David M. Orenstein
EPIDEMIOLOGY
Cystic fibrosis (CF) is inherited as an autosomal recessive disorder. It is most common in those of northern European descent, with an incidence of approximately 1 in every 3200 live births. It is seen in about 1 in every 17,000 births in African Americans and is much less common in Asian populations. It has been found in virtually every ethnic and racial group. Approximately 4% of whites are heterozygous for CF (ie, carry one CF allele); heterozygotes have no evidence of clinical disease.
PATHOPHYSIOLOGY AND GENETICS
CF affects virtually every organ system with epithelial surfaces—most importantly, the lungs, pancreas, intestinal mucus glands, liver, the reproductive tracts, and sweat glands. A common pathogenetic mechanism in major target systems is abnormal ion transport across epithelial surfaces. Impermeable chloride channels and over-active sodium pumps of these epithelial cells lead to biochemical and bioelectric abnormalities within organ lumina, leading in turn to viscid intralumenal secretions in the affected organs. These abnormally viscous secretions cause the blockage of ducts and air passages.
The most common mutation in the CF gene is a three-base-pair deletion that leads to the loss of a single phenylalanine at position 508 of the protein product (“ΔF508”).4 The ΔF508 mutation accounts for 70% to 80% of CF chromosomes; about 50% of CF patients in North America are homozygous for this mutation. More than 1500 other mutations at the CF locus have been discovered, but these account for only a small percentage of CF cases. In a few ethnic groups, a small number of mutations account for a large proportion of CF cases (Table 514-1). Prenatal testing and carrier testing can be accomplished in virtually every family desiring this information.
Table 514-1. Characteristics of Various CFTR Mutations
The gene for CF is on the long arm of chromosome 7 and spans 250 kb. Its product is a 1480–amino acid protein that regulates transmembrane ion transport.4 It serves as the most important apical membrane chloride channel and influences sodium and water transport across epithelial cells of many organs and glands.2,3 Because of this functional role, both the protein product and the gene itself are called cystic fibrosis transmembrane conductance regulator (CFTR). The gene is transcribed into mRNA, which is translated into protein in the endoplasmic reticulum (Fig. 514-1). Then, the CFTR protein is glycosylated in the Golgi apparatus and folded into a configuration that allows it to travel through the cytoplasm to the apical surface of epithelial cells. Once it resides in the apical membrane, it must have appropriate regulation, in that it must be able to respond to regulatory molecules. Finally, normal conductance of chloride and other ions depends on the channel remaining open for the appropriate time. CFTR mutations can be classified according to which step in this sequence of events is defective (Fig. 514-1).
FIGURE 514-1. Molecular consequences of cystic fibrosis transmembrane conductance regulator (CFTR) mutations.
The ion transport abnormalities result in diminished amounts of airway surface liquid and therefore interfere with clearance of airway mucus, resulting in the airway problems common to patients with CF.3There does seem to be a genotype-phenotype correlation for pancreatic status, with most CF genotypes, notably homozygosity for the ΔF508 mutation, associated with pancreatic insufficiency and a few alleles apparently conferring pancreatic sufficiency. Very few CF alleles appear to be associated with a delayed onset and slower progression of pulmonary disease, but by and large, genotype-phenotype relations for CF lung disease and survival have eluded discovery.2 Characteristics of some of the most common CFTR mutations are listed in Table 514-1. Because there is substantial phenotypic variation within the population of ΔF508 homozygotes, it is thought that there are genes other than CFTR that can modify the phenotypic expression of CF. Evidence for the existence of these modifier genes includes the observations that monozygotic twins have closer concordance of their clinical disease than do dizygotic twins. Variant alleles for both transforming growth factor β (TGF-β) and mannose binding lectin (MBL) have been associated with more rapid decline in lung function.5
CLINICAL FEATURES
Gastrointestinal Tract
The typical cystic fibrosis (CF) patient has exocrine pancreatic insufficiency, with maldigestion of fats and protein and consequent malabsorption, steatorrhea, and failure to thrive.6 Pancreatic insufficiency is present at birth in 50% of CF patients and develops by age 9 years in another 35% to 40%.6 This is important to keep in mind, since the diagnosis of CF is often delayed or missed in patients without typical gastrointestinal involvement. Pancreatic status is determined in large part by genetic factors, as certain genotypes (eg, ΔF508) are nearly always associated with pancreatic insufficiency, while others confer pancreatic sufficiency (Table 514-1).
Bowel obstruction, a result of thickened intestinal mucus and pancreatic insufficiency, is present at birth (meconium ileus) in 10% to 20% of patients, especially those who are ΔF508 homozygotes. Later in life, distal intestinal obstruction syndrome (DIOS) occurs in 20% to 25% of affected individuals. Rectal prolapse, caused by bowel obstruction and by malnutrition with loss of anal sling musculature, is seen in 20% of CF patients in the first years of life. Intussusception is much less common, but CF patients account for a substantial portion of all patients with intussusception after 1 year of age. Gastroesophageal reflux, which may complicate the pulmonary disease, interfere with nutrition, or both, occurs with increased frequency in infants (and older children) with CF. Reflux may be worsened, especially in infants, by head-down positioning for chest physical therapy. Acid peptic disease can result from gastric acid hypersecretion and deficient pancreatic bicarbonate secretion. Cholelithiasis is more common in CF than healthy control populations. Liver pathology, including nonspecific steatosis; cholestasis; and the specific lesion, focal biliary cirrhosis, occurs in up to 10% of infants and children with CF. However, the clinical manifestation of cirrhosis with hepatic failure or portal hypertension with hypersplenism, bleeding esophageal varices, or both, is much less common. These hepatic complications present most commonly in the first decade and a half and seem not to be increasing in incidence as life span has increased. Children or adults, particularly those with normal exocrine pancreatic function, may develop recurrent episodes of acute pancreatitis. Endocrine pancreas dysfunction also can occur, leading to carbohydrate intolerance and diabetes mellitus that is unassociated with ketoacidosis.
