Cystic Fibrosis

What every physician needs to know:

Cystic fibrosis (CF) is a relatively common disease that is inherited in an autosomal recessive pattern and results in a shortened average life span. CF affects all exocrine glands of the body, but abnormalities in the lungs and pancreas usually dominate the clinical picture.

CF lung disease is a chronic, progressive obstructive process punctuated by exacerbations of infection and inflammation. Pancreatic insufficiency, which occurs in the majority of CF patients, usually presents as malabsorption and malnutrition, often with vitamin deficiencies. The sweat glands produce sweat with an elevated concentration of chloride and sodium, so measurement of sweat chloride concentration is the key diagnostic test. There is tremendous variability in the degree and pattern of organ involvement among patients with CF.

Classification:

The two major clinical issues in CF are chronic obstructive pulmonary disease, secondary to abnormal respiratory tract secretions, and malnutrition secondary to pancreatic insufficiency.

Possible presentations of CF vary with the age at presentation. Table 1 lists the presenting signs and symptoms of CF, beginning in infancy and continuing through childhood, adolescence, and adulthood (Table 1).

Table I.

Are you sure your patient has cystic fibrosis? What should you expect to find?

A number of clinical hallmarks characterize CF, and the diagnosis should be entertained when any of the following features are noted.

Positive cystic fibrosis newborn screen

A positive CF newborn screen (which varies among states but usually includes immunoreactive trypsinogen or genotyping for F508del or several of the most common CFTR mutations) has become the most common presentation of CF. As of 2010, all 50 US states perform a CF newborn screen on all live births. A positive newborn screen should trigger evaluation in an accredited CF center and diagnostic testing for CF.

A sweat test using the Quantitative Pilocarpine Iontophoreseis Sweat Test Method is the first test to be performed in the evaluation. The test should be performed in an accredited laboratory according to the National Committee for Clinical Lab Standards guidelines. A sweat chloride value > 60 meq/L in an infant with a positive newborn screen establishes the diagnosis of CF.

If mutation analysis was not performed as part of the CF newborn screen, and if two CFTR mutations were not identified, testing for mutations which cause CF should be initiated. Several important facts must be considered in the evaluation:

• A positive newborn screen does not establish the diagnosis of CF.

• Obtaining a sufficient quantity of sweat for analysis in the first few months of life may be difficult.

• Recent guidelines have changed threshold for a normal sweat chloride to < 30 mEq/L

Positive prenatal test for cystic fibrosis mutations or prenatal ultrasound

Testing for CF mutations is frequently performed on chorionic villus sampling and amniotic fluid samples obtained in the prenatal period. If either one or two CF mutations are identified, the parents should be referred to a genetic counselor and optimally to an accredited CF center for further counseling. Since only a limited panel of CF mutations is routinely tested, the absence of CF mutations does not exclude the diagnosis of CF.

In the prenatal period, hyperechoic bowel observed on ultrasonography may suggest intestinal obstruction. Approximately 10% of fetuses with hyperechoic bowel have CF.

Meconium ileus

Ten to twenty percent of newborns with CF have intestinal symptoms in the newborn period secondary to abnormally viscous meconium stool with a high protein content. The presentation may vary from delayed passage of meconium to meconium plug syndrome to full-blown meconium ileus with inspissation of meconium in the small intestine. This last entity results in abdominal distension and dilated loops of bowel on imaging. A carefully performed Gastrograffin enema may be both diagnostic and therapeutic. If evidence of peritonitis from an intrauterine perforation is seen, surgical correction is usually required.

Obstructive jaundice

Some infants with CF may present with the inspissated bile syndrome secondary to intrahepatic bile stasis and extrahepatic bile duct obstruction. This condition is often seen as prolonged neonatal jaundice, with an onset at 2-8 weeks of age. The jaundice usually clears spontaneously.

Edema with hypoproteinemia, anemia and hypoprothrombinemia

The constellation of hypoproteinemia, anemia, and hypoprothrombinemia may be the earliest presentation of malabsorption syndrome secondary to pancreatic insufficiency in CF. Eighty-five to ninety percent of patients with CF have pancreatic insufficiency.

Hypoprothrombinemia may occur as an isolated bleeding diathesis. Pancreatic enzyme replacement therapy (PERT) and vitamin K supplementation are required for correction.

Failure to thrive

CF should always be considered in the differential diagnosis of failure to thrive in childhood, especially in children who have a history of frequent, loose, bulky stools and whose velocity of weight gain is decreasing. The combination of these findings, coupled with a history of chronic or recurrent respiratory symptoms, increases the suspicion for CF.

Salty taste or salt loss syndromes

Because of the increased salt loss through the sweat glands, parents will often report that their child “tastes salty”. In the absence of salt supplementation, the child may present with heat prostration. CF can also lead to a chronic hypochloremic metabolic alkalosis.

Rectal prolapse

Rectal prolapse secondary to steatorrhea, bulky stools, and poor muscle tone may occur in up to 20% of patients with CF in the first few years of life.

Intestinal obstruction with or without intussusception or volvulus

Recurrent, crampy abdominal pain associated with a right lower quadrant fecal mass is often a feature of CF. Maldigested food, combined with dehydrated, viscid intestinal mucus, may lead to the formation of a fecal mass at the ileocecal junction.

This partial or complete obstruction is often referred to as meconium ileus equivalent (MIE) or distal intestinal obstruction syndrome (DIOS). The fecal mass may occasionally serve as the leading edge of an intussusception or volvulus. If a fecal mass is present without complete obstruction, Miralax or Golytely orally will clear the mass. In the presence of obstruction (erect abdominal x-ray showing dilated loops of bowel with air fluid levels), and in the absence of signs of compromised integrity of the bowel wall, a Gastrograffin enema is the therapy of choice. Surgery is required if there are signs/symptoms of compromised bowel integrity.

Recurrent pneumonia or bronchiolitis

A history of recurrent pneumonia or bronchiolitis in infants, and pneumonia or bronchitis in older children, adolescents, and adults is a common presentation of CF. Patients with CF who don’t carry these specific diagnoses may simply complain of a chronic cough or a cough that persists following what appeared to be a simple upper-respiratory tract viral infection.

Pulmonary infections with Staphylococcus and Pseudomonas

A patient who has a history of significant respiratory infections and who has persistently positive cultures for Staphylococcus or, occasionally, positive cultures from Pseudomonas from respiratory secretions should be considered for the diagnosis of CF.

Malnutrition with steatorrhea and pancreatic insufficiency

Patients who meet the criteria for malnutrition and who have documented fat malabsorption and pancreatic insufficiency have a high probability of having CF.

Heat prostration with hypoelectrolytemia and metabolic alkalosis

Older patients with CF may present with acute symptoms of a salt loss syndrome, such as fainting in a hot environment, rather than the more chronic presentation for infants.

Atypical asthma with clubbing and bronchiectasis

Asthma is a much more common cause of cough and wheezing than CF. However, in patients whose asthma is refractory to standard therapy and in those who have also demonstrated clubbing and bronchiectasis, CF should be considered.

