Advances in the Management of Cystic Fibrosis

US Pharm. 2007:32(7):HS-5-HS-16.

Cystic fibrosis (CF) is a chronic genetic disease that affects multiple bodily systems, predominantly the lungs and gastrointestinal (GI) tract. In the United States, approximately 30,000 children and adults have CF, and about 1 in 3,500 infants is born with CF each year.¹ CF occurs most commonly among whites. Great advances in CF management have occurred in recent years, extending the predicted survival in 2006 to 37 years.² This improved prognosis is largely due to the newer pulmonary treatments available and to the focus on better nutrition.

An organization known as the CF Foundation (www.cff.org) is ultimately responsible for improving the quality of life for patients with CF through support of innovative research and comprehensive care. Maintaining a national patient registry, accrediting CF care centers, and developing clinical practice guidelines are some ways the CF Foundation aids in CF management. The CF Foundation's slogan, "Adding tomorrows every day," provides a clear understanding of the organization's mission in furthering CF care.

CF is caused by a chromosomal defect that results in a mutation of the CF transmembrane conductance regulator (CFTR) gene. CFTR regulates chloride permeability and sodium transport, leading to obstruction of the exocrine glands by thick, viscous secretions.³ CF is usually diagnosed in infancy by the presence of clinical manifestations and an elevated chloride concentration in induced sweat.⁴ Patients with CF experience a variety of symptoms, including persistent cough, frequent lung infections, failure to thrive, malnutrition, and frequent greasy, bulky stools.

Effective management of CF requires great commitment on the part of the CF health care team, which largely includes the patient and family. Recommendations for preventive and maintenance care for patients with CF have been developed.⁵ Quarterly outpatient visits consisting of a comprehensive patient history and physical examination of respiratory, nutritional, and GI manifestations of CF, along with patient education, are suggested. Recommendations for routine and annual monitoring of many laboratory values and imaging procedures are also included in the guidelines. Therapeutic interventions for outpatient (and inpatient) CF management are discussed in the following sections.

PULMONARY MANAGEMENT
In past years, a trend in the measurement of lung function (forced expiratory volume in one second [FEV₁]) demonstrated major improvements, with an increase in the number of patients with mild lung disease and a decrease in prevalence of severe lung disease.¹ Again, this improvement is a result of the newer CF treatments available for respiratory management.

The main contributors to a decline in respiratory function in CF include airway obstruction by mucus, pulmonary inflammation, and infection with various organisms. Cough, sputum production, chest pain, shortness of breath, and sinus congestion are the common pulmonary complaints for patients with CF. Possible respiratory complications include infectious exacerbations, pneumothorax, hemoptysis, and eventually respiratory failure.

Airway Clearance
Along with drug therapies and nutrition, airway clearance techniques (ACTs) help maintain and improve lung function by loosening secretions for expectoration. This is usually followed by a cough for clearance. Multiple ACTs exist, including different breathing methods, conventional chest physical therapy with postural drainage and percussion, and oscillating devices that vibrate the airways (e.g., Flutter, Acapella) or the entire chest (e.g., Vest). Exercise and proper hydration may also facilitate ACTs. The sequence of drug therapies around airway clearance is an important patient education point; bronchodilators should be taken prior to or with ACTs, and inhaled antibiotics should be taken after ACTs.

Acute Management
CF pulmonary exacerbation refers to a change in respiratory signs and symptoms from the patient's baseline function, necessitating treatment with systemic antibiotics and augmented airway clearance.⁵ Generally, adolescents and adults have more CF exacerbations due to progressive worsening in lung function.¹ Common patient complaints associated with pulmonary exacerbation are increased cough, sputum, shortness of breath, and chest congestion; change in sputum appearance; decreased appetite; and exercise intolerance.

Infectious Etiologies: Once a patient with CF has a pulmonary infection caused by an organism, a cycle may begin between persistent colonization and acute pulmonary exacerbation. The typical CF pathogens for initial infection are Staphylococcus aureus and nontypableHaemophilus influenzae,followed by Pseudomonas aeruginosa (mucoid/nonmucoid), Burkholderia cepacia , and Stenotrophomonas maltophilia for subsequent infections. S aureus is the most common cause of respiratory infection in children, and P aeruginosa is the most common in adolescents and adults.¹ Methicillin-resistant S aureus (MRSA) may also be an organism of concern, particularly for adolescents and adults with CF.¹

Systemic Antibiotics: Initial or mild infections may be treated on an outpatient basis with oral antibiotics; however, subsequent or severe infections usually require inpatient treatment with intravenous (IV) antibiotics until resolution of acute symptoms. Antibiotic selection is based on either pathogens typically isolated in the patient's same age-group or, more preferred, the patient's previous sputum culture and sensitivity. Generally, until the patient has cultured P aeruginosa from the sputum, antibiotic therapy effective against S aureus and H influenzae, such as a beta-lactamase–stable penicillin or cephalosporin, should be prescribed. ^5,6

