Abstract
The effect of the clinical phenotype of Mycobacterium avium complex (MAC) lung disease on treatment outcome and redevelopment of nontuberculous mycobacterial (NTM) lung disease after treatment completion has not been studied systematically.
We evaluated 481 treatment-naïve patients with MAC lung disease who underwent antibiotic treatment for ≥12 months between January 2002 and December 2013.
Out of 481 patients, 278 (58%) had noncavitary nodular bronchiectatic (NB) disease, 80 (17%) had cavitary NB disease and 123 (25%) had fibrocavitary disease. Favourable outcome was higher in patients with noncavitary disease (88%) than in patients with cavitary disease (76% for fibrocavitary and 78% for cavitary NB disease; p<0.05). Cavitary disease was independently associated with unfavourable outcomes (p<0.05). Out of 402 patients with favourable outcomes, 118 (29%) experienced redevelopment of NTM lung disease, with the same MAC species recurring in 65 (55%) patients. The NB form was an independent risk factor for redevelopment of NTM lung disease (p<0.05). In patients with recurrent MAC lung disease due to the same species, bacterial genotyping revealed that 74% of cases were attributable to reinfection and 26% to relapse.
Treatment outcomes and redevelopment of NTM lung disease after treatment completion differed by clinical phenotype of MAC lung disease.
Abstract
Treatment outcomes differ according to clinical phenotype in patients with Mycobacterium avium complex lung disease http://ow.ly/g4WU30dbLHQ
Introduction
The incidence and prevalence of lung disease caused by nontuberculous mycobacteria (NTM) are increasing worldwide [1, 2]. Mycobacterium avium complex (MAC) predominantly consists of M. avium and M. intracellulare and is the most common aetiology of NTM lung disease worldwide [1, 2]. MAC lung disease usually has two major clinical phenotypes: fibrocavitary and nodular bronchiectatic (NB) [3, 4]. The fibrocavitary form is characterised by cavitary lesions that occur predominantly in the upper lobes and usually develops in older males with underlying lung disease, such as previous pulmonary tuberculosis and/or chronic obstructive pulmonary disease (COPD) [3]. The NB form occurs predominantly in postmenopausal, nonsmoking females [3] and can present as bilateral bronchiectasis with multiple nodules and tree-in-bud opacities on high-resolution computed tomography (HRCT). However, some patients with the NB form also have small cavitary lesions [5–7].
Macrolide-based combination antibiotic therapy is recommended for MAC lung disease, and current guidelines recommend different antibiotic regimens according to clinical phenotype: intermittent, three-times-weekly oral administration of three drugs for noncavitary NB (NC-NB) MAC lung disease; and daily oral drugs with or without parenteral drugs such as streptomycin or amikacin for cavitary MAC lung disease, including cavitary NB (C-NB) and fibrocavitary forms [3]. Treatment outcomes of the C-NB forms may be different from the NC-NB forms of MAC lung disease. However, many published studies that evaluated the clinical efficacy of macrolide-based antibiotic therapy did not differentiate between these clinical phenotypes [8–12], or included mainly NC-NB MAC lung disease and not cavitary disease [13–15].
In addition, recurrence of MAC lung disease or redevelopment of NTM lung disease is not uncommon after treatment completion [13, 16–18]. However, the impact of the clinical phenotype of MAC lung disease on treatment outcomes and on the recurrence of MAC lung disease or redevelopment of NTM lung disease has not yet been studied systematically. The purpose of the present study was to evaluate associations between clinical phenotypes and treatment outcomes, including recurrence of MAC lung disease or redevelopment of NTM lung disease after treatment completion, in patients with MAC lung disease.
Methods
Study population
Consecutive patients with MAC lung disease who received combination antibiotic treatment between January 2002 and December 2013 were identified using the database of the NTM registry of Samsung Medical Center (a 1979-bed referral hospital in Seoul, South Korea). Data from January 2002 to December 2007 were obtained from the retrospective cohort [19, 20], and data since January 2008 were obtained from an ongoing institutional review board-approved prospective observational cohort study to investigate NTM lung disease. Written informed consent was obtained from all participants (ClinicalTrials.gov identifier NCT00970801) [14].
