{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T03:16:49Z","timestamp":1790738209807,"version":"4.1.0"},"reference-count":47,"publisher":"MDPI AG","issue":"4","license":[{"start":{"date-parts":[[2025,4,3]],"date-time":"2025-04-03T00:00:00Z","timestamp":1743638400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Lung Foundation","award":["6.1.18.244JO"],"award-info":[{"award-number":["6.1.18.244JO"]}]},{"name":"Lung Foundation","award":["20220809"],"award-info":[{"award-number":["20220809"]}]},{"name":"C.J. Vaillant Stichting","award":["6.1.18.244JO"],"award-info":[{"award-number":["6.1.18.244JO"]}]},{"name":"C.J. Vaillant Stichting","award":["20220809"],"award-info":[{"award-number":["20220809"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Metabolites"],"abstract":"<jats:p>Background: Severe acute asthma (SAA) in children can be life-threatening. There has been a significant rise in paediatric intensive care unit (PICU) admissions due to SAA over the past two decades. While asthma is a heterogeneous disease, its underlying pathophysiological pathways remain underexplored. This study aimed to assess the value of non-invasive targeted exhaled breath metabolomics analysis to better characterise SAA. Methods: Breath samples from 17 children admitted to the PICU with SAA (cases) and 27 children with controlled severe asthma (controls) were analysed using thermal desorption gas chromatography\u2013mass spectrometry (TD-GC-MS). Results: A targeted volatile organic compound (VOC) analysis identified 25 compounds, of which 16 were shared between groups. Four VOCs were significantly more often present in SAA, and nine VOCs exhibited higher concentrations in SAA. Longitudinal analysis of VOCs from follow-up samples of 10 cases showed no significant temporal differences, reinforcing the reproducibility of identified biomarkers. Conclusions: This study exemplifies the potential of exhaled breath analysis to provide insights into the molecular background of SAA. Breath metabolomics may enable early recognition of severe asthma attacks and preventive therapeutic interventions in children with severe asthma.<\/jats:p>","DOI":"10.3390\/metabo15040247","type":"journal-article","created":{"date-parts":[[2025,4,4]],"date-time":"2025-04-04T06:52:56Z","timestamp":1743749576000},"page":"247","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Uncovering Non-Invasive Biomarkers in Paediatric Severe Acute Asthma Using Targeted Exhaled Breath Analysis"],"prefix":"10.3390","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7334-1549","authenticated-orcid":false,"given":"Sarah","family":"van den Berg","sequence":"first","affiliation":[{"name":"Paediatric Intensive Care Unit, Emma Children\u2019s Hospital, Amsterdam University Medical Centre, Location AMC, 1105 AZ Amsterdam, The Netherlands"},{"name":"Department of Pulmonary Medicine, Amsterdam University Medical Centre, Location AMC, 1105 AZ Amsterdam, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Annabel S.","family":"Zaat","sequence":"additional","affiliation":[{"name":"Faculty of Medicine, University of Amsterdam, 1105 AZ Amsterdam, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Isabel F.","family":"van der Poel","sequence":"additional","affiliation":[{"name":"Faculty of Medicine, University of Amsterdam, 1105 AZ Amsterdam, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0004-2381-9403","authenticated-orcid":false,"given":"Yoni E.","family":"van Dijk","sequence":"additional","affiliation":[{"name":"Department of Pulmonary Medicine, Amsterdam University Medical Centre, Location AMC, 1105 AZ Amsterdam, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Simone","family":"Hashimoto","sequence":"additional","affiliation":[{"name":"Department of Pulmonary Medicine, Amsterdam University Medical Centre, Location AMC, 1105 AZ Amsterdam, The Netherlands"},{"name":"Department of Paediatric Pulmonology, Emma Children\u2019s Hospital, Amsterdam University Medical Centre, Location AMC, 1105 AZ Amsterdam, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Niels W. P.","family":"Rutjes","sequence":"additional","affiliation":[{"name":"Department of Paediatric Pulmonology, Emma