6
Johne’s Disease and Crohn’s Disease

Understanding the human health implications of Johne’s disease (JD) will depend on resolution of a central question: Is the etiologic agent of Johne’s Disease, Mycobacterium avium subsp. paratuberculosis (Map), a significant cause of disease in humans? More specifically, is Map a cause or the cause of Crohn’s disease (CD), or is it an incidental bystander without clinical significance? This has been a controversial subject attracting strong adherents to both positions, but its resolution is essential for the development of rational approaches to disease management and prevention. Programs designed to limit human exposure to organisms from zoologic and other environmental sources will present enormous challenges if Map is found to be a significant human pathogen. However, the stated task of this committee is not to determine the etiology of CD, or even to determine the link between Johne’s and Crohn’s disease, but to review and make recommendations regarding the control and diagnosis of JD, which, of course, may include human health implications. The question of the JD/CD link was therefore examined in the context of the primary study focus. In addition, because there are two recent and thorough investigations of the relevant evidence by the National Institutes of Health (National Institute of Allergy and Infectious Diseases [NIAID], 1998) and the



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6 Johne’s Disease and Crohn’s Disease Understanding the human health implications of Johne’s disease (JD) will depend on resolution of a central question: Is the etiologic agent of Johne’s Disease, Mycobacterium avium subsp. paratuberculosis (Map), a significant cause of disease in humans? More specifically, is Map a cause or the cause of Crohn’s disease (CD), or is it an incidental bystander without clinical significance? This has been a controversial subject attracting strong adherents to both positions, but its resolution is essential for the development of rational approaches to disease management and prevention. Programs designed to limit human exposure to organisms from zoologic and other environmental sources will present enormous challenges if Map is found to be a significant human pathogen. However, the stated task of this committee is not to determine the etiology of CD, or even to determine the link between Johne’s and Crohn’s disease, but to review and make recommendations regarding the control and diagnosis of JD, which, of course, may include human health implications. The question of the JD/CD link was therefore examined in the context of the primary study focus. In addition, because there are two recent and thorough investigations of the relevant evidence by the National Institutes of Health (National Institute of Allergy and Infectious Diseases [NIAID], 1998) and the

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European Union (European Commission, 2000), these data are dealt with in more general terms. CROHN’S DISEASE Crohn’s disease is an inflammatory disorder of the intestine of unknown cause. The disease is chronic, and patients tend to remit and relapse. Symptoms include general malaise, chronic weight loss, abdominal pain, and diarrhea. It is a life-long disease that has no cure. CD usually begins early in life, with peak incidence between the ages of 16 and 25, but it can occur in early childhood or later in life. Although the disease can occur in any portion of the gastrointestinal tract, it has a predilection for the terminal ileum. The three most common patterns of disease are the involvement of the terminal ileum and cecum, the ileum alone, and the colon alone. The disease is treated with various agents—aminosalicylates, corticosteroids, azathioprine, anti-TNF antibody, antibiotics—to inhibit the inflammatory response in the intestine. Unfortunately, therapy is imperfect and relapses are common. The disease can be complicated by perforation, abscess formation, fistula formation, strictures, and intestinal obstruction. Several of those complications can require surgery in which sections of the bowel are removed. Some patients suffer many intestinal resections which leave them with a “short bowel” (insufficient small bowel to maintain hydration, nutrition, and health). Those patients are sustained with total parenteral nutrition—intravenous feeding with a specialized formulation. Etiology of Crohn’s Disease The cause or causes of Crohn’s disease are unknown. Prominent hypotheses include an aberrant or autoimmune host inflammatory response to undefined antigens, infectious etiologies including Map, and aberrant immune response to a specific infectious agent. There is conflicting evidence for and against each of these proposed pathogenetic mechanisms for Crohn’s disease. As it is currently understood, the disease could, in fact, be more than one malady (Gilberts et al., 1994; Mishina et al., 1996). If this is true, then the existing conflicts in interpretation of evidence for causation may be resolved by clear categorization of Crohn’s disease into multiple syndromes having distinct etiologies. If Map is involved in some cases of Crohn’s disease, it does not appear to be a simple case of infection by an agent in a susceptible host. The generally favorable response of Crohn’s patients to profound immunosuppression and/or bone marrow transplantation supports the notion that immune dysfunction or dysregulation is an important element of the disease (James, 1988; Kashyap and Forman, 1998; Lopez-Cubero et al, 1998; Soderholm et al., 2002; Yoshida et al, 1996). This suggests that if Map is involved at all, it is as a result of an aberrant host immune response to the presence of the agent. In addition to Map, various other causes of Crohn’s disease have been proposed: chronic ischemia and microinfarction, persistent measles infection, chronic viral infection, infection with pathogenic E. coli, abnormal response to a

