May 062012
Chronic Obstructive Pulmonary Disease (COPD) Review
Epidemiology of COPD
  • Globally, ~10% of people older than 40 have airflow limitation of GOLD stage 2 or worse (FEV1 < 80% predicted); up to 25% may have GOLD stage 1 (FEV1 ≥ 80% predicted but FEV1/FVC < 0.7).
  • Up to 60-85% of people with COPD (mostly mild/moderate severity) are undiagnosed.
  • Besides tobacco smoking, biomass exposure (wood burning stoves), secondhand smoke, air pollution and work exposures to fumes and dusts cause COPD in susceptible people.
  • COPD is the 4th leading cause of death worldwide; its mortality is rising, while cardiovascular disease's is falling; COPD is expected to be the 3rd leading cause of death in the next 20 years.
Pathophysiology of COPD

COPD is characterized both by destruction of lung parenchyma with loss of elastic recoil (causing emphysema) and infiltration of the walls of the small airways by inflammatory cells (causing chronic bronchiolitis / bronchitis). Although students are still taught these two broad phenotypes are distinct entities, in truth they coexist and overlap in varying degrees in virtually everyone with COPD. The reasons for these variable phenotypes and their clinical importance are poorly understood.

Alpha-1 antitrypsin deficiency is present in 1-2% of people with COPD, and is likely underrecognized. Genome-wide association studies have identified various gene polymorphisms associated with increased (and a few with decreased risk) for developing COPD.

COPD continues to be frequently described as chronic and progressive, and this is so in many patients. However, COPD is a highly heterogeneous disease, and this applies to its progression between individuals. Among people with COPD who stop smoking, some will continue to experience accelerated decline in lung function compared to healthy non-smokers; however, recent evidence suggests the majority will experience FEV1 declines no more rapid (and in some cases, less rapid) than the average nonsmoker. [1, 2, 3]

COPD Exacerbations

Many (not all) patients with COPD experience days-long episodes of increased dyspnea, cough, and sputum production, called COPD exacerbations. Most COPD exacerbations occur at home, resulting in increased use of bronchodilators, impaired function and enjoyment of life; more severe COPD exacerbations require systemic steroids, antibiotics, and sometimes hospitalization.

People with moderate COPD have one exacerbation per year on average; those with severe COPD have 2 on average. However, these averages mask wide heterogeneity: many patients with COPD have exacerbations never or very infrequently; a few experience them almost every month.

Recent research using invasive sampling of sputum from patients with COPD exacerbations strongly suggests that infections cause the majority (~80%) of COPD exacerbations, especially severe exacerbations. Common-cold bacteria and viruses including H. influenzae, S. pneumoniae, M. catarrhalis, rhinovirus, coronavirus, and parainfluenza cause the majority of infectious exacerbations (or about 50-60% of all COPD exacerbations), with less common organisms like Pseudomonas aeruginosa, S. aureus, and atypical bacteria (Mycoplasma, Chlamydia pneumonia) causing a minority of COPD exacerbations.

Congestive heart failure, systemic infections, pulmonary embolism, pneumonia, air pollution, cold air, allergies, and smoking are thought to cause 20-40% of COPD exacerbations.

How to prevent COPD exacerbations


Treatments for COPD

The GOLD guideline treatment table is the most well-known and accepted guideline for the treatment of COPD. It can be summarized as follows. This table may be outdated as  the GOLD guidelines were revised in 2017 -- read more here.


Stage:* 1 (mild) 2 (moderate) 3 (severe) 4 (very severe)
FEV1/FVC <0.70 <0.70 <0.70 <0.70
FEV1 >= 80% pred. 50-80% pred. 30-50% pred. <30% pred., or <50% pred.
w/chronic respiratory failure
 Treatment Short-acting bronchodilator as needed for all patients with COPD.
Consider pulmonary rehabilitation. Consider pulmonary rehabilitation. Consider pulmonary rehabilitation.
One or more long-acting bronchodilators. One or more long-acting bronchodilators. One or more long-acting bronchodilators.
Inhaled corticosteroid, if repeated exacerbations. Inhaled corticosteroid, if repeated exacerbations.
Long-term oxygen if needed; consider lung volume reduction surgery

* All patients should receive smoking cessation counseling and influenza vaccination.

Long-acting Bronchodilators, Inhaled Corticosteroids, and Tiotropium

Long-acting bronchodilators (formoterol, salmeterol) and long-acting anticholinergics (tiotropium) have similar efficacy:

  • Improvements in post-bronchodilator FEV1 (~50-100 mL)
  • Improvements in dyspnea (~3 points on the St. George's questionnaire)
  • Reduction in daily short-acting beta-agonist use by ~1 inhalation.
  • Tiotropium prevented COPD exacerbations better than salmeterol in one randomized trial, but the effect was quite small.

