ECCMID-曲霉菌指南簡介-慢性肺曲霉菌病感染

1、ECCMID-曲霉菌指南簡介-慢性肺曲霉菌病感染ECCMID-曲霉菌指南簡介-慢性肺曲霉菌病感染Present by David Denning ECCMID 10th May 2015 in Barcelona慢性肺曲霉菌病-疾病分類Chronic Pulmonary Aspergillosis - subsets單發(fā)曲霉球Simple/single Aspergilloma曲霉肉芽腫病Aspergillus nodule(s)慢性空腔曲霉菌病/復(fù)雜曲霉球病Chronic Cavitary Pulmonary Aspergillosis/Complex Aspergilloma (CCPA)

2、慢性纖維化肺曲霉菌病Chronic Fibrosing Pulmonary Aspergillosis (CFPA)亞急性侵襲性/半侵襲性/慢性壞死性肺曲霉菌病Subacute invasive(SIA)/Semi-Invasive/Chronic Necrotizing Pulmonary Aspergillosis (CNPA)注：真菌球（曲霉球）可出現(xiàn)在以上除曲霉菌肉芽腫之外的任意一種情況中 fungal balls (aspergilloma) may be seen in any of these conditions, except Aspergillus nodulePresen

3、t by David Denning ECCMIPresent by David Denning ECCMID 10th May 2015 in Barcelona慢性曲霉菌病臨床表現(xiàn)分類Clinical phenotypes of chronic Aspergillus spp diseases單發(fā)曲霉球Single/simple aspergilloma慢性壞死性/亞急性肺曲霉菌病Chronic necrotizing pulmonaryaspergillosis (CNPA) or subacuteInvasive aspergillosis (SAI)慢性空腔性肺曲霉菌病Chronic

4、 cavitary pulmonaryaspergillosis (CCPA)慢性纖維化肺曲霉菌病Chronic fibrosingpulmonary aspergillosis (CFPA)曲霉菌肉芽腫Aspergillus nodule(s)Present by David Denning ECCMIPresent by David Denning ECCMID 10th May 2015 in Barcelona不同類型的慢性曲霉菌病Different patterns of CPA曲霉菌肉芽腫Aspergillus nodule(s)單發(fā)曲霉球 Single/simple asperg

5、illoma慢性空腔性肺曲霉菌病Chronic cavitary pulmonary aspergillosis (CCPA)慢性纖維化肺曲霉菌病Chronic fibrosing pulmonary aspergillosis (CFPA)Present by David Denning ECCMI慢性肺曲霉菌病-診斷標(biāo)準(zhǔn)Chronic Pulmonary Aspergillosis Diagnostic criteria需要滿足以下條件：1.1 CT影像學(xué)表現(xiàn)為肺部真菌球 或 胸腔內(nèi)空腔，或支氣管擴(kuò)張Characteristic CT appearance of a fungus ball

6、 in a pulmonary or pleural cavity, or dilated bronchus,+1.2 任何與曲霉菌感染相關(guān)的直接或間接的微生物證據(jù)Any direct or indirect microbiological evidence of Aspergillus infection (see below).,或：2.1 影像學(xué)特征持續(xù)表現(xiàn)為慢性肺曲霉菌病（包括空腔，胸膜增厚，嚴(yán)重的纖維化或肉芽腫）Radiological features consistent with chronic pulmonary aspergillosis (including cavity

7、(ies), pleural thickening, extensive fibrosis or nodule)+2.2 患者的臨床表現(xiàn)和影像學(xué)證據(jù)至少存在3個(gè)月以上時(shí)間注意半侵襲性/慢性壞死性肺曲霉病的疾病療程相對CPA較短，可逐漸演化成慢性肺曲霉病Clinical or radiological evidence of at least 3 months disease (sometimes inferred) Note shorter durations of disease may be seen in SIA/CNPA, which becomes CPA because of it

8、s chronicity,+2.3 獲得與曲霉菌感染相關(guān)的組織病理或微生物證據(jù)或免疫學(xué)證據(jù)（如：肺活檢中組織病理發(fā)現(xiàn)曲霉樣菌絲或經(jīng)皮肺穿刺培養(yǎng)陽性；肺泡灌洗液抗原強(qiáng)陽性；IgG抗體陽性/曲霉沉淀素陽性）呼吸道分泌物培養(yǎng)或PCR方法檢測曲霉樣性 Histological or microbiological or immunologic evidence of Aspergillus infection (e.g.histological evidence of Aspergillus-like hyphae in lung biopsy or Aspergillus culture from

