Cystic fibrosis (CF) is a multi-organ disease best managed in a multidisciplinary setting in conjunction with a specialist centre for CF, with treatment tailored to the individual.
Conventional treatment has improved greatly over the past few decades. Newer approaches such as gene and small molecule-based treatments may have more potential to halt disease progression.
Nov 2017 - Dr Hayley Willacy draws your attention to the recently released NICE guideline dealing with the diagnosis and management of cystic fibrosis. They advise that assessment for cystic fibrosis should be made and, when clinically appropriate, a sweat test performed (for children) or a cystic fibrosis gene test (for adults) in people with any of the following: family history; congenital intestinal atresia; meconium ileus; symptoms and signs that suggest distal intestinal obstruction syndrome; faltering growth (in infants and young children); undernutrition; recurrent and chronic pulmonary disease; chronic sinus disease; obstructive azoospermia (in young people and adults); acute or chronic pancreatitis; malabsorption; rectal prolapse (in children) and pseudo-Bartter syndrome.
CF is an autosomal recessive disease caused by mutations in the CF transmembrane conductance regulator (CFTR) gene, on chromosome 7. There are at least 2,000 mutations in the CFTR gene. Different mutations result in different phenotypes. Some mutations result in milder forms of the disease. One study identified some mutations which appeared to have no pathological effect at all. The most common mutation in Caucasians is the delta-F508 (DF508).
CFTR is an ATP-responsive chloride channel that also affects other cellular activities, such as sodium transport across the respiratory epithelium, composition of cell surface glycoprotein and antibacterial defences.
CF is the most common inherited disease in white populations.
- Prevalence is 1 in 2,500 newborn infants, with calculated carrier frequency of 1 in 25. Just over 10,000 people were recorded as having CF in the 2013 UK CF Registry.
- The only risk factor is a family history of the condition.
The abnormality in the CFTR gene explains the pathology of CF.
High sodium sweat
Primary secretion of sweat duct is normal but CFTR does not absorb chloride ions, which remain in the lumen and prevent sodium absorption.
Production of pancreatic enzymes is normal but defects in ion transport produce relative dehydration of pancreatic secretions, causing their stagnation in the pancreatic ducts.
Defective ion transfer across the bile duct causes reduced movement of water in the lumen so that bile becomes concentrated, causing plugging and local damage.
Low-volume secretions of increased viscosity, changes in fluid movement across both the small and large intestine and dehydrated biliary and pancreatic secretions cause intraluminal water deficiency.
Dehydration of the airway surfaces reduces mucociliary clearance and favours bacterial colonisation, local bacterial defences are impaired by local salt concentrations and bacterial adherence is increased by changes in cell surface glycoproteins.
Increased bacterial colonisation and reduced clearance produce inflammatory lung damage due to an exuberant neutrophilic response involving mediators such as IL8 and neutrophil elastase.
- As normal digestive function is possible with <5% pancreatic function, CF can present at any age.
- The most common presentation is with respiratory problems - usually recurrent lower respiratory tract infection (LRTI) with chronic sputum production.
However, immunoreactive trypsinogen (IRT) is now measured on a dried blood spot obtained on the Guthrie card at day six of life. Samples with abnormally raised IRT levels will undergo CFTR mutation screening. This was introduced in 2007. This therefore means that clinical presentation of CF will become rarer. However, screening failures do sometimes occur. Presentation of CF varies with age.
|Presentation and diagnosis|
|Infancy and childhood|
These may include:
- Finger clubbing.
- Cough with purulent sputum.
- Wheezes (mainly in the upper lobes).
- Forced expiratory volume in one second (FEV1) showing obstruction.
Babies diagnosed with CF will usually have no signs or symptoms.
- Sweat testing confirms the diagnosis and is 98% sensitive. Chloride concentration >60 mmol/L with sodium concentration lower than that of chloride on two separate occasions.
- Molecular genetic testing for CFTR gene.
- Sinus X-ray or CT scan - opacification of the sinuses is present in almost all patients with CF.
- CXR or CT of thorax.
- Lung function testing - spirometry is unreliable before 6 years.
