CYSTIC FIBROSIS

CYSTIC FIBROSIS

Cystic fibrosis (CF) is an autosomal recessive disorder affecting the exocrine glands, causing abnormal viscosity of secretions. It primarily affects the pulmonary and GI systems. Approximately 4% to 5% of Caucasians are symptomless carriers of the CF gene. Slightly more males than females are affected. Incidence is estimated at approximately 1 in 3,200 live Caucasian births. CF is found in all racial groups.  There are approximately 30,000 people living with CF in the United States, 45% of whom are age 18 or older. Presently the predicted survival age extends to the late 30s, compared with a life expectancy of less than 1 year in the 1950s.

Pathophysiology and Etiology

• CF is caused by a genetic defect in a single gene located on the long arm of chromosome 7 that encodes the cystic fibrosis transmembrane conductance regulator (CFTR).
• The variations in the onset of the disease, symptomatology and clinical presentation within the CF population are attributed to the over 1,000 mutations of the CF gene. CFTR is responsible for the fluid balance across epithelial cells.

Clinical Manifestations

Presentation usually occurs younger than age 6 months but may occur at any age. Signs and symptoms and severity of the disease vary and change over time as the disease progresses.

Respiratory Manifestations

• Recurrent pulmonary infections—H. influenza, S. aureus, P. aeruginosa.
• Cough, dry to productive. Chronic clearing of throat may indicate increased mucus production.
• Wheezing, crackles on auscultation are indicative of respiratory exacerbation.
• Dyspnea.
• Barrel-shaped chest (increased anteroposterior chest diameter).
• Cyanosis.
• Clubbing of fingers and toes.
• Nasal polyps and pansinusitis.
• Progressive chronic obstructive pulmonary disease (COPD). A 10% drop in FEV₁ is a sign of an acute exacerbation or worsening lung disease.
• Mild form of CF—slightly decreased FEV₁ (70% to 90%).
• Moderate CF—FEV₁ of 40% to 69%.
• Severe forms of CF—life-threatening pulmonary disease with FEV₁ of less than 40%.

GI Manifestations

• Meconium ileus found in neonates.
• Failure to thrive and failure to gain weight in the presence of a good appetite.
• Abdominal distention.
• Vomiting, dehydration, and electrolyte imbalance.
• Maldigestion, steatorrhea (fatty stools, loss of fat-soluble vitamins).
• Rectal prolapse.
• Distal intestinal obstructive syndrome.
• Biliary cirrhosis, obstructive jaundice.
• Pancreatitis.

Other Manifestations

• Thin extremities, sallow skin, wasted buttocks.
• Hyperglycemia, glucosuria, polyuria, weight loss.
• Salty taste when parents kiss skin.
• Sterility in males.
• Hypoproteinemia and anemia.
• Bleeding diathesis.
• Hyponatremia and heat prostration.
• Kyphosis.

Diagnostic Evaluation

• Quantitative sweat chloride test; pilocarpine iontophoresis, performed at a CF Foundation accredited center, by skilled personnel. Measures sodium and chloride content in sweat.
• Chloride level greater than 60 mEq/L is virtually diagnostic.
• Chloride of 40 to 60 mEq/L is borderline and should be repeated, followed by genotype for the most frequent CFTR mutations.
• Sodium level greater than 60 mEq/L is diagnostic.
• Measurement of trypsin concentration in duodenal secretions; absence of normal concentration virtually diagnostic.
• Analysis of digestive enzymes (trypsin and chymotrypsin) in stool—reduced, used for initial screening for CF.
• Chest X-ray—may be normal initially; later shows areas of infection, overinflation, bronchial thickening and plugging, atelectasis, fibrosis, and emphysema.
• Sinus radiograph or computed tomography shows mucus plugging.
• Analysis of stool for steatorrhea.
• BMC (Boehringer-Mannheim Corporation) meconium strip test for stool includes lactose and protein content; used for screening.
• Sputum or throat cultures to rule out infection.
• Pulmonary function studies (after age 4).
• Decreased vital capacity and flow rates.
• Increased residual volume or increased total lung capacity.
• Diagnosis made when a positive sweat test is seen in conjunction with one or more of the following:
• Positive family history for CF.
• Typical COPD.
• Documented exocrine pancreatic insufficiency.
• Failure to thrive.
• History of frequent respiratory infections.
• Prenatal diagnostic tests—prenatal genetic screening for families affected with CF:
• Chorionic villus sampling at approximately 12 weeks' gestation.
• Deoxyribonucleic acid (DNA) probes.
• Microvillar enzymes.
• Neonatal screening: immunoreactive trypsinogen (IRT); if elevated, DNA assay for single and multiple CFTR mutations.

