Chapter 1

Tuberculosis: The Disease

Tuberculosis is a contagious disease that occurs in many animals (including humans, cattle, and birds) and is caused by microorganisms of the genus Mycobacterium. These microorganisms cause the formation of nodules or tubercles in the tissues of infected individuals. The discovery of these tubercles in the meat and viscera of slaughtered animals and in humans dying of “phthisis” or “consumption” in the 19th century resulted in the disease being called “tuberculosis” (Konyha et al., 1980).

Tuberculosis primarily effects the respiratory system, but the bacteria may spread throughout the body, disseminated through the lymph system and blood vessels. In many animals the disease is most often caused by a species of Mycobacterium that has adapted to the host animal species (Timoney et al., 1988). For example, most tuberculosis in humans is caused by Mycobacterium tuberculosis, in cattle by Mycobacterium bovis, and in birds by Mycobacterium avium. Most species of Mycobacterium, however, are capable of infecting a variety of animal species.

Although the incidence of all tuberculosis in humans has declined dramatically since the 19th century, national attention has been refocused on this disease since the Centers for Disease Control (CDC) reported a resurgence of M. tuberculosis infection. From 1985 to 1992 the number of cases of human tuberculosis in the United States was more than 51,000, which was more than was expected based on historical trends (Centers for Disease Control, 1993a). This increase is caused by M. tuberculosis spread person to person. In addition, there has been a rising incidence of multiple drug resistant M. tuberculosis isolates in immunocompromised patients (Centers for Disease Control, 1991). Although it is important to note that this overall increase in M. tuberculosis infection is unrelated to any increase in M. bovis infection in the animal population, it is of great importance to reduce the exposure of these patients to any form of tuberculosis, including those of animal origin (Centers for Disease Control, 1990).

The documentation of tuberculosis in humans and in cattle reveals a four-way relationship: tuberculosis in humans caused by M. tuberculosis, tuberculosis in humans caused by M. bovis, tuberculosis in cattle caused by M. bovis, and tuberculosis in cattle caused by M. tuberculosis.

HISTORICAL OVERVIEW

Although archaeologic evidence documents the existence of tuberculosis in Egyptian and Andean mummies, the disease was apparently not of great importance (Rieder, 1989) until it began to increase in Europe during the 17th and 18th centuries, probably as a result of three factors. First, the European population was highly susceptible, having no innate resistance (a legacy of genes from individuals who survived the disease). [Differences in innate resistance have been documented in animal species and humans (Youmans, 1979)]. Second, poor housing and crowded conditions created



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LIVESTOCK DISEASE ERADICATION: EVALUATION OF THE COOPERATIVE STATE–FEDERAL BOVINE TUBERCULOSIS ERADICATION PROGRAM Chapter 1 Tuberculosis: The Disease Tuberculosis is a contagious disease that occurs in many animals (including humans, cattle, and birds) and is caused by microorganisms of the genus Mycobacterium. These microorganisms cause the formation of nodules or tubercles in the tissues of infected individuals. The discovery of these tubercles in the meat and viscera of slaughtered animals and in humans dying of “phthisis” or “consumption” in the 19th century resulted in the disease being called “tuberculosis” (Konyha et al., 1980). Tuberculosis primarily effects the respiratory system, but the bacteria may spread throughout the body, disseminated through the lymph system and blood vessels. In many animals the disease is most often caused by a species of Mycobacterium that has adapted to the host animal species (Timoney et al., 1988). For example, most tuberculosis in humans is caused by Mycobacterium tuberculosis, in cattle by Mycobacterium bovis, and in birds by Mycobacterium avium. Most species of Mycobacterium, however, are capable of infecting a variety of animal species. Although the incidence of all tuberculosis in humans has declined dramatically since the 19th century, national attention has been refocused on this disease since the Centers for Disease Control (CDC) reported a resurgence of M. tuberculosis infection. From 1985 to 1992 the number of cases of human tuberculosis in the United States was more than 51,000, which was more than was expected based on historical trends (Centers for Disease Control, 1993a). This increase is caused by M. tuberculosis spread person to person. In addition, there has been a rising incidence of multiple drug resistant M. tuberculosis isolates in immunocompromised patients (Centers for Disease Control, 1991). Although it is important to note that this overall increase in M. tuberculosis infection is unrelated to any increase in M. bovis infection in the animal population, it is of great importance to reduce the exposure of these patients to any form of tuberculosis, including those of animal origin (Centers for Disease Control, 1990). The documentation of tuberculosis in humans and in cattle reveals a four-way relationship: tuberculosis in humans caused by M. tuberculosis, tuberculosis in humans caused by M. bovis, tuberculosis in cattle caused by M. bovis, and tuberculosis in cattle caused by M. tuberculosis. HISTORICAL OVERVIEW Although archaeologic evidence documents the existence of tuberculosis in Egyptian and Andean mummies, the disease was apparently not of great importance (Rieder, 1989) until it began to increase in Europe during the 17th and 18th centuries, probably as a result of three factors. First, the European population was highly susceptible, having no innate resistance (a legacy of genes from individuals who survived the disease). [Differences in innate resistance have been documented in animal species and humans (Youmans, 1979)]. Second, poor housing and crowded conditions created

