Volume 124, Issue 5, Pages 873-880 (November 2009)

9 of 63

ABSTRACT

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Management of chronic obstructive pulmonary disease: Moving beyond the asthma algorithm

Received 15 July 2009; received in revised form 24 September 2009; accepted 25 September 2009.

For many years, chronic obstructive pulmonary disease (COPD) was considered a disease of fixed airflow obstruction for which there was no good treatment. Out of desperation and frustration, health care providers extrapolated from asthma to COPD, and standard asthma therapy was adopted without evidence for efficacy. In recent years, we have gained a better understanding of the pathophysiologic differences between asthma and COPD, and prospective controlled trials have provided a rationale for therapy. Smoking cessation is critically important, both as primary prevention and as an effective way to slow the decrease in lung function in patients with established disease. β2-Adrenergic and anticholinergic agonists improve lung function and relieve symptoms in most patients. Tiotropium improves exercise tolerance and quality of life and reduces exacerbations and hospitalizations. The increase in lung function seen with tiotropium is sustained with continued use over at least 3 to 4 years. Inhaled corticosteroids decrease exacerbations and improve quality of life, and their effect seems greatest in patients with lower lung function and in exacerbation-prone patients. There is no evidence that inhaled corticosteroids alone affect mortality, despite the reduction in exacerbations and increased risk of pneumonia. In some patient populations, inhaled fluticasone, salmeterol, or the combination might slow the rate of loss of lung function.

Rather than reflexively using effective asthma therapy in the patient with COPD, current and future therapy for COPD is increasingly evidence based and targeted to specific inflammatory pathways that are important in patients with COPD.

Key words: Chronic obstructive pulmonary disease, asthma, airflow obstruction, inhaled corticosteroids, oral corticosteroids, bronchodilators, long-acting bronchodilators, β2-agonists, anticholinergics, mucolytics, antioxidants, pulmonary rehabilitation, home oxygen, smoking cessation, immunization

Abbreviations used: COPD, Chronic obstructive pulmonary disease, FVC, Forced vital capacity, ISOLDE, Inhaled Steroids in Obstructive Lung Disease, OR, Odds ratio, TORCH, Towards a Revolution in COPD Health

Article Outline

• Abstract

• Corticosteroids

• Inhaled corticosteroids

• Oral corticosteroids

• Bronchodilators

• Anticholinergic bronchodilators

• β-Adrenergic bronchodilators

• Mucolytics

• Antioxidants

• Novel pharmacologic therapies

• Nonpharmacologic therapies

• Oxygen

• Smoking cessation

• Pulmonary rehabilitation

• Immunizations

• Influenza

• Pneumococcal vaccine

• Summary

• References

• Copyright

Information for Category 1 CME Credit

Credit can now be obtained, free for a limited time, by reading the review articles in this issue. Please note the following instructions.

Method of Physician Participation in Learning Process: The core material for these activities can be read in this issue of the Journal or online at the JACI Web site: www.jacionline.org. The accompanying tests may only be submitted online at www.jacionline.org. Fax or other copies will not be accepted.

Date of Original Release: November 2009. Credit may be obtained for these courses until October 31, 2011.

Overall Purpose/Goal: To provide excellent reviews on key aspects of allergic disease to those who research, treat, or manage allergic disease.

Target Audience: Physicians and researchers within the field of allergic disease.

Accreditation/Provider Statements and Credit Designation: The American Academy of Allergy, Asthma & Immunology (AAAAI) is accredited by the Accreditation Council for Continuing Medical Education (ACCME) to provide continuing medical education for physicians. The AAAAI designates these educational activities for a maximum of 1 AMA PRA Category 1 Credit™. Physicians should only claim credit commensurate with the extent of their participation in the activity.

List of Design Committee Members: Authors: Erin Gordon, MD, and Stephen C. Lazarus, MD

Activity Objectives

1. To identify therapeutic options for chronic obstructive pulmonary disease (COPD): evidence based on prospective controlled trials.

2. To describe specific benefits of pharmacologic agents (inhaled corticosteroids [ICSs], long-acting β-agonists, and anticholinergics) in patients with COPD.

3. To describe the benefits of nonpharmacologic therapies in patients with COPD.

4. To name the recommended vaccinations for patients with COPD.

Recognition of Commercial Support: This CME activity has not received external commercial support.

