Sweat chloride concentration, a diagnostic feature in cystic fibrosis (CF), reflects CF transmembrane conductance regulator (CFTR) activity. CFTR modulator therapies, especially elexacaftor/tezacaftor/ivacaftor (ETI), has improved CF outcomes. We report nationwide, real-world data on sweat chloride concentration in people with CF (pwCF) with and without modulator therapies. All Danish pwCF with a minimum of one F508del allele were included. Sweat chloride measurements were stratified by genotype and modulator treatment. Differences were assessed using mixed-effects models. We included 977 sweat chloride measurements from 430 pwCF, 71% of which were F508del homozygous. Heterozygous and homozygous ETI-treated pwCF had an estimated mean sweat chloride concentration of 43 mmol/L (95% confidence interval: 39; 48) and 43 mmol/L (39; 47), respectively-48% and 59% lower than those without treatment. High variation in concentrations remained regardless of treatment status. Despite ETI treatment, 27% heterozygous and 23% homozygous pwCF had elevated concentrations (≥60 mmol/L). These real-world data confirm a substantial decrease in sweat chloride concentration during modulator treatment, especially ETI, where mean concentrations halved. However, large variation remained, including persistently high concentrations. These findings emphasize the potential of sweat chloride concentration as a treatment response biomarker and the need to explore its heterogeneity and relationship with clinical outcomes.

The landscape of care for children with cystic fibrosis (CF), a genetic disorder of chloride transport with multisystem manifestations including inspissated mucus, recurrent sinopulmonary infections, obstructive lung disease, and exocrine pancreatic insufficiency, is rapidly changing. Early diagnosis via newborn screening enabling timely nutritional support, chronic therapies to improve mucociliary clearance, and prompt treatment of pulmonary infections have improved overall outcomes in children with CF. More widespread availability of novel cystic fibrosis transmembrane conductance regulator modulator therapies for children continues to revolutionize pediatric CF care.However, significant challenges exist to optimize care and outcomes for all children with CF.

BACKGROUND: Access to elexacaftor/tezacaftor/ivacaftor (ETI) for people with cystic fibrosis (PwCF) without a F508del variant is limited due to lack of clinical data supporting efficacy.
METHODS: In this systematic review and meta-analysis, we examined patient-level data from studies reporting the clinical response to ETI for PwCF with non-F508del CFTR variants. We searched electronic data sources including Embase, MEDLINE, and CENTRAL from January 1st, 2019 to May 14th, 2024.
RESULTS: Our search results identified 4,795 studies and 20 met the eligibility criteria. 120 of 164 (73 %) individuals had a positive clinical response to ETI, defined by a sweat chloride (SwCl) decrease of ≥10 mmol/L or percent-predicted FEV1 (ppFEV1) improvement of ≥5 %. 51 unique ETI-responsive variants were represented across these 120 individuals and 27 of these variants (53 %) have not been previously approved by the U.S. FDA. For variants with at least 10 individuals treated with ETI to date, a consistent positive clinical response was observed for N1303K and G85E. For N1303K (n = 48), the median increase in ppFEV1 was 16 % (IQR: 8 %, 29 %), with a median decrease in SwCl of -9 (IQR: -4, -22) mmol/L. For G85E (n = 16), the median increase in ppFEV1 was 13.5 % (IQR: 8 %, 19 %) with a median decrease in SwCl of -46 (IQR: -39, -66) mmol/L.
CONCLUSIONS: Additional ETI-responsive variants were identified following a comprehensive review of ETI clinical use in PwCF without F508del. This data can be used by the CF community in efforts to expand the labelled indications or to help advocate for off-label ETI reimbursement.

