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

J Allergy Clin Immunol. 2021 Apr;147(4):1269-1280. doi: 10.1016/j.jaci.2020.08.007. Epub 2020 Aug 15.

Abstract

Background: 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.

Objective: Our aim was to investigate immune mediator profiles in the lower airways of patients with N-ERD.

Methods: 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.

Results: 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).

Conclusions: 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.

Keywords: Asthma; NSAID-exacerbated respiratory disease; airway inflammation; asthma endotypes; biomarkers.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Anti-Inflammatory Agents, Non-Steroidal / adverse effects*
  • Aspirin / adverse effects
  • Asthma / immunology*
  • Biomarkers
  • Bronchoalveolar Lavage Fluid / chemistry
  • Bronchoalveolar Lavage Fluid / cytology
  • Bronchoalveolar Lavage Fluid / immunology
  • Eosinophilia / immunology*
  • Eosinophils / immunology
  • Female
  • Humans
  • Inflammation / immunology
  • Leukotriene E4 / immunology
  • Male
  • Middle Aged
  • Nasal Lavage
  • Neutrophils / immunology
  • Rhinitis / immunology*
  • Sinusitis / immunology*

Substances

  • Anti-Inflammatory Agents, Non-Steroidal
  • Biomarkers
  • Leukotriene E4
  • Aspirin