sci 1983;59:265-75.iii. Davies PTG, Jahtar S, Ferguson IT, Windl 0. Creutzfeldt-Jakob disease in an individual occupationally exposed to BSE. Lancet 1993;342:680.
iv. Sawcer SJ, Yuill GM, Esmonde TFG, Estibeiro P, Ironside JW, Bell JE, et al Creutzfeldt-Jakob disease in an individual occupationally exposed to BSE. Lancet 1993;341:642.
v. Smith PEM, Zeidler M, Ironside JW, Estibeiro P, Moss TH. Creutzfeldt-Jakob disease in a dairy farmer. Lancet 1995;346:898
vi. Delasnerie-Laupretre N, Poser S, Pocchiari M, Wientjens DPWM, Will R. Creutzfeldt-Jakob disease in Europe. Lancet 1995;346:898.
vii. Monreal J. Collins GH, Masters CL, Fisher CM, Kim RC, Gibbs CJ, et al.. Creutzfeldt-Jakob disease in an adolescent. J Neurol Sci 1981,52 341-50.
viii. Brown P, Cathala F, Labauge R, Pages M, Alary JC, Barton H. Epidemiologic implications of Creutzfeldt-Jakob disease in a 19-year-old girl. Eur. J Epidemiol 1985;1:42-7.
ix. Berman PH, Davidson GS, Becker LE. Progressive neurological deterioration in a 14-year-old girl. Pediatric Neuroscience 1988,14 42-9
x. Kulczycki J, Jedrzejowska H, Gajkowski K, Tamowska-Dziduszko E, Lojkowska W. Creutzfeldt-Jakob disease in young people. Eur J Epedemiol 1991;7:501-4.
xi. Britton TC, Al-Sarraj S, Shaw C, Campbell T, Collinge J. Sporadic Creutzfeldt-Jakob disease in a 16-year-old in the UK.Lancet 1995;346:1155.
xii. Bateman D, Hilton D, Love S, Zeidler M, Beck J, Collinge J. Sporadic Creutzfeldt-Jakob disease in a 18-year-old in the UK. Lancet 1995,346:1155-6.
G W Roberts
Anxieties over the possibility that material from or contact with cows infected with bovine spongiform encephalopathy might cause Creutzfeldt-Jakob disease revolve around three questions.
Could it happen?
Bovine spongiform encephalopathy in cows, scrapie in sheep and experimental animals, and Creutzfeldt-Jakob disease are all caused by the same class of pathogen and are more accurately called prion diseases.[i] Human prion disease is rare, but the public health importance of prion disease far exceeds its rarity for the following reasons. It has been transmitted experimentally to various animal species[i,ii] (bovine spongiform encephalopathy has been transmitted experimentally in primates), and accidental person to person transmission has occurred.[iii] In addition, it has been shown that prion disease can be transmitted orally by the ingestion of infected foodstuffs or infected tissues.[iv,v] The available data provide ample evidence to support the theoretical possibility that one of the naturally occurring animal forms of prion disease could be transmitted accidentally, to man by inoculation with, or ingestion of, infected material.
Has it happened?
It is accepted that cows infected with bovine spongiform encephalopathy entered the human food chain before the introduction of controls in 1988 and possibly until the introduction of legislation listing proscribed offal in November 1989. Only one attempt has been made to calculate the volume of infected material that entered the food chain.[vi] Dealer and Kent estimated that about 1.8 million cows incubating bovine spongiform encephalopathy would enter the food chain between 1983 and 1999. The number of people who have ingested this food and thus have had a theoretical exposure to infection is substantial (estimated at 34 million for a dose of 10 cubed infective units, through to 0.4 million at a dose of 10 to power of five units and 0.14 million at a dose of 10 to power nine units). The actual number of infective units required to cause disease in humans is unknown. Of course, these are calculations based on assumptions that are open to argument, and it would be interesting to see a full public discussion of the data. Whether any of this material could have provided sufficient infected material to cause prion disease in humans is unknown.
How will we know if it happens?
Simply put, doctors will see more patients dying of prion disease. The government has decided to monitor new cases of prion disease (Creutzfeldt-Jakob disease) as they arise in the community. Cases must be recognised during life and verified after death.[vii]With this surveillance system the number of cases of Creutzfeldt-Jakob disease in Britain has risen from around 30 cases a year during the 1980s (incidence 0.5 per million per year)[viii] to 54 in 1994 (incidence 0-94).[ix] Such rising figures have increased anxiety.
