74 - Diaphragmatic Injuries
Editors: Shields, Thomas W.; LoCicero, Joseph; Ponn, Ronald B.; Rusch, Valerie W.
Title: General Thoracic Surgery, 6th Edition
Copyright 2005 Lippincott Williams & Wilkins
> Table of Contents > Volume I - The Lung, Pleura, Diaphragm, and Chest Wall > Section XIV - Congenital, Structural, and Inflammatory Diseases of the Lung > Chapter 87 - Pulmonary Tuberculosis and Other Mycobacterial Diseases of the Lung
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Chapter 87
Pulmonary Tuberculosis and Other Mycobacterial Diseases of the Lung
Sridhar Neralla
Jeffrey Glassroth
The mycobacteria are a diverse group of aerobic acid-fast bacilli that are distributed worldwide in the environment and in human hosts. Many species of mycobacteria have been identified, but a smaller number of these are medically important in causing pulmonary disease in humans (Table 87-1). Among this group are the Mycobacterium tuberculosis (MTB) complex (which includes M. tuberculosis, M. bovis, and M. africanum), Mycobacterium avium complex (MAC), and Mycobacterium kansasii, to name a few. Disease manifestations in humans are virtually as diverse as the number of different mycobacteria. The lung is the most frequent organ involved, though by no means the only one, and medically refractory pulmonary disease is the most common reason for surgical intervention. This chapter discusses the diagnosis and management of the various mycobacterial diseases as they pertain to modern thoracic surgical practice.
Mycobacterium tuberculosis
Epidemiology
Mycobacterium tuberculosisA (MTB) causes one of the most common infections affecting humans worldwide. The disease has plagued mankind since antiquity and has been known by many names, including phthisis by the Greeks and the Galloping Consumption during medieval times, reflecting the wasting nature of the disease. Only recently in the course of human history has the understanding of the etiology of this disease evolved and effective drug therapy subsequently developed. In 1882 Koch was the first to identify MTB as the causative organism, although treatment for the next several decades still consisted of isolating patients in sanatoria where they rested and were nourished. Later, various forms of collapse therapy and surgical interventions such as thoracoplasty and plombage were applied. None of these interventions reliably effected a durable cure, nor did they effectively reduce the transmission rate. It was not until the first decade after Word War II that these goals became attainable with the advent of streptomycin in 1946 and isoniazid in 1952. The latter half of the 20th century has seen the development of multiple other antituberculous drugs as well as the development of drug combinations and strategies that, when used for a sufficiently long period of time, have led to lasting cures (and associated reduction in transmission rates) for patients with access to medical therapy. Indeed, elimination of tuberculosis (TB) has become a realistic public health goal, at least in many affluent parts of the world.
The attainment of this goal, however, remains elusive due in part to the biology of the organism and its relatively slow rate of multiplication, necessitating long periods of treatment. Indeed, the rising number of cases worldwide since the early 1980s in both the developing world and parts of the developed world attest to this fact. Some of the reasons for this rise include the human immunodeficiency virus (HIV) pandemic (particularly in sub-Saharan Africa), the lack of sufficient monetary or governmental resources to combat the infection in high-prevalence areas of the world, the emergence of drug-resistant strains of MTB, and increased immigration from highly endemic areas. It is no surprise that against this background, TB remains one of the most common communicable infectious diseases worldwide, with nearly one-third of the world's population infected with the MTB organism. In fact, in 1993 the World Health Organization (WHO) declared TB a global health emergency. This large group of several billion infected persons represents the pool from which most active cases are drawn each year.
Annually, 8 million new cases and 3 million deaths are caused by this organism, according to Corbett and associates (2003). Twenty-two so-called high-burden countries, which annually report the greatest number of new cases superimposed on already large numbers of prevalent cases, are responsible for a large portion of the global TB cases. Dye and colleagues (1999) have noted that these countries
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include many sub-Saharan African nations, former European eastern bloc nations (e.g., Russia), South American countries, and Asian countries (e.g., China, India, and the Philippines). The situation is particularly serious, as emphasized by Corbett and associates (2003), in sub-Saharan Africa, where access to anti-TB medications is limited and almost one in three patients with TB is coinfected with HIV. Drobniewski and coauthors (1997) suggest that these figures probably represent an underestimation of the true incidence of cases because they are dependent on the reporting of national TB control programs, the performance of which can vary from country to country. In many of these nations, HIV coinfection increases susceptibility to TB infection and then accelerates progression of TB infection to active disease. Moreover, inconsistent treatment facilitates the emergence of resistant TB, which is then transmitted within the community, further challenging limited treatment programs.
Table 87-1. Common and Uncommon Causes of Mycobacterial Lung Disease in the United States | ||||||||||||
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In the United States, where a robust health care infrastructure exists, the burden of MTB is much less and the goal of TB elimination seems much more attainable. However, MTB still poses a significant public health challenge in the United States, according to Cantwell and colleagues (1994), as illustrated by a nearly 20% rise in the number of reported cases from 1985 (22,201 cases) to 1992 (26,673 cases). The factors primarily responsible for the increased number of cases were an increase in foreign-born cases (accounting for 60% of the 20% increase), the HIV/AIDS epidemic, and increased active TB transmission. Increased TB transmission occurred primarily in populations at high risk for infection, such as HIV-infected persons and persons of low socioeconomic status. Indeed, these are populations for which the Centers for Disease Control and Prevention (CDC) recommends screening for infection with tuberculin skin testing. Much of the increased morbidity was largely preventable if treatment for latent infection had been prescribed.
Why was there a relative failure of TB control and elimination programs to maintain or reduce the rate of TB transmission? The reasons are multiple and include failure of TB control programs to keep pace with screening the rapidly expanding high-risk populations for latent infection due to limited resources that were allocated preferentially to those persons with active disease. Subsequent reemphasis on screening for latent TB infection during the 1990s, as well as an emphasis on control of TB transmission through the use of directly observed therapy (DOT), has helped to reduce the annual case rate to 16,377 in 2000, which represents the lowest number of new cases in U.S. history. These rates are continuing to decline, with over half of annual cases now occurring in immigrants to the United States, as recorded in the surveillance report of the CDC Division of Tuberculosis (2001). The epidemiology of TB in the United States over the last two decades serves to illustrate how even a nation with the resources available to eliminate TB can fall short of achieving this goal.
Microbiology and Pathogenesis
Mycobacteria are rod-shaped, thin aerobic bacteria measuring approximately 0.5 m by 3 m (Fig. 87-1). Humans are the main reservoir for MTB, although it has now been reported in moose and deer. Less is known about nontuberculous mycobacteria (NTM), also known as environmental mycobacteria because most are presumed to exist in the environment. The organism grows slowly, with visible growth apparent by 3 to 6 weeks on solid media. The cell walls of mycobacteria contain high concentrations of mycolic acids and long-chain cross-linked fatty acids, which account for the acid-fast quality of the mycobacterium whereby the organism cannot be decolorized once Gram's stained. This cell wall structure confers very low permeability to macromolecules, which, in part, accounts for the relative ineffectiveness of most conventional antibiotic agents against MTB and many other species of mycobacteria.