The radiological phenotypes were classified according to the main features on chest radiography and HRCT. The fibrocavitary form was defined by the presence of cavitary opacities and pleural thickening, mainly in the upper lobes on chest radiograph and HRCT (online supplementary figure S1). The NB form was defined by the presence of multifocal bronchiectasis and clusters of small nodules on chest HRCT, regardless of the presence of small cavities in the lungs [6, 14]. The NB form was further classified into cavitary (C-NB) versus noncavitary (NC-NB) according to the presence of cavitary lesion(s) (online supplementary figures S2 and S3). When the disease did not belong to either the fibrocavitary form or the NB form, such as for cases with solitary pulmonary nodules, it was deemed unclassifiable.
During a 12-year period, 714 patients with MAC lung disease started antibiotic treatment. All patients met the diagnostic criteria for NTM lung disease [3]. After excluding patients who had a history of previous treatment of NTM lung disease (n=25), patients who had received prior antibiotic therapy for >1 month before transfer to our hospital (n=82), and patients with an unclassifiable form (n=41), 566 patients were started on MAC therapy during the study period. 85 (15%) patients were further excluded from the main analysis, because they received <12 months of antibiotic treatment due to discontinuation of antibiotics, loss to follow-up, transfer-out or death. The remaining 481 patients with newly diagnosed MAC lung disease, either the fibrocavitary or NB form, who received antibiotic therapy for ≥12 months were included in the final study (figure 1).
Study population. MAC: Mycobacterium avium complex; NTM: nontuberculous mycobacterial; NB: nodular bronchiectatic.
Microbiological examinations
During the study period, MAC species were identified using PCR-restriction fragment length polymorphism analysis of the rpoB gene or reverse-blot hybridisation of rpoB [14, 20]. Drug susceptibility testing was performed using the broth microdilution method [21]. Isolates with a minimum inhibitory concentration of ≥32 μg·mL−1 were considered resistant to clarithromycin [21]. For MAC isolates with clarithromycin resistance, mutations in the 23S rRNA gene were detected using PCR sequencing, as described previously [22].
In this study, “redevelopment” of NTM lung disease was defined as the subsequent diagnosis of NTM lung disease, regardless of causative NTM organism, after treatment completion of MAC lung disease. Cases where MAC lung disease had reappeared due to a different species were classed only as redevelopment. “Recurrence” of MAC lung disease was defined as two or more positive cultures of a MAC species after treatment completion for the same species, i.e. a redevelopment of M. avium (or M. intracellulare) lung disease after treatment completion of lung disease due to the same organism [13]. In cases of recurrent MAC lung disease, “relapse” with the same MAC genotype and “reinfection” with a new MAC genotype were distinguished. Mycobacterial genotyping was performed using repetitive sequence-based PCR (rep-PCR), which was standardised according to the DiversiLab Mycobacterium kit protocol [23]. Reports for rep-PCR were generated based on the Kullback–Leibler method, and isolates with identical profiles or >97% similarity were regarded as indistinguishable [24, 25].
Antibiotic therapy and treatment outcomes
All patients who began antibiotic therapy received standardised combination antibiotic therapy, which consisted of an oral macrolide (clarithromycin or azithromycin), rifampicin and ethambutol [3]. Streptomycin was administered intramuscularly three times a week in patients with severe disease for the first several months, at the discretion of the attending physician. In our institution, all patients with MAC lung disease were treated with daily regimens before January 2011. After January 2011, all patients with the NC-NB form were initially treated with intermittent, three-times-weekly therapy regimens [14].
