Pulmonary Medicine

Cystic Fibrosis

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What every physician needs to know:

Cystic fibrosis (CF) is a relatively common disease that is inherited in an autosomal recessive pattern and that 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.

This lung disease is a chronic, progressive obstructive process punctuated by exacerbations of infection and inflammation. Pancreatic insufficiency, which occurs in the majority of patients with CF, 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, which is secondary to abnormal respiratory tract secretions, and malnutrition, which is 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 1.

Presenting signs and symptoms of CF

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 fifty states in the United 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 above 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 studies indicate that values of sweat chloride as low as 30 meq/L may be found in infants with CF in the first six months of life.

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 genetics 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 percent of fetuses with hyperechoic bowel have CF.

Meconium Ileus

Ten to twenty percent of newborns with CF have intestinal symptoms in the newborn period, which symptoms are 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.

The last entity noted results in abdominal distension and dilated loops of bowel noted on imaging studies. 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 that is secondary to intrahepatic bile stasis and extrahepatic bile duct obstruction. This condition is often seen as prolonged neonatal jaundice, with an onset at two to eight 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 the malabsorption syndrome, which is 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

The causes of failure to thrive in childhood are legion. However, CF should always be considered in the differential diagnosis, 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. A German folk song that was first transcribed in 1856 contained the lines, "the child who tastes salty when kissed will soon die." This may represent the earliest written reference to CF. CF has been also reported to occur as failure to thrive, with chronic hypochloremic, metabolic alkalosis.

Rectal prolapse

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

Intestinal obstruction with or without intusseception 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 taken orally will clear the mass. In the presence of obstruction (as indicated by an 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 or 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 probablility 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 certainly a much more common cause of cough and wheezing across the life span than is 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. However, in about 5 percent, the cirrhosis is significant enough to cause portal hypertension, which eventually results in esophageal varices and/or hypersplenism. The presenting symptom of some of these patients may be bleeding esophageal varices.

Nasal Polyps

Nasal polyps are relatively common in adults who have chronic allergic rhinitis and sinusitis, but nasal polyps are relatively rare in children, so finding nasal polyps in children or adolescents 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 CF patients have developed bronchiectasis, the dilated, tortuous bronchial arteries that develop around the bronchiectatic airway are a common source of pulmonary hemorrhage and 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 insufficiency. Approximately 10-20 percent of patients with recurrent idiopathic pancreatitis have two abnormal CFTR genes, at least one of which is considered a mild mutation.

Obstructive asperemia

The mildest form of CF occurs in males who have obstructive aspermia and congenital bilateral absence of the vas deferens (CBAVD). CF genetic mutations (in CFTR) are found in about 50 percent 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

The gastrointestinal, respiratory, and metabolic findings that suggest the diagnosis of CF have been discussed elsewhere. Additional details of the clinical manifestations are discussed below.

Gastrointestinal manifestations

Gastroesophageal reflux

The incidence of reflux varies in patients with CF from 19 percent in infants to 94 percent 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. Clinical symptoms vary from the obvious (regurgitation, vomiting, spitting up, hiccoughs of long duration, and chest pain) to that of pulmonary 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 modification, pharmacological therapy, and surgery, namely fundoplication. Medications used consist of gastric acid blocking medications (H2 receptor antagonists and proton pump inhibitors) and promotility agents (metoclopromide, bethanechol). Erythromycin may be useful in patients with delayed gastric emptying. Fundoplication is indicated in patients who fail medical therapy and in those who have aspiration secondary to reflux. Iundoplication 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; while the exact incidence is unknown, it may be as high as 56 percent. 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 Clostridium difficile infection is rare, carrier rates are high. In patients who have received lung transplants, Clostridium 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, reported since the early 1990s, appears to be temporally related to the availability of high-potency pancreatic enzyme products. While the exact cause has not been determined, 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.

Clinical 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, CAT scan, or ultrasound. Pathology reveals submucosal fibrosis extending to the serosal surface, beginning in the ascending colon and extending to the distal colon. The differential diagnosis is primarily inflammatory bowel disease. Treatment consists of reducing the enzyme dose, nutrition support, and surgery.

Malignancy

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

Liver disease

Liver disease is frequently asymptomatic in patients with CF. Prevalence varies from 13 percent to 27 percent. Hepatic conditions include neonatal cholestasis, elevated liver enzymes, hepatomegaly, fatty liver, focal biliary cirrhosis, and multilobular cirrhosis. Biliary conditions include microgallbladder, gall stones, and gall bladder dysfunction.

Elevated liver enzymes may be seen in 10-46 percent of patients. The degree of elevation of liver enzymes does not reflect the severity of the liver damage, and patients with cirrhosis may have minimal elevations in liver enzymes. Patients who have liver enzyme elevations that are 1.5 to 3 times the upper limit of normal should have repeat measurements in three months; if these elevations are persistently three times above the upper limit of normal, further evaluation is warranted, including ultrasound 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 percent 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 gall bladder is frequently dysfunctional, and a small gall bladder can be seen in 20-30 percent of patients. Gall stones are seen in 1-10 percent of patients. Treatment of CF liver disease consists of avoiding hepatotoxic medications, alcohol, and complimentary 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 the complications of portal hypertension should be done in conjunction with a pediatric gastroenterologist. Liver transplantation is indicated in patients with severe liver dysfunction, life-threatening complications from portal hypertension, or hepato-pulmonary 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. However, left untreated, the end result of atelectasis is a severely bronchiectatic segment or lobe. Vigorous chest physiotherapy, 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 physiotherapy 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 the evidence that the affected segment is responsible for intolerable, severe symptoms (fever, cough, or sputum production) is convincing.

