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

Most of the clinical features of pulmonary tuberculosis can be attributed to one of two aspects of the disease: the presence of a poorly controlled chronic infection or a chronic destructive process within the lung parenchyma. A variety of other manifestations result from extrapulmonary spread of tuberculosis, but these consequences are not considered here.

Why chronic infection within the lung produces systemic manifestations is not entirely clear. However, as implied by the term “consumption,” used so frequently in the past, tuberculosis is a disease in which systemic manifestations such as weight loss, wasting, and loss of appetite are prominent features. These and other systemic effects of tuberculosis are discussed in the section on clinical manifestations.

The chronic destructive process involving the pulmonary parenchyma entails progressive scarring and loss of lung tissue. However, respiratory function is generally preserved more than would be expected, perhaps because the disease often is limited to the apical and posterior regions of the upper lobes as well as to the superior segment of the lower lobes. Oxygenation also tends to be surprisingly preserved, presumably because ventilation and perfusion are destroyed simultaneously in the affected lung. Consequently, ventilation-perfusion mismatch is not nearly so great as in many other parenchymal and airway diseases.

Clinical Manifestations

There is an important distinction—and important clinical differences—between latent tuberculous infection and tuberculous disease (active tuberculosis). Latent tuberculous infection is the consequence of primary exposure, by which the bacilli have become established in the patient; however, host defense mechanisms have prevented any clinically apparent disease. Specific immunity to the tubercle bacillus can be demonstrated by a positive reaction to a skin test for delayed hypersensitivity or a positive IGRA; otherwise, there is no evidence for proliferation of bacteria or for tissue involvement by disease. Patients with infection but without disease are not contagious. In contrast, tuberculous disease is associated with proliferation of organisms, accompanied by a tissue response and generally (although not always) clinical problems of which the patient is aware.

Patients with pulmonary tuberculosis can manifest (1) systemic symptoms, (2) symptoms referable to the respiratory tract, or (3) an abnormal finding on chest radiograph but no clinical symptoms. When symptoms occur, they are generally insidious rather than acute in onset.

Systemic symptoms are often relatively nonspecific: weight loss, anorexia, fatigue, low-grade fever, and night sweats. The most common symptoms resulting from pulmonary involvement are cough, sputum production, and hemoptysis; chest pain occasionally is present. Many patients have neither systemic nor pulmonary symptoms and come to the attention of a physician because of an abnormal finding on chest radiograph, often performed for an unrelated reason.

Patients with extrapulmonary involvement frequently have pulmonary tuberculosis as well, but occasional cases are limited to an extrapulmonary site. The pericardium, pleura, kidney, peritoneum, adrenal glands, and central nervous system each may be involved, with symptoms resulting from the particular organ or region affected. With miliary tuberculosis, the disease is disseminated, and patients usually are systemically quite ill.

Physical examination of the patient with pulmonary tuberculosis may show the ravages of a chronic infection with evidence of wasting and weight loss. This presentation is uncommon in patients with access to health care but is frequently seen in the developing world. Findings on chest examination tend to be relatively insignificant, although sometimes evidence of crackles or rales over affected areas is observed. If a tuberculous pleural effusion is present, the physical findings characteristic of an effusion may be found.

Common presenting problems with tuberculosis are:

Diagnostic Approach

One of the most commonly used diagnostic tools, the tuberculin skin test, documents tuberculous infection rather than active disease. A small amount of protein derived from the tubercle bacillus (purified protein derivative [PPD]) is injected intradermally on the inner surface of the forearm. Individuals who have been exposed to M. tuberculosis and have acquired cellular immunity to the organism demonstrate a positive test reaction, seen as induration or swelling at the site of injection after 48 to 72 hours. The criteria for determining a positive skin test reaction vary according to the clinical setting, specifically the presence or absence of immunosuppression and/or epidemiologic risk factors affecting the likelihood of previous exposure to tuberculosis. Importantly, the test does not distinguish between individuals who have active tuberculosis and those who merely have acquired delayed hypersensitivity from previous infection. However, because reactivation tuberculosis occurs in patients with previous tuberculous infection, a positive skin test reaction does identify individuals at higher risk for subsequent development of active disease.

As for most diagnostic tests, false-negative results can occur with the tuberculin skin test. Faulty administration, an inactive batch of skin-testing material, and underlying diseases that depress cellular immunity such as HIV or even advanced tuberculosis itself, are a few causes of false-negative skin test reactions. On the other hand, not all patients who react to tuberculoprotein have been exposed to M. tuberculosis. Infection with nontuberculous mycobacteria, often called atypical mycobacteria, is sometimes associated with a positive or a borderline positive skin test reaction to PPD.

