Urinary eicosanoids in T2-low severe asthma: relationship with symptoms
and exacerbation profile
Abstract
BACKGROUND: 5-10% of patients with asthma have severe disease. Many
patients experience persistent symptoms despite being T2-low. Obesity is
associated with increased asthma symptoms. Eicosanoids have
well-described roles in the pathophysiology of asthma and may contribute
to persistent symptoms in T2-low severe asthma. OBJECTIVE: To examine
the relationship between urinary eicosanoids, asthma symptoms, obesity
and T2-biomarkers in severe asthma. METHODS: Urine samples were
collected during a randomized controlled trial assessing corticosteroid
optimization using T2-biomarker directed care at scheduled study visits
(n=728) and at exacerbation (n=103). Eicosanoid concentrations were
quantified from urine samples using mass-spectrometry. Metabolite
concentrations were log 2-transformed, z-scored and
concentrated by pathway to generate 6 pathway scores. Results were
stratified by T2-biomarker status (T2-Low: fractional-exhaled
nitric-oxide [FeNO]<20ppb AND blood eosinophil count
[BEC]<0.15x10 9cells/L) vs T2-high:
(FeNO≥20ppb AND BEC≥0.15x10 9cells/L), symptoms
(symptom-low: Asthma control Questionnaire-7 (ACQ-7)<1.5)] vs
symptom-high [ACQ-7≥1.5]), and obesity. RESULTS: The
cysteinyl-leukotriene (CysLT) pathway score was elevated in T2-high
versus T2-low participants (P=0.0007), regardless of symptom burden. The
isoprostane pathway score was higher in symptom-high versus symptom-low
participants, regardless of T2-status (P=0.01). Higher isoprostane
(P=0.02) and thromboxane (P=0.04) pathway scores were associated with
increased symptoms in T2-low participants. Corticosteroid exposure,
obesity and exacerbations were not associated with raised pathway scores
(P≥0.05). CONCLUSION: Thromboxane pathway metabolites were elevated in
symptom-high/T2-low participants whereas isoprostane pathway metabolites
were associated with increased symptoms, regardless of T2-status. These
pathways are not affected by CS exposure. Further research is needed to
define the role of eicosanoids in T2-low severe asthma using
interventions to perturb these pathways.