Journal of Cystic Fibrosis最新文献

{"title":"WS10.06Pre-clinical validation of GY971, a new anti-inflammatory agent targeting Nuclear Factor kappa B (NF-kB)","authors":"C. Tupini ,&nbsp;S. Fagnani ,&nbsp;G. Raso ,&nbsp;A. Chilin ,&nbsp;G. Marzaro ,&nbsp;A. Tamanini ,&nbsp;N. Pedemonte ,&nbsp;V. Capurro ,&nbsp;A. Bragonzi ,&nbsp;G. Cabrini ,&nbsp;I. Lampronti","doi":"10.1016/j.jcf.2025.03.551","DOIUrl":"10.1016/j.jcf.2025.03.551","url":null,"abstract":"<div><h3>Objectives</h3><div>Despite the introduction of novel CFTR modulator treatments, the progressive pulmonary damage and lung inflammation hallmarks of <em>cystic fibrosis</em> (CF) continue to persist. Although bacterial infections and inflammatory biomarkers show improvement, they do not fully normalize, highlighting the need for further anti-inflammatory (AI) strategies. Given the severe side effects of chronic AI therapies, such as ibuprofen, which can cause gastrointestinal bleeding, new anti-inflammatory drugs are urgently needed. A key mediator of CF inflammation is the NF-kB transcription factor, which can regulate the expression of pro-inflammatory genes, such as <em>interleukin-8</em> (IL-8), a significant biomarker of lung inflammation in <em>people with CF</em> (pwCF).</div><div>This study outlines the development and characterization of synthetic compounds aimed at modulating the NF-kB activity as a new innovative therapy for CF.</div></div><div><h3>Methods</h3><div>In the first phase of the research, we focused on the analysis of various synthetic derivatives in CF bronchial epithelial cell lines exposed to <em>Pseudomonas aeruginosa</em> (Pa) or TNF-alpha <em>in vitro</em> and in mouse models of Pa lung infection <em>in vivo</em>.</div></div><div><h3>Results</h3><div>The new furocoumarin derivative GY971 proved to be the best derivative identified in this screening, and it demonstrated promising anti-inflammatory effects, both <em>in vitro</em> and <em>in vivo</em>, providing a foundation for further investigations. In the second phase of our study, the anti-inflammatory effects of GY971 were also validated in primary HBE (Human Bronchial Epithelial cells) derived from pwCF without any genotoxic or phototoxic effects.</div></div><div><h3>Conclusion</h3><div>Thanks to the promising results, GY971 was recently approved by the <em>European Medicines Agency</em> (EMA) as an orphan drug for CF. Our ongoing research aims to consolidate its efficacy and safety profile, bringing it closer to clinical application as an innovative AI treatment for CF lung disease.</div></div>","PeriodicalId":15452,"journal":{"name":"Journal of Cystic Fibrosis","volume":"24 ","pages":"Page S21"},"PeriodicalIF":5.4,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144205585","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"WS12.06Exploring the impact of excessive BMI on metabolic health in patients with cystic fibrosis: a 2-year experience with CFTR modulators at the Warsaw CF Centre","authors":"M. Mielus ,&nbsp;K. Zybert ,&nbsp;K. Walicka-Serzysko ,&nbsp;L. Wozniacki ,&nbsp;J. Milczewska ,&nbsp;D. Sands","doi":"10.1016/j.jcf.2025.03.563","DOIUrl":"10.1016/j.jcf.2025.03.563","url":null,"abstract":"<div><h3>Objectives</h3><div>CFTR modulator therapies have transformed cystic fibrosis (CF) management, improving nutritional status. The emergence of overweight and obesity (OW/OB) in people with CF (pwCF) raises concerns about complications associated with excessive weight. Data on the long-term consequences of OW/OB in pediatric pwCF remain scarce.</div><div><strong>This study aimed</strong> to compare changes in body composition and metabolic parameters in pediatric pwCF who developed OW/OB with those who maintained normal nutritional status (NNS) over 2 years of CFTR modulator therapy.