Blood tests that detect latent tuberculosis have been developed. The tests involve incubating the patient’s T cells with M. tuberculosis antigens. Cells from previously sensitized individuals release IFN-γ in response to the antigens, and the IFN-γ is detected by an enzyme-linked assay. Tuberculin skin testing remains more commonly performed than IFN-γ assays. However, blood tests have the advantage of lower labor costs by not requiring patients to return for an office visit for the skin test interpretation. These assays are unaffected by prior bacille Calmette-Guérin (BCG) vaccination (see section on principles of therapy) or exposure to most atypical mycobacteria, but false-positive results can occur in individuals exposed to or infected with Mycobacterium marinum and Mycobacterium kansasii.

For diagnosis of tuberculosis (i.e., actual tuberculous disease), an important initial diagnostic tool is the chest radiograph. In primary disease, the chest radiograph may show a nonspecific infiltrate, often but certainly not exclusively in the lower lobes (in contrast to the upper lobe predominance of reactivation disease). Hilar (and sometimes paratracheal) lymph node enlargement may be seen, reflecting involvement of the draining node by the organism and by the primary infection. Pleural involvement may be seen, with development of a pleural effusion.

Common features of the chest radiograph in primary tuberculosis are:

When the primary disease heals, the chest radiograph frequently shows some residua of the healing process. Most common are small calcified lesions within the pulmonary parenchyma, reflecting a collection of calcified granulomas. Calcification within hilar or paratracheal lymph nodes may be seen. The radiographic terminology can be confusing as it is commonly used. The term granuloma is actually a pathologic term that describes a microscopic collection of lymphocytes and histiocytes. A calcified nodule on a chest radiograph is frequently called a calcified granuloma, but it really represents a small mass of numerous microscopic granulomas.

With reactivation tuberculosis, the most common sites of disease are the apical and posterior segments of the upper lobes and, to a lesser extent, the superior segment of the lower lobes. A variety of patterns can be seen: infiltrates, cavities, nodules, and scarring and contraction (Fig. 24-1). The presence of abnormal findings on a chest radiograph does not necessarily indicate active disease. The disease may be old, stable, and currently inactive, and it is difficult, if not impossible, to gauge activity on the basis of radiographic appearance.

Radiographic location of reactivation tuberculosis: most commonly apical and posterior segments of upper lobe(s), superior segment of lower lobe(s)

Definitive diagnosis of tuberculosis rests on culturing the organism from either secretions (e.g., sputum) or tissue, but the organisms are slow growing, with possibly 6 weeks required for growth and final identification. Culture of the organism is important not only for confirmation of the diagnosis but also for testing sensitivity to antituberculous drugs, particularly in light of concerns about resistance to some of the commonly used antituberculous agents.

Another extremely useful procedure that can provide results almost immediately is staining of material obtained from the tracheobronchial tree. The specimens obtained can be sputum, expectorated either spontaneously or following inhalation of an irritating aerosol (sputum induction), or washings or biopsy samples obtained by fiberoptic bronchoscopy. While staining positive with Gram stain, a hallmark of mycobacterial organisms is their ability to retain certain dyes even after exposure to acid. Their acid-fast property is generally demonstrated with Ziehl-Neelsen or Kinyoun stain or with a fluorescent stain that uses auramine-rhodamine. The finding of a single acid-fast bacillus from sputum or tracheobronchial washings is clinically significant in the majority of cases. One qualification is that nontuberculous mycobacteria, which either cause less severe disease or are present as colonizing organisms or contaminants, have the same staining properties. Therefore, it is critical to determine whether acid-fast bacilli seen on smear represent M. tuberculosis or nontuberculous mycobacteria. This distinction can be made either by certain growth characteristics on culture or, more recently, by molecular biologic techniques.

For even one tubercle bacillus to be seen on smear, large numbers of organisms must be present in the lungs. Therefore, if few organisms are present, even if they are causing disease, the smear results may be negative, whereas culture findings often will be positive in this setting. In general, the infectiousness of a patient with tuberculosis correlates with the number of organisms the patient is harboring and the presence of organisms on smear. Patients whose sputum is positive by smear tend to be much more infectious than patients whose sputum is positive by culture but negative by smear.