Hemoptysis

Expectoration of a small amount of blood-streaked sputum is a fairly common occurrence in CF that is generally managed by intensifying home therapy for a pulmonary exacerbation of CF. For significant hemoptysis (defined here as the expectoration of 30 to 60 ml of fresh blood), admission to the hospital for observation and the initiation of intravenous 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 (more than 240 ml of blood is a serious situation that requires the consideration of bronchial artery embolization and, rarely, pulmonary resection. There is insufficient data to make evidence-based recommendations. A CF Foundation committee using the Delphi method 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. There was no agreement on a demarcation between mild and moderate hemoptysis, and no recommendations for an approach to treatment.

Pneumothorax

Recurrent pneumothax is common in CF, particularly in older patients. Tension pneumothorax occurs in up to 30 percent of patients with CF who develop pneumothorax. Tube thoracostomy should be considered, and it is usually indicated when the pneumothorax occupies more than 10 percent of the area of the hemithorax seen on the postero-anterior chest radiograph. The clinical stability of the patient is often factored into the decision regarding placement of a chest tube. 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 checmical pleurodesis at preventing recurrence of a pneumothorax and is no longer considered an absolute contraindication to lung transplantation. A CF Foundation committee using the Delphi method achieved some consensus on the management of pneumothorax in CF and acknowledged that there have been no controlled studies from which to make evidence-based recommendations. Rather than using the percent of the hemithorax affected , they use greater or less than 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 a tube thoracostomy and less agreement on when and whether to perform pleurodesis.

Respiratory Failure

When respiratory failure (hypercarbia in addition to hypoxemia) develops in a patient with CF, management decisions become extremely difficult. Mechanical ventilation is generally instituted when an acute episode, such as a viral pneumonia or status asthmaticus, thrusts the patient into acute respiratory failure. This approach is particularly indicated in a patient who has had good pulmonary function before the acute episode; institution of mechanical ventilation is less apt to be successful if the patient has had a prior episode of respiratory failure.

When the 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 bilevel positive airway pressure has been used successfully in end-stage CF patients who are awaiting lung transplantation 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. None of these indications or contraindications for ventilator support is absolute. If a patient is already listed for lung transplantation, that is an important factor in making a decision.

Electrolyte-Related Findings

Hypoelectrolytemia and metabolic alkalosis

These are serious complications that are especially apt to occur in hot weather and when the recommendation for regular salt supplementation has 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 that occurs in approximately 20 percent of adolescents and 40-50 percent of adults with CF. Delayed and blunted insulin secretion are evident following a meal or glucose challenge, even before diabetes is evident. With progression of insulin deficiency, mild hyperglycemia, impaired glucose tolerance (IGT), 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; he or she is considered to have CFRD.

CFRD is associated with worsening nutritional status, worsening pulmonary function, and increased mortality, and treatment improves these CF-related outcomes. Microvascular complications also occur in the setting of 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 by the CF Foundation. Annual screening with a two-hour oral glucose tolerance test (OGTT) by age ten is ecommended. Table 4 outlines the various glucose abnormalities that are currently defined in CF. Blood glucose monitoring should also be performed during hospitalizations, in the outpatient setting, during continuous overnight feeds at initiation of the feeds and monthly thereafter, and during intercurrent illness that requires intravenous antibiotic or systemic glucocorticoids.

Insulin is recommended for the treatment of CFRD, 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, a matching of insulin dose for carbohydrates can be adopted, but dosing may require creativity. Frequent blood glucose monitoring with initiation of insulin is important to achieving blood glucose in the 100 to 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 alternative method for some patients.

For a number of patients, 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 by the CF Foundation. Given the already intense medical regimens required of individuals with CF, the addition of multiple daily insulin injections may not be readily accepted. In a case series of twenty subjects, outcomes were not different among adults with CFRD treated with insulin versus those given oral agents; however, the study design and 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 seven 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 at the dose used. Neither drug completely 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 (soda and sugar-based candies—i.e., those that lack protein and complex carbohydrates) 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 may occur in patients with CFRD, but the presence of fasting hyperglycemia may be necessary. In one series, over a fifteen-year period, no patient with CFRD, in the absence of fasting hyperglycemia, developed retinopathy or microalbuminuria; 16 percent of patients with CFRD with fasting hyperglycemia of greater than ten years' duration had retinopathy, and 14 percent had microalbuminuria.

The overall prevalence of microvascular complications is less than that with 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 were reported to occur as commonly in CFRD as in other forms of diabetes. Urine microalbumin and a dilated retinal exam should be obtained in patients who have had fasting hyperglycemia for five years or at the time of diagnosis of CFRD if routine screening has not been practiced.

Special consideration in cystic fibrosis: Infection with unusual organisms

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

Mycobacteria

The prevalence of infection with mycobacteria in CF is approximately 12 to 15 percent. Frequently, the sputum culture is overgrown with pathogenic bacteria, so the culture should be handled to enhance isolation. Patients with CF should be screened for M. tuberculosis infection with yearly PPD skin tests. Prophylaxis and treatment of M. tuberculosis in CF are the same as for patients without CF.