Management

Goals of treatment are to prevent and minimize pulmonary complications, ensure adequate nutrition for growth, and assist the family and child to adapt to chronic disease.

Pulmonary Interventions

• Antimicrobial therapy as indicated for pulmonary infection.
• Oral antibiotics may be given prophylactically or when symptomatic.
• I.V. antibiotics are given when the child fails to respond to oral antibiotics; this may be inpatient or at-home therapy.
• Inhaled antibiotics such as tobramycin (Tobi). Colistin (Coly-Mycin) may be used for severe lung disease or colonization of organisms. Recently, some practitioners advocate using nebulized antibiotics earlier in therapy.
• Patients with CF metabolize antibiotics rapidly; drug dosage is higher than normal, monitor for signs of toxicity.
• Bronchodilators to increase the airway size and assist with mucociliary clearance. Many CF patients also have airway hyperreactivity.
• Long-term clinical improvement with inhaled bronchodilators has not been well supported in the literature. Salmeterol, a long-acting bronchodilator, has demonstrated improvements in pulmonary function and is effective in decreasing nocturnal hypoxia.
• Inhaled steroids for treatment of airway hyperreactivity.
• Aerosol, expectorants, and mucolytic agents to decrease viscosity of secretions.
• Recombinate human DNase (Pulmozyme). Administered via nebulizer improves pulmonary function and decreases sputum viscosity and pulmonary exacerbations.
• Hypertonic saline solution 3% to 7%. Improves airway clearance and lung function, although it is not as effective as recombinant human DNase.
• Acetylcysteine solution (Mucomyst) is not recommended due to irritant effect on airways.
• Chest physiotherapy (CPT) for bronchial drainage, especially during acute exacerbations.
• Postural drainage.
• Coughing and deep-breathing exercises, huffing helps move secretions from smaller airways.
• Active cycle of breathing, a new technique, improves lung function without decreasing oxygenation. Consists of breathing control, thoracic expansion, forced expiratory technique, and huffing. An assistant is not required.
• Autogenic drainage—breathing at various lung volumes to move and evacuate mucus. Oxygenation should not be affected during procedure.
• Positive expiratory pressure (PEP) and flutter. PEP airway technique is utilized by those with severe disease. It reduces airway collapse due to bronchiectasis. Available as low pressure PEP, high pressure PEP, and oscillating PEP with a flutter or acapella device.
• High-frequency chest compressions—externally applied device provides oscillation to the chest, resulting in release of mucus from the airway wall.
• Bronchopulmonary lavage—treatment of atelectasis and mucoid impaction using large volumes of saline (used in some institutions in the United States).
• Lobectomy—resection of symptomatic lobar bronchiectasis to retard progression of lesion to total lung involvement.

GI Interventions

• Pancreatic enzyme supplementation is provided with each feeding.
• Favored preparation is pancrelipase (Pancrease).
• Occasionally, antacid is helpful to improve tolerance of enzymes.
• Favorable response to enzymes is based on tolerance of fatty foods, decreased stool frequency, absence of steatorrhea, improved appetite, and lack of abdominal pain.
• Provide a high-energy diet by increasing carbohydrates, protein, and fat (possibly as high as 40%). Increases in dietary intake should consider growth and repair, infection, the work of breathing and energy expenditure for coughing, malabsorption, and physical activity.
• Provide zinc and iron supplements and water-soluble and fat-soluble vitamins.
• Ensure adequate fluid and salt intake.

Controversial and Experimental Treatments

• Heart-lung, double-lung, or single-lung transplantation for end-stage lung disease.
• Liver transplant.
• Gene therapy.

Complications

• Pulmonary infections:
• Most frequently caused by P. aeruginosa, S. aureus, H. influenzae, and Burkholderia cepacia. Pseudomonas is the most difficult organism to treat.
• Bronchiectasis and bronchiolitis.
• Other pulmonary complications—emphysema, atelectasis, pneumothorax, hemoptysis (primarily seen in adolescents), and pulmonary hypertension.
• Biliary cirrhosis, leading to portal hypertension, esophageal varices, and splenomegaly.
• Pancreatic fibrosis with islets of Langerhans involvement, resulting in glucose intolerance, and CF-related diabetes.
• Cor pulmonale.
• Chronic sinusitis.
• Rectal polyps (3 months to 3 years).
• Rectal prolapse.
• Intussusception (younger than 2 years).
• Pancreatitis.
• Hypertrophic pulmonary osteoarthropathy—arthritis, clubbing, periosteitis; the long tubular bones are most commonly involved.
• Bone thinning and demineralization.
• Depression.
• Heat prostration.
• Fibrosis of epididymis and vas deferens in male; aspermia.
• Growth retardation.
• Gastroesophageal reflux.
• Allergic bronchopulmonary aspergillosis.
• Respiratory failure and death.