Modelling the expected numbers of preclinical and clinical cases of bovine spongiform encephalopathy in Switzerland.

The objective of this study was to model the expected numbers of cattle incubating bovine spongiform encephalopathy (BSE) and the numbers of clinical cases of BSE in the Swiss cattle population between 1984 and 2005. The results were compared with the observed number of clinical BSE cases and with the results of a culling and testing scheme on herdmates of cattle with BSE. The age distribution of the Swiss cattle population, the age-at-death distribution of the first 235 BSE cases and exposure information were used to calculate the expected number of infected cattle in each birth cohort and the resulting numbers of clinical cases and survivors incubating the disease for each year. The model which did not assume any under-reporting of cases fitted the observed epidemic curve of clinical cases reasonably well, and predicted that the Swiss BSE epidemic would come to an end between 2003 and 2005. The age of survivors incubating BSE is increasing. The higher than expected incidence of subclinical cases observed in animals from the culling scheme is most probably the result of the heterogeneous distribution of infected animals and affected herds in the population. The results of the model need to be taken into account when designing surveillance and testing schemes for BSE.     

Bovine spongiform encephalopathy in Northern Ireland: epidemiological observations 1988-1990.

This study describes the epidemiological features of bovine spongiform encephalopathy (BSE) in Northern Ireland where the first case occurred in November 1988. They were very similar to those observed in Great Britain except that the annual incidence of BSE in 1990 in Northern Ireland, 2.3 confirmed cases per 10,000 adult cows, was approximately one 10th of that in Great Britain. The findings were also consistent with the current hypothesis that affected cattle had been exposed to a scrapie-like agent via cattle feedstuffs containing ruminant-derived protein. However, a preliminary investigation of the potential sources of infection for cattle in Northern Ireland did not provide any conclusive evidence.     

Epidemiological model development using BSE as an example--observations from a statistical viewpoint

Since first BSE cases in cattle born in Germany were recognized, questions have been raised concerning the future development of the disease and the epidemiological dynamics of BSE, and, consequently, modelling approaches that might answer these questions. The database for such modelling efforts is formed by BSE incidence numbers or incidence rates, broken down by age at onset of clinical disease, and by time of onset or time of birth, respectively, from available information gathered for suspect and confirmed BSE cases. To describe such data, statistical age-period-cohort-models and two epidemiologically/biologically oriented modelling approaches are discussed: the so-called three-factor-model used by the Central Veterinary Laboratory of the British Ministry for Agriculture, Fisheries and Food (MAFF) (now Department of the Environment and Rural Affairs (DEFRA)), and a back-calculation-model developed by a working group at the University of Oxford. Resulting model calculations are supposed to serve several purposes, including a prediction of future BSE incidence numbers, and, especially based on the "Oxford"-model, a back-calculation of the epidemic of BSE infections from the epidemic of clinically diseased BSE cases. Analysis of these approaches reveals some problems even to identify unique age, period, or birth cohort effects. An additional estimation of epidemiological components of BSE, for example the frequency distribution of incubation times, has to rely on further assumptions that cannot be validated by the model fit as such. Therefore, modelling results should be interpreted with caution. However, the limitations demonstrated by this discussion emphasize the need for specific studies to investigate certain aspects of the BSE epidemic, for example the distribution of times from infection to disease onset, and for the centralised collection of valid and detailed population data for cattle.     

