Online Medical Reference

Cystic Fibrosis

Marie M. Budev

Atul C. Mehta

Published: August 2010

Cystic fibrosis (CF) is the most common, classic mendelian autosomal recessive, life-limiting disease among the white population.1,2 It is a multisystem disease that results from loss of function in the CF transmembrane conductance regulator (CFTR) gene, classically leading to respiratory tract, gastrointestinal (GI), pancreatic, and reproductive abnormalities.2 CF was recognized as a distinct clinical entity in 1938 and was believed to be invariably fatal during infancy.3

Since the 1970s, the life spans of CF patients have been prolonged, with advances in early diagnosis, care, and disease therapy. Early diagnosis has been improved by newborn screening. Advances in care include management of meconium ileus and improved methods of sputum clearance and managing respiratory failure. Improvements in disease therapy include better antibiotics, especially macrolides, and better pancreatic enzymes. With current management, almost 80% of patients with CF will reach adulthood; thus, CF is no longer a purely pediatric disease.4-6 For patients born in the 1990s, the median survival is predicted to be greater than 40 years.5 As more CF patients are surviving longer, adult issues including careers, relationships, and family are becoming important.6 A range of comorbid conditions that are more prevalent in adult CF patients are also being encountered with increasing frequency as this population matures, including osteoporosis, diabetes, joint diseases, malnutrition, severe lung disease with bronchiectasis, colonization by resistant pathogens, severe gastric reflux, chronic sinusitis, and periportal fibrosis.7

Delivery of health care to the CF patient is now relevant to the nonpediatric physician. In fact, the multifaceted needs of the adult CF patient have led to the development of a nationwide network of more than 83 adult CF care programs in conjunction with the Cystic Fibrosis Foundation.8 These comprehensive CF centers provide patients with a multidisciplinary approach based on the original pediatric CF centers. The aims of adult CF care include delivery of optimum care, access to pertinent medical resources, coordination of care among specialists and primary care providers, and a strong emphasis on independence and improving the quality of life of the patient who has CF.5 The physician is also faced with another challenge, in which the adult CF patient presents with atypical features that might have gone unrecognized. In this chapter, we cover the salient features of CF, including prevalence and the issues surrounding neonatal screening, pathophysiology, diagnosis, and new and emerging therapies for this complex multisystem disease.

Definition

CF is a genetic disease affecting approximately 30,000 children and adults in the United States. A defective gene causes the body to produce an abnormally thick, sticky mucus that leads to airway obstruction, subsequent life-threatening lung infections, end-stage lung disease, and bronchiectasis. These thick secretions also obstruct the pancreas, preventing digestive enzymes from reaching the intestines, leading to pancreatic insufficiency, malabsorption, and, in extreme cases, malnutrition.

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Prevalence

Ethnicity

CF is a disease that occurs predominantly in the white population, with a rate of one in 2500 live births. Two percent to 5% of whites are carriers of the CFTR gene mutation (having one normal and one abnormal gene) but have no overt clinical signs of disease. CF is not rare in African American populations, but it occurs at the much lower frequency of approximately one in 17,000 live births.9 In general, mutations of the CF gene are most prevalent in persons of northern and central European ancestries or of Ashkenazi Jewish descent, and they are rarely found in Native Americans, Asians, or native Africans.10 Although the prevalence of CF is lower in the African American population, the mean age at diagnosis is younger in black patients than in white patients. Overall, the clinical manifestations are similar in both racial groups except that black patients tend to have more severe GI issues, including poor nutritional status.10 There are more than 23,000 patients with CF in the United States.6

Gender

CF occurs equally often in male and female patients. In general, female patients with CF fare significantly worse than male patients. Female patients become infected with Pseudomonas aeruginosa earlier and have worse pulmonary function, worse nutritional status, and earlier mortality.11-13 A Cystic Fibrosis Registry analysis from the University of Wisconsin14 demonstrated that CF is diagnosed in girls at a later age than boys by at least 4 months, or even later when the analysis was limited to children presenting with only respiratory symptoms (40.7 months for diagnosis in girls vs. 22.3 months for diagnosis in boys). Implications for disease outcomes caused by delayed diagnosis of CF in girls may be present based on this recent analysis, but the reason for this delay is not clear or obvious.15

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Pathophysiology

CF is an autosomal recessive trait caused by mutations at a single gene locus on the long arm of chromosome 7. The gene product cystic fibrosis transmembrane conductance regulator (CFTR) is a 1480-amino acid polypeptide.16,17 CF reflects the loss of function of the CFTR protein. The CFTR protein normally regulates the transport of electrolytes and chloride across epithelial cell membranes.18

More than 1000 mutations of the CFTR gene have been described.19 The most common mutations of CFTR can be classified into six groups based on their known functional consequences.20 This classification allows categorization of CFTR mutations based on molecular mechanisms, but phenotypic appearance depends on the type of mutation (class), location of the gene, molecular mechanism, and interaction with other mutations, as well as genetic and environmental influences.21

The most common mutation of the CFTR gene is caused by deletion of phenylalanine at position 508 (ΔF508) and occurs with varying frequency in different ethnic groups.22 Worldwide, this allele is responsible for approximately 66% of all CF chromosomes.23

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Screening

About 1000 infants are born with CF every year. CF is diagnosed in most of these children at a mean age of 3 to 4 years.24 Nearly 10% of CF patients receive their diagnosis when they are older than 18 years.