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dietary component, and abnormal inflammatory response to normal intestinal microflora, or components of the flora, in genetically predisposed individuals (Fiocchi, 1998; Podolsky, 1991; Rath et al, 2001; Sartor, 1997; Selby, 2000). Various polymorphisms of a human gene, NOD2, that confers increased susceptibility to CD, has recently been described (Hugot et al., 2001; Ogura et al., 2001). The role of this gene, which may function as an apoptosis regulator, is currently unclear. Epidemiology of Crohn’s Disease The occurrence of Crohn’s disease is not uniform throughout the world or even throughout the United States (Eisen and Sandler, 1994; Ekbom et al., 1991; European Commission, 2000; Kyle, 1992; Sonnenberg and Wasserman, 1991; Sonnenberg et al., 1991). In general, Crohn’s disease is much more common in developed countries than in developing nations. Whether this reflects a true difference in prevalence or is the result of variations in disease diagnosis, definition, recognition, and reporting is not clear (Eisen and Sandler, 1994). However, most authorities believe there are true geographic differences (Garland et al., 1981; Sonnenberg et al., 1991; Yang et al., 2001). The incidence in the United States and in Sweden has increased over the past 60 years. The reasons for this are unclear. The highest rates in Europe are found in Sweden (Ekbom et al., 1991) and in the United Kingdom, especially Scotland (Kyle, 1992). Disease rates are lower in Mediterranean countries (European Commission, 2000; Shivananda et al., 1996). Prospective studies of European incidence show a variation of 0.9 to 9.5 per 100,000 population (European Commission, 2000; Shivananda et al., 1996). Prevalence rates may more accurately reflect the magnitude of the problem. Prevalence rates as high as 133 per 100,000 have been observed in Olmstead County, Minnesota (Loftus et al., 1998). There is a substantial difference in rates throughout the United States (Sonnenberg et al., 1991), with as much as a three-fold variation in prevalence from state to state. A study of veterans cared for within the Veterans Administration hospital system (Sonnenberg et al., 1991) showed a marked difference in prevalence among states. The highest-prevalence states were Oregon, Idaho, Nebraska, Wisconsin, West Virginia, Maine, New Hampshire, Massachusetts, Connecticut, and Rhode Island (Sonnenberg et al., 1991). It has been suggested that there is a gradient of prevalence from northern Europe to Mediterranean countries (Eisen and Sandler, 1994; European Commission, 2000) and from northern to southern states in the U.S. (Sonnenberg et al., 1991). The significance of these observations is not clear. In both the United States and Sweden, Crohn’s disease is more common in urban areas than in rural areas (Eisen and Sandler, 1994). It is more common in white Americans than in blacks (Garland et al., 1981; Sonnenberg and Wasserman, 1991), in Jews compared with other ethnic groups (Eisen and Sandler, 1994; Yang et al., 1993), and in smokers versus nonsmokers (Calkins, 1989; Tobin et al., 1987). The disease can affect more than one member of a family, and rare clusters of Crohn’s disease have been reported (Bennett et al.,

