Executive Summary

Johne’s disease (JD) is a chronic, progressive intestinal disease caused by infection with Mycobacterium avium subspecies paratuberculosis (Map). The agent was first identified in European cattle a century ago, and it was discovered in the United States in the early 1900s. Control of JD has been problematic because it has a long incubation period, it is clinically similar to many other common diseases of cattle, available diagnostic tests are expensive and relatively low in sensitivity, and there are no accepted standards for diagnosis and control. These problems are compounded by a lack of awareness of the disease and the fact that its slow progression makes financial losses not easily perceptible to the individual producer.

In recent decades, concern has been growing about the apparent increase in the global prevalence of JD and the attendant animal health, economic, and trade implications. The recognition that the Map host range includes ruminant and nonruminant wildlife also has raised concerns. The spread of JD from domesticated animals to wildlife could alter wildlife populations, and, if wildlife reservoirs become established, it could limit the ability to control or eradicate JD in domesticated livestock.

Finally, there is increasing concern over the human health implications of JD. The possibility that Map infection could be a cause of some cases of



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Executive Summary Johne’s disease (JD) is a chronic, progressive intestinal disease caused by infection with Mycobacterium avium subspecies paratuberculosis (Map). The agent was first identified in European cattle a century ago, and it was discovered in the United States in the early 1900s. Control of JD has been problematic because it has a long incubation period, it is clinically similar to many other common diseases of cattle, available diagnostic tests are expensive and relatively low in sensitivity, and there are no accepted standards for diagnosis and control. These problems are compounded by a lack of awareness of the disease and the fact that its slow progression makes financial losses not easily perceptible to the individual producer. In recent decades, concern has been growing about the apparent increase in the global prevalence of JD and the attendant animal health, economic, and trade implications. The recognition that the Map host range includes ruminant and nonruminant wildlife also has raised concerns. The spread of JD from domesticated animals to wildlife could alter wildlife populations, and, if wildlife reservoirs become established, it could limit the ability to control or eradicate JD in domesticated livestock. Finally, there is increasing concern over the human health implications of JD. The possibility that Map infection could be a cause of some cases of

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Crohn’s disease in humans, combined with concern that Map is becoming widespread in the environment and the food chain, could transform JD into a serious public health problem. Several approaches have been taken to begin addressing growing concern over JD. The National Johne’s Disease Working Group (NJWG) of the United States Animal Health Association has implemented an educational program to increase awareness among livestock producers, developed a voluntary herd status program to encourage producers to rear JD-free herds, and has developed minimum standards for state JD control programs. All of these efforts are yielding positive results, but the lack of a nationally coordinated control effort has limited progress and the sense of urgency continues to grow. THE TASK Participants at national and international meetings have reviewed the status of JD research and developed strategies to control the spread of Map. In July 2000, the U.S. Department of Agriculture (USDA) requested that the Board on Agriculture and Natural Resources of the National Academies convene a committee on the diagnosis and control of JD. Specifically, the committee was instructed to conduct a thorough review, evaluation, and compilation of all scientific research related to JD in domesticated and wild ruminants. The committee’s task was to: (1) review and synthesize current information regarding diagnostic techniques, mode of transmission, clinical expression, global prevalence, and potential animal and human health implications associated with JD in domesticated and wild ruminants; (2) evaluate current programs for controlling and preventing JD in ruminants; (3) provide policy recommendations for identification, monitoring, and management strategies applicable to U.S. livestock herds; (4) conduct an objective, critical assessment and summary of the state of knowledge regarding the relationship of JD in ruminants and Crohn’s disease in humans; and (5) provide recommendations on future research priorities and potential mechanisms to facilitate prevention and control of the disease. The committee reviewed the literature on diagnosis, modes of transmission, clinical expression, global prevalence, and potential animal and human health implications of JD with the following goals in mind: Determine whether JD presents a problem sufficient to warrant control efforts. Objectively review the data that provide the basis for control plans. Identify significant gaps in knowledge that affect diagnosis and control. Differentiate well-established facts from dogma or prevailing opinion. Determine whether available diagnostic tests are adequate for control programs.

