Chapter 3

Pulmonary diseases caused by non-tuberculous mycobacteria

Jakko van Ingen*, David E. Griffith#, Timothy R. Aksamit" and Dirk Wagner+
SUMMARY: Pulmonary disease due to non-tuberculous mycobacteria (NTM) is an emerging infection, mainly in regions with a decreasing prevalence of tuberculosis (TB). Patients with existing pulmonary diseases (e.g. cystic fibrosis, chronic obstructive pulmonary disease (COPD) and/or bronchiectasis), or patients with local or systemic immunosuppression are at risk of developing NTM lung disease. Disease manifestations can be: fibrocavitary, resembling TB; nodular/bronchiectatic, usually in elderly lean, nonsmoking female patients; or hypersensitivitylike after exposure to contaminated water. Since the clinical relevance of pulmonary NTM isolates differs significantly between NTM species, correct laboratory identification of NTM isolates is important to guide treatment decisions and drug-susceptibility testing (DST) efforts. Diagnosis requires the application of clinical and microbiological criteria according to published American Thoracic Society (ATS)/Infectious Diseases Society of America (IDSA) guidelines. Treatment decisions need to be individualised; long-term antibiotic therapy may be combined with surgical resection of affected portions of the lung. KEYWORDS: Lung disease, Mycobacterium abscessus, Mycobacterium avium , Mycobacterium intracellulare , Mycobacterium xenopi, non-tuberculous mycobacteria
*Dept of Medical Microbiology, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands. # Dept of Pulmonology, University of Texas Health Science Center, Tyler, TX, " Division of Pulmonology and Critical Care Medicine, Mayo Clinic College of Medicine, Rochester, MN, USA. + Center of Infectious Diseases and Travel Medicine, and Centre of Chronic Immunodeficiency, University Medical Center Freiburg, Freiburg, Germany. Correspondence: D. Wagner, Center of Infectious Diseases and Travel Medicine, and Centre of Chronic Immunodeficiency, University Medical Center Freiburg, Hugstetter Str. 55, 79106 Freiburg, Germany. Email: [email protected]

Eur Respir Monogr 2012; 58: 2537. Copyright ERS 2012. DOI: 10.1183/1025448x.10022511 Print ISBN: 978-1-84984-027-9 Online ISBN: 978-1-84984-028-6 Print ISSN: 1025-448x Online ISSN: 2075-6674

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n settings in which the incidence and prevalence of tuberculosis (TB) have fallen during recent decades, clinicians now face what appears to be an emergence of disease caused by nontuberculous mycobacteria (NTM), i.e. all mycobacteria other than the Mycobacterium tuberculosis complex and Mycobacterium leprae. The NTM can cause a wide range of infections, of which pulmonary infections are most frequent [1]. Owing to their similarities to conventional pulmonary TB in terms of clinical presentation, and the overlap in diagnostic tools and treatment modalities, pulmonary NTM diseases are mostly diagnosed by physicians who also treat TB patients. Hence, this European Respiratory Monograph on TB would not be complete if it did not cover pulmonary NTM disease. In this chapter, we review the entire breadth of this emerging field of medicine, from epidemiology to clinical presentation, treatment and laboratory aspects.

