Section 1: Epidemiology and aetiology
Cystic fibrosis (CF) is a common autosomal recessive disease, affecting more than 10,000 people in the UK.
It has a higher prevalence in Caucasian people. The carrier frequency is approximately one in 25 people in the UK Caucasian population.
The gene responsible for CF is the cystic fibrosis transmembrane regulator (CFTR) and is located on chromosome seven.
There are more than 1,200 disease-causing mutations in the CFTR gene, and more are being discovered.
However, they do not all lead to the same disease severity. There are also genetic modifiers that may affect disease severity although their role has not been clearly elucidated to date.
The most common gene mutation, present in approximately 70% of CF chromosomes worldwide, is the Phe508del, a deletion of the amino acid phenylalanine at position 508.
The CFTR protein that the gene encodes is a chloride channel and mutations leading to disruption of the function or production of the protein, lead to the basic defect of CF.1
There are several ways to classify the disease; one is based on the mutation type and another on disease severity.
The different types of mutations determine the severity of the functional and structural loss of the CFTR channel and thus play a role in the severity of illness.
Pancreatic sufficiency status has been shown to reflect prognosis and severity and the classification of patients into pancreatic sufficient and insufficient is useful in clinical practice.
Patients with pancreatic insufficiency tend to have greater morbidity and mortality than patients who are pancreatic sufficient.
|Classification of mutations|
Class I: Absence of synthesis of CFTR.
Class II: Defect in CFTR protein maturation and/or premature degradation (Phe508del).
Class III: Abnormal regulation, for example, decreased ATP binding and hydrolysis.
Class IV: Defective chloride conductance or channel gating.
Class V: Promoter or splicing abnormality leading to diminished CFTR transcripts.
Section 2: Making the diagnosis
The sweat test is the gold standard test for the diagnosis of CF. Sweat sodium and chloride levels are raised in CF due to a failure of CFTR in the sweat gland to absorb chloride. An unequivocally abnormal result is a sweat chloride > 60mmol.
DNA analysis can confirm the diagnosis when two disease causing mutations are found in an individual. Nasal potential difference is another diagnostic test for CF, which is only available in a few centres in the UK. It tends to be used when the diagnosis of CF is in doubt, usually if there have been equivocal sweat test results. The abnormal potential difference across mucosal surfaces can be measured by passing a soft catheter under the inferior turbinate.
Faecal elastase is a useful test to diagnose pancreatic insufficiency. However, faecal elastase is not a diagnostic test for CF, as there are other causes of pancreatic insufficiency.
Furthermore, if the faecal elastase is normal, the individual may still have CF, as up to 15% of CF patients are pancreatic sufficient.
All newborn babies born in the UK are offered screening for CF by measuring the immunoreactive trypsinogen (IRT) in the blood spot from a Guthrie test.
IRT is a pancreatic enzyme that is elevated for the first days of life in patients with CF.
If the IRT is raised above the cut-off level, the newborn screening laboratory determines the genetic mutations in the blood sample using a panel of the four most common mutations initially.
In the era prior to newborn screening, patients with CF were often diagnosed after repeated episodes of respiratory tract infections, persistent steatorrhoea and failure to thrive. Now, infants diagnosed with CF through newborn screening are often clinically well at diagnosis.
CF is a multisystem disease and the symptoms can vary in different age groups. Respiratory disease is the major cause of morbidity and mortality in patients with CF.2
CF lung disease is characterised by the presence of thick, inspissated secretions in the airways, which impair mucocilliary clearance. This promotes cycles of infection and inflammation in the lungs, which lead to progressive irreversible lung damage, bronchiectasis and ultimately respiratory failure.
CF patients are susceptible to respiratory tract infections with Staphylococcus aureus, Pseudomonas aeruginosa, Burkholderia cepacia and other pathogens.
Approximately 85% of patients with CF have exocrine pancreatic insufficiency. These patients present clinically with signs of malabsorption (particularly of fat), steatorrhoea, abdominal distension and failure to thrive. There is also deficiency of the fat soluble vitamins (A,D,E,K). The endocrine portion of the pancreas may become affected as well and patients may develop CF-related diabetes.
In the neonatal period, approximately 10% of CF patients present shortly after birth with abdominal distension and bile-stained vomiting due to meconium ileus. In older children, inspissation of malabsorbed material in the terminal ileum and caecum can cause severe constipation leading to subacute bowel obstruction. This condition is called distal intestinal obstruction syndrome (DIOS). Rectal prolapse is also commonly seen and may be the presenting feature of CF.
