Abstract: Although cystic fibrosis (CF) is typically diagnosed during infancy or childhood, it may escape detection until adulthood. Diagnostic accuracy can be sharpened by maintaining a high index of suspicion for CF in an adult who is pancreatic-sufficient but has unexplained recurrent respiratory infections, bronchiectasis, or nutritional deficiencies. The workup begins with the quantitative pilocarpine iontophoresis sweat test. If necessary, additional tests include mutation analysis, full-gene sequencing of CF transmembrane conductance regulator protein, and measurement of nasal transepithelial potential difference. Multidisciplinary care is essential and includes nutritional support, chest physiotherapy, exercise, appropriate antibiotics, and other pulmonary interventions. Dornase alpha, inhaled tobramycin, and azithromycin have been associated with improved outcomes and are considered to be the standard of care for patients with moderate lung involvement. (J Respir Dis. 2006;27(1):32-41)
Traditionally regarded as a pediatric disorder, cystic fibrosis (CF) has become a disease of adults. In 2002, of the approximately 30,000 persons who had CF, roughly 40% were older than 18 years and 37% were older than 30 years.1
Contributing to this is a steady increase in the median survival of affected patients--from 6 months in 1938, to 14 years in 1969, to 33.4 years in 2001--that continues to rise annually (Figure 1).2 Based on current projections, persons with CF who were born in 1990 are expected to survive an average of 40 years. This improved outlook is the result of numerous factors, including improvements in diagnosis, advances in treatments that alter the natural course of CF-associated lung disease, and better care that now includes nutritional support and more effective antibiotics (Figure 2).1
As patients with CF continue to live longer, it will become increasingly important for physicians to know how to treat not just the disease but the patient as well. In this article, I will summarize current insights into the pathologic processes underlying CF, review the clinical presentation of CF, and offer guidelines for management.
CF is a genetic disorder (see "CF: All in the family") that affects a variety of organ systems (Table 1).3,4 In the lungs, abnormal secretions obstruct the airways, leading to chronic inflammation, recurrent infections, and bronchiectasis. Most patients have a typical pattern of airway colonization that begins with Staphylococcus aureusinfection during childhood and progresses to Pseudomonas aeruginosainfection by adulthood.3 A few patients may harbor other organisms, such as Stenotrophomonas maltophilia, Burkholderia cepacia,and nontuberculous mycobacteria.
In the pancreas, abnormal secretions lead to duct inflammation and damage. This results in exocrine insufficiency and, in some cases, endocrine insufficiency and frank diabetes mellitus. (CF-related diabetes is probably multifactorial, with islet cell destruction being only part of the pathogenesis.) Uncontrolled pancreatic insufficiency leads to significant malabsorption, with protein-calorie malnutrition and fat-soluble vitamin deficiency. Conditions such as osteopenia and osteoporosis can follow.
Obstruction of the GI tract may result in distal intestinal obstructive syndrome, a condition resembling meconium ileus of infancy. Biliary stasis, cholelithiasis, and intrahepatic biliary duct obstruction with cirrhosis are also possible. CF can even affect the reproductive tract. Most males with CF have obstruction or, in some cases, absence of the vas deferens, leading to azoospermia.5
Despite these widespread effects, pulmonary disease remains the major cause of morbidity and mortality in CF. More than 70% of patients succumb to respiratory failure.1
Most cases of CF are diagnosed in infancy or childhood, especially if the patient is homozygous for the DF508 genotype.5 Usually, patients have a known family history of CF or present with associated signs and symptoms, such as meconium ileus, failure to thrive, greasy diarrhea, recurrent respiratory symptoms or infections, or salty sweat. Less often, CF is detected during a neonatal screening program (some states have this type of program) that involves measurement of the serum immunoreactive trypsinogen level, which is elevated in persons with CF.