J. VAN INGEN ET AL.

Epidemiology of pulmonary NTM infections

NTM are a group of over 140 different species that can cause a wide array of infections in humans and animals [2]. NTM lung disease is most frequent and represents 6590% of all clinical NTM disease [1, 3, 4]. There is growing evidence that the incidence of NTM lung disease and associated hospitalisations is on the rise, mainly in regions with a low prevalence of TB [510]. In the USA, prevalences of 1.46.6 in 100,000 have been measured [510]. In parallel, skin sensitisation to Mycobacterium intracellulare has also increased in the USA [11]. Factors that may underlie this changing epidemiology are increases in the prevalence of the susceptible host; for example, the number of patients with systemic (e.g. HIV infection, haematological malignancy, inheritable disorders of immunity, immunosuppressive drug use including tumour necrosis factor (TNF)-a inhibitor therapy [12], or systemic or inhaled corticoid therapy [13]) or local immunosuppression (e.g. pre-existing pulmonary disease, such as cystic fibrosis patients and patients with chronic obstructive pulmonary disease (COPD)) has increased [2, 14]. The growing awareness of the entity of pulmonary NTM disease may contribute to this epidemiological trend. The prevalence of NTM in respiratory specimens differs significantly in different parts of the world (W. Hoefsloot, Radboud University Nijmegen Medical Center, Nijmegen, the Netherlands; personal communication) [15], and changes over time in the isolation frequency of the different NTM species from respiratory specimens or in patients with cervical lymphadenitis have been described [2, 14, 16]. These differences are partly explained by the ever more precise taxonomy of the genus Mycobacterium, but they may also be related to changes in environmental exposure [17, 18] or a decrease of cross-protection due to rin (BCG) vaccination [1921]. reduced TB prevalence or diminished use of bacille CalmetteGue

Key laboratory features of NTM

NTM PULMONARY DISEASES

Identification and taxonomy

Correct identification of clinical NTM isolates is important because NTM species differ in their clinical relevance, i.e. the percentage of patients from whom the species is isolated who are ultimately considered to have true disease caused by this NTM (fig. 1) [1]. Identification results can thus help determine the level of suspicion of true NTM disease. Treatment regimens and methods of drug-susceptibility testing (DST) also differ according to NTM species, mainly between slowly and rapidly growing species [26].
M. n M. ovio go ma rd ge on n a se M. for e (1 (0/ /48 17 t M. uit ) ) int um rac (1 ell /11 M. ula ) ch re elo (2/ na M. 16 ) sim e (8 / 44 M. iae ) ab (6 / s bo ces 28) lle su tii s (3 su /12 bs ) p. M. k M. ansa sz sii ulg (1 ai 2/1 M. ( 7 ma 11/1 ) 5) lm oe ns e( 32 /40 )
75 100

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Clinical relevance %

Figure 1. Clinical relevance of common non-tuberculous mycobacteria (NTM) in pulmonary isolates as

measured in the Netherlands. Clinical relevance is expressed as the percentage of patients with isolates of the respective species that ultimately met American Thoracic Society (ATS) diagnostic criteria. Numbers in parenthesis indicate the number of true cases/number of patients with the respective NTM isolate. Please note that clinical relevance of certain species may vary in different geographical regions. Data from [1, 2225].

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(2 4/ x M. eno 59) p a i ab bsc (21 sc es /44 es su ) su s s s ( ub 9/1 sp 8) .

50

M. a

M.

viu m

Laboratory identification of NTM has moved from phenotypic and biochemical analyses to molecular tools, with a huge increase in discriminatory power as a result; all these techniques have their characteristic advantages and disadvantages (table 1). Owing to these molecular tools, including 16S ribosomal DNA (rDNA) gene sequencing, .140 different NTM species have now been described, yet some 20 species make up 95% of all clinical isolates. This top 20 shows important regional differences (W. Hoefsloot, personal communication) [27, 28]. To identify NTM without the use of sequencers, molecular probes have been designed that can identify multiple species within a single assay (table 1). The latest addition to the identification tools is matrix-assisted laser desorption ionization time-of-flight (MALDI-TOF) mass spectrometry. This technique is currently being optimised for application in mycobacteriology ([29] and unpublished data). With the many new species now described, the debate on exact species definitions in the genus Mycobacterium continues and the first moves to reassign species as subspecies (e.g. Mycobacterium bolletii and Mycobacterium massiliense to Mycobacterium abscessus subsp. bolletii) are now being seen [30].