A decision about therapy for isolation of atypical mycobacteria is based on the likelihood that the organism is contributing to airway infection and to a decline in pulmonary function. Isolation of the same organism on several occasions, positive sputum smears, the presence of progressive chest radiographic changes, progressive decline in pulmonary status despite vigorous antipseudomonal (or antistaphylococcal) therapy, persistent night sweats, and fever are clinical clues that atypical mycobacteria are contributing to disease. Demonstration of tissue infection with transbronchial lung biopsy is rarely recommended. A clinical database has been established by the CF Foundation to track results of treatment for atypical mycobacterial infections in patients with CF.

Aspergillus

Molds, especially Aspergillus, are occasionally isolated from patients with CF. Approximately 5 to 15 percent of patients have allergic bronchopulmonary aspergillosis (ABPA). The diagnosis of ABPA in CF is difficult because of overlapping symptoms between the two disorders. 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 itraconazole.

Gram-negative bacteria

The importance of Burkholderia cepacia (formerly Pseudomonas cepacia) was recognized in the late 1970s and early 1980s. B. cepacia is a gram-negative, oxidase-positive rod that is uniformly resistant to polymixin and that is frequently panresistant. Isolation of B. cepacia requires plating on special OFPBL (oxidative fermentive polymixin B bacitracin lactose) or PC (P. cepacia) agar plates to retard growth of other gram-negative rods and enhance growth of B. cepacia. The plates must be maintained for a minimum of four days.

B. cepacia colonization has been associated with septicemia, 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’ disease follows a more benign course. Carefully controlled epidemiologic studies are needed to define risk factors more thoroughly and to establish the true virulence of B. cepacia. 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 the 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 that are 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 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 that is resistant to all agents from at least two different classes of antibiotics. Resistance to oral fluoroquinolones occurs after about three 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

  • bronchioitis

  • 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 an individual 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 approximately 170 kD that is 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 well with the simplest hypothesis offered for the pathogenesis of pulmonary disease in CF, namely, decreased secretion of chloride and water by airway epithelial cells resulting in 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 production and decreased IL-10 in vitro. Together, these factors synergistically increase the inflammatory milieu in the CF airway.

CFTR mutations have been grouped into four or five 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 functions normally in the apical membrane. Understanding the molecular basis of these defects has prompted development of specific small molecules to target different classes of mutations. (See the section on the potential for specific therapy in Special Considerations.)

Pathophysiology

In CF, all exocrine glands appear to be primarily affected, albeit to varying degrees. Because exocrine glands perform highly specialized functions in a variety of organs, such as in the skin, the respiratory tract, the gastrointestinal 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 the age groups in which they most often occur.

Obstruction of exocrine ducts by viscous secretions appears to play a cardinal role in the pathogenesis of almost all manifestations of the disease. A regular feature of the disease is progressive obstruction of exocrine ducts, except those in 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 and distinctive type of 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 any evidence of bacterial infection or chronic colonization of the airways.

With the use of sophisticated culture methods, bacterial pathogens can almost invariably be isolated from the respiratory tract of patients with CF. The most common pathogens isolated from sputum cultures are Staphylococcus aureus and Pseudomonas aeruginosa. Less commonly found are Escherichia coli, Klebsiella, and Hemophilus influenzae. In later stages of the disease, Pseudomonas usually predominates. By adulthood, more than 80 percent of patients are colonized with P. aeruginosa.

Neutrophil-dominated lower-airway inflammation also plays a primary role in the pathogenesis of the characteristic central bronchiectasis of CF. Bronchoalveolar lavage (BAL) fluid demonstrates increased neutrophils and various cytokines, especially interleukin 8 (IL8), 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 most patients with 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 the biliary tract are also affected, and the primary mechanism appears to be obstruction of ducts by abnormally viscid secretions. The earliest pathologic change is focal biliary cirrhosis that may be present in early infancy. In some patients, focal cirrhosis progresses to diffuse cirrhosis and portal hypertension.

In 20-30 percent 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 administration of pancreatic enzymes. However, the 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, in turn, occasionally causes volvulus or intussusception of the bowel.

Reproductive Organs

No consistent pathologic changes occur in the female reproductive tract in patients with CF. However, in the male reproductive tract, the vas deferens is either atretic or absent at birth. Although the pathogenesis of this lesion 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, approximately 98 percent 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. Micropuncture experiments have shown that the precursor solution secreted by the sweat glands is isotonic to plasma both in patients with CF and in normals. In normals, 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 concentrations.

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 quantitative pilocarpine ionotophoresis sweat test. 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 one in four 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 percent.

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

The incidence of CF and the frequency of unaffected carriers of a single CF mutation vary with ethnicity. The incidence in the Caucasian population is 1 in 3,300 live births, and the carrier frequency is 1 in 29 individuals. In contrast, the incidence in Asian populations is approximately 1 in 32,000 live births, with a carrier frequency of 1 in 90 individuals. However, recent studies have indicated that the true incidence and carrier frequency may be higher than previously described for South Asian populations. Therefore, the diagnosis of CF should be aggressively pursued in any patient with the clinical manifestations of CF, regardless of race or ethnic background (Table 2).

Table 2.

Incidence and prevalence of CF in different ethnicity

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

CF is a complex syndrome (Table 1) in which clinical manifestations are sometimes subtle. In addition, family history is not always straightforward. A high index of suspicion, coupled with a battery of clinical tests, is required. Concentrations of sweat chloride greater than 60 meq/L are elevated and diagnostic of CF. Values between 40 and 60 meq/L are borderline elevated; and call for further evaluation. As a result of recent experience with CF newborn screening, it has been suggested that sweat chloride values above 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 the concentrations of sodium and chloride in sweat are abnormally high 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 whether other organs are affected and, if they are, to what extent.