Sweat Glands
The epithelial ion transport defect is expressed in the sweat glands, leading to the high salt content of CF sweat, long recognized as a hallmark of this disorder. In patients without CF, sweat precursor fluid is isotonic to plasma, and as the fluid moves through the sweat apparatus toward the skin, chloride is reabsorbed, with sodium following to maintain electrical neutrality. This results in sweat on the skin surface that is hypotonic to plasma and usually has sodium and chloride concentrations below 40 meq/L. In CF, the absent or poorly functioning cystic fibrosis transmembrane conductance regulator (CFTR) chloride channel makes chloride reabsorption substantially below normal.2,7 The resultant fluid that emerges as sweat has sodium and chloride concentrations greater than 60 meq/L. This ion transport defect in the sweat apparatus provides the basis for the sweat test (discussed under “Diagnosis”). CF patients lose more salt during exercise in the heat and during febrile illnesses than do persons without CF, and they may experience dehydration or heat prostration. Infants may develop hyponatremia and hypochloremia. For unknown reasons, African American infants with CF seem to be at greater risk for this complication than Caucasian infants.6
Respiratory Tract
The upper respiratory tract is involved in virtually all cystic fibrosis (CF) patients, with radiographic evidence of pansinusitis. This is much more evident radiographically than symptomatically.6 It occasionally is helpful diagnostically (particularly in childhood), because persistent pansinusitis is uncommon except in CF, and CF is extremely uncommon without pansinusitis. Nasal polyps may be found in as many as 25% of CF patients and may be recurrent. Indeed, the finding of large nasal polyps in children less than 12 years of age should prompt the clinician to consider CF.
The lower respiratory tract involvement in CF accounts for over 90% of the morbidity and mortality. Although the lungs are histologically and radiographically normal at birth, the respiratory epithelium is abnormal electrophysiologically, leading to obstruction of small airways by viscid mucus, by airway inflammation, and by recurrent endobronchial infection, which typifies the disease.2,3 Invading organisms and inflammatory cells release inflammatory mediators and leave behind large amounts of DNA when the cells lyse, adding further to viscosity of lung mucus. Because of these factors, obstructive pulmonary disease, beginning in the small airways, eventually is present in almost all patients with CF. Recurrent cough, wheeze, or both, which may be diagnosed initially as recurrent bronchiolitis, asthma, or pneumonia, are often the first indications of pulmonary involvement. As the disease progresses, hyperinflation and crackles become apparent, and diffuse bronchiectasis eventually develops.
Pulmonary function tests reveal a pattern of obstructive airway disease: decreased forced expiratory volume in 1 second, decreased peak expiratory flow, and increased residual volume, indicative of air trapping. These obstructive changes show varying responses to bronchodilator inhalation: some patients improve, whereas many do not change, and a few actually worsen, because bronchiectatic airways may require bronchoconstrictor tone to remain stable. The response to bronchodilators is not consistent over time. Exercise testing6 typically shows reduced exercise tolerance and fitness, with relatively high minute ventilation for the oxygen consumed, presumably because of greater-than-normal dead-space ventilation. Often, a higher-than-normal proportion of the ventila-tory capacity is required at peak workloads. Male patients have greater exercise tolerance and cardiopulmonary fitness than female subjects. The pulmonary function and exercise tests are relatively sensitive tools for following progression of disease in the older, cooperative child (see Chapter 503).
Chronic pulmonary infection and inflammation, with episodes of acute exacerbation, are typical of CF patients.6,8 The chronic and acute conditions are most accurately thought of as purulent bronchiolitis and bronchitis. Exacerbations are characterized by increased cough, often producing purulent sputum, particularly in the morning on arising and with exertion; decreased exercise tolerance; lethargy; malaise; and weight loss. Fever is often absent. In the early stages of the disease, the bacterial organisms most commonly colonizing the lower respiratory tract of patients with CF include Staphylococcus aureus, Hemophilus influenzae, and a variety of gram-negative organisms. Eventually, most patients permanently acquire Pseudomonas aeruginosa and related gram-negative organisms, many of which become resistant to conventional antibiotic therapy. Increasing numbers of patients have Pseudomonasspecies at diagnosis; whether this represents a true increase in prevalence or represents better microbiology laboratory performance is uncertain. There seems to be a unique relationship between CF patients and Pseudomonas; at least half of all CF patients are colonized with a peculiar mucoid strain of this organism that is seldom seen in other human disease states. Some studies have suggested that early colonization of the respiratory tract with Pseudomonas is an independent risk factor for progressive pulmonary disease. Recently, other organisms, such as Aspergillus fumigatus, Burkholderia cepacia, Alcaligenes (Achromobacter) xylosoxidans, and Stenotrophomonas maltophilia, have become increasingly important as pulmonary pathogens.
Progression of CF Lung Disease2,3,6,8
The rate of lung disease progression varies widely among individuals, influenced in part by environmental factors; secondhand cigarette smoke, lower socioeconomic status,9 and recurrent viral infection are three proven factors associated with worse pulmonary prognosis.
The initial histological lesion is bronchiolitis, reflected physiologically as small airways obstruction and radiographically as overinflation and prominent bronchial markings (eFig. 514.1 ). Further worsening of the lung disease includes extension from bronchiolitis to bronchitis, with thickened bronchial walls demonstrable on radiographs as circular lesions if the bronchi are projected in cross section or as characteristic parallel linear opacities (“tram tracks”) if the bronchi are projected longitudinally. With further progression and the development of bronchiectasis and small cysts, rounded densities become evident on radiographs. The right upper lobe is commonly affected earlier and more severely than other lobes (eFig. 514.2 ). With more advanced disease, small abnormal areas coalesce to form larger cysts (which may be dense when filled with mucopurulent secretions or may be lucent when relatively empty) and regions of fibrosis. Enlarged tortuous bronchial arteries may contribute to the opacities visible on chest radiographs and may also lead to hemoptysis. Large apical blebs may form and rupture, leading to pneumothorax (eFig. 514.3 ).
