5 курс / Пульмонология и фтизиатрия / Clinical_Tuberculosis_Friedman_Lloyd_N_,_Dedicoat

\43.\ Comstock GW, Baum C, and Snider DE Jr. Isoniazid prophylaxis among Alaskan Eskimos: A final report of the Bethel isoniazid studies. Am Rev Respir Dis. 1979;119:827–30.

\44.\ Marks SM, Mase SR, and Morris SB. Systematic review, meta-analysis, and cost-effectiveness of treatment of latent tuberculosis to reduce progression to multidrug–resistant tuberculosis. Clin Infect Dis. 2017 Jun 15;64(12):1670–7.

\45.\ Seddon JA, Fred D, Amanullah F, Schaaf HS, Starke JR, Keshavjee S, Burzynski J, Furin JJ, Swaminathan S, and Becerra MC. 2015 Post-Exposure Management of Multidrug-Resistant Tuberculosis Contacts: Evidence-Based Recommendations. Policy Brief No. 1. Dubai, United Arab Emirates: Harvard Medical School Center for Global Health Delivery-Dubai.

\46.\ Hanson ML, Comstock GW, and Haley CE. Community isoniazid prophylaxis program in an underdeveloped area of Alaska. Public Health Rep. 1967:82(12):1045–56.

\47.\ Golub JE et al. The impact of antiretroviral therapy and

isoniazid preventive therapy on tuberculosis incidence in HIV-infected patients in Rio de Janeiro, Brazil. AIDS. 2007;21:1441–8.

\48.\ Akolo C, Adetifa I, Shepperd S, and Volmink J. Treatment of latent tuberculosis infection in HIV infected persons.

Cochrane Database Syst Rev. 2010;20:CD000171.

\49.\ Getahun H, Matteelli A, Chaisson RE, and Raviglione M. Latent Mycobacterium tuberculosis infection. N Engl J Med.

2015;372:2127–35.

\50.\ Frieden TR et al. Tuberculosis in New York City—turning the tide. N Engl J Med. 1995;333(4):229–33.

\51.\ Smieja MJ, Marchetti CA, Cook DJ, and Smaill FM. Isoniazid for preventing tuberculosis in non-HIV infected persons. Cochrane Database Syst Rev. 2000;2:CD001363.

\52.\ Cain KP et al. Moving toward tuberculosis elimination: Implementation of a statewide targeted tuberculin testing in Tennessee. Am J Respir Crit Care Med. 2012;186(3):273–9. doi: 10.1164/rccm.201111–2076OC.

\53.\ American Lung Association. Trends in Tuberculosis Morbidity and Mortality. American Lung Association Research and Health Education, Epidemiology and Statistics Unit, 2013. Available at: http://www.lung.org/assets/docu- ments/research/tb-trend-report.pdf

\54.\ Global Tuberculosis Report 2017. Geneva: World Health Organization; 2017.

\55.\ Golub JE et al. Delayed tuberculosis diagnosis and tuberculosis transmission. Int J Tuberc Lung Dis. 2006;10:24–30.

\56.\ Yuen CM, Amanullah F, Dharmadhikari A, Nardell EA, Seddon JA, Vasilyeva I, Zhao Y, Keshavjee S, and Becerra MC. Turning off the tap: Stopping tuberculosis transmission through active case-finding and prompt effective treatment. Lancet. 2015;386:2334–43.

\57.\ Morrison J, Pai M, and Hopewell PC. Tuberculosis and latent tuberculosis infection in close contacts of people with pulmonary tuberculosis in low-income and middle-income countries: A systematic review and meta-analysis. Lancet Infect Dis. 2008;8(6):359–68.

\58.\ Fox GJ, Barry SE, Britton WJ, and Marks GB. Contact investigation for tuberculosis: A systematic review and metaanalysis. Eur Respir J. 2013;41:140–56.

\59.\ Kranzer K, Houben RM, Glynn JR, Bekker LG, Wood R, and Lawn SD. Yield of HIV-associated tuberculosis during intensified case finding in resource-limited settings: A systematic review and meta-analysis. Lancet Infect Dis. 2010;10:93–102.

