scholarly journals Burden of cystic fibrosis in children <12 years of age prior to the introduction of CFTR modulator therapies

2021 ◽  
Vol 8 (1) ◽  
pp. e000998
Author(s):  
Kathryn Bresnick ◽  
Emilio Arteaga-Solis ◽  
Stefanie J Millar ◽  
Glen Laird ◽  
Cecile LeCamus
Keyword(s):  
Cystic Fibrosis ◽  
Respiratory Infections ◽  
Burden Of Illness ◽  
Related Complication ◽  
Cross Sectional ◽  
Cystic Fibrosis Foundation ◽  
Allele Group ◽  
Cf Transmembrane Conductance Regulator ◽  
Us Children ◽  
Cftr Modulators

BackgroundCystic fibrosis (CF) is a genetic, multisystemic, progressive and life-shortening disease caused by mutations in the CF transmembrane conductance regulator (CFTR) gene. Different genotypes have been linked to variations in disease progression among people with CF. The burden of illness (BOI) in children with CF is incompletely characterised, particularly as it relates to CFTR genotypes prior to the availability of the first CFTR modulators. This retrospective, cross-sectional, descriptive study evaluated the BOI in US children with CF <12 years of age prior to the first approval of CFTR modulators.MethodsData from the US Cystic Fibrosis Foundation Patient Registry from 2011 were used to summarise key patient and disease characteristics using descriptive statistics, overall and grouped by age (0 to <2 years, 2 to <6 years and 6 to <12 years) and genotype (F508del/F508del, F508del/minimal function (MF), MF/MF, gating mutation on ≥1 allele, residual function mutation on ≥1 allele and R117H on ≥1 allele) group.ResultsThe analysis included 9185 children. Among 6-year-olds to <12-year-olds, mean (SD) per cent predicted FEV1 in 1 s was 92.6% (17.5%). Among all children <12 years of age, the mean (SD) all-cause hospitalisation and pulmonary exacerbation rates in 2011 were 0.4 (1.0) and 0.3 (0.8), respectively. Most (93.6%) had ≥1 positive lung microbiology culture. CF-related medication and nutritional supplementation use was common across all ages and genotypes. More than half (54.7%) had ≥1 CF-related complication. Evidence of disease burden was observed across the age and genotype groups studied.ConclusionsPrior to the approval of the first CFTR modulator therapies in children <12 years of age, CF was associated with substantial BOI from an early age—including respiratory infections, hospitalisations/pulmonary exacerbations, need for supplemental nutrition and pharmacological treatments—irrespective of genotype.

scholarly journals A European regulatory perspective on cystic fibrosis: current treatments, trends in drug development and translational challenges for CFTR modulators

2018 ◽  
Vol 27 (148) ◽  
pp. 170124 ◽  
Author(s):  
Stefano Ponzano ◽  
Giulia Nigrelli ◽  
Laura Fregonese ◽  
Irmgard Eichler ◽  
Fabio Bertozzi ◽  
...  
Keyword(s):  
Cystic Fibrosis ◽  
Drug Development ◽  
Forced Expiratory Volume ◽  
The European Union ◽  
End Points ◽  
Sweat Chloride ◽  
European Regulatory ◽  
Clinical Models ◽  
Cf Transmembrane Conductance Regulator ◽  
Cftr Modulators

In this article we analyse the current authorised treatments and trends in early drug development for cystic fibrosis (CF) in the European Union for the time period 2000–2016. The analysis indicates a significant improvement in the innovation and development of new potential medicines for CF, shifting from products that act on the symptoms of the disease towards new therapies targeting the cause of CF. However, within these new innovative medicines, results for CF transmembrane conductance regulator (CFTR) modulators indicate that one major challenge for turning a CF concept product into an actual medicine for the benefit of patients resides in the fact that, although pre-clinical models have shown good predictability for certain mutations, a good correlation to clinical end-points or biomarkers (e.g. forced expiratory volume in 1 s and sweat chloride) for all mutations has not yet been achieved. In this respect, the use of alternative end-points and innovative nonclinical models could be helpful for the understanding of those translational discrepancies. Collaborative endeavours to promote further research and development in these areas as well as early dialogue with the regulatory bodies available at the European competent authorities are recommended.

scholarly journals Vancomycin Dosing and Monitoring in the Treatment of Cystic Fibrosis: Results of a National Practice Survey