Sputum examinations were performed at 1, 3 and 6 months after initiation of antibiotic treatment and then at 2–3-month intervals during treatment. Sputum culture conversion was defined as three consecutive negative cultures, and the time to culture conversion was defined as the date of the first negative culture [14]. Favourable outcome was defined as sputum culture conversion after initiation of treatment and maintenance of a negative culture for ≥12 months on treatment. Unfavourable outcome was defined as no sputum culture conversion or by death. Some clinical data were included in previous studies [14, 19, 20]. After treatment completion, the patients were typically followed-up with sputum examinations every 6 months. Data on final treatment outcomes, follow-up information including redevelopment of NTM lung disease, and analyses of stored MAC isolates were collected in the current study.
Statistical analyses
All data are presented as n (%) for categorical variables and median (interquartile range (IQR)) for continuous variables. Data categorised according to the three clinical phenotypes were compared using the Kruskal–Wallis test for continuous variables and Fisher's exact test for categorical variables. If there was a significant difference among the three groups, then post hoc analysis for multiple comparisons was performed with Tukey's test using ranks for continuous variables and Fisher's exact test using the permutation method for categorical variables.
To investigate potential independent factors associated with either unfavourable outcomes or redevelopment of NTM lung disease, multiple logistic regression analysis and multiple Cox regression with backward selection, respectively, were used. Variables including sex, age, body mass index (BMI), aetiological species, clinical phenotypes, sputum smear positivity, combined chronic pulmonary aspergillosis (CPA), COPD, previous lung resection history, combined use of injectable drugs and surgical resection were added to the regression models. p-values and confidence intervals were corrected using Bonferroni's method for multiple testing in multiple regression analysis. When estimating redevelopment of NTM lung disease, death was considered as a competing risk.
The Kaplan–Meier method was used to estimate the cumulative rates of redevelopment of NTM lung disease and the log-rank test was used to compare curves of the rates. A two-sided p<0.05 was considered significant. All data sets were analysed using SAS version 9.4 (SAS Institute, Cary, NC, USA) and R3.2.3 (R Development Core Team, Vienna, Austria; www.R-project.org).
Results
Baseline characteristics
Out of the 481 patients, 278 (58%) had the NC-NB form, 80 (17%) had the C-NB form, and 123 (25%) had the fibrocavitary form of MAC lung disease (table 1). None of the patients tested positive for HIV. M. avium was the more common aetiologic organism in patients with the NC-NB form, whereas M. intracellulare was more common in patients with the fibrocavitary form (p<0.001). No isolates were resistant to clarithromycin in drug susceptibility testing at the time of diagnosis of MAC lung disease.
Baseline characteristics of the study population
Treatment modalities and outcomes
All patients with C-NB and fibrocavitary forms were prescribed three oral drugs daily. About half (51%) of the patients with the NC-NB form received intermittent drug regimens. Streptomycin injection was used more frequently in patients with cavitary (68% (138 out of 203)) than noncavitary disease (26% (72 out of 278), p<0.001). Total antibiotic treatment duration was longer in patients with cavitary (24.0 (18.9–26.5) months) than noncavitary disease (19.7 (15.9–24.1) months; p<0.001) (table 2).
Treatment modalities and outcomes of the study population
A favourable outcome was achieved in 84% (402 out of 481) of patients, and was higher for NC-NB disease (88% (246 out of 278)) than for cavitary disease (76% (94 out of 123) with the fibrocavitary form and 78% (62 out of 80) with the C-NB form; p=0.006 and p=0.037, respectively) (table 2). Unfavourable outcomes occurred in 16% (79 out of 481) patients, and 24 (30%) had died by the end of January 2016.
Risk factors for unfavourable outcomes
Of the 481 patients, the final multiple logistic regression model revealed that male sex (adjusted (a)OR 1.80, 95% CI 1.07–3.02; p=0.027) and cavitary disease, including both the C-NB (aOR 2.36, 95% CI 1.24–4.52; p=0.009) and fibrocavitary form (aOR 1.99, 95% CI 1.11–3.54; p=0.020) were independently associated with unfavourable outcomes (table 3). For 203 patients with cavitary disease, surgical resection was the only independent factor negatively associated with favourable outcome (aOR 0.13, 95% CI 0.02–0.98; p=0.048).
