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Cystic
fibrosis is an inherited disease of the exocrine glands affecting
primarily the GI and respiratory systems. It leads to chronic lung disease,
exocrine pancreatic insufficiency, hepatobiliary disease, and abnormally
high sweat electrolytes. Diagnosis is by sweat test or identification
of 2 cystic fibrosis-causing mutations in patients with characteristic
symptoms or a positive newborn screen test result. Treatment is
supportive through aggressive multidisciplinary care.
Cystic fibrosis (CF) is the most common life-threatening genetic disease in the white population. In the US, it occurs in about 1/3,300 white births, 1/15,300 black births, and 1/32,000 Asian-American births. Because of improved treatment and life expectancy, 45% of patients are adults.
Etiology
CF is carried as an autosomal recessive trait by about 3% of the white population. The responsible gene has been localized on the long arm of chromosome 7. It encodes a membrane-associated protein called the cystic fibrosis transmembrane conductance regulator (CFTR). The most common gene mutation, ΔF508, occurs in about 70% of CF alleles; > 1500 less common CFTR mutations have been identified. CFTR seems to be part of a cAMP-regulated Cl channel, regulating Cl and Na transport across epithelial membranes. A number of additional functions are considered likely. Disease manifests only in homozygotes. Heterozygotes may show subtle abnormalities of epithelial electrolyte transport but are clinically unaffected.
Pathophysiology
Nearly all exocrine glands are affected in varying distribution and degree of severity. Glands may
Respiratory:
Although the lungs are generally histologically normal at birth, most patients develop pulmonary disease beginning in infancy or early childhood. Mucus plugging and chronic bacterial infection, accompanied by a pronounced inflammatory response, damage the airways, ultimately leading to bronchiectasis and respiratory insufficiency. The course is characterized by episodic exacerbations with infection and progressive decline in pulmonary function.
Pulmonary damage is probably initiated by diffuse obstruction in the small airways by abnormally thick mucus secretions. Bronchiolitis and mucopurulent plugging of the airways occur secondary to obstruction and infection. Airway changes are more common than parenchymal changes, and emphysema is not prominent. About 40% of patients have bronchial hyperreactivity that is responsive to bronchodilators; however, benefits of bronchodilator therapy may not persist into adulthood. Chronic hypoxemia results in muscular hypertrophy of the pulmonary arteries, pulmonary hypertension, and right ventricular hypertrophy. Much of the pulmonary damage may be caused by inflammation secondary to the release of proteases by neutrophils in the airways.
The lungs of most patients are colonized by pathogenic bacteria. Early in the course, Staphylococcus aureus is the most common pathogen, but as the disease progresses, Pseudomonas
aeruginosa is most frequently isolated. A mucoid variant of P. aeruginosa is uniquely associated with CF. Colonization with Burkholderia
cepacia occurs in about 3% of patients and may be associated with rapid pulmonary deterioration.
GI:
The pancreas, intestines, and hepatobiliary system are frequently affected. Exocrine pancreatic function is compromised in 85 to 95% of patients. Exceptions are a subset of patients who have certain mild CF mutations, in whom pancreatic function is unaffected. Patients with pancreatic insufficiency have malabsorption of fats (and fat-soluble vitamins) and protein. Duodenal fluid is abnormally viscid and shows absence or diminution of enzyme activity and decreased HCO3
- concentration; stool trypsin and chymotrypsin are absent or diminished. Endocrine pancreatic dysfunction is less common, but about 40% of older patients have abnormal glucose tolerance secondary to reduced and delayed insulin response, and about 17% develop diabetes.
Bile duct involvement with bile stasis and biliary plugging leads to asymptomatic hepatic fibrosis in 30% of patients. About 5 to 6% of patients progress to irreversible multinodular biliary cirrhosis with varices and portal hypertension, usually by 12 yr of age. Hepatocellular failure is a rare and late event. There is an increased incidence of cholelithiasis, which is usually asymptomatic.