Pulmonary complications include chest pain, pneumothorax, hemoptysis, segmental and lobar atelectasis, pulmonary hypertension leading to cor pulmonale, and respiratory failure (see the “Treatment of Pulmonary Complications” section). Digital clubbing is a nearly universal finding in patients with even mildly abnormal lung function.
Reproductive System
The reproductive tract is involved in most male patients, with atresia of the vas deferens and consequent obstructive azoospermia and sterility. However, male CF patients can produce children through in vitro methods. In female patients, thick cervical mucus often results in decreased fertility. Delayed puberty may be seen in either sex as a consequence of chronic illness and poor nutrition.
Impaired Glucose Tolerance and Diabetes
Some teens and adults with CF show an impaired insulin response, characterized initially by an impaired first-phase insulin response, then by a delayed and reduced peak insulin response. Decreased insulin sensitivity (insulin resistance) may also be present in patients with CF. Insulin is the only currently recommended therapy for all types of CF-related diabetes, and many clinicians find that basal/bolus regimens are optimal. Adolescents and adults display a unique pattern of hyperglycemia. Abnormal glucose tolerance tests are frequent, but diabetic ketoacidosis is rare, and microvascular complications of diabetes are less frequent. With improved survival, microvascular diabetic complications are likely to be seen more frequently.
Bone Complications
Patients with CF, especially those who are older, have a higher incidence of bone fracture caused by decreased bone density. This may be secondary to malabsorption of vitamin D and calcium, hypogonadism, inactivity, or cytokines from chronic infection. Contemporary management with appropriate vitamin and nutritional supplementation likely limits this complication. Exercise during childhood may be helpful. Occasional patients, particularly those with severe lung disease, have hyper-trophic pulmonary osteoarthropathy involving the long bones and adjacent joints. This complication is characterized clinically by joint (especially knee) pain and radiographically by periostial thickening. A systemic vasculitis syndrome with arthritis and a vasculitic skin rash has also been described in CF patients.
DIAGNOSIS
The key to diagnosing cystic fibrosis (CF) is a high index of suspicion in the presence of any of the manifestations. Increasingly, the diagnosis of CF is made by newborn screening, but diagnosis still requires confirmatory evaluation and testing in a specialized CF center. CF is rarely diagnosed without a confirmatory positive sweat test. The accepted criteria for diagnosis of CF are shown in Table 514-2.10
Newborn Screening
Most newborns with CF have an elevation of blood immunoreactive trypsinogen (IRT). The assay for IRT can be carried out from the dried blood spots obtained from newborns for routine screening for other genetic and metabolic diseases. The IRT test is used in more than 30 states and in many countries, and its use is likely to continue spreading. There appear to be very few false negatives with this screen, but the false-positive rate is as high as 90%. Some screening programs move directly to genetic analysis for the most common cystic fibrosis transmembrane conductance regulator (CFTR) mutations in blood spots with elevated IRT, while others repeat the analysis for IRT after one elevated level. If the second test still shows elevated IRT, or if one or two CFTR mutations are identified on DNA analysis, prompt referral to a CF center is indicated for definitive genetic or sweat testing and initiation of comprehensive treatment for those confirmed to have CF.
Table 514-2 Diagnostic Criteria for Cystic Fibrosisa
Sweat Testing
Sweat testing remains the gold standard for diagnosis of CF. Table 514-3 lists the indications for performing a sweat test. Most physicians are sufficiently aware of the disease, so few children with the triad of growth failure, steatorrhea, and chronic pulmonary disease escape diagnosis. However, atypical patients, especially those who have no clinically apparent pancreatic involvement (as many as 15% of all CF patients and as many as 50% of young infants with CF) or who have normal growth may escape diagnosis for years.
Theoretically, the sweat test is simple, but false positives and false negatives are extremely common in tests performed outside established CF centers.7 Contrary to widespread belief, sweat tests can be accomplished in young infants, although some young infants might not produce a large enough volume of sweat for analysis. Concentrations of sodium and chloride in sweat are below 40 meq/L in normals, but nearly all patients with CF have values greater than 60 meq/L. Very few patients fall in the intermediate or borderline range (40–60 meq/L); in these individuals, genotype analysis or measuring nasal potential difference may be required for definitive diagnosis. Patients with intact exocrine pancreatic function have somewhat lower sweat chloride concentrations than those with pancreatic insufficiency, but their values are still well outside the normal range. Table 514-4 lists conditions giving false-positive and false-negative sweat test results.
Nasal Potential Difference
The function of the CFTR protein in respiratory epithelium can also be assessed directly in vivo by measuring the bioelectric voltage difference across nasal epithelium (the “nasal potential difference,” or nasal PD); this is available in a few specialized CF centers.10
Table 514-3 Indications for Sweat Testing
|
Gastrointestinal tract |
|
Chronic diarrhea |
|
Steatorrhea |
|
Meconium ileus |
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Meconium plug syndrome |
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Rectal prolapse |
|
Cirrhosis/portal hypertension |
|
Prolonged neonatal jaundice |
|
Pancreatitis Deficiency of fat-soluble vitamins (especially A, E, K) |
|
Respiratory tract |
|
Upper |
|
Nasal polyps |
|
Pansinusitis on radiographs |
|
Lower |
|
Chronic cough |
|
Recurrent bronchiolits |
|
Recurrent wheezing |
|
Intractable “asthma” |
|
Recurrent or persistent atelectasis |
|
Obstructive pulmonary disease |
|
Pseudomonas aeruginosa (especially mucoid colony types) recovered from throat, sputum, or bronchoscopic cultures |
|
Other |
|
Digital clubbing |
|
Family history of cystic fibrosis |
|
Failure to thrive |
|
Hyponatremic, hypochloremic alkalosis |
|
Heat prostration |
|
“Tastes salty” |
|
Male infertility |
Molecular Diagnosis
Although the sweat test remains the gold standard for confirming the diagnosis of CF, DNA analysis is increasingly used for CF diagnosis. Demonstration of two of the known CFTR mutations in DNA in the appropriate clinical setting is considered definitive for the diagnosis. Until more CF gene mutations can be detected inexpensively, there will be some patients with CF who have one or both unidentified alleles. Therefore, DNA analysis cannot yet definitively rule out CF, nor can it positively identify all CF patients. DNA analysis should be performed in those patients for whom sweat testing is logistically difficult (live far from a CF center) or has yielded equivocal results. DNA analysis for CF is relatively easy for the referring physician: blood, buccal brushings, or chorionic villus samples can be sent by overnight courier to any of several commercial laboratories, with results often available within a week. Most commercial laboratories examine DNA for 25 to 100 of the most common mutations, which together account for more than 95% of all CF patients. Therefore, results must be interpreted with caution. For example, an individual may be found to have one abnormal cystic fibrosis allele and one unknown allele. This second allele may be normal, and the person is a CF carrier, or it may be one of the mutations that are not included in the laboratory’s panel, and the person has the disease. In the event of such a result (one CF allele and one “negative”), the physician should seek the advice of an individual who is experienced in the genetics of cystic fibrosis. Some labs can now sequence the entire CFTR gene and therefore minimize the likelihood of missing a mutation.
