Chronic obstructive pulmonary disease

Chronic obstructive pulmonary disease (COPD) is a lung disease characterized by airway obstruction due to inflammation of the small airways. It is caused predominantly by inhaled toxins, especially via smoking, but air pollution and recurrent respiratory infections can also cause COPD. Some individuals are genetically predisposed to COPD, particularly those with α₁-antitrypsin deficiency (AATD). COPD begins with chronic airway inflammation that usually progresses to emphysema, a condition that is characterized by irreversible bronchial narrowing and alveolar hyperinflation. These changes cause a loss of diffusion area, which can lead to inadequate oxygen absorption and CO₂ release, resulting in hypoxia and hypercapnia. Most affected individuals present with a combination of dyspnea and chronic cough with expectoration. In later stages, COPD may manifest with more severe symptoms such as tachypnea, tachycardia, and cyanosis. Diagnosis is primarily based on clinical presentation and lung function tests, which typically show a decreased ratio of forced expiratory volume (FEV) to forced vital capacity (FVC). Imaging studies, such as chest x-ray, are helpful in assessing disease severity and the extent of possible complications, but they are not required to confirm the diagnosis. ABG and pulse oximetry are useful for quickly assessing the patient's O₂ status. All COPD patients should be staged according to the staging system of the Global Initiative for Chronic Obstructive Lung Disease (GOLD), which considers a variety of factors (e.g., exacerbations, symptom severity, FEV₁). Treatment options depend on the GOLD stage and mainly consist of short- and long-acting bronchodilators (beta-agonists and parasympatholytics) and glucocorticoids. Individuals with advanced disease typically require oxygen supplementation, which is the only treatment that decreases mortality. COPD may cause complications such as pulmonary hypertension or respiratory failure. The most significant complication is acute exacerbation of COPD (See AECOPD).

• COPD is a chronic pulmonary disease characterized by persistent respiratory symptoms and airflow limitation (postbronchodilator FEV₁/FVC < 0.70), which is caused by a mixture of small airway obstruction and parenchymal destruction ^[1]
• COPD was formerly subdivided into chronic bronchitis and emphysema. These terms are still widely used to describe patient findings and found as subclasses of COPD in outdated literature. ^[2]
  • Chronic bronchitis: productive cough (cough with expectoration) for at least 3 months each year for 2 consecutive years
  • Emphysema: permanent dilatation of pulmonary air spaces distal to the terminal bronchioles, caused by the destruction of the alveolar walls and the pulmonary capillaries required for gas exchange

• Sex: 3:2 male/female ratio ^[3][4]
• Prevalence: 6% ^[5]

Epidemiological data refers to the US, unless otherwise specified.

Exogenous factors

• Tobacco use (90% of cases) ^[2]
  • Smoking is the major risk factor for COPD, but those who have quit ≥ 10 years ago are not at increased risk. ^[6]
  • Passive smoking
• Exposure to air pollution or fine dusts ^[7]
  • Nonorganic dust: such as industrial bronchitis in coal miners ^[8]
  • Organic dust: ↑ incidence of COPD in areas where biomass fuel (e.g., wood, animal dung) is regularly burned indoors

Endogenous factors

• Lung growth and development abnormalities ^[9]
  • Recurrent pulmonary infections and tuberculosis
  • Premature birth ^[10]
• α₁-Antitrypsin deficiency
• Antibody deficiency syndrome (e.g., IgA deficiency)
• Primary ciliary dyskinesia (e.g., Kartagener syndrome)

Global initiative for chronic obstructive lung disease (GOLD) classifications ^[11]

• GOLD classifies COPD according to the severity of airflow limitation (GOLD 1–4) and the ABCD assessment tool, which takes into account the modified British Medical Research Council (mMRC) dyspnea scale, COPD assessment test (CAT), and risk of exacerbation.
• Previously, COPD was classified into chronic bronchitis and emphysema based on clinical findings. The use of these terms to classify types of COPD is now considered outdated because most individuals with COPD have a combination of both. However, these terms are still widely used to describe patient findings and found as subclasses of COPD in outdated literature.

