Overview of Tuberculosis and other Mycobacterial Infections
Tuberculosis (TB) is considered a reemerging, infectious granulomatous disease in animals and people caused by acid-fast bacilli of the genus Mycobacterium. Although commonly defined as a chronic, debilitating disease, TB occasionally assumes an acute, rapidly progressive course. The disease affects practically all species of vertebrates. The widespread occurrence of multidrug-resistant (MDR) strains and extensively drug-resistant (XDR) strains of M tuberculosis is of concern to clinicians and public health and regulatory officials involved in the control of disease. Bovine TB is still a significant zoonosis in nonindustrialized countries of the world. Signs and lesions are generally similar in the various species.
The main types of M tuberculosis complex (mammalian tubercle bacilli) recognized are M tuberculosis, M canettii, M bovis, M caprae, M pinnipedii, M microti, M mungi, and M africanum. The M avium complex includes M avium avium (avian tubercle bacilli), M avium hominissuis (isolated from people, swine, and other mammals), and M intracellulare. The types differ in cultural characteristics and pathogenicity. Several serovars of M avium avium are recognized; however, only serovars 1, 2, and 3 are pathogenic for birds. M bovis may survive on pasture for ≥2 mo, and M avium may survive in soil for ≥4 yr.
All types may produce infection in host species other than their own. M tuberculosis is most specific; it rarely produces progressive disease in animals other than people and nonhuman primates, infrequently in dogs and pigs, and has very rarely been isolated from skin lesions in exotic birds. M bovis can cause progressive disease in most warm-blooded vertebrates, including people. M caprae, an organism closely related to M bovis, has been isolated from people, goats, cattle, and several other species in Europe. M avium avium is the species of most importance in birds, but it has a wide host range and is also pathogenic for pigs, cattle, sheep, deer, mink, dogs, cats, certain exotic hoofed animals, and some cold-blooded animals. M avium hominissuis is the cause of tuberculosis in people, swine, and other animals. M genavense and other pathogenic mycobacteria are infrequently isolated from exotic and free-living wild and domestic birds (see Mycobacterial Infections Other than Tuberculosis). M intracellulare causes disease in cold-blooded animals and has been isolated from many other species.
Inhalation of infected droplets expelled from the lungs is the usual route of TB infection, although ingestion, particularly via contaminated milk or water, also occurs. Intrauterine and coital methods of infection are recognized less commonly. Inhaled bacilli are phagocytosed by alveolar macrophages that may either clear the infection or allow the mycobacteria to proliferate. In the latter instance, a primary focus may form, mediated by cytokines associated with a hypersensitivity reaction that consists of dead and degenerate macrophages surrounded by epithelioid cells, granulocytes, lymphocytes, and later, multinucleated giant cells. The purulent to caseous, necrotic center may calcify, and the lesion may become surrounded by granulation tissue and a fibrous capsule to form the classic “tubercle.” The primary focus plus similar lesions formed in the regional lymph node is known as the “primary complex.” In alimentary forms of disease, the primary focus may be found in the pharynx or mesenteric lymph nodes or, less commonly, in the tonsils or intestines. The cellular composition of and presence of acid-fast bacilli in tuberculous lesions differ between and within host species.
The primary complex seldom heals in animals and may progress slowly or rapidly. Dissemination through vascular and lymphatic channels may be generalized and rapidly fatal, as in acute miliary TB. Nodular lesions may form in many organs, including the pleura, peritoneum, liver, kidney, spleen, skeleton, mammary glands, reproductive tract, and CNS. A prolonged, chronic course may also ensue, with lesions usually having a more localized pattern of distribution.
The clinical signs of TB reflect the extent and location of lesions. Generalized signs include progressive emaciation, lethargy, weakness, anorexia, and a low-grade, fluctuating fever. The bronchopneumonia of the respiratory form of the disease causes a chronic, intermittent, moist cough with later signs of dyspnea and tachypnea. The destructive lesions of the granulomatous bronchopneumonia may be detected on auscultation and percussion. Superficial lymph node enlargement may be a useful diagnostic sign when present. Affected deeper lymph nodes cannot always be palpated, but they may cause obstruction of the airways, pharynx, and gut, leading to dyspnea and ruminal tympany.
In pigs, lesions caused by M avium hominissuis or M avium avium are most often seen in lymph nodes associated with the GI tract, although generalized disease involving the liver, lung, and spleen does occur.
