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Cystic Fibrosis - Update and Perioperative Considerations

Introduction

Cystic fibrosis (CF) is a systemic, recessively inherited disease affecting the glands that produce mucus, tears, sweat, saliva and digestive juices. Normally, these secretions are thin and slippery. But in CF, a defective gene causes the body’s secretions to become thick and sticky. Instead of acting as a lubricant, the secretions may plug up tubes, ducts and passageways — especially in the pancreas and lungs. In fact, lung disease and respiratory failure are the two most dangerous consequences of CF, which affects mainly children and young adults. The disorder is characterized by a generalized dysfunction of exocrine glands that involves multiple organs and causes a diverse range of pathologic and clinical problems. It remains the most common lethal hereditary disorder in the Caucasian population, and in the United States, it is the major cause of chronic debilitating pulmonary disease and pancreatic exocrine deficiency during the first three decades of life.

Until quite recently CF was a genetic mystery, and most people with the disease died before they reached the teen years. Over the past 10 years researchers have made great progress in understanding the genetic basis of CF, and this has lead to earlier detection. Improved and more consistent treatments for the disease, in addition to earlier detection, enable many people with CF to live into their 30s and have fuller and more comfortable lives.

Each year approximately 3,200 Caucasian babies are born in the United States with CF. The disease is much less common among children of African and Asian descent. Two-thirds of infants born with CF will be diagnosed in the first year of life. In all, about 30,000 adults and children are living with this disorder. Although there is still no cure, the emerging field of gene therapy may soon help to correct lung problems in people with CF.

Historical Background

The first descriptions of infants and children with steatorrhea, pancreatic insufficiency, and meconium ileus are found in literature from the mid-17th century. Conceivably, some of these cases could represent reports of cystic fibrosis. European folklore literature of the 1700s and 1800s contains several references indicating an association between the infants salty skin and early death.

A comprehensive description of cystic fibrosis was published in 1938 by Andersen. She coined the term cystic fibrosis of the pancreas and described various presentations of the disease. In 1945, Farber suggested the generalized dysfunction of exocrine glands, with an inability to clear secretions, as a pathogenic mechanism of cystic fibrosis. He introduced the term mucoviscidosis, used for several years in medical literature to describe cystic fibrosis.

An autosomal-recessive pattern of inheritance was proposed by Andersen and Hodges in 1946. Several years later, excessive salt loss in the sweat of children with cystic fibrosis was demonstrated.8 Subsequently, the pilocarpine iontophoresis sweat test was described by Gibson and Cooke in 1959.

The mechanism of an abnormal electrolyte movement in cystic fibrosis epithelium became the focus of intense research in the mid-1980s. The results of these studies showed that the attenuated chloride transport in the sweat ducts and respiratory epithelium was the basic physiologic defect of the disease.

A cystic fibrosis gene, also called the cystic fibrosis transmembrane conductance regulator (CFTR) gene, was identified and cloned in 1989. Trials of gene therapy for cystic fibrosis using adenoviruses are underway in several centers in the United States.

Genetic Implications

Incidence and Prevalence

In CF, a defective gene alters a protein that regulates the normal movement of salt (sodium chloride) in and out of cells. This results in thick, sticky secretions in the respiratory and digestive tracts, as well as in the reproductive system. It also causes increased salt in sweat on the skin. Thus CF is a genetic disorder found in many ethnic and racial groups. The prevalence of the disease varies with the ethnic origin of a population and, as noted above, is highest in individuals of northern and central European extraction. Cystic fibrosis occurs with an incidence of 1 in 2500 live births in Caucasians in North America, Australia, and northern and central Europe, 1 in 17,000 live births in African-Americans, and 1 in 90,000 live births in Orientals in Hawaii. The disease appears to have the same clinical picture worldwide.

Pattern of Inheritance

Cystic fibrosis is transmitted as an autosomal-recessive trait. It affects males and females with equal frequency. Based on incidence figures, it is estimated that 4% to 5% of Caucasians, or 1 in 25 to 1 in 20, are heterozygous carriers of the defective gene. The risk that a child will inherit cystic fibrosis depends on genotypes of both parents and ranges from 1 in 4 for known carriers to 1 in 2500 for parents with no family history of cystic fibrosis. In the family of a child with cystic fibrosis, the chance of producing another affected child remains 1 in 4 regardless of the number of previous children, whereas two thirds of unaffected siblings will be carriers. Because it is a recessive gene, children must inherit two copies of the gene, one from each parent, in order to have the disease. If children inherit only one copy, they do not develop CF, but they may be carriers and possibly pass the gene to their children. If two people who carry the defective gene conceive a child, there is a 25% chance the child will have CF, a 50% chance the child will also be a carrier of the defective CF gene and a 25% chance the child will be neither a carrier nor have the disease.

People who carry the CF gene (heterozygotes) are healthy and have no symptoms of disease. It is estimated than as many as 10 million people may be unknowing carriers of a defective CF gene. Currently it is not possible to identify all carriers although research in that direction is underway.

The etiology of a remarkably high frequency of cystic fibrosis gene in Caucasian populations has been the subject of controversy for many years. Because the disease is lethal and affected individuals usually die childless, the defective trait would be expected eventually to disappear. A spontaneous, recurrent mutation rate is too low to maintain the current incidence of cystic fibrosis carriers. The heterozygotic advantage has been proposed as one possible explanation of the persistent presence of the cystic fibrosis gene in the population. Increased resistance to tuberculosis as well as to syphilis infections and increased fertility in male heterozygotes all have been postulated, but none has been definitely proven. However, cystic fibrosis heterozygote resistance to cholera toxin in the mouse model has been documented.27 This observation supports the hypothesis that a human cystic fibrosis heterozygote may possess a selective advantage in surviving the potentially fatal effects of secretory diarrhea and possibly provides an explanation for the high incidence of cystic fibrosis carriers.