Once a patient with CF is infected with P aeruginosa, combination antibiotic therapy is recommended for synergistic activity and to slow development of resistance. Typical antibiotic combinations consist of tobramycin plus another antipseudomonal agent listed in Table 1. However, the patient's regimen needs to be individualized based on his or her susceptibility patterns. Management of CF exacerbation in adolescents and adults may be especially complex given the increase in multidrug-resistant organisms. Duration of antibiotic treatment is suggested to be at least 10 days, with the usual course lasting 14 to 21 days.^5,6

Home Therapy: Instead of being hospitalized for a CF exacerbation, some experienced patients may be candidates for home IV therapy either for the entire duration of treatment or for part of the course after hospital discharge. Home therapy requires great family support and understanding, a commitment to ACTs and the prescribed antibiotic regimen, and use of community resources (e.g., nursing care) for meeting eligibility for home care of a pulmonary exacerbation.

Chronic Management
Chronic, daily respiratory therapies for CF management may consist of a variety of regimens from the following drug categories: bronchodilator, mucolytic, inhaled antibiotic, and anti-inflammatory. The latest studied therapy added to potential CF drug regimens is hypertonic saline. Table 2 has more information on the main pulmonary therapies utilized for chronic management of CF.

Any therapy that is administered by inhalation, either by nebulization or metered-dose/dry-powder inhaler is particularly beneficial for patients with CF, compared to other routes. These formulations usually reach the airway more quickly, more easily, and in larger drug concentrations.

Bronchodilators: Short-acting beta-2 agonists (SABAs) such as albuterol and levalbuterol are frequently prescribed for patients with CF despite the lack of clear research supporting their use. Potential benefits of SABAs include dilation of the airways and sputum mobilization. Typical SABA frequencies are scheduled prior to ACTs two to four times a day.

Historically, theophylline had a role in CF management. Limited efficacy and concern for toxicity have reserved its use for patients with documented improvements in lung function.

Mucolytic Therapy: The abnormal, thick secretions in CF are primarily due to mucus glycoproteins and DNA. The enzyme DNase I, which digests extracellular DNA, was created in a human recombinant form known as  dornase alpha (Pulmozyme) inhalation solution. In clinical trials of children and adults with CF, dornase alpha demonstrated a 28% to 37% reduction in respiratory infections requiring IV antibiotics, a decrease in hospital stay by 1.4 days, and a mean increase in FEV₁ of 5%. Dornase alpha is recommended for patients 6 years or older; however, it is likely that patients younger than 5 will also benefit from administration.⁷

Another nebulized agent prescribed to decrease mucus viscosity in patients with CF is acetylcysteine. Its use is limited by inconsistent efficacy data as well as by an objectionable odor.

Inhaled Antibiotics: The sputum concentration achieved by aerosol route is much higher than that by the IV route, which more effectively reduces bacterial density in the lung. Since its approval in 1998, tobramycin inhalation solution has dramatically improved lung function in patients with CF. Ramsey and colleagues found a mean increase in FEV₁ of 10% and a reduction of 36% in the need for IV antibiotics and of 26% for hospitalization in patients using tobramycin inhalation.^8,9

Tobramycin inhalation is recommended for children 6 years or older colonized with P aeruginosa. This agent is currently being studied in children as young as 1 year and is also being studied as a dry-powder inhaler.^10,11 Tobramycin for inhalation has not been researched for the treatment of pulmonary exacerbations or in patients colonized with B cepacia.

Colistimethate administered via nebulization is another antibiotic utilized in CF; however, it is associated with bronchospasm and is not available in an acceptable formulation. Research evaluating aztreonam lysinate for inhalation and aerosolized liposomal ciprofloxacin is under way.^12,13

Anti-inflammatory Therapy: Historically, high-dose ibuprofen or oral corticosteroids have been prescribed for anti-inflammatory management in CF. The use of these agents is limited by long-term safety concerns. Inhaled corticosteroids may also be part of the CF drug regimen, but benefit has not been demonstrated in trials.

Saiman and colleagues evaluated azithromycin in patients with CF and showed a mean increase of 4.4% in FEV₁, a 47% reduction in days hospitalized, and a 39% reduction in days on IV antibiotics.¹⁴ The exact mechanism of azithromycin in CF is unclear, although it may be explained by modulation of neutrophil activity or antagonism of the P aeruginosamucoid biofilm.