9、a percutaneous cavity aspiration; strongly positive BAL antigen; positive IgG antibody/precipitins). Respiratory tract culture or PCR positive for Aspergillus is supportive.排除：對于特定地區(qū)或游歷該地區(qū)患者需要排除組織胞漿菌，球孢子菌和副球孢子菌感染；以及排除肺放線菌病。排除活動性細(xì)菌感染，包括分枝桿菌感染伴或不伴惡性腫瘤。分枝桿菌感染可能與真菌感染相似Exclusion of histoplasmosis, coccid

10、ioidomycosis and paracoccidiodomycosis in endemic areas or those with pertinent travel history; actinomycosis. Active bacterial infection, including mycobacterial infection and/or malignancy may occur concurrently. Mycobacterial infections or malignancy may mimic CPA.Present by David Denning ECCMID

11、10th May 2015 in Barcelona慢性肺曲霉菌病-診斷標(biāo)準(zhǔn)需要滿足以下條件：1.1 CT影像學(xué)慢性肺曲霉菌病-氣道標(biāo)本的診斷Respiratory specimen diagnosis of CPAPresent by David Denning ECCMID 10th May 2015 in Barcelona患者人群Population目的Intention干預(yù)手段InterventionSoRQoE文獻(xiàn)Reference備注Comment在非免疫抑制患者中伴有空腔/結(jié)節(jié)肺浸潤C(jī)avitary or nodularpulmonary infiltrate in Non-i

12、mmunocompromised patients診斷或排除慢性肺曲霉菌病DiagnosisOrexclusionof CPA確診或排除其他病原體To documentor Exclude otherpathogens直接鏡檢發(fā)現(xiàn)菌絲Direct microscopy forhyphae組織病理Histology（氣道分泌物）真菌培養(yǎng)Fungal culture （respiratory secretion）（經(jīng)皮肺穿刺）真菌培養(yǎng)Fungal culture(transparietal aspiration)（氣道分泌物）曲霉菌PCRAspergillusPCR (respiratory se

13、cretion)細(xì)菌培養(yǎng)Bacterial cultureAAABCCIIIIIIIIIIIIItUffredi, 2003Denning, 2003;Horvath, 1994Denning, 2013; Duddy, 2012Horvath, 1994慢性曲霉菌病中病理能夠?qū)肭忠u性曲霉菌?。⊿AIA）/慢性壞死性肺曲霉菌病與慢性空腔性肺曲霉菌病區(qū)分開來。鏡檢陽性是一個(gè)感染的強(qiáng)指證。細(xì)菌培養(yǎng)平板的敏感性叫真菌平板的敏感性較低。PCR的敏感性較培養(yǎng)高慢性肺曲霉菌病-氣道標(biāo)本的診斷Present by Davi慢性肺曲霉菌病-抗原檢測Antigen diagnosis of CPAPresen

14、t by David Denning ECCMID 10th May 2015 in Barcelona患者人群Population目的Intention干預(yù)手段InterventionSoRQoE文獻(xiàn)Reference備注Comment在非免疫抑制患者中伴有空腔/結(jié)節(jié)肺浸潤C(jī)avitary or nodularpulmonary infiltrate in Non-immunocompromised patients診斷或排除慢性肺曲霉菌病DiagnosisOrexclusionof CPA肺泡灌洗液抗原Antigen （BAL）血清學(xué)抗原檢測Antigen （Serum）痰培抗原檢測BCI

15、IIIIzumikawa,2012Izumikawa,2012;Kono,2013; Shin,2014血清和肺泡灌洗液的抗原檢測已經(jīng)建立研究，但痰液的抗原尚未涉及Antigen（Sputum）Nodata慢性肺曲霉菌病-抗原檢測Present by David D慢性肺曲霉菌病-抗體檢測Aspergillus antibody diagnosis of CPAPresent by David Denning ECCMID 10th May 2015 in Barcelona患者人群Population目的Intention干預(yù)手段InterventionSoRQoE文獻(xiàn)Reference備注

