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Original Research: Asthma |

Poor Symptom Control Is Associated With Reduced CT Scan Segmental Airway Lumen Area in Smokers With AsthmaNarrowed Segmental Airways in Smokers With Asthma FREE TO VIEW

Neil C. Thomson, MD; Rekha Chaudhuri, MD; Mark Spears, PhD; Claudia-Martina Messow, PhD; William MacNee, MD; Martin Connell, BSc; John T. Murchison, MD; Michael Sproule, MBChB; Charles McSharry, PhD
Author and Funding Information

From the Institute of Infection, Immunity and Inflammation (Drs Thomson, Chaudhuri, Spears, and McSharry), and the Robertson Centre for Biostatistics (Dr Messow), University of Glasgow, Glasgow; the UoE/MRC Centre for Inflammation Research, Medical Physics and Clinical Radiology (Drs MacNee and Murchison and Mr Connell), University of Edinburgh, Edinburgh; and the Department of Radiology (Dr Sproule), Gartnavel General Hospital, Glasgow, Scotland.

CORRESPONDENCE TO: Neil C. Thomson, MD, Institute of Infection, Immunity and Inflammation, University of Glasgow and Respiratory Medicine, Gartnavel General Hospital, Glasgow, G12 OYN Scotland; e-mail: neil.thomson@glasgow.ac.uk


Part of this article has been presented previously at the 2014 American Thoracic Society International Conference, May 16-21, 2014, San Diego, CA.

FUNDING/SUPPORT: This work was funded by an award [INF-GU-090] from the Translational Medicine Research Collaboration, a consortium made up of the Universities of Glasgow, Edinburgh, Aberdeen, and Dundee; the four associated National Health Service (NHS) Health Boards (Greater Glasgow and Clyde, Lothian, Grampian, and Tayside); Scottish Enterprise; and Pfizer (formerly Wyeth). This study was also supported financially by NHS Research Scotland (NRS) through the Scottish Primary Care Research Network.

Reproduction of this article is prohibited without written permission from the American College of Chest Physicians. See online for more details.


Chest. 2015;147(3):735-744. doi:10.1378/chest.14-1119
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BACKGROUND:  Cigarette smoking is associated with worse symptoms in asthma and abnormal segmental airways in healthy subjects. We tested the hypothesis that current symptom control in smokers with asthma is associated with altered segmental airway dimensions measured by CT scan.

METHODS:  In 93 subjects with mild, moderate, and severe asthma (smokers and never smokers), we recorded Asthma Control Questionnaire-6 (ACQ-6) score, spirometry (FEV1; forced expiratory flow rate, midexpiratory phase [FEF25%-75%]), residual volume (RV), total lung capacity (TLC), and CT scan measures of the right bronchial (RB) and left bronchial (LB) segmental airway dimensions (wall thickness, mm; lumen area, mm2) in the RB3/LB3, RB6/LB6, and RB10/LB10 (smaller) airways.

RESULTS:  The CT scan segmental airway (RB10 and LB10) lumen area was reduced in smokers with asthma compared with never smokers with asthma; RB10, 16.6 mm2 (interquartile range, 12.4-19.2 mm2) vs 19.6 mm2 (14.7-24.2 mm2) (P = .01); LB10, 14.8 mm2 (12.1-19.0 mm2) vs 19.9 mm2 (14.5-25.0 mm2) (P = .003), particularly in severe disease, with no differences in wall thickness or in larger airway (RB3 and LB3) dimensions. In smokers with asthma, a reduced lumen area in fifth-generation airways (RB10 or LB10) was associated with poor symptom control (higher ACQ-6 score) (−0.463 [−0.666 to −0.196], P = .001, and −0.401 [−0.619 to −0.126], P = .007, respectively) and reduced postbronchodilator FEF25%-75% (0.521 [0.292-0.694], P < .001, and [0.471 [0.236-0.654], P = .001, respectively) and higher RV/TLC %.

CONCLUSIONS:  The CT scan segmental airway lumen area is reduced in smokers with asthma compared with never smokers with asthma, particularly in severe disease, and is associated with worse current symptom control and small airway dysfunction.

Figures in this Article

Prevalence rates for active cigarette smoking in asthma range from < 20% to > 35%.14 Adult smokers with asthma have worse symptom control, increased exacerbation rates, and high levels of health-care use compared with never smokers with asthma.1,3,5,6 In addition, the efficacy of corticosteroids is impaired in smokers with asthma.1,710 The mechanisms accounting for poorly controlled asthma in cigarette smokers are currently unclear,1,11 including whether alterations to the structure and function of segmental and/or small airways contribute to worse symptoms in smokers with asthma compared with never smokers with asthma.12,13

Using CT scanning to measure dimensions of the segmental airways in nonsmokers with asthma, it is found that wall thickness is increased in severe asthma compared with mild asthma,1417 that the lumen area is reduced in asthma compared with healthy subjects,13 and that an increased airway wall area is associated with worse symptoms.18 Cigarette smoking in healthy subjects is associated with increased CT scan segmental airway wall thickness19,20 and a reduced lumen area.20 Dysfunction of the small airways (defined as airways with an internal diameter < 2 mm) is associated with poor current asthma control in nonsmokers with asthma.2126

The combined effects of asthma and cigarette smoke could contribute to poor symptom control and an impaired response to treatment, at least in part as a result of dysfunction of the segmental and/or small airways. We wished to test the hypothesis that impaired symptom control in smokers with asthma compared with never smokers with asthma is associated with narrowed segmental airways, increased wall thickness, or both as measured by CT scan dimensions and/or is associated with abnormal tests of small airway function.

