The past six decades have seen remarkable improvements in health outcomes for people with cystic fibrosis, which was once a fatal disease of infants and young children. However, although life expectancy for people with cystic fibrosis has increased substantially, the disease continues to limit survival and quality of life, and results in a large burden of care for people with cystic fibrosis and their families. Furthermore, epidemiological studies in the past two decades have shown that cystic fibrosis occurs and is more frequent than was previously thought in populations of non-European descent, and the disease is now recognised in many regions of the world. The Lancet Respiratory Medicine Commission on the future of cystic fibrosis care was established at a time of great change in the clinical care of people with the disease, with a growing population of adult patients, widespread genetic testing supporting the diagnosis of cystic fibrosis, and the development of therapies targeting defects in the cystic fibrosis transmembrane conductance regulator (CFTR), which are likely to affect the natural trajectory of the disease. The aim of the Commission was to bring to the attention of patients, health-care professionals, researchers, funders, service providers, and policy makers the various challenges associated with the changing landscape of cystic fibrosis care and the opportunities available for progress, providing a blueprint for the future of cystic fibrosis care. The discovery of the CFTR gene in the late 1980s triggered a surge of basic research that enhanced understanding of the pathophysiology and the genotype-phenotype relationships of this clinically variable disease. Until recently, available treatments could only control symptoms and restrict the complications of cystic fibrosis, but advances in CFTR modulator therapies to address the basic defect of cystic fibrosis have been remarkable and the field is evolving rapidly. However, CFTR modulators approved for use to date are highly expensive, which has prompted questions about the affordability of new treatments and served to emphasise the considerable gap in health outcomes for patients with cystic fibrosis between high-income countries, and low-income and middle-income countries (LMICs). Advances in clinical care have been multifaceted and include earlier diagnosis through the implementation of newborn screening programmes, formalised airway clearance therapy, and reduced malnutrition through the use of effective pancreatic enzyme replacement and a high-energy, high-protein diet. Centre-based care has become the norm in high-income countries, allowing patients to benefit from the skills of expert members of multidisciplinary teams. Pharmacological interventions to address respiratory manifestations now include drugs that target airway mucus and airway surface liquid hydration, and antimicrobial therapies such as antibiotic eradication treatment in early-stage infections and protocols for maintenance therapy of chronic infections. Despite the recent breakthrough with CFTR modulators for cystic fibrosis, the development of novel mucolytic, anti-inflammatory, and anti-infective therapies is likely to remain important, especially for patients with more advanced stages of lung disease. As the median age of patients with cystic fibrosis increases, with a rapid increase in the population of adults living with the disease, complications of cystic fibrosis are becoming increasingly common. Steps need to be taken to ensure that enough highly qualified professionals are present in cystic fibrosis centres to meet the needs of ageing patients, and new technologies need to be adopted to support communication between patients and health-care providers. In considering the future of cystic fibrosis care, the Commission focused on five key areas, which are discussed in this report: the changing epidemiology of cystic fibrosis (section 1); future challenges of clinical care and its delivery (section 2); the building of cystic fibrosis care globally (section 3); novel therapeutics (section 4); and patient engagement (section 5). In panel 1, we summarise key messages of the Commission. The challenges faced by all stakeholders in building and developing cystic fibrosis care globally are substantial, but many opportunities exist for improved care and health outcomes for patients in countries with established cystic fibrosis care programmes, and in LMICs where integrated multidisciplinary care is not available and resources are lacking at present. A concerted effort is needed to ensure that all patients with cystic fibrosis have access to high-quality health care in the future.

• MeSH
• celosvětové zdraví MeSH
• cystická fibróza genetika   terapie   MeSH
• genetická terapie metody   MeSH
• kvalita života * MeSH
• lidé MeSH
• poskytování zdravotní péče trendy   MeSH
• progrese nemoci * MeSH
• protein CFTR aplikace a dávkování   MeSH
• transplantace plic metody   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• přehledy MeSH
• Research Support, N.I.H., Extramural MeSH
• Research Support, U.S. Gov't, P.H.S. MeSH
• Názvy látek
• CFTR protein, human MeSH Prohlížeč
• protein CFTR MeSH

BACKGROUND: Cystic fibrosis is caused by mutations in the gene encoding the cystic fibrosis transmembrane conductance regulator (CFTR) protein, and nearly 90% of patients have at least one copy of the Phe508del CFTR mutation. In a phase 2 trial involving patients who were heterozygous for the Phe508del CFTR mutation and a minimal-function mutation (Phe508del-minimal function genotype), the next-generation CFTR corrector elexacaftor, in combination with tezacaftor and ivacaftor, improved Phe508del CFTR function and clinical outcomes. METHODS: We conducted a phase 3, randomized, double-blind, placebo-controlled trial to confirm the efficacy and safety of elexacaftor-tezacaftor-ivacaftor in patients 12 years of age or older with cystic fibrosis with Phe508del-minimal function genotypes. Patients were randomly assigned to receive elexacaftor-tezacaftor-ivacaftor or placebo for 24 weeks. The primary end point was absolute change from baseline in percentage of predicted forced expiratory volume in 1 second (FEV1) at week 4. RESULTS: A total of 403 patients underwent randomization and received at least one dose of active treatment or placebo. Elexacaftor-tezacaftor-ivacaftor, relative to placebo, resulted in a percentage of predicted FEV1 that was 13.8 points higher at 4 weeks and 14.3 points higher through 24 weeks, a rate of pulmonary exacerbations that was 63% lower, a respiratory domain score on the Cystic Fibrosis Questionnaire-Revised (range, 0 to 100, with higher scores indicating a higher patient-reported quality of life with regard to respiratory symptoms; minimum clinically important difference, 4 points) that was 20.2 points higher, and a sweat chloride concentration that was 41.8 mmol per liter lower (P<0.001 for all comparisons). Elexacaftor-tezacaftor-ivacaftor was generally safe and had an acceptable side-effect profile. Most patients had adverse events that were mild or moderate. Adverse events leading to discontinuation of the trial regimen occurred in 1% of the patients in the elexacaftor-tezacaftor-ivacaftor group. CONCLUSIONS: Elexacaftor-tezacaftor-ivacaftor was efficacious in patients with cystic fibrosis with Phe508del-minimal function genotypes, in whom previous CFTR modulator regimens were ineffective. (Funded by Vertex Pharmaceuticals; VX17-445-102 ClinicalTrials.gov number, NCT03525444.).

