特发性肺纤维化诊治进展李志奎2014927

特发性肺纤维化诊治新进展,第四军医大学西京医院呼吸与危重症医学科李志奎,特发性间质性肺炎分类的变迁,经历过三个重要的阶段年病理学家根据不同的组织学表现把慢性间质性 肺炎分为五型：寻常型间质性肺炎（）脱屑型间质性肺炎（）淋巴细胞型间质性肺炎（）巨细胞型间质性肺炎（）细支气管炎伴间质性肺炎（）,特发性间质性肺炎分类的变迁,年美国胸科学会和欧洲呼吸学会共同协商，统一公布了新的分类法并根据临床相对的发病率，排列如下：特发性肺纤维化（）非特异性间质性肺炎（）隐源性机化性肺炎（）急性间质性肺炎（）呼吸性细支气管炎并间质性肺病（）脱屑型间质性肺炎淋巴细胞型间质性肺炎,年美国胸科学会和欧洲呼吸学会再次对特发性间质性肺炎的分类进行了重新修订这次新分类把特发性间质性肺炎分为三个大类：主要的罕见的不可分类,IPF诊治指南新进展,2000 年美国胸科学会/欧洲呼吸学会( ATS /ERS) 发表了特发性肺纤维化( idiopathic pulmonary fibrosis，IPF) 诊断和治疗的共识历经11 年，IPF 的临床和基础研究均取得了许多重要进展,Diffuse Parenchymal Lung Diseases / Interstitial Lung Disease(DPLD / ILD),已知原因：药物、CTD、粉尘、放射 等,肉芽肿性疾病：结节病、外源性过敏性肺炎 等,其他：LAM、PLCH、EP等,特发性间质性肺炎 (IIP),ATS/ERS statement: AJRCCM 2002;165:277,特发性肺纤维化（IPF/UIP）,非特异性间质性肺炎（NSIP）,隐原性机化性肺炎（COP）,淋巴细胞间质性肺炎（LIP）,脱屑型间质性肺炎（DIP）,急性间质性肺炎（AIP）,呼吸性细支气管炎伴间质性肺病（RBILD）,2011指南,美国胸科学会(ATS)、欧洲呼吸学会(ERS) 、日本呼吸学会（JRS )和拉丁美洲胸科学会（ALAT) 间质性肺疾病(ILD) 、特发性间质性肺炎(IIP) 和IPF领域的著名专家2010 年5 月前有关IPF 的文献(第一部以循证为基础的IPF 诊断和治疗指南),专家委员会,IPF和间质性肺疾病领域的公认专家(24位呼吸内科医生，4位放射科医生和4位病理科医生)4位方法学家1位图书馆长2位具有丰富检索肺部疾病文献经验的图书馆员,指南结构,IPF的定义、流行病学资料、危险因素、自然病程、分期及预后、病程监测和未来发展方向。采用了GRADE循证方法，对指南中涉及的所有问题进行了证据质量与推荐强度分级,IPF诊治指南新进展,定 义,原因不明、出现在成人、局限于肺、进行性致纤维化的间质性肺炎，其组织病理学和放射学表现为普通型间质性肺炎( usual interstitial pneumonia，UIP) 与2000 年IPF 的定义相比较， 2011 指南在IPF 的定义中保留组织病理学表现为UIP 型的内容，但首次将放射学表现为UIP 型写入IPF 的定义，强调识别高分辨率CT( highresolution computed tomography，HRCT) 的UIP 型表现的重要性,2017/12/17,15,准确发病率和流行情况尚不清楚,流行病学,以前估计总发病率为3610万,近来IPF 发病率估计为男性10. 7 /10 万， 女性7. 4 /10 万,2017/12/17,16,IPF发病的危险因素,Familial (genetic) IPF的5%SmokingEnvironmental factors (金属粉尘，木屑、务农、养鸟、护发剂、石粉接触、牲畜接触、植物和动物粉尘接触等)Chronic aspiration associated with gastroesophageal reflux disease (多数为“隐性反流”，缺乏胃食管反流临床症状。异常的胃食管反流导致反复微吸入是IPF高危因素之一）Infectious agents,UIP,2011 指南对UIP 型HRCT 和组织病理学定义提出详细分级诊断标准，强调根据HRCT 的UIP 型特点可作为独立的IPF 诊断手段UIP 型的HRCT 特征: 双侧、外周、下肺基底部为主的网状影 数量不等、范围有限的磨玻璃影 病变较重的部位，通常有牵拉性支气管和细支气管扩张，和/或蜂窝样变,HRCT上UIP的特征,HRCT上UIP的特征,胸膜下和肺基底部分布为主网格状阴影蜂窝影，常伴有牵张性支气管扩张，尤其是蜂窝影对IPF的诊断有很重要的意义。 HRCT上的蜂窝影指成簇的囊泡样气腔，蜂窝壁边界清楚。囊泡直径在310 mm之间，偶尔可大至25 mm无不符合UIP型项目,典型,可能,UIP的病理学特征,Surgical lung biopsy specimens demonstrating UIP pattern. (A) Scanning power microscopy showing a patchy process with honeycomb spaces (thick arrow), some preserved lung tissue regions (thin arrow), and fibrosis extending into the lung from the subpleural regions. (B) Adjacent to the regions of more chronic fibrosis (thick arrow) is a fibroblast focus (asterisk), recognized by its convex shape and composition of edematous fibroblastic tissue, suggestive of recent lung injury.,2011 指南强调由富有ILD 诊断经验的肺病学专家、放射学专家、病理学专家之间多学科讨论( multidisciplinary discussions，MDD) 在IPF 诊断中的重要性，特别是在HRCT和病理组织学型不一致的病人,2011 指南,IPF 诊断标准如下: (1) 除外其他已知原因的ILD( 如家庭环境、职业环境暴露、结缔组织病、药物肺毒性损害) (2) HRCT 表现为UIP 型患者不需要外科肺活检 (3) HRCT 表现和外科肺活检组织病理学表现型符合HRCT 和组织病理学表现的特定组合,2011 