International Common Names

• English: avian tuberculosis; avian tuberculosis, mycobacterium infection; bovine tuberculosis; bovine tuberculosis, mycobacterium in cattle; caprine tuberculosis; caprine tuberculosis, mycobacterium in goats; mycobacteriosis; ovine tuberculosis; ovine tuberculosis, mycobacterium in sheep; porcine tuberculosis; porcine tuberculosis, mycobacterium in pigs; tuberculosis-associated focal necrotizing encephalitis in cattle; white plague

English acronym

• TB

Mycobacterium africanum
Mycobacterium bovis
Mycobacterium caprae
Mycobacterium microti
Mycobacterium orygis
Mycobacterium pinnipedii
Mycobacterium tuberculosis

Tuberculosis (TB) is an infectious disease caused by specific slow-growing species of bacteria of the Mycobacterium genus. TB can affect nearly all species of vertebrate animals. Mycobacterium tuberculosis causes most cases of TB in humans. Despite the availability of effective anti-TB agents for decades, TB continues to be the leading cause of human death from infectious pathogens, claiming an estimated 1.5 million lives worldwide in 2018 (World Health Organization, 2019). M. tuberculosis belongs to a closely related cluster of mycobacterial species known as the M. tuberculosis complex (MTBC) that at the time of writing includes Mycobacterium bovis (Karlson and Lessel, 1970), the Bacillus Calmette-Guérin (BCG) vaccine strain (World Health Organization, 2018a), derived from Mycobacterium bovis, Mycobacterium africanum (Castets et al., 1968), Mycobacterium canettii (van Soolingen et al., 1997), Mycobacterium microti (Wells, 1937), Mycobacterium caprae (Aranaz et al., 1999), Mycobacterium pinnipedii (Cousins et al., 2003), Dassie bacillus (Smith, 1960), and the most recent additions to the complex: Mycobacterium mungi (Alexander et al., 2010); Mycobacterium orygis (van Ingen et al., 2012); Mycobacterium suricattae (Parsons et al., 2013); and a novel isolate from a wild chimpanzee (Coscolla et al., 2013). Except for M. bovis that causes TB in a variety of domesticated, sylvatic and companion animal species, as well as humans, the other members of the MTBC are generally considered to be host-adapted pathogens. Additional members of the MTBC may exist but have yet to be isolated and characterised. M. bovis is a zoonosis, considered now by the World Health Organisation (WHO) to be a priority disease to tackle (World Health Organization (WHO), Food and Agriculture Organization of the United Nations (FAO), and World Organisation for Animal Health (OIE), 2017).

TB generally affects the lungs but can also affect other parts of the body, depending on the host species and route of infection. The disease is usually chronic and slow-progressing, although it can occasionally assume an acute, rapidly progressive course especially in immunocompromised hosts (Inglis and Weipers, 1963; Thoen and Waite, 1990). The host response to infection seeks to contain the bacilli within a hallmark lesion known as a granuloma; a dynamic accumulation of macrophages, plasma cells, neutrophils and lymphocytes drawn to the site of infection. The granuloma may contain the infection without overt signs of disease in a form known as latent TB, or fail to do so, leading to multiplication and dissemination of the bacilli (active disease), either within the host or to other susceptible individuals. TB may remain latent in an individual lifelong or reactivate when the immune system is compromised in some way. Death due to TB is a consequence of organ failure arising from damage to infected tissues caused by excessive inflammation and immunopathology. Only one toxin has been described so far among the members of the MTBC: Tuberculosis Necrotizing Toxin (TNT) (Sun et al., 2015).

Diagnosis of TB relies on tests that either detect the bacillus or components thereof or detect the immune response of the host to infection. Direct detection of MTBC bacilli may take the form of sputum smear microscopy, culture (conventional or automated), or nucleic acid-based tests, such as polymerase chain reaction (PCR). Detection of an immune response commonly takes the form of a tuberculin skin test (TST) in which a purified protein derivative prepared from the culture filtrate of M. tuberculosis or M. bovis is injected intradermally and diagnosis made on the basis of the size of any ensuing delayed-type hypersensitivity reaction some days later. Other immune-based tests for TB include antibody-detection assays, interferon-gamma release assays, or assays for the presence of mycobacterial antigens in secretions or blood. In high-burden human populations, chest X-rays may be used routinely for screening and diagnosis of active TB.

