Improvement in Health-Related Quality of Life Following Antibiotic Treatment in Nontuberculous Mycobacterial Pulmonary Disease: Initial Analysis of the NTM-KOREA Cohort

Abstract

Background

Improving health-related quality of life (HRQOL) has emerged as a priority in the management of nontuberculous mycobacterial pulmonary disease (NTM-PD). We aimed to evaluate HRQOL and its changes after 6 months’ treatment in patients with NTM-PD.

Methods

The NTM-KOREA is a nationwide prospective cohort enrolling patients initiating treatment for NTM-PD in 8 institutions across South Korea. We conducted the Quality of Life–Bronchiectasis (QOL-B) at 6-month intervals and evaluated baseline scores (higher scores indicate better quality of life) and changes after 6 months’ treatment. Multivariate logistic regression was performed to identify factors associated with improvement in the QOL-B physical functioning and respiratory symptoms domains.

Results

Between February 2022 and August 2023, 411 patients were included in the analysis. Baseline scores (95% confidence interval [CI]) for physical functioning and respiratory symptoms were 66.7 (46.7–86.7) and 81.5 (70.4–92.6), respectively. Among 228 patients who completed the QOL-B after 6 months’ treatment, improvements in physical functioning and respiratory symptoms were observed in 61 (26.8%) and 71 (31.1%) patients, respectively. A lower score (adjusted odds ratio; 95% CI) for physical functioning (0.93; 0.91–0.96) and respiratory symptoms (0.92; 0.89–0.95) at treatment initiation was associated with a greater likelihood of physical functioning and respiratory symptom improvement, respectively; achieving culture conversion was not associated with improvement in physical functioning (0.62; 0.28–1.39) or respiratory symptoms (1.30; 0.62–2.74).

Conclusions

After 6 months of antibiotic treatment for NTM-PD, HRQOL improved in almost one-third, especially in patients with severe initial symptoms, regardless of culture conversion.

Clinical Trials Registration

ClinicalTrials.gov identifier: NCT03934034.

Nontuberculous mycobacteria (NTM), which encompass approximately 200 species other than Mycobacterium tuberculosis and Mycobacterium leprae, are environmental organisms found in soil, dust, and water [1]. In humans, NTM can cause chronic infection, with pulmonary disease being the most common manifestation [1]. Over the past few decades, the global burden of NTM pulmonary disease (NTM-PD) has been steadily increasing [2, 3]. In South Korea, the annual prevalence of NTM infection rose from 11.4 to 56.7 cases per 100 000 population between 2010 and 2021 [4].

The treatment of NTM-PD requires the use of 3 or more antibiotics for at least 12 months after culture conversion [1]. However, long-term antibiotics use often results in frequent adverse events [5], and the treatment outcomes for NTM-PD remain unsatisfactory. Specifically, the microbiological cure rate for Mycobacterium avium complex pulmonary disease and Mycobacterium abscessus pulmonary disease is approximately 60% and 45%, respectively [6, 7]. Moreover, microbiological conversion does not necessarily guarantee clinical improvement [8].

Given these considerations, improving patient-reported outcomes (PROs) as well as microbiological responses has been suggested as a treatment goal of NTM-PD [9]. Patient-reported outcomes, which measure patients’ symptoms and health-related quality of life (HRQQL), could complement the clinical management and serve as clinical trial endpoints by assessing the impact of treatment [8]. The Quality of Life–Bronchiectasis (QOL-B) questionnaire, initially developed to evaluate HRQOL in patients with bronchiectasis, is a self-administered questionnaire comprising 37 items across 8 domains [10, 11]. The applicability of QOL-B has been gradually extended to NTM-PD [12].

In South Korea, a nationwide prospective observational cohort of patients with NTM-PD (NTM-KOREA) was initiated with the enrollment of the first patient on 28 February 2022 [13]. The primary object of NTM-KOREA is to develop the most optimized patient-centered treatment strategies for NTM-PD. Over a span of 5 years, the project aims to recruit 1000 patients from 8 referral hospitals and 1 central laboratory across the country. In this study, we aimed to evaluate PROs and their changes after 6 months of antibiotic treatment using the QOL-B instrument among patients with NTM-PD who participated in the NTM-KOREA cohort.