Drug-susceptibility testing
The role of DST in the choice of agents for the antimicrobial treatment of NTM disease, mainly that caused by slow growers, remains a subject of debate [31]. There are important discrepancies between minimum inhibitory concentrations (MICs) measured in vitro and the activity of the drug observed in vivo [2, 3237]. Test methods and conditions have a profound impact on results, and use of the methodology recommended by the Clinical Laboratory Standards Institute [38], despite its inherent limitations, is recommended [2, 27]. For the Mycobacterium avium complex (MAC), only susceptibility testing of macrolides (i.e. clarithromycin) is currently recommended, because its results have been clinically validated [38, 39]. For Mycobacterium kansasii, initial testing should include only rifampicin; rifampicin-resistant isolates have been observed in patients who failed treatment with rifampicin-based regimens [40, 41]. For the rapid growers, relations between MICs and outcomes have been studied for several drugs (e.g. tobramycin, co-trimoxazole, cefoxitin and doxycycline), albeit mostly in extrapulmonary disease and key drugs, including amikacin and macrolides, were not included [42]. MICs of any drug other than those mentioned should be interpreted with caution; seeking expert consultation before applying nonstandard drugs in regimens is recommended. Inducible macrolide resistance owing to ribosomal RNA (rRNA) methylase (erm) genes has been demonstrated in many rapid growers, especially in M. abscessus subsp. abscessus; this inducible resistance is often not reflected in the initial susceptibility results and demands specific testing by laboratories. The relationship between inducible macrolide resistance in M. abscessus and the outcome of treatment with macrolide-based regimens remains uncertain [43, 44], although
Table 1. Molecular tools for non-tuberculous myobacterium identification
Type Single-species DNA probes Line probe assays Commonly used assays/ targets AccuProbe (GenProbe, San Diego, CA, USA) GenoType1 Mycobacterium CM/AS (Hain Lifescience, Nehren, Germany) Inno1 LiPA Mycobacteria v2 (Innogenetics, Ghent, Belgium) hsp65, rpoB 16S, 16S23S ITS, hsp65, rpoB, secA1 Discriminatory power Low, species-specific (4 species) Medium (30 species) Disadvantages Low discriminatory power, cost Cost

Medium (16 species) Mediumhigh Very high (all species)

PRA Gene sequence analysis

Cost, low discriminatory power Manually processed, error prone Requires access to sequencers, slow

PRA: PCR product restriction analysis; ITS: internal transcribed spacer.

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outcomes seem better in M. abscessus subsp. bolletii (formerly M. massiliense) in which the erm gene is not functional [27].

Clinical presentations of pulmonary NTM disease

Four distinct manifestations of pulmonary NTM disease are known: 1) fibrocavitary disease; 2) nodular/bronchiectatic disease; 3) hypersensitivity disease; and 4) the rare solitary pulmonary lesion type that mimics malignancy. Note that these are not absolute and mixed types can occur.

Fibrocavitary disease
In his seminal review of NTM diseases from 1979, WOLINSKY [45] noted that, chronic pulmonary disease resembling tuberculosis represents the most important clinical problem associated with NTM and that the chest radiograph typically showed fibrosis and a thin-walled cavity in the right upper lobe. The typical patient was middle-aged, male, smoked cigarettes, had underlying chronic lung disease, including chronic obstructive lung disease, pneumoconiosis and/or previous TB, and presented with chronic cough, sputum production and weight loss. As a consequence of the cavitary abnormalities frequently encountered radiographically, the sputum from these patients is usually acid-fast bacilli (AFB) smear and culture positive. Once the diagnosis of TB has been excluded, the diagnosis of fibrocavitary MAC lung disease is relatively straightforward. While the recognised spectrum of NTM lung disease presentation has broadened with the recognition of NTM disease associated with bronchiectasis and nodular densities, the presentation of a typical fibrocavitary MAC lung disease patient has remained remarkably constant. In the USA, slowly growing NTM species such as MAC and M. kansasii are the NTM species most often associated with fibrocavitary NTM lung disease; however, other species such as Mycobacterium szulgai, Mycobacterium xenopi and Mycobacterium malmoense are also frequently encountered in other geographic areas, especially northern Europe [2, 22, 23, 35, 46, 47]. As opposed to the USA, this form of NTM lung disease appears to be predominant in northern Europe. Although diagnosis of fibrocavitary NTM disease may not present an especially difficult challenge, the management of these patients can be extremely difficult due to underlying lung disease and limited respiratory reserve with the potential for progressive cavitary lung destruction and respiratory compromise. Although not rigorously described, the available evidence supports the view that this type of NTM disease is associated with relatively high mortality and that these patients require aggressive therapy [22, 23, 35, 47].

