美国肺囊性纤维化指南

Cystic Fibrosis Pulmonary Guidelines Chronic Medications for Maintenance of Lung Health Patrick A. Flume1, Brian P. O’Sullivan2, Karen A. Robinson3, Christopher H. Goss4, Peter J. Mogayzel, Jr.5, Donna Beth Willey-Courand6, Janet Bujan7, Jonathan Finder8, Mary Lester9, Lynne Quittell10, Randall Rosenblatt11, Robert L. Vender12, Leslie Hazle13, Kathy Sabadosa14, and Bruce Marshall13 1Departments of Medicine and Pediatrics, Medical University of South Carolina, Charleston, South Carolina; 2Department of Pediatrics, University of Massachusetts Medical School, Worcester, Massachusetts; 3Department of Medicine, Johns Hopkins Medical Institutions, Baltimore, Maryland; 4Department of Medicine, University of Washington, Seattle, Washington; 5Department of Pediatrics, Johns Hopkins Medical Institutions, Baltimore, Maryland; 6Department of Pediatrics, University of Texas Health Science Center at San Antonio, San Antonio, Texas; 7Department of Nursing, Texas Children’s Hospital, Houston, Texas; 8Department of Pediatrics, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania; 9Department of Respiratory Therapy, Medical University of South Carolina, Charleston, South Carolina; 10Department of Pediatrics, Columbia University, New York, New York; 11Department of Medicine, University of Texas Southwestern, Dallas, Texas; 12Department of Medicine, Penn State Milton S. Hershey Medical Center, Hershey, Pennsylvania; 13Cystic Fibrosis Foundation, Bethesda, Maryland; and 14Dartmouth-Hitchcock Medical Center, Lebanon, New Hampshire Rationale: Cystic fibrosis is a recessive genetic disease characterized by dehydration of the airway surface liquid and impaired mucociliary clearance. As a result, individuals with the disease have difficulty clearing pathogens from the lung and experience chronic pulmo- nary infections and inflammation. Death is usually a result of re- spiratory failure. Newly introduced therapies and aggressive man- agement of the lung disease have resulted in great improvements in length and quality of life, with the result that the median expected survival age has reached 36 years. However, as the number of treatments expands, the medical regimen becomes increasingly burdensome in time, money, and health resources. Hence, it is important that treatments should be recommended on the basis of available evidence of efficacy and safety. Objectives: The Cystic Fibrosis Foundation therefore established a committee to examine the clinical evidence for each therapy and to provide guidance for the prescription of these therapies. Methods: The committee members developed and refined a series of questions related to drug therapies used in the maintenance of pulmonary function. We addressed the questions in one of three ways, based on available evidence: (1) commissioned systematic review, (2) modified systematic review, or (3) summary of existing Cochrane reviews. Conclusions: It is hoped that the guidelines provided in this article will facilitate the appropriate application of these treatments to im- prove and extend the lives of all individuals with cystic fibrosis. Keywords: antibiotics; antiinflammatory agents; bronchodilators; mucolytics; saline solution, hypertonic Cystic fibrosis (CF) is a complex multiorgan disease in which lung disease accounts for nearly 85% of the mortality (1). Lung de- struction is caused by obstruction of the airways due to dehydrated, thickened secretions, resultant endobronchial infection, and an exaggerated inflammatory response leading to development of bronchiectasis and progressive obstructive airways disease. Physi- cians treating patients with CF are faced with a growing number of treatment options for the maintenance of lung health for children and adults with CF. At present, the Cystic Fibrosis Foundation has published consensus guidelines for only two of these therapies: aerosolized tobramycin (2) and recombinant human DNase (dor- nase alfa) (3), and additional studies have been published since the release of those guidelines. To provide guidance to the physician whomust choose from an ever-expanding arsenal of treatments for chronicCF lungdisease, theCystic Fibrosis Foundation established the Pulmonary Therapies Committee. This document represents the committee’s recommendations, based on available evidence, for the use of medications intended to maintain lung health. The guidelines are designed for general use in most patients, but may need to be adapted to meet individual needs as determined by the patient’s health care provider. In addition, because of the limited number of studies available involving very young children, unless otherwise noted, recommendations are intended for individuals at least 6 years of age. METHODS A preliminary meeting was held in October 2005 to initiate the process of identifying and prioritizing topics to be covered in these guidelines. The committee was composed of 15 members, all from the United