指南,诊断不再需要经支气管镜肺活检或支气管肺泡灌洗细胞分析BALF最主要的作用是排除慢性外源性过敏性肺泡炎 BALF中淋巴细胞增多(40)时应该考虑慢性外源性过敏性肺泡炎的可能 HRCT表现为UIP型的患者中，有8的患者通过BALF分析更改了诊断推荐意见：绝大多数IPF患者的诊断流程中不应该进行BALF细胞学分析，但可能适用于少数患者(弱推荐，低质量证据),2011 指南,建议在IPF 诊断中进行结缔组织病血清学检测结缔组织疾病可以出现UIP型表现，ILD可以作为某些结缔组织疾病的唯一临床表现先于其他临床症状出现推荐意见：绝大多数疑诊的IPF患者应该进行结缔组织疾病相关的血清学检测，但可能不适用于少数患者(弱推荐，很低质量证据) 类风湿因子、抗环瓜氨酸肽抗体、抗核抗体滴度和模式、抗合成酶抗体、肌酸激酶、醛缩酶、SSA、SSB、抗硬皮病抗体,2011 指南,并没有列入肺功能: IPF 患者肺功能检测也可能是正常除特殊需要外，不建议使用TBLB: 对结节病等肉芽肿性疾病进行TBLB检查有利于诊断，但HRCT表现为UIP者则基本能够排除这些疾病，且进行该项检查能增加IPF急性加重的风险,提示预后不良的相关因素和指标: 肺活检标本中成纤维细胞病灶数量， 用力肺活量( FVC) 和肺一氧化碳弥散量( DLCO) 下降， 6 分钟步行试验中氧饱和度下降的程度， HRCT 的肺纤维化和蜂窝程度， 肺功能和影像学指标的综合评分系统( CPI) ， 血清表面活性蛋白A 和D 浓度的升高， 血清和BALF 生物学标记物(KL-6、SP-A 和D、 CCL18、MMP 和纤维细胞) 合并肺气肿、肺动脉高压,IPF的自然病程,回顾性纵向研究结果提示，IPF患者从确诊到死亡的中位生存时间为23年但从最近纳入临床试验的基础肺功能尚可的IPF患者的临床资料来看，中位生存期可能大于23年,IPF急性加重的诊断标准,1个月内出现不能解释的呼吸困难加重存在低氧血症的客观证据影像学表现为新近出现的肺部浸润影除外其他诊断(如感染、肺栓塞、气胸或心力衰竭)急性加重可在IPF病程任何时候发生，有时还是本病首发症状；临床表现为咳嗽加重，发热，伴或不伴有痰量增加每年约5 一10 的IPF患者会发生急性呼吸功能恶化,IPF诊治指南新进展,2017/12/17,34,缺乏有效治疗方法 皮质激素 免疫抑制药物/细胞毒药物 抗纤维化药物可单独或联合应用,2000指南IPF的治疗,2011指南IPF的治疗,Completed Trials for IPF,Slide adapted from Kevin Brown, MD.,吡非尼酮,波生坦,西地那非,Active or New Trials for IPF,Slide adapted from Kevin Brown, MD.,硫唑嘌呤,安立生坦,IPF诊治指南新进展,Schedule of IIP classification project,May, 2010 ATS/New Orleans September, 2010 ERS/Barcelona January, 2011 Writing committee, NYC April, 2011 Modena, Italy May, 2011 ATS/Denver September, 2011 ERS/Amsterdam January, 2012 Writing committee, NYC April, 2012 Final draft submitted September, 2012 Submission of revision,Members of the ATS/ERS Committee on IIP,William Travis, MD. (Chair)Talmadge E. King, Jr., MD, (Co-Chair)Ulrich Costabel, (Co-Chair)Athol Wells, (Co-Chair),PULMONARY (17+4),Jay H. Ryu, USA (Subcommittee Chair)Jurgen Behr, GermanyDemosthenes Bouros, GreeceKevin Brown, USAHarold Collard, USACarlos Robalo Cordeiro, PortugalVincent Cottin, FranceMarjolein Drent, The Netherlands,Jim Egan, IrelandKevin Flaherty, USATravis, WDYoshikazu Inoue, JapanDong Soon Kim, KoreaFernando Martinez, USAGanesh Raghu, USALuca Richeldi, ItalyDominique Valeyre, France,RADIOLOGY,David Hansell, United Kingdom (Subcommittee co-chair)David Lynch, USA (Subcommittee co-chair)Takeshi Johkoh, JapanNicola Sverzellati, Italy,PATHOLOGY,Andrew Nicholson, United Kingdom (Subcommittee Chair)Thomas V. Colby, USAMasanori Kitaichi, JapanJeffrey Myers, USA,MOLECULAR BIOLOGY,Moises Selman, Mexico (Subcommittee chair)Bruno Crestani, FranceCory Hogaboam, USAJames Loyd, USA,EVIDENCE BASED ANALYSIS,Christopher Ryerson, Canada (Subcommittee chair)Jeffrey Swigris, USA,REFERENCE LIBRARIANS,Rosalind F. Dudden, M.L.S.Shandra Protzko, M.L.S.,新分类方案与2002年IIP专家共识的区别,（1）明确了特发性NSIP（iNSIP）是一种独立的临床病理的类型，其临床过程呈高度异质性；idiopathic nonspecific interstitial pneumonia (NSIP) is now accepted as a distinct