Although there is not yet a cure for CF, significant advances in the treatment of the disease have occurred. With new therapies there has been a remarkable increase in the expected survival of CF patients. Early discoveries of the ability of pancreatic enzyme replacement to permit digestion of proteins and fats allowed CF patients to survive childhood. More recently, advances in techniques to clear the airways of mucous, as well as improved antibiotics, have propelled median survival to over 37 years.
Many of the therapies available or under development for the treatment of CF are medications that are administered by inhalation of an aerosol or mist (nebulization). However, with each new medication and therapy the complexity of the treatment plan increases. Perhaps more than any other chronic disease, successful management of CF requires an enormous commitment by the patient. Especially in the setting of advanced disease, individuals with CF may be required to spend hours each days to keep up with airway clearance and a variety of inhaled, injected, and orally administered medications to combat airway infections, chronic sinusitis, diabetes, and pancreatic insufficiency.
Sputum Mobilization and Clearance From the Airways
The presence of very thick and sticky mucous in the airways of CF patients has clearly been shown to accelerate lung damage and promote infection. Thus, a critical component of CF treatment is to perform effective airway clearance to loosen and get rid of the mucus from the lungs.
A wide variety of methods and devices are available to assist with airway clearance. The classic technique commonly used with children is called “postural drainage and percussion.” The person with CF sits, stands, or lies in a position that will help free up mucus as their chest and back are pounded or clapped by family members or respiratory therapists. Adults with cystic fibrosis usually prefer an airway clearance technique (ACT) that can be done without assistance. A mechanical “vest” has been developed that reproduces the effect of handclapping to the chest. A fitted vest is coupled to a pneumatic compressor capable of high frequency oscillation and compression of the chest wall (shown above).
Many other devices are available that combine the action of blowing against pressure, combined with vibration, to open the airways and help mobilize the thick mucous. No method or technique has been shown to be clearly superior. However, individuals with CF can usually identify the mode of ACT that works best for them, with the goal of facilitating sputum expectoration. As patients get older, they should be given the opportunity to try, and retry, different forms of ACT. Nearly always, aerobic exercise is helpful as an addition to other forms of airway clearance. More then any other CF treatment, airway clearance requires a strong commitment by the patient and their families, as it is time consuming and physically demanding.
Medications to Assist With Airway Clearance
The first agent ever approved by the FDA for the treatment of CF lung disease was the enzyme DNase (Pulmozyme®). DNase is a medication that serves to thin the mucus and is delivered by inhalation of an aerosol. DNase works by degrading the long strands of DNA that are mixed within the sputum, thus resulting in decreased viscosity and improved ability to clear organisms from the bronchi. The DNA in the CF sputum originates from the massive number of white blood cells (neutrophils) that are trapped and eventually die within the mucous layer. A number of studies have demonstrated small but significant improvements in FEV1, as well as general trends toward decreased infection and/or fewer pulmonary exacerbations [9, 14].
More recently, small studies have demonstrated benefits from inhaling concentrated salt water (hypertonic saline) [15]. This therapy appears to rehydrate the very concentrated mucous and thus improves the ability of cilia to clear mucous from the airways. Although much less studied than DNase, it appears that hypertonic saline may also reduce the frequency of pulmonary exacerbations, and in some cases improve lung function [14].
Other Respiratory Therapies
Many people with CF have some degree of bronchospasm or wheezing, which is sometime referred to as CF asthma. In addition, some people experience chest tightness or wheezing after using inhaled DNase, hypertonic saline, and/or tobramycin. Thus, many individuals with CF use one or more bronchodilators. Specific, evidence-based recommendations for bronchodilator use in CF are not available, thus physicians often utilize treatment strategies similar to those recommended for patients with asthma. In people with advanced CF lung disease, oxygen may be required. Assisted ventilation by mask with positive airway pressure may be useful for patients with even more severe lung damage.
Maintenance Antibiotics
Many different antibiotics have been used to try to keep the burden of bacteria at the lowest possible level. Two antibiotics have now been shown to be effective for this purpose [14]. Tobramycin solution for inhalation (TOBI®) when prescribed in one-month intervals (followed by one month off of treatment), has been shown to improve lung function and reduce the frequency of exacerbations in the setting of chronic P. aeruginosa infections [16]. A second antibiotic, azithromycin (taken orally), has been shown to have similar benefits. The two antibiotics are often used together. Interestingly, azithromycin is not an antibiotic known to kill P. aeruginosa in the laboratory, and many scientists believe that it instead acts as an anti-inflammatory drug in the CF airway. While P. aeruginosa has the ability to develop resistance to many antibiotics, this has not emerged as a significant problem as a result of the use of either inhaled tobramycin or azithromycin, and most CF experts believe that the preservation of lung function outweighs the potential risks of developing antibiotic resistance. Although S. aureus is also a common chronic infection of the CF airway, there currently are no recommended antibiotics to suppress its growth.
Anti-Inflammatory Agents
The non-steroidal anti-inflammatory medication ibuprofen has been shown to slow the rate of lung function decline in children and adolescents with mild CF lung disease. However, to be effective in CF, ibuprofen needs to be administered in extremely high doses. Patients on this therapy need to be closely monitored by their CF physician to ensure therapeutic blood levels of ibuprofen have been achieved and that side effects are avoided [9]. For these reasons, this therapy is not widely used, but has helped to establish the principal that anti-inflammatory strategies are important targets for future drug development. Systemic steroids, such as prednisone, also have a poor side-effect profile, but may have a role when used in short bursts with some individuals [9].