METHODS

Participants

The NTM-KOREA is a nationwide prospective cohort study that enrolls patients initiating treatment for NTM-PD in 8 institutions across South Korea (ClinicalTrials.gov identifier: NCT03934034). The eligibility criteria for participation in the study are as follows—(1) age over 19 years; (2) meeting the criteria for NTM-PD as suggested by the American Thoracic Society/European Respiratory Society/European Society of Clinical Microbiology and Infectious Diseases Society of America clinical practice guideline [1]; (3) having 1 of the following etiologic organisms: M. avium complex, M. abscessus subspecies abscessus (referred to as M. abscessus), M. abscessus subspecies massiliense (referred to as M. massiliense), or M. kansasii; (4) starting antibiotic treatment for NTM-PD at enrollment (with a 4-week interval allowed between treatment initiation and enrollment); and (5) providing written informed consent to participate in the NTM-KOREA [13]. The study protocol has been approved by the local institutional review boards at the participating institutions. The study aims to enroll a total of 1000 patients by 31 May 2026 and follow them until 31 December 2029.

Treatment and Follow-up

All patients in the study are treated according to clinical practice guidelines [1, 14] and are followed up at an interval of 4–8 weeks. The specific drugs administered and visit schedules can be modified at the discretion of the attending physician. Data from patients are collected on enrollment and during every subsequent follow-up visit after treatment initiation. The brief protocol is provided in the Supplementary File.

Data Collection

In the present study, the demographic and clinical data at the time of enrollment, including age, sex, body mass index, smoking history, spirometry data, and comorbidities, recorded in the NTM-KOREA database (iCreaT version 2.0; icreat.nih.go.kr), were used. Microbiological data were also recorded, including species of the etiologic organism, smear results, and drug susceptibility pattern based on the minimal inhibitory concentration determined by a broth microdilution system [15]. Culture conversion, defined as 3 consecutive negative mycobacterial cultures, collected at least 4 weeks apart [16], was assessed after final confirmation of the submitted mycobacterial culture results at month 6. Radiographic findings from chest computed tomography scans were interpreted by local thoracic radiologists; the radiographic phenotypes were classified into nodular bronchiectatic (NB) type, fibrocavitary (FC) type, or other type [17, 18]. The other type generally refers to NTM-PD that does not belong to the NB or FC type, such as a focal cavity, nodule, mass, or consolidation [19]. Forced expiratory volume in 1 second (FEV₁), forced vital capacity (FVC), FEV₁/FVC ratio, and the diffusing capacity of carbon monoxide (DL_CO) measured at the time of enrollment were also collected.

QOL-B Measurement

The QOL-B was conducted using a paper-based questionnaire administered under the supervision of trained nurses [10, 11]. The Korean translated version of the QOL-B questionnaire was used with permission from Dr. Alexandra L. Quittner. The questionnaire comprised a total of 37 items, covering domains such as physical functioning (5 items), role functioning (5 items), vitality (3 items), emotional functioning (4 items), social functioning (4 items), health perception (4 items), respiratory symptoms (9 items), and treatment burden (3 items). Each domain score ranged from 0 to 100, with higher scores indicating better quality of life. Assessment was performed at 6-month intervals after treatment initiation. Improvement after 6 months’ antibiotic treatment was determined using the minimal clinically important difference (MCID) for each domain: physical function (MCID = 8), role functioning (MCID = 8), vitality (MCID = 10), emotional functioning (MCID = 7), social functioning (MCID = 9), health perception (MCID = 8), respiratory symptoms (MCID = 8), and treatment burden (MCID = 9) [20].

Statistical Analysis

The data are presented as median values with interquartile ranges (IQRs) for continuous variables and as proportions for categorical variables. The Kruskal–Wallis test and Wilcoxon signed-rank test were used to compare continuous variables, and the Fisher exact test was used for the comparison of categorical variables. The floor and ceiling effects were defined as proportion with minimum and maximum scores higher than 10% to indicate an inability to discriminate between respondents at either end of the scales [12]. The inter-item correlations were calculated using Cronbach's α [21]. Linear and logistic regression analyses were performed to identify factors associated with the initial scale and improvement in physical functioning and respiratory symptoms, both of which exhibited good psychometric properties in M. avium complex pulmonary disease [12]. Variables were chosen using the least absolute shrinkage and selection operator selection methods. A P value less than .05 was considered statistically significant. All statistical analyses were conducted using Stata 17.0 (StataCorp, College Station, TX, USA).