Newborn screening for CF has been instituted in eight states, but national screening plans have not been mandated. In all, CF is diagnosed in 10% of infants in the United States either by prenatal diagnosis (3%) or by newborn screening (7%).25 Newborn CF screening has been advocated by clinicians and CF groups as an early means of identifying asymptomatic patients so as to initiate early therapy to prevent long-term sequelae of the disease.26 The currently available genetic screening tools for CF include the Guthrie test, in which measurements of the immunoreactive trypsinogen in dried blood are taken, and measurement of the most common CF mutations, including ΔF508.26 ΔF508 is the most commonly reported gene mutation and is responsible for 70% of the mutated alleles in white patients. It is caused by a 3-bp deletion in the CFTR gene, resulting in the loss of the amino acid at position 508 of the CFTR protein. Homozygosity of this mutation is severe, resulting in both pulmonary and pancreatic disease.27

Recommendations for carrier screening or population screening have been proposed by the American College of Obstetricians and Gynecologists, the National Institutes of Health, and the American College of Medical Genetics; they are designed to identify at-risk couples before the birth of a child with CF.28 Screening should be offered to adults with a family history of CF, reproductive partners of persons with CF, and white (including Ashkenazi Jewish) patients who are planning pregnancy. Screening should be made available to persons of color.

The efficacy of CF screening program is based on a multitude of factors. One factor is identification of the CF carrier status of each partner, which helps to determine the risk to the fetus. Issues to keep in mind include the gestational age at which the couple presents for prenatal care and the feasibility of pregnancy termination. These factors should be included in the CF screening discussion with parents. The screening of couples can follow two approaches: The female partner is screened first, and if she tests positive for CF carrier status, then the male partner is tested; or both partners are screened concurrently to use time efficiently for decision making, especially if more than one recessive disorder is being considered. Important information to discuss with patients before screening include the aim of screening, the voluntary nature of screening, medical and genetic issues surrounding CF, the prevalence of CF, the interpretation of the test results, and individual values.29

Carrier screening neither detects all mutations that could be present nor estimates the residual risk (the chance that the patient still carries a copy of a CFTR mutation despite negative testing). CF is an autosomal recessive disorder, and persons with CF typically have inherited one mutated allele from each parent. It is very rare to inherit two mutated alleles from one parent and none from the other.29,30

For couples who have one child with CF or who are known to be carriers, prenatal diagnosis of CF is available through chorionic villus sampling in the first trimester or by amniocentesis in the second or third trimester. Some patients undergo prenatal testing to help in deciding to terminate or continue the pregnancy.

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Signs and symptoms

Signs and symptoms of CF are listed in Box 1.

Box 1: Signs and Symptoms of Cystic Fibrosis
Respiratory
  • Airway colonization
  • Asthma
  • Bronchitis
  • Chronic productive cough
  • Clubbing
  • Nasal polyps
  • Pansinusitis
  • Pseudomonas aeruginosa infection
  • Staphylococcal pneumonia
Gastrointestinal
  • Biliary cirrhosis
  • Diabetes
  • Distal intestinal obstructive syndrome
  • Failure to thrive
  • Fat-soluble vitamin deficiency (vitamins A, D, E, and K)
  • Meconium ileus
  • Portal hypertension
  • Recurrent right lower quadrant pain
  • Recurrent pancreatitis
Genitourinary
  • Absence of bilateral vas deferens
  • Cervical plugging
  • Female urinary incontinence
  • Infertility
  • Recurrent vaginal yeast infections

Adapted from Welsh MJ, Tsui L-C, Boat TF, et al: Cystic fibrosis. In Scriver CR, Beaudet AL, Sly WS, et al (eds): The Metabolic and Molecular Basis of Inherited Disease. New York: McGraw-Hill, 1995, p 3801.
© 2005 The Cleveland Clinic Foundation.

Respiratory Inflammation and Infections

Because the epithelial cells of an organ are affected by a variety of CFTR mutations, the consequences of the mutation vary depending on the organ involved. The pathologic changes differ in the secretory cells, sinuses, lungs, pancreas, liver, or reproductive tract. The hallmark of CF and the cause of death in more than 90% of patients is chronic pulmonary disease caused by bacterial and viral pathogens and leading to a host inflammatory response. The most profound changes occur in the lungs and airways, where chronic infections involve a limited number of organisms including P. aeruginosa, which is implicated most often, followed by Staphylococcus aureus, Haemophilus influenzae, and Stenotrophomonas maltophilia.6 Children with CF are first infected with Staphylococcus and Haemophilus species and later with Pseudomonas species.

