1、,2014 ESCMID曲霉菌病治疗指南-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,),欧洲临床微生物与感染性疾病学会(ESCMID,European Society of Clinical Microbiology and Infectious Diseases),滨州医学院附属烟台海港医院急诊科 王功军,Present by David
2、Denning,ECCMID 10th May 2015 in Barcelona,慢性肺曲霉菌病-疾病分类 Chronic Pulmonary Aspergillosis - subsets,单发曲霉球 Simple/single Aspergilloma曲霉肉芽肿病 Aspergillus nodule(s)慢性空腔曲霉菌病/复杂曲霉球病 Chronic Cavitary Pulmonary Aspergillosis/Complex Aspergilloma (CCPA)慢性纤维化肺曲霉菌病 Chronic Fibrosing Pulmonary Aspergillosis (CFPA)
3、亚急性侵袭性/半侵袭性/慢性坏死性肺曲霉菌病 Subacute invasive(SIA)/Semi-Invasive/Chronic Necrotizing Pulmonary Aspergillosis (CNPA)注：真菌球（曲霉球）可出现在以上除曲霉菌肉芽肿之外的任意一种情况中 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
4、霉菌病临床表现分类 Clinical phenotypes of chronic Aspergillus spp diseases,单发曲霉球 Single/simple aspergilloma,慢性坏死性/亚急性肺曲霉菌病 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),慢性纤维化肺曲霉菌病 Chronic fibrosing pulmon
5、ary aspergillosis (CFPA),曲霉菌肉芽肿 Aspergillus nodule(s),Present by David Denning,ECCMID 10th May 2015 in Barcelona,不同类型的慢性曲霉菌病 Different patterns of CPA,曲霉菌肉芽肿Aspergillus nodule(s),单发曲霉球 Single/simple aspergilloma,慢性空腔性肺曲霉菌病 Chronic cavitary pulmonary aspergillosis (CCPA),慢性纤维化肺曲霉菌病 Chronic fibrosing
6、pulmonary aspergillosis (CFPA),慢性肺曲霉菌病-诊断标准 Chronic Pulmonary Aspergillosis Diagnostic criteria,需要满足以下条件：,1.1 CT影像学表现为肺部真菌球 或 胸腔内空腔，或支气管扩张 Characteristic CT appearance of a fungus ball in a pulmonary or pleural cavity, or dilated bronchus,+,1.2 任何与曲霉菌感染相关的直接或间接的微生物证据 Any direct or indirect microbiol
7、ogical evidence of Aspergillus infection (see below). ,或：,2.1 影像学特征持续表现为慢性肺曲霉菌病（包括空腔，胸膜增厚，严重的纤维化或肉芽肿） Radiological features consistent with chronic pulmonary aspergillosis (including cavity(ies), pleural thickening, extensive fibrosis or nodule),+,2.2 患者的临床表现和影像学证据至少存在3个月以上时间注意半侵袭性/慢性坏死性肺曲霉病的疾病疗程相对C
8、PA较短，可逐渐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 its chronicity,+,2.3 获得与曲霉菌感染相关的组织病理或微生物证据或免疫学证据（如：肺活检中组织病理发现曲霉样菌丝或经皮肺穿刺培养阳性；肺泡灌洗液抗原强阳性；IgG抗体阳性/曲霉沉淀素阳性）呼吸道分泌物
9、培养或PCR方法检测曲霉样性Histological or microbiological or immunologic evidence of Aspergillus infection (e.g.histological evidence of Aspergillus-like hyphae in lung biopsy or Aspergillus culture from a percutaneous cavity aspiration; strongly positive BAL antigen; positive IgG antibody/precipitins). Respira
10、tory tract culture or PCR positive for Aspergillus is supportive.,排除：,对于特定地区或游历该地区患者需要排除组织胞浆菌，球孢子菌和副球孢子菌感染；以及排除肺放线菌病。排除活动性细菌感染，包括分枝杆菌感染伴或不伴恶性肿瘤。分枝杆菌感染可能与真菌感染相似 Exclusion of histoplasmosis, coccidioidomycosis and paracoccidiodomycosis in endemic areas or those with pertinent travel history; actinomyc
11、osis. Active bacterial infection, including mycobacterial infection and/or malignancy may occur concurrently. Mycobacterial infections or malignancy may mimic CPA.,Present by David Denning,ECCMID 10th May 2015 in Barcelona,慢性肺曲霉菌病-气道标本的诊断 Respiratory specimen diagnosis of CPA,Present by David Dennin
