Pub Date : 2025-02-19DOI: 10.1016/j.jcf.2025.02.008
Jessica Conti, Dora Angyal, Karina Kleinfelder, Roberta Valeria Latorre, Martina Calicchia, Alessia Farinazzo, Luca Rodella, Francesco Tomba, Arianna Massella, Luca Frulloni, Giovanni Taccetti, Vito Terlizzi, Anny Leung, Tessa A Groeneweg, Marcel J C Bijvelds, Paola Melotti, Claudio Sorio
Introduction: Cystic fibrosis (CF) is caused by mutation of the CFTR gene, encoding an epithelial anion channel. Here we evaluated the effect of the modulator combination elexacaftor-tezacaftor-ivacaftor (ETI) on the function of four rare, poorly characterized CFTR variants: L383S, I507del, L1065P and R1066H.
Methods: Intestinal organoids were obtained from subjects carrying the CFTR variants L383S, I507del, L1065P or R1066H in trans of a minimal function allele (class I mutation). Organoids and epithelial monolayers were used to assess the effect of ETI on CFTR protein abundance and CFTR-mediated chloride, bicarbonate, and fluid transport.
Results: In L383S-CFTR expressing cells, normal levels of fully glycosylated CFTR protein (C-band) were detected. In contrast, in I507del, L1065P or R1066H organoids, only partially glycosylated CFTR (B-band) was detected. Chloride/bicarbonate transport was severely impaired in epithelial monolayers prepared from these latter three variants, while anion transport of the L383S variant was affected to a moderate extent. ETI, but not ivacaftor alone, significantly enhanced CFTR-mediated chloride and bicarbonate transport in L1065P and R1066H monolayers, and stimulated fluid transport. A corresponding increase in the abundance of C-band protein was observed in both variants. ETI also modestly improved L383S-CFTR function, with a marginal effect on I507del-CFTR.
Conclusions: The I507del, L1065P and R1066H variants display severely impaired function. ETI treatment markedly enhanced L1065P- and R1066HCFTR function, whereas its effect on L383S- CFTR was less pronounced. Consequently, ETI may ameliorate disease symptoms in individuals carrying the L1065P or R1066H variant. More tentative, it may also benefit those carrying the L383S variant.
{"title":"Evaluation of the response to elexacaftor-tezacaftor-ivacaftor of the rare CFTR variants L383S, I507del, L1065P and R1066H in intestinal organoid-derived epithelial monolayers.","authors":"Jessica Conti, Dora Angyal, Karina Kleinfelder, Roberta Valeria Latorre, Martina Calicchia, Alessia Farinazzo, Luca Rodella, Francesco Tomba, Arianna Massella, Luca Frulloni, Giovanni Taccetti, Vito Terlizzi, Anny Leung, Tessa A Groeneweg, Marcel J C Bijvelds, Paola Melotti, Claudio Sorio","doi":"10.1016/j.jcf.2025.02.008","DOIUrl":"10.1016/j.jcf.2025.02.008","url":null,"abstract":"<p><strong>Introduction: </strong>Cystic fibrosis (CF) is caused by mutation of the CFTR gene, encoding an epithelial anion channel. Here we evaluated the effect of the modulator combination elexacaftor-tezacaftor-ivacaftor (ETI) on the function of four rare, poorly characterized CFTR variants: L383S, I507del, L1065P and R1066H.</p><p><strong>Methods: </strong>Intestinal organoids were obtained from subjects carrying the CFTR variants L383S, I507del, L1065P or R1066H in trans of a minimal function allele (class I mutation). Organoids and epithelial monolayers were used to assess the effect of ETI on CFTR protein abundance and CFTR-mediated chloride, bicarbonate, and fluid transport.</p><p><strong>Results: </strong>In L383S-CFTR expressing cells, normal levels of fully glycosylated CFTR protein (C-band) were detected. In contrast, in I507del, L1065P or R1066H organoids, only partially glycosylated CFTR (B-band) was detected. Chloride/bicarbonate transport was severely impaired in epithelial monolayers prepared from these latter three variants, while anion transport of the L383S variant was affected to a moderate extent. ETI, but not ivacaftor alone, significantly enhanced CFTR-mediated chloride and bicarbonate transport in L1065P and R1066H monolayers, and stimulated fluid transport. A corresponding increase in the abundance of C-band protein was observed in both variants. ETI also modestly improved L383S-CFTR function, with a marginal effect on I507del-CFTR.</p><p><strong>Conclusions: </strong>The I507del, L1065P and R1066H variants display severely impaired function. ETI treatment markedly enhanced L1065P- and R1066HCFTR function, whereas its effect on L383S- CFTR was less pronounced. Consequently, ETI may ameliorate disease symptoms in individuals carrying the L1065P or R1066H variant. More tentative, it may also benefit those carrying the L383S variant.</p>","PeriodicalId":15452,"journal":{"name":"Journal of Cystic Fibrosis","volume":" ","pages":""},"PeriodicalIF":5.4,"publicationDate":"2025-02-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143468210","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}
