Urinary thromboxane and isoprostane levels are elevated in symptom-high T2-biomarker-low severe asthma.

Abstract

Background: ∼5-10% of patients with asthma have severe disease. A proportion remain symptomatic despite suppression of T2-related inflammation but what drives persistent symptoms remains unclear. Eicosanoids exert a functional role in pulmonary inflammation. We explored the relationship between urinary eicosanoids, asthma symptoms, obesity and T2-biomarker status.

Methods: Urine was sampled during a randomised controlled trial assessing corticosteroid optimisation using T2-biomarker directed care at scheduled study visits (n=728) and at exacerbation (n=103). Urine eicosanoid concentrations were measured by mass spectrometry, then log2-transformed, z-scored and concatenated by biosynthetic pathway generating six pathway scores. Results were stratified by T2 status (T2-low: exhaled nitric oxide fraction (F _ENO) <20 ppb and blood eosinophil count (BEC) <0.15×10⁹ cells·L^-1; versus T2-high: F _ENO ≥20 ppb and BEC ≥0.15×10⁹ cells·L^-1), symptoms (symptom-low: Asthma Control Questionnaire-7 (ACQ-7) <1.5; versus symptom-high: ACQ-7 ≥1.5) and obesity.

Results: Isoprostane (pathway score p=0.02) and thromboxane (pathway score p=0.04) levels were higher in symptom-high versus symptom-low, T2-low participants. Isoprostane levels were greater in symptom-high versus symptom-low participants, irrespective of T2 status (pathway score p=0.01). Cysteinyl-leukotriene E₄ levels (LTE₄) were elevated in T2-high versus T2-low participants (pathway score p=0.0007), irrespective of symptoms. Corticosteroid exposure, obesity and exacerbations were not associated with increased eicosanoid levels (p≥0.05).

Conclusion: Raised urinary eicosanoid levels of isoprostanes and thromboxanes were associated with increased symptoms in T2-low severe asthma. Elevated excretion of these metabolites in T2-low participants could reflect increased thromboxane-receptor (TP) activation, which may be promoting increased asthma severity and bronchoconstriction. Further research and interventions are needed to explore the role of TP modulation in T2-low severe asthma.