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At the heart of general practice since 1960

November 2007:Managing adults with cystic fibrosis

What systems are affected in patients with cystic fibrosis?

How are complications minimised?

Why are patients now living longer?

What systems are affected in patients with cystic fibrosis?

How are complications minimised?

Why are patients now living longer?

Cystic fibrosis (CF) is becoming a chronic disease of adults rather than a fatal disease of childhood. One in 2,500 newborn babies are affected by CF, giving a UK population of around 7,000 patients. Median survival is currently 34 years but has been increasing every year, with recent data suggesting that someone born with CF in 2000 can be expected to live into their fifties or sixties.1 More than half of the 6,000 patients registered on the UK CF Database in 2003 were adults, and more than 50% of these patients were in full-time employment or higher education.2

These improvements in outlook have not come about through the introduction of gene therapy, which is still awaited, but with the application of a multidisciplinary approach to care. Patients are managed by a multidisciplinary team, including a specialist CF respiratory physician and expert physiotherapists, nurses, pharmacists, dietitians, psychologists and social workers. Parents, and then the patient, work in partnership with the CF team to treat each manifestation of the disease at each stage of life in order to prevent progressive loss of lung function and death.

Pathophysiology

Lung disease is the main cause of morbidity and mortality in CF, with 98% of deaths related to respiratory disease.

Understanding of disease mechanisms has helped the development of successful therapeutic strategies. CF is inherited in an autosomal recessive fashion and is caused by mutations in the CF gene, which encodes a protein, cystic fibrosis transmembrane regulator (CFTR), responsible for regulation of sodium chloride and water secretion across secretory epithelia. CFTR malfunction results in dehydrated secretions. Cystic fibrosis is therefore a multisystem disorder causing ‘tube blockage' as a result of inspissated mucus in affected organs. In the lungs, inspissated mucus causes airway obstruction associated with inflammation and infection, leading to airway wall damage and progressive bronchiectasis (see figure 1, attached).

Current therapies target the downstream effects of the abnormalities of mucus plugging, airway infection and inflammation.

For example, rhDNase, a nebulised drug that dissolves viscous DNA left by dead neutrophils as they fail to clear an infection, has been shown to improve pulmonary function and reduce pulmonary exacerbations.3

Recent analysis of registry data suggests that long-term use of rhDNase is associated with reductions in long-term decline of lung function. Furthermore, early intervention is associated with less frequent positive cultures for respiratory pathogens4 and potential prevention of airway wall damage. The majority of CF patients should now be receiving this medication. Treatment is started at a specialist centre outpatient clinic to assess response and safety (as a small number of patients with CF may develop bronchoconstriction on administration of the drug).

Currently there are therapies undergoing clinical trials that alter ion transport across the respiratory epithelium.

Infection

Exacerbations

In children with CF, Staphylococcus aureus is the most common infecting organism, with Haemophilus influenzae causing some exacerbations. However, in adults the most common pathogen is Pseudomonas aeruginosa. Sputum cultures, taken on a regular basis when the patient is well and when symptoms of an exacerbation occur, are critical in planning maintenance and exacerbation therapies.

Pseudomonas aeruginosa can be eradicated when first isolated with a combination of oral ciprofloxacin and nebulised colistin. The introduction of this approach, combined with strict infection control guidelines at CF centres, has been associated with increasing numbers of patients with CF reaching adulthood without chronic Pseudomonas infection.

Once a patient has developed chronic infection with Pseudomonas aeruginosa, treatment with daily nebulised antipseudomonal antibiotics is recommended to prevent decline in lung function and pulmonary exacerbations.5 This treatment is prescribed by the patient's GP.

An exacerbation in an adult with CF presents with an increase in pulmonary symptoms, including cough and sputum production. Many young adults will not have any chest signs and the absence of crackles does not reflect a lack of requirement for antibiotics. It is critically important that young adults with CF have ready access to appropriate antibiotic therapy for exacerbations.

Spirometry is a key indicator in deciding treatment requirements. An exacerbation of infection is associated with a significant fall in FEV1. Adults are encouraged to note their best FEV1 reading and the trend in their lung function so that they can become expert patients and make informed decisions about interventions.

Antibiotic therapy is targeted against the key pathogens that infect the airway in patients with CF. Pulmonary exacerbations of chronic Pseudomonas infection can be treated with oral ciprofloxacin if symptoms are mild but otherwise require therapy with two iv antipseudomonal antibiotics, usually an aminoglycoside and a beta-lactam. Such treatment does not necessarily require hospital admission, as all CF centres support home iv therapies.