Pub Date : 2025-02-18DOI: 10.1016/j.jcf.2025.02.012
Amel Alameeri, Burcu Capraz Yavuz, Francesca Lucca, Ivan Bambir, Paulina Famulska, Renata W F Cohen
The year 2024 marks a pivotal moment in the field of cystic fibrosis (CF) treatment, characterised by significant advancements in clinical care and an expanding body of literature on CF transmembrane conductance regulator (CFTR) modulators. These CFTR therapies have transformed the landscape of CF management, offered systemic benefits, and established new guidelines for assessing clinical manifestations and therapies. Additionally, progress has been made in newborn screening (NBS), diagnosis, and understanding outcomes for individuals with CF-related metabolic syndrome or inconclusive diagnostic results. However, amidst these clinical milestones, disparities in global access to CFTR modulators (CFTRm) persist, threatening to exacerbate existing inequities in CF care. This review provides a focused overview of the most impactful articles from 2024, highlighting both the clinical advancements and the pressing global accessibility challenges that define this transformative era in CF research and treatment.
{"title":"Cystic fibrosis year in review 2024.","authors":"Amel Alameeri, Burcu Capraz Yavuz, Francesca Lucca, Ivan Bambir, Paulina Famulska, Renata W F Cohen","doi":"10.1016/j.jcf.2025.02.012","DOIUrl":"https://doi.org/10.1016/j.jcf.2025.02.012","url":null,"abstract":"<p><p>The year 2024 marks a pivotal moment in the field of cystic fibrosis (CF) treatment, characterised by significant advancements in clinical care and an expanding body of literature on CF transmembrane conductance regulator (CFTR) modulators. These CFTR therapies have transformed the landscape of CF management, offered systemic benefits, and established new guidelines for assessing clinical manifestations and therapies. Additionally, progress has been made in newborn screening (NBS), diagnosis, and understanding outcomes for individuals with CF-related metabolic syndrome or inconclusive diagnostic results. However, amidst these clinical milestones, disparities in global access to CFTR modulators (CFTRm) persist, threatening to exacerbate existing inequities in CF care. This review provides a focused overview of the most impactful articles from 2024, highlighting both the clinical advancements and the pressing global accessibility challenges that define this transformative era in CF research and treatment.</p>","PeriodicalId":15452,"journal":{"name":"Journal of Cystic Fibrosis","volume":" ","pages":""},"PeriodicalIF":5.4,"publicationDate":"2025-02-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143458256","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}
Pub Date : 2025-02-18DOI: 10.1016/j.jcf.2025.02.011
Henryk Mazurek, Andrzej Emeryk, Kamil Janeczek, Eric Derom, Barbara Kuźnar-Kamińska, Tomasz Grzywalski, Adam Biniakowski, Krzysztof Szarzyński, Anna Pastusiak, Dominika Kaminiarczyk-Pyzałka, Dick Botteldooren, Honorata Hafke-Dys, Jędrzej Kociński
Background: AI-aided home stethoscopes offer the opportunity of continuous remote monitoring of cystic fibrosis (CF) patients, reducing the need for clinic visits.
Aim: This study aimed to analyze the possibility of detecting CF pulmonary exacerbations (PEx) at home using an AI-aided stethoscope (AIS).
Materials and methods: In a six-month study, 129 CF patients (85 children, 44 adults) used AIS for at least weekly self-examinations, recording various parameters: wheezes, rhonchi, crackles intensity, respiratory and heart rate, and inspiration-to-expiration ratio. Health state surveys were also completed. Physicians evaluated 5160 examinations to identify PEx. Machine learning models were trained using those parameters, and AUCs were calculated for PEx detection.
Results: 522 self-examinations were diagnosed clinically as exacerbated. AI-aided home stethoscopes detected 415 exacerbated self-examinations (sensitivity 79.5 % at specificity 89.1 %). Among the single-parameter discriminators, coarse crackles intensity exhibited an AUC of 70 % (95% CI: 65-75) for young children, fine crackles intensity demonstrated an AUC of 75 % (95 % CI: 72-78) for older children, and an AUC of 93 % (95 % CI: 92-93) was achieved for adults using fine crackles intensity. The combination of parameters yielded the highest efficacy, with AUC exceeding 83% for objective parameters from the AI module alone and exceeding 90 % when incorporating both objective and subjective parameters across all groups.
