American Journal of Respiratory and Critical Care Medicine

Rationale: One-quarter to one-third of individuals with asthma smoke, which may affect response to therapy and contribute to poor asthma control.

Objectives: To determine if the response to an inhaled corticosteroid or a leukotriene receptor antagonist is attenuated in individuals with asthma who smoke.

Methods: In a multicenter, placebo-controlled, double-blind, double-dummy, crossover trial, 44 nonsmokers and 39 light smokers with mild asthma were assigned randomly to treatment twice daily with inhaled beclomethasone and once daily with oral montelukast.

Measurements and Main Results: Primary outcome was change in prebronchodilator FEV1 in smokers versus nonsmokers. Secondary outcomes included peak flow, PC20 methacholine, symptoms, quality of life, and markers of airway inflammation. Despite similar FEV1, bronchodilator response, and sensitivity to methacholine at baseline, subjects with asthma who smoked had significantly more symptoms, worse quality of life, and lower daily peak flow than nonsmokers. Adherence to therapy did not differ significantly between smokers and nonsmokers, or between treatment arms. Beclomethasone significantly reduced sputum eosinophils and eosinophil cationic protein (ECP) in both smokers and nonsmokers, but increased FEV1 (170 ml, p = 0.0003) only in nonsmokers. Montelukast significantly increased a.m. peak flow in smokers (12.6 L/min, p = 0.002), but not in nonsmokers.

Conclusions: In subjects with mild asthma who smoke, the response to inhaled corticosteroids is attenuated, suggesting that adjustments to standard therapy may be required to attain asthma control. The greater improvement seen in some outcomes in smokers treated with montelukast suggests that leukotrienes may be important in this setting. Larger prospective studies are required to determine whether leukotriene modifiers can be recommended for managing asthma in patients who smoke.

Scientific Knowledge on the Subject

The prevalence of smoking among patients with asthma is approximately the same as in the population at large. Those with asthma who smoke appear to have a blunted response to inhaled and oral corticosteroids. The best strategy for treating these patients is not known.

What This Study Adds to the Field

This study confirms the presence of corticosteroid insensitivity in patients with asthma who smoke, and suggests that leukotriene modifiers may be beneficial in these patients.

Despite the logical expectation that people with asthma would avoid exposure to cigarette smoke, studies suggest that the prevalence of active smoking among individuals with asthma is approximately the same as in the population at large. Thus, during 2005, the median adult smoking prevalence among all 50 states and the District of Columbia was 20.6% (1). Other studies, in the United States and abroad, have reported a smoking prevalence in individuals with asthma of 25 to 35% (28). A recent survey of patients with asthma presenting to emergency departments for treatment of asthma exacerbations found that 35% were smokers (9). Moreover, even nonsmoking patients with asthma may have significant exposure to passive smoke. In recent studies from northern Italy, Canada, and the United States, 42 to 58% of patients with asthma reported living with an active smoker or being exposed to cigarette smoke on a daily basis (1012), and 17.5% of Southern California schoolchildren in the Children's Health Study reported regular exposure to secondhand smoke (13). If biological markers of environmental tobacco smoke exposure (e.g., serum cotinine) are used, up to 90% of patients with asthma have evidence of exposure (14).

Multiple outcomes are known to be worsened when patients with asthma are exposed to cigarette smoke. For example, acute exposure to cigarette smoke triggers bronchoconstriction and symptoms in people with asthma (2, 15). In addition, patients with asthma who smoke regularly have more severe respiratory symptoms, worse quality of life, more emergency department visits and hospitalizations (8, 16), and an accelerated loss of lung function, compared with patients with asthma who do not smoke (17).

Until recently, there has been little information regarding the effect of cigarette smoking on the response to asthma therapy because most studies of asthma therapy have excluded subjects who smoke. Two recent studies of short-term administration of inhaled and oral corticosteroids have suggested that active smoking interferes with the response to corticosteroids (18, 19). A third, larger study suggested that smokers might benefit from higher doses of inhaled corticosteroid; however, the authors of that study cautioned that interpretation of their results is limited by small sample size and by a negative interaction test for a different effect of smoking in the low- versus high-dose inhaled corticosteroid group (20). To our knowledge, no study has tested other, noncorticosteroid asthma therapies in subjects who smoke, especially in the same cohort.

Leukotrienes have been implicated in the pathophysiology of asthma, and leukotriene-modifying drugs have been reported to be efficacious in the treatment of asthma (2123). In addition, studies have shown a dose-related increase in urinary leukotriene E4 (LTE4) excretion in response to cigarettes in habitual smokers (24), an increase in 15-lipoxygenase activity in the airways of healthy smokers (25), and a smoking-induced increase in urinary LTE4 in subjects with asthma, but not in subjects with chronic obstructive pulmonary disease (COPD) or normal subjects (26). These studies provide the rationale for studying montelukast in patients with asthma who smoke.