Esophageal varices and hypersplenism

Focal biliary cirrhosis is present in many patients with CF. In about 5% the cirrhosis is significant enough to cause portal hypertension, which eventually results in esophageal varices and/or hypersplenism. The presenting symptom may be bleeding esophageal varices.

Nasal polyps

Nasal polyps are relatively common in adults with chronic allergic rhinitis/sinusitis, but relatively rare in children, so nasal polyps in children should prompt consideration of CF.

Chronic bronchitis with bronchiectasis

Bronchiectasis is a relatively uncommon complication in most patients with chronic bronchitis. CF is an exception in that most patients with CF eventually develop some bronchiectasis as their lung disease progresses.

Pansinusitis

Opacification of all the sinuses at a relatively early age is a feature of CF.

Hemoptysis

Once patients have developed bronchiectasis, the dilated tortuous bronchial arteries that develop around the bronchiectatic airway are a common source of pulmonary hemorrhage/hemoptysis.

Recurrent pancreatitis

Pancreatitis is unusual in patients with typical or “classic” CF. However, the incidence of recurrent pancreatitis is increased in patients with milder, “atypical” CF, especially in those patients with pancreatic sufficiency. Approximately 10-20% of patients with recurrent idiopathic pancreatitis have two abnormal CFTR genes, at least one of which is considered a mild mutation.

Obstructive aspermia

The mildest form of CF occurs in males with obstructive aspermia and congenital bilateral absence of the vas deferens (CBAVD). CF genetic mutations (in CFTR) are found in about 50% of affected men. These individuals often have no other demonstrable organ abnormality attributable to CF at the time of diagnosis.

Additional clinical features of cystic fibrosis

Additional gastrointestinal, respiratory, and metabolic findings are discussed below.

Gastrointestinal manifestations

Gastroesophageal reflux

The incidence of reflux varies in CF from 19% in infants to 94% in adults. Contributing factors include the presence of hiatal hernias, gastric distension, volume, pressure and motility, dietary composition, intrathoracic pressure, postural drainage techniques, and supine positioning. Symptoms vary from obvious (regurgitation, vomiting, spitting up, hiccups of long duration, and chest pain) to that of overall deterioration (food refusal, irritability, and poor weight gain).

Diagnosis is mainly clinical, and testing is done to answer specific questions. Upper GI barium series are done to document normal anatomy, gastric emptying/milk scan to look for delayed gastric emptying and aspiration, pH probe to assess correlation of reflux with unusual symptoms or prior to fundoplication, and upper endoscopy to look for reflux esophagitis or eosinophilic esophagitis in patients with persistent symptoms.

Treatment consists of postural therapy, dietary changes, medications, and surgery. Medications include gastric acid blocking medications (H2 receptor antagonists and proton pump inhibitors) and promotility agents (metoclopromide, bethanechol). Erythromycin may be useful in those with delayed gastric emptying. Surgical fundoplication is indicated in those who fail medical therapy and those with aspiration secondary to reflux. Fundoplication is highly beneficial in patients who receive lung transplants, especially prior to transplant. Success is variable.

Appendicitis

Appendicitis, both acute and chronic, is seen in patients with CF. Clinical presentation is varied, so delays in diagnosis sometimes result. Appendicitis needs to be differentiated from DIOS in patients with persistent right lower quadrant pain. Enlarged appendiceal diameter should not be the only criteria used in diagnosing acute appendicitis since the majority of patients with CF may have this finding. The complication of appendiceal abscess is frequently seen in those patients with acute appendicitis, and this development is related to the delay in diagnosis.

Rectal prolapse

This complication is usually seen at the time of diagnosis and in patients with constipation and straining, excessive diarrhea, and malnutrition. Treatment consists of manual reduction of the prolapse, treatment of straining by using stool softeners, and correction of malabsorption and malnutrition. Some patients require surgical resection of a persistent prolapse or injection of a sclerosant into the perirectal tissue to prevent further prolapse. Prognosis is generally good.

Small bowel bacterial overgrowth

Patients with CF frequently have problems related to bacterial overgrowth with an incidence as high as 56%. Predisposing factors include dysmotility, poor local antibacterial defenses, use of antibiotics, and previous GI surgery. Use of polyethylene glycol was associated with less bacterial overgrowth. Clinical symptoms include abdominal pain, abdominal distension, increased gas, diarrhea, and poor growth. Secondary malabsorption results in fat-soluble vitamin deficiency, weight loss, or lack of adequate weight gain. Diagnosis may be made clinically or with the help of breath tests. Treatment is based on use of intermittent antibiotics.

Infections

A variety of GI infections, including Clostridium difficile, Helicobacter pylori, and Giardia, have been reported to occur in patients with CF. While true C. difficile infection is rare, carrier rates are high. In patients post-lung transplant, C. difficile infection may be atypical and severe, with a high mortality rate. Helicobacter pylori infection does not appear to be increased in patients with CF. Cross-reactivity between pseudomonas antibodies and helicobacter antibodies has been described, making serological testing less reliable. The incidence of Giardia infection appears to be increased in patients with CF.

Fibrosing colonopathy

Fibrosing colonopathy appears to be temporally related to the availability of high-potency pancreatic enzyme products. Possible mechanisms include failure of the enzyme-containing microcapsules to dissolve in the small intestine, resulting in high cecal enzyme concentration, overfilling of enzyme in capsules to account for stated shelf-life, and mucosal damage from enzymes. Fibrosing colonopathy has also been seen in neonates with CF who have not received enzymes, further clouding the question of etiology. It has also been shown that high doses of enzymes, length of therapy, previous GI surgery, use of gastric-blocking medications, and pulmozyme therapy have been linked to therapy, rather than one particular brand of enzymes.

Symptoms include abdominal pain, constipation, diarrhea, bloody stools, abdominal distension, and intestinal obstruction. Diagnosis is made primarily by demonstrating a narrow, thickened proximal colon on barium enema, CT scan, or US. Pathology reveals submucosal fibrosis extending to the serosal surface, beginning in the ascending colon and extending to the distal colon. Treatment consists of reducing the enzyme dose, nutrition support, and surgery.

Malignancy

As life expectancy in CF has increased, affected patients are developing GI malignancies and pancreatic cancer. The GI malignancies include those of the esophagus, stomach, small bowel, colon (adenocarcinoma), and biliary tree. Age-adjusted risk is 9:1 for GI malignancies and 31:1 for pancreatic cancer.

Liver disease

Liver disease is frequently asymptomatic in patients with CF; prevalence varies from 13-27%. Hepatic conditions include neonatal cholestasis, elevated liver enzymes, hepatomegaly, fatty liver, focal biliary cirrhosis, and multilobular cirrhosis. Biliary conditions include microgallbladder, gallstones, and gall bladder dysfunction.