The Cystic Fibrosis Gene

The cystic fibrosis gene, now known as the CFTR gene (for cystic fibrosis transmembrane conductance regulator), is located on the long arm of chromosome 7 at position q31. It consists of approximately 230-250Kb of DNA and contains 27 coding exons. The gene is expressed in epithelial cells and encodes the CFTR protein. Normal individuals carry unaltered forms of the gene, whereas cystic fibrosis patients and heterozygote carriers bear the mutant copies. The first described and the most common mutation in the CFTR gene is a 3-base pair deletion in exon 10 that results in an absence of phenylalanine at amino acid position 508 (DF508) of the CFTR protein. The DF508 mutation accounts for 50% to 80% of all cystic fibrosis alleles. Its frequency varies, however, among ethnic groups. It is found in 70% to 80% of northern Europeans and white and Hispanic Americans with cystic fibrosis, in 40% to 50% of southern Europeans, in 37% of African-Americans, and 30% of Ashkenazi Jews in North America. Approximately 50% of all cystic fibrosis patients in North America are homozygous for DF508 alleles.

At present, more than 300 mutations have been recognized in the CFTR gene. These consist of missing, nonsense, frame-shift, in-frame deletion, and splicing mutations. The location of these defects is relatively symmetrical, with the majority occurring in exons 4, 7, 11, 13, 17b, and 19. The mutations have been divided into four classes in regard to the final protein product.31 Class I mutations result in completely defective protein production, class II generates premature degradation of partially processed protein, class III leads to impaired regulation of the fully processed protein, and class IV renders the function of the CFTR defective.31 Class I and II mutations result in lack of the CFTR in the affected cell, whereas class III and IV mutations produce nonfunctional CFTR protein.31 The DF508 mutation is a class II defect.

There seems to be some correlation between the type of mutation and the phenotype of the disease produced. Clearly, while the DF508 and other class I and II mutations are associated with classic, and severe cystic fibrosis with pancreatic insufficiency, a few uncommon class III and IV mutations are associated with less severe disease. Although genetic screening for most common mutations allows detection of nearly 90% of cystic fibrosis carriers, the large number of other mutations and the inability to detect all cystic fibrosis mutations limits the prospect of general population screening. At present, DNA screening technologies are used for those with a positive family history.

The CFTR Protein

The CFTR protein is a single polypeptide chain of 168kDa that contains 1480 amino acids. It consists of two symmetrical halves, each containing a hydrophobic membrane spanning domain (MSD) and a hydrophilic cytoplasmic nucleotide binding fold (NBF) (Figure 1). These two halves are joined by a large, highly charged cytoplasmic domain, named the regulatory, or R, domain, that has a number of phosphorylation sites for protein kinases A and C. Each MSD has six regions that span the membrane and contribute to the formation of the chloride channel, whereas each NBF serves as a location for the adenosine triphosphate (ATP) binding and cleavage. The NBF closest to the N-terminus is the locus of the most common cystic fibrosis mutation (ie, DF508). The amino acid sequence and the protein structure of CFTR show a striking resemblance to a superfamily of proteins that are found in various species and are involved in active transport of molecules across cell membranes.

The CFTR protein has been localized to the apical membrane surfaces of specialized transporting epithelial cells in the pancreas, sweat glands, lungs, and intestine. It appears to function to allow conductance chloride channel that is regulated by cAMP-dependent phosphorylation, although it may have other functions. The absence of the fully processed and functional CFTR protein in the apical membrane or the presence of its nonfunctional form results in abnormal chloride ion transport, which is the underlying defect in the cystic fibrosis epithelium.

Pathophysiology

Fundamental pathophysiologic findings in cystic fibrosis include abnormal ion concentrations in the secretions from serous glands, especially increased sodium and chloride content in sweat; decreased water content and increased viscosity of secretions from mucus glands, with failure to clear secretions, obstruction, and ultimate glandular destruction; and a unique propensity for chronic respiratory tract colonization and infection by specific groups of bacteria. The first two observations may be explained by abnormal cAMP-regulated chloride channel activity in cystic fibrosis epithelium, whereas infections are probably secondary developments

Ion Transport

Various types of affected cystic fibrosis epithelium share a common biophysical characteristic: the transepithelial electrical potential difference is higher than that of normal epithelium. The transepithelial electrical potential difference is a reflection of the rate of active ion transport and resistance to ion flow across the epithelium. It is well established that the apical membranes of various cystic fibrosis epithelia are impermeable to the chloride ion. However, because the various types of affected epithelia perform different functions in terms of electrolyte and water transport in their native state, this basic defect of chloride impermeability produces a vast array of diverse effects in diseased epithelia.

The epithelium of the sweat duct and of other serous ducts are normally salt-absorbing. In the cystic fibrosis sweat duct, however, chloride is not reabsorbed because of epithelial cell membrane impermeability to chloride, and thus excessive amounts of salt are lost in the sweat. The airway epithelium normally secretes chloride and, secondarily, sodium and water onto the epithelial surface. This physiologic mechanism maintains hydration of the airway secretions. The cystic fibrosis airway epithelium limits chloride transfer into the airway lumen because of underlying chloride impermeability. In addition, reabsorption of sodium from the airway surface into the cell is abnormally increased, leading to decreased salt and water content in airway secretions. These ion transport abnormalities result in viscous, dehydrated airway secretions that are the hallmark of the clinical picture of cystic fibrosis.

The defective chloride transport in cystic fibrosis pancreatic ductal epithelium leads to inadequate secretion of sodium bicarbonate and water into the pancreatic duct, retention of pancreatic enzymes, and destruction of the organ tissue. Similarly, failure to secrete chloride and water causes obstructive problems resulting from production of sticky, dehydrated material in the intestines, liver, gallbladder, and genitourinary tract.

