特發(fā)性肺纖維化診治新進(jìn)展

特發(fā)性肺纖維化診治

新進(jìn)展

呼吸與危重癥醫(yī)學(xué)科

1特發(fā)性間質(zhì)性肺炎分類的變遷經(jīng)歷過三個(gè)重要的階段１９６９年病理學(xué)家Ｌｉｅｂｏｗ根據(jù)不同的組織學(xué)表現(xiàn)把慢性間質(zhì)性肺炎分為五型：尋常型間質(zhì)性肺炎（ＵＩＰ）脫屑型間質(zhì)性肺炎（ＤＩＰ）淋巴細(xì)胞型間質(zhì)性肺炎（ＬＩＰ）巨細(xì)胞型間質(zhì)性肺炎（ＧＩＰ）細(xì)支氣管炎伴間質(zhì)性肺炎（ＢＩＰ）2特發(fā)性間質(zhì)性肺炎分類的變遷２００２年美國(guó)胸科學(xué)會(huì)和歐洲呼吸學(xué)會(huì)共同協(xié)商，統(tǒng)一公布了新的分類法并根據(jù)臨床相對(duì)的發(fā)病率，排列如下：特發(fā)性肺纖維化（ＩＰＦ）非特異性間質(zhì)性肺炎（ＮＳＩＰ）隱源性機(jī)化性肺炎（ＣＯＰ）急性間質(zhì)性肺炎（ＡＩＰ）呼吸性細(xì)支氣管炎并間質(zhì)性肺?。ǎ遥拢桑蹋模┟撔夹烷g質(zhì)性肺炎淋巴細(xì)胞型間質(zhì)性肺炎3２０１３年美國(guó)胸科學(xué)會(huì)和歐洲呼吸學(xué)會(huì)再次對(duì)特發(fā)性間質(zhì)性肺炎的分類進(jìn)行了重新修訂這次新分類把特發(fā)性間質(zhì)性肺炎分為三個(gè)大類：主要的罕見的不可分類4IPF診治指南新進(jìn)展IPF2011指南概述1IPF2011指南概述1IPF的診斷2IPF的治療3IIP的新分類方法4IPF2013研究進(jìn)展552000年美國(guó)胸科學(xué)會(huì)/歐洲呼吸學(xué)會(huì)(ATS/ERS)發(fā)表了特發(fā)性肺纖維化(idiopathicpulmonaryfibrosis，IPF)診斷和治療的共識(shí)歷經(jīng)11年，IPF的臨床和基礎(chǔ)研究均取得了許多重要進(jìn)展6DiffuseParenchymalLungDiseases/InterstitialLungDisease(DPLD/ILD)已知原因：藥物、CTD、粉塵、放射等肉芽腫性疾病：結(jié)節(jié)病、外源性過敏性肺炎

等其他：LAM、PLCH、EP等特發(fā)性間質(zhì)性肺炎(IIP)ATS/ERSstatement:AJRCCM2002;165:277特發(fā)性肺纖維化（IPF/UIP）非特異性間質(zhì)性肺炎（NSIP）隱原性機(jī)化性肺炎（COP）淋巴細(xì)胞間質(zhì)性肺炎（LIP）脫屑型間質(zhì)性肺炎（DIP）急性間質(zhì)性肺炎（AIP）呼吸性細(xì)支氣管炎伴間質(zhì)性肺?。≧BILD）72011指南美國(guó)胸科學(xué)會(huì)(ATS)、歐洲呼吸學(xué)會(huì)(ERS)、日本呼吸學(xué)會(huì)（JRS)和拉丁美洲胸科學(xué)會(huì)（ALAT)間質(zhì)性肺疾病(ILD)、特發(fā)性間質(zhì)性肺炎(IIP)和IPF領(lǐng)域的著名專家2010年5月前有關(guān)IPF的文獻(xiàn)(第一部以循證為基礎(chǔ)的IPF診斷和治療指南)8專家委員會(huì)IPF和間質(zhì)性肺疾病領(lǐng)域的公認(rèn)專家(24位呼吸內(nèi)科醫(yī)生，4位放射科醫(yī)生和4位病理科醫(yī)生)4位方法學(xué)家1位圖書館長(zhǎng)2位具有豐富檢索肺部疾病文獻(xiàn)經(jīng)驗(yàn)的圖書館員9指南結(jié)構(gòu)IPF的定義、流行病學(xué)資料、危險(xiǎn)因素、自然病程、分期及預(yù)后、病程監(jiān)測(cè)和未來發(fā)展方向。采用了GRADE循證方法，對(duì)指南中涉及的所有問題進(jìn)行了證據(jù)質(zhì)量與推薦強(qiáng)度分級(jí)101112IPF診治指南新進(jìn)展IPF2011指南概述1IPF的診斷2IPF的治療3IIP的新分類方法4IPF2013研究進(jìn)展5IPF的診斷２13定義原因不明、出現(xiàn)在成人、局限于肺、進(jìn)行性致纖維化的間質(zhì)性肺炎，其組織病理學(xué)和放射學(xué)表現(xiàn)為普通型間質(zhì)性肺炎(usualinterstitialpneumonia，UIP)與2000年IPF的定義相比較，2011指南在IPF的定義中保留組織病理學(xué)表現(xiàn)為UIP型的內(nèi)容，但首次將放射學(xué)表現(xiàn)為UIP型寫入IPF的定義，強(qiáng)調(diào)識(shí)別高分辨率CT(highresolution

computedtomography，HRCT)的UIP型表現(xiàn)的重要性14

準(zhǔn)確發(fā)病率和流行情況尚不清楚

流行病學(xué)

