The CASPER study demonstrated a comparable improvement in asthma control for therapy with a pMDI administering an extrafine particle aerosol containing beclometasone dipropionate/formoterol in patients with chronic bronchial asthma subdivided by smoking status (Fig. 2). Although asthmatic patients exposed to tobacco smoke are generally more symptomatic during long-term treatment with an extrafine BDP/F-pMDI, the diurnal and nocturnal asthma symptoms, rescue medication use, and limitation of life activity due to asthma were markedly decreased in all subgroups, and statistically even more decreased in smokers and ex-smokers. At the 6-month follow-up, un improvement in asthma control compared to baseline, according to the GINA criteria, was reported in 77.1% of current smokers, 75.2% of ex-smokers, and 75% of non-smokers. and finally the full and partial asthma control according to GINA guidelines was achieved by 89.8%, of current and ex-smokers and 92.5%of non-smokers. The full asthma control was more frequently achieved in non smokers (64.0% fulfilled GINA criteria of asthma control) compared to current smokers and ex-smokers (54.9% and 51.5%, respectively) (Fig. 3). A considerable clinical effect was achieved in all subgroups when using a standard dose of the formulation; however, lower daily doses of extrafine BDP/F-pMDIwere adequate in a majority of patients (Table 3). Of note, a greater percentage of patients in the ex-smokers group used higher doses compared to those in the other groups, albeit this difference was not statistically significant.
Smoking is a known factor for reducing the clinical response to inhaled corticosteroids. In studies, where smoking asthmatics used inhaled corticosteroids alone [5, 6], there was a weaker response to the treatment, even when the medication was administered at higher doses compared to the non-smokers. The mechanism of the development of resistance to corticosteroids because of the exposure to tobacco smoke is complex and affects both pharmacodynamic and aerodynamic properties of these drugs. Cigarette smoke induces an inflammatory response in the airways by activating both Th1- and Th2-dependent pathways. Inflammatory infiltration is rich in neutrophils that are not sensitive to corticosteroids. In addition, cigarette smoke causes oxidative stress that not only activates the NF-kB-dependent pathway but also affects the histone deacetylase (HDAC)/histone acetyltransferase (HAT) balance via the post-translational modification of HDAC2. Another potential explanatory mechanism regarding corticosteroid resistance may be the reduced expression of glucocorticoid alpha receptor in relation to its beta counterpart, which is observed in healthy smokers as well as in smokers with asthma . The strength of this effect has been shown in a study assessing the passive exposure to tobacco smoke in children of smoking women. Thus, smoking in the case of the mother can cause, through epigenetic mechanisms, a change in DNA methylation, histone modification, and miRNA expression . In addition, exposure to tobacco smoke and air pollution can lead to a synergistic effect at the level of the activation of proinflammatory genes via increased methylation and decreased expression of gamma-interferon (IFNγ) in effector T lymphocytes and the FOXP3 transcription factor in regulatory T lymphocytes, which are of great importance in the development of allergic inflammation and bronchial asthma .
Apart from biochemical mechanisms, particle interaction and growth should be taken into account as another mechanism contributing to the reduced clinical efficacy of inhaled corticosteroid medications in smokers. Invernizzi et al  showed that the particle profile of the inhaled corticosteroid (ICS) is altered when the drug is delivered in the presence of tobacco smoke with a decrease in smaller particles and a concurrent increase of larger particles. The changes in aerosol particle size might modify drug deposition and influence drug efficacy.
In order to achieve the best therapeutic effect of ICS, avoiding drug inhalation in the environmental tobacco smoke presence (a passive exposition or an inhalation short after smoking) is quite easy to achieve. However, breaking the cellular resistance is much more difficult.
It is known that adding long acting beta2 agonist (LABA) improves the clinical response to ICS in smoking patients.
The underlying cellular mechanism for breaking steroid resistance in patients who smoke tobacco and use combination therapy with ICS withLABA remains unknown. However, LABAs intensify the response to ICS at the cellular level. Eickelberg et al.  showed that LABAs could in vitro activate the receptor for ICS and potentiate its effects. Rüdiger et al.  revealed that inhalation of budesonide activated the glucocorticoid receptor in peripheral blood leukocytes within 30 minutes, and the signal declined thereafter. Formoterol inhalation also activated the glucocorticoid receptor, but not before 60 min, maintaining a stable signal intensity up to 4 hours. When combined, the drugs activated the glucocorticoid receptor within 30 minutes to the maximal level which did not reduce within 4 hours.
Profita et al confirmed that BDP with salbutamol or formoterol enhance nuclear translocation of GR and significantly reduces the release of GMC-CSF, RANTES and IL-8 in induced sputum cells as compared with either drug alone (p < 0.0001). Additionally, they found that BDP increased the expression of β2-receptor after 30 minutes of incubation and continued to increase over a time period of 4 hours.
