Chronic Obstructive Pulmonary Disease Is Associated With Decreased Quality of Life in Bronchiectasis Patients: Findings From the KMBARC Registry

Most studies have evaluated the impact of non-cystic fibrosis bronchiectasis (hereafter referred to as bronchiectasis) on quality of life (QoL) in patients with chronic obstructive pulmonary disease (COPD) using COPD cohorts. Accordingly, the impact of COPD on QoL in patients with bronchiectasis is not well-elucidated. We used the Korean Multicenter Bronchiectasis Audit and Research Collaboration (KMBARC) registry between August 2018 and December 2019, a prospective observational cohort that enrolled patients with bronchiectasis in Korea. We evaluated co-occurrence exposure to COPD in bronchiectasis patients, and the primary outcome was QoL according to the Bronchiectasis Health Questionnaire (BHQ). We also investigated factors associated with decreased QoL, defined as the lowest quartile of the total BHQ score. Of 598 patients with bronchiectasis, 372 (62.2%) had COPD. Bronchiectasis patients with COPD had a significantly lower total BHQ score compared with those without COPD [median = 63.1 (interquartile range: 54.8–68.6) vs. 64.8 (57.4–70.8), p = 0.020]. Multivariable analysis revealed that dyspnea [adjusted odds ratio (aOR) = 3.21, 95% confidence interval (CI) = 1.21–8.60], depression (aOR = 1.28, 95% CI = 1.16–1.44), and fatigue (aOR = 1.05, 95% CI = 1.01–1.09) were significantly associated with decreased QoL in bronchiectasis patients with COPD. In conclusion, bronchiectasis patients with COPD had significantly decreased QoL than patients without COPD. In bronchiectasis patients with COPD, dyspnea, depression, and fatigue were associated with decreased QoL.

However, except for studies evaluating COPD prevalence in patients with bronchiectasis, most studies have focused on the impact of bronchiectasis in COPD patients (7)(8)(9)(10). These studies showed that the coexistence of bronchiectasis and COPD was associated with a larger number of symptoms, worse lung function, greater disease severity, and more frequent exacerbations (7)(8)(9)(10). Accordingly, COPD patients with bronchiectasis have worse quality of life (QoL) than patients with COPD only (11,12). Because these studies used COPD cohorts, the impact of bronchiectasis on QoL in COPD patients could have been elucidated better. However, little is known about this association within a bronchiectasis cohort because few studies have evaluated bronchiectasis cohorts; thus, urgent evaluation of this issue is necessary.
The Korean Multicenter Bronchiectasis Audit and Research Collaboration (KMBARC) is a prospective, observational study of bronchiectasis in Korea (13,14). The KMBARC uses the Korean version of the Bronchiectasis Health Questionnaire (BHQ) for QoL measurement (15), which has the advantage of simplicity over other QoL measurements for bronchiectasis. Accordingly, we hypothesized that the BHQ QoL would be worse in bronchiectasis patients with COPD than in those without COPD. We further aimed to evaluate which factors are associated with impaired QoL in bronchiectasis patients with COPD.

Study Population
The KMBARC is a prospective, non-interventional observational cohort study conducted since August 2018 to uncover the natural course of bronchiectasis in Korea. We used baseline data from 598 participants enrolled between August 2018 and December 2019. The KMBARC inclusion criteria were adult patients (aged ≥ 18 years) with stable bronchiectasis. In this study, bronchiectasis was defined when bronchodilation was found in computed tomography of the lung, which included one or more of the followings: (1) bronchoarterial ratio > 1 (internal airway lumen vs. adjacent pulmonary artery), (2) lack of tapering, or (3) airway visibility within 1 cm of costal pleural surface or touching mediastinal pleura (16). The exclusion criteria were (1) cystic fibrosis bronchiectasis, (2) interstitial lung-disease-related traction bronchiectasis, (3) active treatment for pneumonia, pulmonary tuberculosis (TB), or non-tuberculous mycobacterial infection, (4) lack of informed consent, and (5) pregnancy. Detailed information on the KMBARC protocol was provided in a previous study (13).
The study protocol was approved by the institutional review board of each institution that participated in the KMBARC, including Hallym University Chuncheon Sacred Heart Hospital (IRB number: 2018-07-006). All participants provided written informed consent.

