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Cystic Fibrosis Adult Care*: Consensus Conference Report FREE TO VIEW

James R. Yankaskas, MD; Bruce C. Marshall, MD; Beth Sufian, JD; Richard H. Simon, MD; David Rodman, MD
Author and Funding Information

*From the University of North Carolina (Dr. Yankaskas), Chapel Hill, NC; the Cystic Fibrosis Foundation (Dr. Marshall), Bethesda, MD; Sufian & Passamano (Ms. Sufian), Houston, TX; University of Michigan (Dr. Simon), Ann Arbor, MI; and University of Colorado (Dr. Rodman), Boulder, CO.

Correspondence to: James R. Yankaskas, MD, Pulmonary and Critical Care Medicine, 7011 Thurston Bowles Bldg, CB No. 7248, The University of North Carolina, Chapel Hill, NC 27599-7248; e-mail: pwsjry@med.unc.edu



Chest. 2004;125(1_suppl):1S-39S. doi:10.1378/chest.125.1_suppl.1S
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No achievement highlights the striking developments of the past few decades in cystic fibrosis (CF) care more clearly than the tremendous growth of the adult CF population. This demographic shift has created the need for adult-specific CF care programs and protocols. In June 1999, the Cystic Fibrosis Foundation (CFF) convened a consensus conference to discuss the state of adult CF care. This document summarizes the findings of that meeting and incorporates information gathered since the conference convened. The recommendations embodied herein are intended to serve as a template for US adult CF programs and a resource for those wishing to find information specific to adult CF care. In cases in which prior publications sufficiently treat the subject, references are provided. In cases in which insufficient evidence was available to reach consensus, the best consensus opinions are provided. This document is not intended to replace the Clinical Practice Guidelines for Cystic Fibrosis1 but rather to act as an adult-specific complement.

Of the 22,301 patients with CF in the 2000 Cystic Fibrosis Foundation Patient Registry Annual Data Report, 8,637 (38.7%) were ≥ 18 years of age.2 This represents a dramatic increase in the number of adults over the past 3 decades, up from about 700 (10% of all CF patients) in 1970 (Fig 1 ).

These changes are attributable in large part to the significant improvement in survival over the past 30 years. The median predicted survival of only 16 years in 1970 is now up to approximately 32 years. For patients born in the 1990s, the median survival is predicted to be > 40 years.3 The average age for all patients in the Cystic Fibrosis Foundation Registry is now > 16 years. Among adults with CF, 64% are between the ages of 18 and 29 years, 25% are between 30 and 39 years, 10% are between 40 and 49 years, and 2% are > 50 years of age.2 The oldest living patient in the 2000 CFF Patient Registry was 78 years old.2

Data collection techniques and patient definition are two factors that lead some to speculate that there may be an additional 2,000 to 7,000 patients with CF in the United States who are not included in the CFF Patient Registry. Many of these patients are thought to be adults. Patients reported in the CFF Registry primarily fulfill the classic criteria for CF with both phenotypic manifestations and laboratory abnormalities consistent with CF transmembrane conductance regulator (CFTR) dysfunction (see “Diagnosis” section). If patients with CFTR dysfunction manifesting as pancreatitis,45 chronic sinusitis,6or congenital bilateral absence of the vas deferens (CBAVD)79 were included, the number of adults with CF would be considerably higher.

The growth of the adult CF population is predicted to continue in the foreseeable future. Even without further improvements in survival over the next 5 years, the number of adults with CF in the United States in the year 2005 will likely exceed 10,000 and represent > 40% of the total CF population.

Among adults with CF, 53.9% are men, and 46.1% are women.2 This may reflect the reported survival advantage in men.10 The ethnic breakdown is 93.7% white, 3.2% Hispanic, 2.7% African American, and 0.4% of other ethnicity. Nearly 90% of the adults have completed high school, and more than one quarter of them have completed college. About half of the adults with CF are working full-time or part-time, and one quarter are students. Approximately one third of adults with CF are married. There were 97 live births to women with CF in 2000, representing a significant increase in births to CF patients over the past decade.

The lung function of adults with CF is highly variable.2 Using FEV1 as a measure, about 36% of adult patients have normal or mild lung dysfunction (ie, FEV1, > 70% of predicted), 39% have moderate dysfunction (ie, FEV1, 40 to 69% of predicted), and the remainder have severe dysfunction (FEV1 < 40% predicted). The mean FEV1 percent predicted for all adults with CF is 60.8%. As a group, adults have more severe pulmonary disease than children and are at increased risk for serious complications (Table 1 ).

The health-care needs of adults with CF are considerable.2 Each year, they make an average of 4.7 CF clinic visits, experience 1.5 acute exacerbations, and are admitted to the hospital 1.0 times. In response to the increasing numbers of adults with CF, the number of adult CF programs has grown from < 10 in 1992 to > 79 in 2002.

Although CF is usually discovered early in life (70% by the age of 1 year), the diagnosis is being made in adults with increased frequency. Among 22,301 patients in the 2000 CFF Patient Registry, the diagnosis was established at or after the age of 18 in 831 (3.7%).2 Patients diagnosed as adults usually present with chronic respiratory problems. As a group, they have milder lung disease, less pseudomonal infection, and are more likely to be pancreatic-sufficient than patients in whom CF is diagnosed at an earlier age.2,1112 Physicians unfamiliar with the spectrum of CF phenotypic manifestations may not consider a diagnosis of CF, thus delaying the diagnosis. Also contributing to a delay in diagnosis is the finding that some adult patients have normal or borderline sweat test results.1315

Despite these differences, the criteria for establishing a CF diagnosis are the same for adults and children.16CF is usually suspected because of the presence of one or more typical CF phenotypic features (Table 2 ). The diagnosis is confirmed by the documentation of CFTR dysfunction. When performed by an experienced laboratory in accordance with National Committee for Clinical Laboratory Standards,17 the quantitative pilocarpine iontophoresis sweat test remains the single most useful diagnostic test for CF in adults. It should be the initial test performed in a suspected case. Although there is a spectrum of sweat chloride levels ranging from normal (< 40 mM), to borderline (40 to 60 mM), to abnormal (> 60 mM) among patients in whom CF is diagnosed during adulthood, the sweat chloride concentration will be abnormal in > 90% of those diagnosed patients.2 However, as noted, a normal sweat chloride value cannot be used as the sole criterion for ruling out the diagnosis of CF.

In patients suspected of having CF who have a normal or borderline sweat chloride value, CFTR mutation analysis should be performed. The sensitivity of such testing is limited because current commercial panels screen for only a minority of the > 1,000 identified CF mutations, and patients who receive diagnoses after the age of 18 years are more likely to carry infrequent or unidentified mutations.2,1112 Genotype analysis was performed for 673 of the 831 patients in the 2000 CFF Patient Registry who received diagnoses at or after 18 years of age. Of these patients, two of the common ΔF508 mutations were identified in 142 patients (21.1%), one ΔF508 mutation was identified in 348 patients (51.7%), and no ΔF508 mutations were identified in 183 patients (27.2%).2 For patients suspected of having CF in whom a diagnosis cannot be made on the basis of the identification of two CFTR mutations, the measurement of nasal potential difference (PD) may be used to confirm the diagnosis.16,1819 However, this technique is not available at all medical centers. More comprehensive genotype analysis by DNA sequencing is available for patients with unusual clinical and/or CFTR function tests (ie, sweat chloride or nasal PD measurements) through the CFF-sponsored Mutation Analysis Resource Center at Johns Hopkins University (Baltimore, MD; Garry Cutting, MD, Director).

Adult patients also may come to medical attention with atypical presentations such as chronic/recurrent pancreatitis,45 chronic sinusitis,6or CBAVD.79 Men presenting with obstructive azoospermia secondary to CBAVD present a particularly challenging diagnostic problem. The majority have no other phenotypic features of CF, but 50 to 60% of those men carry one identified CF mutation, and 15 to 20% are compound heterozygotes. A diagnosis of CF should be assigned to such patients only if there is documentation of elevated sweat chloride values, two CF mutations, or an abnormal nasal PD measurement.16 It is important to consider alternative diagnoses (eg, immunodeficiency, ciliary dyskinesia, and Young syndrome) in patients with atypical presentations.

People who receive diagnoses of CF as adults may be overwhelmed by the implications of a disease that leads to premature death for many children and young adults. It is important for the CF care team to educate such patients about the disease. In particular, they should be informed that patients who receive diagnoses in adulthood often have much better prognoses than patients who receive diagnoses during early childhood.

