Abstract
Background:
Chronic bronchitis (CB) is strongly associated with cigarette smoking, but not all smokers develop CB. We aimed to evaluate whether measures of structural airway disease on CT are differentially associated with CB.
Methods:
In smokers between ages 45-80 years, and with GOLD stages 0-4, CB was defined by a positive response to cough-related questions on the St. George’s Respiratory Questionnaire. Airway disease on CT was quantified by (1) Wall area percent (WA%) of segmental airways (2) Pi10, the square root of the wall area of a hypothetical airway with 10 mm internal perimeter (3) Total airway count (TAC) and (4) Airway fractal dimension (AFD), a measure of the complex branching pattern and remodeling of airways. CB was also assessed at the 5-year follow-up visit.
Measurements and Main Results:
Of 8,917 participants, 1,734 (19.4%) had CB at baseline. Airway measures were significantly worse in those with CB compared with those without CB: WA% 54.5(8.8) vs. 49.8(8.3); Pi10 2.58(0.67) vs. 2.28(0.59) mm; TAC 156.7(81.6) vs. 177.8(91.1); AFD 1.477(0.091) vs. 1.497(0.092) (all p<0.001). On follow-up of 5,517 participants at 5-years, 399(7.2%) had persistent CB. With adjustment for between-visits changes in smoking status and lung function, greater WA% and Pi10 were associated with significantly associated with persistent CB, adjusted OR per SD change 1.75, 95%CI 1.56-1.97;p<0.001 and 1.66, 95%CI 1.42-1.86;p<0.001, respectively. Higher AFD and TAC were associated with significantly lower odds of persistent CB, adjusted OR per SD change 0.76, 95%CI 0.67-0.86;p<0.001 and 0.69,95%CI 0.60-0.80;p<0.001, respectively.
Conclusions:
Higher baseline AFD and TAC are associated with a lower risk of persistent CB, irrespective of changes in smoking status, suggesting preserved airway structure can confer a reserve against CB.
Keywords: Chronic bronchitis, Airway fractal dimension, Airway remodeling
Introduction
Chronic bronchitis is a major component of chronic obstructive pulmonary disease (COPD). Population data suggest chronic bronchitis affects between 3.4% and 22% of adults, with ten million adults affected within the United States alone.1,2 It is associated with substantial morbidity including dyspnea, poor respiratory-quality of life, and a high frequency of exacerbations.3–9 Longer-term consequences include accelerated lung function decline,6,8 a greater likelihood of airflow obstruction in those without airflow limitation at baseline,10 and higher mortality than in those without chronic bronchitis.6,10
Cigarette smoking is the strongest risk factor for chronic bronchitis, conferring an approximately 3-fold higher risk compared with non-smokers.2 It is, however, not known why only some smokers develop chronic bronchitis and others do not, given similar environmental exposures. Although differences in genetic predisposition is a possibility, twin studies show moderate familial aggregation in women only,11 and genome-wide association studies have found borderline associations,12 or associations that were no longer significant once current smoking or airflow obstruction was taken into account.13 These findings raise important questions about the role of other risk factors as well as the existence of protective factors. It is plausible that the occurrence of chronic bronchitis represents a balance between gene-environment interactions and structural and functional reserve.
Chronic bronchitis is associated with mucosal hypertrophy and thickening of the terminal airways.3 Computed tomography (CT) findings of increased segmental and subsegmental airway wall thickness have been used as surrogates that reflect more distal airway remodeling.14 Indeed, these measures of airway wall thickness on CT are greater in those with chronic bronchitis than in controls.15 The deposition of cigarette smoke is patchy and likely depends on airway anatomy. Furthermore, some CT metrics that sample airways only at certain generations may not provide a complete measure of airway remodeling. Whether structural aspects of airway branching and remodeling confer differential risk for chronic bronchitis has not been examined. In prior studies, thickened segmental airway walls were associated with chronic bronchitis but whether thickened airway wall predicates persistent chronic bronchitis even after smoking cessation is not known. Additional measures of airway disease have been described recently. Total airway count is associated with lung function decline and may be associated with clinical airway disease.16 We recently measured the fractal dimension of airways that takes into account the complex recurring branching patterns and airway remodeling.17 Low airway fractal dimension (AFD) is associated with worse respiratory quality of life and functional capacity and also with frequent exacerbations, lung function decline, and mortality.17 In this study, we aimed to evaluate whether measures of structural airway disease on CT are associated with chronic bronchitis, with the hypothesis that measures of airway remodeling are differently associated with persistent chronic bronchitis on long-term follow-up even after smoking cessation.
