Chapter 38: Cystic Fibrosis

• Cystic fibrosis (CF) is the most common, life-limiting, autosomal recessive disease among Caucasians in the United States.

• It occurs in approximately 1 in 3500 White births and is being diagnosed increasingly in non-Caucasians as well.¹ (Fig. 38-1)

• Most patients with CF have the classic triad of manifestations:

  • Chronic pulmonary disease

  • Malabsorption due to pancreatic insufficiency

  • Elevated concentrations of sweat sodium and chloride.²

• There is considerable individual variation in the clinical manifestations, severity, and course of the disease.

Cystic fibrosis (CF) is caused by mutations in the gene that encodes the cystic fibrosis transmembrane conductance regulator (CFTR) protein.^1,3–5 This protein, which is located in the epithelial cell membrane, functions normally as a cAMP-activated chloride channel, transporting chloride (and passively water) out of the cell into the adjacent lumen.^1,4,5 CFTR also plays a role in bicarbonate transport from the cell into the lumen.^1,4,5 CFTR is involved in regulating sodium channels for airway epithelial cells, helping to limit sodium (and water) reabsorption from the lumen to the cells.^1,4,5 In sweat gland ductal cells, CFTR transports chloride in the opposite direction, that is, from the lumen into the cell.¹ These mechanisms help explain the clinical manifestations of the disease.

The CFTR gene is located on the long arm of chromosome 7. The most common mutation that causes CF (F508del)—and more than 1500 less-common mutations—has been identified.^1,4 Five classes of mutations have been identified.⁶ Organs that express the CFTR gene (particularly the sinuses, lungs, pancreas, liver, gastrointestinal [GI] tract, and reproductive system) are the ones affected by the mutations.⁴ The relationship between genotype and clinical manifestations is not always straightforward, however.^1,4

The most important pathophysiologic consequence of these CFTR “defects” is diminished water in mucus and most exocrine secretions (along with associated electrolyte and other abnormalities).^1,2,4 Mucus and exocrine secretions are more viscid, and they are difficult to clear, causing airway and ductal obstruction.^1–4,7 In the airways, these mucus (and possibly other) abnormalities predispose to chronic infection with a characteristic group of bacterial organisms and inflammation.^1–5,7 Exactly why this predisposition to specific infections occurs has yet to be fully elucidated. Various hypotheses have been proposed which are discussed in some detail in the references^1–5 (Table 38-1).

Pancreatic exocrine insufficiency (which results in GI malabsorption and malnutrition) follows from the low volume of pancreatic secretions reaching the GI tract as well as their abnormal bicarbonate-, enzyme-, and water-deficient content.^1,2,4 Pancreatic endocrine insufficiency (resulting in diabetes mellitus)—or even acute pancreatitis—may ensue eventually, due to pancreatic autodigestion by stagnant activated enzymes.^1–4,7 Abnormal intestinal mucus and biliary secretions also play roles in the malabsorptive and various GI and hepatobiliary obstructive sequelae found in CF.² Patients with CF often have elevated sweat chloride (and sodium) concentrations because of defective chloride transport out of the primary sweat by the sweat gland duct cells.¹

Undiagnosed CF patients, who are untreated, may present to the ED for a variety of complaints. Failure to thrive with a history of chronic GI and/or respiratory problems is a typical presentation.² CF should be considered in any patient with chronic diarrhea, recurrent respiratory infections (especially with bronchiectasis or clubbing), or atypical asthma.² Hypoproteinemia and edema may develop in those with prominent malabsorption.² Malabsorption can lead to vitamin deficiencies, especially of fat-soluble vitamins.^1,2 Hemorrhage due to vitamin K deficiency as well as neurologic abnormalities and hemolytic anemia from vitamin E deficiency have been described.^1,2 Patients with clinical findings suggestive of CF should be referred for diagnostic evaluation.

