NEWS

Eighty-seven years ago, Burrill B. Crohn, Leon Ginzburg, and Gordon D. Oppenheimer published a paper titled Regional Ileitis – A Pathologic and Clinical Entity in the Journal of the American Medical Association (vol. 99, no. 16, pp 1323-1329, October 15, 1932). Honoring the importance of this report, the article was later reprinted as a Landmark Article in The Mount Sinai Journal of Medicine (vol 67, no. 3, pp 263-268, May 2006). We provide the original JAMA article here for users interested in reading this influential publication in its original form. Note: the reprinted version in the Mount Sinai Journal of Medicine has better print quality.

Comment: I appreciate history more as I grow older. Also, it is important to read original published reports to avoid misquoting or perpetuating misunderstandings. Interesting note: As described in Wikipedia, Crohn always preferred the medically descriptive terms "regional ileitis" and "regional enteritis" to "Crohn's disease", but he was not able to prevent the appropriation of his name for the disease.

Without providing much detail, B.B. Crohn’s article mentions efforts to determine if Mycobacterium tuberculosis was involved in the regional ileitis cases he described including culture for M. tuberculosis, inoculation of lymph node homogenates from five patients into guinea pigs, rabbits, and chickens, and acid-fast staining of tissue sections. He concludes that M. tuberculosis was not a cause of these cases of regional ileitis. However, he never mentions the 1913 report by Dalziel or makes any mention of Mycobacterium paratuberculosis or the similarities of regional ileitis in humans to that of cattle, as described by H.A. Johne in 1895. Clearly, Dr. Crohn recognized how the pathology in his afflicted patients resembled that caused by a mycobacterial infection. How might history be different had Dr. Crohn considered the possibility M. a. paratuberculosis was the cause?

Johne's disease is a regional ileitis affecting ruminants.

Dr. Robert Greenstein compared Crohn's disease and Johne's disease in his "personal view" article published in Lancet Infectious Diseases in 2003 (Lancet Infect Dis 2003; 3:507-14).

If you are interested in the history of Johne's disease, check out our timeline of major events.

The picture of B.B. Crohn is credited to Wikipedia.

This question was recently submitted to our website’s “Ask and Expert” feature:

“I have a goat buck who has tested positive for Johne's. If the diagnosis is confirmed, is it OK to collect his semen to store and use for AI purposes? Or can it spread the disease? Should I wait a couple of years before using it to be sure that it is safe?”

How would you answer this goat owner?

There are many reports that bulls (bovine) infected with MAP have the organism in their semen and accessory sex glands. Research publication examples include the following:

• AB Larsen. Mycobacterium paratuberculosis in reproductive organs and semen of bulls. Am. J. Vet.Res. 31:255, 1970.
• WY Ayele. Distribution of Mycobacterium subsp. paratuberculosis in organs of naturally infected bull-calves and breeding bulls. Vet. Microbiol. 103:209, 2004.
• JL Kohl. Consecutive excretion of Mycobacterium avium subspecies paratuberculosis in semen of a breeding bull compared to the distribution in feces, tissue and blood by IS900 and F57 quantitative real-time PCR and culture examinations. J. Vet. Med. Sci. 72:1283, 2010.
• P Münster. A Longitudinal study to characterize the distribution patterns of Mycobacterium avium ssp. paratuberculosis in semen, blood and faeces of a naturally infected bull by IS900 semi‐nested and quantitative real‐time PCR. Transboundary and Emerging Diseases. 60:175, 2013.

While it seems that there is consensus that MAP is found in the semen of infected bulls, a search of scientific literature indicates that only Dr. Richard Merkal tackled the question of what the consequences are for the cow inseminated with MAP-contaminated semen (RS Merkal. Intrauterine inoculation of Mycobacterium paratuberculosis into guinea pigs and cattle. Am. J. Vet. Res. 43:676, 1982).

The study was small (3 cattle) and used a large intrauterine inoculum, 5x10⁸ MAP, and necropsied the cattle up to 4 weeks post-inoculation. MAP was recovered from the body and horns of the uterus of inoculated cattle at 1, 2, 3, and 7 days post-inoculation and from a pelvic lymph node of one cow necropsied 2 weeks post-inoculation but not from tissues of cattle inoculated at 3 and 4 weeks post-inoculation. [The article is provided in full here because of its age and uniqueness. Apologies for the poor photocopy quality.]