Several theories have been proposed to explain the limited number of organisms involved in CF pulmonary infections, including the inflammation-first hypothesis,31 the infection-first hypothesis,32 the cell-receptor hypothesis,17 and the salt defensins hypothesis.33 The salt defensins hypothesis proposes that CF airway cells have properties similar to those of sweat glands that inactivate substances called defensins, leading to bacterial multiplication and infections. These theories, however, do not explain the presence of mucoid S. aureus or mucoid-type P. aeruginosa.

The isotonic fluid depletion and anoxic mucus theory proposes that water- and volume-depleted airway fluid leads to mucus viscosity, subsequent defective ciliary clearance, and a cough that is inadequate to clear the airways. Thus, bacteria in the CF lung are trapped within this viscous airway fluid and multiply within anaerobic growth conditions by changing from a nonmucoid to a mucoid type of organism.34-36 The transformation of these bacteria to a biofilm-encased form is a means of protection from normal host defenses and antibiotics, making eradication difficult.37 A neutrophil-dominated airway inflammation is certainly present in CF lung disease, even in clinically stable patients.31,38

It seems that early pediatric colonization with either P. aeruginosa or S. aureus has a significant impact on CF lung disease in adulthood. Another organism unique to CF with a significant impact on adult CF lung disease is Burkholderia cepacia. Earlier, this organism was uniformly associated with poor clinical outcomes, but now it is recognized that outcomes might depend on the actual genotype of the organism.39

Clinically, CF pulmonary exacerbations are manifested as an increase in respiratory symptoms including cough and sputum production, with associated systemic symptoms that include malaise and anorexia.40 Patients rarely have fever and leukocytosis, and in most cases radiographic changes are minimal during an exacerbation.9 An exacerbation can be documented by a decrease in pulmonary function, which usually returns to normal after the acute exacerbation resolves. As the lung disease progresses, bronchiolitis and bronchitis become evident, with bronchiectasis as a consequence of the persistent obstruction-infection insult. Overall, bronchiectasis in CF is more severe in the upper lobes than in the lower lobes. Pathologic examinations have demonstrated bronchiectatic cysts in more than 50% of end-stage CF lung on autopsy studies.41 Subpleural cysts often occur in the upper lobes and can contribute to the frequent occurrence of pneumothorax in patients with late-stage CF. The reported incidence of spontaneous pneumothorax in CF ranges between 2.8% and 18.9%.42 The patient with spontaneous pneumothorax usually presents with acute onset of chest pain or dyspnea. In one study, chest pain was the manifesting symptom in more than 50% of patients. Dyspnea occurred in more than 65% of patients.43 In the same study, hemoptysis was present in 19% of patients, probably as a result of bronchial artery enlargement, and subsequent tortuosity within ectatic airways made vessels delicate and more prone to bleed.44

Children without a prior, established diagnosis of CF often present with cough and upper respiratory tract infections that persist longer than expected. Patients whose CF is diagnosed when they are older often do not have the underlying pancreatic insufficiency that is typical of the younger patient with classic CF. Patients with CF diagnosed in adulthood usually present with chronic respiratory infections, but these are usually milder and less likely to be pseudomonal.42

Several interstitial lung diseases have been described during autopsy of the CF lung, including the usual interstitial pneumonitis, bronchiolitis obliterans organizing pneumonia, and diffuse alveolar damage.45 The upper respiratory tract is also involved in CF, most patients suffer from acute and chronic sinusitis caused by hypertrophy and hyperplasia of the secretory components of the sinus tract.46 Another common feature is the presence of pedunculated nasal polyps.47 Sleep-disordered breathing and nocturnal hypoxia, mainly during rapid-eye-movement (REM) sleep and hypoventilation, have also been described in CF patients.48

Gastrointestinal Tract

GI symptoms in CF manifest early and continue throughout the life span of a CF patient. Because of defects in CFTR, meconium ileus can occur at birth, and distal intestinal obstruction syndrome (the meconium ileus equivalent) occurs in 40% of older CF patients. The distal intestinal obstruction syndrome has been associated with inadequate use of pancreatic enzyme and dietary indiscretion without appropriate use of pancreatic enzyme.9 CF patients with obstruction can present with abdominal pain and often a palpable mass in the right lower quadrant on physical examination. Associated symptoms include anorexia, nausea, vomiting, and obstipation. With more frequent events, adhesions can develop due to inflammation, leading to a mechanically dysfunctional intestine that can eventually require surgical resection.

