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 hypoxemia 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 group and mainly consist of short- and long-acting bronchodilators (beta-agonists and parasympatholytics) and glucocorticoids. Individuals with advanced disease may benefit from nonpharmacological treatment with oxygen supplementation and/or noninvasive ventilation. COPD can 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) classification

• A system that combines spirometric classification, symptom assessment, and history of exacerbations to determine the impact of COPD on a patient's health status.
• Grade and groups are calculated separately
• GOLD spirometric grades 1–4
  • Assessed using spirometry at the time of diagnosis and then annually to track any decline in FEV₁
  • Inform the prognosis of a patient
• GOLD Groups A–D
  • Calculated based on the history of exacerbations and severity of symptoms
  • Used to guide management

GOLD grades inform the prognosis of a patient; GOLD groups guide management.

GOLD spirometric grades ^[1]

Cutoff points between GOLD spirometric grades according to the FEV₁%: 30 + 50 = 80

GOLD spirometric grades 1–4 inform the prognosis but correlate weakly with symptoms and functional impairment. ^[1]

GOLD groups A–D ^[1]

Emphysema subtypes

Emphysema is characterized by the destruction of lung parenchyma and is often seen in patients with advanced pulmonary disease. The presence of emphysema does not necessarily correlate with spirometric findings. Emphysema can be divided into the following subtypes: ^[1][11]

• 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.
    • Considered a normal consequence of aging

“Smoke rises up:” Centriacinar emphysema is associated with smoking and primarily involves the upper lobes of the lungs.

COPD is characterized by chronic airway inflammation and tissue destruction. ^[2][12]

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. ^[13]
• Smooth muscle hyperplasia of the small airways and pulmonary vasculature (mainly due to hypoxic vasoconstriction) → pulmonary hypertension → cor pulmonale

Tissue destruction ^[14]

• 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 ^[15]

• 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) ^[16]

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 ^[15]

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

Approach ^[1]

• Obtain spirometry in patients with typical symptoms of COPD and/or a history of COPD risk factors (e.g., exposure to air pollution) in order to:
  • Confirm the diagnosis if FEV₁/FVC is < 0.7 (persistent airflow limitation)
  • Determine the GOLD grade (1–4) based on FEV₁ value
• Determine GOLD group (A–D) based on the history of exacerbations and severity of current symptoms.
• Test all patients at diagnosis for AATD.
• Consider imaging to exclude alternative diagnoses and identify significant comorbidities.
• Assess oxygenation in patients with signs of respiratory or right heart failure using pulse oximetry.

Pulmonary function tests ^[17]

Spirometry and body plethysmography ^[1][17]

• Indication: all patients with typical symptoms of COPD and/or exposure to COPD risk factors
• Procedure: Spirometry is performed after inhalation with a short-acting beta-agonist (SABA) or short-acting muscarinic antagonist (SAMA).
• Key finding: : FEV₁/FVC < 70% after bronchodilator inhalation
• Typical supportive findings
  • ↓ FEV₁
  • Normal or ↓ FVC
  • In the presence of significant emphysema and small airway abnormalities:
    • ↑ TLC (total lung capacity), FRC (functional residual capacity), RV (residual volume), and intrathoracic gas volume
    • ↓ DL_CO

FEV₁ should be reassessed annually in patients with COPD. Screening for COPD using spirometry in patients without symptoms is not generally recommended. ^[18]

“A COP with low FEVer:” FEV₁ for COPD patients.

