1. 
   

   How do mutations in the cystic fibrosis (CF) gene relate to the clinical manifestations of the disease?

   
   
2. 
   

   What criteria help determine when a CF patient should be admitted to hospital for respiratory complications of the disease?

   
   
3. 
   

   What treatment modalities are most effective in restoring lung function to baseline for CF respiratory exacerbations?

   
   
4. 
   

   Why is CF–related diabetes (CFRD) one of the most important comorbidities in CF and how does it alter the course of the disease?

   
   
5. 
   

   What are the most effective treatment modalities for the two most common pulmonary complications of CF: massive hemoptysis and pneumothorax?

Definition and Overview

Cystic fibrosis (CF) is an autosomal recessive disease due to mutations in the CF transmembrane conductance regulator (CFTR) gene. The CFTR gene is expressed in epithelial cells in a variety of organs including the lung, sinuses, pancreas, sweat gland, intestine, liver, and vas deferens, and thus CF is a mulitorgan disease. CF is the most common inherited life-shortening disease of Caucasians in the United States. More than 90% of the morbidity and the mortality is due to lung disease. CF lung disease is characterized by the triad of altered mucociliary clearance, chronic polymicrobial infection of the airways, and an exaggerated inflammatory response. The ultimate outcome of CF lung disease is destruction of the normal airway architecture and death due to respiratory failure.

With therapy, primarily aimed at slowing the progression of lung disease and improving nutrition, median survival is approaching 40 years of age. Unfortunately, there is no cure for CF. The average CF adult can expect to spend 2 to 3 hours a day taking a variety of inhaled medications, ingest 30 to 50 pills per day, and be hospitalized about once per year for a period of 1 to 3 weeks. Even with insurance, most CF patients have out-of-pocket health care costs approximating $10,000 per year.

However, there are a significant number of CF patients who have normal lung function, rarely require hospitalizations, and need only a few medications to control their disease. Thus, there can be tremendous variability in the severity of the pulmonary phenotype in this monogenic disease ranging from death in childhood due to respiratory failure to living to retirement and the thought of enjoyment of family and friends as old age ensues.

Genetic Epidemiology—Incidence and Ethnic Distribution

The incidence of CF varies tremendously according to ethnicity. Also, those countries, such as the United States, that have universal newborn screening for CF will have more accurate measures of incidence than those countries that do not. CF occurs in about 1 in 3500 white births, 1 in 17,000 African Americans, and 1 in 90,000 Asians in Hawaii. Once considered a disease affecting only children, the life expectancy in CF has increased dramatically in the past 3 decades. Now 41% are over 18 years of age, and median predicted survival has increased from 28 years for those born in 1990 to 38 years for those born in 2008.

The CFTR protein is a chloride channel in the apical aspect of epithelium in a variety of organs, including the lungs, sweat ducts, vas deferens, liver, pancreas, and intestines. Through unknown mechanisms, expression of mutant CFTR and the resultant failure to conduct chloride also causes marked increase in sodium import through the epithelial sodium channel, ENaC. In the lung epithelium, this results in marked reduction in the depth of the airway surface lining fluid and loss of effective mucociliary clearance.

CFTR also transports glutathione, the major antioxidant in the lung. Thus, expression of mutant CFTR results in failure to export glutathione to the extracellular compartment resulting in extremely low levels of antioxidant capacity in the epithelial lining fluid and more susceptibility to damage. Mutant CFTR also causes failure to transport bicarbonate, contributing to the development of pancreatic exocrine insufficiency and eventual development of malabsorption.

Recent evidence suggests that CFTR may be expressed in pancreatic beta cells thus providing a potential molecular mechanism for the very high prevalence of diabetes in CF.

Expression of mutant CFTR, particularly in neutrophils and airway epithelial cells, results in an abnormal proinflammatory response characterized by an excessive and persistent production of cytokines that generates a neutrophil dominated inflammation. The CF airway shows a tremendous preponderance of neutrophils even shortly after birth. These neutrophils are a source of elastase and reactive oxygen species that destroy lung tissue. Furthermore, dying neutrophils in the CF lung do not undergo apoptosis but rather necrosis, resulting in release of massive amounts of sticky, uncoiled DNA that markedly increases the viscosity of airway secretions.

Persistent bacterial infection (particularly with Pseudomonas aeruginosa and Staphyloccocus aureus) of the airway is the hallmark of CF lung disease, and proposed mechanisms for this include defective phagocytosis, defective intracellular killing, increase in the number of receptors for bacteria on epithelial cells, and promotion of biofilm formation by the bacteria.

The CFTR gene is on chromosome 7, and there are more than 1600 disease causing mutations of this gene, within six classes (Table 240-1). The most common mutation, Δ508 is a three-base pair deletion in exon 10, resulting in deletion of the phenylalanine residue at position 508. This defect accounts for 66% of the CF mutations worldwide. About 15 mutations may account for 80% to 90% of the mutations seen in Caucasians.

