Objectives

1. To familiarize clinicians with the environmental mycobacteria (EM) and the lung diseases they produce.
2. To make clinicians aware of the typical clinical and radiographic presentations of EM lung diseases.
3. To identify risk factors that predispose individuals to EM lung diseases.
4. To assist clinicians in selecting appropriate antimicrobial regimens and bronchial hygiene for patients with EM lung diseases.
5. To review the indications for resectional surgery in the management of patients with EM lung diseases.

Abbreviations

AAT = a₁ -antitrypsin; ATS = American Thoracic Society; CF = cystic fibrosis; EM = environmental mycobacteria; MAC = Mycobacterium avium complex; NTM = nontuberculous mycobacteria; RGM = rapidly growing mycobacteria; RML = right middle lobe; TB = Mycobacterium tuberculosis

The mycobacteria are basically organisms of the soil, belonging to the order Actinomycetales. The most significant pathogenic species, Mycobacterium tuberculosis (TB), is an anomaly that has become adapted to the human body and is transmitted from person to person almost exclusively by cough-generated aerosols. By contrast, the other mycobacterial species commonly associated with human disease (see Table 1) are believed to be acquired from the environment. Historically, these organisms have been referred to in the aggregate as atypicals, mycobacteria other than TB, or nontuberculous mycobacteria (NTM). Perhaps the simplest and most accurate identifier to distinguish them from TB is environmental mycobacteria (EM).

Historically, pulmonary EM lung disease was identified sporadically throughout the latter half of the 20th century. In the United States and Europe in the 1960s to 1980s, such cases were seen primarily in older men with underlying lung diseases including cigarette-induced COPD or inorganic-dust pneumoconioses. However, in the last two decades of the century, an apparent increase in EM lung disease has been noted among female patients without readily apparent risk factors. Possible elements in this seeming medical mystery are discussed below.

Epidemiology

Unfortunately, there are no systematic data on the incidence and prevalence of EM disease. Thus, we are left with anecdotal impressions and extrapolations from laboratory recovery data. Broadly, it appears that the incidence of EM lung disease has surpassed that of TB in many communities in the United States; this probably reflects both rising EM numbers and falling TB rates. Geographically, EM disease no longer appears to be sequestered in the southern or southeastern United States; cases are now appearing in the 48 contiguous states as well as Alaska and Hawaii. However, the "density" of EM disease still seems greatest in the Southeast. As noted, the other feature of recent epidemiology is a shift toward female preponderance; this is discussed below in "Risk Factors."

Risk Factors

Early series of EM lung disease from the United States or Europe were 80 to 100% male, and almost all of these patients had COPD or pneumoconioses. While such cases continue to appear, they have been eclipsed by an apparent "epidemic" among women whose ages range from their 30s to 80s, most of whom do not report significant smoking histories.^1,2 Of note, while AIDS was the cause of the disseminated Mycobacterium avium complex (MAC) cases seen in the 1980s to 1990s, HIV is not related to the current upsurge of EM lung disease.

Common features in recently reported series of EM lung disease are described in Table 2. Whether there is a causal relationship between the prototypic anatomical appearance (slender white woman with narrow anterior-posterior diameter and/or pectus excavatum, subtle scoliosis and/or straight back syndrome, and/or mitral valve prolapse) and vulnerability to EM infection has not been established. Nonetheless, the clinical association is so common as to imply some unique relationship(s).

We have recently analyzed a large consecutive case cohort of patients with EM lung disease seen at the National Jewish Center in Denver.³ The majority of cases involved MAC, but an increasing proportion of those seen recently have had either initial rapidly growing mycobacterial (RGM) disease or RGM disease concurrent with or subsequent to MAC disease. More than 85% of the patients were female and nearly 95% of them were white. For the past decade, we have systematically tested for conditions associated with susceptibility to these infections (Table 3).

The overall frequency of cystic fibrosis (CF) mutations as detected by genotyping (Genzyme Laboratories; Framingham, MA) was approximately 13.5%.³ Although the anticipated prevalence of such mutations in a normal Caucasian population has not been well established, estimates suggest it should be in the range of 5%.⁴ Among our EM patients with CF mutations, 98 of 117 (11.4% of the entire cohort) had a single (heterozygous) abnormal allele. Nonetheless, based on other features typical of CF–such as chronic sinusitis, chronic airflow obstruction, bronchiectasis predominantly in the upper lung zones, and infections with mucoid Pseudomonas aeruginosa or Staphylococcus aureus –we believe the great majority of these cases do represent variant CF. Notably, some of these patients have been identified as having CF as late as the seventh or eighth decade of life.

