Bovine Spongiform Encephalopathy - available
Control ToolsDiagnostics availabilityCommercial kits are available to confirm disease on examination of the brain material removed from an animal. These include automated Western blot and ELISA tests to screen large numbers of samples. Commercial kits are available to confirm disease on examination of the brain material removed from an animal. These include automated Western blot and ELISA tests to screen large numbers of samples. Yes. Methods are prescribed in the OIE Manual of Diagnostic Tests and Vaccines. Also in the consolidated EU directive 999/2001. Diagnostic examination of brain tissue:
Serological: no methods available as no immune response seen or other serological markers detected. High, although declining with the reduction in BSE incidence in Europe and the reduction in testing requirements. The validation process is lengthy for any new tests, and it is increasingly difficult to obtain the necessary numbers of samples in a commercially realistic timeframe. Not applicable. There are limited opportunities for new developments in disease detection. There are sufficient tests available for the post mortem detection of PrP, and no alternative specific marker has been identified which might improve any aspect of disease identification or confirmation. Protein Misfolding Cyclic Amplification (PMCA) or other conversion tests might be an opportunity, though the problem of false positives is difficult to tackle due to the ‘self nature’ of the agent. The development of such tests is unrealistic considering the unusually high specificity demanded of TSE tests. GAPS:
Vaccines availabilityNone. None. None. None. Not applicable. None. None. None. None. If an in vivo test was developed which enabled the identification of disease, there may be the opportunity to develop therapeutic approaches for the treatment of human cases. Pharmaceutical availabilityNone available. Some chemicals such as pentosan are thought to delay disease progression in humans, and antibody therapies have been investigated experimentally. The literature in this area is sparse and in places appears contradictory. None. None. None. None. None. New developments for diagnostic testsLive animal test is the gap in the market, although there are no potential methods for development at this point. GAP: Further developments in in vitro conversion tests should be encouraged. The development of such tests might be unrealistic considering the unusually high specificity required for TSE testing. The current problem with the development of tests is the availability of pathogenic material and of live animals known to be incubating the disease. This makes the development and validation of tests very time consuming and dependent on others providing the material for the laboratory and field validation. From development through validation to commercial availability will be time consuming and would take years. The development and validation of new tests for BSE is time consuming and labour intensive which is costly. Costs cannot be specified as they will depend on the nature of the test and the cost of producing reagents and supplying reading or processing machines if necessary. Once validated there would need to be a commercial company willing to market the test. Identification of an appropriate in vivo specific marker in an accessible body fluid (realistically this limits it to blood or urine). GAP: Needs a live animal test to identify infected incubating animals. New developments for vaccinesNone. In the event of vaccines being required the time will be lengthy as the pathogenesis is not fully understood and there is currently no evidence of an immune response Very high with the research needed to unravel the pathogenesis and to identify whether a vaccine is feasible. None. New developments for pharmaceuticalsNone. With the complexities involved in BSE pathogenesis the development of any pharmaceutical agent with be very time consuming and costly. Success is unlikely. Very costly. None required for animal health applications. While some therapeutic potential would be highly desirable in the human field, the number of cases likely to occur is too low to drive this as a commercial interest. Disease detailsDescription and characteristics.The BSE agent is generally considered to be a prion which is comprised largely of a self replicating protein. A protease resistant protein known as PrPSc is diagnostic. PrPSc is involved in the pathogenesis of the disease and is considered to be the main or only component of the prion. However, infectivity can be identified in the absence of detectable PrPSc, which may simply represent a test sensitivity issue, although it has been speculated that disease-specific but non protease-resistant forms of PrP may also exist. An alternative less accepted theory is that the agent is virus like and possesses nucleic acids although these have never been demonstrated. Similarly, an essential involvement of co-factors (eg protein, mRNA etc) has been mooted but not adequately identified or proven. GAPS: The pathogen cannot be isolated for diagnostic or typing purposes. PrPSc can be extracted from affected tissues such as brain, and used to categorise certain forms of disease, but this on its own does not constitute strain typing. The pathogen elicits no consistent host immune response that can be measured