Chronic obstructive pulmonary disease

Chronic obstructive pulmonary disease (COPD) is characterized by chronic respiratory symptoms resulting from airflow obstruction and alveolar gas exchange abnormalities. It is predominantly caused by inhaled toxins (e.g., tobacco smoke or air pollution). Some individuals are genetically predisposed to COPD, particularly those with α₁-antitrypsin deficiency (AATD). COPD begins with chronic airway inflammation, which 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 (hypoxemia) and CO₂ release (hypercapnia). Clinical features include dyspnea and productive cough and, in later stages, tachypnea, tachycardia, and cyanosis. Diagnosis is primarily based on clinical presentation and pulmonary function tests (PFTs), which typically show a decreased ratio of forced expiratory volume (FEV) to forced vital capacity (FVC). Imaging studies are helpful in assessing disease severity and the extent of possible complications. Treatment options mainly consist of short-acting and long-acting bronchodilators and inhaled corticosteroids. Individuals with advanced disease may benefit from 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.

• Chronic obstructive pulmonary disease: a lung condition characterized by persistent respiratory symptoms (cough, dyspnea) and airflow limitation (postbronchodilator FEV₁:FVC ratio < 0.70), which is caused by a combination of small airway obstruction and parenchymal destruction
• Chronic bronchitis: productive cough for at least 3 months per year for 2 consecutive years that cannot be explained by an alternative diagnosis
• Emphysema: permanent dilatation of pulmonary air spaces distal to the terminal bronchioles that is caused by the destruction of the alveolar walls and pulmonary capillaries required for gas exchange

Chronic bronchitis (a clinically defined condition) and emphysema (an anatomically defined condition) often occur simultaneously in patients with COPD. ^[2]

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

Epidemiological data refers to the US, unless otherwise specified.

Exogenous factors

• Tobacco use ; ^[6]
  • Smoking is the major risk factor for COPD, but those who have quit ≥ 10 years ago are not at increased risk. ^[7]
  • Passive smoking
• Exposure to air pollution or fine dusts ^[8]
  • Nonorganic dust: such as industrial bronchitis in coal miners ^[9]
  • 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 ^[10]
  • Recurrent pulmonary infections and tuberculosis
  • Premature birth ^[11]
• α1-antitrypsin deficiency
• Airway hyperresponsiveness
• Antibody deficiency syndrome (e.g., IgA deficiency)
• Primary ciliary dyskinesia (e.g., Kartagener syndrome)

GOLD classification ^[1]

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

GOLD grades

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

GOLD groups ^[1]

COPD is characterized by chronic airway inflammation and tissue destruction. ^[6][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 ^[6]

• 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

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][17]

• 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 AATD
  • 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.
  • Age-related 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.

Approach ^[1]

• Suspect COPD in patients with either:
  • Typical symptoms of COPD
  • COPD risk factors
• Obtain spirometry to confirm significant airflow limitation (FEV₁:FVC < 70%).
• Screen for AATD.
• Consider additional diagnostic testing as indicated, e.g.:
  • Advanced PFTs
  • Chest imaging

The USPSTF recommends against screening asymptomatic adults for COPD. ^[18]

Initial tests ^[1][2]

• Spirometry
  • FEV₁:FVC < 70% after bronchodilator inhalation confirms the diagnosis.
  • ↓ FEV₁ (FEV1% of the predicted value determines the GOLD spirometric grade.)
  • Normal or ↓ FVC
• Serum AAT level: Screen all patients with confirmed COPD for AATD upon initial diagnosis.

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

Additional testing

Advanced pulmonary function testing

Characteristic changes are observed in patients with significant emphysema and small airway abnormalities.

• Body plethysmography
  • ↑ Total lung capacity (TLC)
  • ↑ Functional residual capacity (FRC)
  • ↑ Residual volume (RV)
• Single-breath diffusing capacity: ↓ DL_CO
• Postbronchodilator test: A negative response (change in FEV₁ < 12%) is more common in patients with COPD than asthma (see “COPD vs. asthma”). ^[1][19][20]

Reversibility of bronchoconstriction is not a reliable factor for differentiating between COPD and asthma. ^[1]

Assessment for respiratory failure

• Pulse oximetry
  • Obtain in patients with signs of respiratory distress or signs of right heart failure.
  • Measure at rest and on ambient air or usual oxygen prescription.
• ABG
  • Obtain in patients with SO₂ < 92% and/or acute illness (e.g., altered mental status, AECOPD).
  • Findings
    • May show hypoxemic respiratory failure (↓ PO₂) with or without hypercapnic respiratory failure (↑ PCO₂)
    • Chronic hypercapnia due to CO₂ trapping is common in patients with severe COPD.

Chest imaging ^[1][2]

Chest imaging is not needed for diagnosis; consider based on clinical context to assess for alternative diagnoses, comorbidities, or complications.

