Transmembrane Conductance Regulator Modulators Research Articles

Cardiac structure and function in people with cystic fibrosis

Abstract Background Cystic fibrosis (CF) is an autosomal recessive disease affecting multiple organs, however the extent of cardiac involvement in CF is yet to be determined. The remarkable therapeutic advancements with new highly effective CF transmembrane conductance regulator (CFTR) modulator treatment and subsequent increase in life expectancy substantiates further research. Purpose We aimed to explore the prevalence of abnormalities and potential subclinical alterations in cardiac structure and function in adults with CF compared to matched controls and investigate potential cardiovascular risk factors in people with CF (pwCF). Methods In this cross-sectional study, 104 adult pwCF in Denmark underwent clinical and echocardiographic examination. All participants were matched 1:1 with controls from the general population on age and sex. Uni- and multivariable linear regression models with adjustment for heart rate, FEV1, smoking status, hypertension and CF-related diabetes (CFRD) were used to test for differences in echocardiographic parameters between cases and controls. Abnormal cardiac function was defined as left ventricular ejection fraction (LVEF) <50%, left ventricular (LV) global longitudinal strain (GLS) < 16% or presence of diastolic dysfunction. Uni- and multivariable logistic regression models adjusted for age, sex, homozygous genotype, FEV1/FVC, BMI, smoking status, CFRD, pancreatic insufficiency, hypertension, and ischemic heart disease were performed to assess associations between potential risk factors and cardiac dysfunction in CF. Forest plots were constructed to visually represent the findings. Results Of 104 pwCF, 44% were female, mean age was 34 years, 93% received CFTR modulator treatment, and 91% had mutations with only minimal CFTR function (mutation class I-III). The prevalence of abnormal cardiac function in pwCF was 44% versus 22% in controls. Compared to controls, pwCF were found to have smaller LV dimensions, worse LV diastolic function, and more impaired right ventricle (RV) as well as LV systolic function (Table). After multivariable adjustment, LV diastolic function as well as LV and RV systolic function remained impaired in pwCF as compared to controls. Male sex and decreasing FEV1/FVC ratio remained independently associated with abnormal cardiac function in pwCF (male sex: OR 3.94 (1.56; 9.95), p=0.004 and FEV1/FVC ratio: OR 2.05 per 0.1 unit decrease (1.21; 3.52), p=0.008, respectively) (Figure). Conclusion Both left- and right-sided cardiac alterations were found in pwCF. After adjustments for potential risk factors, both RV and LV systolic measures remained altered in pwCF, compared to controls. Male sex and decreasing pulmonary function evaluated by FEV1/FVC-ratio were identified as factors associated with abnormal cardiac function in pwCF.Figure

Evaluation of Insulin Secretion and Continuous Glucose Monitoring in Patients with Cystic Fibrosis After Initiation of Transmembrane Conductance Regulator Modulator: A 52-Week Prospective Study

Evaluation of Insulin Secretion and Continuous Glucose Monitoring in Patients with Cystic Fibrosis After Initiation of Transmembrane Conductance Regulator Modulator: A 52-Week Prospective Study

