Journal of Cystic Fibrosis : Official Journal of the European Cystic Fibrosis Society

BACKGROUND: Cystic fibrosis associated liver disease (CFLD) carries a significant disease burden with no effective preventive therapies. According to the gut-liver axis hypothesis for CFLD pathogenesis, dysbiosis and increased intestinal inflammation and permeability permit pathogenic bacterial translocation into the portal circulation, leading to hepatic inflammation and fibrosis. Evaluating the effect of CFTR (cystic fibrosis transmembrane conductance regulator) modulation with elexacaftor/tezacaftor/ivacaftor (ETI) may help determine the role of CFTR in CFLD and increase understanding of CFLD pathogenesis, which is critical for developing therapies...

BACKGROUND: The cystic fibrosis transmembrane conductance regulator (CFTR) mutation I1234V (I1234V, p.Ile1234Val, c.3700A>G), is a missense-mutation that creates a cryptic splice site, with the formation of a protein lacking 6 amino acids, that is misfolded and misprocessed. The in vitro effects of CFTR modulator (CFTRm) therapies on human bronchial cell models and intestinal organoids carrying this mutation are conflicting. The aim of this study was therefore to explore the clinical efficacy of CFTRm in people with cystic fibrosis (pwCF) carrying this mutation...

No abstract text is available yet for this article.

This review synthesizes articles published in 2023, focusing on the impact of elexacaftor-tezacaftor-ivacaftor (ETI) in cystic fibrosis (CF) care. Real-world data highlights sustained benefits of ETI across age groups, while challenges like neuropsychological side effects persist. Beyond CFTR modulators, research explores telemedicine and novel therapies. Prioritizing equitable access and addressing unmet needs remain crucial for comprehensive CF management.

The COVID-19 pandemic necessitated a rapid shift in clinical research to perform virtual visits and remote endpoint assessments, providing a key opportunity to optimize the use of remote endpoints for clinical trials in cystic fibrosis. The use of remote endpoints could allow more diverse participation in clinical trials while minimizing participant burden but must be robustly evaluated to ensure adequate performance and feasibility. In response, the Cystic Fibrosis Foundation convened the Remote Endpoint Task Force (Supplemental Table 1), a multidisciplinary group of CF researchers with remote endpoint expertise and community members tasked to better understand the current and future use of remote endpoints for clinical research...

BACKGROUND: Lung infections antibiotic treatment in Cystic Fibrosis patients (pwCF) is often complicated by bacterial persisters, including the so-called Viable but Non Culturable (VBNC) forms, live cells undetected by the routine cultural microbiological methods. This study investigated the occurrence of VBNC cells of five CF bacterial pathogens in 94 pwCF over one year and the possible associations with the patients' clinical features. METHODS: Sputum samples, recovered at routine visits and during exacerbation episodes, were analyzed for the presence of the five pathogens by both routine culture-based assays and species-specific qPCR...

BACKGROUND: Short palate, lung, and nasal epithelium clone 1 (SPLUNC1) is an innate defence protein that acts as an anti-microbial agent and regulates airway surface liquid volume through inhibition of the epithelial sodium channel (ENaC). SPLUNC1 levels were found to be reduced in airway secretions of adults with cystic fibrosis (CF). The potential of SPLUNC1 as a biomarker in children with CF is unknown. METHODS: We quantified SPLUNC1, interleukin-8 (IL-8) and neutrophil elastase (NE) in sputum of CF children treated with either intravenous antibiotics or oral antibiotics for a pulmonary exacerbation (PEx)s, and in participants of a prospective cohort of CF children with preserved lung function on spirometry, followed over a period of two years...

BACKGROUND: Biofilm-associated pulmonary infections pose therapeutic challenges in cystic fibrosis patients, especially when involving multiple bacterial species. Enzymatic degradation of the biofilm matrix may offer a potential solution to enhance antibiotic efficacy. This study investigated the repurposing of DNase I, commonly used for its mucolytic activity in cystic fibrosis, to target extracellular DNA within biofilms, as well as potential synergies with alginate lyase and broad-spectrum antibiotics in dual-species biofilms of Pseudomonas aeruginosa and Staphylococcus aureus...

BACKGROUND: Lumacaftor/ivacaftor (LUM/IVA) has been shown to be safe and efficacious in people with cystic fibrosis (CF) ≥1 year of age. To assess the impact of early LUM/IVA initiation on CF disease progression, a 6-year observational study leveraging data from existing CF patient registries is being conducted in children with CF homozygous for F508del (F/F genotype) who were aged 2 through 5 years at treatment initiation. Here we present interim results from this study focusing on data from the European CF Society Patient Registry (ECFSPR)...

BACKGROUND: In 2017, the US Food and Drug Administration initiated expansion of drug labels for the treatment of cystic fibrosis (CF) to include CF transmembrane conductance regulator (CFTR) gene variants based on in vitro functional studies. This study aims to identify CFTR variants that result in increased chloride (Cl- ) transport function by the CFTR protein after treatment with the CFTR modulator combination elexacaftor/tezacaftor/ivacaftor (ELX/TEZ/IVA). These data may benefit people with CF (pwCF) who are not currently eligible for modulator therapies...