\60.\ Khan AJ et al. Engaging the private sector to increase tuberculosis case detection: An impact evaluation study. Lancet Infect Dis. 2012;12(8):608–16.

\61.\ Baily GV, Savic D, Gothi GD, Naidu VB, and Nair SS. Potential yield of pulmonary tuberculosis cases by direct microscopy of sputum in a district of South India. Bull WHO. 1967;37(6):875–92.

\62.\ Aluoch JA et al. Study of case-finding for pulmonary tuberculosis in outpatients complaining of a chronic cough at a district hospital in Kenya. Am Rev Resp Dis. 1984;129(6):915–20.

\63.\ Sanchez-Perez HJ, Hernan MA, Hernandez-Diaz S, Jansa JM, Halperin D, and Ascherio A. Detection of pulmonary tuberculosis in Chiapas, Mexico. Ann Epidemiol. 2002;12(3):166–72.

\ 64.\ Theron G, Jenkins HE, Cobelens F, Abubakar I, Khan AJ, Cohen T, and Dowdy DW. Data for action: Collection and use of local data to end tuberculosis. Lancet. 2015;386(10010):2324–33.

\ 65.\ Murray CJ, Styblo K, and Rouillon A. Tuberculosis in developing countries: Burden, intervention and cost. Bull Int Union Tuberc Lung Dis. 1990;65:6–24.

\ 66.\ Lawn SD et al. Screening for HIV-associated tuberculosis and rifampicin resistance before antiretroviral therapy using the Xpert MTB/RIF assay: A prospective study. PLoS Med. 2011;8:e1001067.

\67.\ WHO. Global Tuberculosis Report 2014. Geneva, Switzerland: World Health Organization, 2014.

\68.\ Behr MA et al. Transmission of Mycobacterium tuberculosis from patients smear-negative for acid-fast bacilli. Lancet. 1999;353:444–49.

\69.\ WHO. Systematic Screening for Active Tuberculosis: Principles and Recommendations. Geneva: World Health Organization, 2013.

\ 70.\ WHO. Guidance for National Tuberculosis Programmes on the Management of Tuberculosis in Children. 2nd ed. Geneva, Switzerland: World Health Organization, 2014.

\71.\ Getahun H et al. Development of a standardized screening rule for tuberculosis in people living with HIV in resourceconstrained settings: Individual participant data meta-anal- ysis of observational studies. PLoS Med. 2011;8:e1000391.

\72.\ Ayles H et al. and the ZAMSTAR team. Effect of household and community interventions on the burden of tuberculosis in southern Africa: The ZAMSTAR community-ran- domised trial. Lancet. 2013;382:1183–94.

\73.\ Azman AS, Golub JE, and Dowdy DW. How much is tuberculosis screening worth? Estimating the value of active case finding for tuberculosis in South Africa, China, and India. BMC Med. 2014;12:216.

\74.\ Creswell J, Sahu S, Blok L, Bakker MI, Stevens R, and Ditiu L. A multi-site evaluation of innovative approaches to increase tuberculosis case notification: Summary results. PLOS ONE. 2014;9:e94465.

75.Lin X, Chongsuvivatwong V, Lin L, Geater A, and Lijuan R. Dose response relationship between treatment delay of smear-positive tuberculosis patients and intra-household transmission: A crosssectional study. Trans R Soc Trop Med Hyg. 2008;102(8):797–804.

76.Kamat SR et al. A controlled study of the influence of segregation of tuberculous patients for one year on the attack rate of tuberculosis in a 5-year period in close family contacts in South India. Bull World Health Organ. 1966;34:517–32.

77.Dharmadhikari AS et al. Rapid impact of effective treatment on transmission of multidrug-resistant tuberculosis.

Int J Tuberc Lung Dis. 2014;18:1019–25.

78.WHO. Latent Tuberculosis Infection: Updated and Consolidated Guidelines for Programmatic Management. Geneva: World Health Organization, 2018.

79.Lew W, Pai M, Oxlade O, Martin D, and Menzies D. Initial drug resistance and tuberculosis treatment outcomes: Systematic review and meta-analysis. Ann Intern Med. 2008;149:123–34.

