Treating and preventing acute exacerbations of COPD
ABSTRACTAcute exacerbations of chronic obstructive pulmonary disease (COPD)—characterized by shortness of breath, increased sputum production, increased purulence, or a combination of these signs—are costly and can have major impacts on the patient’s health. Corticosteroids, antibiotics, and bronchodilators are the cornerstones of prevention and therapy, with mucolytics, oxygen supplementation, and ventilatory support also advisable for some patients. Treatment should be evidence-based and tailored to the patient’s history and present needs.
KEY POINTS
- COPD exacerbations usually start with an infection.
- A short course of corticosteroids (eg, prednisone 40 mg daily for 5 to 7 days) improves outcomes with low risk.
- The choice of antibiotic depends on severity and frequency of exacerbations and the patient’s age and condition.
- Inhaled albuterol 2.5 mg, every 1 to 4 hours, should be prescribed with or without a nebulized anticholinergic.
- Ventilation support is important for patients with acute respiratory acidosis (pH < 7.35).
- Exacerbations can be prevented with some combination of inhaled agents (long-acting beta-2 agonist, corticosteroid, long-acting antimuscarinic), roflumilast (an oral phosphodiesterase inhibitor), and a mucolytic, depending on the patient’s needs.
Roflumilast is effective but has side effects
Roflumilast, an oral phosphodiesterase 4 inhibitor, is an anti-inflammatory drug without bronchodilator properties. In randomized controlled trials, the drug was associated with a 17% reduction in acute exacerbations compared with placebo.59
Adding roflumilast to either a long-acting beta-2 agonist or a long-acting antimuscarinic agent resulted in a 6% to 8% further reduction in the proportion of patients with exacerbation.60,61 Martinez et al61 found that roflumilast added to a regimen of a long-acting beta-2 agonist plus an inhaled corticosteroid reduced moderate to severe exacerbations by 14.2%, even in the presence of tiotropium. Compared with placebo, roflumilast treatment reduced exacerbations necessitating hospitalizations by 23.9%.
The FDA has approved oral roflumilast 500 µg once daily to prevent COPD exacerbations.
Roflumilast is frequently associated with side effects, including gastrointestinal symptoms (chiefly diarrhea), weight loss, and psychiatric effects. A benefit-to-harm study in 2014 concluded that using the drug is only favorable for patients who have a high risk of severe exacerbations, ie, those who have a greater than 22% baseline risk of having at least one exacerbation annually.62
Recommendation. Roflumilast should be reserved for patients who have severe COPD with a chronic bronchitis phenotype (ie, with cough and sputum production) and repeated exacerbations despite an optimal regimen of an inhaled corticosteroid, long-acting beta-2 agonist, and long-acting antimuscarinic agent.
Macrolide antibiotics: Role unclear
Macrolide antibiotics have anti-inflammatory and immunomodulatory activities.
Azithromycin: fewer exacerbations but some side effects. A multicenter trial63 in 1,142 COPD patients randomized to either oral azithromycin 250 mg daily or placebo found a 27% reduction in the risk of COPD exacerbation in the intervention arm. No differences were found between the groups in mortality, hospitalizations, emergency department visits, or respiratory failure. Hearing loss and increased macrolide resistance were noted in the intervention arm. In a secondary subgroup analysis,64 no difference in efficacy was found by sex, history of chronic bronchitis, oxygen use, or concomitant COPD treatment.
The COPD: Influence of Macrolides on Exacerbation Frequency in Patients trial65 helped refine patient selection for macrolide therapy. In this single-center study, 92 patients with COPD and at least three exacerbations during the year prior to enrollment were randomized to receive either azithromycin 500 mg three times weekly or placebo. Exacerbations in the intervention group were markedly reduced (42%) with no difference in hospitalization rate.
The place of macrolide antibiotics in the treatment strategy of COPD is unclear, and they are not currently part of the GOLD guidelines. Still unknown is the incremental benefit of adding them to existing preventive regimens, cardiovascular safety, side effects, and potential effects on the resident microbial flora.
Other antibiotics have also been investigated for efficacy in preventing exacerbations.
Moxifloxacin: fewer exacerbations. The Pulsed Moxifloxacin Usage and Its Long-term Impact on the Reduction of Subsequent Exacerbations study66 randomized more than 1,000 patients with stable COPD to receive either moxifloxacin 400 mg or placebo daily for 5 days repeated every 8 weeks for six courses. Frequent assessment during the treatment period and for 6 months afterward revealed a reduced exacerbation rate in the intervention group but without benefit in hospitalization rate, mortality, lung function, or health status.