The liver and hepatic ducts can also become obstructed by thickened secretions and can lead to focal hepatic cirrhosis, portal hypertension and gallstones. Neonates can present with prolonged jaundice.
Other symptoms and signs may include hypochloraemic dehydration, digital clubbing, nasal polyps and azoospermia secondary to congenital absence of the vas deferens.
Section 3: Managing the condition
Chest physiotherapy is an important treatment in CF lung disease. It needs to be performed on a daily basis and the aim is to help patients clear the thickened secretions within the lungs. In some patients, mucoactive treatments are used as an adjunct to physiotherapy. These include dornase alpha and hypertonic saline.
Antibiotics are given as treatment for chest infections or exacerbations of pulmonary symptoms, such as increased cough, either orally, intravenously or nebulised.
They are also given as prophylaxis, with many CF centres routinely commencing newly diagnosed infants with CF on prophylactic antistaphylococcal antibiotics, such as flucloxacillin.
A significant complication of CF is chronic lung infection with P aeruginosa.3 Currently the standard of care is to attempt to eradicate P aeruginosa when it is first isolated with the use of either IV or oral antipseudomonal antibiotics in combination with nebulised antibiotics.4 Unfortunately, the lungs of many patients ultimately become chronically infected with P aeruginosa requiring the use of long-term nebulised antibiotics (colistin, tobramycin).
Azithromycin, one of the macrolide antibiotics, is of benefit particularly in patients chronically infected with P aeruginosa and may work as an anti-inflammatory.
Optimising nutrition and weight gain plays a vital role in the management of CF patients. A high fat, high calorie diet is recommended. Supplemental calories can be administered as high calorie drinks. However, if this fails to meet nutritional demands and weight gain is suboptimal, then enteral feeding via a gastrostomy may be required.
Pancreatic insufficient patients receive pancreatic enzyme supplements to aid absorption. The dose should be tapered to the dietary intake and the patient's weight. They also receive vitamin supplements, particularly the fat soluble ones.
Constipation is managed aggressively with laxatives. However, in patients who develop DIOS, treatment is usually needed with oral gastrograffin or intestinal lavage with balanced electrolyte solution.
When patients develop CF-related liver disease, ursodeoxycholic acid is used. If the disease progresses to cirrhosis and liver failure, patients are referred for liver transplantation.
CF-related diabetes shares characteristics of both type-1 and type-2 diabetes; its management is to commence the patient on insulin. Dietary management is different from that of non-CF diabetes. A high fat, high calorie diet is continued and the insulin dose is adjusted to maintain good glycaemic control.
There is a higher incidence of osteopenia and osteoporosis in CF patients. Vitamin D, vitamin K, calcium supplementation as well as frequent monitoring of bone mineral density are now part of the standard management. Vitamin K is a fat-soluble vitamin vital for the function of osteocalcin and other bone-related proteins, and may be low in CF patients.5
Advanced lung disease
In the more advanced stages of the disease, patients may require oxygen at home or even nocturnal support with non-invasive ventilation. In end stage CF lung disease, patients are referred for lung transplantation evaluation.
Kalydeco (ivacaftor) is the first of a new class of medicines, CFTR potentiators, which target the underlying cause of CF. It is now licensed for patients with CF who are aged six years and over and who have at least one copy of a Class III gene mutation. It has been shown to significantly improve lung function and weight gain.6
Section 4: Prognosis
The life expectancy of a child born with CF has increased greatly over the past few decades. In the 1950s few children lived long enough to attend primary school. In the UK, the median survival is currently around 40 years for babies born today with CF and it is expected to continue to rise.
It is recommended that patients with CF receive care by a multidisciplinary team consisting of doctors, specialist nurses, dieticians, physiotherapists and psychologists.
The team often also includes other specialists, such as endocrinologists and gastroenterologists, depending on the individual patient need. The clinic visits are typically every two to three months, including yearly blood tests and chest X-rays.
Patients are initially managed by a paediatric CF team until the age of between 16 to 18 years, after which patients will be under the care of the adult CF team.
Section 5: Case report
A three-week old baby boy was diagnosed with CF following newborn screening tests. The infant had a raised IRT in the blood spot from the Guthrie test. A sweat test was performed in the specialist CF centre to confirm the diagnosis.
Subsequently the infant and his parents met with the CF consultant and nurse specialist to be given the diagnosis and information about CF. The family then met the rest of the CF team, including the psychologist, dietician and physiotherapist.