As a result of the CFTR defect, the biliary ducts can become plugged and clogged, leading to liver involvement and biliary cirrhosis in 25% of patients with CF. Hepatic steatosis can result from malnutrition, and congestion can result from hypoxia-induced cor pulmonale.2 Symptomatic liver disease with the sequelae of cirrhosis, including esophageal varices, is uncommon. Fecal loss of bile acids is increased in CF, leading to a reduction in the bile salt pool and a propensity for cholelithiasis. Approximately 30% of adult CF patients present with a hypoplastic, poorly functioning gallbladder, and about one third of that population develops gallstones.49,50

About 90% of patients with CF have pancreatic insufficiency. It is believed to be related to reduced volumes of pancreatic secretions and reduced concentrations of bicarbonate excretion. As a result, digestive proenzymes are retained when the pancreatic duct is blocked, leading to organ tissue destruction and fibrosis. Lipids and fat-soluble vitamins (D, E, K, and A) are therefore malabsorbed, and the malabsorption can eventually lead to a hypermetabolic state and increased endobronchial infections because of an inverse relation between metabolic states and lung function in CF patients.51 Patients with no evidence of pancreatic insufficiency usually manifest milder disease and are less likely to have the ΔF508 mutation.9

CF-related diabetes usually develops after the second decade of life and rarely before the age of 10 years, due to sparing of Langerhans cells. Over time, pancreatic destruction and fibrosis occur, caused by obstruction of the pancreatic ducts and later leading to amyloid deposition, and diabetes ensues.52,53 Patients with CF-related diabetes experience more severe lung disease and nutritional deficiencies than CF patients without diabetes. Bone disease, including osteoporosis and osteopenia, is multifactorial in CF because of malnutrition, cytokines, and hormonal disorders in androgen (hypogonadism) and estrogen production and because of glucocorticoid therapy.54

Fertility and Reproduction

Now that many more CF patients are surviving into their 40s, issues of family and children have gained more attention. Most male CF patients are infertile because of aspermia secondary to atretic or bilateral absence of the vas deferens or seminal vesicle abnormalities.55 It is believed that during fetal life, the vas deferens becomes plugged with mucoid secretions and subsequently gets reabsorbed. Libido and sexual performance are not affected. Artificial insemination may be used for couples desiring offspring by obtaining microscopic epididymal sperm sampling. Female CF patients usually have normal reproductive tracts, although the cervical mucus may be tenacious as a result of CFTR mutation, thus blocking the cervical canal and possibly interfering with fertility. Overall, women with CF are not as infertile as their male counterparts, and birth control must be discussed with female patients reaching sexual maturity.56 The endometrium and fallopian tubes contain very small amounts of CFTR and usually remain normal.57 Onset of menarche is usually normal except in girls who are severely ill and undernourished.

Since the 1960s, the prognosis for CF and pregnancy has improved greatly. Maternal deaths usually occur in women with the most severe lung disease. It appears from multiple case studies that the decline of lung function and the absolute value of the FEV1 may be more important in determining fetal outcome.58,59 One study, by Canny and colleagues, recommended an FEV1 of greater than 70% as a requirement for a successful pregnancy outcome.59 Normal lung function leads to a normal pregnancy. Pulmonary status can worsen in women with poor lung function during pregnancy, but this is still debated. Termination of pregnancy has been recommended if the FEV1 is less than 50%; however, reports do exist of successful pregnancies with low FEV1.60 Extremes of low body weight have resulted in terminations and premature deliveries and may be a relative contraindication.61 In terms of infant health, it should be kept in mind that all infants will be carriers of a maternal gene for CF. Case reports have reported fetal anomalies caused either by treatment, by maternal complications, or by chance itself.57

Vaginal yeast infections and urinary incontinence have now become major issues in female CF patients as they mature. Many patients have persistent yeast infections as a result of frequent antibiotic therapy. Suppression of cough in an attempt to prevent urinary leak can prevent women from aggressively continuing chest physiotherapy.62,63

Sweat Glands

During the great summer heat wave of 1939 it was discovered that patients with CF were especially susceptible to heat prostration and associated cardiovascular collapse and death after initial symptoms. This sweat defect was discovered by Di Sant'Agnese and eventually led to the modern day sweat test used in the diagnosis of CF. In the sweat duct, CFTR is the only channel by which chloride can be reabsorbed from sweat.63,64

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Diagnosis

In 1998, the Cystic Fibrosis Foundation issued a consensus statement regarding the diagnosis of CF.1 According to the panel, the diagnosis of CF should be made on the basis of one or more characteristic phenotypic features: history of a CF sibling, presence of a positive newborn screening test, and laboratory confirmation of a CFTR abnormality by an abnormal sweat chloride test, identification of mutations in a gene known to cause CF, or in vivo demonstration of an ion transport abnormality across the nasal epithelium (Figure 1). However, if these classic criteria as described by the committee are not present, CF still cannot be ruled out in its entirety. In patients who present later in childhood or in early adulthood, these classic criteria might not be present. In these patients, typical pulmonary symptoms or GI symptoms may be absent, and instead pancreatitis, male infertility, or sinusitis or nasal polyps may be present.18

Sweat Testing

Sweat testing, in which a minimally acceptable volume or weight of sweat (≥50 mg) must be collected during a 30-minute period to ensure an average sweat rate of 1 g/m2 per minute, using the Gibson and Cooke method.63,64 A sweat chloride reading of more than 60 mmol/L on repeated analysis is consistent with a diagnosis of CF but must be interpreted in the context of the patient's history, clinical presentation, and age.1 Approximately 5% of patients with CF have normal sweat test results.7 A negative sweat test does not rule out the possibility of CF in the presence of appropriate symptoms and clinical signs (pancreatitis, sinus disease, and azoospermia) and should be repeated. False positives can result for many reasons, but poor technique and patient nutritional status, including anorexia, can yield false results.