Interesting results were also obtained in a study of smooth muscle cells of the bronchi. Both classes of drugs activated C/EBP-α and the glucocorticoid receptor and inhibited proliferation. The combination of lower doses of drugs resulted in a synchronised activation of the transcription factors and an enhanced antiproliferative effect. .
Descalzi et al. performed their study on human bronchial fibroblasts. They observed that BDP alone has significant antiproliferative effects on lung fibroblasts treated with basic fibroblast growth factor and the combination of BDP with formoterol or salbutamol strengthen these effects . Montalbano et al. investigated the effect of recombinant human IL-17A (rhIL-17A), in combination with cigarette smoke extracts (CSE) on normal human bronchial epithelial cells. They demonstrated that both IL-17A and CSE increase the degree of oxidative/nitrosative stress by STAT-1 pathway activation or by an alternative signalling pathway but BDP and formoterol treatment reduces this effect, showing an additive action when used in combination .
Clinical data on the effectiveness of treatment with an ICS in combination with LABA in active tobacco users with asthma is positive but limited. In a randomized, placebo-controlled, crossover study by Clearie et al. , sixteen non-smokers with mild asthma and fifteen smokers were administered fluticasone/salmeterol, 250/50 mcg, bis in die (BiD) or fluticasone, 500 mg, BiD for 2 weeks. In this study, the smokers were conferred a significantly greater benefit from combination therapy compared to fluticasone alone in terms of reducing bronchial hyperreactivity and ameliorating lung function.
Van Schayck et al.  compared the effectiveness of therapy with budesonide and formoterol, 160/4.5 mcg, in a single inhaler, concerning maintenance and reliever therapy (2 × 1 or 2 × 2 plus on demand), in 886 smokers with asthma with a maximum history of 10 pack-year to the effectiveness of the same treatment paradigm in patients who were non-smokers. At the beginning of the study, the smokers had worse lung function and used more rescue medications. Over the course of the treatment, comparable number of asthma exacerbations and a similar average time to first exacerbation were observed in both groups, while in smokers, a better effect was achieved at higher doses in terms of maintenance therapy. Similar results were obtained by Pilcher et al.  who examined the data from a 24-week randomized clinical trial with a combined budesonide/formoterol pMDI for maintenance and emergency treatment compared to a traditional treatment regimen with budesonide/formoterol pMDI in maintenance treatment and salbutamol on demand. The study comprised 59 current smokers, 97 ex-smokers, and 147 non-smokers. The effectiveness of the therapy was better in the group treated with one single inhaler than in the group treated with the traditional regimen, regardless of smoking status. There was no significant difference between the smokers and non-smokers regarding their response to the treatment.
Brusselle et al.  observed a cohort of patients with moderate to severe asthma (445 non-smokers and 123 smokers), using an extrafine particle beclometasone dipropionate/formoterolpMDI. The study was conducted in real-life conditions with one-year follow-up. Therapy led to a clinically and statistically significant improvement in lung function and asthma control in both groups although the baseline lung function and the degree of asthma control were worse in the smokers than in non-smokers with asthma. This study confirmed the comparable improvement in lung function and asthma control after treatment with BDP/FpMDI in smoking vs non-smoking patients.
In 2016, Marth et al.  published a prospective, noninterventional study on the effectiveness of beclometasone dipropionate/formoterol pMDI therapy in asthma patients categorized by different phenotypes, including smoking status. During 12-week treatment with BDP/FpMDI smoking patients (current and past) showed significant improvement of asthma symptoms (dyspnoea, cough, chest tightness, wheezing) and asthma control, but at the end of the study the greatest percentage of patients with good asthma control was observed in non-smokers 75.2% vs 58% in smokers and 54.2% in ex-smokers, similar to the CASPER study .
In the last two studies conducted by Brusselle et al.  and Marth et al.  as well as in the CASPER  study, an extrafine particle aerosol was utilized. Subsequently, all three studies demonstrated high clinical effectiveness of the ICS + LABA combination therapy in patients exposed to tobacco smoke. The high effectiveness of the therapy, in these cases, should be related both to the synergistic action of the components and the pharmacodynamic properties of the generated aerosol.
Tobacco smoke deeply penetrates the respiratory system. MMAD for cigarette smoke amounts to approximately 0,5 µm, indicating that particles of its aerosol reach the small airways where they exert harmful effects, hence inducing the inflammatory process. In studies on ICS administered alone, in which efficacy was compared in asthmatic non-smokers vs asthmatic current smokers, aerosols with low pulmonary deposition and a low fraction of fine particles were used (pMDI CFC). The lack of effectiveness of ICS in these studies in smokers with asthma could be partly the result of minimal deposition in the small airways, where the inflammatory process occurred. In the study designed by Roche et al.  to compare the effectiveness of small particle and standard-size-particle ICS, adjusted rates of severe exacerbations in the annual perspective were significantly lower for current/ex-smokers and non-smokers in the small-particle than in the standard-size-particle ICS cohort, with no interaction between treatment and smoking status. In contrast, for current/ex-smokers, adjusted rates of acute respiratory events were significantly lower, and adjusted odds of risk domain asthma control were significantly higher for small-particle ICS than for standard-size-particle ICS; for non-smokers, no difference was found. In another real-life study performed by Park et al. , switching from ICS/LABA DPI to pMDI in the same ICS dose category was associated with decreased asthma exacerbations and improved asthma control compared at 1 year after and before the switch. These results support the concept of the preferential use of small particle aerosols in the treatment of asthma, especially in current or ex-smokers.