Subjects and Study Design

A cross-sectional study was performed in subjects with asthma who were recruited to the Glasgow COPD and Asthma Biomarker study.27 Clinical, physiologic, and CT scan measurements were taken. Participants with mild, moderate, and severe persistent asthma (GINA [Global Initiative for Asthma] classification)28 (both current smokers and never smokers) were recruited. Asthma criteria included the following: age range of 18 to 75 years and duration of asthma ≥ 6 months; symptoms of episodic wheezing, chest tightness, and/or dyspnea; objective confirmation by airway hyperactivity determined by a ≥ 20% drop in FEV1 at a methacholine dose of ≤ 8 mg/mL or when FEV1 < 60% predicted, by evidence of airflow variability with a ≥ 12% and 200 mL increase in FEV1 following 2.5 mg nebulized albuterol. All subjects had been taking stable medication for 4 weeks, and had had no exacerbation of disease for 4 weeks. Smokers were defined as those who had smoked for ≥ 10 pack-years and were currently smoking five or more cigarettes per day. The West Glasgow Research Ethics Committee approved the study, and all patients gave written informed consent (MREC approval number 07/SO709/46).

Measurements
Questionnaire:

The Asthma Control Questionnaire-6 (ACQ-6) score29 was obtained.

Lung Function Tests:

Spirometry was performed according to American Thoracic Society guidelines30; measurements included FEV1, FVC, reversibility, and forced expiratory flow rate, midexpiratory phase (FEF25%-75%). Airway hyperresponsiveness to methacholine (provocation concentration methacholine causing a 20% drop in FEV1 [PC20]) was measured.31 Lung volumes (residual volume [RV] and total lung capacity [TLC]) and diffusing capacity of lung for carbon monoxide (Dlco) were performed using the body box technique (Zan500 Body Plethysmography; nSpire Health, Inc).

CT Scan of the Chest:

Scans were performed at full inspiration using 16-slice Brightspeed and 64-slice Lightspeed scanners (GE CT scanner) with the following parameters: 120 kV; 100 mAs; collimation, 1 mm; reconstruction slice thickness, 0.65 mm; reconstruction slice separation, 0.5 mm; and pitch, 1; the data were reconstructed with a chest (CHST) filter. All scans were evaluated centrally at the University of Edinburgh. Airway dimensions were measured with the software Pulmonary Workstation 2.0 (VIDA Diagnostics, Inc), which plotted an airway path from which airway profiles were generated on cross-sections orthogonal to this airway path. Airway dimensions were measured at 1-mm intervals in the right bronchial (RB) or left bronchial (LB) segment from airway generation 3 (RB3, RB6 or LB3, LB6 larger airways) and airway generation 5 (RB10 or LB10, smaller airway) using the convention of generation number based upon number of branch points from the trachea. The following CT scan airway values were obtained: wall thickness (mm) and lumen area (mm2). Emphysema was quantified as the percentage of lung CT scan voxels below a threshold of −950 Hounsfield units (%LAA950).

Statistical Analysis

Continuous variables were summarized as median (interquartile range). Comparison between different patient groups was by Student t test or one-way analysis of variance for approximately normally distributed variables and by Wilcoxon test or Kruskal-Wallis test for other variables. Categorical variables were summarized by their observed frequencies and percentages within the participant subsets. These values were compared using Fisher exact probability tests including the Freeman-Halton extension for variables with more than two categories. Analyses were considered descriptive or exploratory. Secondary analyses were adjusted for multiple testing (Bonferroni correction). Data were analyzed using R version 2.15 (The R Project for Statistical Computing).32

Demographics and Baseline Clinical Characteristics

Smokers with asthma compared with never smokers with asthma had higher ACQ-6 scores (1.87 [1.27-2.67] vs 1.00 [0.46-1.79], P < .001) (Table 1). Smokers with asthma and never smokers with asthma were similar in terms of age, sex, duration of asthma, dose of inhaled corticosteroid, body surface area, and PC20 (Table 1).

Table Graphic Jump Location
TABLE 1 ]  Demographics and Baseline Clinical, Lung Function, and CT Scan Characteristics

Data are presented as Median (interquartile range) or No. (%). ACQ-6 = Asthma Control Questionnaire-6; BSA = body surface area; COHb = carboxyhemoglobin; Dlco = diffusing capacity of lung for carbon monoxide, corrected for hemoglobin and carboxyhemoglobin; FEF25%-75% = forced expiratory flow rate, midexpiratory range; LB = left bronchial (LB10 [smaller fifth-generation airway], LB6 and RB3 [larger third-generation airway]); PC20 = provocative concentration causing a 20% drop in FEV1; % below −950 = % of lung CT scan voxels below a threshold of −950 Hounsfield units; RB = right bronchial (RB10 [smaller fifth-generation airway], RB6 and RB3 [larger third-generation airway]); RV/TLC = residual volume/total lung capacity.

a 

P < .05.

