5. Diagnosis

Bovine tuberculosis in the live animal is usually diagnosed on the basis of the standard method for the detection of bovine tuberculosis, that is, delayed hypersensitivity reactions. It is done by injecting bovine tuberculin intradermally into the measured area, measuring subsequent swelling at the site of injection after 72 h and measuring skin thickness. Now, purified protein derivative (PPD) products have been replaced by the heat-concentrated synthetic medium tuberculins due to their higher specificity and easier standardization. The identification of the pathogenic agent is done by the demonstration of acid-fast bacilli by microscopic examination. The Mycobacterial isolation on selective culture media and biochemical tests or DNA techniques, such as PCR, confirms infection. A gold standard for routine confirmation of infection is Mycobacterial culture method. Animal inoculation is rarely used because of animal welfare considerations. A number of blood tests are also been used for the identification of M. bovis [63]. These can be advantageous, especially with intractable cattle, zoo animals, and wildlife [64]. Blood-based laboratory tests now available are gamma-interferon assay, which uses an enzyme-linked immunosorbent assay (ELISA) as the detection method for interferon [65], the lymphocyte proliferation assay, which detects cell-mediated immune responses [66], and the indirect ELISA, which detects antibody responses.

Diagnosis of active TB in people in many parts of the world is based on the sputum smear examination or some rapid assays like Xpert MTB/RIF. But these commonly used tests are not able to differentiate the M. tuberculosis complex into the distinct species of M. tuberculosis and M. bovis; therefore, most cases of zoonotic TB are misclassified. The identification of M. bovis can be done by PCR and gene sequencing of culture isolates, but for these tests the proper collection of samples is very essential as zoonotic TB is extra-pulmonary. However, most of the countries lack the capacity to routinely conduct these tests.

### 6. Treatment

from countries where the disease is enzootic. The presence of the disease in wildlife is not only difficult to eradicate and costly but also bovine TB can theoretically affect entire ecosystems with

In 2016, WHO estimated 147,000 new human cases of zoonotic TB in people and around 12,500 deaths due to the disease. The implications of zoonotic TB extend beyond human health. Bovine TB threatens the well-being of communities that rely on livestock for their livelihoods. The African region carries the heaviest burden of disease and death due to zoonotic TB, followed by the Southeast Asian region. However, cases of zoonotic TB in people are uncommon in countries where bovine TB in cattle is controlled and where standards of food safety are high. The true burden of zoonotic TB is likely to be underestimated due to a lack of routine surveillance data from most countries. Therefore, the number of people affected by zoonotic TB annually, and thus suffering from health challenges caused by M. bovis infection, might be higher than currently estimated in particular, countries where bovine TB is endemic and where

Current diagnostics for human TB are focused on pulmonary diseases associated with M. tuberculosis (sputum smears examination) but zoonotic tuberculosis in human beings is frequently associated with extra-pulmonary tuberculosis and therefore initiation of treatment can be delayed [53, 54]. There is lack of testing to identify the Mycobacterium spp.; very few extrapulmonary lesions are being tested, and requirements for mycobacterial culture for diagnostics are often skipped which contribute to under-reporting of human bovine TB cases [55–58]. Determination of species can add important information needed by epidemiological studies

A major challenge in the case of effective treatment and recovery of a patient infected with zoonotic TB is the natural resistance of M. bovis to pyrazinamide, one of the four essential medications used in the standard first-line anti-TB treatment regimen [61]. Most of the healthcare providers initiate the treatment without drug susceptibility testing due to which patients with zoonotic TB may receive inadequate treatment. This may lead to development of resistance to other anti-TB drugs. Resistance to additional drugs has also been reported in some M. bovis isolates, including rifampicin and isoniazid, and resistance to these two essential first-line drugs is defined as a multidrug-resistant TB, which is a major threat to human health globally. Such a shortcoming has significant implications for the treatment of zoonotic TB. Because most patients worldwide begin tuberculosis treatment without identification of the causative mycobacterium species, the risk of inadequate treatment of patients with undiagnosed M. bovis who

Bovine tuberculosis in the live animal is usually diagnosed on the basis of the standard method for the detection of bovine tuberculosis, that is, delayed hypersensitivity reactions. It is done by injecting bovine tuberculin intradermally into the measured area, measuring subsequent swelling at the site of injection after 72 h and measuring skin thickness. Now, purified protein

to identify sources of infection and routes of transmission [57, 59, 60].

do not have drug susceptibility testing is increased [62].

5. Diagnosis

unpredictable impacts in many areas of private interest, for example, tourism [51].

laboratory capacity is limited [60].