Abnormally viscid intestinal secretions often cause meconium ileus in neonates (see Gastrointestinal Disorders in Neonates and Infants: Meconium Ileus) and sometimes meconium plugging of the colon. Older children and adults also may develop intestinal obstruction.
Other GI problems include intussusception, rectal prolapse, periappendiceal abscess, pancreatitis, an increased risk of cancer of the hepatobiliary and GI tracts, gastroesophageal reflux, and esophagitis.
Other:
Infertility occurs in 98% of adult men secondary to maldevelopment of the vas deferens or to other forms of obstructive azoospermia. In women, fertility is decreased secondary to viscid cervical secretions, although many women with CF have carried pregnancies to term. However, the incidence of maternal complications and preterm births is increased.
Other complications include osteopenia/osteoporosis, renal stones, iron deficiency anemia, and episodic arthralgias/arthritis.
Symptoms and Signs
Respiratory:
Fifty percent of patients not diagnosed through newborn screening present with pulmonary manifestations, often beginning in infancy. Recurrent or chronic infections manifested by cough and wheezing are common. Cough is the most troublesome complaint, often accompanied by sputum, gagging, vomiting, and disturbed sleep. Intercostal retractions, use of accessory muscles of respiration, a barrel-chest deformity, digital clubbing, and cyanosis occur with disease progression. Upper respiratory tract involvement includes nasal polyposis and chronic or recurrent sinusitis. Adolescents may have retarded growth, delayed onset of puberty, and a declining tolerance for exercise. Pulmonary complications in adolescents and adults include pneumothorax, infection with nontuberculous mycobacteria, hemoptysis, and right heart failure secondary to pulmonary hypertension.
GI:
Meconium ileus due to obstruction of the ileum by viscid meconium may be the earliest sign and is present in 15 to 20% of affected neonates. It typically manifests with abdominal distention, vomiting, and failure to pass meconium. Some infants have intestinal perforation, with signs of peritonitis and shock. Infants with meconium plug syndrome have a delayed passage of meconium. They can have similar signs of obstruction or very mild and transient symptoms that go unnoticed. Older patients with CF can have partial bowel obstruction similar to what is seen in infancy. Distal intestinal obstruction syndrome (DIOS) can occur in 10 to 20% of adolescents and adults with CF.
In infants without meconium ileus, disease onset may be heralded by a delay in regaining birth weight and inadequate weight gain at 4 to 6 wk of age.
Occasionally, infants who are malnourished, especially if on hypoallergenic formula or soy formula, present with generalized edema secondary to protein malabsorption.
Pancreatic insufficiency is usually clinically apparent early in life and may be progressive. Manifestations include the frequent passage of bulky, foul-smelling, oily stools; abdominal protuberance; and poor growth pattern with decreased subcutaneous tissue and muscle mass despite a normal or voracious appetite. Clinical manifestations may occur secondary to deficiency of fat-soluble vitamins.
Rectal prolapse occurs in 20% of untreated infants and toddlers. Gastroesophageal reflux is relatively common among older children and adults.
Other:
Excessive sweating in hot weather or with fever may lead to episodes of hypotonic dehydration and circulatory failure. In arid climates, infants may present with chronic metabolic alkalosis. Salt crystal formation and a salty taste on the skin are highly suggestive of CF.
Diagnosis
Individuals are suspected of having CF by prenatal or newborn screening, family history, or symptoms. In all cases, diagnosis needs to be confirmed by a quantitative pilocarpine iontophoresis sweat test.
Sweat
testing:
In this test, localized sweating is stimulated with pilocarpine , the amount of sweat is measured, and its Cl concentration is determined (see Table 1: Cystic Fibrosis (CF): Sweat Cl Concentration Ranges ). The results are valid after 48 h of life, but an adequate sweat sample (> 75 mg on filter paper or > 15 μL in microbore tubing) may be difficult to obtain before 2 wk of age. False-negative results are rare but may occur in the presence of edema and hypoproteinemia or an inadequate quantity of sweat. False-positive results are usually due to technical error. Transient elevation of sweat Cl concentration can occur from psychosocial deprivation (eg, child abuse, neglect) and in patients with anorexia nervosa. Although the sweat Cl concentration increases slightly with age, the sweat test is valid at all ages. A positive sweat test result should be confirmed by a 2nd sweat test or by identification of 2 CF-causing mutations.