2017 ◽  
Vol 22 (6) ◽  
pp. 406-411 ◽  
Author(s):  
Rebecca S. Pettit ◽  
Stacy J. Peters ◽  
Erin J. McDade ◽  
Kaci Kreilein ◽  
Radha Patel ◽  
...  
Keyword(s):  
Cystic Fibrosis ◽  
Trough Concentration ◽  
Pediatric Population ◽  
Area Under The Curve ◽  
Monitoring Strategy ◽  
Cross Sectional Survey ◽  
Cross Sectional ◽  
Monitoring Strategies ◽  
Cystic Fibrosis Foundation ◽  
Initial Starting

OBJECTIVES Vancomycin is commonly used in patients with cystic fibrosis (CF) to treat acute pulmonary exacerbations, but few guidelines exist to help dose and monitor patients. The objective of this study was to assess vancomycin use and monitoring strategies at Cystic Fibrosis Foundation (CFF)–accredited centers in hopes of developing and implementing vancomycin dosing and monitoring standards. METHODS An anonymous national cross-sectional survey of pharmacists affiliated with CFF-accredited pediatric and/or adult centers was performed by using Surveymonkey.com. The survey consisted of 3 sections: (1) CF Center Demographic Information (10 questions); 2) vancomycin use in pediatric CF patients (31 questions); and 3) vancomycin use in adult CF patients (29 questions); it was administered from March 9, 2015, to April 13, 2015. RESULTS The survey was completed by 31/69 (45%) pharmacists and 28 (90.3%) reported using vancomycin in the pediatric population. The most common initial starting dose for pediatric patients was 15 mg/kg/dose (57.1%) and every 6 hours was the most common dosing frequency (67.9%). The most common monitoring strategy was collection of a trough concentration (92.9%) with 57.7% of pharmacist targeting a range of 15 to 20 mg/L. The most common initial starting vancomycin dose in adults with CF was 15 mg/kg/dose (61.5%), and initial frequency of every 8 hours (73.1%). The most common monitoring strategy was a trough concentration (96.2%) with 83.3% of pharmacists reporting a goal trough range of 15 to 20 mg/L. CONCLUSIONS The most common vancomycin dosing reported was 15 to 20 mg/kg/dose every 6 hours (pediatric) and 15 to 20 mg/kg/dose every 8 to 12 hours (adults). Serum concentrations measured to meet monitoring parameters of trough concentrations of 15 to 20 mg/L, or area under the curve to minimum inhibitory concentration ratio &gt; 400, were the same in both pediatric and adult patients.

scholarly journals Cystic Fibrosis Transmembrane Conductance Regulator Modulator Therapy: A Review for the Otolaryngologist

2020 ◽  
Vol 34 (4) ◽  
pp. 573-580
Author(s):  
Saangyoung E. Lee ◽  
Zainab Farzal ◽  
M.Leigh Anne Daniels ◽  
Brian D. Thorp ◽  
Adam M. Zanation ◽  
...  
Keyword(s):  
Cystic Fibrosis ◽  
Transmembrane Conductance Regulator ◽  
Transmembrane Conductance ◽  
Respiratory Compromise ◽  
Basic Understanding ◽  
Epithelial Cultures ◽  
Cf Transmembrane Conductance Regulator ◽  
Cystic Fibrosis Transmembrane ◽  
Cftr Modulators ◽  
Initial Results

Background Cystic fibrosis (CF) is a genetic disease that may result in multiple systemic disorders and potentially fatal severe respiratory compromise. However, the advent of CF transmembrane conductance regulator (CFTR) modulators has changed the management of CF for patients with select mutations. Although clinical trials have highlighted increased pulmonary function and decreased exacerbations as a result of these novel therapies, their effect on the sinuses has not been well-described. Objective Our objective is to review the CFTR modulators to provide otolaryngologists, physicians who frequently care for patients with CF, a basic understanding of these drugs and their effects on chronic rhinosinusitis (CRS) in patients with CF. Methods The clinically approved and available CFTR modulators and specific indications for their use are reviewed. Additionally, a systematic review of these therapies and effects on CRS in CF was performed. Results Four Food and Drug Administration approved CFTR modulators are available for patients with CF. Current drugs are approved for gating, residual function, or F508del mutations. Multiple reports describe CFTR modulators’ increase in transepithelial ion transport in nasal epithelial cultures; however, clinical studies regarding effects of these modulators on sinonasal health are limited to 5 studies that present new data of the effects of CFTR modulators in CRS. Conclusions CFTR modulators have changed management of CF. Initial studies of these medications demonstrate promising results in CF; however, there is a paucity of literature describing the effect of CFTR modulators on CF-associated CRS, although initial results are encouraging.