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

Sputum Culture

Isolation of the unique respiratory flora from sputum cultures from patients with CF is helpful in establishing the diagnosis and in guiding antimicrobial therapy for acute exacerbations. In many patients with CF, P. aeruginosa and S. aureus are found alone or in combination with other organisms in the sputum. Once present, the organisms, especially Pseudomonas, are rarely eradicated despite use of intermittent or continuous antibiotics administered intravenously, orally, or by nebulization. Although the organisms are sometimes found in sputum cultures from patients with pulmonary diseases other than CF, 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, more than 80 percent of patients become colonized with Pseudomonas. Recently, several other bacterial pathogens have emerged as important organisms in CF, including MRSA, Stenotrophomonas maltophilia and Burkholderia cepacia. The prevalence of these organisms across age groups in CF (Figure 1).

Figure 1.

Age Specific Prevalence of Respiratory Organisms, 2009

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

A chest x-ray should be obtained for all individuals for whom the diagnosis of CF is being considered. Most patients with CF have at least mild peribronchial thickening and mild hyperinflation on postero-anterior (PA) and lateral chest films.

CT of the 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 distal intestinal obstruction syndrome. Ultrasonography of the pancreas, liver, spleen, and the 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 includes spriometry, measurement of lung volumes, and assessment of gas exchange:

Age-appropriate pulmonary function testing, including spirometry and lung volumes, should be performed in patients six years of age and older. 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, of course, tests are limited almost entirely to those that do not depend on the patient’s understanding and cooperation. A variety of methods to measure infant pulmonary function have been devised; one such method, the raised volume rapid thoracoabdominal compression technique, requires sedation but provides values that are most similar to standard spirometric values, and the technique has detected reduced pulmonary function in infants with CF. Pulmonary function tests originally designed for adults may be performed readily on children age six and older; experienced respiratory technicians may be able to obtain reproducible spirometric testing in children as young as four years of age. Changes in pulmonary performance throughout the natural history of CF can be described with confidence.

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 of the pulmonary function abnormalities seen in chronic bronchitis, emphysema, and asthma may occur. Pulmonary function testing in CF is useful in tracing the natural history of the disease and in assessing the value of therapeutic interventions.

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 that is due to intrinsic airway disease, rather than loss of pulmonary parenchyma.

Airway smooth-muscle tone increases only slightly in CF. Exercise elicits bronchodilation, followed shortly thereafter by bronchoconstriction, but both the bronchodilation and the 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 intrinsic airway disease caused by CF and by 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 in 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 pulmonary abnormalities in CF—that is, when tests of small-airway function alone are abnormal—ventilation-perfusion abnormalities usually result in widening of the 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 in turn. Late in the course of the disease, hypercapnia and respiratory acidosis contribute to the final picture of respiratory failure. At this juncture, the ventilatory response to inhaled CO2 is depressed.

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 the disorder.

Additional diagnostic evaluation

Pancreatic Function

Evaluation of pancreatic function is important in establishing the diagnosis of CF since almost 90 percent of patients have pancreatic insufficiency. The most striking feature of the history and physical examination in infants with pancreatic insufficiency that is 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 hour while the patient is ingesting a known quantity of fat (3-4 gms/kg/day in children andapproximately 100 g/day in adults) and subsequent measurement of the stool fat content. A coefficient of fat absorption higher than 7 percent is usually considered abnormal; in patients with CF, the coefficient of fat absorption is often 20-30 percent.

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

Endocrine function of the pancreas is usually preserved in children, but approximately 50 percent of all adult patients are overtly diabetic by age thirty.

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. Occasionally, patients present with bleeding esophageal varices from advanced cirrhosis, and endoscopy and upper gastrointestinal contrast studies are often helpful in demonstrating the varices. A liver ultrasound with Doppler is helpful is determining liver echotextural abnormalities (fatty liver or fibrosis), splenomegaly, and reversal of blood flow in the portal vessels consistent with advanced portal hypertension. Intrabdominal varices may also be detected.

Semen analysis

Occasionally, a man who is 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 more than 98 percent of men with the disorder.

Mutation analysis

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

Numerous attempts have been made--with limited success--to characterize phenotype on the basis of genotype. In general, homozygotes for ΔF508 have pancreatic insufficiency; patients with CF who have 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 the pulmonary disease has not been found, and the most recent consensus conference strongly recommends against using the CFTR genotype to predict prognosis in a patient with CF.

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

Certain alleles associated with CF (e.g., 3849 + 10kbC → T) are associated with nasal polyposis and 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 persons with atypical presentations, normal sweat test results, and at least one CF-associated mutation. For example, mutations in at least one 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 may become clinically relevant if specific therapies depend on the types of mutations present.

Patients with identical genotypes may have dramatically different phenotypes, raising the possibility that modifier genes play an important role in determining the CF phenotype. Several potential candidates for modifier genes are being evaluated for their impact on lung disease severity. Polymorphisms of TGF-b, have been associated with severe lung disease in a large, well-characterized cohort. Modifier genes may also affect the function of other organs in CF; a modifier locus on chromosome 19 is associated with meconium ileus. Recently, linkage analysis has identified the modifier loci of lung disease severity, and several CFTR mutations have been reported to result in a delay in acquisition of respiratory pathogens in CF patients.

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

A QPIT sweat test and CFTR mutation analysis are the cornerstones of making the diagnosis. Since the presence of the 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. Many of these tests are described separately in other sections.