NTM PULMONARY DISEASES

Nodular/bronchiectatic disease
In 1989, PRINCE et al. [48] convincingly described patients with a progressive noncavitary, nodular/ bronchiectatic form of MAC lung disease. In 1992, REICH and JOHNSON [49] proposed the name Lady Windermere syndrome for this disease manifestation, after the main character in Oscar Wildes play [50], based on the hypothesis that voluntary cough suppression had a role in the aetiology of the disease. It is now clear that this nodular/bronchiectatic form of NTM lung disease can be seen with essentially any NTM respiratory pathogen, albeit most commonly with MAC, and that in the USA, nodular/bronchiectatic NTM disease is the most commonly encountered form of MAC lung disease [5153]. Patients with the greatest apparent predisposition for nodular/ bronchiectatic NTM lung disease include post-menopausal females who share a distinct morphotype and frequently also carry cystic fibrosis transmembrane conductance regulator (CFTR) mutations [54, 55]. The diagnosis of nodular/bronchiectatic NTM lung disease is guided most importantly by clinical suspicion and then by adherence to published diagnostic guidelines (table 2) [2]). In this setting, shared symptoms of bronchiectasis and nodular/bronchiectatic NTM lung disease, including cough, sputum production, fatigue and weight loss, can impede a timely diagnosis. Similarly, radiographic abnormalities of bronchiectasis may mask or confuse radiographic changes associated with NTM disease, although patterns such as tree-in-bud abnormalities, nodules and cavitation may raise suspicion of nodular/bronchiectatic NTM disease [56, 57]. Ultimately, microbiology is the

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Table 2. Summary of the American Thoracic Society (ATS) and Infectious Diseases Society of America (IDSA) diagnostic criteria for pulmonary non-tuberculous mycobacteria (NTM) infection
Clinical (all three need to be fulfilled) 1) Pulmonary symptoms; 2) Nodular or cavitary opacities on chest radiograph, or a HRCT scan that shows multifocal bronchiectasis with multiple small nodules; and 3) Appropriate exclusion of other diagnoses. Microbiological (only one is needed) 1) Positive culture results from at least two separate expectorated sputum samples#; 2) Positive culture results from at least one bronchial wash or lavage; or 3) Transbronchial or other lung biopsy with mycobacterial histopathological features", and positive culture for NTM or biopsy showing mycobacterial histopathological feature", and one or more sputum or bronchial washing that is culture positive for NTM. At least three consecutive respiratory samples are needed to apply these criteria. Expert consultation should be obtained when NTM are recovered that are either infrequently encountered or that usually represent environmental contamination. Patients who are suspected of having NTM pulmonary disease but who do not meet the diagnostic criteria should be followed until the diagnosis is firmly established or excluded. Making the diagnosis of NTM pulmonary disease does not, per se, necessitate the institution of therapy, which is a decision based on the potential risks and benefits of therapy for individual patients. HRCT: high-resolution computed tomography. #: if the results from the initial sputum samples are nondiagnostic, consider repeat sputum acidfast bacilli (AFB) smears; ": granulomatous inflammation or AFB. Reproduced and modified from [2] with permission from the publisher.

