Fibrosis Transmembrane Conductance Regulator Modulators Research Articles

Diabetes is associated with increased burden of gastrointestinal symptoms in adults with cystic fibrosis

BackgroundIndividuals with diabetes mellitus (DM) are known to frequently experience gastrointestinal (GI) symptoms. In contrast, the impact of cystic fibrosis-related diabetes (CFRD) on accentuating GI symptoms in people with cystic fibrosis (pwCF) is unknown. We sought to examine this. MethodsAbdominal symptoms were measured using the validated CF-specific GI symptom questionnaire - CFAbd-Score© - as part of a multicentre cohort study in pancreatic insufficient adults with CF, not on cystic fibrosis transmembrane conductance regulator (CFTR) modulators. The CFAbd-Score total score (0–100pts), its 5 domains, alongside nine specific GI symptoms associated with DM, were compared between the CFRD and non-CFRD groups. Results27 (31%) and 61 (69%) participants with CF were recruited in the CFRD and non-CFRD groups respectively. Total CFAbd-Score and the two domains: gastroesophageal reflux disease and disorders of appetite were significantly higher in the CFRD group compared to the non-CFRD group (p<0.05), with the mean total CFAbd-Score being 25.4 ± 2.5 and 18.4 ± 1.5 in the CFRD and non-CFRD groups respectively. Among the nine GI symptoms commonly reported as elevated in DM, bloating and nausea were significantly more common in individuals with CFRD compared to those without (p<0.05). ConclusionsIndividuals with CFRD overall, have a higher GI symptom burden, according to CFAbd-Scores. Specifically, they experience significantly more bloating and nausea. Close monitoring and further research is needed to better understand and manage GI symptoms in this group.

Role of inhaled antibiotics in the era of highly effective CFTR modulators.

Recurrent and chronic bacterial infections are common in people with cystic fibrosis (CF) and contribute to lung function decline. Antibiotics are the mainstay in the treatment of exacerbations and chronic bacterial infection in CF. Inhaled antibiotics are effective in treating chronic respiratory bacterial infections and eradicating Pseudomonas aeruginosa from the respiratory tract, with limited systemic adverse effects. In the past decade, highly effective cystic fibrosis transmembrane conductance regulator (CFTR) modulators have become a new therapy that partially corrects/opens chloride transport in patients with selected CFTR mutations, restoring mucus hydration and improving mucociliary clearance. The recent triple CFTR modulator combination is approved for ∼80-90% of the CF population and significantly reduces pulmonary exacerbations and improves respiratory symptoms and lung function. CFTR modulators have shifted the focus from symptomatic treatment to personalised/precision medicine by targeting genotype-specific CFTR defects. While these are highly effective, they do not fully normalise lung physiology, stop inflammation or resolve chronic lung damage, such as bronchiectasis. The impact of these new drugs on lung health is likely to change the future management of chronic pulmonary infections in people with CF. This article reviews the role of inhaled antibiotics in the era of CFTR modulators.

SARS-CoV-2-Mediated Lung Edema and Replication Are Diminished by Cystic Fibrosis Transmembrane Conductance Regulator Modulators.