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

CFTR mutation analysis is useful; if it is not confirmatory, performance of complete analysis of deletions and duplications in the CFTR gene and, in some cases, complete sequencing of the CFTR gene to include analysis of TG repeats in specific introns may be warranted. In males, ultrasound evaluation 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. The approximately 117 CF Care Centers are listed, along with their location and contact information, on the CFF website (www.cff.org). Key measures of the pulmonary and nutritional outcomes at each center since 2004 are also listed on this site.

The key elements of therapy in CF include:

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

Twice-daily 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.

At present, most CF centers recommend that all patients with CF attempt to maintain clearance of airway secretions with some ACT that is employed regularly, twice daily. An additional recommendation is that ACT be applied more frequently (e.g., three or four times daily) during an exacerbation of chronic pulmonary infection.

ACT is an arduous and time-consuming therapy that requires considerable support and encouragement from family members and health care professionals if it is to be implemented successfully. Although a CFF expert panel concluded that there was not sufficient evidence to establish the superiority of one method over another, CF centers with the best outcomes have and strongly recommended the first two methods as the cornerstones of ACT, and an editorial that accompanied the expert panel report emphasized that the lack of RCT evidence did not establish the lack of efficacy. There has been an effort to recommend the practices of the CF centers with the best outcomes as benchmarks, but this has not yet gained traction in the CF community.

Antibiotics

Chronic suppressive antibiotic therapy is recommended for patients with chronic infection with Pseudomonas aeruginosa, including every-other-month inhaled antibiotics and/or oral azithromycin (Monday-Wednesday-Friday). The recently described association of azithromycin treatment with an increase in the potential for acquisition of non-tuberculous mycobacteria has prompted reconsideration of the recommendation to treat all CF patients who are colonized with Pseudomonas with chronic azithromycin therapy. The most recent communication from the CF Foundation recommends that the decision to treat with azithromycin be individualized.

Antibiotic therapy is intensified for pulmonary exacerbations. Intravenous antibiotics are selected according to sputum culture sensitivities. Intravenous antibiotic therapy for Pseudomonas includes combinations of an aminoglycoside and a second anti-pseudomonal antibiotic, such as ceftazidime, ticarcillin, pipericillin, aztreonam, meropenem, or imipenem. Therapy is continued until symptoms, signs, and abnormal laboratory values are resolved (usually for fourteen days).

Inhaled Medications

Mucolytics

inhaled mucolytics should precede chest physiotherapy and include one or more of the following inhaled therapies: rhDNase (once daily), 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.

Antibiotics

For chronic colonization with Pseudomonas aeruginosa, inhaled antibiotics--inhaled tobramycin twice daily or inhaled aztreonam three times daily--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 age twelve.

Anti-inflammatory Agents

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

Pancreatic Enzyme Replacement Therapy (PERT)

Current recommendations for PERT dosing is 500 to 2500 units of lipase per kg of body weight per meal, or less than 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 less than two years old is 50 percent; the recommended BMI in older children is at least 50 percent, and in adults at least 22 percent for women and 23 percent for men. Routine energy intake is 110-200 percent of standards for the healthy population.

Treatment of Pulmonary Exacerbations of CF

Pulmonary exacerbations in CF 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 symptoms of increased cough, increased sputum production, change in sputum color, hemoptysis, decreased exercise tolerance, dyspnea, fatigue, decreased appetite, or fever. Physical signs include increased work of breathing, tachypnea, new-onset crackles or diminished air entry on chest exam, weight loss, or fever. Laboratory findings include decreased air flow on spirometry and increased air trapping on plethysmography, new infiltrates on chest x-ray, elevated white blood count, decreased SaO2, , or new supplemental oxygen requirement.

Current standards of therapy for pulmonary exacerbations include intravenous administration of two antibiotics for 14-21 days. Antibiotics are selected according to the sensitivities of organisms isolated from sputum or bronchoalveolar lavage specimens. The rationale for selection of two antibiotics--one aminoglycoside for treating Pseudomonas aeruginosa and other 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 3.

Intravenous Antibiotic Therapy for Pulmonary Exacerbations

Table 4.

Diagnostic criteria for CFRD

Therapy is usually initiated in the 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 risk of toxicity.

Treatment of a pulmonary exacerbation is continued until the patient demonstrates improvement in his or her personal best baseline with respect to signs and symptoms, weight, pulmonary function tests, and chest x-ray findings. There are virtually no well-controlled, prospective studies to guide evidence-based practice; current standards for therapy are supported by the consensus of experience of the top CF care centers.

The Potential for CF-Specific Therapy

Progress toward a cure for CF will require a multidisciplinary approach, and management of the lung disease will probably be based on combined methods. However, the momentum gained from recent improvements in our understanding of basic mechanisms of pathogenesis provides a basis for realistic optimism that CF-specific therapy will result in better outcomes.

The most promising results relate to use of the small molecule, VX-770, which is a specific CFTR “corrector.” The agent is taken orally. In a 28-day trial involving 39 patients with CF who had at least one copy of the G551D mutation, a decrease in sweat chloride and an increase in FEV1 were noted. Larger, longer-term trials are in progress, as is development of molecules specific for the most common mutation in CF, DF508.

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

According to the Cystic Fibrosis Foundation (CFF) Patient Registry, median predicted survival for patients in the United States was 37.2 years of age in the five-year period from 2005 through 2009.

What other considerations exist for patients with cystic fibrosis?

