Small Airway Dysfunction
Conditions
Keywords
Impulse oscillometry, Small airway reversibility, Extrafine inhaled corticosteroid, Type 2 inflammation, Fractional exhaled nitric oxide, Preserved spirometry
Brief summary
This study evaluates whether 4 weeks of extrafine inhaled corticosteroid/long-acting β2-agonist (beclomethasone dipropionate/formoterol fumarate, BDP/FOR) therapy improves clinical, physiological, and type 2 inflammatory outcomes compared with as-needed short-acting β2-agonist (SABA, salbutamol) alone in symptomatic patients who have preserved conventional spirometry but impulse oscillometry (IOS)-defined small airway dysfunction (SAD) and small airway reversibility (SAR) after bronchodilator inhalation. Participants were randomized 1:1 to receive extrafine BDP/FOR plus as-needed salbutamol, or as-needed salbutamol alone, for 4 weeks. Symptom score (Asthma Control Test), spirometry, IOS parameters, type 2 inflammatory biomarkers (FeNO, blood eosinophils, IgE), and rescue medication use were assessed before and after treatment.
Detailed description
Symptomatic patients with asthma-like respiratory symptoms may have preserved conventional spirometry (FEV1/FVC ≥ 0.7, FVC ≥ 80% predicted, negative bronchodilator reversibility) yet still exhibit small airway dysfunction detectable only by impulse oscillometry (IOS). This prospective, single-center, open-label, randomized controlled trial enrolled adult patients (≥20 years) with chronic respiratory symptoms ≥8 weeks, preserved spirometry, IOS-defined SAD, and small airway reversibility (SAR), defined as AX \> 0.44 kPa/L with a post-bronchodilator reduction in AX ≥35% after salbutamol 400 µg. Eligible participants were randomized 1:1 to receive either extrafine beclomethasone dipropionate/formoterol fumarate (100 mcg/6 mcg, 1 puff twice daily) plus as-needed salbutamol, or as-needed salbutamol alone (100 mcg, up to 200 mcg per use, maximum 4 times daily), for 4 weeks. Outcomes assessed before and after treatment included Asthma Control Test (ACT) score, spirometry (FEV1, FVC), IOS parameters (R5-R20, resonant frequency \[Fres\], reactance at 5Hz \[X5\], reactance area \[AX\]) with pre/post-bronchodilator change, fractional exhaled nitric oxide (FeNO), blood eosinophil count, serum total IgE, and frequency of rescue SABA use. The primary endpoint was the between-group difference in change of IOS parameters after 4 weeks of treatment; secondary endpoints included changes in symptom score, conventional spirometry, and inflammatory biomarkers, as well as treatment safety and tolerability.
Interventions
DRUGBeclomethasone dipropionate/formoterol fumarate (extrafine)
Extrafine fixed-dose combination inhaler, 100 mcg beclomethasone dipropionate + 6 mcg formoterol fumarate dihydrate per actuation, 1 puff twice daily for 4 weeks. Arm(s): Extrafine BDP/FOR + as-needed SABA
DRUGSalbutamol
Short-acting β2-agonist metered-dose inhaler, 100 mcg/actuation, used as needed for symptom relief (max 200 mcg/use, max 4 times/day). Arm(s): As-needed SABA alone
Sponsors
Yi-Han Hsiao
Kaohsiung Chest Disease Prevention and Health Education Association
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Masking description
Open-label design; participants and investigators were not blinded to treatment allocation due to differing inhaler devices.
Eligibility
Sex/Gender
ALL
Age
20 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Age ≥20 years * Chronic respiratory symptoms (cough, sputum, chest tightness, dyspnea, or wheezing) for ≥8 weeks * Preserved spirometry: FEV1/FVC ≥0.7, FVC ≥80% predicted, and negative bronchodilator reversibility (increase in FEV1 or FVC \<12% and \<200 mL after salbutamol) * IOS-defined small airway dysfunction and small airway reversibility (SAR): AX \>0.44 kPa/L with post-bronchodilator reduction in AX ≥35% after salbutamol inhalation
Exclusion criteria
* Age \<20 years * Impaired spirometry (FEV1/FVC \<0.7, FVC ≤80% predicted, or positive bronchodilator reversibility) * Absence of SAD or lack of significant SAR * Respiratory symptoms absent or \<8 weeks * Acute respiratory condition within 4 weeks before enrollment (upper/lower respiratory tract infection, acute exacerbation, pneumonia requiring antibiotics, ED visit or hospitalization) * Current diagnosis of COPD, chronic respiratory infection, or structural lung disease (active/prior tuberculosis, bronchiectasis, interstitial/restrictive lung disease, arteriovenous malformation, or prior pulmonary surgery) * Use of any bronchodilator (oral/inhaled), theophylline, steroid (inhaled/oral/IV), or beta-blocker within 4 weeks before enrollment * Known hypersensitivity to beclomethasone dipropionate/formoterol fumarate or salbutamol * Contraindication to pulmonary function testing or venous blood sampling (severe/unstable cardiovascular disease, recent major thoracic/abdominal surgery, unresolved pneumothorax, uncontrolled bronchospasm or hemoptysis, need for FiO2 \>50%, impaired consciousness or dementia) * Other physician-assessed unsuitability for pulmonary function testing or blood sampling * Incomplete informed consent * Known HIV/AIDS infection * Pregnant or breastfeeding women
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change in Impulse Oscillometry (IOS) Parameters After 4 Weeks of Treatment | Baseline (Visit 1) and Week 4 (Visit 2) | Between-group difference in change from baseline (R5-R20, resonant frequency \[Fres\], reactance at 5 Hz \[X5\], and reactance area \[AX\]) at end of the 4-week treatment period. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Frequency of Rescue SABA Use | 4 weeks | Puffs of salbutamol per day, number of days requiring rescue medication, and number of weeks with SABA use ≥2 puffs/week during the 4-week treatment period. |
| Change in Asthma Control Test (ACT) Score | Baseline and Week 4 | — |
| Change in Fractional Exhaled Nitric Oxide (FeNO) | Baseline and Week 4 | — |
| Change in Spirometric Parameters (FEV1, FVC) | Baseline and Week 4 | — |
| Change in Type 2 Inflammatory Biomarkers (Blood Eosinophil Count, Serum Total IgE) | Baseline and Week 4 | — |
Countries
Taiwan
Contacts
PRINCIPAL_INVESTIGATORYi-Han Hsiao, MD, PhD
Taipei Veterans General Hospital, Department of Chest Medicine
Outcome results
None listed