Risk factors for unfavourable outcomes in the study population
Redevelopment of NTM lung disease after treatment completion
Of the 402 patients who completed treatment, 118 (29%) redeveloped NTM lung disease during the median (IQR) follow-up period of 13.6 (4.8–28.3) months, which was the time between treatment completion and the last hospital visit or death. The median (IQR) number of sputum examinations after treatment completion did not differ between patients with the fibrocavitary (2 (1–4)) and NB (2 (1–4)) forms (p=0.429). In these 118 patients, MAC lung disease from the same species recurred in 65 (55%) cases (31 cases of M. avium and 34 cases of M. intracellulare) and NTM lung disease from a different NTM species redeveloped in 53 (45%) cases (table 4). Recurrence rates of MAC lung disease (i.e. only cases involving the same species) did not differ between patients with M. avium (31 (14%) out of 219 patients with favourable outcomes) and M. intracellulare (34 (19%) out of 183 patients; p=0.163).
Redevelopment of nontuberculous mycobacterial (NTM) lung disease in 118 patients after successful treatment of Mycobacterium avium complex (MAC) lung disease
Risk factors for redevelopment of NTM lung disease
NTM lung disease redeveloped in 33% (103 out of 308) of patients with the NB form and 16% (15 out of 94) of patients with the fibrocavitary form (p=0.001). However, rates did not differ between patients with the C-NB (31%, 19 out of 62) and NC-NB forms (34%, 84 out of 246; p=0.602). The cumulative rate of redevelopment of NTM lung disease was higher in patients with the NB form, regardless of the presence of cavities, than in those with the fibrocavitary form (p=0.015; figure 2). These differences remained significant after adjustment using multiple Cox regression (p=0.011; table 5).
Cumulative rate of redevelopment of nontuberculous mycobacterial (NTM) lung disease after treatment completion of Mycobacterium avium complex lung disease.
Risk factors for redevelopment of nontuberculous mycobacterial (NTM) lung disease after successful treatment of Mycobacterium avium complex (MAC) lung disease
Genotyping of paired isolates in recurrent MAC lung disease
In the 65 patients (31 M. avium and 34 M. intracellulare) with a recurrence of MAC lung disease, paired clinical isolates were available for genotyping in 27 (42%) patients, including 12 (39%) out of 31 patients with M. avium and 15 (44%) out of 34 patients with M. intracellulare. According to the rep-PCR profiles, 74% (20 out of 27) of the isolates had genotypes different from those of the original isolates, suggesting reinfection, whereas 26% (seven out of 27) had genotypes identical to the initial genotype, suggesting relapse (table 6 and online supplementary figure S4). The proportion of reinfections was higher in patients with the NB form (82%, 18 out of 22) than in those with the fibrocavitary form (40%, two out of five) among patients with a recurrence and available paired isolates, although the difference was not statistically significant (p=0.091). The median (IQR) time interval between treatment completion and recurrence was shorter in patients with relapse (6.0 (4.8–8.5) months) than with reinfection (13.0 (6.0–23.7) months; p=0.040).
Genotyping results of paired clinical isolates from patients with recurrent Mycobacterium avium complex (MAC) lung disease#
Drug susceptibility testing revealed that all reinfection isolates (20 patients) were susceptible to clarithromycin. However, clarithromycin resistance developed in two (29%) out of seven patients with relapsed MAC lung disease. One of the relapse isolates had a point mutation at position 2058 and the other at position 2059 of the 23S rRNA gene.