Overview

Data comparing the relative effectiveness of various approaches to adult CF care (ie, multidisciplinary vs subspecialty vs primary care-based) are lacking. However, based on the strong association between the establishment of comprehensive CF Care Centers and improved patient outcomes, the committee strongly recommends a multidisciplinary approach modeled on the highly successful pediatric CF care system. The health-care team should include at least a part-time commitment from a physician, nurse, respiratory therapist, dietitian, and social worker. Ideally, all members of the team should have specific training in adult CF care. Back-up personnel should be available in the event that a team member is unable to perform his or her duties. The pulmonary and GI/nutritional manifestations of the disease predominate in adults as in children, but several other issues also emerge.

Comprehensive Care

The primary objectives of the adult health-care team are to: (1) ensure optimum care; (2) facilitate access to pertinent medical resources; (3) coordinate care among specialists and primary care practitioners; and (4) support quality of life and independence for each patient. Frequent patient contact with the Center is necessary to accomplish these objectives. In general, quarterly visits are sufficient, although some patients with special needs or advanced disease may require more frequent attention. The Adult CF Care Team may function in a primary care capacity or in concert with an independent primary care practitioner. Coordination and communication with other medical professionals involved in the patient’s care are essential.

The optimal management of CF requires input from all members of the health-care team. Evaluation and intervention by team members should be individualized to suit each patient’s circumstances. However, a minimum of one comprehensive evaluation per year by each team member (ie, nurse, respiratory therapist, dietitian, and social worker) is recommended. These evaluations should encompass an assessment of adherence with therapies and the identification of relevant psychosocial issues as well as specific medical issues. When the center is serving in a primary care capacity, health maintenance (eg, vaccinations and cancer screening) should be provided according to national guidelines for age and gender. Ideally, the center should have a case management conference or other mechanism in place for a periodic review of the status of each patient and the formulation of a treatment plan. These assessments should be documented in the medical record and communicated with other health-care professionals involved in the care of the patient.

Pulmonary Disease
Assessment:

The pulmonary status of patients should be regularly monitored by an assessment of symptoms, a physical examination, and, on most visits, spirometry. FEV1, expressed as the percent predicted of a healthy nonsmoking reference population, is accepted as the single most useful objective measure of pulmonary status.20 Oxygen saturation should be measured routinely in patients with moderate-to-severe pulmonary disease to assess the need for supplemental oxygen. The measurement of oxygen saturation during exercise and/or sleep may be indicated in some situations.

A complete microbiological assessment of expectorated sputum, including antibiotic susceptibility testing, should be performed at least on an annual basis, and preferably on a quarterly basis. Oropharyngeal swab cultures,2122 which are commonly obtained from children who do not produce sputum, have not been fully studied in adults. The microbiology laboratory should follow published guidelines23for the processing of CF sputum in order to isolate the wide range of organisms found in these specimens. Multiply-resistant Gram-negative organisms, such as Burkholderia cepacia, Stenotrophomonas maltophilia, and Achromobacter xylosoxidans, are found in up to one third of adults with CF.24 This has significant implications for disease management and infection control. The microbiology laboratory must be capable of distinguishing among these organisms and performing extended antimicrobial susceptibility panels if necessary. Antibiotic synergy testing may be helpful in some situations and is available at the CFF-sponsored reference laboratory at Columbia University for patients who have received follow-up at accredited CF care centers.25Confirmed or suspected B cepacia isolates should be sent to the CFF-sponsored reference laboratory at the University of Michigan26 for the confirmation of identity and further characterization.

The role of chest imaging in the monitoring of adults with CF has not been extensively studied. Standardized chest radiograph scoring may be useful in documenting the progression of disease or response to therapeutic intervention.2728 The committee did not support the use of annual surveillance chest radiographs but reached a consensus opinion that posterior/anterior and lateral chest films should be obtained every 2 to 4 years in patients with stable clinical status. Imaging also should be considered for patients with signs or symptoms consistent with a significant acute pulmonary exacerbation, pneumothorax, lobar atelectasis, or hemoptysis. Chest CT scans may be appropriate in certain clinical situations but cannot be recommended on a routine basis.

Additional diagnoses such as asthma, nontuberculous mycobacterial infection, allergic bronchopulmonary aspergillosis, sinus disease, and gastroesophageal reflux, should be considered in patients whose symptoms, clinical course, or response to treatment are atypical for CF.

Treatment:

The cornerstones of treatment for those with CF are antibiotic therapy, airway clearance, and nutritional support; which are similar for children and adults. The reader is referred to several reviews2932 for a more detailed discussion of the specific components of a standard treatment regimen, which include antibiotic therapy for pulmonary exacerbations, and chronic suppressive therapy, airway clearance and exercise, therapy with mucolytic agents, bronchodilators, and anti-inflammatory agents, supplemental oxygen, and nutritional support. Because of the potential complexity, all aspects of the medical regimen should be reviewed on a regular basis with an assessment of adherence and potential side effects from medications.

Basic principles in the treatment of pulmonary exacerbations will be covered first, followed by a discussion of the various components of maintenance therapy for the treatment of pulmonary disease. Nutrition will be covered later in the article.

Pulmonary Exacerbations:

Pulmonary exacerbations are common in adults with CF. The approach to treatment of an exacerbation described in Clinical Practice Guidelines for Cystic Fibrosis1 of the CFF is applicable to the adult population. Specific antibiotics are selected on the basis of a recent sputum culture. Pseudomonas aeruginosa is by far the most common pathogen found in adults with CF. Therapy with fluoroquinolones is often used for mild-to-moderate exacerbations. Two antipseudomonal antibiotics are used in combination (eg, a β-lactam and an aminoglycoside) for the treatment of moderate-to-severe pulmonary exacerbations. Clinicians must be aware that for many antibiotics, differences in the volume of distribution and the rate of elimination in CF patients require higher doses and shorter dosing intervals.,33

As noted above, adults are more likely to be infected with multidrug-resistant organisms such as B cepacia. Antibiotic combinations are typically used for the treatment of exacerbations related to these organisms. Some centers treat empirically and others use synergy testing to select a treatment regimen. Inhaled antibiotics are at times used in combination with parenteral agents. The optimal approach has not been validated in clinical trials. In order to prevent person-to-person spread of these organisms,34 the center must have rigorous infection control practices in place in the outpatient clinics and the inpatient units.

Chronic Suppressive Antibiotic Therapy:

Chronic suppressive antibiotic therapy often is employed because the treatment of pulmonary exacerbations will not eradicate the lung infection. Aerosolized tobramycin (TOBI) has been the most thoroughly studied chronic suppressive therapy. In two large, multicenter, double-blind, placebo-controlled trials conducted over a 24-week period, treatment with TOBI was found to produce significant improvement in pulmonary function, to decrease the density of P aeruginosa in sputum, and to decrease the number of days that subjects were hospitalized.35These studies included patients with moderate-to-severe pulmonary disease, which was defined as an FEV1 between 25% and 75% of predicted. Subset analyses demonstrated that adolescents had the greatest response, although all age groups and disease severity categories showed significant improvement from the therapy. A 24-month open-label follow-up36 of these trials demonstrated sustained improvement in FEV1 compared to the group that had initially received placebo.

A significant long-term concern in using chronic suppressive therapy of any type is the emergence of antimicrobial resistance. The TOBI trials showed no increase in the prevalence of B cepacia or other resistant organisms in the TOBI-treated group. There was a modest but detectable shift in the minimum inhibitory concentrations of the P aeruginosa strains infecting the TOBI-treated subjects. The sustained improvement in pulmonary function appears to outweigh the risk of tobramycin resistance that may develop over time, but this must be carefully considered for each individual.

Who should be considered for this therapy? Any adult patient chronically infected with P aeruginosa is a potential candidate. Certainly, any patient who falls within the patient selection criteria for the phase III clinical trial35 (ie, those with FEV1 between 25% and 75% of predicted) deserves serious consideration for inclusion in a therapeutic trial of this drug. More severely affected patients also may benefit, but they should be carefully monitored during the initiation of therapy. The more difficult issue is the case of the mildly affected patient with an FEV1 of > 75% predicted. Interventions at this point in the disease course may have a profound impact on the subsequent course of disease. The current trend is toward more aggressive therapy and earlier intervention. TOBI should be considered for this mildly affected group, particularly for those in whom the pulmonary disease is more active. Indications of more active disease may include increased symptoms, declining pulmonary function, or increased frequency of pulmonary exacerbations. An ongoing clinical trial of TOBI in this mildly affected patient population hopefully will shed additional light on this issue.