Azithromycin

The use of long-term maintenance therapy with azithromycin in a three times weekly or alternate day regimen is supported by evidence generated by recent clinical trials, showing improvement in lung function and reduction in pulmonary exacerbations independent of the pulmonary pathogen.6-8 Azithromycin is not being used as an antimicrobial in this context, but appears to have an immunomodulatory role and an ability to disrupt Pseudomonas biofilm growth in the lung. Treatment is long term and is continued alongside additional therapies for exacerbations.

Non-pulmonary disease

Pancreatic enzyme replacement therapy

In patients with CF, CFTR can be found in any secretory epithelia. The pancreatic ducts can become obstructed in utero leading to exocrine pancreatic failure with symptoms of bloating and steatorrhoea, which present as soon as feeding starts.

If untreated, such malabsorption would result in severe malnutrition. However, the introduction of effective pancreatic replacement therapy has revolutionised the nutritional management of people with CF and as a result has made a major contribution to improved survival.

A CF specialist dietitian will ensure that the dose of pancreatic enzyme replacement therapy is correctly balanced with the optimal nutritional intake. Doses of pancreatin are individualised and the patient is taught to vary enzyme dose according to the fat content of each meal.

Adequacy of replacement therapy is assessed by stool fat microscopy at the CF centre and by monitoring height and weight in children and BMI in adults. GPs can make a real difference to the lives of patients with CF and their families by being aware of the requirements for varied doses of enzyme therapy, for patient use at home and school or work, and ensuring that such supplies are always available.

Lack of adherence to pancreatic enzyme replacement therapy can result in distal intestinal obstruction, presenting with abdominal pain and distension. This requires specialist CF centre management with intestinal lavage and patients should not be referred directly to general surgeons.

CF-related diabetes

The increase in the adult population with CF has resulted in an increased prevalence of CF-related diabetes.9

There is clear evidence that CF-related diabetes is associated with a more rapid decline in lung function and increased mortality.10 It is therefore recommended that teenagers and adults with CF undergo an annual glucose tolerance test so that diabetes is detected early to allow early intervention.

CF-related diabetes differs from both type 1 and type 2 diabetes and requires a coordinated approach from the CF team and a diabetologist with expertise in CF. As maintenance of good nutritional status and tight control of blood sugar level are required, patients with CF-related diabetes are in general encouraged to continue on their usual high-fat diet without limitation of carbohydrates and to match this with appropriate amounts of insulin.

Adults with CF can develop the microvascular complications of diabetes and annual screening with retinal photography, checks for renal disease and neuropathy are mandatory. These checks can be efficiently and effectively taken on in partnership with the patient's GP.

CF and reproduction

The absence or blockage of the vas deferens results in infertility in 98% of men with CF. Thus, although the testes may contain sperm, the ejaculate has no sperm present. Adult men with CF wishing to father children can be referred for sperm aspiration and assessment with their partner for intracytoplasmic sperm injection.

Women with CF have been reported to have thick cervical mucus, which may reduce sperm penetration, but clinically this has not proved to be a significant problem. Thus it is very important that adolescent and adult women with CF receive appropriate advice about contraception.

Women with CF can have successful pregnancies, but these must be planned carefully to avoid problems in the fetus related to treatment and problems with the mother related to inadequate lung function. Pregnancy can be a life-shortening event in some patients and the CF physician should make this clear to both the patient and her partner when discussing planning a pregnancy.

It is critically important that partners are involved in discussions. If the partner is screened negative for carriage of a CF mutation on standard testing, then the risk of having a baby with CF is less than one in 330. However, the baby will be a CF carrier, a condition that is asymptomatic. If the partner is screened positive as a CF carrier then the chance of having a baby with CF is one in two.

Conclusion

CF has become a chronic disease of adults and the discussion of fertility and pregnancy highlights the need for a robust network of specialists, coordinated by the CF physician.

It is important that GPs are closely involved to ensure a holistic approach to patients with CF and their families. Neonatal screening has recently been introduced nationally, and it is vital that every CF patient has access to specialist care to prevent lung damage and ensure good outcomes in adulthood.11

Key points Figure 1: CF Pathophysiology Useful information

The Cystic Fibrosis Trust provides information and a helpline for patients with cystic fibrosis
tel: 0845 859 1000
www.cftrust.org.uk

Author

Dr Diana Bilton
BSc MD FRCP
consultant in respiratory medicine and Director, Adult Cystic Fibrosis Centre, Papworth Hospital NHS Foundation Trust, Cambridge

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