Infection with MTB occurs from person-to-person spread of aerosolized or airborne tubercle bacilli, so-called infected droplet nuclei, either through coughing, as is the case with pulmonary TB, or rarely through sneezing or speaking (or singing), as is the case with laryngeal TB. Less is known about NTM, although inhalation of infected droplet nuclei is assumed to be critical to the spread of many species. Once aerosolized, the tubercle bacilli can remain suspended for hours; once inhaled, the size of the suspended particle helps determine how distal into the respiratory tree the particle deposits. Smaller particles can bypass the mucociliary ladder and deposit on the surfaces of alveoli, where they are ingested by host alveolar macrophages. From this point on there are several possibilities: The tubercle bacillus or NTM may be destroyed by host defense mechanisms, in which case there is no infection; the tubercle bacillus may not be destroyed but may multiply and remain dormant, which is called latent TB infection (90% of cases); the organism may immediately cause
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clinical tuberculosis, which is called primary tuberculosis (5% of cases); or the organism may be contained initially (latent infection) only to cause disease at some later time, called reactivation tuberculosis (5% of cases). Clinical tuberculosis (disease) therefore develops in about 10% of immunocompetent persons infected with MTB. A much higher proportion of immunocompromised persons (e.g., HIV coinfected) will likely develop active tuberculosis if infected by MTB.
The progression of MTB infection to TB disease (pulmonary or extrapulmonary) is thus dependent mainly on factors endogenous to the host and on poorly defined virulence factors of the infecting organism. Host factors include innate (genetic) susceptibility to the disease, the functioning of cell-mediated immunity (e.g., HIV coinfection), and other factors that increase innate susceptibility, such as diabetes, silicosis, and chronic renal insufficiency. The observation by Ellner (1997) that the histocompatibility DRB1*1501 allele was associated with advanced disease and failure to respond to drug therapy whereas the DRB1*1502 allele was associated with less risk of disease progression illustrates the importance of genetic susceptibility in some individuals. In addition, recent work by Lopez-Maderuelo and coinvestigators (2003) has shown that mutations in the gene responsible for interferon- production (which is important for the host response to MTB) result in an almost fourfold higher risk of developing active disease once infected.
If MTB infection occurs in a host with a normal immune system, particularly a normal cell-mediated immunity (CMI), the MTB host interaction progresses through stages, which have been described by McDonald and Reichman (1998). Following ingestion of the MTB by the resident alveolar macrophages, the MTB population within the macrophages increases in what is called the logarithmic stage. In this stage, the CMI has not yet been fully activated against the MTB, and often the innate antimycobacterial properties of the macrophages are not sufficient to destroy the organisms. Organisms translocate to regional lymph nodes and, through lymphohematogenous dissemination, spread to other organs of the body. Next is the immunogenic phase, where the CMI has been activated, with helper T cells activating macrophages in the areas of infection while cytotoxic T cells kill the tubercle-filled macrophages as part of the delayed-type hypersensitivity reaction. This process is responsible for the formation of a caseous necrotic center of a tuberculous focus. The infection at this point may remain contained locally and may present at distant sites as self-limited primary infection; the only manifestation of its presence may be the tuberculin skin test reaction, which develops some 8 to 12 weeks following infection in immune-competent hosts. For reasons that are not completely clear, this host tubercle bacillus interaction at the center of the granuloma can remain stable or may deteriorate with renewed MTB replication (reactivation) and may progress to liquefaction and even formation of a hollow cavity. During this phase, endobronchial spread of infection can occur to other lung segments, or renewed hematogenous dissemination can occur, or both.
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Fig. 87-1. Characteristic Mycobacterium tuberculosis acid-fast bacilli (AFB) seen in sputum smear for AFB. Mycobacteria are thin, red, beaded rods. |
Once reactivation occurs, however, the population of MTB in this area is by no means homogenous in growth potential or response to antimycobacterial therapy. In fact, as noted by Grosset (1980), the key to understanding the treatment of active disease is understanding that there are subpopulations of MTB bacilli within a given area of disease. These subpopulations can be conceptualized as existing in
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three compartments. The first compartment consists of metabolically active extracellular organisms, as might inhabit a tuberculous cavity. This is the largest population of organisms and the one responsible for the patient's infectivity. Because resistance is dependent on the number of organisms present, this population is also responsible for the emergence of drug resistance if treatment is inadequate. The other two populations are smaller, metabolically less active, and slower to respond to treatment. They have been termed persisters and represent the populations that must be eliminated to attain a lasting cure and to prevent relapse. One of these compartments is intracellular, within monocytes and macrophages, while the other is extracellular, within the area of caseous necrosis.
Antituberculous drugs have variable effectiveness against these three subpopulations. For example, as one of us (J.G.) (2001) has described, isoniazid appears to be most effective against the metabolically active extracellular population, while rifampin and pyrazinamide are more effective against the less metabolically active extra- and intracellular populations, respectively. It is the persisters that require antituberculous therapy to be continued for months after the initiation phase of treatment. Indeed, most MTB present in an active case of tuberculosis are killed within the first 2 weeks of treatment by the drugs used in modern short-course therapy, but much of this killing occurs within the highly metabolically active extracellular population, where killing is most efficiently accomplished by currently available drug regimens.
Although less is known about the nontuberculous mycobacteria, it is presumed that similar processes apply to infection with many of these organisms.
Clinical Manifestations
Because of the phase of lymphohematogenous dissemination, tuberculosis can involve any organ system in the body. The lungs are the most common site, followed in descending order by lymph nodes, pleura, the genitourinary tract, and bones and joints. Generalized spread, miliary TB, and meningitis are even more uncommon forms of disease.
Pulmonary Disease
Pulmonary disease represents the majority of MTB active disease cases occurring in immunocompetent patients. Clinical syndromes include primary tuberculosis and postprimary tuberculosis. The distinction between these two presentations is based in part on the chest radiograph and history of prior TB infection. Most patients who are not immunocompromised (i.e., non HIV-infected) will have the postprimary syndrome with an upper lobe or superior segment lower lobe disease presentation and possibly a prior history of TB infection.
Primary Pulmonary Tuberculosis
Primary tuberculosis occurs soon after the initial MTB inoculum has entered the local alveolar macrophages. In most individuals, the host immune response contains the infection within a few weeks, leaving a small granuloma that may calcify over time (Ghon lesion). However, in patients who cannot contain the initial infection because of impaired host CMI due to, for example, HIV coinfection, poor nutrition, or age, such as in very young children, the infection may progress. The clinical and radiographic features of primary TB relate to lung parenchyma involvement with subsequent lymphohematogenous spread. Syndromes of progressive infection include acute hematogenous dissemination with miliary lung involvement, TB pneumonia with or without pleural effusion, and intrathoracic adenopathy with bronchial compression and atelectasis.
Radiographically, most primary TB involves the mid- to lower-lung zones, where MTB-infected droplet nuclei are most likely to have been inhaled. Often, as observed by Suziki (1995) and Lee and associates (2000), there is associated mediastinal or hilar adenopathy due to lymphatic spread of the infection. The lung involvement is often segmental or lobar with consolidation. Lower-lung zone involvement, however, is not exclusive to primary TB. Postprimary TB can occur in the superior segments of the lower lobes and upper lobes. Cavitary TB can spread endobronchially to the lower lung regions. Additionally, patients with primary TB can also present with pleural effusions due to pleural extension of the parenchymal process secondary to rupture of subpleural granulomas with subsequent immunologic reaction in the pleural space.
