Beyond Type 2 Inflammation: An Innate-Myeloid Axis is Linked to CRSwNP Recurrence.
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- Also identified by DOI 10.1016/j.jaci.2026.07.018.
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Abstract
Chronic rhinosinusitis with nasal polyps (CRSwNP) is a heterogeneous inflammatory disease with variable outcomes following functional endoscopic sinus surgery (FESS). Predictive biomarkers for post-FESS CRSwNP recurrence remain poorly defined. Identify tissue-based predictors of CRSwNP recurrence after FESS and assess dupilumab-induced modifications. From a cohort of patients with CRSwNP (including NSAID-exacerbated respiratory disease [NSAID-ERD]) who underwent FESS, we retrospectively identified 91 who could be dichotomized by clinical outcome as post-FESS "rapid recurrence" (<1 year) or "slow/no recurrence" (>2 years without recurrence). Nasal polyp tissue was analyzed for 69 inflammatory mediators using proteomics and ELISA. Logistic regression with LASSO feature selection identified candidate predictors. In an independent, second prospective cohort of 17 CRSwNP patients initiating dupilumab, nasal fluid was collected at baseline and after two months of dupilumab and profiled for the same mediators. Twenty-three tissue mediators strongly predicted rapid CRSwNP recurrence (AUC >0.70), including markers of type (T) 2 inflammation (IL-4, IL-13, IL-5Rα, ECP, IgE) and innate inflammation and/or myeloid involvement (CCL3/4/7/8/13, CSF2, IL-1β, IL-6, OSM, MMP12, HIF-1α, TNF-α, TNFSF14). Of these, dupilumab significantly reduced IL-5Rα and several chemokines (CCL3, CCL4, CCL13) but had no effect on key myeloid mediators (CCL8, CSF2, IL-1β, MMP12, HIF-1α). Both T2 and non-T2 mediators play a role in rapid post-FESS recurrence in CRSwNP. T2 blockade with dupilumab reduces T2-associated mediators but does not suppress a parallel innate/myeloid inflammatory axis. The persistence of this axis during treatment suggests that innate and myeloid mediators may underlie severe CRSwNP and could influence disease recurrence once T2 signaling is no longer inhibited, representing potential biomarkers and therapeutic targets to improve long-term disease control.