Inflammatory Heterogeneity in Aspirin Exacerbated Respiratory Disease.

ABSTRACT Background Aspirin-exacerbated respiratory disease (AERD) is a mechanistically distinct subtype of chronic rhinosinusitis with nasal polyps (CRSwNP). Though frequently associated with type 2 inflammation, literature characterizing the milieu of inflammatory cytokines and lipid mediators in AERD has been conflicting. Objective To identify differences in the upper airway inflammatory signature between CRSwNP and AERD and determine whether endotypic subtypes of AERD may exist. Methods Levels of 7 cytokines representative of type 1, type 2, and type 3 inflammation, and 21 lipid mediators were measured in nasal mucus from 109 patients with CRSwNP, 30 patients with AERD, and 64 non-CRS controls. Differences in inflammatory mediators were identified between groups and patterns of inflammation among AERD patients were determined by hierarchical cluster analysis. Results AERD could be distinguished from CRSwNP by profound elevations in IL-5, IL-6, IL-13, and IFN-γ, however, significant heterogeneity existed between patients. Hierarchical cluster analysis identified three inflammatory sub-endotypes of AERD characterized by 1) low inflammatory burden, 2) high type 2 cytokines, and 3) comparatively low type 2 cytokines and high levels of type 1 and type 3 cytokines. Several lipid mediators were associated with asthma and sinonasal disease severity, however, lipid mediators showed less variability than cytokines. Conclusion AERD is associated with elevations in type 2 cytokines (IL-5, and IL-13) and the type 1 cytokine, IFN-γ. Among patients with AERD, the inflammatory signature is heterogeneous, supporting sub-endotypes of the disease. Variability in AERD immune signatures should be further clarified as this may predict clinical response to biologic medications that target type 2 inflammation.