Hypersensitivity-like disease
Inhalation of mycobacterial antigen through aerosolised contaminated water in hot tubs (usually M. avium) as well as metalworking fluid (usually Mycobacterium immunogenum) can lead to a hypersensitivity-like disease [5862]. The ability of mycobacteria to grow across a wide range of temperatures and resistance to disinfectants enables replication [2, 63]. Patients are usually nonsmokers [64], and present with subacute onset of dyspnoea and cough. Fever and hypoxaemia can also occur [58, 61]. Key elements for the diagnosis are compatible clinical history and microbiology. Mycobacteria should be isolated from both patient specimens and hot tub samples (or other potential sources) to confirm the diagnosis [2, 59]. The lung histopathology demonstrates non-necrotising granulomas. Other findings may include necrotising granulomas, organising pneumonia or interstitial pneumonia [58]. Culture of tissue is generally positive for mycobacteria. Computed tomography scans demonstrate infiltrates, centrilobular nodules and ground-glass opacities [61, 65, 66]. The differential diagnosis of hypersensitivity-like mycobacterial disease is often hypersensitivity pneumonitis or sarcoidosis [64]. The cornerstone of treatment is removal of the patient from the antigen. In advanced cases, corticosteroids and/or antimycobacterial therapy may be given [2, 61]. If antimycobacterial therapy is started, it may be given for a shortened period of time (i.e. 36 months) [2]. Halogen disinfection over ultraviolet light and hydrogen peroxide for hot tubs has been preferred by some [63].

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most important element of diagnosis. Clinicians must have familiarity with the pathogenic potential, as opposed to the likelihood of recovery through environment contamination, of NTM species. Diagnostic criteria for respiratory NTM isolates aid in the determination of which NTM isolates are clinically significant. Nodular/bronchiectatic NTM prognosis appears to be one of relatively slow disease progression. While the negative impact of NTM infection on quality of life in this setting is readily apparent, a negative effect on life expectancy has not been established. As has often been said, the diagnosis of nodular/bronchiectatic NTM lung disease should trigger careful evaluation of the microbiological and radiographic data over time in conjunction with the patients symptoms to make a reasonable decision about therapy based on an individuals risk/benefit assessment.

Cystic fibrosis
The best described and specific bronchiectasis-associated disease that is a predisposition for NTM infection is cystic fibrosis. In a large multicentre study evaluating the prevalence of NTM respiratory isolates in cystic fibrosis patients in the USA, it was found that 13% of the cystic fibrosis patients had NTM respiratory isolates, including 72% MAC and 16% M. abscessus [67, 68]. The NTM species distribution is reversed in cystic fibrosis patients in Europe, where M. abscessus predominates [69]. Published guidelines suggest that NTM isolates may be clinically significant in this setting if other respiratory pathogens are excluded as a possible cause of the patients clinical deterioration and established diagnostic (microbiological) criteria for NTM disease are met [2]. The applicability of diagnostic guidelines created for non-cystic fibrosis patients is not entirely clear and, to date, no reliable algorithm has emerged that predicts which cystic fibrosis patients with NTM respiratory isolates will have progressive NTM disease and which patients, especially those with MAC respiratory isolates, require therapy directed against the NTM pathogen. The pathogen of most concern is M. abscessus due to case reports describing rapid clinical deterioration and even death in some cystic fibrosis patients infected by M. abscessus [70]. This concern is, unfortunately, confounded by the difficulty in effectively treating M. abscessus, eliminating empirical therapy as a diagnostic tool and resulting in a complicated risk/benefit decision even with established M. abscessus disease in the absence of a mechanism for accurately predicting which patients will have disease progression without therapy and those likely to respond favourably to therapy. The clinician is frequently left with the difficult choice between a period of careful clinical observation with the potential for rapid clinical deterioration versus initiation of potentially toxic therapy with uncertain clinical benefit. Another potential complication is the recommendation for macrolides as immune modulating agents in cystic fibrosis [71]. Macrolide monotherapy may not only predispose cystic fibrosis patients to mycobacterial infection but can result in the emergence of macrolide-resistant MAC isolates, which severely negatively impacts treatment success of MAC infection [72].