Temporal aspects of the epidemic of bovine spongiform encephalopathy in Great Britain: individual animal-associated risk factors for the disease

The objectives of this study were first to determine the cumulative incidence of bovine spongiform encephalopathy (BSE) in the British cattle population from July 1986 to June 1997, secondly, to identify individual animal-associated risk factors that influenced the age of onset of clinical signs in confirmed BSE cases, and, thirdly, to assess the effectiveness of the measures introduced to control BSE during the epidemic. The analyses were based on the population of British cattle at risk, derived from agricultural census data collected between 1986 and 1996, and BSE case data collected up to June 30, 1997. The unit of interest was individual adult cattle recorded on annual agricultural censuses between June 1986 and June 1996. Univariate and multivariate survival analysis techniques were used to characterise the age of onset of clinical signs. In total 167,366 cases of BSE were diagnosed in Great Britain up to June 30, 1997. The cumulative incidence of BSE between July 1986 and June 1997 was 1.10 (95 per cent confidence interval [CI] 1.09 to 1.10) cases per 100 adult cattle at risk. Cattle from the South east, South west and Eastern regions of England had 4.26 to 5.96 (95 per cent CI 4.15 to 6.14) times as great a monthly hazard of being confirmed with BSE as cattle from Scotland. Compared with cattle born before June 1985, those born between July 1987 and June 1988 had 22.5 (95 per cent CI 22.1 to 22.8) times the monthly hazard of being confirmed with BSE, whereas those born in the 12 months after July 1988 had only 7.39 (95 per cent CI 7.24 to 7.54) times the monthly hazard of being confirmed with BSE. This reduction in hazard was directly attributable to the ban on the use of ruminant protein as a feed instituted in July 1988. Successive cohorts from 1989 to 1991 experienced further reductions in the hazard of experiencing BSE. The additional decrease in hazard observed for the 1990 cohort may be attributed to the effect of the Specified Bovine Offal ban instituted in September 1990.     

Potential Risk Factors Associated with Bovine Spongiform Encephalopathy in Cattle from Schleswig‐Holstein,Germany

Since the first detection of bovine spongiform encephalopathy (BSE) in homebred cattle in Germany on 26 November 2000, 382 cases have been confirmed until 30 September 2005. Thirty‐two of these cases were reported from the Federal State of Schleswig‐Holstein (SH). There are hypotheses on the routes of infection for German cattle, but only few efforts have been made to assess potential risk factors by epidemiological studies. The purpose of this study was to identify potential risk factors at the farm level for the occurrence of BSE in cattle in SH. By applying the method of indirect standardization, the prevalence of various structural and management parameters of BSE‐affected farms in SH was compared with the prevalence of these parameters in a standard population of cattle farms from SH. The data describing the standard population were obtained by a cross‐sectional study performed in SH in 2003. Data of the BSE case population were available from the central German BSE case database. A possible association of the occurrence of BSE with the feeding of milk replacers to calves was observed. There was a clear indication that the occurrence of BSE was associated with the presence of pigs and/or poultry on the farm. This finding suggests that cross‐contamination of feed or cross‐exposition may have occurred in SH. The results obtained using the indirect standardization analysis were validated by multiple logistic regression. This study indicates that the feedborne path has been the principal route of transmission for the BSE agent in SH.     

Breed predisposition for BSE: epidemiological evidence in Bavarian cattle

We present epidemiological data from Bavaria that indicates that animals of the Brown Swiss (BS) cattle breed might be more susceptible to BSE than animals from other breeds, both in terms of disease prevalence and length of the incubation period. BS animals were disproportionately represented among the BSE cases (BS represented about 9% of the susceptible population but 27% of actual cases). BS were slaughtered at a higher age (5.8 years vs. 5.0 years for other breeds), and there is a higher prevalence of feeding proprietary feeds to BS calves than calves from other breeds. There was no difference in the recorded feeding practice of BSE-positive animals from BS or other breeds. These results would lead to expect a higher prevalence of BSE in the BS population, with BS BSE animals being of equal age or older than BSE animals from other breeds. In contrast, median age at BSE detection was significantly lower in BS animals than in other breeds (61.4 vs. 68.8 months). There was no difference in the identification categories of BSE between BS animals and animals of other breeds that could explain this difference in age. BS cattle are reported to have more octapeptid repeats in the prion protein gene than other breeds, which could account for shorter incubation periods and higher susceptibility. These observations suggest that BS animals and their tissues should be used in further studies into genetic determinants of BSE susceptibility in cattle.     