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

Infection control in cystic fibrosis

Because of the emergence of virulent, multi-drug-resistant pathogens in many patients with CF, careful attention to infection control is essential to prevent the spread of these organisms in the CF population. The graded recommendations of a CF Foundation Consensus Conference have been published. The four general principles applicable to healthcare settings that received a Category IA recommendation are:

  • Assume that all patients with CF 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 plus transmission-based precautions according to CDC/HICPAC published recommendations for use of contact, droplet, or airborne precautions, as defined by special circumstances, such as infection with B.cepacia complex, multidrug-resistant P. aeruginosa, MRSA, or M. tuberculosis.

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

Lung transplantation in cystic fibrosis

Bilateral lung transplantation is considered in CF when the lung disease has advanced to a life-threatening stage and survival with transplantation is deemed to be longer and of better quality than without transplantation. Timing for lung transplantation evaluation is determined individually in each transplant center; however, considerations include the following consensus-driven factors:

  • FEV1 less than 30 percent or a rapid decline in pulmonary function with increasing frequency of hospitalizations

  • hypoxemia

  • hypercapnia

  • pulmonary hypertension

Absolute contraindications for lung transplantation are: present or recent malignancy, active infection with hepatitis B or C virus and associated significant liver damage, active or recent cigarette smoking, drug abuse or alcohol abuse, severe psychiatric illness, repeated non-adherence to a medical regimen, and absence of a reliable social support. Severe end-stage disease in other organs necessitates consideration of multi-organ transplantation.

Relative risk factors for poor outcomes post-transplantation are the presence of pan-resistant infectious organisms in the respiratory tract and requirement for ventilator support or extracorporeal membrane oxygenation support pre-transplant. To minimize complications, other medical comorbidities, such as gastroesophageal reflux, diabetes mellitus, osteoporosis, obesity, or malnutrition need to be medically managed before and after lung transplantation.

Once patients are deemed potential transplant candidates, the timing for transplantation is based on a lung allocation score that weighs both the level of medical urgency and the net transplant benefit for the recipient. Since this system was adopted by the United States in 2005, it has had profoundly reduced the waiting list for transplantation and significantly reduced the time to transplantation.

The major acute complications associated with lung transplantation are: primary graft dysfunction, manifest by noncardiogenic pulmonary edema; airway complications, such as bronchial stenosis and dehiscence of the anastomosis that is due to airway necrosis; acute cellular rejection because of HLA mismatch between donor and recipient, which is also influenced by innate immune factors; and acute humoral rejection secondary to de novo donor-specific anti-HLA antibodies.

Infection presents both a threat that is both acute and chronic because of the need for immunosuppression to protect the graft, impaired mucociliary clearance, ineffective cough that is due to post-operative pain, and the presence of virulent organisms in the retained upper respiratory tract. Bacterial pneumonias that are due to P. aeruginosa and S. aureus occur early in the post-operative course.

CMV, the most common viral infection, causes viral pneumonitis and gastrointestinal or central nervous system infections. CMV infection is also associated with increased risk of bronchiolitis obliterans. Prophylaxis with a twelve-month course of valganciclovir significantly reduces the risk of CMV infection over that of a three-month course. Infection with Aspergillus is a major threat, with manifestations ranging from asymptomatic infection to invasive pulmonary and extrapulmonary infections. Voriconazole is the preferred therapy. Invasive aspergillosiscarries a 60 percent mortality rate.

The major late-term complication is bronchiolitis obliterans, a fibroproliferative process that destroys small airways, resulting in a decline in pulmonary function and eventual respiratory failure. This process occurs in 50 percent of lung transplant recipients by five years post-transplantation and in 90 percent by ten years post-transplantation. Risk factors include poor HLA match, with cellular or humoral rejection, and non-immune mediated injuries, such as gastroesophageal reflux and CMV and respiratory viral infections. The course of bronchiolitis obliterans is highly variable, but median survival is a few years. Therapy focuses on immunosuppression, including treatment with azithromycin as an immunosuppressant.

Other complications of lung transplant in CF include renal failure, hypercholesterolemia, hypertension, and malignancy. In EBV-seronegative patients, there is an increased risk of post-transplant lymphoma, which may respond to decreased immunosuppressive therapy and treatment with rituximab, an anti-CD20 monoclonal antibody.

In the absence of complications, CF patients achieve normal lung function after lung transplantation and have improved quality of life. Because of improvements in preoperative patient preparation, preparation of donor lung, surgical, and post-surgical care, and monitoring and treatment of complications, the current median survival for patients with CF who receive lung transplantation is 7.1 years.

Reproductive Issues in cystic fibrosis

More than 98 percent of male patients with CF are sterile, secondary to bilateral absence of the vas deferens. Microsurgical epididymal sperm aspiration ( MESA) coupled with in vitro fertilization has been successful in producing pregnancies in a few patients. Since not all males with CF are sterile, 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. Recommendations regarding pregnancy for women who are either mildly affected or severely affected is relatively straightforward: An overall evaluation of the clinical situation is recommended for women with moderately compromised pulmonary status (i.e., FVC under 50-60 percent of predicted), although no firm guidelines can be given.

Men and women with CF who are considering reproducing 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 of appropriate age at the time the diagnosis of CF is made. The basic details of autosomal recessive patterns of inheritance and the specific implications for both immediate and extended family members should be discussed, including a discussion of prenatal diagnosis and options for in vitro fertilization with preimplantation testing and genetic counseling when patients with CF reach child-bearing age.