Disclosure of Significant Relationships with Relevant Commercial

Companies/Organizations: S. C. Lazarus has received research support

from the National Heart, Lung, and Blood Institute (NIH-NHLBI). E. Gordon has declared that she has no conflict of interest.

Chronic obstructive pulmonary disease (COPD) and asthma are chronic lung diseases characterized by airway inflammation and airflow limitation, which is variably reversible. Both are associated with high morbidity and cost to the community.1 The pathogenesis of both diseases depends on the critical interaction between environmental stimuli and a genetically predisposed host. Aeroallergens, air pollutants, and infections are key triggers of asthma exacerbations.2 In the United States and most of the developed world, cigarette smoking is the single most important cause of COPD3; in undeveloped countries biomass fuel has been implicated.4 Inhaled corticosteroids improve asthma control, decrease exacerbations, and help to maintain lung function over time.5 Until recently, smoking cessation was believed to be the only intervention that reduced the accelerated rate of decrease of lung function that characterizes COPD.6 More recently, pharmacologic therapy has been shown to be effective. Unlike asthma, which is characterized predominantly by airway inflammation without structural changes, COPD encompasses the 2 distinct but often related processes of chronic bronchitis and emphysema, both of which result in structural changes that limit airflow. Chronic bronchitis is an inflammatory condition of the large and small airways that results in enlargement of mucus glands, increased numbers of goblet cells, and mucus hypersecretion. Emphysema involves destruction of the lung parenchyma with dilation and destruction of the respiratory bronchioles. The inflammatory patterns seen in patients with asthma and COPD are distinct, with eosinophils and TH2 cells predominating in those with asthma, and macrophages, neutrophils, and CD8+ lymphocytes playing key roles in COPD.7 These cellular patterns are mediated by overlapping but distinct networks of proinflammatory cytokines, chemokines, and growth factors. Although TH2 cytokines, such as IL-13, IL-4, and IL-5, as well as chemokines, such as stem cell factor and thymic stromal lymphopoietin, play an important role in asthma, COPD pathogenesis appears to be dominated by TGF-β, TNF-α, fibroblast growth factor, IL-1β, and IL-6.7 Inhaled and systemic corticosteroids, respectively, are the mainstay of therapy for stable asthma and for acute exacerbations of asthma and COPD and are aimed at decreasing airway inflammation. However, the elucidation of distinct inflammatory networks involved in COPD and asthma promises the development of novel, targeted immunologic therapies. Although asthma is a disease of reversible airflow obstruction that can become fixed in some patients, COPD has been characterized classically by a lack of major reversibility of airflow obstruction. However, like asthmatic subjects, patients with COPD often experience symptomatic and objective improvement with β2-agonists and anticholinergic bronchodilator medications. Thus these agents are widely used and recommended in the management of both asthma and COPD.

Corticosteroids

Inhaled corticosteroids

Although the inflammatory process differs in asthma and COPD, inhaled corticosteroids, which are aimed at decreasing airway inflammation, form the basis for management of symptoms of stable disease. In patients with asthma, inhaled corticosteroids decrease airway inflammation, improve lung function, reduce symptoms and airway hyperresponsiveness, and prevent exacerbations and mortality.8, 9, 10, 11, 12, 13, 14 Until recently, a role for inhaled corticosteroids in the treatment of COPD has been less clear. A number of studies have suggested that inhaled corticosteroid therapy reduces both local and systemic inflammation in patients with COPD. In a double-blind, randomized, placebo-controlled study of 30 patients comparing 500 μg of fluticasone inhaled twice daily with placebo, airway biopsy confirmed that the predominant inflammatory cell types in the airways of patients with COPD include CD8+ T cells, macrophages, and neutrophils and that fluticasone reduced subepithelial mast cell numbers and the ratio of CD8/CD4 T cells in the epithelium.15 These results were not replicated in a study of fluticasone versus placebo over 6 months in 23 patients with COPD.16 Additionally, a number of studies have examined the effects of inhaled corticosteroid therapy on inflammatory indices in the sputum of patients with COPD and have demonstrated little effect.17, 18, 19 However, similar studies analyzing inflammatory indices in bronchoalveolar lavage fluid have shown that inhaled corticosteroid therapy reduces cellularity, as well as levels of albumin, lactoferrin, lysozyme, and IL-8.20, 21 Finally, Sin et al22 demonstrated that the use of inhaled corticosteroid therapy in patients with mild-to-moderate COPD reduced plasma levels of C-reactive protein; however, other investigators have been unable to demonstrate effects on cytokine production from PBMCs studied ex vivo.23

