Invasive Species Compendium

Detailed coverage of invasive species threatening livelihoods and the environment worldwide

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tuberculosis

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Datasheet

tuberculosis

Summary

  • Last modified
  • 15 April 2021
  • Datasheet Type(s)
  • Animal Disease
  • Preferred Scientific Name
  • tuberculosis
  • Pathogens
  • Mycobacterium africanum
  • Mycobacterium bovis
  • Mycobacterium caprae
  • Mycobacterium microti
  • Mycobacterium tuberculosis
  • Overview
  • 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...

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Pictures

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PictureTitleCaptionCopyright
In this case the granulomas are small and widespread and described as 'miliary'.
TitleLung of a pig with tuberculosis
CaptionIn this case the granulomas are small and widespread and described as 'miliary'.
CopyrightJohn Walton (Deceased)
In this case the granulomas are small and widespread and described as 'miliary'.
Lung of a pig with tuberculosisIn this case the granulomas are small and widespread and described as 'miliary'.John Walton (Deceased)
The granuloma is contained within a fibrous capsule. The disease can result in acute illness, but often progresses to a chronic debilitating disease which responds poorly to treatment due to the inability of antimicrobial drugs to penetrate the fibrous capsule of the lesion.
TitlePathology - bovine tuberculosis granuloma in the lung
CaptionThe granuloma is contained within a fibrous capsule. The disease can result in acute illness, but often progresses to a chronic debilitating disease which responds poorly to treatment due to the inability of antimicrobial drugs to penetrate the fibrous capsule of the lesion.
Copyright©Paul R. Greenough
The granuloma is contained within a fibrous capsule. The disease can result in acute illness, but often progresses to a chronic debilitating disease which responds poorly to treatment due to the inability of antimicrobial drugs to penetrate the fibrous capsule of the lesion.
Pathology - bovine tuberculosis granuloma in the lungThe granuloma is contained within a fibrous capsule. The disease can result in acute illness, but often progresses to a chronic debilitating disease which responds poorly to treatment due to the inability of antimicrobial drugs to penetrate the fibrous capsule of the lesion.©Paul R. Greenough

Identity

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Preferred Scientific Name

  • tuberculosis

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

Pathogen/s

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

Overview

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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.

Host Animals

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Animal nameContextLife stageSystem
Acinonyx jubatus
Bos grunniens (yaks)Domesticated host; Wild host
Bos indicus (zebu)Domesticated hostCattle & Buffaloes: All Stages
Bos taurus (cattle)Domesticated hostCattle & Buffaloes: All Stages
Bubalus bubalis (Asian water buffalo)
Canis familiaris (dogs)
Canis latrans (Coyote)
Capra hircus (goats)Domesticated hostSheep & Goats: Mature female
Capreolus capreolus
Cervus dama
Cervus elaphus (red deer)
Equus
Equus caballus (horses)Domesticated host; Wild hostOther: All Stages
Felis
GallusDomesticated hostPoultry: All Stages|Poultry/Mature female
Gallus gallus domesticus (chickens)
Homo sapiens
Kobus leche kafuensis
Lama pacos (alpacas)
Macaca fascicularis (crab-eating macaque)
Meles meles
Mustela putorius
Odocoileus virginianus
Ovis aries (sheep)Domesticated hostSheep & Goats: Mature female
Panthera leo (lion)
Papio ursinus
Phasianus colchicus (common pheasant)
Sus scrofa (pigs)Domesticated host; Wild hostPigs: Growing-finishing pig|Pigs/Gilt|Pigs/Sow
Tragelaphus scriptus

Hosts/Species Affected

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Most vertebrate species are likely to be susceptible to at least one of the MTBC. Humans are most typically infected with M. tuberculosis, M. africanum, or M. bovis. M. africanum may also infect cattle, swine, and non-human primates. M. microti typically infects voles and camelids but has also been isolated from New World monkeys and big cats. M. pinnipedii typically infects pinnipeds, but has also been isolated from camels, tapir, and big cats. M. caprae typically infects goats, sheep and swine, but has also been isolated from red and white-tailed deer, camel, and bison. The Dassie bacillus has been isolated from hyraxes and meerkats. Some MTBC appear to be host adapted or at least have only been isolated from a single species, such as Mycobacterium mungi from banded mongoose and Mycobacterium suricattae from meerkats. M. bovis has the broadest host range of the MTBC and has been isolated from numerous domesticated and wildlife species, including all ruminants, birds, meerkats, non-human primates, apes, rodents, cats, camelids, equines, pigs, wild boars, canids, foxes, mink, badgers, ferrets, tapirs, elephants, rhinoceroses, possums, otters, seals, hares, moles, raccoons, coyotes and several predatory felines including lions, tigers, leopards and lynx. This is not an exhaustive list.