Discussion
This study evaluated treatment outcomes and redevelopment of NTM lung disease, based on the clinical phenotype of MAC lung disease. Our study included nearly 500 patients with MAC lung disease who had not received prior treatment, and we found that treatment outcomes and redevelopment of NTM lung disease differed according to the clinical phenotype. Favourable outcomes were higher in patients with NC-NB MAC lung disease, compared with patients with the C-NB and fibrocavitary forms. Redevelopment of NTM lung disease was not uncommon in patients with NB MAC lung disease, including those with the C-NB form.
Current guidelines recommend intermittent antibiotic therapy for initial treatment of NC-NB MAC lung disease [3], and recent studies have reported high sputum culture conversion rates (74–86%) in these patients [13–15]. The sputum culture conversion rate in the present study was high (88%) in patients with NC-NB disease, although about half of our patients received daily therapy, because intermittent therapy was not introduced until 2011 in our institution. We previously showed that treatment outcomes did not differ between daily therapy and intermittent therapy in these patients [14]. Therefore, intermittent therapy is a reasonable option for patients with NC-NB MAC lung disease [3].
Daily antibiotic therapy is recommended for patients with cavitary MAC lung disease [3], and parenteral drugs should be considered for the first several months for extensive disease, especially the fibrocavitary form [3]. However, information regarding treatment outcomes in patients with fibrocavitary MAC lung disease is limited [8–12]. Our study included >120 patients with the fibrocavitary form. Although favourable outcomes (76%) for the fibrocavitary form were lower than for the NC-NB form (88%), our current study showed that active application of injection drugs and combined surgical resection could result in reasonable treatment outcomes in this type of advanced MAC lung disease.
The proportion of patients with and clinical significance of the combination of cavitary lesions with NB MAC lung disease have not been well studied, although the proportion of patients with this combination is reported to range from 12% to 25% [5–7, 14]. In the original report of NB MAC lung disease, 24% (five out of 21) of patients had cavitary lesions at presentation, and an additional 15% (three out of 21) of patients developed cavities during the course of the disease [26]. In the present study, cavitary lesions were detected in 80 (22%) out of 358 patients with NB MAC lung disease. We found that favourable outcomes for C-NB disease were lower (78%) than for NC-NB disease (88%), but similar to that of fibrocavitary disease (76%). These results suggest that careful evaluation of the presence of cavitary lesions using HRCT scans and differentiation between C-NB and NC-NB forms are important before initiating antibiotic treatment in patients with NB MAC lung disease. In addition, further clinical research is needed to evaluate the clinical efficacy of optimal doses of macrolides [27–29], clofazimine [12, 30] and inhaled amikacin [31, 32] for cavitary MAC lung disease to improve treatment outcome.
Previous studies found that 22–50% of patients with MAC lung disease experience recurrence of MAC lung disease after successful treatment [13, 16–18]. Additionally, NTM lung disease caused by different species such as M. abscessus can develop during or after treatment of NB MAC lung disease [17, 33]. The present study revealed that lung disease due either to the same species of MAC or to a different NTM species could develop after treatment completion of MAC lung disease, and that this occurred more frequently with the C-NB and NC-NB forms than with the fibrocavitary form, consistent with previous reports [16]. Additionally, the majority of recurrences (i.e. from the same MAC species) were due to reinfection rather than true relapse. Patients with NB MAC lung disease were typically postmenopausal women who had a unique body morphotype, slender marfanoid body habitus (scoliosis, pectus excavatum and mitral valve prolapse), altered immunophenotype and mucociliary dysfunction [34–36], making them susceptible to environmental NTM exposure. Therefore, patients with the NB form should be followed-up, potentially for the duration of their lifetime, to detect and evaluate the recurrence of MAC or other NTM lung disease. In contrast, genotyping results indicated that relapse developed more frequently in patients with the fibrocavitary form, suggesting that more effective drugs and longer treatment duration may be warranted with this form. Further studies regarding different treatment strategies against relapse and reinfection in MAC lung disease and methods to reduce environmental exposure in these patients are needed.