28 Basic Biology and Applications of Actinobacteria

The treatment of animals with tuberculosis is not a favored option in eradication-conscious countries and is not economical. The Bacillus Calmette and Guérin (BCG) vaccine has advantages for use in cattle since the vaccine is safe, inexpensive, and is commercially produced for human application. However, the vaccination of animals with BCG is sensitive to the tuberculin skin test, and animals become test positive in the classical skin test at least for a significant period of post-vaccination. This is the reason why the test-and-slaughter-based control strategies based on tuberculin skin testing were favored above BCG vaccination in many countries [67].

In human tuberculosis, drugs like isoniazid, combinations of streptomycin and para-aminosalicylic, and other acids are commonly used. Long-term therapy requirement of the disease can create the chances of the development of multidrug-resistant (MDR), extremely drug resistant (XDR), and even totally drug resistant (TDR) bacterial strains if treatment regime is not properly followed. BCG vaccine is the only TB vaccine licensed for use in humans. BCG vaccine has variable levels of protection efficacy in humans against pulmonary TB in children and adults, ranging from 0–80% [68]. It is reported that the prevalence of MDR-TB in previously treated cases was 13.9% and in new cases only 2.3%, whereas the overall prevalence of MDR-TB was 5.7% in all cases [69]. Thus, previously treated cases were more vulnerable for being infected by the MDR-TB strain. Therefore, enhanced TB infection control activities, earliest case detection and treatment, strengthening and proper implementation of directly observed treatment, short course (DOTS), are suggested to reduce the burden of MDR-TB [69]. In human medicine, the treatment policy is based on second-line drug susceptibility testing. Most drug regimens currently used to treat MDR-TB include an aminoglycoside (e.g., streptomycin, kanamycin, amikacin) or capreomycin and a fluoroquinolone. The patients' MDR-TB should be managed by or in consultation with physicians experienced in the management of MDR-TB. The internationally recommended highly efficient and cost-effective strategy for TB control is DOTS (directly observed treatment short course). In this strategy, a healthcare worker at a healthcare center or family DOTS supporter at home gives the standard regimen to all MDR-TB confirmed cases daily under direct observation [70]. The regimens consist of the four drugs which are expected to be effective and the duration is a minimum of 18 months. Furthermore, continuous monitoring and capacity building for family DOTS supporters are essential components of the DOTS strategy. Effective treatments of drug susceptible to TB cure the patient, interrupt the TB transmission to other persons, and also prevent the development of drug-resistant strains.

the development of a vaccine against all forms of TB. But improved surveillance and data quality will be unsuccessful without strengthened laboratory capacity and better access to appropriate diagnostic tools. Coordination and communication across the sectors is critical for investigating disease epidemiology at the human, livestock, and wildlife interface, including the relative importance of direct and indirect routes of transmission in different populations. Sharing the information within different sectors allows for the identification of patients in a particular geographical area which facilitates a target response for the prevention and control of the disease. To interpret multi-species data there is a need for new methodologies for describing multi-species transmission, such as modeling approaches incorporating genetic data. The biological differences in the host-pathogen interaction of M. tuberculosis versus M. bovis in humans

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Transmission of zoonotic TB at the animal-human interface can be reduced by developing strategies to improve animal health, identifying the pathways for risk and improving food safety. Healthier animal food supply depends on healthier animal population. For the diseasefree state of the animal, both government and private veterinary services must be well organized and should be armed with the tools which can detect disease and reduce the disease prevalence. Developed countries can follow the test-and-slaughter programs by giving compensation to the farmers, post-mortem examinations of the carcass, and can trace-back the herds with appropriate tools to identify and implement control strategies. Similarly, in developing countries, a first step could be a target herd to be disease free in a particular zone of a country and this could gradually expand to other herds and zones. While doing this one must ensure the control of livestock movements from endemic areas to disease-free areas. The disease in a people can be prevented by reducing the risk of exposure and transmission of the infectious agent from animals to humans. Along with the knowledge of the principal routes of transmission some other factors such as sociocultural and economic factors should also be taken into the consideration. The use of modern technologies like sequencing, metagenomics, and phylogenetic analyses helps in characterization of sources of infection, mechanism of transmission, and investigation of drug resistance. Food safety practices can be improved by pasteurization of milk and sanitary inspection of carcasses at abattoirs which lead to removal the contaminated animal products from the food chain and also help in the tracing back

Intersectoral collaboration can be achieved by adopting a "One Health" approach which suggests an intersectoral and multidisciplinary approach by engaging both public and private stakeholders. The most relevant sectors include human health sector, veterinary health sector, wildlife authorities, food safety authorities, farming and trade organizations, consumer groups, educational bodies, and financial institutions. Within these sectors, collaborative relationships among farmers, healthcare providers, veterinarians, laboratory experts, epidemiologists, sociologists, economists, wildlife conservationists, and communication specialists must exist. "One Health" approach also addresses that all relevant sectors should work together for developing legislation and policies, designing, and implementing control strategies. Interventions which jointly address human and animal health can increase health and economic benefits for communities, for example, sharing of human resources, equipment, and transport

across sectors can reduce operational costs which increase cost-effectiveness.

should be further investigated.

animals to herds of origin.

