This study aims to investigate the prognosis and clinical outcomes of patients with chronic obstructive pulmonary disease (COPD) who continue to experience refractory dyspnea despite treatment with long-acting beta-agonist (LABA) and long-acting muscarinic antagonist (LAMA). The research will prospectively follow a cohort of patients to identify clinical factors, lung function parameters, imaging features, and cardiovascular indicators associated with poor treatment response. By comparing these patients with those who show symptom improvement, the study seeks to determine predictors of exacerbations, lung function decline, and mortality. Findings are expected to guide the development of targeted strategies to improve the management of refractory dyspnea in COPD.

The study aims to identify actionable clinical factors and develop predictive models that can enhance personalized management approaches for patients with refractory dyspnea in COPD.

This is a prospective observational cohort study designed to characterize patients with COPD who remain symptomatic despite standard inhaled therapy with LABA/LAMA combination. Participants will be enrolled from outpatient clinics and followed over time to assess changes in respiratory symptoms, lung function, exercise capacity, acute exacerbation frequency, and survival.

Key assessments include:

• Baseline demographic and clinical data (e.g., respiratory symptoms, comorbidities, smoking history).
• Pulmonary function tests (spirometry and lung volumes), exercise capacity evaluations, echocardiography, chest radiographs, and computed tomography (CT).
• Biomarker analysis (blood tests including inflammatory and cardiac markers).

Patients will be classified into two groups:

• Refractory COPD group - Patients with minimal improvement in dyspnea (defined as modified Medical Research Council (mMRC) ≥ 2 with <1 point reduction or COPD Assessment Test (CAT) ≥ 10 with <4 point reduction after ≥3 months of LABA/LAMA therapy).
• Control group - Patients showing symptomatic improvement with the same therapy (mMRC <2 or ≥1 point reduction, or CAT <10 or ≥4 point reduction).

The primary analyses will explore clinical and physiological predictors of poor outcomes, using advanced statistical modeling such as linear mixed-effects models for longitudinal lung function trends, negative binomial regression for exacerbation risk, and Cox proportional hazards models for survival analysis.

Assessments:

Baseline and follow-up evaluations will include demographic and clinical data, comorbidities, smoking history, inhaler adherence and technique, spirometry, lung volume measurements, 6-minute walk tests, echocardiography, chest radiographs, and high-resolution CT scans. Blood tests will include complete blood count, inflammatory markers (C-reactive protein (CRP), fibrinogen), N-terminal pro-B-type natriuretic peptide (NT-proBNP), and cardiac enzymes.

Statistical Analysis:

Longitudinal trends: Changes in lung function, symptoms, and exercise capacity will be assessed using linear mixed-effects models to evaluate the influence of clinical factors.

Acute exacerbations: The frequency of moderate-to-severe exacerbations will be analyzed using negative binomial regression or zero-inflated models when appropriate.

Mortality: Logistic regression will estimate 1-, 3-, and 5-year mortality risk, while Cox proportional hazards models will evaluate time-to-event outcomes.

Predictive modeling: Candidate biomarkers and imaging features will be incorporated into multivariable predictive models to identify key determinants of poor prognosis.

Inclusion Criteria:

• Adults (≥ 18 years) diagnosed with chronic obstructive pulmonary disease (COPD) according to Global Initiative for Chronic Obstructive Lung Disease (GOLD) 2025 criteria:
• Presence of COPD risk factors (e.g., smoking history, occupational exposure, genetic predisposition).
• Typical symptoms such as dyspnea, cough, or sputum production.
• Post-bronchodilator FEV1/FVC < 0.70.
• Regular outpatient follow-up at the respiratory clinic.
• Received LABA/LAMA combination therapy for at least 3 months prior to enrollment.
• Ability and willingness to provide written informed consent.

Exclusion Criteria:

• Poor adherence to LABA/LAMA therapy (medication possession rate < 50%) or refusal of treatment.

• Inability or unwillingness to comply with scheduled visits, examinations, or follow-up procedures.

• Presence of severe comorbid conditions expected to significantly affect prognosis, including:

  • End-stage diseases with life expectancy < 1 year.
  • Terminal malignancies receiving hospice or palliative care.

• Any condition that, in the opinion of the investigator, would interfere with study participation or data reliability.

This study will enroll adult patients (≥ 18 years) diagnosed with chronic obstructive pulmonary disease (COPD) according to the GOLD 2025 criteria, who are receiving combination therapy with long-acting beta2-agonist (LABA) and long-acting muscarinic antagonist (LAMA). Participants include both patients who continue to experience refractory dyspnea despite treatment and those who show symptomatic improvement. All participants must be able to attend regular outpatient visits and provide written informed consent.

Individual participant data will not be shared because the dataset contains sensitive personal health information, and there are no current plans or infrastructure for secure data sharing. Data will be used solely for analyses specified in the approved protocol and will remain confidential in accordance with institutional and IRB guidelines.