以前估計(jì)總發(fā)病率為3—6／10萬

近來IPF發(fā)病率估計(jì)為男性10.7/10萬，女性7.4/10萬15IPF發(fā)病的危險(xiǎn)因素

Familial(genetic)

IPF的5%SmokingEnvironmentalfactors(金屬粉塵，木屑、務(wù)農(nóng)、養(yǎng)鳥、護(hù)發(fā)劑、石粉接觸、牲畜接觸、植物和動(dòng)物粉塵接觸等)Chronicaspirationassociatedwithgastroesophagealrefluxdisease(多數(shù)為“隱性反流”，缺乏胃食管反流臨床癥狀。異常的胃食管反流導(dǎo)致反復(fù)微吸入是IPF高危因素之一）Infectiousagents16UIP

2011指南對(duì)UIP型HRCT和組織病理學(xué)定義提出詳細(xì)分級(jí)診斷標(biāo)準(zhǔn)，強(qiáng)調(diào)根據(jù)HRCT的UIP型特點(diǎn)可作為獨(dú)立的IPF診斷手段UIP型的HRCT特征:

雙側(cè)、外周、下肺基底部為主的網(wǎng)狀影

數(shù)量不等、范圍有限的磨玻璃影

病變較重的部位，通常有牽拉性支氣管和細(xì)支氣管擴(kuò)張，和/或蜂窩樣變17HRCT上UIP的特征18HRCT上UIP的特征胸膜下和肺基底部分布為主網(wǎng)格狀陰影蜂窩影，常伴有牽張性支氣管擴(kuò)張，尤其是蜂窩影對(duì)IPF的診斷有很重要的意義。

HRCT上的蜂窩影指成簇的囊泡樣氣腔，蜂窩壁邊界清楚。囊泡直徑在3～10mm之間，偶爾可大至25mm無不符合UIP型項(xiàng)目典型可能1920UIP的病理學(xué)特征21

SurgicallungbiopsyspecimensdemonstratingUIPpattern.(A)Scanningpowermicroscopyshowingapatchyprocesswithhoneycombspaces(thickarrow),somepreservedlungtissueregions(thinarrow),andfibrosisextendingintothelungfromthesubpleuralregions.(B)Adjacenttotheregionsofmorechronicfibrosis(thickarrow)isafibroblastfocus(asterisk),recognizedbyitsconvexshapeandcompositionofedematousfibroblastictissue,suggestiveofrecentlunginjury.222011指南強(qiáng)調(diào)由富有ILD診斷經(jīng)驗(yàn)的肺病學(xué)專家、放射學(xué)專家、病理學(xué)專家之間多學(xué)科討論(multidisciplinary

discussions，MDD)在IPF診斷中的重要性，特別是在HRCT和病理組織學(xué)型不一致的病人2324252011指南IPF診斷標(biāo)準(zhǔn)如下:(1)除外其他已知原因的ILD(如家庭環(huán)境、職業(yè)環(huán)境暴露、結(jié)締組織病、藥物肺毒性損害)(2)HRCT表現(xiàn)為UIP型患者不需要外科肺活檢

(3)HRCT表現(xiàn)和外科肺活檢組織病理學(xué)表現(xiàn)型符合HRCT和組織病理學(xué)表現(xiàn)的特定組合

262011指南診斷不再需要經(jīng)支氣管鏡肺活檢或支氣管肺泡灌洗細(xì)胞分析BALF最主要的作用是排除慢性外源性過敏性肺泡炎

BALF中淋巴細(xì)胞增多(≥40％)時(shí)應(yīng)該考慮慢性外源性過敏性肺泡炎的可能HRCT表現(xiàn)為UIP型的患者中，有8％的患者通過BALF分析更改了診斷推薦意見：絕大多數(shù)IPF患者的診斷流程中不應(yīng)該進(jìn)行BALF細(xì)胞學(xué)分析，但可能適用于少數(shù)患者(弱推薦，低質(zhì)量證據(jù))272011指南建議在IPF診斷中進(jìn)行結(jié)締組織病血清學(xué)檢測(cè)結(jié)締組織疾病可以出現(xiàn)UIP型表現(xiàn)，ILD可以作為某些結(jié)締組織疾病的唯一臨床表現(xiàn)先于其他臨床癥狀出現(xiàn)推薦意見：絕大多數(shù)疑診的IPF患者應(yīng)該進(jìn)行結(jié)締組織疾病相關(guān)的血清學(xué)檢測(cè)，但可能不適用于少數(shù)患者(弱推薦，很低質(zhì)量證據(jù))類風(fēng)濕因子、抗環(huán)瓜氨酸肽抗體、抗核抗體滴度和模式、抗合成酶抗體、肌酸激酶、醛縮酶、SSA、SSB、抗硬皮病抗體282011指南并沒有列入肺功能:IPF患者肺功能檢測(cè)也可能是正常除特殊需要外，不建議使用TBLB:對(duì)結(jié)節(jié)病等肉芽腫性疾病進(jìn)行TBLB檢查有利于診斷，但HRCT表現(xiàn)為UIP者則基本能夠排除這些疾病，且進(jìn)行該項(xiàng)檢查能增加IPF急性加重的風(fēng)險(xiǎn)29提示預(yù)后不良的相關(guān)因素和指標(biāo):

