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Table of Contents

Published June 29, 2005

Marie M.
Budev, DO

Department of
Pulmonary and
Critical Care
Medicine

Atul C. Mehta, MD

Department of
Pulmonary and
Critical Care
Medicine

Cystic fibrosis (CF) is the most common, classic mendelian autosomal recessive, life-limiting disease among the Caucasian population.^1,2 It is a multisystem disease that results from loss of function in the cystic fibrosis transmembrane conductance regulator (CFTR) gene, classically leading to respiratory tract, gastrointestinal, pancreatic, and reproductive abnormalities.² Cystic fibrosis was recognized as a distinct clinical entity in 1938 and was thought to be invariably fatal during infancy.³ Over the last 30 years, the life span of CF patients has been prolonged, with advances in early diagnosis (eg, newborn screening); care (ie, meconium ileus management, methods for sputum clearance and for managing respiratory failure); and disease therapy (ie, improved antibiotics including the use of macrolides, better pancreatic enzymes). With current management, almost 80% of patients with CF will reach adulthood, further highlighting the fact that 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

In addition, a range of comorbid conditions that are more prevalent in adult CF patients are 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

The delivery of health care to the adult CF patient has thus become 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 (CFF).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 the delivery of optimum care, access to pertinent medical resources, coordination of care among specialists and primary care providers, and a strong stress on independence and improving the quality of life of the patient who has CF.⁵ The adult physician is also faced with another challenge, in which the adult CF patient may present with atypical features that may have gone unrecognized. In this chapter, we will 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

Prevalence

Pathophysiology

Diagnosis

Therapy

Summary

References

Cystic fibrosis 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 and subsequent life-threatening lung infections and endstage lung disease and bronchiectasis (Figure 1). These thick secretions also obstruct the pancreas, preventing digestive enzymes from reaching the intestines leading to pancreatic insuffiency, malabsorption, and in extreme cases malnutrition.

Race
Cystic fibrosis is a disease that occurs predominantly in the white population, with a rate of one in 2,500 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. Cystic fibrosis 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 from northern and central European ancestry or of Ashkenazi Jewish descent, and 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 gastrointestinal issues, including poor nutritional status.¹⁰ There are currently more than 23,000 patients with CF in the United States.⁶

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

Cystic fibrosis is an autosomal recessive trait caused by mutations at a single gene locus on the long arm of chromosome 7. The gene product (CFTR) is a 1480-amino acid polypeptide.^16,17 Cystic fibrosis 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 1,000 mutations of the CFTR gene have been described to date.¹⁹ The most common mutations of CFTR can be classified into six groups based on their known functional consequences.²⁰ This classification allows for categorization of CFTR mutations based on molecular mechanisms, but phenotypic appearance depends on the type of mutation (ie, 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 the deletion of phenylalanine at position 508 (DF508, or delta-F508) and occurs with varying frequency in different ethnic groups.²² Worldwide, this allele is responsible for approximately 66% of all CF chromosomes.²³

Screening
Of the 1,000 or more infants born yearly with CF, most are diagnosed at a mean age of 3 to 4 years.²⁴ Of note, nearly 10% of CF cases are diagnosed in individuals older that 18 years. Newborn screening for cystic fibrosis has been instituted in eight states, although national screening plans have not been mandated. In all, 10% of affected infants in the United States are diagnosed at birth 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 identification of asymptomatic patients in an effort 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 DF508.²⁶ DF508 is the most commonly reported gene mutation and is responsible for 70% of the mutated alleles in Caucasian individuals. 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 (1) adults with a family history of CF, (2) reproductive partners of individuals with cystic fibrosis, (3) couples in whom one or both individuals are Caucasian (including Ashkenazi Jewish persons) and are planning pregnancy, and
• Screening should be made available to non-Caucasian or Ashkenazi-Jewish individuals or couples.

The efficacy of CF screening program is based on a multitude of factors. One factor that is important in a prenatal screening program is to identify the CF carrier status of each partner in an effort 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:

1. The female is screened first, and if positive for CF carrier status, then the partner is tested, or
2. Screening both male and female at the same time in an effort to utilize time efficiently for decision making, especially if more than one recessive disorder is being considered.

Important information to discuss with patients prior to screening include:

1. 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
2. The recognition of individual values.²⁹

Carrier screening neither detects all mutations that could be present nor estimates the residual risk (the chance that the individual still carries a copy of a CFTR mutation despite negative testing). Again, CF is an autosomal recessive disorder, and individuals with CF will 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 an offspring with CF or have been recently diagnosed as 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 individuals undergo prenatal testing for decision making in deciding to terminate or continue the pregnancy.