If patients with asthma who smoke do not respond to inhaled corticosteroids (or if they have a significantly blunted response), then the therapeutic ratio shifts significantly. In addition, the fiscal implications are enormous. If we assume that approximately 30% of the 17 million Americans with asthma smoke (29), and that approximately 60% have persistent asthma (27), requiring 1 canister of inhaled corticosteroid per month at approximately $60 per canister, then the cost of administering inhaled corticosteroids to this population would be $2.2 billion per year. We therefore performed this randomized, crossover trial to examine whether the response to a relatively long (8 wk) course of treatment with an inhaled corticosteroid or with a leukotriene receptor antagonist was blunted in subjects with asthma who smoke. The SMOG (Smoking Modulates Outcomes of Glucocorticoid Therapy) study was sponsored by the National Institutes of Health and conducted by the National Heart, Lung, and Blood Institute's (NHLBI's) Asthma Clinical Research Network (ACRN).


This study was conducted between January 2002 and February 2004 at the six clinical sites that comprise the NHLBI's ACRN. Steroid-naive male and female subjects between the ages of 18 and 50 years with a history of asthma (28) were recruited. All were required to have prebronchodilator FEV1 values of 70 to 90% of predicted and heightened airway reactivity as indicated by 12% or greater reversibility after albuterol inhalation or by PC20 (provocative concentration causing a 20% fall in FEV1) methacholine of less than 8 mg/ml. Nonsmokers were required to have a total lifetime smoking history of less than 2 pack-years, and no smoking for at least 1 year. Subjects were enrolled as smokers if they were currently smoking 10 to 40 cigarettes/day, had a 2 to 15 pack-year smoking history, and a diffusing capacity of carbon monoxide (DlCO) of 80% of predicted or greater. To avoid inclusion of subjects with COPD, exclusion criteria included age older than 50, smoking history of greater than 15 pack-years, active smoking of more than 40 cigarettes/day, and DlCO less than 80% of predicted.

Study Design

The study design was approved by an NHLBI Protocol Review Committee and Data Safety Monitoring Board, and by the institutional review boards at each of the six ACRN clinical centers and the data coordinating center. This was a randomized, double-blind, double-dummy, crossover trial of treatment with an inhaled corticosteroid (hydrofluoroalkane [HFA]–beclomethasone dipropionate [BDP] or QVAR, 160 μg, twice daily) or an oral leukotriene receptor antagonist (montelukast [Singulair], 10 mg, once daily) in subjects with mild to moderate asthma who were or were not current smokers. After a 2-week run-in period, to establish eligibility and adherence to study protocol and forms, subjects entered an 8-week single-blind placebo treatment period. Subjects with asthma who smoked and those who did not were then randomly assigned in parallel to receive either inhaled beclomethasone HFA or oral montelukast for 8 weeks. At randomization, smoking and nonsmoking subjects were matched according to sex, age, and FEV1% predicted, to ensure equal representation in the two groups. After the first 8-week treatment period, subjects entered a 6-week placebo wash-out period, followed by a second 8-week period with the alternate treatment. Spirometry, methacholine reactivity, and asthma-specific quality of life were measured, and sputum induction was performed at the beginning and end of each treatment period. Urinary cotinine levels were measured at the beginning of each treatment period to validate smoking history.

Study Procedures and Measurements

At the time of first contact, all subjects who smoked were counseled and encouraged to attempt smoking cessation. Those who declined were enrolled in the study. Counseling and written referral to smoking cessation programs were provided again at the end of the study.

Written, informed consent was obtained from all subjects using forms that contained standard elements approved by the NHLBI, and which were approved by the individual institutional review boards at each institution. Routine history and physical examination and demographic information were recorded at the beginning of the run-in period. Spirometry and diffusing capacity were measured using standard techniques (29, 30). To test reversibility, FEV1 was measured before and 15 minutes after inhalation of up to 540 μg of albuterol by a standardized procedure. Bronchial hyperresponsiveness was assessed by measuring the PC20 methacholine (31). Asthma-specific quality of life was assessed with a well-validated instrument (32). At the first visit, subjects were provided with an electronic peak-flow meter (AM1; Jaeger, Hoechberg, Germany) and a diary, and instructed in their twice-daily use. In addition, they received single-blind placebo medications. Pill bottles were fitted with an electronic Drug Exposure Monitor (eDEM) (Aardex Ltd., Zug, Switzerland), and metered-dose inhalers were fitted with a Doser device (MediTrack Products, Hudson, MA) to record opening of the pill container and actuation of the metered-dose inhaler, respectively. Sputum induction was performed as described previously (33). Personnel from all sites were trained and certified to perform sputum induction and to prepare slides for analysis, and quality control was maintained throughout the study by periodic overreading and grading of slides. All numerical counts for analysis were performed at a single site (University of California, San Francisco). Cotinine was measured by a reference lab (National Medical Services, Willow Grove, PA).