肺活檢標(biāo)本中成纖維細(xì)胞病灶數(shù)量，

用力肺活量(FVC)和肺一氧化碳彌散量(DLCO)下降，6分鐘步行試驗(yàn)中氧飽和度下降的程度，HRCT的肺纖維化和蜂窩程度，

肺功能和影像學(xué)指標(biāo)的綜合評(píng)分系統(tǒng)(CPI)，

血清表面活性蛋白A和D濃度的升高，

血清和BALF生物學(xué)標(biāo)記物(KL-6、SP-A和D、CCL18、MMP和纖維細(xì)胞)

合并肺氣腫、肺動(dòng)脈高壓30IPF的自然病程回顧性縱向研究結(jié)果提示，IPF患者從確診到死亡的中位生存時(shí)間為2～3年但從最近納入臨床試驗(yàn)的基礎(chǔ)肺功能尚可的IPF患者的臨床資料來看，中位生存期可能大于2～3年31IPF急性加重的診斷標(biāo)準(zhǔn)1個(gè)月內(nèi)出現(xiàn)不能解釋的呼吸困難加重存在低氧血癥的客觀證據(jù)影像學(xué)表現(xiàn)為新近出現(xiàn)的肺部浸潤(rùn)影除外其他診斷(如感染、肺栓塞、氣胸或心力衰竭)急性加重可在IPF病程任何時(shí)候發(fā)生，有時(shí)還是本病首發(fā)癥狀；臨床表現(xiàn)為咳嗽加重，發(fā)熱，伴或不伴有痰量增加每年約5％一10％的IPF患者會(huì)發(fā)生急性呼吸功能惡化32IPF診治指南新進(jìn)展IPF2011指南概述1IPF的診斷2IPF的治療3IIP的新分類方法4IPF2013研究進(jìn)展5IPF的治療３33缺乏有效治療方法

①皮質(zhì)激素

②免疫抑制藥物/細(xì)胞毒藥物

③抗纖維化藥物

可單獨(dú)或聯(lián)合應(yīng)用

2000指南IPF的治療342011指南IPF的治療35TrialNPrimaryEndpointResultPirfenidone(CAPACITY1)344ChangeinFVCNegativePirfenidone(CAPACITY2)435ChangeinFVCPositivePirfenidone(Ogura)275ChangeinFVCPositivePirfenidone(Azuma)107ExercisegasexchangeStoppedPirfenidone(Nagai)8Overallsurvival,PFTs,CTscoreInconclusive(notRCT)Pirfenidone(Raghu)54OverallsurvivalandchangeinPFTsInconclusive(notRCT)Octreotide25MultipleNotreportedImatinibMesylate120Progression-freesurvivalNegativeBosentan(BUILD1and2)132Changein6MWNegativeBosentan(BUILD-3)616Progression-freesurvivalordeathNegativeEtanercept100ChangeinDLCO,FVCNegativeAnticoagulation56SurvivalPositiveN-acetylcysteine(NAC)(IFIGENIA)184ChangeinFVC,DLco

PositiveInterferon-gamma(INSPIRE)826SurvivaltimeNegativeInterferon-gamma(GIPF-001)330Progression-freesurvivalNegativeInterferon-beta(1999)167Progression-freesurvivaltimeNegativeSildenafil(STEP)180Changein6MWDNegativeCompletedTrialsforIPFSlideadaptedfromKevinBrown,MD.吡非尼酮波生坦西地那非36ActiveorNewTrialsforIPFTrialTargetNPrimaryEndpointLatePhasePrednisone,Azathioprine,NAC(PANTHER)Inflammation390ChangeinFVCAmbrisentan(ARTEMIS-IPF)Endothelin600Prog-freesurvivaltimeARTEMIS-PH(PHinIPF)Endothelin2206MWdistanceBIBF1120Tripleangiokinase400FVCrateofdeclineCNTO888AntiCCL2(MCP-1)150FVC,safetyACT-064992(macitentan,MUSIC)Endothelin156FVCWarfarin(ACE-IPF)Coagulation256Death,hospitalization,orFVCdrop>10%EarlyPhaseGC-1008TGF-25SafetyQAX576AntiIL-1315SafetyTreprostinil,inhaledPH16Safety