7522 Effects of Trikafta On Bone Mineral Density And Body Composition In Patients With Cystic Fibrosis

Abstract Disclosure: N. Mon: None. S.S. Krishnasamy: None. G. Bakeerathan: None. L. Healy: None. E. Favier: None. S. Foushee: None. Background: Cystic fibrosis related bone disease (CFBD) is a common complication of adult Cystic fibrosis (CF) patients due to calcium, vitamin D and K malabsorption from exocrine pancreatic insufficiency, increased inflammatory cytokines, glucocorticoid therapy, delayed puberty, physical inactivity, and hypogonadism. Newer CF transmembrane conductance regulator (CFTR) modulator therapy elexacaftor/tezacaftor/ivacaftor (Trikafta) has proven benefit in pulmonary and nutritional outcomes. There is limited data on effects of Trikafta on bone health and body composition. The aim is to examine the effects of Trikafta on bone mineral density (BMD) at the lumbar spine (LS) and femoral neck (FN), and body composition in terms of fat free mass index (FFMI) and fat mass index (FMI) in our CF patients. Method: We conducted a cross sectional and retrospective review of 38 adults with CF (Ages 20-59, 28 males and 10 females) in our CF clinic. Body Mass Index (BMI), Body composition measured by bioelectric impedance analysis, BMD of LS and FN by Dual-energy X-ray absorptiometry, Vitamin D level, and forced expiratory volume in one second (FEV1 % predicted) in patients taking Trikafta were analyzed and compared with control CF group who were not on Trikafta. Results: 38 subjects on Trikafta, aged 33.29 ± 10.36 years with FEV1 % predicted 65.11± 28.14% were studied. Serum 25-hydroxyvitamin D level was 35.92 ± 18.52 ng/dL. Of the 38 study patients, 23 (60.53%) had a diagnosis of CF related diabetes (CFRD). Among the Trikafta cohort, 18 (50%) had low BMD with Z-scores ≤ -2.0 and 7 (19.44%) of them had Z score ≤ -1.0 and > -2.0. Compared with the control group, LS BMD 0.93 ± 0.16 g/cm2 and FN BMD 0.73± 0.13g/cm2 (p >0.05) were not improved significantly. BMI of study population 23.09 ± 4.21 kg/m2 (p <0.05) and FMI 6.11 ± 4.25 kg/m2 (p <0.05) increased significantly; however, there was a decrease in FFMI 9.60 ± 1.44 kg/m2 (p <0.05). Conclusion: Treatment with Trikafta in CF patients was associated with increases in BMI and fat mass index but decrease in fat free mass index. There was no statistically significant difference in BMD at LS and FN in our study cohort. This study has limitations in terms of gender differences within the study cohort, duration of Trikafta use in relation to bone mass, and also extent of glucocorticoid use among the study subjects. Larger prospective clinical trials are needed to study efficacy of Trikafta on CFBD. Presentation: 6/3/2024

A Three-year Longitudinal Assessment of Pseudomonas aeruginosa Antibiotic Susceptibility in Children With Cystic Fibrosis in the Era of Cystic Fibrosis Transmembrane Conductance Regulator Modulator Therapy

fibrosis is a genetic disease characterized by chronic lung infection, often with Pseudomonas aeruginosa, requiring repeated antibiotic treatment for pulmonary exacerbations. In the era of cystic fibrosis transmembrane conductance regulator modulator therapy, we assessed susceptibility to antipseudomonal antibiotics in modulator-eligible and modulator-ineligible children over 3 years and found that P. aeruginosa isolates largely remained susceptible to standard parenteral but not oral antimicrobial agents.

Perception and Participation in Sport and Exercise in Cystic Fibrosis: The Impact of CFTR Modulators

People with cystic fibrosis (pwCF) have barriers to physical activity including exercise intolerance and fatigue. The advent of small molecule cystic fibrosis transmembrane conductance regulator (CFTR) modulators have shown great clinical improvements in pwCF; however, the effect of CFTR modulators on exercise perception and participation is unknown. The purpose of this study was to investigate whether the administration of CFTR modulators changed the perception and participation in sport and exercise in pwCF. A survey-based, retrospective cohort study was conducted including individuals aged 18 and above. Eighty-three participants were recruited with a mean age of 30.0 ± 10.5 years. The majority (82%) of participants were taking CFTR modulators. Participants in the modulator group rated enjoyment of exercise and importance of exercise higher than the non-modulator group and were more likely to exercise as a means to socialize. Participants in the modulator group reported lack of time as the most frequent barrier to sport and exercise whereas fatigue was most reported in the non-modulator group. Twenty-eight percent of the modulator group participated in team/structured sports, whereas no participant engaged in team and structured sports in the non-modulator group. Adults with CF who used CFTR modulators rated exercise more favorably and engaged in more team sport activities compared to pwCF who did not use CFTR modulators. The most frequent barrier to exercise in pwCF who used modulators might no longer be CF-related. More research is needed to confirm whether CFTR modulator administration resulted in increased overall physical activity.

The ageing of people living with cystic fibrosis: what to expect now?

The prognosis of people with cystic fibrosis (pwCF) has improved dramatically with the introduction of cystic fibrosis transmembrane conductance regulator (CFTR) modulators (CFTRm). The ageing of the cystic fibrosis (CF) population is changing the disease landscape with the emergence of different needs and increasing comorbidities related to both age and long-term exposure to multiple treatments including CFTRm. Although the number of pwCF eligible for this treatment is expected to increase, major disparities in care and outcomes still exist in this population. Moreover, the long-term impact of the use of CFTRm is still partly unknown due to the current short follow-up and experience with their use, thus generating some uncertainties. The future spread and initiation of these drugs at an earlier stage of the disease is expected to reduce the systemic burden of systemic inflammation and its consequences on health. However, the prolonged life expectancy is accompanied by an increasing burden of age-related comorbidities, especially in the context of chronic disease. The clinical manifestations of the comorbidities directly or indirectly associated with CFTR dysfunction are changing, along with the disease dynamics and outcomes. Current protocols used to monitor slow disease progression will need continuous updates, including the composition of the multidisciplinary team for CF care, with a greater focus on the needs of the adult population.