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LIVESTOCK DISEASE ERADICATION: EVALUATION OF THE COOPERATIVE STATE–FEDERAL BOVINE TUBERCULOSIS ERADICATION PROGRAM circumstances that were ideal for spread of the disease; and the mobility inherent in urbanization and industrialization meant that infected individuals could carry the disease more rapidly and further afield to more individuals (Holmberg, 1990). A third factor was the commercialization of food production, which led to increased movement of animals and animal products between farms and population centers. This allowed contaminated milk from one herd to be mixed with the milk of many herds and thus reach larger numbers of people (Collins and Grange, 1983). During this period it is estimated that 25 percent of European cattle were infected with M. bovis. The confluence of these factors contributed to long-term interrelated epidemics of tuberculosis in cattle and humans. Discovery of the Pathogen In 1882 Robert Koch, a general practitioner in Germany, isolated an organism he called the “tubercle bacillus” (Myers, 1940). He was specifically interested in tuberculosis because it accounted for one-seventh of all his cases (Sakula, 1979). Koch's proof that this organism M. tuberculosis, was the causative agent of what we know as tuberculosis is the basis for all modern causal associations (Myers, 1940; Daniel and Janicki, 1978; Koch, 1932). The organism that caused tuberculosis in cattle (M. bovis) was found to differ from M. tuberculosis and to cause some tuberculous disease in humans (Collins and Grange, 1983). In an attempt to devise a cure for human tuberculosis, Koch produced a sterile filtrate of the tubercle bacillus culture. He believed that this material would be therapeutic if injected into tuberculous patients. Unfortunately, there was no therapeutic effect from Koch 's tuberculin, although it was observed that patients infected with tuberculosis developed fever, chills, and vomiting after being injected, while nontuberculous patients showed no response after injection (Daniel and Janicki, 1978). Eventually tuberculin was used as a tool to diagnose tuberculosis in animals and humans. Tuberculosis in North America Cattle were introduced to North America in the 1500s by Spanish explorers arriving through the Caribbean and Mexico. One hundred years later cattle from Britain and northern Europe were being imported to the east coast of North America; 25 to 50 percent of these cattle were infected with tuberculosis. At the same time, the majority of human immigrants from Europe had active tuberculosis or had been infected at some time in their life and thus were potential carriers. Through the 19th century 20 percent of all deaths were caused by tuberculosis (Holmberg, 1990). In 1800 in New England, deaths caused by tuberculosis in humans peaked at the estimated rate of 1 percent of the population per year. This rate began to decline in New England after 1820, but peak rates in other population centers followed the development of urbanization. The highest rates in the Midwest occurred in the 1840s and in San Francisco in 1870. After the Civil War the death rate caused by tuberculosis was highest in the African American population as they moved to urban areas and became more mobile (Grigg, 1958). These peaks all related to the spread of the disease among susceptible populations living in crowded conditions. Since peaking in the 1800s in the United States, the prevalence of tuberculosis has declined steadily at a rate of about 5 to 6 percent per year. Several contributing factors have been suggested for this decline. Natural selection has had an opportunity to act on the U.S. population over the past 2 centuries and it is argued that individuals today have greater natural resistance than did their ancestors. Improved housing with a decrease in the number of individuals per housing unit may have

