- Pamela B. Davis, MD, PhD*
Objectives After completing this article, readers should be able to:
Describe cystic fibrosis and outline its pathophysiology.
Interpret the “sweat test” as a diagnostic test and compare its value with other diagnostic tests.
Describe the relationship between cystic fibrosis transmembrane conductance regulator (CFTR) chloride channel function and disease.
List the complications of cystic fibrosis.
Outline appropriate therapeutic modalities for the complications of cystic fibrosis.
Cystic fibrosis (CF), one of the most common fatal genetic disorders in the United States, is recognized by a classic diagnostic triad of elevated sweat chloride concentration, pancreatic insufficiency, and chronic pulmonary disease, although many other organ systems can be involved. The cause of CF is a defect in a single gene on chromosome 7 that encodes a cAMP-regulated chloride channel called the cystic fibrosis transmembrane conductance regulator (CFTR), which usually resides on the apical membrane of epithelial cells lining the airways, biliary tree, intestines, vas deferens, sweat ducts, and pancreatic ducts. When the chloride ion cannot be transported by CFTR at these sites, fluid secretion is insufficient, and the protein portions of the secretions may become more viscid or precipitate and obstruct the ducts, leading to plugging and dysfunction at the organ level. At the cellular level, CFTR regulates the activity of other proteins that conduct ions and affects intracellular regulatory processes. For example, ordinarily CFTR downregulates activity of the epithelial sodium channel in the airway. In the absence of CFTR function, this downregulation is relieved, and sodium reabsorption increases, contributing to reduction in fluid volume and probably to the airway pathophysiology. CFTR also stimulates an outwardly rectifying chloride conductance that may augment its own chloride transport activity. In the absence of functional CFTR, this conductance also is silent.
A number of other systems also are abnormal in CF. For example, epithelial cells lacking CFTR fail to express normal amounts of nitric oxide synthase-2 and, therefore, do not produce normal amounts of the ubiquitous regulator nitric oxide. This lack could contribute to increased sodium reabsorption and exaggerated inflammatory response as well as decreased bacterial killing. Epithelial cells lacking CFTR activity also display abnormal carbohydrate and sialic acid modification of proteins and lipids such as gangliosides; therefore, the surface properties of these cells are abnormal. For example, surface binding sites for Pseudomonas are increased in CF airway epithelial cells. Proinflammatory pathways are upregulated in CF airway epithelial cells, although the precise biochemical mechanisms for this dysregulation are not fully elucidated; it is probably multifactorial. Deficits in interleukin-10 production, inhibition of the Jak-Stat1 signaling cascade, and other abnormalities have been identified in the airways or airway epithelial cells of CF patients and mice. All of these factors can contribute to the cellular pathophysiology of CF in ways that only now are being elucidated and that in the aggregate produce disease.
Although the CF disease process commonly involves the sweat ducts, pancreas, and airways, other organs are also affected. Discovery of the CF gene and the ability to perform DNA diagnostics has allowed identification of mutations in CFTR (Fig. 1⇓ ), less severe at the functional level than the CF-related mutations, that are associated with specific abnormalities, such as congenital bilateral absence of the vas deferens (CBAVD). Some affected patients have two abnormal CF alleles. Persons who have a single abnormal CF allele appear to be at higher risk than the general population for such complications as pancreatitis and sinusitis. Thus, there is some blurring of the borders of what constitutes a CF diagnosis. For the purposes of this review, CF refers to patients who have multiorgan involvement, including the eventual development of pulmonary involvement and pancreatic involvement (if only bicarbonate secretion). Because most patients who have pulmonary disease also have dysfunction of the absorptive function of the sweat duct, the“ sweat test” reliably identifies the vast majority of patients who have CF as defined in this review.
Genetics and Epidemiology
CF is transmitted in an autosomal recessive pattern, that is, both copies of the CF gene must be abnormal if the patient has the disease. Abnormal CF genes are common among Americans; 4% to 5% have at least one CF allele. Among Caucasians, about 1 in 2,500 live births has CF compared with about 1 in 17,000 among African-Americans and 1 in 90,000 among Asians. Both parents of a child who has CF have at least one abnormal copy of the CF gene. Siblings of an affected child have a one in four chance of having the disease, a one in two chance of having a single abnormal CF allele, and a one in four chance of inheriting no abnormal CF allele. First cousins of a CF patient have about a 1 in 120 chance of having the disease.