Unlike asthma, it has been difficult to demonstrate convincing clinical benefits from the daily use of inhaled corticosteroids in patients with COPD, despite clear evidence of both systemic and airway inflammation. In a recent meta-analysis performed by Drummond et al,24 11 randomized controlled trials including more than 14,000 patients were systematically reviewed comparing inhaled corticosteroid therapy with nonsteroid inhaled therapy for 6 months or more. In 5 studies with more than 9,000 patients, all-cause mortality at 1 year was reported. There were 128 deaths in the treatment group and 148 deaths in the control group and no survival difference associated with inhaled corticosteroid use at 1 year. Seven studies including more than 10,000 patients reported pneumonia outcomes. These studies included 777 and 561 events in the inhaled corticosteroid treatment group and non–inhaled corticosteroid group, respectively. Patients receiving inhaled corticosteroid therapy had a higher incidence of pneumonia (relative risk, 1.34; P = .03). Only 3 studies reported fracture events, with 195 and 178 events, respectively; there was no difference in the risk of fracture between patients receiving inhaled corticosteroid therapy and those receiving non–inhaled corticosteroid therapy.

Within the last decade, 4 large studies have examined the effect of long-term inhaled corticosteroids on outcomes in patients with COPD. To the disappointment of many, the Copenhagen City Heart Study, European Respiratory Society Study on Chronic Obstructive Pulmonary Disease, Inhaled Steroids in Obstructive Lung Disease (ISOLDE), and Lung Health Study II all failed to demonstrate an effect of inhaled corticosteroids on lung function over time.25, 26, 27, 28 The observations from these individual studies are bolstered by data from a 2007 meta-analysis performed by the Cochrane Collaboration assessing the effect of inhaled corticosteroid therapy on lung function in patients with stable COPD.29 In this analysis of 47 randomized, placebo-controlled trials of long-term use of inhaled corticosteroids including more than 13,000 patients with stable COPD, there was no reduction in the decrease of FEV1 nor was there a reduction in overall mortality. Inhaled corticosteroids might, however, slow disease progression in patients with more severe COPD. For example, Celli et al30 reported that in subjects in the Towards a Revolution in COPD Health (TORCH) study with moderate-to-severe COPD (mean postbronchodilator FEV1 of approximately 45% of predicted value), treatment with fluticasone propionate for 3 years reduced the rate of decrease in FEV1 compared with placebo (42 vs 55 mL/y, P < .003). Similar reductions were observed with salmeterol alone and with the salmeterol/fluticasone combination.

Despite the lack of survival benefit associated with the daily use of inhaled corticosteroid therapy, a number of randomized controlled trials have demonstrated a reduction in the frequency of exacerbations, as well as the improvement in quality-of-life scores. The Cochrane meta-analysis demonstrated that the long-term use of inhaled corticosteroids reduced the mean rate of exacerbation and slowed the rate of decrease in quality of life, as measured with the St George's Respiratory Questionaire.29 Inhaled triamcinolone reduced exacerbations in the Lung Health Study II from 28.2 per 100 person-years to 21.1 per 100 person-years (P = .005).28 In the ISOLDE study fluticasone significantly reduced exacerbations, and its effect was greatest in subjects with low lung function.27 Two different meta-analyses confirmed this effect of inhaled corticosteroids on exacerbations of COPD.29, 31 Based on these studies, the Global Initiative for Chronic Obstructive Lung Disease guidelines recommend inhaled corticosteroid therapy for symptomatic patients with a FEV1 of less than 50% of predicted value and repeated exacerbations (3 in the last 3 years).32 Additionally, the American Thoracic Society/European Respiratory Society guidelines recommend therapy with inhaled corticosteroids if FEV1 is less than 50% of predicted value and there have been exacerbations of COPD requiring a course of oral corticosteroids or antibiotics at least once within the last year.33

The exact role of inhaled corticosteroids in patients with COPD remains to be determined because data from the literature are seemingly in conflict. Clinical trials have clearly demonstrated a reduction in exacerbations but no effect on mortality. Recent meta-analyses describe an increased risk of pneumonia in patients with COPD who take inhaled corticosteroids. It is likely that these results reflect, in part, the heterogeneity of COPD, with some subpopulations more likely to benefit from inhaled corticosteroids and others who might be more at risk for pneumonia. For now, inhaled corticosteroids appear warranted in the exacerbation-prone patient, and the potential risk for pneumonia might suggest the use of low doses to minimize the potential risk.