Children\u2019s Hospital, Amsterdam University Medical Centre, Location AMC, 1105 AZ Amsterdam, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3305-3745","authenticated-orcid":false,"given":"Suzanne W. J.","family":"Terheggen-Largo","sequence":"additional","affiliation":[{"name":"Department of Paediatric Pulmonology, Emma Children\u2019s Hospital, Amsterdam University Medical Centre, Location AMC, 1105 AZ Amsterdam, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bart E.","family":"van Ewijk","sequence":"additional","affiliation":[{"name":"Department of Paediatric Medicine, Tergooi Medical Centre, 1201 DA Hilversum, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Claudia","family":"Gagliani","sequence":"additional","affiliation":[{"name":"PROMISE Department, Division of Respiratory Medicine, University of Palermo, 90127 Palermo, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fleur L.","family":"Sondaal","sequence":"additional","affiliation":[{"name":"Faculty of Medicine, University of Amsterdam, 1105 AZ Amsterdam, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2241-7806","authenticated-orcid":false,"given":"Job B. M.","family":"van Woensel","sequence":"additional","affiliation":[{"name":"Paediatric Intensive Care Unit, Emma Children\u2019s Hospital, Amsterdam University Medical Centre, Location AMC, 1105 AZ Amsterdam, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0414-3442","authenticated-orcid":false,"given":"Anke-Hilse","family":"Maitland-van der Zee","sequence":"additional","affiliation":[{"name":"Department of Pulmonary Medicine, Amsterdam University Medical Centre, Location AMC, 1105 AZ Amsterdam, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paul","family":"Brinkman","sequence":"additional","affiliation":[{"name":"Department of Pulmonary Medicine, Amsterdam University Medical Centre, Location AMC, 1105 AZ Amsterdam, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Susanne J. H.","family":"Vijverberg","sequence":"additional","affiliation":[{"name":"Department of Pulmonary Medicine, Amsterdam University Medical Centre, Location AMC, 1105 AZ Amsterdam, The Netherlands"},{"name":"Department of Paediatric Pulmonology, Emma Children\u2019s Hospital, Amsterdam University Medical Centre, Location AMC, 1105 AZ Amsterdam, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1450-451X","authenticated-orcid":false,"given":"Berber","family":"Kapitein","sequence":"additional","affiliation":[{"name":"Paediatric Intensive Care Unit, Emma Children\u2019s Hospital, Amsterdam University Medical Centre, Location AMC, 1105 AZ Amsterdam, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,4,3]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Zhou, W., and Tang, J. (2025). Prevalence and risk factors for childhood asthma: A systematic review and meta-analysis. BMC Pediatr., 25.","DOI":"10.1186\/s12887-025-05409-x"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"857","DOI":"10.1002\/ppul.24009","article-title":"Children with severe acute asthma admitted to Dutch PICUs: A changing landscape","volume":"53","author":"Boeschoten","year":"2018","journal-title":"Pediatr. Pulmonol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"e904","DOI":"10.1542\/peds.2009-3239","article-title":"Trends in admissions for pediatric status asthmaticus in New Jersey over a 15-year period","volume":"126","author":"Hartman","year":"2010","journal-title":"Pediatrics"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"243","DOI":"10.4103\/1817-1737.165302","article-title":"Asthma changes at a pediatric intensive care unit after 10 years: Observational study","volume":"10","author":"Temsah","year":"2015","journal-title":"Ann. Thorac. Med."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"192","DOI":"10.1111\/joim.12382","article-title":"Asthma phenotyping: A necessity for improved therapeutic precision and new targeted therapies","volume":"279","author":"Chung","year":"2016","journal-title":"J. Intern. Med."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"e58","DOI":"10.1097\/PCC.0000000000001390","article-title":"Psychological and Psychiatric Outcomes Following PICU Admission: A Systematic Review of Cohort Studies","volume":"19","author":"Rosa","year":"2018","journal-title":"Pediatr. Crit. Care Med."