The first year of life was full of challenges for the infant and his parents. Pancreatic insufficiency was diagnosed by a low faecal elastase. Pancreatic enzyme replacement was initiated promptly preventing the infant from developing steatorrhoea, malnutrition and vitamin deficiency as a result of malabsorption. The infant was also started on prophylactic flucloxacillin, multivitamins, vitamin E as well as chest physiotherapy.
The infant was seen every two months in the CF clinic by the multidisciplinary team. This included close monitoring of the infant's growth and assessment of respiratory pathogens by performing cough swabs at each clinic visit. The infant developed frequent vomiting after feeds and was diagnosed with gastro-oesophageal reflux. This improved following commencement of ranitidine.
The infant developed multiple upper respiratory infections in the first year of life, including bronchiolitis at six months. Being aware of the underlying disease made his parents and treating doctors more vigilant and additional oral antibiotics were commenced with respiratory tract infections.
The infant had a routine flexible bronchoscopy and bronchoalveolar lavage at 12 months of age to assess for lower respiratory pathogens, as is part of the standard management protocol for infants with CF in our centre.
The bronchoscopy was normal, with no bacterial growth on the bronchoalveolar lavage.
As our infant now approaches 18 months, his growth is normal and he has remained well.
Section 6: Evidence base
- Intermittent administration of inhaled tobramycin in patients with CF.
This was an RCT of intermittent administration of nebulised tobramycin in patients with CF and P aeruginosa infection.
It was conducted from 1995 to 1996 in 69 CF centres in the US. The study showed that nebulised tobramycin was well tolerated and improved pulmonary function, decreased the density of P aeruginosa in the sputum, and decreased the risk of hospitalisation.7
- Azithromycin in patients with CF chronically infected with Pseudomonas aeruginosa.
This was an RCT to determine if an association between azithromycin use and pulmonary function existed in CF patients. It was conducted from 2000 to 2002, in 23 CF centres in the US. CF patients were randomised to receive either azithromycin or placebo for 168 days.8
The study showed that azithromycin treatment was associated with an improvement in lung function and a reduction in pulmonary exacerbations.
- Chernick V, Boat TF, Wilmott RW, et al. Kendig's Disorders of the Respiratory Tract in Children (7th edition). Elsevier Saunders, 2006.
Chapters 58 to 62 give a good overview of CF.
This topic is covered in the GP curriculum in statement 15.8 Respiratory Problems.
- www.cftrust.org.uk All the consensus documents and guidelines of the UK Cystic Fibrosis Trust can be found at this website.
- www.ecfs.eu/publications/consensus_reports Consensus documents and guidelines from the European Cystic Fibrosis Society.
- www.cff.org Website of the American Cystic Fibrosis Foundation, where information on new treatments and useful information can be found.
Dr Ranjan Suri is paediatric respiratory consultant, Great Ormond Street Hospital and the Portex Unit, Institute of Child Health University College Hospital
- Davis PB, Drumm M, Konstan MW. Cystic fibrosis. Am J Respir Crit Care Med 1996; 154(5): 1229-56.
- Gibson RL, Burns JL, Ramsey BW. Pathophysiology and management of pulmonary infections in cystic fibrosis. Am J Respir Crit Care Med 2003; 168(8): 918-51.
- Henry RL, Mellis CM, Petrovic L. Mucoid Pseudomonas aeruginosa is a marker of poor survival in cystic fibrosis. Pediatr Pulmonol 1992; 12(3): 158-61.
- Lee TW. Eradication of early Pseudomonas infection in cystic fibrosis. Chron Respir Dis 2009; 6(2): 99-107.
- Jagannath VA, Fedorowicz Z, Thaker V, Chang AB. Vitamin K supplementation for cystic fibrosis. Cochrane Database of Systematic Reviews 2015, Issue 1. Art. No.: CD008482. DOI: 10.1002/14651858.CD008482.pub4
- Ramsey BW, Davies J, Gerard N et al. A CFTR potentiator in patients with cystic fibrosis and the G551D mutation. N Engl J Med 2011; 365: 1663-72.
- Ramsey BW, Pepe MS, Quan JM et al. Intermittent administration of inhaled tobramycin in patients with cystic fibrosis. Cystic Fibrosis Inhaled Tobramycin Study Group. N Engl J Med 1999; 340(1): 23-30.
- Saiman L, Marshall BC, Mayer-Hamblett N et al. Azithromycin in patients with cystic fibrosis chronically infected with Pseudomonas aeruginosa: a randomized controlled trial. JAMA 2003; 290(13): 1749-56.
- This is an updated version of an article that was first published in May 2011