Elevated liver enzymes may be seen in 10-46% of patients. The degree of elevation of liver enzymes does not reflect the severity of liver damage, and patients with cirrhosis may have minimal elevations. Patients who have liver enzyme elevations that are 1.5-3X the upper limit of normal should have repeat values in 3 months; if these elevations are persistently 3X above the upper limit of normal, further evaluation is warranted, including US with Doppler, evaluation of liver synthetic function, and exclusion of other causes of liver disease (e.g., infections, medications, alpha-1-antitrypsin deficiency, autoimmune liver disease, and Wilson’s disease).

Neonatal cholestasis, which presents soon after birth, must be differentiated from biliary atresia and other neonatal liver disease. Fatty liver occurs in 20-60% of patients and may be related to malnutrition and essential fatty acid deficiency. Focal biliary cirrhosis and multilobular cirrhosis represent progressive liver disease and may result in portal hypertension. Disease progression usually occurs prior to adolescence and presents as splenomegaly, variceal bleeding, and poor synthetic function. Fulminant liver failure is uncommon.

The gallbladder is frequently dysfunctional, and a small gallbladder can be seen in 20-30% of patients. Gallstones are seen in 1-10% of patients. Treatment of CF liver disease consists of avoiding hepatotoxic medications, alcohol, and alternative medications. Patients should receive hepatitis A and B vaccinations. A nutritional plan should be developed for each patient to maintain normal growth and nutritional status by providing adequate calorie and protein intake. Any fat-soluble vitamin deficiency should be treated, as should any essential fatty acid deficiency. The CF Foundation Hepatobiliary Disease Consensus Group has recommended treatment with ursodeoxycholic acid, a choleretic agent, in a dose of 10-20 mg/kg/day.

Treatment of complications of portal hypertension should be done in conjunction with a pediatric gastroenterologist. Liver transplant is indicated in patients with severe liver dysfunction, life-threatening complications from portal hypertension, or hepatopulmonary syndrome.

Respiratory Manifestations

Atelectasis

Atelectasis of a lung segment or lobe sometimes occurs in CF. Acute atelectasis is generally associated with few symptoms so it is often not detected immediately. Left untreated, the end result of atelectasis is a severely bronchiectatic segment or lobe. Vigorous chest PT, in conjunction with antibiotics, is often successful in re-expanding the affected lung region. While bronchoscopy is occasionally helpful, as a rule, it is no more effective than chest PT and pulmonary pharmacotherapy.

Resection of a persistently atelectatic or bronchiectatic lobe is undertaken only when the remaining areas of the lung are in relatively good condition, overall pulmonary function is good, and when the evidence suggests that the affected segment is responsible for intolerable, severe symptoms (fever, cough, or sputum production).

Hemoptysis

Expectoration of a small amount of blood-streaked sputum is a fairly common occurrence generally managed by intensifying home therapy for a pulmonary exacerbation of CF. For significant hemoptysis (coughing up 30-60 ml of fresh blood), admission to the hospital for observation and IV antibiotics is the preferred approach. Airway-clearance therapies and inhaled mucolytics should be held for at least 24 hours to ensure that the bleeding does not continue.

Massive hemoptysis (> 240 ml of blood) is a serious situation requiring the consideration of bronchial artery embolization and rarely, pulmonary resection. A CF Foundation committee achieved fairly good consensus on many aspects of the management of scant (<5 mL) and massive (> 240 ml) hemoptysis, but very little consensus on the treatment of mild to moderate (>5 ml but <240 ml) hemoptysis.

Pneumothorax

Recurrent pneumothorax is common in CF, particularly in older patients. Tension pneumothorax occurs in up to 30% of patients with CF who develop pneumothorax. Tube thoracostomy should be considered, and it is usually indicated when the pneumothorax occupies >10% of the area of the hemithorax seen on CXR. The clinical stability of the patient is also factored into this decision. Because the frequency of recurrence of pneumothorax is high, attempts are often made on the first occurrence to achieve chemical or surgical pleurodesis.

Surgical pleurodesis is more effective than chemical pleurodesis at preventing recurrence of a pneumothorax and is no longer considered an absolute contraindication to lung transplant. A CF Foundation committee achieved some consensus on the management of pneumothorax in CF. Rather than using the % of the hemithorax affected, they used > or < 3 cm between cupola and apex to define large and small pneumothoraces, respectively. In general, there was more agreement on the approach to larger pneumothoraces requiring chest tube and less agreement on when and whether to perform pleurodesis.

Respiratory Failure

When respiratory failure (hypercarbia + hypoxemia) develops in a patient with CF, management decisions become difficult. Mechanical ventilation is generally instituted when an acute episode, e.g., viral pneumonia or status asthmaticus, leads to acute respiratory failure. This is particularly indicated in a patient with good pulmonary function before the acute episode; mechanical ventilation is less successful if the patient has had a prior episode of respiratory failure.

When respiratory failure marks the end of a chronic course of progressive deterioration in lung function, mechanical ventilation is less likely to be helpful. Noninvasive mechanical ventilation using bi-level positive airway pressure has been used successfully in end-stage CF patients awaiting lung transplant as a “bridge to transplant.” In these situations, mechanical ventilation has been shown to improve oxygenation and to decrease respiratory rate. Some patients were successfully transitioned to home nocturnal use of noninvasive ventilation. If a patient is already listed for lung transplant, that is an important factor in making a decision.

Electrolyte-Related Findings

Hypoelectrolytemia and metabolic alkalosis

Serious complications are especially apt to occur in hot weather and when recommendations for salt supplementation have not been followed. Electrolyte depletion may be life-threatening, especially in infants and young children. Prompt fluid replacement with isotonic saline is critical.

Special consideration in cystic fibrosis: cystic fibrosis-related diabetes mellitus

CF-related diabetes (CFRD) is a distinct clinical entity occurring in ~20% percent of adolescents and 40-50% of adults with CF. Delayed and blunted insulin secretion are evident following a meal or glucose challenge, even before CFRD is evident. With progression of insulin deficiency, mild hyperglycemia, impaired glucose tolerance, and, subsequently, frank diabetes develop.

CF exacerbations, intercurrent illness, and systemic glucocorticoids may superimpose insulin resistance on the insulin-deficient state and unmask CFRD. With resolution of the intercurrent illness or discontinuation of glucocorticoids, hyperglycemia may resolve, but the individual remains at risk for hyperglycemia during or even in the absence of such episodes.

CFRD is associated with worsening nutritional status, worsening pulmonary function, younger age to lung transplant, and increased mortality, and treatment improves these outcomes. Microvascular complications also occur in CFRD, especially if fasting hyperglycemia is present.

Individuals with CFRD are frequently asymptomatic, and even classic symptoms of diabetes (polyuria, polydipsia) are often absent. Failure to gain or maintain weight, poor growth, and worsening pulmonary function may be symptoms of CFRD.

Because of its insidious nature and implications for CF, routine screening for CFRD is recommended. Annual screening with a 2-hour oral glucose tolerance test (OGTT) by age 10 is recommended. Table 4 outlines the various glucose abnormalities currently defined in CF. Blood glucose monitoring should also be performed during hospitalizations, in the outpatient setting during intercurrent illness that requires IV antibiotics or systemic glucocorticoids, and at least monthly in individuals receiving overnight enteral feeds.