Oral corticosteroids

Although central to the management of acute exacerbations of both asthma and COPD, oral corticosteroids have been successfully used chronically to treat the patient with severe asthma who is refractory to other treatment. The use of systemic corticosteroids in patients with stable COPD has been more controversial. The literature on the use of oral corticosteroids in patients with COPD has been difficult to interpret because of differences in dose and length of treatment. The long-term use of low-dose corticosteroids is not supported by the literature.34, 35, 36, 37 Data on the long-term (>6 weeks) use of high-dose oral corticosteroids in patients with COPD have been limited. In 13 short-term studies the use of high-dose oral corticosteroids (>30 mg of prednisolone) for 2 weeks was associated with an increase in FEV1.38 However, the effect was not uniform and demonstrated marked individual variation. A single study of 67 patients with COPD randomized to 30 mg of prednisolone daily or placebo for 2 weeks found that improvements in FEV1 and quality-of-life scores were greater in those patients with higher baseline sputum eosinophil counts and were associated with a reduction in sputum eosinophil counts, suggesting that this subgroup might benefit from long-term treatment.39 Unlike FEV1, studies of effects on quality-of-life measures, symptom scores, or exacerbation rates either for long- or short-term high-dose corticosteroids are extremely limited and do not show a statistically significant improvement.38 The improvement in FEV1 with short-term use of high doses of oral corticosteroids should be weighed against their well-defined adverse effects, including glucose intolerance, decreased bone density, and adrenal suppression.

Bronchodilators

Treatment of asthma has focused first on the introduction of anti-inflammatory controller medications, with the addition of bronchodilators as adjuvant treatments aimed at relieving episodic symptoms in the case of short-acting medications or controlling daily symptoms in the case of long-acting medications. In contrast, given the unclear benefits and the potential risk associated with inhaled corticosteroids, treatment of stable COPD has focused instead on bronchodilators. Although response to bronchodilators has been used to differentiate asthma from COPD, this distinction is not as absolute as was once believed. Most asthmatic subjects will demonstrate a 15% increase in FEV1 in response to bronchodilators. Although the response in patients with COPD is less consistent, most of these patients will demonstrate significant bronchodilator responsiveness if studied on more than 1 occasion.40 Patients often report symptomatic improvement when treated with β2-agonists and anticholinergic bronchodilator medications. These medications are recommended in the management of symptomatic COPD.

Anticholinergic bronchodilators

Anticholinergic medications, such as ipratropium and tiotropium, act as bronchodilators by means of competitive inhibition of the neurotransmitter acetylcholine at its receptor sites within the vagus nerve, thus preventing the transmission of parasympathetic stimuli that mediate bronchoconstriction. They are generally considered a safer class of medications than the β2-agonists. However, it is widely believed that anticholinergics are less effective than β2-agonists in the symptomatic treatment of chronic asthma, and there is considerable variation in response.41

In comparison with asthma, anticholinergic bronchodilator medications play an important first-line role in the management of COPD. At least 1 clinical trial has demonstrated that ipratropium might be more efficacious in the elderly and those with chronic bronchitis.42 In a meta-analysis of 11 studies containing 3,912 patients, Appleton et al43 demonstrated a small benefit from the regular long-term use of ipratropium alone or in combination with β2-agonists compared with β2-agonist therapy alone in patients with COPD. In 6 studies comparing regular use of ipratropium versus a short-acting β2-agonist, a small but significant increase in prebronchodilator FEV1 (0.03 L; 95% CI, 0-0.06 L) and prebronchodilator forced vital capacity (FVC; 0.07 L; 95% CI, 0.01-0.14 L) was associated with ipratropium use at 3 months, but no significant difference was seen in dyspnea scores. Interestingly, pooled analysis of 4 studies demonstrated that ipratropium was associated with significantly less added or increased use of oral steroids compared with use of a short-acting β2-agonist alone, yielding a number needed to treat of 15. Meta-analysis of 5 studies comparing combination therapy with a short-acting β2-agonist alone demonstrated no differences in prebronchodilator FEV1, prebronchodilator FVC, or symptom scores; however, there was an increase in postbronchodilator lung function outcomes. Again, combination therapy was associated with a reduction in the need for oral corticosteroids (number needed to treat = 20).

