a b s t r a c tRandomized Controlled Trials (RCTs) are the "gold standard" for evaluating treatment outcomes providing information on treatments "efficacy". They are designed to test a therapeutic hypothesis under optimal setting in the absence of confounding factors. For this reason they have high internal validity. The strict and controlled conditions in which they are conducted, leads to low generalizability because they are performed in conditions very different from real life usual care. Conversely, real life studies inform on the "effectiveness" of a treatment, that is, the measure of the extent to which an intervention does what is intended to do in routine circumstances. At variance to RCTs, real life trials have high generalizability, but low internal validity. Recently the number of real life studies has been rapidly growing in different areas of respiratory medicine, particularly in asthma and COPD. The role of such studies is becoming a hot topic in respiratory medicine, attracting research interest and debate.In the first part of this review we discuss some of the advantages and disadvantages of different types of RCTs and analyze the strengths and weaknesses of real life trials, considering the recent examples of some studies conducted in COPD. We then discuss methodological approaches and options to overcome some of the limitations of real life studies.Comparing the conclusions of effectiveness and efficacy trials can provide important pieces of information. Indeed, these approaches can result complementary, and they can guide the interpretation of each other results.

Background: Whether blood eosinophil counts and exhaled nitric oxide (FeNO) are associated with important outcomes in mild asthma is unclear. Methods: This question was explored in a pre-specified analysis of a 52week, open-label, randomized, parallel-group trial in patients with mild asthma receiving only reliever inhalers, comparing salbutamol 200µg asneeded, maintenance budesonide 200µg twice-daily with salbutamol as needed, and budesonide/formoterol 200/6µg as-needed. Outcomes were compared between patients with blood eosinophils of <0.15, 0.15-<0.3 and ≥0.3x109/L; FeNO of <20, 20-50 and >50ppb; and a composite score based on both. Results: The proportion of patients randomised to as-needed salbutamol having a severe exacerbation increased progressively with increasing blood eosinophil sub-group (4.1%, 6.5% and 19.5%; p=0.014). There were no significant interactions between either biomarker and the effect of as-needed budesonide/formoterol compared with as-needed salbutamol for either exacerbations or severe exacerbations. However, there were significant interactions between blood eosinophil sub-groups and the effect of maintenance budesonide compared with as needed salbutamol for exacerbations (p<0.001) and severe exacerbations (p<0.001). Maintenance budesonide was more effective than as-needed salbutamol in patients with eosinophils ≥0.3x109/L for exacerbations (odds ratio 0.13; 95% CI 0.05-0.33) and severe exacerbations (0.11; 0.03-0.45). This was not the case for eosinophils <0.15x109/L (odds ratio for exacerbations 1.15; 0.51-1.28 and severe exacerbations 5.72; 0.97-33.6). There was no consistent interaction between treatment response and FeNO or the composite score. Conclusions: In patients with mild asthma the effects of as-needed budesonide/formoterol on exacerbations are independent of biomarker profile, whereas the benefits of maintenance inhaled budesonide are greater in patients with high blood eosinophil counts.

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Asthma and chronic obstructive pulmonary disease (COPD) are among the most common chronic diseases worldwide, characterized by a condition of variable degree of airway obstruction and chronic airway inflammation. A large body of evidence has demonstrated the importance of small airways as a pharmacological target in these clinical conditions. Despite a deeper understanding of the pathophysiological mechanisms, the epidemiological observations show that a significant proportion of asthmatic and COPD patients have a suboptimal (or lack of) control of their diseases. Different factors could influence the effectiveness of inhaled treatment in chronic respiratory diseases: patient-related (eg, aging); disease-related (eg, comorbid conditions); and drug-related/formulation-related factors. The presence of multiple illnesses is common in the elderly patient as a result of two processes: the association between age and incidence of degenerative diseases; and the development over time of complications of the existing diseases. In addition, specific comorbidities may contribute to impair the ability to use inhalers, such as devices for efficient drug delivery in the respiratory system. The inability to reach and treat the peripheral airways may contribute to the lack of efficacy of inhaled treatments. The recent development of inhaled extrafine formulations allows a more uniform distribution of the inhaled treatment throughout the respiratory tree to include the peripheral airways. The beclomethasone/formoterol extrafine formulation is available for the treatment of asthma and COPD. Different biomarkers of peripheral airways are improved by beclomethasone/formoterol extrafine treatment in comparison with equivalent nonextrafine inhaled corticosteroids/long-acting beta-2 agonist (ICS/LABA) combinations. These improvements are associated with improved lung function and clinical outcomes, along with reduced systemic exposure to inhaled corticosteroids. The increased knowledge in the pathophysiology of the peripheral airways may lead to identify specific phenotypes of obstructive lung diseases that would mostly benefit from the treatments specifically targeting the peripheral airways.

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