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

Kolmert, Johan; Gómez, Cristina; Balgoma, David; Sjödin, Marcus; Bood, Johan; Konradsen, Jon R.; Ericsson, Magnus; Thörngren, 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; Horváth, Ildikó; Krug, Norbert; Montuschi, Paolo; Sanak, Marek; Behndig, Annelie; Shaw, Dominick E; Knowles, Richard G.; Holweg, Cécile T.J.; Wheelock, Åsa M.; Dahlén, Barbro; Nordlund, Björn; Alving, Kjell; Hedlin, Gunilla; Chung, Kian Fan; Adcock, Ian M.; Sterk, Peter J.; Djukanovic, Ratko; Dahlén, Sven-Erik; Wheelock, Craig E.; U-BIOPRED Study Group

Authors

Johan Kolmert

Cristina Gómez

David Balgoma

Marcus Sjödin

Johan Bood

Jon R. Konradsen

Magnus Ericsson

John-Olof Thörngren

Anna James

Maria Mikus

Ana R. Sousa

John H. Riley

Stewart Bates

Per S. Bakke

Ioannis Pandis

Massimo Caruso

Pascal Chanez

Stephen J. Fowler

Thomas Geiser

Peter Howarth

Ildikó Horváth

Norbert Krug

Paolo Montuschi

Marek Sanak

Annelie Behndig

Dominick E Shaw

Richard G. Knowles

Cécile T.J. Holweg

Åsa M. Wheelock

Barbro Dahlén

Björn Nordlund

Kjell Alving

Gunilla Hedlin

Kian Fan Chung

Ian M. Adcock

Peter J. Sterk

Ratko Djukanovic

Sven-Erik Dahlén

Craig E. Wheelock

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.

Journal Article Type Article
Publication Date Jul 15, 2020
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
APA6 Citation Kolmert, J., Gómez, C., Balgoma, D., Sjödin, M., Bood, J., Konradsen, J. R., …U-BIOPRED Study Group, . (2020). 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, https://doi.org/10.1164/rccm.201909-1869oc
DOI https://doi.org/10.1164/rccm.201909-1869oc
Keywords Critical Care and Intensive Care Medicine; Pulmonary and Respiratory Medicine
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
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