@article{cc4429f89bfd4e32934c59c1b417fe25,
title = "Urinary Leukotriene E4 and Prostaglandin D2 Metabolites Increase in Adult and Childhood Severe Asthma Characterized by Type 2 Inflammation",
abstract = "Rationale: New approaches are needed to guide personalized treatment of asthma. Objectives: To test if urinary eicosanoid metabolites can direct asthma phenotyping. Methods: Urinary metabolites of prostaglandins (PGs), cysteinyl leukotrienes (CysLTs), and isoprostanes were quantified in the U-BIOPRED (Unbiased Biomarkers for the Prediction of Respiratory Diseases Outcomes) study including 86 adults with mild-to-moderate asthma (MMA), 411 with severe asthma (SA), and 100 healthy control participants. Validation was performed internally in 302 participants with SA followed up after 12–18 months and externally in 95 adolescents with asthma. Measurement and Main Results: Metabolite concentrations in healthy control participants were unrelated to age, body mass index, and sex, except for the PGE2 pathway. Eicosanoid concentrations were generally greater in participants with MMA relative to healthy control participants, with further elevations in participants with SA. However, PGE2 metabolite concentrations were either the same or lower in male nonsmokers with asthma than in healthy control participants. Metabolite concentrations were unchanged in those with asthma who adhered to oral corticosteroid treatment as documented by urinary prednisolone detection, whereas those with SA treated with omalizumab had lower concentrations of LTE4 and the PGD2 metabolite 2,3-dinor-11b-PGF2a. High concentrations of LTE4 and PGD2 metabolites were associated with lower lung function and increased amounts of exhaled nitric oxide and eosinophil markers in blood, sputum, and urine in U-BIOPRED participants and in adolescents with asthma. These type 2 (T2) asthma associations were reproduced in the follow-up visit of the U-BIOPRED study and were 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 noninvasive approach for molecular phenotyping of adult and adolescent asthma.",
keywords = "Mass spectrometry, Severe asthma, Type 2 inflammation, U-BIOPRED, Urinary eicosanoid metabolites",
author = "Johan Kolmert and Cristina G{\'o}mez and David Balgoma and Marcus Sj{\"o}din and Johan Bood and Konradsen, {Jon R.} and Magnus Ericsson and John-Olof Th{\"o}rngren and Anna James and Maria Mikus and Sousa, {Ana R.} and Riley, {John H.} and Stewart Bates and Bakke, {Per S.} and Ioannis Pandis and Massimo Caruso and Pascal Chanez and Fowler, {Stephen J.} and Thomas Geiser and Peter Howarth and Ildik{\'o} Horv{\'a}th and Norbert Krug and Paolo Montuschi and Marek Sanak and Annelie Behndig and Shaw, {Dominick E.} and Knowles, {Richard G.} and Holweg, {C. cile T. J.} and Wheelock, {Asa M.} and Barbro Dahl{\'e}n and Bj{\"o}rn Nordlund and Kjell Alving and Gunilla Hedlin and Chung, {Kian Fan} and Adcock, {Ian M.} and Sterk, {Peter J.} and Ratko Djukanovic and Sven-Erik Dahl{\'e}n and Wheelock, {Craig E.}",
note = "Funding Information: Supported by the Innovative Medicines Initiative 2 Joint Undertaking (JU) under grant agreement No. 115010 (U-BIOPRED [Unbiased Biomarkers for the Prediction of Respiratory Diseases Outcomes]) and 831434 for Taxonomy, Targets, Treatment, and Remission. The JU receives support from the European Union{\textquoteright}s Horizon 2020 research and innovation program and the European Federation of Pharmaceutical Industries and Associates. Grants were also received from the Swedish Heart–Lung Foundation, the Swedish Research Council (2014-26826, 2014-3281, 2016-02798, 2016-0338, and 2018-02851), the Konsul Th. C. Bergh{\textquoteright}s research foundation, the Center for Allergy Research Highlights Asthma Markers of Phenotype consortium, which is funded by the Swedish Foundation for Strategic Research, the Karolinska Institutet, AstraZeneca, the Science for Life Laboratory Joint Research Collaboration, and the V{\aa}rdal Foundation. A.J. was supported by the Osher Initiative for Severe Asthma Research. C.E.W. was supported by the Swedish Heart–Lung Foundation (20180290). K.A. was supported by the Swedish Government Agency for Innovation Systems (SAMBIO program). The Swedish Search study was funded by the Freemason Child House Foundation in Stockholm, the Konsul Th. C. Bergh{\textquoteright}s Foundation, the Swedish Asthma and Allergy Association{\textquoteright}s Research Foundation, the Center for Allergy Research at Karolinska Institutet, and the Swedish Heart–Lung Foundation. B.N. was supported by Swedish Heart–Lung Foundation (20160338), the Swedish Asthma and Allergy Research Foundation (F2018-0016), and the Stockholm County Council (LS 2018-0792). J.R.K. was supported by the Stockholm County Council (K0138-2015 No. 5). Author Contributions: J.R.K., A.R.S., J.H.R., S.B., P.S.B., I.P., M.C., P.C., S.J.F., T.G., P.H., I.H., N.K., P.M., M. Sanak, A.B., D.E.S., R.G.K., B.D., B.N., K.A., G.H., K.F.C., I.M.A., P.J.S., R.D., S.-E.D., and C.E.W. designed the studies. D.B., J.R.K., J.-O.T., A.R.S., J.H.R., S.B., P.S.B., I.P., M.C., P.C., S.J.F., T.G., P.H., I.H., N.K., P.M., M. Sanak, A.B., D.E.S., R.G.K., B.D., B.N., K.A., G.H., K.F.C., I.M.A., P.J.S., R.D., and S.-E.D. executed the clinical studies. J.K., C.G., D.B., M. Sj{\"o}din, J.B., J.R.K., M.E., A.J., M.M., C.T.J.H., B.N., K.A., and G.H. acquired and analyzed the data. J.K., C.G., M. Sj{\"o}din, J.R.K., {\AA}.M.W., S.-E.D., and C.E.W. interpreted the data. J.K., C.G., J.R.K., M.M., S.J.F., A.B., D.E.S., R.G.K., P.J.S., R.D., S.-E.D., and C.E.W. wrote the manuscript draft, which was reviewed and revised by all authors. All authors attest to the accuracy of the work submitted. Publisher Copyright: {\textcopyright} 2021 American Thoracic Society. All rights reserved.",
year = "2021",
month = jan,
day = "1",
doi = "https://doi.org/10.1164/rccm.201909-1869OC",
language = "English",
volume = "203",
pages = "37--53",
journal = "American journal of respiratory and critical care medicine",
issn = "1073-449X",
publisher = "American Thoracic Society",
number = "1",
}