Comparison of clinical characteristics between mild chronic bronchitis and severe chronic bronchitis in patients with chronic obstructive pulmonary disease

Chronic bronchitis (CB) is associated with poor outcomes in patients with chronic obstructive pulmonary disease. The aim of this study was to identify the characteristics that distinguish chronic bronchitis (CB) from non-CB. In addition, the features of mild CB vs. severe CB were compared and a cut-off level was dened according to CAT1 and CAT2 scores. This study was based on the Korea COPD Subgroup Study (KOCOSS) database, constructed in a multicenter COPD cohort study that recruited patients from 54 centers. CB was dened as CAT1 and CAT2 scores ≥ 3; severe CB was dened as CAT1 and CAT2 scores ≥ 4, while mild CB was dened as either a CAT1 or a CAT2 score < 4. Baseline characteristics, 1-year exacerbation rate, and 3-year FEV 1 decline were compared in non-CB vs. CB patients and in patients with mild CB vs. severe CB.

Pulmonary function test parameters (e.g., FEV1, FVC, FEV1/FVC, diffusion capacity of the lung for carbon monoxide [DLco], and residual volume/total lung capacity) were determined at baseline and annually for 3 years. Emphysema or bronchiectasis was diagnosed based on chest computed tomography ndings interpreted by a radiologist. COPD medication regimens were categorized as long-acting beta-agonist or long-acting muscarinic antagonist, long-acting beta-agonist plus long-acting muscarinic antagonist, inhaled corticosteroid plus long-acting beta-agonist, and triple therapy. Both the occurrence and frequency of moderate-to-severe exacerbations and severe exacerbations during the rst year of follow-up were analyzed. Moderate exacerbation was de ned as a status requiring antibiotic or systemic corticosteroid therapy, administered in an outpatient clinic; severe exacerbation was de ned as a status requiring an emergency room visit or hospital admission.

Statistical analyses
All statistical analyses were performed using R software (ver. 3.6.3; R Development Core Team, Vienna, Austria). Continuous variables are expressed as means ± standard deviations; categorical variables are expressed as numbers and percentages. The above-listed clinical parameters were compared between non-CB patients and CB patients, and between patients with mild CB vs. severe CB. Differences in the categorical and continuous values of two groups were determined using the χ 2 test and Student's t-test, respectively.
Negative binomial regression analysis was performed to predict the frequency of exacerbations in CB patients and non-CB patients. For the subgroup of CB patients, a regression model was used to predict the frequency of exacerbations in patients with severe vs. mild CB. The regression models were adjusted for age, sex, smoking history, and post-bronchodilator FEV1. They were also used to analyze moderate-tosevere and severe exacerbations.
The annual FEV1 decline over 3 years was assessed in a longitudinal analysis that used a linear mixed model in which the interaction was examined between time and CB. The interaction between time and the severity of CB (mild CB vs. severe) was also analyzed; the adjusted covariates were age, sex, and BMI. All analyses were repeated in the subset of patients who were ever-smokers (≥ 10 pack-years).