Statistical Analysis

Descriptive statistics for continuous variables at baseline included means and standard deviations (or medians and quartiles for skewed distributions). The principal outcome was the change in prebronchodilator FEV1 over the 8-week inhaled corticosteroid treatment period, comparing the change in FEV1 in the group of smokers with that observed in the nonsmokers. Secondary outcomes included a.m. and p.m. PEF, PC20 methacholine, daily symptom scores, and quality-of-life measures. To determine if differences between the smoking and nonsmoking groups reflected differences in the character of inflammation, we examined induced sputum for total and differential cell counts, and for concentrations of eosinophil cationic protein (ECP) and tryptase, as markers of airway inflammation, eosinophil activation, and mast cell activation, respectively. A mixed-effects linear model was applied that included a slope–intercept fit for the set of repeated measurements within each treatment period (Weeks 10–18 or 24–32), while accounting for (1) period and sequence effects from the crossover design and (2) correlations among the repeated measurements within one subject and within subject members of a matched pair (34). Contrasts were then constructed to estimate the mean change between the end and beginning of the treatment periods.

The sample size calculation was performed using estimates for the standard deviation for improvement of FEV1 after inhaled corticosteroid from prior ACRN studies (35, 36). We calculated that 42 smokers and 42 nonsmokers would provide 90% statistical power for detecting a 10% improvement in FEV1 in nonsmokers versus a 5% improvement in FEV1 in smokers when inhaled corticosteroid was administered (primary outcome), and 73% power for detecting an 8% improvement in FEV1 in nonsmokers versus a 4% improvement in FEV1 in smokers when a leukotriene receptor antagonist was administered (secondary outcome). Our actual enrollment in this study was 83, providing 89% power for the inhaled corticosteroid comparison and 73% power for the leukotriene receptor antagonist, under the above assumptions.

Randomization and Blinding

Subject randomization was performed online via an Internet connection to the computer system at the data coordinating center. When a subject was deemed eligible for study entry, a clinical center staff member entered and verified the pertinent data and received a drug packet number to give the subject. The study was triple-blinded in that subjects, clinical center personnel, and data analysts were all blinded to treatment identity. Treatment medication for each subject was packaged together, labeled with a unique number, and distributed to the clinical centers. The contents of the drug packages were known only to administrative personnel at the data coordinating center.

Role of the Funding Source

This study was funded by the NHLBI. The study was conceived, designed, implemented, conducted, analyzed, and interpreted by the investigators of the ACRN. The funding organization was not involved in the conduct of the study or in the collection, analysis, or interpretation of the data, nor did it have editorial authority or rights to decisions about publication. 3M, Inc., provided beclomethasone HFA inhalers and matching placebos, but had no input into the design, conduct, or interpretation of this study. Montelukast and matching placebo were purchased/prepared by the ACRN.

Participant Flow

A total of 182 subjects were screened for this study, and 141 entered the run-in at visit 1 (Figure 1). After 20 nonsmokers and 38 smokers were excluded (Figure 1), 44 nonsmokers and 39 smokers were randomized. Each matched pair was randomly assigned to treatment with either beclomethasone in the first treatment period followed by montelukast in the second, or the opposite sequence.

Subject Characteristics

Nonsmokers and smokers were well matched at baseline (Table 1). They did not differ significantly in any major demographic or physiologic characteristics. Subjects were, on average, 29 years old and had asthma for 10 years or more. The average baseline FEV1 was 78 to 80% of predicted, with a mean increase after albuterol of 16 to 18%. Median baseline PC20 methacholine was 1.00 to 1.25 mg/ml, and baseline DlCO was normal in both groups. The smokers averaged 7 pack-years, had urinary cotinine levels of 975 (interquartile range, 575–1,000), and despite similar baseline spirometry, reversibility, and PC20 methacholine measurements in the laboratory, had significantly lower daily a.m. peak flow, a.m. and p.m. symptom scores, and worse asthma quality of life compared with nonsmokers.


Nonsmokers (n = 44)

Smokers (n = 39)

p Value
Age at Week 028.985.9229.066.540.951*
Duration of asthma, yr17.154.9914.966.340.083*
Pack-years0.000.00,, 11.00< 0.001
Cotinine at Week 100.000.00, 0.00975.00575.00, 1,000.00< 0.001
DlCO % predicted at Week 097.9912.7094.4713.120.219*
FEV1 at Week 10, L2.980.542.860.650.379*
FEV1% predicted at Week 1080.169.1678.109.870.328*
Maximum reversibility at Week 2§18.2710.1516.4110.770.421*
Methacholine PC20 at Week 10, mg/ml§1.040.46, 3.721.250.52, 2.160.831
a.m. peak flow 2-wk avg before Week 10, L/min456.71111.62395.5893.690.009*
a.m. symptom score 2-wk avg before Week*
p.m. symptom score 2-wk avg before Week*
AQOL overall score at Week 106.040.655.570.780.004*
Sputum epithelial cells at Week 10, %12.5910.9116.0713.330.231*
Sputum macrophages at Week 10, %39.2620.3337.2221.460.683*
Sputum eosinophils at Week 10, %*
Sputum neutrophils at Week 10, %43.9523.7643.8924.240.991*
Sputum lymphocytes at Week 10, %

Definition of abbreviations: AQOL = Asthma Quality of Life; DlCO = diffusing capacity of carbon monoxide; PC20 = provocative concentration causing a 20% fall in FEV1.

