Elsevier

The Lancet

Volume 388, Issue 10059, 19–25 November 2016, Pages 2519-2531
The Lancet

Seminar
Cystic fibrosis

https://doi.org/10.1016/S0140-6736(16)00576-6Get rights and content

Summary

Cystic fibrosis is a common life-limiting autosomal recessive genetic disorder, with highest prevalence in Europe, North America, and Australia. The disease is caused by mutation of a gene that encodes a chloride-conducting transmembrane channel called the cystic fibrosis transmembrane conductance regulator (CFTR), which regulates anion transport and mucociliary clearance in the airways. Functional failure of CFTR results in mucus retention and chronic infection and subsequently in local airway inflammation that is harmful to the lungs. CFTR dysfunction mainly affects epithelial cells, although there is evidence of a role in immune cells. Cystic fibrosis affects several body systems, and morbidity and mortality is mostly caused by bronchiectasis, small airways obstruction, and progressive respiratory impairment. Important comorbidities caused by epithelial cell dysfunction occur in the pancreas (malabsorption), liver (biliary cirrhosis), sweat glands (heat shock), and vas deferens (infertility). The development and delivery of drugs that improve the clearance of mucus from the lungs and treat the consequent infection, in combination with correction of pancreatic insufficiency and undernutrition by multidisciplinary teams, have resulted in remarkable improvements in quality of life and clinical outcomes in patients with cystic fibrosis, with median life expectancy now older than 40 years. Innovative and transformational therapies that target the basic defect in cystic fibrosis have recently been developed and are effective in improving lung function and reducing pulmonary exacerbations. Further small molecule and gene-based therapies are being developed to restore CFTR function; these therapies promise to be disease modifying and to improve the lives of people with cystic fibrosis.

Introduction

Nearly 80 years ago, cystic fibrosis was identified as a disease by Dorothy Andersen.1, 2 In 1938, she described cystic fibrosis of the pancreas in 49 patients and the disorder was subsequently associated with lung infection and salt loss during a heat wave in New York.1, 2 In the 1950s, median life expectancy for patients with cystic fibrosis was a few months; the main causes of death were meconium ileus and malnutrition subsequent to pancreatic malabsorption.2 During the past six decades, median age of survival has increased progressively, and is now more than 40 years in developed countries.3, 4 Respiratory failure secondary to progressive lung disease is now the most common cause of death in individuals who do not receive a lung transplant. This improvement in life expectancy has been achieved by understanding the importance of augmenting airway clearance, aggressively treating infection, and correcting nutrition deficits. More recent understanding of how abnormal ion transport in airway epithelial cells results in impaired mucus clearance and infection has underpinned the development of effective mucolytic agents and antipseudomonal antibiotics and the delivery of dedicated multidisciplinary cystic fibrosis care.5, 6, 7 Since the sequencing of the causative cystic fibrosis transmembrane conductance regulator (CFTR) gene, laboratory research has focused on developing therapies that correct the underlying basic defect in CFTR function.7 This approach has started to deliver transformational therapies for patients.8

Cystic fibrosis is a classic Mendelian autosomal recessive disorder. It is most common in populations with northern European ancestry where the predominant mutation is Phe508del (also known as F508del).9, 10 People with cystic fibrosis from other regions have a wider range of mutations with the Phe508del mutation being much less prevalent.11, 12 More than 2000 gene variants have been identified, many of which have been associated with disease causation.10 Mutations have different effects on the manufacture of CFTR protein, its processing function, and its stability at the cell membrane, which opens up the opportunity for different molecular approaches to the different functional consequences of the mutations (figure 1).8

Section snippets

CFTR function and dysfunction

The CFTR channel defect is mainly in chloride and bicarbonate transport.7, 8 The interaction of CFTR and other ion channels, particularly the epithelial sodium channel (ENaC), and interactions of CFTR with cellular pathways related to inflammation (inflammasome) might all be important in the pathophysiology of cystic fibrosis.7 The importance of understanding the pathophysiology of this disease in the first few years of life has been emphasised by recent studies showing that by the age of 3

Epidemiology and demographics

The remarkable progress that has been achieved by improving airway mucus clearance and controlling lung infection has changed cystic fibrosis from being predominantly a disease of children to now being predominantly an adult disorder.3, 4, 30 The number of adults with cystic fibrosis will continue to increase with almost all deaths occurring in the adult population.31 Indeed, for the past 5 years, in countries with well funded health-care systems, there have been more adults than children with

Newborn screening

Newborn screening for cystic fibrosis is now implemented in most countries with a high prevalence of the disease (figure 3).36 Newborn screening programmes reduce disease severity, burden of care, and costs of care. They also prevent delayed and missed diagnoses.37, 38 Several methods are used, including immunoreactive trypsinogen (IRT) testing combined with DNA mutation analysis, double IRT testing, and pancreatitis-associated protein (PAP) testing.39 The methodology used depends on

CFTR mutations

Most mutations of the CFTR gene are missense alterations, but frameshifts, splicing, nonsense mutations, and inframe deletions and insertions have been described.8 About 15% of identified genetic variants are not associated with disease. CFTR mutations can be divided into six classes according to their effects on protein function (figure 1).19, 41 This approach is helpful because it relates to the molecular and cellular processes in gene translation and protein processing and has some useful