States, representing internal medicine, pediatrics, nursing, respiratory therapy, systematic review pro- cedures, and the Cystic Fibrosis Foundation. Each member of the committee was involved in developing the recommenda- tions and reviewed and commented on the final version of the guidelines. The committee members developed and refined a series of questions related to drug therapies used in the maintenance of pulmonary function. We addressed the ques- tions in one of three ways, based on available evidence: (1) commissioned systematic review, (2) modified systematic re- view, or (3) summary of existing Cochrane reviews. See the online supplement for details on these methods. Members of the committee were provided with summaries of the evidence. Subcommittees, formed to review the evidence for each specific treatment, drafted recommendations. Their assess- mentof theevidenceanddraft statementswas thenpresented to the full committee for discussion. For each treatment under question, the body of evidence was evaluated by the full committee and recommendations were made on the basis of the U.S. Preventive ServicesTaskForcegrading scheme (4) (seeTable 1).Adraft of the recommendations was presented in November 2006 at the North American Cystic Fibrosis Conference and the committee solicited public commentary for 1 month after the presentation. This input was considered by the committee in the preparation of these guidelines. (Received in original form May 4, 2007; accepted in final form August 24, 2007) Supported by the Cystic Fibrosis Foundation. Correspondence and requests for reprints should be addressed to Patrick A. Flume, M.D., Medical University of South Carolina, 96 Jonathan Lucas Street, 812-CSB, Charleston, SC 29425. E-mail: flumepa@musc.edu This article has an online supplement, which is accessible from this issue’s table of contents at www.atsjournals.org Am J Respir Crit Care Med Vol 176. pp 957–969, 2007 Originally Published in Press as DOI: 10.1164/rccm.200705-664OC on August 29, 2007 Internet address: www.atsjournals.org RESULTS Assessment of Evidence 1. Systematic reviews of original research. A total of 2,670 unique citations were identified through the search process. Fifty-seven studies, published between 1983 and 2006, were deemed eligible for inclusion in this review (Figure 1). 2. Modified systematic reviews. A total of 416 unique cita- tions were identified. Seventeen studies, published be- tween 1983 and 2006, were deemed eligible for inclusion. 3. Existing Cochrane systematic reviews. We identified nine Cochrane reviews that addressed the effectiveness of aero- solized antibiotics, dornase alfa, hypertonic saline, oral corticosteroids, inhaled corticosteroids, oral nonsteroidal antiinflammatory drugs, macrolide antibiotics, inhaled bron- chodilators (including b-agonists and anticholinergic medi- cations), and oral antistaphylococcal antibiotics. A summary of the number and type of studies and total number of patients involved in each trial category is shown in Table 2. The committee’s assessment of the quality of evidence, the estimate of net benefit (benefits minus harms), and grade of the recommendation discussed below are also shown in Table 2. RECOMMENDATIONS Aerosolized Antibiotics The most common airway pathogen in patients with CF is Pseudomonas aeruginosa. Because chronic colonization of the airways with this bacterium is associatedwith amore rapid decline in lung function (5), aerosolized antibiotics have been advocated both for eradication of initial infection and for suppression of the chronic infection. The present systematic review of evidence was focused on the latter. Recommendations are stratified on the basis of the severity of lung disease, defined by FEV1 percentage of predicted as follows: normal, greater than 90% predicted; mildly impaired, 70–89% predicted; moderately impaired, 40–69% pre- dicted; and severely impaired, less than 40% predicted. Tobramycin for moderate to severe disease. A systematic review of original research identified six eligible trials assessing the use of aerosolized tobramycin compared with placebo or standard therapy in patients with moderate to severe airway disease and established P. aeruginosa infection (Table 2). There were 679 participants in these studies with the largest study enrolling 520 subjects (6). Three studies (n 5 619 patients) reported statistically significant improvement in FEV1 for those taking tobramycin compared with placebo or standard treat- ment, with a net benefit to lung function ranging from 7.8 to 12% (6–8). One study (n5 22) reported no significant effects on FEV1 (as a percentage of the predicted value), but the actual values were not provided (9). There were three studies assessing the influence of inhaled antibiotics on the frequency of pulmo- nary exacerbations (6–8). Ramsey and coworkers (8) reported a 26% reduction in hospitalizations and a 36% reduction in the use of intravenous