NTM PULMONARY DISEASES

Infections in the immunocompromised host

Manifestations of NTM pulmonary disease in immunosuppressed patients depend on the type and severity of immunosuppression. Patients with systemic immunosuppression (e.g. HIV infection, haematological malignancy, immunosuppressive drug use including TNF-a inhibitor therapy [12] or systemic corticoid therapy) are at risk of developing disseminated and localised NTM diseases, whereas patients with local immunosuppression (e.g. pre-existent pulmonary disease or inhalative corticoid therapy [13]) are at risk of developing pulmonary NTM disease. The most important examples are summarised as follows. HIV patients with severe CD4 cell depletion usually present with disseminated NTM disease, of which MAC is the most common. Blood cultures are usually positive. Isolation of the pathogen from respiratory secretions is common even without pulmonary involvement [2]. NTM pulmonary disease as a single NTM manifestation is rare in HIV patients and has been found to be present in 2.5% of 200 patients with disseminated MAC infection [7376]. 30% of HIV patients with NTM-associated immune reconstitution inflammatory syndrome (IRIS) present with thoracic disease [77]. Weeks to months after starting active antiretroviral therapy (ART), patients may develop cough (93%), fever (80%), night sweats (73%) or dyspnoea (47%) [77]. Chest computed tomography often demonstrates lymphadenopathy, tree-in-bud infiltrates, cavitary lesions, nodules or pericardial effusion [77]. Treatment includes continuation of ART and mycobacterial therapy. Recommendations regarding the length of NTM-specific treatment in HIV-associated IRIS are not evidence based. Depending on the CD4 count, some experts would discontinue NTM treatment 6 months after culture conversion [77, 78]. NTM pulmonary disease in haematopoietic stem cell and solid organ transplant (SOT) recipients is rare, with an incidence of 0.25% [7981]. Stem cell transplant recipients often present with

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catheter-related infections due to rapid growing mycobacteria, with NTM pulmonary disease being the second most common complication [79]. Graft versus host disease appears to be a risk factor for NTM, with the majority occurring within the first half-year post-transplantation. Whereas skin NTM disease has most often been reported in kidney or heart transplant patients, pleuropulmonary disease is most frequently found in lung transplant recipients (.50% of cases) and heart transplant recipients (.25% of cases) [79]. Median time to presentation with NTM infection was later in patients with SOTs (lung, 15 months; kidney, 24 months; heart, 30 months) [79]. Treatment should be instituted according to published guidelines [2, 80]. Interactions with immunosuppressive agents need to be considered [80].

Clinical relevance and diagnostic criteria

Since the NTM are environmental organisms and are present in tap water, humans are probably exposed to NTM on a daily basis. The human airways are thus occasionally contaminated with NTM and this aspect implies that a single positive culture from a sample of a nonsterile body, such as the human airways, is insufficient to diagnose NTM disease. The American Thoracic Society (ATS) and Infectious Diseases Society of America (IDSA) have issued statements including a set of criteria to differentiate chance NTM isolation from true pulmonary NTM disease, which are summarised in table 2 [2]. To diagnose pulmonary NTM disease, clinical, radiological and microbiological evidence of disease should be gathered. Symptoms are generally nonspecific, in part owing to frequent underlying conditions. Radiological abnormalities are more specific but the most compelling criterion to diagnose NTM lung disease is the microbiological criterion, which was based on the finding that pulmonary disease (infiltrates or cavitary lesions) progressed in 98% of the patients who had two or more positive sputum cultures for MAC, versus just 2% in those with a single positive culture during 12 months of observation. For 97% of patients, the first two positive cultures grew from the initial three sputum specimens [82]. These latter findings are less applicable to the nodular/bronchiectatic type of NTM lung disease, because these patients can have less or no sputum production. Bronchoalveolar lavage (BAL) is likely to be more sensitive than sputum culture to diagnose nodular/bronchiectatic NTM lung disease [83]. In a small study of 26 patients with suspected MAC nodular/ bronchiectatic lung disease, BAL yielded positive cultures in 13, versus only six by sputum cultures [84]. In nodular/bronchiectatic NTM lung disease in patients who do not produce sputum, a single positive culture from BAL, preferably with histological evidence of mycobacterial disease, may be used to diagnose NTM lung disease. This is incorporated in the most recent statement by the ATS and IDSA (table 2) [2]. It needs to be emphasised that a diagnosis of NTM lung disease from a single positive BAL culture is only appropriate in patients who cannot produce additional respiratory samples. Isolation of rare species or species generally considered nonpathogenic (e.g. Mycobacterium gordonae, Mycobacterium terrae and Mycobacterium phlei) in this setting may warrant a conservative approach and repeat bronchoscopy where possible. Of all NTM cultured from pulmonary samples, M. kansasii, M. szulgai, M. malmoense (in northwestern Europe), and the very rare Mycobacterium shimoidei and Mycobacterium heckeshornense have been most strongly associated with true NTM disease (fig. 1). Solitary isolates of these species from pulmonary samples in patients with no additional evidence of pulmonary NTM disease are very rare [1, 22, 23, 85]. However, isolation of M. gordonae, or to a lesser extent Mycobacterium chelonae and Mycobacterium simiae, is rarely associated with clinical disease [1, 34, 86]. For these species, solitary isolates from pulmonary samples without additional evidence of NTM disease are the rule rather than exception. MAC and M. xenopi seem to form an intermediate category, as 40 70% of all isolates are considered clinically relevant in different studies [1, 87, 88]. To prevent unwarranted diagnoses and treatment of NTM disease as well as unnecessary diagnostic delay, it could be helpful to use separate, more stringent criteria for species of low clinical relevance, and less stringent criteria for species of high clinical relevance.