80.Barrera E, Livchits V, and Nardell E. F-A-S-T: A refocused, intensified, administrative tuberculosis transmission control strategy. Int J Tuberc Lung Dis. 2015;19:381–84.

81.Mendoza-Ticona A et al. Effect of universal MODS access on pulmonary tuberculosis treatment outcomes in new patients in Peru. Public Health Action. 2012;2:162–67.

82.Shah NS, Yuen CM, Heo M, Tolman AW, and Becerra MC. Yield of contact investigations in households of patients with drug-resistant tuberculosis: Systematic review and meta-analysis. Clin Infect Dis. 2014;58:381–91.

83.Naidoo P et al. A comparison of multidrug-resistant tuberculosis treatment commencement times in MDRTBPlus line probe assay and XpertR MTB/RIF-based algorithms in a routine operational setting in Cape Town. PLOS ONE. 2014;9:e103328.

84.Detjen A, Gnanashanmugam D, and Talens A. A Framework for Integrating Childhood Tuberculosis into CommunityBased Child Health Care. Washington, DC: CORE Group, 2013.

85.Khan MS, Salve S, and Porter JD. Engaging for-profit providers in TB control: Lessons learnt from initiatives in south Asia. Health Policy Plan. 2015;30(10):1289–95.

86.Ortblad KF, Salomon JA, Barnighausen T, and Atun R. Stopping tuberculosis: A biosocial model for sustainable development. Lancet. 2015;386:2354–6.

87.Houben RMGJ, and Dodd PJ. The global burden of latent tuberculosis infection: A re-estimation using mathematical modelling. PLoS Med. 2016;13(10):e1002152.

88.Behr MA, Edelstein PH, and Ramakrishnan L. Revisiting the timetable of tuberculosis. BMJ. 2018;362:k2738.

89.Rangaka MX et al. Controlling the seedbeds of tuberculosis: Diagnosis and treatment of tuberculosis infection. Lancet. 2015;386:2344–53.

90.Dharmadhikari AS et al. Surgical face masks worn by patients with multidrug-resistant tuberculosis: Impact on infectivity of air on a hospital ward. Am J Respir Crit Care Med. 2012;185(10):1104–9.

91.Lygizos M et al. Natural ventilation reduces high TB transmission risk in traditional homes in rural KwaZulu-Natal, South Africa. BMC Infect Dis. 2013;13:300.

Introduction History Etiology

Pathogenesis and transmission of tuberculosis Epidemiology

Transmission of infection by ingestion Diagnostic tests

Treatment Control

Risk to humans Conclusion References

INTRODUCTION

Mycobacterial infection can clinically affect a wide range of animal species including humans, and several mycobacterial species have the potential to cause zoonotic disease. Mycobacterium bovis infection is currently one of the most significant veterinary public health concerns worldwide and may account for a substantial loss of productivity of cattle. This can lead to a significant economic impact for farmers, impacting on the trade of livestock and associated products both within a country and internationally. Incidence of M. bovis in the human population of most higher middle income countries (HMICs) has decreased significantly since the nineteenth century due to the widespread introduction of milk pasteurization, but the disease remains endemic in the cattle and human population in many countries across the world. Disease control in cattle is challenging, particularly in areas where M. bovis has a significant reservoir in the wildlife population. Solutions to eradicate the disease completely are currently being sought in many countries across the world.

HISTORY

Columella was the first to document the incidence of tuberculosis in cattle in 40 AD. In the seventeenth and eighteenth centuries, the term “Persucht” was recorded in Germany, referring to the grapelike lesions documented on clinical examination, most likely to describe the disease currently known as bovine tuberculosis. At

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this point, the grape-like symptoms were considered to be a symptom of syphilis and their identification in cattle resulted in more rigorous control of disposal of the carcasses of affected animals. However, once the misconception that syphilis was the cause of this clinical sign was corrected, these control measures were discarded.

It was not until 1882 that Robert Koch first discovered the bacilli Mycobacterium tuberculosis, the main causative agent of tuberculosis in humans. Koch postulated at this time that the tuberculous disease also affecting cattle was not pathogenic to man. Theobald Smith, however, disproved this theory in 1898 by demonstrating that there was only a small difference between the mycobacteria that cause disease in humans and cattle.1 Koch later accepted Smith’s theory, under the assumption that the bovine form of tuberculosis was a less pathogenic form in humans than cows, and the reverse to be true upon transmission from humans to cattle.

