Etiology and Pathogenesis

CF is caused by defects in a single gene on the long arm of chromosome 7, which codes for the CFTR. The protein is a cyclic adenosine monophosphate regulated chloride channel. More than 1400 mutations in the CFTR gene have been described to date. Defective CFTR function leads to abnormal electrolyte transport at epithelial surfaces, resulting in the net reabsorption of water and dehydration of luminal secretions (Figure 41-1). Accumulation of these viscid secretions results in obstruction, inflammation, tissue damage, and progressive scarring in a number of organs. Despite the discovery of the gene for CF in 1989, much of the pathogenesis of this complicated condition remains to be understood. The disease is inherited in an autosomal recessive manner, with an annual incidence in the United States of approximately one in 3,500 live births. There is a significantly higher carrier frequency in whites compared with other groups.

Figure 41-1 Abnormal electrolyte transport.

The bulk of morbidity and mortality associated with CF is related to lung disease. Here, excessive sodium and water resorption from the airway surface leads to dehydrated mucus that is hard to clear effectively. Impaired airway clearance and defects in airway innate defense facilitate chronic bacterial colonization and intermittent acute infection. CF lung disease is thus characterized by a self-perpetuating cycle of airway obstruction, chronic bacterial infection, and airway inflammation. Ultimately, inflammatory destruction of lung tissue results in progressive bronchiectasis, further impairing airway clearance and facilitating this chronic cycle of infection and inflammation (Figure 41-2). A similar cycle of chronic inflammation and infection occurs in the paranasal sinuses of patients with CF causing chronic pansinusitis. Nasal polyps are found commonly in patients with CF and can compound chronic sinusitis.

Figure 41-2 Ongoing infection and inflammation in cystic fibrosis lungs.

In the GI system, obstruction of pancreatic ducts with viscid secretions results in exocrine pancreatic insufficiency and intestinal malabsorption in 90% of patients. Pancreatic endocrine function can also be impaired resulting in diabetes. CF-related diabetes (CFRD), which is distinct from both type 1 and type 2 diabetes, rarely occurs in the first decade, but its incidence increases after that with age. Accumulation of viscid secretions can also cause small bowel obstruction, particularly in newborns, a condition known as meconium ileus (Figure 41-3). Bowel obstruction can also occur in older children and adults as a result of mucus impaction in the distal small bowel, a condition known as distal intestinal obstruction syndrome (DIOS) . The liver is also commonly affected in patients with CF. A number of different types of liver disease can be seen, including asymptomatic elevation of liver enzymes, hepatic steatosis, and microgallbladder; however, the most prominent finding is focal biliary cirrhosis. This is likely caused by bile duct obstruction, and disease can progress to widespread cirrhosis with portal hypertension and liver failure in some patients. Other GI problems can occur in CF, including gastroesophageal reflux (GER), which is common in both children and adults, chronic pancreatitis, and rectal prolapse.

Figure 41-3 Common gastrointestinal pathology in cystic fibrosis.

The reproductive system is also affected in patients with CF. Men are almost universally infertile because of congenital bilateral absence of the vas deferens, although sperm is normal and can be harvested for in vitro fertilization. Women with CF also have reduced fertility owing to thick cervical mucus, although pregnancy can occur.

Because CF is a lifelong multisystem disease, many complications may occur. In general, these are more common as the disease progresses and include decreased bone mineral density with fractures and osteoporosis, pneumothoraces, hemoptysis, recurrent acute pancreatitis, gallstones, and side effects of medications such as steroids and aminoglycosides.

Clinical Presentation

With the increasing number of newborn screening programs for CF, many patients are now diagnosed before the development of symptoms. In the absence of screening, clinical presentation can be quite varied. A total of 10% to 15% of infants will present initially with meconium ileus in the first 48 hours of life and develop small bowel obstruction. The most common early manifestation of CF, however, is failure to thrive caused by intestinal malabsorption. This is often accompanied by a history of greasy or malodorous stools caused by a high content of malabsorbed fat.

Pulmonary involvement in CF most often presents with recurrent respiratory infections, which, in infants and small children, may be accompanied by wheeze. Respiratory symptoms in younger children can be hard to differentiate from those of recurrent viral illnesses or asthma. Patients can have a chronic cough, which is usually productive. Sputum, if it is expectorated, can be yellow or green. Chest examination can reveal hyperinflation, wheezing from lower airway obstruction, or crackles caused by peripheral airspace disease. Children with CF often have digital clubbing, although this can be hard to appreciate in infants (Figure 41-4). Sinus disease can present as chronic nasal congestion or facial pain, and examination may reveal nasal polyps and sinus tenderness.

Figure 41-4 Digital clubbing.

Patients with CF characteristically develop chronic lung infections with a limited spectrum of pathogenic bacteria. The predominant organisms include Staphylococcus aureus, Haemophilus influenzae, and Pseudomonas aeruginosa and to a lesser extent Burkholderia cepacia, Stenotrophomonas maltophilia, and Alcaligenes xylosoxidans. Viruses, S. aureus, and H. influenzae are more commonly seen in younger children with CF but decrease in frequency with age as the incidence of P. aeruginosa increases. P. aeruginosa organisms in CF lungs often develop a mucoid phenotype and secrete biofilms that help them to avoid host defense and make them almost impossible to eradicate. P. aeruginosa is responsible for the bulk of infection-related morbidity in the lungs of patients with CF.