Infection

Chronic infection in individuals with cystic fibrosis is confined mainly to the respiratory tract. At birth, the histologic picture of lung tissue of patients with cystic fibrosis is normal. An endobronchial colonization process begins during the first 2 years of life and initially involves the mucociliary layer of the peripheral airways, with minimal parenchymal involvement. Subsequently, persistent colonization and associated peribronchial inflammation results in bronchiectasis and increased parenchymal involvement, with micro abscess formation and focal hemorrhagic pneumonia.

The most common pathogen isolated from the cystic fibrosis airway is Pseudomonas aeruginosa. The colonization rates exceed 70% in most reports. Progressive deterioration of pulmonary status usually follows the initial colonization. Staphylococcus aureus is frequently the initial colonizing organism and is later replaced by P. aeruginosa. It rarely produces fulminant disease in affected patients. Recently, increased rates of colonization with P. cepacia have been reported. Other organisms found less often in patients with cystic fibrosis include Haemophilus influenzae, Escherichia coli, Klebsiella species, Proteus species, Serratia species, Actinobacillus species, P. fluorescens, and P. multiphilia. These pathogens are usually present only transiently and are commonly supplanted by P. aeruginosa. The unique predilection of cystic fibrosis patients for airway colonization and infection with P. aeruginosa and S. aureus is incompletely understood. One proposed explanation suggests the leading role of the abnormal structure of mucous glycoproteins that favors the adherence of the specific bacteria to the affected respiratory epithelial surface. The local immunity defect and possible nutritional deficits also may be contributory factors in the development and persistence of chronic respiratory tract infections.

Clinical Manifestations

Clinical manifestations of cystic fibrosis reflect the underlying pathology of the involved organs and systems. Respiratory tract, gastrointestinal tract, and genitourinary system signs and symptoms are seen most often. Because of multiorgan involvement, cystic fibrosis mimics a number of other clinical entities.

The majority of patients are diagnosed with cystic fibrosis during childhood. Typically, they present with respiratory tract symptoms such as persistent cough and/or refractory pulmonary infiltrates within the first year or two of life. Other common early gastrointestinal presentations include meconium ileus in approximately 10% of patients within the first days of life and subsequent steatorrhea with failure to thrive during infancy. In nearly 10% of cases with cystic fibrosis, however, the diagnosis is not established until adolescence or young adulthood.

The specific symptoms of CF can vary, depending on the severity of the disease. For example, one child with CF may have respiratory problems but not digestive problems, though another child may have both. In addition, the symptoms of CF may vary with age.

In some newborns the first symptom may be meconium ileus. This occurs when meconium, normally passed by an infant in the first day or two after birth, becomes so thick that it does not move. Other symptoms in newborns may include a failure to grow, steatorrhea, and frequent respiratory infections.

Respiratory Tract

The most frequent complications of CF are chronic respiratory infections, including pneumonia, bronchitis and bronchiectasis. Respiratory infections are common because thick mucus secretions block the airways and provide a breeding ground for bacteria. The most common infective agent is Pseudomonas aeruginosa. Although antibiotics can decrease the frequency and severity of attacks, the bacteria are never completely eradicated.

In fact, upper respiratory tract involvement is almost universal in cystic fibrosis. Hyperactive mucus-secreting glands that produce increased volumes of upper airway secretions, as well as edema and hypertrophy of the mucous membranes, lead to chronic nasal congestion and rhinorrhea. Although radiographic evidence of opacification of all sinuses is common, clinically significant acute or chronic sinusitis is observed less frequently.3,34 Nasal polyps are found in 15% to 20%. Polyps tend to be multiple and bilateral. Their incidence is highest during mid childhood and they are rarely seen before age 5 years or after age 20. Polyps often require surgery and recurrence is common.

Lower respiratory tract disease in cystic fibrosis usually dominates the clinical picture. The initial underlying pulmonary lesion is obstruction of the small airways by thick mucus secretions. Progressive bronchiectasis presents in most patients over 18 months. The pulmonary course is characterized by periods of relative clinical stability that are interrupted by recurrent episodes of exacerbations, typically triggered by acute infections. Over the years, exacerbations occur more frequently, and progressive loss of lung function results in respiratory failure.

The earliest and most prominent symptom of cystic fibrosis lung disease is chronic cough. Initially, the cough is intermittent, dry, and associated with acute respiratory tract infection. Later it persists beyond the period of infection and becomes a continuous occurrence. In time, the cough becomes productive particularly with pulmonary exacerbations and then paroxysmal with associated gagging, choking, and vomiting. It is frequently worse at night and in the morning. The sputum is usually viscous, purulent, and often greenish, the last reflecting P. aeruginosa infection. Lung sounds are initially clear or diminished, but with exacerbations, wheezing, rales, and rhonchi become prominent. There is significant hyperinflation of the lungs noted early in the course of the disease. Atelectasis, pneumothorax, and hemoptysis are common complications in advanced stages. Pneumothorax occurs as a result of rupture of apical subpleural blebs and has an incidence of 2% to 10%.3 Life-threatening massive hemoptysis is a result of bleeding from eroded bronchial arteries and carries a high recurrence rate and poor prognosis.3

Other clinical features of pulmonary involvement include a barrel-chest deformity, use of accessory muscles of respiration, growth retardation, hypertrophic pulmonary osteoarthropathy, digital clubbing, decreased exercise tolerance, and in end-stage lung disease, pulmonary hypertension, cor pulmonale, and respiratory failure with cyanosis. In addition to the previously mentioned infections with P. aeruginosa, S. aureus and other bacteria, up to 50% of cystic fibrosis patients have positive growth of Aspergillus fumigatus in their sputum, and up to 10% exhibit the syndrome of allergic bronchopulmonary aspergillosis.

Gastrointestinal Tract

Gastrointestinal symptoms are important and prominent features of cystic fibrosis. They are the most common symptoms suggesting the diagnosis of cystic fibrosis in infants and young children. Meconium ileus is the earliest clinical manifestation. It classically presents as intestinal obstruction with abdominal distention, failure to pass stool, and vomiting within 48 hours of birth in an infant who appears otherwise well. Approximately 50% of cases of meconium ileus are complicated by volvulus, atresia, and/or meconium peritonitis. Infants with cystic fibrosis are at somewhat higher risk of distal intestinal obstruction later in life.