Potential risk factors associated with bovine spongiform encephalopathy in cattle from Schleswig-Holstein, Germany

Since the first detection of bovine spongiform encephalopathy (BSE) in homebred cattle in Germany on 26 November 2000, 382 cases have been confirmed until 30 September 2005. Thirty-two of these cases were reported from the Federal State of Schleswig-Holstein (SH). There are hypotheses on the routes of infection for German cattle, but only few efforts have been made to assess potential risk factors by epidemiological studies. The purpose of this study was to identify potential risk factors at the farm level for the occurrence of BSE in cattle in SH. By applying the method of indirect standardization, the prevalence of various structural and management parameters of BSE-affected farms in SH was compared with the prevalence of these parameters in a standard population of cattle farms from SH. The data describing the standard population were obtained by a cross-sectional study performed in SH in 2003. Data of the BSE case population were available from the central German BSE case database. A possible association of the occurrence of BSE with the feeding of milk replacers to calves was observed. There was a clear indication that the occurrence of BSE was associated with the presence of pigs and/or poultry on the farm. This finding suggests that cross-contamination of feed or cross-exposition may have occurred in SH. The results obtained using the indirect standardization analysis were validated by multiple logistic regression. This study indicates that the feedborne path has been the principal route of transmission for the BSE agent in SH.     

Risk factors for BSE-infections in Lower Saxony, Germany

In order to generate data on the cattle population and farm management in the state of Lower Saxony, Germany, a basic demographic survey was conducted. Afterwards these BSE-free farms as a reference population were compared with the population on BSE farms to identify risk factors for BSE infections. A variety of risk factors for BSE were reviewed, including the import of cattle from the United Kingdom, commercial foodstuff, dairy farming, herd size and cross-contamination with foodstuff for other farm animals. For the basic demographic survey of the reference, a questionnaire was mailed to a representative sample of cattle farms in Lower Saxony where BSE cattle had not occurred before the sample was taken. Distribution of risk factors within this reference population (n=731) and the BSE population (n=49) were compared following the concept of indirect standardisation in stratified populations. The size of farms was used as the stratification variable, with three strata. Under the same rate as in the reference population, the portion of Red Holstein cattle breed was four fold higher than in the BSE population (SER=4.03; p=0.0003). Milk replacer was fed 1.41 times more often on BSE farms (p=0.0478). However, the use of concentrated foodstuff for pigs (SER=0.21) was significantly less frequent in the BSE population than expected (p=0.0001), whereas the husbandry of sheep, goats or game animals seemed to increase the risk of BSE 2.85 times (p=0.0413). There were no significant differences between the two populations concerning the purchase of cattle (p=0.1514) and the use of concentrated feed for calves during the 1990s (p=0.6212). This is an epidemiological indication of increased susceptibility of Red Holstein cattle to BSE. However, this study did not confirm the assumption that the use of commercial foodstuff other than milk replacer or the purchase of cattle increases the risk of BSE infection. It nevertheless remains likely that commercial foodstuffs such as concentrated feed for calves were risk factors in Germany as well.     

BSE/TSE--the present epidemiologic and diagnostic situation

In 1992, 1994 and 1997, first BSE cases were diagnosed among imported cattle. The first domestic BSE case in Germany was confirmed on 26 November 2000. Altogether 192 cases (7 cases in 2000, 125 cases in 2001 and 60 cases in 2002) were reported (at the date: 7. August 2002). Comparing the BSE situation in Germany with other European countries under consideration of the surveillance schemes applied, Germany has a similar BSE incidence based on 100,000 adult cattle as France and Spain but a higher incidence than neighboring countries like The Netherlands, Austria and Denmark. At present, on average 2,3 cases per week are confirmed in Germany. With respect to the age distribution of the BSE cases, about 84% of all domestic cases confirmed originated out of the years 1995 and 1996 with a accumulation in 1996 (about 53% of all cases). Single BSE cases with the years of birth 1990, 1991 and 1993 demonstrate, that the BSE agent is circulating among the German cattle population at least since the beginning of the nineties. Between 1985 und 7 August 2002, scrapie was diagnosed in 26 sheep flocks in Germany, but alone during the year 2002 (until 7 August 2002) 11 scrapie affected sheep flocks were discovered.     

