Nontuberculous Mycobacterial Pulmonary Infections

Marisa Magaña and Antonino Catanzaro

INTRODUCTION

Nontuberculous mycobacterial (NTM) infections encompass a variety of acid-fast bacilli that are biologically distinct from Mycobacterium tuberculosis and M. leprae. They had long been considered saprophytes or culture contaminants. More recently, they have been recognized as significant, although uncommon, human pathogens. Rates of NTM infection have increased due in part to the rising frequency of infection encountered in patients with chronic lung disease and the AIDS epidemic, where disseminated M. avium–intracellulare (MAC) can be life-threatening. Although the rates of tuberculosis (TB) are declining in many industrialized countries, the prevalence of pulmonary disease caused by NTM appears to be increasing.

While over 100 species of NTM have been identified, only a few species account for the majority of human infections. NTM diseases occur in most industrialized countries with an incidence of approximately 3 per 100,000 persons. Pulmonary disease caused by M. avium complex is the most common NTM infection in most areas. There are some regional differences in the prevalence of certain other species. For example, M. abscessus is the second most common in the United States and Korea, whereas M. kansasii is the second most common NTM in Canada. Unlike the M. tuberculosis complex, NTM are widely dispersed in the environment and commonly isolated from soil, drinking water, rivers, hospital instruments (i.e., bronchoscopes), and municipal water sources. Unlike tuberculosis, there is no person-to-person transmission.

DIAGNOSIS

Diagnosis of pulmonary disease caused by NTM may be difficult, as the organisms are commonly isolated from environmental sources, and therefore, many isolates are in fact contaminants. The American Thoracic Society has published guidelines outlining specific diagnostic criteria for pulmonary disease caused by NTMs. Broadly, these guidelines require the presence of a compatible clinical and radiographic presentation, supporting microbiological data, and the exclusion of other potential etiologies. These criteria are based on experience with common and well-described respiratory pathogens, such as MAC and M. abscessus. However, there is little experience with most of the other NTM to know if these criteria are uniformly applicable. Because NTM are ubiquitous, the ATS has recommended specific microbiologic criteria which attempt to differentiate between a contaminant and a true pathogen. The microbiologic criteria may be any one of the following: a positive culture from at least two expectorated sputum samples, a positive culture from at least one bronchial wash, a biopsy with mycobacterial histopathologic features and positive culture, or a biopsy with mycobacterial histopathologic features and one or more sputum/bronchial washings that are culture-positive for NTM. Once a microbiologic confirmation of disease has been made, the guidelines require that the patient display symptoms as well as radiographic evidence of disease before establishing a diagnosis of pulmonary disease due to the NTM. Most series have demonstrated that only 25% to 50% of patients with an NTM isolate will meet the 2007 ATS criteria for infection. The decision to treat a patient is a decision that requires further consideration of various factors that will be discussed later in this chapter.

MICROBIOLOGY

Several recent advances have enabled laboratories to detect and identify mycobacteria more rapidly and accurately. The use of liquid-based culture media such as BACTEC (Becton Dickinson, Sparks, Maryland) has greatly reduced the time in which results are available; many NTM can now be recovered in days rather than weeks. In addition, the increased use of liquid culture is also likely a factor in the increase in isolation of some of these organisms. High-performance liquid chromatography (HPLC) can be used to identify species based on interpretation of the mycolic acid pattern they display. The differentiation between M. tuberculosis and NTM is reliable using this method as is the differentiation of many other mycobacterium species or groups. Chemiluminescent DNA probes (such as AccuProbe, GeneProbe Inc., San Diego, California) are now being used as confirmatory tests to identify some of the more common families. These probes are reported to be nearly 100% sensitive and specific and have become the most commonly used method of rapid mycobacterial identification.

While many mycobacterial species can now be detected more rapidly because of the advent of liquid media and molecular testing, the old growth characteristics are still used as part of the classification system. The rapidly growing mycobacteria or RGM are characterized by visible growth on solid media within 7 days. M. abscessus complex accounts for 65% to 80% of lung disease caused by RGM and will be discussed in detail later in this chapter, as it has become a common cause of NTM lung disease.