RESULTS

Baseline Characteristics of Patients

Between 28 February 2022 and 23 August 2023, a total of 419 patients consented to participate in the NTM-KOREA, and 411 patients were included in the analysis after excluding 8 patients with missing baseline information. Among these patients, the median age was 64 years (IQR, 58–71 years), and females (n = 299) accounted for 72.8% of the cohort. The most common pathogen causing NTM-PD was Mycobacterium intracellulare, present in 192 patients (46.7%), followed by M. avium in 136 patients (33.1%) and M. abscessus in 45 patients (11.0%). The most common radiographic finding was NB type, observed in 304 patients (74.0%), followed by FC type in 66 patients (16.1%) and other types in 41 patients (9.9%) (Table 1).

Psychometric Properties of QOL-B

No floor effect was observed in any of the domains assessed. However, a ceiling effect was observed in the role-functioning domain (15.3%), emotional-functioning domain (25.1%), social-functioning domain (16.3%), and treatment burden domain (18.8%). The reliability of the questionnaire, assessed using Cronbach's α coefficient, showed acceptable reliability for all domains except for the vitality domain, which had a Cronbach's α value of .660. The details of these findings can be found in Supplementary Table 1.

QOL-B Scales and Their Predictors at the Time of Treatment Initiation

The scores of all domains are presented in Table 2. Whereas emotional functioning and respiratory symptoms both showed scores of 80 or higher, health perception scores were only 33.3. The scores of physical functioning, role functioning, vitality, health perception, and respiratory symptoms varied according to radiographic type. In the FC type, the scales of physical functioning and respiratory symptoms were 55.3 (IQR, 33.3–80.0) and 77.8 (IQR, 66.7–88.9), respectively; in the NB type, these were 73.3 (IQR, 53.3–86.7) and 82.4 (IQR, 70.4–92.6). The scores for physical functioning and respiratory symptoms were 73.3 (IQR, 46.7–86.7) and 77.8 (IQR, 66.7–85.2) in the other type.

A previous history of tuberculosis or NTM-PD was associated with worse physical functioning (coefficient, −5.76; 95% confidence interval [CI], −11.4 to −.14) or worse respiratory symptoms (coefficient, −5.95; 95% CI, −9.49 to −2.41) at baseline, respectively. Lung function was also associated with physical functioning and respiratory symptoms at the time of treatment initiation. DL_CO had a coefficient of .23 (95% CI, .08–.38) for physical functioning and .16 (95% CI, .06–.26) for respiratory symptoms in multivariate analysis, respectively. FVC (in liters) was also associated with physical functioning (coefficient, 9.26; 95% CI, 2.64–15.9) (Table 3). Detailed information on the results of univariate and multivariate analyses are provided in Supplementary Tables 2 and 3.

Microbiological Responses After 6 Months of Antibiotic Treatment

Of the 411 patients, 247 completed the QOL-B questionnaire at baseline and 6 months after enrolling in the study. After excluding 19 patients who discontinued antibiotic treatment within 6 months due to adverse events or refusal, we analyzed changes in the QOL-B scales in 228 patients. After 6 months of treatment, 145 patients (63.6%) achieved culture conversion and 74 patients (32.5%) did not, and the remaining 9 patients (3.9%) had changes in the mycobacterial species. Of the 74 patients who remained culture positive, 36 were initially sputum smear positive, and 19 of these became sputum smear negative within 6 months.

Changes in QOL-B after 6 Months of Antibiotic Treatment

After 6 months of treatment, the score of respiratory symptoms changed by a median of 3.7 (IQR, −3.70 to 11.1; P < .001). However, the other scales did not show significant changes over time (Table 4). The proportion of patients who experienced an increase in scale scores equal to or higher than the MCID varied from 19.7% (role functioning) to 52.3% (treatment burden). Improvement in physical functioning was observed in 61 (26.8%) of 228 patients, and improvement in respiratory symptoms was observed in 71 (31.1%) patients from the same group (Table 5).

