Understanding how azithromycin reduces asthma exacerbations and the underlying mechanisms of macrolides

New interventions are needed for non-T2 asthma phenotypes. Although the AMAZES study (Lancet 2017) showed that azithromycin (AZM) reduces asthma exacerbations, the involved mechanisms are not well understood. This study aimed to identify a unique AZM-sensitive protein signature in sputum from AMAZES participants, comparing sputum obtained before and after 48 weeks of AZM or placebo, added to optimal inhaler therapy. Using a robust high throughput method (mass spectroscopy) for the global analysis of the sputum proteome, 52 samples (representative of entire AMAZES cohort) were selected. Protein intensities were extracted for external statistical analyses using R studio. Differentially enriched proteins were identified by a log-fold change of 1.5 and a p-value of 0.05. Findings were validated in a larger cohort of participants. Univariate modelling identified 240 proteins uniquely expressed at week 48 in AZM-treated patients and 214 proteins in placebo-treated patients. An additional 32 proteins were differentially expressed in AZM-treated patients, comparing week 48 to baseline. Finally, 90 proteins were differentially expressed at week 48 between AZM and placebo-treated samples. Multivariate modelling identified a unique 60 protein signature that distinguished AZM from placebo in comparison to the baseline proteome. Protein interactions and pathway analysis identified several overrepresented pathways independent of asthma phenotype: including apoptosis, phagocytosis, IL-5 pathway, endogenous TLR/chemokine signalling and bacterial invasion. Analysis of the proteome provides unique insight into AZMs mechanism and facilitates development of novel treatment options for severe asthma