Abstract
The study was designed to assess the effect of cigarette smoking on the therapeutic response to oral corticosteroids in chronic stable asthma. We performed a randomized, placebo-controlled, crossover study with prednisolone (40 mg daily) or placebo for 2 weeks in smokers with asthma, ex-smokers with asthma, and never-smokers with asthma. All subjects had reversibility in FEV1 after nebulized albuterol of 15% or more and a mean postbronchodilator FEV1% predicted of more than 80%. Efficacy was assessed using FEV1, daily PEF, and an asthma control score. There was a significant improvement after oral prednisolone compared with placebo in FEV1, ml (mean difference, 237; 95% confidence intervals, 43, 231; p = 0.019), morning PEF L/m (mean difference, 36.8; 95% confidence intervals (CI), 11, 62; p = 0.006), and asthma control score (mean difference, −0.72; 95% CI, −1.2, −0.3; p = 0.004) in never-smokers with asthma but no change in smokers with asthma (mean differences of 47, 6.5, and −0.05 with p values of 0.605, 0.47, and 0.865, respectively). Ex-smokers with asthma had a significant improvement in morning and night PEF (mean difference, 29.1; CI, 2.3, 56; p = 0.04 and 52.4; CI, 26, 79; p = 0.003, respectively), but not in FEV1 or asthma control score. We conclude that active smoking impairs the efficacy of short-term oral corticosteroid treatment in chronic asthma.
Active cigarette smoking is common in adult patients with asthma, with over 20% being current smokers (1, 2). A recent survey of adults presenting to emergency departments with acute asthma revealed that 35% were cigarette smokers (3). Current smokers with asthma, compared with never-smokers, have more severe asthma symptoms (1, 2), an accelerated decline in lung function (4), an increase in hospitalization rates for asthma (5), and increased mortality after a near-fatal asthma attack (6). A further 22–43% of adults with asthma are ex-smokers (1, 2).
There is relatively little information on the influence of cigarette smoking on the therapeutic effect of asthma medications. Corticosteroids are currently the best antiinflammatory therapy available for the treatment of asthma and are recommended in international guidelines (7). The evidence for these recommendations is based on clinical trials that have been undertaken largely in nonsmoking patients with asthma. In a randomized controlled trial, we recently found that active cigarette smoking impaired the efficacy of short-term inhaled corticosteroid treatment in steroid-naïve patients with asthma (8). This result confirmed an earlier uncontrolled study that reported a reduced response to inhaled corticosteroids in terms of airway function and eosinophil markers in smokers with asthma compared with nonsmokers (9).
The effect of active cigarette smoking on the therapeutic response to oral corticosteroid treatment in asthma is unclear. Our hypothesis is that active smoking impairs the efficacy of high-dose oral corticosteroids in chronic stable asthma. The aim of this randomized controlled study was to assess the influence of cigarette smoking on the bronchodilator and symptomatic response to high-dose oral corticosteroid treatment.
Some of the results of this study have been previously reported in the form of an abstract (10).
Subjects with chronic asthma (never-smokers, current smokers, and ex-smokers) aged 18–55 years were recruited from hospital clinics and by advertisement. Asthma was diagnosed by the American Thoracic Society criteria (11). All participants signed an informed consent, and approval for the study was obtained from the West Glasgow Ethics Committee. Subjects had a baseline FEV1 that was between 50–85% predicted and demonstrated a reversibility of FEV1 after nebulized albuterol (2.5 mg) of 15% or more. Exclusion criteria were asthma exacerbation, use of oral corticosteroids, or a respiratory tract infection within 4 weeks before inclusion, a recent peptic ulcer, glaucoma, pregnancy, and lactation. Smoking subjects with asthma were defined as those with asthma who had smoked 10 pack-years or more and ex-smokers were those who had smoked 10 pack-years or more and who had quit more than 1 year ago.
This was a randomized, double-blind, placebo-controlled, crossover study using 40 mg of oral prednisolone and identical placebo tablets for 14 days each, with a 2-week washout phase in between. The primary end-point was the change in prealbuterol FEV1 after active treatment compared with placebo, with changes in a validated asthma control score and morning PEF being secondary end-points. Other parameters studied were changes in daily morning and night symptoms, night PEF, and a reduction in the use of β-agonist (rescue) inhalers. A computer-generated randomization sequence was used, with random numbers allocated consecutively. The randomization code was withheld from the investigators until completion of the study. The study medication was packed by the central pharmacy according to the randomization code and was identical in appearance and taste.
