Tuberculosis and Nontuberculous Mycobacteria

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Tuberculosis and Nontuberculous Mycobacteria

Throughout the centuries, few diseases have claimed so many lives, caused so much morbidity, and been so dreaded as tuberculosis. At the turn of the 20th century, tuberculosis was the single most common cause of death in the United States; more than 80% of the population was infected before the age of 20 years. At the beginning of the 21st century, tuberculosis provides a stark example of the disparity in health resources between industrialized nations and the developing world. In the United States and Europe, few diseases have declined so greatly in frequency of cases and mortality as has tuberculosis. Two main factors have been responsible: overall improvement in living conditions and development of effective antituberculous chemotherapy, which has made tuberculosis a curable disease. However, in countries with fewer resources, the disease continues to be a health crisis, often striking the young, most productive members of society.

Now more than 125 years since identification of the tubercle bacillus by Robert Koch in 1882, we still cannot become complacent about the disease. It has been estimated that approximately one third 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, with 8 to 10 million new cases of active tuberculosis and approximately 2 to 3 million deaths occurring worldwide each year. The overwhelming majority of cases of active tuberculosis occur in developing countries. Some 70 million of the 88 million cases of tuberculosis during the 1990s were from Asia and sub-Saharan Africa, where coinfection with the human immunodeficiency virus (HIV) is a major contributor to the increase in infections. Tuberculosis remains an important public health problem in the United States, particularly in indigent and immigrant populations and patients with AIDS (see Chapter 26). Reported cases of tuberculosis in the United States were decreasing until the mid-1980s, at which time the AIDS epidemic and immigration from countries with a high prevalence of tuberculosis combined to result in an increasing frequency of cases. Fortunately, since 1991 the number of cases reported annually in the United States has again been decreasing. Perhaps most alarming, both in the United States and throughout the world, is the relatively recent emergence of drug-resistant strains of the organism, some of which are resistant to multiple antituberculous drugs.

Etiology and Pathogenesis

The etiologic agent that causes tuberculosis, Mycobacterium tuberculosis, is an aerobic rod-shaped bacterium. An important 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, which 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 (i.e., articles of clothing, eating utensils); direct inhalation of droplets aerosolized by another individual is almost exclusively the mode of spread.

Transmission of tuberculosis is by inhalation of small aerosol droplets containing the organism.

When droplets containing mycobacteria are inhaled and reach the alveoli, a small focus of primary infection develops, consisting of the organisms and an inflammatory process mounted by the host. Alveolar macrophages represent the primary initial defense against organisms reaching the parenchyma, and they are a particularly important component of the resulting inflammatory response. After the initial infection has started, organisms frequently spread via lymphatic vessels to draining hilar lymph nodes as well as via the bloodstream to distant organs and other regions of lung, particularly the apices. In the majority of cases, even though lymphatic and hematogenous spread may occur, the body’s defense mechanisms (in the lung and elsewhere) are capable of controlling and limiting the primary infection. 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 cell-mediated immune response generally occur within several weeks of initial exposure.

The patient usually is unaware of the primary infection, although a mild, self-limited febrile illness may be reported. The only tracks 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 (i.e., positive delayed hypersensitivity skin test reaction or interferon-γ release assay). In a few patients, probably 5% or fewer, defense mechanisms are unable to control the primary infection, and clinically apparent primary tuberculosis results. This is most common if the host is immunocompromised because of immunosuppressive medications, alcoholism, HIV/AIDS, or malignancy.

Even when the primary infection apparently has been controlled, the tubercle bacillus may not be completely eliminated from the host. A small number of organisms often remain in a dormant or latent state, not killed but also not proliferating or causing any apparent active disease. The majority of patients will never have any further difficulty with development of clinically active tuberculosis. However, in some patients the delicate balance between the organism and host defense mechanisms eventually breaks down, often after many years, and a dormant focus of infection becomes active. These patients with active disease occurring at a time removed from the primary infection are said to have reactivation tuberculosis. For both primary and reactivation disease, the lungs are the most commonly affected site. However, with either type of disease, distant organ systems may be involved as a result of hematogenous spread during the primary phase of the infection. In addition, a disseminated disease known as miliary tuberculosis may result from hematogenous dissemination of the organisms.

The majority of active tuberculosis cases involve reactivation of a previously dormant focus within the lungs.

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 of 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; about 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 defective cellular immunity due to advanced HIV infection.

Definitions

On the basis of our understanding of disease pathogenesis, a few additional terms are worth defining. 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 interferon (IFN)-γ release assay (IGRA; described under Diagnostic Approach) but no 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 they 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. Several other terms are sometimes used to describe clinical disease on the basis of the presumed pathogenesis. 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. As a general rule, 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 not from reactivation of dormant tubercle bacilli but from new exposure to another source of organisms. This type of infection traditionally has been considered uncommon. It is believed that individuals with prior exposure to 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 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 a relatively nonspecific inflammatory response in the involved region of parenchyma. Regional lymph nodes often become involved by local spread of the organism, and 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 blood and 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 features of the granulomas include multinucleated giant cells and often the presence of tubercle bacilli.

After development of delayed hypersensitivity, the pathologic hallmarks of tuberculosis are granulomas and caseous necrosis, often with cavity formation.

A process of healing tends to occur at the sites of disease. Fibrosis or scarring ensues, often associated with contraction of the affected area and deposition of calcium. When the Ghon complex undergoes progressive fibrosis and calcification, it is referred to as a Ranke complex. With full-blown tuberculosis, extensive destruction of lung tissue results from large areas of inflammation, granuloma formation, caseous necrosis, and cavitation, along with fibrosis, contraction, and foci of calcification. Interestingly, much of the destruction that occurs during tuberculosis requires an intact cellular immune system and appears to be due to the host inflammatory response attempting to contain the infection. As a result, patients with advanced HIV disease often have an atypical presentation in which the organism is widely disseminated but there is little evidence of cavitation and fibrosis.

Tuberculosis is capable of spread, and spread of organisms through the bloodstream at the time of primary infection is probably the rule rather than the exception. When defense mechanisms break down, disease can become apparent at other sites (e.g., liver, kidney, adrenal glands, bones, central nervous system). Spread also occurs to other regions of the lung, either as a result of hematogenous seeding during the primary infection or because of spilling of infected secretions or caseous material into the bronchi and other regions of the lung.

Within the lung, characteristic locations for reactivation tuberculosis are the apical regions of the upper lobes and, to a lesser extent, the superior segment of the lower lobes. It is believed these are not sites of primary infection but rather the favored location for implantation of organisms after hematogenous spread. These regions have a high PO2 and relatively less perfusion and thus are believed to be particularly suitable for survival of the aerobic tubercle bacilli.

Pathophysiology

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