Although cystic fibrosis is the most common lethal inherited disease of Caucasians, with an incidence in Caucasians of approximately 1 in 2000 to 2500 live births, primary care pediatricians would be expected to have few, if any, cystic fibrosis patients within their practice. Moreover, being a multisystem disease with a wide spectrum of clinical problems, patients clearly are better managed by regional centers, which have the range of expertise necessary to manage these patients. Why, therefore, should cystic fibrosis be of interest to primary care pediatricians?
First, in the absence of routine neonatal screening, initial diagnosis is largely dependent on the skills of the physician who first examines these patients. Unfortunately, delay in diagnosis does occur.1 Although a definitive therapy is not yet available, delayed diagnosis and initiation of therapy still may have significant consequences for the patient. Moreover, should definitive therapy become available, its effectiveness will probably be greatest if started early in the disease prior to the onset of significant pulmonary damage. Primary care physicians, therefore, still need to be aware of the presenting symptoms and management of cystic fibrosis.
Second, the recent advances in biotechnology and genetics have opened up the possibility of treating inherited diseases at the genetic or cellular level. Cystic fibrosis is a paradigm for a common genetic disease that may be amenable to therapy either by specific gene therapy targeted at the primary defect or at the cellular level to correct the resulting biochemical abnormality.
Cystic fibrosis is inherited on an autosomal recessive basis; therefore, 5% of the Caucasian population are carriers. There is marked variability in incidence between various racial groups, the exact cause for this variability being still unknown. Some carrier advantage is presumed but remains unproven.
The locus for the cystic fibrosis mutation is on the long arm of chromosome 7. In 70% of cases, cystic fibrosis is caused by a three base pair deletion (AF5Qo)1 which results in loss of phenylalanine from the resulting protein product.2 In a further 20% of cases, cystic fibrosis is caused by one of over 100 other identified mutations, all occurring within the cystic fibrosis locus, while in the final 10% the precise mutation has yet to be characterized. Cystic fibrosis is a heterogeneous disease with a wide range of clinical expression. The AF508 mutation appears to be in general associated with worse prognosis (early presentation, pancreatic insufficiency, and more rapidly progressive pulmonary disease), while the other mutations (the remaining 30% of patients) tend to result in milder disease (later presentation, pancreatic sufficiency, and delayed onset of pulmonary infection).2
Cystic fibrosis is characterized by widespread plugging of exocrine glands, particularly within gastrointestinal and respiratory systems, by apparently hyperviscous secretions. The cystic fibrosis gene codes for a specific protein, called the cystic fibrosis transmembrane regulatory (CFTR) protein. This protein functions as an ionic channel, facilitating and regulating transport of intracellular chloride ions across the apical membrane of epithelial cells.3 Depending on the specific mutation, the CFTR protein may be formed intracellularly but not incorporated into the apical membrane, or it may be incorporated into the apical membrane but be poorly permeable to chloride ions. This results in deficient transport of chloride ions to the luminal surface of the cell. Since water transport across epithelium primarily occurs as a consequence of the osmotic grathent created by transport of sodium chloride, a chloride channel defect presumably results in defective water transport2 with secondary dessication of surface secretions. In addition, there are intrinsic abnormalities in the mucous glycoproteins of patients with cystic fibrosis. Abnormal anionic processing, consequent to the chloride channel defect, may cause secondary changes in intracellular pH. This results in abnormal sulfation of the glycoproteins, resulting in excess gelation. The combination of the relative dessication and excess gelation results in hyperviscosity of exocrine secretions with secondary obstruction of the glandular ducts.2
In utero obstruction of the pancreatic ducts results in pancreatic fibrosis, with complete absence of production of pancreatic enzymes in 85% of cases. This results in maldigestion, and hence malabsorption, of dietary fat and protein. These patients will therefore need oral supplementation with pancreatic enzymes to achieve normal digestion and absorption. In the remaining 15% of cases, although pancreatic exocrine function is abnormal (ranging from 3% to 50% of normal), it is still sufficient for normal digestion.
