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Tuberculosis 

Tuberculosis

Chapter:
Tuberculosis
Author(s):

Richard E. Chaisson

and Jean B. Nachega

DOI:
10.1093/med/9780199204854.003.070625_update_001

Update:

Epidemiology—influence of bacterial genotype (e.g. W-Beijing strain) and host genetics (e.g. genome-wide scan identification of susceptibility loci).

Diagnosis—use of molecular methods (e.g. Gene Xpert RIF/TB).

Treatment—newer agents (e.g. fluoroquinolones, OPC-67683, TMC 207, PA-824, oxazolidinones).

Treatment of HIV-associated tuberculosis—optimal timing of antiretroviral therapy initiation in HIV-associated TB.

Updated on 31 May 2012. The previous version of this content can be found here.
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date: 26 March 2017

Tuberculosis is caused by organisms of the Mycobacterium tuberculosis complex, including M. tuberculosis (the most important), M. bovis, and M. africanum. It has been present since antiquity and is the second leading infectious cause of death after HIV infection. An estimated 2 billion people worldwide carry latent infection, when M. tuberculosis persists within cells and granulomas, with the potential to reactivate to cause disease decades later.

Tubercle bacilli are transmitted between people by aerosols generated when an infectious person coughs. Proximity to an infectious person determines the risk of infection. Host immunity and factors affecting it—most importantly HIV infection but also diabetes, cigarette smoking, and alcohol and drug abuse—determine the risk of active disease following infection.

Clinical presentation of active tuberculosis is highly variable, depending on the site and extent of disease and the immune status of the host. Disease is generally classified as pulmonary or extrapulmonary, with considerable clinical heterogeneity within each group.

Clinical features—pulmonary tuberculosis

Following deposition of tubercle bacilli in the alveoli of the lungs, they are ingested by alveolar macrophages, multiply intracellularly and eventually cause cell lysis with release of organisms. Over a period of weeks, infection spreads to regional lymph nodes, elsewhere in the lungs and systemically. Infected people who successfully contain viable bacilli in granulomas retain a latent infection, with lifetime risk of reactivation of about 10%.

Active pulmonary tuberculosis—this is usually a subacute respiratory illness, the most frequent symptoms of which are cough, fever, night sweats and malaise. The cough is initially nonproductive, but often progresses to sputum production and occasionally haemoptysis. Loss of appetite and excessive weight loss are common.

Clinical features—extrapulmonary tuberculosis

This may be generalized or confined to a single organ, and is found in 15 to 20% of all cases of tuberculosis in otherwise immunocompetent adults, more than 25% of cases under 15 years of age, and in more than 50% of HIV-related cases. Children under 2 years of age have high rates of miliary or disseminated tuberculosis and meningeal disease.

Infection spreads from the lungs by lymphatic and haematogenous routes. The tissues and organs most likely to be affected are the pleura, lymph nodes, kidneys and other genitourinary organs, bone, and central nervous system. Tuberculosis bacteraemia is unusual, but seen most often in patients with HIV infection and low CD4 lymphocyte counts.

Pleural tuberculosis—this is usually the result of relatively small numbers of tubercle bacilli invading the pleura from adjacent lung tissue, in which case the duration of symptoms is generally brief, with patients complaining of symptoms including fever, chest pain, and nonproductive cough. Pleural tuberculosis involving larger numbers of bacilli produces frank empyema and is commoner in older patients.

Lymphatic tuberculosis—classic scrofula of the cervical or supraclavicular lymph node chains is the most common presentation, but multiple lymph node groups can be involved in HIV-infected patients.

Genitourinary tuberculosis—the most common manifestation is renal tuberculosis, resulting from haematogenous seeding of the renal cortex during primary infection; this is frequently asymptomatic, but may be evident as sterile pyuria.

Bone and joint tuberculosis—the most common form is vertebral tuberculosis (Pott’s disease), resulting from haematogenous seeding of the anterior portion of vertebral bodies during primary infection; presentation is typically with back pain; constitutional symptoms are not prominent in most cases.

Tuberculous meningitis—meningeal and leptomeningeal bacterial replication results in a robust inflammatory reaction that increases cerebrospinal fluid pressure and can cause cranial neuropathies. Common symptoms are headache, stiff neck, meningismus, and an altered mental status, including irritability, clouded thinking and malaise. The condition is not common, but usually fatal if untreated.