Azithromycin is also suggested for patients 6 years or older colonized with P aeruginosa. Due to concern for increasing nontuberculous mycobacterial resistance, all patients initiating azithromycin need appropriate screening. Studies in progress using azithromycin in CF include patients not infected with P aeruginosa and patients colonized with B cepacia.^15,16

Hypertonic Saline: Hypertonic saline is thought to improve lung function by increasing airway hydration, which results in better mucus clearance. A recent Australian trial was conducted to evaluate this hypothesis in patients older than 6 with CF. Treatment with hypertonic saline was associated with a reduced frequency of pulmonary exacerbations and a moderate improvement in lung function. Currently, there is insufficient evidence to support routine use of hypertonic saline in CF management, and a larger trial is needed.¹⁷

NUTRITIONAL/GI MANAGEMENT
Over 90% of patients with CF have pancreatic insufficiency requiring enzyme supplement replacement to achieve adequate nutrition and manage GI symptoms.¹ Patients' GI symptoms may include failure to thrive, malnutrition, gastroesophageal reflux, nausea, flatulence, and steatorrhea from malabsorption. Meconium ileus, distal intestinal obstruction, and rectal prolapse are also common GI problems associated with CF.¹⁸

To meet the increased caloric needs in CF, many patients require dietary interventions with oral supplementation or enteral feeding. Agents used to stimulate appetite in other diseases (e.g., megestrol acetate, cyproheptadine) are not recommended for routine use in CF. Growth hormone treatment may be useful in children with CF to improve growth after aggressive nutritional therapy fails.¹⁹

A strong correlation exists between a higher body mass index and better lung function in children and adults with CF.¹ Therefore, proper nutrition and GI management are necessary not only for normal growth, but also for comprehensive management of CF pulmonary disease.

Vitamin Replacement
Fat malabsorption is common in patients with CF, requiring replacement of the depleted fat-soluble vitamins. Table 2 provides age-based dosing recommendations for vitamin A, D, E, and K supplementation.

Other possible minerals and electrolytes needing replacement in CF include calcium for bone health, iron, and zinc. Sodium replacement should be suggested during summer months or for patients living in hot climates.

Pancreatic Enzyme Replacement
Pancreatic enzyme supplements were available prior to the Food, Drug, and Cosmetic Act of 1938 and consequently were not completely evaluated for drug efficacy and safety. This led to two major issues in CF: lack of appropriate dosing information and substantial variations among different agents. The latter caused worsening of GI symptoms when enzyme preparations were substituted for one another. This issue will eventually be resolved because the FDA ruled in 2004 to require makers of pancreatic enzyme supplements to get their drugs approved within four years of the rule.²¹

In the meantime, the CF Foundation recommends individualized dosing of pancreatic enzymes based on either ingested fat or weight (see Table 2) titrated to response in resolution of GI symptoms. Acid suppression with antacids, H₂ receptor antagonists, or proton pump inhibitors may increase enzyme efficacy (and possibly reduce the dosage needed), since the enteric coating requires an alkaline environment to be dissolved. High dosages (>6,000 lipase U/kg/meal) of pancreatic enzyme supplements are associated with fibrosing colonopathy and should be avoided.²⁰

MANAGEMENT OF ASSOCIATED DISORDERS
Diabetes
The prevalence of 14.3% for CF-related diabetes (CFRD) is likely underestimated due to the lack of routine diagnostic screening.¹ The onset of CFRD occurs during adolescence; therefore, annual screening beginning at 10 years of age is recommended. Early disease recognition and treatment is imperative, since poor glucose control correlates with nutritional failure, worsening pulmonary disease, and earlier death. The primary cause of CFRD is insulin deficiency, and as a result, an individualized insulin regimen is most appropriate for CFRD management.²²

Bone Disease

CF-related bone disease occurs in 13.7% of patients, which is also likely an underestimate. Poor nutrition, vitamin D deficiency, severe lung disease, CFRD, and possible corticosteroid use are just some of the factors that increase the risk of osteoporosis in patients with CF. Screening for bone disease should begin at 18 years of age or as young as 8 with risk factors. Weight-bearing exercise along with calcium and vitamin D supplementation are recommended for prevention and treatment of CF-related bone disease. Use of bisphosphonate therapy may be considered in adults at high risk of fragility fractures.²³

Liver and Biliary Tract Disease

In patients with CF, the prevalence of liver disease is 9.4%.¹ Common conditions in CF are cholelithiasis that progresses to biliary cirrhosis, hepatic steatosis, and gallbladder disease. Ursodiol may be beneficial for liver disease by improving bile flow and displacing toxic bile acids. Chronic therapy with beta-blockers is useful in CF patients with cirrhosis to prevent variceal hemorrhage.²⁴

Depression
Depression is the most frequent comorbidity in CF, with a prevalence of 16%. Appropriate psychosocial interventions in addition to drug therapy may be necessary to treat depression in adolescents and adults with CF.

CONCLUSION
CF is an inherited multisystem disease that is characterized by obstruction and infection of the airways and poor growth. Advances in pulmonary and nutritional management continue to increase survival in patients with CF. The newer treatments available along with the agents currently being evaluated will hopefully continue to "Add tomorrows every day."

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