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

Asthma and chronic rhinosinusitis (CRS) often cooccur and share heterogenous inflammatory processes resulting in frequent exacerbations and poor clinical control.

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 remodeling response.

We assessed the number of inflammatory cells and the expression of type 2 (T2), T3 and remodeling biomarkers in the bronchial mucosa of 47 patients with mild-to-severe asthma who had bronchial biopsies by immunohistochemistry and immunofluorescence. We compared the clinical, functional, and biological data of patients with asthma without (As: n = 16) or with CRS (As+CRS: n = 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) versus mild/severe asthma with CRS (MAs+CRS/SAs+CRS: n = 15/16).

Patients with As+CRS had later asthma onset and higher blood eosinophils and fractional exhaled nitric oxide than patients with As (P < 0.01). Patients with As+CRSwNP had a higher exacerbation rate than patients with As (P < 0.01) and higher blood eosinophilia than both As+CRSsNP and As (P < 0.01). Patients with As+CRSsNP showed higher residual volume (% predicted) and lower forced expiratory volume in 1 second/forced vital capacity than patients with As. Immunohistochemistry and immunofluorescence showed that patients with As+CRS, compared with patients with As (P < 0.05), had higher and concomitant expression of T2 and T3 inflammatory biomarkers and remodeling evidence (number of eosinophils, CD4+, eotaxin-3+, IL-5 [interleukin 5]+, IL-9+, IL-17A+, IL-22+ cells and subepithelial basal membrane thickness) in the bronchial lamina propria as well as a higher percentage of GATA-binding protein 3+ (GATA3+) cells and a greater tendency of related orphan receptor gamma T+ (RORγT+) cells (P > 0.05). Higher expression of T2 and T3 cytokines (IL-13+, eotaxin-3+, IL-9+, TSLP+, IL-17A+, and IL-17F+ cells) was observed in patients with SAs+CRS. Two-way analysis of variance showed that both comorbid CRS and asthma severity modulate IL-13 and IL-17A bronchial expression in asthma.

Our results confirm a higher proportion of T2 clinical phenotype (fractional exhaled nitric oxide and blood eosinophils) in asthma with comorbid CRS but revealed a more complex bronchial immune-inflammatory response, suggesting an overlapping interplay of T2 and T3 processes as underlying mechanisms related to this clinical asthma phenotype.