Heterogeneity of lower airway inflammation in patients with NSAID-exacerbated respiratory disease

Abstract

Nonsteroidal anti-inflammatory drug (NSAID)-exacerbated respiratory disease (N-ERD) asthma is characterized by chronic rhinosinusitis and intolerance of aspirin and other COX1 inhibitors. Clinical data point to a heterogeneity within the N-ERD phenotype. Our aim was to investigate immune mediator profiles in the lower airways of patients with N-ERD. Levels of cytokines (determined by using Luminex assay) and eicosanoids (determined by using mass spectrometry) were measured in bronchoalveolar lavage fluid (BALF) from patients with N-ERD (n= 22), patients with NSAID-tolerant asthma (n= 21), and control subjects (n= 11). mRNA expression in BALF cells was quantified by using TaqMan low-density arrays. Lower airway eosinophilia was more frequent in N-ERD (54.5%) than in NSAID-tolerant asthma (9.5% [P= .009]). The type-2 (T2) immune signature of BALF cells was more pronounced in the eosinophilic subphenotype of N-ERD. Similarly, BALF concentrations of periostin and CCL26 were significantly increased in eosinophilic N-ERD and correlated with T2 signature in BALF cells. Multiparameter analysis of BALF mediators of all patients with asthma revealed the presence of 2 immune endotypes: T2-like (with an elevated level of periostin in BALF) and non-T2/proinflammatory (with higher levels of matrix metalloproteinases and inflammatory cytokines). Patients with N-ERD were classified mostly as having the T2 endotype (68%). Changes in eicosanoid profile (eg, increased leukotriene E4 level) were limited to patients with N-ERD with airway eosinophilia. Blood eosinophilia appeared to be a useful predictor of airway T2 signature (area under the curve [AUC]= 0.83); however, surrogate biomarkers had moderate performance in distinguishing eosinophilic N-ERD (for blood eosinophils, AUC= 0.72; for periostin, AUC= 0.75). Lower airway immune profiles show considerable heterogeneity of N-ERD, with skewing toward T2 response and eosinophilic inflammation. Increased production of leukotriene E4 was restricted to a subgroup of patients with eosinophilia in the lower airway.