Clinically, patients can present with constitutional symptoms as well as purulent cough and dyspnea. Additionally, they can present with symptoms attributable to mediastinal or hilar lymphadenopathy, or both, such as wheezing or, particularly in children, acute upper airway obstruction. The latter is seen less frequently in the modern era of effective antimycobacterial therapy, but if surgical management is necessary, Worthington and colleagues (1993) recommend lymph node decompression with incision and curettage as the therapy of choice, although Toppet and co-workers (1990) have used corticosteroids in children with acute bronchial obstruction. Intrathoracic lymphadenopathy is not limited only to primary TB, however. Up to 5% of 56 patients presenting with adult postprimary disease and reported in a study by Woodring and associates (1988) had sizable, nonobstructing intrathoracic lymphadenopathy. Younger patients may also have an immunologic phenomenon, such as erythema nodosum or erythema induratum. Both of these entities represent focal panniculitis, the former being more often pretibial and the latter occurring more often on the posterior calves.
HIV-infected patients represent an important group of patients who may develop progressive primary TB infection.
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According to Long and associates (1991), HIV-seropositive patients with prior AIDS-defining events or low CD4 T-helper cell counts (i.e., advanced HIV infection), or both, are the most likely to present with a primary TB radiographic pattern (up to 80%), followed by HIV-positive patients without AIDS (up to 30%), when compared with immunocompetent HIV-seronegative patients (11%). In addition, HIV/AIDS patients with primary TB, as recorded by Given and associates (1994), can present with normal chest radiographs in 10% to 30% of cases (many of whom may have had endobronchial disease). This observation, as well as the finding that TB patients coinfected with HIV (particularly those patients in the late stages of HIV infection) have disseminated disease more often than non HIV-infected patients do, makes pulmonary TB in HIV-infected patients more of a diagnostic challenge, requiring a lower index of suspicion on the part of the clinician.
Table 87-2. Persons at Particular Risk for Postprimary (Reactivation) Tuberculosis | |
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Postprimary Tuberculosis
Postprimary tuberculosis is also known as adult-onset TB, reactivation TB, or secondary TB. It often results from reactivation of latent TB infection in a variety of at-risk persons (Table 87-2) but can also occur in persons with no identifiable comorbidity or even from new, exogenous reinfection. Any organ system may be the site of reactivation, but the chest is involved in over 80% of immune-competent adults; a much higher proportion of HIV-infected persons will have extrapulmonary disease.
Radiographically, postprimary TB in the chest often presents in the apical or posterior segments of the upper lobes or the superior segments of the lower lobes where alveolar oxygen tension is the highest. Upper lobe alveolar infiltrates (TB pneumonia), thick-walled cavities that often have smooth inner walls, and, over time, fibrosis with volume loss are some characteristic features of postprimary disease. These features contrast with that of primary TB (Table 87-3). Both Krysl (1994) and Khan (1977) and their colleagues have noted that up to 30% of chest radiographs can have presentations that are considered atypical for postprimary disease (e.g., mediastinal lymphadenopathy, lower-lung zone predominance, single or multiple nodules, or isolated pleural effusions). Keiper and associates (1995) have shown an association between a depressed white count and the radiographic presentation of pulmonary tuberculosis. In particular, HIV-positive patients who are severely immunosuppressed (CD4 count < 0.02 109 cells/L) are more likely to present with atypical features in the setting of reactivated disease. This includes intrathoracic lymphadenopathy, which on chest computed tomography (CT) may have a low density quality with contrast enhancement of the periphery, as reported by Pastores and colleagues (1993).
Table 87-3. Comparison of Chest Radiographic Features of Primary and Postprimary Tuberculosis in Immunocompetent Persons | |||||||||||||||||||||||||||
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Chest CT has added another dimension to the diagnosis of pulmonary TB. In addition to the features of postprimary disease just described, recent studies by Im and collaborators (1993, 1995) have shown that the presence of centrilobular nodules and the presence of branching linear structures around distal air spaces corresponded pathologically to caseous material filling bronchioles and was seen mainly in early active disease. This pattern has been termed a tree-in-bud pattern (Fig. 87-2).
Reactivated pulmonary TB can be asymptomatic or can present with persistent cough, constitutional symptoms (malaise, night sweats, weight loss), nonresolving pneumonia with dyspnea and hemoptysis, or any combination of these. Cough is the most common symptom and may be associated with hemoptysis, which is often mild but can be sometimes severe when associated with erosion of a bronchial artery vessel within the wall of a TB cavity (Rasmussen's aneurysm). In a meta-analytical review, Perez-Guzman and associates (1999) found that constitutional symptoms are often a prominent feature of the presentation, particularly in younger patients, whereas dyspnea tends to be a prominent early complaint in the elderly, given the higher prevalence of preexisting cardiopulmonary disease in this population.
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Fig. 87-2. Computed tomographic scan of the chest in a patient treated for multidrug-resistant tuberculosis (TB). A. Large left upper lobe; posterior segment thick-walled cavity with associated area of TB pneumonia prior to treatment. B. Area of tree-in-bud pattern in the lingula (arrowhead). C. Left upper lobe cavity after 7 months of multiple-drug chemotherapy. |
Additional laboratory and physical exam abnormalities may assist in the diagnosis of tuberculosis (Table 87-4). Some of these abnormalities relate to extrapulmonary involvement, which can occur concomitantly with pulmonary disease in about 10% of patients. As noted, the most common sites of extrapulmonary involvement in descending order of frequency are lymph node (scrofuloderma), pleural, genitourinary tract, and bone or joint involvement. Other common sites include the skin, meninges, gastrointestinal tract, and adrenal cortex, producing adrenal insufficiency. Thus, paying detailed attention to these extrapulmonary sites may yield valuable diagnostic information. Some commonly encountered laboratory abnormalities include a normocytic, normochromic anemia (anemia of chronic disease pattern or due to chronic TB adrenalitis), an elevated erythrocyte sedimentation rate, leukocytosis (sometimes with a monocytosis), hyponatremia [due to syndrome of inappropriate antidiuretic hormone (SIADH) or adrenal insufficiency], and sterile pyuria (due to genitourinary tract involvement).
Pleural Tuberculosis
Pleural tuberculosis, as recorded by Aktogu and colleagues (1996), is a relatively common associated manifestation
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of pulmonary parenchymal TB, with up to 7% of active disease complicated by TB pleural effusions. Pleural TB can occur in relation to both primary and postprimary radiographic presentations or can occur in isolation. In the modern era, as noted by Morehead (1998), postprimary (reactivation) pulmonary TB is the most common association. Patients often present acutely with nonproductive cough and pleuritic chest pain.
Table 87-4. Some Commonly Encountered Physical Examination and Laboratory Abnormalities in Pulmonary Tuberculosis | ||||||||||||||||||||||
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Pleural TB represents an immunologic phenomenon whereby local activation of cell-mediated immunity occurs in response to MTB components in the pleural space (often due to ruptured subpleural foci). What follows is an initial neutrophilic pleuritis and then a characteristic lymphocyte-predominant (>80%) exudative effusion that is typically unilateral, small to moderate in size, and rarely compromises the patient's respiratory status. Large to massive effusions can sometimes occur in patients with primary disease, particularly in HIV-positive patients.