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Treatment of NTM lung disease due to common pulmonary NTM species

In contrast with TB, diagnosis of NTM lung disease does not necessarily require specific treatment. The decision to treat needs to be individualised, depending on the specific NTM species, patient acceptance, tolerance and adherence, and treatment goals (reduction of symptoms or sputum conversion). Treatment modalities may include observation with best pulmonary care, intermittent antibiotic treatment, oral antibiotics three times a week or daily, additional intravenous therapy for several months, or surgical therapy [2].

Antibiotic therapy
There are several obstacles peculiar to NTM that impede effective antibiotic therapy. As discussed earlier, in vitro susceptibility testing is frequently not a guide for effective in vivo response to antibiotics. One overriding therapeutic imperative is to avoid the emergence of macrolideresistant MAC [89] or M. abscessus [27] strains during therapy. Still, for unknown reasons, the chance of treatment success for MAC lung disease is greatest with the first treatment effort even without the development of macrolide resistance [3234, 36]. Additionally, in patients who are adequately treated, subsequent isolation of MAC is more likely to represent re-infection with a new MAC genotype than disease relapse with isolation of the pre-treatment MAC genotype [90]. The clinical significance of re-infection MAC isolates must be individually determined. For M. abscessus, no reliably and predictably effective treatment exists. If antimicrobial therapy is administered, two parenteral agents and a macrolide, if appropriate (i.e. if the M. abscessus isolate does not have inducible erm gene activity), should be used [91].
NTM PULMONARY DISEASES

The goal of therapy is 12 months of sputum culture negativity while on therapy. The recommended treatment regimens for selected NTM respiratory pathogens are listed in table 3 [2]. These multidrug regimens lead to significant pharmacokinetic interactions. In particular, rifampicin lowers the serum levels of macrolides and moxifloxacin in patients with NTM pulmonary disease [92].
Table 3. Recommended treatment regimens for selected non-tuberculous mycobacteria (NTM) respiratory
pathogens NTM MAC Regimen Macrolide (azithromycin or clarithromycin), rifamycin and ethambutol daily or three times a week, with or without an injectable agent three times a week Rifampicin, ethambutol and isoniazid daily, or rifampicin, a macrolide and ethambutol daily or three times a week Macrolide (azithromycin or clarithromycin), rifamycin and ethambutol daily or three times a week, with or without an injectable agent three times a week Macrolide (azithromycin or clarithromycin), rifamycin and ethambutol daily or three times a week, with or without an injectable agent three times a week Macrolide (azithromycin or clarithromycin), rifamycin and ethambutol daily or three times a week, with or without an injectable agent three times a week No regimen of proven value Three or four of the following: amikacin, cefoxitin, imipenem, tigecycline, linezolid or a macrolide# A macrolide# plus two of the following: amikacin, cefoxitin, imipenem, or linezolid

