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Is there a hidden sheep epidemic? The legacy of mad cow disease

November 28, 2001 The Daily Telegraph (London) by Roger Highfield
Fifteen years ago this month, a new disease was recognised: bovine spongiform encephalopathy - BSE. It has since killed about 180,000 cattle, led to the destruction of millions more and cost the taxpayer billions. Roger Highfield,

Science Editor, examines the resulting epidemic of human

BSE and the risk that the disease may now have spread to sheep

The BSE epidemic is in fast decline. In the first half of this year the number of cattle to show symptoms was 50 per cent lower than in the same period last year. Less reassuring, however, is a warning that BSE may be present in a few tens of sheep. Even a small outbreak could build into an epidemic over a long period. Although the current prevalence of mad cow disease in the national flock is probably low, a British team says that if sheep can transmit BSE "horizontally" between members of a flock - as happens with the equivalent sheep disease, scrapie - a large epidemic could eventually develop.

Fewer than 50 flocks would have been exposed to BSE by 2015 but the team's mathematical analysis predicts that over the long term, much of the national flock could be exposed to BSE, as perhaps 70 per cent of all sheep may be susceptible to the disease.

If BSE-infected sheep were present after the epidemic in cattle disappeared, scientists would also have to revise upwards the estimates of the size of the human incidence of variant CJD, "human BSE".

However, Dr Rowland Kao of Oxford University, one of the team that reports the sheep study in the current issue of the journal Science, stressed that the risk of BSE in the national flock remains hypothetical - transmission of BSE from sheep to sheep has never been known, except in a blood transfusion experiment.

The possibility that sheep might carry BSE was recognised in 1987. So too was the risk that, if they did so, mad cow disease might become endemic in sheep, as is the case with scrapie.

Because the symptoms of the two brain diseases are similar, there have been concerns that BSE might be masquerading as scrapie and the pounds 30 million BSE inquiry said the issue was "perhaps the most important unanswered question about the BSE epidemic".

In Science, Dr Kao and colleagues in Oxford and the Institute of Animal Health, Compton and Edinburgh, calculate the potential size and duration of a BSE epidemic in sheep, based on the numbers of infected cattle, the dose responses of cattle and sheep to BSE, their levels of exposure to infected feed, and the number of BSE-susceptible sheep.

While a lack of data required the authors to rely on many assumptions, their results suggest that the number of BSE-infected sheep at the epidemic peak in 1990 would have ranged from fewer than 10 to about 1,500.

Today, the figure is fewer than 20, if the disease is transmitted between mother and offspring. But if, like scrapie, it can also spread horizontally through a flock, the consequences would be serious.

A much greater proportion of the population is believed to be susceptible to BSE than to scrapie "and thus if it were to take hold, it could infect a much greater number of animals," said Dr Kao.

"If we account for this, and assume that otherwise BSE transmits like scrapie, there could be few cases of BSE now, but many more later, because we would be in the early stages of a slow-moving epidemic."

But Dr Kao stressed: "It is unlikely that there will be a sudden surge in the probability of eating BSE-infected animals, but that by no means should we be complacent."

The theoretical risk of BSE infecting sheep was originally identified at the Institute for Animal Health's Neuropathogenesis Unit, Edinburgh, when it was shown that sheep fed BSE-infected cows' brains succumbed to infection. British sheep may have been fed BSE-infected bonemeal made from cattle which had the disease until at least 1995. Sheep brains tested from purported scrapie cases from the late Nineties have not shown BSE-like signatures, though the numbers examined - about 150 - are too low to be very reassuring.

There are 40 million sheep in the UK, between 5,000 and 10,000 of which are estimated to contract scrapie each year. Since 1998, any sheep confirmed as having scrapie has been compulsorily slaughtered as a precaution.

The scientists conclude that the study shows the importance of a project to breed sheep with genetic resistance to scrapie. The original programme would take about a decade to have an effect and longer for the problem to be eradicated, but "modifications to accelerate the creation of a resistant national flock are currently under consideration", said Dr Kao.

