Pathobiology of tuberculosis

The natural history and various clinical syndromes of tuberculosis are intimately related to host defenses. Tubercle bacilli do not elaborate classic toxins; rather, the inflammation and tissue injury that characterize the disease are mediated by products elaborated by the host during the immune response to infection.

To initiate infection, the tubercle bacillus must be taken up by phagocytic cells within the body. When an immunologically naive alveolar macrophage engulfs a tubercle bacillus, it initially provides a nurturing environment within its phagosome in which the bacilli survive and replicate. Indeed, part of the pathogenic strategy of the tubercle bacillus is the ability to prevent fusion of the phagosome with the lysosome. However, the infected phagocytic cells release substances that attract a variety of immune effector cells, including peripheral blood monocyte-derived dendritic cells and T lymphocytes. The dendritic cells, which are the primary antigen-presenting cells, participate in both the local inflammatory process and, after migration to regional lymph nodes, initiation of the more comprehensive immune process. Recent studies suggest a significant role for Toll-like receptors in the innate defenses against tuberculosis.

In normal, otherwise healthy adults, the host initially prevails in more than 95% of cases. However, this initial encounter typically extends over a few weeks to several months, during which the bacillary population has proliferated massively and undergone various degrees of dissemination. Tissues that are most heavily seeded during this bacillemia, such as the apices of the lungs, the kidneys, bones, meninges, or other extrapulmonary sites, are common foci for subsequent reactivation tuberculosis. Through complex interactions involving mononuclear phagocytes and various T-cell subsets, host defenses are enhanced. This cell-mediated immunity is related to but not identical with delayed-type hypersensitivity. Delayed-type hypersensitivity is associated with development of the tuberculin reaction, an indurated response 48 to 96 hours after the intradermal injection of tuberculosis protein antigens (e.g., purified protein derivative [PPD]). Skin test reactivity typically appears 4 to 6 weeks after infection, although intervals up to 20 weeks have been reported. It is not known what percentage of newly infected subjects fail to develop delayed-type hypersensitivity, but up to 20% of adults with active tuberculosis do not react to the PPD.

As these defenses gain momentum, involution of the numerous disseminated granulomatous foci occurs in the lungs, lymph nodes, and scattered sites. Typically, all that remains overtly to mark this encounter is the tuberculin skin test reactivity. In a minority of cases, a small, single residual site of the primary infection (i.e., Ghon focus) appears in the lung parenchyma; occasionally, this focus is accompanied by calcifications of the ipsilateral hilar nodes. In some patients, fibronodular shadowing also develops in one or both lung apices (i.e., Simon foci), presumably as the residua of subclinical disease at these sites. This dormant, asymptomatic, noninfectious state is known as latent tuberculous infection.

Tubercle bacilli undergo spontaneous mutations that confer resistance to the various antituberculosis medications. These mutations occur at predictable frequencies, usually in the range of 1 in 105 to 108 replications, and they are unlinked, thus resulting in resistance to only one drug or drug category. In cavitary tuberculosis, the population of bacilli is so great that small numbers of mycobacteria exist that are resistant to each of the standard medications. However, because the mutations are unlinked, there is an extremely low probability of spontaneous resistance to two or more drugs by a single bacillus.