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Advances in Cystic Fibrosis (CF)
The discovery of the gene responsible for cystic fibrosis (CF) in 1989 has led to an explosion of scientific information related to the disease and has transformed our understanding of it. For the first time, investigators are focusing on the development of treatments based on the underlying cellular defect. In this article, we review advances in genetics and molecular biology, as well as in clinical care, during the past decade. We also discuss the significance of the inflammatory response in CF lung disease and new and experimental CF therapies.
THE MOLECULAR BASIS OF CF
In 1989, investigators discovered the CF gene using novel approaches. The gene product, called the cystic fibrosis transmembrane conductance regulator (CFTR), is a membrane-based protein with an active transport function. This is consistent with previous finding that the primary defect in CF cells is faulty transport of ions, especially of chloride. Conclusive information regarding the role of CFTR in the basic CF defect came with the demonstration that defective camp dependent chloride conductance in CF cells was restored when CFTR cDNA was transfected and expressed in those cells.
The functions of CFTR (cystic fibrosis transmembrane conductance regulator) are still being elucidated. CFTR functions as a chloride channel, but it also appears to regulate other channels. There is a regulatory influence on a voltage-sensitive chloride channel known as the outwardly rectifying chloride channel (ORCC), probably through active transport of ATP by CFTR. A regulatory influence on other ion channels is also evident; CF airway cells appear to be important in the pathophysiology of abnormal airway secretions in CF. This observation has led to clinical trials of inhaled amiloride and nucleotide triphosphates during the past few years.
Although CFTR (cystic fibrosis transmembrane conductance regulator) exists in many organs, the most prominent abnormalities are evident in airway epithelia (including the nose and sinus cavities as well as the lungs), sweat glands, pancreas, intestine, liver and genitourinary system. This is consistent wit the common presenting symptoms of CF (cystic fibrosis). At the time of diagnosis, half of patients have either acute or persistent respiratory symptoms; these include chronic cough, persistent wheezing - often of a bronchiolitic nature - and pulmonary infiltrates. More than one third have growth failure, while just under one third have obvious symptoms of malabsorption. Neonatal intestinal obstruction by meconium ileus leads to diagnosis in about 20 percent. More unusual presenting symptoms include nasal polyposis, electrolyte abnormalities (hyponatremic dehydration or persistent metabolic alkalosis), rectal prolapse and obstructive jaundice. Eventually, all patients develop respiratory tract involvement, and 85 to 90 percent will require pancreatic enzyme supplementation. The importance of CFTR in the genital tract is dramatically illustrated by the near-universal finding of congenital bilateral absence of the vas deferens (CBAVD) in males with CF. Since the discovery of the CF gene, it has been shown that men without other clinical signs of CF who are infertile because of CBAVD have defects in the CF gene.
GENE THERAPY
The ultimate treatment for any genetic disease is to replace the faulty gene with a copy of the normal gene, thus reversing the pathophysiologic cascade that leads to organ damage. CF has been considered a good candidate for gene therapy because most of the morbidity and mortality are due to CF lung disease, and airways cells are readily accessible to gene delivery by aerosol therapy or via bronchoscopy. Within a year after the discovery of the CF gene, scientists showed that a normal copy of the CF gene could be inserted into CF airway cells which would express functional CFTR. This rapidly lead to clinical trials of gene therapy, many of which are currently underway in the US and Europe.
Current human gene therapy trials for CF use a variety of vectors attached to the CF gene to allow the gene to be carried across the cell membrane and into the nucleus. Most trials use modified viral vectors, such as adenovirus; some use liposome or liposome nucleotide vectors. While there has been success in transfection of the vector-gene combination to the cell and resultant gene expression and correction of the electrolyte defect in CF cells in vivo, successful gene therapy has been hindered by a number of problems. First, transfection and expression are very inefficient; in many studies, fewer than one percent of cells show evidence of gene expression. Second, there is often a significant inflammatory response, primarily due to host responses to the viral vector. Based on these findings, vectors are being modified to offer more efficient transfection with less toxicity. Progress has been very rapid, and gene therapy for CF may become a reality within the next decade.
REPLACEMENT OF CFTR OR REPAIR OF THE DEFECTIVE CFTR PROTEIN
Another method of correcting the cellular abnormality would be to insert normal CFTR protein into the cell membrane. Early experiments have shown some success in vitro. Another strategy has been the focus of much recent attention. Researchers have observed that in the most common genetic defect causing CF, the delta F508 mutation, a protein is formed that is at least partially functional; the main defect is the lack of transport of the protein to the cell membrane. Sodium 4-phenylbutyrate, currently in use for treatment of rare urea cycle disorders, works as a "chemical chaperone" in CF cells, allowing for transport of the mutant protein to the cell membrane, where partial restoration of ion transport is seen. Early clinical trials of this agent are underway. Other agents, including dimethyl sulfoxide, have been shown to have similar effects in vitro and may be studied in future clinical trials.
CORRECTION OF THE ELECTROLYTE TRANSPORT ABNORMALITY
Agents that can counter the decreased chloride secretion and increased sodium absorption in CF respiratory epithelial cells have been studied. Amiloride is a diuretic that, when given by inhalation, reduces absorption of sodium and water in airway epithelium. In mildly affected CF lungs, inhaled amiloride reaches the cell surface where it increases mucociliary clearance, improves sputum viscosity and slows the decline of pulmonary function. In spite of early enthusiasm, amiloride as a single agent has not shown to be beneficial in large clinical trials. UTP is a nucleotide that increases chloride secretion in CF cells and enhances mucociliary clearance in adult CF patients. The concomitant administration of amiloride and UTP via the nebulized route is under investigation. It is important to consider that any inhalational therapy primarily benefits patients with relatively mild lung disease, since distribution of inhaled drugs to small airways is very impaired as lung disease progresses. Clinical trials are underway to establish the effect of combined therapy on airway clearance in teenagers with mild disease and to evaluate the safety profile for children five to ten years of age. Other agents that alter chloride transport have been proposed but have not yet reached clinical trials.
MUCOLYTICS
Historically, nonspecific mucolytics have been employed to reduce the viscosity of CF mucus. As CF respiratory mucus appears to be over sulfated, N-acetyl cysteine (Mucomyst), an agent that breaks sulfide bonds, has been used to enhance mucociliary clearance. Although the medication is helpful for some patients, many patients experience bronchospasm and an unpleasant taste from it, so it is now infrequently used. Sodium bicarbonate given via aerosol has been used for mucolysis but is also associated with local irritation and bronchospasm. Long-term benefit has not been established for either agent. Hypertonic saline, administered via an ultrasonic nebulizer, has been recently reported to enhance mucus clearance and improve lung function; further studies are underway.