Functional and radiological sinonasal outcomes of CFTR modulators for sinus disease in cystic fibrosis: A meta-analysis.

Cystic fibrosis transmembrane conductance regulator (CFTR) modulators improve pulmonary outcomes in cystic fibrosis (CF) by stabilizing the CFTR protein on respiratory epithelial surfaces. To determine the efficacy of CFTR modulators on sinonasal outcomes in patients with CF, we performed a meta-analysis of clinical trials to date that include functional and radiographic evidence of sinus disease. English full-text articles were searched in PubMed, Embase, and Scopus databases. Two reviewers screened articles and a third reviewer resolved disagreements. Articles were included if they reported functional or radiological sinonasal outcomes in patients with CF before and after CFTR modulator therapies. Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines were followed, and the risk of bias in non-randomized studies of interventions tool was used for quality assessment. The generic inverse variance method with random effects model was used for meta-analysis. Standardized mean difference (SMD) and mean difference (MD) were used as effect measurements. Seven prospective and two retrospective studies representing 248 patients were included in this analysis. There was a significant improvement in sinonasal outcome test-22 scores on elexacaftor‒tezacaftor‒ivacaftor (MD=12.80, [95% confidence interval, CI: 10.46‒15.13], p<0.001, n=222), with no heterogeneity detected (I2=0%, p=0.820). There was also a significant improvement in Lund‒Mackay scores (SMD=1.25, [95% CI: 0.58‒1.91], p<0.001, n=88), with heterogeneity detected (I2=67%, p=0.030). CFTR modulators improve functional and radiologic sinonasal outcomes. Given the utility of CFTR modulators, the treatment paradigm for CF-related chronic rhinosinusitis promises to evolve.

Development of metabolic syndrome in people with Cystic Fibrosis one year after exposure to elexacaftor-tezacaftor-ivacaftor

BackgroundThe constellation of hypertension, truncal obesity, impaired fasting glucose, low high-density lipoprotein, and hypertriglyceridemia is known as metabolic syndrome (MetSyn) and is associated with cardiovascular and other diseases. Elexacaftor-tezacaftor-ivacaftor (ETI) in people with cystic fibrosis (pwCF) is associated with weight gain but effects on cardiovascular risk are unknown. This study sought to investigate ETI exposure and risk for development of MetSyn in pwCF. MethodsA prospective cohort study including pwCF ≥ 18 years old exposed to ETI was performed. All data for calculating MetSyn was collected from the electronic medical record at initiation and 1 year ± 3 months after starting ETI. A total of 152 pwCF exposed to ETI and 34 pwCF never exposed to CF transmembrane conductance regulator modulators were included in the analysis. Changes to hypertension classification was also examined over this period. ResultsAfter 1 year of ETI there was an increase in MetSyn from 13 to 30 pwCF, p < 0.0001. No new cases of MetSyn were seen in the group not exposed to ETI. After 1 year of ETI, more people met criteria for class 1 (BP 130–139/90–99 mm Hg) or class 2 hypertension (BP ≥140/≥90 mm Hg) regardless of prior modulator exposure, p < 0.0001. ConclusionsExposure to ETI for 1 year resulted in an increased number of cases of MetSyn. There was an increased incidence of hypertension associated with ETI exposure. Additional studies are needed to further examine this trend and to determine if these changes will translate to cardiovascular complications over time.

Comparison of Reporting Quality in National Cystic Fibrosis Patient Registries: Implications for Identifying Use of Novel CFTR Modulators.