Infection with MTBC is on the list of diseases notifiable to the World Organisation for Animal Health (OIE). The Distribution section of this datasheet contains data from OIE's WAHIS database on disease occurrence. The AHPC library has further information on this disease. See also, the International Animal Health Code (https://www.oie.int/standard-setting/terrestrial-code/) and the Manual of Standards for Diagnostic Tests and Vaccines (https://www.oie.int/standard-setting/terrestrial-manual/).

Aetiology

Mycobacterium tuberculosis is the principle cause of TB in humans and rarely produces progressive disease in animals other than non-human primates and occasionally, dogs and parrots (Francis, 1958).

Mycobacterium africanum is responsible for most human TB infections in West Africa (Jong et al., 2010).

Mycobacterium canettii is a rare cause of human TB, although possibly an emerging disease in the Horn of Africa (Fabre et al., 2010).

Mycobacterium bovis, the cause of bovine TB, is capable of causing progressive disease in most warm-blooded vertebrates (Thoen, 1995), including humans. Tackling zoonotic TB is considered essential to achieving the WHO target of ending the global human TB epidemic by 2030 (World Health Organization (WHO), Food and Agriculture Organization of the United Nations (FAO), and World Organisation for Animal Health (OIE), 2017).

Mycobacterium microti is also known as the 'Vole bacillus' as it was first described as a pathogen of field voles in England (Wells, 1937). It may infect other rodents and mammals, including cats (Sykes and Gunn-Moore 2014) and rarely humans and new world camelids, such as llamas (Emmanuel et al., 2007).

The remaining MTBC complex members are generally considered host-adapted: Mycobacterium caprae, Mycobacterium pinnipedii, Mycobacterium mungi and Mycobacterium suricattae being the principle causative agents of TB in goats, seals, banded mongoose, and meerkats, respectively.

Three members of the MTBC, Dassie bacillus, chimpanzee bacillus, and Mycobacterium orygis, remain somewhat enigmatic, being originally derived from rock hyrax, a wild chimpanzee, and oryx, respectively. M. orygis has been isolated from members of the Bovidae family as well as humans, although the latter likely represent an accidental, dead-end host (van Ingen et al. 2012). The exact natural host-range for these MTBC members is still unclear.

bone, foot diseases and lameness in large ruminants
bone, foot diseases and lameness in pigs
digestive diseases of large ruminants
digestive diseases of pigs
digestive diseases of poultry
digestive diseases of small ruminants
mammary gland diseases of large ruminants
mammary gland diseases of pigs
mammary gland diseases of small ruminants
muscular skeletal diseases of poultry
nervous system diseases of large ruminants
nervous system diseases of pigs
nervous system diseases of poultry
nervous system diseases of small ruminants
reproductive diseases of large ruminants
reproductive diseases of pigs
reproductive diseases of poultry
reproductive diseases of small ruminants
respiratory diseases of large ruminants
respiratory diseases of pigs
respiratory diseases of poultry
respiratory diseases of small ruminants
skin and ocular diseases of large ruminants
skin and ocular diseases of pigs
skin and ocular diseases of poultry
skin and ocular diseases of small ruminants
urinary tract and renal diseases of large ruminants
urinary tract and renal diseases of pigs
urinary tract and renal diseases of poultry

Clinical Findings

The signs exhibited depend upon the extent and location of the lesions and the species affected. The general signs are weakness, anorexia, dyspnoea, emaciation and low-grade fluctuating fever. The principal sign of TB is wasting or emaciation that occurs despite good nutrition (Nieberle and Cohrs, 1966; Gutiérrez Cancela and García Marín, 1993; Huchzermeyer and Bruckner, 1994; Gutiérrez et al., 1998). Enlarged superficial lymph nodes provide a useful diagnostic sign; however, small lesions located in deep lymph nodes are of little or no value in establishing a clinical diagnosis.