Tiotropium is a newer anticholinergic that differs from ipratropium in its relatively slow dissociation from M1 and M3 muscarinic receptors, resulting in a bronchodilatory effect that lasts more than 24 hours, allowing daily dosing.44 Furthermore, its relatively rapid dissociation from the M2 receptor, which functions in feedback inhibition, might further decrease acetylcholine release.45 In clinical trials of COPD lasting up to 12 months, tiotropium has been shown to improve exercise tolerance and health-related quality of life and to reduce exacerbations and hospitalizations.46, 47, 48, 49, 50, 51 The clinical effects of tiotropium have been compared with those of placebo, ipratropium, and long-acting β2-agonists. In an analysis of 9 studies including 6,584 patients with moderately severe COPD (Global Initiative for Chronic Obstructive Lung Disease stage IIb), tiotropium decreased the odds of COPD exacerbation (odds ratio [OR], 0.74; 95% CI, 0.66-0.83) and hospitalizations (OR, 0.64; 95% CI, 0.51-0.82) compared with placebo or ipratropium but not with salmeterol.52 When applied to an average risk of exacerbation of 45% over 1 year, as found in 2 trials of 12 months' duration, the number needed to treat with tiotropium compared with placebo to prevent 1 exacerbation was 14 (95% CI, 11-22). There was no statistically significant difference in all-cause mortality between tiotropium and placebo, ipratropium, or salmeterol in this pooled analysis. However, tiotropium demonstrated statistically significant increases in FEV1 and FVC from baseline compared with placebo, ipratropium, or salmeterol. Furthermore, the decrease in FEV1 over 1 year was reduced by 30 mL (95% CI, 7-53 mL) in patients treated with tiotropium compared with those receiving placebo or ipratropium. Symptom and quality-of-life scores demonstrated similar patterns. Finally, in the Understanding Potential Long-term Impacts on Function with Tiotropium (UPLIFT) study of 5,993 patients treated with tiotropium or placebo for 4 years, FEV1 increased in the tiotropium group, and this increase over that seen with placebo was maintained throughout the study. Tiotropium was also associated with reduced exacerbations, hospitalizations, and respiratory failure and with improved health-related quality of life.53

β2-Adrenergic bronchodilators

Inhaled short-acting β2-agonists are the major class of bronchodilators used for the symptomatic management of asthma. These agents improve symptoms and airway function in patients with COPD also,40 and the regular use of short-acting β2-agonists in the management of stable COPD has been well studied. In a review of 10 randomized controlled trials of regular use of short-acting β2-agonists versus placebo, Sestini et al54 demonstrated a slight but significant improvement in postbronchodilator FEV1 and FVC, morning and evening peak expiratory flows, and dyspnea scores. None of the studies included reported an effect on exacerbations requiring oral corticosteroids or serious side effects during treatment.

The role of long-acting β-agonist therapy in the treatment of asthmatic subjects is as an adjunct to anti-inflammatory therapy. As monotherapy, these drugs are less effective than inhaled corticosteroids alone and have been associated with increased exacerbations55 and asthma-related deaths.56, 57 As a result, guidelines and the US Food and Drug Administration specifically recommend that long-acting β-agonists not be used alone to treat asthma.58, 59

The role for long-acting β-agonists in patients with COPD is different, and the safety concerns raised regarding asthma seem not to apply to COPD. Long-acting β-agonists have been increasingly used in the management of stable COPD. In an analysis of 8 published randomized controlled trials comparing 50 μg of salmeterol twice daily with placebo for 4 weeks in adults with poorly reversible COPD, Appleton et al60 demonstrated a significant improvement in FEV1 (51 mL; 95% CI, 31.93-70.07 mL) and morning peak expiratory flow (15.81 L/min; 95% CI, 11.96-19.67 L/min). Importantly, pooled analysis of 5 studies and 1,741 patients demonstrated reduced risk of exacerbation in patients treated with salmeterol compared with that seen in those receiving placebo (OR, 0.72; 95% CI, 0.57-0.90). Additionally, the combination of long-acting β-agonist and inhaled corticosteroid therapy has shown benefits in patients with stable COPD beyond those seen with inhaled corticosteroid therapy alone. In a pooled analysis of 7 randomized controlled trials including 5,708 participants comparing combination long-acting β-agonist and inhaled corticosteroid therapy with inhaled corticosteroid therapy alone, combination therapy demonstrated a reduced risk of exacerbation (relative risk, 0.91; 95% CI, 0.85-0.97).61 Furthermore, combination therapy was associated with a reduced risk of death from all causes compared with inhaled corticosteroid therapy alone (0.77; 95% CI, 0.63-0.94). There were no significant differences in adverse events. The TORCH study of more than 6,000 patients, which was specifically designed to compare the effect of salmeterol plus fluticasone with that of salmeterol alone, fluticasone alone, or placebo, did not reach the predetermined level of statistical significance for its primary outcome, death from any cause, in part because results were adjusted for an interim analysis. However, the combination regimen of salmeterol plus fluticasone reduced exacerbations, improved health status, and improved lung function.62 Over the 3 years of monitoring, salmeterol, fluticasone, and salmeterol plus fluticasone each reduced the rate of decrease in FEV1 compared with placebo.30