Postbronchodilator test ^[19][20]

• Used to assess the reversibility of bronchoconstriction
  • Change in FEV₁ < 12%: irreversible bronchoconstriction ^[20]
  • Change in FEV₁ > 12%: reversible bronchoconstriction ^[20]
• The degree of reversibility alone cannot reliably distinguish between the diagnosis of asthma vs. COPD. ^[1]

Routine studies

• Pulse oximetry
  • Indicated in patients with signs of respiratory failure or signs of right heart failure
  • Check O₂ saturation to assess for indications for long-term oxygen therapy.
• ABG
  • Indication: O₂ saturation < 92% or acute illness (e.g., altered mental status, acute exacerbation)
  • Findings: Hypoxemia and hypercapnia are common.
    • 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.
• Serum α1-antitrypsin level: Screen all patients with COPD for AATD at diagnosis. ^[1]

Additional studies ^[1][17]

The following tests are not required for a diagnosis. If performed, they may show typical findings.

• CBC
  • ↑ Hematocrit and secondary polycythemia ^[17]
  • Eosinophil counts impact considerations for the use of inhaled corticosteroids.
• ECG/TTE: may show signs of right ventricular hypertrophy ^[21][22]
• X-ray chest: not indicated for confirming the diagnosis (low sensitivity, especially during the early stages)
  • Indications
    • To assess for alternative diagnoses and/or identify significant comorbidities (e.g., pulmonary fibrosis, bronchiectasis, cardiomegaly)
    • AECOPD
  • Findings
    • Hyperinflated lungs (barrel chest)
    • Hyperlucency of lung tissue (decreased lung markings)
    • Increased anteroposterior diameter
    • Pushed down and flattened diaphragm
    • Horizontal ribs and widened intercostal spaces
    • Long narrow heart shadow
    • Parenchymal bullae or subpleural blebs (pathognomonic of emphysema)
    • Increased retrosternal space on lateral view as a result of emphysematous changes in the lung tissue
• CT chest
  • Indications
    • Evaluation for complications or differential diagnoses
    • Surgery planning (e.g., lung volume reduction, lung transplantation)
  • Findings: similar to x-ray findings
    • Centriacinar emphysema: common in patients with COPD and a history of tobacco use
    • Panacinar emphysema: common in patients with AATD

• Asthma (see “Comparison of asthma and COPD”)
• Congestive heart failure
• Bronchiectasis
• Tuberculosis
• Bronchiolitis
• See also “Differential diagnosis of chronic cough.”

The differential diagnoses listed here are not exhaustive.

Management of acute COPD exacerbation is discussed in AECOPD.

Approach ^[1]

• Communicate treatment goals, including:
  • Symptom control
  • Reduction of frequency and severity of exacerbations
  • Improvement in quality of life
• Counsel all patients on supportive measures, including lifestyle modifications and recommended vaccinations.
• Choose initial medication based on the patient's GOLD group (A–D).
• Follow-up treatment: Assess the adequacy of symptom control.
  • Continue initial treatment if the response is adequate.
  • If not, adjust medications based on the severity of dyspnea and history of exacerbations.
  • De-escalate treatment if there are adverse effects and/or a lack of clinical benefit.
• In patients with chronic respiratory failure, consider:
  • Long-term oxygen therapy
  • Interventional treatment, e.g., lung volume reduction surgery

Patient education and training on inhaler techniques are central to improving self-management skills, the ability to cope with illness, and health status. Make sure that instructions are provided and proper technique is demonstrated when prescribing an inhaler, and that inhaler technique is observed at each visit. ^[1]

Supportive measures

Cessation of tobacco use is the single most effective step to slow the decline in lung function in patients with COPD.

Initial treatment

Factors that influence the choice of initial medications include GOLD group, comorbidities, patient preferences, adverse drug reactions, cost, and availability.

If treatment response is inadequate, consider poor inhaler technique and/or adherence as causes. Common errors include inadequate exhalation prior to inhalation, inadequate inhalation duration, and problems with inspiratory flow.

Bronchodilators are the mainstay of pharmacological treatment of COPD.

Follow-up treatment ^[1]

1. Check for persistent symptoms and adjust the regimen based on the predominant trait (dyspnea or exacerbations).
2. Review the response to treatment escalation; adjust if there is:
   • Insufficient improvement
   • Adverse drug reactions
3. If dyspnea persists after adjustments:
   • Consider changing the inhaler or medication within the same class.
   • Evaluate for other causes of dyspnea.