In addition to the aforementioned features, the pleural fluid is often devoid of mesothelial cells (<1%), and the presence of many mesothelial cells should suggest an alternative diagnosis. Additionally, the pleural fluid, if it is a chronic effusion, is often rich in cholesterol due to breakdown of cell membranes, giving it a milky appearance (pseudochylous effusion). Other diagnostic tests available for pleural TB include pleural adenosine deaminase (ADA, produced by activated T lymphocytes), pleural acid-fast bacilli (AFB) smear, culture, and pleural biopsy (Tables 87-5 and 87-6).
Table 87-5. Sensitivities of Diagnostic Studies in Pleural Tuberculosis | ||||||||||||||
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Table 87-6. Findings of Diagnostic Studies in Pleural Tuberculosis | ||||||||||||||||||||||
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Diagnosis of Infection
The diagnosis of TB infection can be made through the use of targeted tuberculin skin testing, as described by Huebner and associates (1993), or the more recently developed whole-blood interferon- assay. The goal of diagnosing infection is to identify and treat groups of patients who are at high risk for progressing to disease. The tuberculin skin test is the most commonly used screening method. Guidelines for use of the latter assay have recently been published by Mazurek and Villarino (2003).
The tuberculin skin test uses purified protein derivative (PPD) from a culture of filtrate of tubercle bacilli. It is injected as a 5 tuberculin unit (TU) dose on a clean area of skin on the forearm subcutaneously. A delayed-type hypersensitivity reaction will occur in the form of induration at the site of injection approximately 72 hours later if the patient has an intact CMI and has been infected and sensitized by MTB or antigenically related mycobacteria. In general, the larger the reaction size, the more likely that the individual is infected with MTB. The test does not determine activity of the tuberculous infection. The maximal diameter of the induration (not erythema) is then determined.
When used in screening for latent TB infection, the tuberculin skin test should be used in persons who are at higher risk for progressing to active disease. Persons at highest risk who should be screened yearly include HIV-positive patients, organ transplant patients, persons receiving more than 15 mg prednisone for 1 month, persons in close contact with active TB cases, and persons with upper lobe fibrotic changes on chest radiograph. In these patients, a reaction of more than 5 mm induration with the tuberculin skin test is considered positive, and treatment for latent TB infection is recommended if it has not been previously given. Health care workers, institutionalized persons (e.g., prisoners, nursing home residents), and persons with silicosis, chronic renal failure, or diabetes, to name a few conditions, should also be tested yearly and treated for latent infection if an induration of greater than 10 mm is noted. The American Thoracic Society and the CDC (2000) suggest that for otherwise healthy persons, 15 mm is the cutoff point above which to treat; however, these persons should not be routinely screened because they are at low risk for progressing to active disease if they have latent infection. By adjusting the threshold for positive reaction, the sensitivity of the test can be increased (lower reaction size threshold) or decreased (higher threshold). Reciprocal changes in the test specificity can be expected.
It is recommended that the new interferon- assay (QuantiFERON Cellestis Limited, Victoria, Australia) be used as an alternative to tuberculin skin testing in patients who are at increased risk for latent TB infection (e.g., recent immigrants, residents of long-term care facilities, prisoners) or who are at low risk for latent TB infection but who may engage in activities that increase their risk of exposure (e.g., health care workers, U.S.-born college students, military personnel). Mazurek and Villarino (2003) have noted that the whole-blood interferon- test incubates blood lymphocytes with several antigens related to MTB and other mycobacteria and assesses interferon- release to determine likelihood of infection.
In persons with active TB, a positive tuberculin skin test is supportive of the diagnosis, but a negative test does not exclude the diagnosis. Persons with miliary TB, pleural TB, and TB meningitis, as well as HIV-positive and malnourished patients, can all have negative tuberculin skin tests with active disease.
Diagnosis of Active Tuberculosis
Although the tuberculin skin test (and interferon- assay) can indicate the likelihood that an individual has been infected by MTB, history, physical examination, and other tests are required to determine whether TB is active, the anatomic sites of involvement, and the extent of disease. The diagnosis of active pulmonary TB therefore requires consideration of the patient's epidemiologic risk for infection (probability of infection), clinical and radiographic presentation, the results of tuberculin skin testing, and the results of microbiologic evaluation (sputum smear and culture with drug susceptibility testing, nucleic acid amplification techniques).
Patients presenting with a clinical syndrome judged likely to be high risk for active pulmonary TB should be placed in respiratory isolation (or told to remain at home) and started on an empiric, usually four-drug, regimen that includes the first-line agents (see Treatment of Active Pulmonary Tuberculosis) before any microbiologic data have returned, with subsequent therapy adjusted (or terminated) when this information is available. The same approach applies to extrapulmonary disease, although isolation is not needed if pulmonary involvement can be excluded. Although a tuberculin skin test can be placed initially, a negative test should not be used to exclude active disease because between 10% to 25% of patients with active disease do not react to the skin test, according to Huebner and associates (1993). This is particularly true for patients with impaired cell-mediated immunity (e.g., from HIV infection, malnourishment, or disseminated TB), who may have higher rates of skin-test negativity despite the presence of active disease, and for patients with pleural disease.
In patients presenting with a low-risk syndrome for active disease, options include no treatment while obtaining specimens for smear and culture or empiric therapy. If therapy is undertaken and there has been no clinical or radiographic improvement in a culture-negative patient (who initially skin-tested positive) at 2 months, the patient can be treated for latent TB infection (see later in this chapter). Sputum bacteriologically negative patients who show clinical or radiographic improvement while receiving therapy should complete a course of therapy for culture-negative disease, possibly with an abbreviated regimen reported by
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the Hong Kong Chest Service, the Tuberculosis Research Centre of Madras, and the British Medical Research Council (1989) (see Recommended Regimens).
Testing for HIV infection should be considered for all TB patients, whereas testing for the hepatitis viruses (B, C) should be done only for patients who have risk factors for those infections. Finally, blood cultures using lysis centrifugation techniques may permit isolation of MTB, especially in patients with HIV coinfection.
Sputum Smears and Cultures
Sputum smears and cultures are an integral part of the diagnostic evaluation in a patient suspected of having active pulmonary disease. The sputum smear is often positive in patients with cavitary upper lobe disease and less often positive when atypical radiographic presentations occur, such as lower lobe predominance or pleural effusions, or both. Initially, positive sputum cultures should have drug susceptibility testing done for the first-line agents isoniazid, rifampin, and ethambutol. Testing for other antituberculous agents should be done if the patient has a history of prior treatment or resistance to rifampin or two other first-line agents. Most modern mycobacterial laboratories use fluorescence microscopy with auramine-rhodamine staining rather than the more time-consuming light microscopy method, which uses Kinyoun or Ziehl-Nielsen staining.
At least three specimens should be collected in a sterile container on separate days. These specimens may need to be induced with hypertonic saline in patients having difficulty expectorating sputum. The sensitivity of sputum smear for MTB is 45% to 75% when the volume of sputum collected for a given number of patients is heterogeneous but, as pointed out by Warren and colleagues (2000), it increases to 92% when at least 5 mL is reliably collected. AFB smears or cultures of other potentially infected sites should also be collected (e.g., pleura, lymph nodes, bone marrow) in the case of concordant extrapulmonary disease if possible. Bacteriologic yielded from these sites is often less than from pulmonary disease, although inclusion of histologic examination for granulomata raises the yield somewhat.