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Make recommendations on the research needed to fill in knowledge gaps. The committee also evaluated existing state, national, and international control programs with the goal of identifying sound control principles to guide program development and to make recommendations for a national control program. Finally, the committee evaluated the evidence for and against a role for Map in some cases of Crohn’s disease in humans. Considerable controversy has surrounded this issue and there are diverse viewpoints about how some of the evidence should be weighed against other evidence. This problem is not unique to Crohn’s disease. Determining the cause of chronic human diseases is a difficult and often controversial process. One outcome of the debate has been the proposal by Hill and Evans (Evans, 1976) for a set of objective criteria, which, if met, could be considered sufficient evidence to determine that a causal relationship exists between an agent and a chronic disease. To approach this important task most objectively, the committee used the Hill-Evans criteria to develop a list of the research results that would be necessary to establish with reasonable certainty that infection by Map causes some cases of Crohn’s disease. The list of necessary research results was developed before the literature review and it was used to evaluate the strength of the evidence. CONCLUSIONS Based on its review and synthesis of the literature, the evaluation of existing control and herd status programs, and information presented at the public workshop, the committee reached the following conclusions. CONCLUSION 1. JD is a significant animal health problem that warrants implementation of control programs tailored to specific animal species and specific segments of the agriculture industry. Furthermore, JD control deserves high priority from USDA, individual states, and industry. The significance of the disease derives primarily from its consequences for animal and herd health, for the agriculture industry, and for national and international trade. The current concern about JD in industry and government agencies and the potential link with Crohn’s disease in humans provide additional support for making JD control a high priority. CONCLUSION 2. There remains insufficient evidence to prove or disprove that Mycobacterium avium subsp. paratuberculosis is a cause of some or all cases of Crohn’s disease in humans; a new approach is needed to resolve the issue—one that is based on a research agenda that will provide answers to specific criteria set forward in Hill-Evans postulates. A causal link between Map and Crohn’s disease remains a plausible hypothesis that warrants a new research approach and steps by industry and government agencies to identify and mitigate avenues of exposure.

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CONCLUSION 3. Available diagnostic tests and information about the biology of JD and methods to control it are adequate for immediate implementation of control programs. CONCLUSION 4. There are significant gaps in knowledge about some areas relevant to control that are discussed in the recommendations section. The committee emphasizes that closing knowledge gaps will improve control programs, although the need for more information should not delay implementation. CONCLUSION 5. Control will require a long-term commitment and iterative program implementation to maximize the chance of success. This commitment must come from all constituencies, including USDA, state agencies, and industry. CONCLUSION 6. Because control of JD is of greatest concern to the dairy industry, much of the emphasis in control recommendations is directed there. Other industries, however, should consider this an opportune time to deal aggressively with the disease, before infection prevalence increases and the disease becomes more widespread. CONCLUSION 7. The USDA National Animal Health Monitoring System (NAHMS) prevalence surveys have been a critical element in laying the groundwork for control programs. CONCLUSION 8. The Voluntary Bovine Johne’s Disease Control Program proposed by the NJWG has most of the elements necessary for a successful control program, but prospects for success are and will be limited by a lack of uniform implementation among individual states. CONCLUSION 9. The committee endorses the NJWG’s efforts in educating producers and veterinarians, and advocates the expansion of these efforts. DISEASE CONTROL The occurrence of a particular infectious agent in a herd is a consequence of one or more environmental or management risk factors being out of control. If the focus is placed on controlling the risk factor(s), which may be common to a number of infectious agents, rather than on the agent itself, a producer will be more likely to adopt a control practice because the incidental control of other agents will result in a greater return on the investment. While the committee strongly endorses a Best Management Practices approach to control, it felt that control programs should initially focus on JD to take advantage of growing support for control of the disease. In addition, it is

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anticipated that funding for various aspects of control will be more readily available through government-industry partnerships if control has an easily identifiable target, such as JD, rather than a broader concept of Best Management Practices. As control efforts progress, an incremental transition to a Best Management Practices approach should be more feasible. RECOMMENDATION 1. An integrated, bottom-up approach to on-farm disease control is required that meets the needs of the livestock producer and motivates behavioral change, with support at broader industry, state, and federal levels. Components of such a control program are described in Box ES-1. BOX ES-1 Components of a Coordinated Industry/ Government Johne’s Disease Control Program The following elements are important for a successful control program. At the farm level: On-farm risk assessment and development of a farm plan Manure management that minimizes potential for transmission of pathogens by the fecal-oral route Protection of young stock Acquisition of replacement animals free from infection by Map and other significant pathogens that are shed in the feces Removal of infected animals from the farm Reduction of environmental contamination by Map At the state-federal program level: Minimum national standards for program implementation Performance-based criteria for diagnostic testing and laboratory accreditation Rapid identification and protection of JD-free herds that can be used to provide Map-free replacement animals Incremental implementation, progressing from a voluntary herd status program to a system of strong (preferably market-based) incentives for participation and disincentives for nonparticipation, culminating in a mandated herd control program, if JD eradication is the ultimate goal A gradual transition from an exclusive focus on Map to a broader health and market assurance program that emphasizes Best Management Practices to prevent the spread of all pathogens by the fecal-oral route