GI manifestations are common in CF. Children can present with frequent bulky, greasy, or malodorous stools from fat malabsorption. This is often accompanied by abdominal pain, bloating, and flatulence. Symptoms of GER are common in patients of all ages with CF and usually respond well to medical management. Clinical examination commonly reveals fecal masses in the colon, and there can also be epigastric tenderness. Those with CF liver disease may have hepatosplenomegaly or evidence of portal hypertension on examination. Small bowel obstruction is fairly common in CF and can present with abdominal pain, absolute constipation, bilious vomiting, and abdominal distension. Examination can show a distended tender abdomen without bowel sounds. Intussusception, which can be chronic or recurrent, occurs because inspissated fecal material acts as a “lead point” in the terminal ileum. Here, pain is often localized to the right lower quadrant.

Diagnosis

The diagnosis of CF is based on the detection of physiologic evidence of altered epithelial electrolyte transport (e.g., a positive sweat test result), mutations in the CFTR gene, and the presence of typical clinical symptoms. In the case of newborn screening, a sample of heel blood is assayed for immunoreactive trypsin (IRT), a pancreatic proenzyme whose serum concentration is elevated because of obstruction of pancreatic ducts. Samples that show high levels of IRT are further analyzed for common CF mutations. Most combined IRT and DNA screening algorithms have high sensitivity and specificity with low rates of false-positive test results. Children identified by newborn screening undergo further confirmatory testing, including a sweat test.

Management

The management of patients with CF is based on actively maintaining health, preventing decline in nutritional status and lung function, and aggressively treating CF-related disease exacerbations. This is best achieved by frequent contact with a skilled multidisciplinary team in an accredited CF center. CF is a progressive lifelong condition with multisystem involvement and onerous treatment schedules. The psychological impact of this on patients cannot be overestimated, and attention must be paid to this aspect of the disease as well if outcomes are to be optimized. Historically, the major advances in treatment of CF have stemmed from provision of adequate nutrition, aggressive antibiotic treatment of pulmonary disease, and use of regular prophylactic airway clearance. These continue to be the mainstays of treatment today. Clinic visits involve the monitoring of nutritional status; lung function; airway colonization; clinical signs of disease complications; and periodic comprehensive assessment including radiographic studies, serum chemistries and blood count, vitamin levels, and other laboratory tests of renal and hepatic function.

As a result of dehydrated airway secretions and airway inflammation, patients with CF have great difficulty in effectively clearing their airways. As infection, inflammation, and lung tissue damage progress, this becomes more and more challenging. Adequate airway clearance cannot be achieved without the use of chest physical therapy (CPT), which should be performed at least on a daily basis when well and more frequently during acute illnesses. Airway clearance treatments can be aimed at decreasing the viscidity and volume of secretions, facilitating their mobilization and helping to expectorate them. DNA derived from the nuclei of dead neutrophils significantly increases the viscosity of sputum in CF. Recombinant human DNAse is an enzyme that breaks down DNA and can significantly improve the vesicoelastic properties of CF sputum when administered by nebulization. It has been shown to improve sputum clearance and lung function in children older than 6 years. Hypertonic saline (7%) can be used to replete airway salt and water in an attempt to reduce mucus viscosity and facilitate airway clearance. It can also stimulate coughing, which may be very helpful in some patients. It has been shown to improve mucociliary clearance and lung function when used regularly in children older than 6 years.

Mobilization of secretions can be facilitated by techniques such as manual percussion with postural drainage, high-frequency chest wall oscillation, and flutter devices. Expectoration of secretions can be enhanced by various physiotherapy techniques such as active cycle of breathing and with exhalation against positive expiratory pressure. In addition to the regular use of physiotherapy, children are encouraged to exercise as much as possible, which is a very effective adjunct to airway clearance.

In patients with chronic airway colonization and impaired airway clearance, the intermittent use of inhaled antibiotics can help to reduce excessive sputum bacterial density and volume of secretions and improve lung function. Agents that are currently available include tobramycin, aztreonam, and colistin. Chronic infection-driven pulmonary inflammation in CF may also respond to regular oral azithromycin and ibuprofen. In the setting of acute exacerbations of CF lung disease, the use of intensive CPT and oral or intravenous antibiotics are the cornerstones of care. The frequency of acute exacerbations tends to increase as lung function declines. In patients who have severe impairment of lung function, frequent pulmonary exacerbations, and impairment in activities of daily living, evaluation for lung transplantation is often considered.

Maintaining adequate nutritional status in patients with CF is vital for overall care. In those with exocrine pancreatic insufficiency, the use of orally administered supplemental pancreatic enzymes has revolutionized CF nutritional management. Adequate intake of enzymes should result in improvement in nutrition; GI symptoms; and the serum levels of the fat-soluble vitamins A, D, E, and K. The use of supplemental vitamins and minerals is often necessary, particularly the fat-soluble vitamins. In those with signs of cholestatic liver disease, the secondary bile acid ursodeoxycholic acid is often used in an effort to slow disease progression.

The development of glucose intolerance and CFRD occurs with increasing frequency in adolescents and young adults and is associated with poorer lung function and worse nutritional status. Close monitoring of glucose levels is necessary, and most patients with CFRD will ultimately need insulin replacement as caloric restriction is not recommended in patients with CF.

Future Directions

Advances continue to be made in the symptomatic treatment of disease manifestations, and trials are increasingly being conducted in younger children and infants with a view to intervening as early as possible to prevent clinical decline. More recently, attention has focused on novel small molecules that seek to ameliorate the cellular defects in CFTR processing and function. Several of these agents are in advanced clinical trials. Gene therapy has long been touted as the ultimate corrective solution in CF. Despite many problems with this approach initially, momentum is now gathering again, and extensive preparatory work should result in clinical trials in patients in the next few years.