Small Airway Dysfunction in Asthma Is Associated with Perceived Respiratory Symptoms, Non-Type 2 Airway Inflammation, and Poor Responses to Therapy

Abstract

<b><i>Background:</i></b> Emerging evidence has indicated that small airway dysfunction (SAD) contributes to the clinical expression of asthma. <b><i>Objectives:</i></b> The aim of the study was to explore the relationships of SAD assessed by forced expiratory flow between 25 and 75% (FEF_25–75%), with clinical and inflammatory profile and treatment responsiveness in asthma. <b><i>Method:</i></b> In study I, dyspnea intensity (Borg scale), chest tightness, wheezing and cough (visual analog scales, VASs), and pre- and post-methacholine challenge testing (MCT) were analyzed in asthma patients with SAD and non-SAD. In study II, asthma subjects with SAD and non-SAD underwent sputum induction, and inflammatory mediators in sputum were detected. Asthma patients with SAD and non-SAD receiving fixed treatments were prospectively followed up for 4 weeks in study III. Spirometry, Asthma Control Questionnaire (ACQ), and Asthma Control Test (ACT) were carried out to define treatment responsiveness. <b><i>Results:</i></b> SAD subjects had more elevated ΔVAS for dyspnea (<i>p</i> = 0.027) and chest tightness (<i>p</i> = 0.032) after MCT. Asthma patients with SAD had significantly elevated interferon (IFN)-γ in sputum (<i>p</i> &#x3c; 0.05), and Spearman partial correlation found FEF_25–75% significantly related to IFN-γ and interleukin-8 (both having <i>p</i> &#x3c; 0.05). Furthermore, multivariable regression analysis indicated SAD was significantly associated with worse treatment responses (decrease in ACQ ≥0.5 and increase in ACT ≥3) (<i>p</i> = 0.022 and <i>p</i> = 0.032). <b><i>Conclusions:</i></b> This study indicates that SAD in asthma predisposes patients to greater dyspnea intensity and chest tightness during bronchoconstriction. SAD patients with asthma are characterized by non-type 2 inflammation that may account for poor responsiveness to therapy.