Mucolytics

Both asthma and chronic bronchitis are diseases that are characterized by mucus hypersecretion and plugging of the distal airways. Given the benefits derived from mucolytic therapy in other hypersecretory disorders, such as cystic fibrosis, there has been a good rationale for the treatment of patients with poorly controlled asthma and chronic bronchitis with agents that reduce sputum viscosity and increase the expectoration of sputum. In some European countries, mucolytics are widely prescribed for this purpose, whereas in the United States these are used infrequently because they are considered ineffective. Studies of mucolytics have been limited in patients with chronic asthma but have been examined for long-term use in the treatment of chronic bronchitis in a number of small but randomized, double-blind, placebo-controlled trials. In the pooled analysis of 26 trials of chronic bronchitis comparing daily oral mucolytics with placebo for at least 2 months, mucolytic therapy demonstrated a small but significant reduction in the number of exacerbations per patient (−0.05; 95% CI, −0.05 to −0.04).63 However, these benefits seem to be limited to patients not already receiving inhaled corticosteroids. Newer mucolytics, such as recombinant human deoxyribonuclease, that have shown benefit in cystic fibrosis management have been studied in the management of acute asthma without benefit.64 Further study of new mucolytics in patients with COPD is warranted.

Antioxidants

Oxidative stress is believed to play an important role in the pathogenesis of COPD. Meta-analyses have suggested that N-acetylcysteine reduces exacerbations of chronic bronchitis by 22% to 29%,65, 66, 67 but data from large, prospective, controlled trials are limited. The Bronchitis Randomized on N-acetylcysteine Cost-Utility Study (BRONCUS) followed 523 patients for 3 years, comparing the yearly loss of FEV1 and the number of exacerbations per year in subjects taking daily N-acetylcysteine compared with those taking placebo. N-acetylcysteine did not prevent deterioration of lung function, nor did it prevent exacerbations.68 Although subgroup analysis suggested a small effect on exacerbations in subjects who were not taking inhaled corticosteroids, most experts have little enthusiasm for this treatment. Inhaled N-acetylcysteine as a mucolytic agent in the treatment of COPD has not been well studied.

Novel pharmacologic therapies

As our understanding of the distinct pathophysiology of COPD increases, novel targeted therapies are being developed and tested. One such class of medications is the phosphodiesterase 4 inhibitors, which have been shown to inhibit chemotaxis, leukocyte activation, and cytokine production in vitro and in animal models of COPD.69 One such phosphodiesterase 4 inhibitor, roflumilast, reduced the number of neutrophils and eosinophils in the sputum of patients with COPD70 and improved lung function in patients with moderate-to-severe COPD.71, 72 Two recent publications (4 studies) suggest that roflumilast has a beneficial effect on lung function and on COPD exacerbations in selected patients, probably through a specific anti-inflammatory effect.73, 74 The identification of different subsets of patients with different inflammatory pathways involving, for example, TNF-α, CXCL8, IL-17, and neutrophil elastase provides a rationale for testing new anti-inflammatory molecules.

Nonpharmacologic therapies

Oxygen

Despite the importance of pharmacologic therapies for the treatment of chronic asthma and COPD, physicians must also recognize the benefits that nonpharmacologic therapies can provide. Arguably, the most important nonpharmacologic therapy for patients with advanced chronic bronchitis and emphysema who also have chronic hypoxemia is the administration of long-term supplemental oxygen therapy. Two landmark studies performed in the 1970s, the Nocturnal Oxygen Therapy Trial and the Medical Research Council Trial, demonstrated a significant survival benefit in those hypoxemic patients treated with continuous oxygen therapy compared with those receiving no therapy or nocturnal oxygen alone.75, 76 These data are 25 years old, however, and studies included only patients with severe hypoxemia. Survival benefit in patients who experience only mild-to-moderate hypoxemia or who have hypoxemia only with exertion is unknown.77

