特发性肺纤维化诊治进展-李志奎2014-9-27

1、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：1. 寻常型间质性肺炎（）2. 脱屑型间质性肺炎（）3. 淋巴细胞型间质性肺炎（）4. 巨细胞型间质性肺炎（）5. 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：1. 特发性肺纤维化（）2. 非特异性间质性肺炎（）3. 隐源性机化性肺炎（）4. 急性间质性肺炎（）5. 呼吸性细支气管炎并间质性肺病（）6. 脱屑型间质性肺炎7. 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

2、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l2000 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l历经11 年，IPF 的临床和基础研究均取得了许多重要进展l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) l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l2010 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

3、疗指南)lIPF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)l4位方法学家l1位图书馆长l2位具有丰富检索肺部疾病文献经验的图书馆员lIPF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。l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U

4、IP 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2022-3-27152022-3-2716Familial (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

5、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 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: 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型项目典型典型可能可能 Surgical lung biopsy specimens demonstra

6、ting 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 fib

7、roblast 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 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

8、、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 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) 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

9、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 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

10、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 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

11、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2022-3-2734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TrialNPrimary EndpointResultPirfenidone (CAPACITY 1)344Change in FVCNegativePirfenidone (CAPACITY 2)435Change in FVCPositivePirfenidone (Ogura)27

12、5Change in FVCPositivePirfenidone (Azuma)107Exercise gas exchangeStoppedPirfenidone (Nagai)8Overall survival , PFTs, CT scoreInconclusive (not RCT)Pirfenidone (Raghu)54Overall survival and change in PFTsInconclusive (not RCT)Octreotide 25MultipleNot reportedImatinib Mesylate120Progression-free survi

13、valNegativeBosentan (BUILD 1 and 2)132Change in 6MWNegativeBosentan (BUILD-3)616Progression-free survival or deathNegative Etanercept 100Change in DLCO, FVCNegativeAnticoagulation56SurvivalPositiveN-acetylcysteine (NAC) (IFIGENIA)184Change in FVC, DLco PositiveInterferon-gamma (INSPIRE)826Survival t

14、imeNegativeInterferon-gamma (GIPF-001)330Progression-free survivalNegativeInterferon-beta (1999)167Progression-free survival timeNegativeSildenafil (STEP)180Change in 6MWDNegativeSlide adapted from Kevin Brown, MD.吡非尼酮波生坦西地那非TrialTargetNPrimary EndpointLate PhasePrednisone, Azathioprine, NAC (PANTHE

15、R)Inflammation390Change in FVCAmbrisentan (ARTEMIS-IPF)Endothelin600Prog-free survival timeARTEMIS-PH (PH in IPF)Endothelin2206 MW distanceBIBF 1120Triple angiokinase400FVC rate of declineCNTO888Anti CCL2 (MCP-1)150FVC, safetyACT-064992 (macitentan, MUSIC) Endothelin156FVCWarfarin (ACE-IPF)Coagulati

16、on256Death, hospitalization, or FVC drop 10%Early PhaseGC-1008TGF-25SafetyQAX576Anti IL-1315SafetyTreprostinil, inhaledPH16Safety Slide adapted from Kevin Brown, MD.硫唑嘌呤安立生坦 May, 2010 ATS/New Orleans September, 2010 ERS/Barcelona January, 2011 Writing committee, NYC April, 2011 Modena, Italy May, 20

17、11 ATS/Denver September, 2011 ERS/Amsterdam January, 2012 Writing committee, NYC April, 2012 Final draft submitted September, 2012 Submission of revision William Travis, MD. (Chair) Talmadge E. King, Jr., MD, (Co-Chair) Ulrich Costabel, (Co-Chair) Athol Wells, (Co-Chair) Jay H. Ryu, USA (Subcommitte

18、e Chair) Jurgen Behr, Germany Demosthenes Bouros, Greece Kevin Brown, USA Harold Collard, USA Carlos Robalo Cordeiro, Portugal Vincent Cottin, France Marjolein Drent, The Netherlands Jim Egan, Ireland Kevin Flaherty, USA Travis, WD Yoshikazu Inoue, Japan Dong Soon Kim, Korea Fernando Martinez, USA G

19、anesh Raghu, USA Luca Richeldi, Italy Dominique Valeyre, France David Hansell, United Kingdom (Subcommittee co-chair) David Lynch, USA (Subcommittee co-chair) Takeshi Johkoh, Japan Nicola Sverzellati, Italy Andrew Nicholson, United Kingdom (Subcommittee Chair) Thomas V. Colby, USA Masanori Kitaichi,

