ECFS standards of care on CFTR-related disorders: Towards a comprehensive program for affected individuals.

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.

Cystic fibrosis drug trial design in the era of CFTR modulators associated with substantial clinical benefit: stakeholders' consensus view.

CFTR modulators associated with substantial clinical benefit are expected to rapidly improve the baseline condition of people with cystic fibrosis (PWCF) as well as decrease the rate of lung function decline, the occurrence of pulmonary exacerbations and likely even other disease complications. These changes in clinical status of PWCF introduced by clinically effective modulator therapy will have major repercussions on modalities of future CF drug development. As part of its 'Strategic Plan to speed up Access to new Drugs', the European Cystic Fibrosis Society (ECFS) convened a meeting in Brussels on November 27th 2019 with relevant stakeholders (CF researchers and clinicians, patient organization and pharmaceutical company representatives, regulators, health technology assessors; see Acknowledgments for list of attendees) to discuss the future of clinical trials in cystic fibrosis (CF) in the context of HEMT entering the clinical arena. The following is the conclusion of the presentations and discussions. It is hoped that these concepts will be considered in future regulatory guidelines and may provide rationale and support for alternative trial designs.

Building global development strategies for cf therapeutics during a transitional cftr modulator era.

As CFTR modulator therapy transforms the landscape of cystic fibrosis (CF) care, its lack of uniform access across the globe combined with the shift towards a new standard of care creates unique challenges for the development of future CF therapies. The advancement of a full and promising CF therapeutics pipeline remains a necessary priority to ensure maximal clinical benefits for all people with CF. It is through collaboration across the global CF community that we can optimize the evaluation and approval process of new therapies. To this end, we must identify areas for which harmonization is lacking and for which efficiencies can be gained to promote ethical, feasible, and credible study designs amidst the changing CF care landscape. This article summarizes the counsel from core advisors across multiple international regions and clinical trial networks, developed during a one-day workshop in October 2019. The goal of the workshop was to identify, in consideration of the highly transitional era of CFTR modulator availability, the drug development areas for which global alignment is currently uncertain, and paths forward that will enable advancement of CF therapeutic development.

Genomically-guided therapies: A new era for cystic fibrosis.

Since the cloning of the CFTR gene 30 years ago, research aiming at understanding how CFTR mutations translate to abnormal synthesis or function of the CFTR protein has opened the way to genomically-guided therapy to improve CFTR function. A CFTR potentiator to enhance CFTR channel function has been approved in 2012 for specific and quite rare mutations. Subsequently, combinations of a corrector to increase CFTR expression at the cell membrane, plus a potentiator, have been approved for patients homozygous for the p.Phe508del mutation. To obtain robust correction of CFTR, new combinations of drugs are being studied. A triple combination associating two correctors and one potentiator is very promising and if data of clinical trials are confirmed, it could be a robust and well tolerated CFTR modulator for patients bearing at least one p.Phe508del mutation. Many other strategies are also in development to make these genomically-guided treatments available to all patients with CF. © 2020 French Society of Pediatrics. Published by Elsevier Masson SAS. All rights reserved.

[Cystic fibrosis: new treatments targeting the CFTR protein]. / Mucoviscidose : nouvelles thérapeutiques ciblant la protéine CFTR.

Cystic fibrosis is an autosomal recessive genetic disease due to mutations in the (cystic fibrosis transmembrane conductance regulator) CFTR gene. The CFTR protein is a chloride channel expressed at the surface of several epithelial cells. Defective function of the CFTR protein leads to a severe disease in which lung disease is the leading cause of death. Current treatments are symptomatic. Nevertheless, with specialist and holistic care in dedicated cystic fibrosis centres, the median survival has improved. But the average age of death remains 29 years. Innovative molecules aiming to correct the CFTR protein itself are under development. These will be personalised treatments depending on the genotype or the type of CFTR dysfunction. The first molecule, ivacaftor, has just been approved in Europe and the USA. Adults and children treated with ivacaftor in clinical trials had a 10% improvement in FEV1 that was maintained for more than a year. Although at present ivacaftor is approved for only a small percentage of patients, the therapeutic strategy of correcting CFTR protein has been proved a valid approach. Other molecules targeting other defects in the CFTR protein are under evaluation.