Signs of active TB in people include a persistent productive cough, weight loss, night sweats, fever, fatigue, weakness, and loss of appetite. These symptoms will be absent in cases of latent TB. X-ray of the lungs of symptomatic individuals with primary TB will often show as an infiltration in the lower lung. This may be accompanied by signs of cavitation, indicating tissue destruction symptomatic of more progressive disease. In contrast, secondary TB arising from reactivation of latent TB usually presents with infiltrate in the upper lung. Cavitation is more common in secondary than primary TB. Underlying immunodeficiency, such as infection with HIV is a predisposing factor for development of secondary TB. As the immune system is hypo-responsive, cavitation is less likely to be observed but extrapulmonary manifestations of infection are more likely. M. bovis can induce a disease indistinguishable from M. tuberculosis in humans, and is likely underreported, especially in countries that lack the resources to discriminate one bacterial species from the other.

Clinical findings in other species very much depend on the species and the route and duration of the infection. In countries that employ a surveillance programme for bovine TB infected cattle are likely to be detected before they show clinical signs. Where this is not the case, affected animals may show weight loss, fever (often slight and inconsistent), weakness, loss of appetite, swollen lymph nodes (especially in the neck), diarrhoea, and in more severe cases, mastitis.

Macroscopic

The typical gross pathological lesion of TB is the tubercle; a typically circumscribed yellowish granulomatous inflammatory nodule of variable size that is more or less encapsulated by connective tissue and often contains a central core of necrotic tissue with varying degrees of mineralisation, depending on the species. The location of tubercles will depend on the route of infection. In most cases, TB is the consequence of inhaling aerosols of pathogenic mycobacteria, so the tubercles will reside in the lung and regional lymph nodes within the thoracic cavity. Primary lesions may act as the source of further dissemination of bacilli, seeding tubercles elsewhere in the lung, lymph nodes and other organs. Tubercles may grow or shrink independent of one another as the host response seeks to contain each site of infection.

Microscopic

At the microscopic level, regardless of the species and site of infection, the bacilli are contained within a hallmark lesion known as a granuloma; a dynamic accumulation of macrophages, plasma cells, neutrophils and lymphocytes drawn to the site of infection through the action of cytokines and chemokines. At the early stages of their formation, the granuloma may be no more than a small cluster of cells with no necrosis. Over time, the granuloma may develop in size and complexity and begin to show evidence of fibrous encapsulation, central necrosis, and even mineralisation. However, species differ in the manifestation of the granuloma; with varying degrees of fibrosis, necrosis, and mineralisation, with the granulomas of some species exhibiting no fibrosis and/or mineralisation at all. Bacilli may be evident in the granuloma after visualisation using an acid-fast stain, such as Ziehl-Neelsen. At the early stages of the granuloma there may be very few bacilli apparent, mostly within the cytoplasm of macrophages. At later stages, very large numbers of extracellular bacilli may be apparent, especially within regions of necrosis. Again, species differ in the abundance of bacilli associated with tuberculous lesions at different stages of their development.

The table below describes the characteristic macroscopic and microscopic pathology seen following M. bovis infection of different species.

