COPD - Harrison's Principles of Internal Medicine (22nd Ed., 2025)

Definition

• Emphysema - anatomically defined; destruction of alveoli with air space enlargement
• Chronic bronchitis - clinically defined; chronic cough + phlegm production
• Small airway disease - small bronchioles narrowed and reduced in number

Pathogenesis & Pathology

Large Airway Disease

• Cigarette smoking → mucus gland enlargement + goblet cell hyperplasia → chronic cough/sputum (chronic bronchitis)
• Mucus plugs on CT are associated with increased mortality risk
• Squamous metaplasia - disrupts mucociliary clearance, increases carcinogenesis risk
• Neutrophil elastase is a potent secretagogue (independent of its proteolytic activity)

Small Airway Disease

• Primary site of increased airflow resistance in most COPD patients
• Early COPD is driven by small airway disease - narrowed by cellular hyperplasia, mucus, and fibrosis
• The transition zone (respiratory bronchioles) is critical in early disease

Emphysema

• Alveolar destruction results from an imbalance of proteases and antiproteases, and oxidants and antioxidants
• Cigarette smoke activates macrophages and neutrophils → release of elastase, matrix metalloproteinases
• Alpha-1 antitrypsin (AAT) deficiency is the best-defined genetic risk factor
  • Affects ~1-2% of COPD patients; autosomal codominant
  • PiZZ genotype: serum AAT levels ~15% of normal
  • Should be tested in all COPD patients, especially those with early onset (<45 years), panlobular emphysema, or family history
• Panacinar emphysema - associated with AAT deficiency (lower lobes predominant)
• Centrilobular emphysema - associated with cigarette smoking (upper lobes predominant)

Systemic Effects

Diagnosis & Assessment

Spirometry

• Post-bronchodilator FEV1/FVC <0.7 confirms airflow obstruction
• FEV1 % predicted determines GOLD grade severity

GOLD ABE Classification (2024 GOLD Report)

• Group A - Few symptoms (mMRC 0-1, CAT <10), low exacerbation risk (0-1 moderate exacerbations not leading to hospitalization)
• Group B - More symptoms (mMRC ≥2, CAT ≥10), low exacerbation risk
• Group E - High exacerbation risk (≥2 moderate exacerbations OR ≥1 hospitalization per year)

Symptom Scoring Tools

• mMRC (Modified Medical Research Council) Dyspnea Scale: 0 (only with strenuous activity) to 4 (too breathless to leave house)
• CAT (COPD Assessment Test): 0-40 scale; ≥10 = more symptoms

Imaging

• Chest X-ray: hyperinflation, flattened diaphragms, increased AP diameter, bullae
• CT chest: best for characterizing emphysema (centrilobular vs. paraseptal vs. panlobular), airway disease, mucus plugging
• CT is superior to spirometry for assessing emphysema distribution and predicting exacerbation risk

Laboratory

• ABG: assess for hypoxemia (PaO2 <55 mmHg) and hypercapnia - guides oxygen therapy
• CBC: polycythemia in chronic hypoxemia
• Alpha-1 antitrypsin level: test all COPD patients at least once

Management

Stable COPD

Non-Pharmacologic (proven mortality benefit)

1. Smoking cessation - most impactful intervention; slows FEV1 decline
2. Supplemental oxygen (for resting PaO2 ≤55 mmHg, or ≤59 with cor pulmonale/polycythemia) - only non-surgical therapy proven to improve survival
3. Lung volume reduction surgery (LVRS) - in selected patients (upper-lobe emphysema + low exercise capacity after rehab)
4. Pulmonary rehabilitation - improves dyspnea, exercise tolerance, quality of life; reduces hospitalization
5. Vaccinations: influenza (annual), pneumococcal, COVID-19, RSV (recommended)

Pharmacotherapy

• Nicotine replacement therapy (patch, gum, lozenge, inhaler, nasal spray)
• Bupropion
• Varenicline (nicotinic receptor partial agonist - most effective)

• NOT recommended as monotherapy in COPD
• Triple therapy (LABA + LAMA + ICS) - reduces mortality in selected patients, particularly those with:
  • Blood eosinophil count ≥300 cells/μL
  • History of asthma-COPD overlap
  • Frequent exacerbations despite dual bronchodilator therapy
• Risk: increased pneumonia with ICS use

• Roflumilast - oral anti-inflammatory; reduces exacerbations in severe COPD with chronic bronchitis phenotype; GI side effects (nausea, weight loss)

• Azithromycin (250 mg/day or 500 mg 3x/week) - reduces exacerbation frequency in select patients (former smokers, high exacerbation risk); risk of hearing loss and cardiac arrhythmia

• N-acetylcysteine and carbocysteine - modest benefit in reducing exacerbations in non-ICS patients

• IV AAT replacement for patients with AAT deficiency and established airflow obstruction; slows emphysema progression

Initial Treatment Algorithm (GOLD Groups):

• Group A: As-needed bronchodilator (SABA or SAMA)
• Group B: Long-acting bronchodilator (LAMA preferred, or LABA+LAMA)
• Group E: LAMA + LABA; add ICS if eos ≥300 or frequent exacerbations

COPD Exacerbations

• Mild: managed with increased bronchodilators alone
• Moderate: requires antibiotics and/or systemic corticosteroids
• Severe: requires hospital admission

• Bronchodilators: increase frequency of SABA (± SAMA); nebulization in severe cases
• Systemic corticosteroids: prednisone 40 mg/day × 5 days (short course equivalent to longer course); reduces treatment failure and hospital length of stay
• Antibiotics: indicated for purulent sputum, severe exacerbations; aminopenicillin ± clavulanate, macrolides, or tetracyclines; fluoroquinolones for Pseudomonas risk
• Supplemental oxygen: target SpO2 88-92% to avoid hypercapnic respiratory failure
• NIV (Non-invasive ventilation): for acute hypercapnic respiratory failure (pH <7.35, PaCO2 >45); reduces intubation rate and mortality
• Mechanical ventilation: if NIV fails or contraindicated

Interventional & Surgical Options

Bronchoscopic Therapies (for severe emphysema):

• Endobronchial valves (EBV) - one-way valves causing lobar atelectasis; most effective with absent collateral ventilation (Chartis assessment); risk of pneumothorax
• Coils - mechanical compression of hyperinflated lung
• Vapor (thermal) ablation - targeted delivery of heated steam to destroy emphysematous lung

Lung Volume Reduction Surgery (LVRS):

• Best candidates: upper-lobe predominant emphysema + low baseline exercise capacity after pulmonary rehab
• NETT trial showed survival benefit in this subgroup; high-risk if FEV1 <20% + homogeneous emphysema or DLCO <20%

Lung Transplantation:

• Last resort for end-stage COPD; bilateral lung transplant preferred
• Improved quality of life; uncertain survival benefit

Prognosis

• BODE Index predicts mortality: BMI, Obstruction (FEV1), Dyspnea (mMRC), Exercise capacity (6MWT)
• Higher BODE score = worse prognosis
• Frequent exacerbations, low DLCO, hypoxemia, hypercapnia, pulmonary hypertension, low BMI are all adverse prognostic factors