Week 10 = Randomization.

*t Test for differences between smoking groups.

Median and first and third quartiles are reported.

Wilcoxon test for differences between smoking groups.

§Maximum reversibility and PC20 imputed for right-censored observations.

Treatment Endpoints

In the subjects with asthma who did not smoke, 8 weeks of treatment with inhaled beclomethasone was associated with significant increases in FEV1 (170 ml), FEV1% predicted (5%), PEF derived from spirometry (28 L/min), daily a.m. and p.m. PEF (12 L/min and 7 L/min, respectively), and PC20 methacholine (0.63), and with a significant reduction in sputum eosinophils (−2.6%) (Table 2 and Figure 2). In contrast, in the subjects who smoked, the same treatment had no significant effect on any of these variables except for daily a.m. PEF and sputum eosinophils (Table 2 and Figure 2). In general, the changes in the physiologic outcomes in the smokers were in the same direction as in the nonsmokers, but were of smaller magnitude. The between-group differences were not statistically significant, although the greater improvement in FEV1 in nonsmokers trended toward significance (p = 0.09).



95% CI
p Value
95% CI
p Value
Spirometry FEV1, LMontelukast0.08(−0.01, 0.18)NS0.06(−0.04, 0.17)NS
Beclomethasone0.17(0.08, 0.26)0.00030.06(−0.04, 0.16)NS
Spirometry FEV1, % predictedMontelukast2.14(−0.43, 4.70)NS2.00(−0.79, 4.79)NS
Beclomethasone4.66(2.12, 7.21)0.00042.03(−0.69, 4.75)NS
Spirometry PEFR, L/sMontelukast0.08(−0.21, 0.36)NS0.30(−0.02, 0.61)NS
Beclomethasone0.46(0.18, 0.75)0.00150.17(−0.13, 0.48)NS
Diary a.m. peak flow, L/minMontelukast4.51(−2.30, 11.32)NS12.64(4.73, 20.55)0.0019
Beclomethasone11.74(5.08, 18.40)0.00068.30(0.80, 15.81)0.0303
Diary PEFR variability, %Montelukast−0.64(−1.34, 0.07)NS−1.43(−2.38, −0.48)0.0035
Beclomethasone−0.58(−1.27, 0.11)NS−0.63(−1.62, 0.37)NS
Methacholine log2 (PC20)*Montelukast0.00(−0.63, 0.63)NS0.27(−0.29, 0.82)NS
Beclomethasone0.69(0.05, 1.32)0.03420.53(−0.00, 1.07)NS
Sputum eosinophils, %Montelukast−1.02(−3.05, 1.01)NS0.99(−2.26, 4.24)NS
Beclomethasone−2.74(−4.80, −0.69)0.0098−3.44(−6.56, −0.32)0.0314
Sputum neutrophils, %Montelukast−0.23(−6.86, 6.40)NS−2.70(−9.82, 4.43)NS
Beclomethasone1.33(−5.39, 8.05)NS−0.86(−7.71, 6.00)NS
AQOL average scoreMontelukast0.23(0.04, 0.42)0.02000.07(−0.19, 0.32)NS
Beclomethasone0.13(−0.06, 0.32)NS0.12(−0.13, 0.37)NS
Log (ECP)Montelukast−0.19(−0.50, 0.12)NS−0.46(−0.75, −0.17)0.0024
Beclomethasone−0.43(−0.76, −0.11)0.0091−0.48(−0.75, −0.21)0.0007
Log (tryptase)Montelukast−0.14(−0.58, 0.30)NS−0.23(−0.78, 0.31)NS

(−1.00, −0.09)
(−0.72, 0.28)

Definition of abbreviations: AQOL = Asthma Quality of Life; CI = confidence interval; ECP = eosinophil cationic protein; NS = not significant; PC20 = provocative concentration causing a 20% fall in FEV1; PEFR = peak expiratory flow rate.

*PC20 imputed for right-censored observations and responses to diluent.

In smokers, but not nonsmokers, treatment with oral montelukast was associated with a significant increase in daily a.m. PEF (13 L/min) (Table 2, Figure 2B). When expressed as percentage of change from baseline, a.m. PEF increased 4.3 and 0.9% in smokers and nonsmokers, respectively, and the difference between groups was significant (p = 0.02). Montelukast also decreased daily PEF variability in subjects who smoked (p = 0.003), but improved Asthma Quality of Life score in subjects who did not smoke. Neither smokers nor nonsmokers had significant increases in their FEV1 after 8 weeks of oral montelukast.

Analysis of the Doser devices, eDEM monitors, and diary cards demonstrated that adherence to inhaled and oral medication regimens was 77 to 92% and was not significantly different between smokers and nonsmokers (p = 0.13), and that concordance among the three methods of assessing adherence was good.