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Table 1
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Sweat Cl Concentration
Ranges
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Age
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Normal (mmol/L)
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Intermediate (mmol/L)
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Abnormal (mmol/L)
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Infants ≤ 6 mo
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≤ 29
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30–59
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≥ 60
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Patients > 6 mo
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≤ 39
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40–59
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≥ 60
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Intermediate
sweat test results:
A small subset of patients have a mild or partial CF phenotype and sweat Cl values that are persistently in the intermediate or even normal range. In addition, there are patients who have single organ manifestations such as pancreatitis, chronic sinusitis, or congenital bilateral absence of the vas deferens that may be due to partial CFTR protein dysfunction. In some of these patients, the diagnosis of CF can be confirmed by the identification of 2 CF-causing mutations. If 2 CF-causing mutations are not identified, ancillary evaluations such as pancreatic function testing and pancreatic imaging, high-resolution chest CT, pulmonary function testing, urogenital evaluation in males, and bronchoalveolar lavage including assessment of microbial flora may be useful. Additional potentially helpful tests include expanded CFTR genetic analysis and measurement of nasal transepithelial potential difference (based on the observation of increased Na reabsorption across epithelium that is relatively impermeable to Cl in patients with CF).
Pancreatic
tests:
Pancreatic function should be assessed at the time of diagnosis, usually by measuring 72 h fecal fat excretion or the concentration of human pancreatic elastase in stool. This latter test is valid even in the presence of exogenous pancreatic enzymes. Infants who are initially pancreatic sufficient and who carry 2 severe mutations should have serial measurements to detect progression to pancreatic insufficiency.
Respiratory
assessment:
Chest x-rays are done at times of pulmonary deterioration or exacerbations and routinely every 1 to 2 yr. High-resolution CT may be helpful to more precisely define the extent of lung damage and to detect subtle airway abnormalities. Both may show hyperinflation and bronchial wall thickening as the earliest findings. Subsequent changes include areas of infiltrate, atelectasis, and hilar adenopathy. With advanced disease, segmental or lobar atelectasis, cyst formation, bronchiectasis, and pulmonary artery and right ventricular enlargement occur. Branching, fingerlike opacifications that represent mucoid impaction of dilated bronchi are characteristic.
Sinus CT studies are indicated in patients with significant sinus symptoms or nasal polyps in whom endoscopic sinus surgery is being considered. These studies almost always show persistent opacification of the paranasal sinuses.
Pulmonary function tests are the best indicators of clinical status and should be done 2 to 4 times/yr. Pulmonary function can now be evaluated in infants by using a raised volume rapid thoracoabdominal compression technique. Pulmonary function tests indicate hypoxemia; reduction in forced vital capacity (FVC), forced expiratory volume in 1 sec (FEV1), forced expiratory flow between 25% and 75% expired volume (FEF25-75), and FEV1/FVC ratio; and an increase in residual volume and the ratio of residual volume to total lung capacity. Fifty percent of patients have evidence of reversible airway obstruction as shown by improvement in pulmonary function after aerosol administration of a bronchodilator.
Oropharyngeal or sputum cultures should be done 2 to 4 times/yr, especially in patients not yet colonized with P. aeruginosa. Bronchoscopy/bronchoalveolar lavage is indicated when it is important to precisely define the patient's lower airway microbial flora (eg, to direct antibiotic selection).
