Zoonotic Tuberculosis: Mycobacterium bovis and Other Pathogenic Mycobacteria

By Charles O. Thoen and James H. Steele

Zoonotic Tuberculosis: Mycobacterium bovis and Other Pathogenic Mycobacteria, Third Edition is a comprehensive review of the state of the art in the control and elimination of infections caused by Mycobacterium tuberculosis complex in animals and humans. This update to the most complete and current reference available on Mycobacterium bovis includes new coverage of the latest molecular techniques; more information on human infection and One Health; updates to the information on the International Union Against Tuberculosis and Lung Disease (IUATLD), the World Health Organization (WHO), Pan American Health Organization (PAHO), and the United States Department of Agriculture’s (USDA) National Tuberculosis Eradication Program; and coverage of additional African countries. The Third Edition upholds the book’s reputation as a truly global resource on M. bovis.

Written by an international list of tuberculosis experts, chapters cover the status of tuberculosis in many regions throughout the world and deal with issues related to the detection, spread, and control of Mycobacterium bovis, as well as the economic impact of outbreaks. Zoonotic Tuberculosis: Mycobacterium bovis and Other Pathogenic Mycobacteria offers valuable information for public health officials, medical doctors, state and federal regulatory veterinarians, veterinary practitioners, and animal caretakers.

• Language: English
• Publisher: Wiley
• Release date: Feb 12, 2014
• ISBN: 9781118474280

Book preview

Chapter 1

Tuberculosis in animals and humans An introduction

Charles O. Thoen,¹ Philip A. LoBue,² and Donald A. Enarson ³

¹ Iowa State University, USA

² Centers for Disease Control and Prevention, USA

³ International Union Against Tuberculosis and Lung Disease, France

Tuberculosis is an important disease in animals and humans worldwide. It causes substantial morbidity, mortality, and economic loss. There is significant variation in terms of how different organisms of the M. tuberculosis complex affect specific animals, including humans. However, there are also important intersections between animals and humans with regard to TB. The best example is the occurrence of M. bovis disease in humans and domesticated and wild animals.

The tubercle bacillus infects an estimated 2 billion persons or approximately one third of the world's population, and it is estimated that 1.5 to 2 million people die from TB each year. Ninety-five percent of cases occur in people in developing countries. TB is one of the leading causes of infectious disease-related deaths worldwide [1]. The genus Mycobacterium includes several species that cause TB disease in humans and other animals. The Mycobacterium tuberculosis complex includes M. tuberculosis, M. cannettii, M. africanum, M. bovis, M. pinnipedii, M. mungi, M. caprae, and M. microti.

Significant progress has been made toward the elimination of TB caused by M. tuberculosis complex from humans in industrialized countries [2]. However, in many countries where TB programs have only recently been established, there has been only limited progress toward control of the disease. The development of drug-resistant (multidrug-resistant and extensively drug-resistant) strains has compromised the efficacy of TB treatment in humans and has markedly increased the cost associated with the use of multiple drug therapies [3]. Moreover, the susceptibility of human immunodeficiency virus (HIV)–infected individuals to M. tuberculosis complex is of major concern to public health officials in developing countries where the acquired immune-deficiency syndrome is rampant [4].

M. bovis accounts for only a small percentage of the reported cases of TB in humans; however, it is a pathogen of significant economic importance in wild and domestic animals around the globe, especially in countries where little information is available on the incidence of M. bovis infection in humans [5–7].

Tubercle bacilli were identified more than 130 years ago. However, a definitive understanding of the pathogenesis of the disease caused by the M. tuberculosis complex is deficient [8,9]. The tubercle bacillus enters the macrophage by binding to cell surface molecules of the phagocyte. Ingestion of the tubercle bacillus by phagocytes into the phagosome or intracytoplasmic vacuole protects the organism from the natural defenses in the serum. Following ingestion of the bacillus, lysosomes fuse with the phagosome to form phagolysosomes, and it is there that the phagocytes attempt to destroy the bacillus [10]. However, virulent bacilli have the ability to escape killing. Virulent mycobacteria survive inside a mononuclear phagocyte by inhibiting phagosome fusion with preformed lysosomes, thereby limiting acidification. It has been suggested that the pathogenicity of M. tuberculosis complex is a multifactorial phenomenon. However, in cases in which the host response is unable to destroy the bacillus due to conditions that compromise immune function, resulting in low CD4+ T-cell counts, such as immune suppression due to chemotherapy, stress, or HIV, reactivation may occur, resulting in the release of bacilli and transmission of infection.

The susceptibility of different host species varies for the M. tuberculosis complex, depending on the route of exposure, the dose of organisms, and the virulence of the strain [11]. Humans, nonhuman primates, and guinea pigs are very susceptible to M. tuberculosis. Cattle, rabbits, and cats are susceptible to M. bovis and are quite resistant to M. tuberculosis. Wild hoofed stock is generally susceptible to M. bovis, but few reports are available on the isolation of M. tuberculosis [12–14]. Swine and dogs are susceptible to both M. bovis and M. tuberculosis [15].

In humans, TB is a pulmonary and systemic disease caused by M. tuberculosis complex species, predominantly M. tuberculosis. TB infections occur when susceptible individuals inhale droplet nuclei containing tubercle bacilli and the droplet nuclei reach the alveoli of the lungs. The tubercle bacilli that reach the alveoli are ingested by alveolar macrophages and the majority of these bacilli are destroyed or inhibited. A small number multiply intracellularly and are released when the macrophages die. If alive, these bacilli may spread through the lymph or bloodstream to more distant tissues and organs, including areas in which TB disease is most likely to develop: the apices of the lungs, the kidneys, the brain, the bones, and through the lymphatic system to regional lymph nodes. This process of dissemination primes the immune system for systemic responses.

