ECCMID 曲霉菌指南簡(jiǎn)介 慢性肺曲霉菌病感染

1、,2014 ESCMID曲霉菌病治療指南-慢性肺曲霉病,2014 ESCMID Aspergillus Guideline-Chronic Pulmonary Aspergillosis,Present by David W.Denning United Kingdom,ECCMID 10th May 2015 in Barcelona,),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/s

2、ingle 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) 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 (CN

3、PA) 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 nodule,Present 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

4、急性肺曲霉菌病 Chronic necrotizing pulmonary aspergillosis (CNPA) or subacute Invasive aspergillosis (SAI),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),曲霉菌肉芽腫 Aspergillus nodule(s),Present by David Denning,ECCMID 10th May 2015 in Bar

5、celona,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 aspergilloma,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),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：,

6、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 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?。ò涨唬啬ぴ龊?，嚴(yán)重的纖維化或肉芽腫） Radi

7、ological features consistent with chronic pulmonary aspergillosis (including cavity(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(duì)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

8、 shorter durations of disease may be seen in SIA/CNPA, which becomes CPA because of its 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(cè)曲霉樣性 Histological or microbiological or immunologic evidence of Aspergillus infection (e.g.histo

9、logical evidence of Aspergillus-like hyphae in lung biopsy or Aspergillus culture from 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(duì)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

10、染；以及排除肺放線菌病。排除活動(dòng)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, coccidioidomycosis and paracoccidiodomycosis in endemic areas or those with pertinent travel history; actinomycosis. Active bacterial infection, including mycobacterial infection and/or malignancy may occur concurren

11、tly. Mycobacterial infections or malignancy may mimic CPA.,Present by David Denning,ECCMID 10th May 2015 in Barcelona,慢性肺曲霉菌病-氣道標(biāo)本的診斷 Respiratory specimen diagnosis of CPA,Present by David Denning,ECCMID 10th May 2015 in Barcelona,患者人群 Population,目的 Intention,干預(yù)手段 Intervention,SoR,QoE,文獻(xiàn) Reference,備

12、注 Comment,在非免疫抑制患者中伴有空腔/結(jié)節(jié)肺浸潤(rùn),Cavitary or nodular pulmonary infiltrate in Non-immunocompromised patients,診斷或排除慢性肺曲霉菌病,Diagnosis Or exclusion of CPA,確診或排除其他病原體,To document or Exclude other pathogens,直接鏡檢發(fā)現(xiàn)菌絲,Direct microscopy for hyphae,組織病理,Histology,（氣道分泌物）真菌培養(yǎng),Fungal culture （respiratory secretion

13、）,（經(jīng)皮肺穿刺）真菌培養(yǎng),Fungal culture (transparietal aspiration),（氣道分泌物）曲霉菌PCR,Aspergillus PCR (respiratory secretion),細(xì)菌培養(yǎng),Bacterial culture,A,A,A,B,C,C,II,II,III,II,II,IIt,Uffredi, 2003,Denning, 2003;,Horvath, 1994,Denning, 2013; Duddy, 2012,Horvath, 1994,慢性曲霉菌病中病理能夠?qū)肭忠u性曲霉菌病（SAIA）/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

14、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-抗原檢測(cè) Antigen diagnosis of CPA,Present by David Denning,ECCMID 10th May 2015 in Barcelona,患者人群 Population,目的 Intention,干預(yù)手段 Intervention,SoR,QoE,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(rùn),Cavitary or nodular pulmonary infiltrate in Non-imm

15、unocompromised patients,診斷或排除慢性肺曲霉菌病,Diagnosis Or exclusion of CPA,肺泡灌洗液抗原,Antigen （BAL）,血清學(xué)抗原檢測(cè),Antigen （Serum）,痰培抗原檢測(cè),B,C,II,II,Izumikawa, 2012,Izumikawa,2012; Kono,2013; Shin,2014,血清和肺泡灌洗液的抗原檢測(cè)已經(jīng)建立研究，但痰液的抗原尚未涉及,Antigen（Sputum）,No data,慢性肺曲霉菌病-抗體檢測(cè) Aspergillus antibody diagnosis of CPA,Present by

16、David Denning,ECCMID 10th May 2015 in Barcelona,患者人群 Population,目的 Intention,干預(yù)手段 Intervention,SoR,QoE,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(rùn),Cavitary or nodular pulmonary infiltrate in Non-immunocompromised patients,診斷或排除慢性肺曲霉菌病,Diagnosis Or exclusion of CPA,曲霉抗體IgG,Aspergillus IgG antibody,As