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. At the time of diagnosis, it is important to strike an optimistic note while educating the patient and family members about the disease and its management. Identification of the strengths and weaknesses of the family are important in providing appropriate support.

The cost of care in CF is high, and it becomes even more expensive when hospital admissions are required. A skilled social worker may be invaluable in identifying the resources available to patients and their families. Many states have specific programs that provide financial support for children and adults with CF.

As the disease runs its course, counseling and feedback about disease progression are essential. As the patient and family set educational and career goals, they need guidance for realistic planning. When the lung disease is classified as severe or end-stage, options like palliative care and lung transplant should be discussed in detail. A timely referral to a lung transplantation program that is experienced in transplanting patients with CF will usually include counseling for the patient and his or her family concerning the pros and cons of lung transplantation for the patient's specific circumstances.

Specific challenges face the ever-increasing number of patients with CF who are surviving well into their adult years. Managing their chronic illness becomes more complicated when patients must also begin to manage their independence and make life decisions regarding education, relationships, marriage, children, careers, and insurance, so skilled support for both patients and families is required. The adult patient with CF faces unique problems in self-care, as when they experience an exacerbation of their disease, they must increase their level of care at a time when they are least able to do so.

What’s the evidence?

Bombieri, C, Claustres, M, De Boeck, K. "Recommendations for the classification of diseases as CFTR-related disorders". J Cyst Fibros. vol. 10. 2011. pp. S86-10.

Consensus guidelines for the diagnosis of CFTR-related disorders (CFTR-RD) reached by consensus of an international panel of experts after two dedicated workshops. Contains useful algorithms for making or excluding the diagnosis of the three established CFTR-RDs--CBAVD, acute recurrent or chronic pancreatitis, and disseminated bronchiectasis--all with CFTR dysfunction.

Borowitz, DS, Grand, RJ, Durie, PR. "Use of pancreatic enzyme supplements for patients with CF in the context of fibrosing colonopathy". J Pediatr. vol. 127. 1995. pp. 681-4.

This document from the CF consensus committee reviews the use of pancreatic enzyme supplements in CF, including suggested doses.

Collaco, JM, Cutting, GR. "Update on gene modifiers in cystic fibrosis". Curr Opin Pulm Med. vol. 14. 2008. pp. 559-66.

Concise review of the research on genetic and nongenetic modifiers of CF.

Colombo, C, Russo, MC, Zazzeron, L. "Liver disease in cystic fibrosis". J Pediatr Gastroenterol Nutr. vol. 43. 2006. pp. S49-S55.

A review of the manifestations of liver disease in CF.

Durno, C, Corey, M, Zielenski, J. "Genotype and phenotype correlations in patients with cystic fibrosis and pancreatitis". Gastroenterol. vol. 123. 2002. pp. 1857-1864.

This paper reviews pancreatitis in CF, including the genotype and phenotype correlations.

Fitzsimons, SC, Burkhart, GA, Borowitz, D. "High dose pancreatic enzyme supplements and fibrosing colonopathy in children with cystic fibrosis". N Engl J Med. vol. 336. 1997. pp. 1283-9.

Reviews the relationship between high-dose pancreatic enzyme supplements and fibrosing colonopathy in CF.

Flume, PA, Robinson, KA, O' Sullivan, BP. "Cystic fibrosis pulmonary guidelines: Airway clearance therapies". Respir Care. vol. 54. 2009. pp. 522-537.

Report of the CFF Clinical Practice Guidelines for Pulmonary Therapies Committee. The committee acknowledges that there is a paucity of controlled trials from which to make evidence-based recommendations. An accompanying editorial (p. 458) discusses the limitations of the report and suggests benchmarking the practices of CF centers with superior outcomes until future research is able to provide stronger evidence.

Flume, PA, Mogayzel, PJ, Robinson, KA. "Cystic fibrosis pulmonary guidelines: Pulmonary complications: Hemoptysis and pneumothorax". Am J Respir Crit Care Med. vol. 182. 2010. pp. 298-310.

Guidelines established by a CFF Consensus Panel that used the Delphi method to make recommendations for best practices. The panel acknowledge that there is not enough data to make evidenced based recommendations for some situations.

Flume, PA, O' Sullivan, BP, Robinson, KA. "Cystic fibrosis pulmonary guidelines: Chronic medications for maintenance of lung health". Am J Respir Crit Care Med. vol. 176. 2007. pp. 957-69.

The evidence supporting chronic therapies for maintenance of lung health are evaluated by the CFF Pulmonary Therapies Committee. Overall, the strength of evidence supporting most treatments from well-designed studies is limited.

Gibson, RL, Burns, JL, Ramsey, BW. "Pathophysiology and management of pulmonary infections in cystic fibrosis". Am J Respir Crit Care Med. vol. 168. 2003. pp. 918-51.

An excellent review of the pathophysiology of CF lung disease and the microbiology of pulmonary infections with recommendations for management of chronic lung disease and acute infections.

Kotloff, RM, Thabut, G. "Lung transplantation". Am J Respir Crit Care Med. vol. 184. 2011. pp. 159-71.

A comprehensive review of lung transplantation, including patient selection, outcomes and complications.

LiPuma, JJ. "The changing microbial epidemiology in cystic fibrosis". Clin Microbiol Rev. vol. 23. 2010. pp. 299-323.

A comprehensive review of the key and emerging pathogens in the CF airway by an expert and leader in the field.

Martinu, T, Pavlisko, EN, Chen, DF, Palmer, SM. "Acute allograft rejection: Cellular and humoral processes". Clin Chest Med. vol. 32. 2011. pp. 295-310.

