Paratuberculosis - available
Control ToolsDiagnostics availabilityThere are many commercially available kits available for ELISAs for detecting antibody, gamma interferon kits for detecting cellular immune response and culture and PCR kits for detecting the organism and bacterial DNA. There are many commercially available kits available for ELISAs for detecting antibody, gamma interferon kits for detecting cellular immune response and culture and PCR kits for detecting the organism and bacterial DNA. None validated by OIE. Some validated nationally. GAP: There are no globally accepted standards for validating diagnostic tests. Routine methods are described in the OIE Manual of Diagnostic Tests and Vaccines Identification of the agent
Serological Tests
Cell mediated immunity
GAP: The sensitivity of necropsy and bacterial tissue culture in sub-clinically infected cattle has not been well established. There is potential for use in Europe as part of industry control measures to reduce the level of MAP infected herds. A DIVA test will be required if vaccination becomes widely used to control disease with the added requirement to ensure that cross reactions and interference with the tests for bovine TB are avoided. Test to differentiate young animals on the basis of how successfully their immune system is managing/eliminating Map infection so that animals of higher resistance are retained in the herd and population. Vaccines availabilityLive attenuated and killed vaccines are available. Some vaccines are authorised in Europe but varies from country to country. No centralised authorisation. Vaccination is illegal in some countries (e.g. Denmark, The Netherlands). No. No. Vaccination of young animals does not completely prevent infection and shedding of Map can continue although there is a reduction of disease incidence. Management practices combined with vaccination can reduce transmission and as a result may reduce the amount of disease occurring in infected herds and the level of environmental contamination. Current vaccines may interfere with the interpretation of the tuberculin test. Oil adjuvant vaccines can cause severe inflammation if accidentally inoculated into humans. GAPS:
Depends on demand and price. There is a demand to reduce the level of disease caused by MAP in herds especially with the uncertainty about potential links to Crohn’s disease in humans. Use of genetically modified vaccines might be problematic in some countries. The field trials may need specific regulation regarding the release of GMOs into the environment. Feasible. Could be used to protect herds. Development of DIVA vaccine. Pharmaceutical availabilityNone. GAP: Further work on potential preventive effect of monensin in young animals Therapy to treat Map infections could have a potential but it is currently unlikely that any therapy could eliminate the organisms once infection has occurred. High if effective. No specific challenges. Depends on demand and price.
New developments for diagnostic testsGAPS:
In general the development of tests is much faster and less expensive than developing vaccines. From development through validation to commercial availability will be time consuming and can take years. The development and validation of new tests 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 will need to be a commercial company willing to market the test. Identification of cocktails of specific and sensitive antigens, which can be used in either cell-mediated or humoral immuno-diagnostics. Evaluation of these tests in longitudinal field studies. This would be difficult with current technologies and would need a method of detecting Map in the animals. New developments for vaccines
Depending on when a candidate vaccine could be identified the timescale will be 5-10 years. This will involve development, clinical trials and licensing. Potential vaccines need to be identified and subjected to initial trials and depending on the outcome will depend the time to commercial availability. GAPS: There is an urgent need for screening methods through which vaccine candidates can be evaluated in a time of 1-2 years. This means a workable definition of when a vaccine can be considered an effective vaccine, such a definition which is currently missing. Research on correlates of protection or correlates of transmission is essential. Expensive with the need to develop and undertake all the relevant tests to provide data to enable the product to be authorised. Field trial will be difficult as will evaluating the results. GAP: There is an urgent need for screening methods through which vaccine candidates can be evaluated in a time of 1-2 years. This means a workable definition of when a vaccine can be considered an effective vaccine, such a definition which is currently missing. Research on correlates of protection or correlates of transmission is essential.
New developments for pharmaceuticals
Time to develop would depend on the product and the trials necessary to validate the efficacy and safety. Commercial production would then take further time. Five to 10 years seems a realistic timeframe Expensive but difficult to assess as it will depend on the product and the trials necessary to validate and license.