antipseudomonal antibiotics for those taking inhaled tobramycin compared with placebo. Results from both MacLusky and coworkers (7) and Ramsey and coworkers (6) showed fewer days spent in hospital for subjects receiving inhaled tobramycin. Total days of other antibiotics were also lower for the inhaled tobramycin group in these two studies; however, these differences were significant only in the larger study (6). Quality of life was assessed in only one study (6); the tobramycin group reported higher scores on the Health-related Quality of Life scale compared with those in the placebo group, although the actual values were not presented. There were low rates of adverse events reported in all of the studies. Tinnitus occurred more frequently in the tobramycin-treated study parti- cipants, as did throat problems and voice alteration. A Cochrane review of inhaled tobramycin for CF, with the most recent search dated 2006 (10), concluded that aerosolized antipseudomonal antibiotics improved lung function. An in- crease in antibiotic resistance was noted, but this was a low- frequency occurrence. The quality of the summary of the evidence for inhaled tobramycin in cases of moderate to severe lung disease was deemed to be good, as the studies were well designed and well conducted, and the results were consistent. On the basis of the considerable improvement in lung function, reduction in exac- erbations, and low risk of adverse events, the net benefit of aerosolized tobramycin was thought to be substantial. Recommendation: For patients withCF, 6 years of age and older, who havemoderate to severe lungdiseaseandwithP.aeruginosapersistentlypresent in cultures of the airways, the Cystic Fibrosis Foundation strongly recommends the chronic use of inhaled tobramycin to improve lung function and reduce exacerbations. Level of evidence, good; net benefit, substantial; grade of recommendation, A. Tobramycin for mild disease. Two trials (n5 202) identified by systematic review assessed the use of aerosolized tobramycin in TABLE 1. U.S. PREVENTIVE SERVICES TASK FORCE RECOMMENDATION GRADES* Strength of Overall Evidence of Effectiveness Estimate of Net Benefit (benefit minus harms) Substantial Moderate Small Zero/Negative Good A B C D Fair B B C D Poor I I I I Definition of abbreviation: I 5 insufficient evidence. * Strength of overall evidence and estimate of net benefit determine the grade. Reproduced by permission from Harris RP, Helfand M, Woolf SH, Lohr KN, MulrowCD,TeutschSM,AtkinsD;MethodsWordGroup,ThirdUSPreventiveServices Task Force. Current methods of the US Preventive Services Task Force: a review of the process. Am J Prev Med 2001;20(Suppl 3):21–35. Article reproduced on Agency for Healthcare Research and Quality website. Rockville, MD: AHRQ. Available from: http://www.ahrq.gov/clinic/ajpmsuppl/harris1.htm (cited 2007 Sep). Strength of recommendations (4): Recommendation level A—the committee strongly recommends that clinicians routinely provide [the service] to eligible patients. (The committee found good evidence that [the service] improves important health outcomes and concludes that benefits substantially outweigh harms.) Recommendation level B—the committee recommends that clinicians routinely provide [the service] to eligible patients. (The committee found at least fair evidence that [the service] improves important health outcomes and concludes that benefits outweigh harms.) Recommendation level C—the committee makes no recommendation for or against routine provision of [the service]. (The committee found at least fair evidence that [the service] can improve health outcomes but concludes that the balance of the benefits and harms is too close to justify a general recommendation.) Recommendation level D—the committee recom- mends against routinely providing [the service] to patients. (The committee found at least fair evidence that [the service] is ineffective or that harms outweigh benefits.) Recommendation level I—the committee concludes that the evidence is insufficient to recommend for or against routinely providing [the service]. (Evidence that [the service] is effective is lacking, of poor quality, or conflicting, and the balance of benefits and harms cannot be determined.) Quality of evidence: Good—Evidence includes consistent results from well- designed, well-conducted studies in representative populations that directly assess effects on health outcomes. Fair—Evidence is sufficient to determine effects on health outcomes, but the strength of the evidence is limited by the number, quality, or consistency of the individual studies, generalizability to routine practice, or indirect nature of the evidence on health outcomes. Poor—Evidence is in- sufficient to assess the effects on health outcomes because of limited number or power of studies, important flaws in their design or conduct, gaps in the chain of evidenced, or lack of information on important health outcomes. 