Mycobacterium avium complex pulmonary disease in immunocompetent patients.

Abstract: Mycobacterium avium complex is becoming increasingly recognized as one of the most common mycobacterial pathogens in humans. It is rapidly becoming a significant cause of pulmonary disease even in those with an intact immunity. In 1997, the American Thoracic Society published recommendations for the diagnosis and treatment of nontuberculous mycobacteria. On the basis of the authors' clinical experience of the myriad presentations of pulmonary Mycobacterium avium complex disease in an immunocompetent host, a clinical classification is proposed. The current data are summarized, and a practical approach to management of the various pulmonary forms of the disease is provided.

Key Words: bronchiectasis, hypersensitivity pneumonitis, mycobacteria, mycobacteria other than tuberculosis (MOTT)

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Mycobacterium avium complex (MAC) is becoming increasingly recognized as one of the most common mycobacterial pathogens in humans. It has long been known to cause serious disease in those with human immunodeficiency virus-positive infection, where it typically presents as disseminated disease. Now, however, it is rapidly becoming a significant cause of pulmonary disease even in those with an intact immunity. MAC is easily isolated in our environment, cultured from tap water, hot tubs, rivers, and both indoor and outdoor soil. (1) Although it has not been clearly shown, inhalation from the environment is the likely mode of transmission in pulmonary MAC. Person-to-person spread does not seem to play a role. (2) It has been shown that environmental MAC isolates and clinical isolates often belong to different serotypes. (3) However, mycobacteria can become aerosolized from aqueous sources, and the more easily aerosolized strains are often phenotypically the same as those that cause pulmonary infections. Isolates similar or identical with clinical isolates have also been recovered from both naturally occurring surface water and piped hot water systems. (4) In addition, it is not clear why so few people become sick when exposure is so common. Immunogenetic susceptibility and development of pulmonary MAC infection has been associated with specific HLA phenotypes. (5) However, no consistent predisposition or immune deficiency has been identified to explain MAC infection in these patients. Local pulmonary defense mechanism defects such as abnormal clearance of airway secretions may play a role.

Since MAC is not a reportable disease, precise prevalence and incidence data are not available. However, it is widely believed that the frequency of MAC lung disease may be increasing. In 1997, the American Thoracic Society published recommendations for the diagnosis and treatment of nontuberculous mycobacteria, based on clinical, radiographic, and bacteriologic criteria. (6) These recommendations place emphasis on culture with at least 2+ to 4+ growths on solid media if sputum and bronchial secretions are tested. Although the clinical criteria are nonspecific, the radiographic manifestations may range from a single large nodule to multiple small nodules with or without distal bronchiectasis to cavitary disease. Clinically, disease caused by these organisms may take on one of several different forms, ranging from asymptomatic "colonization," endobronchial involvement, progressive pulmonary disease with radiographic deterioration, to hypersensitivity pneumonitis. Also, the need for a long duration of multidrug regimens, side effects, expensive therapy, and frequent "relapses" all hinder successful treatment.

On the basis of our clinical experience of the myriad presentations of pulmonary MAC disease in an immunocompetent host, we propose a clinical classification in this article. While summarizing the current data, we provide a practical approach to management of the various pulmonary forms of the disease.

Type 1

Asymptomatic colonization. Previously thought to be a benign process based on isolated cultures detected incidentally, this entity is now being challenged. The clinical significance of this type of infection is controversial. Depending on the extent of the involvement and the underlying conditions, some experts recommend treatment of this group of patients as bronchiectasis with aerosolized bronchodilator therapy and focus toward "bronchial toilet" to increase mucociliary transport. (7) Reduction in the number of colonies of mycobacteria after a few weeks of an aggressive bronchial hygiene protocol may be an adequate end point in this group. (8) The need for specific anti-MAC therapy in such cases is a matter of continuing debate.

Type 2

Simple disease with symptoms and minimal limited radiographic changes. This presentation occurs predominantly in nonsmoking women over age 50 with intermittent symptoms. These patients have persistent albeit nonprogressive limited interstitial changes on chest radiography. Previously thought to represent airway colonization as described above, the potential serious nature of this disease has become increasingly evident, especially with repeated persistent culture positivity. A syndrome of right middle lobe or lingular infiltrates (Lady Windermere syndrome) has been well described in middle-aged and elderly women without predisposing lung disease. Minimal structural distortion of the lung parenchyma on chest radiography or computed tomography is seen (9) (Fig. 1). These patients present with episodes of recurrent "bronchitis" with or without hemoptysis. A period of observation with measures to improve bronchial toilet is warranted initially. If symptoms continue despite this approach, a modified short course treatment plan consisting of an anti-MAC, two-drug regimen may be enough to suppress this infection (Table 1). The clinical benefit of this approach must be weighed against the risk of side effects and intolerance, especially in elderly patients with comorbid conditions. (7) Also, the likelihood that this condition may progress and lead to a more destructive disease and respiratory failure has not been clearly shown. Should radiographic deterioration occur, more intensive therapy (see type 3B, below) would be warranted. Further investigations in this particular group of patients will help elucidate the natural history and guide more accurate therapy.