Because of the primed immune system, extracellular bacilli attract macrophages and other immunologically active cells. The immune response kills most of the bacilli, and the remaining bacilli are confined through the formation of granulomas. At this point, latent TB infection (LTBI) has been established, which may be detected using the Mantoux tuberculin skin test or interferon-gamma release assays. Within weeks after infection, the immune system is usually able to halt the multiplication of the tubercle bacilli, preventing further progression.

In some people, the tubercle bacilli overcome the defenses of the immune system and begin to multiply, resulting in the progression from LTBI to TB disease. This process may occur soon after or many years after infection. Unless treated, approximately 3%–5% of persons who have been infected with M. tuberculosis will develop TB disease in the first 2 years after infection, and another 2%–5% will develop disease at some time later in life. Thus, approximately 5%–10% of persons with normal immune systems who are infected with M. tuberculosis will develop TB disease at some point in their lives. Immunocompromised persons have a much higher risk of progression from infection to disease. For example, HIV-infected persons not receiving antiretroviral therapy have an 8% annual risk of progression [16].

TB continues to be an important disease both in humans and animals. It causes substantial morbidity, mortality, and economic loss worldwide. There is significant variation in terms of how different organisms of the M. tuberculosis complex affect specific animals, including humans. However, there are also important intersections between animals and humans with regard to TB. Perhaps the best example is the occurrence of M. bovis disease in humans and domesticated and wild animals.

M. bovis persists in humans, causing pulmonary and extrapulmonary disease. Unlike transmission of M. bovis from cattle to humans, the role of human-to-human airborne transmission in the spread of M. bovis has been somewhat controversial [17]; the predominant view has been that human-to-human transmission is a rare event and that it is only likely to occur in populations that are particularly susceptible to TB (e.g., HIV-infected persons). However, reports of clusters of cases with social and molecular epidemiologic links with patients with pulmonary M. bovis have suggested that human-to-human transmission does occur, even in nonimmunosuppressed persons [18].

Investigations are needed to elucidate the relative importance of M. bovis as regards TB incidence in humans, especially in developing countries [1]. Efforts should be concentrated in countries where HIV infection is widespread, as HIV-infected individuals are more susceptible to mycobacterial disease. Eradication of M. bovis in cattle and pasteurization of dairy products are the cornerstones of the prevention of human disease [19]. Standard public health measures used to manage patients with contagious M. tuberculosis should be applied to contagious patients with M. bovis to stop person-to-person spread. Finally, measures should be developed to identify and control M. bovis infection in wild animals, as these animals may be important reservoirs of infection for domesticated food-producing animals.

It is important to emphasize that pathogenic tubercle bacilli have a wide host range; several species of the genus Mycobacterium infect humans as well as wild and domestic animals. There is therefore a need for medical and veterinary medical professionals to cooperate in disease outbreaks [20]. This concept has been promoted previously [21]. However, this is of increasing importance in TB control in the twenty-first century because of the occurrence of drug-resistant M. tuberculosis complex strains and the immunosuppression of host responses from multiple causes, resulting in increased susceptibility to tubercle bacilli.

Acknowledgment

Published with permission from the Journal of International Union Against Tuberculosis and Lung Disease (Int J Tuberc Lung Dis 14[9]:1075–1078 © 2010) prepared from serialization of article: Thoen, C. O., P. A. LoBue, D. A. Enarson, J. B. Kaneene, and I. N. de Kantor. 2009. Tuberculosis: a re-emerging disease in animals and humans. Vet Ital 45:135–181.

Note

This chapter was originally printed in part as the first of an educational series on Mycobacterium bovis as a zoonotic disease and its implications for tuberculosis control in human populations. This series was offered as a reminder that tuberculosis is a disease with an animal reservoir and that therefore ultimate eradication must recognize this animal reservoir and incorporate strategies to deal with it in the global strategy for the control and elimination of tuberculosis in humans. We believe that this has been neglected in the current strategy and needs to be acknowledged and incorporated, however minimally, in future revisions of the global strategy.

References

1. World Health Organization. 2009. Global tuberculosis control 2009: epidemiology, strategy, finances. WHO/HTM/TB/2009.411. Geneva, Switzerland: WHO.

2. Enarson, D. A., and H. L. Rieder. 1995. The importance of Mycobacterium bovis to the tuberculosis epidemic in humans. In: C. O. Thoen and J. H. Steele, eds. Mycobacterium bovis infection in animals and humans, 1st ed. (pp. xix–xxii). Ames, IA, USA: Iowa State University Press.

3. Zignol, M., M. S. Hosseini, and A. Wright, et al. 2006. Global incidence of multidrug-resistant tuberculosis. J Infect Dis 194:479–485.

4. Tiruviluamala, P., and L. B. Reichman. 2002. Tuberculosis. Annu Rev Public Health 23:403–426.

5. Thoen, C. O., P. LoBue, and I. N. de Kantor. 2006. The importance of Mycobacterium bovis as a zoonosis. Vet Microbiol 112:339–345.

6. de Kantor, I N., and V. Ritacco. 2006. An update on bovine tuberculosis programs in Latin American and Caribbean countries. Vet Microbiol 112:111–118.

7. Thoen, C. O., P. A. LoBue, D. A. Enarson, J. B. Kaneene, and I. N. deKantor. 2009. Tuberculosis: a re-emerging disease in animals and humans. Vet Ital 45:135–181.

8. Cole, S. T., R. Brosch, J. Parkhill, et al. 1998. Deciphering the biology of Mycobacterium tuberculosis from the complete genome sequence. Nature 393:537–544.

9. Brosch, R., S. V. Gordon, M. Marmiesse, et al. 2002. A new evolutionary scenario for the Mycobacterium tuberculosis complex. Proc Natl Acad Sci 99:3684–3689.

