Bovine spongiform encephalopathy and new variant Creutzfeldt-Jakob Disease:
Background, evolution and current status of the problem
Scrapie, an endemic spongiform encephalopathy of sheep and goats, has been known to exist in Europe since the middle 18th century, and has since spread to most sheep-breeding countries of the world1. It is particularly widespread in the United Kingdom where, as elsewhere in the developed world, the carcasses of livestock (including sheep) are recycled as a protein-rich nutritional supplement through a "rendering process". In this process, carcasses from which all consumable parts have been removed are milled and then decomposed in large vats by boiling at atmospheric or higher pressures, producing an underlying aqueous slurry of protein and an overlying layer of fat (tallow). The aqueous slurry is desiccated into a ‘meat and bone meal’ product that is distributed to the livestock industry for use as a nutritional protein supplement.
Bovine spongiform encephalopathy
In 1985, in the United Kingdom, the first case of spongiform encephalopathy in cattle was recognized, which subsequently became known as bovine spongiform encephalopathy (BSE), or "mad cow disease"2. Although elements of the ensuing story are still disputed, it appears likely that certain changes in the rendering process that had taken place around 1980 allowed a small amount of infectivity present in the carcasses of scrapie-infected sheep to survive the process and, through ingestion of the resulting contaminated protein supplement, to infect cattle. Cattle carcasses, unsuspected of being infected, were then recycled through the rendering plants, leading to ever greater levels of cattle-adapted infectivity in the protein supplement, and eventually producing a full-scale BSE epidemic3,4.
Recognition of this source of infection led to the imposition, in 1988, of a ruminant feed ban in the United Kingdom that by 1992 had turned the epidemic around. But the loss of some 180,000 cattle to date has brought the British livestock industry to its knees, and has also affected the tallow, gelatin, and pharmaceutical industries, all of which make use of bovine-derived products for human use.
Nor is BSE restricted to the United Kingdom. Either as a result of the importation of live animals or protein supplements, cases of BSE have occurred in many other European countries (Table 1). In most of the countries, the incidence of new cases is decreasing, but in a few countries the incidence is either stable (e.g., France) or increasing (e.g., Portugal). All of these cases are thought to be the result of a ‘tailing’ use of contaminated feed from years past, and there is as yet no proven case of indigenous BSE in any European country, i.e., no indication that any case of BSE has originated "de novo" outside the United Kingdom, or has resulted from cow-to-cow transmission.
* Countries in bold have had cases only in cattle imported from the UK, except for one case in Germany imported from Switzerland.
** Includes 1271 cases in offshore (essentially British) islands.
BSE has not occurred in countries that have historically had little or no importation from the UK of live cattle, beef products, or livestock nutritional supplements. It may be wondered why BSE has apparently arisen solely within the UK, if rendering procedures underwent similar changes in other countries as happened in the UK during the late 1970's. The most plausible explanation is that both the proportion of sheep in the total rendered animal mix, and the proportion of scrapie infections in such sheep was significantly higher in the UK than elsewhere, and that when the rendering process was changed, these proportions were just sufficient to bring the very low levels of infectivity in batches of rendered carcasses over the threshold of transmission in the UK, but not in other countries5. The same argument can be used to support the origin of BSE in scrapie-infected sheep rather than in the recycling of a case of spontaneous BSE in cattle, which should have resulted in similar outbreaks of disease in every country where the rendering process was changed.
New variant Creutzfeldt-Jakob disease
In 1996, a clinically unusual form of Creutzfeldt-Jakob disease (a sporadically occurring spongiform encephalopathy of late middle aged humans) was reported to have afflicted 10 British adolescents and young adults—with the unsettling suggestion that it might be linked to the BSE epidemic6. This link has now been convincingly established in laboratory studies showing identical and distinctive biological and molecular biological features of the pathologic agent isolated from BSE-infected cattle and cases of this "new variant" of CJD (nvCJD)7-9.
The source of contamination appears to have been beef. However, it is almost surely not beef as such that was infectious (muscle has never been shown to be contain the infectious agent in any form of spongiform encephalopathy, whatever the affected species), but rather beef products containing tissue from the central nervous system (CNS). The contamination may have resulted from microscopic brain fragments entering vascular system during the cerebral stunning of cattle before slaughter, contact of muscle with brain or spinal cord tissue by saws or other tools used during the slaughtering process, inclusion of para-vertebral ganglia in cuts of meat, or adulteration with CNS tissues of mechanically removed meat used in beef products.
