Background
Asthma is a chronic inflammatory airway disease in which a variety of inflammatory cells and mediators play a role. Inhaled corticosteroids (ICS) are the cornerstone of treatment, since they exert broad anti-inflammatory effects. They have been shown to improve symptoms and lung function as well as bronchial hyperresponsiveness and markers of airway inflammation in blood, induced sputum and bronchial biopsies [
1]. In addition, the use of ICS reduces the number of asthma exacerbations [
2].
About 20-30% of asthma patients smoke and another 20-40% are ex-smokers [
3‐
6]. Current-smokers appear to have a different airway inflammatory profile than never-smokers, with less eosinophilic and more neutrophilic inflammation [
7‐
12]. Thus far, very little is known about the inflammatory profile of ex-smokers.
The few studies investigating the effects of smoking on the short-term efficacy of oral or inhaled corticosteroid treatment in asthma, demonstrate that the forced expiratory volume in one second (FEV
1) improves significantly in never-smokers, but not in current-smokers [
7,
13‐
15]. However, none of these studies found statistically significant differences in improvement in FEV
1 when directly comparing never- and current-smokers. The only study that included ex-smokers, showed no improvement in FEV
1 or asthma control after 2-week oral corticosteroid treatment in ex- and current-smokers [
15].
We aimed to investigate whether ex-, current- and never-smokers with asthma have different inflammatory profiles and if current number of cigarettes or packyears smoked affect this. Furthermore, we assessed whether the short- and long-term responsiveness to corticosteroids after 2-week and 1-year treatment is different between ex-, current- and never-smoking asthmatics. We have analyzed this in a relatively large group of 114 well-characterized patients with allergic, mild to moderately severe asthma [
16].
Discussion
Our study shows that current-smokers with asthma have a different type of inflammation, i.e. they have less eosinophils and more neutrophils in their sputum and blood than never-smokers, even though the severity of airflow obstruction and bronchial hyperresponsiveness is comparable. Moreover, a higher number of cigarettes smoked daily was associated with a lower percentage of eosinophils in sputum, suggesting that the type of airway inflammation may be influenced by the amount of smoke exposure. Interestingly, the inflammatory profile of a group of asthmatics with a median smoking cessation of 7 years was more similar to that of the current-smoking than that of the never-smokers, suggesting that effects of smoking may persist for a long time after smoking cessation in asthmatics. Additionally, we show that current-smokers have a blunted short-term corticosteroid treatment response. Again, ex-smokers are more similar to current-smokers than to never-smokers, with a trend for a blunted response. However, we found no evidence for a blunted response in both ex- and current-smokers on the long-term.
After short-term treatment with ICS, current-smokers had less improvement in FEV
1 than never-smokers, as reported earlier [
7,
13,
15]. We extend these findings by showing that ex-smokers also tend to respond less to corticosteroid treatment than never-smokers on the short-term. Thus far, the efficacy of corticosteroid treatment in ex-smokers has only been investigated in one study with 15 asthmatic ex-smokers [
15]. Comparable to our findings, they observed that the short-term improvement in FEV
1 after 2-week treatment with oral corticosteroids in ex-smokers was intermediate between current- and never-smokers.
Interestingly, we found that the long-term effects of 1-year ICS treatment were not significantly different in ex- and current-smokers compared to never-smokers. This observation is in line with a study in 492 current- and 2,432 never-smokers, showing that 400 μg/day budesonide or placebo for 3 years was equally effective in current- and never-smokers [
21]. Furthermore, in a large, real-life study in 619 asthmatics, the level of improvement in FEV
1 and asthma control was similar in ex-, current- and never-smokers after 1-year treatment with small particle budesonide/formoterol formulation [
22]. Taken together, these findings suggest that ex- and current-smokers with asthma have a lower corticosteroid treatment response on the short-term than never-smoker, whereas the long-term response is similar between the three groups. We extend these observations by showing that 1-year ICS treatment response is not driven by smoking per se. Rather the underlying inflammatory process present drives the ICS response over 1 year, i.e. a better response with higher sputum and blood eosinophils, independent of smoking. In this context, the findings of Tomlinson and colleagues are of interest [
14]. They found a reduced short-term response to inhaled beclomethasone in current-smokers with asthma, which could be overcome by increasing the dose of beclomethasone from 400 μg/day to 2000 μg/day. It is tempting to speculate that the blunted corticosteroid treatment response in ex- and current-smokers can also be overcome by prolonged treatment, although this remains to be formally demonstrated in future prospective studies.