More than 800 different mutations have been described in the CF gene. The ΔF508 mutation, in which a phenylalanine residue is deleted at position 508 in this 1,480-amino acid protein, is present in about 70% of CF alleles in the United States. Thus, about 50% of American CF patients are homozygous for the ΔF508 mutation. Some mutations are concentrated in particular ethnic groups, such as the A455E mutation in Dutch CF patients and the W1282X mutation in Ashkenazi Jewish patients.
The diagnosis of CF is suspected on clinical grounds or from the family history (Table⇓ ). A few states in the United States and several countries screen newborns for CF by measuring immunoreactive trypsin (IRT) in blood. Most infants who have CF have elevated IRT, but there are also many false-positive results (∼80% of positive infants). Therefore, diagnosis must be confirmed by sweat test or by genotyping.
Genotyping that reveals two alleles that have CF-causing mutations confirms the diagnosis. Conventional commercial genotyping tests for about 80 specific mutations in CFTR, including ΔF508, and identifies about 95% of all CF alleles. However, among the more than 800 reported CF alleles, many are“ private” mutations that occur in only a single family. Thus, a patient in whom two CF alleles are not identified by commercial genotyping still can have CF.
The diagnosis also can be made by a sweat chloride concentration greater than 60 mEq/L in the presence of some appropriate clinical manifestation (chronic pulmonary disease, pancreatic insufficiency, or both) or an appropriate family history (sibling or first cousin who has CF). The sweat test is extremely reliable and is an excellent discriminant for CF if it is performed by experienced personnel and the samples are handled carefully to avoid evaporation or contamination. Typically, the sweat test is performed by iontophoresis of pilocarpine into the skin to stimulate sweating. Sweat then is collected on a preweighed filter that is carefully shielded from evaporation or contamination, leached from the filter, and analyzed for chloride by titrametric analysis. Ordinarily, only laboratories certified as Cystic Fibrosis Foundation-accredited centers perform a sufficient number of tests to maintain proficiency. The accuracy of the test is compromised if the volume of sweat collected is less than 50 mg. However, the Wescor® system (Wescor Company, Logan, UT), because it is a closed system that requires no fluid transfers, can provide accurate readings with less sweat. If testing is attempted during the first month of life, the infant may not produce an adequate amount of sweat, and the test will not be useful. Usually, older infants and children produce sufficient sweat with stimulation by iontophoresis of pilocarpine into the skin in a localized area. Technical errors, except for errors in dilution of the sample, tend to produce elevated values, so a“ positive” result always must be confirmed by a second test.
Among children, very few conditions apart from CF produce sweat chloride concentrations above 60 mEq/L (Fig. 2⇓ ). They include untreated Addison disease, ectodermal dysplasia, some types of glycogen storage diseases, and untreated hypothyroidism. A few normal adults, however, can have sweat chloride concentrations up to 80 mEq/L, so caution must be exercised in older patients. Very few patients who have CF exhibit sweat chloride values less than 60 mEq/L. Occasionally, in the face of malnutrition and edema, a CF patient will have a normal sweat chloride concentration that reverts to typical elevated values when the malnutrition is corrected. Fewer than 1% of CF patients have sweat chloride concentrations consistently below 60 mEq/L when they are well. Most of these have pancreatic sufficiency early in life and have specific, mild CF mutations in one allele, such as 3849 + 10kB C → T, a splice variant that results in production of very small amounts of otherwise normal CFTR.
Suspecting the Diagnosis
Many conditions prompt consideration of the diagnosis of CF (Table⇓ ). In infancy, these include meconium ileus, meconium peritonitis, or prolonged jaundice. About 15% of patients who have CF present in the neonatal period with meconium ileus (obstruction of the distal ileum or proximal colon with thickened, viscid meconium). Sometimes, with complete obstruction, the gut may rupture and soil the peritoneum with meconium, resulting in meconium peritonitis. Meconium ileus is virtually diagnostic of CF, so the patient should be treated presumptively as having CF until a valid sweat test or genotyping can be obtained. A few affected infants present with prolonged jaundice. The precise mechanisms by which this jaundice arises are not well-established, but the malabsorption and malnutrition in CF may lead to hepatic steatosis, the disease can give rise to biliary obstruction, and the abnormal mucus secretions in the biliary tree also can contribute to obstruction.