Methods
Study Population
We included adults enrolled in the Genetic Epidemiology of COPD (COPDGene) study, the details of which have been previously published.18 Briefly, COPDGene is a large multicenter cohort that enrolled current and former smokers between the ages of 45 and 80 years from 21 centers across the United States. We analyzed data from participants with Global Initiative for Obstructive Lung Disease (GOLD) stages 0 through 4; individuals with FEV1/FVC >0.70 and FEV1 %predicted >80 but with respiratory symptoms were classified as GOLD 0. We excluded 1,275 participants with Preserved Ratio Impaired Spirometry (PRISm), with FEV1/FVC >0.70 and FEV1 < 80% predicted. All participants had a smoking burden of at least 10 pack years. Participants were classified as current smokers if they had smoked cigarettes within 30 days of study visit. At enrollment and at follow-up approximately 5 years later, all participants underwent lung function testing with pre-and post-bronchodilator spirometry.
Chronic bronchitis was defined using the classic definition of chronic bronchitis, the presence of cough and phlegm for at least 3 months a year for at least 2 consecutive years. We also defined chronic bronchitis using the responses to the chronic cough-related questions on the St. George’s Respiratory Questionnaire (SGRQ);19 we classified individuals as having chronic bronchitis if they answered “almost every day” or “most days of the week” to both the questions “over the last 4 weeks, I have coughed:” and “over the last 4 weeks, I have brought up phlegm:.”20,21 The SGRQ-based definition classifies more individuals as having chronic bronchitis than the classic definition, with comparable associations with airway disease and symptoms, but identifies more individuals at risk for future exacerbations than the classic definition.21 The classic chronic bronchitis definition was used for the primary analyses. Written informed consent was obtained from all participants prior to enrollment and the study protocol was approved by the institutional review boards of all participating centers.
CT Image Analysis
Volumetric CT scans were acquired at enrollment using multi-detector CT scanners at full inspiration (total lung capacity, TLC) and end- expiration (functional residual capacity, FRC or residual volume, RV).14,18 LungQ, version 1.0.0 (Thirona, Nijmegen, the Netherlands) and Pulmonary WorkStation 2 software (VIDA Diagnostics, Inc., Coralville, IA, USA) were used to segment the lungs and airways from inspiratory CT scans.22,23 The following measures of airway disease were calculated.
Wall area percent (WA%) of segmental airways: The luminal area (AI) and total airway cross-sectional area (AT) were calculated, and the airway wall area estimated by AT- AI. Airway wall area percent was calculated as [WA%] = [(AT- AI)/AT]×100.24
Pi10: The square root of the wall area of a hypothetical airway with 10 mm internal perimeter, was calculated by plotting the internal perimeters of all segmental and distal airways against the square root of their wall areas.25
Total airway count (TAC): The total airway count of sub-tracheal airways was calculated by automated identification of branch points on the airway tree and summing number of branches.
Airway fractal dimension (AFD): AFD of the airway lumen was calculated using the Minkowski-Bougliand box-counting dimension using MATLAB software (MathWorks, Natick, MA), as previously described.17 Briefly, cubes of progressively increasing side length “s” were iteratively laid over the airway tree and the number of cubes “n” that overlapped with the airway were identified at each successive iteration. The slope of the regression line between log (n) and log (1/s) was calculated to derive AFD. The greater the complexity of the airway tree, the higher the AFD.