The first route of transmission of M. bovis from cattle to humans was found to be by ingestion of unpasteurized cows’ milk.1 It was initially thought that eradication of zoonotic tuberculosis should be carried out by banning the sale of milk from tubercular cows, and eradicating tuberculosis in cattle.2 In 1901 the British Government opted to establish a Royal Commission to perform further investigations in an effort to establish whether tuberculosis in animals and humans was the same and investigate the potential main transmission routes from cattle to humans.1 This report was completed in 1911, and concluded that it is possible that M. bovis transmitted from cows can infect humans, and

may cause clinical disease in both species. The main infection route to humans was found to be via ingestion of infected cows’ milk, especially for children,3 and meat ingestion was concluded to be a much lesser risk.

Following this conclusion, control measures were slowly implemented in the United Kingdom and in 1913 the Tuberculosis Order offered local authorities the power to remove infected animals from farmers’ herds. In spite of the high prevalence of infected animals among herds, little was done to prevent the spread of disease and eradication was considered to be only an option for the wealthy cattle owners; the action of this Order was suspended during World War I. The general consensus appeared to be that although the disease was of great economic importance, its presence in the country was largely inevitable. However, over time, the Tuberculosis Order evolved, and in 1925 the government started to offer compensation to farmers for animals withdrawn from herds due to the presence of clinical signs of tuberculosis, a chronic cough, tuberculosis of the udder, weight loss, or tubercular milk. Under this Order, 15,000 cattle were slaughtered, an estimated 2500 of which were producing tubercular milk. In fact, the instigation of the Tuberculosis Order prompted the formation of veterinary services across all areas of the United Kingdom.

Initially there was a resistance to milk pasteurization across the United Kingdom due to both a public preference for raw milk, and the presence of powerful economic forces in the dairy industry that were reluctant to instigate the pasteurization procedure on a large scale. The practice first began in 1923, and by 1938, 98% of milk on sale in London was pasteurized. Over this same period the death rate due to abdominal tuberculosis fell dramatically to 9% for children under 5 years of age in London in comparison to children in more rural areas, where pasteurization of milk prior to ingestion was much less common, which fell to only 25% of the level recorded in 1923.1

In 1934, the Cattle Disease Committee reported that over 40% of cattle in the UK herds were infected with TB, and that 0.5% of cattle were suffering from tuberculous mastitis. Two thousand five hundred humans were reported to die annually due to zoonotic tuberculosis, 6% of the total mortality rate in the United Kingdom in the 1930s.4 This prompted the Cattle Diseases Committee to assert that the only solution to this problem was total eradication of tuberculosis from cattle in the United Kingdom. In 1935, the Tuberculosis (Attested Herds) Scheme was launched by the government providing a reward for the owners of “clean” herds and subsidizing the cost of tuberculin tests in herds that have only a small percentage of reactors.

It was not until 1950 that a national compulsory tuberculosis eradication scheme was introduced by the government in the United Kingdom, and compensation for reacting cattle and movement restrictions of affected herds were effectively enforced. Initially, the scheme was introduced only in areas with the highest numbers of affected herds, and gradually was extended out to reach herds across the whole of the United Kingdom by 1960.1 Following strict implementation of these policies, the incidence of infected cattle dramatically decreased, and in the late 1970s, the lowest prevalence of the disease yet was recorded in the United Kingdom. The number of cattle slaughtered annually decreased significantly over this period, and the percentage of tested herds

offering positive reactions dropped from 3.5% in 1961 to 0.49% in 1979. However, as has remained until this day, the incidence of disease remained higher in the South West of England compared to the remainder of Great Britain.5

The disease became notifiable to the State Veterinary Service in England, Wales, and Scotland under Sections 32 and 34 of the Animal Health Act 1981. The Act has since been variously amended by various instruments and the latest versions are available on the UK Government website (www.legislation.gov.uk).