Mycobacterial sputum cultures require at least a log-order lower organism concentration in the sputum to yield a positive result than the sputum smear. Hence, in a patient who is less infectious, often in the setting of noncavitary disease, sputum smears may be negative while cultures are positive. The culture can be performed on agar or egg-based media such as Lowenstein-Jensen or Middlebrook 7H10 and incubated at 37 C. The mycobacterial colonies can be identified as MTB by their appearance on media (nonpigmented corded colonies), weak catalase activity, and production of niacin. Because MTB is a slow-growing organism, however, up to 8 weeks may be required before colonies are seen on solid media. Growth on liquid media (Middlebrook 7H12) allows mycobacteria to be detected earlier (2 to 3 weeks) when the medium is supplemented with radiometric or calorimetric (which detect consumption of CO2 or production of O2) broths that allow for growth detection. Overall, sputum cultures are about 80% to 85% sensitive in pulmonary TB, as recorded in the Diagnostic Standards and Classification of Tuberculosis in Adults and Children (2000). Bronchoscopy with bronchoalveolar lavage may be considered in patients who are unable to raise sputum even after efforts at sputum induction with saline inhalation. In patients who have positive sputum smears for AFB, false positives can occur, particularly with other mycobacterial species that can cause lung disease, such as M. kansasii and M. avium complex. Methods have been developed that allow for presumptive identification of the acid-fast bacilli as MTB.
More rapid techniques have also been developed. Two of the most important tools are nucleic acid assays and high-performance liquid chromatography (HPLC). Nucleic acid assays use RNA probes (Gen-Probe MTB test) specific for MTB or other mycobacteria. They can be combined with polymerase chain reaction (PCR) to amplify MTB DNA (AMPLICOR MTB test). The American Thoracic Society workshop (1997) pointed out that these assays can be completed within a day or two and have sensitivities comparable to culture and specificities close to 100%. The assays have recently been adapted to identify genetic markers of resistance to commonly used antituberculous drugs, thus creating the possibility of rapid drug susceptibility testing. The nucleic acid assays are FDA approved for sputum-smear-positive patients and should, ideally, be performed on all of these patients in addition to culture and drug susceptibility testing. HPLC detects the unique set of mycolic acids produced by MTB for its cell wall. Like the nucleic acid assays, HPLC can be done rapidly but requires organisms from pure cultures and does not differentiate between M. bovis and MTB. The decision to place a hospitalized patient in respiratory isolation and initiate multidrug antituberculous therapy should, however, be made when the clinical suspicion for TB is high.
Treatment of Active Pulmonary Tuberculosis
The management of active disease is guided by a clear understanding of the principles of drug therapy, which, in turn, reflect the microbiology of the tubercle bacillus. The importance of having a clear understanding of these concepts is illustrated in a study conducted by Mahmoudi and Iseman (1993), in which 35 cases of active pulmonary TB were reviewed retrospectively for errors in management. Of these patients, errors were made in 28, with a rate of about four errors per patient. The most common errors included the addition of a single drug to a failing regimen, failure to address or identify nonadherence to the treatment regimen, failure to identify acquired or preexisting drug resistance, and inappropriate diagnosis of active disease as latent disease, leading to inadequate therapy. These errors led to an
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increased rate of acquired drug resistance when compared with the no-error group, and to an increased number of antituberculous agents used in the error group. The costs of this added therapy averaged an astounding $180,000 per patient. This figure represents 1990 estimates; with inflation taken into account, the average cost of salvage therapy in 2003 is approximately $250,000 per patient.
Table 87-7. Principles of Therapy for Active Pulmonary Tuberculosis | ||
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Some key principles of drug therapy of active disease are noted in Table 87-7. These principles are followed to achieve the goals of therapy, which are to render the patient noninfectious, to eliminate symptoms, to prevent the emergence of drug-resistant organisms, and to provide a lasting cure. These goals are achieved by using multiple drugs to which the organism is susceptible for a sufficient duration of time. The use of initial empiric therapy that reflects prevailing local resistance patterns and that is modified as necessary by the results of in vitro drug susceptibility tests facilitates achieving this. Assessment of the initial chest radiograph for cavities and assessment of smear and culture at 2 to 3 months into therapy to look for possible nonadherence, infection with drug-resistant organisms, or potentially slow response due to extensive disease are also important. The importance of using at least two drugs to which the organism is presumed sensitive for the initiation of treatment, and the addition of at least two new drugs to which susceptibility is likely for those patients who may be failing therapy, cannot be overemphasized. In these situations, the use or addition of a single drug to which the organism is sensitive may result in de facto monotherapy if resistance exists to the other agent being used. The use of at least two drugs to which the organism is sensitive reduces the likelihood of selecting out multidrug-resistant TB (to be discussed later in this chapter). Outpatient therapy can generally be offered if the patient is not seriously ill or debilitated. Directly observed therapy (short course) should be considered in most patients to reduce the likelihood of treatment nonadherence. Finally, each case of TB should be reported promptly to the local public health department to facilitate application of control measures.
For all patients with pulmonary disease, recommended monitoring of therapy includes monthly sputum smears and cultures to document conversion or the lack thereof. After the first sputum culture is negative, another confirmatory negative culture should be obtained. Monitoring radiographic films assumes less importance than sputum smear and culture, although it is recommended that a chest film be obtained upon completion of therapy so that a baseline for future comparison is available. All patients should have initial liver function tests and serum creatinine, platelet count, and uric acid levels obtained.
Recommended Regimens
The results of over three decades of clinical trials, such as those conducted by Snider (1984a, 1984b), Combs (1990), and Cohn (1990) and their colleagues, as well as by the Hong Kong Chest Service and British Medical Research Council (1982, 1991) and the East African and British Medical Treatment Council (1976) have yielded some basic insights upon which modern chemotherapeutic regimens for active TB are based. By utilizing drug combinations that target each of the three subpopulations of MTB present, it is possible to give an effective course of treatment over a period of 6 to 9 months (Table 87-8). This represents a halving of duration from just one generation ago. Implicit in using these regimens are the assumptions that organisms are especially susceptible to rifampin and that most doses of medication are taken. Regimens are satisfactory for both pulmonary and extrapulmonary disease, although some forms (e.g., TB osteomyelitis) may require a somewhat longer course of therapy. Further, it is now clear that although 6 months of therapy (a so-called short-course regimen) is satisfactory for most patients, some will require longer durations of treatment.
Therapy for patients with susceptible organisms can be divided into two phases. The initiation phase generally forms the first 2 months of treatment. Major goals during this phase are to render the patient noninfectious and prevent the emergence of drug resistance by initiating multiple drugs to which the organism is presumed or known to be susceptible. This typically requires a four-drug regimen (which includes isoniazid, rifampin, pyrazinamide, and ethambutol) in the United States, as advised by Small and Fujiwara (2001). Following the initial 2 months is the continuation phase, which lasts for 4 months in most patients, in which a major goal is to eliminate persistent MTB infection. Two drugs, most often isoniazid and rifampin, are used during this phase. The dosing of these medications can be daily (7 days per week, 5 days per week) or intermittent (three times per week, twice per week), with the decision dependent on variables such as cost and perceived patient adherence. If intermittent dosing is considered, directly observed
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therapy [DOT (in which pills are given and consumed under direct health care giver supervision)] is strongly recommended, particularly in some high-priority groups (Table 87-9). Directly observed therapy has been shown by Weis and co-workers (1994) to be cost-effective, to reduce TB relapse rates, and to reduce acquired and primary resistance of MTB to various antimycobacterial drugs.