in the live animal. Understanding why there is no immune response will be key to understanding disease pathogenesis. The first cases of BSE were recognised in the UK 1986 as a neurological disease of adult cattle. BSE is a transmissible spongiform encephalopathy (TSE) which is a degenerative disease of the brain in humans and some domestic and wild animals. Cattle are the main species affected although people have been infected as well as captive wild ungulates, goats and felines. Currently, where sufficient surveillance data are available, the most relevant world-wide epidemiological pattern is a general and constant decline in the frequency of BSE in the field. Where the disease has occurred in other countries, it tends to have the same phenotype as the disease in the UK cattle population, and can usually be linked to the UK (either by movement of cattle or cattle feedstuffs). Studies on the lesion profile indicate uniform brain pathology, including after transmission in mice, suggesting only a single strain of BSE agent was present during the epidemic. Rare variants in older animals (provisionally classified as H- or L-type depending on their molecular characteristics in Western blots) have now been described in a number of countries. Given the rarity of these cases, their occurrence in aged animals and their widespread geographical distribution (including countries with no history of BSE) it is speculated that these cases may be spontaneous. GAPS:
The BSE Agent is extremely stable and resistant to freezing, heating, drying and cooking at normal temperatures, particularly if adhering to a surface. Pasteurisation and sterilisation will not destroy the agent, nor does chemical fixation for histology. Infectious titre can be reduced by some/all of these methods, but they are not absolute. GAPS: There is no fully effective/practical decontamination method. Also no clear understanding of how any of these methods might affect the biological properties of any agent subjected to them. Could incomplete decontamination alter the pathogen in a way that might change pathogenicity/ host species range? Species involvedBSE is primarily a disease of cattle. Disease in household cats (FSE) and in ruminant and feline species in zoos has been caused by the same agent. The pure silent carrier state has not been shown to exist. To our knowledge, infected animals ultimately develop the disease and die, although it could be argued that exposed animals which may be pre-clinical for their entire production lifespan, are effectively carriers. There have been two cases of BSE confirmed in goats in commercial herds, one in France and one in the UK. There is no evidence from retrospective studies that BSE has become established in the commercial sheep population, but experimental data confirms that sheep are susceptible orally, and can transmit the disease under normal husbandry conditions. They were exposed to the same meat and bone meal feed components as cattle during the epidemic. Work in transgenic mouse models has indicated that BSE, once passed through a sheep, has a wider host range and an increased ‘virulence’. GAPS: There is no knowledge about how BSE might behave in a co-infection situation with another TSE, particularly scrapie in sheep, and how this might affect zoonotic potential. There is no reliable means of detecting infection in a live, clinically normal animal, so population screening cannot be undertaken. There is no understanding of what, if any, effect intercurrent illness or infection might have on susceptibility or disease progression, or shedding of infectivity. It is not known why only very small numbers of animals in a herd succumb to disease, when all animals in a cohort will be exposed to the same feed. It is assumed that the non-affected animals are not infected because there is no evidence of disease, or of the disease marker PrP. However, no effective means exists to screen a population for evidence of whether low level infectivity may be present in such animals, which were definitely exposed. Creutzfeldt-Jakob disease (CJD) is the human form of TSEs which can occur sporadically or associated with a hereditary predisposition or following iatrogenic contamination. Variant CJD first reported in March 1996 affects younger patients and is linked to exposure to BSE probably through food. Typical (C-type) BSE as well as L-type BSE has been shown to have the potential to affect humanised transgenic mice and primates. No equivalent data exists yet for H-type BSE. Iatrogenic spread in humans has occurred through blood transfusion only for variant CJD linked to the BSE agent. Iatrogenic spread of other, exclusively human, forms of CJD has occurred through growth hormone preparations, and corneal or dura mater grafts. GAPS: There is no substantial information on the zoonotic potential of atypical forms of BSE, or sufficient epidemiological data with which to undertake any effective risk analysis. There is a lack of clarity/agreement on which humanised transgenic models are the most appropriate for the assessment of zoonotic potential. None. Cattle. The role of environmental contamination and spread on fomites has been established for TSE in other species, such as scrapie in sheep and CWD in cervid populations. Environmental persistence of BSE in experimental conditions has also been established, but the limited peripheral tissue distribution of BSE in cattle probably reduces the likelihood of substantial shedding into the environment. Epidemiology certainly supports the assumption that the disease does not transmit readily if at all through direct animal to animal contact or via the environment, unlike TSE in sheep or cervid populations. In an experimental flock using normal husbandry measures, BSE was shown to spread between related sheep, where shedding and environmental contamination are likely to play a part, although modeling of this data suggests that infection might not be self-sustaining within this experimental flock. On farm burial has been banned in most areas for more than 10 years. However, there has been a recent derogation for outlying areas. GAPS:
Description of infection & disease in natural hostsIn cattle, transmission resulted from oral exposure to the prion agent in feed which contained protein derived from meat and bone meal originating from ruminants. BSE could be transmitted experimentally to a number of species by oral or parenteral exposure to infected cattle brain tissue. It can transmit from animal to animal (route unknown) in sheep. The more recently identified variants in cattle (H and L-type) can both be transmitted experimentally by direct inoculation into the brain of more than one species. It has not yet been shown whether other routes could also be effective, although it has been suggested that the food-borne prion disease reported in ranch-raised mink in the past could have been the result of exposure the L-type BSE agent. Primates have been shown to be highly permissive to L-BSE agents, even by the oral route. GAPS:
Not applicable. The commonest clinical signs are apprehension, hypersensitivity to touch and sound and ataxia. A range of signs can be seen related to changes in the mental state, sensation and alterations in posture and movement. General signs include weight loss and reduced milk yield. In general, morbidity is low, with the majority of cases arising as single cases on a farm despite all the animals on that farm being exposed to the same batches of feedstuffs. Signs may be different for the atypical forms of disease, at least at some stages of the disease. In these cases, dullness, difficulty in rising and ataxia feature most consistently. However, most of these cases have been detected through active surveillance and have not presented clinically, so this clinical data is derived mostly from a very small number of experimentally challenged animals. With about 60 reported atypical cases worldwide it can be assumed that morbidity of these forms is also very low. GAP: There are no signs or diagnostic indicators of infection in infected animals during the long preclinical incubation period. The median incubation period is 4-5 years although a small number of cases early in the epidemic developed at less than 30 months. Incubation period is broadly related to infective dose. The incubation period for the atypical forms is unknown, but they are detected predominantly in much older animals under natural conditions. Most field cases are older than 8 years of age, and some considerably higher than this. It is speculated that these diseases are spontaneous neurodegenerative diseases on this basis, as well as on the basis of epidemiological trends. In experimental inoculation models in cattle, the incubation period of H and L forms are similar to that observed with classical BSE. GAP: All field-based incubation periods make the assumption that animals are effectively exposed within the first year of life. There is some experimental evidence in sheep that age at exposure affects incubation period, with older animals becoming relatively less susceptible, but this has never been unequivocally established for cattle. There is no cure. Once an animal is infected death occurs within weeks to months of the onset of clinical signs. None identified. There is limited involvement of gut associated lymphoid tissues, which in other species such as sheep, is linked to the possibility of shedding in faeces. Infectivity and PrPSc has been detected in tissues such as tonsil in cattle, so again low level shedding cannot be ruled out. GAPS: It is not known if the failure to detect shed infectivity/PrPSc is a consequence of test sensitivity or disease pathogenesis. It is possible that there is some shedding from infected cattle that is below the threshold of detection of the methods available to look for it, but there is no epidemiological evidence that this is a significant route of infection. BSE results in spongiform changes (vacuolation) in specific neuroanatomical areas throughout the brain which are visible on histology. Scrapie associated fibrils can be seen by electron microscopy. The misfolded protease resistant protein PrPSc is a very consistent component in the pathogenesis of the disease and accumulates mainly in the central nervous system and variably in the lymphoreticular system, in general more significantly in some of the affected species such as sheep. However it is not known which - if any- of these abnormalities directly results in clinical disease or death. GAPS: The early pathogenesis, and pathogenesis of the disease at a cellular level are both still poorly understood, not least because of the lack of a good experimental model. There is a very poor understanding of the precise mechanism of disease at either the cellular or the whole animal level, or what leads to strain differences or zoonotic potential. Zoonotic potentialThe annual incidence is extremely low, with most cases occurring in the UK. GAPS:
Low, as the clinical signs are quite distinct although differential diagnosis from other neurodegenerative conditions can be difficult in the living person. Within the UK, the establishment of the CJD surveillance unit, and the use of retrospective studies both greatly reduce the possibility of under-ascertainment of cases. Surveillance levels differ greatly between countries. GAPS:
Most cases of vCJD are believed to be of dietary origin, following ingestion of food containing the infective agent, particularly before the requirement to remove risk materials. The annual incidence of vCJD in the UK has declined but there is the possibility of a second wave in different genetic groups with longer incubation periods. There is also a risk of further cases infected via transfer of material such as blood or organs taken from infected individuals not yet showing clinical signs of vCJD, particularly before risk mitigation measures such as leukodepletion of blood. Sterilisation of instruments used in dentistry and surgery is critical to prevent the spread of infection, but this is not always fully effective and wherever possible disposable instrumentation is recommended. vCJD is a fatal neurodegenerative condition generally affecting younger persons (average age 29 in the UK) with a longer duration of illness compared to other forms of CJD. Low, as person to person transmission is unlikely with the exception of iatrogenic spread. The main risk is therefore through material derived from an infected asymptomatic person such as blood for transfusion, or organ transplants, which in turn is dependent on the prevalence of infection in the donor population. Leucodepletion of blood and risk-based sourcing provide risk mitigation. Impact on animal welfare and biodiversityBSE has an impact on the welfare of the affected animal. Wild species can become infected especially if fed contaminated meat and bone meal, or infected animals, but this only happens in artificial situations such as zoos. It does not affect free-living species. Currently, it is required to slaughter clinical cases, cohorts which may have been fed the same ration within 1 year of the positive case, and recent offspring of BSE confirmed cattle, although this is optional i.e. there is the possibility of applying for a derogation to allow these to live to the end of their productive lives. Indirectly it has also resulted in the slaughter of large numbers of small ruminants in the context of scrapie control measures which have been brought in because of the hypothetical risk of BSE in sheep and the identification of two BSE cases in goats. Geographical distribution and spreadCases have occurred mainly throughout most of Europe. BSE has also been identified in North America and Asia. As a result of effective control measures the incidence has declined to very low levels in the past 5 years. Atypical cases have been identified in several European countries, in North America and in Japan. Atypical cases should be considered sporadic, and do not seem to be related to the epidemic of C-type BSE. GAP: Widely differing levels of surveillance are in place in different countries, so direct comparison is very difficult. The BSE epidemic was linked to an extended common source which was the result of the inclusion of ruminant derived protein (meat and bone meal) in cattle rations. Once meat and bone meal was eliminated from the rations the source of the infection was removed. However, the initial source of contamination was never identified. H and L-type variants of BSE are hypothesised to be rare spontaneous disease, although many of the cases identified so far were born before the implementation of fully effective feed bans in the respective countires. It is possible that classical BSE, like H and L-types are hypothesised to be, is a rare spontaneous disease which could once again be amplified through feed if the ban on intra-species recycling of meat and bone meal is relaxed. Cases of all three types of BSE have been born after the most rigorous feed bans, but the numbers of animals are too small to make any robust epidemiological assessment of this. GAPS: Occasional cases still arise, many years after the feed bans were put in place. It is unclear whether these can still be attributed to poor implementation/policing of the feed bans, or whether this now supports the notion that – like the more recently identified atypical forms of disease- BSE was originally a rare (possibly spontaneous) disease of cattle, in which case occasional cases will continue to occur. Moreover in light of recent experimental findings it can not be excluded that L type BSE might have been the origin of BSE. This highlights the fact that the origin of BSE has never been conclusively identified. This has implications for the time when existing bans and levels of surveillance are both relaxed. There is some seasonality to disease occurrence, but this is linked to seasonal stress factors arising from management e.g. calving patterns, which might precipitate clinical onset, rather than seasonality of the disease itself. Not applicable. The disease is generally spread by infected meat and bone meal. Occasional