{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,14]],"date-time":"2026-10-14T04:35:03Z","timestamp":1791952503408,"version":"4.3.4"},"reference-count":35,"publisher":"Wiley","issue":"5","license":[{"start":{"date-parts":[[2024,2,14]],"date-time":"2024-02-14T00:00:00Z","timestamp":1707868800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Pediatric Pulmonology"],"published-print":{"date-parts":[[2024,5]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:title>Background<\/jats:title><jats:p>While the widespread initiation of elexacaftor\/tezacaftor\/ivacaftor (ETI) has led to dramatic clinical improvements among persons with cystic fibrosis (pwCF), little is known about how ETI affects the respiratory mucosal inflammatory and physiochemical environment, or how these changes relate to lung function.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>We performed a prospective, longitudinal study of adults with CF and chronic rhinosinusitis (CF\u2010CRS) followed at our CF center (<jats:italic>n<\/jats:italic>\u2009=\u200918). Endoscopic upper respiratory tract (paranasal sinus) aspirates from multiple visit dates, both pre\u2010 and post\u2010ETI initiation, were collected and tested for cytokines, metals, pH, and lactate levels. Generalized estimating equations were used to identify relationships between ETI and upper respiratory tract (URT) biomarker levels, and between URT biomarkers and lung function or clinical sinus parameters.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>ETI was associated with decreased upper respiratory mucosal cytokines B\u2010cell activating factor (BAFF), IL\u201012p40, IL\u201032, IL\u20108, IL\u201022 and soluble tumor necrosis factor\u20101 (sTNFR1), and an increase in a proliferation\u2010inducing ligand (APRIL) and IL\u201019. ETI was also associated with decreased URT levels of copper, manganese, and zinc. In turn, lower URT levels of BAFF, IL\u20108, lactate, and potassium were each associated with ~1.5% to 4.3% improved forced expiratory volume in 1\u2009s (FEV<jats:sub>1<\/jats:sub>), while higher levels of IFN\u03b3, iron, and selenium were associated with ~2% to 10% higher FEV<jats:sub>1<\/jats:sub>.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>Our observations suggest a dampening of inflammatory signals and restriction in microbial nutrients in the upper respiratory tract with ETI. These findings improve our understanding of how ETI impacts the mucosal environment in the respiratory tract, and may give insight into the improved infectious and inflammatory status and the resulting clinical improvements seen in pwCF.<\/jats:p><\/jats:sec>","DOI":"10.1002\/ppul.26898","type":"journal-article","created":{"date-parts":[[2024,2,14]],"date-time":"2024-02-14T10:58:32Z","timestamp":1707908312000},"page":"1266-1273","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":19,"title":["Effects of highly effective modulator therapy on the dynamics of the respiratory mucosal environment and inflammatory response in cystic fibrosis"],"prefix":"10.1002","volume":"59","author":[{"ORCID":"https:\/\/orcid.org\/0009-0006-0481-0539","authenticated-orcid":false,"given":"Samar E.","family":"Atteih","sequence":"first","affiliation":[{"name":"Division of Pediatric Pulmonology, Department of Pediatrics University of Pittsburgh Medical Center, Children's Hospital of Pittsburgh Pittsburgh Pennsylvania USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Catherine R.","family":"Armbruster","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Immunology Geisel School of Medicine at Dartmouth Hanover New Hampshire USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yasmin","family":"Hilliam","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Immunology Geisel School of Medicine at Dartmouth Hanover New Hampshire USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Glenn J.","family":"Rapsinski","sequence":"additional","affiliation":[{"name":"Division of Pediatric Infectious Diseases, Department of Pediatrics University of Pittsburgh Medical Center, Children's Hospital of Pittsburgh Pittsburgh Pennsylvania USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Junu Koirala","family":"Bhusal","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Molecular Genetics, School of Medicine University of Pittsburgh Pittsburgh Pennsylvania USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Leah L.","family":"Krainz","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Molecular Genetics, School of Medicine University of Pittsburgh Pittsburgh Pennsylvania USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jordan R.","family":"Gaston","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Molecular Genetics, School of Medicine University of Pittsburgh Pittsburgh Pennsylvania USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matthew","family":"DuPont","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Molecular Genetics, School of Medicine University of Pittsburgh Pittsburgh Pennsylvania USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anna C.","family":"Zemke","sequence":"additional","affiliation":[{"name":"Division of Pulmonary, Allergy, and Critical Care Medicine, Department of Medicine, School of Medicine University of Pittsburgh Pittsburgh Pennsylvania USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John F.","family":"Alcorn","sequence":"additional","affiliation":[{"name":"Department of Pediatrics University of Pittsburgh Medical Center, Children's Hospital of Pittsburgh Pittsburgh Pennsylvania USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John A.","family":"Moore","sequence":"additional","affiliation":[{"name":"Department