20、 Japan Jeffrey Myers, USA Moises Selman, Mexico (Subcommittee chair) Bruno Crestani, France Cory Hogaboam, USA James Loyd, USA Christopher Ryerson, Canada (Subcommittee chair) Jeffrey Swigris, USA Rosalind F. Dudden, M.L.S. Shandra Protzko, M.L.S.idiopathic nonspecific interstitial pneumonia (NSIP)

21、is now accepted as a distinct clinical entity with removal of the term “provisional”including patients with combined emphysema and interstitial fibrosis. In clinical practice, respiratory bronchiolitisinterstitial lung disease is increasingly diagnosed without surgical lung biopsy in smokers on the

22、basis of clinical and imaging features (ground-glass opacities and centrilobular nodules) and bronchoalveolar lavage (smokers macrophages and absence of lymphocytosis).cryptogenic fibrosing alveolitis is removed, leaving idiopathic pulmonary fibrosis (IPF) as the sole clinical termfor this diagnosis

23、AJRCCM 2011; 183: 788-824 (modified)DISEASE PROGRESSIONTIMENATURAL HISTORY OF IPFRAPID PROGRESSIONSLOW PROGRESSIONSTABLEoften because of mixed patterns of lung injurymajor IIPs are distinguished from rare IIPs and unclassifiable cases. It is recognized that there is a need to provide a clinical algo

24、rithm for classifying and managing IIP cases. This is particularly applicable when no biopsy is available and high-resolution computed tomography is not diagnostic Pleuroparenchymal fibroelastosis is recognized as a specific rare entity, usually idiopathic. Other less well-defined histologic pattern

25、s, such as bronchiolocentric inflammation and fibrosis, are also includedl Idiopathic pulmonary fibrosisl Idiopathic nonspecific interstitial pneumonial Respiratory bronchiolitis interstitial lung diseasel Desquamative interstitial pneumonial Cryptogenic organizing pneumonial Acute interstitial pneu

26、monia l Idiopathic lymphoid interstitial pneumonial Idiopathic pleuropulmonary fibroelastosis NSIP IPF 1 ,2, 3 NSIP 4，显示两下肺胸膜下磨玻璃影，小叶间隔增厚，伴牵引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性支气管扩张，两，两下肺网状影，后胸膜下相对正常，有助于与相下肺网状影，后胸膜下相对正常，有助于与相鉴别鉴别图图，显示，显示两肺磨玻璃影及小叶中心小结节（两肺磨玻璃影及小叶中心小结节（箭头）箭头） Acute exacerbation of idiopathi

27、c pulmonary fibrosis (IPF). 4 months later2022-3-27652022-3-27662022-3-2767shows poorly defined arcadelike(拱廊样) and polygonal(多角形的) opacities (perilobular pattern) in the left lower lobe in both subpleural and central regions of the lung. Transverse thin-section CT scan at the level of dome of the r

28、ight hemidiaphragm in a 50-year-old woman 2022-3-2768The perilobular opacities (arrows) in right lower lobe are centrally located and surrounded by aerated lung parenchymaTransverse thin-section CT scan through lower lobes in a 44-year-old man2022-3-2769BOOP in an 81-year-old woman. Thin-section CT

29、scan obtained 1 cm below the level of the tracheal carina patchy bilateral air-space consolidation (open arrows)areas of ground-glass attenuation (curved arrows)Ill-defined nodular(小结的小结的) areas of consolidation (solid straight arrows) also are present 2022-3-27702022-3-27722022-3-27732022-3-2775202

30、2-3-2776RB-ILD : in a 47-year-old heavy cigarette smoker show moderately extensive ground-glass opacities and centrilobular nodules (circles). 2022-3-27782022-3-27792022-3-27802022-3-2781患者，显示两肺外周磨玻璃影及小叶间隔增厚患者，两肺外周灶性实变影及磨玻璃影，内可见支气管充气征患者，右下叶反晕征（病灶中心呈磨玻璃密度，外周为实变影）患者，显示两肺广泛磨玻璃影，右肺可见少许实变影患者，两肺广泛淡磨玻璃影，沿胸

31、膜及血管可见些许小囊状影。2022-3-27842022-3-2785 Idiopathic Pleuroparenchymal Fibroelastosis PPFE is a rare condition that consists of fibrosis involving the pleura and subpleural lung parenchyma, predominantly in the upper lobes. HRCT shows dense subpleural consolidation with traction bronchiectasis, architectu

32、ral distortion, and upper lobe volume loss. The fibrosis is elastotic弹性纤维状弹性纤维状, and intraalveolar fibrosis is present . It presents in adults with a median age of 57 years and has no sex predilection. Approximately half of patients have experienced recurrent infections. Pneumothorax气胸气胸 is common.