CFTR biomarkers: time for promotion to surrogate end-point.

In patients with cystic fibrosis, cystic fibrosis transmembrane conductance regulator (CFTR) biomarkers, such as sweat chloride concentration and/or nasal potential difference, are used as end-points of efficacy in phase-III clinical trials with the disease modifying drugs ivacaftor (VX-770), VX809 and ataluren. The aim of this project was to review the literature on reliability, validity and responsiveness of nasal potential difference, sweat chloride and intestinal current measurement in patients with cystic fibrosis. Data on clinimetric properties were collected for each biomarker and reviewed by an international team of experts. Data on reliability, validity and responsiveness were tabulated. In addition, narrative answers to four key questions were discussed and agreed by the team of experts. The data collected demonstrated the reliability, validity and responsiveness of nasal potential difference. Fewer data were found on reliability of sweat chloride concentration; however, validity and responsiveness were demonstrated. Validity was demonstrated for intestinal current measurement, but further information is required on reliability and responsiveness. For all three end-points, normal values were collected and further research requirements were proposed. This body of work adds useful information to support the promotion of CFTR biomarkers to surrogate end-points and to guide further research in the area.

Guideline on the design and conduct of cystic fibrosis clinical trials: the European Cystic Fibrosis Society-Clinical Trials Network (ECFS-CTN).

We describe the rationale for disease specific research networks in general as well as the aims and function of the European Cystic Fibrosis Society-Clinical Trials Network (ECFS-CTN) specifically. The ECFS-CTN was founded in 2009 with the aim of improving the quality and quantity of clinical research in the area of cystic fibrosis (CF) in Europe. A network of 18 clinical trial sites in 8 European countries was established according to uniform state-of-the-art quality criteria. To support the ECFS-CTN in the acquisition, planning and conduct of clinical trials, the network is equipped with a coordinating centre, steering and executive committees, and committees for protocol review, standardization, training and networking as well as a data safety monitoring board. A strong partnership with European CF patient parent organizations aims to increase awareness of the need for efficient clinical research and the participation of patients in clinical trials.

New clinical diagnostic procedures for cystic fibrosis in Europe.

In the majority of cases, there is no difficulty in diagnosing Cystic Fibrosis (CF). However, there may be wide variation in signs and symptoms between individuals which encourage the scientific community to constantly improve the diagnostic tests available and develop better methods to come to a final diagnosis in patients with milder phenotypes. This paper is the result of discussions held at meetings of the European Cystic Fibrosis Society Diagnostic Network supported by EuroCareCF. CFTR bioassays in the nasal epithelium (nasal potential difference measurements) and the rectal mucosa (intestinal current measurements) are discussed in detail including efforts to standardize the techniques across Europe. New approaches to evaluate the sweat gland, future of genetic testing and methods on the horizon like CFTR expression in human leucocytes and erythrocytes are discussed briefly.

Pseudomonas aeruginosa induces vascular endothelial growth factor synthesis in airway epithelium in vitro and in vivo.

Pseudomonas aeruginosa (PA) airway infection and bronchial blood vessel proliferation are features of bronchiectasis. Because vascular endothelial growth factor (VEGF)-A regulates angiogenesis, we hypothesised that PA infection induces VEGF synthesis in epithelium and peribronchial angiogenesis. Because epidermal growth factor receptor (EGFR) activation regulates VEGF synthesis in cancer, we also evaluated the roles of EGFR. Airway epithelial cells were incubated for 24 h with PA supernatants and VEGF concentrations were measured in culture medium by ELISA. C57BL/6N mice were instilled intratracheally with sterile agarose beads or with agarose beads coated with the PA strain PAO1 (mean ± sem 6 × 10(5) ± 3 × 10(5) cfu · animal(-1)), with or without the EGFR inhibitor AG1478 (12.5 mg · kg(-1) · day(-1) intraperitoneally). Epithelial immunostaining for VEGF and phosphorylated EGFR, and peribronchial vascularity, were quantified using morphometric analysis. VEGF expression was further assessed by western blot in mouse lung homogenates. PA supernatants induced dose-dependent VEGF synthesis in cultured airway epithelial cells, effects which were prevented by EGFR antagonists. In mice, persistent PAO1 infection increased immunostaining for VEGF and phosphorylated EGFR in airway epithelium, and resulted in increased peribronchial vascularity within 7 days. These effects were reduced by EGFR inhibition. Persistent PA infection induced VEGF synthesis in airway epithelium and peribronchial angiogenesis, at least in part via EGFR-dependent mechanisms.