Statistical Analyses
We compared baseline characteristics of individuals with and without chronic bronchitis using Student’s t-test for continuous variables and Chi-squared test of proportions for categorical variables. To test associations of the four airway metrics with presence of chronic bronchitis at baseline, we created binary logistic regression models with chronic bronchitis as the outcome and each airway metric as independent variable in separate models. All models were adjusted for age, gender, race, smoking status, pack-years of smoking, post-bronchodilator FEV1, and CT scanner type. To test the association of each of the airway metrics with the presence of persistent chronic bronchitis at the 5-year follow-up visit, we created four categories: Persistently No CB [CB(−) at both visits], Resolved CB [CB(+) at baseline but CB(−) at follow-up], New CB [CB(−) at baseline and CB(+) at follow-up], and Persistent CB [CB(+) at both visits]. In multinomial logistic regression analyses, associations between each airway metric and the primary outcome of persistent CB were adjusted for age, gender, race, pack-years of smoking, change in smoking status, change in FEV1, and CT scanner type. Persistently no CB was considered the reference group for these tests. Change in smoking status was categorized into one of 4 groups based on smoking status at the two visits: persistent smoker, quitter, resumed smoker, and persistent former smoker. Persistent former smoker status was considered the reference variable. Similar models were created using the SGRQ-based chronic bronchitis classification. Two-sided alpha threshold of 0.05 was considered statistically significant, and all analyses were performed using Statistical Package for the Social Sciences (SPSS 25.0, SPSS Inc. Chicago, IL, USA) and R statistical package (version 3.2).
Results
Subject Characteristics
We included 8,917 participants at baseline, with follow-up data available for 5,517 at the 5-year visit. At baseline, 4,407 (49.8%) had GOLD stage 0 disease, 791 (8.9%) GOLD 1, 1,935 (21.7%) GOLD 2, 1,175 (13.2%) GOLD 3, and 609 (6.8%) had GOLD 4 COPD. The mean (SD) smoking pack-years was 44.5 (25.1) and 4,341 (48.7%) were active smokers. The prevalence of chronic bronchitis at baseline was 19.4% (1,734/8,917). The baseline characteristics of participants by presence of chronic bronchitis are shown in Table 1.
Table 1:
Baseline characteristics of participants with and without chronic bronchitis
| Parameters | Overall (n=8917) |
No Chronic Bronchitis (n= 7183) |
Chronic Bronchitis (n= 1734) |
|---|---|---|---|
| Age (years) | 59.9 (9.1) | 60.0 (9.2) | 59.5 (8.7) |
| Female (%) | 4064 (45.6%) | 3364 (46.8%) | 700 (40.4%) |
| African American (%) | 2838 (31.8%) | 2391 (33.3%) | 447 (25.8%) |
| Body-mass-index (kg/m2) | 28.4 (6.0) | 28.4 (5.9) | 28.3 (6.2) |
| Smoking Pack-years | 44.5 (25.1) | 42.9 (24.2) | 50.8 (27.3) |
| Current Smokers (%) | 4341 (48.7%) | 3744 (52.1%) | 597 (34.4%) |
| FEV1 (L) | 2.3 (1.0) | 2.3 (1.0) | 2.0 (1.0) |
| FEV1 % predicted | 77.1 (27.0) | 79.5 (26.4) | 67.2 (26.9) |
| FVC (L) | 3.4 (1.0) | 3.4 (1.0) | 3.3 (1.0) |
| FVC %predicted | 89.1 (18.2) | 90.1 (17.8) | 84.9 (19.1) |
| FEV1/FVC | 0.65 (0.17) | 0.66 (0.16) | 0.59 (0.17) |
| GOLD Severity, n (%) | |||
| 0 | 4407 (49.8%) | 3851 (53.6%) | 556 (32.1%) |
| 1 | 791 (8.9%) | 666 (9.3%) | 125 (7.2%) |
| 2 | 1935 (21.7%) | 1405 (19.6%) | 530 (30.6%) |
| 3 | 1175 (13.2%) | 821 (11.4%) | 354 (20.4%) |
| 4 | 609 (6.8%) | 440 (6.1%) | 169 (9.7%) |
| CT Emphysema (%)* | 7.0 (10.2) | 6.7 (10.0) | 8.4 (10.9) |
| Wall Area % of segmental airways* | 50.7 (8.6) | 49.8 (8.3) | 54.5 (8.8) |
| Pi10 (mm)* | 2.34 (0.62) | 2.28 (0.59) | 2.58 (0.67) |
| Total Airway Count* | 172.5 (87.4) | 177.8 (91.1) | 156.7 (81.6) |
| Airway Fractal Dimension* | 1.493 (0.092) | 1.497 (0.092) | 1.477 (0.091) |
CT data available in n= 8,322 for CT emphysema, 8,321 for Wall Area%, 8,322 for Pi10, 8,075 for Total airway count, and 8,322 for Airway fractal dimension.