33、A minority has familial interstitial lung disease and nonspecific autoantibodies. Histologically, biopsies may show mild changes of PPFE or other patterns such as UIP. Disease progression occursin 60% of patients with death from disease in 40%Pleuroparenchymal fibroelastosis(A)High-resolution comput

34、ed tomography (HRCT) through the upper lobes shows irregular pleural-based opacities and a reticular pattern associated with parenchymal distortion. The pleura and lungs in the lower lobes appeared normal. (B) Section through the upper lobes shows scattered分散的分散的 pleuroparenchymal opacities and some

35、 distortion变形变形 of the underlying lung parenchyma. In the lower lobes there was no pleural irregularity, but there was a subtle微妙的微妙的 subpleural reticular pattern. 患者，显示两肺尖胸膜下小灶性致密影，伴牵引性 细支气管扩张，右上叶容积缩小，胸膜增厚Pleuroparenchymal fibroelastosis. (A) Low power shows pleural thickening and subpleural fibros

36、is. (B) Dense masses of elastic fibers are highlighted beneath the fibrotically thickened pleura (elastic 弹性的弹性的stain). Rare histologic interstitial pneumonia patterns have been described and these were not included as new IIP entities because of questions concerning whether they are variants of exi

37、sting IIPs or exist only in association with other conditions such as HP or CVD.Acute Fibrinous and Organizing Pneumonia AFOP was first reported in 17 patients with acute respiratory failure and initially regarded to represent a possible new IIP. The principal HRCT findings are bilateral basal opaci

38、ties and areas of consolidation The dominant histologic pattern is intraalveolar fibrin deposition and associated organizing pneumonia. Classical hyaline 透明的透明的membranes of DAD are absent. intraalveolar plugs of alveolar fibrinnodules of alveolar fibrin and organizing pneumonia AFOP may represent a

39、histologic pattern that can occur in the clinical spectrum of DAD（diffuse alveolar damage） and OP（organizing pneumonia） or it may reflect a tissue sampling issue. AFOP may be idiopathic or associated with CVD（Collagen Vascular Disease） , hypersensitivity pneumonitis , or drug reaction . As this patt

40、ern can be seen in eosinophilic pneumonia, this diagnosis should be excluded by absence of tissue and peripheral eosinophilia.Bronchiolocentric Patterns of Interstitial Pneumonia HRCTs in these cases were either normal or showed air trappingenvironmental or occupational exposures in most cases Cases

41、 that are “unclassifiable” in terms of overlap of histologic patterns often prove to be related to CVD (e.g., interstitial pneumonia and follicular小囊的小囊的 bronchiolitis in a patient with rheumatoid arthritis) or drug induced, If ILD is difficult, or impossible, to classify, management should be based

42、 on the most probable diagnosis after MDD and consideration of the expected disease behaviorCLINICAL 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 diseas

43、e behavior classification is complementary补充补充 to the IIP classification Should 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

44、实证实 for practicality and clinical relevanceIMPORTANT DIFFERENTIALDIAGNOSTIC CONSIDERATIONSHypersensitivity Pneumonitis过敏性肺炎 HRCT findings suggesting HP include centrilobular nodules, mosaic air-trapping, and upper lobe distribution Biopsy findings suggesting HP include bronchiolocentric distribution

45、 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 den

46、se opacification,traction bronchiectasis, and patchy ground-glass opacities.Honeycombing is not identified(C) Histology shows a bronchiolocentriccellular and fibrosing interstitial pneumonia. (D) There is a patchy cellular interstitialinfiltrate and poorly formed granulomas肉芽肿肉芽肿Collagen Vascular Di

47、sease胶原血管病胶原血管病 CVD is a frequent cause of interstitial pneumonia patterns, especially NSIP. Clinical, serologic, HRCT, and histologic findings may be helpful in distinguishing IIPs from ILD associated with CVD . The extent of serologic evaluation to be performed in the evaluation of suspected IPF has been suggested previously . A substantial percentage of patients with NSIP have findings suggesting, but not meeting， criteria for a defined CVDFamilial Interstitial Pneumonia家族性间质性肺炎 IIPs have been reported in closely related family