cases have arisen in imported animals in countries without a pre-existing case. If some categories of cases are sporadic, it is anticipated that such cases are present word-wide. GAP: If the disease is spontaneous in origin, then there is every likelihood that it could arise in any cattle population, and it would only be detected in a population with a comprehensive active TSE surveillance programme. No. No. No. No. Route of TransmissionIngestion of feed containing infective material. GAP: The means of disease acquisition is unknown for atypical forms of BSE. There is no evidence of animal to animal spread. A very low level of maternal transmission may have occurred during the epidemic in the UK although it is possible that this was a confounder and that both the dam and the offspring were infected via feed. Experimental sheep to sheep transmission of BSE has been demonstrated under normal commercial husbandry conditions, but modelling suggests that his would not be self-sustaining. Feeding meat and bone meal or other protein derived from cattle in rations fed to cattle has been the principal reason for the spread of disease. In sheep, certain PrP genotypes – such as T rather than M at codon 112, and allelic variation at codon 168 have been shown to confer resistance to BSE specifically. GAP: There is no understanding of why only single animals out of groups fed the same feed will succumb. Some genetic factors have been explored, but there is no clear link to susceptibility. Other factors such as age at exposure and the presence of intercurrent disease are speculated to play a part, but none have been proven. Stress appears to predispose to clinical onset. The possible heterogeneous distribution of infectivity in food could also play a role. Detection and Immune response to infectionThe disease does not elicit a conventional immune response in an affected animal, so this cannot be used as an in vivo marker of infection or disease. The accumulation of PrPSc in the brain, which is the earliest consistent and detectable disease-specific change, occurs without eliciting a classical host immune response, although there is activation of glial cells in the CNS. Antibodies can be raised against the prion protein in antibody production models, but there is no measurable humoral response in an affected individual, presumably because the majority of the abnormal protein is host generated. No measurable humoral immune responses have been detected in BSE cases, and although the glial response in the brain constitutes a form of immune response, it is not one that results in a measurable diagnostic parameter. Various immunochemical tests have been developed for surveillance purposes using PrP specific antibodies, but these can only be applied post mortem. There is therefore no immunological basis for diagnosis in the live animal. Main means of prevention, detection and control
Immunoblotting and ELISA are used to detect PrPSc in unfixed brain tissue. Diagnosis can also be made/confirmed on formalin fixed brain tissue using immunohistochemical or immuno-chemical methods to detect PrP. GAP: No diagnostic test exists to detect BSE in the live animal. None available. None available. BSE is a containment category 3 pathogen for humans. Precautions should be taken when handling BSE infected material. There is no evidence that the live animal presents any specific risk to human health (apart from risk of injury from unpredictable behaviour). While there is no evidence from epidemiological studies that there is any proven occupation link between BSE and related human disease, recent evidence that other forms of TSE (CWD and scrapie) can transmit effectively through aerosol exposure (which is distinct from the pathogen being truly airborne) would nonetheless support the continuing use of precautionary principles when reviewing containment levels for this pathogen. GAPS:
Strict controls are imposed as recommended in the OIE Terrestrial Animal Health code. These controls are based on risk, BSE status of a country and species of animal moved. Current animal disease prevention focuses on the ban on the recycling of ruminant meat and bone meal. Current routine surveillance methods detect bone fragments and muscle fibres in feed. There are both serologic and PCR-based methods to distinguish the species of origin of any feed contaminants, and regulations stipulating feed screening requirements. Controls on the removal and disposal of specified risk material protect the human food chain. GAP: Comprehensive and appropriate detection systems for banned protein in feed e.g. methods which would also detect soft tissue and fluids are being further developed. Passive surveillance involves notification of the suspicion of clinical BSE to the authorities by the cattle owners and veterinarians. Active surveillance, using rapid diagnostic tests was introduced to identify pre-clinical and unidentified clinical cases, and demonstrated the poor performance of passive surveillance in terms of detection of TSEs. Active surveillance requires the removal of the obex section of the medulla from adult cattle either at slaughter, post mortem or point of disposal. Fallen stocks are targeted as the most likely to be affected. The obex is tested using one of the validated tests, as defined in the EU regulations and the OIE Manual. The epidemic declined once the feed controls