Cystic fibrosis (CF) is a multisystem disease affecting the gastrointestinal, respiratory, and reproductive tracts and the sweat glands. It is the most common life-shortening autosomal recessive disorder in the Caucasian population, affecting approximately 1 in 2500 to 3300 live births. However, CF occurs among persons of all races and ethnicities. Although the classic CF triad is chronic obstructive lung disease, exocrine pancreatic insufficiency, and sweat gland abnormalities, CF can mimic many other common pediatric conditions. Its presentation can vary from classic CF with severe manifestations early in life to later presentations with mild or even atypical symptoms.^1-4 In 2009, newborn screening for CF became mandatory in all 50 states.^5-7 With the implementation of universal newborn screening for CF, clinical care guidelines were developed to aggressively identify and address respiratory and nutritional problems prior to the development of symptoms.^8-11 Each of these factors has relevance to the pediatric hospitalist, who may evaluate and treat patients with chronic respiratory or gastrointestinal symptoms in which the differential diagnosis includes CF or manage disease-related complications in individuals with known CF.

CF is caused by mutations in a single gene on the long arm of chromosome 7 that encodes for the cystic fibrosis transmembrane conductance regulator (CFTR) protein.¹² More than 1600 CFTR mutations have been identified of which at least 200 cause disease;¹² six functional classifications have been devised to better understand the implications of specific gene abnormalities (Table 144-1). Despite the sheer number of CFTR mutations that lead to clinical disease (CF), there is a single mutation, F508del, that accounts for approximately 70% of affected alleles.^1-4 The F508del mutation results in the deletion of phenylalanine in the 508 position of the CFTR protein and is an example of a class 2 mutation (see Table 144-1).

The CFTR protein functions as a chloride channel in the apical membrane of cells.^1-3 In addition, it affects other apical membrane conductance pathways. CFTR is expressed in the cells of affected organs, including the respiratory and intestinal epithelia, pancreatic ducts, hepatobiliary tract, and sweat ducts. It is believed that the loss of function of the CFTR ion channel in CF results in abnormal ion and fluid movement across epithelial membranes, which leads to abnormal secretions in the affected organs.^1-4,13 These abnormalities can lead to inspissated mucus and obstruction of glandular ducts, inflammation, and eventual organ destruction. In the lung, it can lead to a slower clearance of microorganisms which can predispose to specific bacterial infections that promote a cycle of inflammation, abnormal secretion, and, over time, lung damage. As a result, individuals with CF universally develop obstructive lung disease, and most patients with CF die of pulmonary complications.

CF affects multiple organ systems, which means that the presentation can be quite variable and can occur at a variety of ages. However, the classic description of CF is a triad of chronic obstructive lung disease, exocrine pancreatic insufficiency, and sweat electrolyte abnormalities. The majority of individuals with CF are diagnosed in early childhood, by a mean age of 2 years. However, the diagnosis of CF can be made in adolescence and even adulthood.^13-19 The diagnosis should be considered if one or more clinical features of the disease are present (Table 144-2), if there is a history of CF in a sibling, or if there is a positive neonatal screening test.

Historically, failure to thrive and pulmonary manifestations have been the most common presenting features. Although gastrointestinal manifestations of the disease may bring a child to medical attention, the pulmonary manifestations usually lead to the eventual decline in a child’s health. Since the institution of newborn screening, many infants are diagnosed prior to developing significant clinical manifestations. Although newborn screening is mandated in all 50 states there is no universal screening protocol.

The diagnosis of CF is most often made and/or confirmed by sweat testing, whereby the chloride concentration of sweat is determined by quantitative pilocarpine iontophoresis. A sweat chloride concentration of greater than 60 mmol/L is consistent with the diagnosis of CF. To confirm the diagnosis, a second sweat test or genetic studies identifying two disease-causing mutations are needed. When a child is younger than 6 months, a sweat chloride concentration of less than 30 mmol/L is considered normal and is inconsistent with typical CF. A sweat chloride concentration between 30 and 60 mmol/L is considered borderline; the test should be repeated, and additional testing may be indicated.