Non-classic cystic fibrosis associated with D1152H CFTR mutation.

BACKGROUND: Limited knowledge exists on phenotypes associated with the D1152H cystic fibrosis transmembrane conductance regulator (CFTR) mutation. METHODS: Subjects with a D1152H allele in trans with another CFTR mutation were identified using the French Cystic Fibrosis Registry. Phenotypic characteristics were compared with those of pancreatic insufficient (PI) and pancreatic sufficient (PS) cystic fibrosis (CF) subjects in the Registry (CF cohort). RESULTS: Forty-two subjects with D1152H alleles were identified. Features leading to diagnosis included chronic sinopulmonary disease (n = 25), congenital absence of the vas deferens (n = 11), systematic neonatal screening (n = 4), and genetic counseling (n = 2). Median age at diagnosis was 33 [interquartile range (IQR, 24-41)] years in D1152H subjects. Median sweat chloride concentrations were 43.5 (39-63) mmol/l in D1152H subjects and were markedly lower than in PI and PS CF subjects (p < 0.05). Bronchiectasis was present in 67% of D1152H subjects, but Pseudomonas aeruginosa colonization and pancreatic insufficiency were present in <30% of subjects. Estimated rates of decline in forced expiratory volume in 1 s (FEV(1)) were lower in D1152H subjects vs PI CF subjects (p < 0.05). None of the D1152H subjects identified since 1999 had died or required lung transplantation. CONCLUSIONS: When present in trans with a CF-causing mutation, D1152H causes significant pulmonary disease, but all subjects had prolonged survival.

[The diagnosis of cystic fibrosis in adults: lessons from a family story]. / Le diagnostic de mucoviscidose chez l'adulte: les enseignements d'une histoire de famille!

INTRODUCTION: Cystic fibrosis is usually diagnosed during the first years of life. Diagnosis may be achieved in adults with milder forms of the disease at any age. CASE REPORTS: We report the diagnosis of cystic fibrosis in three adults within the same family. A 39 yr old man, was diagnosed with congenital absence of the vas deferens; the diagnosis of cystic fibrosis was achieved based on a positive chloride sweat test and the identification of two mutations in the CFTR gene. His mother experienced repeated bronchial infections that began when she was 12 years old. The diagnosis of cystic fibrosis was considered at the age of 74 yr after her son was diagnosed with this disease. Sweat test showed normal chloride concentrations and cystic fibrosis was suspected based on elevated basal transepithelial nasal potential difference. Genetic testing for the 33 most frequent mutations in the CFTR gene showed only one mutation. A second rare mutation was identified by complete sequencing of the CFTR gene, confirming the diagnosis of cystic fibrosis. A third case of pauci-symptomatic cystic fibrosis was diagnosed in a brother of the index case. CONCLUSION: These observations illustrate the challenge of diagnosing milder forms of cystic fibrosis in adult subjects. The recognition of this diagnosis may lead to improvement in patient's care and to genetic counselling.

[Cystic fibrosis: how to use pulmonary function tests]. / Mucoviscidose: du bon usage des explorations fonctionnelles respiratoires.

INTRODUCTION: Neonatal screening for cystic fibrosis (CF) leads to early dedicated specialist care for all patients. BACKGROUND: Pulmonary function tests (PFT) are mandatory for routine monitoring of CF patients. The aim of this article is to review the current guidelines for PFTs in CF, particularly the type of test, the age and the clinical status of the patient. VIEWPOINT: The regular use of spirometry is generally accepted. Many other tests are used but their clinical value in the routine follow-up of CF patients remains to be established. CONCLUSION: Further efforts should be made to evaluate the value of PFTs in CF, particularly in very young children.