Table 87-8. Recommendations for the Treatment of Drug-Sensitive Culture and Smear-Positive Pulmonary Tuberculosis | ||||||||||||||||||||||||||||||||||||||||
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The continuation phase is extended from 4 months to 7 months (to complete a total of 9 months) in persons with both cavitary pulmonary tuberculosis and sputum culture that remains positive at 2 months; patients with silicotuberculosis; patients who did not have pyrazinamide in their initial regimen; and persons who are taking isoniazid and rifapentine (once-a-week dosing) whose sputum cultures are positive at 2 months (see Table 87-10 for drug doses and toxicities).
Patients with multidrug-resistant (MDR) TB, who by definition have resistance to at least isoniazid and rifampin, should be referred to the care of a TB specialist. These patients often have had prior treatment; have immigrated from areas of the world that are endemic for MDR TB, where resistance rates of 25% are often found, according to Raviglione and associates (1997) (particularly if they have had therapy interrupted or have had self-administered therapy); have failed to respond to initial therapy (sputum smear and culture positive at 2 months); or have HIV infection. In the United States, the rate of MDR TB is 2.2%, but, as stressed by Moore and colleagues (1997), still represents an important health care challenge due to the cost of retreatment and the implications of failing therapy for both the patient and the community.
Table 87-9. High-Priority Groups for Receipt of Directly Observed Therapy | |
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Regimens for MDR TB can include up to six to eight drugs, including parenteral second-line agents such as streptomycin, with prolonged therapy that requires up to 18 or more months with variable success. Treatment success can be achieved if a strong commitment to this intensive regimen exists on the part of the patient and strict treatment principles (use of two or more drugs to which the organism is susceptible) are followed by the physician. Indeed, a report from Turkey by Tahaoglu and associates (2001) showed that 77% of patients can achieve success in treatment (defined as cure or probable cure) when a mean of 5.5 drugs are used for 18 months. Patients need to have DOT for the duration of therapy. This may require special domiciliary or hospital arrangements. Steroid therapy as an adjunct to antimycobacterial therapy has been associated with slight improvement in adenopathy radiographically but gives no mortality benefit, as shown by Woodring and associates (1988).
Another treatment option for MDR TB that is anatomically localized, particularly in the face of limited medical therapy options, is resectional surgery. There are, however, no randomized studies looking at the role of surgery in MDR TB. The same report from Turkey reported an overall success rate of 89% in patients who received lung resectional
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surgery in addition to chemotherapy. Patients were highly selected, and this report needs to be validated. If surgery is considered for a patient with MDR TB, it should ideally be performed only after several months of chemotherapy and should be followed by up to 18 months of chemotherapy (see Chapter 88).
Table 87-10. Drug Doses and Toxicities | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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The treatment of extrapulmonary TB follows the same principles of treatment as for pulmonary TB. The total duration of therapy is generally 6 months, except in bone or joint TB, central nervous system TB, and miliary TB, where therapy is ideally extended to a total of 12 months. In addition, pericardial TB and central nervous system TB may benefit from the addition of corticosteroids during the first 6 to 11 weeks of therapy to prevent constrictive pericarditis or adhesive arachnoiditis.
The treatment of active TB in the HIV-coinfected patient is the same as treatment in the non HIV-coinfected patient, but there are some additional considerations. These include the potential for drug interactions, in particular between the rifamycins and protease inhibitors; possible acquired resistance to the rifamycins during intermittent therapy; and the potential for paradoxical reactions during immune reconstitution in those persons concomitantly treated with highly active antiretroviral therapy (HAART). Drug interactions can occur between the protease inhibitors (indinavir, saquinavir, nelfinavir, and ritonavir), nonnucleoside reverse transcriptase inhibitors (nevirapine and efavirenz), and the rifamycins through induction of the hepatic cytochrome P-450 system. Thus, any of the serum drug levels of these antiretroviral agents can be increased, leading to unexpected toxicity, or lowered, leading to inadequate therapy. Of the rifamycins, rifampin is the most potent inducer of the cytochrome P-450 system and has the greatest potential for drug interactions. The American Thoracic Society, the Centers for Disease Control and Prevention, and the Infectious Diseases Society of America (2003) recommend that rifabutin be used in place of rifampin due to the former's lesser potential to induce cytochrome P-450.
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Additionally, HIV-coinfected patients who are severely immunosuppressed (CD4 count < 100/ L) are more likely to develop acquired resistance to a rifamycin when treated with intermittent dosing of less than three times a week, as stated by a report from the Centers for Disease Control and Prevention (2002). Thus, it is recommended that daily or three times a week dosing be used in the continuation phase for patients with a CD4 count below 100/ L.
Paradoxical reactions, the so-called reconstitution syndrome, occurred in 36% of patients receiving antiretroviral therapy in one series published by Narita and colleagues (1998) and are thought to be due to restoration of the immune response to MTB. Clinical features include fever, constitutional symptoms, increasing intrathoracic adenopathy, worsening pulmonary infiltrates, increasing pleural effusions, and in some cases respiratory failure. These features must be differentiated from TB treatment failure, another infection, and drug hypersensitivity. Most paradoxical reactions are mild and self-limited, lasting 10 to 40 days, according to Barnes and associates (2002). Mild reactions can be managed symptomatically, but more severe reactions may require the use of corticosteroids.
For pleural TB, current guidelines by the American Thoracic Society, the Centers for Disease Control and Prevention, and the Infectious Diseases Society of America (2003) recommend treating uncomplicated pleural TB for 6 months with regimens that are used for pulmonary TB. Chest tube drainage is usually avoided.
Treatment of Latent Tuberculosis Infection
The goal of treating latent TB infection (LTBI) is to reduce the risk of progression to active disease. The lifetime risk is approximately 10% in HIV-seronegative persons, with about 5% progressing to active disease with no LTBI treatment in the first 2 years after skin test positivity. Small and Fujiwara (2001) have shown that in HIV-seropositive patients, the risk of progressing to active disease with no LTBI treatment is much higher, at about 10% annually. Four regimens have been approved for the treatment of LTBI (Table 87-11). Because the risk of developing drug-resistant disease is small due to the low number of organisms present, single agents may be used for LTBI treatment.
The preferred regimen is isoniazid for 9 months, with the 6-month regimen an acceptable alternative. Indeed, the 6-month regimen decreases the incidence of active TB by about 70%, with mild additional benefit from 9- and 12-month isoniazid regimens as reported by the
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International Union Against Tuberculosis Committee on Prophylaxis (1982). Because of cost, duration, and potential side effects, the 12-month isoniazid regimen is not considered first line in the treatment of LTBI. The two additional regimens include rifampin and pyrazinamide for 2 months and rifampin alone for 4 months. Rifampin and pyrazinamide given daily for 2 months have recently been shown by Gordin and co-workers (2000) to be equivalent in safety and efficacy to a 12-month course of isoniazid in HIV-seropositive patients.