When a child is older than 6 months, a sweat chloride concentration of less than 40 mmol/L is considered normal and is inconsistent with typical CF. A sweat chloride concentration between 40 and 60 mmol/L is considered borderline; the test should be repeated, and additional testing may be indicated. A number of other tests can be performed to confirm or support the diagnosis, including genotype analysis to directly screen for CF-causing mutations (Table 144-3).^4,18,20

Neonatal screening for CF in the United States has been universally applied since 2009. However, testing protocols vary from state to state. The neonatal screening test for CF is not 100% sensitive; therefore, it may be necessary to perform further diagnostic testing in symptomatic infants with negative newborn screens. The hospitalist should be aware of local neonatal screening practices and its limitations.^5,7,21 In addition, prenatal screening of women for carrier status continues to undergo expansion.^22,23

RESPIRATORY

CF is a chronic inflammatory bacterial bronchitis, and early in the course of CF airway disease, the respiratory tract is colonized with bacterial pathogens and subjected to an abnormal inflammatory environment.^24,25 This sets the stage for the development of chronic and progressive obstructive lung disease and the resulting symptoms, morbidity, and mortality.⁹ Airway inflammation and infection are the main therapeutic targets for current and future CF therapies.⁴

The airways of CF patients are colonized with a number of unusual but specific pathogens, including Staphylococcus aureus, Haemophilus influenzae, Pseudomonas aeruginosa, Stenotrophomonas maltophilia, MRSA, and Burkholderia cepacia.^1-4,26 In addition to chronic airway infection, there is robust and sustained inflammation characterized by neutrophil-dominated inflammation and an abundance of interleukin-8.^24,27 It remains an area of intense debate and investigation whether inflammation precedes chronic infection or whether infection is the inciting event. The role of respiratory viruses in the inflammatory response in the CF airway remains an area of great interest as well, given the large number of “culture-negative” pulmonary exacerbations that are often associated with viral symptoms.²⁸

CF is an example of a true bacterial bronchitis, and chronic bacterial colonization leads to localized peribronchial and endobronchial infection and inflammation. Over time, the infection and robust inflammatory response in the CF airway result in mucopurulent plugging of small and medium-size bronchioles. Eventually, the persistence of neutrophilic inflammation leads to destruction of the normal integrity of the airways. The airways become dilated and bronchiectatic, secondary to proteolysis and chondrolysis of the support tissues. The combination of mucous plugging of the airways and the loss of airway integrity can result in atelectasis, pneumonia, and eventually respiratory failure.^1,26

A pulmonary exacerbation is a common reason for hospitalization. Because the baseline condition varies from patient to patient, it may be difficult for a hospitalist to accurately determine an acute or subacute deterioration. Table 144-4 provides guidelines for this assessment. The course of respiratory deterioration in CF is quite variable.^4,26,28-29 It has been suggested that, on average, there is a 2% to 4% loss in pulmonary function each year.²⁸ Patients are often referred for evaluation for bilateral lung transplantation once their forced expiratory volume in 1 second (FEV₁) reaches 30% of predicted^30,31; however, indications for lung transplantation continue to evolve.^32,33 When patients with CF present with severe respiratory symptoms or acute respiratory failure, admission to the intensive care unit and the implementation of assisted ventilation should be considered on a case-by-case basis.³¹ The general philosophy is that even acute CF manifestations in patients with severe disease may be reversible enough to allow for a meaningful return to baseline. This makes the treatment of very sick patients with CF unique and complex. Although palliative care and attention to end-of-life issues are critical for people with CF, many patients are treated for disease manifestations or complications at the same time that comfort care is being provided and pain and dyspnea are being treated.^34-37 Most CF patients die of respiratory failure. Currently, the median survival is 40-41 years, and CF has become an adult disease in many respects.^18,19,38 This represents a doubling of life expectancy compared with the average life expectancy of CF patients in 1989.

