Cystic fibrosis (CF) is a multiorgan disease best managed in a multidisciplinary setting in conjunction with a specialist centre for cystic fibrosis, with treatment tailored to the individual.

Conventional treatment has improved greatly over the past few decades; however, current treatments at best slow the decline in lung function. Newer approaches such as gene and small molecule-based treatments may have more potential to halt disease progression.

Genetics

Cystic fibrosis (CF) is an autosomal recessive disease caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene, on chromosome 7.¹
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.

Epidemiology

Cystic fibrosis (CF) is the most common inherited disease in white populations.²

• Prevalence is 1 in 2,500 newborn, with calculated carrier frequency of 1 in 25.³ Over 7,000 people currently have CF in the United Kingdom.
• The only risk factor is a family history of the condition.

Pathogenesis

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.

Pancreatic insufficiency

Production of pancreatic enzymes is normal but defects in ion transport produce relative dehydration of pancreatic secretions causing their stagnation in the pancreatic ducts.

Biliary disease

Defective ion transfer across bile duct causes reduced movement of water in the lumen so that bile becomes concentrated, causing plugging and local damage.

Gastrointestinal disease

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.

Respiratory disease

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.

Presentation

• Because normal digestive function is possible with <5% pancreatic function, cystic fibrosis can present at any age.
• The most common presentation is with respiratory problems usually recurrent lower respiratory tract infection (LRTI) with chronic sputum production.

Presentation varies with age.

Signs

These include:

• Finger clubbing.
• Cough with purulent sputum.
• Crackles.
• Wheezes (mainly in the upper lobes).
• Forced expiratory volume in one second (FEV1) shows obstruction.

Investigations

• Sweat testing confirms the diagnosis - chloride concentration >60 mmol/L with sodium concentration lower than that of chloride.
• Sinus X-rays - opacification of the sinuses is present in almost all patients with cystic fibrosis (CF).
• CXR.
• 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.
• Genotyping.
• Semen analysis.

Management

Most patients' care is coordinated by a cystic fibrosis (CF) tertiary centre.² However, the links to local care are highly valued.⁴ CF patients perceive a satisfactory doctor-patient relationship to be influenced by three factors:⁵

• 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.

A doctor-patient relationship based on trust and understanding is seen as desirable, but requires that these factors be addressed both by the GP and the patient.

Respiratory problems

Most of the morbidity and mortality associated with CF is caused by respiratory disease where chronic infection and inflammation lead to bronchiectasis, progressive air flow obstruction, cor pulmonale and finally death.
Management aims will alter depending on the stage of disease:

• 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. The use of a positive expiratory pressure mask during physiotherapy produces a significantly greater improvement in lung function.⁶
  • Avoid cross infection between patients, especially patients sharing physiotherapy.
  • Pre-colonisation pseudomonal eradication protocols include both topical (nebulised) and systemic (usually oral ciprofloxacin) antibiotics. Eradication is achieved in 80-90%, but there is uncertainty regarding the long-term benefit.⁷
• If the patient is chronically infected with, for example, P. aeruginosa confirmed by sputum culture, they are in the intermediate stage. The aim should be to suppress the bacterial load and limit the inflammatory response.
  • Antibiotic choice for infective exacerbations will depend on the organism (pseudomonads require nebulised tobramycin or colomycin); new, faster nebuliser devices (such as eFlow® and I-neb®) are available. There is no consensus advising when treatment should be started.
  • Infection with less common organisms requires specialist microbiological advice.
  • Reduce inflammation with ibuprofen or macrolide antibiotics (azithromycin). There is good evidence of short-term/medium-term benefit, but mechanism of action is uncertain. Anti-inflammatory properties are thought likely.
  • There is no evidence supporting a role for corticosteroids except in treating allergic bronchopulmonary aspergillosis.²
• In the end stage, management focuses on the common complications, which include haemoptysis, pneumothorax and respiratory failure.
  • Bronchial artery embolisation (rarely lobectomy) may be used to prevent bleeding which may be fatal.
  • Pneumothoraces are drained. Pleurodesis is performed if persistent or recurrent; however, this may affect suitability for transplantation in the future.
  • 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.
  • Noninvasive ventilatory support may help keep patients alive until transplant but intubation and conventional ventilation are not recommended.
  • Where transplant is undertaken, there is 70% survival at 1 year, and 50% at 5 years.⁸

Compounds called inbiotics, e.g. tegrins (a porcine polypeptide), have antibacterial properties and are being studied in paediatric infections; and Pulmozyme® (recombinant DNAase) may help with expectorating thick mucus and is currently being investigated.

