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Urinary eicosanoids in T2-low severe asthma: relationship with symptoms and exacerbation profile
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  • Eastwood M,
  • John Busby,
  • Johan Kolmert,
  • Javier Zurita,
  • Sven-Erik Dahlén,
  • Pamela McDowell,
  • Bradley J,
  • David Jackson,
  • Ian Pavord,
  • Ratko Djukanovic,
  • Arron JR,
  • Peter Bradding,
  • Brightling CE,
  • Rekha Chaudhuri,
  • Douglas Cowan,
  • Stephen Fowler,
  • Hardman TC,
  • Holweg CTJ,
  • Lordan J,
  • Adel Mansur H,
  • Robinson DS,
  • Craig Wheelock,
  • Liam Heaney
Eastwood M
Queen's University Belfast School of Medicine Dentistry and Biomedical Sciences
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John Busby
Queen's University Belfast School of Medicine Dentistry and Biomedical Sciences
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Johan Kolmert
Karolinska Institutet Forsakringsmedicin
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Javier Zurita
Karolinska Institutet Forsakringsmedicin
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Sven-Erik Dahlén
Karolinska Institutet Forsakringsmedicin
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Pamela McDowell
Queen's University Belfast School of Medicine Dentistry and Biomedical Sciences
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Bradley J
Queen's University Belfast School of Medicine Dentistry and Biomedical Sciences
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David Jackson
Guy's and St Thomas' NHS Foundation Trust
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Ian Pavord
University of Oxford Nuffield Department of Medicine
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Ratko Djukanovic
NIHR Southampton Biomedical Research Centre
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Arron JR
University of California San Francisco
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Peter Bradding
University of Leicester Department of Respiratory Sciences
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Brightling CE
University of Leicester Department of Respiratory Sciences
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Rekha Chaudhuri
NHS Greater Glasgow and Clyde Public Health Directorate
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Douglas Cowan
NHS Greater Glasgow and Clyde
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Stephen Fowler
The University of Manchester Division of Infection Immunity and Respiratory Medicine
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Hardman TC
Niche Generics Limited
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Holweg CTJ
AbbVie Inc Mettawa
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Lordan J
Newcastle Upon Tyne Hospitals NHS Foundation Trust
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Adel Mansur H
University Hospitals Birmingham NHS Foundation Trust
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Robinson DS
University College Hospital Women's Health Service
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Craig Wheelock
Karolinska Institutet Forsakringsmedicin
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Liam Heaney
Queen's University Belfast School of Medicine Dentistry and Biomedical Sciences

Corresponding Author:[email protected]

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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.
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22 Jun 2024Review(s) Completed, Editorial Evaluation Pending