Version May 2024
INTRODUCTION — The possible presence of nontuberculous mycobacterial (NTM) lung disease often arises clinically when NTM are identified on sputum culture from a patient under evaluation for tuberculosis. The laboratory findings used to confirm the diagnosis of NTM infection in this setting will be reviewed here. The epidemiology, pathogenesis, and treatment of NTM are discussed separately. (See "Epidemiology of nontuberculous mycobacterial infections" and "Pathogenesis of nontuberculous mycobacterial infections" and "Treatment of Mycobacterium avium complex pulmonary infection in adults".)
CLINICAL FEATURES — NTM infections of the lungs often occur in the context of preexisting lung disease, especially chronic obstructive pulmonary disease (COPD), bronchiectasis, pneumoconiosis, cystic fibrosis, and previous tuberculosis [1-4]. As a result, the clinical manifestations of NTM lung disease are often similar to those of the underlying disease. These include cough, fatigue, malaise, fever, weight loss, dyspnea, hemoptysis, and chest discomfort. These same symptoms are also present in patients with NTM lung disease who do not have preexisting pulmonary disease. (See "Overview of nontuberculous mycobacterial infections".)
CHEST IMAGING — The radiographic findings of NTM lung disease are variable, depending in part upon the species. Findings consistent with NTM pulmonary infection on chest radiograph or high-resolution computed tomography scan include infiltrates (usually nodular or reticulonodular), cavities, multifocal bronchiectasis, and/or multiple small nodules. (See "Overview of nontuberculous mycobacterial infections".)
The radiographic pattern of disease can usually be separated into predominantly cavitary versus nodular/bronchiectatic. Some generalizations can be made:
●Cavitary disease in the upper lung zones, similar to pulmonary tuberculosis, is seen in approximately 90 percent of patients with Mycobacterium kansasii infection and perhaps 50 percent of those with Mycobacterium avium complex (MAC) infection. Mycobacterium xenopi lung infection is also frequently associated with cavities. The cavities caused by these organisms tend to have thinner walls and less surrounding parenchymal opacity than those caused by Mycobacterium tuberculosis [5,6].
●At least 50 percent of patients with MAC lung disease have radiographic abnormalities characterized by nodules associated with bronchiectasis or nodular/bronchiectatic disease. The nodules and bronchiectasis are usually present within the same lobe and occur most frequently in the right middle lobe and lingula [7].
One study, for example, evaluated 100 patients with bronchiectasis, 24 of whom also had multiple pulmonary nodules [8]. Among the patients in whom sputum cultures were obtained, a positive culture for MAC was much more likely in those with pulmonary nodules than in those without pulmonary nodules (53 versus 4 percent).
High-resolution CT scans of the chest are especially helpful for diagnosing this pattern of MAC lung disease as bronchiectasis and small nodules may not be easily discernible on plain chest radiograph [9]. The nodular/bronchiectatic radiographic pattern can also be seen with other NTM pathogens, including Mycobacterium abscessus, Mycobacterium simiae, and M. kansasii.
●Solitary nodules and dense consolidation have also been described.
●Pleural effusions are uncommon, but reactive pleural thickening is frequently seen.
The relative percentage of patients with NTM infection who have cavitary versus non-cavitary disease depends on both the pathogen isolated and the geographic origin of the patient. As an example, patients in Northern Europe appear more likely to have cavitary NTM lung disease compared with patients in North America [10]. The reasons for this disparity are uncertain, but it may be related to the relatively high prevalence of M. xenopi lung disease in Northern Europe and the relatively decreasing prevalence of M. kansasii in North America.
MICROBIOLOGIC EVALUATION — Given the lack of diagnostic specificity of chest radiography, the diagnosis of NTM lung disease requires microbiologic confirmation (table 1). The management of patients with NTM lung disease requires access to a reliable mycobacteriology laboratory with the capability to perform accurate identification of NTM species and appropriate in vitro drug susceptibility testing. This level of laboratory support is essential.
Sputum testing — The possible presence of NTM infection should be considered in a patient with a chronic pulmonary infiltrate with or without a cavity and persistence of associated symptoms, such as cough, fatigue, malaise, fever, weight loss, dyspnea, hemoptysis, or chest discomfort. When suspected, respiratory specimens should be submitted for microbiologic testing for NTM.
●Collection of respiratory specimens – The diagnostic evaluation should consist of smear and culture of at least three separate expectorated sputum specimens obtained in the morning. For patients who have difficulty providing expectorated sputum specimens, sputum induction with hypertonic saline is usually effective.
