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 screening 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, about 50% of patients in the US with CF are adults.
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, F508del, occurs in about 70% of CF alleles; > 1900 less common CFTR mutations have been identified. CFTR is 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. The CFTR mutations have been divided into 5 classes, each of which causes different severity of disease. However, there is no strict relationship between specific mutations and disease manifestation, so clinical testing (ie, of organ function) rather than genotyping is a better guide to prognosis.
Nearly all exocrine glands are affected in varying distribution and degree of severity. Glands may
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 50% of patients have bronchial hyperreactivity that responds to bronchodilators. In patients with advanced pulmonary disease, 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 and proinflammatory cytokines by cells in the airways.
The lungs of most patients are colonized by pathogenic bacteria. Early in the course, Staphylococcus aureusis 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 and results in a worse prognosis than nonmucoid Pseudomonas. The prevalence of methicillin-resistant S. aureus (MRSA) in the respiratory tract is now > 25%; patients who are infected with MRSA have lower survival rates than those who are not. Colonization with Burkholderia cepacia complex occurs in about 3% of patients and may be associated with more rapid pulmonary deterioration. Nontuberculous mycobacteria, including Mycobacterium avium complex and M. abscessus, are potential respiratory pathogens. Prevalence varies with age and geographic location and probably exceeds 10%. Differentiating infection from colonization can be challenging. Other common respiratory pathogens include Stenotrophomonas maltophilia,Achromobacter xylosoxidans, and Aspergillus sp.
The pancreas, intestines, and hepatobiliary system are frequently affected. Exocrine pancreatic function is compromised in 85 to 95% of patients. An exception is 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 diabetes mellitus is present in about 2% of children, 20% of adolescents, and at least 40% of adults.
Bile duct involvement with bile stasis and biliary plugging leads to asymptomatic hepatic fibrosis in 30% of patients. About 2 to 3% 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 and sometimes meconium plugging of the colon. Older children and adults also may have intermittent or chronic constipation and intestinal obstruction.
Other GI problems include intussusception, volvulus, rectal prolapse, periappendiceal abscess, pancreatitis, an increased risk of cancer of the hepatobiliary and GI tracts, gastroesophageal reflux, and esophagitis.
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 somewhat decreased secondary to viscid cervical secretions, although many women have carried pregnancies to term. Pregnancy outcome for both the mother and neonate is related to the mother's health.
Other complications include osteopenia/osteoporosis, renal stones, iron deficiency anemia, and episodic arthralgias/arthritis.
Symptoms and Signs
Fifty percent of patients not diagnosed through newborn screening present with pulmonary manifestations, often beginning in infancy. Recurrent or chronic infections manifested by cough, sputum production, 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 include pneumothorax, infection with nontuberculous mycobacteria, hemoptysis, allergic bronchopulmonary aspergillosis, and right heart failure secondary to pulmonary hypertension.
Meconium ileus due to obstruction of the ileum by viscid meconium may be the earliest sign and is present in 15 to 20% of CF-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 may have episodes of constipation or develop recurrent and sometimes chronic episodes of partial or complete small- or large-bowel obstruction (distal intestinal obstruction syndrome). Symptoms include crampy abdominal pain, change in stooling pattern, decreased appetite, and sometimes vomiting.
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 undernourished, 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.
Excessive sweating in hot weather or with fever may lead to episodes of hyponatremic/hypochloremic 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.
Universal newborn screening for CF is now standard in the US; > 90% of cases are first identified by newborn screening, but about 10% are not diagnosed until adolescence or early adulthood. Despite advances in genetic testing, the sweat Cl test remains the standard for confirming a CF diagnosis in most cases because of its sensitivity and specificity, simplicity, and availability.
In this test, localized sweating is stimulated with pilocarpine, the amount of sweat is measured, and the Cl concentration is determined (see Table 1: 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.
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, 1 in each of the CFTR genes. If 2 CF-causing mutations are not identified, ancillary evaluations such as pancreatic function testing and pancreatic imaging, high-resolution chest CT, sinus CT, pulmonary function testing, urogenital evaluation in males, and bronchoalveolar lavage including assessment of microbial flora may be useful. Additional potentially helpful diagnostic 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 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.
Chest x-rays are done at times of pulmonary deterioration or exacerbations and routinely every 1 to 2 yr. High-resolution chest 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 hypertrophy 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 routinely 4 times/yr and at times of clinical decline. 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.
Screening oropharyngeal or sputum cultures should be done 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) or to remove inspissated mucus plugs.
Newborn screening for CF is now universal in the US. Screening is based on detecting an elevated concentration of immunoreactive trypsinogen (IRT) in the blood. There are two methods of following up on 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, more commonly used method, an elevated IRT level is followed by CFTR mutation testing and, if 1 or 2 mutations are identified, then a sweat test is done. For diagnosis, both strategies have about 90 to 95% sensitivity.
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.
The course is largely determined by the degree of pulmonary involvement. Deterioration is inevitable, leading to debilitation and eventual death, usually due to 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 41 yr. Long-term survival is significantly better in patients without pancreatic insufficiency. Outcomes are also affected by CFTR mutation profile, modifier genes, airway microbiology, ambient temperature, exposure to air pollutants (including tobacco smoke), adherence to prescribed therapies, and socioeconomic status. The FEV1, adjusted for age and sex, is the best predictor of survival.