Smoking cessation

The benefits of smoking cessation on morbidity and mortality in patients with chronic asthma and COPD have been well documented and should be a major focus in the clinical care of patients with lung disease in general. Improvements in pulmonary function parameters have been shown as early as 1 month after smoking cessation, and by 3 months, decreases in sputum neutrophil counts are apparent along with improvement in FEV1.78 The Lung Health Study first reported in 1994 that smoking cessation slowed the rate of loss of lung function in patients with COPD.79 In a recently published 14.5-year follow-up, Anthonisen et al80 reported that sustained smoking cessation continued to be associated with a reduced rate of decrease in lung function. Postma et al81 studied a group of 81 patients with moderate-to-severe COPD followed for 2 to 21 years. Those 22 patients who stopped smoking during the study demonstrated a change in FEV1 of −49 ± 7 mL/y, whereas FEV1 in the sustained smokers decreased at a faster rate (−85 ± 5 mL/y). Data on the effects of smoking cessation on all-cause mortality in patients with COPD are also robust. A number of studies have demonstrated improved all-cause mortality and death caused by respiratory disease in patients with COPD who quit smoking compared with current smokers.80, 82, 83 Similar studies in asthmatic subjects have demonstrated that smokers have worse symptom control,84, 85 accelerated decrease in lung function,86, 87 and an increased mortality rate after a near-fatal asthma attack88 compared with nonsmokers with asthma. In addition, asthmatic subjects who smoke have a blunted response to corticosteroids.89 Smoking cessation remains a difficult problem, but newer medications combined with counseling and behavior modification are more effective, with a higher success rate and a lower rate of recidivism than older treatments.90, 91 Unfortunately, bupropion and varenicline have been associated with depression and suicidal ideation in some patients, and the US Food and Drug Administration has now mandated a black box warning that these agents might be associated with serious neuropsychiatric symptoms.

Pulmonary rehabilitation

The benefits of pulmonary rehabilitation in patients with COPD have recently been reviewed.92 A number of randomized controlled (although unblinded) trials have demonstrated unequivocal improvements in exercise capacity, severity of dyspnea, and health-related quality of life.93 In a recent meta-analysis by Lacasse et al94 of 31 randomized controlled trials of pulmonary rehabilitation, health-related quality of life was significantly improved in addition to functional exercise capacity, as assessed by distance walked in 6 minutes. Data on physical exercise in patients with chronic asthma are more limited, but in a pooled analysis of 13 studies, physical training improved cardiopulmonary fitness, as measured by an increase in maximum oxygen uptake, and did not demonstrate any negative effects on resting lung function or number of days with wheezing.95

Immunizations

Influenza

Annual influenza vaccination is recommended for all patients with chronic lung diseases; however, those with COPD are at particular risk of clinical deterioration when infected with such respiratory viruses. Observational studies have shown that influenza vaccines can reduce serious illness and death in patients with COPD by about 50%.96 Despite the almost universal recommendation that persons with COPD should receive annual influenza vaccinations, very few randomized controlled trials have evaluated their effect in these patient populations. In a meta-analysis published by Poole et al97 in 2006, 6 randomized controlled trials of influenza vaccination in patients with COPD were analyzed. Inactivated vaccine resulted in a significant reduction in the total number of exacerbations per subject compared with those receiving placebo (−0.37; 95% CI, −0.61 to −0.11). In patients with COPD, as well as other elderly patients without COPD, there was a significant increase in the occurrence of local adverse reactions, but these were generally mild and transient. The benefit of annual influenza vaccination in patients with chronic asthma has been more controversial. In 2001, the American Lung Association's Asthma Clinical Research Centers demonstrated that inactivated influenza vaccine was safe in adults and children with asthma, including severe asthma.98 However, the recommendation to administer the influenza vaccine to asthmatic subjects is not supported by evidence from any randomized controlled trials. In a systematic review of the literature published by Cates et al99 in 2008, pooled analysis of 2 trials involving 2,306 subjects with asthma did not demonstrate an increase in asthma symptoms in the 2 weeks after administration of the vaccine, suggesting that it is a relatively safe intervention. However, in a randomized controlled trial of 696 children with asthma, Bueving et al100 did not demonstrate a significant reduction in the number, severity, or duration of asthma exacerbations caused by influenza, raising doubts about its role in adult patients with asthma. Based on such evidence, it seems prudent to administer an annual influenza vaccine to patients with COPD and those with asthma who are elderly or have comorbid conditions in the absence of a contraindication.

