Pub Date : 2025-11-01DOI: 10.1016/j.jcf.2025.07.013
Haley Haskett , Christopher Fortner , Laura Shanley , Clement L Ren
Cystic fibrosis transmembrane conductance regulator (CFTR) dysfunction leads to progressive exocrine pancreatic insufficiency, resulting in difficulty in the secretion of digestive enzymes and subsequent malabsorption of nutrients. Case reports have described preserved pancreatic function with prenatal elexacaftor/tezacaftor/ivacaftor (ETI) exposure. However, little is known about pancreatic function and injury as ETI exposure decreases postnatally. Here, we discuss four infants with cystic fibrosis (CF) who were prenatally exposed to ETI, with pancreatic function ranging from preserved to mild insufficiency. All four developed elevated serum lipase, a marker of pancreatic cell injury, as ETI exposure diminished after birth. These cases illustrate the relationship between sweat chloride as a biomarker of CFTR function, fecal elastase as a biomarker of pancreatic function, and serum lipase a biomarker of pancreatic cell injury. While prenatal ETI exposure can preserve pancreatic function in infants with CF, ongoing postnatal ETI exposure may be necessary to prevent pancreatic damage, suggesting a role for early ETI therapy in prenatally exposed infants.
{"title":"Elevated serum lipase in infants with cystic fibrosis exposed to prenatal and postnatal elexacaftor/tezacaftor/ivacaftor","authors":"Haley Haskett , Christopher Fortner , Laura Shanley , Clement L Ren","doi":"10.1016/j.jcf.2025.07.013","DOIUrl":"10.1016/j.jcf.2025.07.013","url":null,"abstract":"<div><div>Cystic fibrosis transmembrane conductance regulator (CFTR) dysfunction leads to progressive exocrine pancreatic insufficiency, resulting in difficulty in the secretion of digestive enzymes and subsequent malabsorption of nutrients. Case reports have described preserved pancreatic function with prenatal elexacaftor/tezacaftor/ivacaftor (ETI) exposure. However, little is known about pancreatic function and injury as ETI exposure decreases postnatally. Here, we discuss four infants with cystic fibrosis (CF) who were prenatally exposed to ETI, with pancreatic function ranging from preserved to mild insufficiency. All four developed elevated serum lipase, a marker of pancreatic cell injury, as ETI exposure diminished after birth. These cases illustrate the relationship between sweat chloride as a biomarker of CFTR function, fecal elastase as a biomarker of pancreatic function, and serum lipase a biomarker of pancreatic cell injury. While prenatal ETI exposure can preserve pancreatic function in infants with CF, ongoing postnatal ETI exposure may be necessary to prevent pancreatic damage, suggesting a role for early ETI therapy in prenatally exposed infants.</div></div>","PeriodicalId":15452,"journal":{"name":"Journal of Cystic Fibrosis","volume":"24 6","pages":"Pages 1090-1093"},"PeriodicalIF":6.0,"publicationDate":"2025-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144717996","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 : 2025-11-01DOI: 10.1016/j.jcf.2025.08.017
Gabriela R. Oates , Elizabeth H. Baker , Lucia D. Juarez , Ariann F. Nassel , Elizabeth A. Cromwell
Introduction
Providing care to under-resourced patients places additional burdens on CF care teams, therefore it is important to identify programs that serve disproportionately disadvantaged populations.
Methods
Using the U.S. CF Foundation Patient Registry data (2015–2022), we linked residential ZIP codes to area-level measures of socioeconomic disadvantage (the Area Deprivation Index - ADI, the Social Vulnerability Index - SVI) and rurality. We supplemented area-level data with patient-level measures, particularly health insurance type. Values were averaged across each program to create a program-level proportion of patients defined as disadvantaged (by either SVI, ADI, or insurance) or rural. CF care programs in the U.S. were then ranked by the proportion of disadvantaged patients for each year.
Results
We analyzed data from 41,577 individuals during the 8-year period. In 2022, 48.8 % of CF patients received care in pediatric programs (N = 130), 46.4 % in adult programs (N = 117), and 4.8 % in affiliate programs (N = 35). About one-quarter of CF programs (23.8 %, n = 67) scored in the worst 20 % for one disadvantage measure, 12.1 % (n = 34) in the worst 20 % for two disadvantage measures, and only 2.5 % (n = 7) scored in the worst 20 % for all three measures of disadvantage. There were distinct regional patterns associated with each classification method.
Conclusion
We recommend a joint use of all measures (SVI, ADI, and health insurance), annual update of rankings, and separate pediatric vs adult classification to identify CF programs that care for disproportionately disadvantaged patients and to design new strategies to meet the care needs of these populations.