[The above-mentioned Science article:

The Potential Size and Duration of an Epidemic of Bovine Spongiform Encephalopathy in British Sheep

R.R. Kao, M. B. Gravenor, M. Baylis, C. J. Bostock, C. M. Chihota, J. C.
Evans,: W. Goldmann, A. J. A. Smith, A. R. McLean

University of Oxford, Department of Zoology, South Parks Rd., Oxford OX1 3PS, UK. Institute for Animal Health, Compton Laboratory, Compton, nr Newbury, Berks. RG20 7NN, UK. Institute for Animal Health, Neuropathogenesis Unit, West Mains Road, Edinburgh, EH9 3JF, UK.

*To whom correspondence should be addressed. E-mail: rowland.kao@zoo.ox.ac.uk

Because there is a theoretical possibility that the British national sheep flock is infected with Bovine Spongiform Encephalopathy (BSE), we examine the extent of a putative epidemic. An age cohort analysis based on numbers of infected cattle, dose responses of cattle and sheep to BSE, levels of exposure to infected feed and number of BSE.susceptible sheep in Britain showed that at the putative epidemic peak in 1990, the number of cases of BSE-infected sheep would have ranged from fewer than 10 to about 1500. The model predicts that fewer than 20 clinical cases of BSE in sheep would be expected in 2001 if maternal transmission occurred at a rate of 10%. Though there are large uncertainties in the parameter estimates, all indications are that current prevalence is low, however a simple model of flock-to-flock BSE transmission shows that horizontal transmission, if it has occurred, could eventually cause a large epidemic.

BSE in Britain was spread through feed containing meat and bone meal (mbm) contaminated with BSE-infected animal material (1). Sheep in Britain were also fed mbm, and it is known that sheep can be infected with BSE by the oral route (2). No field cases of sheep BSE have been observed, but it has been a concern for a number of years (3), and the Food Standards Agency of the UK government has recently demanded a comprehensive search for it (4), in part because sheep are the natural hosts of scrapie, a transmissible spongiform encephalopathy (TSE) that has clinical signs indistinguishable from BSE. If BSE is masquerading as scrapie in the national flock, two independent estimates show that the current number of BSE cases (i.e. sheep that live long enough to show signs of infection) in sheep is likely to be few. First, an extensive survey of UK flocks found no indication of an increase in scrapie incidence during the height of the cattle BSE epidemic (5, 6). The sensitivity of this study implies that fewer than 200 flocks could have been acquiring a case of BSE per year at the peak. Second, in the late 1990's, of 156 brains taken from sheep purported to be infected with scrapie, none contained BSE, indicating that between 0 and 100 or at most 2% of yearly scrapie cases were actually BSE at that time (4).

Using a simple age cohort analysis, we examine the extent of a putative epidemic of BSE in British sheep and compare our results to these estimates. Our calculations are based on the cattle infection rate, the dose responses of cattle and sheep, their relative yearly consumption of mbm and estimates of the number of BSE-susceptible sheep obtained from a survey of sheep PrP genotypes (7, 8). In the year of the epidemic peak, the number of cases of BSE-infected sheep calculated is consistent with both of the existing estimates. Should there be horizontal transmission of BSE from sheep to sheep, a model of flock-to-flock BSE transmission shows that even if current cases are few, such an epidemic could be in its very early stages and a significant epidemic in the future cannot be ruled out.

