2011ATS特发性肺纤维化诊治指南

American Thoracic Society Documents An Official ATS/ERS/JRS/ALAT Statement: Idiopathic Pulmonary Fibrosis: Evidence-based Guidelines for Diagnosis and Management Ganesh Raghu, Harold R. Collard, Jim J. Egan, Fernando J. Martinez, Juergen Behr, Kevin K. Brown, Thomas V. Colby, Jean-Francxois Cordier, Kevin R. Flaherty, Joseph A. Lasky, David A. Lynch, Jay H. Ryu, Jeffrey J. Swigris, Athol U. Wells, Julio Ancochea, Demosthenes Bouros, Carlos Carvalho, Ulrich Costabel, Masahito Ebina, David M. Hansell, Takeshi Johkoh, Dong Soon Kim, Talmadge E. King, Jr., Yasuhiro Kondoh, Jeffrey Myers, Nestor L. Mu¨ller, Andrew G. Nicholson, Luca Richeldi, Moise´s Selman, Rosalind F. Dudden, Barbara S. Griss, Shandra L. Protzko, and Holger J. Schu¨nemann, on behalf of the ATS/ERS/JRS/ALAT Committee on Idiopathic Pulmonary Fibrosis THIS OFFICIAL STATEMENT OF THE AMERICAN THORACIC SOCIETY (ATS), THE EUROPEAN RESPIRATORY SOCIETY (ERS), THE JAPANESE RESPIRATORY SOCIETY (JRS), AND THE LATIN AMERICAN THORACIC ASSOCIATION (ALAT) WAS APPROVED BY THE ATS BOARD OF DIRECTORS, NOVEMBER 2010, THE ERS EXECUTIVE COMMITTEE, SEPTEMBER 2010, THE JRS BOARD OF DIRECTORS, DECEMBER 2010, AND THE ALAT EXECUTIVE COMMITTEE, NOVEMBER 2010 THIS STATEMENT HAS BEEN FORMALLY ENDORSED BY THE SOCIETY OF THORACIC RADIOLOGY AND BY THE PULMONARY PATHOLOGY SOCIETY CONTENTS Introduction Objective Methods Committee Composition Disclosure of Conflicts of Interest Committee Meetings and Evidence Review Process Document Preparation Document Structure Formulation of the Topic Sections and Questions Literature Review and Preparation of Evidence Profiles Quality of Evidence and Strength of Recommendations External Review Process Significance of Evidence-based Recommendations to Clinicians for the Management of IPF Summary Conclusions and Treatment Recommendations Conclusions Treatment Recommendations Definition and Epidemiology Definition Clinical Presentation Incidence and Prevalence Potential Risk Factors Genetic Factors Definition Of UIP Pattern UIP Pattern: HRCT Features UIP Pattern: Histopathology Features Diagnosis Diagnostic Criteria Exclusion of Other Known Causes Bronchoalveolar Lavage Cellular Analysis Transbronchial Lung Biopsy Serological Testing for Connective Tissues Disease Multidisciplinary Discussion Natural History of IPF Acute Exacerbation of IPF Vital Statistics Staging and Prognosis Demographics Dyspnea Physiology HRCT Features Composite Scoring Systems Six-Minute-Walk Testing Histopathology Pulmonary Hypertension Emphysema Serum and Bronchoalveolar Lavage Biomarkers Treatment Pharmacologic Therapies Nonpharmacologic Therapies Selected Complications and Comorbid Conditions Palliative Care Monitoring the Clinical Course of Disease Monitoring for Progressive Disease Monitoring for Worsening Symptoms Monitoring for Worsening Oxygenation Monitoring for Complications and Comorbidities Summary of Clinical Management of IPF Future Directions This document is an international evidence-based guideline on the diagnosis and management of idiopathic pulmonary fibrosis, and is a collaborative effortof the AmericanThoracicSociety, the European Respiratory Society, the Japanese Respiratory Society, and the Latin American Thoracic Association. It represents the current state of knowledge regarding idiopathic pulmonary fibrosis (IPF), and con- tainssectionsondefinitionandepidemiology, risk factors,diagnosis, natural history, staging and prognosis, treatment, and monitoring disease course. For the diagnosis and treatment sections, pragmatic GRADE evidence-based methodology was applied in a question- based format. For each diagnosis and treatment question, the committee graded the quality of the evidence available (high, moderate, low, or very low), and made a recommendation (yes or no, strong or weak). Recommendations were based on majority vote. It is emphasized that clinicians must spend adequate time with This document 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 183. pp 788–824, 2011 DOI: 10.1164/rccm.2009-040GL Internet address: www.atsjournals.org patients to discuss patients’ values and preferences and decide on the appropriate course of action. Keywords: idiopathic pulmonary fibrosis; usual interstitial pneumonia; evidence-based medicine, diagnosis, therapeutics Idiopathic pulmonary fibrosis (IPF) is defined as a specific form of chronic, progressive fibrosing interstitial pneumonia of un- known cause, occurring primarily in older adults, and limited to the lungs. It is characterized by progressive worsening of dyspnea and lung function and is associated with a poor prognosis. The American Thoracic Society and European Re- spiratory Society (ATS/ERS), in collaboration with the Amer- ican College of Chest Physicians (ACCP), published an international consensus statement in 2000 on the diagnosis and management of IPF (1). Importantly, the statement