Newborn
screening:
Newborn screening for CF is rapidly expanding in the US and should be universal by 2010. Screening is based on detecting an elevated concentration of immunoreactive trypsinogen (IRT) in the blood. There are two methods of confirming an elevated IRT level. In one method, a second IRT test is done, which, if also elevated, is followed by a sweat test. In the other method, an elevated IRT level is followed by CFTR mutation testing and, if 1 or 2 mutations are identified, then a sweat test is performed. Both strategies have about 95% sensitivity.
Carrier screening:
CF carrier screening is available in the US and is recommended for couples who are planning a pregnancy or seeking prenatal care. If both potential parents carry a CFTR mutation, prenatal screening of the fetus can be done by chorionic villus sampling or amniocentesis. Prenatal counseling in such cases is complicated by the wide phenotypic variability of CF and incomplete information on the clinical consequences of many of the CFTR mutations that are identified through screening.
Prognosis
The course is largely determined by the degree of pulmonary involvement. Deterioration is inevitable, leading to debilitation and eventual death, usually from a combination of respiratory failure and cor pulmonale. Prognosis has improved steadily over the past 5 decades, mainly because of aggressive treatment before the onset of irreversible pulmonary changes. Median survival in the US is to age 37 yr. Long-term survival is significantly better in patients without pancreatic insufficiency. Outcomes are also affected by CFTR mutation profile, modifier genes, airway microbiology, exposure to air pollutants (including tobacco smoke), and socioeconomic status. The FEV1, adjusted for age and sex, is the best predictor of survival.
Treatment
Comprehensive and intensive therapy should be directed by an experienced physician working with a multidisciplinary team that includes other physicians, nurses, dieticians, physical and respiratory therapists, counselors, pharmacists, and social workers. The goals of therapy are maintenance of normal nutritional status, prevention or aggressive treatment of pulmonary and other complications, encouragement of physical activity, and provision of psychosocial support. With appropriate support, most patients can make an age-appropriate adjustment at home and school. Despite myriad problems, the educational, occupational, and marital successes of patients are impressive.
Respiratory:
Treatment of pulmonary problems centers on prevention of airway obstruction and prophylaxis against and control of pulmonary infection. Prophylaxis against pulmonary infections includes maintenance of pertussis, Haemophilus
influenzae, varicella, Streptococcus
pneumoniae, and measles immunity and annual influenza vaccination. In patients exposed to influenza, a neuraminidase inhibitor can be used prophylactically. Giving palivizumab to infants with CF for prevention of respiratory syncytial virus infection has been shown to be safe, but efficacy has not been documented.
Chest physical therapy consisting of postural drainage, percussion, vibration, and assisted coughing is recommended at the first indication of pulmonary involvement (see Diagnostic and Therapeutic Pulmonary Procedures: Physiotherapy). In older patients, alternative airway clearance techniques, such as active cycle of breathing, autogenic drainage, positive expiratory pressure devices, and mechanical vest therapy, may be effective.
For those with reversible airway obstruction, bronchodilators may be given by aerosol. Corticosteroids by aerosol usually are not effective. O2 therapy is indicated for patients with severe pulmonary insufficiency and hypoxemia.
Mechanical ventilation is generally not indicated for chronic respiratory failure. Its use should be restricted to patients with good baseline status in whom acute reversible respiratory complications develop, in association with pulmonary surgery, or in patients in whom lung transplantation is imminent. Noninvasive positive pressure ventilation nasally or by face mask also can be beneficial. Oral expectorants are widely used, but few data support their efficacy. Cough suppressants should be discouraged. Long-term daily aerosol therapy with dornase alfa (recombinant human deoxyribonuclease) as well as 7% hypertonic saline has been shown to slow the rate of decline in pulmonary function and to decrease the frequency of severe respiratory tract exacerbations.
Pneumothorax can be treated with closed chest tube thoracostomy drainage. Open thoracotomy or thoracoscopy with resection of pleural blebs and sponge abrasion of the pleural surfaces is effective in treating recurrent pneumothoraces.
Massive or recurrent hemoptysis is treated by embolizing involved bronchial arteries.
