25: Tuberculosis and nontuberculous mycobacteria
OUTLINE
Etiology and Pathogenesis, 299
Definitions, 300
Pathology, 300
Pathophysiology, 301
Clinical Manifestations, 301
Diagnostic Approach, 302
Principles of Therapy, 304
Nontuberculous Mycobacteria, 305
Throughout the centuries, few diseases have claimed so many lives, caused so much morbidity, and been so dreaded as tuberculosis. At the beginning of the 20th century, tuberculosis was the single most common cause of death in the United States, and more than 80% of the population was infected before the age of 20 years. At the beginning of the 21st century, tuberculosis provided a stark example of the disparity in health resources between industrialized nations and the developing world. In countries with widely available healthcare, such as in North America and Europe, few diseases have declined so greatly in frequency and mortality as tuberculosis. Two main factors have been responsible: overall improvement in living conditions and the development of effective antituberculous chemotherapy, which transformed tuberculosis into a routinely curable disease. However, in countries with fewer resources, the disease, especially with drug-resistant tuberculosis, continues to be a health crisis, often striking the young, most productive members of society.
Now more than 140 years since identification of the tubercle bacillus by Robert Koch in 1882, we must not become complacent about the disease. It is estimated that approximately 25% of the world’s current population, or over 2 billion people, have been infected (i.e., have either latent or active infection) with the tubercle bacillus. According to the World Health Organization (WHO), the global incidence of tuberculosis peaked in 2003 with a slow decline until 2019. In 2020, the COVID-19 pandemic led to decreased access to healthcare in under-resourced countries, resulting in a drop in reported newly diagnosed cases of tuberculosis. However, the reduced access was associated with an increase in tuberculosis deaths (1.5 million deaths worldwide). This was the first increase in annual deaths
worldwide due to tuberculosis since 2003.
Tuberculosis occurs in every part of the world; however, the incidence varies globally, with the majority of cases of active tuberculosis occurring in resource-limited countries. Poverty, HIV infection, and the presence of drug-resistant organisms are major factors in the variation. In 2020, the largest number of new tuberculosis cases occurred in the WHO South-East Asian Region, with 43% of new cases, followed by the WHO African Region, with 25% of new cases, and the WHO Western Pacific Region, with 18%. In the United States, tuberculosis remains an important public health problem, even though in 2020 the CDC reported the lowest number of cases on record. As with previous years, new cases were more common in individuals born outside the United States from areas with a higher prevalence of tuberculosis (72%). The COVID-19 pandemic probably influenced these numbers, and it is uncertain if this trend will continue.
Etiology and pathogenesis
The etiologic agent that causes tuberculosis, Mycobacterium tuberculosis, is an aerobic rod-shaped bacterium. A distinctive property of the tubercle bacillus is its ability to retain certain stains even after exposure to acid (discussed under Diagnostic Approach); thus, mycobacteria are said to be acid-fast. Transmission of the disease occurs via small aerosol droplets, generally from 1 to 5 μm in size, that contain the microorganism. The source of these droplets is an individual with tuberculosis who harbors
the organism, often excreting tubercle bacilli in the sputum or in small droplets produced during commonplace activities such as speaking, coughing, singing, and laughing. Most commonly, transmission occurs with relatively close contact, often between related individuals or others living in the same household. The disease is not transmitted by fomites (e.g., articles of clothing, eating utensils); direct inhalation of aerosolized droplets is the exclusive mode of spread.
Transmission of tuberculosis is by inhalation of small aerosol droplets containing the organism.
When droplets containing mycobacteria are inhaled, reach the alveoli, and are not immediately cleared by innate host defenses, a small focus of primary infection develops, consisting of the organisms and an inflammatory process mounted by the host. Alveolar macrophages represent the initial primary defense against organisms, and they are a particularly important component of the resulting inflammatory response. Tubercle bacilli proliferate inside alveolar macrophages, which release cytokines and chemokines that result in recruitment of more macrophages and other inflammatory cells. If the infection is not controlled, organisms spread via lymphatic vessels to draining hilar lymph nodes as well as via the bloodstream to distant organs and other regions of the lung, particularly the apices. Even though lymphatic and hematogenous spread may occur, the host immune defense mechanisms (in the lung and elsewhere) control and limit the primary infection in more than 90% of cases. An important component of the body’s acquired defense against M. tuberculosis is the development of cell-mediated immunity (delayed hypersensitivity) against the mycobacterial organisms. This sensitization and development of a cellmediated immune response typically occur within several weeks of initial infection.
The patient often is unaware of the primary infection, although a mild, self-limited febrile illness may be reported. The only residua left by the organism are those related to the host’s response to the bacillus: either the local tissue response or evidence that the host has become sensitized to the tubercle bacillus, which is evidenced by a positive delayed hypersensitivity skin test reaction or interferon (IFN)-γ release assay. In a small minority of patients, probably 5% or fewer, defense mechanisms are unable to control the primary infection, and clinically apparent primary tuberculosis results. This is most common in the
setting of immunocompromise, treatment with immunosuppressive medications, alcoholism, HIV/AIDS,
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malnutrition, or malignancy.
