Surging forwards with cystic fibrosis care

Abstract

When cystic fibrosis was first identified in 1938, babies were not expected to survive beyond their first year of life. Today, those born with cystic fibrosis in the USA and UK are expected to live well beyond 40 years as a result of health-care developments seen in the past decade. This progress has created much expectation that current research approaches will deliver even more remarkable improvements in patient outcome in the next few years. It is with great enthusiasm, then, that The Lancet Respiratory Medicine presents this month's cystic fibrosis-themed issue. The approach towards the treatment of cystic fibrosis has been revolutionised by the discovery nearly 15 years ago that cystic fibrosis is caused by mutations in the CFTR gene. The confluence of genetic research and modern drug design has shifted the focus of pharmaceutical interventions to target this inherited cause of disease, rather than to merely manage symptoms or slow disease progress. In 2011, Bonnie Ramsey and colleagues published the first study to show that correction of the channel defect resulting from a CFTR mutation was possible, using a drug called VX-770 (ivacaftor). Patients with the specific Gly551Asp CFTR mutation who were given ivacaftor had improved predicted FEV1, reduced incidence of pulmonary exacerbations, and increased mean weight gain compared with those given placebo. However, only 4% of patients have the Gly551Asp mutation. Other CFTR mutations are now being targeted by new experimental drugs, such as VC-661 and lumacaftor, in clinical trials. In this issue, Michael Boyle and Kris De Boeck summarise in a Review the state of research and potential treatments for each of the six CFTR mutation groups, and the authors highlight future drug candidates for patients according to their genotype. However, despite the anticipation surrounding these new therapies, many challenges remain. Ivacaftor was approved last year for the treatment of Gly551Asp patients older than 6 years in Europe and the USA. But how can we ensure the timely, fair, and affordable roll-out of such expensive personalised medicine? Before individually-tailored treatment can be considered, a patient must be genotyped. This is not yet universal practice. Furthermore, ivacaftor costs about £182 000 or US$294 000 per patient, per year in the UK and USA, respectively, and Boyle and De Boeck predict that the optimum clinical benefit might be achieved only through complicated combinations of various CFTR-modulators. Such multiple-drug therapy will further drive up costs, leading to the thorny question of how we balance the resources society is willing to provide to any individual group of patients. Another long-standing but increasingly worrisome challenge for patients and practitioners is that of infection control, as highlighted in a recent article in The Lancet. Using whole genome sequencing, Josephine Bryant and colleagues reported the first convincing evidence of person-to-person transmission of the non-tuberculosis mycobacteria, Mycobacterium abscessus, in adults with cystic fibrosis. Until now, the strictest infection control measures have been focused on those patients with Burkholderia cepacia complex, meticillin-resistant Staphylococcus aureus, haemophilus influenza, and multi-resistant Pseudomonas aeruginosa infections. Yet M abscessus infections have increased significantly in the past 10 years, with 3–10% of all US patients with cystic fibrosis now being infected. The disquieting proof that person-to-person transmission of these bacteria is possible demands urgent revision of current, outdated infection-control guidelines. Despite recent breakthroughs in treatment propelling patients with cystic fibrosis to a brighter prognosis in the USA and western Europe, the most elementary obstacles persist in screening for the disease. Neonatal screening methods vary substantially between countries, and remains only partially in practice in Latin America and eastern Europe. As Hartmut Grasemann and Felix Ratjen discuss in a Review in this issue, early diagnosis of the disease, and monitoring of lung damage, is vital for future patient outcomes. Timely interventions can delay disease development, offering a further focus for progress to be made in the fight against cystic fibrosis. As data emerge from the first interventional trials in infants and young children with cystic fibrosis, The Lancet Respiratory Medicine presents itself as an ally to the clinical research community as they determine whether therapies aimed at the very youngest of patients can postpone, or even prevent, the onset of cystic fibrosis lung disease. How should you screen newborn babies for cystic fibrosis?The choice of the best strategy to screen newborn babies for cystic fibrosis is vitally important to avoid overtreatment or missed diagnoses. Use of an immunoreactive trypsinogen (IRT) blood test and a standard CFTR gene panel can identify most babies at risk, but what cutoff values should you use? Should parents of carriers be alerted? Factor in the idea that a standard gene panel might not be that “standard” in every country and the problem intensifies. Furthermore, funding of expensive new techniques might improve diagnosis rates, but how do you get value for money in regions with heavy demands on medical resources? The Lancet Respiratory Medicine asked seven specialists around the world about their newborn screening programmes for cystic fibrosis, asking each to explain their strategy and the challenges unique to their country. Full-Text PDF Early lung disease in cystic fibrosisLung disease in patients with cystic fibrosis is characterised by inflammation and recurrent and chronic infections leading to progressive loss in pulmonary function and respiratory failure. Early management of disease results in substantially improved pulmonary function at first testing (at roughly 6 years of age), but the annual decline in pulmonary function tests in older patients has remained unchanged showing how important the early years are in the disease process. Treatment regimens for patients with cystic fibrosis have changed from predominantly symptomatic treatment to preventive or causal (ie, treatments that address the underlying mechanisms of disease) therapeutic interventions. Full-Text PDF A new era in the treatment of cystic fibrosis: correction of the underlying CFTR defectCystic fibrosis is caused by dysfunction or deficiency of the cystic fibrosis transmembrane conductance regulator (CFTR) protein, an epithelial chloride channel that has a key role in maintaining homoeostasis of the airway surface liquid layer in the lungs. More than 1900 CFTR mutations that might result in a disease phenotype have been identified; these can be grouped into classes on the basis of their effect on CFTR protein production, trafficking, function, and stability. In the past 2 years, landmark clinical trials have shown that correction of CFTR function leads to substantial clinical benefit for individuals with cystic fibrosis. Full-Text PDF Whole-genome sequencing to identify transmission of Mycobacterium abscessus between patients with cystic fibrosis: a retrospective cohort studyWhole genome sequencing has revealed frequent transmission of multidrug resistant NTM between patients with cystic fibrosis despite conventional cross-infection measures. Although the exact transmission route is yet to be established, our epidemiological analysis suggests that it could be indirect. Full-Text PDF Open Access