Comment: In my answer to the goat owner’s question I explained that I was not aware of any research that directly addressed this question in goats but that I did have information on cattle (some cited above). Based on this, I suggested that the semen itself was probably of minimal concern: best summarized as “wrong end & wrong age”.  I also explained that the feces of the infected buck were of greater concern.

Although Merkal’s study raises some concerns, the uterus is the wrong end (oral being the preferred route of infection by MAP) and only adult (post-puberty) animals are inseminated and as such are more resistant to MAP infection than young animals, i.e. wrong age.

However, I think this highlights a knowledge gap in our understanding about Johne’s disease. This has major significance for the artificial insemination (AI) industry and for countries like Sweden that are free of MAP infections in cattle and risk importation of the infection.  And, we obviously know even less about MAP in goat bucks.

Research Article

In a collaboration between the University of Minnesota and scientists in Spain and The Netherlands, Catalina Picasso-Risso and colleagues report on the association between results of diagnostic tests for bovine tuberculosis and Johne’s disease in cattle. Their reports is published in Veterinary Record and first appeared online 25-SEP-2019.

Abstract

Background: Bovine tuberculosis (bTB) diagnosis is impaired by numerous factors including cross-reactivity with Mycobacterium avium subspecies paratuberculosis, which causes Johne’s disease (JD). In addition, the effect of repeated bTB-intradermal testing on the performance of JD diagnostic tests is not fully understood. This study aimed to evaluate the impact of repeated bTB-intradermal tests under field conditions in Spain on the JD serological status of cattle.

Methods: bTB-positive herds (n=264) from Castilla-y-Leon region were selected and matched with officially tuberculosis-free control herds. The association between JD and bTB status at the herd level was assessed using conditional logistic regression and, in herds with both JD-positive and bTB-positive animals, a Bayesian hierarchical mixed-effect model was used for individual-level analysis.

Results: A significantly higher risk of being JD positive (OR: 1.48; 95 per cent CI: 1.01 to 2.15) was found for bTB-positive herds compared with controls. Individual results indicated that cattle tested more than three times per year, within the last 90 days and more than 12 months were more likely to be JD positive. A skin test-related boost in antibody response could be the cause of an apparent increase of the sensitivity of the JD-absorbed ELISA.

Conclusion: The results demonstrate the interaction between bTB repeated testing and JD individual and herd-level results and this improved knowledge will facilitate the design of more effective control programmes in herds co-infected with two of the most important endemic diseases affecting cattle in Spain.

Comment

Spain is not alone in facing the dual challenge of trying to control both JD and bTB and this publication is important in helping veterinarians diagnose these two important cattle diseases without unknowingly causing an interference between diagnostic tests. Unfortunately, this article is not Open Access.

Research Report

B. Barrero-Domínguez and 7 colleagues from the Animal Health Department, University of Cordoba Faculty of Veterinary, Cordoba, Spain reported on a study of dairy goat flocks.  The publication appears in the Veterinary Record - first online 17 September 019. doi: 10.1136/vr.105465

Abstract

Background: Paratuberculosis (PTB) is a chronic, enteric wasting disease of ruminants caused by Mycobacterium avium subspecies paratuberculosis (MAP), with a worldwide distribution. Andalusia, located in southern Spain, is one of the European regions with the highest goat census and the highest milk production; however, current data on the prevalence of MAP in this species are not available.

Methods: A cross-sectional study was performed to determine the seroprevalence and risk factors associated with PTB in dairy goat flocks from southern Spain. A total of 3312 serum samples were collected from 48 flocks located in three different geographical areas. Health and productive parameters were surveyed during the visit to the herds.

Results: A total of 511 goats were seropositive, with overall true seroprevalence of 22.54 per cent (95 per cent confidence interval (CI95  21.12–23.97). Of the goat herds, 87.50 per cent (CI95 78.14–96.98) were seropositive. The intra-herd seroprevalence was 25.43±31.71, distributed as follows: 22 flocks with a seroprevalence under 10%; 18 flocks between 10% and 50%; and eight flocks with a frequency over 50%. Multivariate logistic regression showed significant association between PTB seropositivity and the following variables: intensive production system, lack of management by batches, inappropriate ventilation and seropositivity to caprine arthritis encephalitis virus (CAEV).

Conclusions: The results indicate a widespread PTB infection in goat herds in southern Spain. Thus, control programmes must include management and sanitary measures to reduce the prevalence. Further experimental studies are necessary to determine the influence of CAEV-PTB coinfection on immune status.