Up to 10 percent of the dry weight of CF mucus can be attributed to DNA, which is released primarily from airway neutrophils. The excessive DNA (deoxyribonucleic acid - DNA is a code used within cells to form proteins) content of CF mucus contributes to its abnormally high viscosity. As early as the 1950s, it was shown that aerosolized bovine pancreatic deoxyribonuclease-1 could reduce the viscosity of airway secretions, but significant allergic reactions and bronchospasm precluded its use. With recombinant DNA technology, development of recombinant human deoxyribonuclease-1 (rhDNase) has offered a major therapeutic advance for patients with CF. In the test tube, rhDNase decreased the viscosity, elasticity and adhesiveness of CF sputum, turning a non-flowing viscous gel to a free-flowing liquid. After the efficacy and safety of nebulized rhDNase were established in Phase I and II trials, a multicenter, double-blind placebo-controlled Phase III trial was conducted to determine its long-term effectiveness in adults and children. In the trail, 968 CF patients (>(less than) 5 years of age and FVC > 40 percent of predicted) were randomized to three groups - to placebo, 2.5 mg rhDNase daily and 2.5 mg twice daily for 24 weeks. The main findings were a 31 percent reduction in the relative risk of a pulmonary exacerbation and improved pulmonary function as measured by a 5.8 percent increase in FEV1 in the rhDNase groups. Other therapeutic benefits included enhancement of quality of life, reduction in dyspnea, and fewer days of parenteral antibiotics. The twice-daily dosing was only slightly more effective than once daily dosing. Minimal side effects were seen; the most common were voice alteration and laryngitis. These results are encouraging, and currently about 40 percent of all U.S. CF patients receive rhDNase (Pulmozyme). More widespread use may be limited by the high cost of the product - approximately $900 per patient per month. Evidence suggests that some patients respond better than others; however, there are no accurate ways to predict which ones will benefit from this very expensive therapy. The available data indicates that some patients who have mild lung disease and a productive cough appear to gain ground.
Degenerating neutrophils also release F-actin into the CF mucus, which also increased its viscosity. Gelsolin is a protein that can break the non-covalent bonds between F-actin filaments. Early studies showed that, when used in combination with rhDNase, gelsolin acts synergistically to reduce CF sputum viscosity. Further studies are ongoing with this mucolytic agent.
MUCOCILIARY CLEARANCE
Basic therapy for patients with CF is directed toward enhancing mucociliary clearance through a variety of airway clearance techniques (ACTs) that benefit CF patients with every degree of lung disease. Most patients use Acts daily. Traditional chest physiotherapy with postural drainage is designed to move mucus from smaller airways to larger airways where it can be expectorated effectively. This is done by percussion on the chest wall with the child in varying positions that use gravity to promote mucus clearance. Although the therapy requires no special equipment, it does call for a trained adult caregiver. Because of this and because of the physical demands involved, new modalities have been developed to allow for greater independence; some of these methods may provide superior mucus clearance. For example, the "huff" and autogenic drainage method are special breathing techniques that improve ventilation and maximize the effectiveness of a cough; in order to perform these techniques properly and reproducibly, though, patients must be well trained and motivated. The PEP valve (positive expiratory pressure valve) provides a distending pressure to the airways and, when combined with breathing maneuvers, allows for enhanced mucus clearance. The Flutter® is a pipe-shaped hand-held device that contains a stainless steel ball. During expiration, the ball oscillates, causing oscillatory waves to be transmitted to the lower airways, shearing secretions from the airway walls. The patient then uses a huff cough technique to clear loosened secretions from the airways. Another modality, the ThAIRapy bronchial drainage system®, uses high-frequency chest wall oscillations, which also shear mucus from the airway wall. While this system is much more expensive than the Flutter and PEP devices, it is not effort-dependent; furthermore, the physician can directly monitor compliance as the device records hours of use.
For many CF patients, bronchial hyperreactivity contributes to the respiratory abnormality. Regular use of bronchodilators has been shown in some studies to improve pulmonary function in as many as 50 percent of CF patients. The use of inhaled bronchodilators prior to chest physiotherapy may help facilitate mucociliary clearance via direct bronchodilation effects or enhanced ciliary beat frequency. Beta-adrenergic agents, like albuterol (Proventil, Ventolin), are the most commonly used agents for this purpose. Recently, ipatropium bromide (Atrovent) has been shown to be as effective as albuterol, possibly with fewer side effects. Because some patients have paradoxical bronchospasm with bronchodilators (up to 8 percent in one series), assessment in the pulmonary function laboratory is very helpful in determining individual usage.
ANTI-INFLAMMATORY THERAPY
The role of inflammation in the pathophysiology of CF lung disease has been reviewed. Suppression of inflammation can be achieved by use of several available agents. A recent multicenter study evaluated the role of alternate-day oral corticosteroid (prednisone) therapy in patients with mile to moderate CF lung disease. The study followed 285 children for more than a four-year period; the children were given doses of 1 mg/kg prednisone per day, 2 mg/kg, or placebo. The study showed that children taking either dose of prednisone had better lung function than the placebo group; the higher -dose prednisone groups had an unacceptably higher rate of side effects, leading to an early discontinuation of that study arm. The benefits continued for the duration of the study (four years). This study, along with others, demonstrates that corticosteroids can suppress the inflammatory response and lead to improvement in lung function in children with CF. However, therapy is limited by side effects - suppressed linear growth and increased rates of P. aeruginosa colonization even in the lower-dose group. It is recommended that prednisone be given for no longer than six months and with close clinical monitoring. The role of short bursts of steroids in the acute treatment of CF exacerbations is being investigated.
Because the benefits of oral corticosteroids are apparent, current studies have turned to the efficacy of inhaled corticosteroids on lung function in individuals with CF. A pilot study in 49 patients examined in haled corticosteroids over a 30-day period and concluded that the steroid-treated group had better pulmonary function as evidenced by an improved thoracic gas volume. This route of steroid delivery has obvious appeal and reduced the likelihood of side effects. Further studies are underway.
An alternative to corticosteroids are the non-steroidal anti-inflammatory drugs (NSAIDs). The effects of high-dose ibuprofen, an NSAID, was evaluated in 85 children with mild CF lung disease over a four-year period. For younger children (5 to 13 years), lung function declined by only 1.5 percent per year compared to 4 percent per year in the placebo group. No differences were seen for older children (>13 years). Side effects were infrequent and minor. This agent may slow the progression of lung disease without serious side effects. Because inadequate serum ibuprofen levels may actually promote airway inflammation, the dose of ibuprofen must be based on rigorously performed pharmacokinetic testing. Because high dose ibuprofen has only recently been introduced for patient use, studies documenting the long-term experience are lacking; anecdotal reports of renal insufficiency, renal failure and bleeding mandate close patient follow-up.
Other potentially useful anti-inflammatory agents include alpha-1 antitrypsin (A1AT), pentoxifylline and secretory leukocyte protease inhibitor (SLPI). A1AT is a naturally occurring anti-protease that helps limit the inflammatory damage in the CF lung but is overwhelmed by the presence of large quantities of neutrophil elastase. In a pilot study, aerosolized A1AT increased the amount of the protein in the lung and suppressed elastase activity. Clinical trials are needed to determine whether administration of this agent will slow the progression of lung disease. Pentoxifylline is a xanthine derivative that may reduce the adhesiveness of neutrophils to epithelial cells. A phase III trial is currently underway. SLPI, another antiprotease normally found in the lung, can be given via the aerosolized route. A pilot study in CF patients showed decreased neutrophil elastase activity and interleukin-8 levels. None of these agents is currently recommended for clinical use.
ANTIMICROBIAL THERAPY
The use of antibiotics for CF lung infections continues to evolve. Before effective antistaphylococcal antibiotics, most CF patients died with purulent lung infection due to S. aureus. This organism continues to be isolated frequently from the respiratory tract of infants and young children with CF; however, over time, most patients develop infections with P. Aeruginosa. Other important pathogens include H. influenza (especially in young patients), S. maltophilia and B. cepacia. The latter is relatively rare but is sometimes associated with a rapidly deteriorating clinical course.