Advances in development of cystic fibrosis transmembrane conductance regulator modulator (CFTRm) therapies mean that now people who are heterozygous (instead of having to be homozygous) for the common F508del variant can benefit from these therapies. Recent economic estimates suggest only approximately 15% of the global population have CFTRm access, yet it is unknown how prevalence of F508del and economic factors may affect this availability. Data related to prevalence of cystic fibrosis (CF), CFTRm usage, and prevalence of F508del in 10 countries were extracted from publicly accessible registry reports from 2021. National gross domestic product (GDP) was obtained via open access World Bank data. Descriptive statistics and correlation coefficients assessed relationships. Notable discrepancies were noted in the equity of availability of data between national registries-only four countries reported number of patients eligible for CFTRm. Registry data represented 70,694 patients, with 42,858 found to be using CFTRm (60.6%). Prevalence of CFTRm usage ranged from 1.8% to 76.7% and prevalence of F508del ranged from 35.2% to 94.4%. The correlation between prevalence of CFTRm usage and F508del is positive (r = 0.56, p = 0.10), and the correlation between CFTRm usage and GDP (per capita) was also positive, and significant (r = 0.72, p = 0.02). Both F508del prevalence and GDP are associated with variable CFTRm usage rates, although a predominant reason is unclear as a result of poor consistency in registry reporting. Urgent action is needed to create uniform reporting of registry data and increase availability of novel CFTRm therapies to the global CF population.

Allergic Bronchopulmonary Aspergillosis (ABPA) in the Era of Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) Modulators.

Allergic bronchopulmonary aspergillosis (ABPA) is a hypersensitivity disease caused by Aspergillus fumigatus (Af), prevalent in persons with cystic fibrosis (CF) or asthma. In ABPA, Af proteases drive a T-helper cell-2 (Th2)-mediated allergic immune response leading to inflammation that contributes to permanent lung damage. Corticosteroids and antifungals are the mainstays of therapies for ABPA. However, their long-term use has negative sequelae. The treatment of patients with CF (pwCF) has been revolutionized by the efficacy of cystic fibrosis transmembrane conductance regulator (CFTR) modulator therapy. Pharmacological improvement in CFTR function with highly effective elexacaftor/tezacaftor/ivacaftor (ETI) provides unprecedented improvements in lung function and other clinical outcomes of pwCF. The mechanism behind the improvement in patient outcomes is a continued topic of investigation as our understanding of the role of CFTR function evolves. As ETI therapy gains traction in CF management, understanding its potential impact on ABPA, especially on the allergic immune response pathways and Af infection becomes increasingly crucial for optimizing patient outcomes. This literature review aims to examine the extent of these findings and expand our understanding of the already published research focusing on the intersection between ABPA therapeutic approaches in CF and the rapid impact of the evolving CFTR modulator landscape. While our literature search yielded limited reports specifically focusing on the role of CFTR modulator therapy on CF-ABPA, findings from epidemiologic and retrospective studies suggest the potential for CFTR modulator therapies to positively influence pulmonary outcomes by addressing the underlying pathophysiology of CF-ABPA, especially by decreasing inflammatory response and Af colonization. Thus, this review highlights the promising scope of CFTR modulator therapy in decreasing the overall prevalence and incidence of CF-ABPA.

Impact of CFTR Modulator Therapies on Liver Function in Cystic Fibrosis Patients: A Systematic Review of Hepatic Biomarkers.

Cystic fibrosis transmembrane conductance regulator (CFTR) modulators, including elexacaftor/ivacaftor/tezacaftor (ETI) and lumacaftor/ivacaftor (LI), have revolutionized the treatment of cystic fibrosis. However, their impact on liver function remains unclear, with varying effects reported across studies. The aim of this study was to systematically review the effects of CFTR modulators on liver function in cystic fibrosis patients by evaluating changes in key hepatic biomarkers. A comprehensive literature search was conducted in Europe PubMed Central and PubMed databases for studies published between January 1, 2010, and December 31, 2023. Eligible studies included those assessing the impact of CFTR modulators on liver biomarkers in cystic fibrosis patients. Meta-analyses were performed where possible. Six studies encompassing 195 patients were included, with significant heterogeneity in study design, population, and outcomes. The review found mixed results for alanine aminotransferase (ALT), aspartate aminotransferase (AST), and gamma glutamyltransferase (GGT) levels, with some studies reporting increases and others decreases. LI therapy was associated with significant reductions in GGT and alkaline phosphatase (AP) levels, while ETI therapy showed significant increases in bilirubin levels. Albumin levels increased significantly with both therapies. CFTR modulators have varying effects on liver function biomarkers in cystic fibrosis patients, with LI therapy generally showing more favorable outcomes on liver health. The significant heterogeneity among studies underscores the need for more standardized research to better understand these effects and guide clinical management.

