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.

Background Patients with severe asthma may present with characteristics representing overlapping phenotypes, making them eligible for more than one class of biologic. Our aim was to describe the profile of severe adult asthma patients eligible for both anti-IgE and anti-IL5/5R and to compare the effectiveness of both classes of treatment in real life. Methods This was a prospective cohort study that included adult severe asthma patients from 22 countries enrolled into the International Severe Asthma registry (ISAR) who were eligible for both anti-IgE and anti-IL5/5R. The effectiveness of anti-IgE and anti-IL5/5R was compared in a 1:1 matched cohort. Exacerbation rate was the primary effectiveness endpoint. Secondary endpoints included long-term-oral corticosteroid (LTOCS) use, asthma-related emergency room (ER) attendance and hospital admissions. Results In the matched analysis (n=350/group), the mean annualized exacerbation rate decreased by 47.1% in the anti-IL5/5R group and 38.7% in the anti-IgE group. Patients treated with anti-IL5/5R were less likely to experience a future exacerbation (adjusted IRR 0.76; 95% CI 0.64, 0.89; p<0.001) and experienced a greater reduction in mean LTOCS dose than those treated with anti-IgE (37.44% vs 20.55% reduction; p=0.023).) There was some evidence to suggest that patients treated with anti-IL5/5R experienced fewer asthma-related hospitalizations (IRR 0.64; 95% CI 0.38, 1.08), but not ER visits (IRR 0.94, 95% CI 0.61, 1.43). Conclusions In real life, both anti-IgE and anti-IL5/5R improve asthma outcomes in patients eligible for both biologic classes, however anti-IL5/5R was superior in terms of reducing asthma exacerbations and LTOCS use.