Search Results (105)

Since the development of the first cystic fibrosis transmembrane conductance regulator (CFTR) modulator in 2012, these therapies have revolutionized patients’ health. They are now the most effective treatment for people with cystic fibrosis (pwCF). In fact, elexacaftor/tezacaftor/ivacaftor and vanzacaftor/tezacaftor/deutivacaftor, the latest combination therapies consisting of a CFTR potentiator and two CFTR correctors, improved lung function by 14% in pwCF. Other modulator therapies targeting CFTR mRNA and/or protein are currently under preclinical/clinical investigation. However, due to the variant-specific nature of these therapies, about 10% of pwCF in Europe remains without effective treatment, and many treated pwCF experience various adverse events such as headaches, infections, hepatotoxicity, hypertension, and depression. Therefore, mutation-agnostic strategies such as gene therapy are needed. They could expand treatment eligibility for all pwCF and improve outcomes. In fact, nucleic acid delivery (e.g., pDNA, mRNA, oligonucleotides, genome editing) or targeting non-CFTR channels to restore ion transport represent promising future additional directions for CF therapy. This review aims to discuss a potential combination between gene therapy approaches and existing modulators to improve treatment eligibility, safety, and efficacy. Full article

Background/Objectives: Highly effective cystic fibrosis transmembrane conductance regulator (CFTR) modulator therapy has changed cystic fibrosis (CF) care, but Romanian patient-reported health-related quality of life (HRQoL) data remain limited. This national cross-sectional mixed-methods survey aimed to describe patient- and parent-reported HRQoL in Romanian people with CF (pwCF) aged ≥6 years using age-appropriate Cystic Fibrosis Questionnaire-Revised (CFQ-R) versions, with the respiratory domain as the primary outcome. Methods: The online survey was conducted between February and April 2026. Respondents provided demographic and clinical data, including genotype/F508del status, CFTR modulator status, percent predicted forced expiratory volume in 1 s (ppFEV₁) category, weight, height, and IV antibiotic-treated pulmonary exacerbations in the previous year. CFQ-R scores were summarized descriptively, and exploratory unadjusted associations were assessed using Mann–Whitney U tests and Spearman correlations. Open-ended responses were analyzed descriptively. Results: Of 67 responses, 61 were included: 43 participants aged 6–13 years and 18 aged ≥14 years. Most respondents were currently receiving CFTR modulators (52/61, 85.2%), predominantly elexacaftor/tezacaftor/ivacaftor. Mean CFQ-R Respiratory scores were 74.5 ± 23.1 in parent-proxy questionnaires for children aged 6–13 years, 83.3 ± 11.8 in self-reported questionnaires for children aged 12–13 years, and 69.8 ± 27.4 among respondents aged ≥14 years. Respiratory scores were higher among currently treated respondents and those with at least one F508del variant, and lower among those reporting IV antibiotic-treated exacerbations. Treatment burden remained among the lower-scoring domains. Qualitative responses described perceived respiratory, nutritional, and functional improvements, alongside residual treatment burden, psychosocial challenges, and access-related expectations. Conclusions: This national Romanian mixed-methods survey provides descriptive, exploratory CFQ-R-based HRQoL data in the CFTR modulator era. The findings suggest more favorable respiratory HRQoL among currently treated respondents, while supporting continued multidimensional patient-reported outcome monitoring in Romanian CF care. Full article