Pneumococcal vaccine

Two case-control studies have shown that asthma is an independent risk factor for invasive pneumococcal disease,101, 102 and the Centers for Disease Control and Prevention now recommend that the pneumococcal polysaccharide vaccine be given to all adults 19 to 64 years of age who have asthma.103 Data supporting the use of pneumococcal vaccines in patients with COPD are limited, but a recent study by the National Heart, Lung, and Blood Institute's COPD Clinical Research Network demonstrated that 2 different pneumococcal vaccines induced immunoglobulin and opsonization responses in patients with COPD.104 Whether this immunologic response translates into protection against serious pneumococcal disease remains to be determined. Included in the 2009 Centers for Disease Control and Prevention guidelines is the recommendation that pneumococcal vaccine be administered to all subjects who smoke.

Summary

In summary, over the past decade, there have been significant advances in the treatment of COPD that contribute to better control of this disease over time. Although COPD was once defined by lack of reversibility, it is now clear that short-acting β2-agonists and short-acting anticholinergics improve lung function and relieve symptoms. Tiotropium increases exercise tolerance and health-related quality of life and decreases exacerbations and hospitalizations. Tiotropium has not been shown to change the rate of decrease in lung function over time, but it increases FEV1, and this increase is maintained over at least 3 to 4 years, resulting in better lung function over time compared with that seen in placebo-treated patients. Inhaled corticosteroids reduce the rate of COPD exacerbations and improve quality of life, perhaps at the risk of increased pneumonia. An effect of inhaled corticosteroids on mortality has not been demonstrated.

Although results have been variable, data are now beginning to emerge suggesting that pharmacotherapy can change the natural history of COPD. Thus although the Lung Health Study II, the ISOLDE study, the European Respiratory Society Study on Chronic Obstructive Pulmonary Disease, and the Copenhagen City Heart Study all failed to provide evidence for a reduction in the rate of decrease in FEV1 with inhaled corticosteroids, the TORCH study demonstrated that salmeterol plus fluticasone, fluticasone alone, and salmeterol alone each slowed the rate of progression. Whether this protective effect is greater in a subset of patients remains to be determined. Similarly, although no pharmacologic therapy has been shown to affect mortality, a number clearly decrease exacerbations and hospitalizations, which one would expect might contribute to mortality. It is possible that the heterogeneity of COPD populations makes it difficult to identify a survival benefit in studies of diverse populations. Another confounder is the apparent risk of pneumonia, which in large studies might negate a beneficial effect on mortality in patients who do not experience pneumonia. It is clear that future studies need to focus on the various “phenotypes” of COPD and consider the likelihood that patients with these phenotypes might benefit from specific therapies. In addition, studies are needed to define which statistically significant changes are clinically significant.

What do we know?

•Smoking cessation slows loss of lung function over time and reduces mortality.

•Most patients with COPD have a reversible component.

•Inhaled corticosteroids and tiotropium each reduce COPD exacerbations.

•Tiotropium improves lung function in patients with COPD, and this improvement is maintained over time.

•Salmeterol, fluticasone, and salmeterol plus fluticasone each slow the loss of lung function over time in patients with COPD.

•Inhaled corticosteroids are associated with increased risk of pneumonia in patients with COPD.

What is still unknown?

•Do subgroups of patients with COPD respond differently?

•Are different phenotypes of COPD defined by severity of lung function, symptoms, reversibility, frequency of exacerbations, genotype, or as-yet-undetermined characteristics?

•If decreased exacerbations do not correlate with decreased mortality, is this a valid end point?

•Are there systemic or lung biomarkers that can serve as surrogate markers for disease progression?

References

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a Division of Pulmonary and Critical Care Medicine, University of California, San Francisco, Calif

b Cardiovascular Research Institute, University of California, San Francisco, Calif

Reprint requests: Stephen C. Lazarus, MD, Division of Pulmonary and Critical Care Medicine, University of California, San Francisco, 505 Parnassus Ave, M-1083, San Francisco, CA 94143-0111.

Series editors: Donald Y. M. Leung, MD, PhD, and Dennis K. Ledford, MD

PII: S0091-6749(09)01459-6

doi:10.1016/j.jaci.2009.09.040

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