One caveat with this therapy relates to the delivery of the antibiotic to the airways. Particle size is critical to antibiotic deposition. Too small a particle will tend to deposit in the distal air spaces and alveoli where significant systemic absorption may occur. Too large a particle will tend to deposit in the central airways. TOBI should be administered with the nebulizer systems that were validated in the clinical trials.35

The data presented above specifically refer to the TOBI preparation of tobramycin. A number of smaller, less rigorous clinical trials of other formulations of tobramycin and gentamicin using a variety of dosing regimens ranging from 80 to 600 mg, two to three times a day have been reported.3742 Because of methodological concerns with these trials, the efficacy and safety of preparations other than TOBI have not been established.

Inhaled colistin (Coly-Mycin; Monarch Pharmaceuticals; Bristol, TN) has been reported to be of benefit in case series and uncontrolled clinical trials.4344 The rarity of antimicrobial resistance has been touted as an advantage with this drug; however, the transmission of colistin-resistant P aeruginosa recently has been reported.45 Bioavailability from the aerosolized route of administration has not been studied adequately. Safety is also a concern due to the fact that bronchospasm occurs in a substantial proportion of patients after the nebulization of this medication.4546 In a recent short-term comparison trial47 in the United Kingdom, pulmonary function improved in the TOBI-treated group, but there was no significant change in the colistin group. Thus, the efficacy and safety of aerosolized colistin has not been established.

Scheduled parenteral antipseudomonal therapy is an alternative suppressive strategy that has been popular in Denmark. Retrospective and uncontrolled reports have suggested improved survival in patients treated with 2-week courses of therapy, four times per year irrespective of symptoms.48However, a randomized trial49 comparing suppressive IV antibiotic therapy administered four times per year vs standard treatment for symptoms of an exacerbation showed no difference in outcomes between the two groups. This approach cannot be recommended at this time.

There are few data and no convincing evidence to support the use of chronic oral antibiotic therapy in the adult CF population. However, therapy with macrolide antibiotics have garnered attention based on their effectiveness in the treatment of diffuse panbronchiolitis.50Promising preliminary observations suggested a clinical benefit in CF5153 and led to several randomized, controlled clinical trials. A double-blind, placebo-controlled azithromycin trial in the United Kingdom54included 41 children, 20 of whom did not have persistent P aeruginosa infection. The crossover study design included two 6-month treatment phases and an intervening 2-month washout period. The median relative improvement in FEV1 in the azithromycin phase was 5.4%. Oral antibiotic use was reduced, but the number of pulmonary exacerbations and courses of IV antibiotics did not differ in the azithromycin and placebo phases. A 3-month randomized, placebo-controlled, double-blind trial of azithromycin enrolled 60 stable adults in Australia who were chronically infected with P aeruginosa.55 By chance, the treatment assignments resulted in significant differences between the azithromycin and placebo groups. At baseline, the placebo group contained more men, and on average the patients were taller, heavier, and had better lung function than those in the azithromycin group, requiring adjustments in their statistical analyses. Nevertheless, the azithromycin group had a 3.6% relative improvement in FEV1, had undergone fewer courses of IV antibiotic therapy, and had fewer hospital days. A 24-week, multicenter, randomized, placebo-controlled, double-blind trial of azithromycin56 in the United States enrolled 185 patients who were ≥ 6 years of age and were chronically infected with P aeruginosa. The azithromycin group experienced a 6.2% treatment benefit in relative FEV1 percent predicted change from baseline, decreased pulmonary exacerbations, decreased hospitalizations, and a 0.7-kg weight gain compared to the placebo group. The drug was well tolerated in all three trials. In summary, despite differences in patient populations, study design, and treatment regimens, all three trials demonstrated clinical improvement with azithromycin therapy. The mechanism of action remains to be elucidated. Based on this evidence, we believe that azithromycin should be considered for CF patients who are ≥ 6 years of age who are chronically infected with P aeruginosa. The US trial regimen was 500 mg thrice weekly for patients weighing ≥ 40 kg, and 250 mg thrice weekly for patients weighing 25 to 40 kg. A sputum smear and culture for acid-fast bacilli should be obtained prior to initiating chronic macrolide therapy because of the slight risk of having an undiagnosed nontuberculous mycobacterial infection developing macrolide resistance. For patients receiving chronic macrolide therapy, a smear and culture for acid-fast bacilli should be obtained every 6 months.

Airway Clearance and Exercise:

There are a variety of airway clearance techniques available. Conventional chest physiotherapy (CPT) is the technique of percussion and postural drainage. Despite the absence of randomized, controlled clinical trials, the available evidence and clinical experience supporting conventional CPT appears to be convincing.5758 Potential problems with this modality include hypoxia, particularly in patients with severe lung disease,59and gastroesophageal reflux.60Furthermore, CPT is physically demanding and time-consuming for both the patient and his or her support person(s). Poor adherence is common.61

As patients become older and more independent, they frequently seek airway clearance methods that can be performed without assistance. Several alternative modalities have been developed, including active cycle breathing, forced expiratory technique, positive expiratory pressure (PEP) devices, autogenic drainage, and high-frequency chest wall oscillation systems (ie, The Vest, formerly called ThAIRapy Vest [Advanced Respiratory; St. Paul, MN]; the Flutter device [Axcan Scandipharm; Birmingham, AL]; and the intrapulmonary percussive device). A detailed description of each of these methods can be found in a review.62Meta-analysis suggests that CPT resulted in greater sputum production than no treatment, and that the addition of exercise improved FEV1. No other differences between modalities were found.63

Expiratory resistance or PEP devices may promote mucus clearance by preventing airway closure and increasing collateral ventilation. They are used via a mask or a mouthpiece and can be adapted for the concomitant delivery of bronchodilators. These devices have been extensively studied in Europe, with most trials demonstrating equivalence to conventional CPT.64A long-term (ie, 1 year) trial showed that PEP therapy was superior to conventional CPT with respect to maintaining pulmonary function.65 A report66 demonstrated that PEP was also more effective than the Flutter device in maintaining pulmonary function over the course of a 1-year trial. The devices are relatively inexpensive, portable, and well-tolerated, although some patients find them fatiguing. Theoretical concern that they might increase the risk of pneumothorax has not been borne out in practice.

The Vest is a chest wall compression and oscillation system composed of a fitted vest coupled to a pneumatic compressor. Therapy is delivered to the entire chest at the same time with the patient in a seated position. This allows the administration of nebulized medications during the therapy session, minimizing the patient’s time commitment; but the major advantage over conventional CPT is the degree of independence afforded to the patient. A prospective study67 demonstrated that use of The Vest is equivalent to conventional CPT in patients hospitalized for a pulmonary exacerbation. The major disadvantages with this system are the expense and lack of portability. Some severely affected patients complain that it is harder to breathe during the treatment. Others, particularly those with indwelling venous access devices (eg, the Port-a-Cath; Deltec, Inc; St. Paul, MN), may find The Vest uncomfortable.

Additional clinical trials are needed to define the optimal airway clearance regimens. To provide meaningful results, such studies must involve an adequate number of patients observed over a time frame of at least several months. Sputum production has been the primary outcome variable in many of the published trials to date, but it may prove to be an unreliable marker of efficacy. The preservation of pulmonary function provides more convincing evidence of efficacy.

Physical activity augments airway clearance6870 and should be viewed as an important adjunct to the airway clearance techniques described above. A randomized clinical trial71demonstrated that regular aerobic exercise attenuates the decline in pulmonary function over a 3-year period compared to a control group. In addition, appropriate vigorous physical exercise enhances cardiovascular fitness, increases functional capacity, and improves quality of life. The level of physical fitness, as measured by maximal oxygen uptake, correlates with survival in CF.72 For these reasons, with the exception of those patients whose clinical condition prevents it, all adults with CF should be encouraged to exercise.

Ideally, patients should learn exercise techniques under the supervision of a qualified physical therapist. In patients with moderate-to-severe pulmonary disease, it is important to ensure adequate oxygenation during exercise.73 Aerobic activities, such as swimming, jogging, and cycling, are the most commonly recommended forms of exercise. Patients should be encouraged to exercise several times per week. Pulmonary rehabilitation regimens previously targeted for adults with emphysema and chronic bronchitis will likely prove to be effective in the CF population.

