What is the pathophysiology and management of Chronic Obstructive Pulmonary Disease (COPD)?

How COPD Works: Pathophysiology and Disease Mechanisms

COPD is a progressive lung disease where chronic inflammation from inhaled toxins—primarily cigarette smoke—causes irreversible airflow limitation through two main mechanisms: destruction of lung tissue (emphysema) and narrowing/inflammation of small airways, resulting in air trapping and impaired gas exchange. 1, 2

Core Definition and Diagnostic Criteria

COPD is characterized by persistent respiratory symptoms (dyspnea, cough, sputum production) and airflow limitation that does not change markedly over several months 1. The diagnosis requires:

• Post-bronchodilator FEV1/FVC ratio ≤0.7 on spirometry, confirming non-completely reversible airflow obstruction 2, 1
• Symptoms are commonly underreported by patients, making objective testing essential 1

The Two Primary Pathological Processes

1. Emphysema (Parenchymal Destruction)

• Permanent destructive enlargement of airspaces distal to terminal bronchioles without obvious fibrosis 1, 3
• Loss of alveolar attachments to airway walls causes airways to collapse during expiration 3, 4
• Results in loss of lung elastic recoil, appearing early in disease development 3
• Two major patterns exist:
  • Panacinar emphysema: destruction of entire acinus 3
  • Centriacinar emphysema: destruction of respiratory bronchioles and alveolar ducts at acinus center, with surrounding alveoli remaining intact 3

2. Small Airway Disease (Airway Component)

• Peripheral airways (small bronchi and bronchioles) are the main sites of increased airflow resistance 2
• Pathological changes include:
  • Increased caliciform (goblet) cells and intraluminal mucus 2
  • Inflammation with neutrophils, lymphocytes, and activated macrophages 2, 4
  • Increased airway wall muscle mass and fibrosis 2, 3
  • Airway obliteration and narrowing 2
  • Decreased luminal diameters from wall thickening and changes in lining fluid 1

Central Airway Changes

• Hyperplasia of submucosal tracheobronchial glands and surface goblet cells, even in early disease stages 2
• Increased proportion of acidic mucus in submucosal glands 2
• Upregulation of vascular adhesion molecules that recruits inflammatory cells 2
• Important caveat: Mucus gland thickness relates to sputum production but NOT to loss of respiratory function 3

The Inflammatory Cascade

Cigarette smoking is the primary trigger, causing an exaggerated inflammatory response in susceptible individuals 2, 1:

• Increased neutrophils, lymphocytes, and activated macrophages in airways compared to non-smokers 2
• Inflammatory mediators including oxidants and proteases cause lung damage 4
• Smoke alters lung repair responses: inhibition of repair leads to emphysematous destruction, while abnormal repair causes peribronchiolar fibrosis 4
• Great variation exists in individual susceptibility—not all smokers develop COPD 2

Functional Consequences

Airflow Limitation Mechanisms

• In mild-to-moderate COPD: small airway abnormalities play the greater role 3
• In severe COPD: emphysema becomes the most important factor in airflow limitation 3
• Loss of alveolar attachments to bronchioles contributes to respiratory tract stenosis 2

Gas Exchange Abnormalities

• Hypersecretion of mucus and ciliary dysfunction 2
• Airflow limitation and hyperinflation 2
• Gas exchange anomalies leading to hypoxemia 1

Cardiovascular Complications

• Progressive pulmonary hypertension develops with severe disease 1
• Right ventricular hypertrophy or cor pulmonale 1
• Pulmonary hypertension implies poor prognosis 1

Systemic Effects

COPD is not only a lung disease but also a systemic inflammatory disorder 4:

• Muscular weakness 4
• Increased risk for atherosclerotic vascular disease 4
• Depression 4
• Osteoporosis 4
• Abnormalities in fluid and electrolyte balance 4
• Significant concomitant chronic diseases increase morbidity and mortality 1

Natural History and Progression

• Persistent smoking is the main factor associated with rapid longitudinal decline in FEV1 and poor prognosis 2
• Smoking cessation reduces the rapid decline in FEV1 2
• The disease is slowly progressive and often diagnosed late when already moderately advanced 2
• COPD may be punctuated by acute exacerbations—acute worsening of respiratory symptoms 1

Key Diagnostic Distinctions

COPD vs. Chronic Asthma (Common Pitfall)

The most difficult diagnostic problem is distinguishing COPD from persistent airflow limitation of chronic asthma in older subjects 1, 2:

Features favoring COPD diagnosis:

• Heavy smoking history 1
• Evidence of emphysema on imaging 1
• Decreased diffusing capacity (DLCO) 1, 3
• Chronic hypoxemia 1

Features favoring asthma diagnosis:

• Atopy 1
• Marked spirometric improvement with bronchodilators or corticosteroids 1

Phenotypic Variations

• Airway eosinophilia is associated with measurable bronchodilator response to β-agonists and relatively less emphysema for any degree of airflow limitation 3
• Lower DLCO characterizes emphysema-dominant patients 3
• Less prominent cough and sputum production are typical of emphysema-dominant patients 3

Risk Factors Beyond Smoking

• Environmental exposures: biomass fuel exposure and air pollution 1
• Occupational exposure to dust or fumes 1
• Host factors: genetic abnormalities (notably alpha-1 antitrypsin deficiency), abnormal lung development, and accelerated aging 1, 4