a₁ -Antitrypsin (AAT) deficiencies have been reported in association with both precocious emphysema and bronchiectasis.⁵ In our survey of a large cohort of patients with mixed EM disease (mostly MAC, lesser RGM infections), the overall prevalence of AAT phenotypic anomalies (AAT types other than the normal MM pattern) was 16%.³ Even more striking was the frequency of these anomalies in a subgroup analysis of those patients with RGM disease, in whom the prevalence was 29%.⁶ Again, exact data for the prevalence of AAT mutations in a "normal" Caucasian population are not available, but expert analysis suggests that approximately 4% might be expected.⁷ Our current belief is that, in addition to inhibiting neutrophil elastase, AAT functions to protect against pulmonary infections.^8,9

The relationship between esophageal dysfunction/aspiration and EM lung disease remains murky. In some cases of flagrant aspiration, it seems likely that EM either are introduced into the lungs along with other esophageal contents (as with achalasia) or may secondarily invade after repeated bouts of aspiration resulting in lung damage that leaves the lungs susceptible. Certainly the frequency with which there was evidence of reflux, dysmotility, and/or aspiration among our cohort (roughly 70%) suggests a relationship. This association might take the form either of cause (aspiration® lung damage) or effect (chronic coughing® esophageal dysfunction).

Clinical and Radiographic Manifestations

Broadly, EM lung disease may be present in one of two forms: (1) cavitary lung disease that is readily apparent on plain chest radiographs, is usually associated with dramatic constitutional/respiratory symptoms, and results in large numbers of mycobacteria in respiratory secretions; or (2) a subtler form of disease marked primarily by cough, variable expectoration, a combination of bronchiectasis with centrilobular nodules on CT scan, and sparse numbers of organisms in secretions. The former is typical of EM disease in men with underlying lung diseases, and the latter is seen primarily in women, as noted above.

Because recognition of the former type is rarely a problem, this article will focus on identifying patients with the latter form. Most of the women with bronchiectasis in association with EM give a story of protracted coughing with intercurrent episodes of feverishness, malaise, and lassitude; phlegm is variable and hemoptysis infrequent. Not uncommonly, patients will describe having "the blahs," in which their energy levels are greatly reduced.

Chest radiograph findings are commonly nondescript, although there typically is shadowing in the regions of the right middle lobe (RML) and lingula. The primary diagnostic tool for this condition is CT lung imaging. The finding of bronchiectasis, centrilobular nodules, atelectasis, and the tree-in-bud pattern of cellular bronchiolitis is highly suggestive of EM disease.¹⁰ Sputum should be obtained for mycobacterial smear and culture; if the patient cannot mobilize secretions, sputum induction should be tried; failing that, diagnostic bronchoscopy should be performed. Performing drug susceptibility testing is controversial; the 1997 American Thoracic Society (ATS) recommendations indicate testing only for susceptibility to the macrolides.¹¹ We at National Jewish, however, maintain that a more extensive panel is justified.¹² Diagnostic criteria are reviewed in Table 4.

Treatment

If patients have the typical amalgam of clinical, radiographic, and microbiologic findings noted above, it is highly probable that they have invasive disease, not colonization. However, the natural history, particularly of the bronchiectatic variety of disease, has not been well described. Thus, one cannot be sure whether a patient with modest disease by symptoms and radiographic findings needs to be treated. Options including initiating full treatment, simply employing bronchial hygiene, or performing periodic assessment. However, it is imprudent to merely monitor patients for a few months, observe no progression, pronounce them colonized and dismiss them from observation.

Ideal studies to identify optimal management of EM lung disease have not been performed. The British Thoracic Society conducted a randomized trial comparing isoniazid, rifampin, and ethambutol with rifampin and ethambutol in the treatment of lung disease caused by MAC, Mycobacterium malmoense, and Mycobacterium xenopi.¹³ Unfortunately, by omitting macrolides (the most predictably active drug against these microbes), these results are of little relevance. The best trials for MAC have been conducted by Griffith and Wallace's group in Tyler, TX^14-17; these findings are incorporated in the treatment recommendations given in Table 5.

In our referral experience at National Jewish, we find that the most frequent oversight in the care of bronchiectasis patients is aggressive bronchial hygiene. Mechanical measures such as the acapella valve (DHD Healthcare; Wampsville, NY), Flutter valve (Axcan Scandipharm; Birmingham, AL), Pep Valve (PARI Respiratory Equipment; Monterey, CA), or therapeutic vest may be quite helpful in eliminating secretions. Inhaled b-agonists and mucus-mobilizing agents, including dornase alfa or N -acetyl cysteine, may also be of use. Unfortunately, a recent trial of inhaled interferon- g for pulmonary MAC did not appear to result in improvement (unpublished data).

The role of resectional surgery has not been clarified. In our experience, surgery appears to be of greatest benefit among patients with advanced bronchiectasis and atelectasis involving the RML or lingula.¹⁸ We have also performed resections of other lobes or lungs with extensive cavitation or total destruction. Of particular importance, our experience with disease associated with RGM indicates that these patients are more likely than those with MAC or multidrug-resistant TB to experience postoperative complications. All EM cases entail a high degree of complexity and resectional surgery should only be undertaken by experienced surgeons.

