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.
Cystic fibrosis (CF) is an autosomal recessive disease caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene, on chromosome 7. There are at least 1,500 mutations in the CFTR gene. Different mutations result in different phenotypes. Some mutations result in milder forms of the disease. 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.
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Cystic fibrosis (CF) is the most common inherited disease in white populations.
- Prevalence is 1 in 2,500 newborn, with calculated carrier frequency of 1 in 25. Over 9,000 people currently have CF in the UK.
- The only risk factor is a family history of the condition.
The abnormality in the cystic fibrosis transmembrane conductance regulator (CFTR) explains the pathology of cystic fibrosis.
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 produces 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, cystic fibrosis (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 cystic fibrosis transmembrane conductance regulator (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 though.
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 cystic fibrosis transmembrane conductance regulator (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.
Most patients' care is co-ordinated by a cystic fibrosis (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 Staphylococcus aureus (MRSA) is a growing problem.
The following interventions are commonly used in 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.
- 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 (usually oral ciprofloxacin) antibiotics.
- Antibiotic choice for infective exacerbations will depend on the organism.
- Infection with less common organisms requires specialist microbiological advice.
- 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.
- Hypertonic saline by a nebuliser is often given.
- 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.
- 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.
- Inhaled tobramycin may also improve lung function and reduce the risk of exacerbations in patients with CF.
- Inhaled mannitol is sometimes used to increase mucociliary clearance in CF.
- There is no evidence supporting a role for corticosteroids except in treating allergic bronchopulmonary aspergillosis.
- 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, ≥50% of CF patients on the list never receive a transplant.
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.
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% of CF cases.
- Commonly, liver function tests are abnormal - but only significant if >4 x limit. Usually seen as hepatosplenomegaly.
- 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.
- There is insufficient evidence to evaluate drug therapy for 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.
- There is a 1 in 2 risk of offspring being affected without screening.
Women are generally of normal fertility, but need genetic counselling. There is an inherent risk to pregnancy with severe lung disease (FEV1 <30% predicted).
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.
Particularly stressful times include diagnosis, adolescence and end of life. Seeking advice and support from clinical psychologists with experience of the disease is recommended.
There is an increased risk of osteoporosis in patients with CF. Around 20% 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. 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 past two decades is largely the result of centralisation of care at cystic fibrosis (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 cystic fibrosis transmembrane conductance regulator (CFTR) mutations. Gene therapy should be possible to treat an autosomal recessive disease such as cystic fibrosis (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 nonviral vectors.
Further reading & references
- Cystic Fibrosis; CF, Online Mendelian Inheritance in Man (OMIM)
- Davies JC, Alton EW, Bush A; Cystic fibrosis. BMJ. 2007 Dec 15;335(7632):1255-9.
- Ratjen F, Doring G; Cystic fibrosis. Lancet. 2003 Feb 22;361(9358):681-9.
- Wicks E; Cystic fibrosis. BMJ. 2007 Jun 16;334(7606):1270-1.
- Lowton K, Ballard KD; Adult cystic fibrosis patients' experiences of primary care consultations: a qualitative study. Br J Gen Pract. 2006 Jul;56(528):518-25.
- Halfhide C, Evans HJ, Couriel J; Inhaled bronchodilators for cystic fibrosis. Cochrane Database Syst Rev. 2005 Oct 19;(4):CD003428.
- Jones AP, Wallis C; Dornase alfa for cystic fibrosis. Cochrane Database Syst Rev. 2010 Mar 17;(3):CD001127.
- Lands LC, Stanojevic S; Oral non-steroidal anti-inflammatory drug therapy for cystic fibrosis. Cochrane Database Syst Rev. 2007 Oct 17;(4):CD001505.
- Southern KW, Barker PM, Solis-Moya A, et al; Macrolide antibiotics for cystic fibrosis. Cochrane Database Syst Rev. 2011 Dec 7;12:CD002203.
- Ryan G, Singh M, Dwan K; Inhaled antibiotics for long-term therapy in cystic fibrosis. Cochrane Database Syst Rev. 2011 Mar 16;(3):CD001021.
- Jelalian E, Stark LJ, Reynolds L, et al; Nutrition intervention for weight gain in cystic fibrosis: a meta analysis. J Pediatr. 1998 Mar;132(3 Pt 1):486-92.
- 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 R, Walters S; Oral calorie supplements for cystic fibrosis. Cochrane Database Syst Rev. 2007 Jan 24;(1):CD000406.
- Moran A, Dunitz J, Nathan B, et al; Cystic fibrosis-related diabetes: current trends in prevalence, incidence, and Diabetes Care. 2009 Sep;32(9):1626-31. Epub 2009 Jun 19.
- Onady GM, Stolfi A; Insulin and oral agents for managing cystic fibrosis-related diabetes. Cochrane Database Syst Rev. 2005 Jul 20;(3):CD004730.
- Glasscoe CA, Quittner AL. Psychological interventions for cystic fibrosis. Cochrane Database Syst Rev 2003;(3):CD003148.
- O'Sullivan BP, Freedman SD; O'Sullivan BP, Freedman SD; Cystic fibrosis. Lancet. 2009 May 30;373(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 23;343: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 28;342:d1008. doi: 10.1136/bmj.d1008.
|Original Author: Dr Hayley Willacy||Current Version: Dr Louise Newson||Peer Reviewer: Dr Helen Huins|
|Last Checked: 14/03/2012||Document ID: 1293 Version: 24||© EMIS|
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