There has been widespread interest in the use of prophylactic antibiotics to prevent the progression of CF lung disease. To date, no clinical trial has demonstrated a benefits of prophylactic antibiotics in this population. A recently completed double-blind, placebo-controlled trial of daily cephalexin in children < 5 years of age demonstrated no pulmonary function benefit but rather a disturbing increase in P. aeruginosa colonization. Thus, most patients take antibiotics only for symptomatic pulmonary exacerbation manifested by an increase in cough, a change in quantity or quality (viscosity, color) of sputum, change in appetite and/or weight loss and a variety of other symptoms. The physical exam may be unchanged or reveal new crackles, rhonchi or wheezes. Spirometry often shows a decline in forced expiratory volume in one second (FEV1).
Appropriate treatment of a pulmonary exacerbation depends on the severity of underlying lung disease, the severity of the exacerbation and the patient's respiratory tract flora. For mild or moderate exacerbations in patients primarily colonized with S. aureus or H. influenzae, trimethoprim-sulfamethoxazole, an oral cephalosporin, or amoxicillin-clavulanate is usually effective. For mild or moderate exacerbations in patients colonized with P. aeruginosa, an oral fluoroquinolone antibiotic is often beneficial. This relatively new class of drugs has had a very positive impact on CF patients; however, the emergence of antimicrobial resistance is relatively rapid, so frequent or prolonged courses must be avoided. When oral antibiotics are unsuccessful, when exacerbations occur frequently over time, or in the case of severe exacerbations, intravenous antibiotics are required. Most frequently, a combination of a beta lactam and an aminoglycoside (such as piperacillin and tobramycin) is used. Monobactams (aztreonam) and carbapenems (imipenem, meropenem) also combat P. aeruginosa; these agents are generally reserved for organisms that are resistant to other beta lactams. The choice of antibiotics for an individual depends on sputum culture and sensitivity test results; sputum cultures are recommended at least annually for all patients.
Some studies have suggested that the use of regularly-scheduled intravenous antibiotics, given for two weeks four times yearly, is beneficial to CF patients colonized with P. aeruginosa. Such a strategy is employed in Denmark, which boasts very high survival rates in CF. A number of CF experts have suggested that P. aeruginosa, when first isolated, may be eradicated by aggressive treatment, thus slowing the rate of lung function decline. No rigorous clinical trials of either strategy have been conducted.
A novel approach to antibiotic delivery has developed over the past 15 years: the use of aerosolized antibiotics. Advantages of this delivery system include the ability to achieve very high concentrations of antibiotics in the sputum, which would otherwise be possible only with significant systemic toxicity. Aminoglycosides (gentamicin and tobramycin) are highly effective anti-pseudomonal agents that can be delivered by this route; these agents are frequently used for mild or moderate exacerbations of CF lung disease at doses of 80 to 160 mg two or three times daily. A recent study evaluated the efficacy of high-dose tobramycin by nebulizer (600 mg tid) given for 28 days in stable patients with CF. Pulmonary function was significantly greater during treatment than with placebo. No ototoxicity or nephrotoxicity was seen. Consequently, high doses of tobramycis for the treatment of resistant P. aeruginosa are now being used more often. Other agents successfully given by aerosol include ceftazidime and colimycin (Colistin). Colistin has been used alone and in conjunction with oral ciprofloxacin; this has resulted in slowing the decline in pulmonary function and has reduced recovery of P. aeruginosa from sputum. Although definitive studies have not outlined the role of each of these modalities, the use of inhaled antibiotics clearly offers children with CF additional non-invasive therapeutic approaches.
LUNG TRANSPLANTATION
Although tremendous advances have been made in the understanding of the pathophysiology of CF and in the development of new therapies, over 90 percent of patients with CF will die from pulmonary disease. In 1984, the first heart-lung transplant for CF was performed; since then, more than 650 lung transplants for CF have taken place. Outcomes have improved steadily; current one-year survival for adult lung recipients is about 80 percent; however, survival rates for children are lower. Generally speaking, before being listed for potential transplantation, a patient should have significant impairment in the quality of life, oxygen dependence, and marked lung-function impairment (FEV1 < 30 percent of predicted). As the management of the post-transplant recipient improves, lung transplantation may become a more acceptable option for individuals with end-stage lung disease.
THE MODERN CF CARE CENTER
Since the 1960s, the Cystic Fibrosis Foundation has accredited and financially supported CF Care Centers. There are now 113 such centers in the United States; the CF Foundation, using expert panels of physicians and scientists, guides CF care by the development of consensus documents regarding periodic assessment and treatment of the disease. Current guidelines include quarterly visits to the CF care center and at least annual testing to monitor disease severity and to screen for complications. While the basic goals of CF care centers have remained the same, the complexity of the disease's diagnosis and management continues to increase. The centers have two main functions: to provide state-of-the-art services for diagnosis and treatment of CF and to support research by collecting epidemiologic data, conducting clinical trials and performing basic science research.
The diagnostic criteria for CF have recently been expanded based on a wealth of clinical observations and the widespread commercial availability of CF genotyping. The majority of patients continue to be diagnosed by traditional criteria: demonstration of a sweat chloride level greater than or equal to 60 mEq/L on two quantitative pilocarpine iontopheresis sweat tests in the presence of typical clinical signs and symptoms, or a history of CF in a sibling or first cousin. Alternate diagnostic criteria may be helpful in unusual cases, or in patients with borderline sweat tests (sweat chloride >40 mEq/L but < 60 mEq/L). These include the demonstration of one of two gene mutations causing CF. Because of the large number of different gene mutations that cause CF, it is not possible for laboratories to screen for all mutations; thus, the sensitivity of genetic testing for CF is lower than sweat testing, about 85 percent for Caucasians and lower for other ethnic groups. Demonstration of an abnormal electrical potential across the nasal epithelium is now considered another acceptable diagnostic test for CF. It is based on abnormal bioelectrical properties of the nasal epithelium; although it is minimally invasive, special equipment and trained personnel are critical to successful measurements.
Sweat testing must be performed using rigorously standardized protocol by an experienced technician, with strict adherence to criteria from the National Center for Clinical Laboratory Standards. A minimum of 75 mg of sweat must be collected for accurate measurement of sweat chloride. Most errors are due to inadequate sample collection of technical error. Sweat tests are reliable after 48 hours of age, although inadequate sweat weight may necessitate re-testing at several weeks of age. Rarely, medical complications of CF can lead to false-negative sweat tests. This is most frequently seen in patients presenting with a syndrome of hypoproteinemic edema and anemia. Patients who are suspected of having CF because of severe hypochloremic dehydration should have sweat tests deferred until the electrolyte abnormality is reversed.
Because of the rigorous requirements of pilocarpine iontopheresis sweat tests, other methods of measuring sweat testing, the pediatrician must keep two important caveats in mind. First, only pilocarpine iontopheresis sweat testing is acceptable for the definitive diagnosis of cystic fibrosis. Second, false positive and false negative rates can be substantially higher by alternate methods. Thus, any patient with a positive test by an alternate method, or any patient with a negative test but who has symptoms suggestive of CF, should be referred to a CF care center for definitive testing.
The basic goals for the treatment of CF have remained unchanged for decades. To meet the complex medical and social needs of CF patients and their families, CF centers provide comprehensive care through a multidisciplinary care team that includes physicians, nurses, social workers, nutritionists and respiratory therapists (Figure 3). Furthermore, CF centers offer state-of-the-art diagnostic facilities, including microbiology and pulmonary function laboratories. Adequate nutrition, airway clearance techniques and treatment of acute and chronic chest infection are the major challenges for the CF patients, family and multidisciplinary health care team.