Coronaviruses (CoVs) of genera α, β, γ, and δ encode proteins that have a PDZ-binding motif (PBM) consisting of the last four residues of the envelope (E) protein (PBM core). PBMs may bind over 400 cellular proteins containing PDZ domains (an acronym formed by the combination of the first letter of the names of the three first proteins where this domain was identified), making them relevant for the control of cell function. Three highly pathogenic human CoVs have been identified to date: severe acute respiratory syndrome coronavirus (SARS-CoV) and Middle East respiratory syndrome coronavirus (MERS-CoV), and SARS-CoV-2. The PBMs of the three CoVs were virulence factors. SARS-CoV mutants in which the E protein PBM core was replaced by the E protein PBM core from virulent or attenuated CoVs were constructed. These mutants showed a gradient of virulence, depending on whether the alternative PBM core introduced was derived from a virulent or an attenuated CoV. Gene expression patterns in the lungs of mice infected with SARS-CoVs encoding each of the different PBMs were analyzed by RNA sequencing of infected lung tissues. E protein PBM of SARS-CoV and SARS-CoV-2 dysregulated gene expression related to ion transport and cell homeostasis. Decreased expression of cystic fibrosis transmembrane conductance regulator (CFTR) mRNA, essential for alveolar edema resolution, was shown. Reduced CFTR mRNA levels were associated with edema accumulation in the alveoli of mice infected with SARS-CoV and SARS-CoV-2. Compounds that increased CFTR expression and activity, significantly reduced SARS-CoV-2 growth in cultured cells and protected against mouse infection, suggesting that E protein virulence is mediated by a decreased CFTR expression. IMPORTANCE Three highly pathogenic human CoVs have been identified: SARS-CoV, MERS-CoV, and SARS-CoV-2. The E protein PBMs of these three CoVs were virulence factors. Gene expression patterns associated with the different PBM motifs in the lungs of infected mice were analyzed by deep sequencing. E protein PBM motif of SARS-CoV and SARS-CoV-2 dysregulated the expression of genes related to ion transport and cell homeostasis. A decrease in the mRNA expression of the cystic fibrosis transmembrane conductance regulator (CFTR), which is essential for edema resolution, was observed. The reduction of CFTR mRNA levels was associated with edema accumulation in the lungs of mice infected with SARS-CoV-2. Compounds that increased the expression and activity of CFTR drastically reduced the production of SARS-CoV-2 and protected against its infection in a mice model. These results allowed the identification of cellular targets for the selection of antivirals.

Current and Future Therapeutic Approaches of Exocrine Pancreatic Insufficiency in Children with Cystic Fibrosis in the Era of Personalized Medicine.

This review presents current updates of pancreatic enzyme replacement therapy in children with cystic fibrosis based on literature published in the last decade and some special considerations regarding pancreatic enzyme replacement therapy in the era of new therapies, such as cystic fibrosis transmembrane conductance regulator modulator therapies. Few articles evaluate the efficacy of pancreatic enzyme replacement therapy in the pediatric population, and most studies also included children and adults with cystic fibrosis. Approximately 85% of cystic fibrosis patients have exocrine pancreatic insufficiency and need pancreatic enzyme replacement therapy. Fecal elastase is the most commonly used diagnostic test for exocrine pancreatic insufficiency, although this value can fluctuate over time. While it is used as a diagnostic test, it cannot be used for monitoring the effectiveness of pancreatic enzyme replacement therapy and for adjusting doses. Pancreatic enzyme replacement therapy, the actual treatment for exocrine pancreatic insufficiency, is essential in children with cystic fibrosis to prevent malabsorption and malnutrition and needs to be urgently initiated. This therapy presents many considerations for physicians, patients, and their families, including types and timing of administration, dose monitoring, and therapy failures. Based on clinical trials, pancreatic enzyme replacement therapy is considered effective and well-tolerated in children with cystic fibrosis. An important key point in cystic fibrosis treatment is the recent hypothesis that cystic fibrosis transmembrane conductance regulator modulators could improve pancreatic function, further studies being essential. Pancreatic enzyme replacement therapy is addressed a complication of the disease (exocrine pancreatic insufficiency), while modulators target the defective cystic fibrosis transmembrane conductance regulator protein. Exocrine pancreatic insufficiency in cystic fibrosis remains an active area of research in this era of cystic fibrosis transmembrane conductance regulator modulator therapies. This new therapy could represent an example of personalized medicine in cystic fibrosis patients, with each class of modulators being addressed to patients with specific genetic mutations.