Table IV.

Insulin is recommended for CFRD and tailored to the needs of the individual patient. Short-acting insulin (aspart, lispro) is used just before meals or snacks to cover carbohydrates and to treat hyperglycemia. Doses vary based upon weight, age, pubertal status, and clinical condition, and adjustments are based upon glucose responses to such measures. Intercurrent illness and glucocorticoids may cause significant insulin resistance, and dosage adjustments may be necessary. Long-acting insulin (glargine, detemir, NPH) is used for fasting hyperglycemia.

For continuous overnight feeds, matching insulin dose to carbohydrates can be done, but dosing may require creativity. Frequent blood glucose monitoring with insulin initiation is important to achieve blood glucose in the 100-140 mg/dL range. Insulin pumps deliver basal and bolus insulin so given the frequency with which many patients with CFRD eat and the frequency with which insulin injections need to be delivered, the insulin pump is an attractive option for some patients. For others, carbohydrate counting is too cumbersome; set doses of insulin may be appropriate and safe if the patient eats reliably and consistently.

Oral agents have been used in CFRD, although their use is not recommended. Given the already intense medical regimens in CF, the addition of multiple insulin injections may not be readily accepted. In a case series of 20 subjects, outcomes were not different among adults with CFRD treated with insulin vs. oral agents; however, the small sample size precluded the drawing of firm conclusions. The side effect profiles of many oral medications limit their use in CF (metformin – diarrhea, appetite changes; acarbose – diarrhea, anorexia, malabsorption; and thiazolidinediones – osteoporosis). In 7 adults with CFRD without fasting hyperglycemia, short-acting insulin, the insulin secretagogue repaglinide, and placebo were compared. Repaglinide increased endogenous insulin concentrations but was less effective than short-acting insulin in regulating postprandial hyperglycemia. Neither drug normalized blood glucose at the doses used.

Nutritional therapy is an integral part of both CF and CFRD. Although caloric restriction is not an appropriate option for the treatment of CFRD, avoidance of simple sugars (e.g., soda and sugar-based candies) or their consumption with complex carbohydrates, protein, and fats to slow sugar absorption may be indicated. To optimize caloric intake, carbohydrate counting may be performed and short-acting insulin administered to cover carbohydrate intake.

Microvascular complications can occur in patients with CFRD, but the presence of fasting hyperglycemia may be necessary. In one series, over a 15-year period, no patient with CFRD in the absence of fasting hyperglycemia, developed retinopathy or microalbuminuria; 16% of patients with CFRD with fasting hyperglycemia of >10 years duration had retinopathy, and 14% had microalbuminuria.

The overall prevalence of microvascular complications is less than other forms of diabetes, but such complications may be reflective of the duration of diabetes, the level of glycemic control, the persistence of variable degrees of endogenous insulin secretion, and the relative absence of metabolic risk factors, such as hyperlipidemia and hypertension. Autonomic neuropathy and gastropathy occur as commonly in CFRD as in other forms of diabetes. Urine microalbumin and a dilated retinal exam should be obtained in patients with fasting hyperglycemia for 5 years or at time of CFRD diagnosis if routine screening has not been practiced.

Special consideration in cystic fibrosis: Infection with unusual organisms

Three groups of organisms merit special consideration in CF: mycobacteria, Aspergillus, and select gram-negative bacteria. As with pathogenic bacteria, eradication of these organisms from the airways is virtually impossible, so the focus of therapy is verifying that the organisms are causing worsening of the disease and controlling the infection, rather than microbiologic cure.

Mycobacteria

The prevalence of infection with mycobacteria in CF is ~12-15%. Patients should be screened for TB with yearly PPDs. Prophylaxis and treatment of TB is similar to non-CF patients.

A decision about therapy for atypical mycobacteria is based on the likelihood that the organism is contributing to airway infection and a decline in pulmonary function. Isolation of the same organism on several occasions, positive sputum smears, the presence of progressive CXR changes, progressive decline in pulmonary status despite antipseudomonal or antistaphylococcal therapy, persistent night sweats, and fever are clues that atypical mycobacteria are contributing to disease. A database has been established by the CF Foundation to track results of treatment for atypical mycobacterial infections and guidelines are available for diagnosis and treatment.

Aspergillus

Molds, especially Aspergillus, are occasionally isolated from CF patients. Approximately 5-15% of patients have allergic bronchopulmonary aspergillosis (ABPA). The diagnosis of ABPA in CF is difficult because of overlapping symptoms. Diagnostic criteria for ABPA include reversible airway obstruction, proximal bronchiectasis, history of pulmonary infiltrates, skin test positivity to Aspergillus antigens, precipitating serum antibodies to A. fumigatus, elevated total serum IgE, elevated specific serum IgE and serum IgG to Aspergillus, and peripheral eosinophilia.

A negative skin test for Aspergillus effectively rules out the diagnosis of ABPA. During the active phase of ABPA, elevations in total IgE and eosinophil count are seen. Rises in Aspergillus-specific titers (IgE and IgG) are more specific for ABPA than are serum precipitins. ABPA in patients with CF is treated with corticosteroids and antifungal agents.

Gram-negative bacteria

The importance of Burkholderia cepacia (formerly Pseudomonas cepacia) was recognized in the 1970s. B. cepacia is a gram-negative, oxidase-positive rod uniformly resistant to polymyxin that is frequently panresistant. Isolation of B. cepacia requires special plates to retard growth of other gram-negative rods and enhance growth of B. cepacia. The plates must be kept for ≥4 days.

B. cepacia colonization has been associated with sepsis, which is rarely seen with P. aeruginosa. The clinical course after acquisition of B. cepacia may be fulminant, with death occurring in a matter of months. However, most patients follow a more benign course. There is experimental evidence that at least one strain of B. cepacia may be transmitted in an epidemic fashion.

The combination of a poor clinical course after acquisition of B. cepacia and the evidence supporting epidemic transmission has led to cohorting or isolation of patients with CF infected with B. cepacia, as recommended by the CF Foundation and CDC.

In addition to being colonized with Pseudomonas and Burkholderia species, patients with CF may be colonized with other gram-negative, oxidase-positive organisms, such as S. maltophilia, F. oryzihabitans, and A. xylosoxidans. These are pathogenic organisms similar in importance to P. aeruginosa. Antibiotic therapy should be directed toward these bacteria when they are isolated from patients with CF who are experiencing an acute exacerbation.

The prolonged, prophylactic, aggressive use of antibiotics in CF has led to emergence of resistant organisms. A multiply-resistant Pseudomonas is an organism resistant to all agents from ≥2 different classes of antibiotics. Resistance to oral fluoroquinolones occurs after about 3 weeks of therapy; however, if the agent is withheld, the organism occasionally becomes sensitive again.

Beware: there are other diseases that can mimic cystic fibrosis:

A number of disorders may mimic CF:

• Hirschsprung’s disease

• bronchiolitis

• protein calorie malnutrition

• celiac disease

• giardiasis

• asthma

• immunodeficiency

• biliary atresia

How and/or why did the patient develop cystic fibrosis?

