Control Tools

• Diagnostics availability

• Commercial diagnostic kits available worldwide

  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.

  List of commercially available diagnostics can be found here (Diagnostics for Animals).

  GAP :

  Characteristics of tests in a population that reflects the target population.Reliable on-farm tests.

• Commercial diagnostic kits available in Europe

  See Section “Commercial Diagnostic kits available worldwide”.

• Diagnostic kits validated by International, European or National Standards

  None validated by OIE. Some validated nationally.

  GAP:

  There are no globally accepted standards for validating diagnostic tests.

• Diagnostic method(s) described by International, European or National standards

  Routine methods are described in the OIE Manual of Diagnostic Tests and Vaccines

  Identification of the agent

  • Necropsy
  • Bacterial culture
  • Bacterial microscopy
  • DNA probes and PCR

  Serological Tests

  • CFT
  • ELISA
  • AGID

  Cell mediated immunity

  • Gamma interferon
  • Delayed hypersensitivity

  GAP:

  The sensitivity of necropsy and bacterial tissue culture in sub-clinically infected cattle has not been well established.

• Commercial potential for diagnostic kits in Europe

  There is potential for use in Europe as part of industry control measures to reduce the level of MAP infected herds.

• DIVA tests required and/or available

  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.

• Opportunities for new developments

  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 availability

• Commercial vaccines availability (globally)

  Live attenuated and killed vaccines are available.

• Commercial vaccines authorised in Europe

  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).

• Marker vaccines available worldwide

  No.

• Marker vaccines authorised in Europe

  No.

• Effectiveness of vaccines / Main shortcomings of current vaccines

  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:

  • More effective antigens requiring less inflammatory adjuvants.
  • Does a long term vaccination strategy help or hinder the control of MAP? There are concerns from Australia where vaccination of ewes apparently increased the longevity of infected individuals and allowed the spread of disease to naive flocks.

• Commercial potential for vaccines in Europe

  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.

• Regulatory and/or policy challenges to approval

  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.

• Commercial feasibility (e.g manufacturing)

  Feasible.

• Opportunity for barrier protection

  Could be used to protect herds.

• Opportunity for new developments

  Development of DIVA vaccine.

• Pharmaceutical availability

• Current therapy (curative and preventive)

  None.

  GAP:

  Further work on potential preventive effect of monensin in young animals

• Future therapy

  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.

• Commercial potential for pharmaceuticals in Europe

  High if effective.

• Regulatory and/or policy challenges to approval

  No specific challenges.

• Commercial feasibility (e.g manufacturing)

  Depends on demand and price.

• New developments for diagnostic tests

• Requirements for diagnostics development

  GAPS:

  • Cost-effective and specific immuno-diagnostics that can discriminate between “non-infected”, “exposed”, “MAP infected” and “infectious”.
  • International standards for the above.

• Time to develop new or improved diagnostics

  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.

• Cost of developing new or improved diagnostics and their validation

  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.

• Research requirements for new or improved diagnostics

  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.

• Technology to determine virus freedom in animals

  This would be difficult with current technologies and would need a method of detecting Map in the animals.

• New developments for vaccines

• Time to develop new or improved 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.

• Cost of developing new or improved vaccines and their validation

  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:

  See. section “Time to develop new or improved vaccines”.

• New developments for pharmaceuticals

• Time to develop new or improved 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

• Cost of developing new or improved pharmaceuticals and their validation

  Expensive but difficult to assess as it will depend on the product and the trials necessary to validate and license.

Disease details

• Description and characteristics

• Pathogen

  Paratuberculosis (or Johne’s disease) is caused by Mycobacterium avium subsp paratuberculosis (MAP).

• Variability of the disease

  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.Investigations have determined phenotypic differences among MAP subtypes for a variety of traits, including growth rates and invasion efficiencies, immunogenicity, virulence as measured by macrophage invasion efficiencies and kinomic responses.There are differences among MAP strains in the immune response that they stimulate, as well as differences in host tropism, disease phenotypes and ability to evade control by vaccines

  GAPS:

  • Distribution of MAP genotypes.

