March 03, 2015
Cystic fibrosis (CF) is a multisystem disorder that remains the most common genetic disease of Caucasians. The clinical manifestations leading to chronic lung disease and malnutrition are a direct result of mutation of the CF transmembrane conductance regulator (CFTR) protein, which is expressed predominantly in epithelial cells. Normal CFTR regulates and functions as the chloride channel as well as inhibiting activation of the epithelial sodium channel. These effects result in desiccated obstructing mucus due to enhanced water resorption in epithelial-lined ducts in all tissues affected in CF.
Fortunately, expected survival has increased from about 18 years in 1976 to 38-plus years in 2012, thanks to adherence to recommended therapeutic strategies such as aggressive management of chronic airway infection and nutritional deficiencies.
The Cystic Fibrosis Foundation guidelines have provided the cornerstone for the care principles employed to treat these patients. Mayo Clinic, designated as a CF care center by the Cystic Fibrosis Foundation, has a multidisciplinary care team committed to the overall health and care of these individuals.
Diagnosis
The diagnosis of CF is based on typical phenotypic findings and family history, accompanied by laboratory confirmation of CFTR dysfunction or identification of two CFTR mutations. Presenting signs and symptoms include the following (roughly in order of reason for diagnostic testing):
- Acute or chronic respiratory signs and symptoms
- Failure to thrive or malnutrition
- Steatorrhea, abnormal stools or malabsorption
- Meconium ileus or intestinal obstruction
- Electrolyte imbalance
- Rectal prolapse
- Nasal polyps or sinus disease
- Liver problems
- Edema
Signs and symptoms consistent with a diagnosis of CF differ by age; for example, male infertility presents in adulthood. Family history accounts for about 15 percent of the reasons for diagnostic testing.
Laboratory confirmation of CFTR dysfunction includes sweat testing, genetic mutation analysis and nasal potential difference. The sweat test remains the most available and clinically useful way to diagnose CF when done according to strict guidelines with pilocarpine iontophoresis and a quantitative determination of chloride concentration. A sweat chloride level of 60 mmol/L (normal is < 30 mmol/L) is considered a diagnostic criterion for CF. Several methods of CFTR detection are commercially available that can include specific mutations or full sequencing, which runs the risk of revealing novel mutations and polymorphisms of unknown importance.
There are approximately 2,000 known mutations in CFTR. Measurement of transepithelial nasal potential difference is generally reserved for the more-difficult-to-diagnose patient. Patients with CF have a characteristic bioelectric abnormality in nasal epithelium in vivo.
Treatment
Since pulmonary manifestations of CF often relate to chronic airway infection, antibiotics are a mainstay of treatment for acute exacerbations of pulmonary CF. Specific antibiotic therapy is chosen based on organism identification and the antibiotic susceptibility profile of the last available sputum culture. Outpatient treatment, when possible, is preferred, but a lack of response to oral antibiotic therapy often necessitates hospital admission for provision of IV antibiotics and more intense adjunctive therapies.
Although dual IV antibiotics are often used in the treatment of an acute exacerbation presumed to be due to Pseudomonas aeruginosa, the question of monotherapy versus combination therapy is a relevant one. Use of a single antibiotic may result in reduced toxicity as well as cost in a patient who will be treated with antibiotics multiple times throughout life. On the other hand, single antibiotics will be more likely to select for resistant pathogens. Currently, use of a single antibiotic is considered an appropriate choice in patients with a milder stage of disease, but in more-advanced stages of disease, combination therapy is favored. A recent advance is the use of once-daily dosing of aminoglycosides (as opposed to three times daily) to reduce the risk of nephrotoxicity.
Aerosolized antibiotics are often used on a regular basis for suppression of infection, particularly with pseudomonas. The most commonly used antibiotic is tobramycin, though more recently available inhaled drugs are likely to increase in use, including amikacin, aztreonam and, for staphylococcal infections, vancomycin. Safety and efficacy have not been demonstrated in patients with a forced expiratory volume (FEV) less than 25 percent or more than 75 percent predicted. The Cystic Fibrosis Foundation strongly recommends the chronic use of inhaled tobramycin to improve lung function and reduce the rate of exacerbations, but it has not been shown to be distinctly beneficial during acute exacerbations.
Airway clearance techniques and devices are mainstays for CF lung disease management. Hypertonic saline (3 percent or 7 percent) is an inexpensive and useful therapy to increase hydration of airway surface liquid, thereby improving mucociliary clearance. The Cystic Fibrosis Foundation recommends for patients 6 years of age and older the chronic use of inhaled hypertonic saline to improve lung function and reduce exacerbations. Dornase alfa (DNase) is an endonuclease that cleaves extracellular DNA and decreases the adhesiveness and viscoelasticity of CF mucus laden with DNA from white blood cells. Daily administration of dornase alfa is indicated to improve pulmonary function. In patients with a forced vital capacity (FVC) more than 40 percent of predicted, daily administration of dornase alfa has also been shown to reduce the risk of respiratory tract infections requiring parenteral antibiotics.
Recent drug development has resulted in a paradigm shift in the treatment of CF. In an effort to modulate CFTR function rather than targeting downstream effect, two classes of medications are available or in development:
- Potentiators: Drugs that open CFTR channels that already exist at the cell surface
- Correctors: Drugs that seek to bring CFTR to the cell surface where none previously existed
Ivacaftor was approved by the Food and Drug Administration (FDA) in 2012 (for ages 6 years and older) for the 4.4 percent of CF patients who have a specific class III G551D mutation. The drug binds to the nucleotide binding domain of CFTR and increases channel open probability (a potentiator). There is a near immediate benefit in FEV1, which increases approximately 8 percent within two weeks. In adults and children, these increases are sustained at 48 weeks (10.5 and 10 percent, respectively). The FDA recently granted approval in patients with an additional eight mutations. Importantly, ivacaftor also improves function of other organ systems affected by CF.
The most common CFTR mutation is deltaF508, which prevents translocation of CFTR to the cell surface, and for which ivacaftor alone is ineffective. Yet to be approved for use, lumacaftor is a new corrector that protects the abnormal deltaF508 CFTR from programmed degradation and allows it to move to the airway surface, resulting in about 25 percent more chloride transport. Combination therapy with agents such as lumacaftor is likely to become preferred therapy.
Short courses of systemic corticosteroids also have been utilized in the treatment of acute exacerbations, in a manner similar to the treatment of those patients with exacerbations of chronic obstructive pulmonary disease. Supplemental oxygen is often used in patients who are hypoxemic.
Mayo Clinic Cystic Fibrosis Center
The Mayo Clinic Cystic Fibrosis Center specializes in the care of pediatric and adult patients. The dedicated staff includes physicians, nurses, dietitians, genetic counselors, physical therapists, social workers and respiratory therapists. All patients are discussed at weekly joint pediatric and adult care team meetings, which provide a long-term perspective on the unique needs of each patient. Patient independence is fostered during early adolescence, a particularly difficult time for many patients with CF. The center staff works closely with the Transplant Center, and together, they have performed successful transplants in many patients with advanced CF lung disease.
Areas of active CF-related research at Mayo Clinic in Rochester, Minnesota, include:
- Exploration of the role of ATP in skeletal muscle vasodilation during exercise (Michael J. Joyner, M.D.)
- The role of Staphylococcus aureus toxin as a toxic agent of airway damage in individuals with cystic fibrosis (James R. Phillips, M.D.)
- Slc26 anion transporters interaction with CFTR in transepithelial chloride absorption and bicarbonate secretion (Michael F. Romero, Ph.D.)