CF does not always present classically: there are mild and atypical phenotypes that may escape detection until the person is older.6,7 Therefore, it is important to suspect these variants and to consider a diagnosis of CF in an adult who is pancreatic-sufficient but experiences unexplained recurrent or chronic upper or lower respiratory tract infections, nasal polyposis, bronchiectasis, recurrent acute pancreatitis, nutritional deficiencies, salt wasting syndromes, or obstructive azoospermia.7 Early diagnosis is essential to prevent irreversible systemic decline.8
Several tests are available for confirming the diagnosis of CF (Table 2). The general recommendation is to start with the quantitative pilocarpine iontophoresis sweat test. Two sweat chloride levels of more than 60 mmol/L are diagnostic, with a sensitivity of greater than 90%. A level less than 40 mmol/L is negative, and levels between 40 and 60 mmol/L are borderline. Negative or borderline test results do not rule out CF, and patients with clinical evidence of CF need further evaluation.5,6
When additional testing is required, the next recommended step is mutation analysis. Commercially available screens test for up to 86 of the most common mutations, but only 2 of these mutations must be present to confirm the diagnosis. If mutation analysis is unrevealing and clinical suspicion for CF remains high, 2 diagnostic options remain:
Full-gene sequencing of CF transmembrane conductance regulator (CFTR) protein.
Nasal transepithelial potential difference (NPD) measurement, performed across the nasal mucosa of the inferior turbinate. This test assesses baseline ion transport and response to chloride-free secretions, revealing the increased sodium absorption and impaired chloride secretion that is characteristic of CF. The diagnostic sensitivity of NPD is much higher than that of sweat chloride measurement, and it may become the gold standard for diagnosis. NPD can also be useful for diagnosing atypical cases of CF. However, availability is currently limited.5
CF is a multisystem disease, and issues such as comorbid illness (diabetes mellitus, osteoporosis, and other adulthood diseases) and fertility/pregnancy are common considerations. Some of these comorbidities may affect the progression of pulmonary disease. The association between poorly controlled diabetes and further decline in lung function is one example.9
The outcome is usually best when the patient can be treated at a CF Foundation-accredited medical center. (A directory of these centers is available at the CF Foundation Web site: www.cff.org.) These centers usually have a dedicated pulmonologist, nursing care coordinator, respiratory therapist, nutritionist, and social worker who can deliver specialized care. The patient should also have ready access to other specialists (internists, gastroenterologists, endocrinologists, obstetricians/gynecologists, general surgeons) who have experience in managing CF.
The CF Adult Care Consensus Conference Report recommends that patients with CF be evaluated quarterly at a CF center.5 If the patient cannot get to the center that often, he or she should be seen at least once or twice a year. This evaluation includes:
Detailed review of systems (this guides the physical examination).
Evaluation of current medications and treatment to make sure that the patient is receiving all indicated standard treatments and is compliant with them.
Spirometric assessment of pulmonary function.
Review of the past year to ensure that maintenance/preventive care is current.
Nutritional status review.
Patients who can attend the CF center only once or twice a year should have interim quarterly follow-up with their primary care physician, internist, or pulmonologist. In this case, close cooperation and communication among caregivers is especially important to avoid fragmentation of care and management errors.
I find that interim caregivers can help their CF patients most by focusing on 2 objectives: maintain-ing adequate nutritional status and optimizing pulmonary function. This physician, whether a primary care practitioner or pulmonologist, should also support the patient's ongoing connection with the nearest multidisciplinary accredited CF center.
Defined by weight for age, ideal body weight, or body mass index, nutritional status is strongly associated with survival and other outcomes in patients who have CF.10,11 Most patients with CF have pancreatic insufficiency and require pancreatic enzyme supplements to aid absorption.
Even with pancreatic supplements, CF patients need to consume an unrestricted diet, with 35% to 40% of calories from fat, to attain and maintain a near-ideal body weight. A goal of greater than 90% of ideal body weight is recommended.10,11 This will be easier to accomplish if patients know their ideal body weight, as well as which foods are high in fat and protein.
