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USMLE – Tuberculosis

M. tuberculosis infects about one third of the world’s population and kills about 3 million patients each year and so is the single most important infectious cause of death on earth. With alleviation of overcrowding, which causes the spread of M. tuberculosis, and with the introduction of effective antibiotics in the 1950s, the United States and Western countries enjoyed a long decline in the rates of M. tuberculosis infections and deaths until the mid-1980s. Since that time, tuberculosis has been increasing here and in Europe and especially in Africa, in part because M. tuberculosis frequently and dramatically infects persons with AIDS. These individuals, who have a diminished T cell-mediated resistance to M. tuberculosis, develop disease at much higher rates than do healthy persons, have more abundant pulmonary disease, and are more likely to transmit M. tuberculosis to others. In addition, multidrug-resistant M. tuberculosis has appeared among AIDS patients, threatening close contacts and health care workers. Because mycobacteria grow 20 to 100 times slower than other bacteria, it takes 4 to 6 weeks to obtain a colony of M. tuberculosis for drug sensitivity studies. Resistance to the best antimycobacterial drugs – rifampin and isoniazid-is caused by mutations in the RNA polymerase and catalase, respectively.

Mycobacteria are aerobic, non-spore-forming, nonmotile bacilli with a waxy coat that causes them to retain the red dye when treated with acid (“red snappers”) in the acid-fast stains. Two species of Mycobacterium cause tuberculosis: M. tuberculosis and M. bovis. M. tuberculosis is transmitted by inhalation of infective droplets coughed or sneezed into the air by a patient with tuberculosis. M. bovis is transmitted by milk from diseased cows and first produces intestinal or tonsillar lesions. In developed countries, control of M. bovis in dairy herds and pasteurization of milk have virtually eradicated this organism. M. avium and M. intracellulare, two closely related mycobacteria, have no virulence in normal hosts but cause disseminated infections in 15% to 24% of patients with AlDS. M. leprae is the cause of leprosy.

M. tuberculosis pathogenicity is related to its ability to escape killing by macrophages and induce delayed type hypersensitivity. This has been attributed to several components of the M. tuberculosis cell wall. First is cord factor, a surface glycolipid that causes M. tuberculosis to grow in serpentine cords in vitro. Virulent strains of M. tuberculosis have cord factor on their surface, whereas avirulent strains do not, and injection of purified cord factor into mice induces characteristic granulomas. Second, lipoarabinomannan (LAM), a major heteropolysaccharide similar in structure to the endotoxin of gram-negative bacteria, inhibits macrophage activation by interferon-gamma. LAM also induces macrophages to secrete TNF-alpha, which causes fever, weight loss, and tissue damage, and IL-10, which suppresses mycobacteria-induced T-cell proliferation. Third, complement activated on the surface of mycobacteria may opsonize the organism and facilitate its uptake by the macrophage complement receptor CR3 (Mac-1 integrin) without triggering the respiratory burst necessary to kill the organisms. Fourth, a highly immunogenic 65-kD M. tuberculosis heat-shock protein is similar to human heat-shock proteins and may have a role in autoimmune reactions induced by M. tuberculosis.

M. tuberculosis resides in phagosomes, which are not acidified into lysosomes. Inhibition of acidification has been associated with urease secreted by mycobacteria and with uptake of mycobacteria by complement- or mannose binding receptors rather than Fe receptors.

The development of cell-mediated, or type IV, hypersensitivity to the tubercle bacillus probably explains the organism’s destructiveness in tissues and also the emergence of resistance to the organisms. On the initial exposure to the organism, the inflammatory response is nonspecific, resembling the reaction to any form of bacterial invasion. Within 2 or 3 weeks, coincident with the appearance of a positive skin reaction, the reaction becomes granulomatous and the centers of granulomas become caseous, forming typical “soft tubercles.” The pattern of host response depends on whether the infection represents a primary first exposure to the organism or secondary reaction in an already sensitized host.

The primary phase of M. tuberculosis infection begins with inhalation of the mycobacteria and ends with a T cell-mediated immune response that induces hypersensitivity to the organisms and controls 95% of infections. Most often in the periphery of one lung, inhaled M. tuberculosis is first phagocytosed by alveolar macrophages and transported by these cells to hilar lymph nodes. Naive macrophages are unable to kill the mycobacteria, which multiply, lyse the host cell, infect other macrophages, and sometimes disseminate through the blood to other parts of the lung and elsewhere in the body. After a few weeks, T cell-mediated immunity demonstrable by a positive purified protein derivative (PPD) test reaction develops. Mycobacteria-activated T cells interact with macrophages in three ways. First, CD4+ helper T cells secrete interferon-gamma, which activates macrophages to kill intracellular mycobacteria through reactive nitrogen intermediates, including NO, N02, and HN03. This is associated with the formation of epithelioid cell granulomas and clearance of the mycobacteria. Second, CD8+ suppressor T cells lyse macrophages infected with mycobacteria through a Fas-independent, granule-dependent reaction and kill mycobacteria. Third, CD4-CD8- (double-negative) T cells lyse macrophages in a Fas-dependent manner, without killing mycobacteria. Lysis of macrophages results in the formation of caseating granulomas. Direct toxicity of the mycobacteria to the macrophages may contribute to the necrotic caseous centers. Mycobacteria cannot grow in this acidic, extracellular environment lacking in oxygen, and so the mycobacterial infection is controlled. The ultimate residuum of the primary infection is a calcified scar in the lung parenchyma and in the hilar lymph node, together referred to as the Ghon complex.