We compared the effects of monotherapy with an inhaled corticosteroid or a leukotriene receptor antagonist in two groups of subjects with mild asthma: one group who actively smoked cigarettes (total smoking history, ∼ 7 pack years) and another group who did not. We found that smokers differed from nonsmokers in their responses to beclomethasone and montelukast. Treatment with inhaled beclomethasone was associated with a significant improvement in virtually every physiologic outcome in nonsmokers, whereas the only significant change in smokers was in a.m. PEF. Treatment with montelukast resulted in only small changes in physiologic outcomes in nonsmokers, whereas the change in a.m. peak flow was large in smokers compared with nonsmokers. We conclude that cigarette smoking alters the response to inhaled corticosteroids and leukotriene receptor antagonists in subjects with asthma.

Consistent with many other studies, we found that treatment with inhaled beclomethasone resulted in significant improvements from baseline in many outcomes of asthma control and airway function in nonsmoking subjects with asthma. In contrast, we found that the only significant improvements from baseline in smokers were in a.m. PEF, sputum eosinophils, and sputum ECP. Although these differences in treatment response between the nonsmokers and smokers did not reach statistical significance, the consistency of the differences across outcomes and the consistency with prior data (1820) provide convincing evidence that subjects with asthma who smoke have an attenuated response to inhaled corticosteroids. There are a number of potential mechanisms by which habitual cigarette smoking may induce insensitivity to corticosteroids. Experimental data suggest down-regulation of histone deacetylase (37) and/or enhanced neutrophil-mediated inflammation (38) in smokers. Increased levels of tumor necrosis factor-α (39, 40), or changes in the ratio of the glucocorticoid receptor (GR) isoform GR-α to GR-β (4144), have also been suggested as explanations for steroid insensitivity. In fact, Livingston and colleagues have reported that the GR-α to GR-β ratio is reduced in peripheral blood mononuclear cells of cigarette smokers (45). Our study and others (24) suggest that production of cysteinyl leukotrienes may be important.

The increase in FEV1 after inhaled beclomethasone seen in nonsmokers in this study averaged 5% and was less than the 10 to 20% reported in many published studies, including our own (35, 36, 46). Possible explanations for this result are that the subjects had mild asthma (although they had documented albuterol reversibility of ∼ 15%), or that they received too little inhaled corticosteroid. The subjects did, in fact, have baseline characteristics very similar to the subjects with mild persistent asthma studied in the Improving Asthma Control Trial (IMPACT) (47), in which the response to treatment with inhaled corticosteroid for 1 year was nearly identical (4%) to that obtained in the current study (5%). The inhaled corticosteroid chosen for this study, HFA-BDP (QVAR), is a chlorofluorocarbon (CFC)-free preparation with corticosteroid in solution rather than suspension, a formulation believed to produce an extrafine aerosol that deposits more distally in the lung than CFC-BDP. Because of increased lung deposition of HFA-BDP relative to CFC-BDP, patients with asthma require half the daily dose to achieve the same degree of asthma control (48). Thus, the dose of 160 μg twice daily used here can be considered equivalent to a dose of 320 μg twice daily of CFC-BDP. This is not a low dose, and we think it unlikely that the smaller-than-expected response in nonsmokers is due to underdosing, especially since adherence, inferred from three separate measures, was close to 90%. An alternative explanation is that we recruited, by chance, a group of nonsmoking subjects with asthma whose response to HFA-BDP was modest. Subjects with asthma show considerable heterogeneity in their responsiveness to inhaled corticosteroids as demonstrated in a prior study in which approximately one-third of inhaled corticosteroid–naive subjects had a poor response to this treatment (35).

Montelukast produced a statistically significant increase in a.m. PEF and a decrease in PEF variability in smokers, and these changes were significantly greater than its effects seen in nonsmokers. These findings may be explained by enhanced leukotriene synthesis or sensitivity in smokers. Urinary excretion of LTE4 is closely correlated with the number of cigarettes smoked daily, and urinary LTE4 levels increase significantly in nonsmokers who smoke six cigarettes in 12 hours (24). Gaki and associates have reported that smoking increases urinary LTE4 in patients with asthma, but not in normal subjects or patients with COPD (26). Habitual smokers, such as those enrolled in our study, may therefore have chronically elevated leukotriene levels that may render them responsive to treatment with cysteinyl leukotriene receptor antagonists. Although the smokers with asthma had a significant response to montelukast in terms of a.m. peak flow and sputum ECP, other outcomes were not similarly improved. For example, in smokers, the effects of montelukast on FEV1, PC20 methacholine, asthma symptoms, and asthma quality of life were not significantly greater than in nonsmokers. Nevertheless, our data for improvement in a.m. peak flow warrant follow-up in larger studies, including studies of the effects of leukotriene pathway modifiers on asthma exacerbation rates in smokers.