References

1. Prince DS, Peterson DD, Steiner RM, et al. Infection with Mycobacterium avium complex in patients without predisposing conditions. N Engl J Med 1989; 321:863-868
2. Wallace RJ Jr. Mycobacterium avium complex lung disease and women: now an equal opportunity disease. Chest 1994; 105:6-7
3. DeGroote M, Huitt G, Fulton K, et al. Retrospective analysis of aspiration risk and genetic predisposition in bronchiectasis patients with and without non-tuberculous mycobacteria infection [abstract]. Am J Respir Crit Care Med 2001; 163(5):A763
4. Stern RC. The diagnosis of cystic fibrosis. N Engl J Med 1997; 336:487-491
5. Shin MS, Ho K-J. Bronchiectasis in patients with a₁ -antitrypsin deficiency: a rare occurrence? Chest 1993; 104:1384-1386
6. Kaminska AM, Huitt GA, Fulton KE, et al. Prevalence of alpha-1-antitrypsin mutation in a bronchiectatic population with a high frequency of non-tuberculous mycobaterial infection. Paper presented at: American Thoracic Society; May 16-21, 2003; Seattle, WA
7. de Serres FJ. Worldwide racial and ethnic distribution of a₁ -antitrypsin deficiency: summary of an analysis of published genetic epidemiologic surveys. Chest 2002; 122:1818-1829
8. Lieberman J. Augmentation therapy reduces frequency of lung infections in antitrypsin deficiency: a new hypothesis with supporting data. Chest 2000; 118:1480-1485
9. Shapiro L, Pott GB, Ralston AH. Alpha-1-antitrypsin inhibits human immunodeficiency virus type 1. FASEB J 2001; 15:115-122
10. Lynch DA, Simone PM, Fox MA, et al. CT features of pulmonary Mycobacterium avium complex infection. J Comput Assist Tomogr 1995; 19:353-360
11. Diagnosis and treatment of disease caused by nontuberculous mycobacteria. Am Rev Respir Dis 1990; 142:940-953
12. Horsburgh CR, Mason UG, Heifets LB, et al. Response to therapy of pulmonary Mycobacterium avium intracellulare infection correlates with results of in vitro susceptibility testing. Am Rev Respir Dis 1987; 135:418-421
13. Research Committee of the British Thoracic Society. First randomised trial of treatments for pulmonary disease caused by M avium intracellulare, M malmoense, and M xenopi in HIV negative patients: rifampicin, ethambutol and isoniazid versus rifampicin and ethambutol. Thorax 2001; 56:167-172
14. Wallace RJ Jr, Brown BA, Griffith DE, et al. Clarithromycin regimens for pulmonary Mycobacterium avium complex. Am J Respir Crit Care Med 1996; 153:1766-1772
15. Griffith DE, Brown BA, Cegielski P, et al. Early results (at 6 months) with intermittent clarithromycin-including regimens for lung disease due to Mycobacterium avium complex. Clin Infect Dis 2000; 30:288-292
16. Griffith DE, Brown BA, Girard WM, et al. Azithromycin activity against Mycobacterium avium complex lung disease in patients who were not infected with human immunodeficiency virus. Clin Infect Dis 1996; 23:983-989
17. Griffith DE, Brown BA, Murphy DT, et al. Initial (6-month) results of three-times-weekly azithromycin in treatment regimens for Mycobacterium avium complex lung disease in human immunodeficiency virus-negative patients. J Infect Dis 1998; 178:121-126
18. Pomerantz M, Madsen L, Goble M, et al. Surgical management of resistant mycobacterial tuberculosis and other mycobacterial pulmonary infections. Ann Thorac Surg 1991; 52:1108-1112
19. Kennedy TP, Weber DJ. Nontuberculous mycobacteria: an underappreciated cause of geriatric lung disease. Am J Respir Crit Care Med 1994; 149:1654-1658
20. Reich JM, Johnson RE. Mycobacterium avium complex pulmonary disease: incidence, presentation, and response to therapy in a community setting. Am Rev Respir Dis 1991; 143:1381-1385
21. Huang JH, Kao PN, Adi V, et al. Mycobacterium avium-intracellulare pulmonary infection in HIV-negative patients without preexisting lung disease: diagnostic and management limitations. Chest 1999; 115:1033-1040
22. Iseman MD, Buschman DL, Ackerson LM. Pectus excavatum and scoliosis: thoracic anomalies associated with pulmonary disease due to M. avium complex. Am Rev Respir Dis 1991; 144:914-916
23. Mycobacterium kansasii pulmonary infection:   a prospective study of the results of nine months of treatment with rifampicin ethambutol: Research Committee, British Thoracic Society. Thorax 1994; 49:442-445
24. Iseman MD, DeGroote M. Environmental mycobacterial (EM) infections. In: Blacklow NR, ed. Infectious diseases. 3rd ed. Baltimore, MD: Lippincott Williams & Wilkins, 2003