Some individuals become reinfected with mycobacteria, reactivate dormant disease, or progress directly from the primary mycobacterial lesions into disseminated disease. This may be because the strain of mycobacterium is particularly virulent or the host is particularly susceptible. In mice, susceptibility to mycobacterial (as well as Salmonella and Leishmania) infection is determined by an autosomal dominant gene called Bcg, which encodes a membrane transport protein. Whether the protein acts at the level of the plasma membrane or interferes with bacterial killing in the phagolysosome is unclear. Granulomas of secondary tuberculosis most often occur in the apex of the lungs but may be widely disseminated in the lungs, kidneys, meninges, marrow, and other organs. These granulomas, which fail to contain the spread of the mycobacterial infection, are the major cause of tissue damage in tuberculosis and are a reflection of delayed type hypersensitivity. Two special features of secondary tuberculosis are caseous necrosis and cavities; necrosis may cause rupture into blood vessels, spreading mycobacteria throughout the body, and break into airways, releasing infectious mycobacteria in aerosols.

Miliary tuberculosis refers to hematogenous dissemination of tuberculous lesions throughout the body. The term miliary is descriptive of the small, yellow-white lesions that resemble millet seeds fed to birds and are present in the lungs and systemic organs. Certain tissues are relatively resistant to tuberculous infection, so it is rare to find tubercles in the heart, striated muscle, thyroid, and pancreas. In certain instances, hematogenously spread organisms are destroyed in all tissues but persist in only one organ (isolated end-organ disease). This occurrence is most frequent in the lungs, cervical lymph nodes (scrofula), meninges (tuberculous meningitis), kidneys, adrenals, bones (tuberculous osteomyelitis), fallopian tubes, and epididymis. In vertebral tuberculosis (Pott disease), long fistulas may form along the psoas muscle to open and drain into the groin region.

Mycobacterial infection in patients with AIDS can take three forms, depending on the degree of immunosuppression. (1) In developing countries, where M. tuberculosis infection is frequent, HIV-infected individuals often have primary and secondary M. tuberculosis infection with the usual, well-formed granulomas composed of epithelioid cells, Langerhans giant cells, and lymphocytes. In these lesions, acid-fast mycobacteria are few and often difficult to find. (2) When HIV-positive patients develop AIDS and are moderately immunosuppressed (less than 200 CD4+ helper T cell’s/mm3). M. tuberculosis infection is frequently caused by reactivation or by exposure to new mycobacteria. Because HIV infects both T cells and macrophages, defects in the host immune response to M. tuberculosis may be secondary to the failure of helper T cells to secrete lymphokines that activate macrophages to kill mycobacteria or the failure of HIV-infected and mycobacteria-infected macrophages to respond to lymphokines. The relative increase in the number of CD8+ cytotoxic T cells may also cause macrophage destruction in the M. tuberculosis lesions. On histologic examination, granulomas are less well formed, are more frequently necrotic, and contain more abundant acid-fast organisms. Neutrophils may be present where tuberculous cavities have eroded into the airways. Although the sputum is positive for acid-fast organisms in 31% to 82% of patients with AIDS, only 33% of patients are reactive to PPD. Extrapulmonary tuberculosis occurs in 70% of such patients, involving lymph nodes, blood, central nervous system, and bowel. Despite the severity of M. tuberculosis infection in AIDS patients, treatment with multiple drugs clears all but the multidrug-resistant organisms. (3) Opportunistic infection with M. avium-intracellulare occurs in severely immunosuppressed patients (less than 60 CD4+ cells/mm3). Most infections with these organisms originate in the gastrointestinal tract, although some begin in the lung. M. avium-intracellulare infections are usually widely disseminated throughout the reticuloendothelial systems, causing enlargement of involved lymph nodes, liver, and spleen. There may be a yellowish pigmentation to these organs secondary to the large number of M. avium-intracellulare present in swollen macrophages. Granulomas, lymphocytes, and tissue destruction are rare.

Lillian Thompson By Lillian Thompson

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