Table 87-11. Recommended Drug Regimens for Treatment of Latent Tuberculosis Infection in Adults | |||||||||||||||||||||||||||||||||||||||||||||
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Follow-up of patients being treated for LTBI should include regular clinical assessment for potential adverse drug effects, with subsequent laboratory evaluation directed accordingly. Routine laboratory evaluation is not recommended, with the possible exception of pregnant patients, HIV-seropositive patients, and patients with chronic liver disease. Before treating LTBI, active TB should always be excluded via history, chest radiography, and other appropriate testing.
Nontuberculous Mycobacterial Lung Disease
Nontuberculous mycobacteria, or environmental mycobacteria, are found throughout the environment and are an important cause of pulmonary and extrapulmonary (most commonly lymph node, cutaneous, and disseminated) disease in humans. Although there are nearly 100 known species of NTM, a smaller number are known to cause pulmonary disease (Table 87-12). Pulmonary disease caused by NTM is often chronic in its presentation and often occurs in older male Caucasian patients who have known structural lung disease (e.g., chronic obstructive pulmonary disease, bronchiectasis) but can occur in the absence of known structural lung disease, in women, and in younger patients (e.g., cystic fibrosis).
Lung disease caused by NTM is often progressive, albeit slow, causing significant morbidity and mortality without treatment, thus emphasizing the need for early diagnosis. Diagnosing NTM pulmonary disease, however, can be more difficult than diagnosing MTB pulmonary disease. This is in part due to the poor predictive value of an isolated respiratory tract smear or culture for NTM in predicting disease in the absence of associated clinical and radiographic findings. Because NTM, unlike MTB, are ubiquitous in the environment (particularly water sources, natural sources in the community, and water sources in the hospital or microbiology laboratory), they can contaminate mycobacterial cultures or cause transient airway infection in the host without causing true parenchymal disease. Recent data from the Centers for Disease Control and Prevention (2002) show that NTM (in particular M. avium complex) have surpassed MTB as the most common mycobacterial isolates, but they are not the most common cause of mycobacterial lung disease in immunocompetent persons, as noted in the American Thoracic Society position statement (1997). Thus, positive mycobacterial cultures for NTM are most useful in predicting disease in patients with a suggestive clinical and radiographic presentation. Diagnostic criteria have been recommended by the American Thoracic Society (see Table 87-12).
Table 87-12. Criteria for Diagnosis of Nontuberculous Mycobacterial Pulmonary Disease | ||
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In the United States, three main species have been identified as a cause of pulmonary disease (in descending order of frequency): M. avium complex, M. kansasii, and M. abscessus. M. xenopi infections are not uncommon in western and northern Europe as well as in Canada.
Mycobacterium avium Complex
M. avium complex pulmonary disease is thought to be acquired from aerosolized water droplets that are inhaled in immunocompetent persons, and from dissemination from the gastrointestinal tract in immunosuppressed persons, as presented in the review of Levin (2002). MAC pulmonary disease can occur in patients with and without preexisting lung disease. Preexisting lung diseases that have been associated with MAC include chronic obstructive pulmonary disease (COPD), silicosis, radiation fibrosis, lung cancer, cystic fibrosis, bronchiectasis, and prior granulomatous infection such as MTB. Of these, COPD is the most common
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and is associated with a subacute or chronic syndrome of upper lobe cavitary disease very similar clinically to MTB. MAC can also present in persons with no preexisting lung disease in a nodular-bronchiectatic pattern predominantly in the right middle lobe and lingula. The upper lobe cavitary presentation tends to occur in older Caucasian men who are smokers, according to Prince and associates (1989) as well as Kennedy and Weber (1994), whereas the middle lobe and lingular presentations tend to occur in middle-aged and elderly women who are nonsmokers. The presentation in the middle lobe, described by Reich and Johnson (1992) as the Lady Windermere syndrome over a decade ago (thought to be due to voluntary suppression of cough leading to postobstructive pneumonitis and bronchiectasis), is more indolent, progressing over several years, whereas the upper lobe cavitary form has a somewhat faster rate of progression.
The two radiographic patterns associated with the aforementioned MAC pulmonary disease are not mutually exclusive, and overlap can occur (e.g., upper lobe cavitary disease can be present with multifocal bronchiectasis). Additional features on the chest radiograph or chest CT that suggest MAC include nodular infiltrates, thin-walled upper lobe cavities, and multiple areas of cylindrical bronchiectasis. When comparing upper lobe MAC to postprimary MTB, the MAC cavities are thinner walled, with less surrounding parenchymal infiltrate and more areas of bronchiectasis. A diagnosis of MTB is suggested by the presence of thicker-walled cavities with denser surrounding infiltrate, endobronchial spread of infection (so-called upstairs-to-downstairs pattern), and interlobular septal thickening, as described by Primak and colleagues (1995).
M. avium complex in the HIV/AIDS population represents the most common infection in this group. It most commonly presents as disseminated infection in patients with CD4 counts below 50 cells/ l, and Jones and Havlir (2002) note that the pulmonary disease occurs simultaneously in fewer than 5% of patients. HIV-positive patients are unique in that they can present with minimal pulmonary symptoms and a normal chest radiograph. Miller (1994) noted that chest CT may show mediastinal and hilar adenopathy with minimal parenchymal infiltrate as the most common finding. Because pulmonary MAC disease in the HIV patient often occurs in the setting of disseminated disease and profound immunosuppression, the nonspecific features of dissemination (fevers, weight loss, chills, etc.) tend to predominate. Therefore, if pulmonary symptoms dominate the clinical presentation, consideration should be given to additional or alternative pulmonary pathogens, such as MTB, endemic mycoses, cytomegalovirus, and bacterial pneumonia.
Other NTM that can cause pulmonary disease in the HIV-infected patient include M. kansasii, M. gordonae, M. genavense, M. chelonae, M. marinum, and M. xenopi. Of these, M. kansasii is the most common NTM to cause disease in the HIV-infected patient other than MAC. M. kansasii, according to Jones and Havlir (2002), presents with isolated pulmonary disease and dissemination in only 20% of patients. It often occurs in patients with a lesser degree of immunosuppression (CD4 count > 50) and has a clinical and radiographic pattern similar to MTB.
The treatment of MAC pulmonary disease has advanced within the last decade with the development of macrolide antibiotics such as clarithromycin and azithromycin. Macrolides have been used effectively as a prophylactic measure against MAC in HIV/AIDS patients with severe immune suppression (CD4 < 50) and are also effective when used in combination with rifampin and ethambutol for pulmonary disease. Wallace and colleagues (1996) reported that up to a 90% rate of sputum conversion to negative has occurred when even a low dose of a macrolide (clarithromycin 500 mg twice a day) is added to a regimen of rifampin (rifampin 600 mg/day) and ethambutol (25 mg/kg for 2 months and then 15 mg/kg). The American Thoracic Society currently recommends this regimen given daily for pulmonary MAC disease, with treatment continuing until the patient is culture negative for 1 year. Rifabutin has been shown to have superior in vitro activity against MAC and is considered the better rifamycin in the treatment of MAC pulmonary disease, at a dose of 300 mg/day. Additionally, streptomycin should be considered for the first 2 to 3 months of therapy for patients with extensive pulmonary disease. Isoniazid and pyrazinamide have no role in treating this infection.