Conclusions: The AI-aided home stethoscope has proven to be a reliable tool for detecting PEx with greater accuracy than self-assessment alone. Implementing this technology in healthcare systems has the potential to provide valuable insights for timely intervention and management of PExes.
{"title":"AI-facilitated home monitoring for cystic fibrosis exacerbations across pediatric and adult populations.","authors":"Henryk Mazurek, Andrzej Emeryk, Kamil Janeczek, Eric Derom, Barbara Kuźnar-Kamińska, Tomasz Grzywalski, Adam Biniakowski, Krzysztof Szarzyński, Anna Pastusiak, Dominika Kaminiarczyk-Pyzałka, Dick Botteldooren, Honorata Hafke-Dys, Jędrzej Kociński","doi":"10.1016/j.jcf.2025.02.011","DOIUrl":"https://doi.org/10.1016/j.jcf.2025.02.011","url":null,"abstract":"<p><strong>Background: </strong>AI-aided home stethoscopes offer the opportunity of continuous remote monitoring of cystic fibrosis (CF) patients, reducing the need for clinic visits.</p><p><strong>Aim: </strong>This study aimed to analyze the possibility of detecting CF pulmonary exacerbations (PEx) at home using an AI-aided stethoscope (AIS).</p><p><strong>Materials and methods: </strong>In a six-month study, 129 CF patients (85 children, 44 adults) used AIS for at least weekly self-examinations, recording various parameters: wheezes, rhonchi, crackles intensity, respiratory and heart rate, and inspiration-to-expiration ratio. Health state surveys were also completed. Physicians evaluated 5160 examinations to identify PEx. Machine learning models were trained using those parameters, and AUCs were calculated for PEx detection.</p><p><strong>Results: </strong>522 self-examinations were diagnosed clinically as exacerbated. AI-aided home stethoscopes detected 415 exacerbated self-examinations (sensitivity 79.5 % at specificity 89.1 %). Among the single-parameter discriminators, coarse crackles intensity exhibited an AUC of 70 % (95% CI: 65-75) for young children, fine crackles intensity demonstrated an AUC of 75 % (95 % CI: 72-78) for older children, and an AUC of 93 % (95 % CI: 92-93) was achieved for adults using fine crackles intensity. The combination of parameters yielded the highest efficacy, with AUC exceeding 83% for objective parameters from the AI module alone and exceeding 90 % when incorporating both objective and subjective parameters across all groups.</p><p><strong>Conclusions: </strong>The AI-aided home stethoscope has proven to be a reliable tool for detecting PEx with greater accuracy than self-assessment alone. Implementing this technology in healthcare systems has the potential to provide valuable insights for timely intervention and management of PExes.</p>","PeriodicalId":15452,"journal":{"name":"Journal of Cystic Fibrosis","volume":" ","pages":""},"PeriodicalIF":5.4,"publicationDate":"2025-02-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143458255","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}
Background: Despite the existence of numerous clinical practice guidelines (CPGs) for cystic fibrosis (CF), there is limited understanding of their credibility and consistency. This systematic review aims to comprehensively evaluate the quality of CPGs for CF and its pulmonary complications, focusing on treatment recommendations for pulmonary care.
Methods: We conducted a comprehensive search across four databases and relevant websites to identify eligible guidelines providing treatment recommendations. The quality of these guidelines was assessed using the Appraisal of Guidelines for Research and Evaluation (AGREE) II tool. Pulmonary treatment recommendations were analyzed and synthesized narratively.
Results: A total of 35 guidelines were identified. Most guidelines were of moderate quality according to the AGREE II instrument, with overall scores ranging from 21·05 to 76·13. Only six guidelines were recommended for use. These guidelines provide 359 pulmonary treatment recommendations for seven primary therapies and others. There was inconsistency in the use of airway clearance therapy, anti-inflammatories, antibiotics, inhaled drugs, and cystic fibrosis transmembrane conductance regulator modulator therapy. Four guidelines conditionally advocated for oral corticosteroids, while six opposed routine inhaled corticosteroids. One guideline discouraged lumacaftor-ivacaftor in the general CF population, two recommended only for children under 12 years old, and another strongly advocated for children between 2 and 5 years of age. However, one guideline noted a lack of evidence to recommend it for children under 6.