Differences in general characteristics between non-CB patients and CB patients
Of the 2,162 COPD patients registered in the KOCOSS database between April 2012 and May 2021, 497 (23.0%) had CB as de ned by the CAT score (both CAT1 and CAT2 ≥ 3) (Fig. 1). Differences in clinical characteristics between non-CB patients and CB patients are shown in Table 1. Compared with non-CB patients, CB patients were younger (69.2 ± 7.8 years vs. 68.3 ± 7.7 years, p = 0.02), more likely to be a current smoker (24.5% vs. 35.6%, p < 0.01), and had lower BMI (23.1 ± 3.4 vs. 22.6 ± 3.4, p < 0.01). There were no differences in the sex distribution. Symptom and functional exercise capacity scores were better in the non-CB group than in the CB group: mMRC (1.2 ± 0.8 vs. 1.6 ± 1.0, p < 0.01), total CAT score (12.0 ± 6.4 vs. 22.8 vs. 7.3, p < 0.01), and 6MWT (387.5 ± 117.5 m vs. 371.4 ± 109.8 m, p = 0.02). The two psychological scores showed that non-CB patients were less depressed (Beck Depression Inventory score, 6.1 ± 7.6 vs. 9.7 ± 9.7, p < 0.01) and less anxious (Beck Anxiety Inventory score, 3.8 ± 5.6 vs. 7.0 ± 9.1, p < 0.01) than CB patients. There were no signi cant differences in asthma history, asthma-COPD overlap, or type 2 in ammation markers (e.g., FeNO, blood eosinophil count, and IgE).  21.1%, p = 0.02); the prescription rates of dual bronchodilators, inhaled corticosteroid/long-acting beta-agonist, and triple agents did not signi cantly differ between groups. According to the baseline moderate-to-severe exacerbation history in the previous year, both the occurrence rate and the frequency were signi cantly higher in CB patients than in non-CB patients (51.6% vs. 37.5%, p < 0.01 and 1.6 ± 2.6 vs. 0.9 ± 1.8, p < 0.01); according to the baseline severe exacerbation history, there was no signi cant difference in the occurrence rate but CB patients had more frequent exacerbations (0.3 ± 1.0 vs. 0.1 ± 0.5, p < 0.01). The general characteristics of non-CB patients and CB patients among ever-smokers are shown in Table S1.
The clinical characteristics of these two groups are presented in Table 2. There were no signi cant differences in age, sex, smoking history, or BMI. The symptom and functional exercise capacity scores were consistent with an unfavorable outcome in the severe vs. mild CB groups: mMRC (1.8 ± 1.1 vs. 1.5 ± 0.9, p < 0.01), total CAT score (27.3 ± 6.8 vs. 20.7 ± 6.5, p < 0.01), and 6MWT (353.0 ± 110.9 m vs. 379.9 ± 108.5 m, p = 0.03). The psychological scores indicated more depression and anxiety in the severe CB group than in the mild CB group (Beck Depression Inventory score: 11.4 ± 10.6 vs. 8.8 ± 9.1, p = 0.04; Beck Anxiety Inventory score: 10.5 ± 11.6 vs. 5.2 ± 7.0, p < 0.01). There were no signi cant differences between groups with respect to asthma history, asthma-COPD overlap, and markers of type 2 in ammation (e.g., FeNO, blood eosinophil count, and IgE level). While the rate and frequency of moderate-to-severe exacerbations tended to be higher in patients with severe CB than in patients with mild CB, the differences were not statistically signi cant. Severe exacerbation occurred in a signi cantly larger number of patients with severe CB, compared with patients who had mild CB (21.9% vs. 9.2%, p < 0.01). There was also a larger number of severe exacerbations in the severe CB group than in the mild CB group, but this difference was not statistically signi cant (0.4 ± 1.1 vs. 0.2 ± 0.9, p = 0.07). The general characteristics of patients with mild CB vs. severe CB who were ever-smokers are presented in Table S2.

Association of chronic bronchitis and frequency of exacerbation
Negative binomial regression analysis revealed an association between the frequency of exacerbation and CB (Table 3). Compared with non-CB patients, patients with CB had a larger annual number of moderate-to-severe exacerbations (OR = 1.46, p < 0.01). The frequency of severe exacerbation did not signi cantly differ between groups. Regression analysis to explore an association between CB severity and the frequency of exacerbation (Table 4) showed a signi cant relationship for severe exacerbation but not for moderate-to-severe exacerbation. The same results were obtained in the group of ever-smokers, although CB was also signi cantly associated with the frequency of severe exacerbation (OR = 1.52, p < 0.04) (Tables S3, S4).

