Journal of Cystic Fibrosis最新文献

{"title":"WS15.03Elevated sweat chloride concentrations in people with cystic fibrosis with at least one N1303K, 2789+5G>A or R334W treated with elexacaftor/tezacaftor/ivacaftor","authors":"P.-R. Burgel ,&nbsp;J. Da Silva ,&nbsp;C. Martin ,&nbsp;E. Girodon ,&nbsp;J.-L. Paillasseur ,&nbsp;French CF National Reference network study group","doi":"10.1016/j.jcf.2025.03.578","DOIUrl":"10.1016/j.jcf.2025.03.578","url":null,"abstract":"<div><h3>Objectives</h3><div>Data from the French Compassionate Program have shown that people with CF (pwCF) and no F508del variant but at least one N1303K, 2789+5G&gt;A or R334W treated with elexacaftor-tezacaftor-ivacaftor showed clinical improvement with no or small decrease in sweat chloride concentration. We sought to characterize the sweat chloride concentration with ETI in people with CF with these variants, according to the second <em>CFTR</em> variant.</div></div><div><h3>Methods</h3><div>Data from pwCF treated with ETI were obtained using the French adult ETI-real world study and the French Compassionate program. <em>CFTR</em> variants were classified according to their ETI-responsiveness, as determined in the French Compassionate Program. Sweat chloride concentrations with ETI were described according the second CFTR variant.</div></div><div><h3>Results</h3><div>Among 163 participants with at least one N1303K, 2789+5G&gt;A or R334W variants, 55 had an F508del, 19 had a non-F508del responsive variant, 20 had two N1303K, 2789+5G&gt;A or R334W variants and in 69 participant the other variant was non-responsive to ETI. In these subgroups, median [IQR] sweat chloride concentrations were 48 [37; 65] mmol/l, 28 [22; 50] mmol/l, 88 [79; 95] mmol/l, and 90 [84;100] mmol/l, respectively (<em>P</em>&lt;0.0001). All participants with two N1303K, 2789+5G&gt;A or R334W variants or with one of these variants and a non-ETI responsive variant had sweat chloride concentrations with ETI ≥60 mmol/l; in those with at least one F508del or another non-F508del responsive variant, only 42.6% had sweat chloride concentrations ≥60 mmol/l.</div></div><div><h3>Conclusion</h3><div>These data confirm that sweat chloride concentrations are often elevated in people with CF with N1303K, 2789+5G&gt;A or R334W variants treated with ETI. Only those with another ETI-responsive variant may show sweat chloride concentration &lt;60 mmol/l.</div></div>","PeriodicalId":15452,"journal":{"name":"Journal of Cystic Fibrosis","volume":"24 ","pages":"Page S30"},"PeriodicalIF":5.4,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144205351","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":"WS15.04Elexacaftor/tezacaftor/ivacaftor CFTR modulators mitigates senescence in cystic fibrosis","authors":"V. Bezzerri ,&nbsp;A.M. Hristodor ,&nbsp;T. Gunawardena ,&nbsp;M. Borgatti ,&nbsp;A. Vella ,&nbsp;C. Boni ,&nbsp;D. Olioso ,&nbsp;F. Quiri ,&nbsp;G. Lippi ,&nbsp;T. Moraes ,&nbsp;M. Cipolli","doi":"10.1016/j.jcf.2025.03.579","DOIUrl":"10.1016/j.jcf.2025.03.579","url":null,"abstract":"<div><h3>Objectives</h3><div>Impaired CFTR function causes loss of chloride and bicarbonate efflux across epithelia, leading to dehydration of the airway surface liquid and increased oxidative stress.</div><div>Senescence is a cellular program characterized by irreversible cell cycle arrest largely triggered by oxidative stress. While in the short-term senescence serves as a protective mechanism to prevent damaged cells from proliferating and supporting wound healing, in the long term it may sustain the “inflammaging” process, increasing the risk of age-related disorders.</div><div>Thus, we sought to assess the role of senescence in Cystic Fibrosis (CF) pathophysiology and the effect of elexacaftor/tezacaftor/ivacaftor (ETI) treatment on this cellular program.</div></div><div><h3>Methods</h3><div>CF (F508del) and healthy control airway epithelia (hBEC/hNEC) with similar ages and culture passages, were compared.