CT Imaging
Asthma and Smoking Status:

Median (interquartile range) RB10 (smaller airway) measurements of airways dimensions showed a decrease in airway lumen area in smokers with asthma compared with never smokers with asthma (16.6 mm2 [12.4-19.2 mm2] vs 19.6 mm2 [14.7-24.2 mm2], P = .010), with no difference in wall thickness (1.7 mm [1.5-1.9 mm] vs 1.8 mm [1.5-2.1 mm], P = .366) (Figs 1A, 1B, Table 1). Similar changes were seen in LB10 airway dimensions (lumen area: smokers, 14.8 mm2 [12.1-19.0 mm2] vs never smokers, 19.9 mm2 [14.5-25.0 mm2], P = .003; wall thickness: smokers, 1.8 mm [1.6-2.0 mm] vs never smokers, 1.7 mm [1.6-2.1 mm], P = .790) (Table 1). There were no significant changes in airway dimensions in RB3 or LB3 between smokers with asthma compared with never smokers with asthma (Figs 1A, 1B, Table 1). There was no increase in the extent of emphysema as measured by %LAA950 in smokers with asthma compared with never smokers with asthma (P = .258); values were < 10% and were consistent with values in a healthy population.

Figure Jump LinkFigure 1 –  Asthma, smoking status, and CT scan airway dimensions. CT scan RB airway generation 3 (RB3, RB6) and 5 (RB10) lumen area (mm2) and wall thickness (mm) in S-asthma compared with NS-asthma. Box whisker graph: median, interquartile range, and outliers. A, Lumen area. B, Wall thickness. NS-asthma = never smokers with asthma; RB = right bronchial; S-asthma = smokers with asthma.Grahic Jump Location
Current Symptom Control:

In smokers with asthma, a reduced airway lumen in the smaller airways (RB10 or LB10) was associated with poor symptom control (ACQ-6 score, −0.463 [−0.666 to −0.196], P = .001 [Fig 2A], and −0.401 [−0.619 to −0.126], P = .007, respectively). These associations were not present in the never smokers with asthma group. RB6 and RB3 lumen areas were not significantly associated with ACQ-6 score in either smokers or never smokers with asthma. In patients with uncontrolled asthma (ACQ-6 score ≥ 1.5), the median (interquartile range) lumen area in RB10, but not in RB6 or RB3, was significantly reduced in smokers compared with never smokers with asthma (RB10, 14.5 mm2 [10.6-18.2 mm2] vs 17.5 mm2 [15.3-25.2 mm2], P = .008), whereas there was no difference in patients with controlled/partly controlled asthma (ACQ-6 score < 1.5) (Table 2). The LB10 lumen area was reduced in smokers with uncontrolled asthma compared with never smokers with uncontrolled asthma (P = .016) (Table 2). Airway wall thickness was similar between smokers with uncontrolled asthma and never smokers with uncontrolled asthma (Table 2).

Figure Jump LinkFigure 2 –  Association between CT scan RB10 lumen area, Asthma Control Questionnaire-6 score, and small airway function. In smokers with asthma, the linear regression line (solid) with the true 95% CI (dashed lines) demonstrated that a reduced airway lumen in the smaller airways (RB10) was significantly associated with poor symptom control (high Asthma Control Questionnaire-6 score) (−0.373 [−0.598 to −0.093], P = 0.011) and postbronchodilator FEF25-75 (0.512 [0.261-0.698], P < 0.001). A, Asthma Control Questionnaire. B, FEF25-75. FEF25-75 = forced expiratory flow rate, midexpiratory phase. See Figure 1 legend for expansion of other abbreviations.Grahic Jump Location
Table Graphic Jump Location
TABLE 2 ]  Comparison of CT Scan Measures and Tests of Lung Function in Smokers With Asthma and Never Smokers With Asthma With Uncontrolled Asthma (ACQ-6 Score ≥ 1.5) and Controlled Asthma (ACQ-6 < 1.5)

Data are presented as median (interquartile range). See Table 1 for expansion of abbreviations.

a 

Bonferroni, P ≤ .025.

Asthma Severity:

The lumen area was reduced in the RB10 (P = .049) and RB6 (P = .004) and in the LB10 (P = .007) and LB6 (P = .008) of smokers with severe asthma compared with never smokers with severe asthma, but the differences were not significant in patients with mild or moderate disease (Table 3). There was no increase in the extent of emphysema as measured by %LAA950 in smokers with severe asthma compared with never smokers with severe asthma (P = .711) (Table 3).

Table Graphic Jump Location
TABLE 3 ]  Comparison of CT Scan Measurements and Tests of Lung Function in Smokers With Asthma and Never Smokers With Asthma, and GINA Severity of Asthma

Data are presented as median (interquartile range). See Table 1 for expansion of abbreviations.

a 

Bonferroni, P < .0125.

Lung Function
Asthma and Smoking Status:

Smokers with asthma compared with never smokers with asthma had a lower FEV1/FVC ratio (72% [66%-78%] vs 78% [69%-84%], P = .02), lower FEF25%-75% predicted (44% [30%-58%] vs 55% [37%-76%], P = .018), lower postbronchodilator FEF25%-75% (1.6 L/s [1.0-2.7 L/s] vs 2.3 L/s [1.6-3.2 L/s], P = .016) and lower Dlco (76% [64%-84%] vs 86% [80%-92%], P = .001) (Table 1). Smokers with asthma and never smokers with asthma were similar in terms of RV/TLC % predicted (Table 1).