Table 514-4 Conditions Giving False-Positive and False-Negative Sweat Test Results
|
False positive (> 60 meq/L) |
|
Laboratory error |
|
Adrenal insufficiency syndromes |
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Anorexia nervosa |
|
Ectodermal dysplasia |
|
Familial cholestasis (Byler syndrome) |
|
Fucosidosis |
|
Glycogen storage disease (type 1) |
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Hypoparathyroidism |
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Hypothyroidism |
|
Malnutrition |
|
Mauriac syndrome |
|
Mucopolysaccharidoses |
|
Munchausen by proxy syndrome (addition of table salt to seat sample) |
|
Nephrogenic diabetes insipidus |
|
False negative (< 40 meq/L) |
|
Laboratory error |
|
Edema, hypoproteinemia |
|
Rare cystic fibrosis mutations |
GENERAL APPROACH TO TREATMENT
Cystic fibrosis (CF) is a complex disease, and patients require a comprehensive evidence-based approach. Recent studies demonstrate unequivocally that the early diagnosis of CF and the institution of an aggressive treatment program can improve the quality and length of life. This is usually best carried out in, or at least coordinated by, a center that specializes in diagnosing and treating CF and that has different specialists focusing on cystic fibrosis. Survival is greater for patients followed in CF centers than for those followed outside centers. Patients who are treated aggressively in CF centers that see their patients more frequently, do more intensive monitoring, and use more antibiotics have better outcomes than those followed in centers with a less aggressive approach.
Therapy has three primary components: pulmonary; gastrointestinal; and, importantly, social and psychological support for the patient and family.
STRATEGIES FOR PREVENTING PROGRESSION
The goal of pulmonary therapy is to prevent or delay progression of the pulmonary involvement. This is accomplished by relieving airway obstruction and inflammation and by controlling infection.
Therapy to Improve Mucociliary Clearance
Airway clearance therapy (ACT) is the mainstay of all treatment programs in CF patients who have evidence of pulmonary disease. Most patients undergo ACT one to four times daily, with increased frequency at the time of clinical pulmonary exacerbations. Chest physical therapy (CPT) with percussion and postural drainage is the traditional method of ACT and remains the only method appropriate for infants. Beyond infancy, newer methods of airway clearance are available, including the “flutter valve,” Acapella forced expiratory technique (FET), use of forced expiratory efforts into a mask with positive expiratory pressure (PEP masks), or the use of a vibrating vest. Each method has its own proponents. No definitive studies indicate the ideal time for instituting ACT or the benefits of various techniques. Patient acceptance—and therefore adherence to the prescribed treatment—varies from method to method and patient to patient. Bronchoscopy and airway lavage have demonstrated mucus plugs, inflammation, and infection in the airways of even asymptomatic infants, implying that airway-clearance procedures should be instituted very early in life. Head-down positions should probably be avoided during chest physical therapy in infants, as they increase gastroesophageal reflux.
Aerobic exercise (jogging and swimming) are beneficial for CF patients in terms of increased cardiopulmonary fitness (oxygen consumption, VO2) and work capacity. Further, high aerobic fitness is correlated with prolonged survival.11 There is some suggestion that various kinds of exercise may be as effective as traditional CPT in relieving pulmonary obstruction, but studies examining this question have had conflicting results. Therefore, until a definitive study is available, most experts advise the use of both exercise and CPT.
Inhalation-Based Therapy
Various kinds of aerosols have been employed for patients with CF in order to dilate bronchi, reduce mucus viscosity, reduce mucosal edema and inflammation, suppress microbial growth, and perhaps even to correct the epithelial ion transport abnormality. Bronchodilators increase airflow acutely in some patients, make no difference in many, and actually reduce airflow in a few patients with severe disease where smooth muscle relaxation causes airway instability during exhalation. There have been few studies of the effects of long-term bronchodilator aerosol use. Mucolytic agents (eg, N-acetylcysteine) are effective in vitro, but they may cause irritation, bronchoconstriction, and bronchorrhea in vivo. Recombinant human DNase, which can degrade neutrophil-derived DNA and decrease the viscosity of airway secretions, reduces the rate of pulmonary function decline.12 Hypertonic (7%) saline also improves pulmonary function and increases the time between episodes of worsened airway infection, although it is not clear if its benefit is from replacing airway surface liquid that is depleted via the basic ion and water transport defect or simply by stimulating cough. Antibiotics, especially aminoglycosides13 and semisynthetic penicillin derivatives, can be delivered by aerosols, with favorable results.
