Tuberculosis (TB) is the most common cause of infection-related death worldwide. In 1993, the World Health Organization (WHO) declared tuberculosis to be a global public health emergency. Mycobacterium tuberculosis is the most common cause of tuberculosis. Other rare causes include Mycobacterium bovis and Mycobacterium africanum. Tubercle bacilli belong to the family Mycobacteriaceae and order Actinomycetales. The acid-fast characteristic of the mycobacteria is their unique feature. M tuberculosis is an aerobic, non–spore-forming, nonmotile, slow-growing bacillus with a curved and beaded rod-shaped morphology. It is a very hardy bacillus that can survive under adverse environmental conditions. Humans are the only known reservoirs for M tuberculosis.
TB is caused by an organism called Mycobacterium tuberculosis that is spread from person to person through the air. M. tuberculosis organisms are sometimes called tubercle bacilli. When a person with infectious TB disease coughs or sneezes, droplet nuclei containing tubercle bacilli may be expelled into the air. Other people may inhale the air containing these droplet nuclei and become infected.
TB infection begins when the tubercle bacilli multiply in the small air sacs of the lungs. A small number enter the bloodstream and spread throughout the body, but the body’s immune system usually keeps the bacilli under control. People who have latent TB infection (LTBI) but not TB disease do not have symptoms of TB, and they cannot spread TB to others. They usually have a positive reaction to the tuberculin skin test or QuantiFERON TB Gold Test ®.
In some people who have LTBI, the immune system cannot keep the tubercle bacilli under control and the bacilli begin to multiply rapidly, causing TB disease. This can happen very soon after TB infection or many years after infection. About 10% of people who have LTBI will develop disease at some point, but the risk is greatest in the first year or two after infection, than for other people.
TB disease usually occurs in the lungs (pulmonary TB), but it can also occur in other places in the body (extrapulmonary TB). Miliary TB occurs when tubercle bacilli enter the bloodstream and are carried to all parts of the body, where they grow and cause disease in multiple sites.
Tuberculosis occurs when individuals inhale bacteria aerosolized by infected persons. The organism is slow growing and tolerates the intracellular environment, where it may remain metabolically inert for years before reactivation and disease. The main determinant of the pathogenicity of tuberculosis is its ability to escape host defense mechanisms, including macrophages and delayed hypersensitivity responses.
Among the several virulence factors in the mycobacterial cell wall are the cord factor, lipoarabinomannan (LAM), and a highly immunogenic 65-kd M tuberculosis heat shock protein. Cord factor is a surface glycolipid present only in virulent strains that causes M tuberculosis to grow in serpentine cords in vitro. LAM is a heteropolysaccharide that inhibits macrophage activation by interferon-gamma and induces macrophages to secrete tumor necrosis factor-alpha, which causes fever, weight loss, and tissue damage.
The infective droplet nucleus is very small, measuring 5 micrometers or less, and may contain approximately 1-10 bacilli. Although a single organism may cause disease, 5-200 inhaled bacilli are usually necessary for infection. The small size of the droplets allows them to remain suspended in the air for a prolonged period of time. Primary infection of the respiratory tract occurs as a result of inhalation of these aerosols. The risk of infection is increased in small enclosed areas and in areas with poor ventilation. Upon inhalation, the bacilli are deposited (usually in the midlung zone) into the distal respiratory bronchiole or alveoli, which are subpleural in location. Subsequently, the alveolar macrophages phagocytose the inhaled bacilli. However, these naïve macrophages are unable to kill the mycobacteria, and the bacilli continue to multiply unimpeded.
Thereafter, transportation of the infected macrophages to the regional lymph nodes occurs. Lymphohematogenous dissemination of the mycobacteria to other lymph nodes, the kidney, epiphyses of long bones, vertebral bodies, juxtaependymal meninges adjacent to the subarachnoid space, and, occasionally, to the apical posterior areas of the lungs. In addition, chemotactic factors released by the macrophages attract circulating monocytes to the site of infection, leading to differentiation of the monocytes into macrophages and ingestion of free bacilli. Logarithmic multiplication of the mycobacteria occurs within the macrophage at the primary site of infection.
A cell-mediated immune (CMI) response terminates the unimpeded growth of the M tuberculosis 2-3 weeks after initial infection. CD4 helper T cells activate the macrophages to kill the intracellular bacteria with resultant epithelioid granuloma formation. CD8 suppressor T cells lyse the macrophages infected with the mycobacteria, resulting in the formation of caseating granulomas. Mycobacteria cannot continue to grow in the acidic extracellular environment, so most infections are controlled. The only evidence of infection is a positive tuberculin skin test (TST) result. However, the initial pulmonary site of infection and its adjacent lymph nodes (ie, primary complex or Ghon focus) sometimes reach sufficient size to develop necrosis and subsequent radiographic calcification.
Most persons infected with M tuberculosis do not develop active disease. In healthy individuals, the lifetime risk of developing disease is 5-10%. In certain instances, such as extremes of age or defects in CMI (eg, human immunodeficiency virus [HIV] infection, malnutrition, administration of chemotherapy, prolonged steroid use), tuberculosis may develop. For patients with HIV infection, the risk of developing tuberculosis is 7-10% per year.
Progression of the primary complex may lead to enlargement of hilar and mediastinal nodes with resultant bronchial collapse. Progressive primary tuberculosis may develop when the primary focus cavitates and organisms spread through contiguous bronchi. Lymphohematogenous dissemination, especially in young patients, may lead to miliary tuberculosis when caseous material reaches the bloodstream from a primary focus or a caseating metastatic focus in the wall of a pulmonary vein (Weigert focus). Tubercular meningitis may also result from hematogenous dissemination. Bacilli may remain dormant in the apical posterior areas of the lung for several months or years, with later progression of disease resulting in the development of reactivation-type tuberculosis (ie, endogenous re-infection tuberculosis).’
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