</div></div><div><h3>Methods</h3><div>Twenty pediatric pwCF aged 12-18 who completed 2 years of CFTR modulator therapy by November 2024 were included. Ten pwCF who became OW/OB were matched with 10 who maintained NNS status, based on BMI z-scores (Wilschanski et al., 2023). Body composition was assessed using bioelectrical impedance, focusing on fat-free mass (FFM) and fat mass (FM). Fasting metabolic parameters: glucose, insulin, HOMA-IR, HbA1c, total cholesterol, HDL, LDL, and triglycerides, were measured at baseline and after two years.</div></div><div><h3>Results</h3><div>At baseline, no statistically significant differences were observed between the OW/OB and NNS groups. After 2 years, the OW/OB group showed significantly greater increases in FM (median 6.95 kg vs. 1.8 kg) and FFM (11 kg vs. 2.65 kg) compared to the NNS group. Median weight gain in the OW/OB group was over 4-fold higher (21.7 kg vs. 5.1 kg, p&lt;0.001). Glucose decreased substantially in the NNS group (-11 mg/dL vs. -2 mg/dL). Insulin levels and HOMA-IR significantly increased in the OW/OB group (+4 µIU/ml, +1.37; p=0.04, p=0.01). Lipid profiles and HbA1c showed no significant differences. Changes in FM did not correlate with any metabolic parameters in either group.</div></div><div><h3>Conclusion</h3><div>Pediatric pwCF with OW/OB after 2 years of CFTR modulator therapy exhibited greater FM and FFM increases and significant insulin metabolism disruptions, underscoring the importance of close monitoring and tailored nutrition.</div></div>","PeriodicalId":15452,"journal":{"name":"Journal of Cystic Fibrosis","volume":"24 ","pages":"Page S25"},"PeriodicalIF":5.4,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144203905","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"WS01.06When is best to start treatment with tobramycin in people with chronic Pseudomonas aeruginosa infection? An emulated trial using the UK CF Registry","authors":"E. Granger ,&nbsp;G. Davies ,&nbsp;F. Frost ,&nbsp;R. Keogh","doi":"10.1016/j.jcf.2025.03.497","DOIUrl":"10.1016/j.jcf.2025.03.497","url":null,"abstract":"<div><div><em>Pseudomonas aeruginosa</em> (Pa) is among the most common pathogen detected in people with cystic fibrosis (CF). Once infection is established, the management of chronic Pa infection requires long-term suppressive treatment. In the UK, colistimethate is recommend as a first line treatment for chronic Pa with tobramycin second line. Second line treatment is considered in those who are clinically deteriorating despite regular inhaled colistimethate, however little guidance exists as to what constitutes clinical deterioration.</div><div>Our aim is to determine at what level of lung function is best to add tobramycin in people with CF who are already taking colistimethate to treat chronic Pa.</div><div>Using data from the UK CF Registry, we include individuals who have been taking colistimethate for at least one year, have isolated Pa and are aged at least 6 years. We applied inverse-probability-of-treatment weighting to investigate when is best to add tobramycin in people who met our eligibility criteria. The goal was to optimise X, when the treatment decision rule is to “initiate long-term treatment with tobramycin when the percent forced expiratory volume in one second (FEV₁%) first falls under X”. We considered values of X ranging between 20 and 120 and the outcome of interest was FEV₁% after 1-, 2-, 3-, 4- and 5- years.</div><div>A preliminary analysis, based on UK CF Registry data from 2016-2018, found no evidence that expected outcomes changed for individuals who initiated tobramycin at different levels of lung function. We plan to present the results of an updated analysis which includes more recent data up to 2022.