At the follow-up visit, 33.9% remained active smokers, 12.1% quit, and 2.3% had resumed smoking. Chronic bronchitis was present in 802 of 5,517 (14.5%) at the 5-year visit. 4187 (75.9%) had Persistently No chronic bronchitis, 528 (9.6%) had Resolved chronic bronchitis, 403 (7.3%), had New chronic bronchitis, and 399 (7.2%) had Persistent chronic bronchitis. Table 2 shows a comparison between individuals in the four chronic bronchitis groups.
Table 2:
Baseline characteristics of participants by chronic bronchitis status at follow-up
| Parameters | Overall (n= 5517) |
Persistent No CB (n= 4187) |
Resolved CB (n= 528) |
New CB (n= 403) |
Persistent CB (n= 399) |
|---|---|---|---|---|---|
| Age (years) | 60.4 (8.8) | 60.6 (8.9) | 59.6 (8.6) | 60.2 (8.9) | 59.7 (8.3) |
| Female (%) | 2721 (49.3%) | 2137 (51.0%) | 233 (44.1%) | 182 (45.2%) | 169 (42.4%) |
| African American (%) | 1518 (27.5%) | 1181 (28.2%) | 147 (27.8%) | 111 (27.5%) | 79 (19.8%) |
| Body-mass-index (kg/m2) | 28.7 (5.9) | 28.7 (5.9) | 28.8 (6.1) | 28.6 (5.5) | 28.4 (5.9) |
| Smoking Pack-years | 43.3 (23.9) | 41.3 (23.0) | 47.0 (23.7) | 49.4 (26.1) | 52.6 (27.0) |
| Smoking Status (%) | |||||
| Persistent active | 1868 (33.9%) | 1241 (29.6%) | 208 (39.5%) | 185 (45.9%) | 234 (58.6%) |
| Interval Quit | 667 (12.1%) | 477 (11.4%) | 122 (23.1%) | 34 (8.4%) | 34 (8.5%) |
| Interval New | 126 (2.3%) | 96 (2.3%) | 7 (1.3%) | 17 (4.2%) | 6 (1.5%) |
| Persistent Former | 2855 (51.8%) | 2373 (56.7%) | 190 (36.1%) | 167 (41.4%) | 125 (31.3%) |
| FEV1 (L) | 2.3 (0.9) | 2.4 (0.9) | 2.2 (0.9) | 2.2 (0.9) | 2.0 (0.8) |
| FEV1 %predicted | 80.1 (24.5) | 82.8 (23.7) | 72.2 (25.7) | 74.2 (25.3) | 68.2 (24.1) |
| FVC (L) | 3.4 (1.0) | 3.4 (1.0) | 3.4 (1.0) | 3.4 (1.0) | 3.4 (1.0) |
| FVC %predicted | 90.8 (16.6) | 91.8 (16.1) | 87.6 (18.0) | 89.5 (17.8) | 86.5 (17.2) |
| FEV1/FVC | 0.67 (0.15) | 0.69 (0.15) | 0.62 (0.16) | 0.63 (0.15) | 0.60 (0.15) |
| GOLD Severity, n (%) | |||||
| 0 | 2863(51.9%) | 2396(57.2%) | 208 (39.4%) | 149 (37.0%) | 110 (27.6%) |
| 1 | 542 (9.8%) | 434 (10.4%) | 38 (7.2%) | 44 (10.9%) | 26 (6.5%) |