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A mechanism for periodic program review and self-correction A program to prevent the reemergence of disease after low prevalence or eradication is achieved Recommendations for a stepwise expansion of the federal role in JD prevention and control: The government should promulgate uniform methods and rules (UM&R) for voluntary JD status and control programs. The federal standards would provide consistent definitions and program guidelines for a baseline across all states. Individual states could mandate additional requirements. The federal government should provide control infrastructure, including support and incentives to upgrade diagnostic laboratories across the United States, to promote large-scale testing. All states should be required to implement a control program that is voluntary for producers in accordance with the UM&R. Producers should be encouraged to test all herds and register them either in status programs or in control programs, based on test results. Federal subsidies may be needed to cover the cost of initial testing, in order to encourage participation. Federal restrictions should continue on interstate and international transport of cattle from Map-positive herds. A federal plan should be established to monitor the success of the control program. The plan should provide for periodic program review and self-correction. General control program outlines for a given category of management and husbandry situation will be the same, but must be sufficiently flexible to be easily adaptable to the specific circumstances of each farm. Finally, the information must be packaged and delivered in a manner that is in harmony with the style with which the producer manages information and can motivate them to change their behavior. This motivation may require feedback signals in the form of market price differentials established through testing of the farm product by the downstream purchaser. While control programs for dairy herds may be of highest priority, control programs for beef cattle, sheep, goats, and captive cervids should be developed and implemented. Control programs for zoo animals and wildlife should also be monitored to ensure that a non-domesticated animal reservoir does not compromise control efforts for any species.

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EDUCATION AND TRAINING The National Johne’s Working Group has made education of producers and veterinarians a high priority. The committee endorses this effort and offers the following additional recommendations for action by federal and state authorities: RECOMMENDATION 2. Commodity-oriented (dairy, beef, sheep, goat, llama) materials should be developed that are standardized nationally, and a rationale and guidelines for development of control and certification plans should be provided. These should not be considered the same as national program standards, but they should serve as the information base for participation in national programs. RECOMMENDATION 3. Informational resources should be developed for practicing veterinarians that includes guidance on diagnostic test selection, sample size and selection of animals for testing, interpretation of test results, development of risk assessment methods, writing of herd plans, and monitoring of compliance and progress. RECOMMENDATION 4. Educational resources that emphasize control of risk factors (Best-Management Practices) should be developed instead of materials that emphasize control of a single etiologic agent. RECOMMENDATION 5. Training programs are needed for state Johne’s coordinators, USDA personnel, practicing veterinarians, and laboratory personnel to ensure a uniform base of knowledge and practice. RESEARCH The committee identified significant gaps in the current state of knowledge of the pathophysiology, immunology, diagnosis, and control of JD in domesticated livestock and in wildlife. Choosing the research projects needed to fill those gaps will be important to the success of any JD herd status or control program. The issues also are complex enough to warrant the convening of a USDA expert panel to formulate consensus methods to address the research questions. The committee considered ongoing research to be important for the success of any control program and therefore felt that a research element should be integral to future program development. The committee developed recommendations in several areas. Epidemiology ofMap Infection and JD The committee found significant gaps in the understanding of the epidemiology of JD that could affect the success of proposed control programs. In particular, the committee recommends five additional areas of research.

