Identifying and Treating Neutrophilic Inflammation in Corticosteroid-Refractory United Airway Disease: A Treatable-Trait Approach.

Abstract

Neutrophilic inflammation is increasingly recognized in difficult-to-control asthma, chronic rhinosinusitis with nasal polyps (CRSwNP), and allergic rhinitis, but its clinical interpretation remains challenging. Neutrophilia may coexist with type 2 (T2) inflammation and can also arise from infection, smoking, environmental exposure, obesity, treatment effects, or transient exacerbation biology; therefore, it should not be equated automatically with a stable non-T2 endotype or corticosteroid resistance. This review focuses on how clinicians can identify and act on a clinically meaningful neutrophilic treatable trait across the united airway. Direct airway assessment, particularly induced sputum in asthma and nasal cytology or tissue assessment in upper-airway disease, provides the closest measure of local inflammatory phenotype, whereas peripheral blood and soluble biomarkers remain supportive rather than interchangeable surrogates. Reproducibility, clinical context, and exclusion of secondary causes are essential before assigning therapeutic significance to neutrophilia. No neutrophil-specific biologic is currently approved for asthma, CRSwNP, or allergic rhinitis. Macrolides provide the clearest clinically available bridge in selected patients, but treatment response is not defined by a validated neutrophil cutoff. Trials targeting CXCR1/2 or IL-17 pathways demonstrate that reducing neutrophilic inflammation does not necessarily translate into meaningful clinical benefit, whereas NET- and cGAS-STING-directed strategies remain investigational. A practical treatable-trait approach should integrate validated coexisting T2 traits, direct airway phenotyping where feasible, evidence-based or trial-based treatment selection, and longitudinal reassessment of both inflammatory phenotype and clinical outcomes.