| 2 | 1271(23.0%) | 826 (19.7%) | 162 (30.7%) | 122 (30.3%) | 161 (40.4%) |
| 3 | 659 (11.9%) | 411 (9.8%) | 91 (17.2%) | 74 (18.4%) | 83 (20.8%) |
| 4 | 182 (3.3%) | 120 (2.9%) | 29 (4.5%) | 14 (3.5%) | 19 (4.8%) |
| CT Emphysema (%)* | 6.2 (8.9) | 6.0 (8.6) | 6.9 (9.4) | 7.6 (10.0) | 7.9 (9.3) |
| Wall Area % of segmental airways* | 49.7 (8.4) | 48.6 (7.9) | 53.1 (8.9) | 51.9 (8.9) | 54.2 (8.7) |
| Pi10 (mm)* | 2.26 (0.59) | 2.19 (0.55) | 2.48 (0.67) | 2.43 (0.64) | 2.54 (0.65) |
| Total Airway Count* | 180.7 (95.2) | 186.2 (98.2) | 166.8 (81.7) | 161.6 (74.9) | 161.2 (93.1) |
| Airway Fractal Dimension* | 1.500 (0.093) | 1.506 (0.093) | 1.486 (0.099) | 1.478(0.089) | 1.484 (0.088) |
| Change in FEV1 (ml)¥ | 39.8 (53.2) | 37.3 (51.7) | 41.9 (60.7) | 50.8 (55.5) | 50.1 (53.5) |
CT data available in n= 5,225 for CT emphysema, 5,224 for Wall Area%, 5,225 for Pi10, 5,054 for Total airway count, and 5,225 for Airway fractal dimension.
Change in FEV1 data available in 4,952.
Airway Metrics and Chronic Bronchitis at Baseline
Airway measures were significantly worse in those with CB compared with those without CB: WA% 54.5(8.8) vs. 49.8(8.3); Pi10 2.58(0.67) vs. 2.28(0.59) mm; TAC 156.7(81.6) vs. 177.8(91.1); AFD 1.477(0.091) vs. 1.497(0.092) (all p<0.001). On bivariate regression, both WA% and Pi10 were associated with higher odds of having chronic bronchitis at baseline (OR for each SD change 1.74, 95%CI 1.64 to 1.84;p<0.001 and 1.61, 95%CI 1.52 to 1.69;p<0.001, respectively). Higher TAC at baseline was associated with lower odds of chronic bronchitis, OR for each SD change 0.73, 95%CI 0.68 to 0.79;p<0.001. Greater AFD was also associated with lower odds of chronic bronchitis (OR for each SD change 0.80, 95%CI 0.76 to 0.85;p<0.001). Figure 1 shows representative airways of individuals with and without chronic bronchitis.
Figure 1:
Airway Fractal Dimension (AFD) and Total Airway Count (TAC) for Representative Participants with A. Persistently no chronic bronchitis at baseline and at follow-up B. with chronic bronchitis at baseline but not at follow-up (Resolved chronic bronchitis) and C. Persistent chronic bronchitis at both visits.