Because of their high ratio of surface area to volume, infants who have CF are prone to heat prostration. The frequency of CF infants presenting to Babies Hospital in New York City during the heat wave of 1949 stimulated di Sant’Agnese to study the sweat electrolyte content in CF and ultimately to identify the sweat defect. Because of their high salt loss, infants also may present with hypochloremic alkalosis.
During infancy and beyond, a common presentation of CF is failure to thrive. A child who fails to gain weight despite good appetite and especially who produces frequent, bulky, foul-smelling, oily stools should be evaluated for CF. These children may suffer cramps after feeding and begin to avoid food, with resultant diminished oral intake that worsens the malnutrition. There may be excess flatus. These symptoms usually are the result of pancreatic insufficiency, the failure of the pancreas to produce sufficient digestive enzymes to allow breakdown and absorption of fats and protein. Affected infants also may present with hypoproteinemia with or without edema, anemia, and deficiency of the fat-soluble vitamins A, D, E, and K, which are poorly absorbed in the face of massive steatorrhea. Deficiency of vitamin K may contribute to prolonged prothrombin time, especially if it is present in combination with the liver disease of CF. Deficiency of vitamin E can result in shortened red blood cell survival time as well as peripheral neuropathy. Correction of vitamin E deficiency requires supplementation with a special water-miscible form of the vitamin.
Much of the malabsorption in untreated CF can be corrected by providing pancreatic enzyme supplements to the patient, usually in microencapsulated form to improve their ability to survive gastric acid. Such supplementation usually restores both linear growth and weight gain. However, rarely is correction complete. If adequate growth cannot be achieved with supplementation of 2,500 U/kg lipase per meal or less, clinicians may consider adding inhibitors of gastric acid production to raise the pH of the intestinal contents and allow the enzymes to work at a pH that is closer to their optimum. Simply adding more pancreatic enzyme supplement is hazardous; high doses can lead to inflammation and strictures in the colon (fibrosing colonopathy).
In addition to pancreatic enzyme supplementation and vitamins, patients who have CF require calories in excess of the usual daily requirement for age and need high energy density, which usually implies increased calories in the diet from fat. Provision of normal or high-fat diets also provides essential fatty acids, which are necessary for growth and development.
With these approaches to therapy, children who have CF usually grow well. Therefore, diagnosis and treatment of pancreatic insufficiency is critical. Although the gold standard for diagnosis is measurement of pancreatic enzyme activity in duodenal fluid retrieved by intubation of the duodenum, it is such a frequent complication of CF that less invasive tests, such as measurement of stool fat, blood IRT in infants, or serum carotene, often are used. A test documenting the failure to hydrolyze orally administered benzyl-tyrosyl para-aminobenzoic acid to a metabolite that can be absorbed and measured in blood also may be substituted.
Involvement of the lung by the CF disease process accounts for much of the morbidity and nearly all the mortality from the disease. Although the lungs are histologically normal at birth, patients soon acquire bacterial infection that is difficult to eradicate. In the first year of life, many types of bacteria, including enteric organisms, can be recovered from the CF infant’s lung, but later in childhood, three organisms predominate: Haemophilus influenzae, Staphylococcus aureus, and Pseudomonas aeruginosa. Haemophilus and Staphylococcus appear and disappear. Staphylococcus reaches maximum prevalence of about 50% at ages 6 to 17 years and declines thereafter, and Haemophilus is most prevalent (about 20% to 25% of patients) at ages 2 to 5 years.