• Chest x-ray findings in COPD
  • Signs of pulmonary hyperinflation
    • Increased anteroposterior diameter; (barrel chest)
    • Pushed down and flattened diaphragm
    • Horizontal ribs and widened intercostal spaces
    • Hyperlucency of lung tissue (decreased lung markings)
    • Long and narrow heart shadow
  • Signs of bullous emphysema: parenchymal bullae or pulmonary blebs
• CT chest findings
  • Similar to CXR findings; may additionally reveal characteristic patterns of emphysema
    • Panacinar emphysema: common in patients with AATD
    • Centriacinar emphysema: common in patients with COPD and a history of tobacco use
  • May show signs of bronchiectasis, e.g., thickened bronchial walls

Other

• CBC ^[2]
  • Secondary polycythemia, ↑ hematocrit
  • Eosinophil counts influence decisions on whether to use inhaled corticosteroids.
• ECG/TTE: Right ventricular hypertrophy may be seen in patients with advanced COPD. ^[21]

• 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]

• Assess for both:
  • Symptom severity and history of exacerbations to determine the GOLD group
  • Comorbidities that may influence treatment, e.g., asthma
• Provide nonpharmacological management of COPD for all patients.
• Initiate pharmacological treatment of COPD based on GOLD group.
• At follow-up:
  • Review inhaler technique.
  • Adjust medication based on the adequacy of symptom control.
  • Repeat spirometry annually to track any decline in FEV₁.
• In patients with advanced disease, consider:
  • Long-term oxygen therapy
  • Interventional treatment, e.g., lung volume reduction surgery

Nonpharmacological management of COPD ^[1]

Lifestyle modifications

• Counsel on smoking cessation and options for pharmacotherapy, e.g., varenicline.
• Encourage physical activity to reduce the risk of acute exacerbations.
• Recommend maintenance of a healthy nutritional status.
• Educate patients on:
  • Indoor air pollution mitigation, e.g., nonpolluting cooking stoves
  • Personal protective equipment to prevent work-related lung diseases

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

Supportive care

• Recommended immunizations in COPD
  • Pneumococcal vaccination: for patients ≥ 19 years of age ^[22]
  • Influenza vaccination (annual)
  • COVID-19 vaccination
  • Zoster vaccination: for patients ≥ 50 years of age
  • Tdap vaccination: if not administered in adolescence
  • See also “ACIP immunization schedule.”
• Pulmonary rehabilitation: especially helpful for patients with moderate to severe disease

Vaccinations against pneumococcus and influenza reduce the risk of respiratory infections and complications in patients with COPD. ^[1]

Management of comorbidities

Screen for common comorbidities at the first visit and at regular intervals, then treat as indicated.

• Screening for depression and anxiety
• Screening for osteoporosis
• ASCVD risk assessment
• Assessment for malnourishment
• Lung cancer screening for patients with COPD resulting from tobacco use

See “Pharmacotherapy for AECOPD” for treatment of acute exacerbations.

General principles ^[1]

• Bronchodilators are the mainstay of pharmacological treatment.
• Inhaled corticosteroids (ICS), e.g., budesonide, fluticasone, or beclomethasone, should only be used in combination with long-acting bronchodilators.
• A single inhaler may be more effective than multiple inhalers when available and affordable.
• Patient education on proper inhaler technique is essential for adequate symptom control.
  • Describe and demonstrate when prescribing a new inhaler.
  • Observe the patient's technique for each inhaler at follow-up visits.
  • Identify common errors, e.g., inadequate exhalation prior to inhalation.
• For patients with both COPD and asthma, choose medications based on stepwise treatment of chronic asthma.

Initial treatment

If treatment response is inadequate, consider poor inhaler technique and/or poor adherence as causes.

Follow-up treatment ^[1]

• Maintain inhaler therapy if dyspnea and exacerbations are well controlled with the current regimen.
• If not, assess for:
  • Adherence
  • Inhaler technique
  • Comorbid conditions that could explain symptoms
• Reinforce nonpharmacological management of COPD.
• Adjust treatment based on the predominant trait (i.e., dyspnea or exacerbations), not on the GOLD group at diagnosis.

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, B, or, E) at diagnosis. ^[1]

Other drugs ^[1]

• Palliative pharmacotherapy for dyspnea (e.g., opiates): may be considered for all patients
• Methylxanthines (e.g., theophylline)
  • Nonselectively antagonize adenosine receptors and inhibit phosphodiesterase
  • May be trialed if other bronchodilators are not available
  • Unproven benefit
• Mucolytics (e.g., N-acetylcysteine, erdosteine)
  • Liquefy mucus by reducing the disulfide bonds of mucoproteins
  • Can be useful in reducing exacerbations in certain patients

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 severe resting hypoxemia.

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][24]

• Chronic respiratory failure ^[6]
  • 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. ^[25]
• Survival rates vary significantly depending on the severity of the disease. ^[25]
• Measures that improve survival
  • Cessation of tobacco use
  • Long-term oxygen therapy in patients with severe resting hypoxemia
• COPD is the third most common cause of death worldwide. ^[26]