Long-acting beta agonists have cardiac effects, but have not been found to cause cardiovascular events, and don't have the very slightly increased risk of death associated with LABA monotherapy for asthma.

Tiotropium has been suspected of causing cardiovascular events based on observational trials, but the current consensus (based mainly on UPLIFT randomized trial data and a meta-analysis) is that Spiriva does not cause cardiovascular events.

Inhaled corticosteroid/LABA combination products cause pneumonia in a tiny proportion of patients; however, combination products may also reduce mortality slightly (based on the just-barely-negative TORCH trial). ICS/LABA combination products do not seem to cause an increased risk of death from pneumonia. Inhaled corticosteroids probably cause osteoporosis in a small number of susceptible patients.

The evidence is inconclusive as to whether any drug treatments for COPD modify (slow) the disease course or reduce mortality, but data from several clinical trials suggests that both inhaled corticosteroid/LABA combination products and tiotropium may reduce decline in FEV1 and slightly reduce mortality risk.

An observational study also suggested a benefit of "triple therapy" with inhaled corticosteroid, long-acting beta-agonist, and tiotropium.

The FDA has approved once-daily combination agents indacaterol, Breo Ellipta, aclidinium (Tudorza Pressair), and Anoro Ellipta, starting a new era of easier to use (and more expensive) controller inhalers which should enhance adherence.

Roflumilast and Cilomilast

The role of these new phosphodiesterase inhibitors is unclear. They have not been included in GOLD or other society treatment guidelines. Roflumilast only improved postbronchodilator FEV1 by ~50 mL and reduced exacerbation frequency by a relative 17%, among selected patients with GOLD stage 3-4 COPD who had cough with sputum changes and a history of exacerbations. The Cochrane Collaboration published an analysis on these new agents in 2011. Postmarketing data will be essential to determine the new agents' real-world efficacy and risk of adverse events.


A randomized trial of 1,577 patients treated with azithromycin or placebo for a year showed a 27% reduction in exacerbations in the azithromycin group, but may also have caused hearing loss. Also, azithromycin is associated with sudden cardiac death when taken by patients with cardiac disease. Erythromycin had a similar effect in another trial, but has poor gastrointestinal tolerability.

Lung Volume Reduction Surgery

Consideration for lung volume reduction surgery is recommended for all patients with very severe COPD. The surgery provides a mortality reduction and improvement in quality of life, especially in patients with upper-lobe predominant disease and poor exercise capacity. For unclear reasons, however, lung volume reduction surgery has never caught on: only 105 Medicare beneficiaries underwent LVRS in 2006.

Non-Surgical, Bronchoscopic Lung Volume Reduction

Because of the morbidity and risk associated with lung volume reduction surgery, and its subsequent unpopularity, numerous companies and investigators have sought to produce a medical device that could be placed bronchoscopically and that would reduce dead space ventilation -- lung volume reduction surgery without the surgery, if you will. To date, none of these devices have worked effectively enough to recommend their use outside clinical trials. The most recent example was the EASE trial, published in Lancet 2011, showing that bronchoscopically-placed airway stents with one-way valves (the Exhale device) did not improve airway mechanics or dyspnea.

Why haven't these bronchoscopically placed devices worked? The most likely answer is collateral ventilation, or interalveolar air drift through the pores of Kohn. These are miniscule anatomic intercommunications that allow air to fill back into emphysematous areas after air is removed through the implanted device.

Treatment of COPD Exacerbations

Guidelines are available for treatment of COPD exacerbations; they mainly recommend:

  • Increasing the dose of short acting bronchodilators (albuterol and/or ipratropium).
  • Adding oral corticosteroids if bronchodilators are not successful.
  • Oxygen and ventilatory support for respiratory failure. A recent review showed that non-invasive positive pressure ventilation is likely improving outcomes from COPD exacerbations.
  • Consider theophylline for severe exacerbations.

The 2014 GOLD guidelines advise treating most COPD exacerbations with 40 mg prednisone for 5 days. This was a significant change from the previous recommendation of 10-14 days. The REDUCE study in JAMA suggested 5 days steroids is adequate treatement for COPD exacerbations, in most patients.

More Pulm/CCM Topic Updates and Reviews

Chronic obstructive pulmonary disease. Seminar. Decramer M et al. Lancet 2012;379:1341-1351. 

Qaseem A et al. Diagnosis and Management of Stable Chronic Obstructive Pulmonary Disease: A Clinical Practice Guideline Update from the American College of Physicians, American College of Chest Physicians, American Thoracic Society, and European Respiratory Society. Ann Intern Med 2011;155:179-191.  [ summary]

Celli BR et al. Standards for the diagnosis and treatment of patients with COPD: a summary of the ATS/ERS position paper. Eur Respir J 2004;23:932-946.

Stoller JK. Acute Exacerbations of Chronic Obstructive Pulmonary Disease. N Engl J Med 2002;346:988-984.

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Chronic obstructive pulmonary disease update (COPD Review)