BACKGROUND: Cystic fibrosis (CF) is an autosomal recessive disease caused by variants of CFTR gene. Over 2000 variants have been identified, and new drugs called CFTR modulators have been developed to target specific defects in the CFTR protein. However, these drugs are only suitable for patients with certain variants of CFTR, and eligibility rates vary depending on race and geographical region. This study aimed to reveal the detailed genotype and clinical characteristics of people with CF (pwCF) at our center in Turkey, a developing country, who are not eligible for CFTR modulators.
METHODS: A total of 445 pwCF followed up at Marmara University were reviewed retrospectively. Variants of the patients ineligible to CFTR modulators were classified based on American College of Medical Genetics guidelines, CFTR classification, the change in the encoded protein, and the variant type.
RESULTS: The study revealed that 139 (31.2%) patients weren\'t eligible for CFTR modulators. There were 60 different variants in the 276 alleles, as two were missing. The majority of patients had missense or nonsense variants, and that the most common variant was c.1545_1546del, which can be said unique to this geography.
CONCLUSIONS: The study highlights the importance of detecting the variants of ineligible patients in detail to guide future approaches for more targeted and effective interventions in CF care. Testing the effectiveness of CFTR modulators for rare or newly occurring variants is crucial to ensure equal access for pwCF to these therapies from different racial backgrounds and ethnic minorities.

Cystic Fibrosis (CF) is a progressive condition resulting in reduced lung function and strongly associated with elevated anxiety and depression symptoms. Self-concept refers to an individual\'s overarching sense of identity, a positive level of which is widely associated with reduced anxiety and depression. There is a significant lack of self-concept research within CF. This study explores the association between self-concept and anxiety and depression in adults with CF. 64 adults living with CF in Western Australia completed validated online questionnaires (Generalised Anxiety Disorder-7, Patient Health Questionnaire-9, Tennessee Self-Concept Questionnaire 2: Short-Form) and consented to the collection of medical data. Descriptive, t-test, correlation and multiple regression analysis were undertaken. Higher levels of self-concept were associated with lower levels of anxiety and depression symptoms. Lower self-concept levels were a significant predictor of increased anxiety and depression symptoms after accounting for physical health status. Mean self-concept scores for those who required mental health intervention were significantly lower compared to those that did not. This study identifies a significant relationship between self-concept and anxiety and depression in adults with CF. Further research is required to establish causation and test the feasibility of self-concept interventions in reducing anxiety and depression symptoms.

[This corrects the article DOI: 10.3389/fphar.2024.1362325.].

In the last 10 years, the care of patients with cystic fibrosis (CF) has been revolutionized with the introduction of cystic fibrosis transmembrane conductance regulator (CFTR) modulator drugs, with a major impact on symptoms and life expectancy, especially considering the newest and highly effective elexacaftor/tezacaftor/ivacaftor (ELX/TEZ/IVA) therapy. Conversely, adverse effects are relatively frequent, with some being life-threatening, such as severe hepatitis. Clinical trials on children starting CFTR modulators have reported transaminase elevations >3× upper limit of the norm in 10%-20% of patients, whereas real-life studies have reported discontinuation rates three times higher than those observed in phase 3 trials. We report the case of a 10-year-old boy with CF who developed severe acute hepatitis 2 weeks after starting ELX/TEZ/IVA therapy. An extensive screening for potential causes led to the identification of heterozygous alpha1-antitrypsin (AAT) deficiency with genotype MZ. The Z allele of SERPINA1 gene, encoding AAT, is known as a risk factor for CF liver disease. We hypothesized that it may act as a risk factor for drug-induced liver injury from CFTR modulators, notably ELX/TEZ/IVA. Therefore, checking AAT before starting CFTR modulator therapy can be suggested, in particular for children with previous, even transient, liver disease.

