Cystic Fibrosis

Douglas J. Conrad

Cystic fibrosis (CF) is a systemic disease characterized by acute and chronic sinusitis, progressive bronchiectasis, and pancreatic malabsorption. In the past, patients with CF rarely survived through childhood and were cared for almost exclusively by pediatricians. However, aggressive treatment and newer therapies have dramatically improved prognosis: The predicted median age of survival of CF patients currently is approximately 38 years in North America. Mild or atypical forms of CF are diagnosed in adults because of recent advances in diagnostic technology. For these reasons, primary care providers and adult pulmonologists diagnose and manage CF patients more frequently now than in previous years.

ETIOLOGY AND PATHOPHYSIOLOGY

The CF gene and the most common mutations associated with the disease were identified in 1989. These data characterized the CF gene product, a protein termed the cystic fibrosis transmembrane conductance regulator (CFTR). CF is inherited as an autosomal recessive. Mutations in the CFTR gene are common in the general population (1:29 in North American Caucasians), but the incidence varies significantly in different ethnic populations. Carriers of a single mutated CFTR allele are minimally symptomatic but may have an increased incidence of pancreatitis and allergic rhinitis. The life expectancy of carriers with CFTR mutations is normal.

The CFTR protein is located primarily on the apical membranes of epithelial cells of the respiratory, hepatobiliary, and pancreatic tracts, as well as in the crypts of the large intestine and sweat gland ducts. It forms a large, regulated pore in the apical cell membrane, which functions as a chloride channel but also transports other anions including bicarbonate. Dysfunction of CFTR-dependent ion transport is believed to be responsible for the pulmonary manifestations of CF. The “hydration hypothesis” states that ion transport by CFTR in airway epithelial cells is critical for maintaining hydration and normal function of the airway lining fluid, including the secreted mucus. When these processes are disturbed, the mucociliary clearance mechanism is diminished and bacteria form a chronic polymicrobial biofilm, which elicits a strong innate immune response. Neutrophil proteases stimulate submucosal gland hypertrophy and secretion and eventually cause a breakdown of the airway wall support leading to bronchiectasis. In addition, the neutrophils leave large quantities of cellular DNA, dramatically increasing airway secretion viscosity and further impairing airway clearance. Respiratory failure occurs as a result of a self-perpetuating cycle of inflammation and decreased airway clearance. The bronchiectasis is progressive and leads to respiratory failure in 80% of patients with CF.

Additional studies indicate that the pathophysiology of CF in the gastrointestinal tract and pulmonary systems also involves bicarbonate transport. In these studies, bicarbonate transport is critical for the deployment of mucus over these epithelia. Mutations in CFTR lead to abnormal mucus deployment, mucus plugging, and eventually, end organ dysfunction in the pancreatic and hepatobiliary ducts and intestinal obstruction in the lower gastrointestinal tract.

CLINICAL PRESENTATION

Patients with CF present with a wide variety of respiratory and gastrointestinal complaints that are typically evident in childhood. The more common manifestations include nasal polyps; sinusitis; bronchospasm; recurrent bronchitis or pneumonia; airway colonization with Staphylococcus aureus, Haemophilus influenza, or Pseudomonas aeruginosa; steatorrhea; pancreatic malabsorption; meconium ileus; failure to thrive; rectal prolapse; distal intestinal obstructive syndrome; and hepatic cirrhosis with portal hypertension. Undiagnosed adults frequently present with recurrent bronchitis (in a nonsmoker), asthma associated with the radiographic evidence of diffuse bronchiectasis, chronic sinusitis, allergic bronchopulmonary aspergillosis (ABPA), airway bacterial colonization with atypical mycobacteria or mucoid P. aeruginosa, cirrhosis, idiopathic pancreatitis, or male infertility.

The physical examination is nonspecific but includes findings consisted with chronic sinusitis and obstructive lung disease. Chest examination reveals an increased chest anteroposterior diameter, with decreased diaphragmatic excursion. Diffuse rales and rhonchi are common in most patients and prominent in the apices. Breath sounds are occasionally normal in patients with mild disease. Digital clubbing is frequent. Most patients have pancreatic insufficiency and, thus, have some degree of protein–calorie malnutrition.

Taken individually, the findings on history and physical examination are nonspecific; however, the particular combination of sinusitis, diffuse bronchiectasis, pancreatic malabsorption with malnutrition, obstructive colonopathy, and male infertility is very specific for CF. Although primary ciliary dysfunction and other immunoglobulin deficiencies syndromes mimic some of the pathophysiologic consequences, they are not usually associated with gastrointestinal symptoms. More extensive use of genetic testing has identified patients with milder disease.

DIAGNOSTIC LABORATORY CONFIRMATION

A diagnosis of CF is made after a confirming laboratory study performed in patients with a consistent clinical picture. The sweat chloride test remains the standard in the laboratory confirmation of CF. This test should be performed by experienced laboratory personnel in accredited labs. Pilocarpine iontophoresis is used to stimulate secretion of sweat, which is collected, weighed, and analyzed for its chloride and sodium concentrations. A chloride concentration greater than 60 mEq/L is diagnostic of CF, with most positive tests falling in the 90 to 110 mEq/L range. All positive or indeterminate results (values between 40 and 60 mEq/L) should be repeated at least once. Since the identification of the gene for CF in 1989, more than 1,500 disease-causing mutations have been identified. Several commercial laboratories now offer complete sequencing of the CFTR gene. Combined CFTR sequencing and sweat chloride testing may be particularly helpful in evaluating patients with atypical presentations.

MANAGEMENT

Management of CF is focused on: (1) maintaining optimal nutritional status, (2) promoting airway clearance of inflammatory cells, (3) decreasing bacterial colonization, and (4) minimizing the impact of respiratory and gastrointestinal complications, particularly pulmonary exacerbations.

Management of progressive, chronic bronchiectasis focuses on decreasing the frequency of pulmonary exacerbations by diminishing airway inflammation and promoting airway clearance. Antibiotics are used to decrease the level of bacterial colonization. Although chronic antibiotic suppressive therapy with anti-staphylococcal antibiotics was demonstrated to be not tremendously useful, this practice is being reconsidered in the context of dramatic increase in methicillin-resistant S. aureus

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