Anti-inflammatory Therapy
Several approaches have been proposed to reduce airway inflammation in cystic fibrosis. Clinical trials of alternate-day corticosteroid therapy suggest some benefits (improved pulmonary function over a 4-year period) and some drawbacks (decreased growth velocity and possible glucose intolerance).15 Cromolyn sodium has been shown in a small study to be ineffective. Inhaled topical steroids have shown small benefits in a few small studies but may be useful in patients who have clear-cut evidence of asthma. Ibuprofen therapy seems to benefit some patients and decrease the rate of pulmonary decline,16 but the therapeutic index is narrow, and the logistical bother of needing to monitor blood levels, along with fear of side effects, has limited its use.
Treatment of Infection
More aggressive treatment of pulmonary infection is the single most important factor leading to the markedly improved prognosis in CF. Staphylococcus and Hemophilus may occasionally be eliminated from the bronchial tree in CF, and recent evidence suggests that even Pseudomonas might be eradicated if it is treated aggressively (eg, with an oral quinolone and aerosol aminoglycoside) soon after the initial positive throat or sputum culture.17
A variety of antibiotic treatment strategies are employed at CF centers around the world. Some CF centers advocate continuous inhaled or oral prophylactic antibiotic treatment, with additional treatment with intravenous antibiotics for acute exacerbations. There is some concern that this approach might lead to the early emergence of drug-resistant pathogens in the airways. Another approach is to restrict the use of antibiotics to times of exacerbation of pulmonary disease, as evidenced by increased symptoms or signs (such as cough or sputum production) or worsening objective data, such as chest radiograph or pulmonary function test results. Some patients, especially those with advanced disease, suffer exacerbations whenever they are not being treated with antibiotics; in such patients, virtually continuous treatment is indicated. A third approach is to treat with an aggressive course of antibiotics (oral, aerosol, or IV), based on culture results, for 2 to 3 weeks every 1 or 2 months in patients with any evidence of pulmonary disease (morning cough, abnormal x-ray, etc). For example, in some European countries, CF patients whose cultures grow Pseudomonas aeruginosa are hospitalized for 2 weeks of intravenous antibiotics and aggressive chest physiotherapy every 3 months, regardless of their clinical condition. Survival has increased dramatically since the institution of this approach.17 A 6-month trial of alternate-day azithromycin has been shown to increase pulmonary function and lengthen time between infectious exacerbations, but a European study suggested decreased benefit after a year.
An algorithm for the approach to CF lung infection used in one U.S. center is shown in Figure 514-2. Because of the extremely large variation in CF from patient to patient, most centers employ an individualized approach to this issue, which includes a thorough discussion of the risks and benefits of any proposed therapeutic approach.
A cornerstone of most successful treatment programs is frequent comprehensive clinical evaluation of patients, including microbiological examination of respiratory tract flora by a laboratory that is experienced in detecting potential cystic fibrosis pathogens. Oral antibiotics (amoxicillin/clavulanate, cephalexin, trimethoprimsulfamethoxazole, erythromycin, clarithromycin, or azithromycin) at the first sign of worsening respiratory symptoms may successfully treat a pulmonary exacerbation. Some of these drugs (eg, the macrolides, including azithromycin) have anti-inflammatory effects unrelated to their bactericidal effects. The quinolones (eg, ciprofloxacin, ofloxacin, levofloxacin) are a class of oral antibiotics with impressive in vitro activity against Pseudomonas and good penetration into the lung. The quinolones have been useful and apparently safe in children as young as 4 years, although the possibility of quinolone-associated arthropathy must be considered. Linezolid is a relatively new orally administered antibiotic, effective in vitro and clinically against methicillin-resistant Staphylococcus aureus, which has become more common in patients with CF and in the rest of the population. Simultaneous treatment with rifampin may prevent the rapid emergence of resistant organisms, which is otherwise common during treatment with quinolones.
Aerosolized antibiotics, especially tobramycin, may be effective in many patients colonized with Pseudomonas. High endobronchial concentrations of tobramycin can be achieved via the inhaled route that would be impossible to achieve with intravenous dosage. Twice-daily nebulized tobramycin for a month at a time, alternating with a month off treatment, has been shown to improve pulmonary function and lengthen time between infectious exacerbations, without increasing tobramycin-resistant strains of Pseudomonas.13 Patients who cannot tolerate certain drugs (eg, colistin) intravenously may do well with the same drugs delivered by aerosol. In patients with severe airways obstruction, aerosol penetration into the lung may be limited and render this form of treatment less valuable. The sequential use of inhaled bronchodilators or DNase may increase antibiotic deposition.
FIGURE 514-2. Approach to lung infection at one cystic fibrosis center. In each instance of antibiotic use, the choice of antibiotics will be based in part on recent cultures of respiratory tract secretions. If recent cultures are unhelpful, consider adding empiric treatment for Pseudomonas aeruginosa or Staphylococcus aureus, even if these organisms have not been recovered. Also consider performing bronchoscopy and bronchoalveolar lavage to obtain better cultures and to examine the cells recovered for evidence of aspiration (large numbers of lipid-filled macrophages). In addition, consider evaluating or treating empirically for gastroesophageal reflux. AFB, acid fast bacillus; PPD, tuberculin skin test.
Intravenous antibiotics are indicated when the patient does not respond to outpatient oral or aerosol antibiotic therapy. When deciding whether to begin parenteral therapy, an important consideration is whether the child is sicker than his or her own baseline and not whether the child seems dreadfully ill. It is clear that a significant amount of lung can be lost irreversibly while a child still looks reasonably well. Because Pseudomonas aeruginosa is usually the offending organism, intravenous therapy is commonly carried out with an aminoglycoside and a semi-synthetic anti-Pseudomonas penicillin or a third-generation cephalosporin. It is commonly believed that using two or more antibiotics from different classes improves effectiveness and decreases the emergence of antibiotic-resistant organisms, but strong supporting data for this belief are lacking. Intravenous antibiotics are usually administered during hospitalization, but in carefully selected cases, they may successfully be administered at home, either initially or for 1 or 2 weeks following hospitalization. Response to treatment is often slower or absent at home, and the burden on a family of administering two or three different antibiotics on different schedules around the clock should not be underestimated. The most commonly used intravenous antibiotics, dosing schedules, and toxicities are listed in eTable 514.1. Intravenous antibiotic treatment should be continued until the patient’s pulmonary status has reached a plateau, as assessed by patient/parent report, physical examination, oximetry, and spirometry. The time to reach this plateau is usually 2 to 3 weeks but can be longer in sicker patients. Occasionally, the new plateau may be better than the previous level of functioning. At other times, because cystic fibrosis remains a progressive disease, the patient may not regain his or her previous level of functioning. Most patients will be able to maintain levels they achieve during hospitalization for at least a few weeks after discharge, but most will not continue to improve after intravenous antibiotics have been discontinued.