Because of the insensitivity of sputum smears and the time required for M. tuberculosis to grow in culture, rapid and more sensitive methods for establishing the diagnosis of tuberculosis have been developed. Nucleic acid amplification assays have been developed and can detect M. tuberculosis in respiratory specimens in less than 12 hours and with greater sensitivity and specificity than are generally available by staining techniques. Another technique involves detecting radiolabeled CO2 after incubation of the specimen with radiolabeled palmitic acid, a metabolic substrate for mycobacteria. Results can be obtained much more quickly with this technique than by conventional cultures. Functional assessment of the patient with tuberculosis often shows surprisingly little impairment of pulmonary function. Such testing is useful primarily for the patient who already has compromised pulmonary function, when there is concern about how much of the patient’s reserve has been lost. However, a patient who is potentially contagious should not be evaluated with pulmonary function testing because of the possibility of infecting others during the testing maneuvers. Arterial blood gases are often relatively preserved, with normal or decreased PO2, depending on the amount of ventilation-perfusion mismatch that has resulted.

Principles of Therapy

Effective chemotherapy is available for most cases of tuberculosis. Whereas treatment for tuberculosis used to be minimally effective, involving prolonged hospitalization (usually in a sanatorium) or a variety of surgical procedures, the vast majority of cases now are curable with appropriate drug therapy. Patients are treated for a prolonged period, generally with a minimum of two effective antituberculous agents. Therapy for as few as 6 months with two very effective antituberculous agents, isoniazid and rifampin, supplemented during the first 2 months by a third agent, pyrazinamide, is commonly used in cases of pulmonary tuberculosis, with excellent results in patients with a normal immune system. However, because of concern for organisms resistant to one or more antituberculous agents, a fourth drug (ethambutol) is typically added at the initiation of therapy until drug sensitivity results become available. When resistance to one or more of the usual antituberculous agents is documented, the specific regimen and duration of therapy must be adjusted accordingly.

A common treatment of pulmonary tuberculosis is isoniazid and rifampin given for 6 months, supplemented by pyrazinamide for the first 2 months and ethambutol until the organism’s antimicrobial sensitivity is known.

Treatment can be administered in an outpatient setting unless the patient is sufficiently ill to require hospitalization. Patients whose sputum smears initially were positive are generally considered no longer infectious after they have demonstrated a clinical response to antituberculous therapy and after their sputum has become smear-negative on three successive samples. A critical issue determining the success of antituberculous therapy is the patient’s adherence to the medical regimen. Erratic or incomplete therapy is associated with a risk of treatment failure and emergence of resistant organisms, with potentially disastrous consequences. As a result, use of directly observed therapy, in which the drugs are given in a supervised outpatient setting, has become an important component of treatment for many cases of tuberculosis and is essential when there are concerns regarding patient adherence. Hepatotoxicity can occur with antituberculous medications, necessitating appropriate monitoring of patients during therapy.

Thus, effective therapy for tuberculosis requires long-term chemotherapy for all patients and directly observed therapy for many. Treatment is expensive and labor intensive, and is most successful with a well-funded and effective public health system. Even in industrialized nations, this presents difficulties. In many parts of the world, this type of public health system is nonexistent.

In addition to multiple drug therapy administered for active tuberculosis, therapy with isoniazid alone (typically for 9 months) is generally administered to household members of patients with recently diagnosed tuberculosis and to newly infected persons (documented by recent conversion to a positive skin test reaction). Such therapy substantially decreases the chances of active tuberculosis developing in these individuals, who are at particularly high risk.

Isoniazid alone for 9 months is indicated for selected patients with a positive PPD (i.e., tuberculous infection) but no evidence of active disease.

Certain other patients with latent tuberculous infection documented by a positive tuberculin skin test reaction but no evidence of active disease are considered candidates for 9 months of treatment with isoniazid alone (or an alternative regimen). Specifically, this category includes patients who satisfy additional criteria (besides a positive PPD reaction) that put them at high risk for reactivation of a dormant infection. Examples include the presence of stable radiographic findings of old active tuberculosis but no prior therapy, or the presence of underlying diseases or treatment that impairs host defense mechanisms. Although this form of single-drug therapy was often called “prophylactic” or “preventive,” it actually represents treatment aimed at eradicating a small number of dormant but viable organisms. It has been well demonstrated to be effective in achieving its goal of substantially decreasing the eventual risk for reactivation tuberculosis.

One recent major public health issue has been the development of organisms resistant to one or more of the commonly used antituberculous agents. When a strain is resistant to both isoniazid and rifampin, it is termed multidrug resistant (MDR.) If a strain is resistant to isoniazid and rifampin plus any fluoroquinolone and at least one of the injectable drugs, it is termed extensively drug resistant (XDR). This problem underscores the importance of public health measures to limit person-to-person transmission of tuberculosis, as well as efforts to improve patient adherence with antituberculous medication. When treating a patient with tuberculosis caused by MDR or XDR organisms, close coordination between treating physicians and public health authorities is essential. Molecular diagnostic techniques have been developed to immediately identify drug resistance at the time tuberculosis is diagnosed and may significantly improve the management of these patients.