The health-care team must assist the patient and family in tailoring an airway clearance regimen that provides the best fit to the patient’s lifestyle and activities. Typically, this consists of conventional CPT and/or a suitable alternative airway clearance technique, combined with an aerobic exercise program. The frequency and duration of each treatment should be individualized. Patients with minimal-to-mild symptoms may only require one session a day, whereas others with a greater volume of thick secretions may need three or more sessions per day. Developing an individualized regimen that is acceptable to the patient and the physician is a trial-and-error process that requires staff who are well-versed in airway clearance techniques and exercise physiology. Care providers must consistently encourage and monitor adherence, a major issue with this aspect of care, and modify the regimen as necessary.

Mucolytic Agents:

Recombinant human DNase (also known as α-dornase or Pulmozyme; Genentech; South San Francisco, CA) decreases the viscosity of CF sputum by catalyzing extracellular DNA into smaller fragments.74A large phase III randomized, double-blind, placebo-controlled trial showed a modest improvement in pulmonary function in the DNase-treated groups (5.8% and 5.6% relative improvement in FEV1 from baseline, respectively, in the groups treated once and twice a day compared to the placebo group), decreased pulmonary exacerbation rate (28% and 37% reductions, respectively, in the age-adjusted risk of pulmonary exacerbations in patients treated once and twice a day compared to the placebo group), and some improvement in CF-related symptoms.75 The decrease in respiratory tract infections resulted in fewer days in the hospital and fewer days receiving parenteral antibiotics for the DNase-treated groups.

It is not clear whether the differences in pulmonary function and respiratory tract infection rate observed in this clinical study will impact mortality. The majority of participants in the phase III trial continued receiving DNase for up to 2 years in an open-label extension of the study. Age-adjusted and height-adjusted pulmonary function at the 2-year point was declining at the same rate as in the placebo-treated group during the randomized portion of the trial.76This would suggest that DNase had perhaps delayed but not prevented progression of the disease. However, it should be kept in mind that this trial consisted of a patient population that was not representative of the CF population as a whole. Specifically, this was an older group of patients with more significant obstructive airways disease. Another randomized trial77 in even more severely affected patients with FVC values of < 40% also showed improvement in FEV1 from baseline (DNase-treated group, 9.4%; control group, 2.1%) over the 12-week study period.

More recently, the results of the Pulmozyme Early Intervention Trial have been published.78 This phase III, double-blind, placebo-controlled trial in children with mild disease showed modest improvement in pulmonary function and a reduction in pulmonary exacerbations over a 2-year period. The long-term impact of treating a mildly affected population of patients is not known at present.

Postmarketing clinical experience has confirmed the relative safety of DNase. Hoarseness, voice alteration, and pharyngitis are the major adverse events related to DNase, and, in most cases, these symptoms are self-limited and do not require the cessation of drug therapy.75 In addition, concerns that DNase might release neutrophil elastase bound to DNA and thereby exacerbate the inflammatory state have been resolved. Shah et al79 found a decline in neutrophil elastase activity and interleukin-8 levels in the sputum of CF patients treated with DNase over a 6-month time period.

Should DNase be prescribed to all CF patients? Patients with chronic productive cough, particularly those with moderate-to-severe obstructive airways disease, should be considered for a therapeutic trial of once-per-day DNase for a period of several months. The drug can be started safely during an acute pulmonary exacerbation80 as well as during a stable period. Patients should be monitored by symptoms, pulmonary function tests (PFTs), and pattern of exacerbations. Unfortunately, there are no clear-cut criteria to judge clinical response. In the phase III trial, subjects who did not show an improvement in spirometry still had a reduction in pulmonary exacerbation rate.75 Often the patient’s subjective response to the drug is a major factor in the decision to continue therapy for the long term. This is certainly reasonable; however, patients should be encouraged to give the drug a fair trial of at least several months. Some severely affected patients seem to benefit symptomatically from a twice-a-day regimen.

Mildly affected patients also should be made aware of this drug and its potential benefits. The relatively high cost of DNase may factor into a decision about whether to prescribe this therapy for a mildly affected adult, but a therapeutic trial in an individual patient is justifiable and should be considered with currently available information.

There are no well-validated alternative mucolytic agents available at this time. N-acetylcysteine reduces viscosity of sputum in vitro, presumably by breaking disulfide bonds. The nebulized form of the drug has been used in CF patients but has not been carefully studied. Trials8182 in patients with COPD have not demonstrated a significant beneficial effect. Furthermore, the drug can be very irritating to the upper airway and can cause bronchoconstriction.83Some European studies have suggested a modest benefit from oral N-acetylcysteine, particularly in patients with moderate-to-severe disease,84but others have not confirmed these findings.85It is not even clear that adequate amounts of orally administered drug penetrate into the airways to have a mucolytic effect.86 For these reasons, the efficacy and safety of N-acetylcysteine has not been established.

There has been renewed interest in the use of nebulized hypertonic saline solution to facilitate airway clearance. It improves mucociliary clearance,87likely by its effects on sputum viscoelasticity.8889 A short-term (ie, 2-week) clinical trial90 demonstrated that nebulization of a 6% saline solution twice a day resulted in an improvement in PFTs compared to a control group that nebulized an isotonic saline solution (15.0% vs 2.8% improvement, respectively, in FEV1 from baseline; p = 0.004). Hypertonic saline solution has the potential to cause bronchospasm in patients with CF,91 but this may be preventable by pretreatment with a bronchodilator. The preliminary data are promising, but it is premature to recommend the widespread use of hypertonic saline solution at this time.

Bronchodilators:

The majority of patients with CF demonstrate bronchial hyperreactivity at least some of the time.92Bronchodilators have therefore become a standard component of the therapeutic regimen. Nebulized β-adrenergic agonists are the most commonly prescribed agents. They are often used to provide symptomatic relief and, prior to CPT, to facilitate clearance of the airways. Konig and colleagues93reported that maintenance albuterol treatment reverses the progressive downhill course in lung function in CF patients. A longer term, placebo-controlled, double-blind study94 also showed sustained improvement in PFT scores in a group of patients treated with albuterol, but the difference from the control group was not statistically significant, likely because of an insufficient number of study subjects.

These agents are, in general, well-tolerated in the CF population. Most patients demonstrate improved pulmonary function with bronchodilators,9596 but the occasional patient may actually worsen with bronchodilator therapy.97 Airflow may decrease paradoxically, or hyperinflation may worsen because of smooth muscle relaxation and decreased airway elasticity. Periodic pulmonary function testing and careful attention to symptoms will identify those few patients in whom bronchodilator therapy is counterproductive.

In summary, the potential benefits of inhaled β-agonist agents outweigh the risks. They should be considered for all adults with CF. Long-acting aerosolized β-adrenergic agonists also may have a role in this disease. Salmeterol has been associated with better preservation of pulmonary function and oxygenation through the night.9899 In addition, a 24-week randomized, double-blind, placebo-controlled crossover study100involving 23 patients with mild-to-moderate pulmonary disease showed that high-dose salmeterol (100 μg/d) was equally safe, and was associated with better pulmonary function, fewer antibiotic interventions, and fewer respiratory symptoms compared to twice daily therapy with nebulized albuterol. Oral preparations have no advantage over the inhaled medications in reversing bronchospasm,101 so they are not commonly used.

Anticholinergic bronchodilators may be helpful for some patients with CF. Atropine has been associated with unacceptable systemic side effects, but ipratropium bromide is very poorly absorbed and much better tolerated. It has been shown to have some benefit in asthma102and may be of use in CF patients as well. Weintraub and Eschenbacher103observed that ipratropium may be more effective than β-adrenergic agonists in adults with CF. Adults may have less bronchospasm but more secretions than children. The airway of the adult CF patient may more closely mimic that of the adult with chronic bronchitis, and therefore may be more responsive to the effects of a parasympathomimetic agent. Some patients appear to benefit from combination therapy with a β-adrenergic agonist and an anticholinergic agent.104 A therapeutic trial of combination therapy is indicated for patients with bronchospasm that is not well-controlled by β-agonist therapy alone.

Theophylline increases mucociliary clearance, diaphragmatic contractility, and CNS respiratory drive.105 Unfortunately, it has a narrow therapeutic range that requires the monitoring of plasma concentrations. In addition, a variety of adverse effects occur with this drug, including nausea, vomiting, and gastroesophageal reflux, which limits its utility in patients with CF.