Nasal Potential Measurements Voltage

Nasal potential measurements measure the voltage difference and correlate with the movement of sodium across the cell membrane. In CF, the CFTR mutation renders this physiologic function abnormal, leading to a large drop in the potential in patients with CF. The presence of nasal polyps or irritated nasal mucosa can yield a false-negative result. Overall, testing using this method is complicated and time consuming.65

Genotyping

Because of the more than 1000 CFTR mutations associated with CF, commercially available probes test only for a limited number of mutations, which constitute more than 90% of the most common mutations known to cause CF but which can vary from region to region. A mutation can be found in most symptomatic patients, but in a small percentage the mutation can be absent.66 Therefore, clinical manifestations or family history are important to the diagnosis. If an abnormality does exist, the combination of two CF mutations plus an abnormal sweat chloride test is accepted for diagnosis. Mutation analysis can be used not only to confirm diagnosis but also to provide genetic information for family members, predict certain phenotypic features, and possibly help in allocating patients for research trials.

Ancillary Testing

In patients with atypical features, a number of clinical and radiologic tests may be performed to assess for a CF phenotype, including assessment of respiratory tract microbiology, chest radiographs, computed tomography of the chest, sinus evaluation, genital tract evaluation, semen analysis, and pancreatic functional assessment. The hallmarks of CF are pancreatic insufficiency and malabsorption, which can lend themselves to laboratory examination such as measurement of serum trypsinogen or pancreas-specific elastase, and fecal fat analysis or reduced fecal concentration of chymotrypsin.67,68 In addition, pansinusitis is so common in CF patients and generally uncommon in non-CF children that the presence of this entity on examination and sinus radiographs should prompt a suspicion of CF.69 In a male patient with obstructive azoospermia confirmed with testicular biopsy, CF should be strongly considered, although other diseases, such as Young's syndrome, can cause pulmonary disease and azoospermia.70

Airway inflammation, even in the absence of active infection, is present in young and older patients with CF. Therefore, bronchoalveolar lavage (BAL) can show a predominance of neutrophils in patients with CF. In atypical presentations, with no evidence of pulmonary disease, a BAL with evidence of a high neutrophil count can provide further support for the diagnosis of CF in the presence of azoospermia or pancreatic disease.47 Isolation of the mucoid type of P. aeruginosa by BAL or sputum analysis, oropharyngeal swab, or sinus culture is highly suggestive of CF.1

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Treatment

Gene Treatment

The cure for CF is to restore the function of CFTR. This has been attempted with in vivo gene therapy in CF patients using adenoviral vectors and cationic liposome transfer, although lasting physiologic effects have not been noted.71,72 Although it is still far from being a standard treatment, gene therapy for CF has been making significant strides.

Protein modification is based on the concept that the abnormal CFTR protein can be taught to transport water and electrolytes. The CFTR ΔF508 protein mutation is the most common mutation responsible for CF. This abnormal mutation is recognized by the endoplasmic reticulum and degraded rather than glycosylated and transported to the cell surface. Aminoglycosides, including gentamicin, allow few of the CFTR mutations to reach the respiratory epithelial cells in patients with CF. Other compounds, including phenylbutyrate, phenybutyrate, and genistein, have been tested to act as similar chaperones to the CFTR mutation.73-76

Another ongoing approach includes gene transfer, in which both endogenous stem cells in the lung and mouse-derived cells have been noted to transform into airway and epithelial cells after systemic adminstration.77

Symptomatic Treatment

Since the early 1990s, the Cystic Fibrosis Foundation has developed guidelines to help guide the care of patients with this complex disease (Table 1).1

Table 1: Cystic Fibrosis Foundation Guidelines for Cystic Fibrosis Care
Care Frequency
Outpatient visits 4/yr
Pulmonary function tests ≥2/yr
Respiratory cultures ≥1/yr
Creatinine level 1/yr
Glucose 1/yr for patients >13 yr
Liver enzymes 1/yr

Adapted from Cystic Fibrosis Foundation: Cystic Fibrosis Foundation Patient Registry Annual Data Report 2002. Bethesda, Md, Cystic Fibrosis Foundation, 2003.

Respiratory Care

Respiratory disease is the major cause of mortality and morbidity in CF. All patients with CF should be monitored for changes in respiratory disease. A persistent cough in a CF patient is not normal, and the cause should be aggressively pursued.