recog- nized IPF as a distinct clinical entity associated with the his- tologic appearance of usual interstitial pneumonia (UIP), and provided specific recommendations for clinicians regarding its diagnosis and management. Since the publication of the 2000 ATS/ERS statement, studies have used the ATS/ERS statement recommendations to further our understanding of the clinical manifestations and course of IPF. The accumulated data and observations made in these studies allow us to provide new guidelines for the diagnosis and management of IPF based on the best available evidence using ATS/ERS methodology. OBJECTIVE This document is an international evidence-based guideline on the diagnosis and management of IPF. The purpose of these guidelines is to analyze the additional evidence accumulated since the publication of the 2000 ATS/ERS consensus statement and to provide evidence-based recommendations for manage- ment, with an emphasis on diagnosis and treatment. This document is intended to replace the previous ATS/ERS IPF consensus statement, and will be updated when appropriate in accordance with the policy of the sponsoring societies. The primary objective of this document is to provide recommendations based on a thorough review of the evidence published to date using the GRADE methodology (see below) to clinicians in a transparent manner. It is intended to empower clinicians to interpret these recommendations in the context of individual patient values and preferences, and to make appro- priate decisions regarding all aspects of disease management, tailored to the patient with typical IPF. METHODS Committee Composition This guideline is a collaborative effort between the ATS, ERS, Japanese Respiratory Society (JRS), and Latin American Thoracic Association (ALAT). The project chair (G.R.) nominated two co-chairs (J.J.E. and F.J.M.) and a group of experts in IPF and/or evidence-based method- ology from North America, Europe, Asia, and South America. This group consisted of clinicians with recognized expertise in IPF and interstitial lung diseases (24 pulmonologists, 4 radiologists, and 4 pathologists), 4 methodologist (also a general pulmonologist), and 1 chief librarian, assisted by 2 librarians experienced with literature searches for pulmonary diseases. This group was approved by and represented the membership of the four sponsoring societies. Disclosure of Conflicts of Interest Panel members disclosed all potential conflicts of interest. The chair discussed and resolved all potential conflicts of interest with committee members. All potential conflicts of interest (including those of the chair and co-chairs) were discussed with the chair of the Ethics and Conflict of Interest Committee of the ATS. During all deliberations, members with perceived conflicts of interest abstained from voting on specific recommendations related to the conflict of interest. Furthermore, members were reminded to consider their own and other members’ potential conflicts of interest when discussing and voting on recommendations. In addition, other potential conflict of interest, if any (e.g., academic conflicts of interest), that were not apparent in the formal disclosures were left to be resolved by individual committee members based on their own conscience, judgment, and discretion in making recommendations (i.e., voting). The reference librarians did not participate in voting for any of the recommendations. Committee Meetings and Evidence Review Process The committee was divided into subgroups, and each subgroup was provided with articles relevant to their respective sections and/or questions. The subgroups were tasked with reviewing the literature, developing relevant questions, and developing preliminary section drafts. Four face-to-face meetings were held in which the subgroup drafts were reviewed. For certain sections, evidence-based recommen- dations were discussed, voted on, and finalized by the entire committee. Document Preparation The chair and a member of the committee (H.R.C.) integrated the draft sections and voting results into a preliminary document that was circulated among the committee members for further input. Input from the committee members was incorporated into the document which was read and edited further by an editing committee (G.R., H.R.C., J.H.R., J.B., M.E., K.R.F., and H.J.S.) via live webinar-teleconference. A final draft document was reviewed by the full committee, finalized, approved, and submitted to the ATS and ERS for peer review. The document was revised to incorporate the pertinent comments suggested by the external reviewers and the input provided by the editor of the ATS documenta- tion and implementation committee. The drafted revised document was read and edited via webinar-teleconference (G.R., J.J.E., F.J.M., H.R.C., and H.J.S.) and circulated to the entire committee for further input. A pre-final draft of the