#### 7. Strategies to combat

The epidemiology of zoonotic TB varies throughout the world, depending on the human, livestock, and wildlife populations, and on existing TB control programs, environmental conditions, and the socio-economic status of countries or regions [71]. The relationship between humans, livestock, wildlife, and ecology in the epidemiology of zoonotic TB makes control of the diseases complex [72, 73]. Zoonotic TB is not a new disease but has long been neglected; burden of this disease in humans cannot be fully addressed without considering the animal reservoir and the risk of transmission at the animal-human interface. As with other zoonotic diseases, zoonotic TB cannot be controlled by the human or animal health sector alone. Human, animal health, and food safety sectors must be engaged to address the role of animals in maintaining and transmitting M. bovis. Therefore, "One Health" linking human, animal, and environmental health sector of World Health Organization (WHO), the Food and Agricultural Organization of the (FAO), and the World Organization for Animal Health (OIE) together with the International Union against Tuberculosis and Lung launched a comprehensive roadmap for zoonotic TB in people and bovine TB in animals in October 2017. The roadmap is on the basis of "One Health" approach and is centered under three core themes which consist of improvement of scientific evidence base, reduction in disease transmission at the animal-human interface, and strengthening the intersectoral collaboration.

An improvement in the scientific evidence base can be achieved by collecting, analyzing, and recording and a better quality data of the disease, by improving surveillance and reporting bovine TB in humans, livestock, and wildlife. For the better documentation and to generate accurate representative data which can differentiate M. bovis and M. tuberculosis infections, countries should strive to incorporate zoonotic TB into their routine surveillance activities. A better detection of cases requires health-care provider expertise and strengthened laboratories having improved access to accurate, rapid diagnostic tools coupled with reliable recording and reporting systems, that are case based and preferably electronic. Data regarding consequences of infectiousness, transmission, clinical presentation, and immunologic responses are important for the development of a vaccine against all forms of TB. But improved surveillance and data quality will be unsuccessful without strengthened laboratory capacity and better access to appropriate diagnostic tools. Coordination and communication across the sectors is critical for investigating disease epidemiology at the human, livestock, and wildlife interface, including the relative importance of direct and indirect routes of transmission in different populations. Sharing the information within different sectors allows for the identification of patients in a particular geographical area which facilitates a target response for the prevention and control of the disease. To interpret multi-species data there is a need for new methodologies for describing multi-species transmission, such as modeling approaches incorporating genetic data. The biological differences in the host-pathogen interaction of M. tuberculosis versus M. bovis in humans should be further investigated.

In human medicine, the treatment policy is based on second-line drug susceptibility testing. Most drug regimens currently used to treat MDR-TB include an aminoglycoside (e.g., streptomycin, kanamycin, amikacin) or capreomycin and a fluoroquinolone. The patients' MDR-TB should be managed by or in consultation with physicians experienced in the management of MDR-TB. The internationally recommended highly efficient and cost-effective strategy for TB control is DOTS (directly observed treatment short course). In this strategy, a healthcare worker at a healthcare center or family DOTS supporter at home gives the standard regimen to all MDR-TB confirmed cases daily under direct observation [70]. The regimens consist of the four drugs which are expected to be effective and the duration is a minimum of 18 months. Furthermore, continuous monitoring and capacity building for family DOTS supporters are essential components of the DOTS strategy. Effective treatments of drug susceptible to TB cure the patient, interrupt the TB transmission to other persons, and also prevent the development of

The epidemiology of zoonotic TB varies throughout the world, depending on the human, livestock, and wildlife populations, and on existing TB control programs, environmental conditions, and the socio-economic status of countries or regions [71]. The relationship between humans, livestock, wildlife, and ecology in the epidemiology of zoonotic TB makes control of the diseases complex [72, 73]. Zoonotic TB is not a new disease but has long been neglected; burden of this disease in humans cannot be fully addressed without considering the animal reservoir and the risk of transmission at the animal-human interface. As with other zoonotic diseases, zoonotic TB cannot be controlled by the human or animal health sector alone. Human, animal health, and food safety sectors must be engaged to address the role of animals in maintaining and transmitting M. bovis. Therefore, "One Health" linking human, animal, and environmental health sector of World Health Organization (WHO), the Food and Agricultural Organization of the (FAO), and the World Organization for Animal Health (OIE) together with the International Union against Tuberculosis and Lung launched a comprehensive roadmap for zoonotic TB in people and bovine TB in animals in October 2017. The roadmap is on the basis of "One Health" approach and is centered under three core themes which consist of improvement of scientific evidence base, reduction in disease transmission at

the animal-human interface, and strengthening the intersectoral collaboration.