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LIVESTOCK DISEASE ERADICATION: EVALUATION OF THE COOPERATIVE STATE–FEDERAL BOVINE TUBERCULOSIS ERADICATION PROGRAM reduced the level of spread within family units (Holmberg, 1990). The use of sanitaria to remove patients with cavitary lung disease from society may have reduced the number of new cases per active case of disease and assisted in the decline (Wilson, 1990). Improved general health of the population and improved nutrition may also have contributed. What is clear is that the decline existed through the 19th century prior to the development of accurate diagnosis or effective drug therapy (Grigg, 1958). The disease in cattle and humans was largely uncontrolled until the 1890s when the tuberculin test, developed by Bang in Denmark, was evaluated and applied in the United States. This test determined whether an animal was hypersensitive to proteins derived from Mycobacterium, as originally noted by Koch. Animals that were hypersensitive were deemed to have been exposed to tuberculosis and at that time many of these had active disease. In 1900 the mortality rate from tuberculosis in the U.S. population was 200 per 100,000 annually (Grigg, 1958), and 6 to 30 percent of this was caused by M. bovis acquired from infected milk (Centers for Disease Control and Prevention, 1992). Decline in human tuberculosis (M. bovis and M. tuberculosis) continued with the institution of pasteurization of milk and the Bovine Tuberculosis Eradication Program, almost eliminating human disease due to M. bovis by the 1940s (Karlson and Carr, 1970). The mortality rate caused by tuberculosis declined slightly in the late 1940s and early 1950s with the introduction of effective antituberculous drug therapy, but the incidence of overall disease continued to decrease at about 6 percent per year (Fishman, 1988). In the 1970s M. bovis isolates were found chiefly in immigrants, the elderly who had consumed raw milk in their youth, and individuals in contact with infected animals (Konyha et al., 1980). It is likely that M. bovis isolates are now being found at a rate similar to that of 1981. However, since the number of cases is small, significant upward or downward trends may not be noticed. In 1980 and 1981, the last 2 years for which statistics distinguished between M. bovis and M. tuberculosis, 0.12 percent of human tuberculosis was caused by M. bovis (Kent and Kubica, 1985). Human and Bovine Tuberculosis: Interrelationships As will be described subsequently, there are a number of different species in the genus Mycobacterium including the leprosy bacterium. However, the infections produced by M. tuberculosis, the primary cause of human tuberculosis, and M. bovis, the primary cause of bovine tuberculosis, are the major concern. Most of this report will concentrate on infection associated with M. bovis. Mycobacterium tuberculosis in Humans Mycobacterium tuberculosis is spread through the respiratory system. Its presence in susceptible humans can cause pneumonia. In most cases the pneumonia heals but the infection remains latent. If the primary lung infection fails to heal, cavitary lesions may form in which the disease-causing organisms incubate. Breathing, coughing, or talking releases large quantities of Mycobacterium into the air, thus spreading the disease. If the primary infection heals but reactivates later in the lung, infectious cavities form with the same result. Infection can reactivate in bone, kidney, brain tissue, or elsewhere. In these instances, the patient is less contagious for other individuals. A clinical diagnosis must be supported by observation of the causative organism in tissue biopsies, secretions, or body fluids and confirmed by isolation and identification of M. tuberculosis in