Inhaled hypertonic saline represents an exciting change to the notion of CF care that treats only symptoms to one that corrects the underlying defect. By acting as a hyperosmolar agent, hypertonic saline draws water into the airways even when cystic fibrosis transmembrane conductance regulator (CFTR) dysfunction is present.⁹ Rehydration of the periciliary layer then allows improved mucociliary clearance.

Nasal polyps

50% of adults with CF have nasal polyps. Treat with nasal steroids initially; if this fails, polypectomy (50% require repeat within 2 years).

Pancreatic insufficiency

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.

• All patients take enteric-coated enzyme preparations before meals with dose adjusted to achieve normal stools. Drugs may be needed to reduce acid secretion, as well as vitamin supplements for vitamins A, D and E.
• High calorie intake (130% normal) is usually required.¹⁰
  • Comparing actual resting energy expenditure (REE) to predicted REE is an objective indicator of disease severity and progression as well as energy requirements.¹¹
  • 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, current practice is to opt for enteral feeding via gastrostomy.¹⁰

Distal intestine obstruction syndrome

A loaded colon and constipation are common and normally respond to enzyme supplements, and high fluid and fibre intake.

• Patients may need lactulose occasionally.
• Where patients present with chronic intermittent pain or complete obstruction, exclude appendicitis and treat with balanced intestinal lavage solution by nasogastric tube.

Liver disease

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.

• The 1-year survival rate after transplantation in CF patients is approximately 80%, with beneficial effects on lung function, nutritional status, body composition and quality of life in most cases.¹²

Diabetes and glucose intolerance

This is rare under 10 years age, but affects 14% by age 15 and >65% at age 25, by which time 32% are diabetic.

• Screening is usually performed as part of outpatient clinic care - as HBA1c or random/fasting blood sugar levels.
• Insulin replacement is usually required with the dose adjusted to match high dietary intake.
• The general condition of the patient usually improves with diabetic control, and long-term adverse effects of diabetes are rarely seen.

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 50 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).

Psychological problems

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.¹³

Prognosis

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 past decade.⁹
• Estimated survival for a child born now is 40-50 years.³

The future

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.⁹ 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.

Document references

1. Cystic Fibrosis, Online Mendelian Inheritance in Man (OMIM)
2. Davies JC, Alton EW, Bush A; Cystic fibrosis. BMJ. 2007 Dec 15;335(7632):1255-9.
3. Ratjen F, Doring G; Cystic fibrosis. Lancet. 2003 Feb 22;361(9358):681-9. [abstract]
4. Wicks E; Cystic fibrosis. BMJ. 2007 Jun 16;334(7606):1270-1.
5. 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. [abstract]
6. Thomas J, Cook DJ, Brooks D; Chest physical therapy management of patients with cystic fibrosis. A meta-analysis. Am J Respir Crit Care Med. 1995 Mar;151(3 Pt 1):846-50. [abstract]
7. Wood DM, Smyth AR; Antibiotic strategies for eradicating Pseudomonas aeruginosa in people with Cochrane Database Syst Rev. 2006 Jan 25;(1):CD004197. [abstract]
8. Huddleston CB; Pediatric lung transplantation.; Semin Pediatr Surg. 2006 Aug;15(3):199-207. [abstract]
9. O'Sullivan BP, Freedman SD; Cystic fibrosis. Lancet. 2009 May 30;373(9678):1891-904. Epub 2009 May 4. [abstract]
10. 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. [abstract]
11. 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. [abstract]
12. Colombo C, Russo MC, Zazzeron L, et al; Liver disease in cystic fibrosis. J Pediatr Gastroenterol Nutr. 2006 Jul;43(1 Suppl):S49-55. [abstract]
13. Glasscoe CA, Quittner AL. Psychological interventions for cystic fibrosis. Cochrane Database Syst Rev 2003;(3):CD003148.

Internet and further reading

• Cystic Fibrosis Trust
• Cystic fibrosis. Cystic fibrosis is the most common inherited disorder in the UK. It affects more than 7,500 babies, children and young adults. Dr Alan Day explains how the disorder is treated. A short video from NHS Choices. (October 2007)
• Double lung transplant: Jon's story. Jon was diagnosed with cystic fibrosis as a baby and put on a lung transplant list aged 11. He talks about life before, during and after his transplant. A short video from NHS Choices. (October 2009)
• Sharma GD; Cystic Fibrosis, eMedicine, March 2010

Acknowledgements