Assessing small airway impairment in mild-to-moderate smoking asthmatic patients

To the Editor:

Asthma is characterised by airway inflammation throughout the bronchial tree, including the small airways. In asthma, small airway alterations are associated with poor clinical outcomes [1]. Cigarette smoke is known to induce peripheral airway abnormalities, asthmatic smokers exhibit a more rapid lung function decline, experience more frequent exacerbations and are more likely to be uncontrolled, even when the disease is managed as recommended [2]. The mechanisms accounting for poor responses to treatment in smoking asthmatic patients are currently unclear, although low accessibility to inhaled medications in the peripheral airways is considered a limiting factor for the efficacy of such treatments [3].

Currently, small-particle-size inhaled treatments (mass median aerodynamic diameter <2 μm), which feature increased peripheral deposition relative to standard formulations, are available [4]. A recent observational study reported the efficacy of inhaled small-particle-size formulations in comparison to standard formulations, with regard to the improvements in clinical outcomes in a population of smoking asthmatic patients [5]. Thereby, suggesting that targeting peripheral alterations might yield clinical benefits in this population.

In this study, we hypothesised that cigarette smoking aggravates small airway abnormalities in asthmatic patients. The primary study outcome was an assessment of small airway dysfunction in smoking asthmatics. In addition, we evaluated the effect of switching the pre-existing standard-size particle inhaled treatment to an equipotent small-particle-size inhaled formulation.

Cross-sectional phase and primary outcome. Stable asthmatic patients (i.e. no exacerbations and changes in inhaled treatments during the 3 months preceding the study) were consecutively screened at the Respiratory Department of the University of Ferrara (Ferrara, Italy). Never smokers or current smokers (10–20 pack-years) with mild-to-moderate asthma who ranged in age from 18 to 50 years, free from an exacerbation for a minimum of 2 months and treated for at least 3 months with low-dose standard-particle-size inhaled corticosteroids (ICS) (step 2) alone or together with long-acting β₂ agonists (LABA) (ICS/LABA, fixed-dose combination; step 3) [6] were included. We adopted a lower cut-off limit of 10 pack-years, a usual standard in clinical trials, to qualify smokers. The upper limit of 20 pack-years was arbitrarily chosen to reduce the inclusion of subjects with advanced/irreversible chronic obstructive pulmonary disease-like peripheral alterations. Patients were excluded if they had been treated with small-particle-size formulations before entering the study, had irreversible airflow limitation after inhaling 400 μg of albuterol (i.e. post bronchodilator forced expiratory volume in 1 s (FEV1)/forced vital capacity (FVC) <70%), or had an impaired diffusion capacity (predicted diffusing capacity of the lungs for carbon monoxide <80%).

Longitudinal phase. After the initial assessment, patients entered a 3-month open-label treatment intervention. During this period, inhaled standard-particle-size treatments were switched to small-particle-size formulations at ICS equipotent doses, these included either: 1) small-particle-size beclomethasone (BDP) (Chiesi Farmaceutici Spa, Parma, Italy) alone for patients previously treated with standard-size-particle ICS alone; or 2) small-particle-size BDP/formoterol combination (F) (Chiesi Farmaceutici Spa) for patients previously treated with a standard-particle-size ICS/LABA combination [7–10].

The initial and final visits comprised the following: 1) physical examination; 2) asthma control test (ACT) assessment; and 3) lung function and nitrogen single-breath testing and impulse oscillometry (Vmax and Jaeger Master Screen-IOS; Carefusion Technologies, San Diego, CA, USA). Smoking was not permitted 1 h prior to testing. This study was approved by the local ethics committee, and patients provided signed informed consent before enrolment.

The primary study outcome was the phase III slope (dN₂) during a single-breath nitrogen washout test (SBNT) at baseline. Secondary outcomes included airway resistance at different frequencies (R5, R5–R20) as measured by impulse oscillometry, lung volume, and asthma control. Pre-specified outcomes included changes in the functional and clinical outcomes at the end of the 3-month small-particle-size treatment intervention. As no previous studies specifically investigated dN₂ via SBNT in smoking asthmatic patients, we based our sample size calculation on the existing literature regarding small airway impairment in asthmatic patients [11, 12]. We estimated that 23 patients/group would be sufficient to detect inter-group differences in the dN₂ of at least 25% by SBNT (primary study outcome). At each time point, inter-group differences were calculated using an unpaired t-test or the Mann–Whitney test. Paired t-tests or Wilcoxon matched pair tests, linear regression analysis, and the Pearson test were used when appropriate. p-values of <0.05 were considered significant.

50 asthmatic patients (25 current smokers and 25 nonsmokers matched for demographics, baseline lung volumes, and treatment) completed the study (table 1). The primary objective, dN₂ measured by SBNT, was significantly higher in smokers, compared with nonsmoking asthmatic patients, indicating increased ventilation heterogeneity in the small airways of smokers with asthma (table 1). Impulse oscillometry testing was performed as an additional sensitivity assessment. The R5–R20, which reflects the contributions of small airways to airway resistance, but not R5 (total airway resistance), was significantly higher in smokers, compared to nonsmoking asthmatic patients (table 1), in accordance with previous descriptive reports [13] that envisioned an increasingly impaired small airway function in smoking relative to nonsmoking asthmatic patients. However, pathologic events that lead to increased ventilation heterogeneity and peripheral airway resistance in smoking asthmatics are largely unknown. In a recent study, computed tomography revealed a reduced lumen area in the smaller airways of smoking asthmatic patients, suggesting that peripheral airway narrowing might contribute to small airway dysfunction [14].

In this study, no inter-group differences were observed in the baseline ACT score or the use of rescue medication in the month before the study (table 1). However, a higher percentage of smoking asthmatics reported an ACT score ≤19, compared to nonsmokers (32 versus 20% for smoking versus nonsmoking asthmatics, respectively; p=0.09). We further identified an inverse correlation between the level of asthma control and the magnitude of the dN₂ in smoking asthmatic patients (p<0.05, r=−0.47), but not in nonsmoking asthmatic patients, indicating the impact of small airway abnormalities associated with smoking on relevant clinical outcomes, such as asthma control.

The 3-month small-particle-size inhaled formulation treatment intervention led to significantly reduced dN₂ and R5–R20 values in smoking asthmatic patients (table 1). These reductions were accompanied by a significant improvement in the ACT scores among subjects with a baseline ACT score ≤19 (mean±sem of improvement 2.5±0.26 units from the baseline, p<0.05). No significant changes in small airway measurements were observed in nonsmoking asthmatic patients although, notably, the baseline dN₂ and R5–R20 values of nonsmoking asthmatic patients were near the lower limit of normality. Taken together, these data indicate that small-particle-size treatments could effectively reverse smoking-related small airway abnormalities in smoking asthmatics. Of course, as in all clinical trials, we cannot exclude a study participation effect.

An ancillary finding of this study was the significantly greater improvement in dN₂ following treatment with the BDP/F combination (changes in dN₂ −1.43±0.23 %·L^-1) versus BDP alone (changes in dN₂ −0.54±0.21 %·L^-1), p<0.05 in smoking asthmatics receiving small-particle-size treatment. However, given the small number of patients treated with BDP alone (table 1) this analysis can be considered only exploratory.

This study was the first to identify small airway dysfunction in smoking asthmatics as a primary objective. Although smoking cessation unquestionably remains the primary therapeutic option for these patients, this study has provided a mechanism to explain the efficacy of small-particle-size treatment in smoking asthmatic patients [5, 15].