Management of Stable Chronic Obstructive Pulmonary Disease

Although PDE4 inhibitors are easy to administer (a once-daily pill), they are associated with significant GI side effects (diarrhea, nausea, reduced appetite), weight loss, headache, and sleep disturbance [77]. Adverse effects tend to occur early during treatment, are reversible, and lessen over time with treatment [66]. Studies reported an average unexplained weight loss of 2 kg, and monitoring weight during treatment is advised. In addition, it is important to avoid roflumilast in underweight patients. Roflumilast should also be used with caution in depressed patients [65].

N-acetylcysteine

N-acetylcysteine (NAC) reduces the viscosity of respiratory secretions as a result of the cleavage of the disulfide bonds and has been studied as a mucolytic agent to aid in the elimination of respiratory secretions [78]. Oral NAC is quickly absorbed and is rapidly present in an active form in lung tissue and respiratory secretions after ingestion. NAC is well tolerated except for occasional patients with GI adverse effects. The role of NAC in preventing AECOPD has been studied for more than 3 decades [79–81], although the largest clinical trial to date was reported in 2014 [57]. Taken together, the combined data demonstrate a significant reduction in the rate of COPD exacerbations associated with the use of NAC when compared with placebo (OR, 0.61; CI, 0.37–0.99). Clinical guidelines suggest that in patients with moderate to severe COPD (FEV1/FVC < 0.7, and FEV1 < 80% predicted) receiving maintenance bronchodilator therapy combined with ICS and history of 2 more exacerbations in the previous 2 years, treatment with oral NAC can be administered to prevent AECOPD.

Macrolides

Continuous prophylactic use of antibiotics in older studies had no effect on the frequency of AECOPD [82,83]. But it is known that macrolide antibiotics have several antimicrobial, anti-inflammatory and immunomodulating effects and have been used for many years in the management of other chronic airway disease, including diffuse pan-bronchiolitis and cystic fibrosis [65]. One recent study showed that the use of once-daily, generic azithromycin 5 days/week appeared to have an impact on AECOPD incidence [84]. In this study, AECOPD was reduced from 1.83 to 1.48 per patient-year (RR, 0.83; 95% CI, 0.72–0.95: P = 0.01). Azithromycin also prevented severe AECOPD. Greater benefit was obtained with milder forms of the disease and in the elderly. Azithromycin did not appear to provide any benefit in those who continued to smoke (hazard ratio, 0.99) [85]. Other studies have shown that azithromycin was associated with an increased incidence of bacterial resistance and impaired hearing [86]. Overall data from the available clinical trials are robust and demonstrate that regular macrolide therapy definitely reduces the risk of AECOPD. But due to potential side effects macrolide therapy is an option rather than a strong recommendation [65]. The prescribing clinician also needs to consider the potential of prolongation of the QT interval [84].

Immunostimulants

Immunostimulants have also been reported to reduce frequency of AECOPD [87,88]. Bacterial lysates, reconstituted mixtures of bacterial antigens present in the lower airways of COPD patients, act as immuno-stimulants through the induction of cellular maturation, stimulating lymphocyte chemotaxis, and increasing opsonization when administered to individuals with COPD [66]. Studies have demonstrated a reduction in the severe complications of exacerbations and hospital admissions in COPD patients with OM-85, a detoxified oral immunoactive bacterial extract [87,88]. However, most of these trials were conducted prior to the routine use of long-acting bronchodilators and ICS in COPD. A recent study by Braido et al evaluated the efficacy of ismigen, a bacterial lysate, in reducing AECOPD [89] and found no difference in the exacerbation rate between ismigen and placebo or the time to first exacerbation. Additional studies are needed to examine the long-term effects of this therapy in patients receiving currently recommended COPD maintenance therapy [66].

β Blockers

Observational studies of beta-blocker use in preventing AECOPD have yielded encouraging results, with one study showing a reduction in AECOPD risk (incidence risk ratio, 0.73; CI 0.60–0.90) in patients receiving beta blockers versus those not on beta blockers [90]. Based on these findings, a clinical trial investigating the impact of metoprolol on risk of AECOPD is ongoing [91].

Proton Pump Inhibitors

Gastroesophageal reflux disease is an independent risk factor for exacerbations [92]. Two small, single-center studies [93,94] have shown that use of lansoprazole decreases the risk and frequency of AECOPD. However, data from the Predicting Outcome using Systemic Markers in Severe Exacerbations of COPD (PROMISE-COPD) study [66], which was a multicenter prospective observational study, suggested that patients with stable COPD receiving a proton pump inhibitor were at high risk of frequent and severe exacerbations [95]. Thus, at this stage, their definitive role needs to be defined, possibly with a randomized, placebo-controlled study.