The goal of developing an effective vaccine against M. tuberculosis remains an important step toward achieving worldwide eradication of tuberculosis. Vaccination with BCG, a live, attenuated strain of Mycobacterium bovis, has been used for many years in various countries around the world, but it has not been recommended for use in the United States except in selected rare circumstances. Although BCG vaccination appears to decrease the risk of serious and potentially life-threatening forms of tuberculosis in children, its efficacy in preventing pulmonary tuberculosis in adults is questionable. Of note, patients treated with BCG vaccination will at least initially have a positive response to a PPD test, although the accuracy of IGRAs is unaffected in this setting.

Nontuberculous Mycobacteria

A variety of nontuberculous mycobacteria, sometimes called atypical mycobacteria, are potential pulmonary pathogens. They are generally found in water and soil, which appear to be the sources of exposure rather than person-to-person transmission. The most common organisms in this group are classified as belonging to the Mycobacterium avium complex (MAC), formerly called Mycobacterium avium-intracellulare. Other organisms include M. kansasii, Mycobacterium xenopi, and Mycobacterium fortuitum.

The nontuberculous mycobacteria are primarily responsible for disease in two settings: (1) the patient with underlying lung disease, in whom local host defense mechanisms presumably are impaired, and (2) the patient with a defect in systemic immunity, particularly AIDS (see Chapter 26). Nevertheless, these organisms cause disease in a small number of patients without either of these risk factors. Overall recognition of disease from nontuberculous mycobacteria has increased over the past 10 to 20 years, in large part because of its occurrence in patients with AIDS.

Nontuberculous mycobacteria are most frequently pathogens in patients with underlying lung disease or AIDS.

Disease caused by nontuberculous mycobacteria can be localized to the lung, where it can mimic tuberculosis, or it can be found after hematogenous dissemination throughout the body, particularly in patients with AIDS. Diagnosis of disease caused by these organisms is difficult. They can be found as laboratory contaminants, and in patients with other underlying lung diseases, the organisms can colonize the respiratory system without being responsible for invasive disease.

When these organisms cause disease, treatment typically involves multiple agents. The organisms are frequently resistant to some of the standard antimycobacterial drugs, so treatment regimens traditionally were complicated and often unsuccessful. Fortunately, the newer macrolide antibiotics (e.g., clarithromycin, azithromycin) are often effective; they become particularly useful components of the therapeutic regimen for many of the nontuberculous mycobacteria. A more complete discussion of this topic is beyond the scope of this text, so the reader is referred to the review articles in the References.

References

General Reviews

American Thoracic Society. Diagnostic standards and classification of tuberculosis in adults and children. Am J Respir Crit Care Med. 2000;161:1376–1395.

Anadash, A, Dheda, K, Keane, J, et al. Novel developments in the epidemic of human immunodeficiency virus and tuberculosis coinfection. Am J Respir Crit Care Med. 2011;183:987–997.

Centers for Disease Control and Prevention (CDC). Trends in tuberculosis incidence—United States, 2010. MMWR Morb Mortal Wkly Rep. 2011;60:333–337.

Connell, DW, Berry, M, Cooke, G, Kon, OM. Update on tuberculosis: TB in the early 21st century. Eur Respir Rev. 2011;20:71–84.

Escalante, P. In the clinic: tuberculosis. Ann Intern Med. 2009;150:ITC610–614.

Lawn, SD, Zumla, AI. Tuberculosis. Lancet. 2011;378:57–72.

Yew, WW, Leung, CC. Update in tuberculosis 2007. Am J Respir Crit Care Med. 2008;177:479–485.

Pathogenesis

Barnes, PF, Cave, MD. Current concepts: molecular epidemiology of tuberculosis. N Engl J Med. 2003;349:1149–1156.

Quast, TM, Browning, RF. Pathogenesis and clinical manifestations of pulmonary tuberculosis. Dis Mon. 2006;52:413–419.

Schluger, NW. The pathogenesis of tuberculosis: the first one hundred (and twenty-three) years. Am J Respir Cell Mol Biol. 2005;32:251–256.

Schluger, NW, Rom, WN. The host immune response to tuberculosis. Am J Respir Crit Care Med. 1998;157:679–691.

Schwander, S, Dheda, K. Human lung immunity against Mycobacterium tuberculosis: insights into pathogenesis and protection. Am J Respir Crit Care Med. 2011;183:696–707.