Recommendation. Azithromycin (either 250 mg daily or 500 mg three times weekly) can be considered for patients who have repeated COPD exacerbations despite an optimal regimen of an inhaled corticosteroid, inhaled long-acting beta-2 agonist, and inhaled long-acting antimuscarinic agent. The need to continue azithromycin should be reassessed yearly.
Mucolytics
Greatest benefit to patients not taking inhaled corticosteroids. Mucolytic agents help clear airway secretions by reducing viscosity. N-acetylcysteine and carbocysteine (not available in the United States) also have antioxidant properties that may counteract oxidant stress associated with acute COPD exacerbations.
The Bronchitis Randomized on NAC Cost-Utility Study (BRONCUS)67 randomized 523 COPD patients to N-acetylcysteine 600 mg daily or placebo. After 3 years of follow-up, no differences were found in the rate of exacerbations, lung function decline, and quality of life. Subgroup analysis suggested a reduction in exacerbations for patients who were not taking inhaled corticosteroids.
The Effect of Carbocisteine on Acute Exacerbation of Chronic Obstructive Pulmonary Disease (PEACE) study randomized more than 700 patients from multiple centers in China who had COPD and a recent history of exacerbations; they found a 25% lower exacerbation rate over 1 year with carbocysteine vs placebo.68 Most of the patients (83%) were not on inhaled corticosteroids, which complemented findings of the BRONCUS trial.
The Effect of High Dose N-acetylcysteine on Air Trapping and Airway Resistance of COPD (HIACE) study randomized 120 patients with stable COPD in a hospital in Hong Kong to either oral N-acetylcysteine (600 mg twice daily) or placebo and found a reduced exacerbation rate of exacerbations. Patients were matched at baseline for inhaled corticosteroid use.69
In 2014, the Twice Daily N-acetylcysteine 600 mg for Exacerbations of Chronic Obstructive Pulmonary Disease (PANTHEON) study70 randomized 1,006 patients from multiple hospitals in China with a history of moderate to severe COPD and exacerbations to receive either N-acetylcysteine 600 mg twice daily or placebo for 1 year. They found a 22% reduction in exacerbations in the treatment group vs placebo.
GOLD guidelines2 recommend mucolytics for patients with severe COPD and exacerbations when inhaled corticosteroids are not available or affordable.
Recommendation. Mucolytics may be useful for patients with difficulty expectorating and with a history of exacerbations despite appropriate inhaled therapy.
OTHER INTERVENTIONS CAN HELP
Pulmonary rehabilitation provides multiple benefits
Pulmonary rehabilitation increases exercise tolerance and reduces symptom burden in patients with stable COPD. It is also a multidisciplinary effort that may help reinforce adherence to medications, enhance COPD education, and provide closer medical surveillance to patients at high risk for recurrent exacerbations.
A small randomized controlled trial71 prescribed pulmonary rehabilitation on discharge for a COPD exacerbation and found sustainable improvements in exercise capacity and health status after 3 months.
In a later study,72 the same group started pulmonary rehabilitation within a week of hospital discharge and found reduced hospital readmissions over a 3-month period.
Smoking cessation is always worth advocating
A large observational cohort study concluded that current smokers were at a higher risk for COPD exacerbations compared with former smokers.73 Although there are no randomized controlled trials that assess the effects of smoking cessation at the time of COPD exacerbation, we recommend seizing the opportunity to implement this important intervention.
Vaccinations: Influenza and pneumococcal
Influenza vaccination is associated with reduced incidence of hospitalization among patients with cardiopulmonary disease.74 A meta-analysis of randomized clinical trials of influenza vaccination for patients with COPD75 reported significantly fewer exacerbations from vaccination, mostly owing to fewer episodes occurring after 3 to 4 weeks, coinciding with anticipated vaccine-induced immune protection. Furumoto and colleagues76 reported an added benefit of combined vaccination with 23-valent pneumococcal polysaccharide vaccine and influenza vaccine in reducing hospital admissions over influenza vaccination alone. We also recommend providing the 13-valent pneumococcal conjugate vaccine to patients with COPD, particularly for those older than 65, consistent with CDC recommendations.77