Species	Macroscopic pathology	Microscopic pathology
Cattle (Bos taurus)	Lesions mainly in the respiratory tract, tonsils, gastrointestinal tract, secondary lymphoid organs depending on route of infection (inhalation or ingestion most common; other routes rarely).	Granulomas formed of neutrophils, macrophages, epithelioid macrophages, lymphocytes, Langhans multinucleated giant cells MNGCs). Caseous necrosis, fibrous capsule, and mineralisation at later stages of development. Bacilli few to numerous.
Sheep and goats	Like cattle, but often with more caseous or liquefactive necrosis leading to more cavitations.
Dogs	Disseminated lesions common	Multifocal to coalescing granulomas. MNGCs rare. Neutrophils may predominate. Encapsulation and mineralisation rare. Bacilli rarely reach high numbers.
Cats	Lesions most common in the skin, presumably arising from abrasions or biting. May ulcerate. Accompanied by local or generalised lymphadenitis. Pleura and pericardium often affected where infection is pulmonary.
Horses	Lesions most commonly associated with digestive tract (head and neck lymph nodes, gut and mesenteric lymph nodes). Disseminated infection common, leading to involvement of other organs (liver, spleen).	Granulomas relatively poorly organised with little caseation. Mineralisation rare.
New world camelids (llamas, alpacas)	Severe and extensive lesions mainly in the respiratory tract. Tubercles contain large amounts of soft caseum. Lesions may coalesce and cavitate. Pleurisy common. Extensive lymph node involvement and other organs commonly affected.	Extensive necrosis and bacilli may reach very high number.
European badgers (Meles meles)	Lesions most common in respiratory tract. Tubercles vary in size and distribution within the lung and may be accompanied by pneumonia. Other organs may be affected, including kidney. Disseminated disease may accompany infected bite wounds.	Often observed in absence of visible lesions. Large numbers of epithelioid macrophages, few lymphocytes, MNGCs absent. Limited necrosis that may be caseous. Mineralisation very rare.
Deer	Multiple, caseous tubercles containing pus in lungs and associated lymph nodes, esp. medial retropharyngeal. Pleura often affected.	Lymphocytes, macrophages, MNGCs, caseous necrosis and mineralisation all common. Very large numbers of bacilli may be present.
Wild boar and domestic pigs	Lesions may be contained to the lymph nodes of the head. Disseminated disease less common.	Like cattle but with less B-cell involvement.
African buffalo (Syncerus caffer)	Very few visible lesions in the lung. Lesions mostly restricted to lymph nodes of the head and lung.	Like cattle. Relatively few bacilli.
Antelope (Kobus leche)	Lesions most common in the lung and thoracic lymph nodes.	Central necrosis, little mineralisation (with exceptions). Numerous bacilli.
Brushtail possum	Disseminated lesions common, affecting skin, axillary and inguinal lymph nodes, lung, liver, spleen, kidney, mammary glands. Lesions may contain pus. Infection likely via inhalation and percutaneously.	Little encapsulation, extensive necrosis. Very high numbers of bacilli may be present.

Pathogenesis

Pulmonary TB occurs when the mycobacteria in droplet nuclei are inhaled into the alveoli (Torrelles and Schlesinger, 2017). Passage of the bacteria through the alveolar epithelium and into the lymphatics is a prerequisite to the establishment of infection and development of disease. The initial infection is often contained to lesions within the lung and associated lymph nodes. Lymphatic drainage from the primary focus in mammals leads to the formation of caseous lesions in the adjacent lymph node; this lesion, together with the primary focus, is known as the ‘primary complex’ or ‘Ghon complex’, named after the person whom first described the phenomenon (Ghon, 1912). This primary complex seldom heals in animals, but may progress slowly or rapidly (Nieberle and Cohrs, 1966; Huchzermeyer and Bruckner, 1994).

To-date, studies into mycobacteria-mediated pulmonary pathology has placed significant emphasis on mycobacteria-alveolar macrophage interaction being the initial event. However, alveolar epithelial type II (ATII) cells constitute an estimated 15% of the total lung cell population and constitute the first line of defence in the distal lung (Ariki et al., 2012). It stands to reason that interaction of mycobacteria with alveolar epithelial cells (AECs) is important in the initial stages of colonisation of the host with mycobacteria, especially since the downstream immune responses elicited by AECs contributes to establishment of infection and pathogenesis through avoidance of mechanisms such as phagocytosis, apoptosis, and autophagy (Carreto-Binaghi et al., 2016; Zhai et al., 2019). The ATII cell plays a major role in host-pathogen interaction (Mason and Williams, 1977; Whitsett, 2010; Beytut, 2011; Ariki et al., 2011) and innate immunity (Fehrenbach, 2001), from initial recognition of pathogens and amplitude of the inflammatory response via pattern recognition receptors, to the secretion of antimicrobial effector molecules, peptides, enzymes, reactive nitrogen and oxygen species and a multitude of cytokines, chemokines, and growth factors (Fehrenbach, 2001; Sato et al., 2002; Gupta et al., 2018). Although members of the MTBC have been shown to both invade and replicate within ATII cells (McDonough and Kress, 1995; Castro-Garza et al., 2002; Kleinnijenhuis et al., 2011), the role of these cells in determining the outcome of mycobacterial infection is largely unknown and under-studied.