Systems Affected

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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

Distribution

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TB is one of the top ten causes of human death and the leading cause from a single infectious agent (above HIV/AIDS). According to the WHO, worldwide in 2018 (World Health Organization, 2019):

  • A total of 1.5 million people died from TB (including 208,000 people with human immunodeficiency virus (HIV)).
  • An estimated 10 million people fell ill with TB.
  • TB is present in all countries and age groups.
  • The 30 high TB burden countries accounted for 87% of new TB cases.
  • Eight countries account for two thirds of the total, with India leading the count, followed by Indonesia, China, the Philippines, Pakistan, Nigeria, Bangladesh and South Africa.
  • A total of 206,030 people with multidrug- or rifampicin-resistant TB (MDR/RR-TB) were detected and notified; a 10% increase from 2018.
  • TB incidence is falling at about 2% per year and between 2015 and 2019 the cumulative reduction was 9%. This was less than half way to the End TB Strategy milestone of 20% reduction between 2015 and 2020.

TB data are reported to WHO annually by member states. New human pulmonary bacteriologically confirmed TB cases (smear positive or culture positive or positive by WHO-recommended rapid diagnostics such as Xpert MTB/RIF) were reported to the WHO by 199 countries in 2019 (data extracted from https://www.who.int/teams/global-tuberculosis-programme/data) – table below, first column.

Bovine TB in either wild or domestic animals was reported to the OIE by 29 countries over the period October 2018 to October 2020 (data extracted from World Animal Health Information System (WAHIS)) – table below, second column.

Zoonotic TB (pulmonary cases with test results for speciation reported as M. bovis) was reported to the WHO by 70 countries in 2018 (data extracted from https://www.who.int/teams/global-tuberculosis-programme/data) – table below, third column.

The omission of a country from these lists does not indicate they had no cases of TB for the period of reporting; they may have failed to submit data to either the OIE or WHO.

Countries reporting new human pulmonary bacteriologically confirmed TB cases to the WHO in 2019

Countries reporting bovine TB to the OIE (Oct 2018 to Oct 2020)

Countries reporting zoonotic TB to the WHO in 2018

Afghanistan

Liberia

Benin

Andorra

Albania

Libya

Bolivia

Australia

Algeria

Lithuania

Chile

Austria

American Samoa

Luxembourg

China

Bahamas

Andorra

Madagascar

Chinese Tapei

Bangladesh

Angola

Malawi

Costa Rica

Belgium

Argentina

Malaysia

Dominican Republic

Bermuda

Armenia

Maldives

Egypt

Bolivia

Aruba

Mali

France

Brunei Darussalam

Australia

Malta

Guatemala

Bulgaria

Austria

Marshall Islands

Hungary

Cayman Islands

Azerbaijan

Mauritania

Republic of Korea

China, Hong Kong SAR

Bahamas

Mauritius

Mexico

Croatia

Bahrain

Mexico

Morocco

Cyprus

Bangladesh

Micronesia

Mozambique

Czechia

Belarus

Mongolia

Niger

Denmark

Belgium

Montenegro

Nigeria

Egypt

Belize

Morocco

Peru

Estonia

Benin

Mozambique

Romania

Fiji

Bermuda

Myanmar

Senegal

Finland

Bhutan

Namibia

South Africa

Germany

Bolivia

Nauru

Sri Lanka

Greece

Bosnia and Herzegovina

Nepal

Swaziland

Guam

Botswana

Netherlands

Tanzania

Guatemala

Brazil

New Caledonia

Turkey

Guyana

Brunei Darussalam

New Zealand

Uganda

Honduras

Bulgaria

Nicaragua

United Kingdom

Hungary

Burkina Faso

Niger

Uruguay

Iceland

Burundi

Nigeria

Zambia

Ireland

Cabo Verde

North Macedonia

Israel

Cambodia

Northern Mariana Islands

Italy

Cameroon

Norway

Lithuania

Central African Republic

Occupied Palestinian territory, including east Jerusalem

Luxembourg

Chad

Oman

Malaysia

Chile

Pakistan

Malta

China

Palau

Mauritius

China, Hong Kong SAR

Panama

Micronesia

China, Macao SAR

Papua New Guinea

Mongolia

Colombia

Paraguay

Morocco

Congo

Peru

Netherlands

Cook Islands

Philippines

New Caledonia

Costa Rica

Poland

New Zealand

Côte d'Ivoire

Portugal

North Macedonia

Croatia

Puerto Rico

Northern Mariana Islands

Cuba

Qatar

Norway

Cyprus

Republic of Korea

Oman

Czechia

Republic of Moldova

Pakistan

Republic of Korea

Romania

Palau

Democratic Republic of the Congo

Russian Federation

Paraguay

Denmark

Rwanda

Peru

Djibouti

Saint Lucia

Philippines

Dominica

Saint Vincent and the Grenadines

Poland

Dominican Republic

Samoa

Portugal

Ecuador

Sao Tome and Principe

Puerto Rico

Egypt

Saudi Arabia

Republic of Korea

El Salvador

Senegal

Romania

Equatorial Guinea

Serbia

Saint Lucia

Eritrea

Seychelles

Slovakia

Estonia

Sierra Leone

Slovenia

Eswatini

Singapore

South Africa

Ethiopia

Saint Maarten (Dutch part)