Relatively few studies have focused on the effects of cigarette smoking on outcomes of asthma control and airway inflammation in subjects with asthma. In this regard, we would emphasize some important observations made during the initial characterization visits of the study. First, despite smoking at least 10 cigarettes per day for an average of 7 years, smokers with asthma demonstrated, at baseline, albuterol reversibility and methacholine reactivity that were very nearly identical to nonsmokers. Second, despite similar FEV1, FEV1% predicted, reversibility, and response to methacholine, the subjects with asthma who smoked had significantly more symptoms (across all symptom domains), worse asthma-specific quality of life, and lower PEF measured daily at home than did the nonsmokers. These findings are consistent with previous studies that have described worse clinical status in subjects with asthma who smoke (8, 16, 17). Although several studies have reported that smokers with chronic airflow obstruction have fewer symptoms with induced bronchoconstriction than patients with asthma with similar obstruction (49, 50), perhaps due to depletion of neurotransmitters from sensory nerves (50), the ability to perceive induced bronchoconstriction could not be predicted by smoking history (49). Taken together, these data demonstrate that laboratory-based testing does not capture the impact of cigarette smoking on disease severity in asthma such as is captured by daily symptom diaries and quality-of-life measures. Third, the baseline sputum cell profiles did not differ based on smoking status: We found no differences in the percentages of eosinophils or neutrophils in induced sputum obtained at baseline. We expected to find increased sputum neutrophils in smokers because smoking has been associated with neutrophilic inflammation in the airways (38, 51), which improves with smoking cessation (51, 52), and inhalation of cigarette smoke has been shown to induce chemotactic attraction of neutrophils, probably through induction of release of interleukin-8 (53, 38). Our data may be explained by the relatively young age of the subjects with asthma in our study and their relatively modest smoking history; most studies demonstrating that cigarette smoke causes inflammation and remodeling have enrolled older subjects with high numbers of pack-years of smoking. These results suggest that sputum neutrophilia may be a marker of heavy smoking and may not be causally related to the development of steroid insensitivity in patients with asthma who smoke cigarettes habitually.

Taken together, our data and those of others suggest that corticosteroid resistance occurs in patients with asthma who smoke and should be considered when prescribing treatments for this asthmatic subgroup. For example, Tomlinson and colleagues have suggested that these patients may benefit from increased inhaled corticosteroid dose (20). In addition, for some asthma control outcomes, we found that the lung function response to montelukast was better in patients with asthma who smoke than in nonsmokers. These data are not sufficient to warrant a change in treatment algorithms, but indicate the need for larger studies to further explore the utility of inhibiting leukotrienes in patients with asthma who smoke cigarettes. Meanwhile, our data suggest the need for a specialized approach to patients with asthma who smoke. Clearly, ongoing counsel and assistance with smoking cessation are essential. In addition, because of differences in treatment response, further trials are warranted to establish the optimal management strategies for subjects with asthma who are unwilling or unable to stop smoking.

