Chapter 36: Mycobacterial Diseases in the Lung

Mycobacterial diseases of the lung encompass tuberculous and nontuberculous diseases, which have important differences in pathogenesis, transmissibility, therapeutic approach, and public health implications. The incidence of tuberculosis (TB) disease from Mycobacterium tuberculosis began to significantly rise by approximately 20% in the United States after 1985 due to combination of factors; namely, emergence of human immunodeficiency virus (HIV) infection, increased immigration of persons from region of high TB activity and drug resistance, and increased numbers of medically underserved individuals such as drug abusers and homeless populations. Although at least 15 million persons are infected with TB in the United States, the actual number of cases has been decreasing since 1992, primarily due to more effective public health policies, enhanced awareness resulting in earlier diagnosis, and implementation of directly observed therapy (DOT) as standard of care in appropriate settings.

The present incidence of tuberculosis in the United States varies significantly depending on the place of birth of U.S. nationals. It is as high as 20.6 cases per 100,000 persons among foreign-born individuals versus 2.1 cases per 100,000 among U.S. born persons, respectively. In 2007, moreover, foreign-born persons accounted for approximately 60% of new cases in the United States. These data underscore the importance of ongoing overseas screening for tuberculosis with follow-up evaluation after arrival in U.S. bound immigrants. Elimination of tuberculosis in the United States therefore mandates control and prevention of tuberculosis in foreign-born persons.

Development of disease from Mycobacterium tuberculosis (MTB) is the most common global infectious cause of death. Such disease caused by bacteria of the MTB complex preeminently affects the lungs, although other organs are involved in up to one-third of cases. Transmission of TB occurs when a contagious patient cough, sneezes, or otherwise spreads the bacilli through generation of airborne droplet nuclei to individuals in close proximity sharing the same ventilatory space. Of note, M. bovis belonging to the MTB complex is transmitted by ingestion of contaminated, unpasteurized dairy products from infected cattle. M. tuberculosis is a rod shaped, non-spore-forming, nonmotile, thin aerobic bacterium measuring 0.5 μm × 3 μm. Mycobacteria, including M. tuberculosis, are often neutral on Gram stain; however, once stained, the bacilli are not easily decolorized by acid alcohol and hence the classification acid-fast bacilli (AFB) (Fig. 36.1; see also Fig. 34.15).

Other microorganisms may also display some acid fastness, including species of Nocardia and Rhodococcus, Legionella micdadei, and the protozoa Isospora and Cryptosporidium. With respect to the mycobacteria, the cell wall contains lipids (eg, mycolic acids) that are linked to underlying arabinogalactan and peptidoglycan residues. These collectively confer low permeability characteristics to the cell wall, and so reduce the effectiveness of most antimicrobial drugs.

Pathogenesis and Clinical Manifestations

Tuberculosis is broadly classified as pulmonary or extrapulmonary; pulmonary tuberculosis represents the majority of disease cases. Tubercle bacilli on droplet nuclei are inhaled into the respiratory zone of the host's lungs after exposure to contagious individuals, especially in crowded conditions. MTB bacilli are deposited in the small airways and the alveoli of better-ventilated areas of the lung. This is typically the middle to lower regions (lower lobes) in adults. After phagocytosis by alveolar macrophages, MTB organisms undergo intra-cellular replication. The initial inflammatory response to the MTB infection in the lung is referred to as a primary or Ghon focus. MTB organisms can thereafter spread, during this early stage, via the lymphatics to the draining lymph nodes and result in hilar or mediastinal lymphadenopathy. Alternatively, the bacilli may enter the bloodstream and spread hematogenously to other organs of the body. Disease presenting at this stage is called primary tuberculosis (Fig. 36.2).

However, more commonly the host develops cell-mediated immune reaction involving alveolar macrophages that phagocytize tubercle bacilli, and CD4⁺ T lymphocytes, which induce protection through the production of cytokines, mainly interferon-γ (IFN-γ). Coincident with the development of immunity, delayed-type hypersensitivity to M. tuberculosis develops. This stage is referred to as latent TB infection and is the basis of tuberculin skin testing. In most instances, the immune response successfully controls the tuberculosis infection although 3%-5% of infected subjects progress to active disease within 2 years, termed progressive primary TB (Fig. 36.2). Primary tuberculosis is common among at-risk children up to 4 years of age. Furthermore, among infected individuals, the incidence is highest during late adolescence and early adulthood.