An improvement in the scientific evidence base can be achieved by collecting, analyzing, and recording and a better quality data of the disease, by improving surveillance and reporting bovine TB in humans, livestock, and wildlife. For the better documentation and to generate accurate representative data which can differentiate M. bovis and M. tuberculosis infections, countries should strive to incorporate zoonotic TB into their routine surveillance activities. A better detection of cases requires health-care provider expertise and strengthened laboratories having improved access to accurate, rapid diagnostic tools coupled with reliable recording and reporting systems, that are case based and preferably electronic. Data regarding consequences of infectiousness, transmission, clinical presentation, and immunologic responses are important for

drug-resistant strains.

7. Strategies to combat

30 Basic Biology and Applications of Actinobacteria

Transmission of zoonotic TB at the animal-human interface can be reduced by developing strategies to improve animal health, identifying the pathways for risk and improving food safety. Healthier animal food supply depends on healthier animal population. For the diseasefree state of the animal, both government and private veterinary services must be well organized and should be armed with the tools which can detect disease and reduce the disease prevalence. Developed countries can follow the test-and-slaughter programs by giving compensation to the farmers, post-mortem examinations of the carcass, and can trace-back the herds with appropriate tools to identify and implement control strategies. Similarly, in developing countries, a first step could be a target herd to be disease free in a particular zone of a country and this could gradually expand to other herds and zones. While doing this one must ensure the control of livestock movements from endemic areas to disease-free areas. The disease in a people can be prevented by reducing the risk of exposure and transmission of the infectious agent from animals to humans. Along with the knowledge of the principal routes of transmission some other factors such as sociocultural and economic factors should also be taken into the consideration. The use of modern technologies like sequencing, metagenomics, and phylogenetic analyses helps in characterization of sources of infection, mechanism of transmission, and investigation of drug resistance. Food safety practices can be improved by pasteurization of milk and sanitary inspection of carcasses at abattoirs which lead to removal the contaminated animal products from the food chain and also help in the tracing back animals to herds of origin.

Intersectoral collaboration can be achieved by adopting a "One Health" approach which suggests an intersectoral and multidisciplinary approach by engaging both public and private stakeholders. The most relevant sectors include human health sector, veterinary health sector, wildlife authorities, food safety authorities, farming and trade organizations, consumer groups, educational bodies, and financial institutions. Within these sectors, collaborative relationships among farmers, healthcare providers, veterinarians, laboratory experts, epidemiologists, sociologists, economists, wildlife conservationists, and communication specialists must exist. "One Health" approach also addresses that all relevant sectors should work together for developing legislation and policies, designing, and implementing control strategies. Interventions which jointly address human and animal health can increase health and economic benefits for communities, for example, sharing of human resources, equipment, and transport across sectors can reduce operational costs which increase cost-effectiveness.

Disease eradication programs consist of intensive surveillance which includes farm visits, systematic testing of individual cattle, and removal of infected animals along with the segregation of animals in contact with the infected one similarly in control of animal movement. The identification of infected animals or infected carcass prevents unsafe meat from entering the food chain and allows veterinary services trace back to the infected herd. Pasteurization of milk and meat inspection system should be strengthened and designed to prevent the consumption of contaminated products by people. Vaccine is used in human medicine, but it is not widely used as a preventive measure in animals because its efficacy is variable and it can interfere with testing to eliminate the disease. Thus, the establishment of new TB drugs which can be effective within a short term and capable of controlling the emergence of MDR-TB and XDR-TB is critically urgent.

development program should be taken into account for possible application of vaccines to the animals, particularly in developing countries. Disease surveillance programs especially in areas

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where risk factors are present in animals and humans should be considered as a priority.

Ravi N. Teppawar, Sandeep P. Chaudhari\*, Shilpa L. Moon, Shilpshri V. Shinde,

Maharashtra Animal and Fishery Sciences University, Nagpur, Maharashtra, India

Centre for Zoonoses, Department of Veterinary Public Health, Nagpur Veterinary College,

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Author details

References

Wiqar A. Khan and Archana R. Patil

\*Address all correspondence to: vphsandeep@gmail.com