Meconium ileus equivalent or distal intestinal obstruction syndrome occurs in older children and young adults. It is characterized by right lower quadrant pain, a palpable cecal mass, and partial or complete intestinal obstruction by firm, putty-like material in the terminal ileum and/or right colon. This syndrome can sometimes resemble acute appendicitis. Another occasional cause of intestinal obstruction is intussusception. Rectal prolapse is found in approximately 20% of children with cystic fibrosis.34,36 Factors associated with rectal prolapse include increased intra-abdominal pressure due to distended bowel and coughing, poor muscle tone, and loss of perirectal fat that normally supports the rectum.

Exocrine pancreatic dysfunction is present in 90% of patients with cystic fibrosis. The deficiency of pancreatic enzymes manifests as fat and protein indigestion and results in production of frequent, pale, bulky, and foul-smelling stools. Untreated patients develop steatorrhea, azotorrhea, and growth failure. Chronic diarrhea leads to malnutrition and vitamin deficiency.

Thick secretions obstruct the pancreas, preventing enzymes that digest fats and proteins from reaching the intestines and prevent the body from absorbing the fat-soluble vitamins A, D, E and K. Vitamin A deficiency may lead to increased intra-cranial pressure with bulging fontanelles in infancy, xerophthalmia, and night blindness. Lack of vitamin D can rarely manifest as rickets; however, more often it is associated with secondary hyperparathyroidism, reduced bone mineral content, and delayed bone maturation. Vitamin E deficiency may result in increased red blood cell destruction and neuroaxial dystrophy.34 Vitamin K deficiency can lead to severe bleeding as a result of hypoprothrombinemia and inadequate levels of clotting factors II, VII, IX, and X.

Endocrine pancreatic function is preserved in most patients with cystic fibrosis until the second or third decade of life, when frank diabetes mellitus (type 1 insulin dependent) may occur in a small percentage of patients (about 7%). Hepatobiliary disease manifests as focal biliary cirrhosis as the bile duct becomes occluded. It affects 2% to 5% of patients and presents as hyperbilirubinemia, ascites, and peripheral edema or massive hematemesis caused by esophageal varices.

Genitourinary System

Delayed onset of puberty is common in both males and females with cystic fibrosis. Azoospermia and infertility are seen in 98% of adult males because of mechanical obstruction of sperm transport secondary to absence or atresia of the vas deferens. The incidence of abnormalities associated with testicular descent, such as inguinal hernia, hydrocele, and undescended testicles, is increased. Female fertility may be as low as 20%. However, conception is possible. Many women with cystic fibrosis are anovulatory because of chronic lung disease. Thick, viscous cervical mucus acts as a barrier to sperm penetration. Approximately 90% of completed pregnancies produce a viable infant. Women with cystic fibrosis generally are able to breast-feed normally. Use of oral contraceptives can sometimes aggravate certain symptoms of CF. Every woman should discuss her birth control options with her doctor.

Diagnosis and Assessment

Several tests and evaluations may be used together to diagnose and assess the presence and severity of disease.

Sweat Test

The standard diagnostic test for CF is the sweat test, which measures the amount of salt in sweat. A small amount of an odorless sweat-producing chemical (pilocarpine) is applied to a small area on the arms or legs. An electrode attached to the area stimulates a very weak electric current (iontophoresis), until a warm or tingling feeling is produced. After several minutes, sweat (at least 100mg is required) is collected from the stimulated area and sent for analysis. The test, which is technically cumbersome, is performed twice. A consistently high level of salt is an indication of CF. Normal sweat chloride levels are below 30mEq/L. Chloride sweat concentrations exceeding 60mEq/L in children and 70mEq/L in adults are considered diagnostic for cystic fibrosis. Approximately 1% to 2% of patients with clinical features compatible with cystic fibrosis have normal or borderline (40 to 60mEq/L) chloride results. Other conditions associated with increased sweat chloride levels include un-treated adrenal insufficiency, ectodermal dysplasia, hereditary nephrogenic diabetes insipidus, glucose phosphatase deficiency, hypothyroidism, hypoparathyroidism, familial cholestasis, pancreatitis, mucopolysaccharoidosis, fucosidosis, and malnutrition.1 The sweat test is not useful in diagnosing cystic fibrosis heterozygotes. It does not indicate the severity or prognosis of the disease and may not be useful in newborns who produce little or no sweat.

Genetic analysis of a blood sample may confirm a diagnosis of CF. Researchers have identified more than 800 changes in a gene that when paired with another abnormal gene can result in CF. Testing is possible on approximately 30 of the most common genetic mutations. About 90% of cases of CF can be detected through genetic analysis.

Other tests aid in determining the extent and severity of CF. Among these are tests to measure lung, pancreatic, and liver function.

Because CF is an inherited disease, brothers and sisters of a child with CF may be tested — even if they show no symptoms. Other family members, especially first cousins, also may want to be tested. In most cases family members can be screened with a sweat test, although sometimes gene testing may also be done.

Radiologic Studies

Radiologic findings are not diagnostic for cystic fibrosis pulmonary disease, but may suggest the diagnosis. Hyperinflation of the lungs is noted early in the course of the disease. Subsequent changes include bronchial thickening and plugging in the upper lobes, bronchiectasis, infiltrates, atelectasis, and hilar adenopathy. With advanced disease, segmental or lobar atelectasis, bleb formation, extensive bronchiectasis, impressive hyperinflation, and enlarged pulmonary arteries are seen.

Radiologic pictures of meconium ileus include unevenly distended loops of bowel with absent or scarce air-fluid levels and collections of granular material in the lower central abdomen. Barium enema examination shows a micro colon and may demonstrate obstructing masses in the distal ileum. Again, these findings are not specific for cystic fibrosis.