16、Comment在非免疫抑制患者中伴有空腔/結(jié)節(jié)肺浸潤C(jī)avitary or nodularpulmonary infiltrate in Non-immunocompromised patients診斷或排除慢性肺曲霉菌病DiagnosisOrexclusionof CPA曲霉抗體IgGAspergillus IgG antibodyAspergillus IgM antibodyAspergillus IgA antibodyAspergillus IgE antibodyAADDBIIIIIIIIIIIIGuitard, 2012;Baxter, 2012; VanToorenenberg

17、en,2012BTS,1970;Uffredi, 2003;Kitasato, 2009;Ohba, 2012;Baxter, 2012Schonheyder1987; Nimomiya,1990;Denning, 2003;Agarwal, 2012IgG和曲霉沉淀素的標(biāo)準(zhǔn)建立尚未完成哮喘/變態(tài)反應(yīng)性肺曲霉菌?。ˋBPA）/囊性纖維化(CF)Asthma/ABPA/CFAspergillus precipitins曲霉沉淀素曲霉抗體IgM曲霉抗體IgA曲霉抗體IgEBrouwer, 1988;多數(shù)室內(nèi)測試尚未應(yīng)用，主要原因是不確定的敏感性曲霉肉芽腫的敏感性尚不確定慢性肺曲霉菌病-抗體檢測Pr

18、esent by David D慢性肺曲霉菌病-影像學(xué)診斷和隨訪Radiological diagnosis and follow up of CPAPresent by David Denning ECCMID 10th May 2015 in Barcelona患者人群Population目的Intention干預(yù)手段InterventionSoRQoE文獻(xiàn)Reference備注Comment以空腔，真菌球?yàn)樘卣?，胸膜增厚?不伴上肺葉的纖維化Features of cavitation,fungal ball, pleuralthickening and/or upperlobe fib

19、rosis提高臨床醫(yī)師對慢性曲霉菌病的關(guān)注Raise suspicion ofCPA for physicians影像報(bào)告必須提及慢性肺曲霉菌病的可能性Radiological report mustMention possible CPACT Scan（contrast）AAIIII慢性曲霉菌常被長期誤診并未給予治療CPA is oftenmissed for yearsand patientsmismanaged.微生物檢查結(jié)果需要具備血管成像高分辨CT的對照確認(rèn)Microbiologicaltesting requiredfor confirmationHigh quality CTwi

20、th vesselvisualisation隨訪患者及停藥Follow up on or offtherapyCT掃描（對照）專家的影像方面的建議X胸片提示疑似慢性肺曲霉菌病Suspicion of chronicpulmonary aspergillosison CXR診斷或排除慢性肺曲霉菌病DiagnosisOrexclusionof CPAPET scanPET掃描DIIICT Scan（low dosage）CT掃描（低劑量）CXRX胸片BIIIBIIIInitial FU at 3 - 6 mos andwith change of status初始抗真菌治療3-6個(gè)月并伴有狀態(tài)的改

21、變AIIExpert radiologyadvice慢性肺曲霉菌病-影像學(xué)診斷和隨訪Present by Dav肺曲霉菌病侵襲性肺曲菌病的影像變化：Air-crescent signD 10 -20Halo signD 0-5Air-space consolidationD 5-10肺曲霉菌病侵襲性肺曲菌病的影像變化：Air-crescent肺曲霉菌病發(fā)病初：兩周后：肺曲霉菌病發(fā)病初：兩周后：肺曲霉菌病肺曲菌病-多發(fā)小結(jié)節(jié)型肺曲霉菌病肺曲菌病-多發(fā)小結(jié)節(jié)型肺曲霉菌病肺曲霉菌病Present by David Denning ECCMID 10th May 2015 in Barcelona慢性

22、肺曲霉菌表現(xiàn)為腔內(nèi)曲霉球充滿空腔。胸膜的增厚，臨近軟組織空腔壁可能難以辨別。注意胸膜外脂肪組織的高衰減（如箭頭所示）Present by David Denning ECCMIPresent by David Denning ECCMID 10th May 2015 in Barcelona所示為一位長期吸煙的慢性肺曲霉菌病患者。真菌球（藍(lán)色箭頭所示）幾乎填滿了肺氣腫所形成的肺大泡 a)縱隔窗視角 b）肺窗視角 c-e）逐層掃描冠狀成形和X線胸片呈現(xiàn)進(jìn)行性的增厚。注意因?yàn)楦腥狙仔越橘|(zhì)導(dǎo)致的右鎖骨下靜脈的差異。盡管冠狀面成形清晰的說明了病變，但從胸片影像的陰影上分析卻難得多Present by