Pseudomonas eventually becomes established in the lungs of most CF patients, reaching 80% prevalence by age 18 years. Once established, it is not eradicated despite prolonged intensive antibiotic therapy. Pseudomonas alters its pattern of gene expression in the CF lung to produce especially inflammatory lipid modifications and alginate, a mucoid coating that is characteristic of residence in the CF lung. In fact, recovery of mucoid Pseudomonas from the lung should prompt diagnostic investigation for CF. Acquisition of the mucoid phenotype has been associated with accelerated decline of pulmonary function. When the quantity of Pseudomonas is sufficient, there is evidence that biofilms form in the CF lung. Thus, Pseudomonas adapts to assure its persistence. Later in life, some patients acquire Burkholderia cepacia infection, which is associated with poorer lung function and poorer prognosis. This organism often is acquired by person-to-person transmission from others who have CF, so patients known to be infected should not be permitted contact with noninfected patients. B cepacia is classified into several groups called genomavars, some of which have proven to be especially transmissible (“epidemic strains”).
Bacteria in the CF lung establish an endobronchial infection with relative alveolar sparing. However, the infection and the intense inflammatory response it provokes cause hypertrophy and hyperplasia of the mucus-secreting apparatus and progressive damage to the airway wall. Obstructive airway disease ensues, and the patient eventually succumbs to respiratory insufficiency associated with bronchiectasis. The course of CF lung disease is punctuated by pulmonary exacerbations, which are indications for intensive antibiotic therapy to suppress the infecting organisms and to restore some measure of balance in the lung. Such exacerbations may be heralded by signs and symptoms such as increased cough and sputum production, increased dyspnea, poor appetite, weight loss, occasionally fever, fatigue, reduction in pulmonary function, increased hemoptysis, change in chest radiographic findings, or change in chest physical examination findings (increased rales or rhonchi, decreased air exchange, increased use of accessory muscles of respiration). Such symptoms should prompt intensification of the antibiotic regimen. If oral or inhaled antibiotics do not reverse the signs and symptoms promptly or if the exacerbation is severe, intravenous antibiotics should be instituted, usually in the hospital.
Antibiotics are selected based on the sensitivities of the organisms recovered from cultures of the sputum or a deep throat swab. In most instances, these organisms correspond well to those recovered in the lung by more invasive means. The dose of antibiotics for patients who have CF is usually higher than normal because the pharmacokinetics of most antibiotics are abnormal in these patients. For example, tobramycin is administered in daily doses of at least 10 mg/kg in CF patients compared with a maximum of about 6 mg/kg per day for severe infections in those who do not have CF. The goal of therapy in CF is not eradication of the infecting organism, but rather its suppression to levels at which symptoms and signs are minimized.
Besides antibiotic therapy, intensification of the airway clearance regimen is required for treatment of a pulmonary exacerbation. Ordinarily, means of dislodging inspissated mucus, such as clapping, the Flutter device, the chest vest, or directed cough, may be applied, sometimes with gravity-assisted drainage. Drugs that render the sputum less tenacious, such as recombinant human deoxyribonuclease, appear to be effective in assisting mucus clearance. Bronchodilators, administered before airway clearance, are also beneficial. Bronchodilators and an airway clearance regimen are a regular part of CF therapy between exacerbations, and recent evidence supports the routine use of inhaled tobramycin in alternate months for those infected with Pseudomonas to preserve pulmonary function.
Because the airway infection cannot be eradicated and the bacteria incite an intense inflammatory response in the airways that ultimately fails to control the infection and is deleterious to the host, therapeutic studies to suppress infection chronically or intermittently, regardless of symptoms, and anti-inflammatory therapy have been tried for CF. Early studies of suppressive regimens with oral antibiotics rarely contained a sufficient number of patients to demonstrate benefit. More recent studies, performed in large numbers of patients, of inhaled antibiotics such as tobramycin have shown clear benefit from treatment every other month regardless of symptoms in patients who have mild-to-moderate disease and are old enough to perform pulmonary function tests. Although antibiotic resistance developed following such regimens, it was rarely significant in the face of the very high concentrations of antibiotic achieved by inhalation. However, resistance is significant when the antibiotic is administered intravenously, and renal and neurotoxicity from high blood levels limits dosing. The intravenous route, of course, accesses areas that are not well ventilated as well as bacteria in the tissues and is a mainstay of CF therapy. The implications of selection of resistant organisms over the long course of the CF disease are not known.