It has never been possible to implement universal compulsory pasteurization of milk in England and Wales, despite advice from the Advisory Committee for the Microbiological Safety of Food, which independently reports to the Food Standards Agency. Currently, it is legally possible in England and Wales to sell milk from a cattle herd that is classed as Officially Tuberculosis Free (OTF) to the public.

Tuberculosis remains a major concern in animals in the United Kingdom. Between 1990 and 2004 there was an annual increase of 14% of new herd breakdowns of infections of tuberculosis, as detected by routine surveillance.

In 2004, 4.6 million cattle were tested in 44,720 herd tests across the United Kingdom. Overall in Great Britain at that time there were 93 million cattle herds, and a total of 9 million cattle and calves. These tests revealed 3339 new tuberculosis herd breakdowns, which was 7.5% of the total herds tested. Of these, 1702 breakdowns were confirmed, which equated to 3.6 confirmed herd breakdowns for every 100 nonrestricted cattle herds tested. Nearly 20,000 cattle were slaughtered as tuberculin test reactors in Great Britain in 2004. There were also 3000 cattle removed from herds that were “direct contacts,” i.e., those with a negative or inconclusive tuberculin test, but presented too high a risk of infection with M. bovis. In 2003, although approximately 50% of the new infections were from herds including dairy cattle, the incidence of tuberculosis in dairy herds was comparable to beef and other herd types (Figure 22.1). Updated figures for the incidence and prevalence of tuberculosis among cattle herds in Great Britain are published quarterly by the Department for Environment, Food and Rural Affairs.125

The main aim of eradication of bovine tuberculosis from countries where the disease is endemic has proved to be challenging. This is mainly due to the reservoir of the disease in wildlife. One of the successful eradication stories took place in Australia in the 1970s following a long, 27-year period of abattoir surveillance and culling of affected wildlife reservoirs of water buffalo as part of the Brucellosis and Tuberculosis Eradication Campaign to reduce the reservoir of tuberculosis. Australia was declared free of bovine tuberculosis in 1997. In the United Kingdom and Republic of Ireland the badger (Meles meles) became a source of concern as a possible wildlife reservoir of the disease and potential source of infection for cattle in the mid-1970s.1 In 1989, tuberculosis was made a notifiable disease of deer under the Tuberculosis (Deer) Order 1989 (as amended). Evidence does not suggest that other wild or feral animals (e.g. deer, fox and wild boar) pose a substantial national threat to cattle, although further work needs to be undertaken. Although there is no compulsory testing scheme for this species, postmortem inspection and notification of suspect lesions to the APHA is statutory for farmed, park, or wild deer.

Culling schemes of other animals which act as reservoirs of M. bovis for cattle and humans have taken place worldwide, for example, that of the brushtail possum in New Zealand, with limited effect on the provision of control of the disease.

To this day tuberculosis in animals remains a major veterinary public health concern across the world. This chapter aims to expand on these concerns.

ETIOLOGY

Mycobacteria of veterinary importance have been broken up into three groups.

1.Obligate primary pathogens: These mycobacteria require the presence of a mammalian host to continue their life cycle and include those of M. tuberculosis complex and Mycobacterium lepraemurium.

2.Saphrophytes: These mycobacteria are normally found existing on dead or decaying matter but have the potential to become facultative pathogens causing symptoms of either local or disseminated disease. They can be further categorized into fastor slow-growing opportunistic non-tuberculous mycobacteria and include mycobacteria such as M. avium.

3.Mycobacteria that are difficult to grow: These bacteria are so challenging to grow that it is impossible to determine their natural environmental niche. This group of bacteria is responsible for feline leprosy and canine leproid granuloma syndrome.

Over the last few years, genomic sequencing has begun to play a role in clarifying these taxonomic divisions.7,8 The lack of clarity in taxonomy has meant that specific mycobacteria are more easily classified according to their clinical presentation of disease, speed and ability to grow on culture media, and the mycobacteria’s biochemical properties. The etiological agents of tuberculosis in animals and their classification still remain the subject of debate.9

M. bovis is the main etiological agent of bovine tuberculosis. It carries the highest risk of zoonotic transmission and the greatest economic impact to humans. This acid-fast, aerobic, Gram-positive, nonmotile, non-sporulating, rod-shaped, and slow-growing bacillus can survive for long periods of time in the environment (between 18 and 332 days) at temperatures ranging between 12°C and 24°C.