Longitudinal Changes in Bone Mineral Density in Adults with Cystic Fibrosis.

Improved survival in people with cystic fibrosis (pwCF) presents new complexities of care, including CF-related bone disease, a common complication in older pwCF. The trajectory of bone loss with age in this population remains unclear. The objective of this study was to estimate the average rate of change in bone mineral density (BMD) in adults with CF. This retrospective study included adults with CF, aged 25-48years, followed between January 2000 and December 2021. Subjects with at least one dual-energy X-ray absorptiometry (DXA) scan were included. Scans obtained post-transplantation, after the initiation of bisphosphonates or cystic fibrosis transmembrane conductance regulator (CFTR) modulator therapy were excluded. The primary outcome was BMD (g/cm2) at the lumbar spine (LS) and femoral neck (FN). A linear mixed-effects model with both random intercept and random slope terms was used to estimate the average annual change in BMD. A total of 1502 DXA scans in 500 adults (average age 28.4y) were included. There was a statistically significant annual decline in BMD of -0.008 gm/cm2/year (95% CI -0.009, -0.007) at the FN and -0.006 gm/cm2/year (95% CI -0.007, -0.004) at the LS. Relative to BMD at age 25, there was a -18.8% decline at the FN by age 48years and a -11% decline at the LS. Pancreatic insufficient (PI) subjects had a faster rate of decline in BMD compared to pancreatic sufficient (PS) subjects. After adjusting for markers of disease severity, the annual rate of decline remained significant. Individuals with CF experience bone loss at an age when it is not anticipated, thereby entering early adulthood, where further bone loss is inevitable especially with the decrease in estrogen during menopause, with suboptimal BMD. As the CF population ages, it will become very important to consider interventions to maximize bone health.

The lysogenic filamentous Pseudomonas bacteriophage phage Pf slows mucociliary transport.

Pseudomonas aeruginosa is a major pulmonary pathogen causing chronic pulmonary infections in people with cystic fibrosis (CF). The P. aeruginosa filamentous and lysogenic bacteriophage, Pf phage, is abundant in the airways of many people with CF and has been associated with poor outcomes in a cross-sectional cohort study. Previous studies have identified roles for Pf phage in biofilm formation, specifically forming higher-order birefringent, liquid crystals when in contact with other biopolymers in biofilms. Liquid crystalline biofilms are more adherent and viscous than those without liquid crystals. A key feature of biofilms is to enhance bacterial adherence and resist physical clearance. The effect of Pf phage on mucociliary transport is unknown. We found that primary CF and non-CF nasal epithelial cells cultured at air-liquid interface treated with Pf phage exhibit liquid crystalline structures in the overlying mucus. On these cell cultures, Pf phage entangles cilia but does not affect ciliary beat frequency. In both these in vitro cell cultures and in an ex vivo porcine trachea model, introduction of Pf phage decreases mucociliary transport velocity. Pf phage also blocks the rescue of mucociliary transport by CF transmembrane conductance regulator modulators in CF cultures. Thus, Pf phage may contribute to the pathogenesis of P. aeruginosa-associated CF lung disease via induction of liquid crystalline characteristics to airway secretions, leading to impaired mucociliary transport. Targeting Pf phage may be useful in treatment CF as well as other settings of chronic P. aeruginosa infections.

Impact of Cystic Fibrosis Transmembrane Conductance Regulator Modulators on Maternal Outcomes During and After Pregnancy