Anti-inflammatory strategies are also logical for patients who have CF because the inflammatory response in the CF lung is excessive and deleterious. The target population is younger patients (the trials showed most benefit in children younger than 13 y of age) who have good-to-excellent pulmonary function. Two drugs have been studied in long-term clinical trials. Alternate-day oral prednisone was effective in reducing the decline of pulmonary function, but resulted in a high incidence of CF-related diabetes, growth suppression, and cataracts. High-dose ibuprofen, with dosage individually adjusted according to pharmacokinetic analysis, also was effective in reducing the decline in pulmonary function, preserving weight for height, and reducing changes in the chest radiograph. Adverse effects are rare, but occasionally dramatic, such as gastrointestinal hemorrhage or renal insufficiency. For that reason, some clinicians have been reluctant to apply this very good drug to CF. Other anti-inflammatory agents used for other diseases, such as inhaled corticosteroids or leukotriene inhibitors, have not been tested in CF.
Eventually, these interventions fail, and respiratory failure supervenes. More than 100 lung or heart-lung transplants are performed on patients who have CF every year, but many others who are listed for transplantation succumb while awaiting donor lungs. Although such transplants are associated with a new set of pulmonary complications, a 2-year survival of more than 60% is expected.
Complications of the Lung Disease
Usually, the pulmonary course of CF is progressive, albeit slow, with the median survival age of patients who have CF in the United States currently being about 30 years. However, catastrophic complications of the CF lung disease may hasten the patient’s demise. Massive hemoptysis of more than 500 mL in 24 hours is a life-threatening complication that requires supportive measures and embolization of the bleeding vessel or resection of the offending area. This complication results from the tremendous dilation of bronchial arteries that accompanies severe bronchiectasis. When the inflammatory response in the airway erodes into such a dilated, tortuous systemic artery, bleeding can be brisk. However, if the patient survives the episode, there is little impact on the long-term prognosis.
Spontaneous pneumothorax is another potentially severe complication, with significant mortality during each episode. The widening of the airways far out into the periphery, combined with mucus plugging and air trapping, may trigger rupture of the pleura when intra-airway or intrapleural pressure changes. After the first episode, the rate of recurrence is about 50%, and either definitive therapy by sclerosis of the pleura or constant vigilance is warranted, particularly for patients whose respiratory reserve is limited. Although pleural sclerosis was the standard of care in the pretransplant era, such intervention is a relative contraindication to later lung transplantation because of the bleeding that occurs after removing lung that has become densely adherent to the chest wall. Therefore, sclerosis now is avoided if possible to retain the option for transplant.
Upper Airway Disease
The upper airway is not spared in CF. Most affected patients have opacification of all of the sinuses, which sometimes are maldeveloped. However, such radiographic changes may be asymptomatic, and if they are, they do not require therapy. If signs and symptoms of sinusitis develop, including facial pain, swelling, and tenderness or air-fluid levels on radiograph, treatment should be instituted. Often, the infecting organisms are the same as those in the lung, so broad-spectrum coverage for Pseudomonas should be included in the antibiotic regimen. Patients who have CF have a high incidence of nasal polyposis. In 1999, about 3% of affected patients required surgery for this complication. Occasionally, the diagnosis of CF is suggested only by nasal polyposis or opacification of the sinuses on radiography. In children, such findings are an indication for sweat testing.
CFTR normally is expressed in high quantities in epithelial cells lining the intestine, so its functional lack at this site has pathologic consequences. Failure to secrete chloride and, therefore, water into the gut, combined with abnormal intestinal mucus, can lead to meconium ileus at birth. Later in life, patients who have CF are prone to intestinal obstruction at or near the ileocecal junction (often called the distal intestinal obstruction syndrome [DIOS]) by accumulation of stool that is solid where it should be liquid. Occasionally, stool that is densely adherent to the bowel wall serves as a lead point for intussusception, which may not present with the usual signs and symptoms, such as currant jelly stools or blood per rectum. Diagnosis is made with contrast studies. Osmotic laxatives are often effective for DIOS. For more stubborn obstruction, enemas with Gastrografin® draw fluid into the gut and dislodge the stool. Rarely, surgery is required, but only as a last resort because all of the factors that led to the DIOS will remain postoperatively and will be complicated further by postoperative adhesions from handling the inflamed gut.