SlideadaptedfromKevinBrown,MD.硫唑嘌呤安立生坦37IPF診治指南新進(jìn)展IPF2011指南概述1IPF的診斷2IPF的治療3IIP的新分類方法4IPF2013研究進(jìn)展5IIP的新分類方法４38ScheduleofIIPclassificationprojectMay,2010–ATS/NewOrleansSeptember,2010–ERS/BarcelonaJanuary,2011–Writingcommittee,NYCApril,2011–Modena,ItalyMay,2011–ATS/DenverSeptember,2011–ERS/AmsterdamJanuary,2012–Writingcommittee,NYCApril,2012–FinaldraftsubmittedSeptember,2012–Submissionofrevision39MembersoftheATS/ERSCommitteeonIIPWilliamTravis,MD.(Chair)TalmadgeE.King,Jr.,MD,(Co-Chair)UlrichCostabel,(Co-Chair)AtholWells,(Co-Chair)40PULMONARY(17+4)JayH.Ryu,USA(SubcommitteeChair)JurgenBehr,GermanyDemosthenesBouros,GreeceKevinBrown,USAHaroldCollard,USACarlosRobaloCordeiro,PortugalVincentCottin,FranceMarjoleinDrent,TheNetherlandsJimEgan,IrelandKevinFlaherty,USATravis,WDYoshikazuInoue,JapanDongSoonKim,KoreaFernandoMartinez,USAGaneshRaghu,USALucaRicheldi,ItalyDominiqueValeyre,France41RADIOLOGYDavidHansell,UnitedKingdom(Subcommitteeco-chair)DavidLynch,USA(Subcommitteeco-chair)TakeshiJohkoh,JapanNicolaSverzellati,Italy42PATHOLOGYAndrewNicholson,UnitedKingdom(SubcommitteeChair)ThomasV.Colby,USAMasanoriKitaichi,JapanJeffreyMyers,USA43MOLECULARBIOLOGYMoisesSelman,Mexico(Subcommitteechair)BrunoCrestani,FranceCoryHogaboam,USAJamesLoyd,USA44EVIDENCEBASEDANALYSISChristopherRyerson,Canada(Subcommitteechair)JeffreySwigris,USA45REFERENCELIBRARIANSRosalindF.Dudden,M.L.S.ShandraProtzko,M.L.S.46新分類方案與2002年IIP專家共識(shí)的區(qū)別（1）明確了特發(fā)性NSIP（iNSIP）是一種獨(dú)立的臨床病理的類型，其臨床過程呈高度異質(zhì)性；idiopathicnonspecificinterstitialpneumonia(NSIP)isnowacceptedasadistinctclinicalentitywithremovaloftheterm“provisional”47新分類方案與2002年IIP專家共識(shí)的區(qū)別（2）收集了更多的吸煙相關(guān)性間質(zhì)性肺病的信息，特別是肺氣腫合并肺纖維化（includingpatientswithcombinedemphysemaandinterstitialfibrosis.CEPF）；Inclinicalpractice,respiratorybronchiolitis–interstitiallungdiseaseisincreasinglydiagnosedwithoutsurgicallungbiopsyinsmokersonthebasisofclinicalandimagingfeatures(ground-glassopacitiesandcentrilobularnodules)andbronchoalveolarlavage(smoker’smacrophagesandabsenceoflymphocytosis).48新分類方案與2002年IIP專家共識(shí)的區(qū)別（3）認(rèn)為IPF自然病程多樣性，可長(zhǎng)期穩(wěn)定，可快速進(jìn)行性進(jìn)展，可在病程中出現(xiàn)急性加重；cryptogenicfibrosingalveolitisisremoved,leavingidiopathicpulmonaryfibrosis(IPF)asthesoleclinicaltermforthisdiagnosis49AJRCCM2011;183:788-824(modified)DISEASEPROGRESSIONTIMENATURALHISTORYOFIPFRAPIDPROGRESSIONSLOWPROGRESSIONSTABLE50ThemajorIIPsaregroupedintochronicfibrosing(IPFandNSIP),smoking-related(respiratorybronchiolitis–interstitiallungdisease[RB-ILD]anddesquamativeinterstitialpneumonia[DIP),andacute/subacuteIIPs(cryptogenicorganizingpneumonia[COP]andacuteinterstitialpneumonia[AIP]51新分類方案與2002年IIP專家共識(shí)的區(qū)別（4）對(duì)慢性致纖維化性間質(zhì)性肺炎(IPF及NSIP）的“急性加重（AE）”有了明確定義和描述（5）首次明確提出部分IIP患者病理難以歸入現(xiàn)有的IIP類型中（不能分類的IIP，oftenbecauseofmixedpatternsoflunginjury）.majorIIPsaredistinguishedfromrareIIPsandunclassifiablecases.52新分類方案與2002年IIP專家共識(shí)的區(qū)別（6）提出IIP臨床表現(xiàn)診療途徑，尤其對(duì)沒有病理診斷和HRCT不符合某一典型IIP影像學(xué)表現(xiàn)ItisrecognizedthatthereisaneedtoprovideaclinicalalgorithmforclassifyingandmanagingIIPcases.Thisisparticularlyapplicablewhennobiopsyisavailableandhigh-resolutioncomputedtomographyisnotdiagnostic53新分類方案與2002年IIP專家共識(shí)的區(qū)別（7）提出了一種新的IIP類型－PPFE；Pleuroparenchymalfibroelastosisisrecognizedasaspecificrareentity,usuallyidiopathic.Otherlesswell-definedhistologicpatterns,suchasbronchiolocentricinflammationandfibrosis,arealsoincluded（8）提出了某些分子生物學(xué)標(biāo)記物和基因?qū)W研究結(jié)果可能對(duì)IIP的分類和診斷有一定幫助54MajorIdiopathicInterstitialPneumoniasIdiopathicpulmonaryfibrosisIdiopathicnonspecificinterstitialpneumoniaRespiratorybronchiolitisinterstitiallungdiseaseDesquamativeinterstitialpneumoniaCryptogenicorganizingpneumoniaAcuteinterstitialpneumonia

RareIdiopathicInterstitialPneumoniasIdiopathiclymphoidinterstitialpneumoniaIdiopathicpleuropulmonaryfibroelastosis

Unclassifiableidiopathicinterstitialpneumonias

特發(fā)性間質(zhì)性肺炎分類(2012)

55特發(fā)性間質(zhì)性肺炎（IIP）急性/亞急性IP

COP

AIP吸煙相關(guān)性IP

DIP

RBILD特發(fā)性間質(zhì)性肺炎的分類(2012年)主要的IIP慢性致纖維化性IP

IPF

NSIP家族性2-20%,

非家族性80%56575859NSIP60IPF1,2,3NSIP4，ＨＲＣＴ顯示兩下肺胸膜下磨玻璃影，小葉間隔增厚，伴牽引性支氣管擴(kuò)張５ＮＳＩＰ，兩下肺網(wǎng)狀影，后胸膜下相對(duì)正常，有助于與ＩＰＦ相鑒別圖６ＲＢ－ＩＬＤ，顯示兩肺磨玻璃影及小葉中心小結(jié)節(jié)（箭頭）61Acuteexacerbationofidiopathicpulmonaryfibrosis(IPF).4monthslater6263特發(fā)性間質(zhì)性肺炎（IIP）急性/亞急性IP