Anti-inflammatory Therapies:

Some patients with CF have asthma or asthma-like symptoms that require more than therapy with bronchodilators alone. The full asthma armamentarium can be used to treat their bronchospasm. Inhaled or oral glucocorticoids seem to be generally more efficacious than cromolyn or nedocromil, but both classes of drugs are widely used in the treatment of CF patients. Other patients with CF require glucocorticoids for the treatment of allergic bronchopulmonary aspergillosis. We will not focus on these issues but rather will address the role of anti-inflammatory agents for the nonasthmatic patient with CF with chronic airways infection and inflammation.

Short-term therapy (3 weeks) with daily corticosteroids in stable patients with severe obstruction showed no benefit.106A population with less severe disease treated with 2 weeks of daily therapy with corticosteroids (2 mg/kg/d), followed by alternate-day steroid therapy for an additional 10 weeks (1 mg/kg every other day), showed improvement in pulmonary function, and a decrease in serum cytokine and IgG levels.107A longer study108(4 years) of therapy with alternate-day steroids (2 mg/kg every other day) also suggested a benefit from steroids with respect to pulmonary and nutritional parameters. This promising result led to a larger multicenter randomized trial comparing alternate-day therapy with prednisone at 2 mg/kg and 1 mg/kg to placebo. This trial enrolled only children and adolescents with CF, but the results are of interest to adult care providers. The higher dose group was discontinued because of an unexpectedly high incidence of cataracts, glucose intolerance, and growth retardation.109The 1 mg/kg and placebo groups continued to the end of the 4-year trial. The steroid-treated group showed benefit with respect to pulmonary function, particularly the subset of patients colonized with P aeruginosa.110 However, that benefit was at the expense of growth. A subsequent analysis111 showed that steroid-treated men had persistent growth impairment after steroid therapy was discontinued, as indicated by reduced adult height in comparison with the placebo group. Bone density was not an end point in this trial but is another significant concern with this therapy. In summary, the data suggest that corticosteroids may have a beneficial effect but at significant cost. For this reason, long-term oral corticosteroid therapy, even in an alternate-day regimen, probably should be avoided if possible. These studies do, however, suggest that an anti-inflammatory approach has promise.

Therapy with inhaled steroids is a potential way to reduce inflammation without significant systemic adverse effects. Relatively low doses of inhaled beclomethasone (400 μg/d) showed no effect on various markers of airways inflammation.112Higher doses of inhaled steroids have shown some promise in preliminary studies,113114 but larger trials with longer term data are needed before this therapy can be recommended.

High-dose ibuprofen therapy (20 to 30 mg/kg, up to 1600 mg, bid) slowed the progression of pulmonary disease in mildly affected patients (ie, FEV1 > 60% of predicted), particularly in children 5 to 12 years of age.115 It is important to emphasize that a pharmacokinetic study should be done to verify that therapeutic blood levels of the drug have been achieved. Close monitoring for adverse events is also important, including a semiannual check on renal function. The potential risks of ibuprofen (GI and renal) should be carefully weighed in deciding whether to treat mildly affected adults. There are no data to support this therapy in patients with moderate-to-severe obstructive airways disease (ie, FEV1 < 60% of predicted). Because of concern about an increased risk of hemoptysis, high-dose ibuprofen therapy should be avoided in this subset of patients.

The use of leukotriene modifiers in the CF population deserves careful study. These drugs have some attractive features, but, given the scarcity of data in CF patients, they cannot be recommended at this time.

Oxygen:

Clinically apparent cor pulmonale is a poor prognostic indicator.116The goals should be to prevent the development and/or progression of pulmonary hypertension. Data from Toronto117 demonstrate that subclinical pulmonary hypertension develops in a significant proportion of patients with CF and is strongly correlated with hypoxemia, independent of pulmonary function. Furthermore, subclinical pulmonary hypertension appeared to be associated with increased mortality compared to a group with a similar degree of spirometric impairment without pulmonary hypertension.

The most important therapy for the prevention of pulmonary hypertension is supplemental oxygen, but there are limited data available on its use in treating CF. Zinman et al118 were unable to demonstrate a beneficial effect of nocturnal oxygen therapy in patients with CF. However, there were several weaknesses in this study. A relatively small number of patients were enrolled, and some of them did not meet the usual criteria for receiving supplemental oxygen therapy. In addition, oxygen was used only at night for an average of 7.0 ± 1.9 h. In the absence of persuasive data in CF patients, we must turn to the literature on oxygen administration in COPD patients.

Supplemental oxygen has been shown to improve exercise tolerance and survival in COPD patients. The Nocturnal Oxygen Therapy Trial Group119and the Medical Research Council Working Party120 both demonstrated that oxygen administration improved survival in severely affected, hypoxic COPD patients. The criteria for supplemental oxygen therapy in these studies (ie, Pao2 < 55 mm Hg during the daytime while breathing room air or < 59 mm Hg in the presence of pedal edema, polycythemia, or ECG evidence of impairment of the right side of the heart) have been widely adopted by the medical community. Continuous oxygen therapy is indicated for such patients.

Patients are more likely initially to develop hypoxemia with exercise or during sleep.121123 Clinicians must be aware of this and must intermittently screen patients with moderate-to-severe pulmonary disease accordingly. Oxygen is indicated during exercise if the exercise oxygen saturation level falls below 88 to 90%. Nocturnal oxygen therapy is indicated if oxygen saturation is < 88% to 90% for ≥ 10% of the total sleep time.

Complications:

In general, adults with CF have more severe pulmonary disease than children. This puts them at higher risk for serious complications such as pneumothorax and massive hemoptysis (Table 1). The adult care team must have expertise in dealing with these medical emergencies in a timely and proficient fashion. The CFF consensus statement on pulmonary complications124 details an approach to these problems.

The majority of CF patients die in adulthood of respiratory failure. The health-care team must be prepared to deal with the complex medical and psychosocial end-of-life issues (see “End-of-Life Options” section). The issue of advanced care directives should be addressed in the clinic with all patients, particularly in severely affected patients, when their conditions are stable. An individual patient’s decisions about end-of-life issues and lung transplantation may impact the health-care team’s treatment approach, including decisions about ICU admission, ventilatory support, and management of pneumothorax.

Exocrine Pancreas
Diagnosis of Pancreatic Insufficiency:

Eighty-five to 90% of patients with CF have exocrine pancreatic insufficiency, which is defined as elevated fecal fat excretion.125 The majority of adults with CF have exocrine pancreatic insufficiency, although those with mild mutations of CFTR may have residual pancreatic function and may not require supplemental pancreatic enzymes. These patients are, however, at increased risk for acute or recurrent episodes of pancreatitis.45 The decision to treat a patient with enzyme supplements rests on demonstrating the presence of steatorrhea. This generally correlates with symptoms of diarrhea, foul-smelling greasy stools, weight loss or poor weight gain, flatus and abdominal discomfort, and fat-soluble vitamin deficiency. For young adults who received diagnoses during childhood, enzyme supplementation should be continued. For newly diagnosed adults, a 72-h fecal fat collection should be performed while the patient is on a fixed oral fat intake or with dietary records. Fecal fat excretion ([grams of fat excreted/grams of fat ingested] × 100%) can be calculated from these data. Fecal fat excretion of > 7% indicates steatorrhea in an adult and mandates the initiation of pancreatic enzyme and vitamin supplementation (see “Nutrition” subsection). In specialized CF centers, the quantitative assessment of pancreatic excretory function may be performed to better define the stimulated output of pancreatic enzymes into the duodenum,126but this is not necessary on a routine clinical basis. Levels of fecal chymotrypsin,127serum pancreatic trypsinogen,128and fecal pancreatic elastase-1129may be low in patients with pancreatic insufficiency, however, these tests have not been fully evaluated for use in adults with CF. Recent evidence130 has suggested that the fecal pancreatic elastase 1 immunoassay may prove to be a noninvasive, simple, and reproducible method of assessing pancreatic function.