- Sputum microbiology - common pathogens include Haemophilus influenzae, Staphylococcus aureus, Pseudomonas aeruginosa, Burkholderia cepacia, Escherichia coli and Klebsiella pneumoniae.
- Various blood tests including FBC, U&Es, fasting glucose, LFTs and vitamin A, D and E levels are usually performed.
- Semen analysis if appropriate.
Patient care is most effective when provided in specialist centres by multidisciplinary teams. Most patients' care is co-ordinated by a CF tertiary centre. However, the links to local care are highly valued. CF patients perceive a satisfactory doctor-patient relationship to be influenced by three factors:
- GPs' understanding of how people live with CF.
- GPs' ability to prescribe certain specialist medications.
- Sensitive management of the cost of healthcare for adults with CF.
Most of the morbidity and mortality associated with CF is caused by respiratory disease where chronic infection and inflammation lead to bronchiectasis, progressive airflow obstruction, cor pulmonale and finally death.
Probably as a result of more successful treatment of classic bacterial infections in CF, there are now increasing problems with multi-resistant isolates of P. aeruginosa and innately resistant organisms such as Stenotrophomonas maltophilia, Achromobacter xylosoxidans and non-tuberculous mycobacteria. Meticillin-resistant S. aureus (MRSA) is a growing problem.
The following interventions are commonly used to prevent and treat respiratory problems:
- In the early, pre-infected stages, mucus clearance, preventing infection and maintaining good lung function are the main aims.
- Chest physiotherapy should be given twice-daily and this is increased with infective exacerbations.
- Additional physical exercise is also beneficial and should be encouraged.
- Regular sputum samples are sent for bacterial culture.
- Prophylactic antibiotics are used to reduce S. aureus in children and also to prevent secondary bacterial infections when a patient has a presumed acute viral respiratory infection.
- Antibiotic choice for infective exacerbations will depend on the organism.
- Infection with less common organisms requires specialist microbiological advice.
- Patients with P. aeruginosa have a 2- to 3-fold increased risk of death over eight years. This is eradicated by various combinations of oral, inhaled and intravenous antibiotics. Pre-colonisation pseudomonal eradication protocols usually include both topical (nebulised) and systemic antibiotics. A Cochrane review looking at various combinations of oral ciprofloxacin, inhaled colistin and nebulised tobramycin solution failed to show superiority of any particular regime. Intravenous home treatment using tobramycin and amikacin is often used where suitably trained staff are available.
- The National Institute for Health and Care Excellence (NICE) recommends treatment of chronic P. aeruginosa with nebulised colistimethate sodium or tobramycin. For patients who cannot take the nebulised form, NICE has recommended dry powder inhalation formulations of these drugs.
- Bronchodilators are recommended by metered dose inhaler (MDI) or by nebuliser. Short- and long-acting beta-2 agonists have been shown to be beneficial in the short and long term.
- Dornase alfa is a recombinant form of human deoxyribonuclease and is given by nebuliser. It cleaves neutrophil-derived DNA in sputum to reduce viscosity and therefore aid sputum removal. It has been shown to be associated with improvement in lung function and possibly a reduction in respiratory exacerbations. Cochrane looked at the timing of administration before and after airway clearance but found insufficient evidence to make a definitive recommendation.
- High-dose ibuprofen may slow progression of lung disease, especially in children.
- Azithromycin has also been shown to reduce inflammation and improve respiratory function in CF. However, benefits beyond six months and the issue of emerging resistance require further research.
- Hypertonic saline by a nebuliser is often given for its osmotic action. Other osmotic agents are being developed.
- Mannitol dry powder for inhalation is recommended by NICE as an option for treating cystic fibrosis in adults:
- Who cannot use rhDNase because of ineligibility, intolerance or inadequate response to rhDNase; and
- Whose lung function is rapidly declining (FEV1 decline greater than 2% annually); and
- For whom other osmotic agents are not considered appropriate.
- There is no evidence supporting a role for corticosteroids except in treating allergic bronchopulmonary aspergillosis[4, 18].
- In the end stage, management focuses on the common complications, which include haemoptysis, pneumothorax and respiratory failure.