Classification based on airflow limitation in patients with FEV₁/FVC < 70% ^[1]

GOLD uses FEV₁/FVC (Tiffeneau-Pinelli index) to classify COPD.

For GOLD categories according to the FEV₁%, remember that 30 + 50 = 80.

Classification using combined assessment tools

• CAT score = COPD assessment test score
• mMRC Dyspnea Scale = Modified Medical Research Council Dyspnea Scale
• Low risk = FEV₁/FVC ratio ≤ 0.7, FEV₁ ≥ 50% predicted, and 0–1 exacerbation in the last year
• High risk = FEV₁/FVC ratio ≤ 0.7, FEV₁ ≤ 50% predicted, and ≥ 2 exacerbations in the last year

Classification based on underlying morphological changes

Emphysema is divided into the following subtypes: ^[12]

• Centrilobular emphysema (centriacinar emphysema)
  • Most common type of emphysema
  • Classically seen in smokers
  • Characterized by the destruction of the respiratory bronchiole (central portion of the acinus); spares distal alveoli
  • Usually affects the upper lobes
• Panlobular emphysema (panacinar emphysema)
  • Rare type of emphysema
  • Associated with α1-antitrypsin deficiency
  • Characterized by the destruction of the entire acinus (respiratory bronchiole and alveoli)
  • Usually affects the lower lobes
• Other subtypes
  • Cicatricial emphysema
    • Mainly caused by exposure to quartz dust
    • Results in chronic inflammation and nodular scar formation
  • Giant bullous emphysema
    • Characterized by large bullae (congenital or acquired) that extrude into the surrounding tissue
    • Bullae may rupture, leading to pneumothorax.
    • Depending on the shape of the bullae, resection should be considered.
  • Senile emphysema
    • Loss of pulmonary elasticity with age may lead to an emphysematous lung.
    • Not considered pathological but a normal consequence of aging

To remember that centriacinar emphysema is associated with smoking and that it primarily involves the upper lobes of the lungs, think of: Smoke rising up.

COPD is characterized by chronic airway inflammation and tissue destruction. ^[2][13]

Chronic inflammation

It results from significant exposure to noxious stimuli, increased oxidative stress (most commonly due to cigarette smoke) as well as by increased release of reactive oxygen species by inflammatory cells.

• Increased number of neutrophils, macrophages, and CD8+ T lymphocytes → release of cytokines → amplification of inflammation and induction of structural changes of lung parenchyma (e.g., via stimulation of growth factor release)
  • CD8+ T lymphocytes mediate inflammation in individuals with COPD.
  • CD4+ T lymphocytes and eosinophils mediate inflammation in individuals with bronchial asthma.
• Overproduction of growth factor → peribronchiolar fibrosis → narrowing of airway → obliteration → emphysema (airflow limitation)
• Promotion of goblet cell proliferation and hypertrophy, mucus hypersecretion, and impaired ciliary function → chronic productive cough
  • Reid index is the ratio of the thickness of the submucosal mucus-secreting glands to the thickness between the epithelium and cartilage in the bronchial tree.
  • Reid index > 0.5 is characteristic of chronic bronchitis. ^[14]
• Smooth muscle hyperplasia of the small airways and pulmonary vasculature (mainly due to hypoxic vasoconstriction) → pulmonary hypertension → cor pulmonale

Tissue destruction ^[15]

• Bronchopulmonary inflammation → ↑ proteases
• Nicotine use (or other noxious stimuli) inactivates protease inhibitors (especially α₁-antitrypsin) → imbalance of protease and antiprotease → ↑ elastase activity → loss of elastic tissue and lung parenchyma (via destruction of the alveolar walls), which causes:
  • Enlargement of airspaces → ↓ elastic recoil and ↑ compliance of the lung → ↓ tethering of small airways → expiratory airway collapse and obstruction → air trapping and hyperinflation → ↓ ventilation (due to air-trapping) and ↑ dead space → ↓ DL_COand ↑ ventilation-perfusion mismatch (V/Q) → hypoxemia and hypercapnia
  • Pulmonary shunt and ↓ blood volume in pulmonary capillaries → ↑ number of alveoli that are ventilated but not perfused (↑ dead space) → ↓ DL_CO and ↑ V/Q → hypoxemia and hypercapnia
  • Imbalance of oxidants and anti-oxidants and an overabundance of free radicals → chronic inflammation and inactivation of anti-elastase → breakdown of elastic tissue.