The lungs in patients with cystic fibrosis are structurally normal at birth. However, within the next few years a chronic, low-grade infection of the respiratory tract develops.4 This is presumed to arise as the result of a disturbance in mucociliary clearance secondary to the hyperviscous secretions and preferential binding to the abnormal mucoproteins by a specific group of bacteria (see below). The two major hallmarks of the disease are, therefore, failure to thrive (limited to the 85% of cases with steatorrhoea) and chronic suppurative endobronchial disease (eventually presenting in all patients).
The defect in chloride transport results in failure to re-absorb sodium and chloride from the distal sweat duct, and hence in elevated levels of sodium chloride at high sweat rates. Measurement of sodium chloride levels in sweat induced by pilocarpine iontophoresis is therefore the primary diagnostic test for cystic fibrosis. There is a high degree of discrimination between normal and abnormal, providing the test is performed properly by an experienced technician. Patients with cystic fibrosis almost invariably have sweat chloride greater than 50 mEq/L, with less than 2% of normal individuals having sweat chlorides in that range.5 Alternative screening devices have been developed, although none have proven as accurate.
In utero obstruction of the pancreatic ducts results in leaking of pancreatic enzymes into the bloodstream, with serum immunoreactive trypsinogen levels being characteristically elevated in neonates with cystic fibrosis. The dried blood spot assay is therefore a practical method for neonatal screening for cystic fibrosis.1 However, in the absence of a definitive therapy, it is unclear at this point as to whether neonatal screening for cystic fibrosis is "cost effective." A number of pilot studies currently are underway around the world; until either their results or a definitive therapy are available, this generally is not recommended.6
Figure 1. Percentage of patients over the ages of 18, 25, and 32 years, respectively, reported to the Canadian Cystic Fibrosis Registry. Data are collected yearly from all registered cystic fibrosis clinics across Canada. (Data from this graph was obtained from the annual reports of the Canadian Patient Data Registry, 1970 through 1991. Published with permission of the Canadian Cystic Fibrosis Foundation, Toronto, Canada.)
In families who have already had one affected child, analysis of the gene makeup of the affected child and both parents provides gene markers for detection of affected offspring in future pregnancies. Prenatal diagnosis by genetic analysis of either amniotic fluid cells or chorionic villus samples is therefore readily available in families with a prior affected child.7 Although screening for the six or 10 most common mutations that cause cystic fibrosis (out of the over 100 so far identified) will pick up approximately 85% of cases (depending on die racial mix of the population studied), the incidence of falsenegative testing, the indications for prenatal screening for a disease with a current life expectancy of around 30 years, and the costs of widespread testing have precluded genetic testing for carriers of cystic fibrosis in the general population.
When first described by Anderson in 1938, cystic fibrosis was felt to be an invariably fatal disease of children. Since then, survival of patients with cystic fibrosis has steadily increased, such that the median survival for patients with cystic fibrosis is now into the third decade8 with almost 40% of patients in most clinics now being adults (Figure 1). This increased survival in patients with cystic fibrosis has probably occurred as a consequence of both an improved diagnosis and therapy.
Figure 2. Constellation of common clinical problems presenting in cystic fibrosis.
CLINICAL PRESENTATION AND THERAPY
As a consequence of the mucous hyperviscosity and abnormal electrolyte content of sweat, patients with cystic fibrosis can present with a wide range of clinical problems4 (Figure 2). Moreover, the improved survival of patients with cystic fibrosis has resulted in a changing spectrum of clinical disease8 (Table).
Maiabsorption. With the use of pancreatic supplements and high-calorie diets, normal growth can be achieved in the majority of patients with cystic fibrosis. Malnutrition, however, may still be a problem, usually in a small group of patients either with behavioral eating disorders or more severe pulmonary disease and tends to be associated with a worse prognosis. Maintenance of normal growth and nutrition is therefore a primary feature of the treatment of patients with cystic fibrosis. This is usually readily achieved by the use of aggressive dietary intervention with oral pancreatic enzyme supplements (in the 85% of patients who are pancreatic insufficient) and high-calorie diets. With this approach, normal height and weight is expected in the majority of patients with cystic fibrosis. Additional oral caloric supplementation may sometimes be needed, on rare occasions being supported using invasive approaches such as total parenteral nutrition (indwelling catheters) or gastrostomy/jejunostomy feeds.