On multivariable logistic regression with adjustment for age, gender, race, current smoking status, pack-years of smoking, FEV1, and CT scanner type, WA% (adjusted OR for each SD change 1.34, 95%CI 1.25 to 1.43;p<0.001) and Pi10 (adjusted OR for each SD change 1.24, 95%CI 1.16 to 1.33;p<0.001)showed similar associations with the presence of chronic bronchitis, but TAC (adjusted OR for each SD change 0.95, 95%CI 0.88 to 1.03;p=0.227) and AFD (adjusted OR for each SD change 0.95, 95%CI 0.88 to 1.01;p=0.102) were not significantly associated with chronic bronchitis (Figure 2).
Figure 2: Multivariable* Associations between Airway Metrics and Chronic Bronchitis at Baseline.
Odds Ratios are per one standard deviation change in airway metric.
AFD = Airway Fractal Dimension
TAC = Total Airway Count
Pi10 = Square root of the wall area of a hypothetic airway with 10 mm internal perimeter.
Wall Area% measured of segmental airways.
*Adjusted for age, gender, race, smoking status, pack years of smoking, FEV1 and CT scanner type.
Central lines within the bars represent point estimates, and ends represent 95%CI. Red bars indicate results for the classic definition of chronic bronchitis and blue bars indicate results for the St. George’s Respiratory Questionnaire-based definition of chronic bronchitis.
Airway Metrics and Change in Chronic Bronchitis Status at Follow-up
On bivariate regression, both WA% and Pi10 at baseline were associated with higher odds of having persistent chronic bronchitis, with persistently no CB as the reference group (OR for each SD change 1.97, 95%CI 1.77 to 2.19;p<0.001 and 1.78, 95%CI 1.61 to 1.97;p<0.001, respectively). Higher TAC at baseline was associated with lower odds of persistent chronic bronchitis (OR for each SD change 0.70, 95%CI 0.62 to 0.81;p<0.001. Greater AFD was also associated with lower odds of persistent chronic bronchitis (OR for each SD change 0.79, 95%CI 0.71 to 0.88;p<0.001).
On multivariable logistic regression with adjustment for age, gender, race, change in smoking status (reference persistent non-smoker), pack-years of smoking, change in FEV1, and CT scanner type, WA% (adjusted OR for each SD change 1.75, 95%CI 1.56 to 1.97;p<0.001), Pi10 (adjusted OR for each SD change 1.66, 95%CI 1.48 to 1.86;p<0.001), TAC (adjusted OR for each SD change 0.69, 95%CI 0.60 to 0.80;p<0.001), and AFD (adjusted OR for each SD change 0.76, 95%CI 0.67 to 0.86;p<0.001) were associated with persistent chronic bronchitis (Figure 3). Similar associations were noted between these airway metrics and new chronic bronchitis as well, but with smaller effect sizes than for persistent chronic bronchitis (Supplementary Table 1).
Figure 3: Multivariable* Associations between Baseline Airway Metrics and Persistent Chronic Bronchitis at 5-year Follow-up.
Odds Ratios are per one standard deviation change in airway metric.
AFD = Airway Fractal Dimension
TAC = Total Airway Count
Pi10 = Square root of the wall area of a hypothetic airway with 10 mm internal perimeter.
Wall Area% measured of segmental airways.
*Adjusted for age, gender, race, smoking status (reference persistent no smoking), pack years of smoking, FEV1 and CT scanner type.
Central lines within the bars represent point estimates, and ends represent 95%CI. Red bars indicate results for the classic definition of chronic bronchitis and blue bars indicate results for the St. George’s Respiratory Questionnaire-based definition of chronic bronchitis.
SGRQ-based Definition of Chronic Bronchitis
The use of the SGRQ-based definition resulted in identification of greater number of individuals as having chronic bronchitis than the classic definition (30.7% vs. 19.4%) (Supplemental Table 2), and higher number of individuals were classified as having persistent chronic bronchitis at follow-up (14.9% vs. 7.2%) (Supplemental Table 3). The associations between airway metrics and baseline chronic bronchitis, as well as persistent chronic bronchitis at follow-up, were similar regardless of the chronic bronchitis definition used (Supplemental Tables 4 and 5, Figures 2 and 3).