scholarly journals Adherence to Dietary Recommendations, Nutrient Intake Adequacy and Diet Quality among Pediatric Cystic Fibrosis Patients: Results from the GreeCF Study

Nutrients ◽  
2020 ◽  
Vol 12 (10) ◽  
pp. 3126 ◽  
Author(s):  
Dimitrios Poulimeneas ◽  
Maria G. Grammatikopoulou ◽  
Panagiota Devetzi ◽  
Argyri Petrocheilou ◽  
Athanasios G. Kaditis ◽  
...  
Keyword(s):  
Cystic Fibrosis ◽  
Diet Quality ◽  
Respiratory Infections ◽  
Saturated Fatty Acids ◽  
Ideal Body Weight ◽  
Fiber Intake ◽  
Dietary Recommendations ◽  
Cross Sectional ◽  
Increased Risk ◽  
Optimal Adherence

Nutrition is an important component of cystic fibrosis (CF) therapy, with a high-fat diet being the cornerstone of treatment. However, adherence to the dietary recommendations for CF appears suboptimal and burdensome for most children and adolescents with CF, leading to malnutrition, inadequate growth, compromised lung function and increased risk for respiratory infections. A cross-sectional approach was deployed to examine the degree of adherence to the nutrition recommendations and diet quality among children with CF. A total of 76 children were recruited from Aghia Sophia’s Children Hospital, in Athens, Greece. In their majority, participants attained their ideal body weight, met the recommendations for energy and fat intake, exceeding the goal for saturated fatty acids consumption. Carbohydrate and fiber intake were suboptimal and most participants exhibited low or mediocre adherence to the Mediterranean diet prototype. It appears that despite the optimal adherence to the energy and fat recommendations, there is still room for improvement concerning diet quality and fiber intake.

scholarly journals Esculentin-1a-derived peptides promote clearance ofP. aeruginosainternalized in cystic fibrosis bronchial cells as well as lung cells migration: Biochemical properties and a plausible mode of action

2016 ◽  
pp. AAC.00904-16 ◽  
Author(s):  
Floriana Cappiello ◽  
Antonio Di Grazia ◽  
Segev-Zarko Li-av ◽  
Silvia Scali ◽  
Loretta Ferrera ◽  
...  
Keyword(s):  
Cystic Fibrosis ◽  
Respiratory Infections ◽  
Biochemical Properties ◽  
Airway Epithelial Cells ◽  
Airway Epithelial ◽  
Promising Alternative ◽  
Plausible Mechanism ◽  
Biochemical Analyses ◽  
Cf Transmembrane Conductance Regulator ◽  
Bronchial Cells

Pseudomonas aeruginosais the major microorganism colonizing the respiratory epithelium in cystic fibrosis (CF) sufferers. The widespread usage of available antibiotics has drastically reduced their efficacy, and antimicrobial peptides (AMPs) are a promising alternative. Among them, the frog-skin derived AMPs i.e. Esc(1-21) and its diastereomer Esc(1-21)-1c have recently shown potent activity against free-living and sessile forms ofP. aeruginosa.Importantly, this pathogen also escapes antibiotics treatment by invading airway epithelial cells. Here we demonstrate that both AMPs killPseudomonasonce internalized into bronchial cells which express either the functional or the ΔF508 mutant of CF transmembrane conductance regulator. A higher efficacy is displayed by Esc(1-21)-1c (90% killing at 15 μM in 1h). We also show the peptides' capability to stimulate migration of these cells and restore the induction of cell migration that is inhibited byPseudomonaslipopolysaccharide when used at concentrations mimicking lung infection. This property of AMPs was not investigated before. Our findings suggest new therapeutics that not only eliminate bacteria but also can promote re-epithelialization of the injured infected tissue. Confocal microscopy indicated that both peptides are intracellularly localized with a different distribution. Biochemical analyses highlighted that Esc(1-21)-1c is significantly more resistant than the all-L peptide to bacterial and human elastase, which is abundant in CF lungs. Beside proposing a plausible mechanism underlying the properties of the two AMPs, the data are discussed with regards to differences between them and suggest Esc(1-21)-1c as a candidate for the development of a new multifunctional drug againstPseudomonasrespiratory infections.