Disease detailsDescription and characteristics.Paratuberculosis (or Johne’s disease) is caused by Mycobacterium avium subsp paratuberculosis (MAP). Disease associated with MAP is primarily a disease apparent in the adult cattle, sheep, goats and deer. Cattle and sheep are usually infected with strains adapted to those species although most strains appear to be able to infect a number of different species to some extent. The type of clinical disease varies significantly between species (Mackintosh et al., 2004), and the course of infection can vary greatly within species. GAPS:
MAP are resistant to cold and dessiciation. They can survive for extended periods in soil (greater than a year) and even longer in water. There is a suggestion of prolonged survival in biofilms (Cook et al., 2010). When exposed directly to Summer temperatures and sunlight, the number of MAP decreases under most conditions. GAPS:
Species involvedMAP can affect domestic cattle, sheep goats, camelids and deer. Wildlife, including deer and rabbits are also susceptible. Animals in zoological collections are also frequently infected (Witte et al., 2009). Pathological lesions or occurrence of bacteria have also been reported in horses, pigs, alpaca, llama, stoat, fox, weasel and crow, and other multiple other animals (e.g. Beard et al., 1999; Beard et al., 2001a; 2001b; Larsen et al., 1971; 1972). GAP: The range of animals which can serve as carriers of MAP, with and without becoming clinically affected, has not been fully described. Crohn s disease, which is a chronic inflammatory disorder of the gastrointestinal tract of humans, has been associated with MAP. The main theory is that the lesions seen in Crohn s patients are due to a relative immunodefiency. A number of organisms have been proposed to play a role in the pathogenesis (Marks et al. 2010), including MAP. There are some similarities between MAP associated disease in ruminants and Crohn s disease in humans. On occasions MAP have been isolated from tissues of patients suffering from Crohn s disease. This has led to speculation that MAP may be associated with Crohn s disease in some people. Although a link has been suggested the scientific evidence is insufficient to confirm or refute the link. GAPS: the cause(s) of Crohn s disease remains to be proven. Many studies have demonstrated an association between the occurrence of MAP and Crohn s disease, but the causal link has not been demonstrated. A hypothesis is that there could be regional differences in involvement of MAP in Crohn s. There is major disagreement among experts about the causal relationship between MAP and Crohn s disease. Furthermore, the origin of MAP in some Crohn s patients has not been determined, i.e. are they from agricultural products such as meat and milk, or from other sources? None. Primarily cattle, sheep, deer and goats with possible involvement of wildlife and feral animals, especially deer and rabbits in the epidemiology. GAPS: Wildlife and feral animals can be a reservoir, but their importance may vary greatly between regions, depending on the local animal species and the level of contact between wildlife and production animals. These aspects have only partly been studied. Description of infection & disease in natural hostsMost infected animals may excrete no MAP or amounts below the infectious dose in the early years. Some infected animals may excrete large numbers of organisms in their faeces which contaminate food, water and the environment. MAP can also be excreted in milk and colostrum. Transmission is mainly via the ingestion of contaminated material, but MAP can also be transferred in utero. Bio-aerosol transmission has recently been suggested (Eisenberg et al., 2009). Between-herd transmission is typically via purchase of live infected animals. GAPS:
Not applicable. Paratuberculosis is characterised by a slow progressive wasting of the animal with increasingly severe diarrhoea. It is an untreatable, intestinal disease of ruminants characterised by three stages. 1. Calves are particularly susceptible and often ingest MAP during the first month of life. Some calves may be infectious in the first months of life. This is followed by a long latent period during which the animals are neither clinically affected nor infectious. 2. During the latent period, animals remain clinically normal but then become infectious by intermittently excreting MAP in low numbers in their faeces. These asymptomatic carrier animals may be important sources of transmission. 3. Finally, clinical disease may occur. In cattle, this may be characterised by a profuse and persistent diarrhoea and weight loss, but often the clinical stage include a slowly progressing drop in milk production. In sheep and goats the only clinical signs may be weight loss. Large numbers of MAP are then be excreted in the faeces and possibly also in the milk and colostrum. Generally, there is a period of reduced milk output well before the animals begin to show signs of advanced disease which is inevitably fatal. In deer, the animals usually loose weight over a period of several months and most develop diarrhoea and eventually die. GAP: Early clinical stage can be reverted or significantly slowed by lowering an animal’ metabolic demands, e.g. by drying off cows. The relational between metabolic status and pathogenesis has been largely unexplored. Animals are usually infected in the first few weeks of life but signs of the disease are rarely seen before two years of age. There is huge variation in the incubation period, ranging from a few months to a life-time (15 years or older). The time of infection is assumed to primarily occur in young animals, but may be older animals may also be infected. GAPS:
Affected animals eventually die but clinical disease usually only affects one or two percent of animals at any one time in the herd. Since one of the first symptoms of advanced infection is a drop in milk yield, affected animals in dairy herds are often removed from the herd in early stages of clinical disease. In deer herds losses due to clinical disease can be quite dramatic and result in the loss of a whole “generation”. The faeces of infected animals may contain large numbers of the bacteria and the usual route of infection is the oral-faecal route with the ingestion of food (including milk and colostrum) or water contaminated by the organism. A single diseased animal can pose a high risk to susceptible animals and in particular to the young calves in the herd. GAPS:
The infection progressively damages the intestines of affected animals. As the disease progresses, gross lesions occur in the ileum, jejunum, terminal small intestine, caecum and colon, and in the mesenteric lymph nodes. The organism causes the intestinal walls to become thickened and inflamed. Damage to the intestinal wall allows the leakage of proteins and makes the intestine less able to absorb protein. GAPS: The mechanisms responsible for loss of immunological control of the infection are not well understood. Furthermore, pro-inflammatory immune responses may be able to clear the infection in some animals, but it is not known if this is possible and if it is, what characterises the animals where cell-mediated immune responses cannot cope with the infection. The role of antibodies in infection is not well understood. Zoonotic potentialThe role of MAP in the development of Crohn’s disease is not known. The incidence of CD in developed countries is approximately 4-12 /100.000 people annually. GAPS:
Crohn’s disease is an idiopathic syndrome, i.e. the aetiology is not known. The severity of the clinical symptoms is likely to be correlated with the level of reporting. A common aetiology for all cases of Crohn’s disease seems unlikely. Misclassifications (false-positive and false-negative) are likely to occur for Crohn’s disease, because it is a syndrome, not a specific diagnosis. Some cases of Inflammatory Bowel Disease may not be reported as Crohn’s. GAPS:
The cause of Crohn s disease is not yet known. Currently opinions differ on whether Map causes Crohn s disease, some cases of Crohn s disease or is isolated as a secondary organism from individuals with the disease. Host genetic factors, i.e. mutations in genes of the innate immune system are associated with Crohn s disease.
Several food safety authorities have reviewed causal link between MAP and Crohn s disease and conclude that the current evidence does not support a causal relationship (Anon., 2004; Anon., 2009; European Commission, 200; Rubery, 2001).
GAPS: the cause(s) of Crohn s disease remains to be identified. If MAP is a component cause of Crohn s disease, where do the human patients get exposed to MAP – is it of animal origin? Crohn’s Disease can affect any part of the digestive tract from the mouth to the terminal rectum. The ileum and the colon are the most commonly affected areas. The symptoms include abdominal pain, fever and weight loss. It is a long-term chronic illness. MAP has not been reported to spread between humans. Impact on animal welfare and biodiversityThere are welfare implications for affected animals which have increasing debility and weight loss over long periods from months to years until death intervenes. Some wild life species are endangered. There is not extensive list as diagnostics are not carried out and reported routinely in many zoo collections, but the following species can either be infected or affected. Infection, but not disease, has been reported in some species:
According to the IUCN Red List of Threatened Species. Version 2009.2 and Witte et al.2009. A number of other species which have tested positive by faecal or tissue culture are enlisted as vulnerable or near endangered. Of clinically affected animals in the majority of cases. GAP: The optimal age of culling is not known due to the unpredictable incubation period. However it is recommended that cows that are detected as infected during lactation are culled at the end of that lactation. Geographical distribution and spreadParatuberculosis has been recognised as a widespread problem throughout the world. It is a problem in developed countries in temperate zones and those with well – developed dairy industries. Very low levels of infection may exist in some areas such as northern and western Australia. GAPS:
Usually endemic but with sporadic cases within a herd or flock. GAPS:
No information available. GAP: Seasonality has not been reported but is likely to occur as numbers of shedders and clinical cases vary over time within herds.