Exposure
The exposure state for this study was the coexistence of COPD with bronchiectasis. COPD was defined as physiciandiagnosed COPD, which includes (1) COPD diagnosis by an attending physician in the institution where the patient was enrolled and (2) Patient-reported physician-diagnosed COPD in another institution.

Outcomes
The primary outcome was QoL as measured by BHQ (17). The secondary outcome was factors associated with decreased QoL, defined as the lowest quartile of the total BHQ score.

Covariates
Body mass index (BMI) was calculated by dividing weight by the square of height (kg/m 2 ). Dyspnea was evaluated according to the modified Medical Round Council (mMRC) scale (18). Purulent sputum production was assessed using a sputum color chart (19). Acute exacerbation was defined according to a consensus definition for bronchiectasis (20). Regarding acute exacerbations, we evaluated exacerbation history in the previous year at the time of enrollment. Bronchiectasis severity was assessed by the bronchiectasis severity index (BSI) (21) and FACED score (22). Pseudomonas aeruginosa was isolated from spontaneously obtained sputum, induced sputum samples, or bronchoalveolar lavage. Korean versions of the Patient Health Questionnaire 9 (PHQ-9) and the Fatigue Severity Score (FSS) were used to assess depression and fatigue, respectively (23)(24)(25)(26). Modified Reiff score was calculated as previously reported (27). Comorbidities were defined as patient-reported previous physician diagnoses. Spirometry was performed as recommended by the American Thoracic Society and the European Respiratory Society (28). After obtaining absolute values for FEV 1 and FVC, the percentages of predicted values (% predicted) for FEV 1 and FVC were calculated following recommendations for Korean populations (29). Medication data were based on self-reported use.

Statistical Analyses
We presented data as medians with interquartile ranges (IQRs) for continuous variables and numbers with percentages for categorical variables. The p-values were calculated using the Wilcoxon rank-sum test for continuous variables and Pearson's chi-square test or Fisher's exact test for categorical variables, as appropriate. We performed univariable and multivariable logistic regression analyses to identify factors associated with decreased QoL in bronchiectasis patients with COPD. Factors included in the multivariable logistic regression model were demographics (age, sex, and smoking history), clinically important variables (acute exacerbation), and factors significantly different (p < 0.05) between the bronchiectasis patients with and without COPD (BMI, mMRC, PHQ-9, FSS, FEV 1 % predicted, asthma, modified Reiff score). As each component of BSI or FACED was included in the model, these variables were not included in the multivariable models. In addition, due to the high collinearity between pulmonary function parameters, only FEV 1 % predicted was adjusted. A two-sided p-value < 0.05 was considered significant. All analyses were conducted using R version 4.0.3 (R Core Team 2020; R Foundation for Statistical Computing, Vienna, Austria).

Comparison of Characteristics of Bronchiectasis Patients With COPD According to QoL
As shown in

