Neutrophil-related gene expression profile is associated with future paediatric bronchiectasis exacerbations

Acute respiratory exacerbations in bronchiectasis are important as they impair quality of life and are associated with accelerated lung function decline. Yet, no validated methods exist to identify children at increased risk of exacerbations. We therefore determined if peripheral blood gene expression (GE) signatures can identify those at risk of an impending exacerbation. Thirty-one children with bronchiectasis had RNA extracted from peripheral blood collected whilst they were clinically stable, with 22 having an exacerbation during the next 3 months. Microarray assays using the HumanHT-12 v4.0 Expression BeadChip identified differentially expressed genes (p value ≤ 0.05, fold change > 1.5). The top targets were verified using real-time quantitative polymerase chain reaction (rt-qPCR) assays, and receiver operating characteristics and area under the curve (AUC) were assessed. Functional analysis of these genes was performed using Ingenuity Pathway Analysis. Overall, 647 entities were significantly dysregulated (p < 0.05) in the exacerbation group (n = 22), and pathway analysis identified neutrophil degranulation as the dominant affected pathway, which was also significantly inhibited (p < 0.001). Forty entities (32 genes) were associated with a future exacerbation (p ≤ 0.05, fold change ≥ 1.5) and six genes (ANXA3, ALAS2, DEFA1, ALPL, SNCA, PROK2) were verified using RT-qPCR (all p < 0.04) as the most discriminatory. DEFA1 and ANXA3 had the highest AUC (0.92, 95% confidence interval CI 0.82-1.00, and 0.87, 95% CI 0.73-1.00, respectively). We identified neutrophil-associated genes from peripheral blood that could be potential biomarkers for children with bronchiectasis at increased risk of exacerbations during the next 3 months. These GE signatures warrant further investigation and validation in larger, independent cohorts. KEY MESSAGES: Exacerbations in paediatric bronchiectasis are important. Peripheral blood gene expression may help identify children at risk of exacerbations. Six neutrophil-associated genes were associated with a future exacerbation. Identifying predictive gene expression signatures warrants further investigation.