The Future of Cystic Fibrosis Care: A Global Perspective

Sources: The future of cystic fibrosis care: a global perspective
Posted: September 27, 2019
https://doi.org/10.1016/S2213-2600(19)30337-6

Summary
The past six decades have seen remarkable improvements in health outcomes for people with cystic fibrosis, which was once a fatal condition for infants and young children. However, although the life expectancy of people with cystic fibrosis has increased dramatically, the disease continues to limit survival and quality of life, and places a heavy burden of care on them and their families. In addition, epidemiological studies conducted over the past two decades have shown that cystic fibrosis is more common than previously thought in populations of non-European origin, and the disease is now recognized in many regions of the world. The Lancet Respiratory Medicine Commission on the Future of Cystic Fibrosis Care was created at a time of great change in the clinical care of people living with the disease, with a growing population of adult patients, large-scale genetic tests supporting the diagnosis of cystic fibrosis, and the development of therapies that target 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 professionals, researchers, researchers, donors, service providers and policy makers the various challenges associated with the evolution of cystic fibrosis care and the opportunities for progress, by providing a blueprint for the future of cystic fibrosis care.
The discovery of the CFTR gene in the late 1980s triggered a wave of fundamental research that led to a better understanding of the pathophysiology and genotype-phenotype relationships of this clinically variable disease. Until recently, treatments offered could only control the symptoms and limit the complications of cystic fibrosis, but advances in CFTR-modulating therapies to treat the fundamental defect in cystic fibrosis have been remarkable and the field is evolving rapidly. However, the CFTR modulators that have been approved for use so far are very expensive, which has raised questions about the affordability of new treatments and has highlighted the considerable gap between high-income countries and low-middle income countries (LMICs) in terms of health outcomes for patients with cystic fibrosis.

Advances in clinical care have been multiple and include earlier diagnosis through the implementation of newborn screening programs, formalized airway clearance therapy, and a reduction in malnutrition through the use of effective pancreatic enzyme replacement and a diet rich in energy and protein. Centralized care has become the norm in high-income countries, allowing patients to benefit from the expertise of expert members of multidisciplinary teams.
Pharmacological interventions to treat respiratory manifestations now include medications that target airway mucus and airway surface liquid hydration, as well as antimicrobial therapies such as antibiotic eradication therapy in early stage infections and maintenance therapy protocols for chronic infections. Despite the recent breakthrough in CFTR modulators for cystic fibrosis, the development of new mucolytic, anti-inflammatory, and anti-infective therapies is likely to remain important, especially for patients at more advanced stages
of lung disease.

As the median age of patients with cystic fibrosis increases, with a rapid growth in the population of adults living with the disease, complications of cystic fibrosis are becoming more common. Steps should be taken to ensure that a sufficient number of highly qualified professionals are present in cystic fibrosis centers to meet the needs of aging patients, and new technologies should be adopted to support communication between patients and health care providers.
In examining the future of cystic fibrosis care, the Commission focused on five key areas, which are addressed in this report: the evolution of the epidemiology of cystic fibrosis (section 1); the future challenges of clinical care and its delivery (section 2); the establishment of cystic fibrosis care globally (section 3); new therapies (section 4); and patient engagement (section 2); the establishment of cystic fibrosis care globally (section 3); new therapies (section 4); and patient engagement (section 2); 5).
In panel 1, we summarize the Commission's key messages. The challenges faced by all stakeholders in setting up and developing cystic fibrosis care internationally are considerable, but there are numerous opportunities to improve patient care and health outcomes in countries where cystic fibrosis care programs are in place and in LMICs where integrated multidisciplinary care is not available and where resources are currently lacking. A concerted effort is needed to ensure that all patients with cystic fibrosis have access to high-quality health care in the future.