Spain

Fiji

Slovakia

Sweden

Finland

Slovenia

Switzerland

France

Solomon Islands

Turkey

Gabon

Somalia

Ukraine

Gambia

South Africa

United Kingdom

Georgia

South Sudan

United States of America

Germany

Spain

Uruguay

Ghana

Sri Lanka

Venezuela

Greece

Sudan

Zambia

Greenland

Suriname

Grenada

Sweden

Guam

Switzerland

Guatemala

Syrian Arab Republic

Guinea

Tajikistan

Guinea-Bissau

Thailand

Guyana

Timor-Leste

Haiti

Togo

Honduras

Tonga

Hungary

Trinidad and Tobago

Iceland

Tunisia

India

Turkey

Indonesia

Turkmenistan

Iran

Turks and Caicos Islands

Iraq

Tuvalu

Ireland

Uganda

Israel

Ukraine

Italy

United Arab Emirates

Jamaica

United Kingdom

Japan

Tanzania

Jordan

United States of America

Kazakhstan

Uruguay

Kenya

Uzbekistan

Kiribati

Vanuatu

Kuwait

Venezuela

Kyrgyzstan

Vietnam

Lao People's Democratic Republic

Wallis and Futuna Islands

Lebanon

Yemen

Lesotho

Zambia

Zimbabwe

Distribution Table

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The distribution in this summary table is based on all the information available. When several references are cited, they may give conflicting information on the status. Further details may be available for individual references in the Distribution Table Details section which can be selected by going to Generate Report.

Last updated: 10 Jan 2020
Continent/Country/Region Distribution Last Reported Origin First Reported Invasive Reference Notes

Africa

AlgeriaPresent
AngolaPresent
BeninPresent
BotswanaPresentOriginal citation: AU-IBAR (2011)
Burkina FasoPresent
BurundiPresent
Cabo VerdePresent
CameroonPresent
Central African RepublicPresent
ChadPresent
ComorosPresent
Congo, Democratic Republic of thePresent
Congo, Republic of thePresentOriginal citation: AU-IBAR (2011)
Côte d'IvoirePresent
DjiboutiAbsent, No presence record(s)
EgyptPresentOriginal citation: AU-IBAR (2011)
EritreaPresent
EswatiniPresent
EthiopiaPresent
GhanaPresent
GuineaAbsent, No presence record(s)
KenyaPresent
LibyaPresent
MadagascarPresent
MalawiPresent
MoroccoPresent
MozambiquePresent
NigerPresent
NigeriaPresent
RwandaPresent
São Tomé and PríncipeAbsent, No presence record(s)
South AfricaPresent
TanzaniaPresent
TogoPresent
TunisiaPresent
UgandaPresent
ZambiaPresent

Asia

AfghanistanPresent
BangladeshPresent
BhutanAbsent, No presence record(s)
BruneiAbsent, No presence record(s)
ChinaPresentOriginal citation: YuHai and ZhouShou (1998)
IndiaPresent
IndonesiaAbsent, No presence record(s)
IranPresent
IsraelPresent1999
JapanPresent
JordanAbsent, No presence record(s)
KazakhstanAbsent, No presence record(s)
KuwaitAbsent, No presence record(s)
Malaysia
-Peninsular MalaysiaAbsent, No presence record(s)
-SabahAbsent, No presence record(s)
-SarawakAbsent, No presence record(s)
MongoliaAbsent, No presence record(s)
MyanmarPresent
North KoreaAbsent, No presence record(s)
OmanAbsent, No presence record(s)
PhilippinesPresent
Saudi ArabiaAbsent, No presence record(s)
SingaporeAbsent, No presence record(s)
South KoreaPresent
Sri LankaAbsent, No presence record(s)
SyriaAbsent, No presence record(s)
TaiwanPresent1996
ThailandPresent2001
UzbekistanPresent

