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COPD

COPD includes chronic lung conditions such as emphysema and chronic bronchitis that can cause airflow limitation and breathing symptoms. Treatment has expanded significantly with new inhaled therapies and the first biologics for COPD.[1]

Common symptoms

  • Shortness of breath, especially with activity
  • Chronic cough or mucus production
  • Wheezing or chest tightness
  • Frequent respiratory infections or flare-ups

Management themes

Care may include smoking cessation, inhalers, vaccines, pulmonary rehabilitation, activity planning, and oxygen therapy in selected patients. Newer treatments now include novel inhaled therapies and biologic medications for eligible patients.[1]

Causes

What causes COPD?

COPD results from a complex interplay of long-term exposure to noxious particles and gases, combined with host factors including genetics and abnormal lung development. While smoking is the most recognized cause, 25–45% of COPD cases worldwide occur in people who have never smoked.[1]

Tobacco smoke and inhalational exposures
  • Cigarette smoking: The single most important risk factor, contributing to over 50% of the global burden of COPD. Not all smokers develop COPD, suggesting individual susceptibility plays a role.[1]
  • Secondhand smoke: Chronic passive smoke exposure increases the risk of COPD, particularly in childhood.
  • Biomass fuel smoke: Indoor exposure from burning wood, animal dung, crop residues, and charcoal for cooking and heating — a major cause in low- and middle-income countries, disproportionately affecting women.[1]
  • Occupational exposures: Chronic inhalation of industrial dusts, chemicals, and fumes — including coal mining, textiles, grain handling, construction, cadmium exposure, and farming — can cause or worsen COPD even in non-smokers.
  • Outdoor air pollution: Long-term exposure to elevated particulate matter (PM2.5) is associated with increased COPD incidence and accelerated lung function decline.[1]
  • Cannabis and vaping: Emerging evidence suggests chronic cannabis smoking and e-cigarette use may contribute to airway disease, though long-term COPD risk data remain limited.
Genetic and developmental factors
  • Alpha-1 antitrypsin (AAT) deficiency: The best-characterized genetic risk factor. AAT is a protein that protects the lungs from protease-mediated damage. Severe deficiency (ZZ genotype) leads to early-onset emphysema, particularly in smokers, and can cause liver disease. All COPD patients should be tested at least once. Treatment includes IV AAT augmentation therapy.[1]
  • Other genetic factors: Variants in genes encoding matrix metalloproteinase 12 (MMP-12), glutathione S-transferase, and others have been associated with COPD susceptibility, though the clinical significance of individual variants is still being studied.
  • Impaired lung growth and development: Factors affecting lung growth in utero and early childhood — including low birth weight, prematurity, maternal smoking, childhood malnutrition, and severe childhood respiratory infections — can result in lower peak lung function in early adulthood, increasing COPD risk later in life.[1]
  • Asthma and airway hyperresponsiveness: A history of childhood asthma and chronic airway hyperresponsiveness is associated with increased risk of developing fixed airflow obstruction consistent with COPD.
  • Aging: Lung function naturally declines with age. Aging amplifies the cumulative effects of other risk factors.
  • Socioeconomic status: Poverty is independently associated with higher COPD risk, likely reflecting a combination of increased exposure to pollutants, crowding, poor nutrition, limited healthcare access, and higher smoking rates.[1]

How is COPD diagnosed?

COPD diagnosis requires spirometry showing persistent airflow limitation.[1]

Spirometry
  • Spirometry is required to confirm a COPD diagnosis. A post-bronchodilator FEV1/FVC ratio below the lower limit of normal confirms persistent airflow limitation.[1,2]
  • GOLD staging uses FEV1: GOLD 1 (mild, ≥80% predicted), GOLD 2 (moderate, 50–79%), GOLD 3 (severe, 30–49%), GOLD 4 (very severe, <30%).[1]
Other evaluations
  • Chest imaging: Chest X-ray or CT to evaluate for emphysema, other lung disease, or lung cancer screening eligibility.
  • Pulse oximetry and arterial blood gases: To assess oxygenation.
  • 6-minute walk test: Measures exercise capacity and oxygen desaturation.
  • Alpha-1 antitrypsin testing: Recommended at least once for all COPD patients.[1]
  • Complete blood count: To evaluate for polycythemia or eosinophilia (blood eosinophil count now guides biologic therapy decisions).
Treatment

How is COPD managed?