</div></div><div><h3>Results</h3><div>The p53 pathway was upregulated in CF along all the cell models tested. This was recapitulated by inhibiting CFTR-dependent chloride efflux with CFTR(inh)-172 in healthy hBECs, suggesting a direct role of CFTR function on the onset of senescence. The senescence-associated secretory phenotype (SASP) was found in CF-hBEC. CF airway epithelial cells were enlarged and flattened compared to healthy controls, showing an increased expression of cytoskeletal component vimentin and decreased lamin B1. CFTRinh-172 induced vimentin expression in healthy airway epithelial cells, whereas ETI treatment reduced both vimentin and lamin B1 levels in CF cells. Eventually, clinical data revealed that ETI therapy is able to reduce plasmatic levels of SASP-related soluble mediators in patients with CF.</div></div><div><h3>Conclusion</h3><div>Taken together, these results indicate that CF airway epithelia are generally senescent. Cellular senescence could be a major driver of the constitutive inflammation reported in CF lungs. ETI is able to mitigate senescence both in vitro and in vivo, highlighting potential benefits that may go far beyond the expected effects.</div></div>","PeriodicalId":15452,"journal":{"name":"Journal of Cystic Fibrosis","volume":"24 ","pages":"Page S30"},"PeriodicalIF":5.4,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144205352","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":"WS10.05Downregulation of inflammatory cytokines and miRNAs by novel inhalable formulations bearing Iloprost in primary human cystic fibrosis nasal epithelial cells","authors":"A. Carbone ,&nbsp;P. Soccio ,&nbsp;E.F. Craparo ,&nbsp;P. Vitullo ,&nbsp;S. Bonsignore ,&nbsp;P. Tondo ,&nbsp;C. Scialabba ,&nbsp;G. D'Abrosca ,&nbsp;S. Di Gioia ,&nbsp;D. Lacedonia ,&nbsp;G. Cavallaro ,&nbsp;M. Conese","doi":"10.1016/j.jcf.2025.03.550","DOIUrl":"10.1016/j.jcf.2025.03.550","url":null,"abstract":"<div><h3>Objectives</h3><div>Cystic fibrosis (CF) lung disease hallmarks are mucus obstruction, opportunistic bacterial infections (e.g. by <em>Pseudomonas aeruginosa</em>), and an unresolvable inflammatory response. CF hyper-inflammation remains an orphan drug condition. Our aim is to develop suitable culture models from human beings in order to optimize inhalable smart drug-delivery systems, composed by Nano-into-mycro (NiM) formulations, in models mimicking in vivo airway epithelia and so to translate results into patients with CF to dampen lung inflammation. We have identified nasal epithelial cells (NEC), grown at Air Liquid Interface (ALI) culture conditions, as a suitable model obtained from nasal brushings in CF patients.</div></div><div><h3>Methods</h3><div>To date, nasal epithelial brushings from 8 CF individuals (homozygous or compound heterozygous for the F508del mutation) were collected and isolated cells were expanded under conditional reprogramming culture (CRC) method. ALI cultures, producing endogenous mucus, were challenged with <em>P. aeruginosa</em> lipopolysaccharide (LPS) in the absence or presence of mucopenetrating NiM formulations (pegylated or not) containing Iloprost (Ilo), a prostacyclin analogue. The expression of cytokines (TNF-<em>α</em>, IL-6, IL-1<em>ß</em>, IL-8) and miRNAs (miR-145, -146a, -17), all involved in inflammation, were analyzed by real-time PCR.</div></div><div><h3>Results</h3><div>A downregulation for all cytokines by either free Ilo and both NiM formulations as compared with LPS only was observed. miR-145, -146a, -17 levels were significantly reduced by NiM-PEG-Ilo as compared with LPS only.</div></div><div><h3>Conclusion</h3><div>The CF hyper-inflammation state might be modulated by novel inhalable NiM formulations containing Iloprost in an advanced human respiratory epithelial cell model, an ex-vivo pre-clinical model for precision medicine in CF.</div><div>Funded by European Union-NextGenerationEU Project PE_00000019: “Health Extended ALliance for Innovative Therapies, Advanced Lab-research, and Integrated Approaches of Precision Medicine-HEAL ITALIA”.</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":"144205584","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":"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}