The present study has several limitations. First, this study was conducted at a single referral centre with specialised NTM clinics. Therefore, our results might not be generalisable to other centres and geographical areas. Second, patients receiving <12 months of antibiotic treatment (85 (15%) out of 566) were excluded from the main analysis, and therefore favourable outcomes may have been overestimated; such patients were older, more likely to be male and more likely to have fibrocavitary disease (data not shown), and it is possible that older male patients with fibrocavitary disease might be less tolerant of daily antibiotic therapy with injectable drugs than patients with NC-NB disease who received intermittent antibiotic therapy. However, our results demonstrated that treatment outcomes are reasonably acceptable if patients receive treatment for ≥12 months, which adheres to current guidelines. Third, administration of streptomycin was left to the discretion of the treating physician and not dependent on objective criteria. Fourth, there was no specific measure to monitor patients' compliance with treatment regimens. Fifth, paired clinical isolates were only available in 41% of patients with recurrent MAC lung disease. Sixth, because the follow-up period after successful treatment completion was relatively short, recurrence rates may have been underestimated. Seventh, there is potential overlap between the fibrocavitary and C-NB forms, because patients with the fibrocavitary form can have some nodular and bronchiectatic lesions in lower lung fields. Finally, we only differentiated between M. avium and M. intracellulare in our study, and several new species closely related to M. intracellulare, such as M. chimaera, were recently identified. Some studies suggest that recurrence rates differ between M. intracellulare and M. chimaera [37]. However, M. chimaera appears to be relatively rare in South Korea [38–40].
In conclusion, treatment outcome, including redevelopment of NTM lung disease and recurrence of MAC lung disease differed by clinical phenotype in patients with MAC lung disease. Favourable outcomes were lower in patients with cavitary MAC lung disease (both the fibrocavitary and C-NB forms). Redevelopment of NTM lung disease and recurrence of MAC lung disease were not uncommon in patients with NB MAC lung disease, even in those with the C-NB form. Therefore, different treatment regimens and possible interventions to prevent redevelopment or recurrence according to the clinical phenotype of MAC lung disease should be considered.
Supplementary material
Supplementary Material
Please note: supplementary material is not edited by the Editorial Office, and is uploaded as it has been supplied by the author.
Supplementary material ERJ-02503-2016_Supplement
Disclosures
Supplementary Material
C.L. Daley ERJ-02503-2016_Daley
Acknowledgements
Author contributions are as follows. Study conception and design: W-J. Koh and S.M. Moon; data acquisition and analysis: W-J. Koh, S.M. Moon, M-A. Woo and S. Kim; experimental work: S-Y. Kim, H.J. Huh, Chang-Seok Ki, Nam Yong Lee and Sung Jae Shin; data interpretation and manuscript writing: Won-Jung Koh, Seong Mi Moon, Min-Ah Woo and S. Kim; critical revision and final approval of the manuscript: W-J. Koh, S.M. Moon, S-Y. Kim, M-A. Woo, S. Kim, B.W. Jhun, H.Y. Park, K. Jeon, H.J. Huh, C-S. Ki, N.Y. Lee, M.J. Chung, K.S. Lee, S.J. Shin, C.L. Daley, H. Kim and O.J. Kwon.
Footnotes
This article has supplementary material available from erj.ersjournals.com
Support statement: This research was supported by the Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Science, ICT and future Planning (NRF-2015R1A2A1A01003959) and by a grant of the Korea Health Technology R&D Project through the Korea Health Industry Development Institute (KHIDI), funded by the Ministry of Health & Welfare, Republic of Korea (HI15C2778). The sponsor had no role in the design of the study, the collection and analysis of the data, or the preparation of the manuscript. Funding information for this article has been deposited with the Crossref Funder Registry.
Conflict of interest: Disclosures can be found alongside this article at erj.ersjournals.com
- Received December 20, 2016.
- Accepted June 24, 2017.
- Copyright ©ERS 2017
References
