COPD

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Chronic Obstructive Pulmonary Disease (COPD): Overview & Pathophysiology

Definition

The WHO defines COPD as "a common, preventable and treatable disease characterized by persistent respiratory symptoms and airflow limitation that is due to airway and/or alveolar abnormalities caused by exposure to noxious particles or gases." The airflow limitation is largely irreversible, distinguishing it from asthma.

The GOLD (Global Initiative for Chronic Obstructive Lung Disease) criteria confirm diagnosis with spirometry: a post-bronchodilator FEV1/FVC ratio < 0.70.

COPD is an umbrella term that encompasses two major overlapping patterns of lung injury:

Fig. 11.4 - Schematic showing overlap between emphysema, chronic bronchitis, and asthma. (Robbins & Kumar Basic Pathology)

Epidemiology & Risk Factors

Affects >10% of U.S. adults over age 40; the 3rd leading cause of death worldwide
Smoking accounts for ~80% of all cases; 35-50% of heavy smokers develop COPD
Women appear more susceptible than men
Other risk factors:
- Poor lung development in early life
- Environmental/occupational pollutants (sulfur dioxide, nitrogen dioxide, dust)
- Airway hyperresponsiveness
- Genetic: α1-antitrypsin (AAT) deficiency (~1% of emphysema cases)
- Respiratory infections in childhood
Robbins & Kumar Basic Pathology, p. 447

Component Diseases

1. Emphysema

Emphysema is defined anatomically as permanent enlargement of air spaces distal to the terminal bronchioles, with destruction of alveolar walls but without significant fibrosis.

Four Patterns:

Pattern	Location	Association
Centriacinar (centrilobular)	Central/proximal acinus; upper lobes	Cigarette smoking (most common, ~20x more frequent than panacinar)
Panacinar (panlobular)	Entire acinus uniformly; lower lobes	α1-antitrypsin deficiency
Distal acinar (paraseptal)	Distal acinus, near pleura	Young adults; spontaneous pneumothorax
Irregular	Irregular involvement	Scarring; usually clinically insignificant

Morphology: Pale, voluminous lungs; histology shows destroyed alveolar walls without fibrosis and enlarged air spaces. Alveolar capillaries are diminished. Terminal and respiratory bronchioles deform due to loss of anchoring septa.

Robbins & Kumar Basic Pathology, pp. 447-449

2. Chronic Bronchitis

Defined clinically (not anatomically) as a productive cough for at least 3 consecutive months in at least 2 consecutive years, in the absence of other explanations.

Key pathological feature: Hypersecretion of mucus from enlarged submucosal glands.

Reid Index: Ratio of mucous gland thickness to bronchial wall thickness. Normal ≤0.4. Raised (>0.4) in chronic bronchitis.

Morphology:

Hypertrophy of mucous glands in trachea and large bronchi
Goblet cell metaplasia in smaller bronchi and bronchioles
Inflammatory infiltrate: macrophages, neutrophils, lymphocytes (notably no eosinophils, unlike asthma)
Small airway disease (chronic bronchiolitis): mucous plugging, inflammation, submucosal fibrosis → luminal narrowing → airflow obstruction
Robbins & Kumar Basic Pathology, p. 449

Pathogenesis

Fig. 11.6 - Pathogenesis of emphysema. (Robbins & Kumar Basic Pathology)

Three central mechanisms drive alveolar destruction:

1. Inflammatory Cells & Mediators

Cigarette smoke and noxious particles trigger innate and adaptive immune responses. Key mediators include:

Leukotriene B4 and IL-8 (chemotactic for neutrophils)
TNF-α and other proinflammatory cytokines
Recruited cells: neutrophils, macrophages, CD4+ and CD8+ T cells
Lymphoid follicles are increasingly recognized as central to COPD pathogenesis; lymphatic vessel density increases around alveolar spaces and correlates with disease severity

2. Protease-Antiprotease Imbalance

This is the cornerstone mechanism:

Inflammatory cells release elastase and other proteases (matrix metalloproteinases) that degrade elastin and other extracellular matrix proteins
Normally countered by α1-antitrypsin (AAT) - encoded at the Pi locus on chromosome 14
Pi ZZ genotype (homozygous Z allele, ~0.01% of U.S. population): markedly reduced AAT → panacinar emphysema at an earlier age, worsened by smoking
Loss of alveolar elastic tissue reduces radial traction on respiratory bronchioles → dynamic airway collapse during expiration → functional airflow obstruction even without mechanical blockage

3. Oxidative Stress

Reactive oxygen species (ROS) in cigarette smoke cause direct tissue damage
ROS also stimulate macrophages and neutrophils to release more ROS (amplification loop)
Oxidative stress drives increased apoptosis and cellular senescence of structural lung cells

Airway Infection

Not involved in disease initiation
Bacterial/viral infections trigger acute exacerbations by sustaining inflammation
Robbins & Kumar Basic Pathology, pp. 447-449

Mechanisms of Airflow Obstruction

COPD causes obstruction through two main mechanisms:

Mechanism	Component
Loss of alveolar elastic recoil (radial traction) → dynamic collapse of small airways on expiration	Emphysema
Airway narrowing due to mucous plugging, goblet cell metaplasia, inflammation, and submucosal fibrosis	Chronic bronchitis / small airway disease

Functional Consequences

Spirometry: Reduced FEV1, normal or near-normal FVC → reduced FEV1/FVC ratio (< 0.70)
Air trapping → hyperinflation → barrel chest, flattened diaphragm on imaging
Ventilation-perfusion (V/Q) mismatch → hypoxemia
In advanced disease: hypercapnia (hypoventilation)
Chronic hypoxemia → pulmonary vasoconstriction → pulmonary hypertension → cor pulmonale
Mild PH is common in stable COPD; severe PH (mPAP ≥ 40 mmHg) is rare (~1-3%)

Classic Clinical Phenotypes

Feature	"Pink Puffer" (Emphysema dominant)	"Blue Bloater" (Chronic bronchitis dominant)
Build	Thin, cachectic	Overweight
Cough	Minimal	Productive, chronic
Dyspnea	Prominent	Less prominent early
Gas exchange	Relatively preserved until late	Hypoxemia + hypercapnia
Cyanosis	Absent	Present
Cor pulmonale	Late	Earlier
OSA risk	Lower (lower BMI, hyperinflation)	Higher (higher BMI, lower respiratory drive)

Murray & Nadel's Textbook of Respiratory Medicine, p. 2747

Key Comorbidities & Systemic Effects

OSA-COPD Overlap Syndrome: ~1% of general population; at higher risk for hypercapnia, PH, and COPD exacerbations. CPAP improves survival and reduces hospitalizations in overlap patients.
Weight loss / cachexia: Common; can mimic occult malignancy
Pulmonary hypertension: Primarily due to hypoxic vasoconstriction
Right heart failure (Cor pulmonale)
Sleep-related hypoventilation: REM sleep causes accessory muscle paralysis, worsening hypoxemia and hypercapnia in advanced COPD

Sources:

Robbins & Kumar Basic Pathology, pp. 447-450
Murray & Nadel's Textbook of Respiratory Medicine (2-Volume), pp. 179, 2747
Fishman's Pulmonary Diseases and Disorders (2-Volume Set)

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