</div><div>Our study provides an illustrative example of optimising a dynamic treatment regime, i.e., a sequence of decision rules which dictate a person's subsequent treatment, conditional on their treatment and clinical history. This approach has the potential to improve personalised treatment decisions by informing clinical guidance on treatment regimes that change over time.</div></div>","PeriodicalId":15452,"journal":{"name":"Journal of Cystic Fibrosis","volume":"24 ","pages":"Pages S2-S3"},"PeriodicalIF":5.4,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144204924","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"WS04.01Faecal microbiota changes in people with cystic fibrosis after 6 months of elexacaftor/tezacaftor/ivacaftor: findings from the PROMISE study","authors":"J.T. Duong ,&nbsp;H.S. Hayden ,&nbsp;A.J. Verster ,&nbsp;C.E. Pope ,&nbsp;C. Miller ,&nbsp;K. Penewit ,&nbsp;S.J. Salipante ,&nbsp;S.M. Rowe ,&nbsp;G.M. Solomon ,&nbsp;D. Nichols ,&nbsp;A. Kelly ,&nbsp;S.J. Schwarzenberg ,&nbsp;S.D. Freedman ,&nbsp;L.R. Hoffman","doi":"10.1016/j.jcf.2025.03.510","DOIUrl":"10.1016/j.jcf.2025.03.510","url":null,"abstract":"<div><h3>Objectives</h3><div>People with cystic fibrosis (PwCF) often have fecal dysbioses relative to those without CF, characterized by increased pro-inflammatory microbiota and gastrointestinal (GI) inflammation as measured by fecal calprotectin, suggesting that inflammation contributes to CF GI disease. Consistent with findings in European cohorts, the multicenter observational PROMISE study (NCT04038047) found that calprotectin decreased in PwCF treated with elexacaftor/tezacaftor/ivacaftor (ETI). To better understand the dynamics between fecal dysbiosis and GI inflammation, we characterized the microbiomes of fecal samples from PROMISE and the relationships with calprotectin before, 1-month post, and 6-months post ETI.</div></div><div><h3>Methods</h3><div>Fecal microbiota of stool samples from subjects ≥12 y/o were determined by shotgun metagenomic sequencing with random forest modeling and multivariate linear regression analysis to define relationships between relationships between microbiota and calprotectin before and after ETI.</div></div><div><h3>Results</h3><div>We analyzed 345 samples from 124 subjects. At baseline, we observed community-level differences in the fecal microbiota among subjects with abnormal compared to normal calprotectin. With ETI, the relative abundances of 7 bacterial species–<em>Escherichia coli, Staphylococcus aureus, Clostridium scindens, Enterocloster clostridioformis, Clostridium butyricum, Anaeroglobus geminatus, and Ruminococcus gnavus</em>–decreased significantly, correlating with calprotectin decrease. We found community-level differences in the fecal microbiota based on <em>CFTR</em> genotype and a distinct pattern of microbiota change in F508del homozygous compared to heterozygous subjects after ETI.</div></div><div><h3>Conclusion</h3><div>We identified 7 species for which fecal abundances decreased with ETI and correlated with calprotectin decrease, supporting a close relationship between fecal microbiota and inflammation in PwCF. Future work will define these relationships with metabolites and GI symptoms during long-term ETI therapy.</div></div>","PeriodicalId":15452,"journal":{"name":"Journal of Cystic Fibrosis","volume":"24 ","pages":"Pages S7-S8"},"PeriodicalIF":5.4,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144205327","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"WS07.01‘Silent' lung disease progression in people receiving elexacaftor/tezcaftor/ivacaftor (ETI) therapy revealed by Oxygen Enhanced-MRI (OE-MRI) and Multiple breath washout with Short extension (MBWShX)","authors":"C. Short ,&nbsp;T. Semple ,&nbsp;M. Abkir ,&nbsp;M. Tibiletti ,&nbsp;M. Rosenthal ,&nbsp;S. Padley ,&nbsp;G.J.M. Parker ,&nbsp;J.C. Davies","doi":"10.1016/j.jcf.2025.03.528","DOIUrl":"10.1016/j.jcf.2025.03.528","url":null,"abstract":"&lt;div&gt;&lt;h3&gt;Objectives&lt;/h3&gt;&lt;div&gt;The post modulator era is raising several new challenges, particularly with a need for sensitive pulmonary outcome measures (OM). Current tools are suboptimal; to address this our group developed MBW&lt;sub&gt;ShX&lt;/sub&gt; to assess previously overlooked under ventilated lung units (UVLU), but it cannot provide spatial information. Functional lung MRI has the potential to be a sensitive OM to track CF lung disease. We hypothesised that in the context of improved clinical status, any lung disease progression would be observed more clearly using OE-MRI and MBW&lt;sub&gt;ShX&lt;/sub&gt; than conventional measures.&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Methods&lt;/h3&gt;&lt;div&gt;PwCF were recruited as part of a large observational study to determine the clinimetric properties of OE-MRI; all were on ETI therapy (&gt;6 months at baseline). Participants performed OE-MRI, MBW&lt;sub&gt;ShX&lt;/sub&gt;, and spirometry whilst clinically stable on the same day at baseline and at 6-monthly intervals over 18 months. &lt;em&gt;OE-MRI parameters&lt;/em&gt;: ventilation defect percentage (VDP) and ∆R&lt;sub&gt;2&lt;/sub&gt;* (ventilation signal). &lt;em&gt;MBW&lt;sub&gt;ShX&lt;/sub&gt; parameters&lt;/em&gt;: UVLU and LCI&lt;sub&gt;ShX&lt;/sub&gt; (LCI&lt;sub&gt;2.5&lt;/sub&gt; + UVLU) a measure of global lung health. Data is presented as mean (SD) and ∆baseline (95%CI) and assessed using a mixed effects model with Tukey's test for multiple comparisons.&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Results&lt;/h3&gt;&lt;div&gt;Thirty-six pwCF aged 20.3 (±12.7) completed the baseline visit. FEV&lt;sub&gt;1&lt;/sub&gt; and LCI&lt;sub&gt;2.5&lt;/sub&gt; appeared stable, whereas significant deterioration in the novel MBW&lt;sub&gt;ShX&lt;/sub&gt; and MRI parameters could be observed, with OE-MRI measures demonstrating sensitivity at 12 months.&lt;span&gt;&lt;div&gt;&lt;div&gt;&lt;table&gt;&lt;thead&gt;&lt;tr&gt;&lt;th&gt;Parameter&lt;/th&gt;&lt;th&gt;Baseline (N=36) Mean (SD)&lt;/th&gt;&lt;th&gt;6 months (N=32) Mean (SD)&lt;/th&gt;&lt;th&gt;∆ (95%CI) P value&lt;/th&gt;&lt;th&gt;12 months (N=32) Mean (SD)&lt;/th&gt;&lt;th&gt;∆ (95%CI) P value&lt;/th&gt;&lt;th&gt;18 months (N=28) Mean (SD)&lt;/th&gt;&lt;th&gt;∆ (95%CI) P value&lt;/th&gt;&lt;/tr&gt;&lt;/thead&gt;&lt;tbody&gt;&lt;tr&gt;&lt;td&gt;&lt;strong&gt;ppFEV&lt;sub&gt;1&lt;/sub&gt;&lt;/strong&gt;&lt;/td&gt;&lt;td&gt;89.5% (±19.4%)&lt;/td&gt;&lt;td&gt;88.9% (±19.2%)&lt;/td&gt;&lt;td&gt;-0.5% (-3.8 to 2.7) P&gt;0.05&lt;/td&gt;&lt;td&gt;88.7 (±19.7%)&lt;/td&gt;&lt;td&gt;-0.8% (-4.0 to 2.4%) P&gt;0.05&lt;/td&gt;&lt;td&gt;88.1% (±19.2%)&lt;/td&gt;&lt;td&gt;-1.3% (-4.6 to 2.0%) P&gt;0.05&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td&gt;&lt;strong&gt;LCI&lt;sub&gt;2.5&lt;/sub&gt;&lt;/strong&gt;&lt;/td&gt;&lt;td&gt;9.1 (±4.2)&lt;/td&gt;&lt;td&gt;9.1 (±4.0)&lt;/td&gt;&lt;td&gt;0.02 (-0.62 to 0.58) P&gt;0.05&lt;/td&gt;&lt;td&gt;9.1 (±3.9)&lt;/td&gt;&lt;td&gt;0.02 (-0.61 to 0.57) P&gt;0.05&lt;/td&gt;&lt;td&gt;9.4 (±3.9)&lt;/td&gt;&lt;td&gt;0.25 (-0.36 to 0.87) P&gt;0.05&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td&gt;&lt;strong&gt;LCI&lt;sub&gt;ShX&lt;/sub&gt;&lt;/strong&gt;&lt;/td&gt;&lt;td&gt;12.7 (±9.0)&lt;/td&gt;&lt;td&gt;13.3 (±9.8)&lt;/td&gt;&lt;td&gt;0.58 (-0.5 to 1.7) P&gt;0.05&lt;/td&gt;&lt;td&gt;13.6 (±9.7)&lt;/td&gt;&lt;td&gt;0.91 (-0.2 to 2.0) P&gt;0.05&lt;/td&gt;&lt;td&gt;14.2 (±8.5)&lt;/td&gt;&lt;td&gt;1.54 (0.4 to 2.7) &lt;strong&gt;P&lt;0.01&lt;/strong&gt;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td&gt;&lt;strong&gt;UVLU&lt;/strong&gt;&lt;/td&gt;&lt;td&gt;3.6 (±5.2)&lt;/td&gt;&lt;td&gt;4.2 (±6.3)&lt;/td&gt;&lt;td&gt;0.62 (-0.3 to1.6) P&gt;0.05&lt;/td&gt;&lt;td&gt;4.5 (±6.0)&lt;/td&gt;&lt;td&gt;0.90 (0.0 to 1.8) P&gt;0.05&lt;/td&gt;&lt;td&gt;4.7 (±4.6)&lt;/td&gt;&lt;td&gt;1.1 (-0.2 to 2.1) &lt;strong&gt;P&lt;0.05&lt;/strong&gt;&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td&gt;&lt;strong&gt;∆R&lt;sub&gt;2&lt;/sub&gt;*&lt;s","PeriodicalId":15452,"journal":{"name":"Journal of Cystic Fibrosis","volume":"24 ","pages":"Pages S13-S14"},"PeriodicalIF":5.4,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144205354","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"WS11.04Unraveling the pathogenicity of mycobacterium abscessus in cystic fibrosis pulmonary epithelial cell and mouse models of respiratory infection","authors":"F. Nicola ,&nbsp;F. Saliu ,&nbsp;F. Di Marco ,&nbsp;S. De Pretis ,&nbsp;F. Giannese ,&nbsp;B.S. Orena ,&nbsp;V. Capurro ,&nbsp;G. Saldarini ,&nbsp;L. Cariani ,&nbsp;N. Pedemonte ,&nbsp;D.M. Cirillo ,&nbsp;N.I. Lorè","doi":"10.1016/j.jcf.2025.03.555","DOIUrl":"10.1016/j.jcf.2025.03.555","url":null,"abstract":"<div><h3>Objectives</h3><div><em>Mycobacterium abscessus</em> (<em>Mabs</em>) infections are common in people with cystic fibrosis (PwCF), with outcomes ranging from asymptomatic to pulmonary disease (Mabs-PD). Dominant clones and morphotypes, smooth(S) or rough(R), are associated with severe cases, but their role in CF lung inflammation is unclear. This study aims to elucidate <em>Mabs</em> pathogenic mechanisms in modulating host defence and inflammatory processes during respiratory infections.</div></div><div><h3>Methods</h3><div>We analysed 11 <em>Mabs</em> isolates from 5 PwCF across asymptomatic and Mabs-PD phases using morphotype and genome sequencing. Host responses were studied in CF epithelial cell line via transcriptomics and cytokine assays. Two clonal and longitudinal S and R <em>Mabs</em> strains were studied in air-liquid interface (ALI) model of CF human primary bronchial epithelial cells (CF-HBEpC) and mouse infection models, utilizing single-cell(sc) RNA sequencing, and flow cytometry and Visium spatial transcriptomics, respectively.</div></div><div><h3>Results</h3><div>Epithelial cells infected with <em>Mabs</em> strains revealed that the morphotype primarily drives the host response, as evidenced by over 2,000 differentially expressed genes identified via bulk RNA sequencing and increased IL-6 and IL-8 protein release confirmed by ELISA. Using CF-HBEpC in ALI culture and scRNAseq revealed that basal and secretory cells significantly contribute to the immune response following infection with R and S strains. Specifically, R strain infections upregulated pathways related to cytokine and innate immune responses. We observed that mice chronically infected with R strains had higher inflammatory burden (type 1 and type 17 immunity) compared to mice infected with S strains. Spatial transcriptomics confirmed proinflammatory tissue profiles linked to type 1 immune response.</div></div><div><h3>Conclusion</h3><div>Our findings suggest that morphotype impacts the interaction between the lung epithelium and bacteria, with R strains inducing stronger type 1 proinflammatory immunity during bacterial persistence.</div></div>","PeriodicalId":15452,"journal":{"name":"Journal of Cystic Fibrosis","volume":"24 ","pages":"Page S22"},"PeriodicalIF":5.4,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144205589","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"WS06.02Pharmacology of fetal therapy in cystic fibrosis. Report from the MODUL-CF study","authors":"A.-S. Bonnel ,&nbsp;T. Bihouee ,&nbsp;I. Sermet-Gaudelus ,&nbsp;M. Ribault ,&nbsp;M. Driessen ,&nbsp;S. Benaboud ,&nbsp;D. Grévent ,&nbsp;N.H. Truong ,&nbsp;M. Benhamida ,&nbsp;C. Martin ,&nbsp;P.