{"title":"Identifying cystic fibrosis programs in the United States with disproportionately disadvantaged patient populations: Methodology and implications for care","authors":"Gabriela R. Oates , Elizabeth H. Baker , Lucia D. Juarez , Ariann F. Nassel , Elizabeth A. Cromwell","doi":"10.1016/j.jcf.2025.08.017","DOIUrl":"10.1016/j.jcf.2025.08.017","url":null,"abstract":"<div><h3>Introduction</h3><div>Providing care to under-resourced patients places additional burdens on CF care teams, therefore it is important to identify programs that serve disproportionately disadvantaged populations.</div></div><div><h3>Methods</h3><div>Using the U.S. CF Foundation Patient Registry data (2015–2022), we linked residential ZIP codes to area-level measures of socioeconomic disadvantage (the Area Deprivation Index - ADI, the Social Vulnerability Index - SVI) and rurality. We supplemented area-level data with patient-level measures, particularly health insurance type. Values were averaged across each program to create a program-level proportion of patients defined as disadvantaged (by either SVI, ADI, or insurance) or rural. CF care programs in the U.S. were then ranked by the proportion of disadvantaged patients for each year.</div></div><div><h3>Results</h3><div>We analyzed data from 41,577 individuals during the 8-year period. In 2022, 48.8 % of CF patients received care in pediatric programs (<em>N</em> = 130), 46.4 % in adult programs (<em>N</em> = 117), and 4.8 % in affiliate programs (<em>N</em> = 35). About one-quarter of CF programs (23.8 %, <em>n</em> = 67) scored in the worst 20 % for one disadvantage measure, 12.1 % (<em>n</em> = 34) in the worst 20 % for two disadvantage measures, and only 2.5 % (<em>n</em> = 7) scored in the worst 20 % for all three measures of disadvantage. There were distinct regional patterns associated with each classification method.</div></div><div><h3>Conclusion</h3><div>We recommend a joint use of all measures (SVI, ADI, and health insurance), annual update of rankings, and separate pediatric vs adult classification to identify CF programs that care for disproportionately disadvantaged patients and to design new strategies to meet the care needs of these populations.</div></div>","PeriodicalId":15452,"journal":{"name":"Journal of Cystic Fibrosis","volume":"24 6","pages":"Pages 1038-1042"},"PeriodicalIF":6.0,"publicationDate":"2025-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144992558","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 : 2025-11-01DOI: 10.1016/j.jcf.2025.10.004
Stephen E. Congly , Ranjani Somayaji , Michael D. Parkins , Christina S. Thornton
The introduction of elexacaftor/tezacaftor/ivacaftor (ETI) has led to improved outcomes and survival in patients living with cystic fibrosis (PwCF) although imposes a substantial economic burden. Despite the reduced healthcare utilization that follows ETI initiation, the economic impact on healthcare spending is not well understood. To try and better understand this, the estimated economic impact on healthcare spending of ETI was calculated in Canada. A treatment naïve cohort of PwCF receiving their first ETI prescription during the 2021–2022 fiscal year from 7 provinces had their healthcare utilization and costs collected one year prior and one year following the initiation of ETI for each patient. Data available included physician visits, emergency department presentations, hospitalizations, drug utilization and laboratory and other diagnostic charges. In the year prior to the first ETI prescription, there was an estimated direct health care cost of $17.6 million CDN. The spending decreased significantly in the year post ETI by $6.9 million with the majority attributed to a 75% reduction in hospitalization-associated costs. When the list price of ETI is accounted for, up to an additional $203 million was spent in the first year after ETI. Irrespective of improvements in life quality brought about by ETI, a price of approximately $10,000/year would be required for it to be cost neutral.
{"title":"Economic impact of elexacaftor/tezacaftor/ivacaftor on healthcare expenditure in Canada","authors":"Stephen E. Congly , Ranjani Somayaji , Michael D. Parkins , Christina S. Thornton","doi":"10.1016/j.jcf.2025.10.004","DOIUrl":"10.1016/j.jcf.2025.10.004","url":null,"abstract":"<div><div>The introduction of elexacaftor/tezacaftor/ivacaftor (ETI) has led to improved outcomes and survival in patients living with cystic fibrosis (PwCF) although imposes a substantial economic burden. Despite the reduced healthcare utilization that follows ETI initiation, the economic impact on healthcare spending is not well understood. To try and better understand this, the estimated economic impact on healthcare spending of ETI was calculated in Canada. A treatment naïve cohort of PwCF receiving their first ETI prescription during the 2021–2022 fiscal year from 7 provinces had their healthcare utilization and costs collected one year prior and one year following the initiation of ETI for each patient. Data available included physician visits, emergency department presentations, hospitalizations, drug utilization and laboratory and other diagnostic charges. In the year prior to the first ETI prescription, there was an estimated direct health care cost of $17.6 million CDN. The spending decreased significantly in the year post ETI by $6.9 million with the majority attributed to a 75% reduction in hospitalization-associated costs. When the list price of ETI is accounted for, up to an additional $203 million was spent in the first year after ETI. Irrespective of improvements in life quality brought about by ETI, a price of approximately $10,000/year would be required for it to be cost neutral.</div></div>","PeriodicalId":15452,"journal":{"name":"Journal of Cystic Fibrosis","volume":"24 6","pages":"Pages 1027-1030"},"PeriodicalIF":6.0,"publicationDate":"2025-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145300949","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 : 2025-11-01DOI: 10.1016/j.jcf.2025.07.001
Natalia Smirnova , Scott Gillespie , Jane Lowers , Andrew Jergel , Elisabeth P Dellon , Alexandre Cammarata-Mouchtouris , Anne Fitzpatrick , Dio Kavalieratos
Background
Despite cystic fibrosis transmembrane conductance (CFTR) modulator therapy that may dramatically alter the course of disease, many people living with cystic fibrosis (PwCF) experience co-occurring symptoms that may be interrelated and may synergistically degrade quality of life. We sought to identify symptom factors, or groups of correlated symptoms, connected by underlying latent variable(s). We then examined demographic and clinical characteristics associated with these groups among PwCF.
Methods
Using baseline data from a trial of specialist palliative care in PwCF, we assessed symptoms with the Memorial Symptom Assessment Scale-CF. We used exploratory factor analysis followed by confirmatory factor analysis to identify and validate symptom factors. For each factor (using only the symptoms identified in the factor), we then created a binary variable (Symptom Factor Severity) that identified patients as Low versus High Severity, by mean splitting the sum of each patient’s severity symptom scores for that factor. Multivariable logistic regression was used to examine associations between demographic and clinical characteristics with each split Symptom Factor Severity score.