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1991; Lashner et al., 1986; Meucci et al., 1992; Yang et al., 1993). There could be a cohort effect of age in Sweden (Ekbom et al., 1991) and in Scotland (Kyle, 1992) where persons born between 1945 and 1950 have a higher prevalence of Crohn’s disease. IMPLICATIONS OF THE LINK Whether there are important human health implications associated with the development of a JD control program depends on the degree to which clinically significant human disease results from exposure to Map. It follows that the influence of an animal control program on human health will correspond to its capacity to meaningfully reduce exposure of susceptible persons to strains of Map that can cause disease. There is a paucity of rigorous data on Map’s role in human disease. Without such data, it is not possible to analyze the essential epidemiologic, pathologic, or environmental factors necessary for the rational design of programs that would interrupt transmission to humans. Even if Map is an important human pathogen, it might not be possible to significantly reduce human exposure through epidemiologic control measures alone. Early diagnosis and effective treatment could prove the only practical means of reducing human disease under such circumstances. Methods to improve the sensitivity, specificity, and speed of identifying Map are critical if gaps in current knowledge are to be filled. Any discussion of the human health implications of a JD control program without this information is speculative at best. Map and Human Disease Despite intense interest in the zoonotic potential role of Map, it has still not been unequivocally established as a cause of clinically significant human disease. There have, however, been two well-documented cases of Map infection in humans: a young boy with scrofula (Hermon-Taylor et al., 1998), and a case of widely disseminated mycobacterial disease in an adult male with AIDS (Richter et al., 2002). Because Map infection will be diagnosed only if it is specifically considered and if appropriate specialized laboratory tests are performed, it is possible that Map has passed unrecognized in an unknown number of similar cases. No systematic surveillance studies have been undertaken in humans to identify the extent of disease syndromes attributable to Map infection, nor is it known if the pathogenesis of the disease that may follow Map infection in humans is similar to or distinct from that occurring in other species. However, the clinical manifestations in the two cases cited above closely resemble syndromes associated with M. avium subsp. avium infection (Horsburgh et al., 1985), raising the possibility that Map can cause host damage by mechanisms similar to those of M. avium. In considering whether human disease caused by Map is more widespread than currently documented, a parallel may be drawn with the increased recognition of previously unsuspected clinical disease attributable to infection with M. avium subsp. avium and other atypical mycobacteria of the M. avium complex (MAC) that followed their recognition as important human

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pathogens in AIDS (Zumla and Grange, 2002). For example, before its widespread recognition as a cause of disseminated disease in AIDS, MAC pulmonary disease was regarded as clinically similar to indolent tuberculosis, occurring primarily in men with underlying chronic pulmonary disease such as chronic obstructive pulmonary disease and silicosis. However, in the mid-1980s, MAC was identified as an important cause of nodular pulmonary disease, especially in middle-aged women who had no underlying predispositions (Prince et al., 1989). This recognition arose from an increased appreciation of MAC as a potential human pathogen, from the use of improved diagnostic methods, and from heightened clinical surveillance. It is possible that increased surveillance for Map as a potential etiologic agent will similarly lead to its association with clinical syndromes. Because the frequency of the above described disease syndromes that could be Map-associated is low, it is impossible with available information to predict what effect JD control programs will have on the occurrence of human disease. However, the overall risk to the general public posed by exposure to Map is likely to be very low compared to that posed by the many other potentially zoonotic agents. Increased interest in Map as a potential human pathogen will help to provide valuable information about the possible spectrum and characteristics of human disease caused by Map. If the prevalence of human Map infection increases or is found to be greater than currently believed, independent consideration of JD control programs designed to limit human exposure could be warranted. Map and Crohn’s Disease Important human health implications associated with the control of JD will be most strongly linked to determination of the effect of Map infection on the development of Crohn’s disease. The evidence for a relationship is discussed in detail later, but of note is the case of the child with scrofula caused by Map, referred to above, who subsequently developed Crohn’s disease. That case has been cited as supporting evidence for an etiologic role in at least some cases of Crohn’s disease (Hermon-Taylor et al., 1998), although no similar cases have been reported. Temporal changes in the prevalence and distribution of Crohn’s disease have been documented that could be the result of increased exposure of susceptible populations to the causative agent. If Map is etiologically implicated and if increases in its environmental ubiquity underlie the changing epidemiology of Crohn’s disease, then successful reduction of exposure to Map could reduce rates of associated human disease. There are three possible outcomes to the controversy that surrounds the question of whether or not Map has a clinically important role in the development of Crohn’s disease, which are also relevant to JD control efforts:

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If Map is the cause of all cases of Crohn’s disease, this relationship will then drive animal control programs. If Map causes a subset of Crohn’s disease cases, this linkage will have the same implications for animal control programs as if all cases were caused by Map. If Map is not a cause of Crohn’s disease, recommendations regarding diagnosis and control of JD depend only on animal health and agricultural concerns. If Map is shown to have no role in Crohn’s disease, then considerations for control programs will be based on JD’s effects on commercial animal production. The most practical and convincing evidence that Map is not implicated would be provided by demonstration of an alternative etiology and a highly effective treatment. So far, however, that has not happened. However, if Map is etiologically linked to all or most cases of Crohn’s disease, there will be far-reaching implications. The simplest way to demonstrate a causal relationship would be through significantly altering the clinical course of disease by treatments that are effective against Map. Clinical studies testing this hypothesis are currently under way in Australia, and their outcome will be followed with great interest. However, failure of the treatments used in these trials will not disprove an association between Map and Crohn’s disease, because it is not known whether the regimens being evaluated are truly effective against Map, and the proportion of Crohn’s cases caused by Map is unknown. The stage of disease at which treatment of Map might be optimally effective also has not been identified. However, a convincing response to treatment in all or even in a large proportion of cases in well-controlled studies would strongly support a connection with Map infection. For example, if a subset of Crohn’s patients from which Map could be isolated or identified responded to anti-Map therapy, while a similar subset from which Map could not be isolated or identified did not, a causal role for Map would be strongly supported for the first subset. The clinical understanding of Crohn’s disease would be modified by such studies, and the door would open to developing new diagnostic and therapeutic tools for managing disease caused by Map, and to undertake focused studies of disease pathogenesis. Of greatest importance, there would be new hope for treatment that could relieve the chronic suffering and debilitating manifestations that characterize the disease. Environmental sources of Map may be ubiquitous, and they may include reservoirs that are traditionally subject to surveillance and management to reduce risk of pathogen exposure to the public. Dairy and beef cattle production have been most widely discussed as sources of Map, but it is clear that more diverse species could serve as sources of zoonotic infection. Map is hardy and has been found in open-drainage water systems (Manning and Collins, 2001). Contamination of public-water sources with Map has not been widely studied but, as with other environmental mycobacteria, it is likely to be

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present to some degree, depending on regional factors. Establishing how any of these reservoirs functions in transmission to humans will be a daunting task. Recognition of Map as a possible human health concern should invigorate interest in areas of potential risk and result in public and private resources being directed toward finding ways to reduce the hazard to humans. However, there are insufficient data to determine what specific control measures will reduce transmission to humans. Efforts directed at improved diagnosis and effective treatment might more reliably and economically reduce the associated burden of human disease. If Map is found to cause a subset of cases of Crohn’s disease, it will be more difficult to demonstrate with certainty than if it is found to cause all or most cases. If the proportion is very small, it is not clear that a JD control program will have a significant effect on human disease. Efforts to improve diagnosis will be important in this setting. Several studies have found evidence of Map in up to two-thirds of cases studied (Collins et al., 2000; Dell’Isola et al., 1994, Lisby et al., 1994; Sanderson et al., 1992, Suenaga et al., 1995). If Map causes an equivalent proportion of cases and Crohn’s disease is found to be a heterogeneous entity with diverse causes, discrimination of cases caused by Map will be a priority. Should a large percentage of cases be caused by Map, the general implications are similar to those described should most or all cases be etiologically related. There will, in addition, be new interest in identifying the cause of non-Map related cases of Crohn’s disease. The human health implications of JD control programs will remain speculative until more is known about the capacity of Map to cause human disease. This knowledge will depend on improvements in diagnostic methods and the conduct of well-designed human clinical studies. Provision of adequate resources to gain this information should be a priority. There is insufficient knowledge to determine whether reduction of disease caused by Map should be addressed through treatment of persons already infected, through epidemiologic control programs designed to prevent human exposure, or to a combination of those approaches. Comparison of Johne’s Disease and Crohn’s Disease Crohn’s and Johne’s diseases have been compared clinically and pathologically. Both are granulomatous diseases of the intestine with a predilection for the ileum. But the similarity of the two diseases has been overstated. When they are compared clinically and pathologically (Tables 6–1 and 6–2), several significant differences can be seen (European Commission, 2000; NIAID, 1998; Rubery, 2001; Selby, 2000; Van Kruiningen, 1999). The similarities and differences have been interpreted by experts both in favor of and in opposition to the view that Map is a cause of Crohn’s disease (NIAID, 1998).