Spirometry is a useful tool for monitoring pulmonary status. Initial lung function in most CF patients is normal. Later, the small peripheral airways become obstructed, leading to changes on spirometry at low lung volumes. Later still, decreased flow occurs at larger lung volumes. CF usually produces an obstructive pattern on spirometry, but a restrictive pattern can indicate substantial gas trapping. In general, a 10% decrease in FEV1 is considered a sign of worsening lung function and possibly a sign of a respiratory infection.78 Patients with an FEV1 of less than 30% of predicted are at higher risks for nocturnal hypoxia and hypercapnia and should be evaluated for nocturnal desaturation.

Oxygen saturation should be monitored routinely to assess the need for supplemental oxygen in patients with moderate to severe disease. Structural changes can also be noted using radiographic studies. Annual chest radiographs are recommended for unstable CF patients and may be useful in documenting the progression of disease or response to treatment. In patients with stable clinical states, chest radiographs should be performed every 2 to 4 years instead of annually. If bronchiectasis is suspected, high-resolution computed tomography is indicated (see Fig. 1).78

Inhaled Bronchodilators

Inhaled bronchodilators, specifically β agonists, can be administered by nebulizer, metered-dose inhaler, or oral inhaler in CF patients with a documented drop in FEV1 by 12% or 200 mL, indicating bronchodilator response in the effort to treat airway hyperreactivity.79 Few studies show significant improvement in clinical pulmonary function with routine use of bronchodilator therapy. Long-term use of β agonists should be approached with caution, because animal studies have shown submucosal gland hypertrophy and a possible hypersecretory state with prolonged use, although no human studies have duplicated this finding.80 Salmeterol, a long-acting β agonist, is effective in decreasing nocturnal hypoxia in patients with CF.81 Hypertonic saline, either a 6% or a 3% solution, has been shown to reduce sputum viscoelasticity and to increase cough clearance in CF patients.82

Dornase alfa (recombinant human deoxyribonuclease I; Pulmozyme) in addition to hypertonic saline is believed to improve mucociliary clearance by hydrolyzing extracellular DNA, which is present at high levels in CF patients. Improved lung function has been noted with the use of this drug. In a multicenter placebo-controlled study, patients treated with dornase alfa had a 12.4% improvement in FEV1 above baseline and a 2.1% increase compared with those receiving placebo (P < 0.01).83,84 Side effects of dornase alfa include hoarseness, changes in phonation, and mild pharyngitis.5 A mucolytic agent such as N-acetylcysteine (NAC) can be used for airway clearance, although few data exist to support the use of NAC.85 Given its unpleasant side effects, including noxious odor and potential for bronchospasm, NAC has a limited role in CF.

Airway Clearance

Airway clearance techniques should be routinely performed on a daily basis by all CF patients86 before eating, and usually bronchodilators are used during or before airway clearance treatment. Inhaled corticosteroids and antibiotics should usually be reserved until the airway clearance technique is completed so that airways have fewer secretions, allowing greater penetration of medications. In selecting a particular treatment, the patient's age, preference, and lifestyle should be taken into account, because no one technique is superior.

Chest physiotherapy consisting of chest percussion and postural drainage (chest clapping) is the primary method of secretion clearance. The patient is usually positioned so that gravity assists in draining mucus from areas of the lung while avoiding the head-down position. Using cupped hands or a clapping device, the chest wall is vibrated or percussed to clear mucus. The therapy can be used on patients of all ages and can be concentrated in certain areas of the lungs that need more attention. Usually, an additional caregiver is needed to provide this treatment, but patients who are independent may be able to perform their own percussion on the front and sides of the chest.87 Assisting the cough of a CF patient through external application of pressure to the epigastric or thoracic cage can assist in the clearance.87

A forced exhalation, or huff, during mid or low lung volumes can improve mucus clearance. A technique called forced expiration consists of two huffs followed by relaxed breathing. Unlike postural drainage, the active cycle of breathing treatment improves lung function without decreasing oxygenation and does not need an assistant.88 This airway clearance technique is a combination of breathing control, thoracic expansion, and the forced expiration technique. It improves oxygen delivery to the alveoli and distal airways and promotes clearance of mucus to the proximal airways, to be cleared by huffing.89

Autogenic drainage is a method of breathing performed at three different lung volumes to augment airflow in the different divisions of the airways. Air needs to be moved in rapidly to unstick mucus and avoid airway collapse. No desaturations occur during this technique, but it does require concentration and might not be appropriate for young CF patients.88

The application of positive expiratory pressure (PEP) by mechanical ventilation or by intermittent positive pressure breathing devices can assist in airway collapse in CF. Bronchiectasis resulting in wall weakness can lead to collapse and retained secretions. Low-pressure PEP, high-pressure PEP, and oscillation PEP are three methods to help reduce airway collapse, all using a device that provides expiratory lengthening and manometric measurements at the mouth.87 Oscillating PEP can enhance clearance of secretions in a way that is relatively easy for the patient. It is low cost, and it is easily movable.90