  • Differences in virulence, pathogenicity, immunogenicity, persistence, transmission, survival outside the host and host specificity between genotypes.

  • Effect of mixed genotype infections and superinfections.

  • Not all calves are equally susceptible to (experimental) infection. It is unknown which factors modulate entry of the bacteria through the gut wall and if variation in these factors explains variation in susceptibility. Is there a role for host genetic factors (e.g. enterocyte or M cell adhesion molecules).

• Stability of the agent/pathogen in the environment

  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:

  • Typical survival times for different environments is poorly described, e.g. survival on different types of pasture, with and without application of manure or slurry, and at different temperatures.
  • The role of biofilms needs to be further elucidated.

• Species involved

• Animal infected/carrier/disease

  MAP 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).

• Human infected/disease

  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?

• Vector cyclical/non-cyclical

  None.

• Reservoir (animal, environment)

  Primarily cattle, sheep, deer and goats with possible involvement of wildlife and feral animals, especially deer and rabbits in the epidemiology.

  GAPS:

  The main limitation in considering the role of wildlife species is understanding the circulation of MAP at the livestock–wildlife interface and identifying elements that allow certain wildlife populations to maintain MAP infection and potentially act as a reservoir for livestock. More data needed on distribution of MAP among free-ranging wildlife populations, impacts of infection on the health of these populations, potential for these populations to act as reservoirs for MAP and the extent of MAP transmission between wildlife and livestock in various environments.

• Description of infection & disease in natural hosts

• Transmissibility

  Most 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:

  • Minimal infectious dose for animals of all ages and the importance of single vs. repeated exposures.
  • Role of contact structure in groups of calves on transmission and minimal infectious dose (high intensity contacts within age groups as opposed to sporadic contacts between calves – cows (e.g. at birth)) has yet to be determined.
  • Epidemiological importance of MAP shedding in calves for transmission between calves has only partly be investigated.
  • The relative importance of various transmission routes (including transmission in utero, through bio-aerosols, dust and drinking water).
  • Advice to cull offspring of infected cows is often given, despite of absence of quantification of the in-utero route and can become very costly in selection herds.

• Pathogenic life cycle stages

  Not applicable.

• Signs/Morbidity

  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.

• Incubation period

  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:

  • It is unknown if the outcome of youth vs. adult infection is similar or different.
  • The role of the HPA axis (hypothalamic-pituitary-adrenal axis) is unknown. Various stressors appear to influence disease progression.

• Mortality

  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”.

• Shedding kinetic patterns

  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 mechanism of how bacteria are shed is unknown. It is not known if infected macrophages migrate into the lumen or if only free bacteria translocate to the lumen (and if so actively or passively?).Shedding pattern of MAP-infected animals, including role of supershedders.

  • The role peri-parturient stress may play in precipitating shedding or clinical disease is not understood.

• Mechanism of pathogenicity

  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 potential

• Reported incidence in humans

  The role of MAP in the development of Crohn’s disease is not known (see Section “Species involved > Human infected/diseased”).

  The incidence of CD in developed countries is approximately 4-12 /100.000 people annually.

  GAPS:

  • The proportion of Crohn’s disease patients with MAP is not known, and the causal relationship between MAP and Crohn’s remains to be identified.
  • The proportion of all people with MAP is unknown.

• Risk of occurence in humans, populations at risk, specific risk factors

  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?

• Symptoms described in humans

  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.

• Estimated level of under-reporting in humans

  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(s) of Crohn’s disease remains to be identified.

  • The role of MAP in human disease complexes remains to be identified.

  • If MAP is involved in some cases of “Crohn’s disease”, the proportion of humans infected with and affected by MAP is not known.

• Likelihood of spread in humans

  MAP has not been reported to spread between humans.

• Impact on animal welfare and biodiversity

• Both disease and prevention/control measures related

  There are welfare implications for affected animals which have increasing debility and weight loss over long periods from months to years until death intervenes.