Cystic fibrosis (CF) is an autosomal recessive disorder caused by mutations in the CFTR gene. The sequential approval of CFTR modulators ivacaftor (2012), lumacaftor/ivacaftor (2015), tezacaftor/ivacaftor (2018), and elexacaftor/tezacaftor/ivacaftor (2019) has transformed CF care, but population-level mortality trends across therapeutic periods have not been comprehensively assessed. We conducted a retrospective analysis of CF mortality in the United States from 1999 to 2024 using CDC WONDER Underlying Cause of Death data (ICD-10 codes E84.0–E84.9). Age-adjusted mortality rates (AAMR) per 100,000 were calculated using the 2000 U.S. standard population. The study period was divided into three periods: pre-modulator (1999–2011), early modulator (2012–2018), and elexacaftor/tezacaftor/ivacaftor (2019–2024). Annual mortality trends were evaluated using segmented log-linear Poisson regression, with annual death counts as the outcome and the corresponding U.S. population as an offset. Candidate models with multiple change points were compared to identify distinct temporal segments. Annual percent changes (APCs) and 95% confidence intervals (CIs) were estimated for each segment. Prespecified therapeutic periods, including pre-modulator (1999–2011), early modulator (2012–2018), and ETI period (2019–2024), were retained for descriptive analyses. Trends were stratified by sex and U.S. Census Region. A total of 10,959 CF deaths were recorded over 26 years. In the pre-modulator period, mortality was stable at a mean of 478 deaths/year (AAMR 0.14–0.17). The early modulator period showed a modest 5.4% reduction in mean annual deaths (452/year). The period following ETI availability was associated with a decline to 263/year, a 47% reduction from the pre-modulator period (AAPC −8.6%/year). The AAMR declined from 0.17 (1999) to 0.07 (2024). The female-to-male death count ratio shifted from 1.05 to 0.97 across periods, though age-adjusted rates were identical between sexes within each period, and this finding should be interpreted cautiously. Regionally, the South’s share of CF deaths grew from 37.2% to 41.6% despite absolute declines in all regions, suggesting potential geographic disparities that warrant further investigation with individual-level data. Segmented regression identified change points in 2005 and 2015. Mortality declined significantly from 1999 through 2005 (APC, −2.70%; 95% CI, −4.01% to −1.37%), remained stable from 2006 through 2015 (APC, +0.21%; 95% CI, −0.47% to +0.90%), and declined sharply from 2016 through 2024 (APC, −9.76%; 95% CI, −10.66% to −8.84%). CF mortality in the United States has declined by more than half since the introduction of CFTR modulators. The shift in the sex-based death count ratio and the concentration of remaining deaths in the South are hypothesis-generating observations that require confirmation with individual-level data. These ecological findings cannot establish causation, as concurrent changes in supportive care, lung transplantation practices, and COVID-19 pandemic effects may have contributed to the observed trends. Full article

Background: Young children with Cystic Fibrosis (CwCF) are at risk of fat-soluble vitamin (FSV) deficiencies due to pancreatic insufficiency, despite pancreatic enzyme supplementation. CFTR modulator therapy such as elexacaftor/tezacaftor/ivacaftor (ETI) may improve pancreatic function, but its impact on FSV levels in this age group remains unclear. We evaluated changes in FSV serum levels in a cohort transitioning to ETI, taking a CF-specific, multivitamin formulation with beta-carotene as the primary source of vitamin A (DEKAs Plus Liquid, DPL). Methods: Retrospective data with paired analysis from 23 CwCF (2–5 years old) were analyzed. Serum FSV levels (D, E, A) and fecal elastase-1 (FE-1) were measured at baseline and 12 months post-ETI initiation. Daily FSV doses and covariates (FE-1, naive of CFTR modulators and ETI dose) were documented. Statistical analyses included Wilcoxon signed-rank tests and general linear models. Results: No significant changes were observed in serum FSV levels, while FSV dosing and formulation remained unchanged. Covariates did not influence serum level changes. Interestingly, ETI significantly improved FE-1 (p = 0.018), with 6/18 children achieving pancreatic sufficiency (FE-1 > 200 µg/g). Conclusions: In young CwCF initiating ETI, FSV levels were unchanged while pancreatic function improved. The use of provitamin A (beta-carotene) as in DPL resulted in no change in vitamin A levels and aligns with consensus guidance to prioritize provitamin A in ETI-treated children. Further validation in larger cohorts is warranted. Full article