If MTBC enter through ingestion, a gastrointestinal form of the disease will be established with frequent lesions in the mesenteric and other lymph nodes, such as the hepatic. For other species, a percutaneous route of inoculation may be important, such as through contamination of bite wounds from infectious saliva. In these cases, lesions will be found in the lymph nodes draining the site of inoculation and systemic spread affecting multiple organs may be seen.

Containment of infection will depend on the competence of the host immune response, which may be compromised by age, nutrition, immunodeficiency, and host genetics.

Wherever the organisms localise, their activity stimulates the formation of granulomas and in advanced cases these appear as tumour-like masses called tubercles (Thoen and Chiodini, 1993; Thoen and Bloom, 1995). Because of the continued growth of the organisms, these tubercles often enlarge until they become of a great size. Large masses may develop on the serous membranes of the body cavities. As the granulomas increase in size, necrosis of their central portions may occur. Finally, these are reduced to caseous masses, which have a tendency to undergo mineralisation or liquefaction. In mammals, tubercles may become enclosed in dense fibrous tissue and the disease becomes arrested. Advanced lesions associated with clinical disease include large and extensive, caseous nodules or cavities with liquidation (Gutiérrez Cancela and García Marín, 1993; Huchzermeyer and Bruckner, 1994; Gutiérrez et al., 1998). When the bacilli escape from the primary foci they travel via the lymph and blood streams, becoming lodged in other organs and tissues where they establish other tubercles. When the blood stream is invaded by numerous tubercle bacilli from a local lesion, many tubercles develop in the major organs. The acute form of generalisation, known as miliary tuberculosis, is often rapidly fatal.

If small numbers of bacilli enter the circulation from the primary complex, more isolated lesions develop in other organs. These generalized lesions may become encapsulated and remain small for extended periods, usually causing no detectable signs (Nieberle and Cohrs, 1966; Thoen and Himes, 1986; Huchzermeyer and Bruckner, 1994). The evolution of the lesion from early infection of the lung macrophage, to the development of caseous nodules, calcification and liquidation, as well as the regression or progression of the lesion and possible generalisation, depends on the immune host bacilli balance (Dannenberg, 1989). Different types of lesion, immune response and number of bacilli can be expected. It has been defined as an immunopathological spectrum of mycobacterial infections (Ridley, 1983).

The epidemiology of TB, be it in people or animals, shows considerable variation geographically so generalisations are difficult, although poor nutrition (of people and livestock) coupled with poverty are likely to be universally important epidemiological drivers. The considerable regional variation in the epidemiological drivers of TB means that elimination strategies need to be based upon region-specific risk factors (e.g. screening for TB among persons with HIV, or enhanced biosecurity and control of wildlife reservoir species in the case of bovine TB) (MacNeil et al., 2019). Underpinning modern approaches to describing and understanding the epidemiology of TB are computational models. Numerous mathematical models have been developed and employed to address specific elements of TB epidemiology, such as estimating drug-resistant infection and disease in children (Dodd et al., 2016) or how a lapse in management can alter epidemiological parameters for bovine TB (Moustakas et al., 2018).

Human TB

In countries with high prevalence of HIV infection, such as Africa, coinfection with HIV is a significant factor in the TB epidemic and associated mortality. In other parts of the world other factors may be driving the epidemic. For example, South-East Asia has a relatively low prevalence of HIV infection and yet a TB incidence similar to that of Africa.