COP

AIP吸煙相關(guān)性IP

DIP

RBILD特發(fā)性間質(zhì)性肺炎的分類(2012年)主要的IIP慢性致纖維化性IP

IPF

NSIP家族性2-20%,

非家族性80%64隱源性機(jī)化性肺炎(COP)COP由Davison等1983年提出1985年，Epler等稱本病為阻塞性細(xì)支氣管炎伴機(jī)化性肺炎(BOOP)。后這一稱謂曾獲得普遍接受多數(shù)學(xué)者認(rèn)為COP更符合本病的特點(diǎn)65臨床表現(xiàn)BOOP過程較輕，病程較短，一般2—10周，3/4病人<2周，只有24%病人癥狀持續(xù)1年以上。影象學(xué)圖形以“蝴蝶形”陰影為特征激素治后多可完全恢復(fù),但潑尼松減量（15mg/d以下)或停用時(shí),部分患者在3個(gè)月內(nèi)復(fù)發(fā)。故推薦激素至少應(yīng)用6個(gè)月。少部分患者可自愈,極少發(fā)展為呼吸衰竭66showspoorlydefinedarcadelike(拱廊樣)andpolygonal(多角形的)opacities(perilobularpattern)intheleftlowerlobeinbothsubpleuralandcentralregionsofthelung.Transversethin-sectionCTscanatthelevelofdomeoftherighthemidiaphragmina50-year-oldwomancryptogenicorganizingpneumonia67Theperilobularopacities(arrows)inrightlowerlobearecentrallylocatedandsurroundedbyaeratedlungparenchymaTransversethin-sectionCTscanthroughlowerlobesina44-year-oldmancryptogenicorganizingpneumonia68BOOPinan81-year-oldwoman.Thin-sectionCTscanobtained1cmbelowthelevelofthetrachealcarina

patchybilateralair-spaceconsolidation(openarrows)areasofground-glassattenuation(curvedarrows)Ill-definednodular(小結(jié)的)areasofconsolidation(solidstraightarrows)alsoarepresentcryptogenicorganizingpneumonia69cryptogenicorganizingpneumonia7071AIP（急性間質(zhì)性肺炎）臨床表現(xiàn)平均發(fā)病年齡為50歲往往先有上呼吸道病毒感染史,主訴肌痛、關(guān)節(jié)痛、畏寒、發(fā)熱及乏力數(shù)日后出現(xiàn)進(jìn)行性勞力性呼吸困難。有肺實(shí)變征及廣泛濕啰音多在1個(gè)月內(nèi)死亡，80%--90%半年內(nèi)死亡72AIP

ina48-year-oldwoman.Thin-sectionCTscanoftherightlungobtained2cmbelowthelevelofthetrachealcarinademonstratesdiffuseground-glassattenuationandintralobularreticularopacities(arrows).73特發(fā)性間質(zhì)性肺炎（IIP）急性/亞急性IP

COP

AIP吸煙相關(guān)性IP

DIP

RBILD特發(fā)性間質(zhì)性肺炎的分類(2012年)主要的IIP慢性致纖維化性IP

IPF

NSIP家族性2-20%,

非家族性80%74呼吸性細(xì)支氣管炎一間質(zhì)性肺病(RB-ILD)間質(zhì)性肺病合并呼吸細(xì)支氣管損害呼吸細(xì)支氣管炎R(shí)B是吸煙者的病變,多40一50歲重度吸煙者,100%有長(zhǎng)期吸煙史特征為Ⅰ、Ⅱ級(jí)呼吸細(xì)支氣管腔內(nèi)充滿大量含色素巨噬細(xì)胞癥狀較輕,僅少數(shù)有明顯呼吸困難和低氧血癥,伴咳嗽、咳痰。通常無杵狀指含色素巨噬細(xì)胞充填肺泡,故有人認(rèn)為RBILD是DIP早期階段75RBILD很少有蜂窩肺，X線表現(xiàn)為“臟肺”高分辨CT顯示：小葉中心性小結(jié)節(jié)影及片狀磨玻璃影76RB-ILD:ina47-year-oldheavycigarettesmokershowmoderatelyextensiveground-glassopacitiesandcentrilobularnodules(circles).77脫屑性間質(zhì)性肺炎(DIP)肺泡內(nèi)充填脫落的肺泡上皮細(xì)胞,因而定名為DIP?，F(xiàn)證實(shí)是巨噬細(xì)胞病理與RBILD相似，肺泡內(nèi)有褐色素巨噬細(xì)胞浸潤(rùn)DIP與RBILD區(qū)別：病變更彌漫均一,無細(xì)支氣管中心性改變有學(xué)者認(rèn)為DIP是RBILD的終末階段戒煙后多數(shù)癥狀減輕,激素治療反應(yīng)良好，治療后約70%病人能存活10年以上78DIP肺泡腔內(nèi)褐色素巨噬細(xì)胞浸潤(rùn)肺泡隔略增厚病變更彌漫均一79DIP外周磨玻璃影及部分囊狀影80DIPHRCTofapatientwithDIP,demonstratingbilateralareasofground-glassopacity.81７ＤＩＰ患者，ＨＲＣＴ顯示兩肺外周磨玻璃影及小葉間隔增厚８ＣＯＰ患者，兩肺外周灶性實(shí)變影及磨玻璃影，內(nèi)可見支氣管充氣征９ＣＯＰ患者，右下葉反暈征（病灶中心呈磨玻璃密度，外周為實(shí)變影）１０ＡＩＰ患者，ＣＴ顯示兩肺廣泛磨玻璃影，右肺可見少許實(shí)變影１１ＬＩＰ患者，兩肺廣泛淡磨玻璃影，沿胸膜及血管可見些許小囊狀影。82特發(fā)性間質(zhì)性肺炎（IIP）急性/亞急性IP