Intravenous antibiotics are usually administered during hospitalization. Studies have shown that the benefits of hospitalization cannot be explained completely by the use of intravenous antibiotics alone. Some patients improve in the hospital even if intravenous antibiotics are not given. Possible benefits of hospitalization include effective and frequent chest physical therapy and aerosol treatments, improved nutritional support, relatively clean air, absence of inhalant hazards and aeroallergens, enforcement of a strict therapeutic regimen, and opportunities for continuing patient education.
TREATMENT OF PULMONARY COMPLICATIONS
Chest Pain
Chest pain is relatively common in cystic fibrosis (CF), particularly in patients with advanced lung disease. If the onset of the pain is abrupt, unilateral, pleuritic, and associated with shortness of breath, the most likely and the most ominous cause is pneumothorax (see below). Other causes of chest pain include pleural inflammation and musculoskeletal strains, especially from prolonged paroxysmal coughing episodes. The musculoskeletal strains usually respond to rest, anti-inflammatory treatment, or both. Pleural inflammation is usually secondary to underlying parenchymal infection and is treated with antibiotics. The occasional patient reports chest pain that is relieved when a hard coughing spell produces a large mucus plug. Esophageal pain can be due to “pill esophagitis,” which is prevented by assuring adequate fluids for swallowing the large number of pills and capsules required for CF treatment. It may also be due to esophagitis. Gastroesophageal reflux disease (GERD) is more common in patients with CF, as is Barrett esophagus and adenocarcinoma of the esophagus. Treatment is with proton pump inhibitors. In patients receiving inhaled or systemic steroids, Candida esophagitis may occur.
Pneumothorax
This condition occurs in up to 10% of CF patients when apical blebs, associated with advanced pulmonary disease, rupture. Many pneumothoraces eventually resolve with oxygen therapy or with simple chest tube drainage, but recurrence rates of 50% to 100% are likely. Therefore, therapy to prevent recurrence is advisable. The instillation of chemical sclerosing agents has been used with some success but is painful and may not reduce the risk of recurrences. However, in some centers, surgical or chemical ablation of the pleural space is considered a contraindication to lung transplantation. A stepwise approach to the first episode of pneumothorax has been advocated, whereby simple chest tube drainage is undertaken first. If the air leak does not resolve within the next few days, or if an episode recurs, an attempt should be made to identify and seal apical blebs via a small thoracotomy. The most successful treatment for early resolution of the pneumothorax, prevention of subsequent episodes, with the least morbidity has been open thoracotomy through a small subaxillary incision, identification and excision of any apical blebs, stripping of the apical pleura, and manual abrasion of the remainder of the accessible pleura.18Thoracoscopic surgery is an alternative to small thoracotomy. If these steps fail, physical or chemical pleurabrasion, via thoracoscopy or open thoracotomy, should be performed.
Hemoptysis
Hemoptysis with minor blood-streaking of sputum is a common complication of CF, but massive hemoptysis, defined as more than 300 mL in 24 hours, is much less common. It occurs in 5% to 10% of patients. Although terrifying to patient and family, it rarely is severe enough to interfere with gas exchange or to require transfusion. Deaths have been reported but are exceedingly rare. Massive hemoptysis is thought to be the result of local infection that erodes one of the tortuous bronchial vessels adjacent to bronchiectatic airways. The appropriate treatment for all but the most overwhelmingly brisk bleeding is to reassure the patient and family and to initiate or continue aggressive treatment of pulmonary infection, including intravenous antibiotics. Because infection plays a causative role and blood reduces ciliary function and is a fertile bacterial medium, aggressive chest physical therapy should be continued. In some patients, hemoptysis may be associated with an iatrogenic platelet-aggregation defect (eg, seen with aspirin, carbenicillin, or ticarcillin therapy). Because CF patients malabsorb fat-soluble vitamins, treatment of hemoptysis includes supplementing with vitamin K. With brisk bleeding, intravenous vasopressin can be effective. In the rare recalcitrant case of hemoptysis, embolization of the offending bronchial artery under radiological guidance may be required. Lobectomy is seldom necessary.
Atelectasis
Lobar or segmental atelectasis, particularly of the upper lobes, occurs even early in the course of the disease (eFig. 514.1 ). Segmental or lobar atelectasis is best treated with antibiotics, bronchodilators, and vigorous chest physical therapy. It may take weeks or months for atelectasis to resolve. Bronchoscopy is unlikely to speed the resolution but should be considered when the atelectasis is associated with an otherwise unexplained deterioration; in these cases, culture of bronchoscopically obtained specimens may yield an unexpected organism that can be used to guide antimicrobial therapy.
Cor Pulmonale
Cor pulmonale, characterized by pulmonary hypertension with enlargement of the right ventricle, is common in end-stage CF. Overt heart failure with enlarged liver and peripheral edema is much less common but more ominous. One study has suggested that survival is less than 8 months after the onset of heart failure, although more recent results have been better. Diuretics are usually helpful, but digitalis is not used unless there is also left ventricular dysfunction. Salt intake should be restricted. Treating the underlying suppurative lung disease and administering supplemental oxygen are the approaches most likely to be of benefit. In CF patients with advanced pulmonary disease and cor pulmonale, simultaneous heart and lung transplantation may be employed, although cardiac function most often recovers rapidly with replacement of lungs alone.