The presence of drug-resistant TB exacerbates the TB epidemic through treatment failure and the increased cost and duration of effective treatment. The risk of drug resistance however differs markedly between countries and regions. In 2019, South-East Asia had the largest number of reported multidrug- / rifampicin-resistant TB (MDR/RR-TB) cases at 182,000, and the highest rate of MDR/RR-TB at 9.2 per 100,000 population. In the same year, whilst Europe reported 58% fewer cases of MDR/RR-TB (77,000) it had the second highest rate of MDR/RR-TB at 8.3 per 100,000 population (World Health Organization, 2019), Annex 3.

Bovine TB

As reviewed by Conlan and Wood (2018), the risk of infection, susceptibility and progression of disease in individual animals is highly variable and dependent upon age, breed, host genetics, and production type, which are attributes that will vary geographically as well as regionally. The disease epidemiology will also be heavily influenced by the systematic testing and removal of infected animals, as well as the presence of wildlife reservoirs of infection. Indeed, in many situations bovine TB should be viewed from the perspective of a multi-host system, with different hosts contributing differentially to disease maintenance. In this context, understanding the composition of the host community becomes fundamental to determining the drivers of M. bovis transmission (Webster et al., 2017).

Treatment for TB in humans depends upon whether the disease is active or latent, whether the infection is showing resistance to one or more frontline antibiotics, or whether it is caused by infection with M. bovis. The guidance on treatment is frequently updated so the latest guidance available on the WHO website should be consulted. At time of writing, the WHO have published ‘Guidelines for treatment of drug-susceptible tuberculosis and patient care (2017 update)’ (World Health Organization, 2017) and ‘Latent TB Infection: Updated and consolidated guidelines for programmatic management’ (World Health Organization, 2018b). In 2020, the WHO produced their consolidated guidelines on TB. Module 4 focusses on treatment of drug-resistant TB (World Health Organization, 2020c).

Patients with zoonotic TB caused by M. bovis face an additional challenge for treatment in that M. bovis is inherently resistant to pyrazinamide, a frontline antibiotic in the treatment of TB. Unfortunately, most patients begin treatment before the identity of the causative mycobacterium is identified, or indeed its antibiotic susceptibility profile. Suboptimal treatment may lead to the selection of further drug resistance and higher mortality. A contributory factor in selection of resistance is failure to complete the protracted treatment regimen, either due to cost, side-effects, patient non-compliance or loss to follow-up.

Infection in animals is rarely treated. Although the treatment for bovine TB would be the same in principle as for humans (minus the use of pyrazinamide, to which M. bovis is naturally resistant), with appropriate adjustments to dose and possibly duration, it is not economically viable to do so. There may be national advice for the treatment of TB in pets. In the United Kingdom, the choice to treat or euthanise the pet if it develops TB is a decision for the owner to make in consultation with their vet. As the infection may be spread from the animal to other members of the household, the infected animal represents a public health risk and should ideally be euthanised. There are no drugs licensed in the United Kingdom for treating animals for TB. The drugs which would be used to treat an animal may not work and may carry a risk to the health of the animal. The effectiveness of the drugs used to treat TB in humans is hard to monitor in animals, admitting the risk of relapse and/or emergence of drug resistance. Livestock animals such as goats, camelids (alpacas and llamas), pigs, horses, donkeys and sheep are sometimes kept as pets, but if these animals are infected with M. bovis they will be managed as their farmed counterparts and not treated.

Treatment has been applied to animals in captivity of high conservation value, such as those in zoological collections. For example, giraffes, elephants and black rhinocerosus (Diceros bicornis) have all been treated. In the case of elephants and black rhinoceroses, serological assays have been used to assess whether treatment was successful (Lyashchenko et al., 2006; Duncan et al., 2009; Krajewska-Wędzina et al., 2018). Guidelines for the control of TB in elephants has been published, including for their treatment with antibiotics: http://www.afvpz.com/IMG/pdf/USAHA_TB_Guidelines_2012_Draft_revision_2012-2.pdf. Permission for treatment should be sought from the official authorities.