Mapping inflammatory endotypes of bronchiectasis associated with impaired mucociliary clearance

Abstract

Bronchiectasis is a heterogenous disease associated with chronic cough, sputum production and exacerbations. The pathophysiology is poorly understood. This work aimed to identify inflammatory endotypes and explore the associated ciliary phenotypes. A panel of 14 inflammatory cytokines were measured in soluble sputum and serum by MSD and ELISA from 269 people with bronchiectasis in the international EMBARC BRIDGE study. Inflammatory endotypes were identified by PCA. Bronchiectasis severity index (BSI) and exacerbation frequency were compared. To assess the impact of inflammation, epithelial cell cultures were treated basally with cytokines representing Th1 and Th2 inflammation (IL-8, IL-1β, IL-4 or IL-5) for 3 weeks. Mucociliary clearance (MCC) was measured by tracking fluorescent microbeads through confocal microscopy. Ciliary beating was analyzed by high-speed video-microscopy. We identified 3 clusters of patients defined by systemic inflammation, sputum Th1 inflammation (IL-8, IL-1β) and predominantly Th2 inflammation (IL-4, IL-5, IL-13). There was no significant difference in BSI (<i>p</i>=0.76) or exacerbation frequency (<i>p</i>=0.09) between the clusters. MCC is significantly decreased in cultures treated with IL-8, IL-1β and IL-4. Modifications of the ciliary beat pattern are highlighted by the significantly lower amplitude of beating per second after treatment with IL-8, IL-1β, IL-4 and IL-5 translating a decrease in ciliary beating efficiency. Different inflammatory endotypes are present in bronchiectasis. The similarity in clinical features and symptoms between endotypes could be explained by a similar impairment of mucociliary clearance resulting from both Th1 and Th2 inflammatory cytokines.