Baseline information included asthma history and the American Thoracic Society asthma impairment score (12). Total serum IgE and specific IgE to house dust mite, grass pollen, and cat dander were measured using enzyme-linked immunoassay (Unicap system; Pharmacia, Uppsala, Sweden). A total IgE level of more than 120 IU/L and specific IgE of more than 0.35 IU/L were considered elevated. A subject was defined as atopic when specific IgE to a common allergen was more than 0.35 IU/L (13). Serum cotinine was measured using an enzyme immunoassay (Cozar Bioscience Ltd., Abingdon, UK) to confirm the smoking status of all subjects. Spirometry was performed using a dry wedge spirometer (Vitalograph, Buckingham, UK), and the best of three attempts was taken for analysis. To test reversibility, FEV1 was measured before and 20 minutes after inhalation of 2.5 mg of nebulized albuterol at all visits. A validated asthma control score was completed at each visit (14), with scores ranging from 0 (well controlled) to 6 (poorly controlled). During the treatment phases, patients maintained a validated home diary card (15), recording morning and night PEF (Mini-Wright peak flow meter; Clement Clarke, Harlow, UK), daytime symptoms (range of 0–6, indicating the least to the most asthma symptomatology) and night awakenings (range of 0–3, for increasing severity), use of inhaled rescue medication, and study tablet consumption. Compliance was assessed by counting the number of tablets remaining after each treatment period.
The baseline characteristics of the patients were compared with chi-squared tests, analysis of variance, and Kruskal-Wallis tests. Each of the three cohorts was analyzed separately using analysis of variance techniques that were suitable for the crossover design. The models for the analysis of FEV1 and the asthma control score included adjustments for patient, period, and the baseline measurements (16). The models for the daily PEF as recorded on the diary cards were similar, except that there were no baseline values. The daily symptom score data were analyzed by calculating the differences between the treatment and placebo periods and using t tests. All diary card information was first summarized by the mean of the last 4-day data in each period. With a sample size of 15, a single group t test with a 0.050 two-sided significance level had an 80% power to detect the difference between a null hypothesis mean of 0.000 and an alternative mean with an improvement of 0.4 (FEV1, L). A p value of less than 0.05 was considered significant. All analyses used SAS V8.02 (SAS Institute Inc., Cary, NC) for Windows.
We screened 360 subjects with a history of asthma. Fifty-nine subjects met the inclusion criteria and were randomized; 50 completed all study visits. Five nonsmokers, three smokers, and one ex-smoker dropped out. Seven of them were unwilling to return for follow-up visits, one had a respiratory infection and one was planning a pregnancy. Subjects screened, but not randomized, were excluded because of the lack of reversibility of FEV1 after albuterol of 15% or more, baseline FEV1 out with the inclusion criteria of 50–85% predicted, unwillingness to take corticosteroid tablets for 2 weeks, other medical conditions precluding the use of corticosteroids for research such as osteoporosis/gastric ulcers, and inability to attend for four visits.