OBJECTIVE: Treatment with cystic fibrosis transmembrane conductance regulator (CFTR) modulators in individuals with cystic fibrosis (CF) has brought a significant change in forced expiratory volume in 1 second (FEV1) and clinical parameters. However, it also results in weight gain. The aim of our study is to evaluate the effect of CFTR modulator treatment on body composition, measured by computed tomography (CT).
METHODS: Adult subjects with CF under follow-up at La Princesa University Hospital were recruited. All of them were on elexacaftor-tezacaftor-ivacaftor (ELX/TEZ/IVA) treatment. Body composition analysis was conducted using CT scans and an open-source software. The results were then compared with bioimpedance estimations, as well as other clinical and spirometry data.
RESULTS: Our sample consisted of 26 adult subjects. The fat mass compartments on CT scans correlated with similar compartments on bioimpedance, and normal-density muscle mass exhibited a strong correlation with phase angle. Higher levels of very low-density muscle prior to treatment were associated with lower final FEV1 and less improvement in FEV1 after therapy. We observed an increase in total body area (P < 0.001), driven by increases in total fat mass (P < 0.001), subcutaneous fat (P < 0.001), visceral fat (P = 0.002), and intermuscular fat (P = 0.022). The only muscle compartment that showed an increase after treatment was very low-density muscle (P = 0.032).
CONCLUSIONS: CT scans represent an opportunity to assess body composition on CF. Combination treatment with CFTR modulators, leads to an improvement in FEV1 and to an increase in body mass in all compartments primarily at the expense of fat mass.

BACKGROUND: Cystic fibrosis (CF) is caused by CF transmembrane conductance regulator (CFTR) gene mutations producing dysfunctional CFTR proteins leading to progressive clinical disease. Elexacaftor-tezacaftor-ivacaftor (ETI) remarkably improves lung disease but is associated with substantial weight gain.
METHODS: We performed a single-center longitudinal study predicting 6-month weight gain after ETI initiation. We used linear mixed effects modeling (LME) to determine association of ETI treatment with changing body mass index (BMI). Using linear regression, we examined BMI prediction models with distinct combinations of main effects to identify a model useful for patient counseling. We used up to eight commonly observed clinical characteristics as input variables (age, sex, percent predicted FEV1 [FEV1%], F508del homozygous state, pancreatic sufficiency, HgbA1c, prior modulator use and prior year number of pulmonary exacerbations).
RESULTS: We evaluated 154 patients (19-73 years old, 54% female, FEV1% = 19-121, 0-6 prior year pulmonary exacerbations). LME demonstrated an association between ETI use and weight increases. Exhaustive testing suggested a parsimonious linear regression model well-fitted to data that is potentially useful for counseling. The two variable model shows that on average, BMI decreases by 0.045 (95% Confidence Interval [CI] = -0.069 to -0.021, p < 0.001) for every year of age and increases by 0.322 (CI = 0.142 to 0.502, p = 0.001) for each additional prior year exacerbation at the time of ETI initiation.
CONCLUSIONS: Young patients with many prior year pulmonary exacerbations likely have the largest 6 month weight gain after starting ETI.

BACKGROUND: Cystic fibrosis transmembrane conductance regulator (CFTR) modulator therapy extends the life expectancy of people with cystic fibrosis (PwCF). However, CFTR modulators have not been well studied in patients with cystic fibrosis liver disease (CFLD), specifically those with advanced liver disease with portal hypertension. The purpose of this report is to describe the use of elexacaftor/tezacaftor/ivacaftor (ETI) in pediatric CF patients with advanced CFLD.
METHODS: This retrospective case series included PwCF < 18 years old with baseline advanced CFLD initiated on ETI.
RESULTS: Eleven PwCF and advanced CFLD were treated with ETI; six started a reduced dose regimen. No patient required treatment interruption and four patients received dose changes related to increase in transaminase and/or bilirubin elevations. Mean (SD) change in ppFEV1 from prior to ETI to highest value during therapy was 14.27 % (4.25) (p = 0.007). When evaluating the group as whole, AST decreased from baseline to last reported -15.18 (23.23) units/L (p = 0.054) and ALT slightly increased 0.73 (39.13) units/L (p = 0.96). Bilirubin increased minimally overall for patients with mean change from baseline of 0.83 (1.33) mg/dL [range -0.5-3] (p = 0.17). A model for time on ETI showed a significant decrease in AST over time of 0.955 per month of ETI but no other liver biochemistries were significant. No patient experienced decompensation of CFLD.
CONCLUSIONS: ETI therapy in pediatric CF patients with advanced CFLD can be beneficial in improving pulmonary and nutritional outcomes without negative impact on liver biochemistries or hepatic outcomes. Close monitoring is recommended to ensure safety and tolerability.