Pathophysiology of COPD-Asthma Overlap Syndrome
The COPD-asthma overlap syndrome is characterized by a heterogeneous inflammatory disorder of the airways with features of both persistent airflow limitation and bronchodilator reversibility, demonstrating mixed inflammatory patterns including eosinophilic (35%), neutrophilic (19%), and mixed (10%) phenotypes. 1, 2
Inflammatory Patterns
Airway Inflammation
- Mixed inflammatory profile: Unlike the traditional view that asthma is purely eosinophilic and COPD purely neutrophilic, overlap syndrome demonstrates heterogeneous inflammation 1:
- Eosinophilic bronchitis (35%)
- Neutrophilic bronchitis (19%)
- Mixed inflammatory pattern (10%)
- Majority (>83%) of overlap patients with reduced lung function show sputum neutrophilia either alone or with concurrent eosinophilia 1
Systemic Inflammation
- Systemic inflammatory markers in overlap syndrome resemble those of COPD 1:
- Elevated IL-6
- Elevated C-reactive protein
- Elevated tumor necrosis factor-α
- Elevated surfactant protein A
- Reduced plasma levels of soluble receptor for advanced glycation end-products
Biomarkers
- Increased sputum myeloperoxidase levels (similar to COPD) 1
- Significantly elevated neutrophil gelatinase-associated lipocalin compared to COPD alone 1
- Some studies show association with eosinophilic bronchitis, while others report neutrophilic patterns with elevated IL-1β and bacterial colonization 1
Developmental Origins
Childhood Origins
- Long-standing childhood asthma can lead to incompletely reversible airflow obstruction in adults 1
- Risk factors for progression to overlap syndrome:
- Smoking (greatest effect in asthmatics who smoke)
- Severe childhood asthma (massively increases risk for adult COPD)
- Milder childhood asthma has lower risk (approximately 2%) 1
Structural Changes
- Adult smokers with childhood-onset asthma have smaller airways throughout the entire bronchial path compared to smokers without childhood asthma 1
- Recent evidence shows unsuspected mild diffuse centrilobular emphysema in never-smoked asthma patients at autopsy, despite mild changes on CT and normal diffusing capacity 3
- Loss of lung elastic recoil in never-smoked asthma patients may contribute to persistent airflow limitation 3
Clinical and Epidemiological Features
Prevalence and Demographics
- Affects approximately 20% of patients with obstructive airway diseases and 2% of the general population 2, 4
- Prevalence ranges from 8.6% to 33% among COPD patients 1
- More common in:
- Older patients (mean age 64.6 years)
- Predominantly male (69%, range 54-86%)
- Smokers (mean 38.7 pack-years) 1
Lung Function
- Post-bronchodilator FEV1 averages 49.3% predicted 1
- Mean bronchodilator response of 23.9% 1
- Persistent but partially reversible airflow limitation (post-bronchodilator FEV1/FVC <70%) 5
Clinical Implications
Disease Burden
- Increased morbidity compared to either condition alone 2
- Greater health status impairment 2
- More frequent exacerbations and hospitalizations 2, 6
- Possibly increased mortality (HR 1.45,95% CI 1.06-1.98) 2
- Better response to inhaled corticosteroids compared to pure COPD 1
Diagnostic Challenges
- No specific biomarkers to differentiate overlap syndrome from asthma or COPD 6
- Bronchodilator responsiveness alone is insufficient for recognizing different subgroups 2
- Patients typically excluded from randomized controlled trials, limiting evidence base 2
Treatment Implications
The heterogeneous inflammatory patterns in COPD-asthma overlap syndrome necessitate treatment approaches that address both the asthmatic and COPD components, with inhaled corticosteroids forming a cornerstone of therapy due to the potential eosinophilic component and demonstrated better response to this treatment compared to pure COPD.