Current Symptom Control:

In smokers with asthma, poor symptom control (ACQ-6 score) was associated with a reduced postbronchodilator FEV1/FVC (−0.328 [−0.555 to −0.055], P = .014), reduced FEF25%-75% predicted (−0.393 [−0.605 to −0.129], P = .003), reduced postbronchodilator FEF25%-75% (−0.428 [−0.631 to −0.170], P = .001), and higher RV/TLC % predicted (0.408 [−0.616 to −0.147], P = .003). These associations were not present in the never smokers with asthma group.

Smokers and never smokers with uncontrolled asthma (ACQ-6 score ≥ 1.5) were similar for FEF25%-75% predicted (34.5% [25.8%-50.5%] vs 46% [37.8%-61.0%], P = .175), postbronchodilator FEF25%-75% (1.4 L/s [0.9-2.1 L/s] vs 2.2 L/s [1.5-2.6 L/s], P = .062) and RV/TLC % predicted (123% [108.0%-137.0%] vs 116% [109.0%-139.5%], P = .577) (Table 2). Dlco (69% [60%-77%] vs 85% [77.8%-92.8%], P = .001) was significantly reduced in smokers compared with never smokers in uncontrolled groups (Table 2).

Asthma Severity:

Smokers with severe asthma compared with never smokers with severe asthma had a lower FEV1/FVC ratio (68.5 [59.7-71.5] vs 77.5 [66.0-82.5], P = .01), lower postbronchodilator FEF25%-75% (1.2 L/s [0.9-1.6] vs 2.3 L/s [1.7-2.6], P = .01) and lower Dlco (66.5% [56.0%-76.5%] vs 87.5% [80.0%-94.2%], P = .003) (Table 3). There were no significant differences in smokers and never smokers with mild and moderate asthma.

Association Between CT Scan Measurements and Lung Function

In smokers with asthma, a reduced airway lumen in the smaller airways (RB10) was associated with a reduced FEV1 % predicted (0.446 [0.179-0.652], P = .001), reduced FEF25%-75% predicted (0.478 [0.232-0.688], P < .001), reduced post-bronchodilator FEF25%-75% (0.521 [0.292-0.694], P < .001) (Fig 2B), and a higher RV/TLC % predicted (−0.450 [−0.679 to −0.184], P < .001) . A reduced LB10 lumen area was associated with a reduced FEF25%-75% predicted (0.329 [0.070-0.546], P = .029), reduced postbronchodilator FEF25%-75% (0.471 [0.236-0.654], P = .001), and a higher RV/TLC % predicted (−0.478 [−0.478 to −0.244], P = .001), although not with FEV1 percent predicted (0.229 [−0.039-0.465], P = .135). A reduced airway lumen in the smaller airways (RB10 and LB10) was associated with a high pack-year number (−0.417 [−0.631 to −0.145], P = .003, and −0.332 [−0.548 to −0.074], P = .028, respectively). In never smokers with asthma, CT scan airway dimensions were not significantly associated with tests of lung function.

In this study, we tested the hypothesis that current symptom control in smokers with asthma is associated with narrowed segmental airways and/or increased wall thickness as measured by CT scan. A major strength of the study was the comprehensive assessment of CT scan measures of airway lumen area and thickness in smokers with asthma compared with never smokers with asthma, and their association with clinical outcomes and tests of small airway function.

Chronic cigarette smoking in subjects without asthma is associated with slightly increased wall thickness of the segmental airways,20,33,34 and in patients with asthma, CT scan wall thickness is increased in severe disease compared with patients with mild asthma.1417 We found that CT scan wall thickness in third- to fifth-generation airways was similar in smokers with asthma compared with never smokers with asthma. Neither uncontrolled asthma nor disease severity was associated with increased airway wall thickness in smokers with asthma. Taken together, these findings suggest that chronic cigarette smoking does not increase segmental airway wall thickening in asthma.

The CT scan segmental lumen area in smaller fifth-generation (RB10 and LB10) airways was significantly reduced in smokers with asthma compared with never smokers with asthma, particularly in severe disease. Factors that may influence CT scan airway dimension measurements such as age, sex, duration of asthma, body surface area, and dose of inhaled corticosteroid were similar between the two asthma groups. Current smoking has been associated with narrower airway lumen diameters20 possibly because of acute constriction by cigarette smoke. Against this mechanism, changes in lumen area were not found in the largest, most proximal airways (RB3) that would be expected to be exposed to the highest concentrations of inhaled tobacco smoke. A reduced segmental lumen area (RB10 and LB10) was associated with pack-year history, which may suggest that chronic cigarette smoking contributes to reduced lumen area in asthma. Tobacco smoke induces damage to the structures that support the small airways, which may lead to uncoupling of the peripheral airways from the parenchyma.35 However, values of %LAA950 in both groups with asthma were similar to previous values reported in healthy never smokers.36,37 These data therefore do not indicate significant emphysema in either never smokers with asthma or smokers with asthma. Chronic mucus hypersecretion occurs frequently in smokers with asthma, particularly in those patients with severe disease,4,5,38 and it is plausible that mucus accumulation could reduce the airway lumen area.

In the current study, smokers with asthma had higher ACQ-6 scores, indicating poor current symptom control. A reduced CT scan segmental lumen area was inversely associated with a higher ACQ-6 score and uncontrolled asthma (ACQ-6 ≥ 1.5). These findings suggest that a reduced segmental airway lumen area, along with other factors including corticosteroid insensitivity,1,79 may contribute to worse current symptom control in smokers with asthma compared with never smokers with asthma.