Results
Among 262 participants, median age was 33 years, and 78 % were prescribed a CFTR modulator. We identified three symptom factors: respiratory-energy, mood-gastrointestinal irritability, and pain-gastrointestinal dysmotility. High symptom severity in each factor was associated with specific demographic and clinical characteristics.
Conclusions
CF symptom management strategies have historically focused on single-symptom approaches. Findings from this study may prompt clinicians to consider co-occurring symptoms, and ensure their assessment and management is tailored to the unique experiences of PwCF.
{"title":"Symptom factors and their clinical correlates among adults with cystic fibrosis","authors":"Natalia Smirnova , Scott Gillespie , Jane Lowers , Andrew Jergel , Elisabeth P Dellon , Alexandre Cammarata-Mouchtouris , Anne Fitzpatrick , Dio Kavalieratos","doi":"10.1016/j.jcf.2025.07.001","DOIUrl":"10.1016/j.jcf.2025.07.001","url":null,"abstract":"<div><h3>Background</h3><div>Despite cystic fibrosis transmembrane conductance (CFTR) modulator therapy that may dramatically alter the course of disease, many people living with cystic fibrosis (PwCF) experience co-occurring symptoms that may be interrelated and may synergistically degrade quality of life. We sought to identify <em>symptom factors</em>, or groups of correlated symptoms, connected by underlying latent variable(s). We then examined demographic and clinical characteristics associated with these groups among PwCF.</div></div><div><h3>Methods</h3><div>Using baseline data from a trial of specialist palliative care in PwCF, we assessed symptoms with the Memorial Symptom Assessment Scale-CF. We used exploratory factor analysis followed by confirmatory factor analysis to identify and validate symptom factors. For each factor (using only the symptoms identified in the factor), we then created a binary variable (Symptom Factor Severity) that identified patients as Low versus High Severity, by mean splitting the sum of each patient’s severity symptom scores for that factor. Multivariable logistic regression was used to examine associations between demographic and clinical characteristics with each split Symptom Factor Severity score.</div></div><div><h3>Results</h3><div>Among 262 participants, median age was 33 years, and 78 % were prescribed a CFTR modulator. We identified three symptom factors: respiratory-energy, mood-gastrointestinal irritability, and pain-gastrointestinal dysmotility. High symptom severity in each factor was associated with specific demographic and clinical characteristics.</div></div><div><h3>Conclusions</h3><div>CF symptom management strategies have historically focused on single-symptom approaches. Findings from this study may prompt clinicians to consider co-occurring symptoms, and ensure their assessment and management is tailored to the unique experiences of PwCF.</div></div>","PeriodicalId":15452,"journal":{"name":"Journal of Cystic Fibrosis","volume":"24 6","pages":"Pages 1124-1129"},"PeriodicalIF":6.0,"publicationDate":"2025-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144591306","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 : 2025-11-01DOI: 10.1016/j.jcf.2025.07.005
Alison Carr , Carlos Carneiro , Michael Griffin , Mark Higgins , Heike Wöhling , Fiona Hammond , Donatello Salvatore , Barry J. Plant , J. Stuart Elborn
Background
Five cystic fibrosis transmembrane conductance regulator (CFTR) modulator (CFTRm) therapies are approved for patients with cystic fibrosis (CF). Despite the established efficacy and safety of CFTRm therapy, variability exists in prescribing amongst CF physicians. Here, we describe prescriber factors influencing CFTRm use.
Methods
This observational study used clinical vignettes of patients with CF. Participants were adult pulmonologists and pediatricians specializing in respiratory medicine from Germany, Italy, UK, Ireland, and the Netherlands. Participants took part in a 3-step data collection process: (i) 60-minute individual telephone interview; (ii) decision exercise where physicians made a treatment decision about CFTRm on 10 clinical vignettes; and (iii) 30-minute web-assisted interview to provide rationale for treatment decisions. Univariate analysis, dimensionality reduction via factor analysis, and a random-effects logistic regression model were used to identify factors impacting CFTRm prescribing.
Results
Thirty-eight pulmonologists and 42 pediatricians provided 800 clinical decisions. Only 45 % of pulmonologists and 29 % of pediatricians prescribed a CFTRm for all eligible adult or pediatric vignettes. Pancreatic sufficiency decreased odds of prescribing a CFTRm (OR 0.106; 95 % CI 0.046, 0.244) whereas odds increased for patients’ age >12 years (OR 3.779; 95 % CI 1.579, 9.042). Physician characteristics associated with CFTRm prescribing were being proactive/pushing boundaries (OR 1.772; 95 % CI 1.153, 2.722), having previously prescribed LUM/IVA (OR 2.732; 95 % CI 1.070, 6.974), and belief CFTRm therapies could improve adherence (OR 1.440; 95 % CI 0.946, 2.192).
Conclusions
Behavioral characteristics, attitudes toward CFTRm therapies, and experience with CFTRm therapies impact physician CFTRm prescribing more than individual disease factors.