Conclusion: The quality of CPGs for CF and its pulmonary complications has improved over time, reaching a moderate level generally, but there is still room for further improvement. Future efforts should focus on standardizing methodological frameworks and generating robust clinical evidence to enhance the overall quality and applicability of CF guidelines.
{"title":"Evaluation of clinical practice guidelines on treatment of cystic fibrosis: A systematic review.","authors":"Yuting Huang, Jingxuan Zhang, Mianquan Zhang, Xuetao Kong, Zhufeng Wang, Yuxiang Zhang, Zhili Zou, Zhuyinjun Zong, Jiaying Guo, Quanzhen Liu, Jing Ling, Wangji Zhou, Xueqi Liu, Jie Liu, Xinlun Tian, Mei Jiang","doi":"10.1016/j.jcf.2025.02.005","DOIUrl":"https://doi.org/10.1016/j.jcf.2025.02.005","url":null,"abstract":"<p><strong>Background: </strong>Despite the existence of numerous clinical practice guidelines (CPGs) for cystic fibrosis (CF), there is limited understanding of their credibility and consistency. This systematic review aims to comprehensively evaluate the quality of CPGs for CF and its pulmonary complications, focusing on treatment recommendations for pulmonary care.</p><p><strong>Methods: </strong>We conducted a comprehensive search across four databases and relevant websites to identify eligible guidelines providing treatment recommendations. The quality of these guidelines was assessed using the Appraisal of Guidelines for Research and Evaluation (AGREE) II tool. Pulmonary treatment recommendations were analyzed and synthesized narratively.</p><p><strong>Results: </strong>A total of 35 guidelines were identified. Most guidelines were of moderate quality according to the AGREE II instrument, with overall scores ranging from 21·05 to 76·13. Only six guidelines were recommended for use. These guidelines provide 359 pulmonary treatment recommendations for seven primary therapies and others. There was inconsistency in the use of airway clearance therapy, anti-inflammatories, antibiotics, inhaled drugs, and cystic fibrosis transmembrane conductance regulator modulator therapy. Four guidelines conditionally advocated for oral corticosteroids, while six opposed routine inhaled corticosteroids. One guideline discouraged lumacaftor-ivacaftor in the general CF population, two recommended only for children under 12 years old, and another strongly advocated for children between 2 and 5 years of age. However, one guideline noted a lack of evidence to recommend it for children under 6.</p><p><strong>Conclusion: </strong>The quality of CPGs for CF and its pulmonary complications has improved over time, reaching a moderate level generally, but there is still room for further improvement. Future efforts should focus on standardizing methodological frameworks and generating robust clinical evidence to enhance the overall quality and applicability of CF guidelines.</p>","PeriodicalId":15452,"journal":{"name":"Journal of Cystic Fibrosis","volume":" ","pages":""},"PeriodicalIF":5.4,"publicationDate":"2025-02-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143433253","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}
Pub Date : 2025-02-15DOI: 10.1016/j.jcf.2025.02.003
Jennifer A Bartlett, Eric D Huntemann, Sateesh Krishnamurthy, Stacey M Hartwig, Alvin Pewa, Andrew L Thurman, Michael S Chimenti, Eric B Taylor, Steven M Varga, Paul B McCray
Background: In individuals with cystic fibrosis (CF), respiratory viral infections frequently result in hospitalization and have been linked to secondary bacterial infection and colonization, highlighting viral infections as possible contributors to CF lung disease progression. We hypothesized that expression of antiviral host defense genes is dysregulated in CF airway epithelia.
Methods: We infected primary CF and Non-CF airway epithelia with respiratory syncytial virus (RSV) and characterized their responses at 12 hr, 24 hr, 48 hr, 72 hr, and 120 hr post infection (hpi) by RNA sequencing (RNAseq).
Results: Our analysis revealed strikingly different gene expression profiles for the CF and Non-CF epithelia over the course of the infection. While both CF and Non-CF cells exhibited an early signature for interferon signaling and antiviral defense pathways, this response was relatively exaggerated and sustained in CF epithelia. We also observed, in both genotypes, a transient downregulation of cilia-associated genes and loss of ciliary activity by 72 hpi. Interestingly, recovery of cilia activity was delayed in the CF epithelia.
Conclusions: These findings further our understanding of innate immune dysfunction in the CF airway epithelium and suggest that virus-induced cilia injury may further compromise host defenses in CF airways.