[FIGURE 1 OMITTED]

Type 3

Complex progressive disease with symptomatic and radiographic deterioration. This category of MAC infection encompasses the two most common patterns of disease: cavitary, tuberculosis-like disease (type 3A) and nodular bronchiectasis (type 3B). Both conditions may lead to progressive clinical deterioration with pulmonary function changes and significant morbidity and mortality. (10-12) MAC superinfection has been described in patients with distorted lung architecture secondary to old tuberculosis, bullous emphysema, stage III and IV sarcoidosis, pneumoconiosis, and bronchiectasis (including cystic fibrosis). (13,14) The type 3A disease occurs primarily in white, middle-aged, or elderly men, often alcoholics and smokers with underlying chronic obstructive lung disease. The disease resembles typical tuberculosis clinically and radiographically, with cough, weight loss, upper lobe infiltrates, and cavities (Fig. 2). Symptoms are generally less severe than those associated with tuberculosis. Because of the relatively indolent nature of MAC lung disease, lung destruction may be extensive at the time of diagnosis, with very large cavities seen on chest radiography. In addition, increased awareness of nontuberculous mycobacterial infection in cystic fibrosis, especially MAC and Mycobacterium abscessus, has resulted in developing treatment protocols in this subset of patients. (15)

The nodular bronchiectatic variety (type 3B disease) seems to have predilection for nonsmoking, middle-aged white women with the right middle lobe and lingula being the usual sites of lung involvement, although any lobe may be involved. (16) This probably is a spectrum of the same disease as type 2 described above, this being highlighted by a more extensive multifocal lung involvement and a progressive course. Thoracic skeletal deformities such as pectus excavatum and scoliosis have been observed more commonly among patients with this condition. (17) It is not clear why these abnormalities predispose to this mycobacterial infection. It has been postulated that ineffective mucociliary clearance of secretions may be a possible mechanism. On radiography, multiple small nodules and fibrosis associated with bronchiectasis are visible in the mid-lung fields by high-resolution computed tomography, and this combination of findings is highly suggestive of MAC infection (Fig. 3). Pathologic examination reveals that these nodules represent granulomatous inflammation that may be indistinguishable from that caused by tuberculosis. (18)

[FIGURE 2 OMITTED]

Shedding of MAC into the respiratory secretions in the nodular bronchiectatic variety is less consistent than in the fibrocavitary form of the disease. Sputa may be intermittently positive or positive with low numbers of organisms. Moreover, it has been clinically observed that intermittent growth of other nontuberculous mycobacteria such as Mycobacterium chelonae may occur through the course of the illness. Therefore, before the advent of high-resolution computed tomography, isolation of MAC from the sputum of such patients was frequently dismissed as "colonization." However, this concept is now being questioned and the benign nature of this infection vigorously challenged. In one longitudinal follow up of 21 patients, it was demonstrated that this condition progressed to respiratory failure in 4 of 21 (19%) of the cases. (11) A more recent retrospective review showed symptomatic or radiographic deterioration in 34 of 57 (60%) patients with the nodular bronchiectatic variety of MAC infection. (12)

[FIGURE 3 OMITTED]

Treatment of type 3 disease should begin with an empiric regimen consisting of a macrolide, ethambutol, and a rifamycin. An aminoglycoside such as streptomycin or amikacin may also be used for the first 8 weeks of therapy so that a more rapid decline in the number of organisms may be obtained as well. (6) Multidrug regimens are considered mandatory to prevent resistance. The macrolides clarithromycin and azithromycin have both been studied extensively, and the decision of which to use may best be decided by the individual toxicity experienced. Of the rifamycins, rifabutin has better in vitro activity than rifampin but has a greater side effect profile and drug-drug interactions. Daily therapy has been used historically, but thrice-weekly administration appears to be equally effective and associated with less toxicity and expense. (19,20)

One of the largest barriers to successful treatment for the clinician stems from the problem of drug toxicities and drug-drug interactions. This "drug circus" can be quite confusing and often leads to patient noncompliance and treatment failure. Clarithromycin inhibits the hepatic cytochrome P-450 system, thus increasing the serum levels of rifabutin. (21) Rifabutin toxicities include leukopenia, anterior uveitis, and polyarthralgias, in a dose-dependent manner. Rifampin has much less toxicity but stimulates the cytochrome P-450 system and thus lowers serum levels of clarithromycin, rendering it less effective. (22) Amikacin can cause hearing loss and streptomycin can cause vestibular disturbances. Both may cause renal failure and must be used with caution in those with preexisting renal disease. Ethambutol has been associated with visual symptoms and side effects, especially in higher doses and in the elderly with impaired renal function.