- Lung or heart and lung transplantation listing should be considered where there is respiratory failure. Due to scarcity of donor organs, approximately a third of CF patients on the list die before receiving a donor lung. It is hoped that the new technique of ex vivo lung perfusion will help to increase the stock of lungs available.
50% of adults with CF have nasal polyps. Treat with nasal steroids initially; if this fails, polypectomy is usually performed (50% require repeat within two years).
At least 85% of patients with CF have pancreatic insufficiency so will need to take pancreatic enzymes.
This usually presents with neonatal meconium ileus or failure to thrive, steatorrhoea and malnutrition which can cause anaemia, vitamin deficiency and sometimes oedema. It can cause rectal prolapse, intussusception, volvulus and obstruction.
Pancreatic insufficiency should be confirmed with stool elastase; presence of unsplit fat globules in stool or 2-3 days' stool collection for faecal fat.
Maintaining adequate weight
Patients should be weighed regularly. Patients will have high energy needs, especially those with recurrent chest infections or those who lose a lot of fat in their stools. Protein intake needs to be at least twice the normal recommended amounts.
- All patients take enteric-coated enzyme preparations before meals with the dose adjusted to achieve normal stools. Drugs may be needed to reduce acid secretion, as well as vitamin supplements for the fat-soluble vitamins A, D and E.
- High intake of calories (130% normal) is usually required.
- Comparing actual resting energy expenditure (REE) to predicted REE is an objective indicator of disease severity and progression as well as energy requirements.
- Research supports the use of high-calorie diets in underweight patients but further work needs to be done on the most efficacious route of delivery.
- If the patient is unable to maintain weight, enteral feeding via gastrostomy may be required.
- There is no evidence that oral calorie supplements are beneficial for children with CF. Short-term protein supplements may be of benefit in adults but further research is required.
Liver disease is seen in up to 30% of patients by adulthood. Liver cell failure usually occurs late, with ominous prognosis. It is fatal in 2-4% of CF cases and is the third most common cause of death in CF patients.
- Commonly, LFTs are abnormal and should be treated with caution. They can be a reflection of CF without liver disease, CF-related liver disease or the side-effects of medication.
- Usually seen as hepatosplenomegaly.
- Ultrasound is a useful confirmatory investigation. Other imaging modes - eg, scintigraphy - may be required.
- Ursodeoxycholic acid improves bile flow and produces some improvement but does not alter the course of chronic liver disease.
Liver transplantation should be offered to CF patients with progressive liver failure and/or with life-threatening sequelae of portal hypertension. They should also have relatively good lung function, to support long-term survival.
Diabetes and glucose intolerance
CF-related diabetes is currently present in 2% of children, 19% of adolescents and 40-50% of adults.
- Screening for diabetes is performed at regular intervals.
- Insulin replacement is usually required with the dose adjusted to match high dietary intake. Early insulin therapy may be beneficial but further research is required.
- A Cochrane review found no significant conclusive evidence that long-acting insulins, short-acting insulins or oral hypoglycaemic agents had a distinct advantage over one another in controlling hyperglycaemia or clinical outcomes associated with CF-related diabetes.
Reproductive health and fertility
Nearly all males with CF have obstructive azoospermia with sexual function that is otherwise normal; there is normal spermatogenesis but no vas deferens. Early counselling should be offered about infertility and sperm count. In vitro fertilisation with aspirated sperm has been used successfully.
Women are generally of normal fertility but need genetic counselling. There is an inherent risk to pregnancy with severe lung disease (FEV1 <30% predicted).
Offspring of patients with CF will be carriers of cystic fibrosis.
CF is a huge burden to patients and families. This is because of:
- The life-shortening nature of the disease.
- The time-consuming treatments prescribed.
- The ongoing morbidity.
Insufficient evidence exists on psychological interventions or approaches to support people with CF and their caregivers and multicentre studies are needed.
There is an increased risk of osteoporosis in patients with CF. Around one third of adults with CF have osteoporosis.