23、David Denning ECCMIPresent by David Denning ECCMID 10th May 2015 in Barcelonaabcdef一位有長期吸煙史，堪薩斯分枝桿菌感染，營養(yǎng)不良和肝硬化患者。患者數(shù)度咳血，在給予長期伏立康唑治療的同時(shí)給予動脈栓塞治療。雙側(cè)曲霉球幾乎填滿了整個(gè)空腔（a-d中星形標(biāo)記）。注意（e-f）中左肺的小空腔和不規(guī)則空腔壁。相對于胸膜增厚（黃色箭頭標(biāo)注）和肺泡實(shí)變（藍(lán)色箭頭標(biāo)注），曲霉球表現(xiàn)為較弱地衰減。全身性動脈肥大（紅色箭頭標(biāo)注）Present by David Denning ECCMI肺曲霉菌病曲菌球隨體位的變化：仰臥位胸部CT俯臥

24、位胸部CT肺曲霉菌病曲菌球隨體位的變化：仰臥位胸部CT俯臥位胸部CT肺曲霉菌病曲菌球肺曲霉菌病曲菌球Present by David Denning ECCMID 10th May 2015 in Barcelona偽腫瘤表現(xiàn)的慢性肺曲霉病患者（手術(shù)確認(rèn)）Present by David Denning ECCMIPresent by David Denning ECCMID 10th May 2015 in Barcelona患者人群Population目的Intention干預(yù)手段InterventionSoRQoE文獻(xiàn)Reference備注Comment慢性肺曲霉病進(jìn)展期患者CPA pa

25、tients withprogressive disease控制感染性疾病進(jìn)展Control ofinfection伊曲康唑起始200mg BID，通過血藥濃度檢測調(diào)整劑量Itraconazole Start 200mg BID, adjust with TDMAII無治療藥物對照研究數(shù)據(jù)慢性肺曲霉菌病-三唑類藥物治療Oral triazole therapy for CPA Population伏立康唑起始150-250mg BID，通過血藥濃度檢測調(diào)整劑量Voriconazole Start 150-250mg BID, adjust withTDMAII泊沙康唑起始400mg BIDPo

26、saconazoleStart 400mg BIDBII伏立康唑更適合用于半侵襲性曲霉菌?。⊿IA）/慢性壞死性肺曲霉菌?。–NPA）以及伴有真菌球的患者以減少耐藥的風(fēng)險(xiǎn)Agarwal, 2013; DeBuele, 1998,Dupont, 1990;Campbell, 1991;Tsubura, 1997;Denning, 2003;Nam, 2009;Al-shair, 2013Saito, 2009;Cadranel, 2012,Jain, 2006;Sambatakou,2006; Camuset,2007; Philippe,2009; Al-shair,2013Felton, 2

27、010;應(yīng)用伏立康唑，伊曲康唑時(shí)或權(quán)衡利弊使用泊沙康唑時(shí)需要血藥濃度檢測目標(biāo)濃度來自于侵襲性曲霉菌病，PK/PD和預(yù)防研究數(shù)據(jù)Present by David Denning ECCMIPresent by David Denning ECCMID 10th May 2015 in Barcelona患者人群Population目的Intention干預(yù)手段InterventionSoRQoE文獻(xiàn)Reference備注Comment慢性肺曲霉病進(jìn)展期患者（初始治療失敗，三唑類藥物不耐受，或三唑類藥物耐藥）CPA patients withprogressivedisease, who fail

28、,are intolerant oftriazoles or havetriazole resistance控制感染性疾病進(jìn)展Control ofinfection米卡芬凈 150mg/dItraconazole Start 200mg BID, adjust with TDMBII慢性肺曲霉菌病-針劑替代治療Alternative intravenous therapy for CPA兩性霉素B0.7-1.0 mg/kg/dAmphotericin Bdeoxycholate0.7-1.0mg/kg/dCIII卡泊芬凈50-70 mg/dCaspofungin50-70mg/dCIIaKoh