Known CF patients can present to the ED with various acute complications, and the most common is a pulmonary exacerbation manifested by an increase of respiratory symptoms. Pulmonary exacerbations are thought to be due to more active airway infection. The youngest patients with CF have infections caused by Staphylococcus aureus or Haemophilus influenzae. Eventually, however, Pseudomonas aeruginosa becomes the most prevalent organism.^4,5,8,9 In chronically infected CF patients, P. aeruginosa tends to mutate, becoming more mucoid, less motile, and very difficult to eradicate with antibiotics.^4,8,9 Burkholderia (formerly Pseudomonas) cepacia is a particularly virulent organism in patients with CF patients.^1,5 Nontuberculous mycobacterial infections can occur and are difficult to eradicate.¹ Methicillin-resistant Staphylococcus aureus (MRSA) is an emerging pathogen in the respiratory tracts of patients with CF. Because MRSA infections have been associated with a higher risk of mortality, they should be treated aggressively.¹⁰

Chronic airway infection and inflammation, along with repeated exacerbations, result in destruction of the airway.^1,4,5,11 Bronchiolitis-like manifestations may develop initially, accompanied by bronchitis later.¹ With prolonged disease, bronchiolar obliteration, bronchiolectasis, and bronchiectasis ensue.^1,5 Mucus plugging and airway obstruction are prominent features of CF, leading to atelectasis, enlarged air spaces, and ventilation–perfusion mismatching.^1,5

Pneumothorax (sometimes, a tension pneumothorax) may result from the rupture of an emphysematous bulla or bleb and must be excluded in any patient with CF who deteriorates suddenly.^1,2 It is not unusual in older teenagers and adults, or in patients with significant impairment in lung function, and can often recur.^2,12,13 Pneumothorax is a poor prognostic indicator and is associated with a subsequent increase in hospitalizations, hospital days, and 2-year mortality.¹³

Patients with CF may have hemoptysis, especially during exacerbations.¹ Bleeding is usually minor and not dangerous. Massive hemoptysis—acute bleeding >240 mL/day or >100 mL/day over several days—is not rare and can cause life-threatening asphyxia or hypotension.¹² It is thought to result from persistent airway inflammation and erosion into markedly enlarged bronchial arteries (which contain systemic pressures).¹² Like pneumothorax, massive hemoptysis is more prevalent in older patients and in those with more severe pulmonary impairment.¹² S. aureus in sputum cultures is also associated with an increased risk.¹² Massive hemoptysis is a poor prognostic indicator, similar to pneumothorax.¹²

Hematemesis occurs less often but must be distinguished from hemoptysis.² It is usually due to bleeding esophageal varices secondary to portal hypertension from advanced cirrhosis.²

Patients with progressively worsening lung disease may eventually develop pulmonary hypertension and right ventricular hypertrophy (cor pulmonale).² A respiratory exacerbation may precipitate congestive heart failure.² In time, most patients with CF die of respiratory failure complicated by cor pulmonale.

Acute GI complications of CF include meconium ileus, distal intestinal obstruction syndrome (DIOS), and rectal prolapse.^1,2,14 Meconium ileus is obstruction of the terminal ileum by inspissated stool in the newborn period. These infants most commonly present with no passage of meconium within 24 hours of birth; this may progress to symptoms and signs of intestinal obstruction or even intestinal perforation (which sometimes occurs prenatally)¹⁵ (Fig. 38-2). DIOS occurs in older children with CF and is defined as acute obstruction in the ileocecal region. DIOS can be complete, presenting with bilious emesis, or incomplete, presenting with abdominal pain and distention alone.¹⁴ Intussusception, volvulus, and intestinal perforation are other potential related consequences of DIOS.^1,2 Similarly, constipation and crampy abdominal pain are common in patients with CF. Rectal prolapse is associated with CF and is most commonly seen in children younger than 3 years old.^1,2

Patients with CF usually have elevated sweat chloride and sodium concentrations, giving them their characteristically salty taste.^1,2,4 Sweat salt and water losses, with associated renal compensation, can lead to acute or chronic electrolyte depletion and dehydration.² These occur most commonly in infants with gastroenteritis and poor oral intake, or during the hot summer months, especially in arid climates.^1,2