Symptoms are minimal or nonspecific until the disease reaches an advanced stage.

Presenting findings ^[2]

• Chronic cough with expectoration (expectoration typically occurs in the morning)
• Dyspnea and tachypnea
  • Initial stages: only on exertion
  • Advanced stages: continuously
• Pursed lip breathing
  • The patient breathes in through the nose and breathes out slowly through pursed lips.
  • This style of breathing increases airway pressure and prevents bronchial collapse during the last phase of expiration.
  • More commonly seen in patients with emphysema
• Prolonged expiratory phase, end-expiratory wheezing, crackles, muffled breath sounds, and/or coarse rhonchi on auscultation
• Cyanosis due to hypoxemia
• Tachycardia

Features of advanced COPD ^[16]

• Congested neck veins
• Barrel chest: This deformity is most commonly seen in individuals with emphysema.
• Asynchronous movement of the chest and abdomen during respiration
• Use of accessory respiratory muscles due to diaphragmatic dysfunction
• Hyperresonant lungs; , reduced diaphragmatic excursion, and relative cardiac dullness on percussion
• Decreased breath sounds on auscultation: “silent lung”
• Peripheral edema (most often ankle edema)
• Right ventricular hypertrophy with signs of right heart failure and cor pulmonale
• Hepatomegaly
• Often weight loss and cachexia
• Secondary polycythemia
• Confusion: due to hypoxemia and hypercapnia
• Nail clubbing in the case of certain comorbidities (e.g., bronchiectasis, pulmonary fibrosis, lung cancer) ^[17]

Nail clubbing is not a finding specific to COPD; its presence usually suggests comorbidities such as bronchiectasis, pulmonary fibrosis, or lung cancer.

Pink puffer and blue bloater ^[16]

According to their clinical appearance, patients with COPD are often categorized as either “Pink Puffer” or “Blue Bloater”.

Features of COPD due to AATD

• Age of onset is generally younger (< 60 years)
• Also, often have hepatic signs and symptoms (jaundice) related to hepatitis or cirrhosis

Pulmonary function test (PFT) ^[2]

Spirometry and/or body plethysmography

• FEV₁/FVC < 70%
• Decreased FEV₁
• Normal or decreased FVC
• Increased FRC and RV
• TLC
  • Chronic bronchitis: normal
  • Emphysema: increased
• Increased intrathoracic gas volume
• DL_CO
  • Chronic bronchitis: normal
  • Emphysema: decreased

Postbronchodilator test

• Objective: assesses reversibility of bronchoconstriction
• Procedure
  1. Spirometry to establish a baseline
  2. Inhalation (e.g., salbutamol)
  3. Perform spirometry again after ∼10–15 min.
• Results: FEV₁/FVC < 0.7 is diagnostic of COPD (in patients with typical clinical features and exposure to noxious stimuli).
  • Delta FEV₁ < 12% (irreversible bronchoconstriction): COPD is more likely than asthma.
  • Delta FEV₁ > 12% (reversible bronchoconstriction): Asthma is more likely than COPD.
  • If spirometry is normal, COPD can be excluded.

To remember FEV₁ for COPD patients, imagine a COP with low FEVer.