BSE, feed and cattle in Switzerland: is there a spatial relation?

Cross-contamination of cattle feed with meat and bone meal (MBM) allowed in feed for other species is regarded as the current hypothesis for the infection pathway of Bovine Spongiform Encephalopathy (BSE) cases occurring after the implementation of a ban on feeding MBM to cattle. This study was aimed at establishing a spatial relation between BSE cases in Switzerland and the findings of MBM in cattle feed. A cluster analysis and a cohort study were performed. Two hundred sixteen BSE cases born after December 1990 and detected until August 1st 2005, screening data of 504 feed producers between 1996 and 2001 and population data from the Swiss 2001 cattle census were included. The cluster analysis showed feed producer, positive for MBM contaminations in cattle feed, as possible cluster centres for BSE cases. In the cohort study, farms within a radius of 2 and 10 km around positive feed producers showed significantly higher odds to have a BSE case than the control group. The odds ratio and its 95% confidence interval were 2.23 (1.26-3.93) for the 2 km radius and 1.38 (1-1.9) for the 10 km radius. The results provide evidence for a spatial relation between cross-contamination and BSE occurrence. These findings support the hypothesis of cross-contamination to be an important route for BSE transmission after a feed ban.     

Milk yield, age at first calving, and the risk of BSE: an analysis at the farm level in France

The epidemic of bovine spongiform encephalopathy (BSE) in France, as in the UK, has affected dairy cattle much more than beef cattle. However, the intensification of dairy herd management as a risk factor for BSE has not to date been analyzed. For this purpose, two databases were merged: the French Milk Records database, and the French BSE database, which can be considered as being devoid of notification bias since July 2001, when systematic tests were implemented. Only pure Holstein herds were considered, which represent the vast majority of total and BSE-affected dairy herds in France. A case-control study was designed so that 20 control herds were matched to each case herd according to the location of the farm and the year of birth of the index case. Three thousand and forty five farms were included, among which 145 with a BSE case notified between July 2001 and July 2003, and 2900 controls. With respect to the risk of BSE, odds ratios for each class of milk yield and age at first calving were estimated by using conditional logistic regression models with appropriate adjustments to herd size. The two main results were the following: firstly, whereas most Holstein herds, with average production between 7000 and 10,000kg, had nearly the same BSE risk, a small category of very intensive herds, with annual milk yields above 10,000kg, were significantly more at risk than the other herds. Secondly, a very early first calving (under 26 months of age) was found to be at risk for BSE as compared to other categories, independently of the milk yield. These results are discussed in the light of the known age-dependent susceptibility to BSE.     

Geographical clustering of cases of bovine spongiform encephalopathy (BSE) born in Switzerland after the feed ban

Over one-third of the cases of BSE in Switzerland have been born after the feed ban of December 1, 1990. Evidence for the geographical clustering of these cases emerged in two distinct regions. All the 354 BSE cases recorded until June 30, 2000 (set A), and the 376 cases recorded up to May 14, 2001 (set B), were georeferenced to the centres of the communities in which the herds of origin were located, and control populations were georeferenced to the centres of the communities in which these herds were located at the time of the census. The latitudes and longitudes of these centres were used in the statistical analysis of the spatial clustering. The Cuzick-Edwards test and the spatial scan statistics were applied to assess the significance of the clusters, while controlling for the spatial distribution of the underlying cattle population. There was global clustering of the cases born after the ban, and distinct and significant (P<0.05) spatial clusters were repeatedly identified in the two case datasets, and in several control populations (all cases born before the feed ban on a random sample of control farms) in terms of cattle density by region or cow density by region. Differential reporting was excluded as the underlying reason for the observed clusters.     