Respiratory Inflammation and Infections
Since 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 secretory cells, sinuses, lungs, pancreas, liver, or reproductive tract in CF. 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 lung 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 cystic fibrosis are first infected with Staphylococcus and Haemophilus species and later with Pseudomonas species. Several theories have been proposed to provide an explanation for 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 which proposes that CF airway cells have properties similar to those of sweat glands that inactivate substances called defensins, leading to bacterial multiplication and infections. But the preceding theories do not explain the presence of mucoid S aureus or mucoid-type P aeruginosa. The "isotonic fluid depletion/anoxic theory" proposes that a water/volume-depleted airway fluid exists that leads to mucus viscosity, subsequent defective ciliary clearance, and an inadequate cough to clear the airways. Thus, bacteria in the CF lung are trapped within this thick 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 Of certainty is that a neutrophil-dominated airway inflammation is 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 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, a nihilistic perception was associated with this organism in terms of poor clinical outcomes, but now it has been recognized that outcomes may 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 Rarely will patients 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 will usually return to normal after resolution of an acute exacerbation. 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 that 50% of end-stage CF lung on autopsy studies.⁴¹ Subpleural cysts often occur in the upper lobes and may 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 presenting 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. If diagnosed at an older age, these patients often do not have the underlying pancreatic insufficiency that is typical of the younger patient with classic CF. Adults diagnosed with CF 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, with most patients suffering 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 sleep and hypoventilation, have also been described in CF patients.⁴⁸

Gastrointestinal Tract
Gastrointestinal symptoms in CF present early and continue throughout the life span of a CF patient. Because of defects in CFTR, meconium ileus may 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 pancreatic enzyme use and dietary indiscretion without appropriate enzyme use.⁹ CF patients with obstruction may present with abdominal pain and often a palpable mass in the right lower quadrant on physical examination. Associated symptoms may include anorexia, nausea, vomiting, and obstipation. As more frequent events occur, adhesions may develop due to inflammation, leading to a mechanically dysfunctional intestine that may need eventual surgical resection.

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

Pancreatic insufficiency is present in 90% of patients with CF. It is thought to be related to reduced volumes of pancreatic secretions and reduced concentrations of bicarbonate excretion. As a result, digestive proenzymes are retained with the pancreatic duct and lead to tissue organ destruction and fibrosis. As a result, lipids and fat-soluble vitamins (D, E, K, and A) are malabsorbed, which may eventually lead to a hypermetabolic state and increased endobronchial infections, since an inverse relationship has been shown to exist 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 DF508 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 deficiency 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 finally because of glucocorticoid therapy.⁵⁴

Reproduction/Fertility
Since many more CF patients are surviving into their 40s, issues of family and children have gained more attention. Most males with CF are infertile because of aspermia secondary to atretic or bilateral absence of the vas deferens and/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. Females with CF 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. But overall, females 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 females 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 it is the decline of lung function and the absolute value of the FEV₁ that may be more important in determining fetal outcome.^58,59 One study by Canny et al recommended an FEV₁ of >70% as a requirement for a successful pregnancy outcome.⁵⁹ Normal lung function will lead to a normal pregnancy. Women with poor lung function may have worsening of their pulmonary status during pregnancy but this is still debated. Termination of pregnancy has been recommended if the FEV₁ is <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 or maternal complications, or by chance itself.⁵⁷

Vaginal yeast infections and urinary incontinence have now become a major issue 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 may 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 to 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. It is recognized in the sweat duct CFTR is the only channel by which chloride can be reabsorbed from sweat.^63,64

In 1998, a consensus statement¹ was issued by the Cystic Fibrosis Foundation regarding the diagnosis of CF.¹ It was the consensus of the panel that the diagnosis of CF 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, either by an abnormal sweat chloride test, identification of mutations in a gene known to cause CR, or in vivo demonstration of an ion transport abnormality across the nasal epithelium (Figure 2). 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 may 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 (at least 50 mg of sweat) must be collected during a 30-minute period to ensure an average sweat rate of 1 g/m²/min, 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 will 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 (ie, 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 may yield a false-negative result. Overall, testing using this method is complicated and time consuming.⁶⁵

Genotyping
Because of the more than 1,000 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 patient allocation 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 hallmark of CF is pancreatic insufficiency and malabsorption, which may 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 with obstructive azoospermia confirmed with testicular biopsy, CF should be strongly considered although other diseases, such as Young's syndrome, can cause both 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) may 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 may 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