Switching inhalers within a class (e.g., using a different long-acting beta-agonist) in patients with inadequate treatment response may improve management.

Follow-up treatment adjustments are based on treatable traits (dyspnea and frequency of exacerbations) and are made irrespective of the patient's GOLD group (A–D) before treatment initiation. ^[1]

Inhaled corticosteroids ^[1]

• General principles
  • ICS should only be used in combination with long-acting bronchodilators.
  • Oral glucocorticoid treatment is not recommended for COPD treatment.
• Factors that strongly support initiation of ICS
  • Eosinophil count ≥ 300 cells/μL ^[1]
  • Eosinophil count > 100 cells/μL and either ≥ 2 moderate exacerbations per year or ≥ 1 hospitalization
  • History of, or concomitant, asthma
• Factors against initiation ICS
  • Blood eosinophil count < 100 cells/μL
  • Repeated pneumonia events
  • History of mycobacterial infection
• Indications for stopping ICS ^[23]
  • Incorrect original indication
  • Insufficient response to the addition of ICS
  • Adverse effects (e.g., pneumonia)

Commonly used agents include budesonide, fluticasone, beclomethasone.

Other drugs

• Methylxanthines (e.g., theophylline)
  • Nonselectively antagonize adenosine receptors and inhibit phosphodiesterase
  • May be trialed if other bronchodilators are not available; the benefit is unproven.
• Mucolytics (e.g., N-acetylcysteine, erdosteine)
  • Liquefy mucus by reducing the disulfide bonds of mucoproteins
  • Can be useful in reducing exacerbations in certain patients
• Vitamin D₃: may reduce the risk of exacerbations in patients with low baseline levels ^[24]
• α1-antitrypsin augmentation therapy
  • For patients with AATD and emphysema
  • May be especially beneficial for nonsmokers with an FEV₁ of 35–60%

There is insufficient evidence to support treating stable COPD with antitussives, vasodilators, or leukotriene antagonists. ^[1]

Respiratory support ^[1]

• Long-term oxygen therapy (LTOT)
  • Indications
    • PaO₂ ≤ 55 mm Hg or SaO₂ ≤ 88% at rest despite optimal medication
    • OR PaO₂ 55–60 mm Hg in patients with pulmonary hypertension, CHF, or polycythemia
  • Target oxygen saturation: > 90%
  • Recommended duration: continuous oxygen therapy for ≥ 15 hours/day
  • Reevaluate after 60–90 days (with ABG or pulse oximetry).
• Ventilatory support
  • Continuous positive airway pressure is useful in patients with COPD and obstructive sleep apnea.
  • Long-term noninvasive positive-pressure ventilation may be considered in select patients with severe chronic hypercapnia.

For patients started on LTOT, check blood gasses frequently (with ABG or VBG) to ensure adequate oxygenation without unintended acidosis and CO₂ retention. ^[1]

LTOT Increases survival in patients with COPD.

Invasive treatment

• Surgical bullectomy: indicated in severe emphysema with hyperinflation and large bullae
• Lung volume reduction
  • Indicated for severe emphysema and hyperinflation without large bullae
  • Severely affected emphysematous areas of the lung are removed either surgically (lung volume reduction surgery) or endoscopically
• Lung transplantation: may be indicated for very severe COPD, patients not eligible for bullectomy or lung volume reduction, and those with surgical contraindications

Palliative measures (e.g., low-dose opiates, fans blowing onto the patient's face, or acupuncture) can be used if distressing breathlessness persists despite optimal medical therapy. ^[23][25]

• Chronic respiratory failure ^[2]
  • 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)
  • Occurs in advanced COPD due to progressive emphysematous changes and loss of diffusion surface area
• Acute exacerbation of COPD
• 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. ^[26]
• Survival rates vary significantly depending on the severity of the disease. ^[26]
• 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. ^[27]