Blood gas analysis and pulse oximetry

• Pulse oximetry: assesses O₂ saturation
• ABG: only indicated when O₂ is < 92% or if the patient is severely ill (e.g., altered mental status, acute exacerbation)
  • Hypoxemia and hypercapnia are expected findings in patients with acute or chronic respiratory acidosis.
    • Decreased pO₂: partial respiratory failure
    • Decreased pO₂ and increased pCO₂: global respiratory failure
    • Many individuals with severe COPD have chronic hypercapnia due to CO₂ trapping from hyperinflation and progressive loss of pulmonary elasticity.

Imaging

• Indications: not required for routine diagnosis but often used as an initial modality, mainly to rule out alternative conditions (e.g., pulmonary fibrosis, bronchiectasis)
• Chest x-ray
  • Not sensitive, especially during the early stages of COPD
  • Can be used to determine the etiology for an acute COPD exacerbation (e.g., pneumonia, congestive heart failure)
  • Signs of hyperinflated lungs (barrel chest)
    • Hyperlucency of lung tissue (decreased lung markings)
    • Increased anteroposterior diameter
    • Diaphragm pushed down and flattened
    • Horizontal ribs and widened intercostal spaces
    • Long narrow heart shadow
    • Parenchymal bullae or subpleural blebs (pathognomonic of emphysema)
    • The retrosternal space is increased on lateral view due to emphysematous changes in the lung tissue.
• Chest CT
  • Evaluates possible complications (e.g., pneumothorax, ARDS)
  • Indicated in planning surgery (e.g., lung volume reduction, lung transplantation)
  • Rules out differential diagnoses (e.g., bronchiectasis, lung cancer)
  • Findings
    • In most patients with COPD and history of tobacco use: centriacinar emphysema
    • In patients with AATD: panacinar emphysema , bronchiectasis, bullae

Other tests

• CBC: Increased serum hematocrit
• Testing for AATD: recommended for all patients with COPD regardless of age or ethnicity (see “Inborn errors of metabolism”) ^[18]
  • α₁-Antitrypsin levels
  • Electrophoresis: decreased alpha-1 peak
  • Liver biopsy: PAS-positive, spherical inclusion bodies in periportal hepatocytes
• Gram stain and sputum culture: in the case of suspected pulmonary bacterial infection (e.g., fever, productive cough, new infiltrate on chest x-ray)
• ECG: may show signs of right ventricular hypertrophy (e.g., P pulmonale, low amplitude of QRS complexes, and poor R wave progression) ^[19]

Consider AATD in patients with COPD who are < 60 years of age, have no smoking history, and/or have basilar-predominant COPD. However, testing for AATD is recommended for all new patients with COPD.

• See “Comparison of asthma and COPD.”
• See “Differential diagnosis of chronic cough.”

The differential diagnoses listed here are not exhaustive.

General treatment ^[1][2]

• Cessation of tobacco use: single most effective step to slow the decline in lung function
• Pneumococcal vaccination: reduces the incidence of community-acquired pneumonia and invasive pneumococcal diseases
  • Age 19-64 years: Administer PPSV23.
  • Age ≥ 65 years
    • Vaccinated: Administer PPSV23 (should be at least 5 years after the previous PPSV23 dose and at least 1 year after PCV13).
    • Not vaccinated or unknown vaccination history: Administer PCV13 followed by PPSV23.
      • Immunocompetent patients: Administer PPSV23 after 1 year.
      • Individuals with immunocompromising conditions, cerebrospinal leaks, or cochlear implants: Administer PPSV23 after 8 weeks.
• Influenza vaccination (annual): reduces the incidence of lower respiratory tract infections and death in COPD patients
• Pulmonary rehabilitation
  • Indicated in patients with GOLD B, C, and D
  • Includes physiotherapy with breathing exercises
• Physical activity helps maintain endurance and alleviate dyspnea.
• Supportive treatment (e.g., postural drainage)
• Vitamin D₃ and calcium in cases of deficiency ^[20]

Medical treatment according to GOLD ^[1]

Medical treatment in COPD reduces the severity of symptoms, improves overall health status, and lowers the frequency and severity of exacerbation. The first-line treatment of COPD consists of bronchodilators, inhaled corticosteroids, and phosphodiesterase (PDE) type 4 inhibitors.