Nutritional problems in CF have several origins. In undiagnosed or undertreated patients, exocrine pancreatic insufficiency causes malabsorption of fats and proteins, leading to poor growth, often with associated abdominal pain and steatorrhea. A number of newer pancreatic enzyme supplements are more effective than those used in the recent past, primarily because they are more resistant to degradation by stomach acids. These preparations are available at higher strengths than previously, allowing the CF patient to take fewer pills prior to meals. Unfortunately, the use of very high strength pancreatic enzyme supplements (and even of very high doses of lower-strength products) have been associated with a rare but serious new complication of CF known as fibrosing colonopathy. This disorder leads to stricture and shortening of the colon: most cases require colectomy. Because of this complication, a recent consensus conference recommended that CF patients receive no more than 2500 lipase units per kilogram of body weight per meal, and that patients who have ongoing malabsorption in the face of apparently adequate pancreatic enzyme replacement undergo diagnostic evaluation for other causes of malabsorption.
The CF Foundation recommends that all CF patients have nutrition consultation at least annually; many patients will benefit from even closer monitoring. CF nutritionists offer assessment of growth, of dietary adequacy, and of the important interaction of diet and pancreatic enzyme supplements. Youngsters' diets should provide adequate calories for growth, emphasizing adequate protein intake. Most CF patients need a high calorie diet for at least two reasons: calorie loss through malabsorption and a higher resting energy expenditure produced by lung inflammation and infection, which occurs even in young infants without overt lung disease. Consequently, fat should not be restricted; in fact, adding additional fats to foods (e.g. in the form of oils, butter, margarine or mayonnaise) is an easy, inexpensive, and effective method of increasing caloric intake. Most affected individuals can achieve normal growth through a regular diet that emphasizes liberal fat and protein intake, with a schedule of regular meals and snacks. However, more severely ill patients, those with aversions to a high calorie intake, or those whose school or work schedules interfere with regular snacking, can benefit substantially from the addition of nutritional supplements, generally in the form of a drink or shake. These supplements can be taken orally with or between meals. Patients in need of more nutritional rehabilitation often benefit from the addition of nocturnal enteral tube feedings; although nasogastric tubes are adequate to provide calories, most patients prefer a gastrostomy for long-term nocturnal supplemental feedings. A variety of canned and powdered products are available to meet individual nutritional needs and taste preferences.
The CF respiratory therapist is an essential member of the care team, delivering direct care to hospitalized patients and, even more importantly, assessing, teaching and periodically reviewing the best airway clearance techniques for patients. A skilled social worker is needed for family screening and intervention for this disease, which has significant impact on family function and finances. A genetic counselor is also an important team member; the hereditary aspects of the disorder are discussed at diagnosis, and carrier screening and prenatal diagnosis are offered as desired and appropriate.
A good microbiology laboratory is also extremely important to physicians caring for CF patients because sometimes commercial laboratories misidentify some of the rarer organisms associated with CF, and accurate identification of organisms is essential. Consequently, the CF Foundation uses strict criteria to approve microbiology laboratories within CF centers. A pulmonary function laboratory is also essential; regular monitoring of lung function allows CF physicians to detect progression of lung disease even when clinical symptoms are minimal or absent. Most patients can perform reproducible spirometry by age seven, and many by age five; dedicated pediatric pulmonary function technicians are critical to the success of these measurements in young children.
The optimum care of CF patients requires specialized care with appropriately trained respiratory therapy, nursing, nutrition support staff, as well as specialized equipment. Many programs, including the one at Children's Memorial, incorporate pulmonary rehabilitation exercise programs.
Advances in diagnosis and clinical care, largely related to the coordination of research and patient care by the Cystic Fibrosis Foundation, have led to a tripling of median life expectancy since 1960. Infants and children diagnosed with CF today can expect to live well into adulthood. We continue to hope that advances in CF therapy will lead to a more rapid increase in the length and quality of life for affected individuals.
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Posted August 6th, 2007
THE MOLECULAR BASIS OF CF
In 1989, investigators discovered the CF gene using novel approaches. The gene product, called the cystic fibrosis transmembrane conductance regulator (CFTR), is a membrane-based protein with an active transport function. This is consistent with previous finding that the primary defect in CF cells is faulty transport of ions, especially of chloride. Conclusive information regarding the role of CFTR in the basic CF defect came with the demonstration that defective camp dependent chloride conductance in CF cells was restored when CFTR cDNA was transfected and expressed in those cells.
The functions of CFTR (cystic fibrosis transmembrane conductance regulator) are still being elucidated. CFTR functions as a chloride channel, but it also appears to regulate other channels. There is a regulatory influence on a voltage-sensitive chloride channel known as the outwardly rectifying chloride channel (ORCC), probably through active transport of ATP by CFTR. A regulatory influence on other ion channels is also evident; CF airway cells appear to be important in the pathophysiology of abnormal airway secretions in CF. This observation has led to clinical trials of inhaled amiloride and nucleotide triphosphates during the past few years.
Although CFTR (cystic fibrosis transmembrane conductance regulator) exists in many organs, the most prominent abnormalities are evident in airway epithelia (including the nose and sinus cavities as well as the lungs), sweat glands, pancreas, intestine, liver and genitourinary system. This is consistent wit the common presenting symptoms of CF (cystic fibrosis). At the time of diagnosis, half of patients have either acute or persistent respiratory symptoms; these include chronic cough, persistent wheezing - often of a bronchiolitic nature - and pulmonary infiltrates. More than one third have growth failure, while just under one third have obvious symptoms of malabsorption. Neonatal intestinal obstruction by meconium ileus leads to diagnosis in about 20 percent. More unusual presenting symptoms include nasal polyposis, electrolyte abnormalities (hyponatremic dehydration or persistent metabolic alkalosis), rectal prolapse and obstructive jaundice. Eventually, all patients develop respiratory tract involvement, and 85 to 90 percent will require pancreatic enzyme supplementation. The importance of CFTR in the genital tract is dramatically illustrated by the near-universal finding of congenital bilateral absence of the vas deferens (CBAVD) in males with CF. Since the discovery of the CF gene, it has been shown that men without other clinical signs of CF who are infertile because of CBAVD have defects in the CF gene.
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| Figure 1. Classes of CFTR mutations causing CF. (From Welsh MJ, and Smith AE: Molecular mechanisms of CFTR chloride channel dysfunction in cystic fibrosis. Cell 1993;73:1251- 1254.) |
Cystic fibrosis is caused by many different mutations of the CF gene; to date, more than 600 unique mutations have been described. However, one mutation, the delta F508 mutation, accounts for 70 percent of the CF genes in the United States. Other mutations are much less frequent, although 32 of the most common ones in CF include 85 percent of the genes causing CF in US whites. A commercially available panel currently detects 60 percent of mutations in African-Americans. Four classes of CFTR mutants have been described (Figure 1). Class 1 mutations cause premature termination of CFTR mRNA translation in the nucleus, resulting in severely decreased of absent CFTR protein production. Class 2 mutations, including the delta F508 mutation, lead to degradation of the protein within the endoplasmic reticulum; thus little or no functional protein is transferred to the cell membrane. Class 3 mutants are located in their proper place in the cell membrane but do not respond normally to regulatory signals. Class 4 mutants are also properly located but have faulty transport properties; these are the most active of the CFTR mutants. Genotype-phenotype relationships are related to the severity of the cellular ion transport defect. For example, R117H, a class 4 mutation, is strongly associated with preservation of pancreatic function. Class 1 and 2 mutations, the latter including the delta F508 mutation, are universally associated with exocrine pancreatic insufficiency. Interestingly, little correlation between mutation class and severity of airway disease has been described; this indicates that the progression of CF lung disease may be significantly influenced by environmental factors or immunological events that are not influenced directly by the specific CFTR genotype. In patients who are compound heterozygotes for CF, the "milder" mutation acts in a dominant fashion; this is analogous to the normal health status of carriers of the CF gene.