{"title":"CF airway epithelia display exaggerated host defense responses and prolonged cilia loss during RSV infection.","authors":"Jennifer A Bartlett, Eric D Huntemann, Sateesh Krishnamurthy, Stacey M Hartwig, Alvin Pewa, Andrew L Thurman, Michael S Chimenti, Eric B Taylor, Steven M Varga, Paul B McCray","doi":"10.1016/j.jcf.2025.02.003","DOIUrl":"https://doi.org/10.1016/j.jcf.2025.02.003","url":null,"abstract":"<p><strong>Background: </strong>In individuals with cystic fibrosis (CF), respiratory viral infections frequently result in hospitalization and have been linked to secondary bacterial infection and colonization, highlighting viral infections as possible contributors to CF lung disease progression. We hypothesized that expression of antiviral host defense genes is dysregulated in CF airway epithelia.</p><p><strong>Methods: </strong>We infected primary CF and Non-CF airway epithelia with respiratory syncytial virus (RSV) and characterized their responses at 12 hr, 24 hr, 48 hr, 72 hr, and 120 hr post infection (hpi) by RNA sequencing (RNAseq).</p><p><strong>Results: </strong>Our analysis revealed strikingly different gene expression profiles for the CF and Non-CF epithelia over the course of the infection. While both CF and Non-CF cells exhibited an early signature for interferon signaling and antiviral defense pathways, this response was relatively exaggerated and sustained in CF epithelia. We also observed, in both genotypes, a transient downregulation of cilia-associated genes and loss of ciliary activity by 72 hpi. Interestingly, recovery of cilia activity was delayed in the CF epithelia.</p><p><strong>Conclusions: </strong>These findings further our understanding of innate immune dysfunction in the CF airway epithelium and suggest that virus-induced cilia injury may further compromise host defenses in CF airways.</p>","PeriodicalId":15452,"journal":{"name":"Journal of Cystic Fibrosis","volume":" ","pages":""},"PeriodicalIF":5.4,"publicationDate":"2025-02-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143433200","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}
Pub Date : 2025-02-15DOI: 10.1016/j.jcf.2025.02.001
Lauren J Clayton, Anthony I Shepherd, Jo Corbett, Maria Perissiou, Gary Connett, Julian Legg, Mark Allenby, Thomas Daniels, Don S Urquhart, Kelly A Mackintosh, Melitta A McNarry, Zoe L Saynor
Background: Cystic fibrosis (CF) has been associated with impaired cardiovascular and endothelial function. CF transmembrane conductance regulator (CFTR) modulator therapy, most recently Elexacaftor/Tezacaftor/Ivacaftor (ETI), has led to improved CFTR function and life expectancy. However, the rising prevalence of obesity in adults is concerning. This study assessed the micro- and macrovascular endothelial function, cardiovascular disease (CVD) risk factors, and physical activity (PA) profiles in people with CF (pwCF) on ETI compared to healthy matched controls.
Methods: In 15 pwCF and 15 age- and sex-matched controls, microvascular endothelial function (via transdermal delivery of insulin [INS] and acetylcholine [ACh] on the forearm), macrovascular endothelial function (via flow-mediated dilation [FMD] of the brachial artery), central haemodynamic parameters, including heart rate (HR), stroke volume index (SVi) and cardiac output index (Q̇I) (via thoracic impedance cardiography), body mass index (BMI), blood pressure (BP), and accelerometer-assessed PA were measured.
Results: There were no differences in INS or FMD-mediated vasodilation between the groups (P > 0.05). However, a reduced vasodilatory response was evident in pwCF following ACh-mediated vasodilation (P = 0.01) and FMD normalised for shear rate (P = 0.03). No differences in resting HR, SVi, Q̇I, BP, BMI or PA were found (P > 0.05).
Conclusion: This study demonstrated reduced micro- and macrovascular function in pwCF. This dysfunction may have potential health implications, particularly regarding long-term cardiovascular risk and further longitudinal assessments are warranted.