Background: Highly effective CFTR modulation with Elexacaftor/Tezacaftor/Ivacaftor (ETI) markedly improves clinical outcomes in people with cystic fibrosis (CF). Data on its effects on physical activity, sleep, sinonasal symptoms, and parent-perceived outcomes in preschool-aged children are limited. Methods: In this prospective, observational, single-center cohort study, ten children with cystic fibrosis (aged 2–6 years) and at least one CFTR variant eligible for ETI were included. Data were collected using wrist-worn Garmin vívofit Junior 2 activity trackers and standardized questionnaires one month before ETI initiation and at 1, 3, 6, and 12 months after start of ETI. Outcomes included step count, minutes of moderate-to-vigorous physical activity, sleep parameters, sinonasal symptoms, and parental perceptions. Results: ETI was well tolerated. Sweat chloride levels decreased significantly. Physical activity improved at 3 and 6 months (step count and active minutes/day; p < 0.05) but declined to near-baseline levels at 12 months. Parental assessments of physical and sporting performance showed sustained improvement. Sleep duration remained stable, with no changes in deep or light sleep phases or nighttime awakenings. Sinonasal symptoms remained low. Discussion & Conclusions: Preliminary findings of this exploratory pilot study show that improvement in physical activity after three and six months of ETI therapy might be attributable to seasonality, as therapy was started in winter months. No changes in sleep duration or sleep patterns are reassuring in this small cohort of young children with CF. ETI therapy was safe and well tolerated. Parental appraisal of their children’s physical performance improved after start of ETI. Longitudinal, controlled studies involving larger cohorts are required to validate these findings and to account for potential confounding factors, such as age-dependent changes and individual and environmental factors such as seasonal variation. Full article

Cystic fibrosis is a multi-organ disease in which pancreatic involvement occurs early and contributes significantly to disease progression. Despite this, most mechanistic and pharmacological studies of CFTR have been conducted in airway epithelia, while pancreatic duct models remain relatively poorly represented. In this study, we establish CAPAN-1 cells as a reproducible in vitro model of pancreatic duct epithelium and assess wild-type CFTR function under basal and inflammatory conditions. Cells were cultured as polarized monolayers and analysed for transepithelial conductance, ion transport, luminal fluid pH regulation, and microviscosity. CFTR activity was stimulated with forskolin and further modulated using the potentiator ivacaftor (VX770) and the correctors tezacaftor (VX661) and elexacaftor (VX445), while specificity was confirmed with the CFTR inhibitor PPQ102. Inflammation was induced by lipopolysaccharide (LPS). CAPAN-1 cells formed a functional epithelium. CFTR activation increased epithelial conductance, promoted apical surface fluid alkalinization, and reduced apical surface fluid microviscosity, while PPQ102 consistently inhibited these effects. CFTR modulators enhanced functional responses in the presence of forskolin, although with moderate magnitude, consistent with wild-type CFTR expression. LPS exposure altered epithelial properties, increasing baseline conductance and impairing pH regulation, and induced secretion of pro-inflammatory cytokines. Notably, inflammatory stimulation did not abolish CFTR modulator responses, although it modified some downstream epithelial outputs. These findings identify CAPAN-1 cells as a physiologically relevant model for investigating CFTR function in the pancreatic duct environment and show that CFTR modulator responses are maintained, although functionally reshaped, under inflammatory conditions. Full article

