Beyond type 2 inflammation: An innate-myeloid axis is linked to recurrence of chronic rhinosinusitis with nasal...

Chronic rhinosinusitis with nasal polyps (CRSwNP) is a heterogeneous inflammatory disease with variable outcomes after functional endoscopic sinus surgery (FESS). Predictive biomarkers for post-FESS CRSwNP recurrence remain poorly defined.

We sought to identify tissue-based predictors of CRSwNP recurrence after FESS and assess dupilumab-induced modifications.

From a cohort of patients with CRSwNP (including nonsteroidal anti-inflammatory drug-exacerbated respiratory disease) 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 via proteomics and ELISA. Logistic regression with least absolute shrinkage and selection operator (aka 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 2 months of dupilumab therapy and profiled for the same mediators.

Twenty-three tissue mediators strongly predicted rapid CRSwNP recurrence (area under the curve > 0.70), including markers of type 2 (T2) inflammation (IL-4, IL-13, IL-5Rα, eosinophil cationic protein, IgE) and innate inflammation and/or myeloid involvement (CCL3/4/7/8/13, CSF2, IL-1β, IL-6, oncostatin M, 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.