Miliary/disseminated tuberculosis—these describe widespread infection with absent or minimal host immune responses, usually arising as a result of primary infection, and seen more frequently in children and immunocompromised adults. Typical presentation is with fever and other constitutional symptoms over a period of several weeks.

Diagnosis

Tuberculin skin testing—intracutaneous injection of purified proteins of M. tuberculosis provokes a delayed hypersensitivity reaction which produces a zone of induration in those who are infected, but cannot distinguish disease from latent infection and may be falsely positive from BCG vaccination or nontuberculous mycobacterial infections.

Interferon-γ‎ release-based assays—these detect in vitro responses to M. tuberculosis antigens. These appear to be more specific than tuberculin skin testing because false-positive reactions due to sensitization from BCG vaccination (see below) are less likely to occur. They may also be more sensitive, and are appealing because they do not require patients to return for reading of induration.

Detection of tubercle bacilli—microscopy of acid-fast bacilli in sputum or other tissue is the method most widely used to diagnose tuberculosis because it is inexpensive, rapid, and technologically undemanding. However, a relatively large number of bacilli are needed for a positive test, and up to 50% of patients with sputum cultures positive for M. tuberculosis have negative acid-fast smears. Culture of M. tuberculosis is the gold standard for confirming the diagnosis, but takes 10 to 40 days, depending on the method used. Nucleic acid amplification assays and other rapid diagnostic methods allow faster detection of both the presence of mycobacteria and assessment of drug resistance: these have promise in resource-limited settings, but further validation in endemic countries is needed.

Nucleic acid amplification—several new commercial assays that amplify M. tuberculosis DNA can result in rapid diagnosis of tuberculosis (<1 day). Some tests also can detect drug-resistance mutations, providing timely detection of multidrug-resistant (MDR) tuberculosis.

Particular issues—(1) Pulmonary tuberculosis—this can involve any portion of the lungs, hence radiographic findings are usually only suggestive, not diagnostic. (2) Pleural tuberculosis—diagnosis can be inferred from pulmonary findings when pulmonary parenchymal involvement is manifest, otherwise analysis of pleural fluid is essential. (3) Lymphatic tuberculosis—swelling of involved nodes accompanied by a positive tuberculin skin test and typical biopsy findings are strongly suggestive of tuberculosis and warrant presumptive therapy. (4) Tuberculous meningitis—diagnosis requires a high degree of suspicion; presumptive therapy is frequently necessary.

Treatment

Drug-susceptible tuberculosis—combination therapy with isoniazid and rifampin (and other antituberculosis drugs in the first 8 weeks) is highly effective. Treatment is usually once daily but can be given as infrequently as twice per week, with two major interventions to improve adherence and prevent bad outcomes being directly observed therapy (DOT) and the use of fixed-dose combination tablets. Modern ‘short course’ combination chemotherapy is curative in 6 months, except for bone and central nervous system tuberculosis, which require 12 months. Second-line agents are reserved for treatment of drug resistant tuberculosis and are generally less potent, more toxic and less readily available.

Drug-resistant tuberculosis—this significant challenge arises both through infection with drug-resistant strains (primary drug resistance) and by selection for drug-resistant strains due to ineffective therapy (secondary drug resistance). Multidrug resistant (MDR) tuberculosis is defined as resistance to at least rifampicin and isoniazid. Extensively drug-resistant (XDR) disease, which has been reported in more than 70 countries, is defined as MDR plus resistance to fluoroquinolones and at least one injectable second-line agent (capreomycin, amikacin, or kanamycin). Patients with drug-resistant tuberculosis should be managed by a physician who is a tuberculosis expert because of the complexity of their regimens and their high risk of failure of death.

Prevention

Strategies to control tuberculosis include: (1) Identification and treatment of infectious tuberculosis cases, which rapidly eliminates infectiousness. (2) Treatment of latent tuberculosis infection—the use of preventive therapy in high-risk individuals known or strongly suspected to be latently infected with M. tuberculosis can benefit not only the individual patient who does not fall ill with tuberculosis, but also potential contacts of that patient, who might become secondarily infected were disease to develop. (3) Prevention of exposure to infectious particles in air, especially in hospitals and other institutions—infected patients must be identified and managed in respiratory isolation. (4) Vaccination—the attenuated live vaccine, BCG (bacille Calmette-Guérin), is widely administered throughout the world, but remains controversial. Proponents argue that it provides about 50% protection against active tuberculosis disease and also diminishes haematogenous dissemination of primary tuberculosis infection, thereby reducing the incidence of miliary tuberculosis and tuberculous meningitis in children.

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