Intestina/ Obstruction. Approximately 15% of patients with cystic fibrosis (with pancreatic insufficiency) will develop in utero obstruction of the small bowel (meconium ileus) due to maldigestion of swallowed amniotic cells and abnormal intestinal secretions.9·10 These patients may either be diagnosed on routine prenatal ultrasound or present in the neonatal period with symptoms of intestinal obstruction. Even with pancreatic enzyme supplements, patients with pancreatic insufficiency still have some residual tat malabsorption (6% to 10% of dietary fat compared to 20% to 30% without pancreatic enzyme supplements, normal being less than 2%). Over the years there is gradual build up of rat-laden fecal material, primarily within the cecum and terminal ileum, that can lead to distal intestinal obstruction syndrome. This presents with anorexia, recurrent abdominal pain (usually localized to the right lower quadrant), and a cecal mass. Distal intestinal obstruction syndrome tends to occur with increasing age, particularly in patients less compliant with pancreatic supplements, and may be confused with other surgical conditions. Routine laxatives, such as mineral oil, may be effective. Balanced intestinal lavage solutions taken orally, such as those used for bowel preparation prior to radiological procedures, are usually successful in disimpacting this material, although repeated courses may be required.
Spectrum of Clinical Manifestations of Cystic Fibrosis
Hepatobiliary System. Focal biliary cirrhosis is a common pathologic finding in patients with cystic fibrosis, although it rarely causes a clinical disease. A small group of patients, however, do develop clinical cirrhosis with age, usually presenting with signs of portal hypertension, occasionally progressing to gastrointestinal hemorrhage from esophageal varices or frank hepatic failure.
Pancreas. Recurrent pancreatitis may be a problem in older pancreatic-sufficient patients. As many as 40% of patients with cystic fibrosis may have abnormal glucose tolerance tests, though only a few (around 5% of adults with cystic fibrosis) go on to develop frank diabetes mellitus. Hyperglycemia in these patients is readily controlled with once or twice daily insulin supplements. Dietary restriction is neither necessary nor appropriate.
Loss of excessive quantities of sodium and chloride in the sweat, if not replaced, can lead to hyponatremic dehydration and associated metabolic alkalosis. Presentation is usually with malaise, anorexia, and vomiting. Patients most at risk are infants and toddlers, due both to increased losses (high relative surface area, gastroenteritis) and inability to increase salt intake (supplementation with low-salt-containing formula or juices). Treatment is by intravenous fluid and sodium chloride replacement, with prevention by parental counseling, as well as routine oral sodium chloride supplements to children at risk (infants or those participating in strenuous sports, especially in hot climates).
Males. Ninety-eight percent to 99% of males have congenital obstruction of the epididymis. Secondary sexual characteristics and potency, however, are unaffected. Surgical aspiration of mature spermatozoa and in vitro fertilization may be possible in these individuals.
Females. Fertility in females is reduced (perhaps to 30% of normal). This is due to a combination of mucous plugging and associated chronic cervicitis, and reduced fertility in patients with malnutrition and more severe pulmonary disease. Pregnancy, however, is not unusual, being uncomplicated in the majority of women with cystic fibrosis without preexisting severe pulmonary disease.
In view of the risks of fertility and sexually transmitted diseases, contraceptive and fertility counseling to adolescents and adults are ongoing requirements.
Although there is a marked variability in age of onset and rate of progression, all patients with cystic fibrosis do eventually develop chronic endobronchial infection with a wide variety of potential pathogens.11,12 Thus, progressive bronchiectasis, starting initially in the peripheral airways, is a primary feature of the disease, with respiratory failure due to pulmonary destruction the eventual cause of death in over 95% of cases. In the absence of any therapy for the underlying defect, current treatment of cystic fibrosis is aimed at this chronic infection and its consequences.
Infection. Patients with cystic fibrosis develop progressive endobronchial infection at varying rates and ages, the pattern of infection changing with age and severity of pulmonary damage. Thus, at birth the lungs are uninfected, with infection by increasing numbers and spectrum of organisms subsequently occurring. With advanced disease, patients will have both upper (facial sinuses) and lower airway infection due to an extensive variety of organisms.