Mutations where there is little or no full length CFTR at the outer plasma membrane are considered “severe” and those where there is a full length protein but in some way the protein has defective function are considered “mild.” However, significant discordance between gene mutations and severity of lung disease suggests the importance of modifier genes and environmental interactions in disease expression, and explains why two cystic fibrosis patients with the same gene defect in the CFTR gene can present with very different disease severity and clinical course.

Cystic fibrosis can affect multiple organs but the vast morbidity and of mortality occurs due to lung disease. The triad of impaired mucociliary clearance, persistent airway infection, and exaggerated inflammatory response leads to bronchiectasis and ultimately respiratory failure and death. Lung function declines progressively in most CF patients, with an annual rate of decline in function varying from 1% to 4% decrease per year. The rate of decline may be punctuated by acute pulmonary exacerbations with precipitous drops in lung function and incomplete recovery from the exacerbation. Resetting of baseline lung function at a new lower level may occur following respiratory exacerbations. Frequent respiratory exacerbations are the hallmark of lung disease severity in CF, and significantly impact quality of life, health care costs and survival.

The cause of acute pulmonary exacerbations is currently unknown, but likely is related to increased bacterial load rather than infection by a different strain of bacteria. Other risk factors include increased exposure to particulate air pollutants and viral infections (eg, influenza virus, respiratory syncitial virus) However, nearly 20% of CF pulmonary exacerbations have no identified inciting cause.

The diagnosis of CF can be considered for patients with symptoms of COPD or asthma who are not responding as expected to treatment. Also, the isolation of mucoid Pseudomonas in a person with chronic respiratory symptoms should suggest the diagnosis of CF. CF patients may also present with isolated pancreatitis so patients with recurrent pancreatitis unexplained by alcohol, medications or gallstones should be considered for workup for CF. Pansinusitis is rare in healthy children and adults so this finding should prompt a screening for CF. Nasal polyps are unusual in healthy adolescents younger than 20 years old and should prompt a screening for CF.

CF may be suspected in a patient because of having one or more characteristic phenotypic symptoms, a positive history of CF in a sibling, or a positive newborn screen. The diagnosis of CF is made by two positive sweat chloride results done on separate days using quantitative pilocarpine iontophoresis in a clinical laboratory certified by the Cystic Fibrosis Foundation (Table 240-2). However, 2% of patients with a convincing clinical presentation for CF have a sweat chloride in the indeterminate range and some rare mutations are associated with normal sweat test results. In this situation, a CFTR genotype and sequencing can identify whether the person has two disease causing mutations.

All 50 states in the United States have now implemented newborn screening for CF. Prior to newborn screening, about 3% to 5% of CF patients were diagnosed as adults. This number will decrease with time but it will take several years to decades before diagnosis of CF in adulthood is a rarity. In addition, many states screen only for the most common mutations and thus newborn screening will not identify all CF persons.

Pulmonary Exacerbation Diagnostic Testing

Diagnostic testing in the setting of acute pulmonary CF exacerbation should include CF sputum cultures (using the Cystic Fibrosis Foundation approved methods for detecting polymicrobial isolates), complete blood count, comprehensive chemistry panel, and posterior-anterior and lateral chest x-ray. Pregnancy test should be obtained for women of childbearing age. CF patients with change in symptoms should undergo pulmonary function testing (PFTs) with spirometry to assess FEV1 and any change from the patient’s baseline level. A significant decrease in FEV1 from baseline (even with unimpressive symptoms or physical examination) may prompt inpatient admission for IV antibiotics rather than outpatient management.

Additional testing for patients who have not responded to standard treatment of a CF pulmonary exacerbation as expected may include sputum for fungal stain and cultures, sputum for acid fast bacilli, and immunoglobulin (Ig) E level (to evaluate for allergic bronchopulmonary aspergillosis, [ABPA]).

Chest computed tomography (CT) is not necessary for treatment of routine acute pulmonary exacerbations. However, if suspicion for lung abscess, pulmonary embolus, or nontuberculous mycobacteria (NTM) is high, chest CT may be helpful.

Follow-up inpatient PFTs may be considered to document recovery of lung function after initiation of therapy, but acutely in the hospital setting the results may be discordant with the patient’s clinical course.

For patients with cystic fibrosis-related diabetes (CFRD) who are doing carbohydrate counting to dose their insulin, 2-hour postprandial blood sugars should be obtained in addition to preprandial and bedtime blood sugars in order to determine if failure to achieve glycemic control is responsible for failure to restore lung function to baseline.

Sinus CT is only indicated based on significant new sinus symptoms during the patient presentation. They should not be ordered routinely for pulmonary exacerbation in the absence of new sinus symptoms or signs.