A review of the mechanisms of acute immune-mediated lung rejection following transplantation.

Mascarenhas, MR, Maqbool, A, Allen, JL, Panitch, HB, Rubenstein, RC. "Gastrointestinal complications of cystic fibrosis". Series: Lung biology in health and disease: Cystic fibrosis. vol. v.242. Informa Healthcare USA Inc.. 2010. pp. 266-284.

A comprehensive review of the gastrointestinal manifestations of CF in children including incidence, pathophysiology and management.

Mogayzel, PJ, Flume, PA. "Update in cystic fibrosis 2010". Am J Respir Crit Care Med. vol. 183. 2011. pp. 1620-4.

Review and commentary on recent developments in clinical and basic research on cystic fibrosis, including the areas of pathogenesis, microbiology, and new therapies. It also includes a discussion of the first positive results of the trial of small-molecule therapy for specific mutations in cystic fibrosis.

Moran, A, Brunzell, C, Cohen, RC, Katz, M, Marshall, BC, Onady, G. "Clinical care guidelines for cystic fibrosis-related diabetes: a position statement of the American Diabetes Association and a clinical practice guideline of the Cystic Fibrosis Foundation, endorsed by the Pediatric Endocrine Society". Diabetes Care. vol. 33. 2010. pp. 2697-708.

The authors, all experts in the field of diabetes or cystic fibrosis, met to refine the classification of glucose abnormalities in cystic fibrosis. The team also developed new guidelines for the screening and treatment of cystic fibrosis-related diabetes.

Moran, A, Pekow, P, Grover, P, Zorn, M, Slovis, B, Pilewski, J. "Insulin therapy to improve BMI in cystic fibrosis-related diabetes without fasting hyperglycemia: results of the cystic fibrosis related diabetes therapy trial". Diabetes Care. vol. 32. 2009. pp. 1783-8.

This multi-center study identified a positive benefit of insulin therapy on nutritional status in adults with cystic fibrosis diabetes without hyperglycemia. This study changed previous practice, where insulin treatment was reserved for individuals with CFRD in whom fasting hyperglycemia occurred, and highlighted the potential positive role of earlier diabetes treatment for outcomes relevant to cystic fibrosis.

Moran, A, Phillips, J, Milla, C. "Insulin and glucose excursion following premeal insulin lispro or repaglinide in cystic fibrosis-related diabetes". Diabetes Care. vol. 24. 2001. pp. 1706-10.

This study highlights the delayed and blunted insulin secretion that characterizes cystic fibrosis and profiles the effects of insulin and an insulin secretagogue on insulin levels and blood glucose in cystic fibrosis.

Moss, RB. "Allergic bronchopulmonary aspergillosis and aspergillus Infection in cystic fibrosis". Curr Opin Pulm Med. vol. 16. 2010. pp. 598-603.

Concise, recent review of ABPA in patients with CF.

Saiman, L, Siegel, J. "the Cystic Fibrosis Foundation Consensus Conference on Infection Control Participants. Infection control recommendations for Patients with cystic fibrosis: microbiology, important pathogens, and infection control practices to prevent patient-to-patient transmission". Inf Contr Hosp Epidemiol. vol. 24. 2003. pp. S6-S52.

Comprehensive set of recommendations on infection control practices in cystic fibrosis. These recommendations of a CFF consensus conference on infection control are graded evidence-based recommendations for infection control practices in cystic fibrosis that center on both inpatient and outpatient settings.

Sathe, MN, Feranchak, AP, Allen, JL, Panitch, HB, Rubenstein, RC. "Liver disease". Series: Lung biology in health and disease: cystic fibrosis. vol. v.242. Informa Healthcare USA Inc. 2010. pp. 285-307.

This is a comprehensive review of the incidence pathophysiology, clinical manifestations, and management of CF related liver disease in children.

Schwarzenberg, SJ, Thomas, W, Olsen, TW, Grover, T, Walk, D, Milla, C. "Microvascular complications in cystic fibrosis-related diabetes". Diabetes Care. vol. 30. 2007. pp. 1056-61.

This manuscript concludes that microvascular complications (including retinopathy, neuropathy, nephropathy) do occur in CFRD, but fasting hyperglycemia may be necessary for their development.

Sokol, RJ, Durie, PR. "Recommendations for management of liver and biliary tract disease in cystic fibrosis. Cystic Fibrosis Foundation Hepatobiliary Disease Consensus Group". J Pediatr Gastroenterol Nutr. vol. 28. 1999. pp. S1-S13.

This last review from the CFF hepatobiliary consensus group reviews recommendations for the management of liver and biliary tract disease in CF.

Welsh, MJ, Ramsey, BW, Accurso, F, Cutting, GR, Scriver, CL, Beaudet, AL, Sly, WS, Valle, D. "Cystic fibrosis". The metabolic and molecular basis of inherited diseases. McGraw-Hill. 2001. pp. 5121-5188.

Comprehensive review of CF literature with an extensive list of references (704) up to 1999. Describes identification of the CF gene named (Cystic Fibrosis Transmembrane Conductase Regulator (CFTR). Excellent section on molecular mechanism of CFTR dysfunction.

Wilchanski, M, Durie, PR. "Patterns of gastrointestinal disease in adulthood associated with mutations in CFTR gene". Gut. vol. 56. 2007. pp. 1153-63.

This review discusses the patterns of gastrointestinal disease seen in adults with CF.
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