Because the healed primary infected lung foci often contain bacilli that are viable for many years, progression to subsequent disease can occur if the immunity wanes, which is referred to as post-primary or reactivation pulmonary tuberculosis. Overall, individuals infected with MTB have a 5%-10% risk of reactivation during their lives, particularly in the setting of several well-defined risk factors culminating in relative degrees of immunosuppression (Table 36.1). In this context, the risk of developing TB disease after infection depends largely on the host's innate susceptibility to the disease and level of function of cell-mediated immune responses. Reactivation disease has a predilection for the upper lobes of the lungs as well as having a propensity for cavitation (Fig. 36.3) without accompanying intrathoracic lymphadenopathy. However, the entire pathogenetic sequence represents a continuum and becomes less distinct in conditions of immune deficiency such as in HIV seropositive individuals. Importantly, the distinction between primary and postprimary tuberculosis has questionable clinical relevance, inasmuch as active tuberculosis should always be treated and pharmacological therapy remains similar.

The development of specific immunity results in activation of macrophages and their accumulation in large numbers at the primary site, leading to hallmark pathologic lesion, the necrotizing granuloma. Necrosis results from the tissue damaging effect of delayed-type hypersensitivity. Because the necrotic material resembles soft cheese, it is termed caseous necrosis (Fig. 36.4).

Extrapulmonary tuberculosis can involve lymph nodes (lymphadenitis), pleura (empyema and effusions), genitourinary tract, bones and joints (osteomyelitis), meninges (meningitis), peritoneum (peritonitis), pericardium (pericarditis), gastrointestinal tract, and disseminated disease as a result of hematogenous spread especially in immunocompromised hosts such as those with HIV coinfection.

Diagnostic Tests for Tuberculosis

A comprehensive medical history should be obtained, exploring TB exposure risks, previous TB infection or disease, and risk factors for progression in an individual with clinical symptoms of productive cough, hemoptysis, or shortness of breath along with systemic symptoms such as fever, chills, night sweats, weight loss, and fatigability. However, objective tests are essential in establishing a secure diagnosis. Culturing M. tuberculosis from sputum or other respiratory specimens confirms diagnosis of pulmonary TB, and from other affected body tissues or fluids for extrapulmonary TB (Chap. 19). On an average, it takes about 2 weeks to culture and identify M. tuberculosis in the laboratory, even with rapid culture techniques. Even so, a preliminary diagnosis can be made when acid-fast bacilli are seen on a sputum smear or from other body tissues or fluids in the appropriate clinical setting. With respect to pulmonary TB, three sputum specimens for smear and culture are necessary if initial specimens are negative; if this is not possible because the patient is not expectorating sputum, invasive sampling of the respiratory tract is usually necessary with sputum induction or fiberoptic bronchoscopy.

Tuberculin Skin Test Reactivity

Delayed-type hypersensitivity to M. tuberculosis develops with the appearance of immunity and is the basis of tuberculin skin testing using an intradermal injection of 0.1 mL of five tuberculin units of purified protein derivative (PPD), with tests read 48-72 hours afterwards based on the size in millimeters of the resulting induration. Different cut-points with respect to the amount of induration have been established for interpretation of positive tuberculin skin test reactivity, based on risk of M. tuberculosis infection and progression to active disease (Table 36.2). The previously sensitized CD4⁺ T lymphocytes are attracted to the skin-test site and produce cytokines along with cellular proliferation. PPD skin-test positivity, though suggestive of protective immunity, does not assure protection against postprimary disease (reactivation) disease.

The two overall goals for treatment of tuberculosis are: (1) to cure the individual patient of the disease; and (2) to interrupt transmission by rendering the patient noninfectious. It is imperative that identified or suspected patients be isolated and initiated on proper treatment. Effective isolation of hospitalized patients is achieved by negative pressure rooms with high-level air exchanges. Isolation is discontinued only after either three negative AFB sputum smears (Chap. 19) or clinical improvement on multidrug therapy for at least 2 weeks, and in cases of multidrug resistant- (MDR-) TB not until culture-negative. Four major drugs are considered the first-line agents for the treatment of TB: isoniazid (INH), rifampin (RIF), pyrazinamide, and ethambutol. These agents are recommended on the basis of their bactericidal activity against M. tuberculosis; in other words, their ability to rapidly reduce the number of viable organisms and render patients noninfectious. The sterilizing activity of these drugs contributes to their limiting disease relapse, as do their low rates of induction of drug resistance.