With the long latent period the speed of spread is difficult to assess but high numbers of calves can be infected at any one point in time if hygiene and husbandry are unsatisfactory. Spread as distinct from transmission can be rapid with transport of affected animals from one farm to another – we can send it from one side of a country to the other in 48 hours, but it can then take 7 years to be detected! GAP: Simulation models could be generated for a country based on the degree of movement of infective animals and given the prevalence of disease. Spread by subclinically or latently affected animals, which are very difficult to detect, occurs frequently. GAP: Improved export-import protocols required that commensurate with the risk of animals being infected and infectious. No information available. Not apparent. No. Not known although hotter conditions and decreased stocking densities of grazing animals in drying regions would be expected to reduce the incidence. Route of TransmissionMAP are usually introduced by purchase of infected animals. Transmission is by either direct or indirect contact with infected animals and occurs mainly through the faecal–oral route. A source of infection in calves is considered to be milk from infected cows or milk that is contaminated with the faeces of diseased cows. Contaminated land and housing may also be potent sources of infection. GAPS:
Congenital infection can occur. Semen from animals in the advanced stages of infection can be infected with the organism. GAPS:
Poor hygiene, pooling milk/colostrum to feed to young calves, close contact with adult animals and high stocking densities. Detection and Immune response to infectionCell-mediated immune-responses are initially believed to contain MAP, but at some point in time, lose control over the bacteria. Humoral immune responses gradually take over, but without limiting effect on MAP. GAPS:
Diagnostic tests based on detection of cell-mediated immune responses may be used for early diagnosis of the infection. There is a serological response to infection but this can be variable and appears to depend on the stage of infection, extent of the lesions and the amount of Map present. Antibody detection can be useful in diagnosis but has a number of important limitations. As antibody is produced relatively late in the disease process, the ability of these tests to identify latent infections is low. However, they can often detect the infectious and affected animals. Most of these remarks are also valid for cell mediated immune responses, but they have been studied less frequently. GAPS:
Main means of prevention, detection and controlNational control programmes have been introduced in a number of countries such as Australia, Japan and the Netherlands. The most important measure is to avoid the introduction of infection into a clean herd or flock through the purchase of clinically normal but infected animals. GAPS:
If MAP are present in the herd good sanitation and effective husbandry practices are critical to reduce the level of infection. Measures to prevent the transfer of infection from excreting animals to young stock in particular should be introduced. This includes:
GAPS:
Diagnostic tools are required for multiple purposes.
Existing tools cover a wide range of tests detecting MAP (e.g.), MAP DNA (e.g. PCR), antibody reactions (e.g. antibody ELISA) and cell-mediated immune responses (e.g. interferon-gamma detection with ELISA), and histopathology. None of the existing tests are sensitive enough to detect all infected animals, and all tests may result in low rates of false-positive reactions under field conditions. Tests based on presence of MAP in faeces may be false-positive regarding infection because they just detect transient passive digestive carriers. GAP: There is a need to increase the sensitivity of our diagnostic and screening tools, especially when applied to early infected animals. There are a number of vaccines against MAP infections. These are either live attenuated or killed bacteria either incorporated with an adjuvant or lyophilised and adjuvanted on reconstitution. Vaccines may be prepared from one strain of Map 316F or 2E (Weybridge) or Map 3 and 5 or II (Canadian strains), or as many as three strains may be used. Current classical vaccine (produced by CZV) is in use in small ruminants, licensed in Spain, Australia and NZ and exempted from registration in NL. A similar vaccine is being developed and evaluated in cattle by the same company. The same vaccine is not to be used in cattle (or in small ruminants) in areas where tuberculosis is endemic because of interference with the M.bovis skin test. Current developments aiming at subunit vaccines to be used with skin test for M. bovis diagnosis or whole cell attenuated strains to be used with alternative M.bovis testing e.g. gamma interferon assay in combination with specific antigens. The vaccines are only moderately protective but effective in preventing clinical disease and retarding development of the disease and of faecal excretion. GAPS:
No treatment is available, but there is evidence that monensin decreases shedding, and may therefore be useful as a component of a control strategy. GAPS:
General biosecurity measures to prevent the introduction of MAP or in the case of infected herds/flocks to limit the spread of infection within the herd/flock. GAP: There is a need to understand the relative importance of the various biosecurity practices so that they can be appropriately prioritized. The reasons for lack of compliance with biosecurity protocols, even simple ones, need to be investigated. Some national rules but no international standards to ensure that animals being moved for restocking purposes are from herds/flocks in which there is a low risk of MAP being present. GAP: Tools to identify herds/flocks where there is a low risk that MAP are present are required in a form that is universally accepted. Preventing the introduction of infection through purchase of infected animals. Ensuring in infected herds/flocks that animals do not become infected by ingesting:
GAP: Identification of host genetic factors contributing to resistance or selection markers to identify highly susceptible animals may aid control strategies. Surveys have been carried out in many countries to estimate the herd level prevalence of MAP infections, but the studies vary greatly in quality and are often non-comparable. In many European countries, a herd-level prevalence of >50% is likely in cattle, whereas there is limited information on sheep and goats. There is likely great variation depending on the type (beef, dairy, other) of herd and herd-size. Specific control programmes exists in several countries. Within these programmes, surveillance of herds or flocks are carried out to reduce the prevalence of infection. GAP: Reliable prevalence estimates are not available for most European countries (and the rest of the world). Some farmers have been successful in controlling or eradicating MAP from their herd, and others have not been so successful. However, documentation for these successes and failures are few, and the reasons for success or failure are also poorly described. A genetic base for heterogeneity in susceptibility likely exists. GAPS:
Costs of serological tests, hygienic measures, culling affected animals. The costs are greatly variable from country to country, herd to herd and particularly vary with purpose of intervention and test-strategy used to achieve the goal. Disease information from the OIEYes. Information summary: http://www.oie.int/fileadmin/Home/eng/Media_Center/docs/pdf/Disease_cards/PARATUBERCULOSIS_EN.pdf http://www.oie.int/index.php?id=169&L=0&htmfile=chapitre_1.8.9.htm http://www.oie.int/fileadmin/Home/eng/Health_standards/tahm/2.01.11_PARATB.pdf Socio-economic impactUnknown as the link between MAP and Crohn’s diseases is not known Treatment of Crohn’s disease is expensive and takes place over a long period as the condition is chronic sometimes affecting young persons. Relapses are common. Production losses result from reduced milk output (10-12% in last lactation), deaths, increased involuntary culling, reduced weight at slaughter (10-50% for antibody-positive animals, depending on stage of infection), continued spread of MAP, and loss of genetic potential. GAP: Some reproductive measures may also be affected, but documentation is limited and vague. There are huge differences between countries in the involvement of public funding for control measures. Private costs link to testing, vaccinating and culling of affected animals, loss of access to markets. Low. Trade implicationsThe trade and economic implications are to some extent limited, although some countries require assurances on MAP freedom or disease freedom as part of their import health certification, but with regards to export of live animals and export of milk. GAPS:
EU certification for the intra community movement of breeding sheep and goats includes assurances on recent clinical freedom from MAP infection. GAP: This is inadequate to prevent spread. No specific controls in many countries with no specific movement controls form infected herds or flocks. In some countries (e.g. Austria and Germany), clinical infections are notifiable. This may not impact trade, but to a higher extent impact diagnosis, because many infections are not diagnosed, so that farmers will avoid having to notify authorities. GAP: The effects on spread of MAP of making the paratuberculosis notifiable is not known but can be assumed to be negative where owners are subject to subsequent regulatory or market discrimination. Main perceived obstacles for effective prevention and controlThe chronic nature of infection makes test interpretation a challenge. Appropriate communication of test results is needed in order to use the tests properly for control. If the diagnostics are not properly used, this may affect decision makers trust in them. Animals in early stages of infection are not test positive in the tests, which are operational (agent and antibody detecting tests). Therefore, their detecting of infected animals with a latent infection can rarely occur, and they pose a risk of becoming infectious and diseased later on in life, unless they are tested repeatedly. Tests based on presence of MAP in faeces may be false positive regarding infection because they just detect transient passive digestive carriers. Cross reactions in immune based diagnostics occur to variable degree in different geographic areas and possibly also in different types of production systems. A proportion of infected animals test positive in immune based diagnostics, but immune diagnostics cannot discriminate between infected and non infected vaccinates. Vaccination may interfere with M. bovis surveillance schemes. GAPS:
Main perceived facilitators for effective prevention and controlThe development of the necessary tools to control MAP infections should be a priority. Development of improved diagnostic methods with new tests which can detect the latently infected animal with improved sensitivity. Improved vaccines which prevent excretion of the organism and ideally protect young animals from infection. Vaccines which do not result in interference with diagnostic tests and do not cause cross reactions with the TB test are required. RiskThe incidence of MAP infections is high especially in dairy herds in some developed countries. At present there is conflicting evidence that MAP is the cause of Crohn’s disease but if new evidence is found that supports a causal link there will be pressure to control MAP infections in animals. Both as a precautionary action and for economic reasons new tools to control MAP infections are required. GAP: Association or lack of association between exposure risk factors and incidence of Crohn’s disease and detection of MAP in humans. |
