Metabolomic endophenotypes based on oxo-eicosatetraenoic acids in patients with aspirin-exacerbated respiratory disease.

Abstract

Arachidonic acid metabolism in patients with aspirin-exacerbated respiratory disease (AERD) is characterized by an imbalance between proinflammatory and anti-inflammatory eicosanoids. In this study, we focused on end metabolites of the 15-LOX-1 and 5-LOX pathways. We sought to identify possible metabolomic clusters based on plasma and urinary levels of 15-oxo-eicosatetraenoic acid (15-oxo-ETE) and 5-oxo-eicosatetraenoic acid in combination with other lipoxygenase arachidonic acid metabolites and variables. Hierarchical cluster analysis was performed in 78 patients with AERD and 63 patients with aspirin-tolerant asthma (ATA), both with 23 variables. These variables included demographic, clinical, biochemical, and treatment data; sinus computed tomography findings; and plasma and urinary levels of selected eicosanoids measured by high-performance liquid chromatography and tandem mass spectrometry. Two clusters (endophenotypes) were distinguished in each study group. The Lund-Mackay score on paranasal sinus computed tomography and urinary leukotriene E₄ levels were significantly higher, whereas urinary 15-oxo-ETE levels were significantly lower, in AERD clusters compared with ATA clusters. Patients in cluster 1_AERD (vs cluster 2_AERD) and cluster 1_ATA (vs cluster 2_ATA) were older and had higher body mass index, more severe asthma, and worse asthma control, as well as higher levels of plasma 15-hydroxyeicosatetraenoic acid, 15-oxo-ETE, and 5-hydroxyeicosatetraenoic acid. Patients with AERD had more advanced changes in the sinuses and higher urinary levels of 15-oxo-ETE and leukotriene E₄ than patients with ATA. Higher plasma and lower urinary levels of 15-oxo-ETE are associated with more severe asthma and worse asthma control in patients with AERD with older age and higher body mass index.