Cystic fibrosis (CF) transmembrane conductance regulator (CFTR) modulators are available to the majority of people with CF in the United States; little is known about pregnancy outcomes with modulator use. The aim of this retrospective study was to determine the impact of CFTR modulators on maternal outcomes. Does pregnancy differentially affect outcomes in female subjects with CF with and without CFTR modulator exposure? Data on pregnancies from 2010 to 2021 were collected from 11 US adult CF centers. Multivariable longitudinal regression analysis was performed to assess whether changes in percent predicted FEV1 (ppFEV1), BMI, pulmonary exacerbations (PEx), and Pseudomonas aeruginosa prevalence differed from prior to, during, and following pregnancy according to CFTR modulator use while adjusting for confounders. Infant outcomes are also described based on maternal modulator use. Among 307 pregnancies, mean age at conception was 28.5 years (range, 17-42 years), prepregnancy ppFEV1 was 74.2, and BMI was 22.3kg/m2. A total of 114 pregnancies (37.1%) had CFTR modulator exposure during pregnancy (77 with highly effective modulator therapy [HEMT] and 37 with other modulators). The adjusted mean change in ppFEV1 from prepregnancy to during pregnancy was -2.36 (95%CI, -3.56 to -1.16) in the unexposed group and 2.60 (95%CI, 0.23 to 4.97) in the HEMT group, with no significant change from during pregnancy to 1 year postpregnancy. There was an overall decline in ppFEV1 from prepregnancy to postpregnancy in the no modulator group (-2.56; 95%CI, -3.62 to -1.49) that was not observed in the HEMT group (1.10; 95%CI, -1.13 to 3.34). PEx decreased from prepregnancy to postpregnancy in the HEMT group, and BMI increased from prepregnancy to during pregnancy in all groups but with no significant change postpregnancy. Missing infant outcomes data precluded firm conclusions. We observed superior pregnancy and postpregnancy pulmonary outcomes in individuals who used HEMT, including a preservation of ppFEV1, compared with those unexposed to HEMT.

Cardiac Structure and Function in People with Cystic Fibrosis

BackgroundThe extent of cardiac involvement in cystic fibrosis (CF) remains to be determined. The remarkable therapeutic advancements with new highly effective cystic fibrosis transmembrane conductance regulator (CFTR) modulator treatment and subsequent increase in life expectancy substantiates further research. We aimed to explore the prevalence of cardiac alterations in people with CF (pwCF) compared to matched controls and investigate potential cardiovascular risk factors. MethodsIn this cross-sectional study, 104 pwCF underwent clinical and echocardiographic assessment. All participants were matched 1:1 with controls from the general population. ResultsOf 104 pwCF, 44 % were female, mean age was 34 years, and 93 % received CFTR modulator treatment. The prevalence of abnormal cardiac function in pwCF was 44 %, more than double the prevalence in controls. PwCF were found to have smaller left ventricular (LV) dimensions, worse LV diastolic function, and reduced right ventricle (RV) as well as LV systolic function. After multivariable adjustment, LV diastolic function as well as LV and RV systolic function remained poorer in pwCF as compared to controls. Male sex and decreasing FEV1/FVC ratio remained independently associated with abnormal cardiac function in pwCF (male sex: OR 3.94 (1.56; 9.95), p = 0.004 and FEV1/FVC ratio: OR 2.05 per 0.1 unit decrease (1.21; 3.52), p = 0.008, respectively). ConclusionsBoth left- and right-sided cardiac alterations were found in pwCF. After adjustments for risk factors, both RV and LV systolic measures remained altered in pwCF, compared to controls. Male sex and decreasing pulmonary function evaluated by FEV1/FVC-ratio were associated with abnormal cardiac function in pwCF.

A review of proton pump inhibitor use in cystic fibrosis and considerations for deprescribing.

Use of proton-pump inhibitors (PPIs) is common among people with cystic fibrosis (pwCF) both for the management of suspected GERD, as well as pancreatic enzyme replacement therapy augmentation. Despite their use, limited data exist to demonstrate a clinically significant impact of PPIs on key endpoints in pwCF. Furthermore, the advent of cystic fibrosis transmembrane conductance regulator (CFTR) modulator therapy may modify the need for use. These notions, coupled with the potential for adverse outcomes associated with long-term PPI use in pwCF, should facilitate re-evaluation of long-term PPI use in pwCF and promote potential deprescribing. Despite limited data on PPI deprescribing in pwCF, it intuitively mirrors the existing guidance in adults in the general population, but with added consideration given to tapering strategy, and monitoring for CF-specific outcomes such as nutritional and respiratory status. The development of a monitoring and re-initiation plan is key to reducing deprescribing inertia. This review aims to summarize the evidence that details the concern for long-term use of PPIs and provide CF clinicians with rationale and guidance on how to approach deprescribing in their practice.

Development and clinical implementation of an LC-HRMS method for ivacaftor, lumacaftor, tezacaftor and elexacaftor in human plasma and breast milk.

