Extrafine ICS/LABA Versus As-Needed SABA for Small Airway Dysfunction in Symptomatic Patients With Preserved Spirometry

Effects of Extrafine Inhaled Corticosteroid/Long-Acting β2-Agonist Therapy on Small Airway Dysfunction and Type 2 Inflammatory Biomarkers in Symptomatic Patients With Preserved Spirometry

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.

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.

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