© 2007 American Thoracic Society doi: 10.1164/rccm.200701-017ED
Smokers with AsthmaWhat Are the Management Options?University of Glasgow, Glasgow, United Kingdom The reasons for the variability in individual therapeutic responses to drugs used to treat asthma are complex, involving both genetic and environmental factors as well as levels of adherence with therapy (1, 2). An important environmental factor is active cigarette smoking. It is well known that smoking increases theophylline metabolism, but more importantly, smokers with chronic asthma are less sensitive to the beneficial effects of both inhaled and oral corticosteroids compared with nonsmokers with asthma (3–6). Therapeutic studies in asthma often exclude current smokers because of concerns about recruiting participants with chronic obstructive pulmonary disease (COPD) and so information is lacking on which drugs are most appropriate to treat smokers with asthma. Knowing how best to manage this group of patients is of considerable importance because smoking is common among patients with asthma. For example, in developed countries, one-fifth to one-third of adults with asthma are smokers (7). Smokers with asthma often have poorer symptom control compared with nonsmokers with asthma (7).
In this issue of the Journal (pp. 783–790), Lazarus and colleagues from the Asthma Clinical Research Network (8) report the results of a randomized, controlled crossover study that compared the response to inhaled hydrofluoroalkane (chlorofluorocarbon [CFC]-free) beclomethasone 400 µg daily with the oral leukotriene receptor antagonist montelukast 10 mg daily administered for 8 weeks in 39 smokers and 44 nonsmokers with mild corticosteroid-naive asthma. The entry criteria minimized the risk of including subjects with chronic obstructive pulmonary disease by including participants who were young (mean age, 29 yr), who had physiological evidence of reversible airflow obstruction ( These findings are of considerable interest, although the conclusions of the study must be treated with a degree of caution. First, the participants had very mild asthma and hence there may have been a ceiling on the scope for improvement in both the smokers and nonsmokers with asthma. Second, the changes observed in outcome measures were found within and not between groups. Nevertheless, the study includes new information on drug responses in smokers with asthma and raises some important questions on the management of this group of patients and on future research. What is the role of inhaled corticosteroid treatment in the treatment of smokers with asthma? Several studies using different inhaled corticosteroids, including inhaled beclomethasone, budesonide, and fluticasone, have found impaired lung function and symptom response to corticosteroids in individuals with asthma with a long history of cigarette smoking (3–5, 9). The report by Lazarus and colleagues (8), while confirming corticosteroid insensitivity occurs to a CFC-free inhaled corticosteroid in smokers with mild asthma, also interestingly found that this effect is present in subjects with a relatively low intensity smoking history (7 pack-years). Most studies have administered inhaled corticosteroids for up to 12 wk, although one uncontrolled trial showed that a reduced response to inhaled budesonide was still present in smokers with asthma after 9 months of treatment (9). The insensitivity to inhaled corticosteroids found in these studies, as assessed by the lack of improvement in lung function and symptoms, should not be interpreted as meaning that inhaled corticosteroids are of no value in treating smokers with asthma. Inhaled corticosteroids may influence other important outcomes, such as exacerbation rates (5) or rate of decline in lung function (10, 11). For example, data from several observational studies suggest that the decrease in lung function induced by smoking in asthma may be reduced by inhaled corticosteroids (10, 11), although this effect appears to be lost in those with a heavy smoking history. (10) Should leukotriene receptor antagonists be recommended as first-line treatment of smokers with asthma? Lazarus and colleagues (8) report for the first time that the leukotriene receptor agonist montelukast shows efficacy in smokers with mild asthma, an important finding in view of the data showing corticosteroid insensitivity in this group. However, the beneficial effect on morning peak flow of montelukast in the smokers with asthma was not large nor did the study include supportive data on urinary or sputum leukotrienes in smokers versus nonsmokers. The generalizability of the findings is uncertain and, in particular, it is not known whether a similar beneficial effect would be found in smokers with more severe asthma. Lazarus and colleagues (8) recommend that a larger prospective study of leukotriene receptor antagonists in smokers be performed and at least one such study is reported to be underway, with a projected enrollment of 1,200 participants (12). How do the findings of Lazarus and colleagues (8) fit into the management options for smokers with asthma? Smoking cessation is associated with improved asthma control (13, 14). In one recent study, former smokers achieved considerable short-term improvement in lung function and a decline in sputum neutrophil count compared with smokers with asthma who continued to smoke (14). Despite the known benefits of quitting smoking, successful cessation rates are very low. In the absence of large pragmatic controlled trials of commonly prescribed drugs to guide therapy in smokers with asthma who are unable or unwilling to stop smoking, it seems appropriate to follow international guideline recommendations for the pharmacological management of asthma (15). A caveat, however, should be added, that due to the impaired effects of low- to medium-dose inhaled corticosteroids on asthma symptoms and lung function in smokers, a step up in therapy may be required at an early stage. The study of Lazarus and colleagues (8) highlights the need for well-designed, large, randomized clinical trials of drug treatment in patients with asthma who are active smokers. Some important questions include the following: Do leukotriene-receptor antagonists have a central role in the drug treatment of smokers with asthma? Can the relative corticosteroid insensitivity present in smokers with asthma be overcome by low-dose theophylline, which in vitro restores corticosteroid responsiveness by reversing the suppressed histone deacetylase activity found in smokers (16)? FOOTNOTES Conflict of Interest Statement: N.C.T. received fees from Altana ($3,750 in 2006), GlaxoSmithKline ($2,700 in 2006), Pfizer ($900 in 2005, $750 in 2006), and Trinity-Chiesa ($1,125 in 2005) for lectures or serving on advisory boards; he also received grants from Astra Zeneca ($30,000 in 2006) and GlaxoSmithKline ($111,540 in 2004, $165,000 in 2005, $112,500 in 2006) for participating in clinical trails. 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12%) and bronchial hyperreactivity (< 8 mg/ml), and who, on average, had a duration of asthma longer (mean, 15 yr) than their smoking history (7 pack-years). The main findings were that inhaled beclomethasone significantly increased prebronchodilator FEV1 (primary endpoint) in the nonsmokers only, whereas montelukast increased morning peak flow (secondary endpoint) in smokers only. 