Some patients may need to take commercially available high-calorie supplements, while a few may be candidates for supplemental gastric feeding. Patients with CF and diabetes have similarly high caloric needs and should never be restricted to the standard diabetic diet.5,10 Regular evaluation by a dietitian who is knowledgeable about CF can help patients achieve and maintain their goal weight.
Chest physiotherapy to clear airway secretions remains at the heart of pulmonary care for patients with CF. Several methods are available, such as manual chest percussion and postural drainage, high-frequency chest wall oscillation devices, and handheld positive-pressure devices (oscillating-type or end-expiratory). Because no clinical trials have yet proved the superiority of any one method, the choice is usually guided by the patient and the physician.12
All patients with CF should participate in daily aerobic exercise and use one of the following: manual percussion with postural drainage, an intervention to increase resistance to expiration (flutter valve, positive expiratory pressure valve), or a high-frequency chest wall oscillation system.13
Three interventions are documented to alter the natural progression of lung disease in CF: recombinant human DNase, inhaled tobramycin, and azithromycin.14-18 All 3 are now considered to be the standard of care for CF patients who have moderate to severe lung involvement (Table 3).5
Recombinant human DNase (dornase alpha) reduces the viscoelasticity of respiratory secretions by degrading extracellular DNA. In a multicenter, double-blind, placebo-controlled, randomized trial of 968 patients (who had forced vital capacity greater than 40% of predicted), treatment with dornase alpha improved forced expiratory volume in 1 second (FEV1) by 5.8%, which was significant (Figure 3).14 Patients also had reduced dyspnea, reduced time in the hospital, and fewer missed days of school or work.13 At follow-up of up to 2 years, however, FEV1 did not differ between the dornase alpha and placebo groups.
Nebulized dornase alpha, 2.5 mg/d, is currently recommended for all patients with CF, particularly those with moderate to severe lung disease. The role of dornase alpha in adults with mild disease remains undefined.5
The use of inhaled tobramycin reduces bacterial burden and recurrent Pseudomonas infections. Two multicenter, double-blind, placebo-controlled, randomized trials compared tobramycin, 300 mg inhaled twice a day every other month, with placebo for 24 weeks in 520 patients with FEV1 values of less than 75% of predicted (but no less than 25% of predicted) and sputum colonization with P aeruginosa.15 Patients treated with tobramycin had a 10% improvement in FEV1 (Figure 4). Sputum concentration of P aeruginosa,hospitalizations, and use of intravenous antibiotics were all reduced. The treatment group had no adverse effects, and antibacterial resistance was absent.
Current recommendations for patients with an FEV1 of less than 75% of predicted, but no lower than 25% of predicted, and sputum colonization with P aeruginosa are to receive inhaled tobramycin, 300 mg twice a day for 28 days every other month. This is the only recommended preparation of inhaled tobramycin for CF patients; patients should use the specific nebulization system from the above-mentioned studies15 to ensure adequate drug delivery and optimal benefit.5 It is unknown whether patients with milder or more se-vere pulmonary disease may benefit from inhaled tobramycin.
Azithromycin is effective for treating panbronchiolitis, a disease with some pathologic features that are similar to those of CF.16 A multicenter, randomized, double-blind trial compared azithromycin, 500 mg 3 times a week, with placebo in 185 patients who had CF.17,18 Patients had FEV1 values of 30% of predicted and sputum coloniza-tion with P aeruginosa. Those who had sputum colonization with Mycobacterium-avium intracellulare(MAI) were excluded.
Azithromycin produced a 4.4% improvement in FEV1 at 24 weeks and reduced exacerbations, hospitalizations, and use of other antibiotics (Figure 5). Sputum colonization did not change significantly. Patients reported some improvement in physical functioning on quality-of-life questionnaires.18
Azithromycin, 500 mg 3 times a week, is recommended for all adults with CF who have an FEV1 of 30% of predicted and sputum colonization with P aeruginosa.5 The longer-term impact of this therapy on MAI colonization and resistance patterns is unknown.