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1270","DOI":"10.1016\/j.jaci.2021.04.027","article-title":"Pediatric asthma incidence rates in the United States from 1980 to 2017","volume":"148","author":"Johnson","year":"2021","journal-title":"J. Allergy Clin. Immunol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"219","DOI":"10.1007\/s12016-018-8712-1","article-title":"Understanding Asthma Phenotypes, Endotypes, and Mechanisms of Disease","volume":"56","author":"Kuruvilla","year":"2019","journal-title":"Clin. Rev. Allergy Immunol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"50","DOI":"10.1186\/s13223-018-0279-0","article-title":"Asthma","volume":"14","author":"Quirt","year":"2018","journal-title":"Allergy Asthma Clin. Immunol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"25","DOI":"10.1080\/17476348.2021.1997597","article-title":"Severe acute asthma at the pediatric intensive care unit: Can we link the clinical phenotypes to immunological endotypes?","volume":"16","author":"Hashimoto","year":"2022","journal-title":"Expert. Rev. Respir. Med."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"444","DOI":"10.1164\/rccm.201811-2210OC","article-title":"Exhaled Volatile Organic Compounds Are Able to Discriminate between Neutrophilic and Eosinophilic Asthma","volume":"200","author":"Schleich","year":"2019","journal-title":"Am. J. Respir. Crit. Care Med."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"545","DOI":"10.1016\/j.jaip.2017.05.032","article-title":"Baseline Features of the Severe Asthma Research Program (SARP III) Cohort: Differences with Age","volume":"6","author":"Teague","year":"2018","journal-title":"J. Allergy Clin. Immunol. Pract."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"224","DOI":"10.1378\/chest.14-0781","article-title":"Breathomics in lung disease","volume":"147","author":"Paff","year":"2015","journal-title":"Chest"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"1616","DOI":"10.1002\/ppul.23785","article-title":"Breathomics from exhaled volatile organic compounds in pediatric asthma","volume":"52","author":"Neerincx","year":"2017","journal-title":"Pediatr. Pulmonol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"117","DOI":"10.1186\/1465-9921-13-117","article-title":"Clinical use of exhaled volatile organic compounds in pulmonary diseases: A systematic review","volume":"13","author":"Jobsis","year":"2012","journal-title":"Respir. Res."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"175","DOI":"10.1111\/all.12793","article-title":"Volatile organic compounds in asthma diagnosis: A systematic review and meta-analysis","volume":"71","author":"Rufo","year":"2016","journal-title":"Allergy"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"016016","DOI":"10.1088\/1752-7163\/aa5a8b","article-title":"Can exhaled volatile organic compounds predict asthma exacerbations in children?","volume":"11","author":"Smolinska","year":"2017","journal-title":"J. Breath. Res."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"98","DOI":"10.1183\/09031936.00010712","article-title":"Exhaled volatile organic compounds predict exacerbations of childhood asthma in a 1-year prospective study","volume":"42","author":"Robroeks","year":"2013","journal-title":"Eur. Respir. J."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"1091","DOI":"10.1164\/rccm.202312-2270OC","article-title":"Exhaled Volatile Organic Compounds for Asthma Control Classification in Children with Moderate to Severe Asthma: Results from the SysPharmPediA Study","volume":"210","author":"Neerincx","year":"2024","journal-title":"Am. J. Respir. Crit. Care Med."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"e28","DOI":"10.1016\/j.jcf.2021.04.015","article-title":"Targeted exhaled breath analysis for detection of Pseudomonas aeruginosa in cystic fibrosis patients","volume":"21","author":"Kos","year":"2022","journal-title":"J. Cyst. Fibros."},{"key":"ref_21","doi-asserted-by":"crossref","unstructured":"Mager, D.J., van Dijk, Y.E., Varan, \u00d6., Vijverberg, S.J.H., Terheggen-Lagro, S.W.J., Maitland-van der Zee, A.