The decision to treat is less difficult in patients presenting with a subacutely progressive upper lobe syndrome or the HIV-positive patient with disseminated MAC. In patients who are otherwise healthy and present with a chronic middle lobe presentation, the decision is made more difficult partly because of the prolonged duration of treatment needed, potential drug side effects, patient preferences, and lack of clear mortality data to support therapy in this group. Disease and symptoms are, however, progressive, and treatment is known to lead to radiographic and clinical improvement. Therefore, the American Thoracic Society recommends that consideration be given to treating these patients earlier in their course if they are relatively asymptomatic and sooner if they are more symptomatic. Monitoring should include sputum cultures, which should become negative within 1 year, and serial chest radiographs and CT, along with monitoring for drug toxicity.
Surgical therapy should be considered for localized disease that has not responded to medical therapy (lack of sputum conversion to negative within 1 year, radiographic or symptomatic progression), particularly if macrolide resistance has been documented. In the macrolide era, a recent retrospective single-center review by Nelson and co-workers (1998) of 28 patients with MAC pulmonary disease who underwent lobectomy or pneumonectomy (indications being drug failure, massive hemoptysis, severe destroyed lung, or part of initial therapy) found that more than 90% of patients became culture negative within months after the operation. Morbidity, however, was high in
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32% of patients and included postoperative air leak requiring thoracoplasty and late postoperative bronchopleural fistula requiring omentopexy. Thus, although surgery can be considered for patients with medically refractory disease, it should be performed at centers experienced in mycobacterial surgery (see Chapter 88).
Mycobacterium kansasii
M. kansasii is the second most common cause of NTM pulmonary disease in the United States. It occurs commonly in the southern and central states and is transmitted primarily from contaminated environmental sources. The clinical and radiographic course closely resembles that of upper lobe MTB, but atypical patterns such as a nodular-bronchiectatic pattern similar to what is seen in MAC have also been noted by Griffith (2002). Patients who are at increased risk for acquiring M. kansasii lung disease include those with COPD, pneumoconiosis, HIV infection, lung cancer, and alcoholism, but up to 40% may not have any identifiable predisposing condition, as noted by Bloch and associates (1998).
The antituberculous medications, in particular the rifamycins, form the cornerstone of therapy. Rifampin-containing regimens have a higher sputum conversion rate at 6 months and a lower relapse rate after completing therapy, according to Pezzia (1981) and Ahn (1981) and their co-workers. The American Thoracic Society recommends isoniazid (300 mg/day), rifampin (600 mg/day), and ethambutol (25 mg/kg for 2 months, then 15 mg/kg thereafter) for 18 months. It is recommended that cultures be negative for a minimum of 12 months while on therapy and that patients with HIV coinfection being treated with protease inhibitors have rifabutin or clarithromycin substituted for rifampin to minimize drug interactions.
Mycobacterium abscessus and Rapidly Growing Mycobacteria
Pulmonary disease caused by rapidly growing mycobacteria (most commonly M. abscessus and less commonly M. fortuitum) represents the third most common cause of NTM pulmonary disease in the United States. These mycobacteria are frequently recovered from environmental sources such as soil and water and, in cases of nosocomial infection, from tap water sources. Daley and Griffith (2002) have shown that the rapidly growing mycobacteria produce pulmonary disease very similar to the nodular-bronchiectatic form caused by MAC. Patients are often Caucasian nonsmoking women who often have no known predisposing lung diseases. Approximately 40% of patients do, however, have prior lung conditions such as cystic fibrosis, lung transplantation, or previously treated mycobacterial disease, as Griffith and associates (1993) recorded in a review of 154 patients with pulmonary disease due to rapidly growing mycobacteria. Aspiration of gastric contents due, for example, to esophageal conditions such as achalasia has also become recognized as an important predisposing condition for pulmonary disease from rapidly growing mycobacteria, as has been described by Hadjiliadis and colleagues (1999), and is typically associated with a third species of rapidly growing mycobacteria, such as M. chelonae. Thus, patients should be questioned for an aspiration history.
The diagnosis of pulmonary disease from rapidly growing mycobacteria is made primarily by observing the time to visible growth on solid media in conjunction with a compatible clinical and radiographic presentation. Unlike MTB and the other NTM discussed earlier, which grow to form visible colonies in 4 to 6 weeks on solid media, rapidly growing mycobacteria grow to produce visible colonies on solid media within 1 week. This feature allows for early identification of rapidly growing mycobacteria, but subsequent differentiation of the species is made more difficult by the lack of commercially available DNA probes in the United States and by the unreliability of HPLC in differentiating the different species, particularly M. chelonae from M. abscessus; more time-consuming biochemical studies are used for definitive speciation. The latter two organisms have often been grouped together as the M chelonae/abscessus group in mycobacteriology reports, but M. abscessus carries a worse prognosis than M. chelonae.
The treatment of disease from rapidly growing mycobacteria is more difficult than treating disease from MTB and the other NTM in that the rapidly growing mycobacteria are resistant to the first-line antituberculous agents and have high in vitro resistance to many antimicrobials. However, there is a debate regarding the predictive value of such in vitro assays for treatment of these organisms. In addition, there are no large prospective trials that have shown a mortality benefit of any specific drug regimen in disease from rapidly growing mycobacteria. In particular, M. abscessus lung disease is unlikely to be cured with medical therapy alone, whereas disease caused by M. fortuitum or M. chelonae is more likely to be medically curable. Surgical therapy (particularly in consideration for M. abscessus) may potentially lead to cure when used with medical therapy for focal lung disease. The American Thoracic Society recommends that medical treatment be guided by in vitro susceptibility testing, but that the initial regimen for M. abscessus infection should include the following for a duration of time yet to be determined: clarithromycin 1 g daily, amikacin 15 mg/kg daily, and cefoxitin 200 g/kg daily; or imipenem 750 mg three times daily. As noted, it is unlikely that therapy will eradicate M. abscessus, but remissions may be achieved. Treatment for M. fortuitum infection should include the following for 6 to 12 months: clarithromycin 1 g/day and doxycycline 100 mg daily or trimethoprim-sulfamethoxazole 1 double strength twice
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daily, or levofloxacin 500 mg daily. Selection of agents should favor those with in vitro activity if possible.
CONCLUSION
Mycobacterial lung disease represents an ancient problem in the course of human history and continues to cause substantial morbidity and mortality worldwide. Recent years, however, have seen important advances in the diagnosis and treatment of mycobacterial disease, in particular MTB. The advent of effective antituberculous medications and the results of multiple well-conducted studies demonstrating the potency of combination drug therapy make MTB a very treatable infection. The limiting factor in most parts of the world in achieving the goal of MTB eradication is limited resources. In the United States, where the resources are available, eradicating MTB infection is a realistic goal and is predicated on physician understanding of the principles of diagnosing and treating infection and disease. Most NTM pulmonary disease is also treatable but often requires longer courses of multiple-drug therapy and requires the recognition of varied forms of presentation. The role of surgery in mycobacterial pulmonary disease is usually limited to medically refractory focal disease.
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