The CASPER study, designed to investigate long-term effectiveness of beclometasone dipropionate/formoterol pMDI in patients with chronic bronchial asthma subdivided by smoking status, was conducted following the quotidian clinical practice and the dosage was adjusted by the physicians according to individual patient needs. Our previous multivariate analysis confirmed smoking as a risk factor for poorer asthma control. Additionally, active smoking was shown not to suppress improvement in the clinical status of the studied patients, in contrast to the improper inhaler technique, older age and extensive history of asthma . Even with the load of smoking, treatment with BDP/F-pMDI resulted in a substantial improvement in asthma symptoms, decreased rescue medication needs and limitation of life activity in active and ex-smokers. However, in groups with a history of smoking, a higher percentage of patients was symptomatic throughout the entire study period (Fig. 1).
Statistically, at the end of the study, ex-smokers were the most symptomatic group and the improvement in individual symptoms was statistically lower (Fig. 1 and Tabl. 3; p < 0.05 for both phenomena). This group tended to have worse controlled asthma (the difference in overall asthma control was significant as compare to the non-smokers but was not significant to current smokers Fig. 3), although in ex-smokers the improvement in overall disease control was still found in approximately 75%. Those who quit smoking are usually older with more comorbidities compared to non-smokers and even current smokers. This effect may be attributable to health problems being a strong motivator to cease smoking, as increasingly severe obstructive disease leads to a greater likelihood for permanent departure from tobacco addiction [35, 36]. Therefore, with the ex-smokers group comprising more seriously ill individuals, it is expected that their response to treatment would be incomplete. Taken together, the data presented in the current study add to the previous literature in showing that combination therapy is an effective, albeit potentially muted, therapy across a broad spectrum of asthmatics, irrespective of smoking status.
All of the aforementioned studies demonstrated a comparable response to treatment with combination ICS and LABA in patients with varying tobacco use histories. However, the CASPER project has a number of considerable advantages relative to the above mentioned studies, including the large cohort of patients enrolled, lack of limitations in regard to the intensity and length of smoking, and a comparably long duration of follow-up. With such a large number of patients, the study is more representative of the general population and, more importantly, is characterized by a greater power of statistical inference.
A limitation of the CASPER study was the lack of a control group, for instance, using extrafine particle ICS alone. Furthermore, this study was an observational study; therefore, the interpretation of its outcomes is subject to the inherent restrictions of this form of research. Due to the potential bias or unrecognized confounders, it is difficult to definitively conclude a cause-and-effect relationship considering the observed phenomena. Hence, the study results should be interpreted with caution. However, the large cohort and the diversity of patients observed in terms of quotidian clinical practice elevate the representativeness of the study cohort in relation to the general population.
Another limitation could be the co-existence of chronic obstructive pulmonary disease (COPD) in some asthmatic patients; however, BDP/F pMDI was a physicians’s treatment decision based on their clinical judgement. BDP/F pMDI is registered in both asthma and COPD indication, so the COPD does not exclude its use. In addition, asthma is a strong factor for developing COPD, often considered more significant than smoking . Patients with asthma and COPD are more symptomatic and have worse overall asthma control . These individuals are treated according to the principles of asthma treatment . The study protocol, however, makes it impossible to assess the incidence of Asthma and COPD overlap (ACO)because a spirometry test was performed only in patients who had medical indications during the examination, i.e., patients with more severe disease.
In epidemiological studies, the prevalence of ACO ranged between 9% and 55%, depending on gender and age. The wide variation reflects the different criteria and populations used by different investigators for diagnosing asthma and COPD .
In conclusion, the BDP/F therapeutic regimen in the form of extrafine particle aerosols proved to be effective in achieving and maintaining long-term asthma control and safe for patients with asthma, regardless of their smoking status. The results of our study indicate that, although the overall control of asthma is muted in patients with a previous history of smoking, the clinical response to BDP/F pMDI is comparable among the asthmatics who have never smoked, have smoked in the past and were currently smoking during the observation. However, even when administering effective medication in patients with asthma who smoke tobacco, practitioners should continue efforts to promote smoking cessation, being mindful of the harmful effects of tobacco smoke on the lungs, in particular the high risk of developing COPD and cancer, as well as the increased risk of serious cardiovascular events. Notably, there is a need to train patients on the correct use of the inhaler, to check the inhalation technique on subsequent visits, and to motivate the patients to take medication on a regular basis.