Discussion
In a cohort of current and former smokers, we demonstrated that chronic bronchitis is associated with increased airway wall thickness and lower total airway count and airway fractal dimensions. We also found that increased airway wall thickness is associated with persistent chronic bronchitis even with changes in smoking status, and with new onset chronic bronchitis. In contrast, a higher total airway count and airway fractal dimension appear to confer a reserve against persistent and new onset chronic bronchitis. These findings support consideration of structural airway characteristics as risk factors for chronic bronchitis and its persistence.
Cigarette smoking is the strongest risk factor for chronic bronchitis, with a lifetime cumulative incidence of approximately 40% reported in chronic smokers.16 A number of other external exposures including environmental pollution,26 workplace exposures,27 and biomass fuel,28 are also risk factors. Despite these well-documented associations, host factors are also important given the variable likelihood of occurrence of chronic bronchitis with similar exposures. A number of genetic associations have been reported to explain some of the predisposition to chronic bronchitis. Genome-wide association studies revealed a novel locus on 11p15.5, including EFCAB4A, CHID1, and AP2A2, a region close to that encoding MUC6 and MUC2.13 However, these associations did not hold true for chronic bronchitis when individuals with established airflow obstruction were excluded.13 Other studies have either found modest associations or associations that did not reach genome-wide significance.12,29 Cytotoxic T-lymphocyte antigen (CTLA4) polymorphisms are associated with chronic bronchitis but not with airflow obstruction.30
It is also important to note that chronic bronchitis is likely reversible in some individuals, at least with cessation of those exposures that are more easily quantifiable such as cigarette smoking.31,32 Epidemiologic studies suggest that within a year or two of quitting smoking, symptoms of chronic bronchitis and mucus hypersecretion return to levels close to those reported by non-smokers in many but not all adults.31–33 These facts raise an important question: are there factors that confer a protective effect or reserve against the development and persistence of chronic bronchitis? It is pertinent to note that a number of pathophysiologic alterations in the lung are accentuated or attenuated by structural changes in the lungs. For instance, mechanotransduction likely causes emphysema progression once emphysema has developed.34 A number of measures of small and large airway disease are associated with accelerated decline in FEV1.16,17,35,36 In this study, we show that increased airway wall thickness was associated with the presence of chronic bronchitis. This is consistent with a previous study showing cross-sectional associations between airway wall remodeling and chronic bronchitis.15 Regardless of how chronic bronchitis was defined, even after adjusting for change in smoking status, greater airway wall thickness at baseline was temporally associated with resolved, new and persistent chronic bronchitis, but with higher odds for persistent bronchitis. This suggests that airway remodeling changes persist and may not resolve fully unlike symptoms. In contrast, higher AFD was associated with not only a lower odds of presence of chronic bronchitis at baseline, and also with a lower odds of its persistence at 5-years, irrespective of any changes in smoking status. Although chronic bronchitis itself can result in some of the observed airway remodeling, the longitudinal assessment of chronic bronchitis status and the relationship with baseline airway remodeling suggests that these airway metrics inform risk. Lower airway count and lower airway fractal dimension at baseline were also associated with new chronic bronchitis but to a much lesser degree than persistent chronic bronchitis, again suggesting that some changes are likely irreversible, but also that preserved airway count and preserved airway branching tree confer a reserve against persistence of chronic bronchitis.