The need to develop strategies to decrease drug toxicity and improve tolerance is of paramount importance. One logical idea proposed by experts in the field is to start one drug at a time and cautiously add a drug over a short period of time to improve tolerance and monitor side effects. (7) In addition, since most of the problems related to side effects and drug tolerance stem from the rifamycins, using regimens without them may be a better option. One recent report of clofazimine combined with a macrolide and ethambutol without the use of any rifamycin showed successful treatment with an 87% sputum conversion rate after 10 months of therapy. (23)

Duration of therapy and management of "relapses" is another important area of discussion. The American Thoracic Society guidelines recommend that treatment be continued for 1 year after sputum cultures become negative. (6) There have been no convincing data to dispute this, and this should be routine practice in cases in which it is feasible. Small studies have indicated that shorter duration of therapy with as little as 7 months of culture negativity may be adequate, but long-term follow-up and larger studies are needed. (24) If sputum culture negativity cannot be obtained, yet symptoms and radiographic progression halt, best clinical judgment should be used. A period of close observation off specific anti-MAC therapy is reasonable. Also, when MAC could be demonstrated from a "cured" patient, it was historically thought to be secondary to treatment failure. This paradigm has been challenged lately, such that it is now more likely that new symptoms and growth of MAC in those in whom it was previously eradicated represents reinfection. (25)

Type 4

Complicated disease. This group includes those cases in which empiric treatment has failed or the disease process is recurring. This may be due to drug resistance, inability to convert sputum cultures to negative because of poor drug penetration to damaged lung, or patient intolerance to therapy (Fig. 4). Strategies for the treatment of these individuals include surgery in selected patients and the use of anti-MAC antibiotics, based on the mycobacterial sensitivity results. Although it is not clear whether in vitro sensitivities reflect efficacy, sensitivity testing of the isolates is strongly recommended in these situations so that appropriate drug therapy is ensured and the possibility of treatment failure is reduced. (6) Several drugs have been evaluated in drug-resistant MAC and have potential as adequate therapy. Use of multiple drugs to which the isolate is susceptible is preferred to avoid future resistance. Treatment failure is generally defined as symptoms persisting beyond 3 to 6 months or the inability to clear MAC from the sputum with 12 months of adequate first-line therapy. This paradigm may change as well, because most cases of treatment failure can be attributed to MAC isolates that are resistant to macrolides. (26,27) Thus, initial therapy with agents to which the isolate is susceptible might decrease the number of treatment failures.

Of the alternate drugs, the fluoroquinolones have been studied the most. Many MAC isolates may be resistant to achievable serum levels of ciprofloxacin. Moxifloxacin, a newer quinolone, appears to have a much more favorable in vitro and in vivo mouse model profile. Most notably, there are reports of lower minimum inhibitory concentrations against the majority of human MAC isolates for moxifloxacin compared with older quinolones. (28-30) Also, moxifloxacin has been shown to achieve very high levels in human alveolar macrophages and lung epithelial lining fluid, which may indicate clinical effectiveness. (31) Human efficacy studies and head-to-head trials have not been performed, however, and the safety of this drug given for an extended time period, as required in the treatment of MAC, will also warrant further investigation.

[FIGURE 4 OMITTED]

According to one report, MAC has historically been universally susceptible to clofazimine. (21) This drug is also attractive because it is easy to take and has a low side effect profile. Studies in those with disseminated MAC and HIV, however, are disappointing. (32,33) Larger studies with a longer follow-up period in immunocompetent patients are needed.

Mefloquine is another treatment that holds some promise, although human studies are lacking. (34) Safety and side effects is again a concern. Linezolid has also received some attention, but the data are preliminary. (35,36) Cycloserine, ethionamide, and isoniazid (INH) have all been evaluated for MAC therapies, but resistance is common. (37,38) Specifically, the role of INH in MAC therapy has been unclear and at times conflicting. (26,37) Up to the late 1980s, INH with other drug combinations was considered standard of care. However, due to data suggesting little in vitro activity, the use of INH was not recommended by most MAC experts. (7) A recent study published by the Research Committee of the British Thoracic Society showed a cure rate of 31% with a 36% mortality rate with the use of ethambutol and rifampicin with or without INH. (39) Macrolides were not used in any of the combinations. The use of INH in treatment combinations for MAC needs to be revisited, using more updated protocols.

The role of immune modulator therapy, specifically interferon-gamma, in mycobacterial disease has been studied. (40) Except for isolated reports related to its use in disseminated disease in conjunction with conventional therapy, these results are preliminary at best and not convincing.