were strictly enforced and the specified risk materials banned. Sporadic cases have occurred after the feed bans in the UK. The origin of these is not clear. The epidemic continues to decline in countries where BSE existed. Additional control measures are in place to safeguard the human food chain as well as the animal one. GAP: There is still no satisfactory conclusion regarding the origin of the BSE epidemic. If C-BSE is, like H and L type are hypothesised to be, a rare spontaneous disease, then relaxation of the ban on intra-species recycling of meat and bone meal could ultimately result in a repeat of the epidemic. All aspects of disease control are expensive. The greatest costs are surveillance, SRM and feed controls. Disease information from the OIEYes. http://www.oie.int/animal-health-in-the-world/oie-listed-diseases-2011/ http://www.oie.int/fileadmin/Home/eng/Media_Center/docs/pdf/Disease_cards/BSE_EN.pdf http://www.oie.int/fileadmin/Home/eng/Health_standards/tahc/2010/en_chapitre_1.11.5.pdf http://www.oie.int/fileadmin/Home/eng/Health_standards/tahm/2.04.06_BSE.pdf Socio-economic impactHigh impact on individuals with vCJD, which is a chronic degenerative condition leading to death. However, the limited number of cases means that the overall impact in a country was not high. Treatment expensive, and currently unsuccessful, for individuals affected with vCJD. Animal disease is not treated and the animals are culled. Limited impact as most farms only had one case of BSE for which compensation was paid. However, this may not cover consequential loss. Also, the impact of a cohort cull could be greater as it might involve a number of animals in a herd. Major impact in the UK and many other European countries. In the UK the number of cases dropped from a peak of over 37,000 in 1992 to 11 in 2010. A similar picture although on a much smaller scale is seen in the other affected countries.
Variable impact depending on the status of the country and the loss of export markets for animals and their products. Little impact on food security or on livestock production. Major impact on public confidence in food production. Trade implicationsMajor impact on international trade in live cattle, meat and other products which were banned from countries with high incidence of BSE. As it was not possible to provide BSE clearance to herds or individual animals, restrictions and bans on movements were imposed. Bans were also imposed on milk, semen and embryos although there was no evidence that they posed a risk. GAPS: If it is shown that BSE cases - including C-type BSE – are indeed sporadic, then the trade limitations currently imposed for EU countries would also have to apply to other continents where SRM measures are not in place if animal protein is not actively excluded from animal feed in those countries. Major impact, with bans on imports from countries considered to have a high incidence of BSE and which were thought to pose a risk in cattle. Variable depending on the country and the measures imposed. In some countries whole herds were slaughtered following a single confirmed case. Overall the impact on national trade was minimal. Main perceived obstacles for effective prevention and controlLack of a diagnostic test to identify BSE in live animals. Inability to screen herds to identify those which were completely free of BSE. Main perceived facilitators for effective prevention and control
GAPS:
RiskProvided infected material (SRM) is prohibited from entering the animal feed chain BSE cases should continue to decline. The current strain of BSE does not spread between cattle as, for example, scrapie will do in sheep. If new strains of BSE should appear which have the pathogenic characteristics of scrapie then control would be considerably more difficult and with the potential for higher risks to humans. Unusual or atypical forms of BSE have been identified. Two different molecular PrPSc patterns have been described, the L type with low molecular mass and the H type with high molecular mass of the protease-resistant prion protein. These do no have the same pathology, such as pattern of lesions in the brain, and the distribution of the PrPSc is also different. The animals may not display the same clinical signs as classical BSE. Two different molecular PrPSc patterns have been described, the L type with low molecular mass and the H type with high molecular mass. .Laboratory transmission experiments indicate that the L-BSE agent has a significant zoonotic potential, which appears even higher than that of the Classical BSE agent. Main critical gaps
ConclusionThe outbreaks of BSE are declining rapidly. According to the OIE the number of cases of BSE in 25 countries fell from 2215 in 2001 to 70 in 2009. There is no doubt that the strict controls on ruminant protein and its use in animal feed is the main reason for the decline. GAPS: There is current pressure to relax feed controls, and at the same time pressure from other sources to reduce surveillance. While the cost benefit argument can be applied successfully to either of these approaches, it would be necessary to maintain the ban on intraspecies recycling, and some baseline surveillance. However, the potential risk is not limited to intra-species recycling; recycling with cross-species transmission may be an ideal way to select or/and modify properties of TSE agents in the future. |
