subject: Clinical features and diagnosis of cystic fibrosis [print this page] Clinicalexamination of adolescents and adults usually shows finger clubbing secondary to chronic respiratory infection,retarded growth and development, and a hyperinflated chest with coarse crackles and wheezes. Gynaecomastia isoccasionally seen, and there may be hepatosplenomegaly and other signs of chronic liver disease.
The chest X-ray shows hyperinflated lungs and widespreadbronchiectasis (parallel line and ring shadows, with multiple nodular opacities, mainly in the mid and upperzones; the hila are usually prominent). Lung functiontesting shows a progressive obstructive defect. The singlemost important diagnostic test is the sweat sodium, whichis consistently greater than 70mmol/L in children with thedisease and greater than 90mmol/L in affected adults,although the results in adults are less reliable. Sputum bacteriology will often yield S. aureus, and later in lifePs. aeruginosa becomes a major problem.
Haemophilusmay be an important pathogen, and patients occasionallydevelop tuberculosis.Prenatal diagnosis can be achieved by the measurementof elevated levels of enzymes such as alkaline phosphatase in the amniotic fluid or by DNA analysis of chorionic villusbiopsies; these techniques are only of value for 'at-risk'pregnancies. Neonatal screening for immunoreactivetrypsin in the blood is simple and inexpensive.The differential diagnosis includes hypogammaglobulinaemia, immotile cilia syndromes, asthma, coeliac diseaseand Schwachman's syndrome (pancreatic insufficiency,neutropenia, metaphyseal chondrodysplasia, growth retardation and frequent infections).
Management
The outlook for patients with cystic fibrosis has improved,and predicted average survival for children born in the1990s is now 40 years. These improvements have beenachieved by aggressive physiotherapy, antibiotic treatment,pancreatic enzyme supplementation and dietarysupport.
The cornerstone of treatment of respiratory disease isregular chest physiotherapy, particularly postural drainage.In the first year of life prophylactic antistaphylococcal drugs may be helpful. Severe infective exacerbations require intravenous antibiotics, usually antipseudomonalagents (e.g. gentamicin, ceftazidime, piperacillin, ciprofloxacin).As the disease progresses regular nebulized antibioticsare of value. To facilitate home care, some patientswith repeated flare-up of infection have indwelling centralvenous lines and administer their own antibiotics. Bronchodilators,and occasionally oral corticosteroids, may beuseful in patients with airflow obstruction. Pneumothoracesare not uncommon and should be treated conservativelywhenever possible.
Malabsorption is treated by oralpancreatic enzyme supplements. Abdominal emergenciesoccur, including adult meconium ileus equivalent, intussusception,acute pancreatitis and bleeding from oesophagealvarices. Diabetes is common. Adult patients willneed counselling about fertility, as 98% of the males areinfertile (owing to maldevelopment of the vas deferens)and for females pregnancy can be hazardous. Patients andtheir family need constant moral, psychological and practicalsupport. Genetic counselling of the parents of childrenwith cystic fibrosis and of the patients themselves isessential.
Gene therapy
There are now many studies reporting gene therapy incystic fibrosis patients. These have viral or non-viral vectorsto deliver CFTR-cDNA topically to the nose or the lungsby aerosol or by liquid instillation. Although in theory thetransfer of normal CFTR-cDNA into affected CF cells inearly life should cause the production of enough normalCFTR to prevent the clinical manifestations of cystic fibrosis,technical problems with the vectors and the clinicalresponse have meant that gene therapy is not yet curative.
In particular, the target cell type, the target airways (largeor small) and the barrier created by viscous mucus areproving difficult to overcome. Furthermore, it is not clearhow much CFTR mRNA is necessary to get into cells toprevent disease. These topics are still the focus of intensiveresearch and are likely to lead to important therapeutic advances in the relatively near future.
Lung transplantation in cystic fibrosis
Lung transplantation programmes around the world nowincorporate a significant number of patients with cysticfibrosis. Transplantation is reserved for those with the mostadvanced lung disease, and presents special difficulties. Inparticular because of the level of infection present the procedureis often complicated by postoperative sepsis, andthis can be very difficult to manage.
Furthermore, previouspleural disease or tracheostomies can either be contraindicationsor make the surgical techniques difficult.Live related lobar donor transplantation has also been carried out, with mixed success. Patients with cystic fibrosiswho have advanced liver disease have had successfulliver transplantations in recent years.Clearly, however, the best strategies for the treatment of cystic fibrosis and all its complications are preventative,and in the long term it is in this arena that the most successis likely.
Clinical features and diagnosis of cystic fibrosis