Late diagnosis

Cystic fibrosis is usually identified following newborn screening or during the first few years of life.40 People who are diagnosed after 20 years of age usually have a mutation associated with residual CFTR function such as Arg117His (also known as R117H; figure 4).40, 47 These individuals might have mild respiratory symptoms in childhood but develop bronchiectasis, pancreatitis, or present with infertility later in life. The diagnosis is made by a sweat test and DNA analysis.48, 49

Lung disease in cystic fibrosis

The dominant pathology in the lung is inflammation generated primarily by failure to clear microorganisms and the generation of a toxic pro-inflammatory local microenvironment.50, 51 Lung disease starts early in life with CT scan evidence of bronchiectasis in about a third of patients within the first few months.20, 21 Bronchiectasis is associated with raised concentrations of neutrophil elastase, which further disrupts innate immunity, increases mucus production, damages peptides and proteins

Infection control

The high level of transmissibility of many important microorganisms that cause infection in the cystic fibrosis lung has been a troubling issue during the past three decades.67, 68 There is strong evidence that B cepacia complex organisms, P aeruginosa, meticillin-resistant S aureus, and M abscessus can be transmitted from patient to patient.68, 69 All of these organisms are associated with poor clinical outcomes and substantial effort is now made in cystic fibrosis centres to reduce

Inflammation in the cystic fibrosis lung

The cystic fibrosis lung is an inflammatory microenvironment.6, 51, 72 There are some data to support the hypothesis that mutations in CFTR make epithelial cells intrinsically more pro-inflammatory compared with healthy cells.7, 72, 73 How important this characteristic is in the initiation of inflammation in the cystic fibrosis lung is still debated. It is possible that it has a role in early life and as infection becomes a regular and subsequently chronic contributor to the airway

Treatment of lung disease in cystic fibrosis

The treatment of lung disease in cystic fibrosis is central to clinical management.35, 75, 76, 77 Airway clearance is almost universally taught to parents of newborn infants dignosed with cystic fibrosis and is encouraged throughout the rest of the individual's life.76, 78 There are good theoretical principles for use of airway clearance and the range of techniques increase sputum production. However, there are few appropriately powered randomised controlled trials to support the use of airway

Pancreatic and biliary disease in cystic fibrosis

Epithelial cells in the pancreatic and biliary ducts are also affected by CFTR dysfunction.91 Mucus obstruction occurs early in utero and most individuals with severe mutations have pancreatic insufficiency at birth and soon after.92, 93, 94 This is caused by a chronic obstructive pancreatitis. By contrast, individuals with class IV, V, or VI mutations are often pancreatic sufficient at birth, although some develop pancreatic insufficiency later in life.93, 94

Pancreatic insufficiency can be

Metabolic consequences of cystic fibrosis

The development of cystic fibrosis-related diabetes mellitus is an increasing problem, occurring in up to 40% of adults, and is associated with poorer survival, particularly in female patients.98 This disorder is caused by insulin deficiency resulting from the destructive pancreatic disease that ultimately destroys islet cell function.99, 100 Management of cystic fibrosis-related diabetes requires expertise from a cystic fibrosis dietician and input from a specialist diabetes team who

Management of end-stage disease in cystic fibrosis

The progressive effects of infection and inflammation of the airways lead to extensive bronchiectasis and bronchiolitis obliterans, which inevitably result in respiratory failure. All patients with cystic fibrosis who develop respiratory failure should be offered the option of lung transplantation when they are on a trajectory of declining lung function, frequent exacerbations, and an FEV1 of less than 30% predicted.106, 107 This presentation now occurs very infrequently in children in

Psychosocial consequences of cystic fibrosis

Chronic disorders can have substantial psychosocial effects on the wellbeing of affected individuals and their families.111 During childhood, the disease affects the person with cystic fibrosis, their parents, caregivers, and siblings, and often the wider family. The effects of having a life-limiting disease, progressively increasing symptoms including exacerbations, and a very high burden of care can affect behaviour and result in psychological distress.18, 112 In general, psychological

Innovative therapies

The recent development of drugs that correct the basic defect in CFTR function has substantially improved the prospect of effective disease-modifying treatment for cystic fibrosis.8 The prevention of lung disease with effective therapies that correct CFTR function is a clear objective and might be particularly effective if they can be started close to the time of diagnosis by newborn screening.

Two approaches have attempted to deliver effective disease-modifying therapies. The first approach is

Clinical trials in cystic fibrosis

With the improving quality of life and outcomes for cystic fibrosis, selecting endpoints for clinical trials has become more difficult.133 Absolute change in FEV1, time to next exacerbation, or frequency of exacerbations have been acceptable endpoints for licensing authorities. However, decline in lung function and frequency of exacerbations are decreasing with improved treatment and these endpoints could become too insensitive for use in clinical trials. New biomarkers are being developed that

Cystic fibrosis care

Delivery of clinical care in patients with cystic fibrosis depends upon specialist multidisciplinary teams with an appropriate discipline and skill mix to ensure that all aspects of cystic fibrosis disease are managed effectively.136 This process has been helped by national and international standards of care and guidelines that offer cystic fibrosis centres standards to benchmark high performance, which has driven high quality improvement culture. Most countries have a cystic fibrosis registry

Search strategy and selection criteria

I searched MEDLINE using the term “cystic fibrosis” for articles publications between Jan 10, 2008 and Dec 31, 2015. Publications from the past 8 years were the primary source of the review. Review articles and book chapters are cited to provide readers with more details. Consensus statements and guidelines are cited where evidence has been assessed for clinical practice. In the discussions of treatment and prevention, more weight was given to randomised controlled trials and meta-analyses than

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