Comment: This is yet another report illustrating that the MAP infection rate in goats is high.  These findings in Spain are comparable to those by Bauman et al. in Ontario Canada (Canadian Veterinary Journal, 2016).  What is very concerning is that consumers commonly consider that goat milk has superior health benefits.  Given these high infection rates in goats and that MAP can infect humans and can survive pasteurization and cheese production, goat milk may not be as healthy a choice as many consumers think.

Research Report – OPEN ACCESS

Nora Navarro-Gonzalez and 12 colleagues from BIOEPAR, INRA, Oniris, 44307, Nantes, France just published an article describing diagnostic testing patterns for paratuberculosis in naturally infected dairy cattle. The publication, titled “Longitudinal study of Mycobacterium avium ssp. paratuberculosis fecal shedding patterns and concurrent serological patterns in naturally infected dairy cattle“, appears in the Journal of Dairy Science October issue (vol 102, issue 10, pages 9117-9137.

Abstract
Mycobacterium avium ssp. paratuberculosis (MAP) is the etiological agent of paratuberculosis, a disease that affects ruminants worldwide. Despite global interest in the control of this disease, gaps exist in our knowledge of fecal shedding patterns and concurrent serological patterns. This longitudinal study in dairy cattle herds with high MAP seroprevalence in France aimed at accurately describing fecal shedding patterns over 1 year; relating those shedding patterns to individual animal characteristics (age, breed, parity); and exploring the association between fecal shedding patterns and serological patterns. To describe temporal fecal shedding patterns and continuity of shedding, along with the standard quantitative PCR (qPCR) threshold cycle we used a cutoff value that related to low or nonculturable fecal shedding. We also defined a threshold cycle indicative of shedding in high quantities to describe infection progression patterns. Twenty-one herds completed the study, and 782 cows were tested 4 times each. We obtained 4 sets of paired fecal qPCR and serum ELISA results from 757 cows. Although we targeted highly likely infectious animals, we found a large diversity of shedding patterns, as well as high variability between herds in the proportion of animals showing a given pattern. The fecal qPCR results of almost 20% of the final study sample were positioned at least once in the range that indicated low or nonculturable fecal shedding (between the adjusted and the standard cutoff value). Although these animals would typically be classified as non-shedders, they could be important to infection dynamics on the farm. Animals that shed at least twice consecutively and animals that shed in high quantities rarely reverted to negativity. Repeated fecal qPCR can be used to detect temporal fecal shedding traits, and the decision to cull an animal could practically be based on temporal, semiquantitative results. Overall, we found a mismatch between fecal shedding and ELISA seropositivity (637 animals were ELISA-negative 4 times, but only 13% of those animals were qPCR-negative 4 times). We found that having more than 2 ELISA-positive samples was strongly related to persistent and continuous shedding. We suggest that although serological testing is much less sensitive than qPCR, it can also be used, particularly over the course of multiple testing events, to identify animals that are most likely to contribute to the contamination of the farm environment.

Comment: This is another important contribution that highlights the importance of a regular testing program in dairy herds and the higher sensitivity of qPCR over ELISA methods for MAP infection detection. Sample pooling makes the cost of qPCR testing almost the same as that of ELISA testing (depending on the laboratory used) and offers far higher diagnostic accuracy, i.e. “more bang for the buck”! However, samples must be pooled by the testing lab, and be pooled according to animal age (animals of similar birth dates pooled together). Laboratories should be contacted to discuss how samples should be submitted to achieve this age-based pooling.

For more about strategic polling of fecal samples form dairy cattle see the article published in 2000 by Dr. Kees Kalis in the Journal of Veterinary Diagnostic Investigation 12:547-551.

Research Report

Dr. Mitch Palmer and colleagues from the USDA-ARS National Animal Disease Center in Ames, IA, USA. just published an article describing diagnostic testing patterns for paratuberculosis in a captive white-tailed deer farm in the U.S. The publication titled “Characteristics of subclinical Mycobacterium avium ssp. paratuberculosis infection in a captive white-tailed deer herd“ appears in the Journal of Veterinary Diagnostic Investigations; first published online September 11, 2019.