Small airway dysfunction may contribute to poor symptom control in never smokers with asthma.2126 In the current study, we found that the findings of tests thought to reflect small airway function, including measurement of FEF25%-75% and RV/TLC %, were worse in smokers with asthma compared with never smokers with asthma, suggesting a greater degree of small airway dysfunction, particularly in the severe smoking group. Tests of global lung function (FEV1/FVC), as well as small airway function, in the smoking group were significantly associated with worse asthma symptoms, although lung function was not significantly different in patients with uncontrolled asthma with a different smoking status. CT scan dimension measurements in this study were from segmental third- to fifth-generation airways, whereas small airways are approximately 12th generation airways and above.39 Several tests of small airway function in the smokers with asthma, such as a reduced FEF25%-75% predicted and an increased RV/TLC % predicted, were associated with a reduced CT scan lumen area (RB10 and LB10).

There are several potential limitations to our study, including a lack of bronchial biopsy data to confirm the CT scan evidence that segmental airway wall thickness is not increased in smokers with asthma compared with never smoker with asthma. The cross-sectional study design used did not allow us to determine the variability of CT scan and lung function measurements over time. Potential inaccuracy of CT scan measurements of airway measurements may exist because no standard methodology exists. For example, narrowing of the lumen could be a result of remodeling of the airway wall, which was not shown as an increase in airway wall thickness, possibly because of the difficulty of measuring the outer airway wall in these smaller airways. The version of the software used to analyze the CT scan dimensions in the study did not have the facility to label subsegmental airways, although there are issues about the accuracy of measurements made in smaller airways. It would have been interesting to have undertaken expiratory scans, but unfortunately, this was not included in the protocol. The analyses of the data were exploratory, involving multiple statistical testing, and as such, the results will need to be confirmed by further studies and may provide pilot data for an appropriate future power analysis.

In conclusion, the segmental airway lumen area is reduced in smokers with asthma compared with never smokers with asthma, particularly in severe disease, and it is associated with worse current symptom control and small airway dysfunction. Further research is indicated to determine the mechanisms accounting for the segmental and small airway dysfunction in smokers with asthma and whether targeting these airways with, for example, extrafine particle inhaled corticosteroids12 or other therapies,40 may improve asthma control in this patient group.

Author contributions: N. C. T. is the guarantor of this study and takes responsibility for the content of the manuscript, including the data and analysis. He is accountable for all aspects of the work and will ensure that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. N. C. T., R. C., C.-M. M., W. M., and C. M. contributed to the conception of the study; N. C. T., R. C., M. Spears, C.-M. M., W. M., M. C., J. T. M., and C. M. contributed to the design of the study; R. C., M. Sproule, and C. M. contributed to the acquisition of the data; N. C. T., R. C., M. Spears, C.-M. M., W. M., M. C., J. T. M., M. Sproule, and C. M. contributed to the interpretation of the data, drafting of the submitted article, and final approval of the version to be published.

Financial/nonfinancial disclosures: The authors have reported to CHEST the following conflicts of interest: Dr MacNee has acted in an advisory capacity for GlaxoSmithKline, Pfizer Inc, Novartis, and Almirall. He has received payment from GlaxoSmithKline and Pfizer Inc for research programs and clinical activities and has received payments from Boehringer-Ingelheim, GlaxoSmithKline, AstraZeneca, Novartis, and Janssen Pharmaceuticals, Inc to travel to meetings and/or present at conferences. Drs Thomson, Chaudhuri, Spears, Messow, Murchison, Sproule, McSharry and Mr Connell have reported that no potential conflicts of interest exist with any companies/organizations whose products or services may be discussed in this article.

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 are grateful to Joyce Thompson, RGN; Jane Lafferty, RGN; Maureen Brannigan, RGN; Lisa Jolly, BSc; and Iona Donnelly, BSc, for assistance with data collection.

ACQ-6

Asthma Control Questionnaire-6

Dlco

diffusing capacity of lung for carbon monoxide

FEF25%-75%

forced expiratory flow rate, midexpiratory phase

LB

left bronchial

PC20

provocation concentration methacholine causing a 20% drop in FEV1

%LAA950

percentage of lung CT scan voxels below a threshold of −950 Hounsfield units

RB

right bronchial

RV

residual volume

TLC

total lung capacity

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Burgel PR, Bourdin A, Chanez P, et al. Update on the roles of distal airways in COPD [published correction appears inEur Respir Review. 2011;20(120):123]. Eur Respir Review. 2011;20(119):7-22. [CrossRef]
 
Donohue KM, Hoffman EA, Baumhauer H, et al. Cigarette smoking and airway wall thickness on CT scan in a multi-ethnic cohort: the MESA Lung Study. Respir Med. 2012;106(12):1655-1664. [CrossRef] [PubMed]
 
Lipworth B. Targeting the small airways asthma phenotype: if we can reach it, should we treat it? Ann Allergy Asthma Immunol. 2013;110(4):233-239. [PubMed]
 
van der Wiel E, ten Hacken NHT, Postma DS, van den Berge M. Small-airways dysfunction associates with respiratory symptoms and clinical features of asthma: a systematic review. J Allergy Clin Immunol. 2013;131(3):646-657. [PubMed]
 
van den Berge M, ten Hacken NHT, Cohen J, Douma WR, Postma DS. Small airway disease in asthma and COPD: clinical implications. Chest. 2011;139(2):412-423. [PubMed]
 