• Endangered wild species affected or not (estimation for Europe / worldwide)

  Some wild life species are endangered. There is no 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):

  • Addax /screwhorn antelope (Addax nasomaculatus) (critically endangered)
  • Lowland Anoa (Bubalus depressicornis, ante-mortem evidence only)
  • Mountain Anoa (Bubalus quarlesi, ante-mortem evidence only)
  • Black Rhinoceros (Diceros bicornis) (Critically endangered)
  • Hog deer (Axis porcinus)
  • East Caucasian tur, West Caucasian tur (Capra caucasica)
  • Turkomen markhor (Capra falconeri)
  • Père David's Deer (Elaphurus davidianus) (extinct in the wild)
  • Slender-horned Gazelle (Gazella leptoceros)
  • Nilgiri Tahr (Nilgiritragus hylocrius)
  • Dama Gazelle (Nanger dama) (critically endangered)

  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”.

• Slaughter necessity according to EU rules or other regions

  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 spread

• Current occurence/distribution

  Paratuberculosis 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:

  • Prevalence in most regions is currently unknown, and prevalence studies have low design uniformity, making comparisons among regions unreliable due to different sampling strategies and case definitions. Thus, the results of these studies and the reported prevalence estimates of MAP infection can currently not be compared directly.
  • Harmonized and multi-country prevalence studies using the same methodology are needed.
  • Identification of cost-effective methods to reliably classify herds or regions free of infection or as having low within and among herd prevalence is needed.
  • Genomic epidemiology of MAP is new, but has already provided important insights into transmission dynamics.
  • Data are needed on the distribution of different MAP genotypes and how these are linked to virulence and pathogenicity.

• Epizootic/endemic- if epidemic frequency of outbreaks

  Usually endemic but with sporadic cases within a herd or flock.

  GAP:

  For extensively managed animals on pasture, there is a need for research into the rate of faecal-oral transmission under various stocking densities and in various ages of animals.

• Seasonality

  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.

• Speed of spatial spread during an outbreak

  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.

• Transboundary potential of the 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.

• Route of Transmission

• Usual mode of transmission (introduction, means of spread)

  MAP is 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 milk from infected cows or milk that is contaminated with the faeces of infected cows. Contaminated land and housing and in utero infection are also considered as sources of infection.

  GAPS:

  • We need to know what the percent attribution to the various modes of transmission is in order to prioritize control strategies. Recent advances in PCR technologies (digital droplet PCR) should enable a determination of the exact number of organisms associated with the different modes of transmission (faeces, milk, colostrum) for all different stages of infection (susceptible/uninfected, transiently infectious, latently infected, infectious, resistant stages).

  • This knowledge would be especially meaningful if in parallel the corresponding infectious dose and the corresponding infection risk associated with the various transmission routes were determined for animals of all ages.Survival and spread in dust raises the possibility of pharyngeal infection via the respiratory route (or oral infection following ingestion of contaminated sputum) this could account for long term low dose exposure in young animals.

• Occasional mode of transmission

  Congenital infection can occur. Semen from animals in the advanced stages of infection can be infected with the organism.

  GAPS:

  • The epidemiological significance of congenital infection is not known.
  • The role of faecal-contaminated water needs to better described.

• Conditions that favour spread

  Poor hygiene, pooling milk/colostrum to feed to young calves, close contact with adult animals and high stocking densities.

• Detection and Immune response to infection

• Mechanism of host response

  Cell-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:

  • There are massive knowledge gaps about protective immune responses – we know very little. The assumption that cell mediated immunity is protective and antibodies are not may not be valid and should be studied in much more detail with relevant antigens in relevant host tissues besides blood. (Immuno)genetics of disease susceptibility / resistance may aid understanding of pathogenesis and host response.
  • Most research has focused on assessing immune changes via the peripheral blood, but understanding the local immune changes in the infected gut will be important in understanding the disease further.
  • Better understanding of immune evasion and immune modulation strategies of MAP.
  • We need to better categorize the CMI response to MAP so that it might be used as part of a diagnostic strategy in young animals.
  • Kinetic patterns of sequences in responses may vary between animals. This has to be further documented

