on 31-Jul-2025 (Thu)

The term tuberculosis describes a broad range of clinical illnesses caused by Mycobacterium tuberculosis (or, less commonly, Mycobacterium bovis)

Tuberculosis (TB) is the leading cause of death due to a single infectious agent worldwide, and ranks ninth among all causes of death.

There is evidence of spinal TB in Neolithic, pre-Columbian, and early Egyptian remains. However, TB did not become a major problem until the Industrial Revolution, when crowded living conditions favored its spread.

In the 17th and 18th centuries, TB caused one-fourth of all adult deaths in Europe.

Before antimicrobial agents became available, the cornerstone of treatment was rest in the open air in specialized sanatoria. Sanatorium regimens probably benefited some patients who were diagnosed before cavitation but had little impact on cavitary disease. When it became clear that cavitation was the pivotal event in progressive pulmonary TB, most special therapies focused on cavity closure

The modern era of TB began in 1946 with demonstration of the efficacy of streptomycin (STM). In 1952, the availability of isoniazid (INH) made TB curable in most patients, and the addition of rifampin (RIF) in 1970 allowed for even more effective combination therapy

The duration of chemotherapy progressively decreased from approximately 2 years before the availability of RIF, to 9 months with INH plus RIF, and to 6 months with multidrug therapy including INH, RIF, and pyrazinamide (PZA).

With INH it also became practical to treat asymptomatic people believed to harbor tubercle bacilli based on positive tuberculin test results

In the United States, reported cases of TB had declined nearly every year since accurate statistics became available. However, in 1985, case rates began increasing, driven largely by human immunodeficiency virus (HIV) infection. TB-control programs in some large cities were not equipped to manage this emerging problem. The often-interrelated factors of illicit drug use, homelessness, and HIV infection predispose to reactivation of remote TB, to the acquisition and spread of new disease, and, because of irregular adherence to drug therapy, to the development and spread of drug-resistant strains. Epidemics involving strains that were resistant to at least INH and RIF (i.e., multidrug-resistant [MDR] strains) emerged in these populations and spread to HIV-negative persons, including health care workers.

The global situation has, unfortunately, not been as successful. The HIV pandemic fueled increased TB case rates in resource-limited coun- tries worldwide, especially in sub-Saharan Africa. Scant resources and fragile infrastructure, together with a high prevalence of HIV infection and acquired immunodeficiency syndrome (AIDS), have driven the global burden of TB.

Since 2011, WHO has recommended that MDR-TB be treated using mainly ambulatory care, which appears to be more effective than hospitalization.4

With widespread use of second-line agents, selection for M. tuber- culosis resistant to both first- and second-line drugs was inevitable. Extensively drug-resistant tuberculosis (XDR-TB), defined as resistance to at least INH, RIF, a fluoroquinolone, and a second-line injectable drug (kanamycin, capreomycin, amikacin), first occurred as early as 2001 in KwaZulu-Natal, South Africa,5,6 and by 2016 it had been reported in at least 121 countries worldwide.1

Almost all infections with M. tuberculosis are due to inhalation of droplet nuclei—infectious particles from a person with pulmonary TB aerosolized by coughing, sneezing, or talking—which dry while airborne, remain suspended for long periods, and reach the terminal air passages. A cough can produce 3000 infectious droplet nuclei, talking for 5 minutes an equal number, and sneezing many more than that

Accordingly, the air in a room occupied by a person with pulmonary TB may remain infectious for approximately 30 minutes even after his or her absence.

Although in theory one droplet nucleus may be sufficient to establish infection, prolonged exposure and multiple aerosol inocula are usually required.

Strains may vary widely in their transmissibility,87 but infection does not generally occur outdoors because M. tuberculosis is killed by ultraviolet light.

Although homes are the focus of TB contact investiga- tions, evidence is mounting that in high-TB settings, approximately 85% of transmission occurs in other social spaces including medical facilities, public transportation vehicles, workplaces, schools, churches, bars, and other areas where people congregate.120

Large drops of respiratory secretions and fomites are unimportant in transmission, and special housekeeping measures for dishes and bed linens are unnecessary. Other modes of transmission are rare.

Infection with M. bovis from ingestion of contaminated milk was once com- monplace. Skin inoculation of M. tuberculosis from contamination of an abrasion occurs in pathologists and laboratory personnel (prosector’s wart), and venereal transmission has been recorded.