EFFECT OF ELEXACAFTOR/TEZACAFTOR/IVACAFTOR ON ANNUAL RATE OF LUNG FUNCTION DECLINE IN PEOPLE WITH CYSTIC FIBROSIS

Elexacaftor/tezacaftor/ivacaftor (ELX/TEZ/IVA) was shown to be safe and efficacious in people with cystic fibrosis (CF) with ≥ 1 F508del-CFTR allele in Phase 3 clinical trials. ELX/TEZ/IVA treatment led to improved lung function, with increases in percent predicted forced expiratory volume in 1second (ppFEV1) and Cystic Fibrosis Questionnaire-Revised respiratory domain score. Here, we evaluated the impact of ELX/TEZ/IVA on the rate of lung function decline over time by comparing changes in ppFEV1 in participants from the Phase 3 trials with a matched group of people with CF from the US Cystic Fibrosis Foundation Patient Registry not eligible for cystic fibrosis transmembrane conductance regulator (CFTR) modulator therapy. Participants treated with ELX/TEZ/IVA had on average no loss of pulmonary function over a 2-year period (mean annualized rate of change in ppFEV1, +0.39 percentage points [95% CI, -0.06 to 0.85]) compared with a 1.92 percentage point annual decline (95% CI, -2.16 to -1.69) in ppFEV1 in untreated controls. ELX/TEZ/IVA is the first CFTR modulator therapy shown to halt lung function decline over an extended time period.

Pregnancy in women with cystic fibrosis and diabetes: An audit of outcomes at two tertiary obstetric hospitals in Australia in the pre-cystic fibrosis transmembrane conductance regulator modulator era

Background Pregnancy in women with cystic fibrosis (CF) is becoming more common. Long-term metabolic issues such as diabetes are also becoming more common and have potentially important impacts on pregnancy outcomes. This study aimed to assess the impact of diabetes on pregnancy outcomes for women with CF. Methods We undertook a retrospective chart audit of pregnancies to women with CF at the two tertiary obstetric hospitals in Southeast Queensland associated with CF and transplant management clinics between 2006 and 2016. Results A total of 38 pregnancies among 26 women were identified. Four women (five pregnancies) had cystic fibrosis-related diabetes (CFRD) diagnosed prior to pregnancy, and 12 women (15 pregnancies) developed gestational diabetes (GDM) complicating pregnancy. CFRD and GDM were associated with higher rates of delivery complications, prematurity, and the need for neonatal intensive care unit admission. Conclusion Diabetes is common during pregnancy in women with CF and impacts pregnancy outcomes.

Exercise and Airway Clearance Techniques in Cystic Fibrosis.

Exercise and airway clearance techniques (ACTs) have been a cornerstone of treatment for people with cystic fibrosis (pwCF) for many decades. Exercise may confer both respiratory and nonrespiratory benefits for pwCF, with greater exercise capacity associated with improved survival. A wide variety of exercise interventions for pwCF have been investigated. ACTs may assist in reducing respiratory symptoms for pwCF and are currently recommended to be performed daily, with the types of ACTs used varying globally. While recommended components of care, both exercise and ACTs are time-intensive and maintaining adherence to the recommendations over the longer term can be challenging. It has been proposed that with advances in the therapeutic options for pwCF, a rationalization of the therapeutic regimen may be possible. We summarize the current evidence for the use of exercise and ACTs by pwCF, discuss the implications of the introduction of cystic fibrosis transmembrane conductance regulator modulators on both exercise and ACTs, and highlight areas for further research.

The influence of exocrine pancreatic function on the exposure and pharmacokinetics of ivacaftor in people with cystic fibrosis

BackgroundCystic fibrosis transmembrane conductance regulator (CFTR) modulator therapies target the underlying cause of cystic fibrosis (CF), and show robust treatment effects at group level. The individual effect however, is variable which might be (partially) related to differences in drug exposure. The profound influence of fat containing food compared to fasting on drug exposure gives need to investigate if the exocrine pancreatic function changes the degree and rate of absorption of ivacaftor and thereby may contribute to differences in drug exposure. MethodsPharmacokinetic parameters of ivacaftor were measured in 10 pancreatic sufficient (PS) and 10 pancreatic insufficient (PI) patients with CF on current treatment with tezacaftor/ivacaftor and compared between both groups. In PI patients pharmacokinetic parameters were investigated with and without the use pancreatic enzymes and compared in each individual. ResultsWe demonstrated that the pharmacokinetic parameters of ivacaftor did not differ significantly between PS and PI people with CF (pwCF). Pancreatic enzymes did not significantly change the absorption or exposure to ivacaftor in PI pwCF using tezacaftor/ivacaftor. ConclusionThe exocrine pancreatic function of pwCF does not significantly influence the absorption and exposure of ivacaftor. The use of pancreatic enzymes in PI pwCF does not change the absorption and exposure of ivacaftor. Therefore, the dosing advice as mentioned in the SmPC for ivacaftor can be maintained independent of the exocrine pancreatic function.