• Immunological basis of diagnosis

  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:

  • Immuno-diagnostics cannot discriminate between “exposure”, “infection” and “diseased”, thus limiting their use. Furthermore, specific and sensitive antigens are lacking.
  • The ability of immuno-diagnostics to predict whether an animal is infectious or not remains to be characterised. Some animals shedding minor amounts of bacteria may be non-infectious and therefore, some antibody tests may be sufficient for control, but the correlation between “infectivity” and “antibody-production” or “infectivity” and cell-mediated responses needs further characterisation.

• Main means of prevention, detection and control

• Sanitary measures

  National 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:

  • Apart from depopulation of infected herds and flocks, there are relatively few descriptions of strategies which have successfully controlled or eradicated MAP from herds or regions.
  • Bio-aerosol spreading of life bacteria may severely limit effects of sanitary measures, relevance for transmission of infection should be studied.

• Mechanical and biological control

  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:

  • Culling of highly infectious animals
  • Animals should be born in areas free of manure
  • Neonates should be removed from the dam immediately after birth and fed colostrum from non-infectious animals
  • Avoid feeding pooled colostrum in infected herds
  • Ensure discarded milk is not fed to calves unless it has been effectively pasteurised to kill MAP.
  • Calves and young cattle to be reared away from adult faecal contamination.
  • Ensure good hygiene in the calving areas
  • Do not breed from the offspring of diseased animals.
  • Do not graze young stock on pasture where adults have grazed or where slurry has been applied in the past three months and ideally in the past year.

  GAPS:

  • Bio-aerosol spreading of life bacteria may severely limit effects of sanitary measures, relevance for transmission of infection should be studied.
  • Temporal and spatial dynamics of with-in farm endemic spread are poorly understood. Observational combined with simulation model studies to quantify role of bio-aerosols, and population contact structure effects for calf shedders, young stock shedders, adult low/intermittent shedders and super shedders in endemic spread and stability are needed.
  • The relative importance of each of the sanitary measures is not known.
  • Our ability to complete clinical trials or cohort studies to examine each of these control points is limited by funding and the time needed to complete such studies. Therefore, there is limited evidence which control methods are the best.

• Diagnostic tools

  Diagnostic tools are required for multiple purposes.

  • to confirm MAP in clinically affected animals
  • to detect infectious animals
  • to certify herds test-negative herds
  • to describe the prevalence of a population
  • to provide historical test-information to derive information on the probability that a population is infection.

  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.

• Vaccines

  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, a 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:

  • Development of a cattle vaccine that limits infection and/or shedding, and does not interfere with diagnostics for other mycobacterial infections.
  • More effective protective vaccines and DIVA (Differentiating Infected from Vaccinated Animals) are required
  • Appropriate level of attenuation of vaccine strains to elicit immune response without causing disease.
  • Cost-effectiveness of vaccination strategies still has to be documented.

• Therapeutics

  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:

  • It is possible that pharmaceuticals that could be produced that would reduce the shedding of viable MAP organisms from infected animals but such a strategy is unlikely to be cost-effective as an intervention in production animals.
  • How can feeding of monensin be used in a control program?

• Biosecurity measures effective as a preventive measure

  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.

• Border/trade/movement control sufficient for control

  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.

• Prevention tools

  Preventing the introduction of infection through purchase of infected animals.Ensuring in infected herds/flocks that animals do not become infected by ingesting:

  • contaminated colostrum;
  • dung that may be present on unclean teats;
  • contaminated feed; and
  • contaminated environment or water supplies
  • being born to an infectious dam

  GAP:

  Identification of host genetic factors contributing to resistance or selection markers to identify highly susceptible animals may aid control strategies.

• Surveillance

  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.

  There are specific control programmes 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).

• Past experiences on success (and failures) of prevention, control, eradication in regions outside Europe

  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:

  • Long-term efficacy of control programmes
  • Is eradication of MAP infection in a herd possible?