Pulmonary Function Tests

Pulmonary function studies can be performed reliably in patients over age 6 years to document the extent of pulmonary involvement and evaluate the effects of therapy. In the initial stages of pulmonary disease, an obstructive pattern is evident. Small-airway obstruction and increased gas trapping decrease maximal midexpiratory flow rate, increase residual volume/total lung capacity (RV/TLC) ratio, and decrease forced expiratory volume in 1 second/forced vital capacity (FEV1/FVC) ratio. The response to bronchodilators remains unpredictable and varies with the underlying pulmonary status. Airway reactivity is increased in 50% of patients with cystic fibrosis as demonstrated by bronchoprovocative challenges. With progression of the lung injury and fibrosis, the restrictive component becomes more prominent, as demonstrated by decreased total lung capacity and vital capacity.

Increased ventilation-perfusion mismatching results in increased alveolar-arterial oxygen gradient, gradual hypoxemia, and pulmonary hypertension. Significant elevation of PaCO2 heralds end-stage disease and carries a poor prognosis.

Microbiology

The isolation of Staphylococcus aureus and/or Pseudomonas aeruginosa from sputum culture strongly supports the diagnosis of cystic fibrosis. Mucoid strains of P. aeruginosa are virtually diagnostic of cystic fibrosis.

Therapy

The current treatment of cystic fibrosis involves a comprehensive, multidiscipline-oriented, intensive care program that is implemented in a nationwide network of specialized centers supported by the Cystic Fibrosis Foundation. Therapeutic goals that were formulated 30 years ago remain valid today: prevention and control of pulmonary infections, promotion of mucus drainage, and provision of adequate nutrition. The fundamental objectives of a therapeutic plan are to maintain prolonged periods of stability and to intervene early with aggressive treatment of clinical exacerbations.

Regular assessments at intervals of 1 to 3 months by the multidisciplinary team—primary physician, nurse, respiratory therapist, physical therapist, dietitian, psychologist, and social worker—allow evaluation and adjustment of the home treatment program and also provide the opportunity for nutritional, genetic, financial, educational, vocational, and premarital counseling, as well as encouragement and psychosocial support for patients and families. Hospital admissions are indicated for the treatment of severe deterioration of the clinical condition and management of life-threatening complications. The modern, comprehensive care of cystic fibrosis includes pulmonary and gastrointestinal therapy.

Pulmonary Therapy

The classic treatment of the pulmonary disease requires antibiotic therapy combined with physical and respiratory therapy and supplemented, in selected individuals, with bronchodilator therapy. Antibiotics remain the mainstay. Although the complete sterilization of respiratory secretions is almost never accomplished, the aim of therapy is to lower the numbers of bacteria, to reduce the intensity of endobronchial infection, and to delay progressive lung damage. An early and aggressive antibiotic intervention is the rule, and there is evidence that such treatment strategy may deter the onset of chronic colonization.

Antibiotic regimens are usually based on sputum culture results and directed against the most commonly encountered organisms such as P. aeruginosa, S. aureus, and Haemophilus influenzae. Antibiotics are administered orally, intravenously, and/or by aerosol (tobramycin can be aerosolized and provide medication directly to the airways). The standard treatment course lasts 14 days or more, and maximal doses are used because of increased total-body clearance and volume of distribution. Traditionally, intravenous antibiotic therapy requires hospitalization, but home therapy with intravenous antibiotics is now possible and effective in patients with secured, permanent intravenous access.13,9 A typical intravenous antibiotic regimen used against P. aeruginosa consists of two agents, such as the combination of an amino glycoside with a third-generation cephalosporin and/or anti-Pseudomonas penicillin, and/or monocyclic ß-lactam.

The quinolones remain the only effective oral agents against P. aeruginosa pulmonary infection, but clinical usefulness is limited by rapid emergence of resistant organisms. Aerosolized antibiotics are an important adjunct in the long-term therapy of chronic, resistant P. aeruginosa infections.S. aureus and H. influenzae colonizations and infections are usually controlled with oral antibiotics, but intravenous semi synthetic penicillin may be used to treat severe S. aureus infections.

Chest physiotherapy remains an important part of the comprehensive treatment program. Daily regimens of postural drainage, manual or mechanical percussion, vibration, and assisted coughing are designed to promote increased clearance of bronchial mucus secretions. Physical activity programs of forced expiratory exercises and positive expiratory pressure breathing are often used as an adjunct to physiotherapy.

Inhalation therapy is frequently used in selected cystic fibrosis patients with reactive airways, in association with chest physiotherapy. Bronchodilator treatment is followed by chest physiotherapy, and then an aerosolized antibiotic is administered.1 Alternatively, a ß2-agonist and/or cromolyn sodium can be nebulized with antibiotics. Bronchodilator treatment should be initiated with caution, however, because some patients may respond with a paradoxical decrease in expiratory flow rates and decreased PaO2, due to increased airway collapse during expiration.

Inhalation of N-acetyl-cysteine, a known mucolytic agent, has not been shown to be clinically effective in improving mucus clearance and/or lung function. But it is toxic to ciliated epithelium, and its administration is associated with a significant incidence of bronchospasm. At present the inhalation route is utilized for investigation of newer forms of treatment aimed at modification of sputum composition, reduction of mucus viscosity, anti-inflammatory effect, and reversal of the underlying genetic defect through application of gene therapy.

As discussed above, cystic fibrosis respiratory secretions are extremely viscous and dehydrated because of abnormally increased sodium absorption from the airway lumen into the epithelial cells and possibly because of lack of chloride secretion from the epithelial cells onto the airway lumen. Conceivably, the inhibition of airway epithelium sodium absorption and/or stimulation of airway epithelium chloride secretion would result in improvement of composition and clearance of sputum. In a pilot study, amiloride, a sodium channel blocker that is used as a diuretic, has been shown to improve sputum viscosity and elasticity in aerosolized form and to reduce the rate of loss of FVC. Although the effects of amiloride on sputum properties also have been demonstrated by others, the beneficial effects on lung function have not yet been confirmed. Chloride secretion from cystic fibrosis epithelial cells onto the airway lumen is stimulated by nebulized adenosine triphosphate and uridine triphosphate (ATP and UTP). These extracellular nucleotides have the obvious potential to become a useful therapeutic modality capable of improving the physical properties of the cystic fibrosis airway secretions.