Patients should be recommended to take calcium, vitamin D and bisphosphonates as appropriate. Patients usually have regular dual-energy X-ray absorptiometry (DEXA) scans.
Follow-up of patients
Patients have regular follow-up by their specialist.
UK standards recommend that:
- Patients should be seen twice a year by a multidisciplinary team working in a specialist centre.
- GPs should provide shared care in conjunction with specialists.
- Children should be transferred to adult services by the age of 18 at the latest.
In general, the following investigations are performed at regular intervals:
- Pulmonary function tests.
- DEXA scan.
- Blood glucose.
- Respiratory cultures.
- Ultrasound scan of the liver.
- Vitamin D levels.
Varicella antibodies are usually checked for and the varicella vaccine is usually offered to those children who need it.
All patients should receive the annual influenza vaccination. They should also receive the pneumococcal vaccine.
The pronounced improvement in life expectancy over the period of two decades is largely the result of centralisation of care at CF centres and aggressive treatment of symptoms.
- Median survival in 1999 was 30 years. Projected life expectancy for patients has increased from 31 years to 37 years over the period of a decade.
- Estimated survival for a child born now is 40-50 years.
- Females and those people from lower socio-economic classes have a worse prognosis.
- The use of recombinant human DNase has been shown to lead to a marked improvement in survival of patients with a low FEV1.
The great hope for the future is that therapies that treat the basic defect will normalise life expectancy for those born with CFTR mutations. Gene therapy should be possible to treat an autosomal recessive disease such as CF with insertion of one copy of normally functioning DNA into the affected cells, independent of the class of mutation the recipient had before gene therapy. Although easy in concept (and in vitro), in practice, gene therapy has proven to be quite difficult. Further work needs to be undertaken on viral and non-viral vectors. One study reported beneficial effects from a combination of lumacaftor (VX-809), a CFTR corrector, in combination with ivacaftor (VX-770), a CFTR potentiator .
Further reading and references
Cystic fibrosis: diagnosis and management; NICE Guideline (Oct 2017)
Cystic Fibrosis, CF; Online Mendelian Inheritance in Man (OMIM)
Sosnay PR, Siklosi KR, Van Goor F, et al; Defining the disease liability of variants in the cystic fibrosis transmembrane conductance regulator gene. Nat Genet. 2013 Oct45(10):1160-7. doi: 10.1038/ng.2745. Epub 2013 Aug 25.
Davies JC, Alton EW, Bush A; Cystic fibrosis. BMJ. 2007 Dec 15335(7632):1255-9.
Ratjen F, Doring G; Cystic fibrosis. Lancet. 2003 Feb 22361(9358):681-9.
Cystic Fibrosis Registry Annual Data Report 2013; Cystic Fibrosis Trust, July 2014
Conway S, Balfour-Lynn IM, De Rijcke K, et al; European Cystic Fibrosis Society Standards of Care: Framework for the Cystic Fibrosis Centre. J Cyst Fibros. 2014 May13 Suppl 1:S3-22. doi: 10.1016/j.jcf.2014.03.009.
Wicks E; Cystic fibrosis. BMJ. 2007 Jun 16334(7606):1270-1.
Lowton K, Ballard KD; Adult cystic fibrosis patients' experiences of primary care consultations: a qualitative study. Br J Gen Pract. 2006 Jul56(528):518-25.
Langton Hewer SC, Smyth AR; Antibiotic strategies for eradicating Pseudomonas aeruginosa in people with cystic fibrosis. Cochrane Database Syst Rev. 2014 Nov 1011:CD004197. doi: 10.1002/14651858.CD004197.pub4.
Colistimethate sodium and tobramycin dry powders for inhalation for treating pseudomonas lung infection in cystic fibrosis; NICE Technology Appraisal Guidance, March 2013
Halfhide C, Evans HJ, Couriel J; Inhaled bronchodilators for cystic fibrosis. Cochrane Database Syst Rev. 2005 Oct 19(4):CD003428.
Dentice R, Elkins M; Timing of dornase alfa inhalation for cystic fibrosis. Cochrane Database Syst Rev. 2011 May 11(5):CD007923. doi: 10.1002/14651858.CD007923.pub2.