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Table 6–1. Clinical Features of Crohn’s Disease and Johne’s Disease Feature Crohn’s Disease Johne’s Disease Preclinical stage Symptoms and signs Not known Decreased milk yield Incubation period Not known Minimum 6 months Clinical stage Presenting symptoms and signs Chronic diarrhea, abdominal pain, weight loss Chronic diarrhea, dull hair, weight loss, decrease in lactation Gastrointestinal symptoms and signs Diarrhea Chronic (3 weeks+) Chronica Blood in stool Rare Rare Vomiting Rare No Abdominal pain Yes Unknown Obstruction Yes No Extraintestinal manifestations Polyarthritis Yes, but rare No Uveitis Yes, but rare No Skin lesions Yes No Amyloidosis Yes, but rare Yesb Hepatic granulomatosis Yes, but rare Yes Renal involvement Yes, but rare Yesc Clinical course Remission and relapse Yes Yes aNot seen in sheep bGoats primarily cGoats, deer, primates primarily, also camelids SOURCE: Adapted from European Commission (2000)

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Table 6–2. Pathologic Features of Crohn’s Disease and Johne’s Disease Feature Crohn’s Disease Johne’s Disease Lesion location Esophagus and oral cavity Yes No Ileum and colon Yes Yesa Mesenteric lymph nodes Yes Yes Rectum, anus Yes Advanced casesb Segmental involvement of intestine Yes Yes Macroscopic features Macroscopic appearance Edema of affected bowel wall, “garden hose” like appearance Thickened bowel wallb Parietal edema Yes Yes Stenosis Yes Rare Perforation Yes Rare Fistula Yes No Pseudopolyps Yes No Mucosal aspect Cobble stone appearance Corrugatedb,c Microscopic appearance Transmural involvement Yes Rare Fibrosis Yes No Lymphoid aggregates Yes Yesc Granuloma Yes (50–70% of cases) Occasionally Caseation No Usually notd Fissures Yes No Visible acid fast bacilli No Yese aIleum and jejunum are the initial and most frequent locations bNot always in sheep cPredominant feature in lymphocytic-paucimicrobial form dVaries with species eScarce or absent in lymphocytic-paucimicrobial form SOURCE: Adapted from European Commission (2000) The data obtained from human studies directed at the cause of Crohn’s disease are varied and conflicting: Culture of mycobacteria (including, but not limited to Map) from Crohn’s tissues (Chiodini et al., 1984; Collins et al., 2000; Coloe et al., 1986; Gitnick et al., 1989; Graham et al., 1987; Haagsma et al., 1988; Moss et al., 1992; Schwartz et al., 2000; Thorel et al., 1990a)

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Serum antibody responses to various Map antigens (Cohavy et al., 1999; Elsaghier et al., 1992; El-Zaatari et al., 1999; Naser et al., 2000; Olsen et al., 2001; Suenaga et al., 1999; Vannuffel et al., 1994) PCR of Crohn’s tissues with primers directed against IS900 (thought to be specific for Map; see Chapter 3) (Al-Shamali et al., 1997; Cellier et al., 1998; Chiba et al., 1998; Collins et al., 2000; Dell’Isola et al., 1994; Dumonceau et al., 1996; Fidler et al., 1994; Frank et al., 1996; Kanazawa et al., 1999; Lisby et al., 1994; Mishina et al., 1996; Murray et al., 1995; Rowbotham et al., 1995; Sanderson et al., 1992; Schwartz et al., 2000; Suenaga et al., 1995) Hybridization studies of Crohn’s tissues in situ using probes directed against IS900 (Hulten et al., 2000b, 2001) Treatment of Crohn’s patients with anti-mycobacterial therapy (Table 6–3) (Borody et al., 2002; Grahamand Al-Assi, 1995; Gui et al., 1997; Hampson et al., 1989; Prantera et al., 1994; Rutgeerts et al., 1992; Schultz et al., 1987; Shaffer et al., 1984; Swift et al., 1994; Warren et al., 1986). The work has been summarized by Collins, 1998; Van Kruiningen, 1999; Hulten and colleagues, 2000a; Goswami, 2000; and Chamberlin and colleagues, 2001. Table 6–3. Antimycobacterial Therapy Studies for Crohn’s Disease Drug Number of Patients Duration (months) Outcome Reference Rifampicin, Ethambutol 14 12 No improvement Shaffer et al., 1984 Rifampicin, Ethambutol, Isoniazid, Pyrazinamide 1 7 Remission Warren et al., 1986 Rifampicin, Ethambutol, Isoniazid, Pyrazinamide 1 4 Remission Schultz et al., 1987 Dapsone 1 Remission Prantera, 1988 Rifampicin, Ethambutol, Isoniazid, Pyrazinamide 20 9 Remission, 50% Hampson et al., 1989 Ethambutol, Isoniazid, Pyrazinamide, Rifampicin 5 Up to 12 Patients not stabilized; recurrence of symptoms during treatment Jarnerot et al., 1989