Although the source is pulmonary in the vast majority of cases, aerosolization of organisms during irrigation of cutaneous lesions or at autopsy has caused spread to health care workers.121,122

The special case of organ-donor–transmitted infection should be noted because transplant recipients have a higher frequency of TB than the general population, and high mortality.123 Because donor-derived disease develops late (>90 days) in the majority of cases, and many donors have identifiable risk factors for tuberculous infection, it has been proposed that screening protocols using donor histories that would heighten surveillance of recipients, in addition to cultures and smears, and testing for latent TB in donors should be undertaken.124

The most important determinants of infection of tuberculin-negative persons are closeness of contact and infectiousness of the source.

Cases with positive smears are highly infectious; those positive only on culture are less so. The degree of sputum positivity and pattern of coughing are important.

Compared with measles, one case of which will infect 80% of susceptible casual contacts, TB is only moderately infectious in most circumstances. In the United Kingdom, a study of 111 cases with 825 contacts found that a shorter interval to liquid culture positivity identified patients at high risk of transmitting infection and was also superior to detection by means of smear.126

Persons coinfected with HIV do not appear to be more infectious than HIV-negative source cases and because they are more likely to be smear negative than are HIV-negative patients, they may be less infectious.

In one large study from the Democratic Republic of Congo, household contacts of HIV-positive patients with pulmonary TB were no more likely to become infected with M. tuberculosis than were household contacts of HIV-negative TB patients.128

A study in Uganda demonstrated that transmission from an HIV-infected index case to contacts was dependent on the index patient’s sputum smear positivity and presence of a cavity on chest radiograph.129

In the United States, approximately 27% of household contacts of individuals with smear-positive cases become infected, although rates as high as 80% occur in closed environments.127

Patients receiving appropriate chemotherapy promptly become noninfec- tious as cough subsides and the concentration of organisms in sputum decreases. The time required to become noninfectious depends on the patient’s burden of organisms, but there is indirect evidence that this occurs within 2 weeks in patients with drug-sensitive TB.132

In general, 3% to 4% of infected individuals acquire active TB during the first year after tuberculin conversion and an additional 5% do so thereafter, although the uniformity of these rates has been challenged in a study from Victoria, Australia, in which the cumulative hazard for progression to disease after infection was 14.5%, with most risk occurring within the first 5 months and greater risk in children younger than 5 years (50.6%).133,134

In one study of 12,876 unvaccinated adolescents, 10.4% of those who converted their tuberculin tests acquired clinical TB, 54% of these within 1 year and 78% within 2 years.77 The three periods of life during which infection is most likely to produce disease are infancy, ages 15 to 25 years, and old age.

Persons infected with small inocula or during disease-resistant periods probably have a much smaller risk,135

The likelihood of active disease developing varies with the intensity and duration of exposure. Persons with intense exposures are most at risk not only for infection but also for disease.127 The degree of tuberculin positivity has some predictive value.

Malnutrition, renal failure, and immunosuppression all favor progression of infection to active disease, but by far the strongest risk factor is HIV infection. Among tuberculin- positive, HIV-positive injection drug users in one methadone clinic population, 8% per year acquired active TB.136

In the 1980s, numerous explosive outbreaks of TB occurred among HIV-infected patients in specialized wards and hospices in the United States and Europe.137–141 In the first reported outbreak on an HIV ward, the index patient had fever, cough, a normal chest radiograph, and negative acid-fast smears, but a positive sputum culture for M. tuberculosis.138 On the same ward, 39% of other HIV-positive patients acquired active TB within 60 days. Major factors contributing to these outbreaks included (1) delays in diagnosis, especially in HIV-infected patients with atypical chest radiographs; (2) inadequate negative-pressure ventilation inpatient rooms; (3) use of aerosol-generating procedures such as bronchoscopy and sputum induction; (4) rapid progression to active TB in HIV-positive patients; and (5) in the case of MDR-TB, prolonged infectivity despite antituberculous chemotherapy.142

In reaction to outbreaks of MDR-TB, the CDC in 1994 established very stringent criteria for removing from respiratory isolation patients who were suspected to have pulmonary TB and had not begun empirical treatment. These criteria now include three consecutive negative sputum smears on good-quality specimens obtained at least 8 hours apart.145 Studies have demonstrated that two negative sputum Xpert MTB/RIF tests improve sensitivity and specificity for identifying patients who will be found to be culture and smear negative. Use of the Xpert MTB/ RIF will decrease time in isolation and will be more cost-effective than use of three AFB smears.146,147

Airborne droplet nuclei containing tubercle bacilli reach the terminal air spaces where multiplication begins. The initial focus is usually subpleural and in the midlung zone (the lower parts of the upper lobes and the upper parts of the lower and middle lobes), where greater airflow favors deposition of bacilli. (Very rarely, nonpulmonary initial foci will involve abraded skin, the intestine, the oropharynx, or the genitalia, all associated with foci in regional lymph nodes.)