clinical entity with removal of the term “provisional”,新分类方案与2002年IIP专家共识的区别,（2）收集了更多的吸烟相关性间质性肺病的信息，特别是肺气肿合并肺纤维化（including patients with combined emphysema and interstitial fibrosis.CEPF）；In clinical practice, respiratory bronchiolitisinterstitial lung disease is increasingly diagnosed without surgical lung biopsy in smokers on the basis of clinical and imaging features (ground-glass opacities and centrilobular nodules) and bronchoalveolar lavage (smokers macrophages and absence of lymphocytosis).,新分类方案与2002年IIP专家共识的区别,（3）认为IPF自然病程多样性，可长期稳定，可快速进行性进展，可在病程中出现急性加重；cryptogenic fibrosing alveolitis is removed, leaving idiopathic pulmonary fibrosis (IPF) as the sole clinical termfor this diagnosis,AJRCCM 2011; 183: 788-824 (modified),DISEASE PROGRESSION,TIME,NATURAL HISTORY OF IPF,RAPID PROGRESSION,SLOW PROGRESSION,STABLE,The major IIPs are grouped into chronic fibrosing (IPF and NSIP), smoking-related (respiratory bronchiolitisinterstitial lung disease RB-ILD and desquamative interstitial pneumonia DIP), and acute/subacute IIPs (cryptogenic organizing pneumonia COP and acute interstitial pneumonia AIP,新分类方案与2002年IIP专家共识的区别,（4）对慢性致纤维化性间质性肺炎(IPF及NSIP）的“急性加重（AE）”有了明确定义和描述（5）首次明确提出部分IIP患者病理难以归入现有的IIP类型中（不能分类的IIP，often because of mixed patterns of lung injury）. major IIPs are distinguished from rare IIPs and unclassifiable cases.,新分类方案与2002年IIP专家共识的区别,（6）提出IIP临床表现诊疗途径，尤其对没有病理诊断和HRCT不符合某一典型IIP影像学表现It is recognized that there is a need to provide a clinical algorithm for classifying and managing IIP cases. This is particularly applicable when no biopsy is available and high-resolution computed tomography is not diagnostic,新分类方案与2002年IIP专家共识的区别,（7）提出了一种新的IIP类型PPFE；Pleuroparenchymal fibroelastosis is recognized as a specific rare entity, usually idiopathic. Other less well-defined histologic patterns, such as bronchiolocentric inflammation and fibrosis, are also included（8）提出了某些分子生物学标记物和基因学研究结果可能对IIP的分类和诊断有一定帮助,Major Idiopathic Interstitial PneumoniasIdiopathic pulmonary fibrosisIdiopathic nonspecific interstitial pneumoniaRespiratory bronchiolitis interstitial lung diseaseDesquamative interstitial pneumoniaCryptogenic organizing pneumoniaAcute interstitial pneumoniaRare Idiopathic Interstitial PneumoniasIdiopathic lymphoid interstitial pneumoniaIdiopathic pleuropulmonary fibroelastosisUnclassifiable idiopathic interstitial pneumonias,特发性间质性肺炎分类 (2012),特发性间质性肺炎（IIP）,急性/亚急性IP COP AIP,吸烟相关性IP DIP RBILD,特发性间质性肺炎的分类(2012年),主要的IIP,慢性致纤维化性IP IPF NSIP,家族性 2-20%, 非家族性 80%,NSIP,IPF 1 ,2, 3NSIP 4，显示两下肺胸膜下磨玻璃影，小叶间隔增厚，伴牵引性支气管扩张，两下肺网状影，后胸膜下相对正常，有助于与相鉴别图，显示两肺磨玻璃影及小叶中心小结节（箭头）,Acute exacerbation of idiopathic pulmonary fibrosis (IPF). 4 months later,特发性间质性肺炎（IIP）,急性/亚急性IP COP AIP,吸烟相关性IP DIP RBILD,特发性间质性肺炎的分类(2012年),主要的IIP,慢性致纤维化性IP IPF NSIP,家族性 2-20%, 非家族性 80%,2017/12/17,65,隐源性机化性肺炎(COP),COP由Davison等 1983年提出1985年，Epler等称本病为阻塞性细支气管炎伴机化性肺炎(BOOP)。