• Bronchodilators
  • Short-acting beta agonists (SABAs): e.g., salbutamol, fenoterol
  • Long-acting beta agonists (LABAs): e.g., salmeterol, formoterol
  • Short-acting muscarinic antagonists (SAMAs): e.g., ipratropium bromide
  • Long-acting muscarinic antagonists (LAMAs): e.g., tiotropium bromide
• Inhaled corticosteroids (ICS): e.g., budesonide, fluticasone, beclomethasone
• PDE type 4 inhibitors: e.g., roflumilast

Other treatment options ^[1]

• Theophylline
  • Mechanism of action: adenosine receptor blockade and nonspecific PDE inhibition
  • Indication: usually only severe and refractory COPD
• Long-term oxygen therapy (LTOT) indicated in the case of:
  • PaO₂ ≤ 55 mm Hg or SaO₂ ≤ 88% at rest
    • Increases the chance of survival in patients with COPD
    • Supplemental O₂ can worsen hypercapnia
    • The target oxygen saturations is 90–93%.
  • PaO2 between 55 and 60 mm Hg or SaO₂ of 88%, if there is evidence of pulmonary hypertension, congestive cardiac failure, or polycythemia
• Mucolytics (e.g., N-acetylcysteine) liquefy mucus by reducing the disulfide bonds of mucoproteins.
  • Other indications include:
    • Cystic fibrosis
    • Acetaminophen overdose (antidote): acetylcysteine restores depleted hepatic glutathione
    • Prophylaxis of contrast agent nephropathy
• Ventilatory support: CPAP is useful in patients with COPD and obstructive sleep apnea.
• Surgery may be beneficial in severe cases
  • Lung resection for giant bullae in emphysema
  • Lung transplantation for nonrepairable damage
• Bronchoscopic interventions may be used to reduce end-expiratory lung volume and improve exercise tolerance.

Chronic respiratory failure ^[2]

• Description: occurs in the advanced stages of COPD due to progressive emphysematous changes and loss of diffusion surface area
• Criteria
  • Long-standing partial respiratory failure (pO₂ at rest < 60 mm Hg)
  • Global respiratory insufficiency failure (pO₂ changes at rest < 60 mm Hg and pCO₂ > 45 mm Hg)
• Management: depends on the severity and etiology ^[1]
  • Long-term oxygen therapy (LTOT): 16 hours oxygen administration per day (minimum dosage) is associated with lower mortality rates.
    • Indication: patients with COPD GOLD D and severe respiratory insufficiency failure that exhibit long-standing pO₂ < 55 mm Hg, despite administration of optimal medication
    • Oxygen administration is regulated in a way that the pO₂ value rises and pCO₂ drops to a level of 60–70 mm Hg. Hypercapnia would lead to respiratory acidosis and disorientation and should be prevented. ^[21]
  • Portable respiration
    • Principle: a type of non-invasive respiration done overnight when the patient is asleep
    • Goal: This allows recovery of the respiratory muscles and in turn permits better respiratory function during the day.
  • Lung volume reduction surgery
    • Principle: Surgical or endoscopic removal of severely affected emphysematous areas of the lung.
    • Goal: This procedure reduces lung hyperinflation, which improves dyspnea and lung function.
  • Lung transplantation: considered the last resort in patients with emphysema associated with advanced COPD and severe diffusion dysfunction

Other complications ^[2]

• Acute exacerbation: See AECOPD.
• Cor pulmonale (right heart failure)
• Secondary spontaneous pneumothorax due to rupture of bullae (especially in bullous emphysema)

We list the most important complications. The selection is not exhaustive.

• 40–70% of all COPD patients survive the first 5 years after diagnosis. ^[22]
• Survival rates vary significantly depending on the severity of the disease. ^[22]
• Measures that improve survival
  • Cessation of tobacco use
  • Long-term oxygen therapy is the only treatment that improves mortality.
• COPD is the third most common cause of death worldwide. ^[23]

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