-H., Janssens, H.M., and Brinkman, P. (2024). Characterization of the SPIRITAS: A Disposable Sampling Setup for Volatile Organic Compound Collection and Analysis. Separations, 11.","DOI":"10.3390\/separations11050150"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"2875","DOI":"10.1002\/ppul.27145","article-title":"Factors influencing the initiation of biologic therapy in children with severe asthma: Results of the pediatric asthma noninvasive diagnostic approaches (PANDA) study","volume":"59","author":"Brandsen","year":"2024","journal-title":"Pediatr. Pulmonol."},{"key":"ref_23","first-page":"98","article-title":"Systematic review: Insufficient validation of clinical scores for the assessment of acute dyspnoea in wheezing children","volume":"15","author":"Bekhof","year":"2014","journal-title":"Paediatr. Respir. Rev."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"S19","DOI":"10.1016\/j.jaip.2021.10.032","article-title":"2020 NAEPP Guidelines Update and GINA 2021-Asthma Care Differences, Overlap, and Challenges","volume":"10","author":"Chipps","year":"2022","journal-title":"J Allergy Clin Immunol Pract"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"00965-2016","DOI":"10.1183\/13993003.00965-2016","article-title":"A European Respiratory Society technical standard: Exhaled biomarkers in lung disease","volume":"49","author":"Horvath","year":"2017","journal-title":"Eur. Respir. J."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"047110","DOI":"10.1088\/1752-7155\/9\/4\/047110","article-title":"Comparison of sampling bags for the analysis of volatile organic compounds in breath","volume":"9","author":"Ghimenti","year":"2015","journal-title":"J. Breath. Res."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"046008","DOI":"10.1088\/1752-7155\/10\/4\/046008","article-title":"Storage stability of exhaled breath on Tenax TA","volume":"10","author":"Harshman","year":"2016","journal-title":"J. Breath. Res."},{"key":"ref_28","unstructured":"(2025, March 25). Albuterol. Available online: https:\/\/go.drugbank.com\/drugs\/DB01001."},{"key":"ref_29","first-page":"20150202","article-title":"Principal component analysis: A review and recent developments","volume":"374","author":"Jolliffe","year":"2016","journal-title":"Philos. Trans. A Math. Phys. Eng. Sci."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"1159","DOI":"10.1111\/cea.12965","article-title":"Exhaled breath profiles in the monitoring of loss of control and clinical recovery in asthma","volume":"47","author":"Brinkman","year":"2017","journal-title":"Clin. Exp. Allergy"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"348","DOI":"10.1038\/sj.jea.7500287","article-title":"Respiratory symptoms and peak expiratory flow in children with asthma in relation to volatile organic compounds in exhaled breath and ambient air","volume":"13","author":"Delfino","year":"2003","journal-title":"J. Expo. Anal. Environ. Epidemiol."},{"key":"ref_32","first-page":"00143","article-title":"Exhaled volatile organic compounds associated with risk factors for obstructive pulmonary diseases: A systematic review","volume":"9","author":"Vijverberg","year":"2023","journal-title":"ERJ Open Res."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"395","DOI":"10.1164\/rccm.200206-507OC","article-title":"Aldehydes and glutathione in exhaled breath condensate of children with asthma exacerbation","volume":"167","author":"Corradi","year":"2003","journal-title":"Am. J. Respir. Crit. Care Med."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"146","DOI":"10.1016\/j.jaci.2008.10.047","article-title":"Airway glutathione homeostasis is altered in children with severe asthma: Evidence for oxidant stress","volume":"123","author":"Fitzpatrick","year":"2009","journal-title":"J. Allergy Clin. Immunol."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"00427-2022","DOI":"10.1183\/23120541.00427-2022","article-title":"Validation of volatile metabolites of pulmonary oxidative injury: A bench to bedside study","volume":"9","author":"Fenn","year":"2023","journal-title":"ERJ Open Res."