M. bovis has been classified as part of the M. tuberculosis complex. This complex includes genetically related bacilli including M. tuberculosis, Mycobacterium microti, first discovered in the vole population, Mycobacterium caprae, the main agent that causes tuberculous disease in goats, and Mycobacterium pinnipedii, which usually clinically affects marine dwelling mammals such as seals and sea lions. This complex has a 99.9% similarity at a nucleotide level and almost identical 16S rRNA sequences.10 M. tuberculosis, the host-restricted mycobacteria that is the main mycobacterium to cause disease in humans, has evolved as a separate lineage of the MTB complex.11 Non-tuberculous mycobacteria are all those mycobacteria that are not part of the complex and contain fewer identical nucleotide sequences. These mycobacteria still have pathogenic potential and include the M. avium complex, the species of which include M. avium and M. avium paratuberculosis (MAP), the mycobacterium that is implicated in Crohn’s disease in humans and is the causative agent of Johne’s disease in cattle and sheep.

PATHOGENESIS AND TRANSMISSION

OF TUBERCULOSIS

Mycobacteria can infect a very broad range of hosts. M. bovis, which is the main agent responsible for tuberculosis in domestic animals and wildlife, has the broadest host range of the Mycobacterium complex group. Alternatively, M. tuberculosis rarely affects species other than humans, although cases in dogs have been occasionally reported.

Cattle are the natural host of M. bovis. These mycobacteria are distributed worldwide and most terrestrial animals and some birds are susceptible to these bacteria. Some host species, for example cattle, humans, pigs and goats are “maintenance” hosts, in which infection can become established and cause clinical disease while other species such as dogs and cats can act as “spillover” hosts, in which infection does not transmit onwards to other members of the same species. The innate resistance of “spillover” hosts’ immune systems is one of the reasons as to why these species do not go on to develop clinical disease when exposed to an infected individual of the same species. Other epidemiological factors, such as population density, husbandry, and habitat also affect the degree of interaction between the susceptible and the infected individuals and therefore the potential for clinical infection to occur.

M. bovis is a highly contagious, chronic debilitating disease of the maintenance hosts. Characteristically, tubercles, or nodular granulomas, may be seen on postmortem examination in the lymph nodes or affected tissue. The resulting caseation and calcification, excluding the skeletal muscles, contribute to the clinical symptoms of the disease. In all maintenance hosts, the disease can be contracted either via aerosol or ingestion, causing a non-pul- monary or pulmonary form of the disease and clinical symptoms of either form can take months or years to develop.

As expected, the clinical symptoms of the pulmonary form include a chronic cough due to granulomatous, caseous, necrotizing inflammation in the lungs and associated lymph nodes,12 the commonest of which to be affected are the bronchial, mediastinal, retropharyngeal, and portal lymph nodes. Enlargement of other lymph nodes can also be detected and tubercles can also be discovered in the liver, spleen and body cavities. In advanced cases of the disease, enlarged lymph nodes have the potential to cause significant obstruction, for example, of the trachea, alimentary tract, or blood vessels. Enlargement of the peripheral lymph nodes can be viewed on external examination, and these nodes have the potential to rupture and their caseous contents to drain. Symptoms due to the involvement of the digestive tract may include intermittent diarrhea and bloating, due to the presence of enlarged mediastinal lymph nodes and retropharyngeal lymph node enlargement can lead to dysphagia. Clinical symptoms can therefore be attributed to the organs involved and may vary between cases. They may include weight loss, weakness, inappetence, fluctuating fever, an intermittent hacking cough, diarrhea, anorexia, and induration of the udder, depending on the manifestation of the disease. Tuberculous mastitis in cattle is a major public health concern, as the disease can spread easily from infected cattle to both calves and humans consuming the milk, and mastitis caused by M. bovis is clinically indistinguishable from other forms of mastitis.

An understanding of the immune response of the host will help to understand the pathogenesis of the disease.13 During the initial infection a cell-mediated response, with activity of T cells and macrophages, predominates. As the infection progresses, the immune response converts to humoral and there is a change from the T helper 1 to T helper 2 immune response. A deviation of interleukin responses also occurs, which can be detected on investigation by cytokine analysis.