As patients approach adulthood, they may develop additional complications, such as CF-related diabetes, which occurs in up to 20% of adolescents and 40%–50% of adults.¹⁶ CF-related diabetes is primarily a result of insulin insufficiency, although fluctuating levels of insulin resistance also play a role, and is generally managed by insulin alone.¹⁶ Diabetic ketoacidosis is rare.¹⁶ Other complications include obstructive biliary tract disease (up to 30% of adults) and obstructive azospermia (95% of postpubertal males).¹

All 50 states now test for CF in newborn screens, leading to earlier detection in most cases and, probably, improved survival.^4,17,18 A referral for evaluation should be made for any patient in whom the diagnosis is suspected.² Recommended criteria and testing for diagnosing CF are identified in Figure 38-1. DNA mutation analysis is available for detection of patients and carriers.¹ Traditionally, a pilocarpine iontophoresis sweat test has been a part of the diagnostic evaluation in any patient with suspected CF.^1,17 This test measures the chloride concentration in sweat. Values >60 mEq/L are considered positive; however, this cutoff is not 100% sensitive for diagnosing CF.^1,4 Of note, sweat testing can be difficult to perform accurately, is time-consuming, and is not available in the ED.¹

During pulmonary exacerbations, oxygen saturation should be measured via pulse oximetry initially. Blood-gas determinations may be useful in managing patients with respiratory failure, particularly those who have had good lung functions and suffer acute decompensation.² The evaluation should include sputum or, if unobtainable, lower pharyngeal or throat culture, to guide antibiotic therapy.^1,9

The chest x-ray during an exacerbation should be compared with the most recent previous ones.² Common chest x-ray findings include hyperinflation, diffuse peribronchial thickening, and areas of atelectasis and fluffy infiltrates.^1,2 Patients with cor pulmonale have comparatively larger hearts—as opposed to the narrow hearts usually seen in CF patients—and prominent pulmonary vasculature.² Consider pneumothorax in any patient with a sudden deterioration in pulmonary status and obtain a chest x-ray.

Patients with meconium ileus or DIOS have dilated loops of bowel on abdominal films. A bubbly granular density in the lower abdomen, representing the meconium or fecal mass, may also be seen.²

In patients with significant hemoptysis or hematemesis, blood should be sent for complete blood count, type and cross-match, and prothrombin time. Hyponatremic, hypokalemic, hypochloremic alkalosis is the classic electrolyte abnormality, and can be a diagnostic clue, particularly when seen in a patient with other findings suggestive of CF.^1,2

CF may be confused with a variety of different disorders. Table 38-2 lists some non-CF causes of protracted or recurrent pulmonary symptoms. Table 38-3 lists other causes of exocrine pancreatic insufficiency.¹ Table 38-4 lists other conditions that are associated with elevated sweat electrolyte concentrations.¹

Much of the decision making in CF involves issues of chronic care. However, sometimes the ED physician must begin treating one of the acute complications of the disease, most commonly a pulmonary exacerbation (Fig. 38-3). Therapy for the latter is aimed at relieving airway obstruction and treating infection.¹ Oxygen should be administered if indicated by pulse oximetry or arterial blood gas.² Airway obstruction in CF tends to be only partially reversible, because of the inflammation as well as any preexisting structural damage. Inhaled β₂-adrenergic bronchodilators are often effective in the short term and should be used in those who respond clinically.^1,2

Antimicrobial therapy during an exacerbation results in a decreased bacterial load and improved pulmonary function.^8,19 Until current sputum culture results are known, prior results can help guide antibiotic selection.^1,2,5,9 If recent results are unavailable, empiric therapy should be aimed at the most common organisms seen in CF patients: S. aureus and H. influenzae in infants and young children, and P. aeruginosa, which is often present by the end of the first decade of life.^4,5,8,9 Patients with CF with exacerbations due to P. aeruginosa should be treated with combination antibiotics, because treatment with a single antibiotic may be associated with rapid resistance.^1,9 Inhaled antibiotics, particularly tobramycin, was noted to be safe and effective for patients colonized with P. aeruginosa and can be used in an acute exacerbation. For patients with massive hemoptysis, anti-staphylococcal therapy should be considered.¹² Decisions regarding specific antibiotics must be individualized and should be made in consultation with the patient's CF specialist.