背景：五种囊性纤维化跨膜传导调节剂（CFTR）调节剂（CFTRm）疗法被批准用于囊性纤维化（CF）患者。尽管CFTRm治疗的有效性和安全性已经确立，但CF医生之间的处方存在差异。在这里，我们描述了影响CFTRm使用的处方因素。方法：这项观察性研究使用CF患者的临床小样本。参与者是来自德国、意大利、英国、爱尔兰和荷兰的呼吸医学专业的成年肺科医生和儿科医生。参与者参与了三个步骤的数据收集过程：(i) 60分钟的个人电话访谈；（ii）医生根据10个临床小样本对CFTRm作出治疗决定的决策练习；（iii） 30分钟的网络辅助访谈，为治疗决策提供依据。采用单因素分析、因子分析降维和随机效应logistic回归模型确定影响CFTRm处方的因素。结果：38名肺科医生和42名儿科医生提供了800项临床决策。只有45%的肺科医生和29%的儿科医生为所有符合条件的成人或儿科患者开CFTRm处方。胰腺充足率降低处方CFTRm的几率(OR 0.106；95% CI 0.046, 0.244)，而0 ~ 12岁患者的风险增加(OR 3.779；95% ci 1.579, 9.042)。与CFTRm处方相关的医师特征是积极主动/突破界限(OR 1.772；95% CI 1.153, 2.722)，既往开过LUM/IVA (OR 2.732；95% CI 1.070, 6.974)，相信CFTRm疗法可以提高依从性(OR 1.440；95% ci 0.946, 2.192)。结论：行为特征、对CFTRm治疗的态度和CFTRm治疗经验对医师CFTRm处方的影响大于个体疾病因素。
{"title":"Treatment decision-making for using CFTR modulator therapy in patients with cystic fibrosis","authors":"Alison Carr , Carlos Carneiro , Michael Griffin , Mark Higgins , Heike Wöhling , Fiona Hammond , Donatello Salvatore , Barry J. Plant , J. Stuart Elborn","doi":"10.1016/j.jcf.2025.07.005","DOIUrl":"10.1016/j.jcf.2025.07.005","url":null,"abstract":"<div><h3>Background</h3><div>Five cystic fibrosis transmembrane conductance regulator (CFTR) modulator (CFTRm) therapies are approved for patients with cystic fibrosis (CF). Despite the established efficacy and safety of CFTRm therapy, variability exists in prescribing amongst CF physicians. Here, we describe prescriber factors influencing CFTRm use.</div></div><div><h3>Methods</h3><div>This observational study used clinical vignettes of patients with CF. Participants were adult pulmonologists and pediatricians specializing in respiratory medicine from Germany, Italy, UK, Ireland, and the Netherlands. Participants took part in a 3-step data collection process: (i) 60-minute individual telephone interview; (ii) decision exercise where physicians made a treatment decision about CFTRm on 10 clinical vignettes; and (iii) 30-minute web-assisted interview to provide rationale for treatment decisions. Univariate analysis, dimensionality reduction via factor analysis, and a random-effects logistic regression model were used to identify factors impacting CFTRm prescribing.</div></div><div><h3>Results</h3><div>Thirty-eight pulmonologists and 42 pediatricians provided 800 clinical decisions. Only 45 % of pulmonologists and 29 % of pediatricians prescribed a CFTRm for all eligible adult or pediatric vignettes. Pancreatic sufficiency decreased odds of prescribing a CFTRm (OR 0.106; 95 % CI 0.046, 0.244) whereas odds increased for patients’ age >12 years (OR 3.779; 95 % CI 1.579, 9.042). Physician characteristics associated with CFTRm prescribing were being proactive/pushing boundaries (OR 1.772; 95 % CI 1.153, 2.722), having previously prescribed LUM/IVA (OR 2.732; 95 % CI 1.070, 6.974), and belief CFTRm therapies could improve adherence (OR 1.440; 95 % CI 0.946, 2.192).</div></div><div><h3>Conclusions</h3><div>Behavioral characteristics, attitudes toward CFTRm therapies, and experience with CFTRm therapies impact physician CFTRm prescribing more than individual disease factors.</div></div>","PeriodicalId":15452,"journal":{"name":"Journal of Cystic Fibrosis","volume":"24 6","pages":"Pages 1031-1037"},"PeriodicalIF":6.0,"publicationDate":"2025-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144717997","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 : 2025-11-01DOI: 10.1016/j.jcf.2025.08.014
Joe A Wrennall , Matthew GS Biggart , Charles D Bengtson , M Flori Sassano , Robert Tarran
Rationale
People with cystic fibrosis (pwCF) exhibit chronic and hyperactive neutrophilia which results in a progressive loss of lung function. CF neutrophils have elevated store operated Ca2+ entry (SOCE) relative to healthy non-CF neutrophils, which contributes to persistent neutrophilia. The vast majority of pwCF now take CFTR modulators such as elexacaftor/tezacaftor/ivacaftor (ETI), which effectively increase CFTR function in multiple organs including the lung. However, ETI’s impact on neutrophils is poorly understood. Orai1 is a plasma membrane Ca2+ channel that contributes to SOCE. We have developed a novel peptide (ELD607) that specifically inhibits Orai1, which we evaluated in CF neutrophils.
Objectives
To characterize Orai1/SOCE in neutrophils from pwCF taking ETI, and to evaluate the impact of SOCE inhibition by ELD607 on pwCF neutrophil Ca2+ signaling/function.
Methods
Peripheral blood neutrophils were isolated by negative selection. SOCE was characterized using fluorescent approaches. Protein expression was characterized by proteomics and confocal microscopy. Neutrophil degranulation was measured using a multiplex assay.
