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The pathophysiological mechanisms underlying an increased frequency of pulmonary exacerbations have not been explored.<\/jats:p><\/jats:sec><jats:sec><jats:title>Objectives<\/jats:title><jats:p>To compare host immune response during intravenous antibiotic treatment of pulmonary exacerbations in people with CF who have a history of frequent<jats:italic>versus<\/jats:italic>infrequent exacerbations.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Adults with CF were recruited at onset of antibiotic treatment of a pulmonary exacerbation and were categorised as infrequent or frequent exacerbators based on their pulmonary exacerbation frequency in the previous 12\u2005months. Clinical parameters, sputum bacterial load and sputum inflammatory markers were measured on day 0, day 5 and at the end of treatment. Shotgun proteomic analysis was performed on sputum using liquid chromatography-mass spectrometry.<\/jats:p><\/jats:sec><jats:sec><jats:title>Measurements and main results<\/jats:title><jats:p>Many sputum proteins were differentially enriched between infrequent and frequent exacerbators (day 0 n=23 and day 5 n=31). The majority of these proteins had a higher abundance in infrequent exacerbators and were secreted innate host defence proteins with antimicrobial, antiprotease and immunomodulatory functions. Several differentially enriched proteins were validated using ELISA and Western blot including secretory leukocyte protease inhibitor (SLPI), lipocalin-1 and cystatin SA. Sputum from frequent exacerbators demonstrated potent ability to cleave exogenous recombinant SLPI in a neutrophil elastase dependent manner. Frequent exacerbators had increased sputum inflammatory markers (interleukin (IL)-1\u03b2 and IL-8) and total bacterial load compared to infrequent exacerbators.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>A diminished innate host protein defence may play a role in the pathophysiological mechanisms of frequent CF pulmonary exacerbations. Frequent exacerbators may benefit from therapies targeting this dysregulated host immune response.<\/jats:p><\/jats:sec>","DOI":"10.1183\/13993003.01228-2023","type":"journal-article","created":{"date-parts":[[2023,12,22]],"date-time":"2023-12-22T11:45:15Z","timestamp":1703245515000},"page":"2301228","update-policy":"https:\/\/doi.org\/10.1183\/ers-crossmark-policy","source":"Crossref","is-referenced-by-count":9,"title":["Diminished airway host innate response in people with cystic fibrosis who experience frequent pulmonary exacerbations"],"prefix":"10.1183","volume":"63","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4076-5596","authenticated-orcid":false,"given":"Claire J.","family":"Houston","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aya","family":"Alkhatib","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"G\u00edsli 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