Background: The CFTR modulator elexacaftor/tezacaftor/ivacaftor (ETI) has transformed cystic fibrosis (CF) care, but national-level real-world data on long-term effectiveness, durability of response, and treatment de-escalation remain limited. Methods: We conducted a nationwide longitudinal study using the Italian Cystic Fibrosis Registry. People with CF aged ≥6 years who initiated ETI between October 2019 and December 2022 and received ≥3 months of continuous therapy were included. Lung function (percent predicted FEV₁, ppFEV₁), nutritional status (BMI or BMI z-score), hospital days, complications, microbiology, and chronic treatments were assessed during the two years before and up to two years after ETI initiation. Longitudinal changes were analyzed using generalized estimating equations with multiple imputation for missing data. Results: The cohort included 2276 individuals (mean age 27.9 ± 13.3 years; 49% female). Mean ppFEV₁ declined during the pre-ETI period but increased by 9.9 percentage points at 12 months after ETI initiation (p < 0.001) and remained 6.8 percentage points above baseline at 24 months. A decline between 12 and 24 months was observed overall, except in individuals with severe baseline lung disease (ppFEV₁ < 40%), who maintained stable improvements. Mean annual hospital days decreased by approximately 65% and remained low throughout follow-up. Nutritional status improved, with a mean BMI increase of approximately 1.05 kg/m² compared with immediate pre-treatment in adults and a BMI z-score increase of 0.2 SD compared with pre-treatment timepoints in children. Use of most standard CF therapies declined substantially, particularly among individuals with ppFEV₁ ≥ 40%. The prevalence of allergic bronchopulmonary aspergillosis decreased, while liver disease prevalence increased modestly, largely reflecting transient elevations in liver enzymes. Conclusions: In this nationwide real-world cohort, ETI was associated with sustained improvements in lung function, nutritional status, and hospitalization burden. The attenuation of lung function gains after the first year, particularly in less severe disease, supports the need for individualized monitoring and cautious treatment de-escalation in the ETI era. Full article

Introduction: Cystic fibrosis (CF) frequently presents prenatally with meconium ileus (MI), a condition associated with significant neonatal morbidity and long-term gastrointestinal complications. The advent of highly effective CFTR modulators, particularly elexacaftor/tezacaftor/ivacaftor (ETI), during pregnancy remains off-label, and their role as in utero therapy for affected fetuses of carrier mothers is still emerging. Methods: We conducted a narrative literature review using PubMed, Embase, and Scopus to identify published reports of in utero CFTR modulator therapy for MI between 2022 and 2026. Seven relevant studies were identified and qualitatively synthesized. Their findings were interpreted in comparison with the present case. Results: We describe the first Italian case of prenatal ETI therapy for fetal CF. At 32 weeks’ gestation, ultrasound (US) findings were suggestive of evolving MI. Both parents were carriers of F508del CFTR and subsequent testing confirmed fetal homozygosity. Following urgent multidisciplinary consultation and ethics committee approval, maternal ETI therapy was initiated at 33 weeks’ gestation. After 21 days of treatment, follow-up fetal US demonstrated improvement in bowel dilatation and hyperchogenity. The infant was delivered at 36 + 2, passed meconium spontaneously, and required no surgical intervention. Pharmacokinetic assessment showed substantial transplacental transfer of all three ETI components, with cord-to-maternal plasma ratios of 0.34 (elexacaftor), 2.48 (tezacaftor), and 0.58 (ivacaftor), and detectable concentrations in amniotic fluid. Postnatally, sweat chloride was elevated, and pancreatic function transitioned from initially preserved to pancreatic insufficiency within the first month of life. Conclusions: This case and literature review suggest that prenatal CFTR modulation may influence the early trajectory of CF, potentially by preventing MI and potentially delaying the progression to pancreatic insufficiency and potentially reducing later gastrointestinal complications. While evidence remains limited, these findings highlight a potential therapeutic window during fetal life and underscore the need for prospective data collection, structured registries, and harmonized clinical guidance in this evolving field. Full article

CFTR modulators have transformed the clinical evolution of patients with CF. The number of pregnancies is increasing in women with CF, most of whom are now treated with CFTR modulators such as elexacaftor/tezacaftor/ivacaftor (ETI) or Tezacaftor/Ivacaftor. This raises some questions as we still lack data on foetal and maternal safety. The preliminary data seem to support the continuation of modulators. Some of these mothers may also give birth to newborns with CF and this raises more questions. We report here four cases of CF newborns whose mothers were treated with CFTR modulators throughout pregnancy to help refine potential foetal outcomes of in utero administration of CF modulators. No maternal or foetal complications could be attributed to CFTR modulators. Three CF newborns were exposed to ETI and were false negative of the newborn screening. Two of them were pancreatic sufficient at birth. The remaining patient, exposed to Tezacaftor/Ivacaftor (TI) alone, showed elevated immunoreactive trypsin (IRT) and severe pancreatic insufficiency at birth. These cases highlight that in utero administration of ETI could potentially improve neonatal outcomes of CF newborns and cause newborn screening false negative. Full article