The approach to management of pulmonary disease due to NTM depends primarily on the causative species. Therefore, treatment for some of the more common NTMs will be discussed in this chapter by species.

M. avium Complex

Pulmonary infection with NTM is most often caused by MAC. There are at least two species within this complex, M. avium and M. intracellulare, and they may sometimes be referred to as MAC or MAI. M. avium appears to be more linked with disseminated disease, while M. intracellulare is more often found as an isolated respiratory pathogen. At present, there does not appear to be any prognostic advantage to differentiating these two species, and therefore, this is not routinely done.

In HIV-negative patients with pulmonary disease caused by MAC, two main types of radiographic presentation, are currently recognized. The first is an apical fibrocavitary disease, resembling findings seen in TB patients. This tends to occur in males aged 40 to 50 with a history of tobacco and alcohol use. This type of presentation tends to progress, leading to lung destruction and loss of lung function, without treatment. The second type of pulmonary MAC disease is a nodular and bronchiectatic presentation that tends to occur in patients without any underlying lung disease. Most often, these radiographic changes are present in the lingula and right-middle lobes. This presentation tends to be slowly progressive and occurs mostly in postmenopausal, tall, thin and nonsmoking women. This second type of presentation is sometimes called the “Lady Windermere syndrome.” Lady Windermere syndrome was first described in 1892 after the character in Oscar Wilde’s play Lady Windermere’s Fan.

In addition to its occurrence in the above-mentioned at-risk patient populations, pulmonary disease due to MAC is increasingly being recognized as a pathogen in patients with cystic fibrosis. One potentially important discovery is the presence of CFTR mutations (the gene responsible for cystic fibrosis) in patients without cystic fibrosis who have a diagnosis of bronchiectasis, pulmonary NTM, or both. The significance of this is unclear. When MAC is recovered from patients with cystic fibrosis, it is often difficult to determine whether the radiographic changes are due to MAC, the underlying cystic fibrosis or nonmycobacterial pathogens such as pseudomonas. It is recommended that all potential nonmycobacterial pathogens be aggressively treated prior to initiation of MAC therapy in patients with cystic fibrosis. In recent years, there has been increasing use of the macrolides in cystic fibrosis patients for their anti-inflammatory effects. This phenomenon could potentially lead to the development of macrolide resistant strains of NTM. It is recommended that cystic fibrosis patients undergo evaluation for NTM disease prior to initiation of macrolide monotherapy.

M. avium Complex—Treatment

Treatment of MAC can be difficult, especially due to the fact that with the exception of the macrolides (azithromycin and clarithromycin), the in vitro susceptibilities do not predict clinical outcomes. Based on the available literature, the ATS has recommended that treatment regimens contain a macrolide (clarithromycin 1,000 mg/day or azithromycin 250 mg/day), ethambutol (15 mg/kg/day), and rifampin (10 mg/kg/day, 600 mg/day max.). If there is severe disease or previous treatment, then an IV aminoglycoside (streptomycin or amikacin) should be added for the first 2 to 3 months. Three times weekly treatment can be considered in patients with less-severe nodular, bronchiectatic disease who are treatment naive. There are some patients in whom a microbiological cure will not be possible because of the potential side effects or drug interactions. In these patients, the MAC infection may be viewed as a noncurable, chronic, indolent infection, and other treatment regimens may be more appropriate for suppressive-type therapy.

Bronchial hygiene is an important, often overlooked adjunctive therapy for those patients with preexisting lung disease. Routine drug susceptibility testing is not recommended as the organism shows in vitro resistance to most antituberculous drugs. However, in vitro sensitivities should be obtained for those patients who are failing therapy or experiencing a relapse after prior treatment. Sputum should be sampled monthly to document negative conversion, and blood tests should be monitored routinely while on treatment as the potential for drug toxicity is high.

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