Discussion
Our analysis of a nationwide COPD cohort database revealed differences in clinical characteristics between non-CB patients and CB patients. By stratifying CB patients into patients with mild disease and patients with severe disease based on CAT sub-questionnaires, we were able to quantify the degrees of symptoms. The results showed that, compared with patients who had mild CB, patients with severe CB had worse outcomes in terms of respiratory symptoms, functional exercise capacity, and depression and anxiety scores; they also had more frequent severe exacerbations.
The clinical signi cance of the CB phenotype in COPD is well-established. CB is associated with poor health-related quality of life [22][23][24][25], poor functional exercise capacity [26], low lung function [11,22,23,27, 28], more frequent exacerbations [11,17,22,23,27], and higher mortality [24,29]. Consistent with those previous ndings, our study showed higher mMRC and CAT scores, worse 6MWT performance, worse lung function, and more frequent exacerbations in CB patients than in non-CB patients. In most studies, including ours, CB patients were younger and had lower BMI; however, con icting results have also been reported [11,23,26,27,30]. Furthermore, in our study and other studies, CB was strongly associated with a history of smoking [11,23,31]. In a study concerning the association of CB with mental health, Meek et al. found poor outcomes for CB patients in terms of emotional and mental health sections of the 36-Item Short Form Health Survey (SF-36). Their assessment of SF-36 items related to depression showed that CB patients had higher scores for all of those items. Our CB patients also had higher depression and anxiety scores, compared with non-CB patients.
To our knowledge, the present study is the rst to stratify CB patients according to disease severity, then to analyze the clinical characteristics of patients with mild CB vs. severe CB. A previous study classi ed the severity of cough and sputum by using CAT1 and CAT2 scores [32]. Similar to our ndings, the previous study showed that patients with more severe cough or sputum had higher mMRC scores and more frequent exacerbations. Patients with severe symptoms also had poor outcomes in terms of anxiety, depression, fatigue, physical function, social ability, sleep disturbance, and pain interference, as determined using the Patient-Reported Outcome Measurement Information System Scores (PROMIS-29).
These results are consistent with our ndings and highlight the broader implications of severe cough and sputum in patients with severe CB. In our study, there were no signi cant differences in baseline characteristics (age, sex, and BMI) between patients with severe vs. mild CB; while patients with severe CB were more likely to be current smokers, the difference between groups was not statistically signi cant.
However, patients with severe CB experienced more frequent severe exacerbations than did patients with mild CB (OR = 2.52); thus, patients with severe CB should be more carefully monitored.
Although our study showed worse lung function in CB patients than in non-CB patients, the 3-year followup data showed no signi cant differences in the FEV1 decline rate between groups. Similar results were obtained in patients with mild CB vs. severe CB. However, according to the Coronary Artery Risk Development in Young Development in Young Adults (CARDIA) study, a prospective cohort study that repeatedly measured lung function in young adults over 30 years, the presence of cough or sputum was signi cantly associated with an excess annual decline in both FEV1 (−2.71 ml/year, p < 0.01) and FVC (−1.94 ml/year, p = 0.03) [33]. In the Rotterdam Study, the rate of FEV1 decline during a median 6.5 years of follow-up was higher in CB patients (−38 ml/year, p = 0.02) [23].  [12,13,36]. Symptom-based scores (e.g., SGRQ and CAT) have also been employed [11,15,17,21,27].
Such scoring systems allow symptom severity to be quanti ed based on cut-off values, rather than subjective de nitions. In this study, CB was de ned as both CAT1 and CAT2 scores ≥ 3, as initially recommended by Lim et al. [21]. This cut-off value results in similar proportions of CB among COPD patients, as determined using classically de ned CB. In addition, Lim et al. showed that a CAT-based de nition explained computed tomography airway parameters, such as mean wall thickness and mean wall area. In a previous study, we showed that patients with CAT score-de ned CB shared clinical characteristics and outcomes with patients who had classically de ned CB [15]. Availability of data and materials The datasets supporting the conclusions of this article are available from the corresponding author on reasonable request.