10. Olsen, I., R. G. Barletta, and C. O. Thoen. 2010. Mycobacterium. In: C. L. Gyles, J. F. Prescott, J. G. Songer, and C. O. Thoen. Pathogenesis of bacterial infections in animals, 4th ed. (pp. 113–139). Ames, IA, USA: Wiley-Blackwell.

11. Thoen, C. O. 1994. Tuberculosis in wild and domestic mammals. In: B. R. Bloom, ed. Tuberculosis: pathogenesis, protection and control (pp. 157–162). Washington, DC: American Society for Microbiology Press.

12. Francis, J. Tuberculosis in animals and man. 1958. London, UK: Cassell: p. 357.

13. Lomme, J. R., C. O. Thoen, E. M. Himes, J. W. Vincent, and R. E. King. 1976. Mycobacterium tuberculosis: infection in two East African oryxes. J Am Vet Med Assoc 169:912.

14. Schmitt, S. M., D. J. O'Brien, C. S. Bruning-Fann, and S. D. Fitzgerald. 2002. Bovine tuberculosis in Michigan wildlife and livestock. Ann NY Acad Sci 969:262–268.

15. Thoen, C. O. Tuberculosis. 2012. In: J. J. Zimmerman, L. A. Karriker, A. Ramirez, K. J. Schwartz, and G. W. Stevenson, eds. Diseases of swine, 10th ed. (pp. 856–865). Ames, IA, USA: Wiley-Blackwell.

16. Selwyn, P. A., D. Hartel, V. A. Lewis, et al. 1989. A prospective study of the risk of tuberculosis among intravenous drug users with human immunodeficiency virus infection. N Engl J Med 230:545.

17. LoBue, P. Public health significance of M. bovis. In: C. O. Thoen, J. H. Steele, and M. J. Gilsdorf, eds. Mycobacterium bovis infection in animals and humans, 2nd ed. (pp. 6–12). Ames, IA, USA: Blackwell.

18. Evans, J. T., P. Sonnenberg, E. Grace Smith, et al. 2007. Bovine tuberculosis: multiple human-to-human transmission in the UK. Lancet 14:1270–1276.

19. Ashford, D. A., L. Voelker, and J. H. Steele. 2006. Bovine tuberculosis: environmental public health preparedness considerations for the future. In: C. O. Thoen, J. H. Steele, and M. J. Gilsdorf, eds. Mycobacterium bovis infection in animals and humans, 4th ed. (pp. 305– 315). Ames, IA, USA: Blackwell.

20. Moda, G., and M. Valpreda. 1994. Bovine tuberculosis eradication: need of collaboration between physicians and veterinarians. Alpe Adria Microbiol J 3:296–297.

21. Thoen, C. O., D. E. Williams, and T. C. Thoen. 2008. Discovery of streptomycin for treatment of tuberculosis. One Health Newsletter 1:5–6.

Chapter 2

One Health approach for preventing and controlling tuberculosis in animals and humans

John B. Kaneene,¹ Bruce Kaplan,² James H. Steele,³ and Charles O. Thoen ⁴

¹ Michigan State University, USA

² One Health Initiative, USA

³ University of Texas, USA

⁴ Iowa State University, USA

The term One Health, previously referred to as One Medicine in the 20th century, is now used to describe the unified human and veterinary approach to zoonoses [1,2]. Part of the unified human and veterinary medical approach of One Health is a worldwide strategy for expanding coequal, all-inclusive multidisciplinary and interdisciplinary collaborations and communications directed to the development of disease control and prevention programs, as well as biomedical clinical research investigations. Understanding the effects of zoonoses on socioeconomic well-being; addressing social, cultural, and economic conditions that facilitate spread and maintenance of disease; and development of programs with active stakeholder input and participation are critical to the success of One Health [3,4]. In addition, utilization of the One Health approach currently has (and will in the future) expanded the scientific knowledge base, improved medical education and clinical care, and developed effective disease control programs in both human and animal populations, resulting in the protection and saving of untold millions of lives today and in future generations.

History of the One Health approach

Associations between animal and human diseases have been observed in ancient civilizations to the present [5]. Parallels in the progression of disease between humans and domestic animals, and the historic use of animals as sentinels for human disease [6], acknowledge these associations. The evidence of shared risk in humans and animals in recent history include Minamata disease (mercury poisoning in humans and cats), anthrax in livestock and humans, and West Nile virus in humans and animals [6]. Further, studies of human and animal ethnopharmacology have found commonality in the descriptions, symptoms, and treatments for humans and animals in traditional medicine, as well as the fact that many remedies were used to treat both humans and animals [7].

Some of the earliest applications of the concept of associations between human and animal disease were prompted by veterinarians in the United States. Dr. J. Law, a professor of veterinary medicine at Cornell University, advised the U.S. Board of Health on the effects of zoonoses on public health in 1880 [5]. The focus of early proponents of veterinary public health impacting human public health involved hazards of milk from diseased cows in the 1880s, from diseases including tuberculosis (TB), typhoid fever, diphtheria, and brucellosis [5]. Actions to control milk-borne diseases included pasteurization after production and control of bovine TB and brucellosis in cattle through Grade A milk requirements for cattle herd health status [5]. The success of this program has resulted in the near eradication of these diseases as foodborne hazards in the United States.

Acceptance of the One Health approach

In the first decade of the 21st century, the One Health concept was promoted by the veterinary medical community through the American Veterinary Medical Association (AVMA) [5,8], which established a unique One Health collaborative liaison with the American Medical Association (AMA) in 2006. In 2007, the AMA passed a landmark One Health resolution, and the AVMA officially established the One Health Initiative Task Force (OHITF) to develop strategies to enhance collaboration between human and veterinary medical professionals. The OHITF produced a strategic framework for reducing risks of infectious diseases at the human-animal-ecosystem interface, and developed the recommendations that formed the bases of the current One Health Initiative [9]. As a result, the One Health Commission (OHC) was officially chartered in 2009 for the wide spectrum purpose of promoting One Health in the United States and worldwide.