Severity of scleroderma lung disease is related to alveolar concentration of nitric oxide.

The alveolar concentration of exhaled nitric oxide (CA,(NO)) is increased in patients with systemic sclerosis (SSc), but whether this increase is related to the severity of interstitial lung disease (ILD) in SSc has not yet been investigated. In total, 58 SSc patients prospectively underwent pulmonary function tests (PFTs), echocardiogram and fibrosis scoring on pulmonary computed tomography (CT). Patients were divided into two groups according to the presence (or not) of ILD. Measurements of CA,(NO) were assessed in all SSc patients and compared with those obtained in 19 healthy volunteers. Relationships were sought between CA,(NO) PFTs and CT scan fibrosis scores. Overall, CA,(NO) was significantly increased in SSc patients (median (range) 6.2 (3.8-9.9) ppb) as compared with controls (2.0 (1.2-3.0) ppb). Among SSc patients, CA,(NO) was significantly higher in patients with ILD compared with patients without ILD (n = 33, 7.5 (5.2-11.9) ppb versus n = 25, 4.9 (3.1-7.0) ppb, respectively). CA,(NO) was inversely related to total lung capacity (r = -0.34) and the diffusing capacity of the lung for carbon monoxide (r = -0.37) and was directly related to CT scan fibrosis scores (r = 0.36). An increased alveolar concentration of exhaled nitric oxide could, at least in part, either reflect or contribute to the severity of lung disease and could be used to noninvasively assess the extent of interstitial lung disease in systemic sclerosis.

Reduced exhaled NO is related to impaired nasal potential difference in patients with cystic fibrosis.

Nitric oxide (NO) plays a central role in many airway physiological functions, and its production appears to be related with progression of lung disease in patients with cystic fibrosis (CF). However, underlying mechanisms which specifically link NO and CF-related lung disease remain unclear. Following in vitro and animal studies suggesting a role for NO in ion transport in various epithelia, this work investigates the relationship between transepithelial baseline potential difference (BPD), an index of airway ion transport, and exhaled NO in the airways of adult patients with CF. Association with other phenotypic traits, lung function tests and CFTR genotype was also assessed. Using simple linear regression, F(E)NO and transepithelial BPD values were significantly inversely correlated (p<0.001, r=-0.53). Polynomial analysis evidenced an asymptotic relationship between F(E)NO and BPD values, yielding a plateau for absolute BPD values above 50 mV. This relation was not altered by adjustment for clinical and genetic characteristics of the patients. The relationship between exhaled NO and transepithelial BPD suggests that low NO concentrations likely worsens airway ion transport impairment resulting from CFTR defect. These results fit with experimental studies that suggest the inhibitory effect of NO on sodium absorption, which is the main determinant of airway basal transepithelial conductance.

Nasal airway ion transport is linked to the cystic fibrosis phenotype in adult patients.

BACKGROUND: This study was conducted to determine whether the major nasal airway ion transport abnormalities in cystic fibrosis (that is, defective cAMP regulated chloride secretion and basal sodium hyperabsorption) are related to the clinical expression of cystic fibrosis and/or to the genotype. METHODS: Nasal potential difference was measured in 79 adult patients with cystic fibrosis for whom clinical status, respiratory function, and CFTR genotype were determined. RESULTS: In univariate and multivariate analysis, patients with pancreatic insufficiency were more likely to have low responses to low chloride (odds ratio (OR) 8.6 (95% CI 1.3 to 58.5), p = 0.03) and isoproterenol (OR 11.2 (95% CI 1.3 to 93.9), p = 0.03) solutions. Similarly, in univariate and multivariate analysis, patients with poor respiratory function (forced expiratory volume in 1 second <50% of predicted value) were more likely to have an enhanced response to amiloride solution (OR 3.7 (95% CI 1.3 to 11.0), p = 0.02). However, there was no significant relationship between nasal potential difference and the severity of the genotype. CONCLUSIONS: Nasal epithelial ion transport in cystic fibrosis is linked to the clinical expression of the disease. The pancreatic status appears to be mostly related to the defect in epithelial chloride secretion whereas the respiratory status is mostly related to abnormal sodium transport and the regulatory function of the CFTR protein.