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Cystic fibrosis (CF) is the most common autosomal recessive life-shortening disease among whites but also affects all races. There are approximately 30,000 individuals in the United States with diagnosed CF. Progress in the understanding of the underlying genetic defect and pathophysiology and the impact of this knowledge on CF care have been rapid over the past 20 years, resulting in remarkable improvements in quality of life and survival. These gains have converted CF from a respiratory and digestive disease of young children to a complex, multisystem disorder extending into adulthood.

CF is caused by mutations in the CF transmembrane conductance regulator (CFTR), a 230-kb gene on chromosome 7 encoding a chloride channel expressed in epithelial cells in the sweat duct, airway, pancreatic duct, intestine, biliary tree, and vas deferens. More than 1000 mutations in CFTR have been described, although far fewer have been clearly identified as causing disease. These mutations can be grouped into six classes based on their function (Plate 4-45). The level of functional CFTR is important in determining the manifestations of CF, and the broad spectrum of disease related to CFTR dysfunction is increasingly being recognized (Plate 4-45). Attempts to predict the severity of lung disease, the major cause of morbidity and mortality in CF, from the CFTR genotype have been unsuccessful. It is likely that environmental factors and modifier genes play important roles in determining the phenotype of patients with CF.

Updated guidelines for the diagnosis of CF have recently been published. Although symptoms suggestive of CF include poor weight gain, steatorrhea, rectal prolapse, chronic cough, and recurrent sinusitis, CF is increasingly diagnosed via prenatal or newborn screening. Until the advent of widespread newborn screening for CF, suspicion for CF arose only from the appearance of symptoms or a family history of the disease. But by 2010, newborn screening for CF will be universal throughout the United States, and most individuals will enter the diagnostic algorithm because of a positive newborn screen result. The primary test for establishing the diagnosis of CF remains the sweat chloride test, which is performed by the pilocarpine iontophoresis method. The identification of two CF disease-causing mutations can also establish the diagnosis.

Manifestations of CF may include chronic sinusitis, recurrent nasal polyposis, progressive obstructive pulmonary disease, exocrine pancreatic insufficiency, biliary disease, CF-related diabetes, and male infertility. Given the chronic, complex, multisystem nature of the illness, patients with CF should be followed in a specialized CF center, such as those accredited in the United States by the Cystic Fibrosis Foundation.

Lung disease is the primary cause of morbidity and mortality in people with CF. It is characterized by a vicious cycle of endobronchial bacterial infection and a vigorous host neutrophilic inflammatory response, resulting in progressive structural damage (bronchiectasis) and obstructive lung disease (see Plate 4-46). The airways of CF patients become infected with a distinctive spectrum of bacterial pathogens, generally acquired in an age-dependent fashion. Common pathogens at an early age include Staphylococcus aureus and Haemophilus influenzae. Later, infection with Pseudomonas aeruginosa becomes increasingly prevalent. At first, P. aeruginosa infection is intermittent and non-mucoid, but it eventually becomes chronic and mucoid in phenotype. Acquisition of P. aeruginosa, particularly mucoid strains, is associated with more rapid clinical deterioration.
Respiratory treatments vary by age and disease severity; guidelines have recently been published. These treatments, although dramatically improving pulmonary outcomes over the past 2 decades, also represent the greatest challenge to patients and families. The inhaled therapies and airway clearance can take more than 1 hour each day and can cause financial hardships. Chronic treatments may include airway clearance techniques; mucolytics such as inhaled rhDNase and hypertonic saline; and in patients chronically infected with P. aeruginosa, oral macrolides and alternate-month inhaled antibiotics.
Individuals with CF intermittently experience episodes of increased cough, increased sputum production, and decline in lung function, often in conjunction with anorexia and fatigue, termed a pulmonary exacerbation. Milder exacerbations are typically treated with oral or inhaled antibiotics coupled with increased airway clearance. Severe exacerbations or those that fail to resolve with outpatient therapy require treatment with intravenous antibiotics, generally in the inpatient setting. In an effort to slow or avoid the decline in lung function associated with chronic Pseudomonas infection, first acquisition of Pseudomonas spp. is treated with an eradication protocol, which may include oral, inhaled, or intravenous antibiotics, often in combination.
Complications include hemoptysis and pneumothoraces. Bilateral lung transplantation is an option for some CF patients with end-stage lung disease.

Approximately 20% of infants with CF present acute intestinal obstruction caused by meconium ileus in the neonatal period. Exocrine pancreatic insufficiency occurs in approximately 90% of individuals affected with CF. Patients with two severe CFTR mutations (class 1, 2, or 3) present with pancreatic insufficiency, and those with one or more mild mutations (class 4 or 5) may be pancreatic sufficient. Pancreatic insufficiency places CF patients at risk for fat malabsorption, suboptimal nutrition, and inadequate circulating levels of fat-soluble vitamins. CF patients with pancreatic insufficiency are treated with a high-fat, high-calorie diet and pancreatic enzyme replacement therapy in the form of capsules taken with each meal. Patients with pancreatic sufficiency are at increased risk of acute or chronic pancreatitis.
Some level of liver disease is common in CF patients, with the prevalence increasing with advancing age. Abnormalities may include elevated transaminases, hepatosteatosis, or biliary tract disease. Cholelithiasis is also common. A small number of patients develop frank biliary cirrhosis with portal hypertension. Management of CF liver disease often includes ursodeoxycholic acid.

The prevalence of CF-related diabetes also increases with advancing age. The prevalence is 9% at ages 5 to 9 years, increasing to 43% for age older than 30 years. CF-related diabetes is a risk factor for more accelerated decline in lung function and higher mortality. There- fore, routine screening is recommended. Treatment generally involves maintenance of a high-fat, high-calorie diet plus insulin therapy.
Osteopenia is also an increasingly recognized com- plication of CF. The cause is likely related to poor nutritional status, malabsorption of vitamins K and D, delayed pubertal maturation, steroid exposure, inactivity, and chronic pulmonary inflammation. Routine screening is recommended, and prevention via aggressive nutritional interventions, fat-soluble vitamins, and maximization of pulmonary health is critical.

At least 98% of men with CF are infertile because of absence or atresia of the vas deferens and absent or dilated seminal vesicles. Men with CF can become fathers with artificial insemination procedures. Female reproduction is normal, and an increasing number of women with CF are becoming mothers.

Survival of patients with CF has made continuous, sustained improvements over the past 50 years, with median survival in the United States improving from 8 years in 1969 to more than 37 years today (see Plate 4-47). Female survival has been lower than male, but this “gender gap” appears to be closing. Potential contributors to improved survival include CF center care, aggressive nutritional support, and the introduction of new pulmonary therapies. Major quality improvement initiatives, the widespread uptake of newborn screening, and new therapies aimed at restoring CFTR function and combating chronic inflammation are sure to result in continued improvement in quality of life and survival for individuals with CF.