After three publications defining an updated guidance on the diagnostic criteria for people with cystic fibrosis transmembrane conductance regulator (CFTR)-related disorders (pwCFTR-RDs), establishing its relationship to CFTR-dysfunction and describing the individual disorders, this fourth and last paper in the series addresses some critical challenges facing health care providers and pwCFTR-RD. Topics included are: 1) benefits and obstacles to collect data from pwCFTR-RD are discussed, together with the opportunity to integrate them into established CF-registries; 2) the potential of infants designated CRMS/CFSPID to develop a CFTR-RD and how to communicate this information; 3) a description of the challenges in genetic counseling, with particular regard to phenotypic variability, unknown long-term evolution, CFTR testing and pregnancy termination 4) a proposal for the assessment of potential barriers to the implementation and dissemination of the produced documents to health care professionals involved in the care of pwCFTR-RD and a process to monitor the implementation of the CFTR-RD recommendations; 5) clinical trials investigating the efficacy of CFTR modulators in CFTR-RD and how endpoints and outcomes might be adapted to the heterogeneity of these disorders...

Vitamin D sufficiency has been difficult to achieve consistently in patients with cystic fibrosis (CF), even with robust oral supplements. To assess vitamin D status and resistance to supplementation, we studied 80 adults using 25-hydroxyvitamin D (25OHD) determinations and whole genome sequencing to construct polygenic risk scores (PRS) that aggregate variants associated with vitamin D status. The results revealed that 30 % of patients were below the threshold of 30 ng/mL and thus should be regarded as insufficient despite normal vitamin E status, a reflection of adherence to fat soluble vitamin supplementation...

BACKGROUND: Sweat chloride (SC) concentrations in people with cystic fibrosis (PwCF) reflect relative CF transmembrane conductance regulator (CFTR) protein function, the primary CF defect. Populations with greater SC concentrations tend to have lesser CFTR function and more severe disease courses. CFTR modulator treatment can improve CFTR function within specific CF genotypes and is commonly associated with reduced SC concentration. However, SC concentrations do not necessarily fall to concentrations seen in the unaffected population, suggesting potential for better CFTR treatment outcomes...

BACKGROUND: Prescribers have an increasing range of inhaled antimicrobial formulations to choose from when prescribing both eradication and chronic suppression regimens in cystic fibrosis (CF). This study aimed to investigate the decision-making process behind prescribing of inhaled antimicrobials for Pseudomonas aeruginosa infections. METHODS: A questionnaire was developed using Microsoft Forms and then forwarded to 57 Principal Investigators (PIs), at each of the CF centres within the European Cystic Fibrosis Society-Clinical Trials Network (ECFS-CTN)...

No abstract text is available yet for this article.

Many people with CF (pwCF) desire a reduction in inhaled treatment burden after initiation of elexacaftor/tezacaftor/ivacaftor. The randomized, open-label SIMPLIFY study showed that discontinuing hypertonic saline (HS) or dornase alfa (DA) was non-inferior to continuation of each treatment with respect to change in lung function over a 6-week period. In this SIMPLIFY substudy, we used gamma scintigraphy to determine whether discontinuation of either HS or DA was associated with deterioration in the rate of in vivo mucociliary clearance (MCC) in participants ≥12 years of age...

BACKGROUND: Relieving gastrointestinal symptoms is a research priority in cystic fibrosis. Emerging evidence highlights effects of cystic fibrosis transmembrane conductance regulator (CFTR) modulators on gastrointestinal function, including pancreatic sufficiency. This study explores ivacaftor licensing and treatment on recorded pancreatic enzyme replacement therapy (PERT) prescription in the US and UK CF registries. METHODS: Retrospective longitudinal registry study of recorded pancreatic PERT use between 2008 and 2017...

BACKGROUND: Nutritional challenges are common in early CF care and stressful for caregivers of children with CF (cwCF) to navigate. Gastrostomy tube (G-tube) placement can improve weight gain, however the decision to proceed with placement is personalized and preference-sensitive. Little is known about the experiences of caregivers of cwCF and the G-tube decision-making process. OBJECTIVES: The present study used a qualitative approach to explore the perceptions and experiences of caregivers of cwCF with G-tube introductions and recommendations, as well as factors influencing G-tube decision-making...

Cystic fibrosis (CF) is the most common severe autosomal recessive genetic disorder among Caucasians. The improvement of genetic techniques has allowed the identification of an increasing number of genetic variants, including large rearrangements such as duplications. We report the first case of a whole CFTR gene duplication in a healthy newborn, who had normal sweat test, also carrying R74W and V855I variants on the same allele. Familial segregation analysis and the observed frequencies of all the CFTR gene variants, revealed that R74W and V855I were probably both present in a cis arrangement on the allele also containing the duplication (i...

This systematic review summarizes the impact of cystic fibrosis (CF) on sexual and reproductive health (SRH) in males and females, covering pubertal development, hormonal function, family planning, and fertility. Included articles featured historical CF diagnostic criteria, preclinical or clinical data (retrospective cohorts or open label trials), while excluded articles lacked full text availability, explicit methodology, or comparisons between CF and non-CF patients. Genotype differences in CFTR mutations influenced symptom severity...