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In 1989, when the Southwood Working Party1 reported on the apparently new disease bovine spongiform encephalopathy (BSE), there were few hard scientific data from which to assess the danger to public health. In particular the nature of the agent causing the disease was obscure. The working party was presented with the plausible hypothesis that BSE was derived from scrapie agent present in meat and bone meal (MBM) fed to cattle; and the correctness of this idea2 became plain when, with the ban on MBM as an animal feed, the incidence of BSE declined. Twelve years on from Southwood (on 21 February), the RSM's Section of Comparative Medicine met to debate subsequent developments including the advent of variant Creutzfeldt—Jakob disease (vCJD) in man.
Since scrapie in sheep had existed for over 200 years in the UK without any evidence of spread to man, the overwhelming probability in 1989 was that the new disease would present little hazard to man. To their credit the Southwood panel, especially MA Epstein, recognized the fallacy of this line of reasoning: if the disease was indeed scrapie in cattle, there was no certainty that it would behave in the same way as scrapie in sheep. For example, Kimberlin3 had shown that, when a strain crosses the species barrier, the manner of its spread in the new host becomes unpredictable. The working party saw that precautions must be based on the possibility of spread to man. In particular, a unit should be established to monitor the incidence of CJD (the principal known spongiform encephalopathy of man), new research into the agent should be undertaken, potentially infective material should be removed from the human food chain and meat and bone meal should be banned as a food for ruminants.
The first cases of BSE were detected in 1986. The UK ban on feeding MBM to cattle, the first of several such measures, was introduced in 1988 when the seriousness of the disease was apparent and the epidemiological evidence supported MBM as the culprit. The incidence of BSE was unexpectedly slow to decline. This was partly because the ban was at first not rigorously applied or enforced; the scrapie analogy was perhaps engendering a false sense of security. But even when the ban was well applied, cross-contamination by infected material was occurring in mills, in the distribution system and on farms. Research prompted by the outbreak indicated that only a very small dose, less than a gram of infected central nervous system tissue, was sufficient to infect cattle by the oral route. Nonetheless, the number of cases showed an increasing rate of decline. The peak of the epidemic was in 1992 when there were 36 680 confirmed cases; at one time as many as 1000 cases a week were being reported. Last year only 1310 cases were confirmed.
How were human beings to be protected, pending eradication of the disease from cattle? A succession of steps were taken to remove from the food chain any material likely to harbour the agent of BSE. First, whole diseased animals were taken out. Then, in seemingly healthy animals, brain and spinal cord, and specified other potentially infected materials, were excluded; and, finally, all animals for food consumption were killed at 30 months or younger. At this age—about half the average incubation period of 5 years—it was estimated that even subclinically infected animals were unlikely to contain high levels of the agent.
Unfortunately the lessons learned in the UK were not fully taken up by our European neighbours. Thus, when MBM was quite legally exported for feeding to pigs and poultry, much was apparently diverted to cattle. Apart from cases among the small number of live animals exported to Europe before the disease was recognized, MBM of UK origin is thought to be the cause of the cases of BSE in European countries. The disease has been reported in the Republic of Ireland, Portugal, Switzerland, France, Denmark, Germany, Italy, Belgium, Netherlands and Spain. Only very belatedly was MBM banned as an animal foodstuff throughout Europe, and not before material had been exported to other countries in the world. Another area of policy is the question of slaughter and compensation. In the UK we learned the importance of a policy that encourages compliance; thus, when an animal has to be slaughtered, the farmer should be paid its full value. If proper steps are in place to remove potentially contaminated material from the food chain, slaughter of birth cohorts is preferable to slaughter of whole herds.