Particularly in patients who have CF and have suffered malnutrition, the tissue quality may be poor and support for the rectum inadequate. This, combined with abnormal stools, may lead to rectal prolapse. The association of rectal prolapse with CF is so strong that this is an indication for sweat testing. Ordinarily, simply reducing the prolapse, correcting the underlying malnutrition, and improving the stool quality by pancreatic enzyme therapy and extra calories will suffice, but occasionally support for the rectum is created surgically.
Pancreatic disease is progressive throughout life. Almost all patients who have CF, even those who retain exocrine pancreatic enzyme activity sufficient for digestion, have reduced volumes of pancreatic fluid and reduced bicarbonate content of the fluid. Therefore, the gastric acid is not properly neutralized, and the pancreatic enzymes, even if present in normal quantities, may not be working at optimal pH. Patients whose exocrine function is normal early in life may lose it gradually, a process that may be marked by recurrent episodes of pancreatitis. Sometimes these episodes are triggered by particular drugs (eg, tetracycline) or they may be spontaneous. However, exocrine function gradually becomes compromised, and most patients develop pancreatic insufficiency. Eventually, the progressive fibrosis of the pancreas can affect its endocrine function, and CF-related diabetes develops. This complication occurs in about 14% of adults who have CF and about 3% of affected children. The strangulation of the islets of Langerhans reduces the secretion of both insulin and glucagon, so despite serious lack of insulin, ketoacidosis is rare. Stresses such as pregnancy, corticosteroid therapy, or even pulmonary exacerbations can produce increased hyperglycemia that requires treatment.
Congenital Bilateral Absence of the Vas Deferens (CBAVD)
Most males who have CF have absent or atretic vas deferens, which leads to azoospermia. Even modest lack of CFTR function associated with very mild CF mutations or a single mutant allele for CFTR that is insufficient to cause disease in other organ systems is associated with CBAVD, and this is a significant cause of male infertility. Occasionally the diagnosis of CF is suggested to an alert examiner by the absence of the vas on a genital examination.
The biliary system is affected by CF in most patients, but frank biliary cirrhosis is rare. Eosinophilic concretions observed in histologic sections of bile ducts are nearly universal in CF, and the incidence of gallbladder disease, including microgallbladder or gall stones, is high. However, only 1% to 3% of patients have cirrhosis sufficient to cause complications or warrant portal decompression transplantation. This biliary obstruction is associated with portal hypertension, splenomegaly, esophageal varices, and sometimes hepatic failure. For a very few patients, the liver disease dominates the clinical picture and leads to death or liver transplantation.
When CF was first described in the late 1930s, life expectancy was less than 1 year. Late in the 1950s, some centers adopted an aggressive approach to complications of CF, and the median survival age began to increase. During the last decade, the median survival age for patients who have CF in the United States has hovered around 30 years. Of course, some patients succumb much earlier in life, but there are also long-term survivors.
The probability that patients who have CF will survive into adulthood introduces issues of planning for adult life, including educational and vocational counseling, strategies for self-management of the complications of the disease, living alone, planning an occupation that allows the patient to pursue treatment as needed, and marriage and family. Most men who have CF are sterile, but sperm can be retrieved from the testes for artificial insemination or donor semen can be used. For women, reproductive issues are also complex. Although many women have completed pregnancies without difficulty, the worse the lung disease, the greater the chances of maternal complications during pregnancy and the greater the chance that the woman will require intense intravenous antibiotic treatment during pregnancy (with some risk to the fetus). Meticulous attention to nutrition and maintenance pulmonary therapy probably reduces the risk of serious complications during pregnancy. Any CF patient who becomes a biologic parent donates one abnormal CF allele to the child, and there is a 1 in 40 risk of having an affected child. Adoption is an alternative for some patients, although it may be difficult for a chronically ill parent to be approved as an adoptive parent. Thus, the increase in median survival age for patients who have CF brings with it both challenges and joys.
- Copyright © 2001 by the American Academy of Pediatrics