Europe

AndorraPresentCAB Abstracts Data Mining
BelgiumPresent
Bosnia and HerzegovinaPresent2002
BulgariaPresent2002
CroatiaPresent
CzechiaPresent
DenmarkPresent1988
FinlandPresent1982
FrancePresent
GermanyPresent
GreecePresent2000
HungaryPresent
IrelandPresent
ItalyPresent
JerseyAbsent, No presence record(s)
LiechtensteinAbsent, No presence record(s)
LithuaniaPresent2001
MoldovaPresent
NetherlandsPresent
North MacedoniaPresentCAB Abstracts Data Mining
PolandPresent
PortugalPresent
RussiaAbsent, No presence record(s)
-Russia (Europe)Present, WidespreadOriginal citation: OIE(1997)
SloveniaPresent
SpainPresent
SwedenPresent
UkrainePresent
United KingdomPresent
-Northern IrelandPresent

North America

Antigua and BarbudaAbsent, No presence record(s)Original citation: OIE(1997)
BarbadosAbsent, No presence record(s)
BermudaAbsent, No presence record(s)
British Virgin IslandsAbsent, No presence record(s)
Cayman IslandsAbsent, No presence record(s)
Costa RicaPresent
CubaAbsent, No presence record(s)
CuraçaoAbsent, No presence record(s)
DominicaAbsent, No presence record(s)
Dominican RepublicPresent2003
GuatemalaAbsent, No presence record(s)
HaitiAbsent, No presence record(s)
HondurasPresent
JamaicaAbsent, No presence record(s)
MartiniqueAbsent, No presence record(s)
MexicoPresent
PanamaAbsent, No presence record(s)
Saint Kitts and NevisAbsent, No presence record(s)
Saint Vincent and the GrenadinesAbsent, No presence record(s)
Trinidad and TobagoAbsent, No presence record(s)
United StatesPresent
-MichiganPresent, Localized
-TexasPresent, Localized

Oceania

AustraliaPresent
French PolynesiaAbsent, No presence record(s)
New CaledoniaAbsent, No presence record(s)
New ZealandPresent
SamoaAbsent, No presence record(s)
VanuatuAbsent, No presence record(s)

South America

ArgentinaPresent
BrazilPresent
ChilePresent1989
ColombiaPresent1985
EcuadorPresent1960
French GuianaAbsent, No presence record(s)
GuyanaAbsent, No presence record(s)
PeruAbsent, No presence record(s)
UruguayPresent
VenezuelaPresent

Pathology

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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.

Diagnosis

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No test is 100% accurate. The most suitable combination of test sensitivity and specificity will be situation-specific.

Clinical diagnosis is usually possible only after TB has reached an advanced stage. Most infected animals have become shedders of bacilli by this time and present a risk of onward transmission of infection to other animals either directly or through contamination of the shared environment.

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 in humans, culture (conventional or automated) of clinical samples or tissues obtained post mortem, or nucleic acid-based tests, such as polymerase chain reaction (PCR).

The most reliable and practical method of reaching tentative diagnosis in large domestic animals is to apply the tuberculin skin test (TST). Animals infected with mycobacteria are allergic to the proteins contained in tuberculin and develop characteristic delayed-type hypersensitivity (DTH) reactions when exposed to tuberculoproteins. If tuberculin is deposited in the deep layers of the skin (intradermally), a local reaction characterised by inflammation and swelling is usually elicited in infected animals, whereas non-infected animals fail to develop such reactions at the injection site. Animals suffering from infection with either M. bovis or M. tuberculosis react equally to tuberculin prepared from the culture filtrate of either organism. In the USA the larger mammals are usually injected in one of the folds at the base of the tail or in skin of the cervical region, swine in the skin behind the ear or vulva. The injection sites are examined by observation and palpation for characteristic swelling 48 hours after injection for swine, and in 72 hours for cattle, sheep and goats. In some countries, such as the United Kingdom and Ireland, cattle are tested with both tuberculin derived from M. bovis (PPD-B) and from Mycobacterium avium (PPD-A) in a single intradermal comparative cervical tuberculin test (SICCT). The size and nature of any reactions at the avian and bovine injection sites are measured and compared. The SICCT can better distinguish between animals infected with M. bovis and animals previously exposed to or infected with other types of mycobacteria found in the environment which do not cause bovine TB. The TST is better at diagnosing infection at the level of the herd rather than the individual animal.

The TST skin test as applied to the diagnosis of TB in people uses tuberculin derived from M. tuberculosis and may be referred to as the Mantoux test, Mendel-Mantoux test, Heaf test, or Pirquet test, depending on the method of tuberculin administration. The test has low sensitivity of detection in cases of latent TB. Its specificity is compromised by prior vaccination with BCG or exposure to mycobacteria other than the MTBC, since many of the antigens within the vaccine or other mycobacteria are present in tuberculin. However, in countries where BCG vaccination is not routinely applied, the TST may be useful for detecting occupational exposure to MTBC.

