Clinical Tuberculosis

CLINICAL TUBERCULOSIS

M. tuberculosis contagion occurs when a susceptible person inhales bacilli-containing infectious droplets that have been expelled from the lungs of a tuberculous individual by sneezing, coughing, or simply talking. Of those infected, only a minority (around 10 percent) will develop disease; about half will do so within a few months to a couple of years immediately following infection (primary TB), while the other half will do so only after an indeter-minately long period of latency (postpri-mary TB).

Primary TB

After reaching the alveoli, phagocytosis of the bacilli by resident macrophages is fol-lowed by unrestricted bacterial and expo-nential intracellular growth. Uptake of bacteria by DCs and migration of infected DCs to the draining lymph nodes for anti-gen presentation likely contribute to the lymphohematogenous dissemination of bacteria to extrapulmonary organs and uninfected parts of the lung, leading to the formation of secondary lesions. Expo-nential bacillary growth is thought to con-tinue in primary and secondary lesions until a specific T-cell response is gener-ated around each lesion, curtailing bacil-lary growth and likely killing some of the bacteria within macrophages as these bac-teria become mycobacteriostatic or myco-bacteriocidal after activation. The caseous centers of newly formed lesions are sur-rounded by activated macrophages. Pre-sumably, bacterial antigens being released by the bacteria or captured from them are constantly being processed and presented to surrounding T cells in the context of IL-12 and other cytokines that induce a type of immune response. Constant presence of antigen likely contributes to expansion of the T-cell populations and continued acti-vation of macrophages, which avidly ingest and inhibit or kill bacilli accumulated dur-ing the acute phase of the infection. In a lesion where the bacteria are effectively controlled by cell-mediated immunity, the caseous center becomes surrounded by a capsule, forming a protective granuloma. Over time, the number of viable bacilli in these granulomas likely diminishes. Old caseous foci of this sort contain little to no bacilli, and some of the old lesions can ossify and be reabsorbed as Opie and Aron-son demonstrated in 1927. The interactions just described result in control of the infec-tion in most infected individuals.

For reasons poorly understood, some individuals fail to generate the protective type of immune response just described. In these cases, bacteria continue to replicate and the granulomas become increasingly necrotic. Part of the tissue damage that occurs is the result of immunopathology, that is, an excessive host-mediated inflam-matory response to bacterial antigens. When the centers of granulomas undergo caseating necrosis, the sheaths of mono-cytes and T cells that normally suppress the intracellular growth of the bacilli can also become necrotic; as the bacteria con-tinue to replicate in nonactivated mac-rophages at the periphery of the lesion, progressive destruction of lung tissue ensues, ultimately leading to the death of the host. Massive inflammation and tis-sue damage can also be caused directly by some components of the bacterial cell wall as well as by secreted lipids and proteins; lipoarabinomannan, for instance, triggers TNF-α secretion by macrophages, while some secreted lipids lead to secretion of proinflammatory IL-6.

Although M. tuberculosis is not an obli-gate intracellular pathogen, whether it is capable of extracellular growth in the acel-lular necrotic centers of caseous lesions is unclear. In contrast, solid caseum that has undergone liquefaction is believed to be permissive for bacillary replication. The coughing up of this highly infectious material is in fact responsible for the trans-mission of the bacilli. These observations illustrate how pathology is a necessary step in the life cycle of M. tuberculosis infec-tion in humans.

Latent TB Infection and Reactivation

Little is known about the factors that deter-mine whether an individual that is exposed to M. tuberculosis will go on to develop pri-mary TB or become latently infected. That the immune status of the host is involved in both the establishment and maintenance of latency can be inferred from the obser-vation that HIV–M. tuberculosis co-infected individuals have a much higher risk of developing TB after infection. The only sign of infection in individuals with latent TB infection (LTBI) is the appearance (between two and six weeks postexposure) of a detectable delayed-type hypersensi-tivity (DTH) reaction to a mycobacterial purified protein derivative (tuberculin). By taking necropsy specimens of lung lesions from immune-competent individuals who had died of causes other than TB and inoc-ulating necropsy speciments into guinea pigs to determine the presence of infectious bacilli, Opie and Aronson (1927) showed that some individuals can harbor viable tubercle bacilli for many years without

showing any symptoms of disease. In this and other early studies, it was found that while specimens from encapsulated or cal-cified lesions rarely were infectious, those isolated from caseous lesions in the lung’s apex generally were. Unexpectedly, appar-ently healthy tissues were also often infec-tious. Recently, Gomez and McKinney (2004) have reviewed several other studies from the pre-antibiotic era that indicated that lung lesions from asymptomatic indi-viduals can harbor viable bacilli to differ-ent degrees. Recent molecular evidence of potential LTBI in normal human lung tissue was provided by the finding that about 30 to 50 percent of samples from individuals from endemic regions (Mexico and Ethiopia) could harbor M. tuberculosis DNA.

Perhaps the most compelling evidence for the prevalence of LTBI has come from the observed increased rates of TB in AIDS patients, as well as the high reactivation TB associated with the intake of TNF-α inhibi-tors prescribed for rheumatoid arthritis. These observations indicate that many individuals with LTBI accomplish life-long suppression of the bacillus, but never actually achieve sterilization. Reactivation TB usually presents clinically as a slowly progressive, chronic condition; individuals with chronic subacute TB may infect scores of contacts without realizing that they have the disease. Patients with cavitary TB are particularly infectious because they shed enormous numbers of tubercle bacilli in their sputa. Cavitation is caused by the liq-uefaction of necrotic tuberculous tissue and its expulsion through the airways; liquefac-tion is linked to a strong DTH response and is an important example of immunopathol-ogy in TB. The molecular basis of cavity formation has not been determined, nor is it clear whether the immune mechanisms responsible for pathogenesis and protec-tion are the same.