M.J. Welsh and A.E. Smith, RAC Application 
2.0 BACKGROUND AND RATIONALE 
2.1 Morbidity and Mortality in Cystic Fibrosis 
Cystic fibrosis is the most common lethal genetic disease afflicting the Caucasian 
population (1). Approximately one in every 2,500 infants in the United States is bom with 
the disease. There are approximately 30,000 CF patients in the United States. It is the 
predominant cause of severe chronic lung disease in children and young adults. Although 
improvements have been made over the last 20 years in alleviating certain symptoms of the 
disease and delaying its progress, the underlying disease remains untreated and patients 
have a life expectancy of only 20 to 30 years. Statistics from the U.S. Cystic Fibrosis 
Foundation reveal that with intensive therapy, the prognosis has reached 75% survival to 
late teens, 50% survival to 26 years of age, but survival remains only 40% to the fourth 
decade. Individuals with CF rarely live into the fifth and sixth decades of life. In 1986, the 
United States CF Patient Registry revealed only 20% of patients to be older than 18 years 
of age. 
Disease of the pulmonary airways is the major cause of morbidity and is responsible for 
95% of the mortality (1,2). The first manifestation of lung disease is often a cough, 
followed by progressive dyspnea. Tenacious sputum becomes purulent because of 
colonization with Staphylococcus and then with Pseudomonas. Chronic bronchitis and 
bronchiectasis can be partially treated with current therapy, but the course is punctuated by 
increasingly frequent exacerbations of the pulmonary disease. As the disease progresses, 
the patient's activity is progressively limited. End-stage lung disease is heralded by 
increasing hypoxemia, pulmonary hypertension, and cor pulmonale. 
The upper airways of the nose and sinuses are also involved by CF. Most patients with CF 
develop chronic sinusitis (1,2). Nasal polyps occur in 15-20% of patients and are common 
by the second decade of life. 
Gastrointestinal problems are also frequent in CF (1,2); infants may suffer meconium ileus. 
Exocrine pancreatic insufficiency, which produces symptoms of malabsorption, is present 
in the large majority of patients with CF. Males are almost uniformly infertile and fertility 
is decreased in females. 
2.2 Current Treatment of Cystic Fibrosis 
To date, the primary objectives of treatment for CF have been to control infection, promote 
mucus clearance, and improve nutrition (1). Intensive antibiotic use and a program of 
postural drainage with chest percussion are the mainstays of therapy. However, as the 
disease progresses, frequent hospitalizations are required. Nutritional regimens include 
pancreatic enzymes and fat-soluble vitamins. Bronchodilators are used at times. 
Corticosteroids have been used to reduce inflammation, but they may produce significant 
adverse effects and their benefits are not certain. In extreme cases, lung transplantation is 
sometimes attempted (12). 
Most efforts to develop new therapies for CF have focused on the pulmonary 
complications. Because CF mucus consists of a high concentration of DNA, derived from 
lysed neutrophils, one approach has been to develop recombinant human DNase (13,14). 
Preliminary reports suggest that aerosolized enzyme may be effective in reducing the 
viscosity of mucus. This could be helpful in clearing the airways of obstruction and 
perhaps in reducing infections. In an attempt to limit damage caused by excess of 
neutrophil derived elastase, protease inhibitors have been tested. Alpha- 1 -antitrypsin 
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