Asthma Patients With Isolated Sputum Eosinophilia Exhibit Distinct Nasal Gene Expression Profile

Abstract RATIONALE: Asthma is a heterogeneous inflammatory airways disease with approximately 50% of asthma patients classified as having eosinophilic asthma. In recent years, it has been recognized that eosinophilic inflammation contributes to the clinical phenotype. In daily clinical practice eosinophilia is usually measured in blood. Although this gives a good representation of the inflammatory phenotype for most patients, a subset may exhibit elevated eosinophil levels in sputum despite low blood eosinophil counts. Our recent study demonstrated isolated sputum eosinophilia to occur in up to 20% of patients and, when present, to be associated with a more severe clinical phenotype. While important, more accessible biomarkers are needed, as sputum collection and processing are time-consuming and are not feasible for all patients. Nasal brushing is more accessible and has generated important information regarding asthma pathobiology. In this study, we performed gene profiling in nasal brush samples to find a gene signature related to isolated sputum eosinophilia in the ATLANTIS study [1]. METHODS: We analysed available clinical and gene expression data from 158 patients included in the ATLANTIS study. Isolated sputum eosinophilia was defined as low blood eosinophil counts (<300 cells/µl) and sputum eosinophils ≥2%. Analysis was performed in R, differential gene expression was performed using edgeR package. Generalized linear model was corrected for age, sex, and smoking status. RESULTS: Participants with isolated sputum eosinophilia (n=17) demonstrated worse lung function reflected by FEV1% predicted compared to those with low eosinophil levels in both blood and sputum (81 vs 87, p=0.038). We identified a total of 48 up- and 4 down-regulated genes (false discovery rate (FDR) <0.05) in isolated sputum eosinophilia compared to the non-eosinophilic group (Figure 1A). When compared to patients without eosinophilia, 26 and 31 genes were up- and down-regulated, respectively (Figure 1B). The most significant genes in both comparisons were MAL, CRNN, LINC02899, TMPRSS11B, SPINK7, RPTN, ECM1, KLK7, FLG, MUC21. CONCLUSIONS: We identified gene signature associated with isolated sputum eosinophilia in asthma patients including genes that may play a role in T-cell differentiation, serine peptidase activity and calcium ion binding pathways. Our findings may suggest that discordant eosinophilic numbers between the blood and sputum compartments are not a random phenomenon, but it is driven by clinically relevant biological pathways. References: 1.Postma DS et al. PMID:30876830 Figure 1. Volcano plot representation of nasal brushes differential expression analysis, FDR<0.05 is considered significant. Patients with isolated sputum eosinophilia compared to A) non-eosinophilic asthma; B) eosinophilic asthma.