Smith, I, Nathan, C, Peavy, HH. Progress and new directions in genetics of tuberculosis: an NHLBI working group report. Am J Respir Crit Care Med. 2005;172:1491–1496.

van Crevel, R, Ottenhoff, TH, van der Meer, JW. Innate immunity to Mycobacterium tuberculosis,. Clin Microbiol Rev. 2002;15:294–309.

Clinical Manifestations and Diagnostic Approach

Alvarez, S, McCabe, WR. Extrapulmonary tuberculosis revisited: a review of experience at Boston City and other hospitals. Medicine. 1984;63:25–55.

American Thoracic Society. Diagnostic standards and classification of tuberculosis in adults and children. Am J Respir Crit Care Med. 2000;161:1376–1395.

American Thoracic Society. Targeted tuberculin testing and treatment of latent tuberculosis infection. Am J Respir Crit Care Med. 2000;161:S221–S247.

Dosanjh, DPS, Hinks, TSC, Innes, JA, et al. Improved diagnostic evaluation of suspected tuberculosis. Ann Intern Med. 2008;148:325–336.

Gopi, A, Madhavan, SM, Sharma, SK, Sahn, SA. Diagnosis and treatment of tuberculous pleural effusions in 2006. Chest. 2007;131:880–889.

Horsbaugh, CR, Rubin, EJ. Clinical practice: Latent tuberculosis infection in the United States. N Engl J Med. 2011;364:1441–1448.

Jacob, JT, Mehta, AK, Leonard, MK. Acute forms of tuberculosis in adults. Am J Med. 2009;122:12–17.

Lalvani, A. Diagnosing tuberculosis infection in the 21st century. New tools to tackle an old enemy. Chest. 2007;131:1898–1906.

Schluger, NW. Changing approaches to the diagnosis of tuberculosis. Am J Respir Crit Care Med. 2001;164:2020–2024.

Schluger, NW, Burzynski, J. Recent advances in testing for latent TB. Chest. 2010;138:1456–1463.

Weir, MR, Thornton, GF. Extrapulmonary tuberculosis. Am J Med. 1985;79:467–478.

Treatment

American Thoracic Society. Targeted tuberculin testing and treatment of latent tuberculosis infection. Am J Respir Crit Care Med. 2000;161:S221–S247.

American Thoracic Society, Centers for Disease Control and Prevention, and Infectious Diseases Society of America. Treatment of tuberculosis. Am J Respir Crit Care Med. 2003;167:603–662.

Centers for Disease Control and Prevention (CDC). Emergence of Mycobacterium tuberculosis with extensive resistance to second-line drugs—worldwide, 2000–2004. MMWR Morb Mortal Wkly Rep. 2006;55:301–305.

Cohn, DL. Treatment of latent tuberculosis infection. Semin Respir Infect. 2003;18:249–262.

Jasmer, RM, Nahid, P, Hopewell, PC. Latent tuberculosis infection. N Engl J Med. 2002;347:1860–1866.

Leung, CC, Rieder, HL, Lange, C, Yew, WW. Treatment of latent infection with Mycobacterium tuberculosis: update 2010. Eur Respir J. 2011;37:690–711.

Nahid, P, Gonzalez, LC, Rudoy, I, et al. Treatment outcomes of patients with HIV and tuberculosis. Am J Respir Crit Care Med. 2007;175:1199–1206.

Richeldi, L. An update on the diagnosis of tuberculosis infection. Am J Respir Crit Care Med. 2006;174:736–742.

Small, PM, Fujiwara, PI. Management of tuberculosis in the United States. N Engl J Med. 2001;345:189–200.

World Health Organization. Treatment of tuberculosis guidelines, 4th edition. http://whqlibdoc.who.int/publications/2010/9789241547833_eng.pdf, 2010. Accessed July 17, 2012

Yew, WW, Lange, C, Leung, CC. Treatment of tuberculosis: Update 2010. Eur Respir J. 2011;37:441–462.

Nontuberculous Mycobacteria

American Thoracic Society, Infectious Disease Society of America. Diagnosis, treatment, and prevention of nontuberculous mycobacterial disease. Am J Respir Crit Care Med. 2007;175:367–416.

Ellis, SM, Hansell, DM. Imaging of non-tuberculous (atypical) mycobacterial pulmonary infection. Clin Radiol. 2002;57:661–669.

Field, SK, Fisher, D, Cowie, RL. Mycobacterium avium complex pulmonary disease in patients without HIV infection. Chest. 2004;126:566–581.

Glassroth, J. Pulmonary disease due to nontuberculous mycobacteria. Chest. 2008;133:243–251.

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