LBODP085 Effects Of Elexacaftor-tezacaftor-ivacaftor On Glucose Tolerance And Other Metabolic Parameters In Children With Cystic Fibrosis

Abstract Cystic fibrosis related diabetes (CFRD) occurs in up to 20% of teenagers and has detrimental effects on lung function and nutritional status. Cystic fibrosis transmembrane conductance regulator (CFTR) modulators have had positive and mixed effects on glucose tolerance in children. Our study aimed to investigate the effect of elexacaftor-tezacaftor-ivacaftor (ETI) on glucose tolerance, as well as on anthropometric measures and lipids, in children. We hypothesized that glucose tolerance and BMI would improve. We completed a retrospective study of children at a Pediatric Cystic Fibrosis (CF) Center who were started on ETI after December 2019. Our inclusion criteria were children 12 years and older who were on ETI for at least one year. We did not include children on long-term corticosteroids, with type 1, type 2, or other secondary diabetes, or who were post-transplant. Blood glucose at 2 hours after an oral glucose tolerance test (2-hour BG), Hemoglobin A1c (HgbA1c), lipids, and weight and BMI z-scores were assessed after at least one year on ETI. For patients with CFRD, only HgbA1c was performed for monitoring glycemic control. These measures were compared to corresponding measures in control groups of children older than or at 12 years old, heterozygous or homozygous for F508d, who were seen at the CF Center 4 years prior, and therefore were not receiving ETI. Patients with normal and impaired glucose tolerance (NGT/IGT) were compared to controls with similar glucose tolerance and separated by age. Patients with CFRD were compared to controls with CFRD only. Average length of time on ETI was 18.7 months. CFRD was diagnosed in 8.6% of patients and impaired glucose tolerance in 13.8% of patients. Previous CFTR modulators were used in 31.6% of patients. Average 2-hour BG increased by 3.2 mg/dl (n=44, p=0.6) and average HgbA1c decreased by 0. 05% (n=53, p=0.18) after the use of ETI. Weight z-score increased by 0. 07 (n=54, p=0.38) and BMI z-score increased by 0.13 (n=58, p=0.31). Total cholesterol increased significantly by 17.6 mg/dl (n=56, p&amp;lt;0. 0001), but in contrast, triglycerides only increased by 4.75 mg/dl (p=0.46). Change in average 2-hour BG for children in the NGT/IGT control group (total n=30) were similar to children receiving ETI: 12-13 years: 3.6 versus 3.2 mg/dl, 13-14 years: -9. 0 versus -3.5 mg/dl, and 14-18 years: 18.5 versus 8.6 mg/dl (all p&amp;gt;0. 05). In children with CFRD, the control (n=7) and ETI (n=5) groups had similar changes in HgbA1c (-0.56% versus -0.5%, p=0.94). In a retrospective analysis of children, 2-hour BG and HgbA1c changed minimally after at least one year on ETI and did not differ significantly when compared to controls. Minimal changes were also seen for BMI, weight, and triglycerides after use of ETI. However, total cholesterol increased significantly with the use of ETI. Presentation: No date and time listed