Respiratory Failure
Respiratory failure in CF is almost always the end result of a long, devastating course. Occasionally, it can be seen acutely in a previously stable patient who had been doing well and abruptly worsens due to a severe viral infection, trauma, or surgery for nonpulmonary problems. For acute respiratory failure in a previously relatively healthy patient, treatment should be aggressive with oxygen, antibiotics, aerosols, and airway clearance. Mechanical ventilation may be indicated for those individuals with good lung function before an acute deterioration. The prognosis for regaining the previous status is good. With chronic respiratory failure, the prognosis is much different; therefore, the approach to the patient is different. Oxygen therapy is indicated to keep oxygen saturation above 90%. If the patient has carbon-dioxide retention (a very late finding in CF), oxygen should be administered with caution in order to avoid suppressing the hypoxic drive to breathe. This is much more a theoretical problem than a real one, however, because the majority of patients with cystic fibrosis will either not change or will actually improve their ventilation with supplemental oxygen. In these patients, supplemental oxygen may improve gas exchange by reducing anxiety and improving respiratory muscle function. Emphasis should be on patient comfort. Terminally ill CF patients may have CO2 narcosis and be comfortable, whereas in others, air hunger from hypoxemia may dominate the clinical picture. Morphine may be helpful in these latter patients by decreasing anxiety and promoting comfort. Morphine must be used carefully in this setting, as some terminal CF patients appear to be exquisitely sensitive to the drug, perhaps because of acidosis. Some centers use a starting dose as low as 0.1 mg (not 0.1 mg/kg) and double the dose until the desired result is achieved.
A number of options are available to support ventilation in CF patients with respiratory failure. These include conventional invasive approaches using endotracheal intubation or tracheotomy and mechanical ventilation, and less invasive devices such as mask BiPAP or intermittent positive-pressure breathing. The choice of techniques may be different in those patients who are lung transplant candidates and those who are not. Without transplantation, once patients begin these therapies, they have little chance of being able to stop them. Long-term mechanical ventilation is unlikely to enhance the quality of life of CF patients with respiratory failure and is not recommended. At some centers, some patients accepted for lung transplantation have been supported for weeks or months with mask BiPAP or conventional mechanical ventilation as a “bridge” to transplantation. Some patients have died on ventilators awaiting the availability of suitable donor lungs. Some centers view mechanical ventilation as a contraindication to transplantation and feel that initiating such treatment unconscionably complicates the letting-go, dying, and grieving process. These issues are best addressed with patients and families on multiple occasions when the patient is not in impending respiratory failure.
Lung Transplantation for CF
Heart-lung or double-lung transplantation has been successful in a limited number of CF patients with end-stage disease. One-year survival ranges from 50% to 85%.19 Donor-organ availability is a limiting factor for most North American lung transplant programs, and pretransplant mortality is high among those on transplant waiting lists. After transplantation, medical care is even more complex than that for cystic fibrosis before transplantation. Postoperative problems with immunosuppression, infection, acute and chronic organ rejection, finances, and psychological adjustment require constant attention. Nonetheless, some patients have had excellent results, with return to full-time work or school. Because waiting lists for donor lungs are as long as 2 years, most centers begin discussing transplantation with patients before they have respiratory failure, perhaps when pulmonary status begins to decline rapidly and oxygen therapy is required. Some recent studies have questioned the benefit of lung transplantation in CF, indicating that it seldom increases longevity, particularly in children.20
TREATMENT OF GASTROINTESTINAL AND NUTRITIONAL COMPLICATIONS
Nutrition
Longitudinal surveys of growth patterns in cystic fibrosis (CF) patients indicate that maintaining a normal weight-to-height ratio is associated with a slower pace of lung function deterioration.21 For this reason, the main goal of gastrointestinal therapy is to provide good nutrition and to teach and reinforce age-appropriate nutritional habits. A diet specific for the CF patient is not necessary, but usually a high-fat diet is useful to ensure adequate total caloric intake. Energy intakes of 110% to 200% greater than the standard for the general population are often required for appropriate weight gain and growth in children and for weight maintenance in adults with CF. Oral nutritional supplements are often useful, but even these supplements may prove inadequate in a subset of CF patients who simply cannot consume adequate calories. These patients may have anorexia related to chronic illness or may have greater-than-normal caloric expenditure because of chronic infection or increased ventilatory muscle energy expenditure. Many of these patients do well with nocturnal enteral feeds provided through a gastrostomy or jejunostomy tube. Formula can be provided continuously overnight to provide much of the patient’s caloric needs, including “catch-up” needs. Elemental formulas can be used and may reduce the need for pancreatic enzyme supplements, but many patients have thrived on much more standard, less expensive formulas with enzyme replacement at bedtime and in the morning. The Cystic Fibrosis Foundation consensus panel recommends that behavioral therapy; oral nutritional supplements; and, if required, enteral nutritional supplements can improve the weight gain goals of maintaining a weight/length at or above the 50th percentile in children under 2 years and a BMI above the 50th percentile in children and adolescents ages 2 to 20 years. These recommendations are based upon retrospective findings showing a favorable effect on prognosis.
Supplemental vitamins, especially the fat-soluble vitamins A and E, require supplementation. The recommended daily supplements that usually achieve normal plasma levels in infancy are vitamin A, 4000 IU (120 mcg); vitamin D, 400 IU (10 mcg); and vitamin E, 37 to 75 IU (25 to 50 mg). The recommended doses for children over 1 year of age are vitamin A, 8000 IU; vitamin D, 800 IU; and vitamin E, 100 to 200 mg. These doses are considerably higher than the usual dietary intake, and plasma levels should be monitored intermittently.