In the UK, the outbreak of BSE in cattle is now largely controlled—a fact that does great credit to the much-maligned officials at the Ministry of Agriculture dealing with a new disease. Most of the cases that arose after the ban became effective are attributable to cross-contamination of one sort or another. Cow to calf transmission can occur but is thought to be of negligible importance. Nonetheless, a diagnostic test to detect infected carcasses—or more important to certify uninfected carcasses and to pick up subclinically infected living animals—would be of immense value. Much work is in progress to evaluate tests for detection of abnormal prion protein (PrP) post mortem in cattle brain and spinal cord4. Some of these tests have been extensively validated and can show infection before the appearance of clinical signs5. Eight European countries are using such tests to try to protect the human food chain—a useful extra precaution, possibly, but no substitute for the removal of central nervous tissue and specified bovine offals from the food chain. The hope is that tests of this kind will be applicable in living animals.
What of vCJD? Several lines of evidence lead to the general view that infection with the BSE agent is the cause of this disease. The number of cases of vCJD now stands at 95, of which 83 are confirmed and 12 suspect. All but 3 of the cases have been in Britain. The most important question is what will happen in the future. What is the likely final number of cases? At present there are too many uncertainties for accurate prediction. The key unknowns include the infective dose, the number exposed and infected and the incubation period. All the patients seen so far are homologous for methionine (MM) at codon 129 of the PrP gene. It may be that other human PrP genotypes are also susceptible but with a longer incubation period. One way in which the possible spread of the infection to man might be estimated is by sampling and testing of lymphoid tissue from human beings. Hilton et al.6 were the first to raise this possibility when they reported the presence of PrPSC in formalin-fixed slides of appendix tissue removed from a patient 8 months before the onset of vCJD. A large-scale retrospective study of 3073 appendix samples and 95 tonsils did not yield a single positive7, a reassuring result, but tests of greater sensitivity are required. Collinge and his co-workers have devised a test, based on molecular strain typing by glycoform analysis, which can be applied to fresh tonsil and appendix tissue8. So far 11 of 23 samples from suspected cases of CJD have proved positive for vCJD and 12 negative, the negative samples being from patients whose illnesses have proved not to be due to vCJD. Efforts are in hand to increase the sensitivity of the test, and results are promising; similarly tests that might be applied to other samples, such as buffy coat, are being developed. With the emergence of more sensitive tests of this sort, performable on easily available samples, we should get a better idea of how many people in the population are incubating the disease. Another line of investigation is the epidemiological study of clusters of cases. The most high profile study is that at Queniborough and the surrounding area, where 5 cases of vCJD have been confirmed. The onset of these cases was between 1996 and 1999 and the patients died between 1998 and 2000.
Investigating this cluster, P. Monk and colleagues from the Leicester Health Authority began by surveying individuals who had been in the meat trade in the 1980s (farmers, butchers and others), enquired from parents about the eating habits of children at that time, and questioned relatives of the vCJD patients about possible sources of exposure. From these findings they developed the hypothesis that the disease was associated with consumption of beef purchased from small butchers whose working practices led to a high risk of meat contamination by brain. In a case-control study they interviewed one relative for each index case and one relative for each of 30 controls (6 age-matched controls per patient). The interview included enquiries about the source of meat consumed, and the investigators then questioned all the butchers, supermarkets and other retailers who had been mentioned. Monk et al. concluded that the individuals who contracted vCJD were ‘fifteen times more likely to have purchased meat from a butcher who removed the brain from a beast compared with controls who purchased meat from outlets where cross contamination with brain material was not a risk’9. From their study they were also able to estimate the incubation period as between 10 and 16 years. This is a small study that needs confirmation, but important in identifying a risk factor that can be investigated in other cases.
A vast amount of research has been undertaken on prion disease—especially BSE and vCJD, but also scrapie—during the past decade. The nature of the disease still remains elusive. How, for example, can a prion protein replicate and maintain stable strain differences through many generations? The long incubation period makes experimental work slow and difficult. Despite the immense amount that has been learned about BSE and vCJD in the past decade and the control of the disease in cattle, the most important questions about the future remain unanswered.