Pulmozyme (recombinant human deoxyribonuclease) is a “mucolytic” medication, which is administered via nebulization. It reduces sputum viscosity by enzymatically degrading the excessive DNA from dead neutrophils and other cells in airway mucus.^4,5 Pulmozyme improves pulmonary function and decreases the number of exacerbations when used for long-term treatment in selected patients with CF.¹ Although it is generally employed for chronic management, it can be continued during an acute exacerbation as well. Nebulized hypertonic saline has been proposed as an alternative method of clearing secretions.^1,4,5 Chest physiotherapy and postural drainage techniques are well accepted (although not as well proven) for clearing secretions in patients with CF; however, it is important to note that expert consensus recommends these techniques be withheld in patients with pneumothoraces.^1,2,4,5,20

Although still under study, anti-inflammatory medications may be beneficial in the long-term—and possibly acute—care of certain patients with CF. Macrolides (e.g., azithromycin), which possess anti-inflammatory and antibacterial properties, and high-dose ibuprofen seem promising.^{1,4,5,21–25} Inhaled steroids are commonly used for long-term care, but this is controversial.^1,4,5,22 Some CF centers administer intravenous steroids for acute exacerbations. However, chronic administration of oral steroids is not recommended for most patients.^1,4,5,22

Pneumothoraces greater than 10% of the hemithorax on PA chest x-ray may require evacuation by tube thoracostomy (via a chest tube or pleural drain).² A tension pneumothorax should be aspirated first (through a large-bore IV catheter), followed by tube thoracostomy.²

Significant hemoptysis (>10–60 mL) is an indication for inpatient observation, and vitamin K should be administered if the prothrombin time is prolonged.^1,2 Guidelines for replacement with packed red blood cells, fresh-frozen plasma, etc., are the same as for bleeding from other sources. For massive hemoptysis, ligation or embolization of the bleeding vessel may be necessary.^1,2 Both hemoptysis and pneumothorax may be signs of infection and antibiotic treatment should be considered.²⁰

Cor pulmonale may require treatment with oxygen and diuretics, in addition to treatment for the underlying lung disease. Before deciding to intubate and mechanically ventilate a patient with CF in respiratory failure, the ED physician must consider the baseline pulmonary function, disease course, and patient and parental expectations.² In general, a patient is a candidate for ventilation if the pulmonary function has been good and this bout of respiratory failure was precipitated by an acute insult, such as asthma or pneumonia.^1,2 Ventilation may not be warranted, however, if the pulmonary function has been very poor and had been steadily declining despite aggressive medical therapy. This is a terribly difficult decision, of course, and should be made in conjunction with the patient, parents, and chronic care provider. Recently, a number of patients with CF have undergone double lung (or heart-lung) transplants, although further study is required to determine whether these truly lengthen survival.²⁶

For meconium ileus or DIOS, a diluted diatrizoate (Gastrografin®) enema should be administered to relieve the obstruction. Surgery is indicated for bowel perforation or volvulus, or if the enema is unsuccessful in relieving the obstruction or reducing an intussusception.¹⁵

Infants with significant dehydration and electrolyte losses should receive a 20 mL/kg normal saline bolus initially; more than one bolus may be necessary.² Once urine output is established (and after the bolus[es]), potassium chloride should be added to the fluids. Serum electrolytes should be monitored frequently to help guide fluid therapy.²

Many more patients with CF now survive to adulthood, with their median cumulative survival exceeding 35 years of age.¹ Factors contributing to this improved survival include earlier diagnosis, better nutrition, aggressive treatment of pulmonary infections, and prompt recognition and treatment of the numerous life-limiting and life-threatening complications of CF.