Apart from abnormal electrolyte content, viscosity of infected sputum is increased by its high concentration of deoxyribonucleic acid (DNA) derived mainly from the nuclei of polymorpho-nuclear neutrophils. Bovine pancreatic DNA was shown to reduce the viscosity of lung secretions, but the clinical use of its aerosolized form was abandoned in the late 1960s because of severe allergic reactions. Pulmozyme (dornase alfa), is a clear, highly purified solution of recombinant deoxyribonuclease (rhDNase), an enzyme that selectively cleaves DNA. The protein is produced from genetically engineered Chinese hamster ovary cells containing DNA encoding for the native human protein, deoxyribonuclease . It is administered by inhalation of an aerosol mist produced by a compressed air-driven nebulizer system. The medication has been found to significantly reduce the number of respiratory infections by fragmenting DNA, thus making mucus thinner and easier to expectorate. Also slight-to-significant improvement in pulmonary function and quality of life, as well as reduction of exacerbations of respiratory symptoms, hospital days, and use of parenteral antibiotics for lung infections was shown. Transient voice alteration was the only significant side effect noted, and anaphylactic reactions were not associated with rhDNase administration. Despite the high cost, the aerosolized form of rhDNase appears to be a promising addition to classic cystic fibrosis therapy.

Pulmonary inflammation in response to chronic bacteria colonization is a well-recognized contributing factor to lung damage in cystic fibrosis. Theoretically, administration of agents with an anti-inflammatory effect would delay the progress of lung tissue destruction. Steroids were shown to reduce morbidity and to improve pulmonary function in one investigation, but a subsequent, larger study failed to confirm these results. At present the role of steroids in the treatment of cystic fibrosis is not defined.

Other approaches to anti-inflammatory therapy include the use of non-steroidal anti-inflammatory drugs as well as the application of aerosolized antiproteases, such as alpha 1-antitrypsin and secretory leukoprotease inhibitors. These antiproteases have the potential to inhibit the inflammatory process by neutralization of natural proteolytic enzymes released by activated neutrophils and by reduction of the activity of chemotactic factors that attract neutrophils. Early results are encouraging, and further studies are anticipated.

A means to allow bronchial airway drainage is essential for sufferers of CF. Chest physiotherapy requires manual clapping on both sides of the chest. In some cases an electric clapper or mechanical percussor is used. Inflatable vests with an attached machine that vibrates at high frequency can also help coughing. Bronchial airway drainage is recommended at least twice per day for 20 to 30 minutes.

Gene therapy for cystic fibrosis lung disease is a focus of intense investigation. The objective of this new form of treatment is to correct the ion transport defect by introducing the normal CFTR gene into affected cells of the airway epithelium. Localization studies and functional analysis indicate that targeted cells are situated mostly in the proximal respiratory surface epithelium as well as in significant portions of the distal respiratory surface epithelium. These types of cells can be reached easily by inhalation or lavage.

Vector systems capable of transferring normal CFTR gene into abnormal cells include liposomes and adenoviruses. The liposomes have been shown to correct the cystic fibrosis defect in transgenic mice. Clinical human studies of gene therapy using liposomes are under way in Great Britain and elsewhere. Adenoviruses are nonenveloped DNA viruses known to produce mild, self-limited respiratory illness in humans.

The safety of the E1-deleted (and therefore replication-deficient) adenoviruses has been evaluated in nonhuman primates. The results of these investigations demonstrated that effective CFTR gene transfer to respiratory epithelium was accompanied by local inflammatory and immune response only at higher virus doses. The E1-deleted adenoviruses are currently being tested in patients with cystic fibrosis in the United States.

Although the advent of gene therapy carries the promise of an ultimate cure for cystic fibrosis, this form of treatment may not generally be available for some time, after all safety and efficacy concerns have been studied and addressed. These newer modalities of treatment are likely to benefit recently diagnosed patients who are in the early stages of the disease, as well as individuals with advanced pulmonary involvement.

At present the therapeutic regimen of advanced cystic fibrosis lung disease consists of antibiotics, chest physiotherapy, and the treatment of major life-threatening pulmonary complications. Lobar atelectasis is managed with aggressive intravenous antibiotic therapy and chest physiotherapy directed at the collapsed lobe. Bronchoscopy is indicated if atelectasis persists beyond 5 to 7 days of treatment.1Lobectomy may be necessary in refractory cases.

Management of pneumothorax in cystic fibrosis is determined by the size of the pneumothorax and the presence or absence of symptoms. A small (<10%), stable, and asymptomatic pneumothorax may be initially observed. The recurrence rate with this approach is almost 60%. Larger and/or symptomatic pneumothoraces require a more aggressive regimen. Initial evacuation of the pneumothorax using a chest tube, and followed by chemical pleurodesis (quinacrine sclerosis), has been recommended. Recurrent pneumothorax may be an indication for upper partial pleurectomy with obliteration of pleural blebs by anterior thoracotomy or thoracoscopy.

Mild hemoptysis is usually successfully managed with bed rest, intravenous antibiotics, and supplemental doses of vitamin K if the prothrombin time is prolonged. Massive hemoptysis exceeding 250ml in 24 hours requires bronchoscopy to localize the site of bleeding. Selective bronchial artery embolization may be necessary to control persistent, recurrent endobronchial hemorrhage.