Oral corticosteroids are indicated in infants with prolonged bronchiolitis and in patients with refractory bronchospasm, allergic bronchopulmonary aspergillosis, and inflammatory complications (eg, arthritis, vasculitis). Long-term use of alternate-day corticosteroid therapy can slow the decline in pulmonary function, but because of corticosteroid-related complications, it is not recommended for routine use. Patients receiving corticosteroids must be closely monitored for evidence of diabetes and linear growth retardation.
Ibuprofen , when given over several years at a dose sufficient to achieve a peak plasma concentration between 50 and 100 μg/mL, has been shown to slow the rate of decline in pulmonary function, especially in children 5 to 13 yr. The appropriate dose must be individualized based on pharmacokinetic studies.
Antibiotics:
Antibiotics should be used in symptomatic patients according to culture and sensitivity testing. A penicillinase-resistant penicillin (eg, cloxacillin or dicloxacillin ) or a cephalosporin (eg, cephalexin ) is the drug of choice for staphylococci. Erythromycin , amoxicillin-clavulanate , ampicillin , tetracycline , linezolid , trimethoprim-sulfamethoxazole , or occasionally chloramphenicol may be used individually or in combination for protracted ambulatory therapy of pulmonary infection due to a variety of organisms. Fluoroquinolones are effective against sensitive strains of P. aeruginosa and have been used safely in young children.
For severe pulmonary exacerbations, especially in patients colonized with P. aeruginosa, parenteral antibiotic therapy is advised, often requiring hospital admission but safely conducted at home in carefully selected patients. Combinations of an aminoglycoside ( tobramycin , gentamicin ) and an anti-pseudomonal penicillin are given IV. IV administration of cephalosporins and monobactams with anti-pseudomonal activity also may be useful. The usual starting dose of tobramycin or gentamicin is 2.5 to 3.5 mg/kg tid, but higher doses (3.5 to 4 mg/kg tid) may be required to achieve acceptable serum concentrations (peak level 8 to 10 μg/mL [11 to 17 μmol/L], trough value of < 2 μg/mL [< 4 μmol/L]). Alternatively, tobramycin can be given safely and effectively in one daily dose (10 to 12 mg/kg). Because of enhanced renal clearance, large doses of some penicillins may be required to achieve adequate serum levels. The goal of treating pulmonary infections should be to improve the patient's clinical status sufficiently so that continuous use of antibiotics is unnecessary. However, in patients who are colonized with P. aeruginosa, long-term use of alternate-month aerosol tobramycin therapy and oral azithromycin given 3 times/wk may be effective in improving or stabilizing pulmonary function and decreasing the frequency of pulmonary exacerbations.
In symptomatic patients who are chronically colonized with P. aeruginosa, the role of antibiotic therapy is to improve clinical parameters and possibly reduce the bacterial burden in the airways. Eradication of Pseudomonas is not usually possible. It has been shown, however, that early antibiotic treatment around the time of initial airway colonization with nonmucoid strains of P. aeruginosa may be effective in eradicating the organism for some period of time. Treatment strategies vary but usually consist of inhaled tobramycin or colistin, often in association with an oral fluoroquinolone.
GI:
Neonatal intestinal obstruction can sometimes be relieved by enemas containing a hyperosmolar or iso-osmolar radiopaque contrast material; otherwise, surgical enterostomy to flush out the viscid meconium in the intestinal lumen may be necessary. After the neonatal period, episodes of partial intestinal obstruction (distal intestinal obstruction syndrome) can be treated with enemas containing a hyperosmolar or iso-osmolar radiopaque contrast material or acetylcysteine , or by oral administration of a balanced intestinal lavage solution. A stool softener such as dioctyl sodium sulfosuccinate or lactulose may help prevent such episodes. Ursodeoxycholic acid, a hydrophilic bile acid, is often used in patients with liver disease caused by CF, but there is little evidence to support its efficacy.
