Urinary Leukotriene E<sub>4</sub>and Prostaglandin D<sub>2</sub>Metabolites Increase in Adult and Childhood Severe Asthma Characterized by Type 2 Inflammation. A Clinical Observational Study
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, H. Ahmed, C. Auffray, A. T. Bansal, E. H. Bel, J. Bigler, B. Billing, F. Baribaud, H. Bisgaard, M. J. Boedigheimer, K. Bønnelykke, J. Brandsma, P. Brinkman, E. Bucchioni, D. Burg, A. Bush, A. Chaiboonchoe, C. H. Compton, J. Corfield, D. Cunoosamy, A. D’Amico, B. De Meulder, V. J. Erpenbeck, D. Erzen, K. Fichtner, N. Fitch, L. J. Fleming, E. Formaggio, U. Frey, M. Gahlemann, V. Goss, Y. Guo, S. Hashimoto, J. Haughney, P. W. Hekking, T. Higenbottam, J. M. Hohlfeld, A. J. Knox, N. Lazarinis, D. Lefaudeux, M. J. Loza, R. Lutter, A. Manta, S. Masefield, J. G. Matthews, A. Mazein, A. Meiser, R. J. M. Middelveld, M. Miralpeix, N. Mores, C. S. Murray, J. Musial, D. Myles, L. Pahus, S. Pavlidis, A. Postle, P. Powel, G. Praticò, M. PuigValls, N. Rao, A. Roberts, G. Roberts, A. Rowe, T. Sandström, J. P. R. Schofield, W. Seibold, A. Selby, R. Sigmund, F. Singer, P. J. Skipp, M. Smicker, K. Sun, B. Thornton, M. Uddin, W. M. van Aalderen, M. van Geest, J. Vestbo, N. H. Vissing, A. H. Wagener, S. S. Wagers, Z. Weiszhart, S. J. Wilson, J. Östling, H. Ahmed, C. Auffray, A. T. Bansal, E. H. Bel, J. Bigler, B. Billing, F. Baribaud, H. Bisgaard, M. J. Boedigheimer, K. Bønnelykke, J. Brandsma, P. Brinkman, E. Bucchioni, D. Burg, A. Bush, A. Chaiboonchoe, C. H. Compton, J. Corfield, D. Cunoosamy, A. D’Amico, B. De Meulder, V. J. Erpenbeck, D. Erzen, K. Fichtner, N. Fitch, L. J. Fleming, E. Formaggio, U. Frey, M. Gahlemann, V. Goss, Y. Guo, S. Hashimoto, J. Haughney, P. W. Hekking, T. Higenbottam, J. M. Hohlfeld, A. J. Knox, N. Lazarinis, D. Lefaudeux, M. J. Loza, R. Lutter, A. Manta, S. Masefield, J. G. Matthews, A. Mazein, A. Meiser, R. J. M. Middelveld, M. Miralpeix, N. Mores, C. S. Murray, J. Musial, D. Myles, L. Pahus, S. Pavlidis, A. Postle, P. Powel, G. Praticò, M. PuigValls, N. Rao, A. Roberts, G. Roberts, A. Rowe, T. Sandström, J. P. R. Schofield, W. Seibold, A. Selby, R. Sigmund, F. Singer, P. J. Skipp, M. Smicker, K. Sun, B. Thornton, M. Uddin, W. M. van Aalderen, M. van Geest, J. Vestbo, N. H. Vissing, A. H. Wagener, S. S. Wagers, Z. Weiszhart, S. J. Wilson, J. Östling
Journal: American Journal of Respiratory and Critical Care Medicine (2020)

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-11β-PGF2α. 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.Clinical trial registered with www.clinicaltrials.gov (NCT 01976767).