The optimum treatment regimen as supported by the results of randomized clinical trials for virtually all forms of tuberculosis in both children and adults consists of a 2-month initial or bactericidal phase of INH, RIF, pyrazinamide, and ethambutol followed by 4-month continuation or sterilization phase with INH and RIF. This regimen can also be administered intermittently by direct observed therapy (DOT) given several times a week, which is the standard of therapy by improving completion rates of treatment and thereby limiting development of resistant strains. Treatment of patients with tuberculosis is most successful within a comprehensive framework that addresses both clinical and social issues of relevance to the patient. After initiation of therapy, the treating clinician must monitor its effects on the patient's presenting symptoms and signs, as well as evaluate for possible adverse specific anti-tubercular drugs effects. In this regard, noteworthy are the hepatotoxicity due to INH and RIF, hepatotoxicity and goutlike symptoms of pyrazinamide, optic neuritis due to ethambutol, and peripheral neuritis secondary to B₆ (pyridoxine) deficiency related to INH. For this latter reason all patients receiving INH treatment should also receive 50 mg/d of Vitamin B₆.

In HIV-infected individuals with active TB disease, anti-retroviral therapy may paradoxically worsen symptoms and signs via the immune reconstitution syndrome, in which fever, new pulmonary lesions, pleural effusions, and other manifestations of TB may become manifest. It is important to recognize this phenomenon in individuals who might otherwise be suspected of therapeutic failure of their TB antimicrobial regimen.

Special mention of MDR-TB is warranted given its increased prevalence and the new challenge it brings to effective treatment and control of TB. Multidrug resistance is defined when Mycobacteriae demonstrate resistance to at least INH and RIF. Median prevalence is >4% worldwide; more than 80% of cases occur in HIV-infected individuals yielding a high mortality rate. In addition to prescribing prolonged courses of combination therapy, patients with MDR-TB and localized disease may benefit from surgical resection. However, complication rates are high in this group of patients.

Nearly one-third of the world's population is likely infected with Mycobacterium tuberculosis. In most persons, infection with MTB is initially contained by host defenses and the infection remains latent. This latent tuberculosis infection (LTBI) has the potential to develop into tuberculosis at any time, especially with reduced immunity. These individuals with active tuberculosis become sources of new infections. Thus, an important priority in countries with low incidence of disease like the United States is to identify and treat persons with LTBI. Treatment of latent infection greatly reduces the likelihood of developing active TB. The diagnosis of LTBI requires not only a positive tuberculin skin test, but also that active TB be ruled out by careful medical history, evaluation of symptoms, and radiographic examination of chest. Medical conditions that increase the risk of developing tuberculosis in the presence of LTBI are noted in Table 36.1.

Environmental opportunistic mycobacteria are those that are recovered from natural and human-influenced environments and can infect and cause disease in humans, animals, and birds. The terminology for these mycobacteria is nontuberculous mycobacteria (NTM), even though they cause tuberculous lesions that are referred to as "atypical" to distinguish them from typical M tuberculosis. NTM are ubiquitous in the environment, including water sources and soil. They are opportunistic pathogens in individuals with cell-mediated immunodeficiency, underlying structural bronchopulmonary disease, or localized cutaneous injury. These NTM encompass many species and have been associated with both pulmonary and extrapulmonary infections and disease. The NTM have variable patterns of susceptibility to antimicrobial agents. Therefore, isolation of the mycobacterium, identification, and susceptibility testing are essential for appropriate and effective treatment.

The epidemiology of pulmonary NTM disease can be challenging, as reporting of this disease to public health authorities is not required. Also, since the organisms are commonly isolated from environmental sources, their growth in culture may raise the question of specimen contamination. There is evidence that the frequency of NTM pulmonary disease is increasing. Unlike infection with M. tuberculosis, however, there is no evidence for person-to-person transmission of these environmental opportunistic NTM organisms.

Like M. tuberculosis, NTM organisms are acid-fast bacilli (AFB). They have been conventionally classified according to the time required for clinical specimens to show visible growth on solid media. The so-called rapid growers (within 7 days) include M. abscessus, M. fortuitum, and M. chelonae, while slow growers (within 2-3 weeks) include M. avium, M. kansasii, M. ulcerans, and M. marinum among others. Of particular note, M. avium and M. intracellulare are grouped together as the M. avium complex (MAC). These have become prevalent in HIV-infected subjects, causing not only pulmonary disease but also disseminated disease. MAC-related pulmonary disease is also encountered in individuals with hairy cell leukemia, patients with chronic kidney disease undergoing hemodialysis, and increasingly, in individuals with cystic fibrosis.

The risk factors for acquiring NTM disease are similar in many respects to those for TB (Table 36.1) since cell-mediated immunity is important in containing the disease. Impairment of immunity and pulmonary defenses as in HIV infection and cystic fibrosis confer a high risk. Preexisting lung diseases including silicosis and other pneumoconioses, bronchiectasis, COPD, and radiographic changes consistent with prior TB have been identified as important risk factors. Diabetes mellitus, alcoholism, malignancy, and smoking have all been associated with NTM.