Measurements and main results
Proteomic analysis revealed major global differences between non-CF and pwCF neutrophils, despite use of ETI. Several proteins involved in SOCE, including Orai1, were significantly elevated in pwCF neutrophils. ELD607 dose-dependently inhibited SOCE, leading to reduced neutrophil degranulation. Ca2+ homeostasis was significantly elevated in pwCF compared to non-CF neutrophils. ELD607-sensitive SOCE inversely correlated with lung function (FEV1pp).
Conclusions
Our findings highlight SOCE as a novel biomarker of CF lung disease. ELD607 can be used to reduce SOCE and subsequent degranulation in CF neutrophils. We therefore hypothesize that ELD607 may be of benefit in the management of inflammation in pwCF.
{"title":"Neutrophil store-operated Ca2+ entry: A correctable biomarker of cystic fibrosis lung disease progression","authors":"Joe A Wrennall , Matthew GS Biggart , Charles D Bengtson , M Flori Sassano , Robert Tarran","doi":"10.1016/j.jcf.2025.08.014","DOIUrl":"10.1016/j.jcf.2025.08.014","url":null,"abstract":"<div><h3>Rationale</h3><div>People with cystic fibrosis (pwCF) exhibit chronic and hyperactive neutrophilia which results in a progressive loss of lung function. CF neutrophils have elevated store operated Ca<sup>2+</sup> entry (SOCE) relative to healthy non-CF neutrophils, which contributes to persistent neutrophilia. The vast majority of pwCF now take CFTR modulators such as elexacaftor/tezacaftor/ivacaftor (ETI), which effectively increase CFTR function in multiple organs including the lung. However, ETI’s impact on neutrophils is poorly understood. Orai1 is a plasma membrane Ca<sup>2+</sup> channel that contributes to SOCE. We have developed a novel peptide (ELD607) that specifically inhibits Orai1, which we evaluated in CF neutrophils.</div></div><div><h3>Objectives</h3><div>To characterize Orai1/SOCE in neutrophils from pwCF taking ETI, and to evaluate the impact of SOCE inhibition by ELD607 on pwCF neutrophil Ca<sup>2+</sup> signaling/function.</div></div><div><h3>Methods</h3><div>Peripheral blood neutrophils were isolated by negative selection. SOCE was characterized using fluorescent approaches. Protein expression was characterized by proteomics and confocal microscopy. Neutrophil degranulation was measured using a multiplex assay.</div></div><div><h3>Measurements and main results</h3><div>Proteomic analysis revealed major global differences between non-CF and pwCF neutrophils, despite use of ETI. Several proteins involved in SOCE, including Orai1, were significantly elevated in pwCF neutrophils. ELD607 dose-dependently inhibited SOCE, leading to reduced neutrophil degranulation. Ca<sup>2+</sup> homeostasis was significantly elevated in pwCF compared to non-CF neutrophils. ELD607-sensitive SOCE inversely correlated with lung function (FEV1pp).</div></div><div><h3>Conclusions</h3><div>Our findings highlight SOCE as a novel biomarker of CF lung disease. ELD607 can be used to reduce SOCE and subsequent degranulation in CF neutrophils. We therefore hypothesize that ELD607 may be of benefit in the management of inflammation in pwCF.</div></div>","PeriodicalId":15452,"journal":{"name":"Journal of Cystic Fibrosis","volume":"24 6","pages":"Pages 1173-1183"},"PeriodicalIF":6.0,"publicationDate":"2025-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144955842","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 : 2025-11-01DOI: 10.1016/j.jcf.2025.07.014
Jennifer L. Butcher , Christopher Siracusa , Hannah Grabowski , Dana Yablon , Benjamin Ertman , Emma McWilliams , Tia Woo , Robin S. Everhart , Jill Maggs , Michelle Prickett , Alex H Gifford , Nicole Mayer-Hamblett , David P Nichols , Kristin A. Riekert , Gregory S. Sawicki
Background
Reducing treatment burden is a priority within the CF community. Improved outcomes for many people with CF (PWCF) following treatment with Elexacaftor/Tezacaftor/Ivacaftor (ETI) have led to considering whether daily CF regimens can be reduced. It is important to understand perceptions of PWCF when making decisions about care changes. We investigated how PWCF conceptualize treatment burden, including the types of burdens experienced, how burden has changed with ETI therapy, and how burden impacts treatment-related decision-making.
Methods
The Qualitative Understanding of Experiences with the SIMPLIFY Trial (QUEST) study recruited PWCF aged 14+ prescribed ETI and caregivers of teenagers for interviews following completion of the SIMPLIFY treatment discontinuation trial. Two semi-structured interviews were conducted, recorded, and transcribed. Treatment burden language was identified, coded, and thematically analyzed without prior hypotheses.
Results
68 adults, 23 teenagers, and 23 caregivers participated in at least one interview. Treatment burden codes were identified and organized into 3 themes: 1) Defining Treatment Burden (time, organizational, social-emotional domains), 2) How Treatment Burden has Changed with ETI (increased, decreased), and 3) Strategies to Decrease Treatment Burden (combining treatments, skipping treatments, communicating with care team).
Conclusion
Definitions of CF treatment burden are expansive and personalized. Interventions to reduce treatment burden should be individualized without assuming burden is perceived, or how each individual views and manages burdens. Personalized definitions of treatment burden will allow for tailored assessment and intervention strategies that match the needs of the individual.