Staphylococcus aureus, Hemophilus influenzae. Both of these organisms are commonly found in younger patients. When cystic fibrosis was first described, S aureus was the major organism, frequently associated with rapidly progressive pulmonary disease. This no longer seems to be the rule, and there is an ongoing debate about the exact role of S aureus in the evolution of the pulmonary disease. Thus, unless there is evidence of progressive pulmonary disease, we do not aggressively treat this organism if found on routine sputum culture. With H influenzae immunization, infections due to this organism will occur less frequently.
Pseudomonas aeruginosa is the primary pathogen in patients with cystic fibrosis. There is, however, an ongoing debate as to the exact mode of acquisition, since P aeruginosa is present throughout the environment. Patients with cystic fibrosis seem to be particularly predisposed to acquisition of mucoid strains of P aeruginosa, the majority developing chronic endobronchial infection toward the end of the first or beginning of the second decade of life. The chronic endobronchial infection results in an aggressive immune response by the patient, which is ineffective in eradicating the infection but does cause a marked inflammatory reaction of the airways. With time, this results in destruction of the airway, with progressive bronchiectasis and destructive lung disease.
Pseudomonas cepacia is a distant relative to P aeruginosa, being poorly pathogenic in immunocompetent individuals. A number of clinics around the world, however, have reported chronic endobronchial infection with P cepacia in up to 30% of patients with cystic fibrosis. It is primarily found in older patients and patients with more severe pulmonary disease. There is an ongoing debate as to the significance of P cepacia in cystic fibrosis. It is an inherently resistant organism, and can cause rapidly progressive bronchopneumonia in a small subpopulation of patients. In addition, it poses a major problem in immunosuppressed individuals following lung transplantation, the facial sinuses continuing to constitute a reservoir for infection.
Prevention. An effective vaccine to prevent P aeruginosa colonization in patients with cystic fibrosis has yet to be found. Since P aeruginosa is ubiquitous in the environment with no conclusive proof of interpatient transmission, isolation of patients colonized with P aeruginosa has not been deemed effective or necessary. However, there is now significant evidence of interpatient transmission of P cepacia.4 This has been best described in situations of close, ongoing exposure (such as in shared rooms in hospital, or shared cabins at camps, etc). Isolation programs do appear to be effective in preventing spread of this organism.
Antibiotics. There are a number of effective antipseudomonal agents.11,12 Most (such as fourthgeneration cephalosporins) have required parenteral administration. Until recently, this meant that patients presenting with evidence of respiratory deterioration (increased cough, malaise, anorexia, with or without fever), required hospitalization. However, die development of orally absorbed antipseudomonal agents, such as the nalidixic acid derivatives, now allows for effective ambulatory therapy of acute exacerbations. In addition, long-term inhaled antipseudomonal antibiotics seem effective at least in delaying the progression of the disease, although they rarely, if ever, eradicate the infection.
Figure 3. Incorporation of cystic fibrosis transmembrane regulatory (CFTR) DNA into epithelial cells, using liposomes. Complexes of cationic liposomes and plasmids expressing DNA for normal CFTR protein are inhaled. The aim is to provide adequate quantities for absorbtion into the airway epithelium in order to induce the production of sufficient functioning CFTR protein, and hence correct the underlying biochemical defect,
Anti-Inflammatory Agents. Patients with cystic fibrosis mount an aggressive but ineffective inflammatory reaction to the endobronchial infection, in itself possibly being a major cause of the progressive airways destruction. Use of anti- inflammatory agents have been proposed as adjuvant dierapy for cystic fibrosis. An initial report on the use of systemic steroids sounded promising but seems to not have been supported by a more recent, multicenter study. Other less toxic agents such as Ct1 antitrypsin (to block released neutrophil proteases) may have a place in treatment, however.