Cystic fibrosis (CF) is a multisystem genetic disorder in which malnutrition has historically been a major determinant of disease severity. The advent of CFTR modulators has significantly altered the nutritional and functional profile of CF patients. This systematic review, conducted following PRISMA guidelines and registered on PROSPERO, summarizes studies published from 2012 to 2025 that evaluated the impact of CFTR modulators on nutritional status, body composition, and respiratory function, with a particular focus on the relationship between BMI changes and FEV₁. Seventeen studies including both pediatric and adult populations were identified and analyzed. All studies reported significant increases in BMI following modulator therapy, ranging from +0.9 to +1.6 kg/m² after 6–12 months of elexacaftor/tezacaftor/ivacaftor (ETI), accompanied by improvements in FEV₁ of 7–13 percentage points. Weight gain was primarily due to increases in fat mass (60–75%). Improvements in albumin, prealbumin, and vitamin levels, along with reductions in C-reactive protein (CRP) and fecal calprotectin, reflected systemic metabolic recovery. However, a marked increase in overweight and obesity (up to 40%), together with increased visceral adiposity, has also been observed. Overall, CFTR modulators result in significant nutritional and functional improvements, highlighting the need for strategies that prioritize overall metabolic health rather than weight gain alone. Full article

Background: Pediatric cataracts are a main cause of irreversible vision loss and a significant public health challenge. This study aimed to identify pharmacovigilance signals by analyzing large-scale data from the U.S. Food and Drug Administration Adverse Event Reporting System (FAERS). Methods: Using real-world data from FAERS (Q1 2004 to Q3 2025), we investigated associations between medications and pediatric cataracts. Following data standardization, signal detection was performed using multiple disproportionality analyses, including the Reporting Odds Ratio (ROR), Proportional Reporting Ratio (PRR), Bayesian Confidence Propagation Neural Network (BCPNN), and Multi-item Gamma Poisson Shrinker (MGPS). The time to onset was also evaluated. Results: Among 690,374 reports for individuals aged 0–17 years, 671 reports involving 232 drugs were reported with cataracts. Disproportionality analysis identified 24 drugs with significant signals, predominantly glucocorticoids (11/24), followed by immunosuppressants, monoclonal antibodies, cystic fibrosis transmembrane conductance regulator (CFTR) modulators, antineoplastic agents, an antiepileptic drug, and a colony-stimulating factor. Difluprednate showed the highest pharmacovigilance signal (ROR: 963.67; 95% CI: 316.27–2936.31; n = 4). Notably, CFTR modulators exhibited striking signals: ivacaftor (ROR: 30.75; 95% CI: 18.06–52.37; n = 14), elexacaftor-ivacaftor-tezacaftor (ROR: 15.58; 95% CI: 9.86–24.63; n = 19), and ivacaftor-lumacaftor (ROR: 13.2; 95% CI: 7.9–22.07; n = 15). Conclusions: This study provides a comprehensive large-scale pharmacovigilance profile of drug-induced pediatric cataracts, identifying agents with high-risk pharmacovigilance signals and underscoring the need for proactive ocular monitoring. These findings can inform clinical decision making and prevention strategies and guide future mechanistic research. Full article

Pharmacological modulators of CFTR have significantly changed the cystic fibrosis (CF) phenotype of subjects affected by this multi-organ disease. Here, we evaluated the CFTR function analysis (short-circuit chamber in colonoids) in response to Elexacaftor/Tezacaftor/Ivacaftor (ETI) with the clinical benefits of in vivo treatment with ETI in ten CF subjects. We found that the functional response of ETI-corrected PDROS significantly correlated with the absolute change in the sweat chloride test. Thus, our work reinforces the use of organoid-derived human intestinal monolayers to guide clinicians in selecting CFTR-targeted therapies. Full article

