© 2008 American Thoracic Society doi: 10.1164/rccm.200801-018ED
Help for the Diagnosis of Some, but Not All Cases of Mycobacterium avium–Complex Pulmonary Disease
Mount Sinai School of Medicine In 1959, Runyan classified nontuberculous mycobacteria (NTM) by growth rate, colony morphology, and pigment response to light. (1) With the advent of new molecular techniques, the number of species identified is multiplying. At present, there are more than 128 species of NTM, starting with M. abcessens and going to M. xenopii (2). Although common in the environment, and originally thought rarely to cause disease, many NTM have the potential to become pathogenic. The most clinically important of these nontuberculous organisms are M. avium and M. intracellulare, grouped as M. avium complex (MAC). Four major MAC syndromes have become important clinical entities: (1) pulmonary nodules simulating lung cancer (growing, positron emission tomography [PET] positive) (3); (2) fibrocavity lesions, often in lungs damaged by preexisting emphysema or treated tuberculosis (4); (3) fibronodular bronchiectasis, common in elderly females (5); and (4) opportunistic infections in immunocompromised hosts (6). In addition, recent reports note emerging cases of MAC-related hypersensitivity pneumonitis (7) and high rates of infection in patients with cystic fibrosis (8). The report of acid fast bacilli on sputum smear usually provokes immediate isolation of the patient and, in many instances, empiric treatment with multiple antituberculous drugs. A period of watchful waiting ensues while confirmatory culture or molecular techniques identify the organism. The clinical presentation and radiographic abnormalities often point to the differentiation between M. tuberculosis and NTM before the organism is definitively identified. However, there is always a degree of uncertainty until the positive culture or polymerase chain reaction arrives. In this issue of the Journal (pp. 793–797), Kitada and colleagues (9) offer a new test that specifically addresses the difficult clinical problems posed by a sputum smear obtained from an immunocompetent host that is positive for acid fast bacilli. Is the organism M. tuberculosis or MAC? If the latter, is it an environmental contaminant? Does it herald the presence of MAC-related pulmonary disease? If so, which one—nodular bronchiectasis or fibrocavitary? The most recent American Thoracic Society/Infectious Diseases Society of America (ATS/IDSA) statement on MAC-related pulmonary disease begins with a 123-word introduction to the diagnostic criteria, closing with two clinical and six microbiologic guidelines (10). This diagnostic pathway is cumbersome, confusing, and often difficult to fulfill, especially in elderly women without sputum who may be poor candidates for bronchoscopy. Building on their previous study, which demonstrated the presence of serum antibodies to the glycopeptidolipid (GPL) core antigen found on the membrane of MAC organisms in patients with MAC-related pulmonary disease, Kitada and colleagues have developed an enzyme immunoassay (EIA) kit that can differentiate MAC-related pulmonary disease from tuberculosis, environmental contaminants, and other lung diseases. Furthermore, the EIA can distinguish most nodular bronchiectasis from fibrocavitary MAC infection. In a six-institution study, the authors achieved a sensitivity and specificity for MAC-related pulmonary disease of 84.3 and 100%, respectively, and higher levels of antibody in nodular bronchiectatis compared with fibrocavitary disease. When combined with the epidemiologic presentation and typical chest CT scan pattern found in patients with nodular bronchiectatic MAC infection (11), the new EIA should be an important aid to the diagnosis of MAC. The GPL antigen is present in the cell walls of all atypical mycobacteria. Atypical mycobacteria tend to vary in geographic loci. Unfortunately, this multisite study was conducted only in a single geographic location, in a single racial cohort. Larger studies in other locations and involving patients of differing races will be required to validate the specificity of the EIA test for MAC-related pulmonary disease. A small number of false-positive and false-negative EIA tests was reported by the authors. Thus, the responsible physician must adhere to good mycobacterial practices and confirm the EIA test by culture or molecular techniques. There are new, sensitive microbiologic methods available that can identify mycobacterial species within a few days, including molecular probes (12) and mycolic acid patterns by HPLC (13). It should be remembered that, while rapid identification of infection due to M. tuberculosis has important public health implications, there is rarely such urgency for treatment and isolation of patients with MAC, except for those with immunosuppressed medical conditions. There remain several outstanding clinical problems in the diagnosis and treatment of MAC that are not addressed by the new EIA test. At least one group vigorously attacked the recent official ATS/IDSA statement for failing to proclaim strict guidelines for treatment of MAC-related pulmonary disease (14). Instead, the review states, "making the diagnosis of NTM lung disease does not, per se, necessitate the institution of therapy, which is a decision based on potential risks and benefits of therapy for individual patients." The new EIA test does not address therapy. A positive EIA test is not a mandate to treat MAC. That decision still rests with the experienced clinician who must base treatment on the clinical status, radiographic and physiologic severity, progression of disease, and the ability of the patient to tolerate prolonged multidrug therapy. Furthermore, no data exist that suggest that the new EIA test is applicable as a guide to therapy. Most of the patients with MAC-related pulmonary disease in this study continued to have positive sputum cultures and positive EIA tests despite multidrug treatment. Nor are there data that support the value of the EIA test in the diagnosis of the other important MAC-related pulmonary syndromes, such as growing, PET-positive MAC nodules that mimic lung cancer, opportunistic disseminated MAC in immunosuppressed patients, MAC infection in cystic fibrosis, and hypersensitivity disease due to MAC. At this time, it is reasonable to state that Kitada and coworkers have developed a promising, rapid, noninvasive test that has potential to aid in deciding whether or not a sputum smear containing acid fast bacilli is due to tuberculosis, contamination, or MAC. If it is MAC, when coupled with the clinical and radiographic presentation, the EIA test can discriminate MAC fibrocavitary disease from nodular bronchiectesis. The test requires validation in a larger number of patients, at diverse geographic locations, and among other races. A positive test does not liberate the clinician from the responsibility to obtain confirmatory microbiologic tests. Unfortunately, the EIA does not contribute to the solution of the outstanding important issue of when to treat MAC-related pulmonary disease. FOOTNOTES Conflict of Interest Statement: The author has no financial relationship with a commercial entity that has an interest in the subject of this manuscript. REFERENCES
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