Introduction
Since its initial description in 1938, substantial advances in our understanding of the cause and underlying mechanisms of cystic fibrosis have made it possible to transform it from a fatal early childhood disease to one whose median age of survival is (and in some populations exceeds) 50 years. The recognition of the increased salt content in sweat in people with cystic fibrosis by di Sant'Agnese and colleagues in the early 90s made it possible to develop a new method for analyzing sweat. The gene responsible for cystic fibrosis, an autosomal recessive disorder, was discovered in 1989 through a concerted effort by teams led by Tsui, Riordan, and Collins, with the subsequent identification of its protein product, called the cystic fibrosis transmembrane conductance regulator (CFTR). CFTR is responsible for transporting chloride ions across the apical membranes of epithelial cells in the tissues of the respiratory tract, intestine, pancreas, kidneys, sweat glands, and the male reproductive system. It is now known that this protein has additional functions, such as the secretion of bicarbonate, which regulates the pH of airway surface fluid, and the inhibition of the epithelial sodium channel (ENaC), which plays an important role in the hydration of secretions and mucins.

More than 2000 variants of the CFTR gene have been described to date, although the functional consequences have not been defined for all of these variants. When the functional consequences are known,
variants can be divided into different functional classes. Class I, II and III variants
(in inherited terminology, mutations) are associated with little or no CFTR function and are therefore linked to a more serious phenotype, including exocrine pancreatic insufficiency; class IV and V variants have residual CFTR function, which is often associated with preserved exocrine pancreatic function in early life. Overall, CFTR dysfunction is at the root of a spectrum of diseases, with a varying number of organs involved and varying severity of the disease. For example, diseases of the pancreas, liver, and lungs may be present from birth to 5 years of age, while the congenital bilateral absence of the vas deferens
inflammation in the male reproductive system may sometimes be the only noticeable characteristic of cystic fibrosis in an adult. In addition, phenotypic manifestations vary widely, even among individuals with severe CFTR variants, underlining the role of other factors, such as environmental triggers and modifying genes, in defining disease severity.

The cystic fibrosis phenotype is characterized by lung disease (bronchiectasis with persistent infection and inflammation of the respiratory tract), exocrine pancreatic insufficiency associated with malabsorption of nutrients contributing to undernutrition, growth retardation, growth retardation, liver and bile manifestations, and male infertility (panel 2). Evidence-based care for people with cystic fibrosis is coordinated by multidisciplinary care teams and cystic fibrosis therapies have developed rapidly over the past three decades. The health of children with cystic fibrosis continues to improve, with increased lung function and growth as patients transition from pediatric to adult care, and a reduction in the frequency of chronic infections, especially Pseudomonas aeruginosa. The gradual improvement in the survival of patients with cystic fibrosis over the past five decades has led to a dramatic increase in the number of surviving adults. As a result, the number of cystic fibrosis care centers has increased rapidly.

Despite these improvements, the morbidity associated with cystic fibrosis is still dominated by recurrent respiratory infections (often multidrug-resistant), ultimately leading to lung destruction and respiratory failure. The emergence of complications of cystic fibrosis (panel 2), including diabetes linked to cystic fibrosis, metabolic bone disease, gastrointestinal malignancy, and comorbidities, including the increase in mental disorders (depression and anxiety), required the development of specific expertise in the clinical care of patients with the disease.
Although structured care in specialized centers and the improvement of strategies for treating the manifestations of the disease have been the main drivers for improving patient outcomes, over the past 15 years, a therapeutic pipeline has been established in order to develop safe and effective treatments that target the basic defect of cystic fibrosis (dysfunctional CFTR protein). The first successful drug —
Ivacaftor, a potentiator of CFTR function that increases the probability of opening the CFTR channel — has been associated with remarkable clinical benefit in patients with residual CFTR expression on the cell surface but a reduced probability of opening. Improvements in lung function, nutritional status, and health-related quality of life (HRQoL), as well as a lower frequency of respiratory exacerbations were reported in participants receiving placebo. Subsequently, combinations of CFTR potentiators and correctors that address the traffic defect associated with the most common variant, p.Phe508del (also known as F508del), have a positive effect on clinical outcomes and we are rapidly approaching the time when more than 90% of the current global population with cystic fibrosis will benefit from these therapies.