The initial pulmonary focus is typically single, although multiple foci are present in about one-fourth of cases. The bacteria are ingested by alveolar macrophages, which may be able to eliminate small numbers of bacilli. However, bacterial multiplication tends to be mostly unim- peded, destroying the macrophage. Bloodborne lymphocytes and monocytes are attracted to this focus, the latter differentiating into macrophages, which ingest bacilli released from degenerating cells, and pneumonitis slowly develops.

Infected macrophages are carried by lymphatics to regional (hilar, mediastinal, and sometimes supraclavicular or retroperitoneal) lymph nodes, but in the nonimmune host may spread hematogenously throughout the body. During this occult preallergic lymphohematogenous dissemination, some tissues favor retention and bacillary multiplication. These include the lymph nodes, kidneys, epiphyses of the long bones, vertebral bodies, and juxtaependymal meningeal areas adjacent to the subarachnoid space, but, most important, the apical-posterior areas of the lungs.

Before the development of hypersensitivity (tuberculin reactivity), microbial growth is uninhibited, both in the initial focus and in metastatic foci, providing a nidus for subsequent progressive disease in the lung apices and in extrapulmonary sites, either promptly or after a variable period of latency

Tuberculin positivity appears 3 to 9 weeks after infection and marks the development of cellular immunity and tissue hypersensitivity. In most instances the infection is controlled, with the only evidence of infection being a positive skin test result. In a minority of cases, antigen concentration in the primary complex, consisting of the initial pulmonary focus (the Ghon focus) and the draining regional nodes, will have reached sufficient size that hypersensitivity results in necrosis and radiographically visible calcification, producing the Ranke complex (parenchymal and mediastinal calcific foci). Much less commonly, pulmonary apical and subapical metastatic foci contain sufficient bacilli that necrosis ensues with the onset of hypersensitivity, producing tiny calcific deposits (Simon foci) in which viable bacilli may persist.

The onset of tuberculin hypersensitivity may be associated with erythema nodosum or phlyctenular keratoconjunctivitis (a severe unilateral inflammation of the eye), although these manifestations are unusual in the United States. The primary complex may progress.

In children, large hilar or mediastinal lymph nodes may produce bronchial collapse with distal atelectasis or may erode into a bronchus and spread infection distally. Also, typically in children but also in those infected in advanced age97 and HIV-infected patients,193 the primary focus may become an area of advancing pneumonia, so-called progressive primary disease, which may cavitate and spread via the bronchi.

Again, typically in the very young, preallergic lymphohematogenous dissemination may progress directly to hyperacute miliary TB as a result of caseous material directly reaching the bloodstream, either from the primary complex or from a caseating metastatic focus in the wall of a pulmonary vein (Weigert focus).

Hematogenous dissemination in the very young is often followed within weeks by tuberculous meningitis. In adolescents and young adults, the subpleural primary focus may rupture, delivering bacilli and antigen into the pleural space to produce serofibrinous pleurisy with effusion

Overwhelmingly, the most important consequence of preallergic lymphohematogenous dissemination is seeding of the apical-posterior areas of the lung, where disease may progress without interruption or after a latent period of months or years, resulting in pulmonary TB of the adult or reactivation-type TB (endogenous reinfection)

Apical-posterior localization with a tendency to cavitation and progression is characteristic of pulmonary TB in adolescents and adults. In contrast, infection acquired by the elderly often causes nondescript lower lobe pneumonia similar to progressive primary infection of childhood.97

Apical Localization In adults, apical localization of pulmonary TB has often been attributed to the hyperoxic environment of the apices and the aerobic nature of the organism. A more plausible theory attributes it to deficient lymphatic flow at the lung apices, especially the posterior apices, where the pumping effect of respiratory motion is minimal. Deficient lymph traffic would favor retention of bacillary antigen and, when hypersensitivity ensues, tissue necrosis.

In countries where the level of contagion is low, most cases of active TB reflect reactivation of latent foci.194 However, when contagion is high, exogenous reinfection may be more common.77,195

Repeated inhalational exposures to tubercle bacilli maintain tissue hypersensitivity and cellular immunity, making superinfection more difficult; however, when the airborne inoculum is large, or in immunocompromised hosts, superinfection may occur.

Influence of Age on Tuberculous Infection Many of the best clinical descriptions of TB come from the preantimi- crobial era, when infection occurred early in life and cellular immunity was maintained by frequent exposure to tubercle bacilli. However, in industrialized countries, infection more often occurs later in life and cellular immunity may wane in the absence of restimulation. Accordingly, clinical patterns have changed.