{"title":"Cardiovascular function in people with cystic fibrosis on Elexacaftor/Tezacaftor/Ivacaftor: A cross-sectional, observational, single-centre study.","authors":"Lauren J Clayton, Anthony I Shepherd, Jo Corbett, Maria Perissiou, Gary Connett, Julian Legg, Mark Allenby, Thomas Daniels, Don S Urquhart, Kelly A Mackintosh, Melitta A McNarry, Zoe L Saynor","doi":"10.1016/j.jcf.2025.02.001","DOIUrl":"https://doi.org/10.1016/j.jcf.2025.02.001","url":null,"abstract":"<p><strong>Background: </strong>Cystic fibrosis (CF) has been associated with impaired cardiovascular and endothelial function. CF transmembrane conductance regulator (CFTR) modulator therapy, most recently Elexacaftor/Tezacaftor/Ivacaftor (ETI), has led to improved CFTR function and life expectancy. However, the rising prevalence of obesity in adults is concerning. This study assessed the micro- and macrovascular endothelial function, cardiovascular disease (CVD) risk factors, and physical activity (PA) profiles in people with CF (pwCF) on ETI compared to healthy matched controls.</p><p><strong>Methods: </strong>In 15 pwCF and 15 age- and sex-matched controls, microvascular endothelial function (via transdermal delivery of insulin [INS] and acetylcholine [ACh] on the forearm), macrovascular endothelial function (via flow-mediated dilation [FMD] of the brachial artery), central haemodynamic parameters, including heart rate (HR), stroke volume index (SVi) and cardiac output index (Q̇I) (via thoracic impedance cardiography), body mass index (BMI), blood pressure (BP), and accelerometer-assessed PA were measured.</p><p><strong>Results: </strong>There were no differences in INS or FMD-mediated vasodilation between the groups (P > 0.05). However, a reduced vasodilatory response was evident in pwCF following ACh-mediated vasodilation (P = 0.01) and FMD normalised for shear rate (P = 0.03). No differences in resting HR, SVi, Q̇I, BP, BMI or PA were found (P > 0.05).</p><p><strong>Conclusion: </strong>This study demonstrated reduced micro- and macrovascular function in pwCF. This dysfunction may have potential health implications, particularly regarding long-term cardiovascular risk and further longitudinal assessments are warranted.</p>","PeriodicalId":15452,"journal":{"name":"Journal of Cystic Fibrosis","volume":" ","pages":""},"PeriodicalIF":5.4,"publicationDate":"2025-02-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143433186","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}
Pub Date : 2025-02-15DOI: 10.1016/j.jcf.2025.02.007
Ana Piñar-Gutiérrez, Esther Quintana-Gallego, Pablo J Remón-Ruiz, Ángeles Pizarro, Irene González-Navarro, Andrés Jiménez-Sánchez, Silvia García-Rey, María Del Carmen Roque-Cuéllar, Sheila Gato, Inmaculada Domínguez, Francisco Javier Castell, Manuel Romero-Gómez, Pedro Pablo García-Luna
Background & aims: Cystic fibrosis hepatobiliary involvement is a heterogeneous and systemic entity. The primary objective was to determine the prevalence of steatosis, by magnetic resonance-proton density fat fraction (MR-PDFF), and liver fibrosis, by magnetic resonance elastography (MRE), in a cohort of adults with cystic fibrosis. The secondary objective was to determine the diagnostic yield of widely available non-invasive liver markers for steatosis and fibrosis, and vibration controlled transitional elastography (VCTE) releasing Control Attenuation Parameter (CAP) (dB/m) and stiffness (kPa), with the aim of proposing a diagnostic algorithm.
Methods: We conducted a cross-sectional study including 101 adult patients with cystic fibrosis seen in a multidisciplinary unit. The study encompassed a clinical evaluation, morpho-functional assessment, VCTE, non-invasive liver markers and MR-PDFF and MRE. Diagnostic accuracy was assessed using ROC curves and 2 × 2 tables.
Results: MR-PDFF detected hepatic steatosis in 18 of 101 (17.8 %) patients, while MRE detected significant liver fibrosis in 15 of 101 (14.9 %). The VCTE cut-off with the best diagnostic yield, determined by the Youden index, was 222 dB/m for the presence of steatosis (AUC 0.864 (95 % CI 0.768-0.961; p < 0.001) and the VCTE cut-off was 6.65 kPa for liver fibrosis (AUC 0.951(95 % CI 0.81-1; p = 0.053). A screening algorithm for hepatic steatosis was developed using the fatty liver index (FLI) and CAP, with a negative predictive value of 83.3 %. For liver fibrosis, it was outperformed by the Hepamet Fibrosis Score (HFS) and VCTE, with a negative predictive value of 100 %.
Conclusions: The prevalence of hepatic steatosis and liver fibrosis was 17.8 % and 14.9 %, respectively. VCTE alone or in combination with FLI for steatosis or HFS for fibrosis demonstrated high diagnostic accuracy. This approach effectively allows for the exclusion of steatosis and fibrosis, thereby reducing the need for MR-PDFF and MRE studies.