Bovine spongiform encephalopathy: epidemiological studies on the origin.

The results of further epidemiological studies of bovine spongiform encephalopathy (BSE) support the previous findings that the onset of exposure of the cattle population to a scrapie-like agent, sufficient to result in clinical disease, occurred in 1981/82. The onset of this exposure was related to the cessation, in all but two rendering plants, of the hydrocarbon solvent extraction of fat from meat and bone meal. A further possible explanation, related to the geographical variation in the reprocessing of greaves to produce meat and bone meal, was identified for the geographical variation in the incidence of BSE.     

The unrecognised French BSE epidemic

In France, implementation of systematic screening programs in 2000, as a complement to the mandatory reporting of animals with clinical signs of BSE (passive surveillance), revealed certain limitations of the mandatory system. Indeed, systematic screening showed that some BSE cases were not detected by the clinical surveillance system, implying considerable BSE case under-reporting throughout the epidemic. As the most likely explanation for variant Creutzfeldt-Jakob disease (vCJD) is exposure to the aetiologic agent of BSE, it is essential to reconstruct the French BSE epidemic pattern accounting for this under-reporting. We estimated age- and year-specific incidence rates of BSE by using a back-calculation method. This approach relies on the principle that the number of clinical BSE cases is the consequence of the number of BSE-infected animals after a known incubation time, defined as the time between infection and clinical onset. We generalized this model to take into account epidemiological characteristics of BSE, such as French cattle mortality, BSE case reporting probability, and age-dependent susceptibility and/or exposure to the BSE agent. We confirmed that the average BSE incubation period is five years and that the peak risk of bovine infection occurs between 6 and 12 months of age. The results also showed that the proportion of underreporting is the most influential parameter in the model, and that BSE was substantially underreported until rapid tests were introduced. Indeed, only 103 BSE cases were detected by passive surveillance up to June 2000, while we estimated that there was 301 200 (95% confidence interval (CI) [27 600-837 600]) cattle infected by the BSE agent. Despite uncertainty over the beginning of the epidemic, we showed that the French BSE epidemic in the late 1980s was completely undetected, and only the second wave, after 1990, was observed.     

How the surveillance system may bias the results of analytical epidemiological studies on BSE: prevalence among dairy versus beef suckler cattle breeds in France

Until recently, epidemiological studies on Bovine Spongiform Encephalopathy (BSE) were based on Mandatory Reporting Systems (MRS) of clinically suspect bovines only, but rapid diagnostic tests were validated in 1999 and are used for targeted surveillance in Switzerland, France and other countries, as a complementary and secondary tool. Data on 30491 cattle issued from a French pilot program targeted at cattle having died on the farm, subjected to euthanasia or sent for emergency slaughter, did not show any significant difference in BSE risk between dairy and beef suckler breeds. The data also revealed that part of the clinical cases of BSE escaped the MRS, which permitted to detect more dairy than beef suckler affected cattle compared to the targeted surveillance in the same period (from August to December 2000) and region (Bretagne, Pays de la Loire and Basse Normandie regions). Analyzing together the data of the targeted surveillance and mandatory reporting system programs with a non-conditional logistic regression, we found that the odds of a dead cow being a BSE case among all dead cattle was 3.2 times higher for dairy breeds compared to beef suckler breeds. This confirmed British findings but points out to the fact that considering either MRS or targeted surveillance data alone may possibly create biases in epidemiological studies on BSE.     