Molecular Basis of CF

CF is an autosomal recessive disorder inherited by a person who acquires two disease-causing mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. Discovery of the gene responsible for CF and description of its product, CFTR, have provided the necessary foundation for understanding the pathogenesis of the disorder at molecular and cellular levels.

CFTR is an integral membrane glycoprotein of ~170 kD expressed in epithelial cells of affected organs. Localization of CFTR to the apical aspect of airway epithelial cells, the ciliated duct of submucosal gland cells, and the submucosal serous cells, coupled with the role of CFTR as an apical chloride channel, fits with the hypothesis of the pathogenesis of pulmonary disease in CF – decreased secretion of chloride and water by airway epithelial cells leading to dehydrated mucus.

CFTR may have other functions, such as regulation of other ion channels, including the epithelial sodium channel. Loss of CFTR causes increased reabsorption of sodium; increased epithelium sodium channel activity alone alters regulation of ions and water, resulting in obstruction of airways by mucus.

In addition to the effect of CFTR on epithelial ion channels and glycoprotein processing, loss of CFTR function negatively impacts innate immunity and accentuates inflammation. Absence of CFTR function is associated with impaired bacterial killing in vitro, defective function of antimicrobials, and increased IL-8 and decreased IL-10.

CFTR mutations have been grouped into 5-6 classes, depending on the effect of the mutation on the expression, processing, and function of the protein. The most common mutation, ΔF508, is a processing mutation in which little of the mutant protein reaches the apical membrane surface. However, if the mutant protein escapes normal intracellular processing, ΔF508 protein has some function in the apical membrane. Understanding the molecular basis of these defects has prompted development of specific small molecules to target different classes of mutations.

Pathophysiology

In CF, all exocrine glands are affected, albeit to varying degrees. Because exocrine glands perform highly specialized functions in a variety of organs, such as the skin, respiratory tract, GI tract, and the reproductive system, the number of possible symptoms and complications in CF is large. Table 1 highlights the complications and symptoms of CF according to age groups.

Obstruction of exocrine ducts by viscous secretions plays a role in the pathogenesis of almost all disease manifestations. A regular feature of the disease is progressive obstruction of exocrine ducts, except the sweat glands, where ductal obstruction has not been implicated in pathogenesis.

Organ-Specific Findings

Respiratory Tract

In the lungs, hypersecretion of viscid mucus and chronic bacterial infection combine to produce a progressive chronic obstructive airway disease that eventually leads to diffuse, severe bronchiectasis. The earliest pathologic lesions are found in the distal bronchioles. Whether the viscid secretions are primary or secondary to chronic bacterial infections remains unsettled, but in favor of a primary disturbance is the demonstration of mucus obstructing submucosal gland ducts in the airways of neonates with CF, who have not yet developed significant lung infections.

The most common pathogens isolated from sputum cultures are S. aureus and P. aeruginosa. Less common are E. coli, Klebsiella, and H. influenzae. In later stages of disease, Pseudomonas usually predominates. By adulthood, >80% of patients are colonized with P. aeruginosa.

Neutrophil-dominated lower-airway inflammation also plays a primary role in the pathogenesis of the central bronchiectasis of CF. Bronchoalveolar lavage (BAL) fluid demonstrates increased neutrophils and various cytokines, especially IL-8, even in infants whose BAL is sterile.

Gastrointestinal Tract

Although pancreatic function may be either normal or abnormal at birth, it gradually becomes increasingly abnormal in CF as the pancreatic ducts become progressively obstructed by thick, viscous secretions from the exocrine portion of the organ. Pancreatic enzymes are trapped in the ducts, leading to autodestruction of the pancreas, and a cycle of destruction and obliteration of the ducts is set into motion, leading to cystic dilatation of ducts proximal to sites of obstruction and fibrosis of the body of the pancreas.

The liver and biliary tract are also affected, and the primary mechanism is obstruction of ducts by abnormally viscid secretions. The earliest pathologic change is focal biliary cirrhosis that may be present in early infancy. In some, focal cirrhosis progresses to diffuse cirrhosis and portal hypertension.

In 20-30% of patients, the gallbladder is small, presumably because of underdevelopment as a result of obstruction by viscid secretions. The risk of cholelithiasis and cholecystitis is increased in adults with CF compared to age-matched controls.

The most striking pathologic change in the intestines is hyperplasia of the mucous glands and goblet cells. Biochemical abnormalities in intestinal mucins may contribute to malabsorption of specific nutrients and bile acids. Much of the malabsorption in CF can be corrected by giving pancreatic enzymes. However, abnormal mucins may lead to slowing of intestinal transit time, which, combined with maldigestion of food substances, sometimes causes fecal impaction in the terminal ileum and ileocecal area, a condition referred to as distal intestinal obstruction syndrome. The fecal impaction occasionally causes volvulus or intussusception of the bowel.

Reproductive Organs

No consistent pathologic changes occur in the female reproductive tract in CF patients. In the male reproductive tract, the vas deferens is either atretic or absent at birth. Although the pathogenesis of this is uncertain, viscous secretions may contribute to obstruction in utero followed by failure of development of the vas deferens. Spermatogenesis and testicular development are otherwise normal. Because of either partial or complete obstruction of the vas deferens, ~98% of males with CF are aspermic.

Sweat Glands

The sweat glands of patients with CF manifest no distinctive histologic changes, but their function is abnormal. In normal patients, as the sweat flows along the duct of the gland, sodium and chloride are reabsorbed so that sweat at the skin surface is hypotonic to plasma with respect to both sodium and chloride. In CF the relative impermeability to chloride ions is thought to be responsible for the elevated chloride and sodium concentrations, which is the basis for the diagnostic test for CF. The elevated ion concentrations are also responsible for the characteristic increase in potential differences across the nasal epithelium of patients with CF.

Which individuals are at greatest risk of developing cystic fibrosis?

A child whose parents are each unaffected heterozygote carriers of a single disease-causing mutation or deletion in the CFTR gene has a 1 in 4 chance of having CF. If one parent has CF and the other is a carrier of a single CFTR mutation, the risk to the child for having CF is 50%.

A family history of CF should increase suspicion and prompt a sweat test and CFTR mutation analysis, as well as tests to evaluate pulmonary and nutritional status. Patients with family members who have signs/symptoms suggestive of CF should have the diagnosis considered.

The incidence of CF and the frequency of unaffected carriers of a single CF mutation vary with ethnicity. The incidence in Caucasians is 1 in 3300 live births, and the carrier frequency is 1 in 29 individuals. In contrast, the incidence in Asian populations is 1 in 32,000 live births, with a carrier frequency of 1 in 90 individuals. The diagnosis of CF should be aggressively pursued in any patient with clinical manifestations of CF, regardless of race or ethnic background (Table 2).

Table II.

What laboratory studies should you order to help make the diagnosis, and how should you interpret the results?