The pathophysiologic events that lead from faulty ion transport to organ abnormalities are a subject of intensive investigation. In the sweat duct, CFTR is the only channel capable of chloride reabsorption. Thus, from birth throughout adult life, CF sweat has a markedly elevated chloride concentration. This is the basis for the diagnostic test for CF; the sweat test was first developed after di Sant'Agnese and colleagues noted that many infants presenting with heat prostration during a heat wave in 1949 in New York City had CF.
Pathophysiologic events leading to chronic lung infection and bronchiectasis are more complicated. It has been hypothesized that desiccated mucus leading to bronchial obstruction sets off an inflammatory response and a vicious cycle of infection and inflammation. Infection precedes inflammation in the CF lung, says the theory, but recent studies suggest that signs of inflammation are present at a very early age despite the inability to recover bacteria from the lung, and evidence of significant airways inflammation has been demonstrated in infants and children with CF who otherwise have minimal or no evidence of lung disease. Regardless of the precipitating event, once the cycle is started, it becomes unrelenting; purulent lung infection, most commonly due to Pseudomonas aeruginosa and Staphylococcus aureus, lead to bronchiectasis and, ultimately, death. P. aeruginosa and S. aureus have enhanced ability to bind to the CF airway epithelium because of the altered CF mucus, higher mucus osmolarity, or altered glycoconjugate composition of the airway cells.
During the past year (1996), the first evidence that chronic lung infection is directly related to the CFTR abnormality has been produced. Smith et al reported a series of experiments conducted on normal and CF airway cells. When the bacteria P. aeruginosa and S. aureus are applied to normal cells, bacterial killing occurs rapidly; very few if any bacteria are recovered after 24 hours. In contract, in CF cells, bacteria proliferate on the cell surface. Further experiments showed that fluid removed from the surface of normal airway cells or CF cells had bactericidal activity. However, the dehydrated environment of CF airway surface fluid was found to inactivate this bactericidal activity. In the presence of high NaCl concentrations, as found in dehydrated CF airway fluid, normal cells behaved as CF cells, with abnormal bacterial killing. Conversely, rehydration of CF cells leads to normal bacterial killing. These studies provide strong evidence that abnormal CF airway secretions, caused by mutant CFTR, are directly linked to chronic airways infection in CF.
The immune response to lung infection in individuals with CF is not impaired and may actually be too vigorous, leading to overly aggressive lung inflammation. In healthy lungs, introduction of P. aeruginosa results in a rapid influx of neutrophils with eradication of the bacteria. Similar findings are also observed for S. aureus, with an influx of alveolar macrophages. In CF, these pathogens are not eradicated in spite of this robust cellular response. The virulence of these bacteria may be due to the production of exotoxins, exopolysaccharides, or proteinases that allow the bacteria to escape the normal host immune response. P. Aeruginosa grows into macrocolonies which, because of sheer size, escape neutrophil phagocytosis; these huge complexes may act as a further chemoattractant for neutrophil influx. Neutrophils release lysosomal contents resulting from successful phagocytosis, frustrated phagocytosis (inability to attack macrocolony), or cell death. A major component of neutrophil lysosomes, neutrophil elastase (NE) overwhelms the body's normal elastase inactivation, alpha 1-protease inhibitor. The unchecked activity of NE (neutrophil elastase) results in significant lung damage by several mechanisms; elastolytic damage (potential bronchiectasis), stimulation of airway gland secretion (airway obstruction), reduced ciliary beat frequency (airway obstruction), impairment of opsonophagocytosis of the bacteria (persistence of bacteria), and increased binding of P. aeruginosa to lung tissue via cleavage of fibronectin. The increased neutrophil load also leads to increased oxygen radical production, increased airway-surface DNA after cell death, and increased interleukin 8 stimulation and leukotriene B4 levels, which lead to further neutrophil recruitment.
Based on the pathophysiologic cascade of cystic fibrosis, which arises from gene abnormality and progresses to respiratory failure, therapies have been designed to intervene at multiple levels (figure 2). These therapies, many of which are still experimental, are reviewed below.
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| Figure 2. The pathophysiologic cascade of cystic fibrosis lung disease. |
GENE THERAPY
The ultimate treatment for any genetic disease is to replace the faulty gene with a copy of the normal gene, thus reversing the pathophysiologic cascade that leads to organ damage. CF has been considered a good candidate for gene therapy because most of the morbidity and mortality are due to CF lung disease, and airways cells are readily accessible to gene delivery by aerosol therapy or via bronchoscopy. Within a year after the discovery of the CF gene, scientists showed that a normal copy of the CF gene could be inserted into CF airway cells which would express functional CFTR. This rapidly lead to clinical trials of gene therapy, many of which are currently underway in the US and Europe.
Current human gene therapy trials for CF use a variety of vectors attached to the CF gene to allow the gene to be carried across the cell membrane and into the nucleus. Most trials use modified viral vectors, such as adenovirus; some use liposome or liposome nucleotide vectors. While there has been success in transfection of the vector-gene combination to the cell and resultant gene expression and correction of the electrolyte defect in CF cells in vivo, successful gene therapy has been hindered by a number of problems. First, transfection and expression are very inefficient; in many studies, fewer than one percent of cells show evidence of gene expression. Second, there is often a significant inflammatory response, primarily due to host responses to the viral vector. Based on these findings, vectors are being modified to offer more efficient transfection with less toxicity. Progress has been very rapid, and gene therapy for CF may become a reality within the next decade.
REPLACEMENT OF CFTR OR REPAIR OF THE DEFECTIVE CFTR PROTEIN
Another method of correcting the cellular abnormality would be to insert normal CFTR protein into the cell membrane. Early experiments have shown some success in vitro. Another strategy has been the focus of much recent attention. Researchers have observed that in the most common genetic defect causing CF, the delta F508 mutation, a protein is formed that is at least partially functional; the main defect is the lack of transport of the protein to the cell membrane. Sodium 4-phenylbutyrate, currently in use for treatment of rare urea cycle disorders, works as a "chemical chaperone" in CF cells, allowing for transport of the mutant protein to the cell membrane, where partial restoration of ion transport is seen. Early clinical trials of this agent are underway. Other agents, including dimethyl sulfoxide, have been shown to have similar effects in vitro and may be studied in future clinical trials.
CORRECTION OF THE ELECTROLYTE TRANSPORT ABNORMALITY
Agents that can counter the decreased chloride secretion and increased sodium absorption in CF respiratory epithelial cells have been studied. Amiloride is a diuretic that, when given by inhalation, reduces absorption of sodium and water in airway epithelium. In mildly affected CF lungs, inhaled amiloride reaches the cell surface where it increases mucociliary clearance, improves sputum viscosity and slows the decline of pulmonary function. In spite of early enthusiasm, amiloride as a single agent has not shown to be beneficial in large clinical trials. UTP is a nucleotide that increases chloride secretion in CF cells and enhances mucociliary clearance in adult CF patients. The concomitant administration of amiloride and UTP via the nebulized route is under investigation. It is important to consider that any inhalational therapy primarily benefits patients with relatively mild lung disease, since distribution of inhaled drugs to small airways is very impaired as lung disease progresses. Clinical trials are underway to establish the effect of combined therapy on airway clearance in teenagers with mild disease and to evaluate the safety profile for children five to ten years of age. Other agents that alter chloride transport have been proposed but have not yet reached clinical trials.