Changes in QOL-B after 6 months of treatment did not differ according to culture conversion. Although the respiratory symptom scores increased in both those who achieved culture conversion (median, 3.7; IQR, −3.70 to 11.1; P = .002) and those who did not (median, 3.7; IQR, −3.70 to 11.1; P = .019), no significant difference between those groups was observed (P = .868) (Table 4). The proportion of patients with improvement greater than the MCID was also not different according to culture conversion (Table 5). The changes in QOL-B scales according to radiographic findings are detailed in Supplementary Tables 4 and 5.

Predictors of Physical Functioning and Respiratory Symptom Improvement

Improvement in physical function was associated with worse initial physical functioning. A lower score for physical functioning at the start of treatment was associated with a greater likelihood of improvement higher than the MCID (adjusted odds ratio, .93; 95% CI, .91–.96). Similarly, a lower score for respiratory symptoms at baseline was associated with a greater probability of improvement in respiratory symptoms (adjusted odds ratio, .92; 95% CI, .89–.95) (Table 6). Further details of the univariate and multivariate analysis for physical functioning and respiratory symptoms can be found in Supplementary Tables 6 and 7, respectively. These results remained consistent when analyzing only individuals with initial respiratory symptoms and physical functioning scores below 90 points (Supplementary Tables 8 and 9).

DISCUSSION

Treatment outcomes of NTM-PD are unsatisfactory in terms of low microbiological cure and high reinfection rates [6, 22, 23]. Therefore, improving patients’ HRQOL has been regarded as an alternative treatment goal [9, 24]. In the nationwide prospective cohort study of patients with NTM-PD (NTM-KOREA), we evaluated the baseline HRQOL and its early changes with antibiotic treatment using the QOL-B instrument. Among 411 patients, baseline physical functioning and respiratory symptoms were worse in those with FC type NTM-PD. After 6 months of antibiotic treatment, improvements in physical functioning and respiratory symptoms were observed in 26.8% and 31.1% of patients, respectively. These improvements were not associated with culture conversions with treatment. Rather, the greater the severity of initial respiratory symptoms and physical functioning, the greater the likelihood of improvement in those domains with antibiotic treatment.

The QOL-B was measured for the first time in Korean patients with NTM-PD. However, in our study, some domains (role functioning, emotional functioning, social functioning, and treatment burden) showed ceiling effects. These findings indicate that a proportion of patients obtained the highest possible score in these domains, suggesting the questionnaire's limited ability to capture further improvements in these areas. However, it remains valid for the domains of physical functioning, vitality, health perception, and respiratory symptoms because the QOL-B uses a multidimensional approach to independently assess each domain rather than considering as a whole. Moreover, the scale demonstrated good reliability overall, based on Cronbach's α. Similar to a study conducted in the United States [12], the physical functioning and respiratory symptom domains, which were the main focus of this study, exhibited favorable psychometric properties in the context of NTM-PD.

Fibrocavitary type NTM-PD is associated with unfavorable treatment outcomes and higher mortality compared with NB type [22, 25]. Importantly, our study demonstrated that patients with FC type had worse HRQOL in terms of physical functioning, role functioning, vitality, health perception, and respiratory symptoms. This can be explained by the male predominance, older age, lower body mass index, and higher proportion of previous tuberculosis in FC type NTM-PD [26, 27]. The higher bacterial burden, as indicated by smear positivity, could also contribute to the worse respiratory symptoms observed in FC type.

In our cohort, a significant improvement in QOL-B scores was observed in 19.7% to 52.3% of patients following antibiotic treatment. In a previous study, we investigated longitudinal changes in HRQOL using the St. George's Respiratory Questionnaire and found that antibiotic treatment led to an improvement in HRQOL [28]. In our cohort, the overall score of respiratory symptoms increased by 3.7 points within 6 months, consistent with a previous study showing a similar improvement in respiratory symptoms after 12 months of antibiotic treatment in NTM-PD [29]. Notably, the score in respiratory symptoms increased by 6.7 points among patients with FC type NTM-PD. These findings suggest that patients with FC type, who initially had worse respiratory symptoms, had a greater chance of improvement in respiratory symptoms.