1. Centers for Disease Control and Prevention. State-specific prevalence of current cigarette smoking among adults and secondhand smoke rules and policies in homes and workplaces: United States, 2005. MMWR Morb Mortal Wkly Rep 2006;55:1148–1151.
2. Higenbottam TW, Feyeraband C, Clark TJ. Cigarette smoking in asthma. Br J Dis Chest 1980;74:279–284.
3. Fitzmaurice DA, Bradley CP. Helping asthma patients to stop smoking. Br J Gen Pract 1994;44:533.
4. Wakefield M, Runnin R, Campbell D, Roberts L, Wilson D. Smoking-related beliefs and behaviour among adults with asthma in a representative population sample. Aust N Z J Med 1995;25:12–17.
5. Cunningham J, O'Connor GT, Dockery DW, Speizer FE. Environmental tobacco smoke, wheezing, and asthma in children in 24 communities. Am J Respir Crit Care Med 1996;153:218–224.
6. Ben-Noun L. Is there a relationship between smoking and asthma in adults? J Int Med Res 1999;27:15–21.
7. Peters JM, Avol E, Navidi W, London SJ, Gauderman WJ, Lurmann F, Linn WS, Margolis H, Rappaport E, Gong H, et al. A study of twelve Southern California communities with differing levels and types of air pollution: I. Prevalence of respiratory morbidity. Am J Respir Crit Care Med 1999;159:760–767.
8. Althuis MD, Sexton M, Prybylski D. Cigarette smoking and asthma symptom severity among adult asthmatics. J Asthma 1999;36:257–264.
9. Silverman RA, Boudreaux ED, Woodruff PG, Clark S, Camargo CA. Cigarette smoking among asthmatic adults presenting to 64 emergency departments. Chest 2003;123:1472–1479.
10. Agabiti N, Mallone S, Forastiere F, Corbo GM, Ferro S, Renzoni E, Sestini P, Rusconi F, Cicconi G, Viegi G, et al. The impact of parental smoking on asthma and wheezing. Epidemiology 1999;10:692–698.
11. Eisner MD, Katz PP, Yelin EH, Hammond SK, Blanc PD. Measurement of environmental tobacco smoke exposure among adults with asthma. Environ Health Perspect 2001;109:809–814.
12. Leech JA, Wilby K, McMullen E. Environmental tobacco smoke exposure patterns: a subanalysis of the Canadian Human Time-Activity Pattern Survey. Can J Public Health 1999;90:244–249.
13. Gilliland FD, Islam T, Berhane K, Gauderman WJ, McConnell R, Avol E, Peters JM. Regular smoking and asthma incidence in adolescents. Am J Respir Crit Care Med 2006;174:1094–1100.
14. Pirkle JL, Fleagal KM, Bernert JT, Brody DJ, Etzel RA, Maurer KR. Exposure of the US population to environmental tobacco smoke: the Third National Health and Nutrition Examination Survey, 1988–1991. JAMA 1996;275:1233–1240.
15. Nadel JA, Tierney DF. Effect of a previous deep inspiration on airway resistance in man. J Appl Physiol 1961;16:717–719.
16. Eisner MD, Yelin EH, Henke J, Shiboski SC, Blanc PD. Environmental tobacco smoke and adult asthma: the impact of changing exposure status on health outcomes. Am J Respir Crit Care Med 1998;158:170–175.
17. Lange P, Parner J, Vestbo J, Schnohr P, Jensen G. A 15-year follow-up study of ventilatory function in adults with asthma. N Engl J Med 1998;339:1194–1200.
18. Chalmers GW, Macleod KJ, Little SA, Thomson LJ, McSharry CP, Thomson NC. Influence of cigarette smoking on inhaled corticosteroid treatment in mild asthma. Thorax 2002;57:226–230.
19. Chaudhuri R, Livingston E, McMahon AD, Thomson L, Borland W, Thomson NC. Cigarette smoking impairs the therapeutic response to oral corticosteroids in chronic asthma. Am J Respir Crit Care Med 2003;168:1308–1311.
20. Tomlinson JEM, McMahon AD, Chaudhuri R, Thompsom JM, Wood SF, Thomson NC. Efficacy of low and high dose inhaled corticosteroid in smokers versus non-smokers with mild asthma. Thorax 2005;60:282–287.
21. Israel E, Cohn J, Dubé L, Drazen JM; Zileuton Clinical Trials Group. Effect of treatment with Zileuton, a 5-lipoxygenase inhibitor, in patients with asthma. a randomized controlled trial. JAMA 1996;275:931–936.
22. Fish JE, Kemp JP, Lockey RF, Glass M, Hanby LA, Bonuccelli CM. Zafirlukast for symptomatic mild-to-moderate asthma: a 13-week multicenter study. Clin Ther 1997;19:675–690.
23. Reiss TF, Chervinsky P, Dockhorn RJ, Shingo S, Seidenberg B, Edwards TB. Montelukast, a once daily leukotriene receptor antagonist, in the treatment of chronic asthma. Arch Intern Med 1998;158:1213–1220.
24. Fauler J, Frolich JC. Cigarette smoking stimulates cysteinyl leukotriene production in man. Eur J Clin Invest 1997;27:43–47.
25. Zhu J, Kilty I, Granger H, Gamble E, Qiu YS, Hattotuwa K, Elston W, Liu WL, Oliva A, Pauwels RA, et al. Gene expression and immunolocalization of 15-lipoxygenase isozymes in the airway mucosa of smokers with chronic bronchitis. Am J Respir Cell Mol Biol 2002;27:666–677.
26. Gaki E, Papatheodorou G, Ischaki E, Grammenou V, Papa I, Loukides S. Leukotriene E4 in urine in patients with asthma and COPD: the effect of smoking habit. Respir Med 2007;101:826–832.
27. Schulman, Ronca, Bucuvalas, Inc. Asthma in America: a landmark survey. Washington, DC: Asthma in America Survey Project; 1998.
28. American Thoracic Society. Standards for the diagnosis and care of patients with chronic obstructive pulmonary disease (COPD) and asthma. Am Rev Respir Dis 1987;136:225–234.
29. American Thoracic Society. Standardization of spirometry: 1987 update. Am Rev Respir Dis 1987;136:1285–1298.
30. American Thoracic Society. Single-breath carbon monoxide diffusing capacity (transfer factor): recommendations for a standard technique, 1995 update. Am J Respir Crit Care Med 1995;152:2185–2198.