-R. Burgel ,&nbsp;P. Reix ,&nbsp;F. Foissac ,&nbsp;Y. Ville ,&nbsp;Modul-CF study group","doi":"10.1016/j.jcf.2025.03.523","DOIUrl":"10.1016/j.jcf.2025.03.523","url":null,"abstract":"<div><h3>Objectives</h3><div>Data on the impact of CFTR modulator (CFTRm) therapies on fetal intestinal complications, potential adverse fetal outcomes and maternal foetal pharmacology are lacking.</div></div><div><h3>Methods</h3><div>Dyads were included if the foetus had a genetic diagnosis of CF and carried at least one variant responsive to CFTRm. Standardized assessment included pre-CFTRm Magnetic Resonance Imaging (MRI), repeated ultrasound (US), and CFTRm drug concentrations in blood cord, maternal and infant plasma at birth.</div></div><div><h3>Results</h3><div>We enrolled 14 dyads from the ongoing real-world French MODUL CF study. One withdrew. CFTRm therapies (Elexacaftor (ELX)/Tezacaftor (TEZ)/Ivacaftor (IVA) (ETI) n=12, ivacaftor (IVA) n=1) were administered to the pregnant women between 19 and 36 weeks of gestation for a median [IQR] of 35[55] days, either as a curative indication of MI (n=9) or as a tertiary prevention of fetal CF-related intestinal symptoms (n=4). One foetus experienced increased bowel dilatation 3 days after ETI introduction. MRI revealed intestinal atresia. One dyad received only 2 doses. In the other 7 cases, resolution of MI was observed within 14[10] days of ETI. Fetal development and neonatal tolerance were excellent. Placental transfer was assessed by cord-to-maternal plasma concentration ratio in 6 dyads for ELX/TEZ and 7 dyads for IVA. It was very high for TEZ, with a median [IQR] range of 1.59 [1.00–1.85] (0.77-3.59), but low for IVA and ELX, with a respective cord-to-maternal ratio at delivery of 0.54 [0.44–0.55] (0.26–0.57) and 0.40 [0.36–0.44] (0.23-0.65). Fecal elastase at birth was always below 200 ng/g even in the ETI breast-fed infant who had a very low plasma concentration residual and peak concentration of the 3 compounds.</div></div><div><h3>Conclusion</h3><div>ETI administration from the second trimester of pregnancy enables MI resolution thanks to in utero transfer. Fetal tolerance at ETI initiation needs to be monitored by a standardized assessment. Benefit of ETI administration by lactation is unclear.</div></div>","PeriodicalId":15452,"journal":{"name":"Journal of Cystic Fibrosis","volume":"24 ","pages":"Pages S11-S12"},"PeriodicalIF":5.4,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144204933","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"WS01.01Predicting future pulmonary exacerbation (PEx) rates for cystic fibrosis (CF) clinical trials","authors":"D. VanDevanter ,&nbsp;C. O'Rourke ,&nbsp;K. Odem-Davis ,&nbsp;J. Clancy ,&nbsp;M. Konstan ,&nbsp;N. Mayer Hamblett","doi":"10.1016/j.jcf.2025.03.492","DOIUrl":"10.1016/j.jcf.2025.03.492","url":null,"abstract":"<div><h3>Objectives</h3><div>Due to the clinical importance of CF pulmonary exacerbations (PEx), regulators accept PEx rate difference as clinical trial efficacy endpoint. Although CFTR modulators have reduced overall PEx rates, this endpoint remains relevant to future CF drug development, provided study populations can be enriched for individuals with elevated PEx risk. Although the number of prior-year PEx treated with intravenous antimicrobials (IV-PEx) strongly predicts future IV-PEx risk [JCF. 2016;15(3):372-9], IV-PEx incidence has fallen to a point where it has little if any utility as a clinical trial endpoint: today PEx treated with antibiotics <em>by any route</em> (anyPEx) are studied despite little knowledge of associations between prior year anyPEx number and future PEx rates. We tested whether prior year anyPEX number predicted future anyPEx rates in CF adults receiving and not receiving the CFTR modulator elexacaftor/tezacaftor/ivacaftor (ETI).