Prior studies in people with cystic fibrosis (CF) demonstrated a positive impact of ivacaftor on the stool microbiome. However, studies evaluating the impact of elexacaftor–tezacaftor–ivacaftor (ETI) on gut dysbiosis are limited. In this prospective, observational study, we evaluated the differences in stool microbiome in children (aged 2–17 years) with CF who were treated with ETI for at least two months and compared with children with CF who did not receive ETI. We also included healthy siblings as controls. There were no significant differences in the demographics between the groups. There were no significant differences in alpha diversity between the groups for both bacteriome and mycobiome. Alpha diversity showed a negative trend with the duration of ETI therapy for both bacteriome and mycobiome. Firmicutes and Proteobacteria were the most abundant phyla and core members across all samples, regardless of disease status or treatment. Ascomycota and Basidiomycota were the most abundant and core members across all samples, regardless of disease status or treatment. Alpha diversity showed a negative trend with the duration of ETI therapy for both bacteriome and mycobiome in children with CF treated with ETI. Future studies are needed to confirm or refute our preliminary findings. Full article

Cystic fibrosis (CF) is a genetic disorder caused by mutations in the CFTR gene, leading to multi-system impairment. Sleep respiratory disorders (SRDs) are frequent in individuals with CF—even in those with normal or mildly impaired lung function—and may adversely affect overall health. The triple combination of elexacaftor, tezacaftor, and ivacaftor (ETI) has markedly improved clinical outcomes in CF; however, its long-term impact on SRDs remains unclear. This study aimed to assess the effects of ETI on nocturnal cardiorespiratory parameters in individuals with CF over a two-year period. Thirty-five clinically stable patients aged ≥13 years, eligible for ETI therapy, were enrolled. Nocturnal cardiorespiratory polygraphy and spirometry were performed at baseline (T0), one year (T1), and two years (T2) after ETI initiation. After one year, significant improvements were observed in mean oxygen saturation (mSpO₂), time with SpO₂ ≤ 90% (t ≤ 90%), and respiratory rate. Spirometric indices (FEV₁, FVC, FEF) also significantly increased (p < 0.05). Correlation analysis revealed positive associations between mSpO₂ and FEV₁ (ρ = 0.515, p = 0.002) and between FEV₁ and FVC (ρ = 0.894, p < 0.001), while t ≤ 90% negatively correlated with FEV₁ (ρ = −0.404, p = 0.016). No additional significant changes were found at T2. ETI therapy resulted in sustained improvements in nocturnal oxygenation and lung function, supporting the importance of nocturnal respiratory monitoring during follow-up. Full article

Despite the progressive extension of CFTR variant eligibility to the triple combination of elexacaftor/tezacaftor/ivacaftor (ETI), most rare CFTR pathogenic variants remain ineligible for CFTR modulators. It is crucial to determine whether unexplored variants are rescuable by clinical modulators and to identify innovative therapeutic strategies for rescuing non-responder variants. The approach known as “theratyping” (in vitro testing of genotypes) has been accepted by the Food and Drug Administration (FDA) for the extension of clinical modulators’ approval for in vitro responding genotypes. We used one of the most advanced models for theratyping: organoids derived from nasal epithelia of people with cystic fibrosis (pwCF). We optimized the forskolin-induced swelling (FIS) of organoids to assess CFTR basal or modulator-restored function. Nasal organoids mimicked the original epithelial tissue, CFTR residual activity, and modulator response. We set up the FIS assay using nasal organoids with reference genotypes and theratyped 38 rare (non-F508del) CFTR genotypes, either eligible or non-eligible for FDA approval, for treatment with ETI or ivacaftor. We found strong correspondence between the in vitro response of CFTR variants to modulators and their FDA approval status. Additionally, some previously uncharacterized CFTR variants have proven responsive to clinical modulators, with significant therapeutic implications. These results suggest that the nasal organoid FIS assay, pending confirmation of the prediction in the corresponding pwCF, might be considered as a powerful in vitro tool to predict modulator efficacy in each pwCF, guiding out-of-label prescription in CF, and to identify uncharacterized variants responsive to modulators. This approach may allow comparison of the efficacy of different therapeutics or the identification of innovative strategies for non-responding genotypes, improving personalized therapy and quality of life for pwCF. Full article