31. Tashkin DP, Altose MD, Bleecker ER, Connett JE, Kanner RE, Lee WW, Wise R. The Lung Health Study: airway responsiveness to inhaled methacholine in smokers with mild to moderate airflow limitation. Am Rev Respir Dis 1992;145:301–310.
32. Juniper EF, Guyatt GH, Ferrie PJ, Griffith LE. Measuring quality of life in asthma. Am Rev Respir Dis 1993;147:832–838.
33. Fahy JV, Liu J, Wong H, Boushey HA. Analysis of cellular and biochemical constituents of induced sputum after allergen challenge: a method for studying allergic airway inflammation. J Allergy Clin Immunol 1994;93:1031–1039.
34. Vonesh EF, Chinchilli VM. Linear and nonlinear models for the analysis of repeated measurements. New York: Marcel Dekker & Sons; 1997.
35. Szefler SJ, Martin RJ, King TS, Boushey HA, Cherniack RM, Chinchilli VM, Craig TJ, Drazen JM, Fagan JK, Fahy JV, et al. Significant variability in response to inhaled corticosteroids for persistent asthma. J Allergy Clin Immunol 2002;109:410–418.
36. Martin RJ, Szefler SJ, Chinchilli VM, Kraft M, Dolovich M, Boushey HA, Cherniack RM, Craig TJ, Drazen JM, Fagan JK, et al. Systemic effect comparisons of six inhaled corticosteroid preparations. Am J Respir Crit Care Med 2002;165:1377–1383.
37. Ito K, Lim S, Caramori G, Chung KF, Barnes PJ, Adcock IM. Cigarette smoking reduces histone deacetylase 2 expression, enhances cytokine expression, and inhibits glucocorticoid actions in alveolar macrophages. FASEB J 2001;15:1110–1112.
38. Chalmers GW, MacLeod KJ, Thomson L, Little SA, McSharry C, Thomson NC. Smoking and airway inflammation in patients with mild asthma. Chest 2001;120:1917–1922.
39. Kuschner WG, D'Alessandro A, Wong H, Blanc PD. Dose-dependent cigarette smoking-related inflammatory responses in healthy adults. Eur Respir J 1996;9:1989–1994.
40. Keatings VM, Collins PD, Scott DM, Barnes PJ. Differences in interleukin-8 and tumor necrosis factor-alpha in induced sputum from patients with chronic obstructive pulmonary disease or asthma. Am J Respir Crit Care Med 1996;153:530–534.
41. Oakley RH, Jewell CM, Yudt MR, Bofetiado DM, Cidlowski JA. The dominant negative activity of the human glucocorticoid receptor beta isoform: specificity and mechanisms of action. J Biol Chem 1999;274: 27857–27866.
42. Sousa AR, Lane SJ, Cidlowski JA, Staynov DZ, Lee TH. Glucocorticoid resistance in asthma is associated with elevated in vivo expression of the glucocorticoid receptor beta-isoform. J Allergy Clin Immunol 2000;105:943–950.
43. Pujols L, Mullol J, Perez M, Roca-Ferrer J, Juan M, Xaubet A, Cidlowski JA, Picado C. Expression of the human glucocorticoid receptor alpha and beta isoforms in human respiratory epithelial cells and their regulation by dexamethasone. Am J Respir Cell Mol Biol 2001;24:49–57.
44. Hauk P, Goleva E, Strickland I, Vottero A, Chrousos GP, Kisich KO, Leung DY. Increased glucocorticoid receptor beta expression converts mouse hybridoma cells to a corticosteroid-insensitive phenotype. Am J Respir Cell Mol Biol 2002;27:361–367.
45. Livingston E, Darroch CE, Chaudhuri R, McPhee I, McMahon AD, MacKenzie SJ, Thomson NC. Glucocorticoid receptor α:β ratio in blood mononuclear cells is reduced in cigarette smokers. J Allergy Clin Immunol 2004;114:1475–1478.
46. Malmstrom K, Rodriguez-Gomez G, Guerra J, Villaran C, Pineiro A, Wei LX. Oral montelukast, inhaled beclomethasone, and placebo for chronic asthma. Ann Intern Med 1999;130:487–495.
47. Boushey HA, Sorkness CA, King TS, Sullivan SD, Fahy JV, Lazarus SC, Chinchilli VM, Craig TJ, Dimango E, Deykin A, et al. Regular controller therapy versus intermittent inhaled corticosteroids for mild persistent asthma. N Engl J Med 2005;352:1519–1528.
48. Vanden Burgt JA, Busse WW, Martin RJ, Szefler SJ, Donnell D. Efficacy and safety overview of a new inhaled corticosteroid, QVAR (hydrofluoroalkane-beclomethasone extrafine inhalation aerosol), in asthma. J Allergy Clin Immunol 2000;106:1209–1226.
49. Ottanelli R, Rosi E, Ronchi MC, Grazzini M, Lanini B, Stendard L, Romagnoli I, Bertini S, Duranti R, Scano G. Perception of bronchoconstriction in smokers with airflow limitation. Clin Sci 2001;101:515–522.
50. Massasso DH, Salome CM, King GG, Seale JP, Woolcock AJ. Do subjects with asthma have greater perception of acute bronchoconstriction than smokers with airflow limitation? Respirology 1999;4:393–399.
51. Rennard SI, Daughton D, Fujita J, Oehlerking MB, Dobson JR, Stahl MG, Robbins RA, Thompson AB. Short-term smoking reduction is associated with reduction in measures of lower respiratory tract inflammation in heavy smokers. Eur Respir J 1990;3:752–759.
52. Chaudhuri R, Livingston E, McMahon AD, Lafferty J, Fraser I, Spears M, McSharry CP, Thomson NC. Effects of smoking cessation on lung function and airway inflammation in smokers with asthma. Am J Respir Crit Care Med 2005;174:127–133.
53. Mio T, Romberger DJ, Thompson AB, Robbins RA, Heires A, Rennard SI. Cigarette smoke induces interleukin-8 release from human bronchial epithelial cells. Am J Respir Crit Care Med 1997;155:1770–1776.
Correspondence and requests for reprints should be addressed to Stephen C. Lazarus, M.D., University of California, San Francisco, 505 Parnassus Avenue, M-1083, San Francisco, CA 94143–0111. E-mail:


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