After support of the One Health concept by the AVMA, AMA, U.S. Centers for Disease Control and Prevention (CDC), and the American Society for Microbiology, it has been embraced by the World Health Organization (WHO), the World Organisation for Animal Health (Office International des Epizooties—OIE), the United Nations Food and Agriculture Organization (FAO), UNICEF, the United Nations System Influenza Coordination, and the World Bank. The World Bank has specifically recognized the importance of One Health and its economic benefits [10, 11]. Other major organizations promoting One Health include the U.S. Department of Agriculture (USDA), the U.S. National Environmental Health Association (NEHA), the European Union, the American Academy of Pediatrics, and many others. Recognition of the importance of One Health has also expanded beyond the medical and economic sciences: in the United States, The National League of Cities has formally recognized and supported the work of the OHITF and has acknowledged how the success of the One Health Initiative will rely on leadership, communication skills, and cooperation.

One Health is now being embraced by many different countries to address different zoonotic diseases, and One Health principles are an important part of global health training for medical professionals and in development programs. In a review of the scientific literature describing surveillance programs for emerging zoonosis, a trend toward integrated human-animal surveillance systems was seen and is consistent with One Health principles. Despite awareness of the advantages of the One Health paradigm, however, barriers to implementation in some industrialized countries include absence of evidence, governmental structures, and relatively low degree of suffering.

As the One Health concept has emerged as an approach to dealing with public and veterinary health, the scope of One Health has been expanding to encompass other concepts. Ecosystem Health is an approach that links ecosystem change with human health, and Ecohealth expands on Ecosystem Health to include sociology, which can be viewed as logical extensions of One Health. The One Health–One Medicine concept, while historically incorporating conservation medicine under its umbrella, has also been viewed as an expansion of conservation medicine, whose goal is the pursuit of the health of the ecosystems and the species that live within them [4].

Advantages of the One Health approach

The AVMA One Health Task Force report comprehensively outlined the following advantages to be gained through a One Health approach [8]. By coupling human health, animal health, ecology, sociology, and economics, the One Health approach can: (a) improve animal and human health globally through collaboration among all the health sciences, especially between the veterinary and human medical professions to address critical needs; (b) meet new global challenges head-on through collaboration among multiple professions—veterinary medicine, human medicine, and environmental, wildlife, and public health; (c) develop centers of excellence for education and training in specific areas through enhanced collaboration among colleges and schools of veterinary medicine, human medicine, and public health; and (d) add to the body scientific knowledge to create innovative programs to improve health.

Many professionals consider the One Health approach a critical necessity to managing zoonotic diseases, either existing, emerging, or re-emerging, because One Health deals with the very nature of zoonoses—that the transmission of disease between human and animal species must be addressed at multiple levels, rather than singularly focusing on only humans or only animals. Recognizing that synergistic relationships in human and animal populations can be used for prevention-oriented planning and research will support One Health goals. The emergence of new or old diseases has been linked to changing ecological conditions; deforestation, urbanization, population growth, and climate change create situations where human exposure to new ecosystems with novel pathogens, creating opportunities for zoonotic disease transmission. The One Health approach includes consideration of environmental and ecological factors in the development of effective disease control programs [12,13]. Coordinating human and veterinary medical professionals and institutions through One Health is critical in regions where resources are scarce. Surveillance programs for humans and livestock are often absent or lacking, making it difficult to identify zoonotic disease outbreaks and conduct the risk assessments necessary to formulate effective control programs. In areas where human health services are poor, there has been recognition that zoonoses typically affect populations where veterinary medical services are poor and animals harbor more zoonotic diseases (rural livestock-keeping communities, urban slums), and regional disease surveillance may be more advanced in animals than humans due to efforts by the FAO and OIE.

Combined public health and veterinary ministries, and integrated surveillance programs under a One Health approach will result in efficiency gains that will help reduce costs, improve access to health services, and allow for more cost-effective disease controls in regions with limited resources and where diagnostic and surveillance programs are scarce [11]. Examples of efficiency gains using the One Health approach identified by the World Bank include joint animal-human vaccination campaigns in Chad, dog vaccination and sterilization to reduce human rabies in India, joint public health and veterinary worker farm visits to reduce costs in Kyrgyzstan, and integration of human and animal health facilities to lower operation costs in Canada [11].

Wildlife conservation and ecosystem preservation also benefit from a One Health approach. If these components are included into more holistic approaches to disease control and prevention, stakeholders will be more aware of the negative impacts of potential interventions, and more favorable approaches can be used [4].

The One Health approach can have positive impacts on the economic costs of zoonotic diseases. These economic burdens fall more heavily on developing countries than on the developed world. Epizootics of disease that can be controlled by vaccination have serious consequences for livestock industries, in both upstream (inputs, genetic resources) and downstream (slaughter, processing, marketing) jobs, income, or market access, and also have serious consequences for food security and food safety. Zoonotic diseases also have negative consequences for livestock production: decreased milk production, reduced fertility, slower growth, animal mortality, and losses when the presence of disease restricts the markets for animal products. The indirect costs of zoonoses are often overlooked. The impact of zoonoses in terms of disability-adjusted life-years can be quantified using a One Health approach: a cost-benefit analysis of vaccinating livestock in Mongolia for brucellosis found that the estimated costs for vaccination (US$8.3 million) were exceeded by the overall benefit (US$26.6 million), with an average benefit-cost ratio of 3.2. Economic losses from outbreaks of Nipah virus, West Nile fever, SARS, HPAI, BSE, and RVF from 1997 to 2009 reached at least US$80 billion; prevention would have avoided losses of US$6.7 billion per year [11], and cost-benefit analyses have determined that interventions in animal populations to reduce levels of zoonotic diseases were cost effective: control of the animal diseases was less expensive than the costs of disease in humans [11].