Pancreatic Enzyme Supplementation
Treatment of pancreatic insufficiency uses pancreatic enzyme supplements that are available in a variety of formulations. Enteric-coated varieties are generally more effective. Correct dose of enzyme is determined by trial and error, titrating against the symptoms and signs of maldigestion and malabsorption (steatorrhea, abdominal discomfort, excessive hunger, and poor weight gain). Generally, doses of 500 to 2500 units lipase per kilogram body weight per meal, or less than 10,000 units lipase per kilogram body weight per day, or less than 4000 units lipase per gram dietary fat per day are adequate. Enzyme doses greater than 2500 units/kg per meal of the lipase component are rarely necessary and are associated with complications of fibrosing cholangiopathy and hyperuricemia. Some patients who seem to require very large numbers of enzyme capsules may do better if they are treated with H2 blockers or proton pump inhibitors, which enhance the bioavailability of ingested enzymes. In these patients, it is likely that gastric acid hypersecretion, along with the usual absence of pancreatic bicarbonate, has rendered their duodenum and jejunum sufficiently acidic to prevent the complete dissolution of the enteric coating of the enzyme supplements.
Pain Due to Gastrointestinal Disorders
This is relatively common in patients with CF and can be caused by a large number of problems, not all of which are CF-related (Table 514-5).
Table 514-5. Gastrointestinal Causes of Pain in Cystic Fibrosis
Constipation, Meconium Ileus, and Distal Intestinal Obstruction Syndrome
Clinical presentations of these disorders are described above. Treatment of distal intestinal obstruction syndrome (DIOS) can be initiated with careful administration of hyperosmolar enemas, such as meglumine diatrizoate (Gastrografin) or, if in its early stages, with (ie, abdominal distension and constipation without complete obstruction) polyethylene glycol (MiraLAX or large volumes of oral or nasogastric GoLYTELY22), eliminating the need for enemas. Chronic constipation can often be prevented from leading to DIOS by adjusting pancreatic enzyme dosing or by the use of lactulose or MiraLAX.
Fibrosing Cholangiopathy
This serious complication of very high doses of pancreatic enzymes emerged in the 1990s. Patients may have abdominal pain, bloody diarrhea, or signs of obstruction. Surgery is usually required. The problem has not been seen in patients taking less than 5000 units of lipase per kilogram of body weight per meal and has become uncommon with the reformulation of many enzyme preparations.
As in any patient, appendicitis, cholecystitis, Clostridium difficile colitis, hepatitis, trauma, and other causes must be considered in the differential diagnosis of acute abdominal pain.
Rectal prolapse is treated by gentle manual pressure on the protruding rectum and is prevented by adjusting the diet and enzymes to reduce bulky stools.
Gastroesophageal reflux in infants should be treated conservatively by using the prone position and avoiding the seated position, which provokes reflux. The head-down chest physical therapy position should be avoided in infants. Reflux that manifests in infants as regurgitation with loss of calories is treated by thickening formula feedings with one tablespoon of rice cereal per ounce of formula. Reflux that manifests at any age as esophagitis with heartburn or feeding refusal is treated with H2 blockers or proton pump inhibitors. Reflux that manifests as reflex bronchospasm is also treated with acid suppression and bronchodilators. In any of these manifestations of reflux, the administration of a prokinetic agent may increase lower esophageal sphincter tone and promote gastric emptying.
In patients with reflux symptoms who do not respond to medical management, the possibility of gastric outlet obstruction should be excluded with gastric-emptying studies.
Liver Disease
Liver disease associated with cystic fibrosis is discussed in Chapter 423.
OTHER COMPLICATIONS
Diabetes
Carbohydrate intolerance, with or without overt diabetes, occurs in a small but important group of cystic fibrosis (CF) patients. In some patients, dietary manipulations, including use of high-calorie, low-carbohydrate supplements, may help. In others, oral hypoglycemic agents have eliminated or delayed the need for insulin injections. However, reluctance to begin insulin therapy may be misguided, as institution of insulin therapy can improve growth and pulmonary function.
Dehydration
Salt loss may be excessive, especially during febrile illnesses or exertion in warm weather, but it can be prevented if patients are well hydrated. Older children and adults will generally regulate their salt intake quite adequately if given free access to salt and water. CF patients underestimate their fluid needs during exercise in the heat and need to be encouraged to drink more than they think they need at such times. Salt tablets are not necessary and may be harmful.
Social and Psychological Support
The emotional burdens of a genetic, incurable, progressive, life-shortening, financially draining, and activity-limiting disease on patient and family are substantial. It is remarkable how well the large majority of patients and families adjust, with a very low incidence of depression. Issues that patients must face include education and vocation, marriage, reproduction, medical expenses, independent living, and anticipation of disability and death. Establishing and maintaining a positive, optimistic, yet realistic attitude are extremely important. These goals are attainable, especially if the primary physician shares this attitude and maintains a close, supportive relationship with the patient and family. Knowledge of the tremendously improved prognosis over the past decades facilitates such an attitude. High-quality CF centers provide appropriate social work and psychological support resources such that access to these resources is ensured when needed.
OUTCOMES
Institution of specialized CF centers and comprehensive aggressive treatment programs beginning in the 1950s has improved the prognosis tremendously. Projected national median survival was 10.6 years in 1966, 20 years in 1981, and 37 years in 2006. It is important to note that these advances in survival have not resulted entirely from major conceptual breakthroughs or new classes of antibiotics but mostly from the adoption of aggressive treatment programs that emphasize daily attention to the complex details of CF care. There are currently many CF patients in their 30s and 40s with excellent lung function, and in 2008, 43% of CF patients in the United States were 18 years old or older. Survival probably depends on several factors, including inherent severity of the disease, determined in part by genotype; aggressiveness of the treatment program as prescribed by the physician and carried out by the patient and family; and some degree of chance, especially concerning contact with various bacterial and viral pathogens. Exposure to cigarette smoke speeds pulmonary decline. In general, the survival of male patients is better than that of females. Recently, survival has been shown to be closely correlated with physical fitness, as measured during an exercise test, with fitness being a stronger correlate of survival than even pulmonary function. Perhaps most importantly, long-term prognosis may depend on the timing of diagnosis and the institution of treatment. Several studies indicate that those CF patients who are diagnosed early and who begin an aggressive treatment program before the onset of significant pulmonary damage have significantly better pulmonary function and survival than those discovered and treated only after considerable pulmonary tissue has been lost.