Surgical resection is advocated by some early in the course of disease, because it is well tolerated and may provide a cure without the prolonged treatment and its associated problems. Eradication of MAC in sputum with low relapse rates has been reported. (41) However, this is a technically difficult surgery, and bronchopleural fistula is the most common surgical complication. This therapy is usually reserved for cases with focal disease with failed treatment when either drug resistance or intolerance exists.

Type 5

MAC hypersensitivity pneumonitis. One of the most intriguing presentations of MAC is "hot tub lung." (42-44) It occurs in young, healthy subjects and is thought most likely to be a form of hypersensitivity pneumonitis. MAC appears to have a predilection for warm water and is readily isolated from hot tubs. The disease presents as a diffuse interstitial process, and cultures are typically positive from sputum samples (Fig. 5). Biopsy specimens almost universally show granulomas, although histologically they are well organized, in contrast to the loosely formed granulomas typical of hypersensitivity pneumonitis. Once the diagnosis is suspected, avoidance of the offending hot tub provides potential cure. Steroids and anti-MAC therapy have also been used with treatment success. However, long-term follow-up of such patients is lacking, and we hope that a better understanding of the pathophysiology of this condition will continue to emerge.

[FIGURE 5 OMITTED]

Conclusion

MAC, which is ubiquitous in our environment, may have protean manifestations in humans. This is especially true in those with no recognizable impairments in their immune system. Recent reports have described new types of pulmonary presentation as well as given us a better and more detailed description of the classic presentations. The natural history of the multiple forms of disease is not well understood, but it is clear that all forms can cause progressive disease and will need treatment of some kind. The cornerstone of such a treatment protocol is aggressive bronchial hygiene and nebulized therapy with or without specific antimycobacterial drugs. Drug treatment, however, remains difficult, secondary to medication side effects, expense, and high failure rates. With this in mind, we believe that treatment should be tailored for the individual patient and their particular presentation. In milder disease, it is not unreasonable to try a 3-month period of observation focusing on bronchial toilet before specific antimicrobial therapy is begun. When an antimycobacterial regimen is needed, it should be designed on the basis of the clinical situation and begun gradually, to increase the chances of treatment compliance. Novel approaches to therapy are evolving to overcome the specific problems encountered in the treatment of this disorder. Large randomized trials are needed to shed light on the problems encountered in managing and treating MAC lung disease, especially in relation to its various presentations.

Every artist dips his brush in his own soul and paints his own nature
into his pictures.
--Henry Ward Beecher

Table 1. Monthly clinical and bacteriologic follow up with monitoring
following parameters during therapy as clinically indicated (a)

Type of disease              Treatment                  Duration

Type 1                       Aerosolized/saline         4-12 wk
Asymptomatic colonization      nebulizations/
                               bronchodilator
                               therapy with "bronchial
                               hygiene and toilet"
Type 2                       Treat as type 1 plus       3 mo
Symptoms with minimal        Macrolide (b) plus
  radiographic changes       Ethambutol (25 mg/kg) (c)
Type 3                       Macrolide (b) plus         12 mo beyond
Symptoms with radiographic   Ethambutol (25 mg/kg)        sputum culture
  deterioration and diffuse    plus                       negativity
  involvement                Rifabutin (300 mg) (d)
                               [+ or -]
                             Amikacin (15 mg/kg IV)
Type 4                       Initial susceptibility     12-18 mo
Recurrent disease and          testing and a treatment
  drug-resistant MAC           plan using at least two
                               drugs to which the
                               isolate is susceptible
Type 5                       Avoidance of hot tub       Clinical
Hot tub lung                   [+ or -] Steroids          resolution
                               [+ or -] Macrolide and
                               ethambutol

(a) 1. Liver function tests; 2, renal function tests; 3, audiogram; 4,
ophthalmologic examination.
(b) Azithromycin (600 mg) or clarithromycin (500 mg) BID thrice weekly.
(c) Treat thrice weekly. Dosage may need to be reduced in elderly
patients with impaired renal function.
(d) Consideration of drug-drug interaction may dictate dosage changes.

Acknowledgments

The authors thank Carol Mason, MD, for help in reviewing the manuscript.

Accepted November 4, 2004.

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RELATED ARTICLE: Key Points

* Mycobacterium avium complex is increasingly recognized as one of the most common mycobacterial pathogens in humans.

* Mycobacterium avium complex is rapidly becoming a significant cause of pulmonary disease even in those with intact immunity.

* A practical approach to management of the various pulmonary forms of the disease must be used.

Stephen A. Chitty MD, and Juzar Ali, MD, FRCP, FCCP 

From Louisiana State University Health Sciences Center, Section of Pulmonary /Critical Care Medicine, LSU School of Medicine, New Orleans, LA.

Reprint requests to Dr. Stephen Chitty, LSUHSC, 1901 Perdido Street, Suite 3205, New Orleans, LA 70112-1393. Email: [e-mail]