Interdisciplinary One Health research efforts can address gaps in existing information for the purpose of developing control programs that promote the health and well-being of humans, animals, and ecosystems. In addition to advances in laboratory sciences, a common toolbox of protocols for integrated disease surveillance, joint animal/human epidemiological studies, and health services should be developed, using expertise from human and veterinary medicine, social sciences, ecology, economics, and other fields. Systems theory can be used to study these complex systems and identify properties and determinants of health from micro to macro scales [13]. Examples of systems biology models include one of persistent tuberculosis in humans, which could be expanded to include livestock, wildlife, and ecological and sociological drivers as part of a TB control [13].

Using a One Health approach for the control of zoonotic tuberculosis

Zoonotic TB, disease due to bacteria of the Mycobacterium tuberculosis (MTB) complex, is a recognized public and veterinary health problem in developing countries [14,15]. The disease is also recognized as a public health issue in developed countries, but at lower levels due to the effectiveness of bovine tuberculosis (BTB) control programs in livestock and mandated pasteurization of milk [14,15]. Disease caused by M. tuberculosis, M. bovis, and other species of the MTB complex, including M. africanum and M. caprae appear in humans, livestock, and wildlife [15]. Other atypical mycobacteria (not members of MTB complex) have been found in humans and small mammals from farms with BTB-infected cattle in Tanzania. The significance of the public health threats from zoonotic TB resulted in the adoption of a resolution by the OIE in 1983 calling for the eradication of M. bovis for public health and economic reasons, adoption of stringent meat inspection and pasteurization or boiling of milk for human consumption, and continued research into BTB, particularly in improvement of diagnostic tests. Coinfections of BTB with HIV and other diseases are increasing across the globe, and many diseases involved in these complexes are zoonotic high risk for humans [14]. Rates of BTB in HIV-AIDS patients are higher than those in the general population, and the majority of BTB in developed countries are cases of BTB-HIV/AIDS coinfection [14]. Other forms of BTB seen include recrudescent cases in older persons who were infected before BTB control was completed, cases in developed countries that were imported from other regions of the world where BTB control is absent or ineffective, cases associated with consumption of contaminated foods of animal origin, or exposure to tuberculous animals and their carcasses [14]. Workplace exposure to BTB can occur in veterinarians, livestock workers, and slaughterhouse workers. While the majority of BTB cases are zoonotic, there are documented cases of human-to-human transmission of pulmonary BTB.

In the developing world, nonpulmonary human TB is underreported, and often is not a reportable disease. Rates of human M. bovis infection are higher in populations that own or live in areas with higher cattle populations, and living in close proximity to livestock with BTB has been associated with human BTB infection [14]. Studies have also found that herds belonging to households with human cases of TB were more likely to have BTB skin test–positive cattle than herds of households without TB cases in Ethiopia, Niger, Zambia, Sweden, and Denmark [16]. Traditional livestock management practices in developing countries, such as transhumance, communal grazing, or keeping livestock longer due to economic constraints, are associated with increasing risks for BTB in cattle. Controlling BTB in livestock can reduce risks for human infection by decreasing human exposure to M. bovis through livestock [10,11].

Differentiation of mycobacterial species responsible for pulmonary TB is often not pursued. Use of inappropriate diagnostic protocols or laboratory techniques (e.g., using culture media that inhibits M. bovis), or lack of additional testing to identify the species MTB, contributes to underreporting of human BTB. This shortcoming has significant implications for the treatment of zoonotic TB: M. bovis is resistant to pyrazinamide, a drug often used for the treatment of M. tuberculosis infection [14], and the proportion of deaths among BTB patients is higher than among patients with MTB. Determination of species also adds important information needed by epidemiological studies to identify sources of infection and routes of transmission.

One Health integrates human and animal medicine with ecology, sociology, and economics

The interplay between humans, livestock, wildlife, and ecology in the epidemiology of zoonotic diseases, including TB, makes control of the diseases complex and an ideal target for the application of the One Health approach. The importance of ecology and climate to the epidemiology of zoonotic TB has been recognized. The Wildlife Conservation Society includes tuberculosis among its deadly dozen—potentially lethal zoonoses that could spread around the world due to behavioral changes to compensate for the effects of global warming. Overall reductions in health (and immune systems) in humans and livestock due to water and food insecurity can contribute to the spread of zoonotic disease. The geographic distribution of different clonal complexes of BTB (e.g., Africa2, Af2) that infect both livestock and humans suggests that geographically distributed factors (e.g., wildlife habitats, climate, water availability) are integral to the transmission of these clones. Environmental/ecological conditions can promote contact between wildlife and livestock, which can increase transmission of TB at livestock-wildlife interfaces. Ecological change, both natural and anthropogenic, can increase or concentrate wildlife populations, which can promote the spread of BTB or increase competition between wildlife and livestock for water and food. Finally, associations may exist between climate/weather and the ability of mycobacteria to survive outside a host, which would make indirect transmission of tuberculosis between species possible.

Control of livestock BTB in developed countries relies on test-and-cull policies for affected animals. The socioeconomic costs of this approach can be economically impossible for livestock owners in developing countries, resulting in refusals to participate in BTB control programs [14]. In addition, this approach is not effective when wildlife reservoirs of disease are present and capable of reinfecting livestock [14]. However, when levels of BTB in wildlife reservoirs were reduced, or the wildlife reservoir populations were decreased, levels of BTB in livestock or wildlife spillover species were also seen to decline.