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Drug Number of Patients Duration (months) Outcome Reference Rifampicin, Ethambutol 10 6 No clinical improvement Rutgeerts et al., 1992 Clofazimine, Dapsone, Ethambutol, Rifampicin 40 9 Remission in some patients Prantera et al., 1994 Ethambutol, Isoniazid, Rifampicin 130 24 Treatment ineffective Swift et al., 1994 Clarithromycin 15 6 Remission, 50% Graham et al., 1995 Rifabutin, Macrolide 46 18 Remission, 93% for more than 2 years Gui et al., 1997 Rifabutin, Clarithromycin 12 24 Full remission for 6 patients; partial response from 2 patients Borody et al., 2002   SOURCE: Adapted from Collins, 1998. The lack of uniform results in pathogen isolation studies, serologic response, or responses to antimycobacterial therapy could reflect the possibility that only a subgroup (of unknown size) of Crohn’s disease cases is related to Map. Studies of human disease tend to be small and highly selected, and studies of the effectiveness of antimycobacterial chemotherapy in Crohn’s disease have frequently been uncontrolled and not based upon in vitro antimicrobial sensitivity. The finding of Map in Crohn’s tissues by culture, PCR, in situ hybridization, or other methods may reflect several possibilities (an innocent bystander has merely colonized the intestine; a secondary infection that is not the cause of Crohn’s disease; a surrogate marker for another agent that has not been detected; a false positive result especially in the case of PCR; an actual cause of Crohn’s disease). For instance, PCR will be necessary to identify sequences from a normal commensal bacterium in the tissues to control for increased intestinal permeability in IBD, and another pathogen not felt to be an etiologic agent in IBD should also serve as a control (e.g., Salmonella). When considering treatment studies, based upon experience with MAC, isoniazide and pyrazinamide are unlikely to contribute meaningfully to therapeutic regimens, while rifampin and ethambutol by themselves may have limited potency and durability (Young et al., 1986). Regimens using clarithromycin or azithromycin plus rifabutin and ethambutol have been the mainstay of effective treatments for MAC (Shafran et al., 1996) and there is evidence of similar efficacy against Map in vitro (Williams et al., 1999). Their

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empiric use for treating Map understandably follows from this evidence, but there has been little rigorous preclinical testing that might provide strong assurances of success. Confirmation of the effectiveness of these regimens against Map has not been confirmed in a suitable animal model, since no such model exists. There are important precautionary notes to interpretation of studies that use these regimens, for which the experience with MAC is again instructive. The contribution of rifabutin to effective treatment of disseminated MAC in AIDS is far less than predicted (Gordin et al., 1999), and the fluoroquinolones, which appear very potent in vitro, are either of limited benefit or counterproductive (Fernandes et al., 1989; Shafran et al., 1996). Additionally, the optimal length of treatment for serious MAC disease, which is much easier to diagnose and follow clinically than JD or CD, has not been established and relapses have been described both on and after treatment (Dunne et al., 2000). Finally, these agents may have activity against a wide variety of organisms whose role in CD may be underappreciated. Consequently, if there is a striking response to these treatment regimens in clinical trials, the role of Map, while strongly supported, will not be proven. For those who are afflicted, this will be a detail that can be sorted out later. However, if response rates are marginal or of limited durability, a role for Map will not be excluded since the anti-microbials used may not have been sufficiently potent or durable. The lack of agreement among studies could be attributable to the low sensitivity and questionable specificity of the microbiologic and immunologic methods. Moreover, laboratory techniques vary widely and have exhibited poor reproducibility, thus making it difficult to compare results among studies. The result is a body of scientific literature that is confusing and often contradictory. Furthermore, it is possible that Crohn’s disease as currently defined is not a single entity (Gilberts et al., 1994; Mishina et al., 1996). The lack of uniform results in pathogen isolation studies, serologic response, or responses to antimycobacterial therapy could derive, in part, from the possibility that only a subgroup is related to Map. Evidence Required to Support a Cause-and-Effect Relationship What evidence would establish Map as a human pathogen and as a cause of Crohn’s disease? The generally accepted standard for establishing a specific infectious agent as the cause of a human disease has been the fulfillment of Koch’s postulates (Koch, 1884). Briefly stated, with current status by available evidence, these are: The microorganism must be found in all cases of the disease. Partially fulfilled Met for some but not all cases. Wide range of association in different studies employing diverse methodologies. It must be isolated from the host and grown in pure culture. Fulfilled It must reproduce the original disease when introduced into a susceptible host.