</div></div><div><h3>Methods</h3><div>CF adults with data present in the CF Foundation Patient Registry (CFFPR) in 2022 &amp; 2023 were studied, provided they had received either</div><div>a) ETI or</div><div>b) no modulators in both years.</div><div>AnyPEx were counted; treatments starting &lt;28 days of a previous treatment start were considered part of the previous PEx. 2023 PEx rates were compared among subgroups having 0, 1-2, or 3+ PEx in 2022.</div></div><div><h3>Results</h3><div>PEx counted in 2022 strongly correlated with mean 2023 PEx rates within both the ETI and No Modulator groups (P&lt;.001, table), with the mean rate for the entire ETI group lower than that of the No Modulator group, as well as within subgroups with <u>0 and 1-2 PEx</u> in 2022 (table).<span><div><div><table><thead><tr><td><span>Empty Cell</span></td><th>No 2022 PEx</th><th>One or Two 2022 PEx</th><th>Three plus 2022 PEx</th><th>Overall</th></tr></thead><tbody><tr><th><strong>2023 ETI group PEx rate (N)</strong></th><td>0.23/yr (9452)</td><td>0.78/yr (3267)</td><td>2.19/yr (469)</td><td>0.43/yr (13,188)</td></tr><tr><th><strong>2023 No Modulator group PEx rate (N)</strong></th><td>0.32/yr (1356)</td><td>1.08/yr (633)</td><td>2.37/yr (159)</td><td>0.70/yr (2148)</td></tr><tr><th><strong>Relative rate (ETI/No Modulator), [95% CI]</strong></th><td>0.71 [0.63, 0.79]</td><td>0.72 [0.65, 0.80]</td><td>0.92 [0.78, 1.10]</td><td>0.62 [0.57, 0.68]</td></tr></tbody></table></div></div></span></div></div><div><h3>Conclusions</h3><div>An unmet need for therapeutic interventions to reduce CF PEx risk remains, even in populations receiving CFTR modulators. The number of anyPEx counted in a prior year strongly predict future anyPEx rates in adults, suggesting an enrichment approach for CF trials using difference in PEx rates as an efficacy endpoint.</div></div>","PeriodicalId":15452,"journal":{"name":"Journal of Cystic Fibrosis","volume":"24 ","pages":"Page S1"},"PeriodicalIF":5.4,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144204941","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"WS14.01Primary nasal epithelial cells for personalized medicine in non-eligible cystic fibrosis patients","authors":"J. Berger ,&nbsp;A. Balázs ,&nbsp;T. Rubil ,&nbsp;A. Gonzáles ,&nbsp;J. Berges ,&nbsp;Y. Yu ,&nbsp;O. Sommerburg ,&nbsp;M. Stahl ,&nbsp;M.A. Mall ,&nbsp;S.Y. Graeber","doi":"10.1016/j.jcf.2025.03.570","DOIUrl":"10.1016/j.jcf.2025.03.570","url":null,"abstract":"<div><h3>Objective</h3><div>Patients with cystic fibrosis (pwCF) without any <em>F508del</em> allele in the cystic fibrosis transmembrane conductance regulator (<em>CFTR</em>) have currently no access to CFTR modulator therapy in Europe. To test the potential of pharmacological rescue of CFTR by ETI in non-eligible pwCF, we tested the <em>in vitro</em> and <em>in vivo</em> effects of ETI in non-<em>F508del</em> pwCF.</div></div><div><h3>Methods</h3><div>Highly differentiated primary human nasal epithelial cultures (pHNECs) were cultivated from nasal swabs of 39 pwCF and non-<em>F508del CFTR</em> mutations and 29 healthy controls. CFTR activity was assessed by short-circuit currents in non-perfused Ussing chamber after ETI or DMSO incubation. In 10 pwCF, who received ETI therapy after a preclinical response in pHNECs, we assessed lung function (FEV₁% predicted) and the <em>in vivo</em> CFTR biomarkers sweat chloride concentration (SCC) and intestinal current measurements (ICM) or nasal potential difference (NPD) at baseline and 1 to 3 months after ETI.