High-frequency chest wall compression is performed using a compression vest that allows therapy to large chest-wall areas simultaneously. No assistance is needed with this therapy, and it may be ideal for the independent CF patient.91

Intrapulmonary percussive ventilation provides frequent, small, low-pressure breaths to the airways in an oscillatory manner. This method is limited by its high cost and lack of portability, but unlike some other devices it can be used to deliver medications.78

The effect of exercise in CF is not clear. Whether it enhances mucus clearance is debatable, but quality of life improves and there is a lower mortality rate among CF patients who exercise regularly.78 Regular exercise enhances cardiovascular fitness, improves functional capacity, and improves quality of life; therefore, exercise should be advocated strongly in the adult CF patient.5

Some of the contraindications to airway therapy include poorly controlled reflux disease, massive hemoptysis, and the presence of an untreated pneumothorax.

Antibiotics

Improved antibiotics against bacterial infections, especially P. aeruginosa, have resulted in an increased life span for the CF patient. The aim of CF therapy should be prevention of bacterial lung infections. Environmental hygiene measures, including cohorting patients according to infection status, can limit cross-reaction.92 The most important bacterial organisms in CF are S. aureus, P. aeruginosa, and B. cepacia, but others have also emerged including S. maltophilia, Achromobacter xylosoxidans, and nontuberculous bacteria.93 Intravenous antibiotics are the mainstay of therapy for acute exacerbations. The choice of antibiotic is difficult in CF because of resistance patterns; therefore, the choice should be based on the most recent sensitivities of the surveillance sputum cultures. If a recent culture is not available, antibiotic coverage should include treatment for both Staphylococcus and Pseudomonas species. Most centers typically choose a third-generation cephalosporin and an aminoglycoside, given for 2 to 3 weeks intravenously at higher doses because of the volume of distribution in CF patients.

Inhaled antibiotic aerosols can effectively minimize toxicity and allow certain aminoglycosides to be administered at ome. Limiting factors include cost, taste, and distribution in severe disease and acute exacerbations.9 Many CF centers have adopted the Copenhagen Protocol in dealing with infection when, with the first isolation of Pseudomonas species, oral ciprofloxacin and inhaled colistin are started, with intravenous antibiotics given every 4 months to prevent reinfection. Cohorting and environmental and nutritional issues are monitored as well, leading to a significant reduction of chronic infection with Pseudomonas species and better pulmonary function.76

Several large randomized studies have demonstrated a benefit of macrolides in CF patients. The results of these investigations seem to indicate that the immunomodulatory effect of these medications and not the antibacterial effect is responsible for the outcomes of the medication. Experts have suggested using macrolides for 6 months (azithromycin or clarithromycin) in CF children or in adults not improving on conventional therapy.94 Azithromycin has been shown to be highly effective in improving pulmonary function over a 6-month period in CF patients homozygous for ΔF508 and not receiving dornase alfa.95

Other Treatments

In patients with allergic bronchopulmonary aspergillosis or asthma, oral corticosteroids can be used. Although alternate-day steroids have been used in the past for CF exacerbations to reduce airway inflammation, experts agree that this method should be used more cautiously. Ibuprofen has been used as an anti-inflammatory agent, and in one trial lung function declined more slowly in ibuprofen users.96 Other therapies currently undergoing trials include surfactant to reduce sputum adhesiveness, gelsolin to sever F-actin bonds in sputum (thus reducing the tenacity of sputum), and thymosin B 4 to improve sputum transport.76

Lung Transplantation

In advanced lung disease resulting from CF, the options for treatment are limited. Lung transplantation is the only effective therapeutic option not only to prolong survival (1 year survival >80%; 5-year survival, 60%97 ) but also to improve quality of life. The International Lung Transplant Committee issued guidelines in 1998 for the selection of lung transplantation candidates.98 Based on these criteria, CF patients should be referred for transplantation when the FEV1 is less than 30% of predicted, if hypoxia or hypercapnia is present, if hospitalizations increase in frequency, or if hemoptysis or cachexia is an issue (Box 2). Early in the history of lung transplantation, CF patients colonized with B. cepacia were not candidates for transplantation, but recent advances in careful, specific taxonomic testing of B. cepacia have allowed this patient population to be eligible for transplantation at many centers, including our own.99

Box 2: Indications for Lung Transplantation in Cystic Fibrosis
FEV1 predicted < 30%
Rapidly progressive respiratory deterioration
Increasing number of hospital admissions
Massive hemoptysis
Recurrent pneumothorax
PaO 2 < 55 mm Hg
PaCO 2 > 50 mm Hg
Multiresistant organisms
Wasting

Note: Young female patients should be referred earlier due to overall poor prognosis.
Adapted from Boehler A: Update on cystic fibrosis selected aspects related to lung transplantation. Swiss Med Wkly 2003;133:111-117.


