3. Clinical presentation

#### 3.1. In animals

Bovine TB is a chronic debilitating disease usually characterized by formation of nodular granulomas known as tubercles. In many animals the course of the infection is chronic and signs may be absent, even in advanced cases when many organs may be involved. Subclinical signs include weakness, dyspnea, anorexia, emaciation, enlargement of lymph nodes, and cough, particularly with advanced tuberculosis. Lesions are commonly observed in the lymph nodes mainly of the head and thorax, lungs, intestines, liver, spleen, pleura, and peritoneum. Head and neck lymph nodes may become visibly affected, sometimes rupture, drain, and in advanced cases may be greatly enlarged and may obstruct air passages, alimentary tract, or blood vessels. Clinical signs vary with the involvement of the lung manifested through cough, dyspnea, and other signs of low-grade pneumonia which can be induced by changes in temperature or manual pressure on the trachea. Digestive tract involvement is manifested by intermittent diarrhea or constipation, extreme emaciation, and acute respiratory distress may occur during the terminal stages of tuberculosis [26].

#### 3.2. In humans

increase the rate of transmission [28]. Other factors like long survival periods of the organism in the environment also contribute to an increased risk of infection [29, 30]. Suckling calves can get the infection through consumption of infected milk. The infected bull semen may transmit

Humans acquire the M. bovis infection from cattle directly by erogenous route or through the direct contact with material contaminated with the secretions of an infected animal or the herd [31, 32]. The individuals at risk are farm workers, zookeepers, milkers, animal dealers, veterinarians, abattoir workers, meat inspectors, autopsy personnel, laboratory personnel, and owners of potential tuberculous pets [33–35]. People in these occupations may develop pulmonary tuberculosis from M. bovis and in turn put other humans and susceptible animals at risk [36, 37]. Indirectly, man acquires the disease from animal sources by consumption of unpasteurized infected milk and ingestion of meat and meat products from slaughtered infected cattle [13, 38–41]. Therefore tuberculosis can be foodborne also [42]. The consumption of contaminated milk products possesses more risks than infected meat products because badly infected carcasses are mostly condemned and meat is generally thoroughly cooked [43]. People suffering from M. bovis tuberculosis can retransmit the infection to cattle; however,

Zoonotic TB is distributed globally and is more prevalent in most of Africa, parts of Asia and of the Americas except Antarctica, Caribbean islands, parts of South America and Australia, Iceland, Denmark, Sweden, Norway, Finland, Austria, Switzerland, Luxembourg, Latvia, Slovakia, Lithuania, Estonia, the Czech Republic, Canada, Singapore, Jamaica, Barbados, and Israel [45]. Although most of the developed countries have reduced or eliminated bovine TB from their cattle population, however, the disease is still present in the wildlife of United Kingdom, Canada, the United States, and New Zealand [23]. Eradication programs are in progress in other European countries, Japan, New Zealand, the United States, Mexico, and some countries of Central and South America where it has been eradicated by following strict

Bovine TB is a chronic debilitating disease usually characterized by formation of nodular granulomas known as tubercles. In many animals the course of the infection is chronic and signs may be absent, even in advanced cases when many organs may be involved. Subclinical signs include weakness, dyspnea, anorexia, emaciation, enlargement of lymph nodes, and cough, particularly with advanced tuberculosis. Lesions are commonly observed in the lymph nodes mainly of the head and thorax, lungs, intestines, liver, spleen, pleura, and peritoneum. Head and neck lymph nodes may become visibly affected, sometimes rupture, drain, and in advanced cases may be greatly enlarged and may obstruct air passages, alimentary tract, or

diseases through artificial insemination [18].

26 Basic Biology and Applications of Actinobacteria

this is not common [44].

2.4. Geographic distribution

test-and-slaughter policies [46].

3. Clinical presentation

3.1. In animals

M. bovis infection in humans has similar clinical forms as those caused by M. tuberculosis [27, 34, 44]. Most of the studies have suggested that the common clinical manifestation of M. bovis infection in man is associated with the extra-pulmonary form of the disease; however, about half of the post-primary cases involve the lung which is responsible for human-tohuman transmission of tuberculosis due to M. bovis [13, 31, 44, 47]. The primary infection of the organism in the intestine may heal or it may progress in the intestines or disseminate to other organs [48]. Cervical lymphadenopathy, intestinal lesions, chronic skin tuberculosis, and other non-pulmonary forms are particularly common [13]. Infection due to M bovis in humans usually has a prolonged course and symptoms generally takes months or years to appear. Sometimes, the bacteria remain dormant in the host without causing diseases [23]. The common clinical signs of zoonotic TB include loss of appetite, diarrhea, weight loss, intermittent fever, intermittent hacking cough, large prominent lymph nodes, weakness, and so on.

Young children infected with M. bovis typically have abdominal infections and older patients suffer from swollen and sometimes ulcerated lymph glands in the neck [49]. Pulmonary disease is more common in people with reactivated infections [50] and this would occur only when some of the animals had active tuberculosis [32]. The symptoms may include fever, cough, chest pain, cavitation, and hemoptysis [50]. The pulmonary form of tuberculosis occurs less frequently and is usually occupationally related [44].

## 4. Zoonotic TB: a concern

Bovine TB affects the national and international economy in different ways. It is extremely difficult to determine the economic impact of bovine TB on livestock production. The presence of bovine TB infection in livestock reduces the livestock productivity and economically devastates the cattle industry especially the dairy sector. Some losses are related to the animal production, marketing, or trading of the animals as well as the cost involvement while implementing surveillance and control programs. These losses are also extremely important when endangered wildlife species get involved [51, 52]. The direct productivity losses due to bovine TB can be categorized into "on-farm" losses and losses after the slaughtering of animals. On-farm losses consist of the losses from decreased milk and meat production, the increased reproduction efforts, and replacement costs for infected cattle while losses during slaughter consist of the cost of cattle condemnation and retention, with the loss from condemnation being essentially the purchased value of a slaughter animal and the loss [51]. Along with the direct productivity losses, bovine TB has profound economic consequences on international trade; it affects access to foreign markets due to import bans on animals and animal products 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 unpredictable impacts in many areas of private interest, for example, tourism [51].

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

Zoonotic Tuberculosis: A Concern and Strategies to Combat

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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

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

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].

on tuberculin skin testing were favored above BCG vaccination in many countries [67].

indirect ELISA, which detects antibody responses.

countries lack the capacity to routinely conduct these tests.

6. Treatment

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 laboratory capacity is limited [60].

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

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