17、pergillus IgM antibody,Aspergillus IgA antibody,Aspergillus IgE antibody,A,A,D,D,B,II,II,III,III,II,Guitard, 2012; Baxter, 2012; Van Toorenenbergen, 2012,BTS,1970; Uffredi, 2003; Kitasato, 2009; Ohba, 2012; Baxter, 2012,Schonheyder 1987; Nimomiya, 1990;,Denning, 2003; Agarwal, 2012,IgG和曲霉沉淀素的標(biāo)準(zhǔn)建立尚未完

18、成,哮喘/變態(tài)反應(yīng)性肺曲霉菌?。ˋBPA）/囊性纖維化(CF),Asthma/ABPA/CF,Aspergillus precipitins,曲霉沉淀素,曲霉抗體IgM,曲霉抗體IgA,曲霉抗體IgE,Brouwer, 1988;,多數(shù)室內(nèi)測(cè)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-影像學(xué)診斷和隨訪 Radiological diagnosis and follow up of CPA,Present by David Denning,ECCMID 10th May 2015 in Barcelona,患者人群 Population,目的 Intenti

19、on,干預(yù)手段 Intervention,SoR,QoE,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, pleural thickening and/or upper lobe fibrosis,提高臨床醫(yī)師對(duì)慢性曲霉菌病的關(guān)注,Raise suspicion of CPA for physicians,影像報(bào)告必須提及慢性肺曲霉菌病的可能性,Radiological report must Mention possible CPA,CT Scan（contrast

20、）,A,A,II,II,慢性曲霉菌常被長(zhǎng)期誤診并未給予治療 CPA is often missed for years and patients mismanaged. 微生物檢查結(jié)果需要具備血管成像高分辨CT的對(duì)照確認(rèn) Microbiological testing required for confirmation High quality CT with vessel visualisation,隨訪患者及停藥,Follow up on or off therapy,CT掃描（對(duì)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 chronic pulmo

21、nary aspergillosis on CXR,診斷或排除慢性肺曲霉菌病,Diagnosis Or exclusion of CPA,PET scan,PET掃描,D,III,CT Scan（low dosage）,CT掃描（低劑量）,CXR,X胸片,B,III,B,III,Initial FU at 3 - 6 mos and with change of status,初始抗真菌治療3-6個(gè)月并伴有狀態(tài)的改變,A,II,Expert radiology advice,肺曲霉菌病,侵襲性肺曲菌病的影像變化：,Air-crescent sign D 10 -20,Halo sign D 0

22、-5,Air-space consolidation D 5-10,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,Present by David Denning,ECCMID 10th May 2015 in Barcelona,慢性肺曲霉菌表現(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,ECCMID 10th May 2015 in Barcelona,所示為一位長(zhǎng)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

23、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 David Denning,ECCMID 10th May 2015 in Barcelona,a,b,c,d,e,f,一位有長(zhǎng)期吸煙史，堪薩斯分枝桿菌感染，營(yíng)養(yǎng)不良和肝硬化患者。 患者數(shù)度咳血，在給予長(zhǎng)期伏立康唑治療的同時(shí)給予動(dòng)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(duì)于胸膜增厚（黃色箭頭標(biāo)注）和肺泡實(shí)變（藍(lán)

24、色箭頭標(biāo)注），曲霉球表現(xiàn)為較弱地衰減。 全身性動(dòng)脈肥大（紅色箭頭標(biāo)注）,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,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,ECCMID 10th May 2015 in Barcelona,患者人群 Population,目的 Intention,干預(yù)手段 Intervention,SoR,QoE,文獻(xiàn) Reference,備注 Comment,慢性肺

25、曲霉病進(jìn)展期患者,CPA patients with progressive disease,控制感染性疾病進(jìn)展,Control of infection,伊曲康唑起始200mg BID，通過血藥濃度檢測(cè)調(diào)整劑量,Itraconazole Start 200mg BID, adjust with TDM,A,II,無治療藥物對(duì)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(cè)調(diào)整劑量,Voriconazole Start 150-250mg BID, adjust

26、 with TDM,A,II,泊沙康唑起始400mg BID,Posaconazole Start 400mg BID,B,II,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病（CNPA）以及伴有真菌球的患者以減少耐藥的風(fēng)險(xiǎn),Agarwal, 2013; De Buele, 1998, Dupont, 1990; Campbell, 1991; Tsubura, 1997; Denning, 2003; Nam, 2009; Al-shair, 2013,Saito, 2009; Cadranel, 2012, Jain, 2006; Sambatakou, 2006; C