29、no, 2011;Kohno, EJCMID2013; Saito, 2009;Kohno, 2011;Kohno , 2004;Izumikawa, 2007;Yasuda, 2009;Nam, 2009Denning, 2003Kier, 2014; KohnoECCMID 2013兩性霉素B脂質(zhì)體3mg/kg/dLiposomal AmB3mg/kg/dBIIaNewton, 2014Present by David Denning ECCMIPresent by David Denning ECCMID 10th May 2015 in Barcelona患者人群Population目

30、的Intention干預(yù)手段InterventionSoRQoE文獻(xiàn)Reference備注Comment伴有曲霉球的慢性肺曲霉病患者，不愿意或不能給予口服治療，唑類藥物多耐藥以及不能手術(shù)治療患者CPA withaspergilloma,unwilling or unableto take oraltherapy, multiazoleresistanceand inoperable控制感染性疾病進(jìn)展Control ofinfection兩性霉素B腔內(nèi)注射Instillation of amphotericin BDeoxycholate into cavityCII慢性肺曲霉菌病-局部空腔治療

31、Local cavity therapy for CPAGiron, 1998;Kravitz, 2013實(shí)驗(yàn)性治療Present by David Denning ECCMIPresent by David Denning ECCMID 10th May 2015 in Barcelona患者人群Population目的Intention干預(yù)手段InterventionSoRQoE文獻(xiàn)Reference備注Comment慢性肺曲霉病抗真菌治療CPA patients onAntifungal therapy控制感染性疾病進(jìn)展，組織肺纖維化，預(yù)防出血，改善甚或質(zhì)量Control of infe

32、ction,arrest of pulmonaryFibrosis, prevention ofHaemoptysis, improvedquality of life.6個(gè)月抗真菌治療6 mo antifungaltherapyBII治療慢性肺曲霉菌病的最佳療程尚未知曉；在部分患者中長期哦抑制治療可能是恰當(dāng)?shù)穆苑吻咕?抗真菌治療療程Duration of antifungal therapy for CPAAgarwal, 2013:Yoshida, 2012;Nam, 2010:Felton, 2010;Camuset,2007:Jain, 2006:Cadranel, 2012亞急

33、性肺曲霉菌病/慢性壞死性肺曲霉菌病SubacuteIA/CNPA治愈Cure長療程抗真菌治療，療程取決于患者狀態(tài)和藥物耐受性Long term antifungalTherapy, dependingon status and drug toleranceCII6個(gè)月6 moBIIFelton, 2010;Camuset,2007;Jain, 2006;Cadranel, 2012Camuset, 2007Cadranel, 2012Optimal duration oftherapy inCPA is unknown,Indefinite suppressivetherapy may beA

34、ppropriate in selectedpatientsPresent by David Denning ECCMIPresent by David Denning ECCMID 10th May 2015 in Barcelona患者人群Population目的Intention干預(yù)手段InterventionSoRQoE文獻(xiàn)Reference備注Comment單個(gè)/簡單曲霉球病Simple/single aspergilloma治愈病預(yù)防威脅生命的出血Cure andprevention of lifethreateninghaemoptysis肺葉摘除或其他局部切除Lobectomy

35、 or any othersegmental resectionAII患者需要嚴(yán)格的手風(fēng)險(xiǎn)評估：手術(shù)評估=風(fēng)險(xiǎn)/獲益慢性肺曲霉菌病-手術(shù)指證Indications for surgery in CPADaly, 1986;Regnard, 2000;Kim, 2005; Pratap,2007; Brik, 2008;Muniappan, 2014;Farid, 2013; Chen,2012; Nacera,2012; Lejay, 2011;IDSA 2008圖像引導(dǎo)下胸腔鏡手術(shù)（VATS）Video-assisted thoracicsurgery (VATS)BIIChen, 2014;Muniappan, 2014.抗真菌治療下慢性空腔性肺曲霉菌病復(fù)發(fā)（包括多重三唑類耐藥），伴有/不伴威脅生命的出血CCPA refractory tomedical management(including multi-azoleresistance) withantifungal treatmentand/or life-threateninghaemoptysis.改善疾病的控制，可能治愈Improved controlof disease,possibly cure謹(jǐn)慎的評估下，肺葉拆