If the etiology of the patient's symptoms remains uncertain (eg, sputum cultures are uninformative or sputum specimens cannot be obtained) and the infiltrate persists, bronchoscopy with bronchoalveolar lavage (BAL) and/or transbronchial biopsies should be performed. However, for most patients, sputum induction provides adequate specimens for acid-fast bacilli (AFB) analysis.
●Microbiologic testing – Sputum should be submitted for AFB smear (microscopy) and culture. Sputum sent for culture of NTM must first be chemically decontaminated to eliminate common bacteria and fungi that would overwhelm the culture. (See "Microbiology of nontuberculous mycobacteria", section on 'Culture'.)
For patients at risk for tuberculosis or with a radiographic appearance consistent with pulmonary tuberculosis, sputum nucleic acid amplification testing (NAAT) for tuberculosis should also be done. Clinicians should have a low threshold for ordering NAAT to avoid missing active tuberculosis with atypical radiographic findings. (See "Diagnosis of pulmonary tuberculosis in adults", section on 'Molecular testing'.)
Highly accurate nucleic acid probes (Accuprobe, GenProbe, Inc) are also commercially available that can identify M. avium complex (MAC) isolates within one day after recognizable growth is evident, a technique currently used by most reference laboratories. A similar nucleic acid probe is also available for the identification of M. kansasii and Mycobacterium gordonae.
●Sputum culture interpretation – Positive sputum cultures for NTM must be interpreted cautiously, since NTM isolation does not always indicate NTM lung disease. These organisms have variable virulence and can be recovered from the respiratory tract without causing progressive infection (ie, they can cause transient infection). In addition, NTM are common in the natural environment and may contaminate laboratory specimens. Tap water (liquid or frozen) especially may contain NTM and contaminate clinical and laboratory specimens. The presence of consistent symptoms cannot necessarily distinguish between transient infection or contamination and true infection, as many patients with suspected NTM have underlying lung disease that causes similar symptomatology. Thus, diagnostic criteria require that more than one expectorated sputum specimen is culture positive; critical assessment over time is often necessary. (See 'Diagnostic criteria' below.)
Some studies suggest that time to positive sputum culture detection could help discriminate NTM lung disease from transient infection or contamination. It has been theorized that a heavier mycobacterial burden in the specimen (which may be more likely associated with lung disease) results in earlier detection. In a retrospective study of 125 patients who had NTM isolated on sputum culture, a shorter time to positive sputum culture was associated with NTM lung disease, for which 65 percent of the study population met diagnostic criteria v [11]. The median time to culture positivity was 12 days; a threshold of 10 days or less was associated with NTM lung disease, AFB smear positivity, and ultimate treatment initiation within three to six months.
DIAGNOSTIC CRITERIA — In an attempt to address the difficulties in diagnosis (eg, distinguishing transient infection, colonization, or contamination from true infection), the American Thoracic Society (ATS), European Respiratory Society (ERS), European Society of Clinical Microbiology and Infectious Diseases (ESCMID), and Infectious Diseases Society of America (IDSA) jointly endorse specific criteria for the diagnosis of NTM lung disease (table 1) [4,12]:
The diagnostic criteria consist of:
●Clinical and radiographic criteria: Consistent symptoms with evidence of pulmonary disease on imaging studies and exclusion of other processes such as fungal disease, malignancy, and tuberculosis
PLUS
●Microbiologic criteria: These are findings that support NTM clinical infection over colonization or transient infection and include one of the following:
•Positive cultures with the same NTM species from at least two separate expectorated sputum samples (regardless of acid-fast bacilli [AFB] smear result)
•Positive culture result from at least one bronchial wash or lavage (regardless of AFB smear result)
•Transbronchial or other lung biopsy with mycobacterial histopathologic features (granulomatous inflammation or AFB) and positive culture for NTM
•Biopsy showing mycobacterial histopathologic features (granulomatous inflammation or AFB) and one or more sputum or bronchial washings that are culture positive for NTM
•A positive culture from pleural fluid or any other normally sterile extrapulmonary site
Isolation of M. gordonae, M. mucogenicum, M. nonchromogenicum, M. haemophilum, M. flavescens, M. gastri, M. terrae, or M. triviale indicates probable colonization or contamination. These organisms are generally not pathogenic for humans except in the context of severe cellular immunodeficiency, such as end-stage HIV. M. fortuitum is relatively frequently isolated but rarely associated with significant NTM lung disease. Expert consultation should be obtained when NTM are recovered that are either infrequently encountered or that usually represent environmental contamination. Making a diagnosis of NTM infection may not necessitate the initiation of treatment. (See "Treatment of Mycobacterium avium complex pulmonary infection in adults".)