of Otolaryngology\u2014Head and Neck Surgery University of Pittsburgh Pittsburgh Pennsylvania USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vaughn S.","family":"Cooper","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Molecular Genetics, School of Medicine University of Pittsburgh Pittsburgh Pennsylvania USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stella E.","family":"Lee","sequence":"additional","affiliation":[{"name":"Division of Otolaryngology, Head and Neck Surgery, Department of Surgery, Brigham and Women's Hospital Harvard Medical School Boston Massachusetts USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6497-9885","authenticated-orcid":false,"given":"Erick","family":"Forno","sequence":"additional","affiliation":[{"name":"Division of Pediatric Pulmonology, Department of Pediatrics University of Pittsburgh Medical Center, Children's Hospital of Pittsburgh Pittsburgh Pennsylvania USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jennifer M.","family":"Bomberger","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Immunology Geisel School of Medicine at Dartmouth Hanover New Hampshire USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2024,2,14]]},"reference":[{"issue":"9","key":"e_1_2_9_2_1","article-title":"Newly discovered cutting\u2010edge triple combination cystic fibrosis therapy: a systematic review","volume":"14","author":"Dawood SN","year":"2022","journal-title":"Cureus"},{"key":"e_1_2_9_3_1","doi-asserted-by":"publisher","DOI":"10.1164\/rccm.202108-1986OC"},{"key":"e_1_2_9_4_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jcf.2022.03.002"},{"key":"e_1_2_9_5_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jcf.2015.03.003"},{"key":"e_1_2_9_6_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jcf.2006.12.001"},{"key":"e_1_2_9_7_1","doi-asserted-by":"publisher","DOI":"10.1186\/s12931-021-01722-y"},{"key":"e_1_2_9_8_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jcf.2019.10.015"},{"issue":"2","key":"e_1_2_9_9_1","first-page":"32","article-title":"Chronic rhinosinusitis in cystic fibrosis: diagnosis and medical management","volume":"7","author":"Safi C","year":"2019","journal-title":"Med Sci"},{"key":"e_1_2_9_10_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jcf.2004.06.006"},{"key":"e_1_2_9_11_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.otc.2022.09.009"},{"key":"e_1_2_9_12_1","doi-asserted-by":"publisher","DOI":"10.1002\/lary.27454"},{"key":"e_1_2_9_13_1","doi-asserted-by":"publisher","DOI":"10.1002\/alr.22332"},{"key":"e_1_2_9_14_1","doi-asserted-by":"publisher","DOI":"10.1177\/0194599815572097"},{"key":"e_1_2_9_15_1","doi-asserted-by":"publisher","DOI":"10.1136\/thorax-2022-219943"},{"key":"e_1_2_9_16_1","doi-asserted-by":"publisher","DOI":"10.1016\/S2213-2600(21)00103-X"},{"key":"e_1_2_9_17_1","doi-asserted-by":"publisher","DOI":"10.1002\/JLB.3MR0620-550R"},{"key":"e_1_2_9_18_1","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.169.5.2653"},{"key":"e_1_2_9_19_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0095892"},{"key":"e_1_2_9_20_1","doi-asserted-by":"publisher","DOI":"10.4193\/Rhin13.154"},{"key":"e_1_2_9_21_1","doi-asserted-by":"publisher","DOI":"10.1084\/jem.188.6.1185"},{"key":"e_1_2_9_22_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jaci.2008.04.016"},{"key":"e_1_2_9_23_1","doi-asserted-by":"publisher","DOI":"10.1128\/spectrum.01251-22"},{"key":"e_1_2_9_24_1","doi-asserted-by":"publisher","DOI":"10.3389\/fped.2021.640184"},{"key":"e_1_2_9_25_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00109-016-1391-6"},{"key":"e_1_2_9_26_1","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.2100424"},{"key":"e_1_2_9_27_1","doi-asserted-by":"publisher","DOI":"10.1126\/scitranslmed.aav3488"},{"key":"e_1_2_9_28_1","doi-asserted-by":"publisher","DOI":"10.3109\/00016489109137364"},{"key":"e_1_2_9_29_1","doi-asserted-by":"publisher","DOI":"10.1378\/chest.09-1047"},{"key":"e_1_2_9_30_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.2221542120"},{"key":"e_1_2_9_31_1","doi-asserted-by":"publisher","DOI":"10.1038\/ncomms11951"},{"key":"e_1_2_9_32_1","doi-asserted-by":"publisher","DOI":"10.3345\/kjp.2010.53.8.795"},{"key":"e_1_2_9_33_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jcf.2010.09.004"},{"key":"e_1_2_9_34_1","article-title":"Pseudomonas aeruginosa senses and responds to epithelial potassium flux via Kdp operon to promote biofilm biogenesis [Internet]","author":"Rapsinski GJ","year":"2023","journal-title":"bioRxiv"},{"key":"e_1_2_9_35_1","doi-asserted-by":"publisher","DOI":"10.1172\/JCI167957"},{"key":"e_1_2_9_36_1","doi-asserted-by":"publisher","DOI":"10.1034\/j.1600-0463.2000.d01-64.x"}],"container-title":["Pediatric Pulmonology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/ppul.26898","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,2,11]],"date-time":"2025-02-11T10:26:52Z","timestamp":1739269612000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1002\/ppul.26898"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,2,14]]},"references-count":35,"journal-issue":{"issue":"5","published-print":{"date-parts":[[2024,5]]}},"alternative-id":["10.1002\/ppul.26898"],"URL":"https:\/\/doi.org\/10.1002\/ppul.26898","archive":["Portico"],"relation":{},"ISSN":["8755-6863","1099-0496"],"issn-type":[{"value":"8755-6863","type":"print"},{"value":"1099-0496","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,2,14]]},"assertion":[{"value":"2023-08-29","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2024-01-27","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2024-02-14","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}