• MeSH
• aktivátory chloridových kanálů aplikace a dávkování   škodlivé účinky   MeSH
• aminofenoly aplikace a dávkování   škodlivé účinky   MeSH
• benzodioxoly aplikace a dávkování   škodlivé účinky   MeSH
• chinolony aplikace a dávkování   škodlivé účinky   MeSH
• chloridy analýza   MeSH
• cystická fibróza farmakoterapie   genetika   patofyziologie   MeSH
• dítě MeSH
• dospělí MeSH
• dvojitá slepá metoda MeSH
• fixní kombinace léků MeSH
• genotyp MeSH
• indoly aplikace a dávkování   škodlivé účinky   MeSH
• lidé MeSH
• mladiství MeSH
• mladý dospělý MeSH
• mutace * MeSH
• pot chemie   MeSH
• protein CFTR genetika   MeSH
• pyrazoly aplikace a dávkování   škodlivé účinky   MeSH
• pyridiny aplikace a dávkování   škodlivé účinky   MeSH
• pyrrolidiny aplikace a dávkování   škodlivé účinky   MeSH
• usilovný výdechový objem MeSH
• Check Tag
• dítě MeSH
• dospělí MeSH
• lidé MeSH
• mladiství MeSH
• mladý dospělý MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• klinické zkoušky, fáze III MeSH
• multicentrická studie MeSH
• práce podpořená grantem MeSH
• randomizované kontrolované studie MeSH
• Research Support, N.I.H., Extramural MeSH
• Názvy látek
• aktivátory chloridových kanálů MeSH
• aminofenoly MeSH
• benzodioxoly MeSH
• CFTR protein, human MeSH Prohlížeč
• chinolony MeSH
• chloridy MeSH
• elexacaftor MeSH Prohlížeč
• fixní kombinace léků MeSH
• indoly MeSH
• ivacaftor MeSH Prohlížeč
• protein CFTR MeSH
• pyrazoly MeSH
• pyridiny MeSH
• pyrrolidiny MeSH
• tezacaftor MeSH Prohlížeč

The association between oxidative stress and neutrophilic inflammation in cystic fibrosis (CF) lung disease is well recognized. 8-Isoprostane is a product of non-enzymatic oxidation of arachidonic acid. The aim of the present study was to examine the relationship between lung function decline and 8-isoprostane concentrations in exhaled breath condensate (EBC) in CF patients with Burkholderia cenocepacia airway colonization. Concentrations of 8-isoprostane in EBC were measured in 24 stable CF patients with B. cenocepacia airway colonization. The median (interquartile range) age of the cohort was 23.9 (22.0; 26.6) years. All patients underwent clinical examinations and pulmonary function tests at the time of EBC collection and in 1-, 3-, and 5-year intervals. 8-Isoprostane concentrations in EBC correlated to 1- and 3-year declines of forced expiratory volume in 1 s (FEV1) with r(S) values of -0.511 (p = 0.0011) and -0.495 (p = 0.016), respectively. In multiple regression analysis, 8-isoprostane concentrations in EBC were the only independent predictor for 1-year FEV1 decline (p = 0.01). When the median value of 8-isoprostane concentration in EBC (10.0 pg/mL) was used as a cutoff, subgroups of patients with lower and higher level of oxidative stress had significantly different median (interquartile range) FEV1 declines in 1-year interval, -2.4% (-5.3; 0.8) and -7.3% (-10.3; -5.8) predicted (p = 0.009). In conclusion, 8-isoprostane concentrations in EBC correlated to short-term lung function decline in CF patients with B. cenocepacia airway colonization. This correlation reflects the role of oxidative stress in CF lung pathogenesis and contributes to prediction of prognosis in these patients.

• MeSH
• Burkholderia cenocepacia * MeSH
• časové faktory MeSH
• cystická fibróza komplikace   metabolismus   patofyziologie   MeSH
• dinoprost analogy a deriváty   metabolismus   MeSH
• dospělí MeSH
• infekce bakteriemi rodu Burkholderia komplikace   mikrobiologie   MeSH
• lidé MeSH
• mladý dospělý MeSH
• oportunní infekce * MeSH
• oxidační stres * MeSH
• respirační funkční testy MeSH
• usilovný výdechový objem MeSH
• vydechnutí MeSH
• Check Tag
• dospělí MeSH
• lidé MeSH
• mladý dospělý MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• 8-epi-prostaglandin F2alpha MeSH Prohlížeč
• dinoprost MeSH