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RECOMMENDATION 6. Age-dependent dose-response curves are needed to clarify the magnitude and significance of age-related susceptibility or resistance to infection and the degree to which horizontal transmission occurs in different age groups. Use of epidemiologic modeling would help to determine the best measure of infectivity. With the increase in concentrated calf-rearing operations, there is an urgent need to investigate the possibility of horizontal transmission in young animals. Current control strategies assume that horizontal transmission among adult cattle is insignificant, but this should be confirmed because the success of control strategies could be at stake. RECOMMENDATION 7. The effects of chronic, low-level exposure on infectivity and on the outcome of infection should be studied. Much of the data on infectivity and age susceptibility has been derived from decades-old studies in which one or a few large infective doses typically were administered. Although this provides valuable information, because it does not mimic natural exposure, the conclusions that can be drawn are limited. It would be helpful to have a better understanding of the outcome of chronic, low-level, or intermittent exposure to Map in the environment. RECOMMENDATION 8. Experimental studies and field investigations of natural infection in nonruminant and ruminant wildlife in the United States should focus initially on native lagomorphs and other small mammals prevalent on or around livestock operations with endemic JD. Recent investigations on the role of wildlife in the epidemiology of JD in livestock in Scotland, Australia, and the Czech Republic have yielded interesting results. The identification of endemic Map infections in European rabbits in Scotland has important ramifications for control programs there. Little work has been done in the United States on the susceptibility of nonruminant wildlife to Map infection. Determining the prevalence of Map infection in wildlife on or around livestock operations will be important to understanding the success or failure of any livestock JD control programs. RECOMMENDATION 9. Results of diagnostic testing, control practices, and other epidemiologic data should be evaluated and used to answer remaining research questions and to refine and optimize control programs. RECOMMENDATION 10. The USDA NAHMS prevalence surveys should continue, with attention paid to maximizing the data obtained from the samples collected through “add-on” projects and investigations. As control programs are implemented, they present opportunities to take advantage of resulting “natural experiments.” The committee recommends that these opportunities not be lost. Results of the two investigations proposed

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above will help regulators to establish a scientific basis for several control measures, including how long to wait before restocking contaminated land, whether environmental decontamination can expedite restocking, and whether removal of calves from dams at birth is the best means of breaking the transmission cycle. Diagnostics and Immunology Although the committee acknowledges that available diagnostic tools are sufficient to implement control programs, significant deficiencies still exist. To address these important gaps, the committee recommends the following: RECOMMENDATION 11. Epidemiologically sound sampling and sample-pooling protocols should be developed and validated to facilitate screening and monitoring of large cattle herds and sheep flocks. Recent research in Australia suggests that pooling of sheep fecal samples could enable more cost-effective flock screening for control programs. This work should be repeated in the United States and expanded to include cattle. Another important need is for a rapid, sensitive test to detect the presence of Map in bulk-milk samples. This would promote more efficient and cost-effective collection of herd prevalence data, which will be important for control. Some promising studies have been conducted, but additional research is needed in this area. RECOMMENDATION 12. Sensitive and specific serologic and fecal culture methods should be developed and validated for use in sheep and goats. The development of diagnostic tests for JD in sheep, goats, and other species has trailed that for cattle. Although much of the current control emphasis is on dairy cattle, development of more sensitive and specific tests is needed for these other species. Recent reports suggest that the difficulty in isolating sheep strains of Map by fecal culture has largely been overcome, but methods are still slow and not ideal for use in control programs. RECOMMENDATION 13. Methods for detecting an early, specific immune response to Map should be developed. There are no reliable tests to identify animals in the early stages of infection, before fecal shedding. Early identification of infected animals would be helpful for control programs, especially for prepurchase testing of replacement animals. Exposure to other mycobacteria, such as M. avium subsp. avium, is likely to be common in cattle, so it is essential that any test to identify animals in the early stages of infection be highly specific for Map. This might require identification of unique antigenic epitopes in Map, against which an early immune response is generated.

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Map Genome Studies As the committee evaluated knowledge gaps and research needs, the importance of complete sequencing of the Map genome became evident. Sequencing would yield many benefits, including identification of unique Map antigens for development of diagnostic tests and vaccines, improvement of diagnostic methods based on PCR, and identification of potential virulence factors. The Map genome sequencing project at USDA’s National Animal Disease Center is nearing completion, and the committee strongly recommends the following: RECOMMENDATION 14. USDA and other agencies should seize the opportunity presented by the completion of the Map genome project to accelerate progress in JD research, diagnostic test improvement, and vaccine development. Information about the completion of this project needs to be disseminated to the international research communities for JD and Crohn’s disease, and the sequence data should be made available as soon as possible. Research funds should be directed to research and development that use the results of the Map genome project. The paucity of funds available for JD research has limited progress in several important areas. The completion of the Map genome project provides a unique opportunity to correct this oversight, and it should not be neglected. Vaccine Development Current vaccines for Map are highly problematic. There are conflicting data on their ability to reduce shedding of Map, and the fact that they generate cross-reactions to intradermal tests for M. bovis makes them unsuitable for widespread use in control programs. Because vaccines can expedite the reduction of disease prevalence, the committee recommends the following: RECOMMENDATION 15. Research should be done on the nature and evolution of the immune response to Map, and ways to modulate the immune response to elicit protection should be studied. RECOMMENDATION 16. Research is needed on the feasibility of using recombinant-vaccine technology to create a vaccine that generates a specific, protective immune response in domesticated livestock without interfering with diagnostic tests for JD, bovine tuberculosis, or other diseases. Development of an efficacious vaccine will require identification of unique Map antigens that will elicit a protective immune response without

