Effects of inflammatory endotypes on disease trajectory in chronic rhinosinusitis with nasal polyps.

Abstract

Although phenotypic features have traditionally guided treatment in chronic rhinosinusitis, recent research has favored categorization on the basis of inflammatory endotype. However, the impact of endotypic differeces on clinical outcomes remains largely unknown. We sought to compare disease trajectory, primarily time-to-polyp recurrence, between chronic rhinosinusitis with nasal polyp (CRSwNP) endotypes. Samples were obtained from patients with CRSwNP undergoing surgery between 2015 and 2023, and cytokine levels were measured using a multiplex bead assay. Principal-component analysis followed by hierarchical cluster analysis was used to identify endotype clusters. Clinical outcomes were subsequently compared between clusters. Six CRSwNP disease clusters were identified among the 269 included patients. Cluster 1 (46.5%) was characterized by relatively low inflammation. Cluster 4 (13.3%) and cluster 6 (7.1%) also exhibited low inflammation but with elevated levels of IL-12/IL-21 and CCL5, respectively. Cluster 2 (4.5%) represented a mixed type 1/3 inflammatory endotype (IFN-γ^High/IL-4^High/IL-17A^High), and cluster 3 (10.0%) was characterized by an innate, proinflammatory response (IL-1β^High/IL-6^High/IL-8^High). Cluster 5 (18.9%) exhibited type 2-dominant inflammation (IL-5^High/IL-9^High/IL-13^High). When comparing disease trajectory, cluster 2 (IFN-γ^High/IL-4^High/IL-17A^High) and cluster 4 (IL-12^High/IL-21^High) had the shortest time-to-polyp recurrence, whereas cluster 3 (IL-1β^High/IL-6^High/IL-8^High) demonstrated the longest time-to-recurrence (P < .001). Time-to-oral steroid course (P = .13) and time-to-biologic therapy (P = .43) were similar across clusters. The study highlights the heterogeneous nature of CRSwNP and differences in disease trajectory between endotypes, notably that patients with mixed type 1 and type 3 inflammation demonstrate more recalcitrant disease. These findings suggest that therapies beyond traditional type 2 inflammation treatments may be needed to effectively reduce CRSwNP disease recurrence.