Ibuprofen and corticosteroids are not currently recommended for long-term treatment of CF-associated lung disease.3
As investigators learn more about the relationship between specific CF mutations and the type of functional alteration they produce, better-targeted therapies can be designed.19 Gentamicin, for instance, reduces fidelity of translation and allows "read-through" of some stop codon (class I) mutations. Early trials suggest that this agent may be clinically effective for persons who have CF.20
Similarly, curcumin inhibits endoplasmic reticulum calcium pumps, allowing the misfolded but functional CFTR that results from the DF508 mutation (class II) to reach plasma membranes. Curcumin will enter phase 1 clinical trials next year.21
Other investigations are attempting to bypass CFTR and instead are testing treatments that activate alternative chloride channels. Gene therapy research is ongoing but is limited by identification of safe vectors/methods, efficiency, and longevity of DNA transfer.19
Some evidence suggests that adults with CF may be at increased risk for GI cancer. The strongest association was reported in a retrospective review of cancer incidence in more than 38,000 patients from the United States, Canada, and Europe over an 8-year period. Although there was no increase in overall risk of cancer compared with the general population, the risk of GI cancer was significantly increased for patients in all cohorts (odds ratio, 6.5, increasing to greater than 20 for patients aged 20 to 29 years).22
Further work in this area is clearly warranted. Currently, there are no consensus guidelines regarding screening for GI cancer in adults with CF.
In the past, pregnancy was thought to accelerate pulmonary decline and decrease survival in women with CF. However, a 12-year comparison of all pregnant and nonpregnant women in the US CF Foundation Registry found no difference in long-term survival--even for patients with evidence of severe lung disease (FEV1 of less than 40% of predicted).23
Women with CF can be reassured that pregnancy will not adversely influence their health. It is important, however, to discuss with women the usual long-term course of CF and its potential implications for children and families. Based on current data, 20% of women with CF who bear children will die by the time the child is 10 years old.23
Another recently dispelled myth of CF care is that of uniformly poor outcomes following mechanical ventilation. Investigators from the University of North Carolina Cystic Fibrosis Center reported 9 years of experience with patients who required management in the ICU.24 Those who presented with acute illnesses (other than progression of underlying lung disease), such as hemoptysis or pneumothorax, had excellent outcomes: 86% to 100% survival at 1 year.
Among patients with respiratory failure caused by exacerbations of CF-related lung disease, 45% died in the hospital and 55% survived to discharge. Of the survivors, 40% had undergone lung transplantation and were alive at 1 year. Half the patients who did not receive lung transplantation were dead at 1-year follow-up.24
This and other reports suggest that short-term mechanical ventilation and ICU admission for reversible conditions may be warranted in patients with CF. They also suggest that in the event of primary progression of respiratory disease, ventilatory support should be considered for patients who are candidates for lung transplantation. These issues should be discussed routinely with patients at "well visits," and clear advanced directives should be prepared.
When lung disease progresses despite all medical interventions, the only option is lung transplantation. CF is the second or third leading indication for lung transplantation, accounting for 15% to 20% of all lung transplants.
In 2003, 170 patients with CF underwent lung transplantation. The suppurative nature of lung involvement in CF necessitates that transplantation be bilateral.
Post-transplantation survival for patients with CF is better than it is for all other indications except emphysema.25 Median survival at 3 and 5 years is 58% and 44%, respectively.25 The exception is the markedly poor outcome for patients with sputum colonization by B cepaciagenomovar III.26 The average wait time ranges from 6 to 24 months, and up to 40% of patients may die while on the waiting list.25,27
Multiple studies have tried to identify predictors of outcome in CF to guide optimal timing for lung transplantation. FEV1 of less than 30% of predicted appears to be the most reliable indicator, since it has a very high negative predictive value (more than 95%).28,29 Because the positive predictive value of FEV1 is poor (less than 40%), it is important to remember that some patients may be referred earlier than necessary.28,29 Nevertheless, it remains the focus of guidelines for transplant referral (Table 4).30 Investigations continue to identify better predictors for timing of lung transplantation.
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