Control of BTB in wildlife reservoirs has relied on population reduction through increased hunting, trapping, or poisoning and vaccination, and these strategies have met with mixed success. Efforts to reduce wildlife populations for disease control can be difficult and often are met with public criticism, and vaccination of either the wildlife reservoir or the livestock population is an anticipated alternative to culling. Development of novel approaches to control diseases in livestock and wildlife that are both biologically relevant and acceptable to livestock owners is an important goal of One Health. Ultimately, successful control of BTB in wildlife and livestock will reduce human infection, reduce losses to productivity, and reduce market restrictions from countries where eradication programs are in place.

Culturally appropriate education and active participation of livestock owners and other stakeholders is critical for the success of zoonotic disease control programs. Studies in sub-Saharan Africa found that knowledge about BTB in cattle owners was low: few were aware of the disease and how it was spread, fewer were aware of wildlife reservoirs in the area, and awareness was associated with personal history with BTB and geographic regions. In these instances, the One Health multidisciplinary/interdisciplinary approach, incorporating veterinary medical, ecological, public health, and sociological expertise, can provide useful disease control strategies.

Control programs for zoonotic TB require action at all levels of its epidemiology

The epidemiology of zoonotic TB varies throughout the world, given different human, livestock, and wildlife populations, existing TB control programs, environmental conditions, and the socioeconomic status of countries or regions (developing versus industrial countries). Isolation of both M. bovis and M. tuberculosis from livestock and humans [17], as well as M. caprae in livestock and humans, indicates cycling of M. tuberculosis–complex organisms between livestock and humans. In addition, findings of cattle and goats with M. tuberculosis infection [17] demonstrates that the traditional paradigm of MTB being strictly transmitted from human to human is incorrect, and animal reservoirs must also be included in MTB control and prevention programs.

Milk from infected cattle is one of the most common sources of BTB infection for humans, and many regional cultures and customs (consumption of undercooked animal products, direct contact) support transmission of BTB from animals to humans [14]. In abattoirs in Tanzania, the most common cause for carcass condemnation was BTB (1.2% of all carcasses in one year), highlighting the public health risks to consumers of foods from these animals and to abattoir workers. Other atypical mycobacteria (mycobacteria not in the MTB complex) have been recovered from milk, which poses a significant danger to immunocompromised consumers of raw or unprocessed milk (e.g., persons with HIV).

The ability of BTB and other MTB to infect a wide diversity of animals beyond cattle indicates that more than one host species should be taken into consideration when developing BTB control programs. Outbreaks of BTB have been reported in different livestock species when BTB was transmitted from cattle to small ruminants and swine, and once infection is present, it may become self-sustaining in some cases. Presence of wildlife reservoirs has made BTB eradication difficult in countries where conventional BTB control programs had effectively eliminated the disease from livestock, and makes control of BTB in livestock challenging when complete segregation of livestock and wildlife is problematical.

An important route of infection, particularly between wildlife and domestic animals, is the indirect transmission of mycobacteria by environmental substrates. Studies have demonstrated that wildlife reservoirs are capable of excreting M. bovis capable of serving as a source of infection for other animals, and M. bovis can exist in environmental samples for extended period of time. Experimental studies have demonstrated that M. bovis can be transmitted between white-tailed deer [18] and from white-tailed deer to dairy calves, and studies have found evidence for environmental contamination as a source of infection for cattle.

Wildlife disease detection and surveillance programs are rare, due to difficulties in enumerating and testing free-ranging wildlife populations. In instances where wildlife reservoirs are commonly hunted, surveillance programs have relied on postmortem testing of hunter-harvested wildlife. However, when harvesting wildlife for surveillance is not feasible (e.g., rare or endangered species), programs involve trapping, sampling, and releasing animals to collect samples for immunological tests. Once detected, control programs for wildlife disease, including BTB, can be difficult to implement and maintain, and are often unpopular. While culling infected wildlife is a useful strategy for reducing BTB risk for livestock in many situations, there have been instances where culling has had mixed impacts on livestock BTB. In fact, some critics have suggested that, given the economic costs and unpopularity of BTB control in wildlife reservoirs and the successes of pasteurization and food hygiene, the costs far outweigh the benefits of control programs, and BTB should not be considered a public health issue.

Sharing human and veterinary resources

Sharing resources between public health and veterinary medical scientists takes advantage of existing infrastructure and reduces unnecessary duplication, and also has the shared benefit of increasing interaction between professionals in these disciplines. These interactions will raise awareness in all areas, from medical professionals to governmental agencies and other stakeholders. Combined public health and veterinary laboratory resources will result in efficiency gains that will help reduce costs and improve access to health services, particularly in developing countries where zoonotic TB is an important issue and resources are limited [11].

Training for current and future health sciences workers requires a paradigm shift to the perspective of shared risk between humans and animals. Communications between medical and veterinary medical students are critical and must include crossover education and opportunities for communication and exploration of local priorities and perceived needs. An example of one training program designed to meet these needs is the analytical epidemiology curriculum being developed under a One Health approach to address regional zoonoses, including BTB, in Zambia [19]. Educational efforts should also be expanded to span different disciplines (e.g., ecology, sociology, etc.) to create a cadre of multidisciplinary professionals for One Health programs, and curricula at academic institutions should be designed with the One Health approach in mind. In addition to formal education programs, development of virtual Centers of Expertise for One Health approaches to TB control and research have been proposed. Using these resources, new researchers will be able to contribute to transdisciplinary research on zoonotic TB in a holistic approach, where these researchers will work jointly, using shared conceptual frameworks that integrate the disciplinary-specific concepts, theories, and approaches from their areas of expertise.