Not all infected species produce a discernible cutaneous DTH reaction following intradermal injection of tuberculin. The need to measure the reaction at the site of inoculation days after administration renders the TST impractical for use with many wild animals, as well as costly and challenging practically in surveillance programmes involving domesticated animals and people. Other general limitations of the TST are that its interpretation is subjective, even where measurement of the DTH reaction is taken. Administration of the TST in short succession within the same individual may be problematic as the immune response to the initial administration of tuberculin may influence the response to its subsequent administration. In general, with all immune-based tests of TB, any form of immunocompromise and certain co-infections (HIV, parasitic worms, and others) will reduce the performance of the TST, either due to immune hyporesponsiveness or false positive (cross-) reactions.

Other immune-based tests for TB include antibody-detection assays (for blood, secretions, milk), 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. Serological tests in cattle work best if applied shortly after the immune system has been stimulated by administration of tuberculin. This may not be necessary, and certainly not feasible, for wild animals. The development of discriminatory tests based on interpretation of complex patterns of biomarkers is a promising avenue of research still somewhat in its infancy, underpinned by the need for a greater understanding of the immune response to the diverse members of the MTBC infection in different species. A challenge surrounding the introduction of any new test is its standardisation and validation to ensure reproducibility and accuracy in the context of its use. This extends to the promotion of the test and overcoming barriers to its adoption.

In 2020, the WHO produced their consolidated guidelines on TB. Module 3 focusses on rapid diagnostics for TB detection (World Health Organization, 2020b).

The European Association of Zoo and Wildlife Veterinarians (EAZWV) has published guidance on the most appropriate diagnostic tests to be used in various zoo species (EAZWV Tuberculosis Working Group, 2010). Comprehensive reviews of the diagnosis of TB in non-bovid wildlife species using immunological methods have also been undertaken (Chambers 2009, 2013). 