There were no significant differences in age, sex, duration of asthma, baseline FEV1, FEV1 percentage predicted, reversibility to albuterol, asthma symptom score, and the American Thoracic Society asthma impairment score among smokers with asthma, ex-smokers with asthma, and never-smokers with asthma (Table 1)
Smokers with Asthma (n = 14) | Ex-smokers with Asthma (n = 10) | Never-smokers with Asthma (n = 26) | |
|---|---|---|---|
| Age, yr | 41.8 (8.3) | 47.1 (5.2) | 40.8 (10.3) |
| Sex, male/female | 7/7 | 7/3 | 22/4 |
| Duration of asthma, yr | 16 (9.8) | 23.9 (14.1) | 25.3 (15.6) |
| Inhaled corticosteroid, mcg daily, equivalent of beclomethasone | 436 (645) | 500 (356) | 538 (520) |
| Pack years smoked | 26.2 (15.6) | 19.3 (9.7) | — |
| Serum cotinine, ng/ml, median, IQR | 452 (253–660)* | 2.3 (2–25.9) | 2.35 (2.1–2.9) |
| Total IgE, IU/ml, median, IQR | 153 (77–282) | 146 (82–644) | 185 (81–420) |
| Specific IgE positive, % | 64 | 80 | 96† |
| FEV1, L | 2.23 (0.5) | 2.21 (0.55) | 2.57 (0.49) |
| FEV1% predicted, prealbuterol | 70.5 (5.9) | 68.4 (14.5) | 69 (10.7) |
| FEV1% predicted, postalbuterol | 84.2 (6.69) | 87.7 (9.6) | 85.5 (12.7) |
| FEV1 reversibility to albuterol, %, median, IQR | 17.3 (16–21) | 22.6 (17–30) | 18.9 (17–28) |
| Improvement in FEV1, ml, after albuterol | 422.8 (123) | 640 (333) | 614.8 (293) |
| FEV1/FVC %, prealbuterol | 70.0 (8.98) | 67.7 (11.3) | 70.2 (13.3) |
| FEV1/FVC %, postalbuterol | 66.8 (14.4) | 71.2 (6.6) | 72.8 (10.9) |
| Asthma control score | 2.64 (0.6) | 2.06 (0.9) | 2.03 (0.9) |
| ATS impairment score | 3.6 (1.3) | 4.7 (1.8) | 4.5 (1.4) |
After high-dose oral corticosteroids, there was a significant improvement in mean and 95% confidence interval (95% CI) prealbuterol FEV1 in the never-smokers with asthma (mean, 237; 95% CI, 43, 231; p = 0.019) but no change in the smokers or ex-smokers (mean, 47; 95% CI, −148, 243; p = 0.605; and mean, 143; 95% CI, −223, 510; p = 0.386, respectively) (Table 2
Smokers with Asthma | Ex-smokers with Asthma | Never-smokers with Asthma | |||||||
|---|---|---|---|---|---|---|---|---|---|
| (n = 14) | p | (n = 10) | p | (n = 26) | p | ||||
| Δ FEV1 prealbuterol, ml | 47 (−148, 243) | 0.605 | 143 (−223, 510) | 0.386 | 237 (43, 431) | 0.019 | |||
| Δ Morning PEF, L/m | 6.5 (−13, 26) | 0.47 | 29.1 (2.3, 56) | 0.04 | 36.8 (11.4, 62) | 0.006 | |||
| Δ Nighttime PEF, L/m | −14.3 (−45,16) | 0.3 | 52.36 (26, 79) | 0.003 | 30.3 (6.5, 54) | 0.015 | |||
| Δ Daytime symptoms, diary card | −0.33 (−3, 3) | 0.8 | −1.6 (−5, 2) | 0.33 | −2.7 (−5, −0.3) | 0.031 | |||
| Δ Night symptoms, diary card | 0.09 (−0.1, 0.3) | 0.37 | −0.54 (−1, 0.04) | 0.06 | −0.3 (−0.5, −0) | 0.048 | |||
| Δ Use of rescue medication, puffs per 24 hr | −8.3 (−2, 0.5) | 0.211 | −0.51 (−1.5, 0.4) | 0.243 | −1.3 (−2, −0.2) | 0.026 | |||
| Δ Asthma control score | −0.05 (−0.7, 0.6) | 0.865 | −0.61 (−1, 0.2) | 0.108 | −0.72 (−1, −0.3) | 0.004 | |||
Figure 1. Mean difference (95% confidence interval) after placebo (closed circles) and after prednisolone (open circles) in smokers with asthma, ex-smokers with asthma, and never-smokers with asthma for (A) change in FEV1, L and (B) asthma control score. A reduction in the score implies an improvement in asthma control.
[More] [Minimize]The asthma control score (Table 2, Figure 1) and the daytime and nighttime symptoms in the diary card were significantly reduced in the nonsmokers but not in the other two groups. Morning and nighttime PEF significantly improved in the never-smokers and ex-smokers, but not in current smokers. The compliance level, assessed by tablet count, was over 90% with treatment in all groups. There was no correlation between responsiveness to oral prednisolone and either the dose of inhaled corticosteroids (r2 0.00, p = 0.664) or specific IgE levels (r2 0.00, p = 0.931).