Sharing research between disciplines

Research that integrates human and animal health across different disciplines is critical for the success of One Health approaches to disease control.

Several programs that can provide important information to One Health–based TB control are being conducted in sub-Saharan Africa. The Health for Animals and Livelihood Improvement (HALI) program in Tanzania is currently involved in detection of M. bovis in cattle that provide milk for human consumption, and from wildlife sharing water and habitat with infected cattle; sampling water for the presence of M. bovis and other waterborne pathogens and parasites; and identifying possible animal sentinel species for human TB (rats). Another project is the Federation of American Scientists' Animal Health Emerging Animal Diseases (AHEAD), which directs the International Lookout for Infectious Animal Disease (ILIAD) program in South Africa. ILIAD has been designed to develop regional programs to detect and document the extent of infectious diseases shared by wildlife and livestock, and provide disease treatment, prevention, and control programs to increase livestock production, protect the health of wildlife, develop physical and professional resources to sustain the programs, and bring communications and epidemiology information technologies to rural areas. Additionally, the Southern Center for Infectious Disease Surveillance (SACIDS) is conducting research using a One Health approach in the Serengeti National Park, to describe interactions at the human-livestock-wildlife interface to determine how TB is transmitted between these groups [12].

Current diagnostics for human TB are focused on pulmonary disease associated with M. tuberculosis (sputum smears, very few extrapulmonary lesions tested), and requirements for mycobacterial culture for diagnostics are often skipped, resulting in missed diagnoses of M. bovis [14]. Using One Health approaches, particularly in sharing resources, training, and knowledge of laboratory and health care workers should decrease this form of misdiagnosis. Refinement of currently used tests for BTB to improve sensitivity and specificity, particularly those that can be readily used in the field in developing countries, and the development of new tests are goals for TB research. Serological diagnostic tests for human and animal tuberculosis, which measure cell-mediated and humoral immune responses (gamma-interferon assay, ELISA, multiantigen print immuno-assay [MAPIA], immunochromatographic rapid test [ICT or RT], lab-on-a-chip [LOC] devices) are being developed, refined, and tested under field conditions. Microarray analysis to identify specific genetic markers that identify cattle more likely to be false positives on screening tests is being conducted to improve the effectiveness of the screening protocol. Researchers also continue to make improvements to traditional TB tests, including skin testing in cattle.

Improving diagnostic tools for MTB infections is an ongoing goal for research in both human and veterinary medical sciences. For example, molecular techniques (spoligotyping, MIRU-VNTR, IS6110 RFLP, deletion typing, nested PCR) are being developed and refined for use with isolates from both humans and animals. Molecular approaches for detection of mycobacteria are more sensitive, specific, and rapid than traditional mycobacterial culture [17]. These tools are being used to identify circulating strains and species of mycobacteria in given regions and populations, which provides needed data to describe the transmission and molecular diversity of mycobacteria. Molecular techniques are gaining acceptance as a tool for use in outbreak investigations.

Research into novel approaches to the prevention of tuberculosis can be used not only for animal but human disease control and prevention. Current studies into the immunology, diagnostics, and treatment of TB involve research using information gleaned from both humans and animals. Experimental trials are being conducted to determine if drug-assisted protective immunity against M. bovis infection in calves may have application for human BTB control.

The development of effective TB vaccines has been identified as an important goal by the STOP TB partnership and other international TB control agencies. Even though the bulk of vaccine research is directed toward the development of human MTB vaccines, discoveries in human vaccine research can be applied to the development of novel animal vaccines. The TBVAC Consortium has been funded by the European Union, with the goal of development of new vaccines against TB. These efforts include interdisciplinary research involving identification of new antigens, testing in animal models, new delivery systems, and adjuvants. Recently, efforts to develop DNA vaccines for TB that induce cellular immunity against TB have been successfully tested in animal models. The Gates Foundation has funded a study of biomarkers for TB in Africa through their Grand Challenges: the goal of this study is to longitudinally follow cohorts in seven different sites to identify biomarkers for the development TB or for protection from TB. To date, investigators have detected differences in human immune responses in different populations (Malawi vs. UK), demonstrating the impact of environment on immune response, and are currently studying the effects of helminth coinfection on immunity against TB and other diseases.

Vaccination of livestock and wildlife for BTB control has been investigated in developing countries and in countries with wildlife reservoirs of BTB [14,20]. In some instances, vaccination does not prevent infection but reduces the burden of disease in the vaccinated wildlife. With ongoing research to develop better vaccines and delivery methods, vaccination has been recognized as a future option for control of BTB control between wildlife and livestock. In addition to efficacy studies, there are concerns that vaccination may confound screening tests for BTB. Cattle exposed to BCG (bacillus Calmette-Guérin, an attenuated strain of M. bovis used for vaccination) will be false positive through skin testing, and concerns have been raised that vaccinated wildlife may transmit BCG to livestock [21] and hunters may be exposed to BCG from vaccinated deer. However, current studies have demonstrated that, while BCG is shed from vaccinated wildlife, the risk of transmitting BCG from wildlife to livestock or humans is considered to be low.

Research is also ongoing in the development of vaccines and vaccine delivery systems for use in cattle and wildlife reservoirs of BTB, which will be critical in situations where conventional test-and-slaughter control programs are not practical, and where it is impossible to segregate wildlife reservoirs from livestock or when slaughter of infected wildlife is socially controversial. Vaccination can reduce the impact of BTB on wildlife populations [20,22], particularly where threatened or endangered species (e.g., lions and cheetahs in South Africa, Iberian lynx in Spain) are susceptible.