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Partially fulfilled Experimental animals have been infected with human isolates but do not reproduce the disease syndrome. It must be found in the experimental host so infected. Fulfilled If all of the criteria are fulfilled, then the organism isolated is the definitive etiological agent of the disease syndrome in question. When such a link has been established, clinical diagnosis of the disease is sufficient to implicate the presence of the specific organism before it is confirmed in the laboratory. This is not presently the case for Map. Partial fulfillment of Koch’s postulates support an association with disease but may or may not support causation. It is commonly the case that different pathogens may be responsible for a single clinical syndrome. Koch’s postulates are not fulfilled for a single organism in such diseases as pneumonia, meningitis, endocarditis, hepatitis, and urinary tract infection among many others. Thus, many well-recognized etiological agents have only partially satisfied Koch’s postulates for the diseases they cause. Koch’s postulates can be difficult or impossible to apply in chronic diseases of complex or multifactorial etiology. Many parasitic illnesses and viral diseases have unique host-dependent clinical manifestations, such that animal models imperfectly reflect human clinical disease syndromes. The most notorious recent example of this was the claim that HIV did not cause AIDS because the third postulate was not fulfilled in that human viruses do not reproduce the disease in animal models (Duesberg et al., 1989). Only the tragic accidental infection and disease of laboratory workers and recent dramatic responses to effective antiretroviral therapy has settled this controversy. Finally, lack of even partial fulfillment of the criteria does not rule out an etiological relationship between an organism and a disease. This is exemplified by leprosy whose etiological agent, M. leprae, has never been isolated in pure culture, leaving the second criterion unsatisfied to this day. A reasonable interpretation of Koch’s postulates is that evidence supports an association but is insufficient to prove or disprove definitively an etiological relationship between Map and Crohn’s disease. The Hill-Evans criteria have been formulated (Evans, 1976) as epidemiologically based criteria for evaluating the causal link between environmental factors, including infection, and disease. While fulfillment of all ten of the Hill-Evans criteria would strongly incriminate Map, fulfillment of all ten is not likely. A listing of the Hill-Evans postulates, with the committee’s interpretation of the available data and whether they satisfy the attendant criteria, illustrates the point: Prevalence of Crohn’s disease should be significantly higher in those exposed to Map than those not. Direct data insufficient Geographic differences in rates of CD and emergence of disease in unaffected populations migrating to areas of higher prevalence suggest that there

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are environmental factors influencing rates of CD (Probert et al., 1996; Shivananda et al., 1996). Furthermore, no systemic studies that identify regional human exposures to Map with which to correlate CD incidence have been performed. However, it should be noted that Sweden has one of the highest prevalence rates of Crohn’s disease in the world yet has little Johne’s disease (Ekbom, 1991; Viske, 1997). Exposure to Map should be more frequent among those with Crohn’s disease than those without. Data insufficient No studies specifically evaluate the exposure of patients with CD to Map. Detailed surveys of potential environmental sources of Map would be required to conduct these studies and this information is not available. In prospective studies, the incidence of Crohn’s disease should be higher in those exposed to Map than those not. Data insufficient Such prospective studies have not been conducted. Crohn’s disease should follow exposure to Map with a normal or log-normal distribution of incubation periods. Data insufficient Knowing the time of exposure of a susceptible population is necessary to satisfy this condition. A spectrum of host responses along a biologic gradient from mild to severe should follow exposure to Map. Data insufficient Specific and sensitive assays of host response to Map that are necessary to address this criterion are not available (see Chapter 3). A measurable host response should follow exposure to the Map in subjects who lack this response before exposure, or it should increase in those with the response before exposure. The response should be infrequent in those not exposed to Map. Data conflicting and insufficient Specific and sensitive assays of host response to Map that are necessary to address this criterion are not available (see Chapter 3). In experiments, Crohn’s disease should occur more frequently in those exposed to Map than in unexposed control subjects. Data insufficient It is unethical to perform this experimentally in humans; however, disease caused by Map does occur in non-human primates (McClure et al., 1987), but no experimental studies have been conducted in these species. Reduction or elimination of Map should reduce the risk of the disease.