General Considerations

The diagnosis of CF requires demonstration of an abnormally high sweat chloride concentration in a person with a typical history and symptoms. The most prominent clinical features include chronic pulmonary disease and pancreatic insufficiency. The most compelling family history is CF in a sibling. If the clinical picture or family history supports the diagnosis, and if 2 sweat tests using the quantitative pilocarpine iontophoresis method are clearly positive, the diagnosis of CF can be made with assurance. Identification of 2 pathologic mutations, in addition to the characteristic clinical picture, is also accepted as diagnostic.

CF is a complex syndrome (Table 1) and clinical manifestations can be subtle. Family history is also not always straightforward. A high index of suspicion, coupled with clinical tests, is required. Concentrations of sweat chloride >60 meq/L are elevated and diagnostic of CF. Values 30-60 meq/L are borderline elevated and call for further evaluation. As a result of experience with CF newborn screening, it has been suggested that sweat chloride values >30meq/L may be diagnostic in the first few months of life. The concentration of sodium and chloride in sweat increases gradually with age, and some adults without CF may have elevated sweat chloride levels. A positive sweat test in any individual should always be repeated for confirmation.

Conditions other than CF in which concentrations of sodium and chloride in sweat are elevated include malnutrition, adrenal insufficiency, hereditary nephrogenic diabetes insipidus, ectodermal dysplasia, and fucosidosis. Except in some instances of malnutrition, these conditions are readily distinguished from CF. The finding of an abnormal concentration of chloride in sweat should automatically prompt evaluation of the patient to determine other affected organs.

Other testing to document the degree of organ involvement should include a culture of sputum or other respiratory secretions, CBC, electrolytes, liver function tests (including GGT), prothrombin time, serum protein and albumin, fat soluble vitamin levels, 72-hr fecal fat collection and coefficient of fat absorption, and fecal elastase-1.

Sputum Culture

Isolation of the unique respiratory flora from sputum cultures from CF patients is helpful in establishing the diagnosis and in guiding antimicrobial therapy for acute exacerbations. In many CF patients, P. aeruginosa and S. aureus are found alone or with other organisms in the sputum. Once present the organisms, especially Pseudomonas, are rarely eradicated despite intermittent or continuous antibiotics administered IV, orally, or by nebulization. Although these organisms are sometimes found in sputum cultures in other pulmonary diseases, their association with the disorder is so consistent that a dedicated attempt to obtain a sputum culture is an integral part of evaluating all patients suspected of having CF, including infants and young children.

Eventually, >80% of patients become colonized with Pseudomonas. Other bacterial pathogens have also emerged as important organisms in CF including MRSA, Stenotrophomonas maltophilia and Burkholderia cepacia. The prevalence of these organisms across age groups in CF is shown (Figure 1).

Figure 1.

What imaging studies will be helpful in making or excluding the diagnosis of cystic fibrosis?

A CXR should be obtained for all individuals for whom a diagnosis of CF is being considered. Most CF patients have at least mild peribronchial thickening and mild hyperinflation on CXR.

A CT chest may be useful in documenting bronchiectasis. In individuals who present with bowel obstruction, a Gastrograffin enema may be both diagnostic and therapeutic for meconium ileus or DIOS. US of the pancreas, liver, spleen, and vas deferens (in males) may reveal abnormalities, atresia, or absence.

What non-invasive pulmonary diagnostic studies will be helpful in making or excluding the diagnosis of cystic fibrosis?

Pulmonary function testing (PFTs) includes spirometry, measurement of lung volumes, and assessment of gas exchange. Age-appropriate PFTs, including spirometry and lung volumes, should be performed in patients ≥6 years of age. Pre- and post-bronchodilator studies may also be useful in detecting concomitant asthma and bronchial hyper-responsiveness.

The earliest stages of the pulmonary disorder are the most difficult to quantify. In infants, tests are limited to those that do not depend on the patient’s cooperation. One method, the raised volume rapid thoracoabdominal compression technique, requires sedation but provides values most similar to standard spirometric values, and the technique has detected reduced pulmonary function in infants with CF. PFTs originally designed for adults may be performed readily on children age ≥6; experienced technicians may be able to obtain reproducible spirometric testing in children as young as 4 years of age.

The lungs of patients with CF are usually morphologically and functionally normal at birth. Over time, accumulation of tracheobronchial secretions and recurrent infections progressively impair pulmonary function in almost all CF patients. In the fully developed clinical syndrome, all PFT abnormalities seen in chronic bronchitis, emphysema, and asthma may occur. PFTs in CF are useful in tracing the natural history of the disease and in assessing the value of therapies.

Three factors interact in producing airways obstruction in CF: (1) intrinsic disease of the smaller airways, often noted in association with bronchiectasis in the proximal, larger airways; (2) viscid secretions, impaired ciliary action, and impaired cough; and (3) progressive decrease in lung elastic recoil. The progressive reduction in lung elastic recoil in CF is predominantly a function of overinflation due to intrinsic airway disease, rather than loss of pulmonary parenchyma.

Airway smooth-muscle tone increases only slightly in CF. Exercise elicits bronchodilation followed by bronchoconstriction, but both the bronchodilation and bronchoconstriction are far less impressive in CF than in asthma. Indeed, exaggerated bronchomotor responses in CF raise the possibility of superimposed asthma. Maximal expiratory flow-volume curves are sometimes helpful in distinguishing between contributions to airway obstruction by CF vs. asthma.

The results of tests for small-airway disease are apt to be abnormal even when tests for obstruction of large airways are still normal. As with chronic bronchitis, emphysema, and asthma, residual volume in CF increases. Thereafter, an increase in functional residual capacity and sometimes total lung capacity is seen. Later in the course of the disease, air-trapping occurs, manifesting as an elevated ratio of residual volume to total lung capacity. This change decreases the compliance of the lung and increases the work of breathing.

Early in the evolution of the PFT abnormalities in CF—i.e. when tests of small-airway function alone are abnormal—ventilation-perfusion abnormalities usually result in widening of alveolar-arterial oxygen gradient and an increase in the ratio of dead space to tidal volume (Vd/Vt). As obstructive disease of the airways progresses and exaggerates the imbalances between alveolar ventilation and blood flow, arterial hypoxemia develops, and pulmonary hypertension, cor pulmonale, and right ventricular failure follow. Late in the course of disease, hypercapnia and respiratory acidosis lead to respiratory failure.

Bouts of infection punctuate the course of the illness, and pulmonary function deteriorates during each episode, but it usually returns toward baseline, except in the pre-terminal stages of CF.

Additional diagnostic evaluation

Pancreatic Function

Evaluation of pancreatic function is important in establishing the diagnosis of CF since almost 90% of patients have pancreatic insufficiency. The most striking feature of the history and exam in infants with pancreatic insufficiency due to CF is often failure to thrive, and the record of bowel movements may disclose only loose or frequent stools. In the older child, whose diet includes more fat and protein, a history of bulky, foul, malodorous stools is often easier to elicit.