{"title":"Non-invasive evaluation of steatosis and fibrosis in the liver in adults patients living with cystic fibrosis.","authors":"Ana Piñar-Gutiérrez, Esther Quintana-Gallego, Pablo J Remón-Ruiz, Ángeles Pizarro, Irene González-Navarro, Andrés Jiménez-Sánchez, Silvia García-Rey, María Del Carmen Roque-Cuéllar, Sheila Gato, Inmaculada Domínguez, Francisco Javier Castell, Manuel Romero-Gómez, Pedro Pablo García-Luna","doi":"10.1016/j.jcf.2025.02.007","DOIUrl":"https://doi.org/10.1016/j.jcf.2025.02.007","url":null,"abstract":"<p><strong>Background & aims: </strong>Cystic fibrosis hepatobiliary involvement is a heterogeneous and systemic entity. The primary objective was to determine the prevalence of steatosis, by magnetic resonance-proton density fat fraction (MR-PDFF), and liver fibrosis, by magnetic resonance elastography (MRE), in a cohort of adults with cystic fibrosis. The secondary objective was to determine the diagnostic yield of widely available non-invasive liver markers for steatosis and fibrosis, and vibration controlled transitional elastography (VCTE) releasing Control Attenuation Parameter (CAP) (dB/m) and stiffness (kPa), with the aim of proposing a diagnostic algorithm.</p><p><strong>Methods: </strong>We conducted a cross-sectional study including 101 adult patients with cystic fibrosis seen in a multidisciplinary unit. The study encompassed a clinical evaluation, morpho-functional assessment, VCTE, non-invasive liver markers and MR-PDFF and MRE. Diagnostic accuracy was assessed using ROC curves and 2 × 2 tables.</p><p><strong>Results: </strong>MR-PDFF detected hepatic steatosis in 18 of 101 (17.8 %) patients, while MRE detected significant liver fibrosis in 15 of 101 (14.9 %). The VCTE cut-off with the best diagnostic yield, determined by the Youden index, was 222 dB/m for the presence of steatosis (AUC 0.864 (95 % CI 0.768-0.961; p < 0.001) and the VCTE cut-off was 6.65 kPa for liver fibrosis (AUC 0.951(95 % CI 0.81-1; p = 0.053). A screening algorithm for hepatic steatosis was developed using the fatty liver index (FLI) and CAP, with a negative predictive value of 83.3 %. For liver fibrosis, it was outperformed by the Hepamet Fibrosis Score (HFS) and VCTE, with a negative predictive value of 100 %.</p><p><strong>Conclusions: </strong>The prevalence of hepatic steatosis and liver fibrosis was 17.8 % and 14.9 %, respectively. VCTE alone or in combination with FLI for steatosis or HFS for fibrosis demonstrated high diagnostic accuracy. This approach effectively allows for the exclusion of steatosis and fibrosis, thereby reducing the need for MR-PDFF and MRE studies.</p>","PeriodicalId":15452,"journal":{"name":"Journal of Cystic Fibrosis","volume":" ","pages":""},"PeriodicalIF":5.4,"publicationDate":"2025-02-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143433255","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}
Pub Date : 2025-02-12DOI: 10.1016/j.jcf.2025.01.016
Marijn Berg, Lisette Krabbendam, Esmee K van der Ploeg, Menno van Nimwegen, Tjeerd van der Veer, Martin Banchero, Orestes A Carpaij, Remco Hoogenboezem, Maarten van den Berge, Eric Bindels, Joachim G J V Aerts, Antoine Collin, Pascal Barbry, Lieke S Kamphuis, Rudi W Hendriks, Martijn C Nawijn, Ralph Stadhouders
Background: Chronic pulmonary inflammation strongly contributes to respiratory failure and mortality in patients with cystic fibrosis (pwCF). Effective anti-microbial immunity and maintaining lung homeostasis require continuous structural-immune cell communication. Whether and how this crosstalk is altered in CF remains poorly understood, obscuring potential new angles for therapy development to restore airway homeostasis in pwCF.
Methods: We performed droplet-based single cell RNA-sequencing on bronchial biopsies from pwCF to investigate structural-immune cell crosstalk. Computational analyses were used to compare these data to samples obtained from healthy controls.
Results: CF airway wall biopsies showed lower proportions and altered transcriptomes of basal cells, submucosal gland cells and endothelial cells, and a higher abundance of ciliated cells, monocytes, macrophages and T cells. Both B and T lymphocytes displayed aberrantly activated phenotypes with transcriptional changes linked to hypoxia and vascular endothelial growth factor signaling, indicative of crosstalk with endothelial cells. The CF lung displayed unique changes in intercellular communication potential involving ionocytes, macrophages, endothelial cells and lymphocytes. This included interactions between HLA-E on structural cells and the druggable CD94/NKG2A immune checkpoint on CD8+T cells.
