Urinary Leukotriene E4 and Prostaglandin D2 Metabolites Increase in Adult and Childhood Severe Asthma Characterized by Type-2 Inflammation

Kolmert, Johan; G�mez, Cristina; Balgoma, David; Sj�din, Marcus; Bood, Johan; Konradsen, Jon R.; Ericsson, Magnus; Th�rngren, John-Olof; James, Anna; Mikus, Maria; Sousa, Ana R.; Riley, John H.; Bates, Stewart; Bakke, Per S.; Pandis, Ioannis; Caruso, Massimo; Chanez, Pascal; Fowler, Stephen J.; Geiser, Thomas; Howarth, Peter; Horv�th, Ildik�; Krug, Norbert; Montuschi, Paolo; Sanak, Marek; Behndig, Annelie; Shaw, Dominick E; Knowles, Richard G.; Holweg, C�cile T.J.; Wheelock, �sa M.; Dahl�n, Barbro; Nordlund, Bj�rn; Alving, Kjell; Hedlin, Gunilla; Chung, Kian Fan; Adcock, Ian M.; Sterk, Peter J.; Djukanovic, Ratko; Dahl�n, Sven-Erik; Wheelock, Craig E.; U-BIOPRED Study Group

Abstract

Rationale: New approaches are needed to guide personalized treatment of asthma.

Objective: To test if urinary eicosanoid metabolites can direct asthma phenotyping.

Methods: Urinary metabolites of prostaglandins (PG), cysteinyl-leukotrienes (LT) and isoprostanes were quantified in the Unbiased Biomarkers for the Prediction of Respiratory Diseases Outcomes (U-BIOPRED) study including 86 adults with mild-to-moderate asthma (MMA), 411 with severe asthma (SA), and 100 healthy controls (HC). Validation was performed in 302 SA subjects followed-up after 12-18 months, and externally in 95 adolescents with asthma.

Measurement and Main Results: Metabolite levels in HC were unrelated to age, BMI and sex, except for the PGE2-pathway. Eicosanoid levels were generally greater in MMA relative to HC, with further elevations in SA, except for PGE2-metabolites in males, which were the same or lower in non-smoking asthmatics as in HC. Metabolite levels were unchanged in asthmatics adherent to oral corticosteroid treatment as documented by urinary prednisolone detection, whereas SA treated with omalizumab had lower levels of LTE4 and the PGD2 metabolite 2,3-dinor-11β-PGF2α. High levels of LTE4 and PGD2-metabolites were associated with lower lung-function, and increased levels of exhaled nitric oxide and eosinophil markers in blood, sputum and urine in U-BIOPRED and in adolescents with asthma. These type-2 (T2) asthma associations were reproduced in the follow-up visit of the U-BIOPRED study, and found to be as sensitive to detect T2 inflammation as the established biomarkers.

Conclusions: Monitoring of urinary eicosanoids can identify T2 asthma and introduces a new non-invasive approach for molecular phenotyping of adult and adolescent asthma.

Citation

Kolmert, J., Gómez, C., Balgoma, D., Sjödin, M., Bood, J., Konradsen, J. R., Ericsson, M., Thörngren, J.-O., James, A., Mikus, M., Sousa, A. R., Riley, J. H., Bates, S., Bakke, P. S., Pandis, I., Caruso, M., Chanez, P., Fowler, S. J., Geiser, T., Howarth, P., …U-BIOPRED Study Group. (2021). Urinary Leukotriene E4 and Prostaglandin D2 Metabolites Increase in Adult and Childhood Severe Asthma Characterized by Type-2 Inflammation. American Journal of Respiratory and Critical Care Medicine, 203(1), 37–53. https://doi.org/10.1164/rccm.201909-1869oc

• Journal Article Type: Article
• Acceptance Date: Jun 8, 2020
• Online Publication Date: Jul 15, 2020
• Publication Date: Jan 1, 2021
• Deposit Date: Jun 29, 2020
• Publicly Available Date: Jul 16, 2021
• Journal: American Journal of Respiratory and Critical Care Medicine
• Print ISSN: 1073-449X
• Electronic ISSN: 1535-4970
• Publisher: American Thoracic Society
• Peer Reviewed: Peer Reviewed
• Volume: 203
• Issue: 1
• Pages: 37–53
• DOI: https://doi.org/10.1164/rccm.201909-1869oc
• Keywords: Critical Care and Intensive Care Medicine; Pulmonary and Respiratory Medicine
• Public URL: https://nottingham-repository.worktribe.com/output/4737555
• Publisher URL: https://www.atsjournals.org/doi/10.1164/rccm.201909-1869OC
• Additional Information: Received: 2019-09-27; Accepted: 2020-07-10; Published: 2020-07-15