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Data insufficient Evidence for this criterion is unlikely to be available in the foreseeable future. Modifying or preventing the host response should decrease or eliminate the disease. Various therapeutic trials performed, but data not conclusive See Table 6–3. All findings should make biologic and epidemiologic sense. Johne’s and Crohn’s diseases have many clinical and pathological similarities, but there are significant differences as well. It seems biologically plausible that Map could cause at least a subset of Crohn’s disease. It is unlikely that the data needed to satisfy all the criteria will be obtained soon. What data could be obtained to moderately or strongly support a causal role for Map? The following specific lines of evidence would provide varying degrees of support for a cause-and-effect relationship. Epidemiologic Association between Map Exposure and Crohn’s Disease Strong evidence of causation: A higher incidence of Crohn’s disease among those in direct contact with Map than in those without such exposure. Requires detailed knowledge of environmental sources of exposure currently not available. Strong evidence of causation: Low prevalence of Crohn’s disease in populations with no potential exposure compared to those with potential exposure. Requires detailed knowledge of environmental sources of exposure currently not available. Moderate evidence of causation: A higher incidence of Crohn’s disease among people who work with Map-infected animals or herds. Conditions conferring host susceptibility are not well understood. Moderate evidence of causation: A higher incidence of Crohn’s disease among susceptible people who consume products containing or contaminated with Map. Conditions conferring host susceptibility are not well understood. Moderate evidence of causation: Identification of a common susceptibility gene in animals and humans. Moderate evidence of causation: Identification of similar responses to a specific treatment in affected animals and humans. Moderate evidence of causation: More Map seroreactivity among Crohn’s disease patients than in controls with

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other causes of diarrhea or intestinal disease or in normal control subjects. Currently available assays lack adequate specificity to address this question. Pathologic Evidence Strong evidence of causation: Identification of Map in tissues from patients with Crohn’s disease, but not in controls Moderate evidence of causation: Isolation of Map from human milk in Crohn’s-affected mothers, but not from unaffected control subjects. Inoculation Studies Moderate evidence of causation: Inoculation studies in humans are unethical and cannot be done. However, inoculation studies are possible in primates. Because it is unlikely that all of these studies will be done, two lines of evidence would provide strong evidence to support a role for Map in the causation of Crohn’s disease. Briefly stated, the regular isolation or identification of Map or of Map RNA-DNA from Crohn’s disease tissues and not from appropriate control groups, with the unequivocal therapeutic response of patients with Crohn’s disease to therapy directed at Map, would strongly implicate Map as a human pathogen and as a cause of Crohn’s disease. A large-scale therapeutic trial is being conducted in Australia. If properly designed and large enough, and if the anti-microbial regimen selected has potent and durable activity against Map, it could help to provide an answer to the question of therapeutic response. CONCLUSIONS The critical questions outlined above are not new. They have been debated for at least the past 10 years, and they are the subject of innumerable publications. Furthermore, they have been addressed in depth by three authoritative bodies in the past four years: the National Institute of Allergy and Infectious Diseases Division of Microbiology and Infectious Diseases: Crohn’s Disease—Is There a Microbial Etiology? Recommendations for a Research Agenda, 1998 (NIAID, 1998); the Scientific Committee on Animal Health and Animal Welfare, European Commission: Possible Links Between Crohn’s Disease and Paratuberculosis (European Commission, 2000); and the United Kingdom Food Standards Agency: A Review of the Evidence for a Link Between Exposure to Map and Crohn’s Disease in Humans (Rubery, 2001). All reached similar conclusions: There is insufficient evidence to prove or disprove that Map is a significant human pathogen.

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There is insufficient evidence to prove or disprove that Map is a cause of Crohn’s disease. The problem is of such importance and the hypothesis sufficiently plausible to warrant increased research to resolve the questions. The committee has not seen evidence to warrant any other conclusions; however, a new approach to resolving the issue is needed and is proposed by the committee in this report.