COPD treatment aims to relieve symptoms, improve exercise tolerance, reduce exacerbations, and slow disease progression.[1]

Inhaled medications

  • Short-acting bronchodilators: Rescue inhalers for quick symptom relief (albuterol, ipratropium).
  • Long-acting bronchodilators (LABA/LAMA): Maintenance inhalers for 12–24 hour airway opening (tiotropium, umeclidinium, salmeterol, formoterol).[1]
  • Inhaled corticosteroids (ICS): Added in patients with frequent exacerbations and/or elevated blood eosinophils. Not recommended as monotherapy.[1]
  • Triple therapy: ICS + LABA + LAMA for patients with frequent exacerbations despite dual therapy.
  • PDE4 inhibitors: Oral medications (roflumilast) for chronic bronchitis phenotype with frequent exacerbations.

Non-pharmacologic

  • Smoking cessation: The single most important intervention.[1] Learn more →
  • Pulmonary rehabilitation: Structured exercise, education, and self-management.[1] Learn more →
  • Supplemental oxygen: For chronic resting hypoxemia.
  • Vaccines: Annual influenza, pneumococcal, COVID-19, and RSV vaccines.[1]
  • Action plan: Written plan for recognizing and managing exacerbations.
Novel Inhaled Therapy

Ensifentrine (Ohtuvayre)

Ensifentrine is the first inhaled medication with a novel mechanism of action for COPD maintenance treatment in over 20 years. It was approved by the FDA in June 2024.[3]

How it works
  • Ensifentrine is a first-in-class dual inhibitor of the enzymes phosphodiesterase 3 (PDE3) and phosphodiesterase 4 (PDE4).
  • This dual mechanism provides both bronchodilation (airway relaxation) and non-steroidal anti-inflammatory effects in a single molecule.[3]
  • It is complementary to existing inhaled therapies (LABA, LAMA, ICS) and can be added on top of them.
  • Delivered via a standard jet nebulizer — does not require strong inspiratory effort, which can be advantageous for patients who have difficulty using dry powder inhalers.
Evidence
  • The ENHANCE-1 and ENHANCE-2 phase 3 trials enrolled over 1,500 patients with moderate-to-severe symptomatic COPD across 250 centers in 17 countries.[3]
  • Ensifentrine significantly improved lung function (FEV1) compared to placebo in both trials: average improvement of 87 mL (ENHANCE-1) and 94 mL (ENHANCE-2) above placebo.
  • Improvements were observed in patients already taking LAMA or LABA maintenance therapy.
  • The 2025 GOLD guidelines acknowledged ensifentrine as a potential add-on therapy for patients with persistent breathlessness despite dual long-acting bronchodilator therapy.[1]

Side effects and precautions

  • Common side effects include back pain, high blood pressure, urinary tract infection, and diarrhea.
  • Not for use as a rescue inhaler for acute bronchospasm.
  • A rare but notable increase in psychiatric adverse reactions (<1%) has been reported, including insomnia, anxiety, depression, and suicidal ideation. Patients and caregivers should be aware of mood changes.[3]
  • Can cause paradoxical bronchospasm (rare).
Biologic Therapies

Biologics for COPD

For the first time, biologic medications are now FDA-approved for COPD — specifically for patients with an eosinophilic phenotype who continue to have exacerbations despite optimized inhaled therapy. This represents a shift toward targeted, biomarker-driven treatment.[4,5]