The gold standard for documentation of malabsorption is the collection of stools for 72 hrs while the patient is ingesting a known quantity of fat (3-4 gms/kg/day in children and ~100 g/day in adults) and subsequent measurement of the stool fat content. A coefficient of fat absorption >7% is usually considered abnormal; in CF patients, the coefficient of fat absorption is often 20-30%.

Recently, determination of fecal elastase-1 in stool samples has been described as an accurate, easily obtained test to classify CF patients as pancreatic insufficient or pancreatic sufficient.

Endocrine function of the pancreas is usually preserved in children, but ~50% of all adult patients are overtly diabetic by age 30.

Liver function

Evaluation of liver function is important in the diagnosis of CF. In infants and children, the concentrations of bilirubin and transaminases in serum sometimes increase transiently, but concentrations of these substances are usually normal even in patients with mild or moderate focal biliary cirrhosis.

The prothrombin time is sometimes prolonged because of a combination of malabsorption and decreased synthesis of clotting factors by the liver. Patients may present with bleeding esophageal varices from cirrhosis, and endoscopy and upper GI contrast studies are helpful in demonstrating the varices. A liver US with Doppler is helpful in determining liver textural abnormalities (fatty liver or fibrosis), splenomegaly, and reversal of blood flow in the portal vessels consistent with portal hypertension. Intrabdominal varices may also be detected.

Semen analysis

Occasionally, a man found to have aspermia during the course of an evaluation for infertility is also found to have CF. A complete semen analysis is part of the evaluation in men with CF, as azoospermia is found in >98% of men with the disorder.

Mutation analysis

Genetic testing is not required to establish or confirm the diagnosis of CF when a compatible history, exam, and abnormal sweat test results are found. Genetic testing is useful in identifying patients who have a compatible history and exam but whose sweat test results are negative.

Numerous attempts have been made to characterize phenotype on the basis of genotype. In general homozygotes for ΔF508 have pancreatic insufficiency; CF patients with pancreatic insufficiency tend to have a worse prognosis. Several mutations, including R117H, are associated with pancreatic sufficiency and a mild phenotype. However, a direct association of a particular genotype with progression of pulmonary disease has not been found, and guidelines strongly recommend against using the CFTR genotype to predict prognosis in CF patients.

One genotype-phenotype correlation is the increased frequency of genotype R117H in males with congenital bilateral absence of the vas deferens (CBAVD). Males with this recessive disorder lack a vas deferens, but they are otherwise healthy and have normal sweat test results. Approximately 35% of the chromosomes of all patients with CBAVD carry a CF-associated mutation and 8% of patients with CBAVD without clinical CF have 2 CF-associated mutations.

Certain alleles associated with CF are associated with nasal polyposis, bronchiectasis, and normal sweat test results. The diagnosis of CF can be made with confidence in these patients.

Establishing a diagnosis of CF may be problematic in those with atypical presentations, normal sweat test results, and ≥1 CF-associated mutation. For example, mutations in ≥1 CFTR allele are associated with idiopathic chronic pancreatitis. More extensive genotyping should be attempted for all patients with a high clinical suspicion for CF because mutation analyses have become clinically relevant now that specific therapies are available for specific CFTR mutations.

Patients with identical genotypes may have dramatically different phenotypes, raising the possibility that modifier genes play an important role in determining the phenotype. Several candidates for modifier genes are being evaluated for their impact on lung disease severity.

What diagnostic procedures will be helpful in making or excluding the diagnosis of cystic fibrosis?

A sweat test and CFTR mutation analysis are the cornerstones of making the diagnosis. Since the presence of clinical features of CF is also required to establish the diagnosis, complete evaluation of the pulmonary and nutritional status of the patient and evaluation of all organs that may manifest characteristic abnormalities in CF may also be necessary.

What pathology/cytology/genetic studies will be helpful in making or excluding the diagnosis of cystic fibrosis?

CFTR mutation analysis is useful; if not confirmatory, performance of complete analysis of deletions and duplications in the CFTR gene +/- complete sequencing of the CFTR gene to include analysis of TG repeats in specific introns may be warranted. In males, US of the vas deferens and a complete semen analysis in age-appropriate patients are also useful.

If you decide the patient has cystic fibrosis, how should the patient be managed?

The single most important aspect of treatment in CF is that that patients must be followed in, and have their care directed by, a CF Foundation-accredited center (www.cff.org).

The key elements of therapy in CF include:

Chest Physiotherapy (CPT)/Airway Clearance Therapy (ACT)

BID airway clearance therapy following bronchodilator and mucolytic therapy employing percussion and postural drainage, high-frequency chest compression vest, oscillatory positive expiratory pressure, autogenic drainage, active cycle of breathing technique, or exercise is recommended.

Most CF centers recommend that all patients attempt to maintain clearance of airway secretions with some ACT that is employed regularly BID. An additional recommendation is that ACT be applied more frequently (e.g., TID or QID) during a respiratory exacerbation.

ACT is an arduous and time-consuming therapy that requires support and encouragement from family and healthcare professionals to be implemented successfully. Though there are no RCTs, CF centers with the best outcomes have employed and strongly recommended manual percussion and postural drainage and high frequency oscillatory vest therapy as the cornerstones of ACT.

Antibiotics

Chronic suppressive antibiotic therapy is recommended for patients with chronic infection with P. aeruginosa, including every-other-month inhaled antibiotics +/- oral azithromycin (qMWF). The recently described association of azithromycin with an increase in the potential for acquisition of non-TB mycobacteria has prompted reconsideration of the recommendation to treat all CF patients colonized with Pseudomonas with chronic azithromycin therapy. The CF Foundation recommends that the decision to treat with azithromycin be individualized.

Antibiotic therapy is intensified for pulmonary exacerbations with IV antibiotics selected based on sputum culture sensitivities. IV antibiotic therapy for Pseudomonas includes combinations of an aminoglycoside and a second anti-pseudomonal antibiotic, such as ceftazidime, ticarcillin, piperacillin, aztreonam, meropenem, or imipenem. Therapy is continued until symptoms, signs, and abnormal lab values are resolved (usually 14 days).

Inhaled Medications

Mucolytics

Mucolytics should precede CPT and include ≥1 of the following inhaled therapies: rhDNase, 7% hypertonic saline, or inhaled N-acetylcysteine (5-10%) following albuterol inhalation.

Bronchodilators

Inhaled beta-2 agonists are indicated in patients who have reactive airways disease and prior to the administration of irritant mucolytics.

Antibiotics

For chronic colonization with P. aeruginosa, inhaled antibiotics e.g., inhaled tobramycin BID or inhaled aztreonam TID are indicated every other month. However, a recent large clinical trial found no difference between cycled therapy and treatment of positive cultures in preventing colonization in CF in patients younger than 12.

Anti-inflammatory Agents

The only approved anti-inflammatory drugs for CF are azithromycin and ibuprofen. These agents have proven efficacy for patients colonized with Pseudomonas. Therapy with high-dose ibuprofen requires pharmacokinetic studies to ensure that patients achieve appropriate levels.