scholarly journals Clinical development of triple-combination CFTR modulators for cystic fibrosis patients with one or two F508del alleles

2019 ◽  
Vol 5 (2) ◽  
pp. 00082-2019 ◽  
Author(s):  
Jennifer L. Taylor-Cousar ◽  
Marcus A. Mall ◽  
Bonnie W. Ramsey ◽  
Edward F. McKone ◽  
Elizabeth Tullis ◽  
...  
Keyword(s):  
Cystic Fibrosis ◽  
Anion Channel ◽  
Triple Combination ◽  
Open Label ◽  
Cftr Protein ◽  
Trafficking Defects ◽  
Cf Transmembrane Conductance Regulator ◽  
And Function ◽  
Cftr Modulators

Cystic fibrosis (CF) is caused by mutations in the CF transmembrane conductance regulator gene (CFTR) that result in diminished quantity and/or function of the CFTR anion channel. F508del-CFTR, the most common CF-causing mutation (found in ∼90% of patients), causes severe processing and trafficking defects, resulting in decreased CFTR quantity and function. CFTR modulators are medications that increase the amount of mature CFTR protein (correctors) or enhance channel function (potentiators) at the cell surface.Combinations of CFTR correctors and potentiators (i.e. lumacaftor/ivacaftor, tezacaftor/ivacaftor) have demonstrated clinical benefit in subsets of patients. However, none are approved for patients with CF heterozygous for F508del-CFTR and a minimal function mutation, i.e. a mutation that produces either no protein or protein that is unresponsive to currently approved CFTR modulators. Next-generation CFTR correctors VX-659 and VX-445, each in triple combination with tezacaftor and ivacaftor, improve CFTR processing, trafficking and function in vitro and have demonstrated clinical improvements in phase 2 studies in patients with CF with one or two F508del-CFTR alleles.Here, we present the rationale and design of four randomised phase 3 studies, and their open-label extensions, evaluating VX-659 (ECLIPSE) or VX-445 (AURORA) plus tezacaftor and ivacaftor in patients with one or two F508del-CFTR alleles.

scholarly journals Frequency of Cystic Fibrosis in Children with Recurrent Respiratory Infections by Sweat Chloride Testing: A Hospital-Based Cross-sectional Study

2020 ◽  
Vol 24 (4) ◽  
pp. 302-305
Author(s):  
Nahdia Zaman ◽  
Anam Zafar ◽  
Maryam Amjad ◽  
Shahzadi Sumbal Ghazi ◽  
Uzma Abid ◽  
...  
Keyword(s):  
Cystic Fibrosis ◽  
Respiratory Infections ◽  
Cross Sectional Study ◽  
P Value ◽  
Sectional Study ◽  
Cross Sectional ◽  
Sweat Chloride ◽  
Recurrent Respiratory Infections ◽  
Ethical Approval ◽  
Tract Infections

Objective: This study was designed to find out the frequency of cystic fibrosis in children with recurrent respiratory infections by performing a sweat chloride test.Material and Methods: This cross-sectional study was carried out from 1st September 2015 to 28th February 2016 in the department of Pediatric Medicine at the Children’s Hospital and the Institute of Child Health, Lahore after ethical approval. A total of 300 cases of recurrent respiratory tract infections were included. The sweat chloride test was done by using pilocarpine-induced iontophoresis and measuring chloride levels on the forearm or thigh by sweat analyzer at the time of induction. Cystic fibrosis was labeled if sweat chloride level ranges above 60 mEq/L. Data was collected on Performa and SPSS version 23 was used to analyze the data. Results: Mean age of patients was 6.24 ± 2.7 years with 52.7% males and 47.3% females. Most patients (86.3%) have more than 5 episodes of respiratory infection in a year. Cystic fibrosis was diagnosed in 19 (6.3%) patients. There was no relationship between the frequency of respiratory infections in a year and cystic fibrosis (p-value 0.78).Conclusion: This hospital-based study showed quite a high incidence of cystic fibrosis in our population. So facilities including neonatal screening along with sweat chloride testing and genetic analysis should be increased.

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