We did not find any differences in the level of lung function or severity of bronchial hyperresponsiveness between ex-, current- and never-smokers at baseline. However, we did observe a lower level of eosinophilic inflammation in blood and sputum and higher blood neutrophil counts in current-smokers than in never-smokers. These findings are consistent with earlier studies [
7‐
12]. Additionally, we demonstrated that the level of eosinophilic inflammation was also lower in ex-smokers and very similar to that seen in current-smokers. To date, only one other study, also from our research group, reported on the inflammatory profile in ex-smoking asthmatics [
23]. This study demonstrated that ex-smoking asthmatics have lower percentages of eosinophils in airway wall biopsies than never-smokers and that the percentage of sputum neutrophils is significantly higher in ex- than in never-smokers. The above findings suggest that smoking does not only have an acute effect on airway inflammation, but also a chronic effect that may persist for years after smoking cessation.
More severe neutrophilic inflammation in asthma has been associated with a reduced corticosteroid treatment response [
24,
25]. Therefore, the shift from eosinophilic to neutrophilic inflammation that we observed in ex- and current-smokers may be a possible explanation for the reduced short-term corticosteroid treatment response in ex- and current-smokers. Support for the hypothesis that the type of inflammation in ex- and current-smokers influences the corticosteroid treatment response is provided by our observation that smoking status was not independently associated with improvement in FEV
1 %predicted, whereas less eosinophilic inflammation in sputum and blood was independently associated with lower improvement in FEV
1 %predicted, both after 2-week and after 1-year ICS treatment. In addition, higher levels of blood neutrophils were also independently associated with lower improvement in FEV
1 %predicted after 2-week ICS treatment. Interestingly, after 1-year ICS treatment there were no longer any significant differences in inflammation between ex-, current- or never-smokers (Additional file
1: Table S5). This suggests that long-term ICS treatment is able to correct the inflammatory differences in ex- and current-smokers, thereby normalizing their ICS treatment response. Other possible explanations for a lower corticosteroid responsiveness in ex- and current-smokers are epigenetic changes, e.g. reduced expression of histone deacetylases (HDAC) [
26] and DNA methylation [
27], more expression of the less active β isoform of the glucocorticoid receptor [
28‐
30] and increased expression of pro-inflammatory transcription factors, such as nuclear factor-kappa B and activator protein 1 [
31,
32]. Finally, NO in cigarette smoke reduces the affinity of the glucocorticoid receptor for corticosteroids and reduces the binding of corticosteroids to the glucocorticoid receptor [
33].
There are several strengths to our study. Our patients were extensively characterized, including lung function, bronchial hyperresponsiveness and inflammation in sputum and blood, at baseline and after 2-weeks and 1-year treatment with ICS. Our study also has some limitations. First, we performed post-hoc analyses on data from a study that was not originally designed to investigate the effects of smoking on inflammation or corticosteroid treatment response. Our study was originally a three-arm study (Figure
1). However, in the 2-week treatment analyses we included only patients treated with ICS, and in the 1-year treatment analyses we excluded one group of patients who were treated according to a program with step-down and eventually complete discontinuation of corticosteroids, which is not in agreement with the current guidelines. Due to this study design, the short- and long-term corticosteroid response was not investigated in the same groups. In this context, it is important to mention that the randomization of the study was performed with minimization for smoking status, age, previous dose of ICS, FEV
1 %predicted, reversibility after 200 μg of salbutamol, PC
20 methacholine, and serum IgE. This minimization ensures comparable treatment arms with minimal baseline differences. Second, current- and never-smokers were significantly younger than ex-smokers and therefore we had to adjust for age in all analyses.
Competing interests
E.D Telenga has no conflicts to declare. The University of Groningen received funding for research by Prof. H.A.M. Kerstjens from the following manufacturers of inhaled corticosteroids: GlaxoSmithKline, the manufacturer of beclometasone and fluticasone; AstraZeneca, the manufacturer of budesonide; and Nycomed, the manufacturer of ciclesonide. The University of Groningen received funding for research by Dr. N. H. T. ten Hacken from Boehringer Ingelheim, GSK, AstraZeneca, Nycomed and Chiesi. He has been consultant to Chiesi. The University of Groningen received funding for research by Prof. D. S. Postma from AstraZeneca, GSK, Nycomed. Travel to ERS or ATS has been partially funded by AstraZeneca, GSK, Chiesi, Nycomed. She has been consultant to AstraZeneca, Boehringer Ingelheim, Chiesi, GSK, Nycomed, TEVA. The University of Groningen received a research grant for research by dr. M. van den Berge from GlaxoSmithKline and Chiesi.
Authors’ contributions
EDT Performed analysis, wrote the manuscript and approved the final version of the manuscript. HMK. Supervised the original study, critically revised the manuscript and approved the final version of the manuscript. NHTTH Critically revised the manuscript and approved the final version of the manuscript. DSP Supervised the original study, critically revised the manuscript and approved the final version of the manuscript. MB Supervised analysis, co-authored the manuscript and approved the final version of the manuscript.