Pancreatic Enzyme Supplements:

Most modern pancreatic enzyme products are capsules that contain enteric-coated microencapsulated enzymes, either as microspheres or microtablets. The enteric coating prevents inactivation of the enzymes in the acidic gastric environment. The dissolution of generic microspheres or microtablets may not be equivalent to that of proprietary brands.131The substitution of one brand for another by the pharmacist may result in vastly different clinical responses despite equal enzyme doses and should not be allowed. The ratio of proteases to lipases differs in various brands of enzymes; however, it is uncertain whether this is clinically relevant. The US Pharmacopoeia requirements state that enzyme products may contain not < 90% of the amount stated on the label but do not set an upper limit for the content. The manufacturers usually overfill the capsules to compensate for enzyme degradation during storage.132

Enzyme supplements should be given with meals and snacks, with the number of capsules divided between the beginning and the end of the meal. Some patients may be able to take all of the capsules at the beginning of the meal without problems. Enzyme dosing can be calculated on the basis of the amount of fat ingested with each meal.133In general, patients need 500 to 4000 U lipase per gram of fat ingested per day. This method of dosing mimics the body’s response to adjusting pancreatic enzyme excretion but may be tedious to calculate. Although less physiologic, it is frequently more practical and convenient to determine the enzyme dose based on body weight.134 Adults should start with approximately 500 U lipase per kg body weight per meal, and half of that with snacks. If this dose quickly corrects the fat malabsorption, then attempts should be made to reduce the dose to the minimum effective dose. If symptoms of steatorrhea continue (or if the results of 72-h fecal fat collection tests are still abnormal), then the dose should be increased in increments of approximately 150 to 250 U lipase per kilogram per meal until symptoms improve, up to a maximum of 2500 U lipase per kilogram per meal (or 4000 U lipase per gram of fat per day). Doses higher than this level should be used with caution because of the risk of the occurrence of fibrosing colonopathy with higher doses.134136 Patients receiving doses > 2500 U lipase per kilogram per meal should be reevaluated, and attempts should be made to reduce the dose of enzyme supplements.

Poorly Responding Patients:

Some patients may continue to have symptoms of steatorrhea despite taking appropriate doses of enzyme supplements. Adherence to the enzyme therapy should be assessed in this situation. Giving some of the enzyme capsules at midmeal may be of some benefit. The hyperacidity of the upper GI tract in CF patients is one of the most common reasons for suboptimal response to enzyme therapy. Gastric acid output may not be neutralized because of inadequate bicarbonate secreted by the pancreas. This retards the dissolution of the enteric-coated microspheres or microtablets.137Drugs that reduce gastric acid production (eg, H2-blockers and proton-pump inhibitors) may help to improve the dissolution of these products and reduce steatorrhea.139 Other therapeutic considerations include the addition of non-enteric-coated, powdered preparations (eg, Viokase; Axcan Scandipharm), or a trial of an alternate brand of microencapsulated product with a different dissolution profile.

Short bowel syndrome, previous intestinal resections, and rapid GI transit are other conditions in which the microencapsulated enzyme preparations may not dissolve well. The addition of small amounts of pancreatic enzyme non-enteric-coated, powdered preparations with or without gastric acid suppression may improve fat digestion in the more proximal intestine and may improve steatorrhea. In patients who have continued symptoms despite adequate enzyme supplementation and acid suppression, other diagnoses should be considered, including infectious gastroenteritis, parasitic infestation (eg, giardiasis), lactose intolerance, bacterial overgrowth of the small intestine, cholestasis, Clostridium difficile disease, celiac disease, short bowel syndrome, Crohn disease, food allergies, or intestinal tumors. Appropriate evaluation and treatment for these disorders should be conducted when indicated.140

Nutrition
General Principles:

The importance of nutritional status in the long-term survival of patients with CF is well-documented.141144 The prevention of malnutrition should be a primary goal of the health-care team. A standard North American diet with 35 to 40% of calories from fat is recommended.133 The tendency to restrict fat consumption in these patients should be discouraged since dietary fat is the highest density source of calories, improves the palatability of foods, and is needed to maintain normal essential fatty acid status. In general, CF patients with pancreatic insufficiency are not at risk for developing hyperlipidemia.145However, patients with pancreatic sufficiency may be at risk and should be screened according to national guidelines for the general population.146

Individuals with CF should be encouraged to follow a normal dietary pattern with no specific restrictions. The dietitian can assist patients in selecting more energy-dense foods with additional snacks to improve energy intake. Snacks such as nuts, muffins, cheese, and milkshakes may be helpful. Commercial oral supplements also may be used, but one must ensure that these costly supplements are an addition to, rather than a replacement for, calories from food.

Careful monitoring of patient nutritional status is aimed at the early detection and correction of unfavorable trends. Patients should be made aware of their ideal body weight (IBW) range, as estimated by using the Metropolitan Life Insurance Company height and weight tables for individuals of small frame.147 Instructions can be provided for patients to monitor their weight at home and to report promptly significant weight loss. Weight should be measured on each clinic visit and compared to IBW based on height. The Clinical Practice Guidelines for Cystic Fibrosis1 of the CFF suggests that patients be categorized as adequately nourished (> 90% IBW), underweight (85 to 89% IBW), mildly malnourished (80 to 84% IBW), moderately malnourished (75 to 79% IBW), or severely malnourished (< 75% IBW). Some centers track body mass index (BMI); BMI is calculated as follows: weight (kg)/height (m2) with a normal range of 20 to 25. A BMI of < 19 indicates significant malnutrition and a need for aggressive nutritional intervention. Some centers also find it helpful to measure triceps skinfold and midarm circumference as indicators of body fat and lean body mass.,133

Approach to the Malnourished Patient:

Patients who are malnourished or are losing weight should be evaluated in more detail and observed more closely. A dietitian should assist in the evaluation. Caloric need and actual intake should be assessed. Energy needs are based on individual requirements and can be calculated based on basal metabolic rate using the World Health Organization equations.133 It is also important to assess malabsorptive symptoms. The approach to patients who continue to have steatorrhea despite taking appropriate doses of enzymes has been reviewed above. For patients with weight loss unrelated to caloric intake or malabsorption, alternative GI diagnoses and diabetes mellitus (DM) should be considered in the differential diagnosis.

Patients with moderate or severe malnutrition are candidates for more aggressive nutritional interventions. There are data suggesting that nutritional repletion has a positive impact on the course of the disease for such patients.148151 The placement of a nasogastric tube each night for supplemental feedings during sleep is an option for some patients, but this is inconvenient and poorly tolerated by some patients, particularly those with severe pulmonary disease. The insertion of a gastrostomy or jejunostomy tube is an acceptable method for increasing caloric intake in selected patients. Placement is generally well tolerated; however, the risk/benefit ratio must be carefully considered in patients with severe pulmonary disease because of the potential for respiratory compromise following the procedure. Choice of an enteral supplement must be individualized. Semi-elemental formulas do not require pancreatic enzymes, but complete formulas are generally well tolerated when given with enzyme therapy.152Parenteral nutrition may be appropriate for short-term nutritional repletion in a severely malnourished patient,153 but the enteral route is more appropriate and safer for long-term support.

Vitamin Supplementation:

Patients with pancreatic insufficiency are prone to malabsorption of the fat-soluble vitamins (ie, A, D, E, and K). Clinicians must be aware that patients may manifest clinically important vitamin deficiency states (eg, night blindness in vitamin A deficiency, spinocerebellar degeneration or hemolytic anemia in vitamin E deficiency, metabolic bone disease in vitamin D deficiency, and bleeding diathesis in vitamin K deficiency). Vitamin supplementation is recommended, including the following: vitamin A, 10,000 IU/d; vitamin E, 200 to 400 IU/d; vitamin D, 400 to 800 IU/d and adequate sunlight exposure; and vitamin K, 2.5 to 5 mg/wk.133 The vitamins containing vitamins A, D, E, and K that are specially formulated for CF patients are sufficient for most adult patients when taken at a dosage of two tablets per day. Some patients require additional supplementation. To ensure adequate amounts of vitamin K, patients receiving frequent courses of antibiotics or those with a history of hemoptysis should be given an additional 2.5 to 5 mg vitamin K each week.154 Serum levels of retinol, vitamin E, and 25-hydroxyvitamin D (25-OHD) should be checked annually, and vitamin doses should be adjusted accordingly. Clinicians should be aware that other nutrient deficiency states (eg, zinc, essential fatty acids, and antioxidants) have been reported in CF patients, but routine monitoring or supplementation is not recommended at this time. As in the general population, menstruating women often need supplemental iron to prevent iron-deficiency anemia. Other patients with CF are also at risk of developing iron-deficiency anemia. In some cases, iron-deficiency anemia must be distinguished from anemia resulting from chronic disease.