In reality the increase probably reflects improve ment in diagnostic methods. It has been proposed that the clinical spectrum of prion disease is much wider than that encompassed under Creutzfeldt-Jakob disease and in particular that atypical cases of prion disease (older age of onset, few motor signs, and prominent symptoms of dementia) are more likely to be overlooked in life.[x,xi] Such misdiagnoses have been documented in a large retrospective survey.[xii] It seems that our understanding and monitoring of the epidemiology of prion disease is not as robust as once thought. The interest aroused by media reports of patients with prion disease (be they teenagers or farmers), and any changes in public health practices they stimulate, need to be viewed against this recent exposure of the limitations in the epidemiological metrics traditionally ascribed to Creutzfeldt-Jakob disease. This problem is far from academic as cases of prion disease that slip through the diagnostic net probably have and certainly will represent a source of 'iatrogenic infection. Furthermore, if changing environmental factors (such as material infected with bovine spongiform encephalopathy) lead to a change in the clinical presentation of prion disease the situation may become even more difficult to interpret.
| Number of cases of bovine spongiform encephalopathy in British cattle (data from John Wilesmith, Ministry of Agriculture, Fisheries and Food) | |
| 1986 | 12 |
| 1987 | 461 |
| 1988 | 3072 |
| 1989 | 7627 |
| 1990 | 14371 |
| 1991 | 25644 |
| 1992 | 36924 |
| 1993 | 33574 |
| 1994 | 22699 |
| 1995 (Jan-Jun) | 7141 |
i. Prusiner SB, Collinge J, Powell J, Anderton B, eds. Prion diseases in humans and animals. London: Ellis Horwood, 1992.ii. Schreuder BEC. Animal spongiform encephalopathies - an update. Part 1: scrapie and lesser known animal spongiform encephalopathies. Vet Q 1994;16 174-81.
iii. Brown P, Preece MA, Will RG. 'Friendly fire' in medicine: hormones, homografts and Creutzfeldt-Jakob disease. Lancet 1992-340 24-7.
iv. Gibbs CJ Jr Amyx HL, Bacote A, Masters CL Gajdusek DC. Oral transmission of kuru, Creutzfeldt-Jakob disease and scrapie to non-human primates. J Infect Dis 1980;142 705-8.
v. Barlow RM, Middleton DI. Dietary transmission of bovine spongiform encephalopathy to mice. Vet Rec 1990;126: 111-2 .
vi. Dealer SF, Kent JT. BSE: an update on the statistical evidence. British Food Journal 1995;47 3-19.
vii. Bell JE, Ironside JW. Neuropathology of spongiform encephalopathies in humans. Br Med Bull 1993;49 738-77.
vii. Will RG. Epidemiology of Creutzfeldt-Jakob disease Br Med Bull 1993;49 960-70 .
ix. Delasnerie-Laupretre N, Poser S, Pocchiari M, Wientjens DPWM, Will R. Creutzfeldt-Jakob disease in Europe. Lancet 1995;346:898-9
x. Prion disease: spongiform encephalopathies unveiled. Lancet 1990;336 71-2.
xi. Harrison PJ, Roberts GW. "Life, Jim, But Not as We Know It" Transmissible dementias and the prion protein. Br J Psychiatry 1991;158 457-70.
xii. Bruton CJ, Bruton RK, Gentleman SN, Roberts GW. Diagnosis and incidence of prion (Creutzfeldt-Jakob disease: A retrospective archival survey with implications for future research. Neuroreport (in press).
Kenneth L Tyler
Recent reports of prion disease developing in four dairy farmers and two teenagers in Britain have raised renewed concerns about the potential health risk of bovine spongiform encephalopathy to humans. Documented transmission of bovine spongiform encephalopathy to non-human primates indicates that such concerns are not without foundation.[i] Although prions are not conventional pathogens, many of the basic principles governing microbial pathogenesis seem to apply to the infectious forms of prion diseases. In this context human risk of infection after exposure to bovine spongiform encephalopathy can be considered in terms of the size of the infecting inoculum, the potential routes of entry into the host, and factors of host susceptibility.