In deciding whether to initiate antibiotic treatment for patients with NTM-PD, potential tradeoffs between symptom relief and potential adverse effects of medication should be considered [24]. In our study, we found that the more severe the initial respiratory symptoms, the greater the improvement observed with treatment. Similarly, improvement in physical functioning was associated with lower values at the time of treatment initiation. These findings suggest that patients with more severe respiratory symptoms and limited physical functioning may benefit more from antibiotic treatment. These results provide evidence to support a more proactive approach in considering antibiotic treatment for patients with more severe respiratory symptoms and impaired physical functioning.

Another notable finding in our study is the comparable improvement in QOL-B observed in patients who achieved culture conversion and those who did not. This finding aligns with our prior research, wherein patients who failed to achieve culture conversion exhibited improved HRQOL as measured using the St. George's Respiratory Questionnaire, over the 2 years following the initiation of treatment [28]. One possible explanation for these observations is that antibiotic treatment reduces the bacterial burden. In our study, approximately half of the patients who did not achieve culture conversion became sputum smear negative. Considering that antibiotic treatment can improve survival even in cases where culture conversions are not achieved [30], our study underscores the necessity of continuing antibiotic treatment irrespective of microbiological cure.

The main strength of our study is its prospective design, which allowed us to collect data in real time and capture the actual experiences of patients with NTM-PD in clinical practice. This enhances the generalizability of our findings to real-world settings. Additionally, the study included patients treated at referral hospitals that were representative of each region of South Korea. While acknowledging the potential for bias in patient referrals, our study ensured the representativeness of the study population, thereby strengthening the external validity of our results. Although validation in other populations is needed, these strengths contribute to the robustness and reliability of our study findings.

Our study also has certain limitations that should be acknowledged. First, the lack of a control group that did not receive antibiotic treatment may have limited the ability to assess the exact effect of antibiotic treatment on HRQOL. Second, although we used sputum smear results, we could not assess bacterial burden in terms of time to culture positivity. Third, the correlation between QOL-B scales and microbiological cure was not assessed owing to the relatively short follow-up period. However, future studies with longer follow-up durations will allow us to examine the impact of microbiological cure on changes in QOL-B scores. In future analyses, we also plan to explore the association between QOL-B scales and other important clinical parameters, such as lung function and 6-minute-walk test results. In particular, further investigation is needed to evaluate the balances between HRQOL benefits and adverse events associated with antibiotic treatment. By incorporating these additional measures, we aim to provide a more comprehensive understanding of the relationship between HRQOL and various clinical outcomes in patients with NTM-PD.

In conclusion, after 6 months of antibiotic treatment, HRQOL improved in almost one-third of patients, regardless of microbiological responses. Improvements in HRQOL were more pronounced in individuals with severe initial symptoms. Our preliminary results strengthen the rationale for proactive initiation of antibiotic treatment in targeted populations, such as patients with impaired HRQOL.

Supplementary Data

Supplementary materials are available at Clinical Infectious Diseases online. Consisting of data provided by the authors to benefit the reader, the posted materials are not copyedited and are the sole responsibility of the authors, so questions or comments should be addressed to the corresponding author.

Notes

Author contributions. N. K. and J.-J. Y. conceived and designed the project. N. K., H. H., D. J., B. W. J., K.-W. J., Y. A. K., H.-J. K., J.-Y. K., Y. R. K., Y.-S. K., J. H. L., J. M., Y. P., T. S. S., J. W., and J.-J. Y. contributed to the data acquisition. N. K., E. H., H. H., D. J., B. W. J., K.-W. J., Y. A. K., H.-J. K., J.-Y. K., Y. R. K., Y.-S. K., J. H. L., J. M., Y. P., T. S. S., H. S., J. W., and J.-J. Y. analyzed the data. All authors drafted and approved the manuscript.

Acknowledgments. The authors thank Dr. Alexandra Quittner, who generously allowed us to utilize the Quality of Life–Bronchiectasis (QOL-B) instrument in the NTM-KOREA cohort.

Data availability. De-identified clinical data can be shared with qualified researchers. Proposals for data usage will undergo review by the NTM-KOREA committee board. Upon obtaining ethics approval, the data can be shared through a secure online platform, contingent on signing a data access agreement. Proposal should be submitted to Jae-Joon Yim ([email protected]).

Financial support. This work was supported by a grant from the Korea Health Technology R&D Project through the Korea Health Industry Development Institute, funded by the Ministry of Health and Welfare, Republic of Korea (grant number: HC21C0015).

References

Author notes