However, access to these medicines varies considerably from country to country, which could further worsen the gap in patient outcomes in different regions of the world.
At a time when therapeutic developments are very rapid, where genetic diagnostic tests are progressing, and where the population of adult patients with cystic fibrosis is increasing dramatically, especially in developed countries — with a dramatic increase in the median survival of those affected —, it seems appropriate to take stock of the progress made in this field, to highlight the unmet needs of patients in developed and developing regions and to consider what could be the case. To resemble
cystic fibrosis care in the future. This document from the Lancet Respiratory Medicine Commission aims to draw the attention of patients, health professionals, researchers, funders, service providers, and policy makers to the diverse challenges associated with the changing landscape of cystic fibrosis care and the opportunities for progress. A concerted effort is needed to take full advantage of these opportunities, in order to improve health outcomes for people with
cystic fibrosis around the world.

Conclusion
Over the past few decades, we have seen major advances in approaches to the early diagnosis and treatment of people with cystic fibrosis. These advances include, among others, the widespread recognition of Nijmegen Syndrome (NBS), a better understanding of the importance of highly qualified multidisciplinary care teams, and a better definition of optimal strategies for treating and managing the main manifestations of cystic fibrosis.

All of these aspects of health care have led to changes in the global population of people.
patients with cystic fibrosis and those suffering from CFTR dysfunction.
With the evolution of the cystic fibrosis spectrum, new challenges have emerged. Many patients now have a milder phenotype than in previous decades, and finding the right balance between implementing the necessary therapies and the burden of treatment has become a growing priority in clinical care. Advances in genetic technologies have made it easier to annotate variants as potentially pathogenic, the
Many of these variants increase rapidly over time, but genetic tests have made it easier to identify individuals with few phenotypic manifestations, for whom the risk of disease progression, and therefore the benefit of a diagnosis, is not yet well defined. Despite the wide availability of genome sequencing technologies, functional tests aimed at defining the extent of CFTR dysfunction must
still be widely applied in a clinical setting and require additional validation. How researchers will use these various methods in the future is not only relevant to countries where cystic fibrosis is traditionally diagnosed, but also to LMICs where access to facilities offering functional tests such as the sweat chloride test is currently limited.

New drugs that target the core defect of cystic fibrosis have given hope to patients, and advances in drug development have been substantial over the past decade. However, these drugs have a high economic cost, which is mainly due to the costs associated with drug development rather than production costs. How people with cystic fibrosis and their advocates respond to health system funding decisions — the availability of current compounds already varies considerably, even between developed countries — could impact the availability of new treatments in the future, not only for cystic fibrosis, but also for other rare diseases.

New types of partnerships between pharmaceutical companies and reimbursement agencies may be required, and innovative solutions may be required for LMICs, in order to ensure that patients around the world have access to effective therapies and that the gap between those who benefit from therapy may be required.
and those who don't benefit don't get any deeper.
With continuous progress, cystic fibrosis has gone from being an essentially pediatric disease to a disease that gives many patients with it the chance to reach early adulthood while maintaining a good level of health (although at the cost of continuous and often intense treatments). As early mortality becomes less common, care for elderly patients with cystic fibrosis will no longer be rare, and this care may require a new generation of health care providers with specific training and soft skills to manage emerging cystic fibrosis complications at a later age. The growing adult population may also require health care providers to reconsider which elements of care should be provided directly by the multidisciplinary team at cystic fibrosis centers and which can be undertaken remotely using new technologies to monitor patient well-being.

We are living in an exciting time for cystic fibrosis, a condition that is often considered a model for care and a model of progress in the development of targeted therapies for genetic diseases. Advances in health come with new opportunities and challenges, and the CF community must now prepare for them so that health professionals, working in highly qualified multidisciplinary teams, can continue to provide exceptional care to people living with this multifaceted condition in the future.

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