{"title":"“Time out for an hour, every day, my whole life”: understanding treatment burden in cystic fibrosis in the era of Elexacaftor/Tezacaftor/Ivacaftor (ETI)","authors":"Jennifer L. Butcher , Christopher Siracusa , Hannah Grabowski , Dana Yablon , Benjamin Ertman , Emma McWilliams , Tia Woo , Robin S. Everhart , Jill Maggs , Michelle Prickett , Alex H Gifford , Nicole Mayer-Hamblett , David P Nichols , Kristin A. Riekert , Gregory S. Sawicki","doi":"10.1016/j.jcf.2025.07.014","DOIUrl":"10.1016/j.jcf.2025.07.014","url":null,"abstract":"<div><h3>Background</h3><div>Reducing treatment burden is a priority within the CF community. Improved outcomes for many people with CF (PWCF) following treatment with Elexacaftor/Tezacaftor/Ivacaftor (ETI) have led to considering whether daily CF regimens can be reduced. It is important to understand perceptions of PWCF when making decisions about care changes. We investigated how PWCF conceptualize treatment burden, including the types of burdens experienced, how burden has changed with ETI therapy, and how burden impacts treatment-related decision-making.</div></div><div><h3>Methods</h3><div>The Qualitative Understanding of Experiences with the SIMPLIFY Trial (QUEST) study recruited PWCF aged 14+ prescribed ETI and caregivers of teenagers for interviews following completion of the SIMPLIFY treatment discontinuation trial. Two semi-structured interviews were conducted, recorded, and transcribed. Treatment burden language was identified, coded, and thematically analyzed without prior hypotheses.</div></div><div><h3>Results</h3><div>68 adults, 23 teenagers, and 23 caregivers participated in at least one interview. Treatment burden codes were identified and organized into 3 themes: 1) Defining Treatment Burden (time, organizational, social-emotional domains), 2) How Treatment Burden has Changed with ETI (increased, decreased), and 3) Strategies to Decrease Treatment Burden (combining treatments, skipping treatments, communicating with care team).</div></div><div><h3>Conclusion</h3><div>Definitions of CF treatment burden are expansive and personalized. Interventions to reduce treatment burden should be individualized without assuming burden is perceived, or how each individual views and manages burdens. Personalized definitions of treatment burden will allow for tailored assessment and intervention strategies that match the needs of the individual.</div></div>","PeriodicalId":15452,"journal":{"name":"Journal of Cystic Fibrosis","volume":"24 6","pages":"Pages 1130-1140"},"PeriodicalIF":6.0,"publicationDate":"2025-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144956045","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 : 2025-11-01DOI: 10.1016/j.jcf.2025.10.003
Raynuka Lazarus , Cassandra Thompson , Jennifer Bishop , Nicholas Perry , Jackson Foster , Catherine Banks , Peter Middleton , Michael Doumit
Background
The sinus cavity may be an alternative sampling site for microbial pathogens in people with cystic fibrosis. However, the congruence between sinus and cough-based sputum sampling is unknown. This study aimed to determine the diagnostic accuracy of nasal irrigation sampling to detect microbial pathogens present in the lower airway.
Methods
People with CF (pwCF) suspected of having chronic rhinosinusitis (CRS) provided an expectorated sputum and a nasal irrigation sample on the same day. Sensitivity and specificity with 95 % confidence intervals were calculated, using the expectorated sputum sample as the reference sample. A non-parametric test of equivalence was used to assess non-inferiority of the nasal irrigation procedure to the standard cough method.
Results
103 paired samples were collected. Nasal irrigation had a sensitivity and specificity for Pseudomonas aeruginosa of 84 % (95 % CI, 70.9-91.4 %) and 91 % (95 % CI, 80.1-95.6 %), respectively, and for Staphylococcus aureus of 79 % (95 % CI, 61.6-90.2 %) and 85 % (95 % CI, 75.3-91.5 %), respectively. Nasal irrigation demonstrated poor diagnostic accuracy for detecting fungal pathogens [Sensitivity, 0.4 % (95 % CI, 0.08-2.27); Specificity, 99 % (95 % CI, 93.8-99.8)]
Conclusions
Bacterial pathogens common in pwCF can be isolated from nasal irrigation samples, indicating nasal irrigation as a potential alternative diagnostic tool to sputum samples in those suspected of having CRS. Nasal irrigation was not an accurate method to diagnose lower respiratory tract fungal infections. Further research is needed to determine the diagnosis yield of nasal irrigation sampling in pwCF who are asymptomatic for CRS and in a paediatric CF population.