Pancreatic Enzyme Replacement Therapy (PERT)

Current recommendations for PERT dosing is 500-2500 units of lipase per kg of body weight per meal, or <4000 units of lipase per gram of dietary fat per day.

Nutritional Guidance/Supplementation

Maintenance of normal weight for height is associated with better FEV₁ and improved survival. The recommended weight-to-length in children ≤2 years is 50%; the recommended BMI in older children is ≥50%, and in adults ≥22% for women and 23% for men. Routine energy intake is 110-200% of standards for the healthy population.

Treatment of Pulmonary Exacerbations of CF

Pulmonary exacerbations are defined as acute episodes of increased airway infection and inflammation associated with a decline in lung function and increased symptoms. Pulmonary exacerbations are diagnosed when patients present with increased cough, increased sputum production, change in sputum color, hemoptysis, decreased exercise tolerance, dyspnea, fatigue, decreased appetite, or fever. Findings include increased work of breathing, tachypnea, new-onset crackles or diminished air entry on exam, weight loss, or fever. Other findings include decreased air flow on spirometry and increased air trapping on PFTs, new infiltrates on CXR, elevated white blood count, decreased SaO₂, or new supplemental oxygen requirement.

Current standards of therapy for pulmonary exacerbations include IV administration of 2 antibiotics for 14-21 days. Antibiotics are selected according to the sensitivities of organisms on sputum or bronchoscopy cultures. The rationale for 2 antibiotics—an aminoglycoside for treating P. aeruginosa and another for treating gram-negative rods—is that therapy with antibiotics with two different pharmacologic actions may have a synergistic effect that inhibits development of antibiotic resistance (Table 3).

Table III.

Therapy is usually initiated in-hospital to ensure that appropriate antibiotic levels are achieved, that the patient does not have any adverse side effects, and that the patient’s respiratory symptoms are not progressing. Patients also receive increased frequency of inhaled bronchodilator and mucolytic therapies, increased frequency of airway clearance therapies, and supplemental nutrition via enteral or parenteral routes. Weekly monitoring of antibiotic levels and chemistries is performed to achieve optimal antibiotic dosing and minimize toxicity.

Treatment of a pulmonary exacerbation is continued until the patient demonstrates improvement back to their personal baseline with respect to signs and symptoms, weight, PFTs, and CXR findings. There are no well-controlled, prospective studies to guide practice and current standards for therapy are supported by the consensus of the top CF care centers.

Small Molecule Therapy

The FDA has approved 2 specific small molecule drugs for CF designed to improve the function of the CFTR chloride channel. The first drug approved was initially only for patients with the G551D mutation (~4% of CF population). This drug Kalydeco ® has recently been approved for 23 additional mutations. The second drug Orkambi ® was for patients homozygote for the ∆F508 mutation (~50% of CF population). This drug has two components; one to improve the folding/processing of the protein and the second to improve the function of the CFTR channel. The benefits to the patient of the latter drug were more modest and this has caused some to question the value of this expensive drug. Fortunately, there are more drugs in the pipeline and the goal is to have specific effective therapies for every CF patient regardless of their mutations.

What is the prognosis for patients managed in the recommended ways?

Median predicted survival for patients in the US was 41.1 years of age between 2011-2015.

What other considerations exist for patients with cystic fibrosis?

Special considerations in CF include infection control policies, use of lung transplant, reproductive issues, genetic counseling, and psychosocial concerns.

Infection Control in CF

Because of the emergence of virulent, multi-drug-resistant pathogens in many CF patients, careful attention to infection control is essential to prevent the spread of organisms in the CF population. The 4 general principles applicable to healthcare settings are:

• Assume all CF patients could have transmissible pathogens in respiratory tract secretions.

• Apply standard precautions to all patients with CF to contain their secretions and to minimize the potential for other patients with CF to come into contact with the secretions.

• Implement standard + transmission-based precautions according to CDC guidelines for for contact, droplet, or airborne precautions, as defined by special circumstances such as infection with B. cepacia complex, multidrug-resistant P. aeruginosa, MRSA, or TB.

• Avoid activities and risk factors associated with transmission of pathogens in patients with CF (i.e., activities that involve close contact between patients with CF).

Lung transplant in cystic fibrosis (see CDS section on lung transplantation)

Bilateral lung transplant is considered when the lung disease has become life-threatening and survival with transplant is deemed to be longer and of better quality than without transplant. Considerations for timing of lung transplant evaluation include the following factors:

• FEV₁ <30% or rapid decline in PFTs with increasing frequency of hospitalizations

• hypoxemia

• hypercapnia

• pulmonary hypertension

Risk factors for poor outcomes post-transplant are the presence of pan-resistant organisms in the respiratory tract and requirement for ventilator support or extracorporeal membrane oxygenation pre-transplant. To minimize complications, other conditions such as GERD, diabetes, obesity, osteoporosis, or malnutrition need to be medically managed before and after lung transplant.

Post-transplant, infection presents both an acute and chronic threat because of the need for immunosuppression, impaired mucociliary clearance, ineffective cough due to post-operative pain, and the presence of virulent organisms in the retained upper respiratory tract. Bacterial pneumonias due to P. aeruginosa and S. aureus occur early in the post-operative course.

CF patients can achieve normal lung function after lung transplant with improved quality of life. The current median survival for CF patients who receive lung transplant is 7.1 years.

Reproductive Issues in cystic fibrosis

>98% of males with CF are sterile secondary to CBAVD. Microsurgical epididymal sperm aspiration with in vitro fertilization has been successful in producing pregnancies in some patients. Fertile men with CF should be offered semen analysis and counseling.

Pregnancy among women with CF is increasingly common. Maternal clinical status before pregnancy is the most important prognostic factor of maternal outcome. An overall evaluation of the clinical situation is recommended for women with moderately compromised pulmonary status (i.e., FVC <50-60% of predicted), although no firm guidelines can be given.

Men and women with CF who are considering reproduction should understand that all of their offspring will be at least obligate heterozygotes for CF. They should also consider the ethical issues of premature parental death and its effect on the family.

Genetic counseling and psychosocial Issues

Genetic counseling

Formal referral to a genetics counselor should be offered to parents, patients, and relevant family members at the time of diagnosis. The details of autosomal recessive patterns of inheritance and the specific implications for immediate and extended family members should be discussed.

Psychosocial issues

Careful attention to the emotional, social, and financial well-being of CF patients and their families is of utmost importance in favorably influencing the course of the disease.

The cost of care in CF is high, and it becomes even more expensive when hospital admissions are required. Social workers and state programs may be helpful for financial assistance.

As the disease progresses, counseling and feedback about disease progression are essential. When the lung disease becomes severe or end-stage, palliative care and lung transplant should be discussed. A timely referral to a lung transplant experienced in CF will usually include counseling regarding the pros/cons of lung transplant for the specific patient.

Specific challenges face the increasing number of CF patients surviving into adulthood. The adult CF patient faces unique problems in self-care, as when they experience an exacerbation, they must increase their level of care at a time when they are least able to do so.

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