Key learning points

  • Cystic fibrosis is a genetic life-shortening condition that affects many organs in the body 
  • The effects on the lower airway are the main feature of the condition, with thickened ductal secretions resulting in a cycle of increased airway infections and inflammation, leading to progressive airways damage
  • FEV1 is used to inform clinical decisions relating to airway infection, inflammation and mucus, and responses to treatment, as well as to monitor disease and severity
  • Multidisciplinary, specialist care is essential in the management of patients with cystic fibrosis
  • Novel therapies have shown improvements in lung function and a reduced frequency of pulmonary exacerbations

Introduction

Cystic fibrosis (CF) is a multisystem, monogenic disease predominantly affecting Caucasian people. It is caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene which encodes for the CFTR protein, an epithelial ion channel located at the apical surface of the cell membrane of specific organ tissues: sweat glands, conducting airway, pancreatic and biliary ducts, intestinal mucosa and the male vas deferens. Absent or net reduction in quantity or function of the CFTR protein produces features of abnormal ion transport and leads to the clinical syndrome within these organ-sites, which is typified by thickened luminal secretions. Treatments to date have considerably improved morbidity and increased life expectancy, but despite an increasing emergence of new treatments and therapies, CF remains a life-shortening condition. 

Epidemiology

CF is inherited in an autosomal recessive manner and thus requires both parents to pass one mutated gene to their affected child; the parents, being heterozygotes (‘carriers’) for CFTR, are unaffected by the disease. The incidence and prevalence of CF varies globally. One in 25 people in the UK are carriers of a faulty CFTR gene, and it is estimated that in the UK CF occurs in one in 2,500 live births. Data from UK CF registry data compiled by the CF Trust (2018) records over 10,500 patients currently living with CF, with a current median age of death of 32 years.1 The median predicted survival is, however, increasing annually, with epidemiological modelling predicting that individuals born in the year 2000 will have a median survival of >50 years old,1,2 and with modern therapies aiming to correct the underlying cellular defect, exponential increases in life expectancy are a realistic potential.

Clinical features

It is the consequences in the lower airway that is the predominant feature of the condition, leading to premature death in approximately 80% of patients.3 Thickened ductal secretions result in a perpetuating cycle of increased airway infections and inflammation, leading to progressive airways damage. This process may be extrapolated to explain the extra-pulmonary manifestations of the disease with end-organ failure. The clinical features seen in people living with CF are summarised in Table 1. 

Measurements of lung function, in particular the forced expiratory volume in one second (FEV1), are important clinical tools in the care of CF patients. They inform clinical decisions relating to airway infection, inflammation and mucus, and responses to treatment; and are used longitudinally to monitor disease and severity.4

Table 1. Organ- and system-specific clinical features in cystic fibrosis 

Organ affectedClinical features
Lower airwayIncreased, thickened mucus production
Acute and chronic airway infection especially with Pseudomonas aeruginosa, Staphylococcus aureus and Haemophilus influenzae
Atypical mycobacterium infection
Allergic bronchopulmonary aspergillosis
Bronchiectasis
Spontaneous pneumothorax
Haemoptysis
Respiratory failure
Upper airwaySinusitis
Nasal polyps
PancreasPancreatic insufficiency (exocrine failure) leading to malabsorption and vitamin deficiency states
CF-related diabetes (endocrine failure)
Recurrent pancreatitis
Gastroinestinal tractGastro-oesophageal reflux
Constipation
Distal intestinal obstruction syndrome
Meconium ileus
Intussusception
Increased risk of GI tract malignancy
Hepatobiliary systemCF-related liver disease (encompassing cholestatic cirrhosis and liver failure)
Biliary stasis and cholelithiasis
Genitourinary systemMale infertility (congenital bilateral absence of the vas deferens)
Reduced female fertility (thickened cervical mucus)
Delayed puberty (probably secondary to nutritional, inflammatory and/or drug effects rather than primary)
Stress incontinence
SkinRaised sweat chloride (diagnostic gold standard)
Electrolyte depletion (pseudo-Bartter’s syndrome)
Vasculitis
BonesLow bone mineral density and osteoporosis
CF arthropathy

Diagnosis

Since 2007, the UK has implemented universal newborn screening for CF by the measurement of immune-reactive trypsinogen in the serum following a heel-prick test. Positive results are next assessed for common CFTR mutations, with diagnosis still requiring a sweat test for confirmation.5 Patients with mild or ‘atypical’ CF disease may present in later life with at least one organ-specific CF symptom, most commonly bronchiectasis. Such patients should be evaluated in a specialist bronchiectasis or CF service by CFTR genetic analysis and functional CFTR testing.6 

Management of cystic fibrosis

Multidisciplinary, specialist care is essential in the management of patients with CF. To date, the UK has 25 adult and 27 paediatric CF centres, each with multidisciplinary teams (CF dedicated physicians, specialist nurses, physiotherapists, dietitians, pharmacists, psychologists and social workers), and supported by specialty services (including diabetes, gastroenterology, hepatology and ENT) and a clinical research team. 

Until recently, CF management has concentrated on the downstream effects of CF. The treatment of chronic airways disease centres around airway clearance by physiotherapy, aided by nebulised or inhaled mucolytic agents, and treatment of airway infection and inflammation. Acute and chronic pulmonary infection with S. aureus (methicillin sensitive and resistant), Pseudomonas aeruginosa and non-tuberculous Mycobacteria are common in CF, alongside other emerging organisms. Treatment for an acute pulmonary exacerbation is managed with oral or intravenous antibiotics targeted at the likely organism; long-term nebulised, inhaled or oral antibiotics are prescribed for established, chronic infection. 

In the last decade, novel therapies have emerged that correct or potentiate the CFTR protein, demonstrating improvements in lung function and a reduced frequency of pulmonary exacerbations. Such drugs are CFTR mutation-specific and costly and, at the time of writing, in the UK only the CFTR potentiator ivacaftor is approved for clinical use in eligible patients based on their mutation genotype (4–5%).7 Two further licensed therapies (a combination of a corrector and potentiator) are only available to eligible patients (aged >12 years) on a compassionate access management programme – these are lumacaftor–ivacaftor8 and tezacaftor–ivacaftor.9 Following an announcement reporting a positive trial outcome, a new triple combination (elexacaftor, tezacaftor and ivacaftor) will be added to the extended assess programme in 2019.10

Optimisation of weight by the oral replacement of pancreatic (digestive) enzymes, and by appropriate vitamin and mineral supplementation is key, along with the management of CF-related diabetes. 

Bilateral lung transplantation, as a treatment for end-stage lung disease, is considered in more than 200 patients each year. Approximately 100–130 patients each year are accepted on to the transplant waiting list, with on average 50–60 patients successfully receiving a pair of ‘new lungs’ each year.1 

Future of CF care

The importance of providing personalised care is becoming ever more important as novel therapies develop and target the disease at the cellular level. Next-generation CFTR correctors, including triple combination therapies, are emerging along the CF therapeutics pipeline.10 Genetic therapies, CFTR gene therapy and genome editing, both correcting the underlying genetic defect, remain the holy grail in CF treatment. To date, CFTR gene therapy has proven concept but its efficacy remains to be established. It seems likely that in an era of CFTR modulator therapy, the life expectancy of patients with CF will continue to rise over and above previous modelling.

Dr Michael Waller, consultant in cystic fibrosis and respiratory medicine; Dr Caroline Elston, consultant in respiratory medicine and adult cystic fibrosis, Department of Adult Cystic Fibrosis, King’s College Hospital, London

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