</div></div><div><h3>Results</h3><div>Twenty-five pwCF showed no increased CFTR activity in pHNECs after treatment with ETI compared to DMSO. However, pHNECs from 14 pwCF showed a response to ETI with a mean correction of CFTR activity of 20% of the healthy level. The 10 pwCF who received ETI showed a mean improvement in FEV₁% predicted by 12%. All 10 pwCF showed a pathological SCC above 60 mmol/L, which was reduced by at least 5 mmol/L after ETI. In ICM, the cAMP-dependent chloride secretory response increased from -12 µA/cm² to 32 µA/cm² after ETI and the total chloride secretory response increased from -16 µA/cm² to 123 µA/cm². A subgroup of 6 pwCF, where NPD was performed, showed an increase in total chloride response in NPD from -0.25 mV to -14 mV after ETI.</div></div><div><h3>Conclusion</h3><div>We identified non-<em>F508del CFTR</em> mutations responding to ETI <em>in vitro</em> with improvements in FEV₁%, SSC, ICM, and NPD. Our data show that <em>in vitro</em> CFTR modulator testing in pHNECs, confirmed by <em>in vivo</em> biomarkers, is a promising approach for personalized medicine in non-eligible pwCF.</div></div>","PeriodicalId":15452,"journal":{"name":"Journal of Cystic Fibrosis","volume":"24 ","pages":"Page S27"},"PeriodicalIF":5.4,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144205073","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"WS13.04Management of intermediate sweat chloride results and diagnosis of CFTR related disorders in a large tertiary paediatric centre","authors":"K. Rose ,&nbsp;C. Bradford ,&nbsp;A.F. Robson ,&nbsp;L. Tetlow ,&nbsp;B. Hird ,&nbsp;A. Shawcross","doi":"10.1016/j.jcf.2025.03.567","DOIUrl":"10.1016/j.jcf.2025.03.567","url":null,"abstract":"<div><h3>Objectives</h3><div>This study aimed to review the management of children and young people who have had a sweat test with a sweat chloride concentration (SCC) in the intermediate range between 30 and 59mmol/L.</div></div><div><h3>Methods</h3><div>All sweat tests with a result in the intermediate range undertaken at our large tertiary paediatric hospital between 01/01/2019 and 31/12/2023 were identified from laboratory records. Electronic health records were reviewed retrospectively to obtain further patient data. Patients diagnosed with CF or CF SPID following newborn screening were excluded.</div></div><div><h3>Results</h3><div>A total of 47 patients were identified. The primary indication for performing a sweat test included chronic respiratory concerns (74%), pancreatitis (6%), poor growth (6%), surgical concerns (rectal prolapse, bowel stricture - 4%), gastrointestinal symptoms (4%) and nasal polyps (4%).</div><div>A total of 31 patients (66%) underwent genetic testing. Five patients were found to have two <em>CFTR</em> mutations, in each case one known to be CF causing and one variant of varying clinical consequence. Four were heterozygous for one CF causing mutation. Eight patients (17%) had not been seen by a CF physician. Only 14 patients had documented advice on CFTR dysfunction.</div></div><div><h3>Conclusions</h3><div>In our large paediatric centre we identified a significant number of patients with an intermediate SCC who had not received further genetic investigations. There were also a number in whom documented advice on CFTR dysfunction had not been provided and a group who had not been reviewed by the CF team. In the era of modulator therapies and their potential clinical benefit, accurate diagnosis of CFTR related disorders is increasingly important. This work, along with the 2022 publication ‘ECFS standards of care on CFTR-related disorders: Updated diagnostic criteria’ (Castellani, JCF 2022) will be used to define a new local guideline for referral of all patients with intermediate SCC to clinicians with expertise in CF diagnosis.</div></div>","PeriodicalId":15452,"journal":{"name":"Journal of Cystic Fibrosis","volume":"24 ","pages":"Pages S26-S27"},"PeriodicalIF":5.4,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144205076","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}