CF-Related DM

A CFF consensus conference155 addressed the diagnosis, screening, and management of CF-related DM (CFRD). This section will briefly highlight the salient points of that report. Glucose intolerance and CFRD are age-related complications of CF. The CFF patient registry of > 22,000 individuals indicates that the incidence of insulin-requiring DM in CF-affected children < 10 years of age is similar to that of unaffected children (ie, < 1%). However, from adolescence into adulthood there is a progressive increase in the incidence of CFRD. More than 15% of patients > 35 years of age have CFRD and are receiving insulin therapy.,2,156 An even larger percentage may have undiagnosed CFRD. Using oral glucose tolerance tests (OGTT) to screen a large patient population, one US CF center has reported155156 a prevalence of 43% in patients > 30 years of age (Fig 2 ). The pathogenesis of CFRD is complex, but largely is related to fibrosis and the destruction of the pancreas. Therefore, CFRD is seen most commonly in individuals who have exocrine pancreatic insufficiency.

CFRD is associated with increased morbidity and mortality.144,157158 Several studies155 have shown deterioration in pulmonary function and BMI in the 2 to 4 years preceding the diagnosis of CFRD. In an analysis of 3,227 adults who were observed in the CFF patient registry from 1991 to 1996, the presence of CFRD requiring insulin was associated with more than a 2.5-fold increase in the relative risk of mortality during the observation period. A cause-and-effect relationship between CFRD and excess morbidity and mortality cannot be definitively established. CFRD simply may be a marker of advanced disease and concomitant metabolic stress. However, one study159showed that the initiation of insulin therapy reversed the deterioration in body mass and pulmonary function in patients with CFRD. This lends weight to the hypothesis that untreated CFRD is an independent risk factor for poor outcomes. Also in favor of this hypothesis are the recent data showing that patients with relatively mild lung disease and impaired glucose tolerance appear to be at risk for a more rapid decline in pulmonary function compared to patients with normal glucose tolerance.160

Microvascular complications occur in patients with CFRD, with a reported incidence of 5 to 16% for retinopathy, 3 to 16% for nephropathy, and 5 to 21% for neuropathy.161163 However, the occurrence of macrovascular complications (eg, atherosclerosis, myocardial infarction, and stroke) appears to be rare.164

Several clinical situations that are more common in the adult patient appear to be associated with CFRD. Women with CF who become pregnant may be at increased risk of gestational diabetes. Of note, women with CFRD who become pregnant appear to be at increased risk of deterioration in pulmonary function and excess mortality in the 2 years following parturition compared to nonpregnant CF women with CFRD.165 CFRD frequently develops in those patients with end-stage lung disease and has been associated with frequent pulmonary exacerbations, the use of corticosteroids, and supplemental (enteral or IV) feedings. The posttransplantation immunosuppressive regimen is frequently associated with onset and/or exacerbation of CFRD.

Screening and Diagnosis:

A casual or random glucose determination should be performed annually in all adults with CF. A value < 126 mg/dL (7 mmol/L) is considered to be normal. A value of ≥ 126 mg/dL is considered to be abnormal and warrants measurement of fasting blood glucose (FBG) level. A casual glucose value of > 200 mg/dL (11.1 mmol/L) on two or more occasions is diagnostic of CFRD, as are either an FBG level of ≥ 126 mg/dL on two or more occasions or an FBG level of ≥ 126 mg/dL in association with a casual glucose level of > 200 mg/dL.155 In ambiguous cases, an OGTT (using 1.75 g/kg up to a maximum of 75 g) should be performed. A 2-h postprandial glucose value of > 200 mg/dL is considered to be diagnostic of CFRD. An OGTT also should be performed in all women with CF who are contemplating pregnancy. It should be repeated soon after conception, and early in the second and third trimesters.166 Certain clinical situations such as unexplained weight loss or failure to gain weight, delayed onset of puberty, and unexplained deterioration in pulmonary function suggest the possibility of undiagnosed CFRD. Glucose tolerance should be assessed in these situations.

Treatment of CFRD:

The consensus of the committee was to treat CFRD aggressively in patients with fasting hyperglycemia. The principles of insulin and nutritional therapy in CFRD differ from those in either type 1 or type 2 DM. Therefore, the optimal management of CFRD is by the multidisciplinary CF team in conjunction with an endocrinologist or diabetologist. The goals of therapy are as follows:

  • Maintain optimal nutritional status;

  • Control hyperglycemia to reduce acute and chronic diabetes complications;

  • Avoid severe hypoglycemia;

  • Promote psychological, social, and emotional adaptation to living with CFRD; and

  • Be as flexible as possible within the framework of the patient’s lifestyle.

Patients with CFRD and fasting hyperglycemia should be treated with insulin. The use of oral hypoglycemic agents cannot be recommended at this time. The nutritional management of CFRD is similar to the general approach for all patients with CF except that more attention is paid to the timing of meals and the avoidance of concentrated carbohy-drates. The pattern of hyperglycemia in CFRD differs from that in type 1 DM. Some basal insulin secretion is usually preserved, making fasting hyperglycemia less severe and ketosis extremely uncommon. In contrast, postprandial hyperglycemia is often a prominent feature of CFRD. Therefore, a typical regimen often includes the use of very short-acting insulin (eg, lispro) prior to each meal. Appropriate dosing requires that patients either eat a predictable meal or use a carbohydrate counting system to estimate insulin requirements. A small amount of long-acting insulin may be required as well. Regular home glucose monitoring is essential in making the necessary adjustments in the insulin regimen.

Monitoring of therapy also should include the quarterly measurement of hemoglobin A1c. Hemoglobin A1c values are often a less useful guide than in type 1 DM, but similar target values of < 7% for adults and < 8% for adolescents should be the goal. However, even a “good” glycohemoglobin value may be associated with an unacceptable degree of postprandial hyperglycemia in some individuals. Goals for glycemic control in pregnant women are more stringent than those for men and nonpregnant women.167

All patients with CFRD should be screened annually for microvascular complications with a dilated eye evaluation and a urinalysis for microalbumin measurement. The presence of proteinuria should be taken particularly seriously in patients with CFRD, as it may indicate the onset of diabetic nephropathy. The concomitant use of nephrotoxic drugs (eg, aminoglycoside antibiotics, nonsteroidal anti-inflammatory drugs, and posttransplant immunosuppressive agents) may increase the susceptibility to nephropathy. As with all people with diabetes, hypertension should be aggressively treated, usually with a regimen that includes an angiotensin-converting enzyme inhibitor.

The natural history of the abnormalities in glucose metabolism in CF patients is not fully understood. At this point in time, the treatment for impaired glucose tolerance and CFRD without fasting hyperglycemia is not recommended except in the context of clinical trials or in the clinical situations detailed above (eg, unexplained weight loss).155

The diagnosis of diabetes is difficult for some adults who see it as yet another burdensome imposition or as a sign of end-stage disease. Monitoring and treatment of CFRD are relatively labor-intensive and add to an already complex regimen. The support and understanding of the CF team will help the patients to incorporate this additional challenge into their daily regimen.

Hepatobiliary Disease

A CFF consensus conference168addressed the clinical features, diagnostic evaluation, and management of liver and biliary disease. The salient features of that document are highlighted here. The involvement of the liver and biliary tree in CF may lead to a gradually progressive biliary fibrosis and cirrhosis. It is estimated that up to 17% of children have clinically significant liver disease.169170 Data about the prevalence in adults are incomplete, but in one retrospective review170 of 233 adults (> 15 years of age), 24% were found to have hepatomegaly or persistently abnormal liver blood test results. As the median survival time for CF patients increases, clinically significant liver disease and its complications will likely become a more important consideration.

Screening for Liver Disease:

Examination and measurement of the liver and spleen by palpation and percussion should be performed at each clinic visit. A panel of liver function tests (LFTs) including serum aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase, γ-glutamyl transferase (GGT), and bilirubin should be obtained yearly. None of these tests correlates with the degree of hepatic fibrosis. Nevertheless, if any of these values is > 1.5 times the upper limit of normal, repeat testing should be performed within 3 to 6 months. Patients with persistent elevations (ie, occurring for > 6 months) or high elevations (ie, more than three to five times the upper limit of normal) of LFT results should be investigated more completely.

Diagnostic Evaluation:

A workup for liver disease should begin with a focused history and physical examination. Other causes of elevated aspartate aminotransferase and alanine aminotransferase levels (eg, hepatitis A, B, or C virus; cytomegalovirus; Epstein-Barr virus; alcohol; drugs; or toxins) and/or elevated GGT or alkaline phosphatase levels (eg, gallstones, cholecystitis, biliary obstruction, or bone disease) should be considered in the differential diagnosis. In addition to the routinely measured LFTs, biochemical evaluation should include total and direct bilirubin levels, total protein level, albumin level, prothrombin time, blood ammonia level (if significant portal hypertension is suspected clinically), cholesterol and glucose levels, and a CBC count to check for hematologic consequences of hypersplenism.