• Costs of above measures

  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 WOAH

• Disease notifiable to the WOAH

  Yes.

• WOAH disease card available

  Not available.

• WOAH Terrestrial Animal Health Code

  Available here.

• WOAH Terrestrial Manual

  Available here.

• Socio-economic impact

• Zoonosis: impact on affected individuals and/or aggregated DALY figures

  Unknown as the link between MAP and Crohn’s diseases is not known.

  Meta-analyses have demonstrated that the association of MAP with Crohn's disease in humans is specific and cannot be denied, although a causal role has not yet been demonstrated.

• Zoonosis: cost of treatment and control of the disease in humans

  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.

• Direct impact (a) on production

  MAP infections occur in ruminants and other herbivores worldwide and is of moderate socio-economic importance.

  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. In a recent review (Garcia and Shalloo, 2015) substantial losses due to MAP infection were reported, which escalate as the within-herd MAP prevalence and incidence of clinical JD cases increase. In Canada, the economic damage caused by JD was estimated at $50 CAN per cow per year in MAP-infected herds, resulting in an average loss per infected farm of nearly $3,000 CAN annually (Tiwari et al., 2008). Raizman et al. (2009) estimated the income over feed cost losses at $366 per MAP-shedding cow per lactation. Bhattarai et al. (2014) estimated a loss of $1,644 US per 100 cows in a herd with a true prevalence of 7%. The cost of the disease to the US cattle industry was estimated at $250M US per year (Ott, 1999).

  GAP:

  Some reproductive measures may also be affected, but documentation is limited and vague.

• Direct impact (b) cost of private and public control measures

  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.

• Indirect impact

  Low.

• Trade implications

• Impact on international trade/exports from the EU

  The 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:

  • A unique and universally accepted definition of the infection in animals and occurrence of MAP in animal-derived products does not exist. This result in trade barriers which make little sense in respect of risk assessment and management.
  • Ineffective tests are prescribed by some countries for animal imports (eg CFT)

• Impact on EU intra-community trade

  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.

• Impact on national trade

  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 control

  The 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:

  • Communication tools for different types of decision makers clearly explaining how to use the individual tests are required.
  • Test strategies, including testing frequencies, for different purposes of testing need to be identified.
  • Tools to distinguish transient passive digestive carriers from infected animals
  • Identification of specific and sensitive antigen cocktails for use in various types of immune-diagnostics.
  • Development of DIVA vaccine is needed

• Main perceived facilitators for effective prevention and control

  The development of the necessary tools to control MAP infections should be a priority. Development of improved diagnostic methods with new tests which can reliably and pro-actively (pre-shedding) identify infected animals should lead to progress in JD control.

  The introduction of a JD vaccine has made a huge impact in the Australian sheep industry. Development of a JD vaccine with accompanying diagnostic tests that prevents infection and shedding and does not impair tuberculosis diagnostics remains 1 of the most pressing gaps for the livestock industry.

  GAPS :

  • Veterinary practitioner’s role in promoting control programme participation including communication.
  • Potential of approaches that address JD in combination with other faecal-orally transmitted diseases.

• Links to climate

  Seasonal cycle linked to climate

  No information available.

• Distribution of disease or vector linked to climate

  Not apparent.

• Outbreaks linked to extreme weather

  No.

• Sensitivity of disease or vectors to the effects of global climate change (climate/environment/land use)

  Not known although hotter conditions and decreased stocking densities of grazing animals in drying regions would be expected to reduce the incidence.

Risk

• The 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.