{"title":"Nasal irrigation as an alternate method to monitor airway microbiology in cystic fibrosis","authors":"Raynuka Lazarus , Cassandra Thompson , Jennifer Bishop , Nicholas Perry , Jackson Foster , Catherine Banks , Peter Middleton , Michael Doumit","doi":"10.1016/j.jcf.2025.10.003","DOIUrl":"10.1016/j.jcf.2025.10.003","url":null,"abstract":"<div><h3>Background</h3><div>The sinus cavity may be an alternative sampling site for microbial pathogens in people with cystic fibrosis. However, the congruence between sinus and cough-based sputum sampling is unknown. This study aimed to determine the diagnostic accuracy of nasal irrigation sampling to detect microbial pathogens present in the lower airway.</div></div><div><h3>Methods</h3><div>People with CF (pwCF) suspected of having chronic rhinosinusitis (CRS) provided an expectorated sputum and a nasal irrigation sample on the same day. Sensitivity and specificity with 95 % confidence intervals were calculated, using the expectorated sputum sample as the reference sample. A non-parametric test of equivalence was used to assess non-inferiority of the nasal irrigation procedure to the standard cough method.</div></div><div><h3>Results</h3><div>103 paired samples were collected. Nasal irrigation had a sensitivity and specificity for <em>Pseudomonas aeruginosa</em> of 84 % (95 % CI, 70.9-91.4 %) and 91 % (95 % CI, 80.1-95.6 %), respectively, and for <em>Staphylococcus aureus</em> of 79 % (95 % CI, 61.6-90.2 %) and 85 % (95 % CI, 75.3-91.5 %), respectively. Nasal irrigation demonstrated poor diagnostic accuracy for detecting fungal pathogens [Sensitivity, 0.4 % (95 % CI, 0.08-2.27); Specificity, 99 % (95 % CI, 93.8-99.8)]</div></div><div><h3>Conclusions</h3><div>Bacterial pathogens common in pwCF can be isolated from nasal irrigation samples, indicating nasal irrigation as a potential alternative diagnostic tool to sputum samples in those suspected of having CRS. Nasal irrigation was not an accurate method to diagnose lower respiratory tract fungal infections. Further research is needed to determine the diagnosis yield of nasal irrigation sampling in pwCF who are asymptomatic for CRS and in a paediatric CF population.</div></div>","PeriodicalId":15452,"journal":{"name":"Journal of Cystic Fibrosis","volume":"24 6","pages":"Pages 1105-1109"},"PeriodicalIF":6.0,"publicationDate":"2025-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145345582","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 : 2025-11-01DOI: 10.1016/j.jcf.2025.08.016
Jan Christoph Thomassen , Christina Vohlen , Ernst Rietschel , Miguel A. Alejandre Alcazar , Silke van Koningsbruggen-Rietschel
Background
Cystic Fibrosis (CF) lung disease is characterized by inflammation and progressive matrix remodeling. These processes are influenced by genetic modifiers such as Transforming Growth Factor β1, (TGFβ1) which is enhanced by an imbalance of proteases, e.g. neutrophile elastase (NE) and its inhibitor elafin.
Elevated TGFβ1 concentrations in sputum are linked to impaired lung function in people with CF (pwCF); and decreased elafin levels in sputum are associated with P. aeruginosa infection. The direct influence of CFTR-mutations and the impact of TGFβ1 on the expression of elafin has not yet been examined. Therefore, we investigated (1) the direct impact of the CFTR-mutation itself on elafin expression, (2) the interaction of TGFβ1 and CFTR-mutation on elafin expression, and (3) the effect of inhibiting TGFβ1 on the expression of elafin in human bronchial epithelial cells (HBE).
Methods
(1) Gene expression of elafin was measured by qRT-PCR and ELISA in CFTR-diseased (delF508 homozygous; CF-DHBE) and wildtype HBE cells (NHBE). (2) CF-DHBE and NHBE were stimulated with TGFβ1 or vehicle and finally (3) TGFβ1 was inhibited by Pirfenidone/SB43. Gene expression of elafin and inflammatory mediators, as well as inhibitors of proteases were analyzed by qRT-PCR or immunoblot.
Results
(1) mRNA and protein expression of elafin is significantly reduced in CFTR-mutated HBE when compared to NHBE cells. (2) Furthermore, the expression of elafin is inhibited by the genetic modifier TGFβ1. (3) Inhibition of TGFβ1 induced elafin expression in CF-DHBE cells and abrogated the CFTR- TGFβ1 mediated inhibitory effect in HBE.
Conclusions
Our study shows that CFTR-mutation itself mediates effects on the homeostasis of proteases by reducing the expression of elafin. Furthermore, the exposure to high TGFβ1 concentrations increases the CFTR-mutation mediated reduction of elafin expression. Restoring elafin levels and/or inhibiting TGFβ1 might be possible therapeutic options to reduce pulmonary inflammation and remodelling in CF.
{"title":"Elafin expression is regulated by CFTR-mutation and TGFβ1 in human bronchial epithelial cells","authors":"Jan Christoph Thomassen , Christina Vohlen , Ernst Rietschel , Miguel A. Alejandre Alcazar , Silke van Koningsbruggen-Rietschel","doi":"10.1016/j.jcf.2025.08.016","DOIUrl":"10.1016/j.jcf.2025.08.016","url":null,"abstract":"<div><h3>Background</h3><div>Cystic Fibrosis (CF) lung disease is characterized by inflammation and progressive matrix remodeling. These processes are influenced by genetic modifiers such as Transforming Growth Factor β<sub>1</sub>, (TGFβ<sub>1)</sub> which is enhanced by an imbalance of proteases, e.g. neutrophile elastase (NE) and its inhibitor elafin.</div><div>Elevated TGFβ<sub>1</sub> concentrations in sputum are linked to impaired lung function in people with CF (pwCF); and decreased elafin levels in sputum are associated with <em>P. aeruginosa infection.</em> The direct influence of CFTR-mutations and the impact of TGFβ<sub>1</sub> on the expression of elafin has not yet been examined. Therefore, we investigated (1) the direct impact of the CFTR-mutation itself on elafin expression, (2) the interaction of TGFβ<sub>1</sub> and CFTR-mutation on elafin expression, and (3) the effect of inhibiting TGFβ<sub>1</sub> on the expression of elafin in human bronchial epithelial cells (HBE).