Despite apparent control of the primary infection, tubercle bacilli may persist in the host. A small number of organisms often remain in a dormant or latent state, not proliferating or causing any apparent active disease, but still potentially viable. These patients are considered to have latent infection. Most patients with latent infection will never develop clinically active tuberculosis. However, in some patients, the delicate balance between the organism and the host defense mechanisms eventually breaks down, sometimes after many years, and a dormant focus of infection becomes active. Patients with active disease occurring at a time removed from the primary infection are said to have reactivation tuberculosis. Over the course of a lifetime, it is estimated that approximately 10% of individuals with a normal immune system who have been infected with M. tuberculosis (and have not received treatment for latent tuberculosis infection to eradicate dormant organisms) will develop active disease. The risk of developing active tuberculosis is greatest within the first 2 years after the initial infection; approximately one-half of patients who develop active disease do so within this time frame. The other half who develop active disease do so at some later point in life. These estimates of risk apply to patients with normal host defenses. The risk of developing active tuberculosis is dramatically higher in patients with defects in host immunity such as advanced HIV infection, chronic corticosteroid use, and treatment with tumor necrosis factor (TNF)-α receptor blockers.
For both primary and reactivation disease, the lungs are most commonly affected. However, with either type of disease, other organs may be involved due to hematogenous spread during the primary phase of the infection. When the host immune response is overwhelmed, whether due to primary or reactivation disease, extensive hematogenous spread of organisms leads to disseminated disease known as miliary tuberculosis (Fig. 25.1).
FIGURE 25.1 Chest CT image from a patient with miliary tuberculosis. There are
countless small nodules resulting from hematogenous dissemination of M.
tuberculosis. Source: (Courtesy Dr. Seth Kligerman.)
The majority of active tuberculosis cases involve reactivation of a previously dormant focus within the
lungs.
Definitions
On the basis of our understanding of disease pathogenesis, a few terms are worth clarifying. First is the distinction between tuberculous infection and tuberculous disease. Tuberculous infection (or latent tuberculous infection) is defined by a positive tuberculin skin test or a positive blood IFN-γ release assay (IGRA; described under Diagnostic Approach) but no clinical evidence of active disease. Patients with latent tuberculous infection have been infected by the organism, but the initial infection was controlled by the body’s host defense mechanisms and subsequently can be traced only by a positive delayed hypersensitivity skin test or positive IGRA response. The small number of remaining organisms are in a dormant or latent state, but do pose a risk for reactivation at a later time, especially with any impairment in the host’s cellular immunity. Tuberculous disease (or active tuberculosis), on the other hand, is defined by the presence of clinically active disease in one or more organ systems, ideally with confirmation of the diagnosis by isolation of M. tuberculosis.
Other terms worth defining are those that describe different subsets of tuberculous disease. Most common are the terms primary and reactivation tuberculosis, which refer to disease following the initial exposure and disease that reactivates after a period of latency, respectively. The term progressive primary tuberculosis reflects primary disease that has not been controlled by host defense mechanisms and has continued to be active beyond the point at which delayed hypersensitivity has developed. Typically, cellular immunity develops 2 to 10 weeks after the initial infection, and continuing active disease beyond this time has many of the features of reactivation tuberculosis. The term postprimary tuberculosis refers to disease beyond the initial primary infection. Although this term usually refers to reactivation disease, it sometimes includes cases of progressive primary tuberculosis.
The term reinfection tuberculosis refers to disease in a previously infected person that results from an infection due to exposure to new organisms rather than from reactivation of dormant tubercle bacilli. This type of infection traditionally has been considered uncommon. It is believed that individuals with prior infection with tuberculosis who manifest delayed hypersensitivity to the organism are relatively resistant to exogenous reinfection from another source. However, studies using DNA fingerprinting techniques suggest that reinfection with another organism is more common than previously thought, particularly in highly endemic regions and in patients who are infected with HIV.
Pathology
The pathologic features of pulmonary tuberculosis vary according to the stage of infection. The primary infection in the lung consists of the organisms and an inflammatory response involving alveolar macrophages, neutrophils, and monocyte-derived macrophages in the involved region of parenchyma. If the inflammatory response does not control the infection, the organisms spread to regional lymph nodes, leading to ipsilateral hilar and mediastinal lymphadenopathy. The combination of the primary area in the lung (the Ghon lesion) and involved lymph nodes is termed a Ghon complex.
When delayed hypersensitivity is present, either weeks after the primary infection or during a period of reactivation disease, a different pathologic pattern emerges. The hallmarks are the presence of (1) granulomas (collections of activated bloodand tissue-derived macrophages termed epithelioid histiocytes surrounded by a rim of lymphocytes), and (2) caseous necrosis (foci of necrosis and softening at the center of a granuloma). Within the region of caseous necrosis, the contents can liquefy and slough, leaving behind a cavity, another hallmark of tuberculosis. Other microscopic features of the granulomas
include multinucleated giant cells and the frequent presence of visible tubercle bacilli when proper stains
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