Conclusion

• Nearly a century of JD control programmes has, particularly in the dairy industry, not resulted in sufficient progress. Except for goats in Norway, no reports can be found in a herd in which MAP infection has been eradicated, and in many countries, herd- and animal-level prevalence has not decreased. As a result, JD continues to cause considerable losses to the livestock industry. The insufficient progress has been the result of gaps in our knowledge about this difficult disease. Research has focused on test development and evaluation, vaccine development, and design and evaluation of management strategies to prevent MAP infection. Many of the knowledge gaps identified are in these areas However, the authors are optimistic that if sufficient progress can be made addressing these knowledge gaps, progress in the control of this insidious disease in the next decades will be better. The introduction of a JD vaccine has made a huge impact in the Australian sheep industry. Development of a JD vaccine with accompanying diagnostic tests that prevents infection and shedding and does not impair tuberculosis diagnostics remains 1 of the most pressing gaps for the livestock industry. Reliably and pro-actively (pre-shedding) identifying infected animals that will very likely shed the pathogen, potentially involving biomarkers, is another research priority. Susceptibility for MAP infection differs among breeds. Identification of genetic markers that distinguish very susceptible from more resistant animals has the potential to advance JD control. Quantification of the role of calf-to-calf transmission will be necessary to improve cattle control programmes. Uptake of JD control programmes will improve if these knowledge gaps have been satisfactorily addressed. However, because of the voluntary nature of JD programmes, it will still be important to identify factors that motivate farmers to enrol in these programmes.

Sources of information

• Expert group composition

  H.W. Barkema, University of Calgary, Canada – [Leader]

  K. Orsel, University of Calgary, Canada

  S.S. Nielsen, University of Copenhagen, Denmark

  A.P. Koets, Utrecht University and Wageningen Bioveterinary Research, The Netherlands

  V.P.M.G. Rutten, Utrecht University (The Netherlands) and University of Pretoria (South Africa)

  J.P. Bannantine, USDA-ARS, USA

  G.P. Keefe, University of Prince Edward Island, Canada

  D.F. Kelton, University of Guelph, Canada

  S.J. Wells, University of Minnesota, USA

  R.J. Whittington, University of Sydney, Australia

  C.G. Mackintosh, AgResearch, New Zealand

  E.J. Manning, University of Wisconsin, USA

  M.F. Weber, GD Animal Health, The Netherlands

  C. Heuer, Massey University, New Zealand

  T.L. Forde, University of Glasgow, UK

  C. Ritter, University of Calgary, Canada

  S. Roche, University of Guelph, Canada

  C.S. Corbett, University of Calgary, Canada

  R. Wolf, Amt der Steiermärkischen Landesregierung, Austria

  P.J. Griebel, VIDO-Intervac, Canada

  J.P. Kastelic, University of Calgary, Canada

  J. De Buck, University of Calgary, Canada

• Reviewed by

  Project Management Board.

• Date of submission by expert group

  1 October 2018

• References

  The information in this analysis was provided by experts, in some cases supplemented by selected references. The information could in some cases be affected by the opinions of experts. The information should therefore be considered as such, and the reader is urged to seek further information if specific information is used.

  Additional information can be found in the review paper produced by the DISCONTOOLS expert group on paratuberculosis: “Knowledge gaps that hamper prevention and control of Mycobacterium avium subspecies paratuberculosis infection”, Transboundary and Emerging Diseases 65, S1, 125-148.

  Selected references

  Anon., 2004. Association between Johne's disease and Crohn's disease. A microbiological review. Food Standards Australia New Zealand, Technical Report series no. 35. Available at: http://www.foodstandards.govt.nz/_srcfiles/edit_Report_JD%20and%20CD-%20Final%20Dec%202004.pdf.

  Anon., 2009. Mycobacterium avium subsp. paratuberculosis and the possible links to Crohn's disease. Report of the Scientific Committee of the Food Safety Authority of Ireland. Available at: http://www.foodauthority.nsw.gov.au/_Documents/corporate_pdf/FSAI_Report_on_MpTB_May_2009.pdf

  Beard PM, Henderson D, Daniels MJ, Pirie A, Buxton D, Greig A, Hutchings MR, McKendrick I, Rhind S, Stevenson K, Sharp JM, 1999. Evidence of paratuberculosis in fox (Vulpes vulpes) and stoat (Mustela erminea). Vet Rec. 145: 612-613.