</div></div><div><h3>Methods</h3><div>(1) Gene expression of elafin was measured by qRT-PCR and ELISA in CFTR-diseased (delF508 homozygous; CF-DHBE) and wildtype HBE cells (NHBE). (2) CF-DHBE and NHBE were stimulated with TGFβ<sub>1</sub> or vehicle and finally (3) TGFβ<sub>1</sub> was inhibited by Pirfenidone/SB43. Gene expression of elafin and inflammatory mediators, as well as inhibitors of proteases were analyzed by qRT-PCR or immunoblot.</div></div><div><h3>Results</h3><div>(1) mRNA and protein expression of elafin is significantly reduced in CFTR-mutated HBE when compared to NHBE cells. (2) Furthermore, the expression of elafin is inhibited by the genetic modifier TGFβ<sub>1</sub>. (3) Inhibition of TGFβ<sub>1</sub> induced elafin expression in CF-DHBE cells and abrogated the CFTR- TGFβ<sub>1</sub> mediated inhibitory effect in HBE.</div></div><div><h3>Conclusions</h3><div>Our study shows that CFTR-mutation itself mediates effects on the homeostasis of proteases by reducing the expression of elafin. Furthermore, the exposure to high TGFβ<sub>1</sub> concentrations increases the CFTR-mutation mediated reduction of elafin expression. Restoring elafin levels and/or inhibiting TGFβ<sub>1</sub> might be possible therapeutic options to reduce pulmonary inflammation and remodelling in CF.</div></div>","PeriodicalId":15452,"journal":{"name":"Journal of Cystic Fibrosis","volume":"24 6","pages":"Pages 1184-1188"},"PeriodicalIF":6.0,"publicationDate":"2025-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145064806","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 : 2025-11-01DOI: 10.1016/j.jcf.2025.07.012
Amanda S. Bruce , Sakinah C. Suttiratana , Hannah Grabowski , Liam Sweeney , Alexandra Ward , Sylvia Mazuera , Jessica A. Alvarez , Dana Yablon , Diana Naranjo
Background
Maintaining optimal nutrition is often an important concern for persons with cystic fibrosis (PWCF). With the introduction of effective modulators, the focus has now shifted from preventing malnourishment to instead stabilizing weight and preventing further weight gain. Research on how PWCF experience and manage their nutrition in this new era remains limited.
Methods
The Exploring Attitudes Toward Nutrition (EATN) study employed a qualitative, multi-site approach to conduct semi-structured interviews with 44 adults living with CF. These interviews explored participants' definitions of “good” nutrition, the facilitators that help support their diet and lifestyle, and the barriers they face. Thematic analysis was used to identify key barriers and facilitators across personal, social, and healthcare-related domains.
Results
Interviews revealed PWCF defined nutrition in a multitude of ways, from ‘a means to achieve optimal health,’ to categorizing foods as "good" or "bad." Key facilitators for maintaining good nutrition included support from registered dietitian/CF care teams, convenience, physical activity, social support, and observations of weight stabilization after elexacaftor/tezacaftor /ivacaftor (ETI). Conversely, barriers included lack of convenience or time, gastrointestinal symptoms, sick days/ hospitalization, negative dietitian/care team member experiences, finances, and the impact of medications or enzymes.
Conclusions
Understanding these supports and challenges is essential for developing effective and personalized nutritional strategies for PWCF. Enhancing access to knowledgeable dietitians, simplifying nutritional recommendations, and addressing cost barriers can significantly improve nutritional outcomes. Future research should focus on applicable solutions that utilize existing successful strategies while addressing common barriers many with CF face.
{"title":"“All my food is customized*”: Barriers & facilitators concerning nutrition for persons living with cystic fibrosis","authors":"Amanda S. Bruce , Sakinah C. Suttiratana , Hannah Grabowski , Liam Sweeney , Alexandra Ward , Sylvia Mazuera , Jessica A. Alvarez , Dana Yablon , Diana Naranjo","doi":"10.1016/j.jcf.2025.07.012","DOIUrl":"10.1016/j.jcf.2025.07.012","url":null,"abstract":"<div><h3>Background</h3><div>Maintaining optimal nutrition is often an important concern for persons with cystic fibrosis (PWCF). With the introduction of effective modulators, the focus has now shifted from preventing malnourishment to instead stabilizing weight and preventing further weight gain. Research on how PWCF experience and manage their nutrition in this new era remains limited.</div></div><div><h3>Methods</h3><div>The Exploring Attitudes Toward Nutrition (EATN) study employed a qualitative, multi-site approach to conduct semi-structured interviews with 44 adults living with CF. These interviews explored participants' definitions of “good” nutrition, the facilitators that help support their diet and lifestyle, and the barriers they face. Thematic analysis was used to identify key barriers and facilitators across personal, social, and healthcare-related domains.</div></div><div><h3>Results</h3><div>Interviews revealed PWCF defined nutrition in a multitude of ways, from ‘a means to achieve optimal health,’ to categorizing foods as \"good\" or \"bad.\" Key facilitators for maintaining good nutrition included support from registered dietitian/CF care teams, convenience, physical activity, social support, and observations of weight stabilization after elexacaftor/tezacaftor /ivacaftor (ETI). Conversely, barriers included lack of convenience or time, gastrointestinal symptoms, sick days/ hospitalization, negative dietitian/care team member experiences, finances, and the impact of medications or enzymes.</div></div><div><h3>Conclusions</h3><div>Understanding these supports and challenges is essential for developing effective and personalized nutritional strategies for PWCF. Enhancing access to knowledgeable dietitians, simplifying nutritional recommendations, and addressing cost barriers can significantly improve nutritional outcomes. Future research should focus on applicable solutions that utilize existing successful strategies while addressing common barriers many with CF face.</div></div>","PeriodicalId":15452,"journal":{"name":"Journal of Cystic Fibrosis","volume":"24 6","pages":"Pages 1081-1089"},"PeriodicalIF":6.0,"publicationDate":"2025-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144717994","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}
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