At one time, most patients were ado- lescents and young adults with apical cavitary disease. In developed countries, the incidence of TB (cases per 100,000) is now greatest in older persons, in whom hypersensitivity is less marked and in whom the clinical manifestations may be different and more subtle. Hyper- sensitivity and cellular immunity likely become less vigorous with age (see “Epidemiology”)

Infection in Infancy and Childhood Infection in infants often results in disease with local progression and dissemination (miliary-meningeal disease). The younger the patient, the greater the risk for progressive disease until the age of 5 years. From age 5 until puberty is a time of relative resistance to progressive disease, although not to infection. When disease occurs, it is usually the childhood type of pulmonary TB. Involvement of lymph nodes, bones, and, less commonly, other progressive extrapulmonary foci may develop, but TB confined to the lung in this age group usually heals spontaneously. The short-term prognosis in these individuals is good even if untreated, but there is a high frequency of relapse with chronic cavitary TB when the more disease-prone periods of adolescence and young adulthood arrive.199

Infection in Adolescence and Young Adulthood Clinical disease developing after infection in adolescence or young adulthood may resemble childhood infection (lower lung field pneu- monitis, hilar adenitis) but with less parenchymal and hilar calcification (Fig. 249.2). This is particularly the case in immunocompromised patients, including those living with HIV.194 Rarely, the radiographic picture may be mixed, with features of childhood disease subsiding while chronic upper lobe (adult) disease progresses. However, disease in this age group frequently first appears as chronic upper lobe TB with no clinical manifestations of childhood disease. The tendency toward apical cavita- tion soon after the initial infection appears soon after puberty and is marked in young adults.172 Evidence suggests that adolescents (and adults) may have a subclinical tuberculous pneumonia for months prior to the onset of overt disease.200,201 Because most young people in industrialized countries are tuberculin negative (Fig. 249.3), most pulmonary TB in adolescents and young adults is due to recent initial infection rather than to late progression of childhood infection

Infection in Midadulthood Infection acquired during the middle years has a much better immediate and probably long-term prognosis than infection acquired in the teens and early 20s, presumably because of a reduced tendency to tissue necrosis.199,202 One study demonstrated progression from infection to cavitary TB in 23% of patients infected from 15 to 19 years of age, 13% of those infected from 20 to 24 years of age, 4% of those infected from 25 to 29 years of age, and only 2% of those infected after 30 years of age. Progression occurred in 3 months in many and within 1 year in most.203 (Elderly individuals were not included in the study.)

Infection in Old Age In the elderly, infection acquired years earlier can progress as age compromises immunity, producing typical apical-posterior disease. Studies of TB in nursing homes, however, have demonstrated that elderly patients are often tuberculin negative, either because they had never been infected or because remote past infection had been completely cleared, with a loss of tissue hypersensitivity. Such tuberculin-negative persons are susceptible to new infection; and if this occurs, they acquire active disease with a frequency similar to that of adolescents. This is typically a nondescript, poorly resolving pneumonitis in the lower or middle lobes or anterior segments of the upper lobes, sometimes with pleural effusion and resembling primary infection in children except with much less hilar-mediastinal lymphadenopathy.97 Even with prompt diagnosis and treatment, TB after age 65 appears to be more frequently associated with death

Late Hematogenous Tuberculosis Chronic TB is probably always associated with recurrent abortive episodes of hematogenous spread. However, when aging or other factors com- promise cellular immunity, such episodes may become progressively more frequent, producing the subtle and often fatal syndrome of late hematogenous or progressive generalized TB

General stress, poor health, and malnutrition favor progression of infec- tion.

Therapy with corticosteroids or other immunosuppressive agents compromises host defenses, as do hematopoietic-reticuloendothelial diseases, particularly malignancies. TB in complicating myeloprolif- erative disorders may cause confusion because disseminated TB can cause aplastic anemia, thrombocytopenia, leukopenia, and leukemoid reactions that may mimic leukemia. However, most patients with TB and hematologic findings that suggest leukemia will have both diseases.

The development of bone and joint TB after physical injury and late generalized hematogenous TB after major trauma both illustrate that the balance between host and infection can be altered by both systemic factors and local physical disturbance.

Provision of ART restores immune function and decreases risk for TB, although not to levels seen among HIV-negative individuals.211

The earliest descriptions of TB with AIDS emphasized the very great risk for reactivation of remote infection as a result of progressively compromised cellular immunity. Among Haitians, all of whom were likely infected with M. tuberculosis in childhood, HIV infection was associated with development of active TB in 60%.103

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