Case 3

A 65-year-old male with severe COPD (FEV1/FVC 27, FEV1 25% of predicted, residual volume 170% of predicted for his age and height) was seen in the pulmonary clinic. His medications include a LABA/LAMA combination that he uses twice daily as advised. He uses his rescue albuterol inhaler roughly once a week. The patient complains of severe disabling shortness of breath with exertion and severe limitation of his quality of life because of his inability to lead a normal active life. He is on 2 L/min of oxygen at all times. He has received pulmonary rehabilitation in hopes of improving his quality of life but can only climb a flight of stairs before he must stop to rest. He asks about options but does not want to consider lung transplantation today. His most recent chest CT scan demonstrates upper lobe predominant emphysematous changes with no masses or nodules.

• What are the patient's options at this time?

Lung volume reduction surgery (LVRS) attempts to reduce space-occupying severely diseased, hyperexpanded lung, thus allowing the relatively normal adjoining lung parenchyma to expand into the vacated space and function effectively [96].Hence, such therapies are suitable for patients with emphysematous lungs and not those with bronchitic-predominant COPD. LVRS offers a greater chance of improvement in exercise capacity, lung function, quality of life, and dyspnea in the correctly chosen patient population as compared with pharmacologic management alone [97]. However, the procedure is associated with risks, including higher short-term morbidity and mortality [97]. Patients with predominantly upper-lobe emphysema and a low maximal workload after rehabilitation were noted to have lower mortality, a greater probability of improvement in exercise capacity, and a greater probability of improvement in symptoms if they underwent surgery compared to medical therapy alone [97]. On the contrary, patients with predominantly non–upper-lobe emphysema and a high maximal workload after rehabilitation had higher mortality if they underwent surgery compared to receiving medical therapy alone [97]. Thus, a subgroup of patients with homogeneous emphysema symmetrically affecting the upper and lower lobes are considered to be unlikely to benefit from this surgery [97,98].

Valves and other methods of lung volume reduction such as coils, sealants, intrapulmonary vents, and thermal vapor in the bronchi or subsegmental airways have emerged as new techniques for nonsurgical lung volume reduction [99–104]. Endobronchial-valve therapy is associated with improvement in lung function and with clinical benefits that are greatest in the presence of heterogeneous lung involvement. This works by the same principle as with LVRS, by reduction of the most severely diseased lung units, expansion of the more viable, less emphysematous lung results in substantial improvements in lung mechanics [105,106]. The most important complications of this procedure include pneumonia, pneumothorax, hemoptysis and increased frequency of COPD exacerbation in the following thirty days. The fact that high-heterogeneity subgroup had greater improvements in both the FEV1 and distance on the 6-minute walk test than did patients with lower heterogeneity supports the use of quantitative high-resolution computed tomography (HRCT) in selecting patients for endobronchial-valve therapy [107].The HRCT scans also help in identifying those with complete fissures; a marker of lack of collateral ventilation (CV+) between different lobes. Presence of CV+ state predicts failure of endobronchial valve and all forms of endoscopic lung volume reduction strategies [108]. Bronchoscopic thermal vapor ablation (BTVA) therapy can potentially work on a subsegmental level and be successful for treatment of emphysema with lack of intact fissures on CT scans. Other methods that have the potential to be effective in those with collateral ventilation would be endoscopic coil therapy and polymeric lung volume reduction [106,109].Unfortunately^, there are no randomized controlled trial data demonstrating clinically meaningful improvement following coil therapy or polymeric lung volume reduction in this CV+ patient population. Vapor therapy is perhaps the only technique that has been found to be effective in upper lobe predominant emphysema even with CV+ status [108].

Our patient has evidence of air trapping and emphysema based on a high residual volume. A CT scan of the chest can determine the nature of the emphysema (heterogeneous versus homogenous) and based on these findings, further determination of the best strategy for lung volume reduction can be made.

• Is there a role for long-term oxygen therapy?

Long-term oxygen therapy (LTOT) used for > 15 hours a day is thought to reduce mortality among patients with chronic obstructive pulmonary disease (COPD) and severe resting hypoxemia [110–113].More recent studies have failed to show similar beneficial effects of LTOT. A recent study examined the effects of LTOT in randomized fashion and determined that supplemental oxygen for patients with stable COPD and resting or exercise-induced moderate desaturation did not affect the time to death or first hospitalization, time to first COPD exacerbation, time to first hospitalization for a COPD exacerbation, the rate of all hospitalizations, the rate of all COPD exacerbations, or changes in measures of quality of life, depression, anxiety, or functional status [114].

Our patient is currently on long-term oxygen therapy and in spite of some uncertainty as to its benefit, it is prudent to order oxygen therapy until further clarification is available.

• What is the role of pulmonary rehabilitation?

Pulmonary rehabilitation is an established treatment for patients with chronic lung disease [115]. Benefits include improvement in exercise tolerance, symptoms, and quality of life, with a reduction in the use of health care resources [116].A Spanish population-based cohort study that looked at the influence of regular physical activity on COPD showed that patients who reported low, moderate, or high physical activity had a lower risk of COPD admissions and all-cause mortality than patients with very low physical activity after adjusting for all confounders [117].

As previously mentioned, patients in GOLD categories B, C, and D should be offered pulmonary rehabilitation as part of their treatment [7]. The ideal patient is one who is not too sick to undergo rehabilitation and is motivated to his or her quality of life.