The single most important diagnostic test for TB is the intradermal tuberculin test. Old tuberculin prepared from the culture filtrate of M tuberculosis is used to detect disease in nonhuman primates exposed to M tuberculosis or M bovis. In other animals, purified protein derivatives (PPDs) prepared from the culture filtrate of M bovis or M avium can be used. Diagnosis based on clinical signs alone is very difficult, even in advanced cases. Radiography is useful in nonhuman primates and small animals. Microscopic examination of sputum and other discharges is sometimes used. Necropsy findings of the classic “tuberculous” granulomas are often very suggestive of the disease. Confirmation of diagnosis is by isolation and identification of the organism, with culture usually taking 4–8 wk, or by PCR, which requires only a few days. Molecular techniques, such as restriction fragment length polymorphism (RFLP) or variable number tandem repeat (VNTR) provide definitive information useful in conducting epidemiologic investigations.
The delayed-type hypersensitivity response of the host, responsible for much of the pathology of TB, is fundamental to the tuberculin skin test widely used for diagnosis in large animals. The single intradermal (SID) test involves inoculation of PPD prepared by precipitation of protein from the culture filtrate of M bovis. PPD preparations improve specificity. In a reactor, the antigen stimulates a local infiltrate of inflammatory cells and causes skin swelling that can be detected by palpation and measured by calipers. The reaction is read at 48–72 hr for maximum sensitivity and at 96 hr for maximum specificity. Test sites used vary in sensitivity and between countries/areas and include the neck region, caudal fold at the tail base, and vulval lip. One disadvantage of the M bovis SID test is that cross-reactions may occur in animals infected with M kansasii, M avium, M tuberculosis, M avium paratuberculosis, or other mycobacteria that share some antigenic determinants with M bovis.
In areas with a high incidence of avian TB or other mycobacterial infections such as paratuberculosis, the comparative tuberculin skin test can be used, with biologically balanced M bovis and M avium PPD tuberculins inoculated simultaneously but at separate sites in the neck. The agent causing sensitization provokes the greater skin reaction. Other diagnostic tests used for TB include the thermal test, which may detect a pyrexic peak (104°F [>40°C]) at 6–8 hr after SC inoculation with tuberculin. The Stormont test uses an intradermal inoculation of PPD followed by a second inoculum at the same site 7 days later. The test is read for swelling 24 hr later.
False-negative results may occur in animals with poor immune response such as those in the early stages of infection, nonresponsive cases in advanced disease, or old animals. Cattle that have recently calved may also have false-negative results. Current research is focused on the identification of antigens such as secretory proteins and genetically engineered proteins of M bovis for use in improved in vitro diagnostic tests. Serologic tests such as ELISA appear to be of limited diagnostic use, consistent with the lesser role of antibody compared with the cellular immune response in TB. In vitro cellular assays have been developed (ie, interferon-γ assay) using WBCs stimulated with M bovis antigen and may be used as a supplemental test to the widely used SID test; however, they have not come into widespread use in many nonindustrialized countries because of cost and the necessity to conduct cellular assays in the laboratory within 24 hr after collection of blood specimens.
The main reservoir of M bovis infection is cattle. However, other animals have been found to be reservoirs in some countries, including badgers and red deer (England, Ireland); red deer, possums, and ferrets (New Zealand); mule deer, white-tailed deer, elk, and American bison (North America); African buffalo (South Africa); and water buffalo (Australia). The prevalence of disease in such reservoirs influences the incidence of disease in other species. Carnivores and scavengers can acquire M bovis by consumption of infected carcasses. These species include lion, coyote, wolf, hyena, cheetah, black bear, bobcat, and leopard. Warthogs, ferrets, raccoon, European wild boar, opossums, and feral pigs have also been found to be infected with M bovis.
The three principal approaches to the control of TB are test and slaughter, test and segregation, and chemotherapy. The test and slaughter policy is the only one assured of eradicating TB and relies on the slaughter of reactors to the tuberculin test. In an affected herd, testing every 2 mo is recommended to rid the herd of individuals that can disseminate infection. Routine hygienic measures aimed at cleaning and disinfecting contaminated food, water troughs, etc, are also useful. Test and slaughter has been used widely in the UK, USA, Canada, Germany, New Zealand, and Australia. In some European countries, where test and slaughter would have been impractical, varying forms of test and segregation have been used, with test and slaughter used only in the final stages of eradication.
The BCG (bacille Calmette-Guérin) vaccine, sometimes used to control TB in people, has proved to provide little protection against virulent M bovis in most animal species, and inoculation often provokes a severe local granulomatous reaction. Moreover, BCG-vaccinated animals usually respond on the tuberculin skin test.