The susceptibility of sheep to BSE is strongly associated with the encoding of glutamine (Q) at codon 171 in the PrP gene (9); sheep that are QQ171 homozygous for this allele are characterized by shorter incubation periods than QR171 heterozygotes (10). Sheep that do not encode Q at position 171 appear to be resistant to BSE. The number of susceptible sheep in the UK was calculated from a study of UK sheep farms in which over 10,000 sheep in 36 flocks from 27 breeds have been PrP genotyped (11). We restricted our analysis to 4,580 sheep born prior to 1997, because the introduction of genotyping at this time began to significantly increase the numbers of TSE-resistant sheep in our study. These data were combined with the breed distribution of British sheep revealed by a recent postal survey (12) to obtain an estimate of the total genetic contribution of the various breeds. All flocks were categorized as either "Hill and Upland" or "Lowland," and the genotype profiles for these two sectors calculated from the breed proportions. These sectors were considered separately because of their different breeding structure, and different per capita consumption of feed concentrate that was potentially BSE-contaminated (13). Average genotype proportions were assumed for breeds for which there were insufficient data, and genotypes of crossbreeds were inferred from the genotype profile of the sire and dam breed types. Of approximately 8.0 million breeding ewes in the Hill and Upland sectors in 1987, we calculate that 35% were QQ171 homozygous, 49% were Q(R/H)171 heterozygous and 16% did not encode Q at position 171. Of 8.6 million breeding ewes in the lowland sector, the percentages are 31, 52, and 17% respectively. We assume equal susceptibility for all Q171 carriers but (based upon experimental sheep infections) different incubation periods. Oral exposure of QQ171 sheep to high doses of BSE, resulted in 30% with clinical signs after 2 years post infection (ypi), and another 20% by 4 ypi (14). The experiment is ongoing, and we assumed that the remainder would develop clinical signs by the end of their next year post infection, i.e., another 20% at 5 ypi, and the last 30% at 6 ypi. Only one incubation period is known for QR171 heterozygotes; at approximately 5 ypi it is consistent with incubation periods for heterozygotes in intracerebral inoculation experiments (14). We assumed an incubation period for Q(R/H)171 heterozyogotes that took the same shape as for the homozygotes, but shifted to be three years longer.

We calculated the dose response for sheep using a logistic curve, with a slope estimated from titrations of scrapie in mice (15). The intercept is obtained by noting that 2 of 10 (95% CI 4%-56%) susceptible sheep developed BSE after consuming 0.5 g of infected cattle brain (i.e. 20% of sheep developed BSE after being fed an infectious dose of 0.5g, or ID20=0.5 g) (10). These parameters are consistent with the prevalence in two ongoing experiments of BSE infection observed in QQ171 sheep fed 5 g of brain (14, 16). For cattle we assumed the same slope, and noted that 70% (95% CI 35%-92%) of cattle exposed to 1 g of brain became infected (IDT0= 1 g) (17). The difference between the two curves (fig. 1A) represents the species barrier (17). As the confidence intervals overlap, we considered that at worst, contaminated mbm is equally infectious to sheep and cattle.

We considered four factors when determining the exposure of sheep to contaminated mbm: consumption of contaminated mbm by cattle, distribution of contaminated material in mbm, relative consumption of feed concentrate by sheep compared to cattle, and relative proportion of mbm in sheep and cattle feed concentrate. We did not consider the possible, but unquantifiable effects of scrapie infectivity also being in mbm, as any effect of competition between scrapie and BSE strains (18) would only be to lower the limit on the number of BSE infections initiated in sheep.

The first cases of BSE in cattle may have occurred as early as the 1970's. Due to recycling of infectivity in feed, the force of infection of BSE on cattle increased every year, with cattle born in 1988 at greatest risk of BSE infection. In that year the ruminant feed ban greatly reduced the force of infection, and the comprehensive ban of mammalian mbm in all animal feed in 1996 is likely to have virtually eliminated it (1). It was estimated that 17% of cattle born in 1988 year were infected with BSE and would have shown clinical signs had they lived to 10 years of age (19). Dairy cattle were at the greatest risk, accounting for almost 90% of cases (19), implying 28% of dairy cattle would have been infected. While there are indications that exposure was likely to have been broad and at low dose (20), we used two scenarios to calculate the exposure limits. In the first scenario, we assumed cumulative ID28's were fed to 100% of cattle in dairy herds. In the second scenario, we consider highly aggregated doses, where 24% of all cattle (or 37% of dairy) are assumed to have received ID75 doses. As an additional scenario to illustrate the range of possible results, we also calculate the epidemic size for the situation where 56% of dairy cattle received ID50 doses. We assume that aggregation of infectivity in cattle and sheep feed is proportionate (for example, if all cattle were exposed this implies that all sheep were exposed), and this resulted in more infected sheep in the second scenario than in the first, with intermediate values in the third scenario.