MUCOLYTICS
Historically, nonspecific mucolytics have been employed to reduce the viscosity of CF mucus. As CF respiratory mucus appears to be over sulfated, N-acetyl cysteine (Mucomyst), an agent that breaks sulfide bonds, has been used to enhance mucociliary clearance. Although the medication is helpful for some patients, many patients experience bronchospasm and an unpleasant taste from it, so it is now infrequently used. Sodium bicarbonate given via aerosol has been used for mucolysis but is also associated with local irritation and bronchospasm. Long-term benefit has not been established for either agent. Hypertonic saline, administered via an ultrasonic nebulizer, has been recently reported to enhance mucus clearance and improve lung function; further studies are underway.
Up to 10 percent of the dry weight of CF mucus can be attributed to DNA, which is released primarily from airway neutrophils. The excessive DNA (deoxyribonucleic acid - DNA is a code used within cells to form proteins) content of CF mucus contributes to its abnormally high viscosity. As early as the 1950s, it was shown that aerosolized bovine pancreatic deoxyribonuclease-1 could reduce the viscosity of airway secretions, but significant allergic reactions and bronchospasm precluded its use. With recombinant DNA technology, development of recombinant human deoxyribonuclease-1 (rhDNase) has offered a major therapeutic advance for patients with CF. In the test tube, rhDNase decreased the viscosity, elasticity and adhesiveness of CF sputum, turning a non-flowing viscous gel to a free-flowing liquid. After the efficacy and safety of nebulized rhDNase were established in Phase I and II trials, a multicenter, double-blind placebo-controlled Phase III trial was conducted to determine its long-term effectiveness in adults and children. In the trail, 968 CF patients (>(less than) 5 years of age and FVC > 40 percent of predicted) were randomized to three groups - to placebo, 2.5 mg rhDNase daily and 2.5 mg twice daily for 24 weeks. The main findings were a 31 percent reduction in the relative risk of a pulmonary exacerbation and improved pulmonary function as measured by a 5.8 percent increase in FEV1 in the rhDNase groups. Other therapeutic benefits included enhancement of quality of life, reduction in dyspnea, and fewer days of parenteral antibiotics. The twice-daily dosing was only slightly more effective than once daily dosing. Minimal side effects were seen; the most common were voice alteration and laryngitis. These results are encouraging, and currently about 40 percent of all U.S. CF patients receive rhDNase (Pulmozyme). More widespread use may be limited by the high cost of the product - approximately $900 per patient per month. Evidence suggests that some patients respond better than others; however, there are no accurate ways to predict which ones will benefit from this very expensive therapy. The available data indicates that some patients who have mild lung disease and a productive cough appear to gain ground.
Degenerating neutrophils also release F-actin into the CF mucus, which also increased its viscosity. Gelsolin is a protein that can break the non-covalent bonds between F-actin filaments. Early studies showed that, when used in combination with rhDNase, gelsolin acts synergistically to reduce CF sputum viscosity. Further studies are ongoing with this mucolytic agent.
MUCOCILIARY CLEARANCE
Basic therapy for patients with CF is directed toward enhancing mucociliary clearance through a variety of airway clearance techniques (ACTs) that benefit CF patients with every degree of lung disease. Most patients use Acts daily. Traditional chest physiotherapy with postural drainage is designed to move mucus from smaller airways to larger airways where it can be expectorated effectively. This is done by percussion on the chest wall with the child in varying positions that use gravity to promote mucus clearance. Although the therapy requires no special equipment, it does call for a trained adult caregiver. Because of this and because of the physical demands involved, new modalities have been developed to allow for greater independence; some of these methods may provide superior mucus clearance. For example, the "huff" and autogenic drainage method are special breathing techniques that improve ventilation and maximize the effectiveness of a cough; in order to perform these techniques properly and reproducibly, though, patients must be well trained and motivated. The PEP valve (positive expiratory pressure valve) provides a distending pressure to the airways and, when combined with breathing maneuvers, allows for enhanced mucus clearance. The Flutter® is a pipe-shaped hand-held device that contains a stainless steel ball. During expiration, the ball oscillates, causing oscillatory waves to be transmitted to the lower airways, shearing secretions from the airway walls. The patient then uses a huff cough technique to clear loosened secretions from the airways. Another modality, the ThAIRapy bronchial drainage system®, uses high-frequency chest wall oscillations, which also shear mucus from the airway wall. While this system is much more expensive than the Flutter and PEP devices, it is not effort-dependent; furthermore, the physician can directly monitor compliance as the device records hours of use.
For many CF patients, bronchial hyperreactivity contributes to the respiratory abnormality. Regular use of bronchodilators has been shown in some studies to improve pulmonary function in as many as 50 percent of CF patients. The use of inhaled bronchodilators prior to chest physiotherapy may help facilitate mucociliary clearance via direct bronchodilation effects or enhanced ciliary beat frequency. Beta-adrenergic agents, like albuterol (Proventil, Ventolin), are the most commonly used agents for this purpose. Recently, ipatropium bromide (Atrovent) has been shown to be as effective as albuterol, possibly with fewer side effects. Because some patients have paradoxical bronchospasm with bronchodilators (up to 8 percent in one series), assessment in the pulmonary function laboratory is very helpful in determining individual usage.
ANTI-INFLAMMATORY THERAPY
The role of inflammation in the pathophysiology of CF lung disease has been reviewed. Suppression of inflammation can be achieved by use of several available agents. A recent multicenter study evaluated the role of alternate-day oral corticosteroid (prednisone) therapy in patients with mile to moderate CF lung disease. The study followed 285 children for more than a four-year period; the children were given doses of 1 mg/kg prednisone per day, 2 mg/kg, or placebo. The study showed that children taking either dose of prednisone had better lung function than the placebo group; the higher -dose prednisone groups had an unacceptably higher rate of side effects, leading to an early discontinuation of that study arm. The benefits continued for the duration of the study (four years). This study, along with others, demonstrates that corticosteroids can suppress the inflammatory response and lead to improvement in lung function in children with CF. However, therapy is limited by side effects - suppressed linear growth and increased rates of P. aeruginosa colonization even in the lower-dose group. It is recommended that prednisone be given for no longer than six months and with close clinical monitoring. The role of short bursts of steroids in the acute treatment of CF exacerbations is being investigated.
Because the benefits of oral corticosteroids are apparent, current studies have turned to the efficacy of inhaled corticosteroids on lung function in individuals with CF. A pilot study in 49 patients examined in haled corticosteroids over a 30-day period and concluded that the steroid-treated group had better pulmonary function as evidenced by an improved thoracic gas volume. This route of steroid delivery has obvious appeal and reduced the likelihood of side effects. Further studies are underway.
An alternative to corticosteroids are the non-steroidal anti-inflammatory drugs (NSAIDs). The effects of high-dose ibuprofen, an NSAID, was evaluated in 85 children with mild CF lung disease over a four-year period. For younger children (5 to 13 years), lung function declined by only 1.5 percent per year compared to 4 percent per year in the placebo group. No differences were seen for older children (>13 years). Side effects were infrequent and minor. This agent may slow the progression of lung disease without serious side effects. Because inadequate serum ibuprofen levels may actually promote airway inflammation, the dose of ibuprofen must be based on rigorously performed pharmacokinetic testing. Because high dose ibuprofen has only recently been introduced for patient use, studies documenting the long-term experience are lacking; anecdotal reports of renal insufficiency, renal failure and bleeding mandate close patient follow-up.
