Cystic fibrosis

Contributed by Dr Jim Littlewood OBE, chairman of the Cystic Fibrosis Trust, London

1. Epidemiology and aetiology

Cystic fibrosis (CF) is the most common life-shortening recessively inherited disorder of Caucasian people, affecting one in 2,500 newborn infants. The parents are healthy carriers of one CF gene, as is one in 25 of the general population.

If untreated, signs of severe intestinal malabsorption, failure to thrive and lower respiratory infections, which are slow or fail to clear, are present from an early age.

The faulty CF gene fails to code for cystic fibrosis transmembrane regulator (CFTR), which functions as a chloride channel in many epithelial cells, resulting in reduced chloride secretion and excessive sodium absorption causing reduced airway surface liquid. 

The outlook for children with CF has improved remarkably since Dorothy Andersen’s description in 1938 when most died in infancy from pneumonia and malnutrition. Now half will survive beyond their mid-thirties and infants born now may well have a normal life span.

Presentation
Around 15 per cent of newborn infants with CF present with intestinal obstruction (meconium ileus).

In most infants the abnormal airway secretions soon predispose to chest infections, which are difficult to eradicate and, if not treated early and effectively with antibiotics, usually become chronic, damaging and eventually fatal. Viscid secretions obstruct the pancreatic ducts causing severe malabsorption in most and the bile ducts in some causing liver damage. Men with CF are infertile because of maldevelopment of the vas deferens.

2. Diagnosis 

Measuring the immunoreactive trypsin (IRT) in the Guthrie blood spots and identifying CF mutations in the IRT positive spots is a well-validated method for newborn CF screening.

Neonatal screening was promised for the UK by the government in May 2001, but is still not routine in some parts of England, though all babies are screened in the rest of the UK.

The sweat test to measure excessive salt in the sweat is still the main diagnostic test for CF and is used to exclude the condition in unscreened symptomatic infants and young children with failure to thrive, recurrent chest infections and signs of intestinal malabsorption when CF is suspected.

Once an infant has been identified by neonatal screening, the diagnosis is confirmed at the CF unit with a sweat test, a check on the CF mutations present, some evidence of fat malabsorption (faecal microscopy for fat) and of pancreatic abnormality (pancreatic elastase 1).

Early treatment
Early treatment before malnutrition and chronic chest infections occur will significantly improve the long-term outlook. Early diagnosis following neonatal CF screening is therefore very important.

The future
Neonatal CF screening should be UK-wide by late 2007.

Antenatal screening for CF carrier couples is feasible but precluded by the high cost and lack of counselling facilities at present.

Antenatal diagnosis is possible for women with high-risk pregnancies, but pre-implantation genetic diagnosis may be a more acceptable alternative for some couples.

3. Managing the condition 

Management is the long-term responsibility of the CF specialist and the team at the CF centre. Children may have some hospital care at their local clinic and paediatric CF centre but adults should receive all their hospital care at a specialist adult CF centre.

Following diagnosis and in the later stages of the condition there are important roles for the GP who knows the family . Symptomatic infants and young children with CF may be encountered and require referral for a sweat test.

The GP is likely to be familiar with the viral-type illnesses that are prevalent in the community at any one time and can make an initial assessment of any new symptoms such as rashes, fevers and vomiting in the patient with CF, and treat where appropriate.

The GP should ensure that children with CF are fully immunised and receive an annual influenza vaccine. In the NHS the GP prescribes routine treatment as recommended by the CF centre.

The cost of some preparations (such as rhDNase or tobramycin for inhalation) might cause problems.

Cross-infection with Pseudomonas aeruginosa, Burkholderia cepacia and other organisms may occur between people with CF.

Therefore, in all CF centres and clinics patients are segregated according to their microbiological status and discouraged from mixing socially.

Treatment
Treatment is started with pancreatic enzymes, fat-soluble vitamins, advice from the dietitian and physiotherapist and regular flucloxacillin to prevent staphylococcal infection.

Attendance includes weighing, measuring, obtaining a throat swab for culture and, from the age of five years, respiratory function tests.

Respiratory interventions include physiotherapy, avoiding exposure to viral infections (even colds), early immunisations, regular respiratory cultures to identify potential pathogens, long-term prophylactic anti-staphylococcal flucloxacillin, early resort to an anti-H influenzae antibiotic with colds, with a rapid resort to IV antibiotics if respiratory symptoms are slow to clear.

Home IV antibiotic treatment is widely available. Prompt eradication of early P aeruginosa infection with nebulised colistin and oral ciprofloxacin for a minimum of three weeks will prevent or delay chronic infection — the most important factor determining long-term health and survival.

About 50 per cent of those with CF in the UK are adults. In a recent survey, 28 per cent had diabetes, 23 per cent arthritis, 20 per cent sinusitis, 19 per cent infertility, 14 per cent liver problems and 10 per cent recurrent bowel problems and allergic bronchopulmonary aspergillosis.

Many have chronic Pseudomonas infection and require regular physiotherapy, twice-daily nebulised antibiotics, and periodic courses of IV antibiotics and nebulised rhDNase — an effective mucolytic for the very viscid sputum.

Regular azithromycin has a proven beneficial effect, probably due to its anti-inflammatory action. For those with advanced chest disease (FEV1 <30 per cent predicted) heart–lung or double lung transplantation may be an option. Most patients will tolerate a high-energy diet and normal fat intake, with pancreatic enzymes and fat-soluble vitamins. Some take regular ursodeoxycholic acid for liver involvement.

The future
Since the identification of the CF gene in 1989, there has been much research into gene replacement therapy and pharmacological treatments for the dysfunctional CFTR.

The UK Gene Therapy Consortium is due to start clinical trials of a product it has developed over the past six years.

For infertile men with CF, intracellular sperm injection has allowed some to father children.

Cystic fibrosis month runs through May. For more information see www.cftrust.org.uk

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