DISCUSSION
In this prospective observational study, we compared QoL scores in bronchiectasis patients in Korea according to COPD presence.
We found that ∼38% of patients with bronchiectasis have COPD, and these patients had lower QoL as measured by the BHQ than do patients without COPD. We additionally found that dyspnea estimated by mMRC (≥ 2), depression by PHQ-9, and fatigue by FSS were significant factors associated with decreased QoL among bronchiectasis patients with COPD. The coexistence of COPD and bronchiectasis in Western countries is < 20% (1, 2, 4). Although COPD prevalence according to India's bronchiectasis registry was higher than the prevalences in Western countries, it was still only around 20% (3). In comparison, the COPD prevalence in the KMBARC registry was higher than expected, but it is not clear why. There are some possible explanations for the phenomenon. In this study, COPD was defined as physician-diagnosed COPD. Thus, the definition of COPD was not as strict as that in the previous Taiwan study that included smoking history as well as spirometric results (30). Another possibility is that that bronchiectasis with obstructive ventilatory impairment might have been regarded as having COPD. Bronchiectasis itself can cause obstructive ventilatory impairment (31). The high rate of COPD can be also attributable to the relatively high prevalence of asthma and TB in this cohort (14). The current Global Initiative for Chronic Obstructive Lung Disease (GOLD) recommendations indicate asthma or TB as a risk factor of COPD (32). We carefully suggest that asthmatic patients with fixed airflow obstruction and prior TB patients with airflow obstruction might have been regarded as COPD by attending physicians. Thus, the burden of COPD-related risk factors other than smoking was relatively high in our cohort, which might have led to a high rate of never-smokers in bronchiectasis patients with COPD. Although there are prevalence differences between our study and previous studies, these results suggest that at least one-fifth of bronchiectasis patients have COPD, and appropriate diagnosis and treatment are important for proper management. It is well-recognized that bronchiectasis patients have lower QoL than patients without bronchiectasis (33), especially patients with exacerbations and respiratory symptoms (34). However, the QoL of bronchiectasis patients with COPD has rarely been evaluated. One European study analyzed bronchiectasis patients' QoL according to etiology, and patients with COPDrelated bronchiectasis were shown to have lower QoL compared with patients with bronchiectasis caused by other etiologies (35). However, because that study evaluated QoL according to etiology, COPD patients whose COPD was not considered to be the cause of bronchiectasis were not included in the COPD group. By viewing COPD as comorbidity and not taking an etiology-based approach, our study showed that COPD significantly affected the QoL of patients with bronchiectasis. However, it should be mentioned that the minimal clinically important difference in the BHQ scores is not known. As a result, although the median difference of 1.7 units was statistically different in bronchiectasis patients by the presence or absence of COPD, this difference may not be clinically significant. Future studies are needed.
Among factors associated with QoL in bronchiectasis patients with COPD, dyspnea measured by mMRC had the most significant association with decreased QoL. This suggests that poorly controlled dyspnea can lead to poor QoL in bronchiectasis patients with COPD. Consistent with our results, a previous study using a COPD cohort showed that COPD patients with bronchiectasis have a high degree of dyspnea, which affected patients' QoL as measured by SGRQ score (12). Other important findings of our study are that depression and fatigue measured by PHQ-9 and FFS, respectively, affected QoL in bronchiectasis patients with COPD. Fatigue and depression are frequent in patients with COPD as well as those with bronchiectasis and have significant impacts on QoL in these patients (36)(37)(38). Accordingly, it can be postulated that these two conditions can affect the QoL in patients with bronchiectasis and COPD overlap. Regarding these conditions affecting the QoL in bronchiectasis patients with COPD, previous study findings suggest that these symptoms can be interactively connected, and one symptom may affect others. For example, a patient who complains of dyspnea may have unrecognized fatigue or depression as well. Thus, a strategy focusing on one component might not be as effective as a comprehensive approach to managing all these factors (e.g., bronchodilator use, pulmonary rehabilitation, as well as anti-depression treatment). Future studies are needed to optimize the assessment and treatment strategies to improve QoL in bronchiectasis patients with COPD.
There are some limitations to our study. First, this study was performed in Korean bronchiectasis patients. Thus, to generalize our findings, further studies using other bronchiectasis cohorts are needed. Second, because our study design was crosssectional, we could not evaluate the association between COPD and longitudinal changes in QoL in bronchiectasis patients. Thus, future studies are needed. Third, although we suggested some potential reasons (TB, asthma, etc.) to explain the high proportion of never-smokers in bronchiectasis patients with COPD, the role of other important risk factors (e.g., biomass exposure) on this issue could not be evaluated due to the lack of data in KMBARC.

CONCLUSIONS
COPD was a significant factor associated with decreased QoL in patients with bronchiectasis. Dyspnea, depression, and fatigue were associated with reduced QoL in bronchiectasis patients with COPD. In managing patients with bronchiectasis, appropriate diagnosis and treatment of COPD might help improve QoL.

DATA AVAILABILITY STATEMENT
The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.

ETHICS STATEMENT
The study protocol was approved by the institutional review board of each institution that participated in the KMBARC, including Hallym University Chuncheon Sacred Heart Hospital (IRB number: 2018-07-006). All participants provided written informed consent.

AUTHOR CONTRIBUTIONS
HL and YK are guarantors of the manuscript. SK, HL, and YK designed the study and wrote the initial draft of the manuscript. SK performed data analysis. All authors were involved at all stages of the critical revision of the manuscript, read and approved the final manuscript, and meet the criteria for authorship as recommended by the International Committee of Medical Journal Editors.