Isolation of NTM in symptomatic patients, regardless of whether the above 2020 ATS/IDSA/ERS/ESCMID criteria are met, may itself be a marker for poor prognosis [12]. In a retrospective review of patients with at least one positive culture for NTM (predominantly from pulmonary specimens), four-year mortality rates were high and not significantly different among the 61 patients who met and the 59 patients who did not meet ATS/IDSA criteria for NTM infection (28 versus 41 percent mortality); a similar percentage of the patients who were treated for NTM did and did not meet criteria [13]. Prognosis was most related to the severity of underlying diseases, which was greater among patients who did not meet criteria. However, determining the prognostic impact of the current diagnostic guidelines is complicated, and the diagnostic criteria remain useful for determining which patients are likely to have significant NTM lung disease and should be considered candidates for therapy.
INVESTIGATIONAL TESTS
●Skin tests – Species-specific skin test antigens may show considerable cross reactivity and are not commercially available or approved for diagnostic purposes. However, epidemiologic and laboratory studies with well-characterized antigens have shown that dual skin testing with tuberculosis versus NTM-derived tuberculins can discriminate between prior NTM and prior tuberculosis [14-18].
●Serodiagnosis/anti-GPL-core IgA antibody – The glycopeptidolipid (GPL) core is a cell wall component of M. avium, M. intracellulare, and rapidly growing mycobacteria (including M. abscessus) [19]. Other mycobacterial species lack this core component. Emerging data suggest that detection of anti-GPL-core IgA antibody may be a useful tool for diagnosis of MAC or M. abscessus lung disease (eg, to meet microbiologic criteria in patients with a single positive sputum culture). Interpretation may be difficult in the setting of MAC and M. abscessus co-isolation.
Several studies have indicated that anti-GPL-core IgA antibody levels are higher in patients who meet diagnostic criteria for MAC or M. abscessus lung disease than in those without [19-21]. In a meta-analysis of 16 studies that included 1098 subjects with clinically diagnosed MAC lung disease and 2270 controls, the sensitivity and specificity of the anti-GPL-core IgA antibody at a cutoff value of 0.7 units/mL were 70 and 91 percent [19]. Another study suggested that a cutoff value of 0.3 units/mL resulted in the best combination of sensitivity and specificity (70 and 94 percent) [22]. Studies also suggest that the antibody level declines with treatment, suggesting that they may reflect disease activity [19,20].
SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Nontuberculous mycobacteria".)
SUMMARY AND RECOMMENDATIONS
●Clinical features – Nontuberculous mycobacterial (NTM) infections of the lungs often occur in the context of preexisting lung disease, especially chronic obstructive pulmonary disease (COPD), bronchiectasis, pneumoconiosis, cystic fibrosis, and previous tuberculosis. The clinical manifestations of NTM lung disease are often similar to those of the underlying disease. These include cough, fatigue, malaise, fever, weight loss, dyspnea, hemoptysis, and chest discomfort. These same symptoms are also present in patients with NTM lung disease who do not have preexisting pulmonary disease. (See 'Clinical features' above.)
●Imaging findings – The radiographic findings of nontuberculous mycobacterial (NTM) lung disease are variable, depending in part upon the species. Findings consistent with NTM pulmonary infection on chest radiograph or high-resolution computed tomography scan include infiltrates (usually nodular or reticulonodular), cavities, multifocal bronchiectasis, and/or multiple small nodules. (See 'Chest imaging' above.)
●Microbiologic testing – Given the lack of diagnostic specificity of chest radiography, the diagnosis of NTM lung disease requires microbiologic confirmation. In patients with a chronic pulmonary infiltrate with or without a cavity and persistent symptoms consistent with NTM, microbiologic evaluation should consist of smear and culture of at least three separate expectorated sputum specimens obtained in the morning. Some patients may require induction with nebulized saline to produce sputum. If the etiology of the patient's symptoms remains uncertain and the infiltrate persists, bronchoscopy with bronchoalveolar lavage (BAL) and/or transbronchial biopsies should be performed. (See 'Microbiologic evaluation' above.)
●Diagnostic criteria – The following criteria are necessary for the diagnosis of NTM lung disease (table 1):
•Clinical and radiographic criteria – Consistent symptoms with evidence of pulmonary disease on imaging studies and exclusion of other processes
PLUS
•Microbiologic criteria – Positive cultures with the same NTM species from at least two separate expectorated sputum samples; or a positive culture from at least one bronchoscopic specimen; or a biopsy specimen with granulomatous inflammation or AFB on histologic examination with positive culture from biopsy or respiratory specimen; or a positive culture from a pleural specimen
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