Right-sided failure with associated cor pulmonale is treated with diuretics, salt restriction, and oxygen. Digitalis is not generally effective. Vigorous therapy of any underlying pulmonary infection and obstruction is of paramount significance in the management of cor pulmonale and respiratory failure. Oxygen therapy in respiratory failure is aimed at increasing PaO2 above 50mmHg to prevent pulmonary vasoconstriction and exacerbation of cor pulmonale. Increased PaCO2 may limit the use of increased FIO2.1 Mechanical ventilation is indicated in patients with good baseline pulmonary status in whom acute exacerbation leads to respiratory failure and in otherwise stable patients during the perioperative period. Individuals with chronic, progressive respiratory failure do not benefit from ventilatory assistance because they are usually unable to be weaned from ventilatory support.

Heart-lung transplantation is an effective, if not often used, treatment for terminal cardiorespiratory failure in cystic fibrosis. In a domino operation, the recipient heart is donated to another patient.43 Recently, however, the availability of heart-lung blocks has decreased because of the increased number of cardiac transplants. Alternatively, double lung transplants have been performed in patients. Although the overall survival rate in transplantation recipients exceeds 50%, and transplanted lungs do not develop cystic fibrosis pathology, the organ shortage and strict selection criteria limit wider use of this therapeutic option.

Gastrointestinal Therapy

Patients with CF are malnourished because the pancreatic enzymes needed for digestion do not reach the small intestine. As a result they may need 50% to 100% more calories than if they were healthy. Supplemental high-calorie nutrition, vitamins and enteric-coated oral pancreatic enzymes enable most people with CF to maintain or even gain weight.

The treatment of exocrine pancreatic deficiency and the associated abnormal digestion of fat and proteins consists of pancreatic enzyme replacement, adequate nutrition, and vitamin and mineral supplementation. The objective of pancreatic enzyme replacement is to deliver an adequate concentration of digestive enzymes into the duodenum. Several hog pancreas extracts that contain between 4000 and 24,000 units of lipase are commercially available. Enteric-coated capsules designed to protect the enzymes from gastric acid inactivation are most effective. Although pancreatic enzyme replacement significantly reduces fat and nitrogen in stools, it does not completely correct the abnormal fat absorption.

The dose of pancreatic preparations should be adjusted empirically, based on the consistency, size, and number of stools. The usual dose consists of 1 to 3 capsules per meal. Infants may be given powder pancreatine preparations. Persistent steatorrhea, in spite of apparently adequate enzyme replacement, may signal gastric acid inactivation of the enzymes or low duodenal pH because enteric-coated preparations need an alkaline environment to be effective. The addition of bicarbonate or an H2-receptor antagonist may improve fat absorption in these cases.

The importance of adequate nutrition in cystic fibrosis cannot be overemphasized. The goal of nutritional therapy is to promote normal growth.3 Most patients require a higher-than-normal caloric intake because of the increased work of breathing and the incomplete absorption of nutrients. A high-protein, high-calorie diet without fat restriction is currently recommended. A low-fat diet is no longer advised because normal amounts of fat in the diet are usually well tolerated with administration of improved pancreatic enzyme preparations. In addition, a low-fat diet may be associated with essential fatty acid deficiency.

Infants may be breast-fed if adequate enzyme supplements are provided.3 Formula-fed infants should be given predigested protein formulas with medium-chain triglycerides. Nocturnal enteral feeding via a nasogastric tube or gastrostomy and parenteral hyperalimentation are reserved for patients who have poor growth in spite of adequate oral intake. Daily supplementation of fat-soluble vitamins is necessary to avoid symptoms of deficiency resulting from malabsorption. Vitamins A and D are usually provided as multivitamin products. Vitamin E is given commonly in doses of 100 to 200 units. Vitamin K supplementation is indicated only in the newborn period, the perioperative period, during hemoptysis, and in patients with documented extensive liver involvement and coagulation defects. Routine supplementation of vitamin K is not recommended. Iron deficiency is relatively common in cystic fibrosis, and iron therapy may be required in the face of anemia. Glucose intolerance and clinically significant diabetes mellitus that is occasionally seen in the second and third decades are managed with dietary adjustments and small doses of insulin.

The management of intestinal obstruction due to meconium ileus includes an initial Gastrografin (Bristol-Myers Squibb) enema, intravenous hydration and, ultimately, surgical intervention if obstruction persists. Partial intestinal obstruction in distal intestinal obstruction syndrome is treated with increased doses of pancreatic enzymes, laxatives or stool softeners, increased fluid intake, and large-volume bowel lavage with salt solution containing polyethylene glycol. Complete obstruction due to distal intestinal obstruction syndrome or intussusception requires a Gastrografin enema. Volvulus, as well as persistent intussusception, is an indication for surgery. Rectal prolapse is usually treated with manual reduction followed by stool softeners. Surgical intervention is occasionally indicated.

Treatment of patients with hepatobiliary complications of cystic fibrosis is similar to the treatment of other individuals with liver disease. Ultimately, liver transplant may be necessary in end-stage liver disease, especially if the pulmonary status is good.

Prognosis

There has been significant improvement in the survival of patients with cystic fibrosis over the past 30 to 40 years. The median survival age has increased from less than 2 years in the 1940s to almost 30 years. Now, nearly half of the cystic fibrosis patients are 18 years of age or older. The clinical course and prognosis depend on the degree of pulmonary and pancreatic involvement. Patients who initially present with respiratory symptoms have a generally poorer prognosis. Individuals with established pulmonary disease who do not have severe pancreatic insufficiency have better survival rates.3,46 Finally, early diagnosis and aggressive antibiotic therapy appear to correlate with longer survival. Recent progress in the genetics of cystic fibrosis may not only produce an effective cure but may also have profound implication in terms of prevention of this still life-limiting disease.

h4.Surgery

Many patients with cystic fibrosis undergo elective and emergency surgery during their lifetimes. Surgical procedures for these patients can be divided into two groups: operations for complications related to cystic fibrosis and procedures for other conditions.