COP

AIP吸煙相關(guān)性IP

DIP

RBILD特發(fā)性間質(zhì)性肺炎的分類(2012年)主要的IIP慢性致纖維化性IP

IPF

NSIP家族性2-20%,

非家族性80%少見的IIP特發(fā)性淋巴細(xì)胞間質(zhì)性肺炎特發(fā)性胸膜肺纖維彈性組織增生癥83

肺泡壁有淋巴細(xì)胞和漿細(xì)胞浸潤(rùn)，肺泡腔內(nèi)有大量淋巴細(xì)胞

Ⅱ型肺泡上皮細(xì)胞增生。常見有生發(fā)中心的淋巴濾泡。可有非壞死性肉芽腫及肺泡腔機(jī)化發(fā)病高峰40—50歲女多于男LIP臨床上多與干燥綜合癥并存對(duì)糖皮質(zhì)激素反應(yīng)較好，預(yù)后比IPF明顯為好淋巴細(xì)胞間質(zhì)性肺炎(LIP)84

centrilobularnodulesandbranchinglinearstructures(straightarrow)intherightlung.Manythin-walledcysts(curvedarrows)wereseeninbothlungs

ina32-year-oldwoman.(a)Thin-section(1-mmcollimation)CTscanobtainedatthelevelofthecarinaSj?grensyndromeandlymphocyticinterstitialpneumonia

85特發(fā)性胸膜肺纖維彈性組織增生癥IdiopathicPleuroparenchymalFibroelastosisPPFEisarareconditionthatconsistsoffibrosisinvolvingthepleuraandsubpleurallungparenchyma,predominantlyintheupperlobes.HRCTshowsdensesubpleuralconsolidationwithtractionbronchiectasis,architecturaldistortion,andupperlobevolumeloss.86特發(fā)性胸膜肺纖維彈性組織增生癥Thefibrosisiselastotic彈性纖維狀,andintraalveolarfibrosisispresent.Itpresentsinadultswithamedianageof57yearsandhasnosexpredilection.Approximatelyhalfofpatientshaveexperiencedrecurrentinfections.Pneumothorax氣胸iscommon.Aminorityhasfamilialinterstitiallungdiseaseandnonspecificautoantibodies.Histologically,biopsiesmayshowmildchangesofPPFEorotherpatternssuchasUIP.Diseaseprogressionoccursin60%ofpatientswithdeathfromdiseasein40%87Pleuroparenchymalfibroelastosis(A)High-resolutioncomputedtomography(HRCT)throughtheupperlobesshowsirregularpleural-basedopacitiesandareticularpatternassociatedwithparenchymaldistortion.Thepleuraandlungsinthelowerlobesappearednormal.(B)Sectionthroughtheupperlobesshowsscattered分散的pleuroparenchymalopacitiesandsomedistortion變形oftheunderlyinglungparenchyma.Inthelowerlobestherewasnopleuralirregularity,buttherewasasubtle微妙的subpleuralreticularpattern.88ＰＰＦＥ患者，ＨＲＣＴ顯示兩肺尖胸膜下小灶性致密影，伴牽引性細(xì)支氣管擴(kuò)張，右上葉容積縮小，胸膜增厚89Pleuroparenchymalfibroelastosis.(A)Lowpowershowspleuralthickeningandsubpleuralfibrosis.(B)Densemassesofelasticfibersarehighlightedbeneaththefibroticallythickenedpleura(elastic彈性的stain).90特發(fā)性間質(zhì)性肺炎（IIP）急性/亞急性IP

COP

AIP吸煙相關(guān)性IP

DIP

RBILD特發(fā)性間質(zhì)性肺炎的分類(2012年)主要的IIP少見的IIP慢性致纖維化性IP

IPF

NSIP特發(fā)性淋巴細(xì)胞間質(zhì)性肺炎特發(fā)性胸膜肺纖維彈性組織增生癥由于證據(jù)不夠下列二個(gè)病理類型未被列入疾病分類:急性纖維素性機(jī)化性肺炎氣道中心性間質(zhì)性肺炎家族性2-20%,

非家族性80%91少見病，但未被列入疾病分類RarehistologicinterstitialpneumoniapatternshavebeendescribedandthesewerenotincludedasnewIIPentitiesbecauseofquestionsconcerningwhethertheyarevariantsofexistingIIPsorexistonlyinassociationwithotherconditionssuchasHPorCVD.92急性纖維素性機(jī)化性肺炎