Gene Therapy
The ultimate 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 in the last decade. In addition, protein modification is based on the concept that the abnormal CFTR protein can be "taught" to transport water and electrolytes. The CFTR DF508 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, may 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 CF Foundation has developed guidelines to help guide the care of patients with this complex disease (Table 2).¹

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 will occur at larger lung volumes. CF usually produces an obstructive pattern on spirometry, but if a restrictive pattern is present, substantial gas trapping may exist. 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 <30% of predicted are at higher risk of nocturnal hypoxia and hypercapnia, and evaluation for nocturnal desaturation should be sought. 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. Yearly 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 yearly. In addition, if bronchiectasis is suspected, high-resolution computed tomography is indicated (Figure 2).⁷⁸

Inhaled bronchodilators, specifically beta agonists, can be administered by nebulization, metered-dose inhalers, or orally 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 beta agonists should be approached with caution, since 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 beta 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 thought 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 techniques should be routinely performed on a daily basis by all CF patients⁸⁶ prior to 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, since 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 provide mucus clearance. The therapy can be used on patients of all ages or be concentrated in certain areas of the lung 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 pressure to the epigastric or thoracic cage may assist the cough clearance.⁸⁷

Also, a forced exhalation, or "huff," during mid or low lung volumes may improve mucus clearance. A technique called the "forced expiration technique" 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 may 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 may assist in airway collapse in CF. Bronchiectasis resulting in wall weakness may lead to collapse and retained secretions. The application of PEP by either low-pressure PEP, high-pressure PEP, or 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 Another technique, high-frequency chest wall compression, is performed using a compression vest that allows for 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 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.

The improvement in 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 the prevention of bacterial lung infections. Environmental hygienic measures, including cohorting hygienic measures where patients are placed into separate subgroups according to infection status, may limit cross-reaction.⁹² The most important bacterial organisms in CF are S aureus, P aeruginosa, and B cepacia, but others have also emerged over that past few years including Stenotrophomonas 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 for the home administration of certain aminoglycosides. Limiting factors in their use include cost, taste, and distribution in severe disease and acute exacerbations.⁹ Many CF centers have adopted the "Copenhagen Protocol" in dealing with infection where, 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

There have been several large randomized studies demonstrating the use of macrolides in benefiting 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 DF508 and not receiving dornase alfa.⁹⁵

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 showed a slower decline in lung function in 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% and 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 <30% of predicted, if hypoxia or hypercapnia is present, or if hospitalizations increasing in frequency or hemoptysis, or cachexia are an issue (Table 3). 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 now eligible for transplantation at many centers, including our own.⁹⁹

Severe liver disease, including portal hypertension, is present in 3% of the CF population. In this population, combined liver/lung transplantation should be considered. Overall survival in combined liver/lung transplantation is 64% at 1 year and 56% after 5 years.¹⁰⁰ Patients who are severely cachectic and have a low body mass index of <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 for transplantation. If pleurodesis is indicated, we recommend that it be performed in conjunction with a transplantation center such as ours to minimize any complications that may occur at the time of transplantation. Unstable CF patients requiring mechanical ventilation are not candidates for lung transplantation at any transplant center. Meyers et al 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 to those using cadaveric transplants. Noteworthy is that this procedure involves three patients and thus a possible increase in the potential morbidity and mortality, although no donor deaths have been reported as yet.¹⁰⁴

For more information in 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 web site. To date, more than 1,400 people have received lung transplants since 1988.⁶

Nutritional Care and Supplementation
CF patients should have 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 should be 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/wk. 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 the need for surgical intervention. In addition, aggressive hydration, addition of pancreatic enzymes, H₂ blockers, and the use of agents to thin bowel contents (including the radiographic contrast solution diatrizoate) can be used. Complete obstructions should be treated with enemas, mineral oil ingestion, and polyethylene glycol-3350 oral solutions.⁹

Overall, the life expectancy in CF has risen in the last two decades, with recent figures showing the median age of survival increased by 14 years in 2000 compared to figures from two decades ago with a predicted survival age of 31.6 years.⁶ In 1990, 30% of patients in the CF Registry were more than 18 years old. This has continued to rise: 40.2% of patients in 2002 were over the age of 18. 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 may last for half a decade 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 cystic fibrosis were pregnant in 2002.⁸ But despite advances in therapies for CF, patients many times do have a normal lifespan, 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

Return to Medicine Index

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