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Hence, we aimed to evaluate the association of bronchiectasis and NTM-PD and the risk factors of NTM-PD in patients with bronchiectasis, using a nationwide longitudinal cohort.
We used the National Health Insurance Service—National Sample Cohort (NHIS-NSC), a 2.2% representative sample data of Koreans. Bronchiectasis was defined as one or more claim under the International Classification of Diseases 10th revision code J47.
NTM-PD was defined by a diagnostic code of NTM disease (A31.0, A31.8, and A31.9) and claims data for acid-fast bacilli smears or mycobacterial cultures. Bronchiectasis-associated comorbidities were also defined using the International Classification of Diseases 10th revision codes.
To account for competing risks due to mortality, a proportional subdistribution hazards regression model for NTM-PD with death as a competing event was used. We used the Cox proportional hazards regression model to evaluate risk factors for NTM-PD in the bronchiectasis cohort (see footnotes in Table 1 for adjusted factors). The institutional review board approved the study and waived the requirement for informed consent because the NHIS-NSC was de-identified (IRB No. CBNUH 2020-07-020).
Table 1Risk Factors for Nontuberculous Mycobacterial Pulmonary Disease in Patients With Bronchiectasis
Between January 1, 2003 and December 31, 2012, the database recorded data for 861,808 adult patients of at least 20 years of age. Among the 17,679 patients with bronchiectasis, we excluded those diagnosed with NTM-PD before bronchiectasis diagnosis (n = 22) and those who died within 1 year after enrollment in the cohort (n = 690). Among the 843,414 patients without bronchiectasis, we excluded those diagnosed with NTM-PD before matching (n = 2) and those who died within 1 year after enrollment (n = 4,665). After 1:4 matching for age and sex using a greedy match algorithm, we established the NTM-naive bronchiectasis cohort (n = 16,967) and the NTM-naive matched cohort (n = 67,868), and they were followed (after a 1-year washout period) until the development of NTM-PD, death, or December 31, 2013, whichever occurred first.
The bronchiectasis and matched cohorts were well balanced in terms of age and sex (standardized differences were 0% for both). The proportion of patients who received medical aid was higher in the bronchiectasis cohort than in the matched cohort (2.9% vs 2.4%, P < .001). Regarding pulmonary comorbidities, the rates of asthma (34.4% vs 9.1%), COPD (27.8% vs 5.3%), previous pulmonary TB (12.1% vs 2.8%), pulmonary hypertension (0.2% vs 0%), and lung cancer (3.8% vs 0.4%) were greater in the bronchiectasis cohort than in the matched cohort (P < .001 for all). Concerning extrapulmonary comorbidities, diabetes mellitus (20.4% vs 15.6%), cardiovascular disease (10.6% vs 6.1%), gastroesophageal reflux (24.5% vs 13.7%), chronic liver disease (6.0% vs 3.3%), inflammatory bowel disease (0.6% vs 0.3%), and rheumatoid arthritis (5.8% vs 3.4%) were significantly more frequent in the bronchiectasis cohort than in the matched cohort (P < .001 for all).
During the median follow-up duration of 6.1 years (interquartile range, 3.3-8.7 years), the age- and sex-adjusted incidence of NTM-PD was 109.1/100,000 person-years in the bronchiectasis cohort and 5.6/100,000 person-years in the matched cohort (subdistribution hazard ratio [HR] = 19.27; 95% CI = 12.82-28.95). The cumulative incidence of NTM-PD was significantly higher in the bronchiectasis cohort than in the matched cohort (Gray’s test, P < .001), which was consistent in the subgroups (Fig 1).
Regarding risk factors of NTM-PD among the bronchiectasis cohort, as shown in Table 1, age ≥ 40 years (greatest HR among patients aged 40-49 years [adjusted HR (aHR) = 5.50; 95% CI = 1.90-15.88]), females (aHR = 1.64; 95% CI = 1.11-2.41), previous pulmonary TB (aHR = 4.26; 95% CI = 2.84-6.39), and long-term macrolide (aHR = 6.82; 95% CI = 4.26-10.90) were associated with an increased incidence of NTM-PD in a multivariable analysis.
A previous study showed that bronchiectasis was associated with increased odds of NTM-PD.
the age group of 40 to 59 years had the highest risk of NTM-PD, and females had a higher risk of NTM-PD than males in our study. Whereas smoking and socioeconomic status were risk factors for NTM infection in previous studies,
these factors were not associated with NTM-PD in this study. Previous pulmonary TB was associated with a more than fourfold increase in NTM-PD in patients with bronchiectasis, in agreement with previous findings.
In contrast to the previous findings, inhaled or oral corticosteroid use did not increase NTM-PD in bronchiectasis patients in our study. Because a possibility exists that the results might have been caused by a relatively small number of NTM-PD, future studies are needed to address this issue.
This study showed that long-term macrolide therapy was associated with incident NTM-PD in patients with bronchiectasis. Although macrolide plays a central role in the treatment of NTM-PD, long-term use in subjects with chronic lung disease may increase NTM infection.
—it would be very important to collect sputum samples for NTM culture in bronchiectasis patients undergoing long-term macrolide treatment.
There were several limitations to this study. First, the NHIS-NSC database did not provide data regarding BMI, pulmonary function, and smoking. Second, our study lacked NTM culture results. The NHIS-NSC provides claims of NTM cultures; however, it does not indicate whether the results are positive or negative. Thus, the definition of NTM-PD without NTM culture results might have exaggerated the risk of NTM-PD in bronchiectasis patients. Third, because of the lack of microbiological data, we could not identify the species of NTM-PD, which is important from a global perspective and extrapolation.
In conclusion, the incidence of NTM-PD in bronchiectasis patients was approximately 19-fold higher than that in patients without bronchiectasis. Age, female sex, previous pulmonary TB, and long-term macrolide use were associated with increased NTM-PD in patients with bronchiectasis.
Author contributions: H. Choi and H. Lee are guarantors of manuscript. J. Ryu did the data analysis. B, Yang, J. Ryu, H. Choi, and H. Lee wrote the initial draft of the manuscript and all authors were involved at all stages of critical revision of manuscript. All of the authors read and approved the final manuscript.
Role of sponsors: The sponsor had no role in the design of the study, the collection and analysis of the data, or the preparation of the manuscript.
Other contributions: We thank Sun-Young Kong, MD, PhD (National Cancer Center, Goyang, Korea), for providing us the NHIS-NSC dataset.
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