Inoculum size
Infectivity in human prion diseases is concentrated primarily in neural (brain, spinal cord, eye) and Iymphoreticular (liver, spleen, Iymph nodes) tissues.[ii] Human brain material has been estimated to contain 10 cubed to 10 to the power of five infectious units per gram of tissue,[ii] and bioassay in mice has shown brain material from cattle with bovine spongiform encephalopathy to contain 10 to the power of five to 10 power six infectious units per gram.[iii] In both human prion diseases and bovine spongiform encephalopathy, infectivity is not found in skeletal muscle, adipose tissue, or body fluids (blood, saliva, urine, faeces, semen, milk).[ii-v] Fortunately, with the exception of people occupationally exposed to cattle (farmers, veterinary surgeons, abattoir workers), potential human exposure to bovine spongiform encephalopathy is primarily through beef or milk products, neither of which are likely to contain high infectivity. If infectivity were present in these tissues, conventional methods of food preparation might reduce infectivity but presumably would not fully destroy it given the resistance of prions to decontamination.[vi]
Route of inoculation
Transmission studies on prion diseases have consistently shown that both route and dose of inoculum affect disease transmission. Studies indicate that intracerebral inoculation is the most efficient route of transmission, followed in descending order by intravenous, intraperitoneal, subcutaneous, and intragastric or oral inoculation.[iii,v-ix] Nonetheless, kuru provides an instructive example that ingestion - in this case of highly infectious brain material - can be the source of transmission of human prion diseases.7 In experimental models, bovine spongiform encephalopathy has been transmitted by the oral route to mice by infected bovine brain material but not by blood, milk, muscle, or Iymphoreticular tissues.[iv,v] Potential human exposure to material infected with bovine spongiform encephalopathy would predominantly involve oral exposure to tissues of low infectivity (such as beef or milk products). People working in animal husbandry, health care, and slaughter would be at additional risk of inadvertent subcutaneous or intramuscular inoculation with material of high infectivity.
Host factors
Experiments on the transmission of prion diseases between different types of animals have shown the existence of a "species barrier." The inoculum required to transmit disease between animals of different species is considerably higher than that required for intra species transmission. Such a barrier has been found during experiments of transmission of bovine spongiform encephalopathy to mice,[x,xi] and would be expected to exist for transmission of bovine spongiform encephalopathy to humans. The species barrier should be viewed as an additional impediment, rather than an absolute obstacle, to disease transmission. It would be expected to increase the minimal dose of contaminated material required for human infection.
Susceptibility to the development of sporadic and iatrogenic human prion diseases is probably modulated by polymorphisms in the human prion gene (PrP gene). The prevalence of homozygosity for methionine or valine at PrP codon 129 has been reported to be significantly increased in people with sporadic Creutzfeldt-Jakob disease.[xii] Polymorphisms at this codon may also modulate the phenotypic expression of inherited prion diseases.[xiii] About 50 people have developed Creutzfeldt-Jakob disease after having been treated with growth hormone or gonadotropins derived from pools of human cadaveric pituitary glands. These people also show an increased prevalence of methionine or valine homozygosity at PrP codon 129.[xiv] Large numbers of people exposed to similar doses of the same lots of pituitary hormones for the same period of time and by similar routes as those who subsequently developed iatrogenic Creutzfeldt-Jakob disease have remained disease free. This would suggest that host factors may be a critical determinant of human susceptibility to infectious prion diseases. Different inbred strains of mice have been shown to vary in their susceptibility to bovine spongiform encephalopathy and other prion diseases,[xi]which is consistent with previous identification of genetic determinants of susceptibility to prion disease in a wide variety of animal species. It might be predicted that similar host factors might dramatically influence the risk of the disease developing in a person exposed to bovine spongiform encephalopathy.
Implications for disease prevention
Since no effective treatment of prion diseases currently exists, the emphasis of public health measures must be on preventing disease. Animals known to have bovine spongiform encephalopathy should be immediately destroyed, and their tissues should not be used as food for humans or other animals. The long incubation period between exposure and development of symptomatic bovine spongiform encephalopathy poses a considerable problem, as people might be inadvertently exposed to tissues of presymptomatic cattle harbouring bovine spongiform encephalopathy. Development of reliable tests for presymptomatic detection of bovine spongiform encephalopathy would obviously alleviate this problem and should remain a high research priority. The risk to people can be minimised by preventing human exposure to bovine tissue known to harbour the highest levels of bovine spongiform encephalopathy infectivity, including all neural and Iymphoreticular tissue. Beef and milk are not known to harbour important infectivity, and consumption of these items does not seem to pose an important health hazard. Reducing the incidence of bovine spongiform encephalopathy in cattle would also substantially decrease the risk of human exposure. Current statutory measures designed to prevent contamination of cattle feed with bovine spongiform encephalopathy and its continued transmission within herds should be maintained and modified as needed on the basis of ongoing scientific and epidemiological studies. Research should continue into reliable, practical, and economically efficient measures for the decontamination of potentially infective bovine tissues. Finally, much of the potential increased risk of developing human prion disease in farmers and workers with occupational exposure to bovine spongiform encephalopathy can be reduced or eliminated by preventing accidental inoculation with infected tissues. The use of appropriate protective clothing and specific safety training and education would be expected to diminish risk for these people.