Physiotherapy. Patients with advanced pulmonary disease may produce large volumes of purulent sputum, which is one of their primary symptomatic complaints. Endobronchial infection causes peribronchial inflammation and hypersecretion from the bronchial glands. This, therefore, creates a vicious circle, the endobronchial secretions providing a medium for further bacterial growth, as well as causing bronchial obstruction, which inhibits clearance. Moreover, the large quantities of bacterial and white cell DNA consequently released may bind with airway mucoproteins. This increases gelation of the mucoproteins, further adding to the viscosity of the endobronchial secretions. In an effort to maintain clearance of the infected endobronchial secretions, physiotherapy, using a variety of techniques, has been a time-honored part of the treatment of cystic fibrosis.4
Sequelae. The chronic endobronchial infection results in bronchiectasis and progressive pulmonary destruction.4 This leads to increasing ventilation/ perfusion mismatching and progressive hypoxemia. The disease, at least initially, is patchy. Increasing ventilation to relatively unaffected areas will maintain normocapnea until late in the disease. With increasing airways obstruction and bronchiectasis, there is increasing risk of pneumothorax from ruptured pulmonary bullae and hemoptysis from hyperplastic bronchial blood vessels around the areas of bronchiectasis. Both of these are markers of deteriorating pulmonary disease. Once carbon dioxide retention occurs, survival is generally less than 1 year, with pulmonary transplantation remaining the only alternative. Although this is a "cure" for at least the pulmonary disease (since the donor lungs always retain the tissue type of the donor, and hence do not subsequently develop cystic fibrosis), the problems associated with the procedure (costs and shortage of donor organs) and the poor survival rate (around 50% after 3 years, due to both surgical complications and long-term complications of immunosuppression/rejection) means that this procedure will remain an option for only a limited number of patients.
Recombinant DNA is an enzyme now commercially produced that cleaves bacterial and white cell DNA and should, in theory, help liquefy these secretions. Preliminary studies as to its clinical effectiveness are underway.13
Modulation of Transmembrane Sodium/Chloride Transport
There is the potential for pharmacological modulation of the defective chloride channel in patients in whom the mutation results in incorporation of poorly functioning CFTR into the apical cellular membrane2; several agents are currently under evaluation. However, these agents will be of no use for the patients who have no functioning CFTR within the apical membrane. As a consequence of the gene defect, the CFTR is imperfectly permeable to chloride ions because of hyperpermeability to sodium ions.2 This sets up an electrochemical grathent across the epithelium, preventing sodium chloride transport and reabsorption. Amiloride (a sodium channel blocker) may be a potential adjuvant therapy. Initial trials with inhaled amiloride14 have suggested some therapeutic effectiveness, yet to be confirmed by larger trials.
Airway epithelium is well differentiated, containing up to 10 different cell types, with a slow rate of cellular turnover. The progenitor cells, which might be amenable to in vitro genetic replacement therapy, have yet to be identified. Extracorporeal manipulation and reinsertion of stem cells, as is being tried in inherited defects of enzyme function using autologous bone marrow transplantation, therefore does not seem to be an option for cystic fibrosis. The problems, therefore, are the dissemination and insertion of genetic material throughout the respiratory tract. A number of vectors have been suggested as possible modalities for in vivo insertion of genetic material into respiratory epithelium.15 Encapsulating genetic material into liposomes, which may then be incorporated into the epithelial cell walls, may be one potential technique (Figure 3). There is question as to exactly how much DNA will be incorporated into airway epithelium using this technique. Cell targeting, by incorporating proteins associated with specific surface receptors such as bacterial protein receptors or surface ligands such as transferrin into the complex, may increase the efficiency of this process.2 Respiratory viruses also have been suggested as possible vectors, of which the adenovirus group seems the most promising.
It is now possible to perform manipulation of genetic DNA. Thus, by removing the replicant (infective) portion of viral DNA and inserting the DNA coding for normal CFTR protein, it may be possible to use adenoviruses as a vector for inserting normal CFTR DNA into human epithelial cells without producing actual adenoviral infection. This has been successfully accomplished in laboratory rats,16 and approval for testing in human subjects has recently been granted. Administering these agents by inhalation may allow dissemination of sufficient quantities throughout the respiratory tract to be effective.
Although we have been remarkably successful in improving the longevity of patients with cystic fibrosis, they are still faced with the slow development of progressive pulmonary disease, with eventual death from respiratory failure. Conventional therapy is unlikely to further alter this picture, therefore, novel approaches directed at the underlying genetic and biochemical defects are urgently needed. This forms the best hope of preventing (rather than simply delaying) the progressive pulmonary disease that still remains the lot of these patients.
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Spectrum of Clinical Manifestations of Cystic Fibrosis