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generating cross-reactions to other mycobacteria. The Map genome project has the greatest potential for providing the basis for these advances. Human and Animal Health Issues After evaluating all of the available evidence for and against a causal role for Map in Crohn’s disease, the committee was of the unanimous opinion that the evidence was insufficient either to establish or to refute a causal connection. The committee considered the following research to be important to the resolution of this question: RECOMMENDATION 17. A blinded study should be done for the detection of Map and Map RNA-DNA in identical coded intestinal tissue samples sent to various laboratories using standardized methods for Map culture and detection. This will help clarify the degree to which conflicting research results have been the result of variations in methods versus operators. RECOMMENDATION 18. A large-scale, double-blind, multicenter study should be done to detect the presence of Map and Map RNA-DNA in tissue specimens from patients with Crohn’s disease, using the same standardized methods as above. The specimens should be stratified by type of disease, duration of disease, presence or absence of known Crohn’s susceptibility genes, and treatment. Control subjects without Crohn’s disease should be included in the study. RECOMMENDATION 19. A large-scale, multicenter, double-blind study of the treatment of Crohn’s disease patients with anti-Map combination antimicrobial therapy should be undertaken. The patients should be stratified by type of disease, duration of disease, presence or absence of known susceptibility genes, treatment, and presence or absence of Map by culture or PCR methods. There also should be an appropriate control group of patients with Crohn’s disease who do not receive anti-Map therapy. RECOMMENDATION 20. A multicenter, double-blind study is needed on the presence of Map, Map antigens, and Map RNA-DNA in breast milk of lactating women with Crohn’s disease, compared to controls. Finding such in lactating women with Crohn’s disease would provide strong support for the proposed connection between Map and Crohn’s disease. If a subset of CD patients responds to anti-Map therapy, or Map is otherwise implicated as a cause of CD in a subset of patients, research on methods to better identify this subset will be needed. Other research considered important by the committee included on-going studies of Crohn’s susceptibility genes and familial tendencies, gene microarray studies to determine which genes

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are up- and down-regulated in Crohn’s disease and animal models, especially in genetically altered animals. RECOMMENDATION 21. The National Institutes of Health or a similar body should convene a panel with experts in gastroenterology, Crohn’s disease, infectious disease, mycobacteriology, biostatistics, epidemiology, etc., to define the precise study designs and to rank order the various studies to be done. Although the committee did not find sufficient evidence to implicate Map as a cause of Crohn’s disease, there was consensus that efforts to identify and mitigate avenues of exposure to Map would be prudent while awaiting definitive resolution of this important question. Identifying environmental sources of Map also is an important element of JD control in livestock, so there is additional justification for such investigations. The committee therefore recommends researching the following projects: RECOMMENDATION 22. Research should be conducted to determine the prevalence of viable Map in potable-water supplies, streams, ponds, and other bodies of water with potential for Map contamination. This may require development of better methods for identifying and quantifying Map in environmental samples. RECOMMENDATION 23. Additional studies are needed to determine whether Map is present in retail milk or other dairy products, as well as in pasteurized colostrum or commercial colostrum replacers that are fed to calves. RECOMMENDATION 24. Research should be done to determine the prevalence of viable Map in peripheral lymph nodes, muscle, and other tissues that are processed for human consumption. RECOMMENDATION 25. Research should be done to determine the prevalence and concentration of Map in other environmental materials likely to be contaminated with ruminant manure and associated with exposure to humans or susceptible animals. Those materials could include composted manure, fruits and vegetables, pastures, and crops fed to livestock. If a causal relationship is established between human Map infection and even a subset of Crohn’s disease cases, the above research recommendations will be essential for implementation of new control programs aimed at protecting public health by minimizing exposure to Map. Additional research would then be needed to develop methods for routine screening of dairy products, meat, and meat products for Map.