Diagnosis of NTM Lung Disease

The greatest challenge in diagnosing NTM-related lung diseases is distinguishing between an individual with NTM-related disease versus those who are only "colonized," since NTM are often found in respiratory secretions due to the ubiquitous nature of the organism. The most recent statement by the American Thoracic Society (ATS) issued in 2007 provides the best guide to the diagnosis and treatment of pulmonary disease caused by NTM (Table 36.3). The cited clinical, radiological, and microbiological criteria are equally important, and all must be met to make a diagnosis of NTM lung disease. These criteria apply to symptomatic patients with radiographic opacities (nodular or cavitary), or an HRCT scan that shows multifocal bronchiectasis with multiple small nodules. Further, these criteria best fit with Mycobacterium avium complex (MAC), M. Kansasii, and M. abscessus infections.

Accordingly, the minimum evaluation of a patient suspected of NTM lung disease should include: (1) performance of a chest radiograph and, in the absence of cavitation, a chest HRCT scan; (2) three or more sputum specimens for acid-fast bacilli; and (3) exclusion of other diagnoses such as TB.

Pulmonary Disease due to NTM Infection in the Immunocompetent Host

Infection with NTM is an increasingly important cause of pulmonary disease in the immunocompetent host. In this population, pulmonary infection occurs following inhalation of aerosolized water droplets. The clinical presentation of disease in such patients is discussed here due to two important species of NTM accounting for the bulk of NTM pulmonary disease. Mycobacterium avium complex (MAC)-related pulmonary disease is more common than TB as a cause of mycobacterial disease in the United States. The typical MAC pulmonary disease presents either in the nodular/bronchiectatic form, especially as in its primary form, versus the fibrocavitary form as often is the case when it develops as a secondary complication of underlying lung disease. Notably, fibrocavitary features of MAC disease are radiographically indistinguishable from TB. Macrolide antibiotics (eg, clarithromycin or azithromycin) are the primary drug class for treatment of MAC infection. Thus, MAC isolates from patients with a history of prolonged earlier macrolide exposure or of treatment failure should be tested for susceptibility to clarithromycin.

Hypersensitivity Pneumonitis—"Hot-Tub" Lung Disease

A well-defined manifestation of pulmonary NTM most commonly due to MAC in immunocompetent patients without preexisting lung disease has been described in association with the use of hot tubs and spas. Thus, this form of NTM is an infectious form of hypersensitivity pneumonitis, and almost all affected patients present with diffuse, bilateral lung opacities consisting of centrilobular nodules or ground-glass opacities in conjunction with cough, dyspnea, and periodic fever. The treatment involves mandatory avoidance of the heated water source, and in some cases of severe disease, adjunctive corticosteroids to suppress the granulomatous inflammatory response.

M. kansasii is the most pathogenic NTM species affecting the lung. The clinical features of M. kansasii resemble those of TB, including upper lobe pulmonary involvement with cavitation (Fig. 36.6). Most patients have predisposing factors, but pulmonary infections without notable risk factors have been reported. Testing of M. kansasii isolates for susceptibility to RIF is recommended. Disseminated disease occurs primarily among patients with advanced AIDS and CD4⁺ T lymphocyte cell counts of <100/μL, as well as in patients with leukemia, lymphoma, or solid-organ transplant recipients.

Cystic fibrosis (CF) is an autosomal recessive disorder resulting in defective or deficient cystic fibrosis transmembrane conductance regulator (CFTR) protein resulting in extremely viscous respiratory and gastrointestinal secretion (Chap. 38). CF is considered to be a risk factor for development of NTM pulmonary infection. Sputum cultures from patients with CF often reveal multiple pathogens and with increased patient longevity, more NTM infections are being recognized. It is recommended that all adult patients with CF be screened for the presence of NTM in their pulmonary secretions on a yearly basis.

The most common NTM isolated from sputum of patients with CF is MAC, though M. kansasii, M. abscessus, M. fortuitum, and others have been isolated. The diagnosis of NTM lung disease in patients with CF is particularly challenging, as it can be hard to distinguish colonization from active disease. Persistent presence of organisms in the sputum of CF patients may indicate infection. A patient with CF who repeatedly cultures NTM and has persistent symptoms despite adequate conventional antimicrobial therapy should be evaluated for mycobacterial disease. The characteristic radiographic opacities (Fig. 36.7) include concomitant bronchiectasis and small nodules or associated consolidation, favoring a diagnosis of active infection. The treatment of NTM infection in CF in itself can be challenging given variation and alteration in drug absorption and elimination patterns, the need for longer therapy, and implications for lung transplant candidacy at most centers.