Southern KW, Barker PM, Solis-Moya A, et al; Macrolide antibiotics for cystic fibrosis. Cochrane Database Syst Rev. 2012 Nov 1411:CD002203. doi: 10.1002/14651858.CD002203.pub4.
Anderson P; Emerging therapies in cystic fibrosis. Ther Adv Respir Dis. 2010 Jun4(3):177-85. doi: 10.1177/1753465810371107.
Mannitol dry powder for inhalation for treating cystic fibrosis; NICE Technology Appraisal Guidance, November 2012
Balfour-Lynn IM, Welch K; Inhaled corticosteroids for cystic fibrosis. Cochrane Database Syst Rev. 2012 Nov 1411:CD001915. doi: 10.1002/14651858.CD001915.pub3.
Transplants in cystic fibrosis; Cystic Fibrosis Trust
Machuca TN, Cypel M; Ex vivo lung perfusion. J Thorac Dis. 2014 Aug6(8):1054-62. doi: 10.3978/j.issn.2072-1439.2014.07.12.
Baker SS; Delayed release pancrelipase for the treatment of pancreatic exocrine insufficiency associated with cystic fibrosis. Ther Clin Risk Manag. 2008 Oct4(5):1079-84.
Kaplan A et al; Medical Issues And The Eating Disorders: The Interface, 2013.
Moudiou T, Galli-Tsinopoulou A, Vamvakoudis E, et al; Resting energy expenditure in cystic fibrosis as an indicator of disease severity. J Cyst Fibros. 2006 Jul 14.
Smyth RL, Rayner O; Oral calorie supplements for cystic fibrosis. Cochrane Database Syst Rev. 2014 Nov 311:CD000406. doi: 10.1002/14651858.CD000406.pub4.
Kobelska-Dubiel N, Klincewicz B, Cichy W; Liver disease in cystic fibrosis. Prz Gastroenterol. 20149(3):136-41. doi: 10.5114/pg.2014.43574. Epub 2014 Jun 26.
Mayer-Hamblett N, Kloster M, Ramsey BW, et al; Incidence and clinical significance of elevated liver function tests in cystic fibrosis clinical trials. Contemp Clin Trials. 2013 Mar34(2):232-8. doi: 10.1016/j.cct.2012.11.005. Epub 2012 Nov 29.
Moran A, Dunitz J, Nathan B, et al; Cystic fibrosis-related diabetes: current trends in prevalence, incidence, and Diabetes Care. 2009 Sep32(9):1626-31. Epub 2009 Jun 19.
Hameed S, Jaffe A, Verge CF; Cystic fibrosis related diabetes (CFRD)--the end stage of progressive insulin deficiency. Pediatr Pulmonol. 2011 Aug46(8):747-60. doi: 10.1002/ppul.21495. Epub 2011 May 27.
Onady GM, Stolfi A; Insulin and oral agents for managing cystic fibrosis-related diabetes. Cochrane Database Syst Rev. 2013 Jul 267:CD004730. doi: 10.1002/14651858.CD004730.pub3.
Goldbeck L, Fidika A, Herle M, et al; Psychological interventions for individuals with cystic fibrosis and their families. Cochrane Database Syst Rev. 2014 Jun 186:CD003148. doi: 10.1002/14651858.CD003148.pub3.
Conwell LS, Chang AB; Bisphosphonates for osteoporosis in people with cystic fibrosis. Cochrane Database Syst Rev. 2014 Mar 143:CD002010. doi: 10.1002/14651858.CD002010.pub4.
O'Sullivan BP, Freedman SD; Cystic fibrosis. Lancet. 2009 May 30373(9678):1891-904. Epub 2009 May 4.
Barr HL, Britton J, Smyth AR, et al; Association between socioeconomic status, sex, and age at death from cystic BMJ. 2011 Aug 23343:d4662. doi: 10.1136/bmj.d4662.
George PM, Banya W, Pareek N, et al; Improved survival at low lung function in cystic fibrosis: cohort study from 1990 BMJ. 2011 Feb 28342:d1008. doi: 10.1136/bmj.d1008.