List of Symptoms/Signs

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SignLife StagesType
Digestive Signs / Abdominal distention Sign
Digestive Signs / Anorexia, loss or decreased appetite, not nursing, off feed Cattle & Buffaloes:Cow,Cattle & Buffaloes:Steer,Cattle & Buffaloes:Bull,Cattle & Buffaloes:Ox,Pigs:Sow,Sheep & Goats:Mature female Sign
Digestive Signs / Ascites, fluid abdomen Cattle & Buffaloes:Cow,Cattle & Buffaloes:Steer,Cattle & Buffaloes:Bull,Cattle & Buffaloes:Ox,Cattle & Buffaloes:Not known,Poultry:All Stages,Pigs:Sow,Sheep & Goats:Mature female Sign
Digestive Signs / Bloat in ruminants, tympany Sign
Digestive Signs / Diarrhoea Sign
Digestive Signs / Diarrhoea Sign
Digestive Signs / Tongue protrusion Sign
Digestive Signs / Tongue ulcers, vesicles, erosions, sores, blisters, cuts, tears Sign
Digestive Signs / Tongue weakness, paresis, paralysis Sign
Digestive Signs / Vomiting or regurgitation, emesis Sign
General Signs / Cyanosis, blue skin or membranes Sign
General Signs / Dehydration Cattle & Buffaloes:All Stages,Poultry:All Stages,Pigs:Growing-finishing pig,Pigs:Gilt,Pigs:Sow,Sheep & Goats:Mature female Sign
General Signs / Fever, pyrexia, hyperthermia Sign
General Signs / Forelimb lameness, stiffness, limping fore leg Sign
General Signs / Forelimb swelling, mass in fore leg joint and / or non-joint area Sign
General Signs / Generalized lameness or stiffness, limping Sign
General Signs / Generalized weakness, paresis, paralysis Sign
General Signs / Head, face, ears, jaw, nose, nasal, swelling, mass Sign
General Signs / Hindlimb lameness, stiffness, limping hind leg Sign
General Signs / Hindlimb swelling, mass in hind leg joint and / or non-joint area Sign
General Signs / Icterus, jaundice Sign
General Signs / Inability to stand, downer, prostration Sign
General Signs / Increased mortality in flocks of birds Poultry:All Stages Sign
General Signs / Internal abdominal mass, swellings, adhesions abdomen Cattle & Buffaloes:All Stages,Poultry:All Stages,Pigs:Growing-finishing pig,Pigs:Gilt,Pigs:Sow,Sheep & Goats:Mature female Sign
General Signs / Intraocular mass, swelling interior of eye Sign
General Signs / Lack of growth or weight gain, retarded, stunted growth Sign
General Signs / Lameness, stiffness, stilted gait in birds Sign
General Signs / Lymphadenopathy, swelling, mass or enlarged lymph nodes Cattle & Buffaloes:All Stages,Poultry:All Stages,Pigs:Growing-finishing pig,Pigs:Gilt,Pigs:Sow,Sheep & Goats:Mature female Sign
General Signs / Mammary gland swelling, mass, hypertrophy udder, gynecomastia Cattle & Buffaloes:Cow,Pigs:Gilt,Pigs:Sow,Sheep & Goats:Mature female Sign
General Signs / Oral cavity, tongue swelling, mass in mouth Sign
General Signs / Orbital, periorbital, periocular, conjunctival swelling, eyeball mass Sign
General Signs / Pale comb and or wattles in birds Poultry:All Stages Sign
General Signs / Pale mucous membranes or skin, anemia Sign
General Signs / Polydipsia, excessive fluid consumption, excessive thirst Sign
General Signs / Swelling mass penis, prepuce, testes, scrotum Sign
General Signs / Swelling mass uterus Sign
General Signs / Swelling of the limbs, legs, foot, feet, in birds Sign
General Signs / Swelling skin or subcutaneous, mass, lump, nodule Sign
General Signs / Trembling, shivering, fasciculations, chilling Sign
General Signs / Underweight, poor condition, thin, emaciated, unthriftiness, ill thrift Pigs:Piglet,Pigs:Weaner,Pigs:Growing-finishing pig
General Signs / Weight loss Cattle & Buffaloes:All Stages,Poultry:All Stages,Pigs:Growing-finishing pig,Pigs:Gilt,Pigs:Sow,Sheep & Goats:Mature female Sign
Nervous Signs / Dullness, depression, lethargy, depressed, lethargic, listless Sign
Ophthalmology Signs / Abnormal corneal pigmentation Sign
Ophthalmology Signs / Blindness Sign
Ophthalmology Signs / Chemosis, conjunctival, scleral edema, swelling Sign
Ophthalmology Signs / Conjunctival, scleral, injection, abnormal vasculature Sign
Ophthalmology Signs / Conjunctival, scleral, redness Sign
Ophthalmology Signs / Corneal edema, opacity Sign
Ophthalmology Signs / Corneal swelling, mass, nodule Sign
Ophthalmology Signs / Corneal ulcer, erosion Sign
Ophthalmology Signs / Exophthalmos, eyes protruding, proptosis Sign
Pain / Discomfort Signs / Mouth, oral mucosal or tongue pain Sign
Pain / Discomfort Signs / Pain mammary gland, udder Sign
Reproductive Signs / Abortion or weak newborns, stillbirth Sign
Reproductive Signs / Agalactia, decreased, absent milk production Sign
Reproductive Signs / Decreased, dropping, egg production Sign
Reproductive Signs / Edema of mammary gland, udder Sign
Reproductive Signs / Female infertility, repeat breeder Sign
Reproductive Signs / Mastitis, abnormal milk Sign
Reproductive Signs / Purulent discharge, vulvar, vaginal Sign
Reproductive Signs / Purulent or mucoid discharge, cervix or uterus Sign
Respiratory Signs / Abnormal breathing sounds of the upper airway, airflow obstruction, stertor, snoring Cattle & Buffaloes:All Stages,Poultry:All Stages,Pigs:Growing-finishing pig,Pigs:Gilt,Pigs:Sow,Sheep & Goats:Mature female Sign
Respiratory Signs / Abnormal lung or pleural sounds, rales, crackles, wheezes, friction rubs Cattle & Buffaloes:All Stages,Poultry:All Stages,Pigs:Growing-finishing pig,Pigs:Gilt,Pigs:Sow,Sheep & Goats:Mature female Sign
Respiratory Signs / Coughing, coughs Cattle & Buffaloes:All Stages,Pigs:Growing-finishing pig,Pigs:Gilt,Pigs:Sow,Sheep & Goats:Mature female Sign
Respiratory Signs / Dull areas on percussion of chest, thorax Cattle & Buffaloes:All Stages,Pigs:Growing-finishing pig,Pigs:Gilt,Pigs:Sow,Sheep & Goats:Mature female Sign
Respiratory Signs / Dyspnea, difficult, open mouth breathing, grunt, gasping Cattle & Buffaloes:All Stages,Poultry:All Stages,Pigs:Growing-finishing pig,Pigs:Gilt,Pigs:Sow Sign
Respiratory Signs / Enlarged lung on percussion of chest, thorax Cattle & Buffaloes:All Stages,Poultry:All Stages,Pigs:Growing-finishing pig,Pigs:Gilt,Pigs:Sow,Sheep & Goats:Mature female Sign
Respiratory Signs / Haemoptysis coughing up blood Cattle & Buffaloes:All Stages,Pigs:Growing-finishing pig,Pigs:Gilt,Pigs:Sow,Sheep & Goats:Mature female Sign
Respiratory Signs / Increased respiratory rate, polypnea, tachypnea, hyperpnea Sign
Respiratory Signs / Mucoid nasal discharge, serous, watery Sign
Respiratory Signs / Purulent nasal discharge Cattle & Buffaloes:All Stages,Poultry:All Stages,Pigs:Growing-finishing pig,Pigs:Gilt,Pigs:Sow,Sheep & Goats:Mature female Sign
Skin / Integumentary Signs / Loss of feathers, loose feathers Sign
Skin / Integumentary Signs / Ruffled, ruffling of the feathers Sign
Skin / Integumentary Signs / Skin fistula, sinus Sign
Skin / Integumentary Signs / Skin ulcer, erosion, excoriation Sign
Urinary Signs / Polyuria, increased urine output Sign