Abstract
Paratuberculosis (Johne’s disease) is caused by Mycobacterium avium ssp. paratuberculosis (MAP), and affects both domestic and wild ruminants, including cattle, goats, sheep, and deer. In cattle, most infections occur during calfhood followed by a prolonged incubation period of 1–2 y or more before cows shed culturable numbers of MAP bacilli in their feces. As disease progresses, infected animals develop protein-losing enteropathy, intractable diarrhea, and weight loss. In a cohort of 32 clinically normal deer from a herd with a history of periodic clinical paratuberculosis, we found that subclinical infection was characterized by high rates of infection, common involvement of mesenteric lymph nodes, minimal lesion formation, few intralesional acid-fast bacilli, and low-level fecal shedding of MAP. The characteristics of subclinical paratuberculosis in white-tailed deer resemble those of cattle and red deer, although microscopic lesions were less common in subclinical deer than reported for subclinical cattle, and we did not see necrotizing granulomas as described in subclinical red deer and elk.

Comment: This is another important contribution that highlights how different animal species handle MAP infections differently and that a prolonged period where animals are infectious (shedding MAP in feces) while appearing clinically normal fosters continued spread of the infection within and among animal herds. Unfortunately this article is not open access.

Excerpt from Hoard’s Dairyman September 10, 2019 issue, “Veterinary Column” (page 544).

Although there are many components to Johne’s control programs on dairy farms, the use of the Johne’s vaccine became important and relied upon for some producers. As such, the relatively recent news that the single manufacturer in the U.S. with federal licensure for vaccine production was no longer producing new vaccine came as a blow.

At this point in time there does not appear to be a replacement product. Similarly, none of the newer technology vaccines coming to market will have obtained federal approval by the time the existing stocks run out.

Veterinarians and producers on farms affected by the loss of vaccination may need to refocus their collective efforts on newborn calf and maternity pen management, manure handling and removal, and possibly some environmental testing and tough culling decisions for high shedding animals.

The Hoard’s Dairyman article is based on this Livestock Health Alert issued by the Wisconsin Department of Agriculture Trade and Consumer Protection (DATCP).

More background:

The U.S. Johne’s vaccine is called Mycopar™ and was sold by Boehringer-Ingelheim. Multiple academics report progress toward a more effective vaccine for Johne’s disease.

This links you to a 2011 review article about paratuberculosis and the role of vaccination for control.

This links you to a 2016 review article about Johne’s (paratuberculosis) vaccines.

This link takes you to a publication describing the most recent trial of Mycopar™, the only commercial vaccine ever used for Johne’s disease in the U.S.

The Guidair® and Silirum® vaccines (both sold by Zoetis, a sponsor of this website) are used outside the U.S. for protection of sheep and goats.

Comment: Commercialization of new vaccines for Johne’s disease is a high-risk high-reward challenge. Many companies are reluctant to take on this challenge because of the high cost and long time required to prove vaccine efficacy in each target animal species. However, given the significant and rising prevalence of MAP infections in multiple animal species and the likelihood that MAP is a food-borne zoonotic infection with worldwide distribution, there is huge economic potential for sale a truly safe and effective vaccine. Most producers would rather "control Johne's disease via syringe" rather than do the necessary herd management changes and diagnostic testing.

Chronic Wasting Disease (CWD) is in the news as experts raise concerns about its unchecked spread. Read here the Opinion/Hypothesis article in the July/August issue of mBio titled: Chronic Wasting Disease in Cervids: Implications for Prion Transmission to Humans and Other Animal Species. The authors of the article conclude: Available data indicate that the incidence of CWD in cervids is increasing and that the potential exists for transmission to humans and subsequent human disease. Given the long incubation period of prion-associated conditions, improving public health measures now to prevent human exposure to CWD prions and to further understand the potential risk to humans may reduce the likelihood of a BSE-like event in the years to come.

Today's Johnes.org news item contrasts CWD with a more common chronic wasting disease known as Johne’s disease (JD). I do this with the intention of questioning the relative importance of CWD and JD to society and urging science-based decisions on animal disease control investments. The evidence in the table below and the references that follow speak for themselves.

Footnotes:

• ¹ Crohn’s disease affects more than 1 in 800 people in North America, and while the incidence has plateaued in more industrialized countries, since 1990 the incidence has been rising in newly industrialized countries in Africa, Asia, and South America, including Brazil.
• ² Type 1 Diabetes Mellitus affects roughly 1 in 550 youth (<20 years old) in the U.S. and Canada, and the incidence is rising.
• ³ Multiple Sclerosis affects roughly 1 in 700 in the U.S., and the incidence is rising.