Epidemiological features and economical importance of bovine virus diarrhoea virus (BVDV) infections

Infections with bovine virus diarrhoea virus (BVDV) are widespread throughout the world. Although the prevalence of infection varies among surveys, the infection tends to be endemic in many populations, reaching a maximum level of 1-2% of the cattle being persistently infected (PI) and 60-85% of the cattle being antibody positive. Persistently infected cattle are the main source for transmission of the virus. However, acutely infected cattle as well as other ruminants, either acutely or persistently infected, may transmit the virus. Transmission is most efficient by direct contact. However, as infections have been observed in closed, non-pasturing herds, other transmission routes seem likely to have some practical importance. Differences in BVDV prevalence among regions or introduction of virus in herds previously free of BVDV are often associated with particular epidemiological determinants such as cattle population density, animal trade and pasturing practices. However, on a few occasions there have been no obvious explanations for infection of individual herds. Estimates of economic losses due to BVDV infection vary depending on the immune status of the population and the pathogenicity of the infecting virus strains. Introduction of the infection into a totally susceptible population invariably causes extensive losses until a state of equilibrium is reached. Infection with highly virulent BVDV strains causing severe clinical signs and death after acute infection gives rise to substantial economical losses. At an estimated annual incidence of acute infections of 34%, the total annual losses were estimated as US$ 20 million per million calvings when modeling the losses due to a low-virulent BVDV strain. At the same incidence of infection, the losses due to a high-virulent BVDV strain were estimated as US$ 57 million per million calvings. Low-virulent BVDV infections caused maximum losses at an incidence of 45%, whereas high-virulent BVDV infections caused maximum losses at an incidence of 65%. Thus, cost-benefit analyses of control programs are highly dependent on the risks of new infections under different circumstances and on the strains of the virus involved.     

Area-level risks for BSE in British cattle before and after the July 1988 meat and bone meal feed ban

In this paper we investigate area-level risk factors for BSE for the cattle population present in Great Britain between 1986 and 1997. By dividing this population into two birth cohorts, those born before the July 1988 ban on feeding ruminant-derived meat and bone meal to ruminants and those born after, second-order regional influences are distinguished from the strong first-order south-to-north gradient of area-level BSE risk using Bayesian hierarchical models that account for structured (spatially correlated) and unstructured heterogeneity in the data. For both cohorts area-level risk of BSE was increased by a more southerly location and greater numbers of dairy cattle, relative to non-dairy cattle. For the cohort of cattle born after the July 1988 ban on feeding ruminant-derived meat and bone meal area-level BSE risk was additionally associated with greater numbers of pigs, relative to cattle. These findings support the role of low level cross-contamination of cattle feed by pig feed as an influence on BSE incidence risk as the epidemic evolved. Prior to the 1988 meat and bone meal ban unexplained BSE risk was relatively uniformly distributed across the country whereas after the ban there were spatially aggregated areas of unexplained risk in the northern and eastern regions of England suggesting that local influences allowed BSE control measures to be less-successfully applied in these areas, compared with the rest of the country. We conclude that spatially localised influences were operating in divergent ways during the two phases of the epidemic.     

A temporal-spatial analysis of bovine spongiform encephalopathy in Irish cattle herds, from 1996 to 2000

This study investigated the distribution of bovine spongiform encephalopathy (BSE) in herds of cattle in Ireland over the years 1996 through 2000, prior to the introduction of widespread active surveillance. Mappings of index herds, herd density, and standardized morbidity ratios, by county, were employed to help visualize areas of potential clustering of BSE. The hypothesis of spatial clustering was tested using a spatial scan statistic applied to the location of the herd where exposure likely occurred. Both Bernoulli and Poisson spatial models indicated marked clustering of BSE herds centred on Monaghan county, with secondary clusters detected by Bernoulli approaches and some Poisson models in Wexford and Cork. The number of cases increased with time, but clear temporal-spatial clusters were rarely detected, except in the case of a cluster in Wexford. The focussed spatial scan analyses using the location of large-scale feed suppliers provided support for the hypothesis that clustering of BSE may be associated with feed source. The results of our analyses provided strong evidence in support of the hypothesis that herds, in which animals were most likely to have been exposed to the BSE agent, cluster geographically.