Conclusions: We report the first single cell transcriptome atlas of the CF lung containing the full spectrum of structural and immune cells, providing a valuable resource for investigating changes to cellular composition, phenotypes and crosstalk linked to CF. Our analyses highlight dysregulated basal cell function and adaptive immunity in pwCF - despite favorable responses to CFTR modulator therapy. We identify novel aspects of CF pathophysiology and potential entry points for therapeutic strategies.
{"title":"Evidence for altered immune-structural cell crosstalk in cystic fibrosis revealed by single cell transcriptomics.","authors":"Marijn Berg, Lisette Krabbendam, Esmee K van der Ploeg, Menno van Nimwegen, Tjeerd van der Veer, Martin Banchero, Orestes A Carpaij, Remco Hoogenboezem, Maarten van den Berge, Eric Bindels, Joachim G J V Aerts, Antoine Collin, Pascal Barbry, Lieke S Kamphuis, Rudi W Hendriks, Martijn C Nawijn, Ralph Stadhouders","doi":"10.1016/j.jcf.2025.01.016","DOIUrl":"https://doi.org/10.1016/j.jcf.2025.01.016","url":null,"abstract":"<p><strong>Background: </strong>Chronic pulmonary inflammation strongly contributes to respiratory failure and mortality in patients with cystic fibrosis (pwCF). Effective anti-microbial immunity and maintaining lung homeostasis require continuous structural-immune cell communication. Whether and how this crosstalk is altered in CF remains poorly understood, obscuring potential new angles for therapy development to restore airway homeostasis in pwCF.</p><p><strong>Methods: </strong>We performed droplet-based single cell RNA-sequencing on bronchial biopsies from pwCF to investigate structural-immune cell crosstalk. Computational analyses were used to compare these data to samples obtained from healthy controls.</p><p><strong>Results: </strong>CF airway wall biopsies showed lower proportions and altered transcriptomes of basal cells, submucosal gland cells and endothelial cells, and a higher abundance of ciliated cells, monocytes, macrophages and T cells. Both B and T lymphocytes displayed aberrantly activated phenotypes with transcriptional changes linked to hypoxia and vascular endothelial growth factor signaling, indicative of crosstalk with endothelial cells. The CF lung displayed unique changes in intercellular communication potential involving ionocytes, macrophages, endothelial cells and lymphocytes. This included interactions between HLA-E on structural cells and the druggable CD94/NKG2A immune checkpoint on CD8<sup>+</sup>T cells.</p><p><strong>Conclusions: </strong>We report the first single cell transcriptome atlas of the CF lung containing the full spectrum of structural and immune cells, providing a valuable resource for investigating changes to cellular composition, phenotypes and crosstalk linked to CF. Our analyses highlight dysregulated basal cell function and adaptive immunity in pwCF - despite favorable responses to CFTR modulator therapy. We identify novel aspects of CF pathophysiology and potential entry points for therapeutic strategies.</p>","PeriodicalId":15452,"journal":{"name":"Journal of Cystic Fibrosis","volume":" ","pages":""},"PeriodicalIF":5.4,"publicationDate":"2025-02-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143414369","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}
Pub Date : 2025-02-12DOI: 10.1016/j.jcf.2025.01.017
Anastasia Ward, Ramil Mauleon, Chee Y Ooi, Nedeljka Rosić
{"title":"Letter to the Editor: Additional considerations for addressing pain in people living with cystic fibrosis.","authors":"Anastasia Ward, Ramil Mauleon, Chee Y Ooi, Nedeljka Rosić","doi":"10.1016/j.jcf.2025.01.017","DOIUrl":"https://doi.org/10.1016/j.jcf.2025.01.017","url":null,"abstract":"","PeriodicalId":15452,"journal":{"name":"Journal of Cystic Fibrosis","volume":" ","pages":""},"PeriodicalIF":5.4,"publicationDate":"2025-02-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143414371","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}
Pub Date : 2025-02-11DOI: 10.1016/j.jcf.2025.02.006
{"title":"Advertisement for Editor-in-Chief, Journal of Cystic Fibrosis.","authors":"","doi":"10.1016/j.jcf.2025.02.006","DOIUrl":"https://doi.org/10.1016/j.jcf.2025.02.006","url":null,"abstract":"","PeriodicalId":15452,"journal":{"name":"Journal of Cystic Fibrosis","volume":" ","pages":""},"PeriodicalIF":5.4,"publicationDate":"2025-02-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143408108","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}