Pancreatic
enzyme replacement should be given with all meals and snacks. The most effective enzyme preparations contain pancrelipase in pH-sensitive, enteric-coated microspheres or microtablets. Infants are usually started at a dose of 2000 to 4000 IU lipase per 120 mL of formula or per breastfeeding session. After infancy, weight-based dosing is used starting at 1000 IU lipase/kg/meal for children < 4 yr and at 500 IU lipase/kg/meal for those > 4 yr. Usually, half the standard dose is given with snacks. Doses > 2500 IU lipase/kg/meal or > 10,000 IU lipase/kg/day should be avoided because high enzyme dosages have been associated with fibrosing colonopathy. In patients with high enzyme requirements, acid suppression with an H2 blocker or proton pump inhibitor may improve enzyme effectiveness.
Diet therapy includes sufficient calories and protein to promote normal growth—30 to 50% more than the usual recommended dietary allowances may be required (see Table 4: Nutrition: General Considerations: Recommended Dietary References Intakes* for Some Macronutrients, Food and Nutrition Board, Institute of Medicine of the National Academies) as well as a normal-to-high total fat intake to increase the caloric density of the diet; a water-miscible multivitamin supplement in double the recommended daily allowance; and salt supplementation during infancy and periods of thermal stress and increased sweating. Infants receiving broad-spectrum antibiotics and patients with liver disease and hemoptysis should be given supplemental vitamin K. Formulas containing protein hydrolysates and medium-chain triglycerides may be used instead of modified whole milk formulas for infants with severe malabsorption. Glucose polymers and medium-chain triglyceride supplements can be used to increase caloric intake. In patients who fail to maintain adequate nutritional status, enteral supplementation via nasogastric tube, gastrostomy, or jejunostomy may restore normal growth and stabilize pulmonary function (see Nutritional Support). The use of appetite stimulants to enhance growth may be helpful in some patients.
Other:
Patients with symptomatic right heart failure should be treated with diuretics, salt restriction, and O2
Surgery may be indicated for localized bronchiectasis or atelectasis that cannot be treated effectively with drugs, nasal polyps, chronic sinusitis, bleeding from esophageal varices secondary to portal hypertension, gallbladder disease, and intestinal obstruction due to a volvulus or an intussusception that cannot be medically reduced. Liver transplants have been done successfully in patients with end-stage liver disease. Bilateral cadaveric lung and live donor lobar transplants have been done successfully in patients with advanced cardiopulmonary disease, as well as combined liver-lung transplants for patients with end-stage liver and lung disease. Double lung transplantation for severe lung disease is becoming more routine and more successful with experience and improved techniques. About 60% of people are alive 5 yr after transplantation of both lungs, and their condition is much improved.
Gene therapy, in which normal CF genes are delivered directly to the airways, holds promise for treating CF. However, this therapy is only available in research trials. A number of new drugs to improve chloride channel function, delivered by mouth or aerosol, are under investigation.
End-of-life
care:
The patient and family deserve sensitive discussions of prognosis and preferences for care throughout the course, especially as the patient's pulmonary reserves become increasingly limited. Most people facing the end of life with CF will be older adolescents or adults and will be appropriately responsible for their own choices. Thus, they must know what is in store and what can be done. One mark of respect for patients living with CF is to ensure that they are given the information and opportunity to make life choices, including having a substantial hand in determining how and when to accept dying. Often, discussion of transplantation is needed. In considering transplantation, patients need to weigh the merits of longer survival with a transplant against the uncertainty of getting a transplant and the ongoing (but different) illness of living with an organ transplant.
Deteriorating patients need to discuss the eventuality of dying. Patients and their families need to know that most often dying is actually gentle and not profoundly symptomatic. Palliative care, including sufficient sedation, should be offered to ensure peaceful dying, when that is appropriate. One of the useful strategies for the patient to consider is to accept a time-limited trial of fully aggressive treatment when needed, but to agree in advance to parameters that should indicate when to stop aggressive measures.
Last full review/revision August 2008 by Beryl J. Rosenstein, MD
Content last modified August 2008
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