Effects of Particle Size in Small Airways Dysfunction

The small airways are gaining greater recognition for their role in the pathophysiology of persistent asthma and as a relevant target for asthma treatment(1). Pathological abnormalities in the small airways have been demonstrated regardless of asthma severity and seem to persist even in patients with stable asthma(2, 3). Historically, the small airways have been difficult to assess. Spirometry generally reflects large airways function although the mean forced expiratory flow (FEF) between 25% and 75% of FVC (FEF25-75) has been used to assess small airway obstruction.(4) More recently, impulse oscillometry (IOS) has been used to assess the role of small airways in asthma(5). IOS is an effort-independent test, using oscillation of differing sound waves to derive a variety of output measurements determining both the degree of total and peripheral airway resistance. Resistance at 5 Hz reflects total airway resistance and central airway resistance is approximated using resistance at 20 Hz (R20). The peripheral or small airway component can thus be evaluated by calculating the difference between these two measurements i.e. R5 - R20. We have identified from our database of primary care referrals, a cohort of patients who appear to have evidence of an unmet physiological need in terms of persistent small airways dysfunction, on the basis of impairment of R5 and R5-R20 despite taking step 2/3/4 asthma treatment(6). Approximately 32% of patients across steps 2/3/4 had severely abnormal values for both R5-R20 (\>0.05 kPa/L.s) and R5 (\> 150%). Such small airway dysfunction at step 3/4 occurred despite patients being prescribed ICS with LABA, although there were no patients being prescribed extra fine ICS/LABA or extra fine LABA (i.e. Fostair or Atimos). In terms of the ICS moiety, observational data has shown that patients taking extra fine HFA-beclometasone solution (Qvar) have equal or better control than those taking Fluticasone suspension, while receiving a lower maintenance dose of ICS(7). In another study, patients switched from beclometasone suspension to solution at half the dose had an improvement in asthma quality of life. In neither of these studies was there any information available regarding small airway dysfunction in order to explain the potential improvements with HFA-beclometasone(8). There is a paucity of information on the potential benefits of extra fine formoterol on the small airways. In a single dosing study comparing extra fine HFA versus coarse particle dry powder formulations of formoterol, there was a 30% difference (absolute difference of 2.9 kPa/L.s.min)in R5 AUC0-60min and 63% difference (absolute difference of 2.4 kPa/L.s.min) in R5-R20 AUC0-60min, although this was not the primary end point(9). 1.2 RATIONALE Thus, the primary objective for the present study is to compare the two extremes of available long acting beta-agonist formulations - i.e. extra fine HFA formoterol ( Atimos ) versus coarse particle DPI salmeterol (i.e. Serevent Accuhaler). If there turns out to be a significant improvement in small airways function conferred by extra fine formoterol, then this would in turn support the rationale for performing a further chronic study to assess the clinical impact of treating persistent small airways dysfunction at step 3/4 by switching patients to Fostair HFA and comparing to Seretide DPI, in terms of improving asthma control in patients with the small airway phenotype who are already taking conventional ICS/LABA formulations. We will use impulse oscillometry to assess the small airways response using the difference between resistance measured at 5Hz and 20Hz (R5-R20) as the primary outcome. In this regard we have previously reported in asthmatic patients receiving propranolol that there was a 104.1 % (95%CI 22.6-185.6%) worsening of R5-R20 in terms of the bronchoconstrictor response to propranolol, and following subsequent histamine challenge, there was a 115.6 % (95%CI 55.6-175.7% ) improvement in R5-R20 in terms of the bronchodilator response to nebulised salbutamol.(10)