The effect of different inhaled corticosteroid and long-acting bronchodilator combinations on the airway microbiome in patients with severe chronic obstructive pulmonary disease: A randomized trial (MUSIC)

Introduction The microbiome is associated with exacerbation risk, quality of life and mortality in COPD. Inhaled corticosteroid (ICS) treatment has been reported to alter the microbiome through modulating host defence. How ICS alters the microbiome and whether effects are equal between different ICS preparations is debated. The aim of the MUSIC trial was to investigate whether commonly used ICS therapies have different effects on the airway microbiome in COPD. Methods Multicentre randomized controlled trial. After a four-week washout period during which they withdrew from ICS, patients with COPD (FEV 1 <50% predicted at baseline and/or a history of 2 or more exacerbations per year) were randomized to one of 4 treatments (budesonide/formoterol 400/12 mcg, fluticasone/salmeterol 500 mcg, fluticasone/salmeterol 250 mcg or aclidinium/formoterol 340/12 mcg, twice daily). Patients were followed-up for 3 months with monthly induced sputum, oropharyngeal and nasopharyngeal swabs for bacterial load and 16S rRNA sequencing to characterise the microbiome. Inflammatory markers were measured in sputum and blood. The primary outcome was bacterial load in oropharyngeal swabs comparing budesonide/formoterol versus fluticasone/salmeterol 500, with sputum bacterial load the key secondary endpoint. Results 122 participants started the washout period. ICS withdrawal was poorly tolerated, 61 participants withdrew before randomization with 45 experiencing an exacerbation. 61 patients were randomized. No statistically significant differences were observed for the primary comparison of budesonide/formoterol versus fluticasone/salmeterol 500 in oropharyngeal bacterial load. There was however a significant increase in sputum bacterial load with fluticasone/salmeterol 500 compared to budesonide/formoterol by month 3. This difference was not seen with fluticasone/salmeterol 250. No significant differences in microbiome alpha diversity were observed over time. Adverse events were similar between the groups. Conclusion Fluticasone/salmeterol 500 increased sputum but not upper airway bacterial loads. ICS withdrawal was poorly tolerated in severe COPD.