Improved efficiency of TB surveillance, diagnosis, and control programs

Improved diagnostic tests, better wildlife and transboundary surveillance programs, application of control measures to livestock and wildlife, and additional research into the role of different wildlife species and the role of ecosystem environments on the transmission of BTB are necessary to develop comprehensive zoonotic TB control programs. The transboundary nature of zoonotic TB automatically expands the scope of surveillance and control programs: in sub-Saharan Africa, wildlife reservoirs, livestock, and pastoralists constantly traverse large geographic areas, providing opportunities to both acquire and transport zoonotic diseases as they move across borders.

Early detection, a cornerstone of One Health approach to zoonoses control, of BTB in both human and animal populations is critical to control of the disease in all populations. Simultaneous surveillance of human and animal populations, which would reduce detection time, is an emerging strategy in zoonotic disease surveillance, and the integration of human and animal surveillance and prevention programs has been strongly recommended for BTB [14].

Collaborative efforts between public health, agriculture, and wildlife professionals, with support from the public, are critical to the control of BTB. Lack of stakeholder support can seriously reduce the effectiveness of BTB control programs, as seen in the control of BTB in wild white-tailed deer in Michigan and Minnesota. Control programs have successfully reduced BTB levels in wild deer in Minnesota with public acceptance and support, while lack of cooperation with farmers and hunters in Michigan has made control programs more difficult to maintain.

Conclusions

In summary, the One Health approach offers many advantages in controlling disease. These include (a) efficiency as a result of shared surveillance programs, laboratory facilities, training of personnel, and research; (b) potentially positive impacts on the disease in livestock, wildlife, and humans; and (c) the opportunity to involve transdisciplinary teams of professionals in biomedical sciences, social sciences, and ecological sciences. Given the complex nature of the epidemiology of zoonotic TB and the influences of sociological, economic, and ecological factors, One Health provides an excellent economical approach for conducting research and developing effective disease control and prevention programs for zoonotic tuberculosis.

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Chapter 3

Public health significance of zoonotic tuberculosis caused by the Mycobacterium tuberculosis complex

Adam J. Langer and Philip A. LoBue

Centers for Disease Control and Prevention, USA

Introduction

Numerous members of the genus Mycobacterium can cause disease in animals and humans manifested by inflammation, formation of granulomas, and subsequent tissue destruction caused both by the pathogen and by the infected individual's immune response to infection. In humans, the term tuberculosis is strictly limited to disease caused by species of the Mycobacterium tuberculosis complex (MTC). In animals, tuberculosis may be defined more broadly to include disease caused by Mycobacterium avium complex (MAC). For example, MAC disease in birds is referred to as avian tuberculosis. While MAC causes disease in humans, it is often associated with concurrent illness that results in immunocompromise or impaired pulmonary function, and MAC infections in humans are not considered to be cases of tuberculosis. Mycobacteria outside of these two complexes, while still opportunistic pathogens of humans and animals, are generally not considered to cause tuberculosis. From the human public health perspective, one of the key distinguishing features between disease caused by MTC (i.e., tuberculosis) and disease caused by nontuberculous mycobacteria (NTM) is that MTC are transmitted from person to person (and sometimes from animal to person and vice versa) via the airborne route. The route by which susceptible humans become infected by NTM is not completely understood, but it appears to be from environmental exposure as these organisms are ubiquitous in the water and soil. Therefore, the discussion of zoonotic tuberculosis in this chapter will be restricted to the disease caused by infection with one or more members of the MTC.

MTC is composed of seven or eight currently recognized species, depending on whether M. caprae is considered a separate species or a subspecies of M. bovis (a point of some debate among taxonomists). In this chapter, M. caprae will be treated as a subspecies of M. bovis. The MTC species are believed to have evolved through host adaptation from a common ancestral species of M. tuberculosis (Figure 3.1). Table 3.1 shows that three of the seven MTC species are primarily pathogens of humans, while the remainder are adapted to various animal species. However, the fact that member species of MTC are host-adapted to particular species does not preclude infection of one host species with MTC from a reservoir in another species.

c03f001

Figure 3.1 Scheme of the proposed evolutionary pathway of the tubercle bacilli illustrating successive loss of DNA in certain lineages (shaded boxes). From: Brosch, R., et al. PNAS 2002; 99:3684–3689. Copyright (2002) National Academy of Sciences, U.S.A., used with permission.

Table 3.1 Species of Mycobacterium tuberculosis complex by primary host species.

Tuberculosis in humans generally occurs after inhalation of MTC (estimated 99% M. tuberculosis) that were expelled (usually via coughing) into the air by another person with active disease. Once inhaled, MTC may establish infection, usually in the lower lobes of the lung. However, based on microbial and initial host defense factors, only up to 30% of household contacts to a person with tuberculosis become infected. MTC are ingested by alveolar macrophages, which attempt to contain and kill the bacteria [1]. The macrophages also act as antigen presenting cells for lymphocytes that subsequently trigger and control the host cell–mediated immune response. Shortly after infection, MTC can disseminate, initially to the thoracic lymph nodes (possibly carried by macrophages) and then hematogenously to organs and tissues throughout the body. In most persons (>95%), the infection is contained by lymphocytes and macrophages that form granulomas at the sites of infection [1]. Once control of the infection is established, MTC enter a semidormant state referred to as latent tuberculosis infection (LTBI). Usually the only indication of LTBI is a positive tuberculin skin test or interferon-gamma release assay. The infected person is asymptomatic, and in most cases the chest radiograph is normal. Only 5%–10% of persons with intact immune function and LTBI will progress to active tuberculosis disease, which is known as reactivation tuberculosis [2]. About half of reactivation occurs within 2 years of infection. The reactivation rate is substantially higher in immunocompromised persons (e.g., HIV infection, treatment with immunosuppressive drugs) [2]. Progression from LTBI to active tuberculosis disease can be prevented by treatment with isoniazid and rifamycins, alone or in combination [2]. If immune control of the infection is lost,