{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,16]],"date-time":"2026-07-16T05:04:40Z","timestamp":1784178280257,"version":"3.55.0"},"reference-count":36,"publisher":"MDPI AG","issue":"4","license":[{"start":{"date-parts":[[2026,7,14]],"date-time":"2026-07-14T00:00:00Z","timestamp":1783987200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["ARM"],"abstract":"<jats:p>Cystic fibrosis (CF) is an autosomal recessive disorder caused by mutations in the CFTR gene. The sequential approval of CFTR modulators ivacaftor (2012), lumacaftor\/ivacaftor (2015), tezacaftor\/ivacaftor (2018), and elexacaftor\/tezacaftor\/ivacaftor (2019) has transformed CF care, but population-level mortality trends across therapeutic periods have not been comprehensively assessed. We conducted a retrospective analysis of CF mortality in the United States from 1999 to 2024 using CDC WONDER Underlying Cause of Death data (ICD-10 codes E84.0\u2013E84.9). Age-adjusted mortality rates (AAMR) per 100,000 were calculated using the 2000 U.S. standard population. The study period was divided into three periods: pre-modulator (1999\u20132011), early modulator (2012\u20132018), and elexacaftor\/tezacaftor\/ivacaftor (2019\u20132024). Annual mortality trends were evaluated using segmented log-linear Poisson regression, with annual death counts as the outcome and the corresponding U.S. population as an offset. Candidate models with multiple change points were compared to identify distinct temporal segments. Annual percent changes (APCs) and 95% confidence intervals (CIs) were estimated for each segment. Prespecified therapeutic periods, including pre-modulator (1999\u20132011), early modulator (2012\u20132018), and ETI period (2019\u20132024), were retained for descriptive analyses. Trends were stratified by sex and U.S. Census Region. A total of 10,959 CF deaths were recorded over 26 years. In the pre-modulator period, mortality was stable at a mean of 478 deaths\/year (AAMR 0.14\u20130.17). The early modulator period showed a modest 5.4% reduction in mean annual deaths (452\/year). The period following ETI availability was associated with a decline to 263\/year, a 47% reduction from the pre-modulator period (AAPC \u22128.6%\/year). The AAMR declined from 0.17 (1999) to 0.07 (2024). The female-to-male death count ratio shifted from 1.05 to 0.97 across periods, though age-adjusted rates were identical between sexes within each period, and this finding should be interpreted cautiously. Regionally, the South\u2019s share of CF deaths grew from 37.2% to 41.6% despite absolute declines in all regions, suggesting potential geographic disparities that warrant further investigation with individual-level data. Segmented regression identified change points in 2005 and 2015. Mortality declined significantly from 1999 through 2005 (APC, \u22122.70%; 95% CI, \u22124.01% to \u22121.37%), remained stable from 2006 through 2015 (APC, +0.21%; 95% CI, \u22120.47% to +0.90%), and declined sharply from 2016 through 2024 (APC, \u22129.76%; 95% CI, \u221210.66% to \u22128.84%). CF mortality in the United States has declined by more than half since the introduction of CFTR modulators. The shift in the sex-based death count ratio and the concentration of remaining deaths in the South are hypothesis-generating observations that require confirmation with individual-level data. These ecological findings cannot establish causation, as concurrent changes in supportive care, lung transplantation practices, and COVID-19 pandemic effects may have contributed to the observed trends.<\/jats:p>","DOI":"10.3390\/arm94040047","type":"journal-article","created":{"date-parts":[[2026,7,15]],"date-time":"2026-07-15T01:05:58Z","timestamp":1784077558000},"page":"47","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Cystic Fibrosis Mortality Trends 1999\u20132024\u2014A CDC Wonder Study"],"prefix":"10.3390","volume":"94","author":[{"given":"Palak","family":"Grover","sequence":"first","affiliation":[{"name":"Henry Ford Jackson Hospital, Jackson, MI 49201, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rahul","family":"Jain","sequence":"additional","affiliation":[{"name":"Sri Manakula Vinayagar Medical College, Puducherry 605107, India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gurleen","family":"Kaur","sequence":"additional","affiliation":[{"name":"Government Medical College, Amritsar 143001, Punjab, India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0008-9774-5020","authenticated-orcid":false,"given":"Niroshan","family":"Ranjan","sequence":"additional","affiliation":[{"name":"Henry Ford Jackson Hospital, Jackson, MI 49201, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bipneet","family":"Singh","sequence":"additional","affiliation":[{"name":"University of Kentucky, Lexington, KY 40506, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,7,14]]},"reference":[{"key":"ref_1","unstructured":"Cystic Fibrosis Foundation (2022). 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