The four cystic fibrosis (CF) transmembrane conductance regulator (CFTR) modulators, ivacaftor, lumacaftor, tezacaftor, and elexacaftor, have revolutionised the treatment of CF by direct action on the protein target behind the disease's development. The aim was to develop and validate a quantification method for these CFTR modulators in plasma and breast milk to better understand inter-patient variability in pharmacokinetics and treatment outcome, including the risk of adverse drug reactions. The ability to monitor CFTR modulators in breast milk enables the estimation of the exposure of breastfed infant, with a potential concern for CFTR modulator-induced liver injury. The analysis was performed on a Thermo Vanquish Flex Binary UHPLC system coupled to a high-resolution mass spectrometer (HRMS), Thermo Q Exactive. The analytes were detected using positive electrospray ionisation in full scan mode. After sample preparation by protein precipitation, the supernatant was injected onto the LC system and the analytes were separated using a Zorbax SB-C18 Rapid Res HPLC column (3.5µm, 4.6 × 75mm). This is the first published method for CFTR modulators in breast milk. The validated quantification range for ivacaftor is 0.0050-10µg/mL with a coefficient of variation < 6% and a mean accuracy of 97-106%; for lumacaftor, tezacaftor, and elexacaftor, the validated quantification range is 0.050-100µg/mL with a coefficient of variation < 8% and a mean accuracy 93-106%. A simple and sensitive quantification method for CFTR modulators has been developed and used for routine analysis of human plasma and breast milk samples since 2022.

Assessing the health impacts of parenthood on people with cystic fibrosis: the HOPeCF prospective cohort protocol

IntroductionPeople with cystic fibrosis (CF) are living longer and healthier lives with a growing number considering and pursuing parenthood. The decision of whether to become a parent is complex for...

Kidney effects of triple CFTR modulator therapy in people with cystic fibrosis.

Elexacaftor/tezacaftor/ivacaftor (ETI) is a new cystic fibrosis transmembrane conductance regulator (CFTR) modulator that has transformed the respiratory prognosis of people with cystic fibrosis (pwCF). However, its impact on other organs such as the kidneys, where CFTR is expressed, remains unclear. Since pwCF are risk of both kidney disease and urolithiasis, we aimed to study the potential effects of ETI on renal function, volume status, and risk factors for urolithiasis. This prospective, observational, single-center, before-after cohort study, involved adult pwCF eligible for ETI. The changes in plasma and urinary profiles were assessed by comparing renal function (using 2021 CKD-EPIcreatinine and 2021 CKD-EPIcreatinine-cystatin C formulas), volume status (using aldosterone/renin ratio and blood pressure), and risk factors for urolithiasis, at the time of ETI introduction (M0) and 7 months after (M7). Nineteen pwCF were included. No significant change in renal function was observed between M0 and M7 (2021 CKD-EPIcreatinine: 105.5ml/min/1.73 m² at M0 vs. 103.3ml/min/1.73 m² at M7; P=.17). There was a significant reduction in aldosterone level (370.3pmol/l at M0 vs. 232.4pmol/l at M7; P=.02) and aldosterone/renin ratio (33.6 at M0 vs. 21.8 at M7; P=.03). Among the risk factors for urolithiasis, a significant reduction in magnesuria level was found (4.6mmol/d at M0 vs. 3.8mmol/d at M7; P=.01). These findings suggest that ETI seem to have no short-term impact on the renal function of adult pwCF and appears to correct secondary hyperaldosteronism due to excessive sweat losses. Further investigations are needed to determine the potential impact of decreased magnesuria observed under ETI therapy on the risk of urolithiasis.

Pregnancy and fertility in people with cystic fibrosis following lung transplantation.

The purpose of this review is to summarize available data on fertility, fertility preservation, pregnancy and parenthood following lung transplantation for people with cystic fibrosis (pwCF). In the era of cystic fibrosis transmembrane conductance regulator (CFTR) modulator use, oral therapies that positively impact fundamental CFTR protein abnormalities, the number of pregnancies has increased dramatically with a concomitant decrease in lung transplantation. Nonetheless, some pwCF still require lung transplantation as a life-saving measure, and a fraction of those individuals desires parenthood. Cystic fibrosis (CF) providers infrequently discuss fertility preservation with pwCF, and pwCF feel uneducated about their fertility options posttransplant. However, because the immunosuppression required to successfully maintain lung allografts may impact future fertility, pwCF should receive genetic and reproductive counseling prior to lung transplantation. While pregnancies posttransplantation are high-risk, selected females with CF may be able to pursue this path to parenthood. Although there is a paucity of data specific to pwCF who have undergone lung transplantation, recently developed general guidelines should inform discussions regarding fertility, pregnancy and parenthood in pwCF who desire parenthood following lung transplantation for optimal shared decision-making.