Scichilone N, Battaglia S, Taormina S, Modica V, Pozzecco E, Bellia V. Alveolar nitric oxide and asthma control in mild untreated asthma. J Allergy Clin Immunol. 2013;131(6):1513-1517. [PubMed]
 
Contoli M, Bousquet J, Fabbri LM, et al. The small airways and distal lung compartment in asthma and COPD: a time for reappraisal. Allergy. 2010;65(2):141-151. [CrossRef] [PubMed]
 
Lipworth B, Manoharan A, Anderson W. Unlocking the quiet zone: the small airway asthma phenotype. Lancet Respir Med. 2014;2(6):497-506. [PubMed]
 
Chaudhuri R, McSharry C, Brady J, et al. Sputum matrix metalloproteinase-12 in patients with chronic obstructive pulmonary disease and asthma: relationship to disease severity. J Allergy Clin Immunol. 2012;129(3):655-663. [PubMed]
 
Global Strategy for Asthma Management and Prevention. Global Initiative for Asthma website. http://www.ginasthma.com. Accessed February 12, 2014.
 
Juniper EF, O’Byrne PM, Guyatt GH, Ferrie PJ, King DR. Development and validation of a questionnaire to measure asthma control. Eur Respir J. 1999;14(4):902-907. [PubMed]
 
Miller MR, Hankinson J, Brusasco V, et al; ATS/ERS Task Force. Standardisation of spirometry. Eur Respir J. 2005;26(2):319-338. [PubMed]
 
Cockcroft DW, Killian DN, Mellon JJ, Hargreave FE. Bronchial reactivity to inhaled histamine: a method and clinical survey. Clin Allergy. 1977;7(3):235-243. [PubMed]
 
R Foundation for Statistical Computing. R: a language and environment for statistical computing. http://www.R-project.org. Accessed February 12, 2014.
 
Deveci F, Murat A, Turgut T, Altuntaş E, Muz MH. Airway wall thickness in patients with COPD and healthy current smokers and healthy non-smokers: assessment with high resolution computed tomographic scanning. Respiration. 2004;71(6):602-610. [CrossRef] [PubMed]
 
Berger P, Perot V, Desbarats P, Tunon-de-Lara JM, Marthan R, Laurent F. Airway wall thickness in cigarette smokers: quantitative thin-section CT assessment. Radiology. 2005;235(3):1055-1064. [CrossRef] [PubMed]
 
Saetta M, Ghezzo H, Kim WD, et al. Loss of alveolar attachments in smokers. A morphometric correlate of lung function impairment. Am Rev Respir Dis. 1985;132(4):894-900. [PubMed]
 
Gevenois PA, Scillia P, de Maertelaer V, Michils A, De Vuyst P, Yernault JC. The effects of age, sex, lung size, and hyperinflation on CT lung densitometry. AJR Am J Roentgenol. 1996;167(5):1169-1173. [PubMed]
 
Gietema HA, Müller NL, Fauerbach PV, et al; Evaluation of COPD Longitudinally to Identify Predictive Surrogate Endpoints (ECLIPSE) investigators. Quantifying the extent of emphysema: factors associated with radiologists’ estimations and quantitative indices of emphysema severity using the ECLIPSE cohort. Acad Radiol. 2011;18(6):661-671. [PubMed]
 
Lange P, Parner J, Vestbo J, Schnohr P, Jensen G. A 15-year follow-up study of ventilatory function in adults with asthma. N Engl J Med. 1998;339(17):1194-1200. [PubMed]
 
Evans DJ, Green M. Small airways: a time to revisit? Thorax. 1998;53(8):629-630. [CrossRef] [PubMed]
 
Spears M, Donnelly I, Jolly L, et al. Bronchodilatory effect of the PPAR-gamma agonist rosiglitazone in smokers with asthma. Clin Pharmacol Ther. 2009;86(1):49-53. [PubMed]
 

Figures

Figure Jump LinkFigure 1 –  Asthma, smoking status, and CT scan airway dimensions. CT scan RB airway generation 3 (RB3, RB6) and 5 (RB10) lumen area (mm2) and wall thickness (mm) in S-asthma compared with NS-asthma. Box whisker graph: median, interquartile range, and outliers. A, Lumen area. B, Wall thickness. NS-asthma = never smokers with asthma; RB = right bronchial; S-asthma = smokers with asthma.Grahic Jump Location
Figure Jump LinkFigure 2 –  Association between CT scan RB10 lumen area, Asthma Control Questionnaire-6 score, and small airway function. In smokers with asthma, the linear regression line (solid) with the true 95% CI (dashed lines) demonstrated that a reduced airway lumen in the smaller airways (RB10) was significantly associated with poor symptom control (high Asthma Control Questionnaire-6 score) (−0.373 [−0.598 to −0.093], P = 0.011) and postbronchodilator FEF25-75 (0.512 [0.261-0.698], P < 0.001). A, Asthma Control Questionnaire. B, FEF25-75. FEF25-75 = forced expiratory flow rate, midexpiratory phase. See Figure 1 legend for expansion of other abbreviations.Grahic Jump Location

Tables

Table Graphic Jump Location
TABLE 1 ]  Demographics and Baseline Clinical, Lung Function, and CT Scan Characteristics

Data are presented as Median (interquartile range) or No. (%). ACQ-6 = Asthma Control Questionnaire-6; BSA = body surface area; COHb = carboxyhemoglobin; Dlco = diffusing capacity of lung for carbon monoxide, corrected for hemoglobin and carboxyhemoglobin; FEF25%-75% = forced expiratory flow rate, midexpiratory range; LB = left bronchial (LB10 [smaller fifth-generation airway], LB6 and RB3 [larger third-generation airway]); PC20 = provocative concentration causing a 20% drop in FEV1; % below −950 = % of lung CT scan voxels below a threshold of −950 Hounsfield units; RB = right bronchial (RB10 [smaller fifth-generation airway], RB6 and RB3 [larger third-generation airway]); RV/TLC = residual volume/total lung capacity.

a 

P < .05.