Disease Course

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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).

Epidemiology

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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).

Disease Treatment

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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.

Prevention and Control

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Human TB

In 2015, the WHO published a refreshed strategy for tackling TB in people: ‘The End TB Strategy’ sets out ambitious plans to end the global TB epidemic by 2030 (https://www.who.int/tb/strategy/en/). The strategy is built upon three strategic pillars, each containing key components, as follows:

  • Pillar 1: integrated, patient-centred TB care and prevention
    Key components: early diagnosis of TB; treatment of all people with TB; collaborative TB/HIV activities; preventive treatment of persons at high risk
  • Pillar 2: bold policies and supportive systems
    Key components: political commitment with adequate resources for TB care and prevention; engagement of communities, civil society organisations, and all public and private care providers; universal health coverage policy and regulatory frameworks; social protection, poverty alleviation and actions on other determinants of TB
  • Pillar 3: intensified research and innovation
    Key components: discovery, development and rapid uptake of new tools, interventions and strategies; research to optimise implementation and impact

Leading from The End TB strategy, in 2020 the WHO produced their consolidated guidelines on TB; Module 1 focusses on prevention (World Health Organization 2020a).

Bovine TB

The OIE provides standards in its Terrestrial Animal Health Code (https://www.oie.int/standard-setting/terrestrial-code/) to guide countries in the control and eradication of bovine TB. The guidance provides measures for detection, reporting and control to prevent the transfer of bovine TB (and other diseases of humans and animals), whilst enabling international trade of animals and animal products.

No diagnostic test for TB is 100% accurate. The most suitable combination of test sensitivity and specificity will be situation-specific. As a rule, for disease control purposes when TB prevalence is high, emphasis should be given to maximising test sensitivity. However, as this is often at the cost of increased numbers of false-positive test results, a situation-specific cost-benefit exercise will need to be undertaken. Since tests vary in their performance, this must also take account of the cost of the test; not only the purchase cost of the test itself, but its shelf-life and cost of any associated infrastructure (transport, laboratory, utilities, personnel). Careful thought must be given to communicating test results and how they will be acted upon. Testing is only one part of disease management and will need to be introduced in the context of stakeholder engagement and herd/species management, including treatment, culling, vaccination, and biosecurity, as required. Success with any prevention and control programme will be critically dependent on the availability of adequate resources, which may be lacking for many countries.

Different management options for bovine TB that take account of available resources have been helpfully laid out (Livingstone and Hancox, 2018). They propose that countries with high gross national income (GNI) should first define the purpose of any TB programme before clear strategic management objectives are set. They propose that a successful bovine TB programme requires:

  • Adequate funding
  • Effective legal status
  • Careful planning
  • Stakeholder support based on a clear cost-benefit analysis
  • Sound scientific base and on-going research
  • Appreciation of the industry and societal contexts
  • Policies that take account of the above
  • Effective communication and consultation
  • A competent administrative organisation or agency to deliver the programme

Livingstone and Hancox (2018) also present the options that may be considered in countries of lower GNI that wish to implement a bovine TB programme. These include:

  • Empowering people through knowledge
  • Pasteurisation of milk
  • Slaughterhouse TB surveillance
  • Vaccination of cattle
  • TB testing

As the burden of MTBC infection lies towards those countries of lower GNI there should also be an emphasis on reducing the potential for zoonotic transmission in such countries. It is recognised by the WHO and others that failure to tackle zoonotic TB will hamper efforts to achieve the End TB Strategy goal of eliminating TB in people by 2030. To this end, the WHO, OIE, FAO, and the International Union Against Tuberculosis and Lung Disease collectively have published a Roadmap for Zoonotic Tuberculosis, detailing ten priorities for addressing zoonotic TB in people and bovine TB in animals (World Health Organization (WHO), Food and Agriculture Organization of the United Nations (FAO), and World Organisation for Animal Health (OIE), 2017).

In some countries, the presence of one or more known wildlife reservoirs of infection will introduce additional complexity to the programme. In other countries there may be little information regarding the presence of MTBC in wildlife and whether it presents a threat to livestock or humans that needs to be managed.