Predictions about extent of nvCJD outbreak
The onset of illness in the first case of nvCJD occurred in early 1994, about 10 years after the first case of BSE was recognized in cattle. Assuming that the earliest appearance of nvCJD reflects the earliest exposure to BSE, this "incubation period" of about a decade is entirely consistent with incubation periods in experimentally induced CJD in animals, and in accidental iatrogenic cases of CJD in humans. Since 1994, a small but variable number of additional cases of nvCJD have been occurring each year, with no clear-cut decrease or increase in annual numbers, and presently totalling 52 cases, all in the United Kingdom except for 2 confirmed and 1 possible case in France and a single confirmed case in Ireland (Table 2). The Irish patient had resided for some years in the UK; however, none of the French patients had resided in (or even visited) the UK, so that their infection must have come either from beef imported from the UK (approximately 20% of beef consumed in France was imported), or from BSE-affected cattle in France.
From a French standpoint, it matters little whether the source is imported or 'home grown' beef; however, from a European standpoint, it would be much more troubling to learn that imported beef is the source, as most European countries also imported beef from the UK, albeit in smaller quantities.
* Parentheses indicate still living suspect cases not yet confirmed by neuropathological examination.
The more or less linear "leading edge" of the BSE epidemic lasted just a few years before it assumed an exponential increase. During the past 6 years, the annual incidence of nvCJD cases has remained nearly constant (Figure 1), giving hope to the expectation that despite the massive epidemic of BSE and potential human exposure to contaminated beef, the outbreak in humans may remain limited, and represent an unusual occurrence of a species-crossing infection only in "susceptible individuals".
However, mathematical modelling of the human case incidence urges caution, as depending on the variables employed, the predicted number of human cases could range from several hundred to as many as a hundred thousand cases currently in the incubation phase of disease10,11.
Recent policy decisions
Because of this continuing uncertainty about the numbers of British residents that may be harboring silent infections, policies have been put in place by several governments to minimize the risk of human-to-human disease transmission via blood or blood products. In the United Kingdom, all plasma is now imported from other countries, and all blood is subjected to filtration to eliminate leukocytes, which are probably the carriers of infectivity that might be present in blood. In the United States and Canada, a blood donor policy has just been announced that will exclude donations from anyone who has resided in or visited the United Kingdom for 6 months or more during the period 1980-1996.
There is nothing 'magic' about the choice of 6 months. Because of a lack of scientific evidence about the risk posed by BSE, the committee advising the US Food and Drug Administration requested an evaluation of the deficit to the blood supply that would result from residency exclusions ranging from one week to five years. The committee was first asked if any exclusion was needed, and in a close vote, responded in the affirmative. The committee was then asked what length of cumulative residence between 1980-1996 would be appropriate. The majority choice was 6 months, based on testimony that the resulting 2-3% deficit of blood donors could be absorbed by the blood banking industry without creating undue shortages or the need to recruit new donors.
These conservative positions would appear to be justified both by the uncertainty about the extent of incubating nvCJD infections in the United Kingdom, and by uncertainty about the presence and level of infectivity in the blood of such individuals. Similar considerations apply to donations of any other bodily tissue from United Kingdom residents. Within the next 2-3 years, we should have a much better idea of how the nvCJD outbreak will evolve, and the need for such restrictions will either to be tightened or relaxed.
Paul Brown, M.D.,
1. Brown P, Bradley R. 1755 and all that: a historical primer of transmissible spongiform encephalopathy. Brit Med J 1998; 317:1688-92.
2. Wells GAH, Scott AC, Johnson CT, et al. A novel progressive spongiform encephalopathy in cattle. Vet Rec 1987; 121: 419-20.
3. Collee JG, Bradley R. BSE: a decade on - Part 1. Lancet 1997; 349: 636-42.
4. Collee JG, Bradley R. BSE: a decade on - Part 2. Lancet 1997; 349: 715-21.
5. Brown P. The risk of bovine spongiform encephalopathy ("mad cow disease") to human health. J Amer Med Assoc 1997; 278: 1008-11.
6. Will RG, Ironside, JW, Zeidler M, et al. A new variant of Creutzfeldt-Jakob disease in the UK. Lancet 1996; 347: 921-25.
7. Collinge J, Sidle KC, Heads J, Ironside J, Hill AF. Molecular analysis
of prion strain variation and the aetiology of ‘new variant’ CJD. Nature
8. 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.
9. Scott MR, Will R, Ironside J, et al. Compelling transgenetic evidence for transmission of bovine spoingiform encephalopathy prions to humans. Proc Natl Acad Sci USA 1999; 96: 15137-42.
10. Cousens SN, Vynnycky E, Zeidler M, Will RG, Smith PG. Predicting the CJD epidemic in humans. Nature 1997; 385: 197-98.
11. Ghani AC, Ferguson NM, Donnelly CA Hagenaars TJ, Anderson RM. Epidemiological determinants of the pattern and magnitude of the vCJD epidemic in Great Britain. Proc Royal Soc London (Series B) 1998; 265: 2443-52.