AFD provides a summary measure of the size and complex branching pattern of the airways. It is essentially a measure of the space-filling capacity of a structure. In the box-counting method we applied, more boxes of smaller sizes would be needed to fill in more complex structures. Thus, the AFD is affected by the size of the airways, luminal diameters and airway narrowing, loss of airway segments, tortuosity, and changes in branching angles. The human airways have a homothetic character such that there is a fixed relationship between parent and daughter branch diameters.37 A change in this relationship due to upstream airway narrowing or loss may introduce changes in flow dynamics with more turbulence and differences in particle deposition. The branching pattern of airways also has considerable implications for smoke and drug deposition.38 Harmful cigarette smoke particles may deposit more at bifurcations and abnormalities in airway geometry can alter the deposition patterns and density of both harmful particles as well as beneficial inhaled medications.39,40 Of note, the seminal pathologic study of chronic bronchitis by Reid suggested that mucosal involvement in chronic bronchitis is not uniform and a focal process with areas of significant goblet cell hypertrophy interspersed with normal mucosa.41
AFD is affected by both innate airway anatomy and later-life changes. Embryonic airway budding and early life morphogenesis are regulated by a number of genetic and cellular factors.42 Airway narrowing and remodeling due to external exposures later in life, or changes in airway geometry induced by adjacent emphysema, may alter AFD.17 Low AFD due to native airway structure or remodeling later in life may predispose individuals to a higher risk of chronic bronchitis in the setting of resumed or continued smoking. A recent study by Smith and colleagues suggested that the presence of central airway branch variation in the form of either additional accessory airways or missing branches predisposes to developing airflow obstruction and COPD.43 Dysnapsis has also been shown to be a predictor of incident airflow obstruction.44 Total airway count changes are likely permanent and confer a higher risk for chronic bronchitis and its persistence. Decimal changes in AFD imply a significant remodeling as AFD in non-smokers is 1.56 (SD 0.07) in the COPDGene study.17 Our results may aid identification of and targeting individuals with chronic bronchitis who may need interventions consisting of just avoiding exposures versus more prolonged medical therapies or interventional therapies.45
Our study has several strengths. The COPDGene study included well-characterized participants with a wide range of airflow obstruction. All spirometry and CT studies were subject to stringent quality control. We classified chronic bronchitis using two definitions. Although this led to differences in prevalence rates, the associations with airway metrics were similar, supporting the robustness of the results. Our study also has a few limitations. First, we defined persistence of chronic bronchitis using participant responses 5-years apart. Chronic bronchitis status may have fluctuated in the interval between the two visits. Persistent chronic bronchitis status is less affected by this, but we may have missed some individuals who did not have chronic bronchitis at the second visit but changed status just prior to the follow-up visit. However, the use of both the classic definition and the SGRQ-based definition alleviates this concern. Second, we also did not have information on when participants quit smoking. This should not however affect the results significantly as symptoms of chronic bronchitis improve within weeks after quitting smoking, albeit not return to normal, and also because we applied the alternative SGRQ-based definition of chronic bronchitis which has a shorter period of 1-month recall of symptoms compared with the classic 2-year definition. Third, COPDGene included non-Hispanic Whites and African Americans, and these findings should be tested in other populations.
Conclusions
Airway remodeling features are differentially associated with the presence of chronic bronchitis and its persistence over time, regardless of changes in smoking status. These structural risk factors may help identify individuals at differential risk, and hence targeting personalized preventative and therapeutic interventions.
Supplementary Material
What is the key question?
Although chronic bronchitis is strongly associated with cigarette smoking, not all smokers develop chronic bronchitis.
What is the bottom line?
In a cohort of current and former smokers, we demonstrated that higher total airway count and airway fractal dimension appear to confer a reserve against persistent chronic bronchitis.
Why read on?
These findings support consideration of structural airway characteristics as risk factors for chronic bronchitis.
Acknowledgements
The views expressed in this manuscript are those of the authors and so not necessarily reflect the position or policy of the Department of Veterans Affairs or the United States Government.
Funding: This work was supported by NHLBI R01 HL151421 (SPB and AN), NHLBI K23HL133438 (SPB), and NIBIB R21EB027891 (SPB). SF is supported by the Department of Veterans Affairs (Award No. 14380). The COPDGene study is supported by NIH Grants R01 HL089897 and R01 HL089856. The COPDGene project is also supported by the COPD Foundation through contributions made to an Industry Advisory Board comprised of AstraZeneca, Boehringer Ingelheim, Novartis, Pfizer, Siemens, Sunovion and GlaxoSmithKline.
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