后这一称谓曾获得普遍接受多数学者认为COP更符合本病的特点,2017/12/17,66,临床表现,BOOP过程较轻，病程较短，一般210周，3/4病人 10% of IIPs,不能分类IIP的原因,Cases that are “unclassifiable” in terms of overlap of histologic patterns often prove to be related to CVD (e.g., interstitial pneumonia and follicular小囊的 bronchiolitis in a patient with rheumatoid arthritis) or drug induced,“Unclassifiable disease” 10% of IIPs,If ILD is difficult, or impossible, to classify, management should be based on the most probable diagnosis after MDD and consideration of the expected disease behavior根据疾病行为提出实用的临床分类CLINICAL CLASSIFICATION OF DISEASE BEHAVIOR,This approach is most useful in unclassifiable cases and for some IIPs, such as NSIP, that can be associated with all five patterns of disease behavior. This disease behavior classification is complementary补充 to the IIP classificationShould not be used as a justification for delaying SLB（surgical lung biopsy）. Such delays increase the risk of surgical complications and may result in inappropriate management. This classification system needs to be validated证实 for practicality and clinical relevance,根据疾病行为提出了实用的临床分类,Historically既往, the primary question has been “what is the diagnosis”?Pragmatically实用上, the primary question is “what are you going to do about it”?,We need a different question,（A pragmatic clinical classification）,临床分类的综合考量因素-1,疾病预后：虽然ILD病因不同，临床表现各异，但疾病预后大致可归纳如下：自限性炎症稳定性纤维化炎症为主伴有不同程度纤维化进行性纤维化可逐渐达到稳定状态不可终止的纤维化,临床分类的综合考量因素-2,疾病和患者的特征： 诊断病因主要的形态学异常疾病严重程度疾病的动态改变患者个人情况,临床分类的综合考量因素-3,处理方法： 对不同预后疾病采取不同临床策略：观察：自限性炎症/稳定性纤维化积极治疗，达到目标后，维持治疗结果：炎症为主(大部分可逆）伴有不同程度纤维化治疗防止其进展：进行性进展有逐渐达到稳定状态可能的纤维化治疗让其缓慢进展：不可终止的纤维化,疾病临床行为综合判定,Patient-specific modifiersAgeSuspected etiologyDisease severityReversibility of disease,MD Diagnosis-Clinical-Radiologic-Pathologic(when available),Longitudinal behaviour:“Prior history”-Impact of therapy-Rate of progression (symptoms, PFTs, radiology),Group 1,Reversible,Irreversible,+,+,Group 2,Group 3,Group 4,Group 5,IMPORTANT DIFFERENTIALDIAGNOSTIC CONSIDERATIONS,Hypersensitivity Pneumonitis过敏性肺炎HRCT findings suggesting HP include centrilobular nodules, mosaic air-trapping, and upper lobe distributionBiopsy findings suggesting HP include bronchiolocentric distribution and poorly formed granulomas,Fibrotic hypersensitivity pneumonitis. (A) Axial and (B) coronal computed tomography (CT) reconstructions in a 76-year-old bird-keeper with progressive shortness of breath over 6 years show upper lungpredominant subpleural reticulation with some confluent汇合 areas of dense opacification,traction bronchiectasis, and patchy ground-glass opacities.Honeycombing is not identified,(C) Histology shows a bronchiolocentriccellular a