Other potentially useful anti-inflammatory agents include alpha-1 antitrypsin (A1AT), pentoxifylline and secretory leukocyte protease inhibitor (SLPI). A1AT is a naturally occurring anti-protease that helps limit the inflammatory damage in the CF lung but is overwhelmed by the presence of large quantities of neutrophil elastase. In a pilot study, aerosolized A1AT increased the amount of the protein in the lung and suppressed elastase activity. Clinical trials are needed to determine whether administration of this agent will slow the progression of lung disease. Pentoxifylline is a xanthine derivative that may reduce the adhesiveness of neutrophils to epithelial cells. A phase III trial is currently underway. SLPI, another antiprotease normally found in the lung, can be given via the aerosolized route. A pilot study in CF patients showed decreased neutrophil elastase activity and interleukin-8 levels. None of these agents is currently recommended for clinical use.
ANTIMICROBIAL THERAPY
The use of antibiotics for CF lung infections continues to evolve. Before effective antistaphylococcal antibiotics, most CF patients died with purulent lung infection due to S. aureus. This organism continues to be isolated frequently from the respiratory tract of infants and young children with CF; however, over time, most patients develop infections with P. Aeruginosa. Other important pathogens include H. influenza (especially in young patients), S. maltophilia and B. cepacia. The latter is relatively rare but is sometimes associated with a rapidly deteriorating clinical course.
There has been widespread interest in the use of prophylactic antibiotics to prevent the progression of CF lung disease. To date, no clinical trial has demonstrated a benefits of prophylactic antibiotics in this population. A recently completed double-blind, placebo-controlled trial of daily cephalexin in children < 5 years of age demonstrated no pulmonary function benefit but rather a disturbing increase in P. aeruginosa colonization. Thus, most patients take antibiotics only for symptomatic pulmonary exacerbation manifested by an increase in cough, a change in quantity or quality (viscosity, color) of sputum, change in appetite and/or weight loss and a variety of other symptoms. The physical exam may be unchanged or reveal new crackles, rhonchi or wheezes. Spirometry often shows a decline in forced expiratory volume in one second (FEV1).
Appropriate treatment of a pulmonary exacerbation depends on the severity of underlying lung disease, the severity of the exacerbation and the patient's respiratory tract flora. For mild or moderate exacerbations in patients primarily colonized with S. aureus or H. influenzae, trimethoprim-sulfamethoxazole, an oral cephalosporin, or amoxicillin-clavulanate is usually effective. For mild or moderate exacerbations in patients colonized with P. aeruginosa, an oral fluoroquinolone antibiotic is often beneficial. This relatively new class of drugs has had a very positive impact on CF patients; however, the emergence of antimicrobial resistance is relatively rapid, so frequent or prolonged courses must be avoided. When oral antibiotics are unsuccessful, when exacerbations occur frequently over time, or in the case of severe exacerbations, intravenous antibiotics are required. Most frequently, a combination of a beta lactam and an aminoglycoside (such as piperacillin and tobramycin) is used. Monobactams (aztreonam) and carbapenems (imipenem, meropenem) also combat P. aeruginosa; these agents are generally reserved for organisms that are resistant to other beta lactams. The choice of antibiotics for an individual depends on sputum culture and sensitivity test results; sputum cultures are recommended at least annually for all patients.
Some studies have suggested that the use of regularly-scheduled intravenous antibiotics, given for two weeks four times yearly, is beneficial to CF patients colonized with P. aeruginosa. Such a strategy is employed in Denmark, which boasts very high survival rates in CF. A number of CF experts have suggested that P. aeruginosa, when first isolated, may be eradicated by aggressive treatment, thus slowing the rate of lung function decline. No rigorous clinical trials of either strategy have been conducted.
A novel approach to antibiotic delivery has developed over the past 15 years: the use of aerosolized antibiotics. Advantages of this delivery system include the ability to achieve very high concentrations of antibiotics in the sputum, which would otherwise be possible only with significant systemic toxicity. Aminoglycosides (gentamicin and tobramycin) are highly effective anti-pseudomonal agents that can be delivered by this route; these agents are frequently used for mild or moderate exacerbations of CF lung disease at doses of 80 to 160 mg two or three times daily. A recent study evaluated the efficacy of high-dose tobramycin by nebulizer (600 mg tid) given for 28 days in stable patients with CF. Pulmonary function was significantly greater during treatment than with placebo. No ototoxicity or nephrotoxicity was seen. Consequently, high doses of tobramycis for the treatment of resistant P. aeruginosa are now being used more often. Other agents successfully given by aerosol include ceftazidime and colimycin (Colistin). Colistin has been used alone and in conjunction with oral ciprofloxacin; this has resulted in slowing the decline in pulmonary function and has reduced recovery of P. aeruginosa from sputum. Although definitive studies have not outlined the role of each of these modalities, the use of inhaled antibiotics clearly offers children with CF additional non-invasive therapeutic approaches.
LUNG TRANSPLANTATION
Although tremendous advances have been made in the understanding of the pathophysiology of CF and in the development of new therapies, over 90 percent of patients with CF will die from pulmonary disease. In 1984, the first heart-lung transplant for CF was performed; since then, more than 650 lung transplants for CF have taken place. Outcomes have improved steadily; current one-year survival for adult lung recipients is about 80 percent; however, survival rates for children are lower. Generally speaking, before being listed for potential transplantation, a patient should have significant impairment in the quality of life, oxygen dependence, and marked lung-function impairment (FEV1 < 30 percent of predicted). As the management of the post-transplant recipient improves, lung transplantation may become a more acceptable option for individuals with end-stage lung disease.
THE MODERN CF CARE CENTER
Since the 1960s, the Cystic Fibrosis Foundation has accredited and financially supported CF Care Centers. There are now 113 such centers in the United States; the CF Foundation, using expert panels of physicians and scientists, guides CF care by the development of consensus documents regarding periodic assessment and treatment of the disease. Current guidelines include quarterly visits to the CF care center and at least annual testing to monitor disease severity and to screen for complications. While the basic goals of CF care centers have remained the same, the complexity of the disease's diagnosis and management continues to increase. The centers have two main functions: to provide state-of-the-art services for diagnosis and treatment of CF and to support research by collecting epidemiologic data, conducting clinical trials and performing basic science research.
The diagnostic criteria for CF have recently been expanded based on a wealth of clinical observations and the widespread commercial availability of CF genotyping. The majority of patients continue to be diagnosed by traditional criteria: demonstration of a sweat chloride level greater than or equal to 60 mEq/L on two quantitative pilocarpine iontopheresis sweat tests in the presence of typical clinical signs and symptoms, or a history of CF in a sibling or first cousin. Alternate diagnostic criteria may be helpful in unusual cases, or in patients with borderline sweat tests (sweat chloride >40 mEq/L but < 60 mEq/L). These include the demonstration of one of two gene mutations causing CF. Because of the large number of different gene mutations that cause CF, it is not possible for laboratories to screen for all mutations; thus, the sensitivity of genetic testing for CF is lower than sweat testing, about 85 percent for Caucasians and lower for other ethnic groups. Demonstration of an abnormal electrical potential across the nasal epithelium is now considered another acceptable diagnostic test for CF. It is based on abnormal bioelectrical properties of the nasal epithelium; although it is minimally invasive, special equipment and trained personnel are critical to successful measurements.
Sweat testing must be performed using rigorously standardized protocol by an experienced technician, with strict adherence to criteria from the National Center for Clinical Laboratory Standards. A minimum of 75 mg of sweat must be collected for accurate measurement of sweat chloride. Most errors are due to inadequate sample collection of technical error. Sweat tests are reliable after 48 hours of age, although inadequate sweat weight may necessitate re-testing at several weeks of age. Rarely, medical complications of CF can lead to false-negative sweat tests. This is most frequently seen in patients presenting with a syndrome of hypoproteinemic edema and anemia. Patients who are suspected of having CF because of severe hypochloremic dehydration should have sweat tests deferred until the electrolyte abnormality is reversed.