  Beard PM, Rhind SM, Buxton D, Daniels MJ, Henderson D, Pirie A, Rudge K, Greig A, Hutchings MR, Stevenson K, Sharp JM, 2001. Natural paratuberculosis infection in rabbits in Scotland. J Comp Pathol. 124:290-299.

  Beard PM, Daniels MJ, Henderson D, Pirie A, Rudge K, Buxton D, Rhind S, Greig A, Hutchings MR, McKendrick I, Stevenson K, Sharp JM, 2001. Paratuberculosis infection of nonruminant wildlife in Scotland. J Clin Microbiol. 39:1517-1521.

  Bhattarai, B., Fosgate, G. T., Osterstock, J. B., Fossler, C. P., Park, S. C., & Roussel, A. J. (2014). Comparison of calf weaning weight and associated economic variables between beef cows with and without serum antibodies against or isolation from feces of Mycobacterium avium subsp paratuberculosis. J Am Vet Med Ass 243, 1609–1615.

  Cook KL, Britt JS, Bolster CH, 2010. Survival of Mycobacterium avium subsp. paratuberculosis in biofilms on livestock watering trough materials. Vet Microbiol. 141:103-109.

  Eisenberg SW, Nielen M, Santema W, Houwers DJ, Heederik D, Koets AP, 2009. Detection of spatial and temporal spread of Mycobacterium avium subsp. paratuberculosis in the environment of a cattle farm through bio-aerosols. Vet Microbiol. (in press, doi:10.1016/j.vetmic.2009.11.033)

  European Commission, 2000. Possible links between Crohn's disease and paratuberculosis. Report of the Scientific Committee on Animal Health and Welfare, European Commission. Directorate-General Health and Consumer Protection, SANCO/B3/R16/2000, pp. 76.

  Feller M, Huwiler K, Stephan R, Altpeter E, Shang A, Furrer H, Pfyffer GE, Jemmi T, Baumgartner A, Egger M, 2007. Mycobacterium avium subspecies paratuberculosis and Crohn's disease: a systematic review and meta-analysis. Lancet Infect Dis. 7:607-613.

  Garcia, A. B., & Shalloo, L. (2015). Invited review: The economic impact and control of paratuberculosis in cattle. J Dairy Sci, 98, 5019–5039.

  Larsen AB, Moon HW, Merkal RS, 1972. Susceptibility of horses to Mycobacterium paratuberculosis. Am J Vet Res. 33:2185-2189.

  Larsen AB, Moon HW, Merkal RS, 1971. Susceptibility of swine to Mycobacterium paratuberculosis. Am J Vet Res. 32:589-595.

  Mackintosh CG, de Lisle GW, Collins DM, Griffin JF, 2004. Mycobacterial diseases of deer. N Z Vet J. 52:163-174.

  Ott, S. L., Wells, S. J., & Wagner, B. A. (1999). Herd-level economic losses associated with Johne's disease on US dairy operations. Preventive Veterinary Medicine, 40, 179–192.

  Raizman, E. A., Fetrow, J. P., & Wells, S. J. (2009). Loss of income from cows shedding Mycobacterium avium subspecies paratuberculosis prior to calving compared with cows not shedding the organism on two Minnesota dairy farms. J Dairy Sci, 92, 4929–4936.

  Rubery E, 2001. A review of the evidence for a link between exposure to Mycobacterium paratuberculosis (MAP) and Crohn's disease (CD) in humans. A report for the Food Standards Agency, United Kingdom. Available at: http://www.johnes.org/handouts/files/Review%20of%20evidence.pdf

  Tiwari, A., VanLeeuwen, J. A., Dohoo, I. R., Keefe, G. P., & Weersink, A. (2008). Estimate of the direct production losses in Canadian dairy herds with subclinical Mycobacterium avium subspecies paratuberculosis infection. Can Vet J, 49, 569–576.

  Witte CL, Hungerford LL, Rideout BA, 2009. Association between Mycobacterium avium subsp.paratuberculosis infection among offspring and their dams in nondomestic ruminant species housed in a zoo. J Vet Diagn Invest. 21:40-47. Erratum in: J Vet Diagn Invest. 21:288.