GASTROINTESTINAL

Gastrointestinal manifestations of CF are common (see Table 144-2). Eighty-five percent of CF patients have exocrine pancreatic insufficiency, and gastrointestinal complaints can range from troublesome symptoms of steatorrhea and irritable bowel syndrome to life-threatening intestinal obstruction, liver disease, and an increased risk for gastrointestinal cancers.³⁷ In addition, the important relationship between excellent nutrition and the maintenance of lung health makes careful attention to the increased nutritional needs and gut health of CF patients an ongoing priority.³⁹ The hospitalist needs to be aware of the broad differential diagnosis of gastrointestinal complaints in CF in order to diagnose and effectively manage these CF-related problems.

Gastrointestinal manifestations of CF can begin in utero with meconium ileus, which is thought to be a result of exocrine pancreatic insufficiency. In 10% to 15% of infants with CF, inspissated, tenacious meconium can obstruct the distal ileum in utero, leading to intestinal obstruction in the immediate newborn period. This problem is usually addressed in the special care nursery, and recurrent intestinal obstruction in infancy is uncommon. Exocrine pancreatic insufficiency can also present in the newborn period with symptomatic fat malabsorption resulting in failure to thrive. Other early manifestations include nonspecific feeding difficulties and irritability during feedings. Approximately 50% of infants with CF display signs of pancreatic exocrine insufficiency at birth, and 85% to 90% of individuals with CF develop symptomatic pancreatic insufficiency within the first few years of life.^1-3,40 Poor growth, rectal prolapse, and, rarely, fat-soluble vitamin (A, D, E, K) deficiencies are all signs of fat malabsorption that may prompt an evaluation for CF in an undiagnosed patient; these are also indications of the need for intervention in an individual with known CF.⁴⁰

In addition to exocrine pancreatic insufficiency, CF patients can develop carbohydrate intolerance that can progress to diabetes, most commonly during adolescence, in a small percentage of patients.^4,41 CF-related diabetes most often results in nonketotic hyperglycemia and is exacerbated by acute illness and the concurrent use of corticosteroids. CF-related diabetes is also associated with a more rapid decline in lung function and clinical status; therefore, aggressive management, often with insulin therapy, is needed to optimize glycemic control. As a result, diabetes screening is recommended for all CF patients starting at 10 years, of age, so most patients will undergo annual 2-hour oral glucose tolerance testing as they approach adolescence. Further, CF-related diabetes is associated with the same secondary complications as is diabetes mellitus. The management of carbohydrate intolerance in this population can be challenging. A high-fat, high-calorie diet is recommended because these patients have both increased caloric needs owing to chronic illness and increased losses due to malabsorption.

The hepatobiliary tree can also be affected in CF. Focal biliary cirrhosis is characterized by inspissated eosinophilic amorphous secretions in the intrahepatic bile ducts, which can lead to bile duct obstruction followed by proliferation, inflammation, and fibrosis with focal destruction. Approximately 25% of patients develop liver disease. In a small number of patients, the focal biliary cirrhosis can be associated with portal hypertension and its complications, including hypersplenism and variceal bleeding. In some patients, cirrhosis can progress to frank liver failure, requiring evaluation for liver transplantation.⁴²

Abdominal pain is common in patients with CF, and the list of causes is broad; some however, are specific to CF (Table 144-5). Recurrent intestinal obstruction can occur in older patients and is referred to as distal intestinal obstruction syndrome (Figure 144-1).^1-4,18,37,38 This syndrome presents with symptoms of intestinal obstruction, with abdominal pain, vomiting, and distention. A history of obstipation is often, but not always, elicited. CF patients are also at increased risk for hepatobiliary disease, including cholelithiasis and cholecystitis,⁴⁴ renal stones,⁴⁵ pancreatitis,⁴⁶ antibiotic-associated colitis, and fibrosing colonopathy.³⁸