Dupilumab (Dupixent)
  • FDA approved: September 2024 — the first-ever biologic approved for COPD.[4]
  • Mechanism: A monoclonal antibody that blocks interleukin-4 (IL-4) and interleukin-13 (IL-13), key drivers of type 2 inflammation.
  • Who qualifies: Adults with inadequately controlled COPD and an eosinophilic phenotype (blood eosinophil count ≥300 cells/μL at screening in pivotal trials), already on maximized inhaled therapy who continue to exacerbate.[4]
  • Evidence: The BOREAS and NOTUS phase 3 trials showed dupilumab reduced moderate or severe exacerbations by 30–34% compared to placebo, while also improving lung function and quality of life.[4]
  • Administration: Subcutaneous injection, typically every 2 weeks. Already widely used for other type 2 inflammatory conditions (asthma, eczema, nasal polyps).
  • Side effects: Injection site reactions, upper respiratory infections, and joint pain are most common. Not an immunosuppressant.
Mepolizumab (Nucala)
  • FDA approved: May 2025 — the first biologic with once-monthly dosing for COPD.[5]
  • Mechanism: A monoclonal antibody that targets interleukin-5 (IL-5), which drives eosinophilic inflammation.
  • Who qualifies: Adults with inadequately controlled COPD and an eosinophilic phenotype. Notably, mepolizumab was studied in patients with blood eosinophil counts as low as ≥150 cells/μL (broader than dupilumab's trial population), capturing a larger eligible COPD population.[5]
  • Evidence: The MATINEE and METREX phase 3 trials showed a 18–21% reduction in annualized moderate-to-severe exacerbation rates. The MATINEE trial also showed a trend toward fewer hospitalizations and ED visits.[5]
  • Administration: 100 mg subcutaneous injection once every 4 weeks. Also approved for severe asthma, eosinophilic granulomatosis with polyangiitis, and other conditions.
  • Side effects: Back pain, diarrhea, cough, and headache. Generally well-tolerated.

Understanding eosinophilic COPD

  • What are eosinophils? A type of white blood cell involved in inflammation. Elevated blood eosinophil levels identify a subgroup of COPD patients with type 2 inflammation who are more likely to respond to biologic therapy.
  • Simple blood test: Blood eosinophil count is measured as part of a routine complete blood count (CBC). It helps guide decisions about ICS use and biologic eligibility.
  • About 20–40% of COPD patients have an eosinophilic phenotype, and approximately 70% of patients who remain uncontrolled on triple inhaled therapy have eosinophils ≥150 cells/μL — over one million people in the US alone.[5]
  • Not for all COPD: Biologics target a specific inflammatory pathway. Patients without elevated eosinophils or type 2 inflammation are unlikely to benefit.
Emphysema Treatment

Lung volume reduction

In severe emphysema, hyperinflated lungs trap air and flatten the diaphragm, making breathing inefficient. Lung volume reduction procedures remove or block the most damaged lung tissue, allowing healthier tissue to expand and the diaphragm to function better.[6,7]

Lung volume reduction surgery (LVRS)
  • What it is: A surgical procedure (thoracoscopic or open) that removes 20–30% of the most diseased lung tissue, reducing hyperinflation.
  • Evidence: The landmark NETT trial showed that LVRS improved exercise capacity, lung function, and quality of life — and improved survival in patients with upper-lobe predominant emphysema and low baseline exercise capacity.[6]
  • Who qualifies: Patients with severe emphysema (FEV1 <45% predicted), significant hyperinflation (RV >150% predicted), heterogeneous emphysema distribution (especially upper-lobe predominant), completed pulmonary rehabilitation, and non-smoking status.[6]
  • Complications: Prolonged air leak (most common, ~30–50%), pneumonia, respiratory failure, and perioperative mortality (~5% at 90 days in the NETT trial). High-risk subgroups (very low FEV1 <20% and either homogeneous emphysema or very low DLCO) were identified as having excessive surgical risk.
  • Recovery: Hospital stay of 5–14 days. Full recovery takes 6–12 weeks. Pulmonary rehabilitation before and after surgery is essential.
  • Limitations: Due to surgical risk, LVRS is underutilized. Many patients who could benefit are never referred.
Bronchoscopic lung volume reduction (BLVR)
  • What it is: A minimally invasive bronchoscopic procedure that places one-way endobronchial valves (Zephyr valves, FDA-approved 2018) into the airways of the most diseased lobe. The valves allow air and mucus to exit but prevent air from entering, causing the target lobe to collapse (atelectasis).[7]
  • Evidence: Multiple randomized trials (LIBERATE, TRANSFORM, STELVIO, IMPACT) showed significant improvements in FEV1 (~15–30% improvement), exercise capacity, and quality of life. Real-world data show response rates of ~86% at one year and ~71% at two years.[7]
  • Who qualifies: Severe emphysema with hyperinflation (FEV1 <45%, RV >175–200% predicted), heterogeneous emphysema with a clear target lobe, absent collateral ventilation between lobes (assessed during the procedure with the Chartis system), completed pulmonary rehabilitation, non-smoker, and absence of significant secretions or active infection.
  • Collateral ventilation: A key selection criterion unique to BLVR. If air leaks between lobes through accessory pathways (collateral ventilation), the valves cannot achieve atelectasis and the procedure will not work. This is tested during the bronchoscopy.
  • Complications: Pneumothorax (~20–25%, the most common serious complication — patients are monitored in-hospital for several days), COPD exacerbation, pneumonia, valve migration, and hemoptysis. About 20% of patients require a revision procedure within 2 years due to loss of atelectasis.[7]
  • Recovery: Hospital stay of 3–5 days (mainly for pneumothorax monitoring). Return to usual activity within 1–2 weeks. Valves are reversible — they can be removed or repositioned if needed.