958 AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE VOL 176 2007 patientswithasymptomaticormildairwaydisease (Table2).Gibson and coworkers (11) studied 21 patients less than 6 years of age with P. aeruginosa present in bronchoalveolar lavage and found that P. aeruginosa density was decreased in patients receiving inhaled tobramycin. Because of the young age and generally mild lung disease of the study population, lung function and exacerbation frequency were not primary outcome measures of the trial. In the second trial, Murphy and coworkers (12) compared aerosolized tobramycin with standard therapy in 181 patients (6 to 15 yr of age) over 56 weeks. Of note, the study was halted early because patients treated with standard therapy experienced a greater number of exacerbations requiring hospitalization. Overall, patients receiving aerosolized tobramycin had fewer exacerbations (11.0 vs. 25.6%) than did those receiving standard therapy. There was no improve- ment in FEV1, but those receiving aerosolized tobramycin did have a significant improvement (10%) in the measurement of forced expiratory flow (midexpiratory phase). The quality of the evidence for the use of inhaled tobramycin in patients with mild disease is limited by the number of studies, and patients in the larger study were limited because it was halted early, and so was rated as fair in quality overall. Evidence for its use in the youngest population (i.e., less than 6 yr) is too poor to permit any recommendations. The larger study was halted early because of the benefit of a reduction in exacer- bations, which we have rated as a moderate net benefit. Recommendation: For patients with CF, age 6 years and older who are asymp- tomatic or with mild lung disease, and with P. aeruginosa persistently present in cultures of the airways, the Cystic Fibrosis Foundation recommends the chronic use of inhaled tobramycin to reduce exacerbations. Level of evidence, fair; net benefit, moderate; grade of recommendation, B. Other inhaled antibiotics. Inhaled colistin is used frequently for treatment of patients with CF and who are infected with P. aeruginosa. However, only two eligible trials of colistin in- cluding a total of 155 patients were uncovered by our search (Table 2). Jensen and coworkers (13) compared colistin with placebo in 40 patients over 90 days after a course of intravenous antibiotics. Both groups experienced a decrease in FEV1 (11– 17%) during treatment; no advantage was seen in the colistin group. Hodson and coworkers (14) compared colistin with tobramycin in 115 patients over 4 weeks. The patients treated with colistin did not show any measured improvement in lung function, whereas patients receiving tobramycin experienced an increase in FEV1 of 6.7%. No data were provided on exacer- bations or quality of life. There are even fewer data available for other inhaled anti- biotics (15, 16). Overall, the committee believed the evidence was insufficient to assess the effects on health outcomes of inhaled antibiotics other than tobramycin because of the limited number and power of studies. Recommendation: For patients with CF, age 6 years and older, with Pseudomonas aeruginosa persistently present in cultures of the airways, the Cystic Fibrosis Foundation concludes that the evidence is insuf- ficient to recommend for or against routinely providing other chronically inhaled antibiotics (i.e., colistin, gentamicin, ceftazi- dime) to improve lung function and reduce exacerbations. Level of evidence, poor; net benefit, small; grade of recommendation, I. Recombinant Human DNase Airway obstruction by thickened secretions and cellular debris is the hallmark of CF lung disease. Recombinant human DNase Figure 1. Summary of search and review process. MEDLINE was accessed via PubMed. EMBASE 5 Excerpta Medica data- base; CENTRAL 5 Cochrane Central Register of Controlled Trials. Flume, O’Sullivan, Robinson, et al.: Cystic Fibrosis Pulmonary Guidelines 959 (dornase alfa) was developed to degrade the large amount of free DNA that accumulates within CF mucus, thereby improving the viscoelastic properties of airway secretions and promoting airway clearance. The short-term (not more than 14 d) and long-term effects of dornase alfa on lung function, and the long- term effects of dornase alfa on pulmonary exacerbations, have been studied. As with inhaled tobramycin, recommendations were stratified on the basis of the severity of lung disease (see above). Dornase alfa for moderate to severe disease. Nineteen trials of dornase alfa in a total of 3,140 patients with moderate to severe disease were identified by systematic review (Table 2). Five of these studies evaluated the long-term efficacy of dornase alfa (17–21), including large, multicenter trials lasting 12–96 weeks (17, 18, 20). Most short-term studies of dornase alfa showed a significant improvement in lung function as measured by FEV1. Treatment for 6–14 days increased FEV1 by 11.2–15.4% when