The most common route of transmission of M. bovis between animals is via the respiratory system and therefore humans handling potentially infected cattle should take appropriate precautions. Cutaneous or mucosal transmission routes are extremely rare, especially in industrialized countries, where the bacilli load is much smaller. Previously in the United Kingdom, cutaneous transmission was the source of localized skin, tendon, and lymph node lesions, and otitis and conjunctivitis commonly afflicted milking staff or farm workers in regular contact with infected cattle.3 The incidence of tuberculosis caused by M. bovis in humans is associated with the efficiency of tuberculosis control strategies.

In the United Kingdom, ingestion of infected milk was the main transmission route of M. bovis from cattle to man before the advent of pasteurization.1 In countries where milk pasteurization is common and widespread, transmission of M. bovis to humans from cattle is now a much-decreased risk. Where milk pasteurization is not present or well controlled, transmission of M. bovis from cattle to humans continues to occur.14 The infective dose of tuberculosis has been thought to be 10–100 cfu by inhalation and much higher, in millions, to cause disease by ingestion.15 One cow in a 100 cattle herd infected with M. bovis and shedding bacilli into the milk is sufficient to contaminate the entire bulk milk tank, with the potential to infect a human. M. bovis can remain present and viable in unpasteurized milk for a long period of time, but will only replicate within the udder. Currently in the United Kingdom, due to the instigation of tuberculosis control programmes and milk pasteurization, infection via ingestion of infected milk is rare in humans and currently only 0.5% of all infected cattle slaughtered appear to be shedding M. bovis bacilli into the milk at the time of death.

Transmission of M. bovis to humans from any other animals apart from cattle is thought to occur only sporadically. Normally only those humans with regular contact with other potentially infected maintenance hosts are likely to be infected, such as deer farm owners. Published information documenting transmission from deer to humans is very limited, and no reports have been published in the literature originating from the United Kingdom. One report has documented transmission to a human from an elk (Cervus elaphus canadensis) in Canada.16 In the United Kingdom, there is a high prevalence of M. bovis in the wild deer population, and tuberculosis outbreaks have been confirmed in a small number of farmed deer herds,17 therefore, the potential reservoir for transmission does exist.

EPIDEMIOLOGY

Natural infection with M. bovis has been described in many different species of wild and domestic animals across the world.18 The host range of this bacteria is much broader than that of M. tuberculosis and the complex epidemiology of this pathogen has complicated its eradication.19 To some degree, all terrestrial mammals are susceptible to infection and infection rate depends on exposure, innate resistance, immunological pathways, type of husbandry and ecology, and characteristic pathology of the disease.20

Cattle are the major maintenance host of M. bovis, and therefore are capable of maintaining the infection within their

population. “Spillover” hosts can be defined as those in which the animal species may become infected, but are not particularly effective at transmitting the infection between other members of the same species. In the case of M. bovis, these spillover hosts include, among others, humans, cats, and dogs.

Within the cattle species, different breeds have been found to show differing susceptibilities to disease. Bos taurus, a European lineage of cattle, is more susceptible to disease than Bos indicus, or zebu cattle.21 Zebu cattle appear to have an innate resistance to infection with mycobacteria. In the United Kingdom and Republic of Ireland, Holstein cattle have been shown to pass a significant degree of heritability of resistance to bovine tuberculosis infection on to their young.22–24 The modern Friesian breed of cattle was developed in the 1940s by Dutch cattle breeders as a hardier and more “tuberculosis-resistant” dairy cow.25 Greater genetic variation is expected between beef cattle in comparison to dairy cattle, as the latter are more homogenous in terms of breeding history. Normally dairy herds are more intensively managed than beef cattle due to the nature of their production systems, and this closer and more regular contact between cattle, as well as the longer life expectancy of a dairy cow in comparison to beef cattle, increases the probability of a higher prevalence of M. bovis within the dairy population. Geographically, M. tuberculosis infection has been found to be much less prevalent in areas where cattle farming is more extensive, for example, South America, Asia and Africa, although a higher incidence has been reported across the world in ranch cattle, potentially as the extensively reared cattle cluster around watering points at ranches to drink.