Because of the rigorous requirements of pilocarpine iontopheresis sweat tests, other methods of measuring sweat testing, the pediatrician must keep two important caveats in mind. First, only pilocarpine iontopheresis sweat testing is acceptable for the definitive diagnosis of cystic fibrosis. Second, false positive and false negative rates can be substantially higher by alternate methods. Thus, any patient with a positive test by an alternate method, or any patient with a negative test but who has symptoms suggestive of CF, should be referred to a CF care center for definitive testing.
The basic goals for the treatment of CF have remained unchanged for decades. To meet the complex medical and social needs of CF patients and their families, CF centers provide comprehensive care through a multidisciplinary care team that includes physicians, nurses, social workers, nutritionists and respiratory therapists (Figure 3). Furthermore, CF centers offer state-of-the-art diagnostic facilities, including microbiology and pulmonary function laboratories. Adequate nutrition, airway clearance techniques and treatment of acute and chronic chest infection are the major challenges for the CF patients, family and multidisciplinary health care team.
Nutritional problems in CF have several origins. In undiagnosed or undertreated patients, exocrine pancreatic insufficiency causes malabsorption of fats and proteins, leading to poor growth, often with associated abdominal pain and steatorrhea. A number of newer pancreatic enzyme supplements are more effective than those used in the recent past, primarily because they are more resistant to degradation by stomach acids. These preparations are available at higher strengths than previously, allowing the CF patient to take fewer pills prior to meals. Unfortunately, the use of very high strength pancreatic enzyme supplements (and even of very high doses of lower-strength products) have been associated with a rare but serious new complication of CF known as fibrosing colonopathy. This disorder leads to stricture and shortening of the colon: most cases require colectomy. Because of this complication, a recent consensus conference recommended that CF patients receive no more than 2500 lipase units per kilogram of body weight per meal, and that patients who have ongoing malabsorption in the face of apparently adequate pancreatic enzyme replacement undergo diagnostic evaluation for other causes of malabsorption.
The CF Foundation recommends that all CF patients have nutrition consultation at least annually; many patients will benefit from even closer monitoring. CF nutritionists offer assessment of growth, of dietary adequacy, and of the important interaction of diet and pancreatic enzyme supplements. Youngsters' diets should provide adequate calories for growth, emphasizing adequate protein intake. Most CF patients need a high calorie diet for at least two reasons: calorie loss through malabsorption and a higher resting energy expenditure produced by lung inflammation and infection, which occurs even in young infants without overt lung disease. Consequently, fat should not be restricted; in fact, adding additional fats to foods (e.g. in the form of oils, butter, margarine or mayonnaise) is an easy, inexpensive, and effective method of increasing caloric intake. Most affected individuals can achieve normal growth through a regular diet that emphasizes liberal fat and protein intake, with a schedule of regular meals and snacks. However, more severely ill patients, those with aversions to a high calorie intake, or those whose school or work schedules interfere with regular snacking, can benefit substantially from the addition of nutritional supplements, generally in the form of a drink or shake. These supplements can be taken orally with or between meals. Patients in need of more nutritional rehabilitation often benefit from the addition of nocturnal enteral tube feedings; although nasogastric tubes are adequate to provide calories, most patients prefer a gastrostomy for long-term nocturnal supplemental feedings. A variety of canned and powdered products are available to meet individual nutritional needs and taste preferences.
The CF respiratory therapist is an essential member of the care team, delivering direct care to hospitalized patients and, even more importantly, assessing, teaching and periodically reviewing the best airway clearance techniques for patients. A skilled social worker is needed for family screening and intervention for this disease, which has significant impact on family function and finances. A genetic counselor is also an important team member; the hereditary aspects of the disorder are discussed at diagnosis, and carrier screening and prenatal diagnosis are offered as desired and appropriate.
A good microbiology laboratory is also extremely important to physicians caring for CF patients because sometimes commercial laboratories misidentify some of the rarer organisms associated with CF, and accurate identification of organisms is essential. Consequently, the CF Foundation uses strict criteria to approve microbiology laboratories within CF centers. A pulmonary function laboratory is also essential; regular monitoring of lung function allows CF physicians to detect progression of lung disease even when clinical symptoms are minimal or absent. Most patients can perform reproducible spirometry by age seven, and many by age five; dedicated pediatric pulmonary function technicians are critical to the success of these measurements in young children.
The optimum care of CF patients requires specialized care with appropriately trained respiratory therapy, nursing, nutrition support staff, as well as specialized equipment. Many programs, including the one at Children's Memorial, incorporate pulmonary rehabilitation exercise programs.
Advances in diagnosis and clinical care, largely related to the coordination of research and patient care by the Cystic Fibrosis Foundation, have led to a tripling of median life expectancy since 1960. Infants and children diagnosed with CF today can expect to live well into adulthood. We continue to hope that advances in CF therapy will lead to a more rapid increase in the length and quality of life for affected individuals.
For Further Reading:
- Davis PB, Drumm M, Konstant MW: State of the art: Cystic Fibrosis. Am J. Respir Crit Care Med, 1996: 154:1229-1256.
- Rommens JM, Iannuzzi MC, Kerem E. et al. Identification of the Cystic Fibrosis Gene: Chromosome walking and jumping. Science, 1989; 235:1059-1065.
- Patient registry 1995 annual data report, Cystic Fibrosis Foundation, 1996, Bethesda, Maryland.
- Knowles MR, Hohneker KW, Zhou ZQ, et. al: A controlled study of adenoviral-vector-mediated gene transfer in the nasal epithelium of patients with Cystic Fibrosis. N Engl J Med 1995; 333:823-831.
- Eigen H, Rosenstein BJ, FitzSimmons S, and Schidlow DV: A multi-center study of alternate-day prednisone therapy in Cystic Fibrosis. J Pediatr, 1995; 126:515-523.
- Konstan MW, Byard BJ, Hoppel CL, and David PBL, Effect of high-dose ibuprofen in patients with Cystic Fibrosis. N Engl J Med 1995; 332:848-854.
- Hodson ME: Aerosolized dornase alfa (rhDNase) for therapy of Cystic Fibrosis. Am J Respir Crit Care Med 1995; 151 (Supplement):S70-S74.
- Konstan MW, Stern RC, Doerschuk, CF: Efficacy of the Flutter device for airway mucus clearance in patients with Cystic Fibrosis. J Pediatr 1994;124:689-693.
- Cropp GJ: Effectiveness of bronchodilators in Cystic Fibrosis. Am J Med 1996; 100 (Supplement):1A-19S.
- Ramsey BW, Dorkin HL, Eisenberg JD, et al: Efficacy of aerosolized tobramycis in patients with Cystic Fibrosis. N Engl J Med, 1993: 328:1740-1746.
Links:
The Cystic Fibrosis Foundation's home page at http://www.cff.org/ is a great jumping off point for many topics related to CF. For readers interested in more information on the CF's genetic mutations, see the Cystic Fibrosis Mutation Data Base at http://www.genet.sickkids.on.ca/cftr, which is a site belonging to the Department of Genetics, The Hospital for Sick Children in Toronto, Ontario, Canada.
Comments
thanks
I like this article. It gave me mroe insights about Cystic Fibrosis. i will ask some friends to read this as well. keep it up! sharon
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