References and recommended reading:

• MAP as a zoonosis on this site: https://johnes.org/general-information/zoonotic-potential/
• Race, B. et al. 2014. Chronic wasting disease in nonhuman primates. Emerg Infect Dis 20(5): 833-837.
• Lombard, JE, et al. 2013. Herd-level prevalence of Mycobacterium avium subsp. paratuberculosis infection in United States dairy herds in 2007. Preventive Veterinary Medicine. 108:234-238.
• Nielsen, SS, and Toft, N. 2009. A review of prevalences of paratuberculosis in farmed animals in Europe. Prev Vet Med 88:1-14.
• Ellingson, JLE, et al. 2005. Detection of viable Mycobacterium avium subsp. paratuberculosis in retail pasteurized whole milk by two culture methods and PCR. J Food Protection 68(5):966-972.
• Chiodini, R. et al. 2012. Crohn’s disease and the mycobacterioses: A quarter century later. Causation or simple association? Critical Reviews in Microbiology 38(1):52-93.
• Ng, SC. 2017. Worldwide incidence and prevalence of inflammatory bowel disease in the 21st century: a systematic review of population-based studies. Lancet. 390:2769-2778.
• Waddell, LA, et al. 2015. Review Article: The zoonotic potential of Mycobacterium avium ssp. paratuberculosis: a systematic review and meta-analyses of the evidence. Epidemiol Infect 143:3135-3157.
• National Advisory Committee on Microbiological Criteria for Foods. 2010. Review: Assessment of Food as a Source of Exposure to Mycobacterium avium subspecies paratuberculosis (MAP). J Food Protect 73(7):1357-1397.
• Sechi, L. et al. 2008. Humoral immune responses of Type 1 Diabetes patients to Mycobacterium avium subsp. paratuberculosis lend support to the infectious trigger hypothesis. Clinical and Vaccine Immunology Feb:320-326.
• SEARCH for Diabetes in Youth. 2006. The Burden of Diabetes Mellitus among US youth: Prevalence estimates. Pediatrics 118(4).
• Dilokthornsakul, P. et al. 2016. Multiple sclerosis prevalence in the United States commercially insured population. Neurology 86(11).
• Cossu, D. et al. 2011. Association of Mycobacterium avium subsp. paratuberculosis with Multiple Sclerosis in Sardinian patients. PLoS One 6(4):e18482.

Abstract submission for the 15th International Colloquium on Paratuberculosis to be held in Dublin, Ireland on June 14th to 18th has opened at https://www.icpdublin.com/abstract and will remain open until December 1st. Hope that you will submit an abstract!  Looking forward to a great conference next Summer.

Complete information about the upcoming 15-ICP can be found here.

Dr. Pamela Steur published a study regarding MAP transmission on Chilean dairy farms as part of her doctoral dissertation in the laboratory of Dr. Miguel Salgado, Instituto de Medicina Preventiva Veterinaria, Facultad de Ciencias Veterinarias, Universidad Austral de Chile, Valdivia, Chile. Her article appears in the journal Tropical Animal Health and Production.

This interesting study found an association between the seroprevalence of MAP infections in dairy herds based on ELISA (IDEXX) and the number of MAP in milk intended for feeding to calves. MAP detection in milk was enhanced by use of peptide-mediated magnetic separation (PMS) technology as developed and refined in the laboratory of Dr. Irene Grant, Queens University Belfast. Up to 1 million MAP per milliliter of milk were detected. This figure from their publication illustrates the association of herd seroprevalence and level of MAP in milk intended for feeding to calves.

Comments: This study highlights how a MAP infection epidemic gains momentum as the number of cows shedding MAP steadily rises and the rate of contamination of milk being fed to calves increases in parallel. Milk is perhaps the most efficient vehicle for transmission of MAP to the most susceptible animals in dairy herds, calves. Some of the MAP in milk is directly excreted from the udder but the majority probably come with fecal contamination of the milk. While dairy producers in some countries can afford to use on-farm pasteurizers or purchase calf milk replacer (pasteurized powdered milk) as a means of protecting calves from MAP, this is not always an option. Moreover, when bulk feeding of milk to calves is practiced (instead of milk from one cow to one calf) the infection rate accelerates quickly. Pictured here is an example of a “calfeteria” in use on a Chilean dairy farm.