Table Graphic Jump Location
TABLE 2 ]  Comparison of CT Scan Measures and Tests of Lung Function in Smokers With Asthma and Never Smokers With Asthma With Uncontrolled Asthma (ACQ-6 Score ≥ 1.5) and Controlled Asthma (ACQ-6 < 1.5)

Data are presented as median (interquartile range). See Table 1 for expansion of abbreviations.

a 

Bonferroni, P ≤ .025.

Table Graphic Jump Location
TABLE 3 ]  Comparison of CT Scan Measurements and Tests of Lung Function in Smokers With Asthma and Never Smokers With Asthma, and GINA Severity of Asthma

Data are presented as median (interquartile range). See Table 1 for expansion of abbreviations.

a 

Bonferroni, P < .0125.

References

Thomson NC, Chaudhuri R. Asthma in smokers: challenges and opportunities. Curr Opin Pulm Med. 2009;15(1):39-45. [CrossRef] [PubMed]
 
To T, Stanojevic S, Moores G, et al. Global asthma prevalence in adults: findings from the cross-sectional world health survey. BMC Public Health. 2012;12(1):204. [CrossRef] [PubMed]
 
Thomson NC, Chaudhuri R, Heaney LG, et al. Clinical outcomes and inflammatory biomarkers in current smokers and exsmokers with severe asthma. J Allergy Clin Immunol. 2013;131(4):1008-1016. [CrossRef] [PubMed]
 
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Thomson NC, Chaudhuri R, Messow CM, et al. Chronic cough and sputum production are associated with worse clinical outcomes in stable asthma. Respir Med. 2013;107(10):1501-1508. [CrossRef] [PubMed]
 
Boulet L-P, Lemière C, Archambault F, Carrier G, Descary MC, Deschesnes F. Smoking and asthma: clinical and radiologic features, lung function, and airway inflammation. Chest. 2006;129(3):661-668. [CrossRef] [PubMed]
 
Chalmers GW, Macleod KJ, Little SA, Thomson LJ, McSharry CP, Thomson NC. Influence of cigarette smoking on inhaled corticosteroid treatment in mild asthma. Thorax. 2002;57(3):226-230. [CrossRef] [PubMed]
 
Tomlinson JEM, McMahon AD, Chaudhuri R, Thompson JM, Wood SF, Thomson NC. Efficacy of low and high dose inhaled corticosteroid in smokers versus non-smokers with mild asthma. Thorax. 2005;60(4):282-287. [CrossRef] [PubMed]
 
Chaudhuri R, Livingston E, McMahon AD, Thomson L, Borland W, Thomson NC. Cigarette smoking impairs the therapeutic response to oral corticosteroids in chronic asthma. Am J Respir Crit Care Med. 2003;168(11):1308-1311. [CrossRef] [PubMed]
 
Lazarus SC, Chinchilli VM, Rollings NJ, et al; National Heart Lung and Blood Institute’s Asthma Clinical Research Network. Smoking affects response to inhaled corticosteroids or leukotriene receptor antagonists in asthma. Am J Respir Crit Care Med. 2007;175(8):783-790. [CrossRef] [PubMed]
 
Polosa R, Thomson NC. Smoking and asthma: dangerous liaisons. Eur Respir J. 2013;41(3):716-726. [CrossRef] [PubMed]
 
Contoli M, Kraft M, Hamid Q, et al. Do small airway abnormalities characterize asthma phenotypes? In search of proof. Clin Exp Allergy. 2012;42(8):1150-1160. [CrossRef] [PubMed]
 
Donohue KM, Hoffman EA, Baumhauer H, et al. Asthma and lung structure on computed tomography: the Multi-Ethnic Study of Atherosclerosis Lung Study. J Allergy Clin Immunol. 2013;131(2):361-368. [CrossRef] [PubMed]
 
Niimi A, Matsumoto H, Amitani R, et al. Airway wall thickness in asthma assessed by computed tomography. Relation to clinical indices. Am J Respir Crit Care Med. 2000;162(4 pt 1):1518-1523. [CrossRef] [PubMed]
 
Little SA, Sproule MW, Cowan MD, et al. High resolution computed tomographic assessment of airway wall thickness in chronic asthma: reproducibility and relationship with lung function and severity. Thorax. 2002;57(3):247-253. [CrossRef] [PubMed]
 
Awadh N, Müller NL, Park CS, Abboud RT, FitzGerald JM. Airway wall thickness in patients with near fatal asthma and control groups: assessment with high resolution computed tomographic scanning. Thorax. 1998;53(4):248-253. [CrossRef] [PubMed]
 