An ultrasound evaluation of the right upper quadrant of the abdomen should be obtained to detect the presence of gallstones, common bile duct stones, nodularity of the liver suggesting cirrhosis, findings suggesting steatosis, and bile duct or hepatic vein dilatation. This test provides very useful information but cannot detect or quantify the degree of fibrosis of the liver. Hepatic scintigraphy has limited clinical utility in the evaluation of suspected liver disease.

Endoscopic retrograde cholangiopancreatography (ERCP) can reveal strictures, dilatation, stones, and other abnormalities of the biliary tree. Although changes in intrahepatic bile ducts are relatively common in CF liver disease,171 common bile duct stenosis is much less common (ie, < 10% of patients with advanced liver disease),171 than initially reported.170 Because of the risks associated with this procedure, ERCP should be used only when there are clear-cut clinical indications. MRI cholangiography is a noninvasive technique that is used to visualize the biliary tree. It may be useful in examining the extrahepatic biliary tree, gallbladder, and major intrahepatic ducts.172 This imaging modality should be considered prior to the use of ERCP.

Upper GI endoscopy is the most sensitive way to detect esophageal varices, gastric varices, portal hypertensive gastropathy, or gastric and duodenal ulcers. Endoscopy should be considered in adults with portal hypertension to determine whether varices are present since this information has prognostic and therapeutic implications.

Liver biopsy may be useful in making a specific diagnosis, and in determining the presence and extent of portal fibrosis or cirrhosis. However, not all clinicians believe that liver biopsy is indicated in investigating liver disease in CF because of the patchy nature of CF-related biliary cirrhosis and the lack of definitive therapy. Careful consideration of the risks of a liver biopsy should be made on an individual basis in conjunction with an experienced gastroenterologist.

Management of Liver Disease:

A multidisciplinary approach is recommended for the management of liver disease in CF. The team should include the CF center staff, a gastroenterologist/hepatologist, a surgeon experienced in hepatobiliary surgery, and a radiologist. The reader is referred to the 1999 CFF consensus document168 for a detailed description of each of the following three major CF-related causes of liver disease: (1) cholestasis/biliary cirrhosis/multilobular cirrhosis; (2) hepatic steatosis; and (3) hepatic congestion from cor pulmonale. It is important to establish a definitive diagnosis since each is managed differently and is associated with its own set of complications. For the purposes of this document, we will focus on the most common CF-related liver lesion, cirrhosis. Cholestasis, focal biliary cirrhosis, and multilobular cirrhosis are part of a sequential progression that occurs over a variable period of time, therefore, certain aspects of treatment are similar for these three lesions. The therapeutic approach includes medical therapy, nutritional therapy, management of complications (eg, portal hypertension and liver failure), and prophylactic therapy.

Medical Therapy:

There is convincing evidence of the benefit from therapy with ursodeoxycholic acid (UDCA) in non-CF patients with a similar liver lesion (ie, primary biliary cirrhosis).173174 UDCA therapy significantly retards the progression of this cholestatic liver disease, as evidenced by improved survival times free of liver transplantation. UDCA therapy improves bile flow in CF patients,175may displace toxic hydrophobic bile acids that accumulate in the cholestatic liver,176 may have a cytoprotective effect,176177 and may stimulate bicarbonate secretion into bile.178Several, but not all, clinical trials179185 have demonstrated improvement in LFT results with UDCA therapy. A randomized, double-blinded, placebo-controlled trial186demonstrated significant clinical, nutritional, and biochemical improvement in the group treated with UDCA. Liver histology improved in another prospective 2-year trial of UDCA treatment.187

Conclusive evidence that UDCA alters mortality or the progression to cirrhosis is lacking. Nonetheless, clinicians should strongly consider treating CF patients who have cholestasis/fibrosis/cirrhosis. The appropriate dose is 20 mg/kg/d UDCA administered in two daily doses.188189 Adverse effects and toxicity from UDCA are uncommon. When they occur, they are usually not clinically significant and rarely lead to the discontinuation of treatment. Monitoring during therapy should include LFTs 3 months after initiating therapy and each 6 to 12 months thereafter. Repeat liver biopsy is generally not recommended because the focal nature of the liver lesion may make the assessment of histologic change over time difficult in an individual patient. There is no scientific justification for using UDCA in patients with CF who have little or no documented liver dysfunction or portal fibrosis.

Taurine has been suggested as an adjunctive therapy in liver disease because CF patients are commonly deficient in taurine.185However, in a randomized, double-blind trial, Colombo et al186 showed no significant effect of taurine supplementation (17 to 33 mg/kg/d) on liver blood test results or fecal fat excretion measurements in patients with CF liver disease who were treated with UDCA or placebo.

Nutritional Therapy:

Monitoring fat-soluble vitamin status is even more important in the presence of liver disease190 than in the presence of pancreatic insufficiency alone. All vitamin doses should be given with a meal and with pancreatic enzyme supplements. Supplementation with the water-soluble form of vitamin E (d-α-tocopherol polyethylene glycol [PEG]-1000 succinate) at a dose of 400 to 1200 IU/d will correct or prevent vitamin E deficiency in this setting. Patients also may need large doses of vitamin D2 or D3 (800 to 1,600 IU/d) or 25-OHD (calcifediol; 2 to 4 mg/kg/d) to normalize serum 25-OHD concentrations. The optimal dose of vitamin A supplementation has not been determined; however, patients with low serum retinol levels (ie, < 15 to 20 μg/dL) should be supplemented with 10,000 to 20,000 IU per day. Serum retinol and retinol-binding protein should be monitored to ensure the adequacy of therapy, as well as serum retinyl ester concentration to assess for toxicity (elevated serum retinyl esters). Prothrombin time should be monitored to assess vitamin K status. Significant prolongation of the prothrombin time should be treated with 5 to 10 mg vitamin K given once per week to daily, depending on the response to therapy. Following any change in vitamin dosing, repeat biochemical testing to ensure nutritional adequacy should be performed in 1 to 2 months.

Portal Hypertension and Liver failure:

A detailed description of the management of these complications can be found in the CFF Consensus Statement.168 If esophageal varices are documented by endoscopy, prophylactic β-blocker therapy should be considered. There is no direct evidence of efficacy in CF, but β-blockers reduce the risk of a first episode of variceal bleeding191193 in adults with other forms of liver disease. Adverse effects of β-blockers, such as bronchospasm and depression, need to be taken into consideration. Endoscopic variceal ligation can be considered for patients who have large varices or who do not tolerate β-blocker therapy.194195 Patients who are at high risk of bleeding from varices or have recurrent variceal bleeding may be candidates for a portosystemic shunt.196197 Liver transplantation is a viable consideration for a patient with decompensated cirrhosis, particularly if pulmonary function is relatively well-preserved. Liver transplantation in CF patients results in a 1-year survival rate of approximately 75 to 80%.198199

Prophylactic Therapy:

All patients with CF liver disease should receive a complete immunization series for both the hepatitis A and hepatitis B virus vaccines, unless prior infection with these viruses has been documented. Patients should be counseled about the risks of ethanol use and encouraged to avoid ethanol. Potentially, hepatotoxic medications and herbal therapies also should be avoided, if possible.

Other Hepatobiliary Manifestations:

Micro-gallbladder occurs in about 30% of patients, and cholelithiasis or cholecystitis occurs in 1 to 12% of patients.200Cholelithiasis in CF is not responsive to UDCA therapy.201 Hepatic scintigraphy may be helpful in evaluating a patient for suspected cholecystitis. If, in the presence of gallstones, clinical symptoms of gallbladder dysfunction or pain are present or if LFT results remain abnormal, a laparoscopic or surgical cholecystectomy should be performed, unless end-stage liver disease is present. The health-care team should be aware of the potential impact of any abdominal surgery on pulmonary function, particularly in patients with moderate-to-severe pulmonary dysfunction. A liver biopsy and intraoperative cholangiogram always should be obtained during any cholecystectomy procedure in a patient with CF.

Common bile duct stenosis occurs occasionally in patients, possibly because of compression of the bile duct by the fibrotic pancreas.170171 Primary sclerosing cholangitis may occasionally occur; however, cholangiographic findings consistent with primary sclerosing cholangitis may be caused by CF. Finally, cholangiocarcinoma also has been reported.202

GI Complications