Although there is currently no standard definition of an acute pulmonary exacerbation in CF, a number of different criteria have been devised for clinical trials and clinical care. The majority of definitions capture respiratory symptoms such as increased cough, increased sputum production, shortness of breath and chest pain, as well as other measures such as loss of appetite, fatigue, and missing either work or school. However, CF clinicians put the most reliance on a decrease in lung function and will diagnose a pulmonary exacerbation in the absence of any reported change in symptoms if there is a significant decrease in FEV1. This may be particularly true in those exacerbations that develop over a period of a few weeks and the patient is simply unaware of how much symptoms have increased until lung function and symptoms return to baseline following appropriate treatment.

Treatment of the exacerbation, if not severe, begins with outpatient oral antibiotics, increase in airway clearance, and emphasis on compliance with chronic pulmonary medications. More frequent clinic visits and greater use of antibiotics is associated with better PFT results. Close follow-up, usually within a week or two, is needed to make sure lung function has returned to the patient’s baseline.

If lung function does not improve despite a trial of oral antibiotics, then the standard of care is to start intravenous (IV) antibiotics. The Cystic Fibrosis Foundation recommends that home therapy may be appropriate for select patients, but that intravenous antibiotics in a nonhospital setting should not be done unless resources and support equivalent to the hospital setting can be assured for the treatment of an acute exacerbation of pulmonary disease.

Issues to consider when deciding whether to administer IV antibiotics in the outpatient setting include the severity of the exacerbation, whether adequate delivery of other treatments such as airway clearance therapies can be maintained, and the presence of comorbidites such as malnutrition and diabetes that require in hospital care. The current practice in many Cystic Fibrosis Centers is to admit patients with a pulmonary exacerbation to hospital for intensive treatment if outpatient management using oral antibiotics has not restored lung function to baseline. Once hospital treatment has been initiated, been shown to be tolerated by the patient, and the patient is clinically improving, then it may be appropriate to complete treatment in the home.

Hemoptysis, often a sign of pulmonary exacerbation, is a common presenting complaint, occurring in about 9% of CF patients and can range from slight streaking to massive bleeding. Massive hemoptysis (which occurs in 4% of patients) is defined as more than 240 mL of blood in a 24-hour period. It is due to arterial bleeding from hypertrophied bronchial arteries. There is no evidence-based data to guide triage of hemoptysis in CF patients, but current consensus-based recommendations from the Cystic Fibrosis Foundation are that patients with at least mild hemoptysis (measured as > 5 mL) should contact their health care provider and scant hemoptysis (< 5 mL) should contact their health care provider if it is the first ever episode or if it persists.

Scant hemoptysis may not require hospital admission if there is no other evidence of a significant acute pulmonary exacerbation, but massive hemoptysis (> 240 mL) always requires hospital admission. Some centers admit for hemoptysis greater than 120 mL in a 24-hour period.

About 3% of CF patients will have a pneumothorax during their lifetime with an annual incidence of 0.64%, with attributable mortality as high as 16%. Disease severity predicts pneumothorax complication, with 75% of pneumothoraces occuring in patients with an FEV1 < 40% predicted. CF patients with a pneumothorax should almost always be admitted to hospital as the risk of progression and further respiratory compromise are high.

Acute Pulmonary Exacerbation Management

Many, if not most, of the large, multicenter, double-blind, placebo-controlled clinical trials evaluating efficacy of pulmonary drugs in CF have been for outpatient management to prevent respiratory exacerbations, rather than for the management of an exacerbation once it is severe enough to require hospitalization. Therefore, recommendations for inpatient treatment rely on limited studies of small number of patients and on expert opinion. A sample inpatient admission protocol for CF patients with an acute respiratory exacerbation includes specific details of care in addition to an educational tool.

The current mainstay of treatment for acute respiratory exacerbations consists of IV antibiotics and enhanced airway clearance. In addition, pulmonary and nonpulmonary complications of CF that may impair the ability to restore lung function to baseline require evaluation and management; and nutritional support must be addressed. P aeruginosa is the most frequent organism found during an acute exacerbation. However, polymicrobial infections are also common, particularly with Staphylococcus aureus as well as multiple strains of Pseudomonas, each with a different pattern of antibiotic sensitivity. More recently, organisms previously thought to be commensals, such as Stenotrophomonas maltophilia, are now viewed as potentially pathogenic. Early isolates of pseudomonas are nonmucoid and have a broader range of antibiotic sensitivity. However, in the CF airway the organism can mutate to a mucoid form and also can form a biofilm. Such mutations, particularly toward a biofilm, may make antibiotics less effective.

Antimicrobials

The Cystic Fibrosis Foundation guidelines—for the treatment of a respiratory exacerbation in patients whose culture grows pseudomonas—recommend using two IV antibiotics of different classes (Table 240-3). Depending on the antibiotic sensitivities on the sputum culture, an aminoglycoside and a beta-lactam antibiotic is the preferred combination. Dual therapy may prevent the development of resistance and may have more benefit than monotherapy. There have been some clinical trials comparing monotherapy with combination therapy, but there is insufficient evidence due to the small number of patients in each trial to recommend one over the other.