27、amuset, 2007; Philippe, 2009; Al-shair, 2013,Felton, 2010;,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(cè) 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,ECCMID 10th May 2015 in Barcelona,患者人群 Population,目的 Intention,干預(yù)手段 Intervention,SoR,QoE,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

28、patients with progressive disease, who fail, are intolerant of triazoles or have triazole resistance,控制感染性疾病進(jìn)展,Control of infection,米卡芬凈 150mg/d,Itraconazole Start 200mg BID, adjust with TDM,B,II,慢性肺曲霉菌病-針劑替代治療 Alternative intravenous therapy for CPA,兩性霉素B 0.7-1.0 mg/kg/d,Amphotericin B deoxycholate

29、 0.7-1.0mg/kg/d,C,III,卡泊芬凈50-70 mg/d,Caspofungin 50-70mg/d,C,IIa,Kohno, 2011; Kohno, EJCMID 2013; Saito, 2009; Kohno, 2011; Kohno , 2004; Izumikawa, 2007; Yasuda, 2009; Nam, 2009,Denning, 2003,Kier, 2014; Kohno ECCMID 2013,兩性霉素B脂質(zhì)體 3mg/kg/d,Liposomal AmB 3mg/kg/d,B,IIa,Newton, 2014,Present by David

30、Denning,ECCMID 10th May 2015 in Barcelona,患者人群 Population,目的 Intention,干預(yù)手段 Intervention,SoR,QoE,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 with aspergilloma, unwilling or unable to take oral therapy, multiazole resistance and inoperable,控制感染性疾病進(jìn)展,Control of infection,

31、兩性霉素B腔內(nèi)注射,Instillation of amphotericin B Deoxycholate into cavity,C,II,慢性肺曲霉菌病-局部空腔治療 Local cavity therapy for CPA,Giron, 1998; Kravitz, 2013,實(shí)驗(yàn)性治療,Present by David Denning,ECCMID 10th May 2015 in Barcelona,患者人群 Population,目的 Intention,干預(yù)手段 Intervention,SoR,QoE,文獻(xiàn) Reference,備注 Comment,慢性肺曲霉病抗真菌治療,CP

32、A patients on Antifungal 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 infection, arrest of pulmonary Fibrosis, prevention of Haemoptysis, improved quality of life.,6個(gè)月抗真菌治療,6 mo antifungal therapy,B,II,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(zhǎng)期哦抑制治療可能是恰當(dāng)?shù)?慢性肺曲霉菌病-抗真菌治療療程 Duration of antifungal therapy for CPA,A

33、garwal, 2013: Yoshida, 2012; Nam, 2010: Felton, 2010; Camuset, 2007: Jain, 2006: Cadranel, 2012,亞急性肺曲霉菌病/慢性壞死性肺曲霉菌病,Subacute IA/CNPA,治愈,Cure,長(zhǎng)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 antifungal Therapy, depending on status and drug tolerance,C,II,6個(gè)月,6 mo,B,II,Felton, 2010; Camuset, 2007; Jain, 2006; Cadra

34、nel, 2012,Camuset, 2007 Cadranel, 2012,Optimal duration of therapy in CPA is unknown, Indefinite suppressive therapy may be Appropriate in selected patients,Present by David Denning,ECCMID 10th May 2015 in Barcelona,患者人群 Population,目的 Intention,干預(yù)手段 Intervention,SoR,QoE,文獻(xiàn) Reference,備注 Comment,單個(gè)/簡(jiǎn)單

35、曲霉球病,Simple/single aspergilloma,治愈病預(yù)防威脅生命的出血,Cure and prevention of lifethreatening haemoptysis,肺葉摘除或其他局部切除,Lobectomy or any other segmental resection,A,II,患者需要嚴(yán)格的手風(fēng)險(xiǎn)評(píng)估：手術(shù)評(píng)估=風(fēng)險(xiǎn)/獲益,慢性肺曲霉菌病-手術(shù)指證 Indications for surgery in CPA,Daly, 1986; Regnard, 2000; Kim, 2005; Pratap, 2007; Brik, 2008; Muniappan, 2

36、014; 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 thoracic surgery (VATS),B,II,Chen, 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 to medical management (including multi-azole resistance) with antifungal treatment and/or life-threatening haemoptysis.,改善疾病的控制，可能治愈,Improved control