Pancreatic Enzyme Replacement
Pancreatic enzymes are primarily derived from the pancreas of pigs and contain lipases, proteases, and amylases. Enzymes are taken orally with each meal and snack. As the proteins are combined with the acid of the stomach, enzyme activity rapidly diminishes, and thus large doses are often required. Most products are provided as enteric coated microbeads to reduce activation in the stomach. Co-administration with various acid-reducing medications usually improves efficiency of the enzyme products.
A wide variety of enzymes are available, some with varying ratios of lipases, proteases, and amylases. Many people with CF will have a clear preference for a particular product. Of interest, no pancreatic enzyme currently in use in the United States has undergone FDA approval. In April 2004, the FDA mandated that all pancreatic enzymes undergo the clinical testing required for FDA approval. This difficult process is currently underway.
Other Nutritional Considerations
Good nutrition is an essential component of the treatment of CF. Even with pancreatic enzyme replacement, absorption of fat-soluble vitamins (A, D, E, and K) is impaired, and supplementation of these vitamins is required. In addition to difficulties with nutrient absorption, people with CF have an increased caloric requirement as a result of the demands imposed by increased work of breathing, chronic inflammation, and infection. Thus, recommended diets are high in protein and fat, with approximately 30-50% more calories than a typical diet. Occasionally, patients benefit from supplemental calories at night through a tube entering directly into the stomach ("tube-feeding"). Also, in adulthood, many people with CF will require supplemental insulin (see CF Related Diabetes). The excessive loss of salt in the sweat of individuals with CF can predispose them to dehydration. Care should be taken by children and adults with CF to avoid dehydration through liberal intake of salt and fluids when faced with hot conditions.
Lung Transplant
Lung transplantation has long been an option for people with CF who are approaching respiratory failure. Due to the multiple infections and high volume of sputum production that is characteristic of advanced CF lung disease, double-lung transplants are required. While transplantation can correct the respiratory component of the disease, other organs remain severely affected. The average survival following transplant is approximately 5 years. Surprisingly, recent analysis of children receiving lung transplants from 1992-2002 did not show an overall improvement in survival [17]. While the overall role of lung transplant in the treatment of CF continues to be evaluated, at this point, lung transplant should be considered as an option for patients with advanced CF lung disease.
CF Foundation Care Center Network
Given the complexity of CF care, and with many new therapies emerging, it is recommended that children and adults with CF receive care at CF Care Centers. These Centers utilize a team approach, with doctors and nurses trained and experienced in CF. Also part of the team are respiratory therapists, dietitians, and social workers, and patients typically have access to genetic counselors, mental health professionals, endocrinologists, and other subspecialists familiar with CF. Not surprisingly, patients cared for at CF Centers have been found to have better outcomes than patients cared for by physicians not affiliated with CF Centers. In addition, patients at CF Care Centers may have the opportunity to participate in clinical trials for experimental medications, with the potential to further improve CF care. In the United States, there are presently 115 Care Centers accredited by the CF Foundation, and 95 of these have adult programs. A complete listing and contact information is available on the CF Foundation website.
The Future of CF Care
As discussed above, improving therapies, combined with the availability of better diagnostic testing, has resulted in a steady increase in the average age of CF patients. Very soon, CF will be primarily a disease of adulthood, and increasingly patients with CF are surviving past middle age. While much attention has been focused on the process of adolescents with CF transitioning from the pediatric setting to adult programs within Care Centers, a similar process of transition will need to occur within the medical community, as increasingly adult physicians will be required to provide the majority of CF care. Older men and women with CF have unique healthcare needs, with complex infections, malignancies, and unique forms of diabetes and osteoporosis. Thus, the need for CF Centers with experience and commitment to adult care will continue to grow.
Emerging Treatment Strategies
A wide range of therapeutics are currently undergoing clinical trials for use in the treatment of various aspects of CF. Broad treatment categories and promising examples of each class of medication that are currently being tested include:
Modification of CFTR Function
- VX-770: An oral agent that keeps defective CFTR chloride channels open in CF patients with the CFTR mutation G551D. Mutation of this class results in a chloride channel that is present on the cell surface, but doesn’t function properly.
- PTC124: An oral agent that improves protein translation in CF patients whose type of CFTR mutation (nonsense mutations) results in the premature disruption of protein synthesis, producing a shortened, non-functional protein. Approximately 10% of CF patients have these types of mutations. A phase II trial was published in August 2008.
Correction of Airway Surface Liquid Abnormalities
- Duramycin (Moli 1901): An aerosolized peptide that activates alternative chloride channels to compensate for the lack of CFTR function.
- Denufusol: A P2Y2 agonist that acts to increase airway surface volume and mucous clearance.
- Mannitol: An aerosolized sugar that may work in a similar fashion as hypertonic saline to rehydrate the mucous in the airways.
Antibiotics
- Tobramycin (TIP): A dry powder form of the inhaled antibiotic, which would significantly reduce the time needed to deliver the drug.
- Aztreonam (AZLI): An anti-pseudomonas antibiotic for inhalation.
- SLIT-amikacin: An inhaled anti-pseudomonas antibiotic encased in a liposome.
Anti-inflammatory agents
- N-acetylcysteine: An oral “prodrug” which is converted into the antioxidant glutathione.
Nutritional Supplements
- ALTU-135: A synthetic pancreatic replacement enzyme, that is not derived from pig pancreas, and would require fewer capsules with each meal.
The promise for an ultimate cure to CF lies with gene therapy. With the identification of the normal genetic sequence of the CFTR gene, the potential exists to replace mutant CFTR genes with normal copies. Early preclinical studies demonstrated the feasibility of this approach, but trials with CF patients have proven that the application of this technology is extremely complicated in the clinical setting. More recently, the use of embryonic or adult stem cells to repair damaged lung tissue has gained attention, and may represent a future therapeutic approach [18].