Antibiotic Stewardship und chronische Lungenerkrankungen

HintergrundDie Therapie akuter Exazerbationen von Patienten mit chronischen Lungenerkrankungen ist häufig mit der Gabe von Antibiotika vergesellschaftet. Wiederholte stationäre Aufenthalte, hohe Antibiotikaverbräuche sowie die Gefahr des Auftretens multiresistenter Keime stellen eine Belastung für das Gesundheitssystem dar.Ziel dieser ArbeitZiel dieser Arbeit ist es, einen Überblick über Antibiotic-Stewardship-Strategien für das Management von Patienten mit chronischen Lungenerkrankungen mit besonderem Fokus auf COPD („chronic obstructive pulmonary disease“) sowie Bronchiektasien und zystischer Fibrose (CF) zu geben.Material und MethodenDie Übersichtsarbeit basiert auf einer Literaturrecherche in PubMed.Ergebnisse und DiskussionPoint-of-Care-Tests (POCT) zum schnelleren Erregernachweis ergaben uneinheitliche Ergebnisse in Bezug auf die Reduktion antibiotischer Therapien. Als relativ einfaches Verfahren konnte mittels POCT C‑reaktives Protein (CRP) („cut off“ < 20 bzw. ≥ 40 mg/l) die Anwendung von Antibiotika bei Patienten mit exazerbierter COPD reduzieren, ohne die Sicherheit zu gefährden. Die Rolle von Procalcitonin bleibt unklar. Bei nichtpurulentem Sputum und einer leichten bis mittelschweren COPD-Exazerbation kann Leitliniengerecht auf eine Antibiotikatherapie verzichtet werden. Der Einsatz von Makroliden führt zu einer zunehmenden Resistenzentwicklung und birgt die Gefahr v. a. kardiovaskulärer Nebenwirkungen, sodass eine Dauertherapie bei Patienten trotz häufiger COPD-Exazerbationen kritisch gesehen werden muss. Bei der CF hat sich durch den Einsatz von CFTR(„cystic fibrosis transmembrane conductance regulator“)-Modulatoren das Management der Grunderkrankung so verbessert, dass weniger Antibiotikatherapien gebraucht wurden. Auch bei den Bronchiektasen gibt es Anlass zur Hoffnung, dass durch neue Therapien, wie z. B. Inhibitoren der neutrophilen Elastase, Antibiotika eingespart werden können. Jeder Einsatz von Antibiotika bei chronischen Lungenerkrankungen sollte leitliniengerecht erfolgen.

662 Novel cystic fibrosis transmembrane conductance regulator modulator combinations that address the first nucleotide binding domain defect central to ΔF508 dysfunction enable full correction of cystic fibrosis transmembrane conductance regulator

662 Novel cystic fibrosis transmembrane conductance regulator modulator combinations that address the first nucleotide binding domain defect central to ΔF508 dysfunction enable full correction of cystic fibrosis transmembrane conductance regulator

370 Current prices versus minimum costs of production for cystic fibrosis transmembrane conductance regulator modulators

370 Current prices versus minimum costs of production for cystic fibrosis transmembrane conductance regulator modulators

371 Hospitalization data in the era of highly effective cystic fibrosis transmembrane conductance regulator modulator therapy

371 Hospitalization data in the era of highly effective cystic fibrosis transmembrane conductance regulator modulator therapy

45 Impact of early growth trajectories and cystic fibrosis transmembrane conductance regulator modulator therapy on puberty in cystic fibrosis

45 Impact of early growth trajectories and cystic fibrosis transmembrane conductance regulator modulator therapy on puberty in cystic fibrosis

427 Persistence of cell type–specific transcriptomic changes in the nasal epithelium of people with cystic fibrosis receiving cystic fibrosis transmembrane conductance regulator modulators

427 Persistence of cell type–specific transcriptomic changes in the nasal epithelium of people with cystic fibrosis receiving cystic fibrosis transmembrane conductance regulator modulators

225 Essential fatty acid and lipoprotein status in pediatric cystic fibrosis: Impact of cystic fibrosis transmembrane conductance regulator modulators

225 Essential fatty acid and lipoprotein status in pediatric cystic fibrosis: Impact of cystic fibrosis transmembrane conductance regulator modulators

207 Repeat fecal elastase testing in pediatric patients on cystic fibrosis transmembrane conductance regulator modulator therapy

207 Repeat fecal elastase testing in pediatric patients on cystic fibrosis transmembrane conductance regulator modulator therapy

212 Body mass index changes over time and after initiation of a cystic fibrosis transmembrane conductance regulator modulator in a population with cystic fibrosis

212 Body mass index changes over time and after initiation of a cystic fibrosis transmembrane conductance regulator modulator in a population with cystic fibrosis

17 Fetal impact of cystic fibrosis transmembrane conductance regulator modulator use during assisted and natural reproduction and partner pregnancy in men with cystic fibrosis

17 Fetal impact of cystic fibrosis transmembrane conductance regulator modulator use during assisted and natural reproduction and partner pregnancy in men with cystic fibrosis

661 The PDE4 inhibitor apremilast enhances benefits of cystic fibrosis transmembrane conductance regulator modulators in vitro and in vivo

661 The PDE4 inhibitor apremilast enhances benefits of cystic fibrosis transmembrane conductance regulator modulators in vitro and in vivo