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.
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.
Airway clearance measures consisting of postural drainage, percussion, vibration, and assisted coughing are recommended at the time of diagnosis and should be done on a regular basis (see Pulmonary Rehabilitation). In older patients, alternative airway clearance measures, such as active cycle of breathing, autogenic drainage, positive expiratory pressure devices, and high-frequency chest wall oscillation, may be effective. Regular aerobic exercise is recommended; it may also help airway clearance.
For patients 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 typically 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 to 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 (in patients > 6 yr) has been shown to slow the rate of decline in pulmonary function and to decrease the frequency of respiratory tract exacerbations.
Pneumothorax can be treated with closed chest tube thoracostomy drainage. Open thoracotomy or thoracoscopy with resection of pleural blebs and mechanical 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.
Ivacaftor is a drug that potentiates the CFTR ion channel in patients with mutations in the following genes: G551D, G178R, S549N, S549R, G551S, G1244E, S1251N, S1255P, G1349D, R117H, or G970R; it is the first drug to target a specific CF mutation. Ivacaftor may be used in patients ≥ 6 yr who carry 1 or 2 copies of that specific mutation. The drug is given orally twice a day and can improve pulmonary function, increase weight, decrease CF symptoms and pulmonary exacerbations, and reduce and sometimes normalize sweat Cl concentrations. Other drugs that may correct defective CFTR or potentiate CFTR function in other CF mutations are under study.
For mild pulmonary exacerbations, a short course of antibiotics should be given based on culture and sensitivity testing. A penicillinase-resistant penicillin (eg, cloxacillin or dicloxacillin), a cephalosporin (eg, cephalexin), or trimethoprim/sulfamethoxazole is the drug of choice for staphylococci. Erythromycin, amoxicillin/clavulanate, ampicillin, tetracycline, linezolid, or occasionally chloramphenicol may be used. For patients colonized with P. aeruginosa, a short course of inhaled tobramycin or aztreonam lysine (eg, 4 wk) and/or an oral fluoroquinolone (eg, 2 to 3 wk) may be effective. Fluoroquinolones have been used safely in young children.
For moderate-to-severe pulmonary exacerbations, especially in patients colonized with P. aeruginosa, IV antibiotic therapy is advised. Patients often require hospital admission, but carefully selected patients can safely receive the therapy at home. Combinations of an aminoglycoside (eg, tobramycin, gentamicin) and an antipseudomonal penicillin are given IV. IV administration of cephalosporins and monobactams with antipseudomonal activity may also 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. For patients colonized with methicillin-resistant S. aureus,vancomycin or linezolid can be added to the IV regimen.
In patients who are chronically colonized with P. aeruginosa, antibiotics delivered by aerosol improve clinical parameters and possibly reduce the bacterial burden in the airways. The long-term use of alternate-month aerosol tobramycin or aztreonam lysine therapy along with continuous (every month) oral azithromycin given 3 times/wk may be effective in improving or stabilizing pulmonary function and decreasing the frequency of pulmonary exacerbations.
Eradication of chronic Pseudomonas colonization is not usually possible. It has been shown, however, that early antibiotic treatment around the time the airways are initially infected 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 aerosol tobramycin or colistin sometimes along with an oral fluoroquinolone. Patients who have a clinically significant nontuberculous mycobacterium infection may require long-term therapy with a combination of oral, aerosol, and IV antibiotics.
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 in preventing progression from bile stasis to cirrhosis.
Pancreatic enzyme replacement should be given with all meals and snacks to patients with pancreatic insufficiency. 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. For infants, the capsules are opened and the contents are mixed with food. 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 > 2,500 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: General Considerations:Recommended Dietary Reference Intakes* for Some Macronutrients, Food and Nutrition Board, Institute of Medicine of the National Academies). Diet therapy also includes 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 additional 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 NGT, 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.
Cystic fibrosis-related diabetes (CFRD) is caused by insulin insufficiency and shares features of both type 1 and type 2 diabetes. Insulin is the only recommended treatment. Management includes an insulinregimen, nutrition counseling, a diabetes self-management education program, and monitoring for microvascular complications. The plan should be carried out in conjunction with an endocrinologist with experience in treating both CF and diabetes.
Patients with symptomatic right heart failure should be treated with diuretics, salt restriction, and O2.
Recombinant human growth hormone (rhGH) may improve pulmonary function, increase height and weight and bone mineral content, and reduce the rate of hospitalization. However, because of the added cost and inconvenience, rhGH is not commonly used.
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 transplantation has been done successfully in patients with end-stage liver disease. Bilateral cadaveric lung and live donor lobar transplantation has been done successfully in patients with advanced pulmonary disease, as well as combined liver-lung transplantation for patients with end-stage liver and lung disease. Bilateral 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.
The patient and family deserve sensitive discussions of prognosis and preferences for care throughout the course of illness, 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) burden 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. When appropriate, palliative care, including sufficient sedation, should be offered to ensure peaceful dying. A useful strategy 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 indicate when to stop aggressive measures.
Last full review/revision January 2014 by Beryl J. Rosenstein, MD
Content last modified January 2014