LVRS vs. BLVR: how they compare

  • Invasiveness: BLVR is less invasive (bronchoscopy vs. surgery), with shorter recovery and lower procedural mortality.
  • Candidate selection: BLVR requires absent collateral ventilation, which limits eligibility. LVRS does not have this requirement. Some patients who fail BLVR assessment may be candidates for LVRS.
  • Durability: LVRS effects may be more durable (tissue is permanently removed). BLVR benefits can diminish over time (valve migration, granulation tissue) and revision may be needed in ~20% of cases.
  • Risk profile: LVRS carries higher perioperative risk but does not require absent collateral ventilation. BLVR has lower procedural risk but the main complication (pneumothorax) occurs in up to 25% of patients.
  • Bottom line: Both procedures can meaningfully improve quality of life, exercise capacity, and lung function in carefully selected patients with severe emphysema. The choice depends on the patient's anatomy, comorbidities, institutional expertise, and individual preferences.

Sleep and COPD

COPD symptoms can disturb sleep, and OSA may coexist (overlap syndrome). Addressing both improves quality of life.

Sleep–Lung Connection →

Trusted resources

References

  1. Global Initiative for Chronic Obstructive Lung Disease (GOLD). Global Strategy for Prevention, Diagnosis and Management of COPD: 2026 Report. Available from: goldcopd.org
  2. Graham BL, Steenbruggen I, Miller MR, et al. Standardization of spirometry 2019 update. Am J Respir Crit Care Med. 2019;200(8):e70-e88. doi:10.1164/rccm.201908-1590ST
  3. Anzueto A, Barjaktarevic IZ, Siler TM, et al. Ensifentrine, a novel phosphodiesterase 3 and 4 inhibitor for the treatment of chronic obstructive pulmonary disease: randomized, double-blind, placebo-controlled, multicenter phase III trials (ENHANCE 1 and ENHANCE 2). Am J Respir Crit Care Med. 2023;208(4):406-416. doi:10.1164/rccm.202306-0944OC
  4. Bhatt SP, Rabe KF, Hanania NA, et al. Dupilumab for COPD with type 2 inflammation indicated by eosinophil counts. N Engl J Med. 2023;389(3):205-214. doi:10.1056/NEJMoa2303951
  5. Sciurba FC, Criner GJ, Christenson SA, et al. Mepolizumab to prevent exacerbations of COPD with an eosinophilic phenotype. N Engl J Med. 2025;392(17):1710-1720. doi:10.1056/NEJMoa2413181
  6. Fishman A, Martinez F, Naunheim K, et al. A randomized trial comparing lung-volume-reduction surgery with medical therapy for severe emphysema (NETT). N Engl J Med. 2003;348(21):2059-2073. doi:10.1056/NEJMoa030287
  7. Criner GJ, Sue R, Wright S, et al. A multicenter randomized controlled trial of Zephyr endobronchial valve treatment in heterogeneous emphysema (LIBERATE). Am J Respir Crit Care Med. 2018;198(9):1151-1164. doi:10.1164/rccm.201803-0590OC