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LIVESTOCK DISEASE ERADICATION: EVALUATION OF THE COOPERATIVE STATE–FEDERAL BOVINE TUBERCULOSIS ERADICATION PROGRAM the laboratory (Konyha et al., 1980). Therapy using antituberculous drugs results in a high cure (sterilization of lesions) rate (Centers for Disease Control, 1992). An increasingly frequent problem is the emergence of drug resistant strains of the organism. Mycobacterium bovis in Humans The infectivity of M. bovis in humans depends on both the route of exposure and the virulence of the organism (Gillespie and Timoney, 1981). In the early 20th century in the United States, a significant percentage of tuberculosis in humans (including most infections in children) was caused by ingesting dairy products contaminated with M. bovis. This led physicians to join cattle producers and veterinarians in support of the eradication program (Meyers and Steele, 1969). The effects of milk pasteurization and the national bovine tuberculosis eradication program have reduced the public health risk of M. bovis infection. However, the risk of M. bovis infection in humans still exists in subpopulations. Ingestion of unpasteurized contaminated milk products poses a greater risk than ingestion of infected meat products because badly infected carcasses are condemned; parts of carcasses that are processed as meat products are inspected and thoroughly cooked (Konyha et al., 1980). Thorough cooking [170° F (76.7° C) for 30 minutes] removes virtually all risk of infection (Hagstad and Hubbert, 1991). Following ingestion of the organism, the primary infection in the intestine may heal, it may progress in the intestines, or it may disseminate to other organs (Grange and Collins, 1987). In the 19th century the majority of childhood tuberculosis was of this type; that is, alimentary tuberculosis. When infection spread to the lungs, resulting in cavitary lesions, person-to-person spread or person-to-animal spread caused disease similar to that caused by M. tuberculosis (Wilson, 1990). Farm workers, zookeepers, veterinarians, slaughterhouse workers, and laboratory personnel may be in contact with infected animals or their tissues in situations that produce aerosols of organisms. People in these occupations may develop pulmonary tuberculosis from M. bovis and in turn put other humans and susceptible animals at risk (Kleeberg, 1984; Essey et al., 1991; Dalovisio et al., 1992; Danker et al., 1993). Mycobacterium tuberculosis in Cattle Although M. tuberculosis can cause progressive disease in dogs, parrots, and nonhuman primates, this organism is relatively innocuous for cattle and related species. There have been a few reports of M. tuberculosis in the milk of cows naturally or experimentally infected with this organism. For practical purposes, however, M. tuberculosis in cattle will not sustain itself in the population and, therefore, is not of epidemiologic significance (Timoney et al., 1988). Mycobacterium bovis in Cattle The disease caused by M. bovis in cattle is similar to that caused by M. tuberculosis in humans. It spreads from an infected animal directly to a susceptible one by either inhalation of exhaled contaminated air or ingestion of contaminated secretions or excretions. This results in a primary infection in the lungs or local lymph glands that can lead to dissemination of the microorganism throughout the body (Blood et al., 1989). As in humans, the initial lesion may heal completely, become progressive, or heal and then reactivate. Animals infected with M. bovis are the