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"14","DOI":"10.1186\/s40635-024-00600-3","article-title":"HS-GC-MS analysis of volatile organic compounds after hyperoxia-induced oxidative stress: A validation study","volume":"12","author":"Lilien","year":"2024","journal-title":"Intensive Care Med. Exp."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"403","DOI":"10.1111\/ina.12086","article-title":"Levels and sources of volatile organic compounds in homes of children with asthma","volume":"24","author":"Chin","year":"2014","journal-title":"Indoor Air"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"1277","DOI":"10.1111\/all.13740","article-title":"Exposure to indoor endocrine-disrupting chemicals and childhood asthma and obesity","volume":"74","author":"Paciencia","year":"2019","journal-title":"Allergy"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"527","DOI":"10.1289\/ehp.02110s4527","article-title":"Assessing exposure to air toxics relative to asthma","volume":"110","author":"Weisel","year":"2002","journal-title":"Environ. Health Perspect."},{"key":"ref_40","doi-asserted-by":"crossref","unstructured":"Cordiano, R., Papa, V., Cicero, N., Spatari, G., Allegra, A., and Gangemi, S. (2022). Effects of Benzene: Hematological and Hypersensitivity Manifestations in Resident Living in Oil Refinery Areas. Toxics, 10.","DOI":"10.3390\/toxics10110678"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"112344","DOI":"10.1016\/j.ecoenv.2021.112344","article-title":"Air pollution-related asthma profiles among children\/adolescents: A multi-group latent class analysis","volume":"219","author":"Shakerkhatibi","year":"2021","journal-title":"Ecotoxicol. Environ. Saf."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"286","DOI":"10.1016\/j.envpol.2019.02.034","article-title":"Hebei Spirit oil spill and its long-term effect on children\u2019s asthma symptoms","volume":"248","author":"Noh","year":"2019","journal-title":"Environ. Pollut."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"632","DOI":"10.1016\/j.jaci.2008.09.052","article-title":"Increased asthma and respiratory symptoms in children exposed to petrochemical pollution","volume":"123","author":"Wichmann","year":"2009","journal-title":"J. Allergy Clin. Immunol."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"00126-2020","DOI":"10.1183\/23120541.00126-2020","article-title":"Risk factors for intensive care admission in children with severe acute asthma in the Netherlands: A prospective multicentre study","volume":"6","author":"Boeschoten","year":"2020","journal-title":"ERJ Open Res."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"139010","DOI":"10.1016\/j.scitotenv.2020.139010","article-title":"Association of ambient non-methane hydrocarbons exposure with respiratory hospitalizations: A time series study in Taipei, Taiwan","volume":"729","author":"Qiu","year":"2020","journal-title":"Sci. Total Environ."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"01068-2019","DOI":"10.1183\/13993003.01068-2019","article-title":"Circadian rhythm of exhaled biomarkers in health and asthma","volume":"54","author":"Wilkinson","year":"2019","journal-title":"Eur. Respir. J."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"026011","DOI":"10.1088\/1752-7155\/10\/2\/026011","article-title":"How long may a breath sample be stored for at -80 degrees C? A study of the stability of volatile organic compounds trapped onto a mixed Tenax: Carbograph trap adsorbent bed from exhaled breath","volume":"10","author":"Kang","year":"2016","journal-title":"J. Breath. Res."}],"container-title":["Metabolites"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2218-1989\/15\/4\/247\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,9]],"date-time":"2025-10-09T17:09:44Z","timestamp":1760029784000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2218-1989\/15\/4\/247"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,4,3]]},"references-count":47,"journal-issue":{"issue":"4","published-online":{"date-parts":[[2025,4]]}},"alternative-id":["metabo15040247"],"URL":"https:\/\/doi.org\/10.3390\/metabo15040247","relation":{},"ISSN":["2218-1989"],"issn-type":[{"value":"2218-1989","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,4,3]]}}}