Vaccines

The only licensed vaccine currently available against TB is the Bacillus Calmette-Guérin (BCG) vaccine strain, an attenuated strain of M. bovis. The vaccine has been licensed for use in humans globally, and for use in European badgers (Meles meles) in the United Kingdom. BCG has been shown to confer variable degrees of protection in all species in which it has been evaluated. Its variability has been variously attributed to geographical location, prior or subsequent exposure to other mycobacterial species, and the immune competence of the vaccinated host. BCG appears particularly protective against severe forms of childhood TB, including military TB and TB meningitis. In contrast, BCG appears less effective in general in protecting against pulmonary TB in adult humans.

The biggest impediments to the development of improved vaccines against TB are the remaining ignorance regarding the nature of protective immunity to MTBC infection, the inadequacy of surrogate animal models in which to identify candidate vaccines, and the challenges associated with conducting clinical trials of efficacy. Notwithstanding these challenges there were 14 TB vaccine candidates in clinical trials (Martin et al., 2020) at the time of writing. The target of next generation vaccines for TB is to address one more of the following: prevent infection or generate sterilising immunity; prevent relapse or reinfection; block transmission. To do so it is likely that the vaccine will need to provide protection through a novel mechanism or stimulate a more directed immune response, possibly through targeting of vaccine delivery to the respiratory tract; the principle site of infection.

Vaccines that can be used alongside diagnostic tests in cattle, other domestic animal species and wildlife could make a significant contribution to the control of bovine TB globally. Whilst BCG gives protection to cattle and other species and has been licensed for use in European badgers, as for humans, protection is variable. Furthermore, BCG administration compromises the use of the TST by causing false-positive reactions because of the numerous antigens common to BCG and bovine tuberculin. Since this inhibits disease surveillance, the use of BCG for cattle is prohibited in certain countries, including those within the European Union. To combat this, approaches have been taken to identify antigens that are absent from BCG but present in M. bovis with the intention of using such antigens as the basis of a DIVA test (Differentiation/Discrimination of Infected from Vaccinated Animals) that would permit the use of BCG vaccination without compromising the ability to detect animals with TB. An alternative approach is to develop subunit vaccines that include protective antigens absent from bovine tuberculin, thereby generating protective immunity without inducing false-positive reactions to bovine tuberculin.

An important unknown is how well BCG with or without or other vaccines will work in practice under field conditions, and how these might vary from country to country, especially when set in the context of disease surveillance programmes. This type of information will only come from large-scale field trials. Before such costly trials are undertaken it will be important to have clarity over how a licensed vaccine might be used and to therefore generate field data of relevance. This requires a close dialogue with governmental policy makers. Before any vaccination is licensed for use in cattle, a robust package of safety data will also need to be generated to satisfy the regulatory authority of the appropriate country. Safety studies would need to be repeated for any additional species in which the vaccine might be licensed for use.

References

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Distribution References

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Links to Websites

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Capacity Building for Surveillance and Control of Zoonotic Diseaseshttp://www.fao.org/docrep/009/a0083e/a0083e00.htmFAO Animal Production and Health Proceedings 7
CFSPH: Animal Disease Informationhttp://www.cfsph.iastate.edu/DiseaseInfo/index.php"Animal Disease Information" provides links to various information sources, including fact sheets and images, on over 150 animal diseases of international significance.
OIE Manual of Diagnostic Tests and Vaccines for Terrestrial Animalshttp://www.oie.int/en/international-standard-setting/terrestrial-manual/access-online/The Manual of Diagnostic Tests and Vaccines for Terrestrial Animals (Terrestrial Manual) aims to facilitate international trade in animals and animal products and to contribute to the improvement of animal health services world-wide. The principal target readership is laboratories carrying out veterinary diagnostic tests and surveillance, plus vaccine manufacturers and regulatory authorities in Member Countries. The objective is to provide internationally agreed diagnostic laboratory methods and requirements for the production and control of vaccines and other biological products.
OIE Terrestrial Animal Health Codehttp://www.oie.int/en/international-standard-setting/terrestrial-code/access-online/The OIE Terrestrial Animal Health Code sets out standards for the improvement of terrestrial animal health and welfare and veterinary public health worldwide, including through standards for safe international trade in terrestrial animals and their products. The health measures in the Terrestrial Code should be used by the veterinary authorities of importing and exporting countries to provide for early detection, reporting and control agents pathogenic to terrestrial animals and, in the case of zoonoses, for humans, and to prevent their transfer via international trade in terrestrial animals and terrestrial animal products, while avoiding unjustified sanitary barriers to trade.

Contributors

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17/12/2020 Updated by:

Mark Chambers, University of Surrey, UK

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