This is the first randomized, placebo-controlled study to demonstrate that active cigarette smoking is associated with resistance to short-term high-dose oral corticosteroid treatment in patients with chronic stable asthma.
Cigarette smoking is common in adults with asthma and is associated with increased morbidity and mortality (1, 2, 4–6). In our study, the baseline asthma severity was similar in smokers and never-smokers, but there was a significant difference in the therapeutic response to oral corticosteroids. In all end-points measured, including FEV1, morning PEF, nighttime PEF, asthma control score, and daytime and nighttime symptoms, there was a significant improvement after treatment with oral corticosteroids in the never-smokers but no change in current smokers. The dose and duration of oral prednisolone treatment should have been an adequate trial to identify patients who have responsive airways to oral corticosteroids (17, 18). It is unlikely that the variation in the response to oral corticosteroids can be explained by differences in compliance between the patient groups, as compliance with corticosteroids, as assessed by tablet counting, was over 90% in all three groups.
Smoking is the major factor in the development of chronic obstructive pulmonary disease (COPD), and although it can be difficult to differentiate subjects with asthma and COPD, we believe that the smokers with asthma in this study were clearly distinct from subjects with COPD. The smokers with asthma fulfilled the clinical criteria for the diagnosis of asthma (11), had a mean age of 41 years, and had been symptomatic since their 20s, which would be unexpected for patients with COPD. The smokers with asthma had a mean baseline postbronchodilator FEV1 of greater than 80%, which is higher than typically associated with symptomatic COPD, and had bronchodilator reversibility of 15% or more. The mean (SD, minimum, maximum) improvement in FEV1 (ml) after albuterol in the smokers with asthma was 422.8 (122.8, 280, 720) ml.
The effect of smoking on asthma may be partially reversible (2) because the ex-smokers had a significant improvement in morning and nighttime PEF values after corticosteroids. Our study was principally designed to study smokers and never-smokers, but the addition of the small group of ex-smokers showed that the trend in the results in this group tended to be similar to never-smokers. Prospective studies on the therapeutic response to corticosteroids in smokers with asthma are required to confirm whether corticosteroid responsiveness is regained after smoking cessation.
Previous work by Chalmers and colleagues (8) and Pedersen and colleagues (9) has shown that smokers with asthma are resistant to inhaled corticosteroid treatment. Meijer and colleagues (19), studying mild unstable subjects with asthma, found that smoking was associated with an impaired improvement in bronchial hyperresponsiveness after a course of inhaled or oral corticosteroids. We were able to confirm and extend these findings by using a 2-week course of high-dose oral prednisolone and demonstrating significant differences in FEV1, PEF, and symptoms in subjects with asthma who smoke compared with never-smokers.
There have been no published studies in smokers with asthma examining the etiology of corticosteroid insensitivity. Neutrophilia in the airways is associated with a poor response to inhaled corticosteroids in asthma (20), and the increase in sputum neutrophils in smokers with asthma compared with nonsmokers with asthma (21) may account for the impaired response to corticosteroids. Sputum cell counts were not measured in this study; however, it is known that patients with COPD who stop smoking have a persistent neutrophilia (22), and if the airways of ex-smokers with asthma behave in a similar manner but regain corticosteroid responsiveness, then other mechanisms accounting for corticosteroid insensitivity must be operating. It is possible that raised tumor necrosis factor-α levels in smokers (23) cause an increase in the number of glucocorticoid β receptors (24), which have been associated with corticosteroid resistance. Increased production of other inflammatory cytokines such as interleukin-4 in smokers has been implicated in causing corticosteroid insensitivity (25). Cigarette smoke contains bacterial lipopolysaccharide, which is an activator of nuclear factor-κB (26), which in Crohn's disease has been shown to be associated with steroid unresponsiveness (27), and a similar mechanism could exist in subjects with asthma who smoke. Glucocorticoids require histone deacetylase activity for maximal suppression of cytokine induction (28); however, smokers have decreased histone deacetylase activity, and this might lead to an increase in inflammatory gene expression (29).
In conclusion, our study demonstrates that there is a significantly reduced therapeutic response to oral corticosteroids in stable patients with chronic asthma who smoke. This finding suggests that alternative antiinflammatory treatment may be required for this group of patients. Furthermore, our study serves to emphasize the importance of smoking cessation in asthma.
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