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LIVESTOCK DISEASE ERADICATION: EVALUATION OF THE COOPERATIVE STATE–FEDERAL BOVINE TUBERCULOSIS ERADICATION PROGRAM primary source of exposure for other animals and contact increases the likelihood of transmission. This is a particular problem in dairy operations where close confinement leads to higher rates of transmission than in beef or ranch operations. Animal offspring that feed on contaminated milk may develop infection of the gastrointestinal tract in the absence of pulmonary disease. Presumptive diagnosis of tuberculosis is usually a postmortem finding made at the time of slaughter and requires isolation of M. bovis for definitive diagnosis (Timoney et al., 1988). Mycobacterium bovis can infect virtually all species of mammals, including domestic animals, and wildlife species. Many of these species are included in zoological parks and petting zoos. The reservoir for this disease, therefore, is much broader than the reservoir of M. tuberculosis, and the potential for interspecies spread, including spread to humans, is greater (Konyha et al., 1980). TUBERCULOSIS IN ANIMALS OTHER THAN CATTLE Although cattle are the definitive hosts of M. bovis, the organism also infects other mammalian species, including humans; traditional domestic species including swine, horses, dogs, cats, sheep, and goats; and species traditionally considered to be wildlife, such as cervids (deer, elk, moose), bovids (antelopes, bison, wild cattle, buffalo), camelids (camels, llamas, vicuna), mustelids (mink, badger, ferret, and otter), felids (lion, tiger, leopard, lynx), and giraffes (Thoen and Himes, 1981; Montali, 1978; Ippen et al., 1992; Stockdale, 1992; Bush, et al., 1986). In most instances the sources of the infection for traditional wildlife species are unknown. Mycobacterium bovis is a major problem for the deer farming industry of New Zealand (Beatson, 1985; Griffin, 1991; Buchan and Griffin, 1990) and was recently identified in farmed deer and elk in the United States and Canada. Farmed deer in Sweden (Gavier-Widen et al., 1992), Denmark (Jorgensen et al., 1988), Australia (Robinson et al., 1989), the United Kingdom (Stuart, 1988), and Hungary (Zomborszky et al., 1992) have also been infected with M. bovis. Mycobacterium bovis infection in swine, horses, sheep, and goats are rare in North America at present, a reflection of the low prevalence in cattle. Infection in swine usually produces a progressive disease with lesions in the lymph nodes of the head, neck, and abdomen, as these points are related to entry of the organisms through ingestion. Lesions may also be found in the lungs and abdominal viscera. In horses, lesions occur in the pharyngeal area, mesentery, lungs, liver, and spleen. Lesions in sheep and goats are mainly pulmonary. The disease is progressive only in young kids. Tuberculosis in wild hoofed animals is most frequently caused by M. bovis; however, M. tuberculosis, M. avium, and some of the fast growing mycobacteria such as M. chelonei are occasionally involved. Although of concern in the husbandry of traditional wildlife species, tuberculosis in nonungulates does not currently play a role in the epidemiology of bovine tuberculosis in cattle and other ungulates in the United States. In the United Kingdom, however, European badgers (Meles meles), and in New Zealand, the brush-tailed possum (Trichosurus vulpecula), serve as significant reservoirs of M. bovis (Konyha et al., 1980; Benham and Broom, 1989; Livingstone, 1992; Stockdale, 1992). In primates, M. tuberculosis is the agent most frequently isolated from tuberculous animals, with M. bovis being the next most common. Disease caused by M. avium and saprophytic mycobacteria (such as M. kansasii) occurs infrequently in primates (Francis, 1958; Thoen and Himes, 1981). Mycobacterium avium is the organism most commonly associated with tuberculosis in avian

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LIVESTOCK DISEASE ERADICATION: EVALUATION OF THE COOPERATIVE STATE–FEDERAL BOVINE TUBERCULOSIS ERADICATION PROGRAM species found in zoos. Cases have been reported in almost all orders of birds (Karlson, 1978). Mycobacterial infections and tuberculosis also occur in reptiles (snakes, lizards, turtles, and tortoises) (Brownstein, 1978) and in fish (Wolke and Stroud, 1978), usually as sporadic disease episodes with low morbidity. Mycobacteria isolated from fish include M. marinum and M. fortuitum (Wolke and Stroud, 1978). Organisms isolated from reptiles have all been within the Runyon groups I and IV. Mycobacterium marinum is the species most commonly isolated in reptiles; infections are less frequently caused by M. chelonei and M. thamnopheos. Most of these organisms produce disease only when the host is immunosuppressed or when large numbers of organisms are introduced.