The main route of transmission of M. bovis among cattle and spillover hosts is via aerosolized droplets from infected individuals. The mycobacterial organisms can also be secreted in sputum, feces, urine, vaginal, and uterine discharges, as well as from any draining fluid from ruptured peripheral lymph nodes.26 Ingestion of unpasteurized infected milk or milk products is also an excellent medium for transmission for both calves and humans. If no pasteurization has occurred, mycobacteria present in milk can remain infectious for extended periods of time. This may be up to 200 days in milk and 322 days in certain types of cheese. Environmental transmission of M. bovis can occur, as aerosolized particles may contaminate fomites at pasture or inside housing. The mycobacteria may, more rarely, be transmitted by contact with contaminated feces or urine from infected animals.27 Movement of cattle across the country spreads the bacteria, as infected cattle spread the infection to naïve areas containing susceptible animals.

Eradication of M. bovis has occurred in some areas such as Australia, some states of the United States, Germany and some countries in South America, normally following strict test and slaughter policies, and eradication of the disease to an appropriate extent in wildlife reservoirs.

In the United Kingdom and Ireland, the Eurasian badger (M. meles) is an additional maintenance host for M. bovis. Krebs5 declared this species to be a significant reservoir of infection for cattle, so impeding the eradication of the disease in cattle.5,28 There is a split of opinion as to whether badgers present a significant reservoir of infection in endemically infected areas in the United Kingdom, and whether this infection is passed onto the environment from badgers to infect other species.28

In Africa, generally, a high prevalence of bovine tuberculosis has been reported in cattle, buffalo,56 monkeys, and deer. M. bovis infection is widespread and endemic among cattle and humans in Ethiopia, and has been for many years. This country has the largest livestock population in Africa with a total of 56 million cattle, 29 million sheep, and 29 million goats. The exact current prevalence of bovine tuberculosis infection in cattle is unknown, but suspected to be anywhere between 7.9% and 49%53 of the cattle population affected, and the prevalence in dairy herds ranges between 15.6% and 50%. Most of the prevalence surveys have been based on results from the intradermal skin test and postmortem inspection of cattle carcasses at abattoirs. Prevalence studies in various parts of Ethiopia have confirmed that exotic breeds are more likely to be affected than zebu cattle.54

The main route of transmission in Ethiopia between animals and man is the ingestion of unpasteurized milk, leading to the development of the extrapulmonary form of tuberculosis in humans. As well as the consequences due to human infection, the productivity of the cattle, including the milk yield, is decreased, and the economic impact of bovine tuberculosis infection in Ethiopia has been described.

In Ethiopia, there are four categories of livestock production systems, which are variously affected by bovine tuberculosis infection:

1.Integrated crop−livestock extensive production system

2.Pastoral livestock production system

3.Smallholder production system

4.Intensive production systems

Eighty-five percent of the country’s livestock production occurs in system 1, where crop production is the primary target and animals are kept for draught power and seasonal milk and meat production in the semiarid and highland areas. Animal husbandry is traditional, with low hygiene standards. Those who implement the pastoralist production system derive the bulk of their food supply from animals in the lower altitude areas of the country. The cattle herds are either constantly or partially mobile. This system covers 12% of the total livestock production and 61% of the total land area of the country. The smallholder production system mainly occurs near towns, and is mainly practised in highland areas where dairy animals are reared for milk production and subsistence. Prevalence of bovine tuberculosis in these systems has not been adequately surveyed but has been thought to be low, mainly due to the extensive nature of the production systems. One survey found a 3.5% prevalence in Asela, Southeast Ethiopia. However, drinking raw milk is a common practice for cattle owners in these areas, so the risk of human infection with bovine tuberculosis remains.

There are a small number of intensive production systems, mainly located in urban and peri-urban areas, for which milk and milk product production is the main concern. The animals in these more intensive systems are normally housed and managed more intensively, so increasing the risk of spreading M. bovis. Overall targets for milk and meat production are mainly met by the introduction of exotic breeds to increase productivity. However, these exotic, non-native breeds have an increased susceptibility to bovine tuberculosis and this has created a conducive environment for the spread of infection and an increased risk to