Evidence of T2/T3 Endotype Overlap in Mild-to-Severe Asthma with Chronic Rhinosinusitis: A Pilot Study

Rationale: Asthma and chronic rhinosinusitis (CRS) often co-occur and share heterogenous inflammatory processes resulting in frequent exacerbations and poor clinical control. Objectives: This observational cross-sectional study aims to characterize asthma with comorbid CRS and to understand whether CRS could influence asthma severity focusing on the bronchial immune-inflammatory and remodelling response. Methods: We assessed the number of inflammatory cells and the expression of T2/T3 and remodelling biomarkers in the bronchial mucosa of 47 mild-to-severe asthmatics' bronchial biopsies by immunohistochemistry/immunofluorescence. We compared the clinical, functional and biological data of asthmatics without (As) or with CRS (As+CRS) (As/As+CRS: N=16/31) in the presence/absence of nasal polyps (As+CRSwNP/As+CRSsNP: N=15/16) and further stratified in mild and severe asthma without CRS (MAs/SAs: N=11/5) vs mild/severe asthma with CRS (MAs+CRS/SAs+CRS: N=15/16). Measurements and main results As+CRS patients had later asthma onset and higher blood eosinophils and FENO than As (p<0.01). As+CRSwNP had a higher exacerbation rate than As (p<0.01) and higher blood eosinophilia than both As+CRSsNP and As (p<0.01). As+CRSsNP showed higher RV(%predicted) and lower FEV1/FVC than As. Immunohistochemistry and immunofluorescence showed that As+CRS, compared to As (p<0.05), had higher and concomitant expression of T2/T3 inflammatory biomarkers and remodelling evidence (number of eosinophils, CD4+, eotaxin-3+, IL-5+, IL-9+, IL-17A+, IL-22+ cells and sub-epithelial basal membrane thickness) in the bronchial lamina propria as well as higher percentage of GATA3+ cells and a greater tendency of RORγT+ cells (p>0.05). Higher expression of T2/T3 cytokines - IL-13+, eotaxin-3+, IL-9+, TSLP+, IL-17A+ and IL-17F+ cells - was observed in SAs+CRS. Two-way ANOVA showed that both comorbid CRS and asthma severity modulate IL-13 and IL-17A bronchial expression in asthma. Conclusions Our results confirm a higher proportion of T2 clinical phenotype (FENO and blood eosinophils) in asthma with comorbid CRS, but revealed a more complex bronchial immune-inflammatory response suggesting an overlapping interplay of T2/T3 processes as underlying mechanisms related to this clinical asthma phenotype.