{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T01:50:35Z","timestamp":1790646635248,"version":"4.1.0"},"reference-count":48,"publisher":"Wiley","issue":"11","license":[{"start":{"date-parts":[[2025,11,6]],"date-time":"2025-11-06T00:00:00Z","timestamp":1762387200000},"content-version":"vor","delay-in-days":5,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"},{"start":{"date-parts":[[2025,11,1]],"date-time":"2025-11-01T00:00:00Z","timestamp":1761955200000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"DOI":"10.13039\/100000060","name":"National Institute of Allergy and Infectious Diseases","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100000060","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000049","name":"National Institute on Aging","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100000049","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Pediatric Allergy Immunology"],"published-print":{"date-parts":[[2025,11]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Multiple risk factors for asthma severity have been identified by epidemiological studies. Yet, the pathophysiological mechanisms driving the severity of clinical asthma manifestations remain incompletely understood. In asthmatic children, Notch4 expression on circulating Treg cells and levels of circulating GDF15 have been shown to be increased as a function of disease severity, suggesting a contribution of Treg dysfunction to disease phenotype.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>126 children with asthma (intermittent\u2009=\u200940; mild persistent\u2009=\u200943; moderate persistent\u2009=\u200929, and severe persistent\u2009=\u200914) and 83 non\u2010asthmatic controls were recruited in the Allergy clinic at Boston Children's Hospital and from asthma cohorts. Untargeted metabolomic analysis and cytokine profiling were performed in plasma and results correlated with disease severity, Notch4 expression, and presence of other atopic comorbidities.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>Children with moderate\/severe asthma had higher levels of select lipids (triglycerides, ceramides) and carboxylic acids (lactic acid, aconitic acid) and lower levels of amino acids (sarcosine and arginine) and of IFN\u03bb 2\/3 compared to children with intermittent\/mild asthma. Treg Notch4 expression and GDF15 levels, which increase with disease severity, correlated positively with lactic acid and xanthine levels and inversely with sarcosine and arginine. The concomitant presence of food allergy was associated with alterations in microbiome\u2010related metabolites and allergic rhinitis with marked triglyceride dysregulation.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>Untargeted metabolomic profiling identified both shared and unique pathways associated with known asthma severity contributors, Notch4 dysregulation and GDF15 elevation, suggesting that different mechanisms may both converge or independently contribute to determining clinical manifestations of asthma severity in asthmatic children.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1111\/pai.70242","type":"journal-article","created":{"date-parts":[[2025,11,6]],"date-time":"2025-11-06T11:43:38Z","timestamp":1762429418000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Metabolomic and immunological signatures of asthma severity in children"],"prefix":"10.1111","volume":"36","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-7718-0431","authenticated-orcid":false,"given":"Elena","family":"Crestani","sequence":"first","affiliation":[{"name":"Division of Immunology Boston Children's Hospital and Department of Pediatrics, Harvard Medical School  Boston Massachusetts USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hani","family":"Harb","sequence":"additional","affiliation":[{"name":"Division of Immunology Boston Children's Hospital and Department of Pediatrics, Harvard Medical School  Boston Massachusetts USA"},{"name":"Institute for Medical Microbiology and Virology Medical Faculty, University Hospital Dresden  Dresden Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1532-8642","authenticated-orcid":false,"given":"Mehdi","family":"Benamar","sequence":"additional","affiliation":[{"name":"Division of Immunology Boston Children's Hospital and Department of Pediatrics, Harvard Medical School  Boston Massachusetts USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rima","family":"Kaddurah\u2010Daouk","sequence":"additional","affiliation":[{"name":"Department of Psychiatry and Behavioral Sciences Duke University  Durham North Carolina USA"},{"name":"Duke Institute of Brain Sciences Duke University  Durham North Carolina USA"},{"name":"Department of Medicine Duke University  Durham North Carolina USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wanda","family":"Phipatanakul","sequence":"additional","affiliation":[{"name":"Division of Immunology Boston Children's Hospital and Department of Pediatrics, Harvard Medical School  Boston Massachusetts USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Talal A.","family":"Chatila","sequence":"additional","affiliation":[{"name":"Division of Immunology Boston Children's Hospital and Department of Pediatrics, Harvard Medical School  Boston Massachusetts USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2025,11,6]]},"reference":[{"key":"e_1_2_10_2_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2021.02.016"},{"key":"e_1_2_10_3_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(13)61536-6"},{"key":"e_1_2_10_4_1","doi-asserted-by":"publisher","DOI":"10.1183\/13993003.00731-2021"},{"issue":"1","key":"e_1_2_10_5_1","doi-asserted-by":"crossref","first-page":"1","DOI":"10.5588\/ijtld.22.1010","article-title":"The global asthma report 2022","volume":"26","year":"2022","journal-title":"Int J Tuberc Lung Dis"},{"key":"e_1_2_10_6_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jaip.2024.06.010"},{"key":"e_1_2_10_7_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.alit.2016.04.011"},{"key":"e_1_2_10_8_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jaip.2017.04.031"},{"key":"e_1_2_10_9_1","doi-asserted-by":"publisher","DOI":"10.1016\/S2213-2600(20)30399-4"},{"key":"e_1_2_10_10_1","doi-asserted-by":"publisher","DOI":"10.1111\/all.15444"},{"key":"e_1_2_10_11_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41590-020-0777-3"},{"issue":"4","key":"e_1_2_10_12_1","article-title":"Application of metabolomics in pediatric asthma: prediction, diagnosis and personalized treatment","volume":"11","author":"Papamichael MM","year":"2021","journal-title":"Meta"},{"key":"e_1_2_10_13_1","doi-asserted-by":"publisher","DOI":"10.1183\/13993003.01740-2016"},{"key":"e_1_2_10_14_1","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkab382"},{"issue":"5","key":"e_1_2_10_15_1","first-page":"327","article-title":"Allergic rhinitis and its impact on asthma update (ARIA 2008). 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