i. Baker HF, Ridley RM, Wells GAH. Experimental transmission of BSE and scrapie to the common marmoset. Vet Rec 1993;132:406.ii. Brown P, Gibbs CJ Jr, Rodgers-Johnson P, Asher DM, Sulima MP, Bacote A, et al Human spongiform encephalopathy: the National Institutes of Health series of 300 cases of experimentally transmitted disease. Ann Neurol 1994;35:513-29.
iii.Kimberlin RH, Wilesmith JW. Bovine spongiform encephalopathy. Epidemiology, low dose exposure and risks. Ann NY Acad Sci 1994;724: 210-20.
iv. Bradley R. The research programme on transmissible spongiform encephalopathies in Britain with special reference to bovine spongiform encephalopathy. Dev Biol Stand 1993;80:157-70.
v. Middleton DL Barlow RM. Failure to transmit bovine spongiform encephalopathy to mice by feeding them with extraneural tissues of affected cattle. Vet Rec 1993;132:545-7.
vi. Taylor DM, Fraser H, McConnell I, Brown DA, Brown KL, Lamza KA, et al. Decontamination studies with the agents of bovine spongiform encephalopathy and scrapie. Arch Vlrol 1994;139:313-26.
vii. Gibbs CJ Jr Amyx HL, Bacote A, Masters CL Gajdusek DC. Oral transmission of kuru, Creutzfeldt-Jakob disease and scrapie to non-human primates. J Infect Dis 1980;142 705-8.
viii. Prusiner SB, Cochran SP, Alpers MP. Transmission of scrapie in hamsters. J Infect Dis 1985;152:971-8.
ix. Kimberlin RH, Walker CA. Pathogenesis of scrapie in mice after intragastric infection. Virus Res 1989;12:213-20.
x. Bruce M, Chree A, McConnell I, Foster J, Pearson G, Fraser H. Transmission of bovine spongiform encephalopathy and scrapie to mice - strain variation and the species barrier. Philosophical Transactions of the Royal Society of London series B - Biological Sciences 1994-343:405-11.
xi. Fraser H, Bruce ME, Chree A, McConnell I, Wells GA. Transmission of bovine spongiform encephalopathy and scrapie to mice. J Gen Virol 1992;73:1891-7.
xii. Palmer MS, Dryden AJ, Hughes JT, Collinge J. Homozygous prion protein genotype predisposes to sporadic Creutzfeldt-Jakob disease [letter]. Nature 1991;352:340-2
xiii. Goldfarb LG, Petersen RB, Tabaton M, Brown P, LeBlanc A, Montagna P, et al. Fatal familial insomnia and familial Creutzfeldt-Jakob disease: disease phenotype determined by a DNA polymorphism.Science 1992;258:806-8.
xiv. Collinge J, Palmer MS, Dryden AJ. Genetic predisposition to iatrogenic Creutzfeldt-Jakob disease.Lancet 1991;337:1441-2.
School of Animal and Microbial Sciences University of Reading Reading RG6 2AH Jeffrey W Almond professor
Laboratory of Central Nervous Studies National Institute of Neurological Disorders and Stroke National Institutes of Health Bethesda MD 20892 USA Paul Brown medical director (US Public Health Service)
MRC Biostatistics Unit Institute of Public Health Cambridge CB2 2SR Sheila M Gore senior statistician
Department of Epidemiology and Biostatistics Erasmus University Medical School PO Box 1738 3000 DR Rotterdam Netherlands Albert Hofman professor of epidemiology Dorothee P W M Wientjens research physician
MRC Comparative Cognition Team Department of Experimental Psychology School of Clinical Veterinary Medicine Cambridge CB3 0ES R M Ridley head of team H F Baker senior scientific officer
Molecular Neuropathology SmithKline Beecham Pharmaceuticals New Frontiers Science Park-North Harlow CM19 5AW G W Roberts professor
University of Colorado Health Sciences Center Denver VA Medical Center Denver CO 80220 USA Kenneth L Tyler professor of neurology, medicine, microbiology, and immunology