AcuteFibrinousandOrganizingPneumoniaAFOPwasfirstreportedin17patientswithacuterespiratoryfailureandinitiallyregardedtorepresentapossiblenewIIP.TheprincipalHRCTfindingsarebilateralbasalopacitiesandareasofconsolidation93急性纖維素性機(jī)化性肺炎Thedominanthistologicpatternisintraalveolarfibrindepositionandassociatedorganizingpneumonia.Classicalhyaline透明的membranesofDADraalveolarplugsofalveolarfibrinnodulesofalveolarfibrinandorganizingpneumonia94急性纖維素性機(jī)化性肺炎AFOPmayrepresentahistologicpatternthatcanoccurintheclinicalspectrumofDAD（diffusealveolardamage）andOP（organizingpneumonia）oritmayreflectatissuesamplingissue.AFOPmaybeidiopathicorassociatedwithCVD（CollagenVascularDisease）,hypersensitivitypneumonitis,ordrugreaction.Asthispatterncanbeseenineosinophilicpneumonia,thisdiagnosisshouldbeexcludedbyabsenceoftissueandperipheraleosinophilia.95氣道中心性間質(zhì)性肺炎

BronchiolocentricPatternsofInterstitialPneumonia最近文獻(xiàn)報(bào)道了以特發(fā)性細(xì)支氣管中心性間質(zhì)性肺炎

(idiopathicbronchiolocentricinterstitialpneumonia，BrIP)、小葉中心性纖維化(centrilobularfibrosis，CLF)

、氣道中心性間質(zhì)纖維化(airwaycenteredinterstitialfibrosis，ACIF)和細(xì)支氣管化生(peribronchiolarmetaplasia，PBM)性間質(zhì)性肺疾病(PBM—lED)命名的具有細(xì)支氣管為中心的纖維化及炎性浸潤(rùn)為特征的ILD96氣道中心性間質(zhì)性肺炎病理上缺乏HP的典型病理特征——間質(zhì)性肉芽腫缺乏UIP的明顯胸膜下或外周小葉的纖維化和炎癥HRCTsinthesecaseswereeithernormalorshowedairtrapping多發(fā)生在女性;預(yù)后也較差沒有已知的過敏、職業(yè)粉塵、藥物或結(jié)締組織疾病證據(jù)Onestudly:environmentaloroccupationalexposuresinmostcases這些以細(xì)支氣管為中心的間質(zhì)性肺炎不同于既往已知的HP、RBILD、UIP等，可能是一種新的間質(zhì)性肺炎類型97特發(fā)性間質(zhì)性肺炎（IIP）急性/亞急性IP

COP

AIP吸煙相關(guān)性IP

DIP

RBILD特發(fā)性間質(zhì)性肺炎的分類(2012年)主要的IIP少見的IIP不能分類的IIP慢性致纖維化性IP

IPF

NSIP特發(fā)性淋巴細(xì)胞間質(zhì)性肺炎特發(fā)性胸膜肺纖維彈性組織增生癥由于證據(jù)不夠下列二個(gè)病理類型未被列入疾病分類:急性纖維素性機(jī)化性肺炎氣道中心性間質(zhì)性肺炎家族性2-20%,

非家族性80%98不能分類IIP的原因

1.臨床、放射或病理學(xué)資料不充分；2.臨床、放射或病理學(xué)發(fā)現(xiàn)存在顯著不一致：先前的治療導(dǎo)致放射或病理學(xué)表現(xiàn)出現(xiàn)重要改變

,(如病理證實(shí)的DIP隨著激素治療后表現(xiàn)為殘留NSIP表現(xiàn))出現(xiàn)不認(rèn)識(shí)的表現(xiàn)或已認(rèn)識(shí)的表現(xiàn)出現(xiàn)了不尋常的變異，而不能放在目前ATS/ERS分類中,(如OP表現(xiàn)同時(shí)伴有顯著的纖維化)同一個(gè)患者出現(xiàn)多種HRCT和/或病理學(xué)類型“Unclassifiabledisease”>10%ofIIPs99不能分類IIP的原因

Casesthatare“unclassifiable”intermsofoverlapofhistologicpatternsoftenprovetoberelatedtoCVD(e.g.,interstitialpneumoniaandfollicular小囊的bronchiolitisinapatientwithrheumatoidarthritis)ordruginduced,“Unclassifiabledisease”>10%ofIIPs100IfILDisdifficult,orimpossible,toclassify,managementshouldbebasedonthemostprobablediagnosisafterMDDandconsiderationoftheexpecteddiseasebehavior根據(jù)疾病行為提出實(shí)用的臨床分類CLINICALCLASSIFICATIONOFDISEASEBEHAVIOR101ThisapproachismostusefulinunclassifiablecasesandforsomeIIPs,suchasNSIP,thatcanbeassociatedwithallfivepatternsofdiseasebehavior.Thisdiseasebehaviorclassificationiscomplementary補(bǔ)充totheIIPclassificationShouldnotbeusedasajustificationfordelayingSLB（surgicallungbiopsy）.Suchdelaysincreasetheriskofsurgicalcomplicationsandmayresultininappropriatemanagement.Thisclassificationsystemneedstobevalidated證實(shí)forpracticalityandclinicalrelevance102根據(jù)疾病行為提出了實(shí)用的臨床分類Historically既往,theprimaryquestionhasbeen“whatisthediagnosis”?Pragmatically實(shí)用上,theprimaryquestionis“whatareyougoingtodoaboutit”?Weneedadifferentquestion（Apragmaticclinicalclassification）