As discussed previously, approximately 10% of newborns with cystic fibrosis initially present with meconium ileus. Although nonoperative treatment with Gastrografin enema is frequently effective, complicated cases require operative intervention. Surgical procedures range from irrigation or insertion of a T-tube to ileostomy followed in a few weeks by its closure. Some patients may require bowel resection. The mortality rate decreased dramatically, from an average 55% to 15% in recent reports, mainly because of more frequent performance of less extensive procedures, thereby minimizing surgical time and trauma.

Other intraabdominal operations undertaken at an older age include procedures prompted by complaints of right lower quadrant pain. Differential diagnoses in these cases include, among others, appendicitis, intussusception, and distal intestinal obstruction syndrome. Procedures related to hepatobiliary complications of cystic fibrosis are also common. Surgical correction of rectal prolapse is associated with frequent recurrence.

By far the most common surgery in patients with cystic fibrosis beyond the neonatal period is nasal polypectomy to relieve symptoms of nasal obstruction. The operation is safe, and surgical complications are rare. However, recurrences are common, and patients may require more than one procedure. Patients are usually admitted 1 day prior to the procedure and discharged within 24 to 48 hours postoperatively; surgery performed on an outpatient basis is generally not recommended. In most patients, nasal packing is left overnight to control persistent nasal bleeding.

Thoracic procedures are reserved for the treatment of persistent bronchiectasis, atelectasis, pneumothorax, and hemoptysis that do not respond to conservative medical management.54 Surgical resection of lung tissue is limited to the most severely affected areas.54 Preoperative optimization of pulmonary status and intraoperative sparing of functional lung parenchyma minimizes the incidence of perioperative complications. However, careful selection of patients is crucial for favorable surgical outcome. Patients with preoperative FEV1 or FVC less than 30% of predicted values are not likely to benefit and will tolerate pulmonary resection poorly. Although pleural stripping procedures carry a significant anesthetic risk because of advanced pulmonary disease, in at least one review no intraoperative complications were seen, and the recurrence rate of pneumothorax was low.

Insertion of a permanent central vascular access cannula or device for multiple courses of antibiotics is another procedure frequently performed in patients with cystic fibrosis. Although many or these surgeries can often be successfully completed with sedation techniques only, general anesthesia and control of the airway may be indicated for a patient who has poor lung function or is actively coughing.

Apart from operations related to their disease, patients with cystic fibrosis are subject to the same elective and/or emergent surgeries as their peers. Conceivably, with the improved therapy of cystic fibrosis and increasing longevity, these patients may become suitable candidates for ambulatory or same-day procedures.

Preanesthetic Assessment

Patients with cystic fibrosis may present for surgery at different stages of their disease. The clinical spectrum ranges from an asymptomatic individual scheduled for a minor elective procedure to a moribund patient for emergency thoracotomy. In any case, a thorough preoperative evaluation should minimize the risk of postanesthetic morbidity.

Preanesthetic assessment of the patient with cystic fibrosis should be directed at the most commonly affected organs and systems. The severity of pulmonary and cardiac compromise, and the extent of liver involvement should be assessed by history, physical examination, and additional studies as indicated. Information elicited during the preoperative interview should include the duration of pulmonary disease, the frequency and severity of exacerbations, the quality and quantity of recent sputum production, the degree of exercise intolerance, and current medical treatment. Past surgical and anesthetic history should be discussed and available medical records reviewed.

Physical examination should focus on general nutritional status, signs of respiratory distress, respiratory rate, abnormal breath sounds, and evidence of right-sided heart failure, such as peripheral edema and hepatomegaly. Cyanosis and digital clubbing should be noted. If nasal intubation is planned, the presence of nasal polyps should be excluded. Signs of liver disease should be sought.

Laboratory data should include complete blood count, electrolyte panel, blood sugar, and coagulation profile. Baseline liver function tests should document the extent of hepatic involvement. Chest X-ray should be scrutinized for evidence of active pulmonary disease and cardiomegaly. Preoperative ECG has been recommended in all patients with cystic fibrosis. Recent spirometry tests should be reviewed to quantify the degree of pulmonary dysfunction, and arterial blood gas analysis should be obtained to determine the preoperative values of pO2 and pCO2.

Anesthetic Plan

The anesthetic plan for patients with cystic fibrosis scheduled for elective surgical procedure depends upon the extent of surgery and the age of the patient. The patient should be in optimal medical condition consistent with the stage of pulmonary disease.57,58 Parenteral vitamin K preparations are administered to patients who are not on oral vitamin K supplements.

Premedication with oral benzodiazepines is safe, but opioids are avoided because of their respiratory depressant effect. Although use of atropine has not been associated with any increase in pulmonary complications, its administration is controversial because of possible further inspissation of secretions. If used, atropine should be given during induction.

Regional anesthesia is preferred for appropriate procedures, but general anesthesia can be safely administered; coagulopathy should be excluded prior to regional anesthesia. If general anesthesia is selected, intravenous induction is preferred because pronounced V/Q mismatch may prolong inhalation induction in patients with advanced pulmonary disease. Ketamine should be avoided as it may increase bronchial secretions. Endotracheal intubation and controlled ventilation are recommended. Because compliance can change rapidly during the operative period, an airway pressure monitor should be incorporated in the circuit.

Maintenance of general anesthesia with an inhalation agent is preferred because it allows the use of higher concentrations of oxygen, causes bronchodilation, and decreases the responsiveness of hyper reactive airways. The choice of inhalation anesthetic should take into consideration the possibility of silent hepatic disease and frequent use of epinephrine (and the associated cardiovascular effects) by otolaryngologists during polypectomy. All cystic fibrosis patients are at risk of sudden rupture of emphysematous bullae, but nitrous oxide has been used safely in patients undergoing nasal polypectomy. Adequate hydration and humidification of inspired gases as well as frequent tracheal suction are important in preventing intraoperative inspissation of secretions. Fully awake tracheal extubation is performed after appropriate criteria are met and thorough tracheal suction is accomplished.


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