revised document was subsequently finalized via webinar-teleconference (G.R., J.J.E., F.J.M., H.R.C., and H.J.S.). Con- cerns raised by some committee members regarding the choice of most appropriate words to convey the significance of recommendations were resolved by consensus reached by all concerned, which included the chair (G.R.), co-chairs (F.J.M. and J.J.E.), and committee members (H.J.S., H.R.C., A.U.W., U.C., and J.B.), and incorporated in the document. One committee member (R.D.B.) requested not to be a co-author of the final document due to his concerns regarding the methodology used for the treatment section. Since he participated in voting and document preparation, he is listed as a committee member. The revised document was reviewed by the authors, finalized, approved, and submitted to the editor of the ATS documentation and implementation committee. Document Structure This document is structured to provide an evidence-based review of the current state of knowledge regarding IPF, and contains guidelines for the management of IPF that include definition and epidemiology; risk factors; natural history; staging and prognosis; monitoring disease course; future directions. For the diagnosis and treatment sections, pragmatic GRADE evidence-based methodology was applied (2, 3). These sections were organized around specific questions as described below. The committee performed a complete systematic review of the literature for the questions focused on treatment. The literature searches and assessment of the evidence followed the GRADE ap- proach to rate the quality of evidence and strength of the recommen- dations for all questions in the diagnosis and treatment sections. The remaining sections were written after a thorough review of the available literature in a narrative review format. Formulation of the Topic Sections and Questions Relevant section topics and questions were identified by committee members. Additional input was sought from general pulmonologists in the community and at academic centers. American Thoracic Society Documents 789 Literature Review and Preparation of Evidence Profiles An evidence profile was created for each question using the GRADE methodology (2, 3). A MEDLINE search from 1996 to December 2006 was performed at the beginning of the committee’s work, with periodic updates during document development and finalization through May 31, 2010. Searching the literature before 1996 was not done systemat- ically, since it had been searched extensively for the 2000 Consensus Statement (1). The current search was augmented by searches of EMBASE and committee member files. The literature search was limited to manuscripts published in the English language and English abstracts available from articles published in other languages. For the section on IPF treatment, we utilized the methodology of systematic review, which included meta-analysis of studies where appropriate (4– 7). This review examined all relevant studies including randomized controlled trials, cohort studies, case-control studies, and cross-sectional studies. A few studies were not included in this question-based document due to the preliminary nature of their observations (8–11). For details of the literature search methodology and results, please see the online supplement. Quality of Evidence and Strength of Recommendations The quality of evidence was determined according to the ATS GRADE criteria (3) (Tables 1 and 2). The GRADE approach identifies all outcomes that are of importance to patients and differ- entiates the critical outcomes from the important but not critical ones. Recommendations depend on the evidence for all patient-important outcomes and the quality of evidence for each of those outcomes. GRADE evidence profiles are tabulated in this document for random- ized controlled trials (see TREATMENT below). For each question, the committee graded the quality of the evidence available (high, moder- ate, low, or very low), and made a recommendation for or against. Recommendations were decided on the basis of majority vote. There were 31 voting members of the committee (the reference librarians were not voting members). The number of votes for, against, abstain- ing, and absent are reported for all treatment votes. Recommendations were either ‘‘strong’’ or ‘‘weak.’’ The strength of a recommendation reflects the extent to which one can, across the range of patients for whom the recommendation is intended, be confident that desirable effects outweigh undesirable effects (3). All recommendations were made after face-to-face, detailed dis- cussions of the evidence profile and quality by committee members present at the face-to-face discussions. While the recommendation on the use of pirfenidone had been made by the committee members during the face-to-face discussions, the question was revisited because of the subsequent release of substantial additional scientific evidence. The ATS and ERS also recommended including the additional scientific data from just-completed clinical trials of pirfenidone that had been released to the scientific and public domain in the commit- tee’s recommendation. This new evidence, including a meta-analysis of the available pirfenidone data, was sent to all members of the committee electronically, and the final voting for pirfenidone was made by e-mail. Thus, the total number of votes for the pirfenidone question reflects all the voting members of the committee; that is, it included the votes of the members who were not present during the prior face-to-face discussions of pirfenidone and other topics. Newer data published subsequent to the final formal face-to-face voting was not considered for evidence-based recommendations because there was not sufficient time for a thorough review and consideration of the data by the committee members. These newer data that were not subjected to formal face-to-face discussion are provided as a summarized narrative in the text of the document. These and all other new pertinent published data will be considered for formal evidence-based recommen- dations in future updates of this document. External Review Process This document was subjected to review by the ATS Board of Directors and ERS Science Committee as well as external peer review. The final document met the approval of the governing bodies of the ATS, ERS, JRS, and ALAT. SIGNIFICANCE OF EVIDENCE-BASED RECOMMENDATIONS TO CLINICIANS FOR THE MANAGEMENT OF IPF Over the last decade, there has been an increasing body of evidence pertinent to the clinical management of IPF. This committee has reviewed the extensive literature published to date, and recommendations are provided based on a robust and transparent methodology. Since the process is transparent, the recommendations provided empower the clinician confronted with the patient with typical IPF to make the most appropriate decisions tailored to the patient’s values and preferences. Clinicians need guidance to interpret evidence-based rec- ommendations, in particular the direction and strength of a recommendation (Table 3). Recommendations against certain interventions are particularly important if an expert committee (guideline panel) is concerned that current practice needs to change and if the evidence indicates that there may be more harm than benefit from an intervention that is frequently used. It should be emphasized that evidence-based recommendations TABLE 1. QUALITY OF EVIDENCE DETERMINATION Quality of Evidence Study Design Lower If: Higher If: High Randomized controlled trial d Limitation in study quality d Indirectness d Important inconsistency d Sparse or imprecise data d High probability of publication bias d Strong association, no plausible confounders d Evidence of a dose–response gradient d Plausible confounders would have reduced the effect Moderate Downgraded randomized controlled trial or upgraded observational study Low Well done observational study with control groups Very low Any other evidence (e.g., case reports, case series) TABLE 2. QUALITY OF THE EVIDENCE RATING AND IMPLICATIONS Quality of the Evidence (GRADE) The quality of the evidence is a judgment about the extent to which we can be confident that the estimates of effect are correct. These judgments are made using the GRADE system, and are provided for each outcome. The judgments are based on the type of study design (randomized trials versus observational studies), the risk of bias, the consistency of the results across studies, and the precision of the overall estimate across studies. For each outcome, the quality of the evidence is rated as high, moderate, low, or very low using the following definitions: High (4444) Further research is very unlikely to change our confidence in the estimate of effect. Moderate (444s) Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate. Low (44ss) Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate. Very low (4sss) We are very uncertain about the estimate. (For more information about the GRADE system, see: www.gradeworkinggroup.org) 790 AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE VOL 183 2011 are for typical patients. For individual patients, the best decision may sometimes not be the one recommended by evidence- based guidelines. Factors that influence such decisions are primarily related to patients’ values and preferences. Some patients may be willing to accept possible adverse consequences even if expected benefits are small; others may not. The strength of the recommendations is either strong or weak based on the quality of evidence and the voting of the committee members. When the recommendation is for the use of a specific treatment (or a specific question), it is denoted as a ‘‘YES,’’ and when the recommendation is against the use of the specific treatmen