Mycobacterium kansasii Mycobacterium szulgai Mycobacterium malmoense Mycobacterium xenopi Mycobacterium simiae Mycobacterium abscessus M. abscessus subsp. abscessus M. abscessus subsp. bolletii

MAC: Mycobacterium avium complex. #: may be inactive if erm gene is functional.

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The clinical implications of these low serum levels remain unknown but they may partly explain the poor outcomes of drug treatment. Treatment outcomes differ according to species; in most settings, the best outcomes are seen in M. kansasii and M. malmoense, slightly worse outcomes are seen in MAC, and very poor outcomes are recorded in patients with NTM pulmonary disease caused by M. xenopi, M. simiae and particularly M. abscessus subsp. abscessus [76, 87].

Surgery
The potential benefits of surgery should be considered for every individual patient in whom NTM pulmonary disease is diagnosed and re-evaluated during treatment. Cavitary disease, destroyed lung tissue and continued sputum positivity despite maximal drug therapy have been proposed as indications for adjunctive surgery in NTM pulmonary disease [93, 94]. Surgery should be given full consideration at the outset of treatment plans of patients with select localised rapidly growing mycobacteria (e.g. M. abscessus subsp. abscessus) in which medical therapy alone has been particularly daunting. Lobectomy or bilobectomy is a possibility if cavitary lesions in an upper lobe are accompanied only by minor nodular lesions in other areas of lung. In eligible patients who present with a destroyed lung, pneumonectomy is the procedure of choice. Adjunctive surgical treatment for NTM lung disease yields encouraging results in the few published case series. Conversion rates are generally very high (90100%) and few relapses are noted, marking the efficacy of combined medical and surgical treatment [93, 94]. These positive results underscore the importance of continuing medical therapy before and after surgical intervention for optimal success. The recent experiences with a video-assisted thoracoscopic approach have been very positive and may yield lower complication rates [95]. For all surgical procedures, careful patient selection based on the extent and type of disease, and on cardiopulmonary fitness, is of critical importance. Moreover, surgery for mycobacterial disease should be performed by experienced thoracic surgeons in centres that can offer long-term follow-up including continuation of drug treatment with an effective regimen.

Conclusion
NTM pulmonary disease has emerged as an increasingly important subject in medicine in countries with a low prevalence of TB. Because its importance has only been perceived in the past two decades and this disease has remained relatively rare, a large number of undiagnosed NTM pulmonary disease cases certainly exist among patients with chronic pulmonary disease, especially COPD. Every effort has to be made to further increase the awareness and knowledge of the diagnosis and therapy of NTM pulmonary disease among respiratory specialists who care primarily for patients with chronic pulmonary diseases. In addition, little clinical research has been performed and, as a result, treatment regimens have a very limited evidence base. The exact pathogenesis of NTM lung disease also remains largely unknown. These issues require urgent attention from pulmonologists, microbiologists, immunologists and basic scientists. With increased international cooperation, necessary and adequately powered clinical trials can be conducted. New drugs and combinations, as well as optimal dosing of drugs in current regimens to counter pharmacokinetic interactions, should be the subject of trials. Optimal regimens for nodular/bronchiectatic disease may differ from those in cavitary disease and separate trials are probably helpful to address this issue. Although the poor outcomes of current treatment regimens are frustrating, the future challenges of developing new regimens, and unravelling the exact pathogenesis and the intricacies of diagnosing and treating NTM pulmonary disease in individual patients, often with many comorbidities, render this a particularly exciting and evolving field of medicine.

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Statement of Interest
None declared.

References
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