A sputum 6 gene signature predicts future exacerbations of poorly controlled asthma.

BACKGROUND: Improved diagnostic tools for predicting future exacerbation frequency in asthma are required. A sputum gene expression signature of 6 biomarkers (6GS - including CLC, CPA3, DNASE1L3, ALPL, CXCR2, IL1B) predicts inflammatory and treatment response phenotypes in stable asthma. We recently demonstrated that azithromycin (AZM) add-on treatment in uncontrolled moderate-to-severe asthma significantly reduced asthma exacerbations (AMAZES clinical trial).

OBJECTIVES: To test whether the 6GS predicts future exacerbation and inflammatory phenotypes in a subpopulation of AMAZES. To test the impact of AZM therapy on 6GS expression and prognostic capacity.

METHODS: 142 patients (73 placebo-treated, 69 AZM-treated) had sputum stored for qPCR of 6GS markers at baseline and after 48 weeks of treatment. Logistic regression, ROC and AUC were performed on baseline measures, and in an exploratory analysis the predictive value of 6GS was compared with conventional biomarkers for exacerbation and inflammatory phenotypes.

RESULTS: The 6GS significantly predicted all future exacerbation phenotypes tested. Calculated AUCs for 6GS were significantly higher than AUCs for peripheral blood eosinophil counts, sputum neutrophil counts and combined sputum eosinophils and neutrophil counts. 6GS AUCs were also were numerically, but not significantly, higher than FeNO and sputum eosinophil counts. AZM treatment neither altered the 6GS expression nor the predictive capacity of the 6GS for future exacerbation phenotypes. The 6GS was a significant predictor of airway inflammatory phenotype in this population.

CONCLUSION: We demonstrate that a sputum gene signature can predict future exacerbation phenotypes of asthma, with greatest biomarker performance in identifying those who would experience frequent severe exacerbations. AZM therapy did not modify 6GS expression or biomarker performance, suggesting the therapeutic action of AZM is independent of 6GS-related inflammatory pathways.