Aysola RS, Hoffman EA, Gierada D, et al. Airway remodeling measured by multidetector CT is increased in severe asthma and correlates with pathology. Chest. 2008;134(6):1183-1191. [CrossRef] [PubMed]
 
Brillet P-Y, Grenier PA, Fetita CI, et al. Relationship between the airway wall area and asthma control score in moderate persistent asthma. Eur Radiol. 2013;23(6):1594-1602. [CrossRef] [PubMed]
 
Burgel PR, Bourdin A, Chanez P, et al. Update on the roles of distal airways in COPD [published correction appears inEur Respir Review. 2011;20(120):123]. Eur Respir Review. 2011;20(119):7-22. [CrossRef]
 
Donohue KM, Hoffman EA, Baumhauer H, et al. Cigarette smoking and airway wall thickness on CT scan in a multi-ethnic cohort: the MESA Lung Study. Respir Med. 2012;106(12):1655-1664. [CrossRef] [PubMed]
 
Lipworth B. Targeting the small airways asthma phenotype: if we can reach it, should we treat it? Ann Allergy Asthma Immunol. 2013;110(4):233-239. [PubMed]
 
van der Wiel E, ten Hacken NHT, Postma DS, van den Berge M. Small-airways dysfunction associates with respiratory symptoms and clinical features of asthma: a systematic review. J Allergy Clin Immunol. 2013;131(3):646-657. [PubMed]
 
van den Berge M, ten Hacken NHT, Cohen J, Douma WR, Postma DS. Small airway disease in asthma and COPD: clinical implications. Chest. 2011;139(2):412-423. [PubMed]
 
Scichilone N, Battaglia S, Taormina S, Modica V, Pozzecco E, Bellia V. Alveolar nitric oxide and asthma control in mild untreated asthma. J Allergy Clin Immunol. 2013;131(6):1513-1517. [PubMed]
 
Contoli M, Bousquet J, Fabbri LM, et al. The small airways and distal lung compartment in asthma and COPD: a time for reappraisal. Allergy. 2010;65(2):141-151. [CrossRef] [PubMed]
 
Lipworth B, Manoharan A, Anderson W. Unlocking the quiet zone: the small airway asthma phenotype. Lancet Respir Med. 2014;2(6):497-506. [PubMed]
 
Chaudhuri R, McSharry C, Brady J, et al. Sputum matrix metalloproteinase-12 in patients with chronic obstructive pulmonary disease and asthma: relationship to disease severity. J Allergy Clin Immunol. 2012;129(3):655-663. [PubMed]
 
Global Strategy for Asthma Management and Prevention. Global Initiative for Asthma website. http://www.ginasthma.com. Accessed February 12, 2014.
 
Juniper EF, O’Byrne PM, Guyatt GH, Ferrie PJ, King DR. Development and validation of a questionnaire to measure asthma control. Eur Respir J. 1999;14(4):902-907. [PubMed]
 
Miller MR, Hankinson J, Brusasco V, et al; ATS/ERS Task Force. Standardisation of spirometry. Eur Respir J. 2005;26(2):319-338. [PubMed]
 
Cockcroft DW, Killian DN, Mellon JJ, Hargreave FE. Bronchial reactivity to inhaled histamine: a method and clinical survey. Clin Allergy. 1977;7(3):235-243. [PubMed]
 
R Foundation for Statistical Computing. R: a language and environment for statistical computing. http://www.R-project.org. Accessed February 12, 2014.
 
Deveci F, Murat A, Turgut T, Altuntaş E, Muz MH. Airway wall thickness in patients with COPD and healthy current smokers and healthy non-smokers: assessment with high resolution computed tomographic scanning. Respiration. 2004;71(6):602-610. [CrossRef] [PubMed]
 
Berger P, Perot V, Desbarats P, Tunon-de-Lara JM, Marthan R, Laurent F. Airway wall thickness in cigarette smokers: quantitative thin-section CT assessment. Radiology. 2005;235(3):1055-1064. [CrossRef] [PubMed]
 
Saetta M, Ghezzo H, Kim WD, et al. Loss of alveolar attachments in smokers. A morphometric correlate of lung function impairment. Am Rev Respir Dis. 1985;132(4):894-900. [PubMed]
 
Gevenois PA, Scillia P, de Maertelaer V, Michils A, De Vuyst P, Yernault JC. The effects of age, sex, lung size, and hyperinflation on CT lung densitometry. AJR Am J Roentgenol. 1996;167(5):1169-1173. [PubMed]
 
Gietema HA, Müller NL, Fauerbach PV, et al; Evaluation of COPD Longitudinally to Identify Predictive Surrogate Endpoints (ECLIPSE) investigators. Quantifying the extent of emphysema: factors associated with radiologists’ estimations and quantitative indices of emphysema severity using the ECLIPSE cohort. Acad Radiol. 2011;18(6):661-671. [PubMed]
 
Lange P, Parner J, Vestbo J, Schnohr P, Jensen G. A 15-year follow-up study of ventilatory function in adults with asthma. N Engl J Med. 1998;339(17):1194-1200. [PubMed]
 
Evans DJ, Green M. Small airways: a time to revisit? Thorax. 1998;53(8):629-630. [CrossRef] [PubMed]
 
Spears M, Donnelly I, Jolly L, et al. Bronchodilatory effect of the PPAR-gamma agonist rosiglitazone in smokers with asthma. Clin Pharmacol Ther. 2009;86(1):49-53. [PubMed]
 
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