103臨床分類的綜合考量因素-1疾病預(yù)后：雖然ILD病因不同，臨床表現(xiàn)各異，但疾病預(yù)后大致可歸納如下：自限性炎癥穩(wěn)定性纖維化炎癥為主伴有不同程度纖維化進(jìn)行性纖維化可逐漸達(dá)到穩(wěn)定狀態(tài)不可終止的纖維化104臨床分類的綜合考量因素-2疾病和患者的特征：診斷病因主要的形態(tài)學(xué)異常疾病嚴(yán)重程度疾病的動(dòng)態(tài)改變患者個(gè)人情況105臨床分類的綜合考量因素-3處理方法：對(duì)不同預(yù)后疾病采取不同臨床策略：觀察：自限性炎癥/穩(wěn)定性纖維化積極治療，達(dá)到目標(biāo)后，維持治療結(jié)果：炎癥為主(大部分可逆）伴有不同程度纖維化治療防止其進(jìn)展：進(jìn)行性進(jìn)展有逐漸達(dá)到穩(wěn)定狀態(tài)可能的纖維化治療讓其緩慢進(jìn)展：不可終止的纖維化106疾病臨床行為綜合判定Patient-specificmodifiersAgeSuspectedetiologyDiseaseseverityReversibilityofdiseaseMDDiagnosis-Clinical-Radiologic-Pathologic

(whenavailable)Longitudinalbehaviour:“Priorhistory”-Impactoftherapy-Rateofprogression(symptoms,PFTs,radiology)Group1

ReversibleIrreversible++Group2Group3Group4Group5107108臨床行為治療目標(biāo)監(jiān)測(cè)策略1可逆性/自限性(RBILD)去除可能的原因短期(3-6month)觀察以確定疾病回歸2可逆性疾病，具有進(jìn)展風(fēng)險(xiǎn)可能

(某些

細(xì)胞性NSIP,DIP,COP)積極治療取得初始效果，然后合理的長(zhǎng)期治療短期觀察證實(shí)治療有效，長(zhǎng)期觀察保證治療效果能維持。3穩(wěn)定病變，伴有部分殘留(某些纖維化性NSIP)維持目前狀態(tài)長(zhǎng)期觀察評(píng)估疾病病程4進(jìn)展性、不可逆病變，具有潛在穩(wěn)定可能(某些

f-NSIP)預(yù)防進(jìn)展長(zhǎng)期觀察評(píng)估疾病病程5即使積極治療，仍不可逆、進(jìn)行性進(jìn)展(IPF,某些f-NSIP)延緩疾病進(jìn)展長(zhǎng)期觀察評(píng)估疾病程，判定肺移植或有效輔助治療109IMPORTANTDIFFERENTIAL

DIAGNOSTICCONSIDERATIONSHypersensitivityPneumonitis過敏性肺炎HRCTfindingssuggestingHPincludecentrilobularnodules,mosaicair-trapping,andupperlobedistributionBiopsyfindingssuggestingHPincludebronchiolocentricdistributionandpoorlyformedgranulomas110Fibrotichypersensitivitypneumonitis.(A)Axialand(B)coronalcomputedtomography(CT)reconstructionsina76-year-oldbird-keeperwithprogressiveshortnessofbreathover6yearsshowupperlung–predominantsubpleuralreticulationwithsomeconfluent匯合areasofdenseopacification,tractionbronchiectasis,andpatchyground-glassopacities.Honeycombingisnotidentified111(C)Histologyshowsabronchiolocentriccellularandfibrosinginterstitialpneumonia.(D)Thereisapatchycellularinterstitialinfiltrateandpoorlyformedgranulomas肉芽腫112CollagenVascularDisease

膠原血管病CVDisafrequentcauseofinterstitialpneumoniapatterns,especiallyNSIP.Clinical,serologic,HRCT,andhistologicfindingsmaybehelpfulindistinguishingIIPsfromILDassociatedwithCVD.TheextentofserologicevaluationtobeperformedintheevaluationofsuspectedIPFhasbeensuggestedpreviously.AsubstantialpercentageofpatientswithNSIPhavefindingssuggesting,butnotmeeting，criteriaforadefinedCVD113FamilialInterstitialPneumonia

家族性間質(zhì)性肺炎IIPshavebeenreportedincloselyrelatedfamilymembersin2–20%ofcases.ThesecasesremainclassifiedasIIPsdespitethegeneticpredisposition傾向MostFIPfamilies(80%)haveevidenceofverticaltransmissionsuggestingsingleautosomal常染色體dominantmechanisms,butmostresponsiblegeneshavenotyetbeenidentified114FamilialIIPscanbeindistinguishable難區(qū)分fromnonfamilialcasesonHRCTandlungbiopsy.AllpatientswithsuspectedIIPshouldthereforebequestionedaboutrelevantfamilyhistoryasthismayguidegenemutationsearch,andmanagementorevaluationofotherfamilymembers115CoexistingPatternsDifferentpatternsmaybeseeninasinglebiopsyorinbiopsiesfrommultiplesites(e.g.,usualinterstitialpneumonia[UIP]inonelobeandNSIPinanother),orwhenpathologicandHRCTpatternsdiffer.Insmokers,multipleHRCTandhistologicfeaturesmaycoexistincludingLangerhans’cellhistiocytosis,respiratorybronchiolitis(RB),desquamativeinterstitialpneumonia(DIP),pulmonaryfibrosis(UIPorNSIP),andemphysema116Combinedpulmonaryfibrosisandemphysema(CPFE)isanexampleofcoexistingpatterns.CPFEcomprisesaheterogeneouspopulationofpatients,notbelievedtorepresentadistinctive獨(dú)特IIP.PatientswithCPFEhaveincreasedrisk