Severe liver disease, including portal hypertension, is present in 3% of the CF population. In this population, combined liver and lung transplantation should be considered. Overall survival in combined liver and lung transplantation is 64% at 1 year and 56% after 5 years.100 Patients with severe cachexia and a low body mass index (<18 kg/m2) are at an increased risk of death while on the waiting list for lung transplantation, and interventions for nutritional support should be instituted to prevent further weight loss.101

Pleural adhesion and previous pleurodesis are not contraindications to transplantation. If pleurodesis is indicated, we recommend that it be performed in conjunction with a transplantation center to minimize any complications that can occur at the time of transplantation.

Unstable CF patients requiring mechanical ventilation are not candidates for lung transplantation at any transplant center. Meyers and colleagues reported 1-year outcomes in stable, mechanically ventilated patients who underwent transplantation.102 Currently, only a limited number of centers perform lung transplantation in ventilator-dependent patients.

Recent attention has focused on living lobar transplantation, which involves the removal of a lower lobe from each of two donors and subsequent transplant into a child or small adult.103 Short-term outcomes have been comparable with those using cadaveric transplants. This procedure involves three patients and thus a possible increase in the potential morbidity and mortality, although no donor deaths have been reported.104

For more information on identifying which patients are more likely to benefit from receiving a lung transplant, contact the Cleveland Clinic Foundation Lung Transplant Center or the Cystic Fibrosis Foundation's website. More than 1400 people have received lung transplants since 1988.6

Nutritional Care and Supplementation

CF patients should eat a well-balanced diet (a standard North American diet with 35%-40% fat calories) without fat restriction, always given with enteric-coated pancreatic enzymes. Anthropomorphic measurements should be made every 3 to 4 months, and CF patients should be educated regarding their ideal body weight range. Annual complete blood cell count, albumin, retinol, and tocopherol measurements are recommended. Pancreatic enzymes should be given with each meal and snack, along with vitamin A 10,000 IU/day, vitamin E 200-400 IU/day, vitamin D 400-800 IU/day with adequate sunlight exposure, and vitamin K 2.5 to 5.0 mg/week. If the body mass index decreases, enteral feeding should be considered through gastrostomy tubes or jejunostomy tubes.

For CF patients with partial obstructions or distal intestinal obstructive syndrome, early recognition is vital to avoid surgical intervention. In addition, aggressive hydration, addition of pancreatic enzymes, H2 blockers, and agents to thin bowel contents (including the radiographic contrast solution diatrizoate) may be used. Complete obstructions should be treated with enemas, oral mineral oil, and oral polyethylene glycol-3350 solutions.9

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Prognosis

Overall, the life expectancy in CF has risen since the 1980s. Recent figures show the median age of survival increased by 14 years in 2000 compared with figures from 1980; the predicted mean survival age was 31.6 years in 2000.6 In 1990, 30% of patients in the CF Registry were older than 18 years. This has continued to rise: 40.2% of patients in 2002 were older than 18 years. Although overall survival rates have improved, female patients have had consistently poorer survival rates than male CF patients in the age range from 2 to 20 years. It is not clear why this is the case.105

Lung function predictions over time are difficult to estimate, but CF patients often have extended periods of stabilized lung function that can last for 5 years or more. Most patients have full-time or part-time jobs, and many are married and have children. In the patient registry,6 more than 185 women who had CF were pregnant in 2002.8

Many patients have normal life spans, and end-of-life options need to be addressed with patients and their families. Advance-care planning should be done early in the disease course. The goal of advance-care planning is to respect the patient's wishes.5

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Summary

  • CF is the most common autosomal recessive, life-limiting disease among the white population.
  • With current management, almost 80% of patients with CF will reach adulthood. The delivery of health care to the adult CF patient has thus become relevant to the nonpediatric physician.
  • CF is caused by a defective gene that causes the body to produce an abnormally thick, sticky mucus that leads to airway obstruction, subsequent life-threatening lung infections, and end-stage lung disease.
  • CF is an autosomal recessive trait; the most common mutation in the CFTR gene is caused by the deletion of phenylalanine at position 508 (ΔF508).
  • Newborn screening for CF has been instituted in eight states, although national screening plans have not been mandated.
  • The most profound changes from CF occur in the lungs and airways, where chronic infections involve a limited number of organisms including P. aeruginosa, which is implicated most often, followed by S. aureus, H. influenzae, and S. maltophilia.
  • Gastrointestinal symptoms in CF occur early and continue throughout the life of a CF patient. Problems include intestinal obstruction and various aspects of pancreatic insufficiency.
  • Female patients with CF are not as infertile as their male counterparts, and birth control must be discussed with female patients reaching sexual maturity.
  • The Cystic Fibrosis Foundation has guidelines to help guide the care of patients with this complex disease.

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Suggested Readings

  • Elborn JS. How can we prevent multisystem complications of cystic fibrosis? Sem Res Crit Care Med. 2007, 28: 303-311.

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