The yearly production of feed concentrate for sheep and cattle in the UK is known (21) as well as the number of breeding ewes and cattle that consumed it. Lowland sheep consumed the most feed concentrate, and all lambs consume little. Here we assume that their consumption is negligible (13). The sheep per capita consumption of concentrate rose slowly in the years of interest. Compared to cattle, sheep were fed about 100-fold less concentrate in 1986 and 50-fold less in 1995. Throughout the time frame considered here, the proportion of mbm in sheep feed concentrate would have varied, but would have been at most equal to the proportion in cattle feed concentrate, and probably much less (13, 21, 22). In this analysis we investigated a range of between 10% and 75% inclusion of mbm in sheep feed compared to cattle feed. Using these scenarios we calculated that, at the peak of exposure in 1988, between 0.0016% and 0.0046% of susceptible Hill and Upland sheep and between 0.0067% and 0.19% of Lowland sheep became infected. Exposures were calculated in a similar fashion for all years between 1986 and 1995 (fig. lC). Exposure through mbm in other years was assumed to be negligible.

There is evidence for the maternal transmission of natural scrapie in sheep (23) and it must therefore be considered a possibility for BSE in sheep. Scrapie infectivity has been found in the placenta of infected ewes as early as 477 days prior to their developing clinical signs (24). In our analysis we considered maternal transmission rates of 0%, 10% and 30% occurring over the entire course of the infection.

We calculated the time course of the feed-borne epidemic using an iterative model, updated in yearly time steps. Variables included infection status, age cohort, genotype and flock type (25). For 50% mbm inclusion in sheep feed compared to cattle, at the epidemic peak in 1990 there were about 210, 110, and under 80 clinical cases, for the scenarios where 37% of cattle received ID75's, 58% received ID50's, and all received ID28's respectively. For 30%, 10% and 0% maternal transmission, the number of cases of BSE in 2001 was calculated to be 19, 4 and 0 for the upper limits of infected feed exposure, 16, 4 and 0 for the intermediate values, and 14, 4 and 0 for the lower limits. Example epidemics are shown in figure 2. The "worst" of these scenarios presents a sensible outer limit for parameters values. However, data on key parameters are scarce and so in figure 3 we present the impact of extreme parameter values, while stressing that they lie at the limits of consistency with the best information currently available. Even these extreme scenarios, the predicted number of current cases of BSE in sheep is few.

If BSE in sheep behaves like scrapie, it may be horizontally transmissible. Further, because of the high prevalence of the Q171 codon, virtually all sheep flocks would have some susceptible animals and be considered to be at risk. This is very different from scrapie, for which the epidemic peaked several hundred years ago, possibly due to selection against susceptible genotypes (26), and thus a BSE epidemic is potentially much larger than one might infer from the current low prevalence of scrapie. TSE's have very long incubation periods and so the impact of horizontal transmission may not yet be felt. A hypothetical scenario based on a flock-to-flock model of scrapie in sheep (27, 28) which is consistent with existing within-flock scrapie transmission models (29, 30) and known large scrapie outbreaks (26) shows that a epidemic based on horizontal transmission may yet be in its early stages, and below the detection level of prior analyses (figure 4).

The uncertainties in some parameters leave wide margins on our estimate of how many sheep may currently be infected with BSE, but these analyses provide reassurance that, so long as BSE is not horizontally transmitted and is vertically transmitted at rates comparable with other TSE's, the current population of UK sheep contains none or at most only tens of individuals that are infected with BSE. These are most likely in lowland flocks that consume the majority of feed concentrate. Should horizontal transmission be occurring at a significant level, current numbers are still likely to be low, but they may be rising, emphasizing the importance of the rapid implementation of the National Scrapie Plan to create a TSE-resistant national flock(31)...

full text with charts, graphs and ref. are at;

http://www.sciencemag.org/sciencexpress/recent.shtml
]


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