12、g,ECCMID 10th May 2015 in Barcelona,患者人群 Population,目的 Intention,干预手段 Intervention,SoR,QoE,文献 Reference,备注 Comment,在非免疫抑制患者中伴有空腔/结节肺浸润,Cavitary or nodular pulmonary infiltrate in Non-immunocompromised patients,诊断或排除慢性肺曲霉菌病,Diagnosis Or exclusion of CPA,确诊或排除其他病原体,To document or Exclude other pathoge
13、ns,直接镜检发现菌丝,Direct microscopy for hyphae,组织病理,Histology,（气道分泌物）真菌培养,Fungal culture （respiratory secretion）,（经皮肺穿刺）真菌培养,Fungal culture (transparietal aspiration),（气道分泌物）曲霉菌PCR,Aspergillus PCR (respiratory secretion),细菌培养,Bacterial culture,A,A,A,B,C,C,II,II,III,II,II,IIt,Uffredi, 2003,Denning, 2003;,H
14、orvath, 1994,Denning, 2013; Duddy, 2012,Horvath, 1994,慢性曲霉菌病中病理能够将半侵袭性曲霉菌病（SAIA）/慢性坏死性肺曲霉菌病与慢性空腔性肺曲霉菌病区分开来。镜检阳性是一个感染的强指证。细菌培养平板的敏感性叫真菌平板的敏感性较低。PCR的敏感性较培养高,慢性肺曲霉菌病-抗原检测 Antigen diagnosis of CPA,Present by David Denning,ECCMID 10th May 2015 in Barcelona,患者人群 Population,目的 Intention,干预手段 Intervention,S
15、oR,QoE,文献 Reference,备注 Comment,在非免疫抑制患者中伴有空腔/结节肺浸润,Cavitary or nodular pulmonary infiltrate in Non-immunocompromised patients,诊断或排除慢性肺曲霉菌病,Diagnosis Or exclusion of CPA,肺泡灌洗液抗原,Antigen （BAL）,血清学抗原检测,Antigen （Serum）,痰培抗原检测,B,C,II,II,Izumikawa, 2012,Izumikawa,2012; Kono,2013; Shin,2014,血清和肺泡灌洗液的抗原检测已经
16、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-抗体检测 Aspergillus antibody diagnosis of CPA,Present by David Denning,ECCMID 10th May 2015 in Barcelona,患者人群 Population,目的 Intention,干预手段 Intervention,SoR,QoE,文献 Reference,备注 Comment,在非免疫抑制患者中伴有空腔/结节肺浸润,Cavitary or nodular pulmonary infiltrate in Non-imm
17、unocompromised patients,诊断或排除慢性肺曲霉菌病,Diagnosis Or exclusion of CPA,曲霉抗体IgG,Aspergillus IgG antibody,Aspergillus 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; Ohb
18、a, 2012; Baxter, 2012,Schonheyder 1987; Nimomiya, 1990;,Denning, 2003; Agarwal, 2012,IgG和曲霉沉淀素的标准建立尚未完成,哮喘/变态反应性肺曲霉菌病（ABPA）/囊性纤维化(CF),Asthma/ABPA/CF,Aspergillus precipitins,曲霉沉淀素,曲霉抗体IgM,曲霉抗体IgA,曲霉抗体IgE,Brouwer, 1988;,多数室内测试尚未应用，主要原因是不确定的敏感性,曲霉肉芽肿的敏感性尚不确定,慢性肺曲霉菌病-影像学诊断和随访 Radiological diagnosis and
19、follow up of CPA,Present by David Denning,ECCMID 10th May 2015 in Barcelona,患者人群 Population,目的 Intention,干预手段 Intervention,SoR,QoE,文献 Reference,备注 Comment,以空腔，真菌球为特征，胸膜增厚伴/不伴上肺叶的纤维化,Features of cavitation, fungal ball, pleural thickening and/or upper lobe fibrosis,提高临床医师对慢性曲霉菌病的关注,Raise suspicion of
20、 CPA for physicians,影像报告必须提及慢性肺曲霉菌病的可能性,Radiological report must Mention possible CPA,CT Scan（contrast）,A,A,II,II,慢性曲霉菌常被长期误诊并未给予治疗 CPA is often missed for years and patients mismanaged. 微生物检查结果需要具备血管成像高分辨CT的对照确认 Microbiological testing required for confirmation High quality CT with vessel visualisa
21、tion,随访患者及停药,Follow up on or off therapy,CT扫描（对照）,专家的影像方面的建议,X胸片提示疑似慢性肺曲霉菌病,Suspicion of chronic pulmonary aspergillosis on CXR,诊断或排除慢性肺曲霉菌病,Diagnosis Or exclusion of CPA,PET scan,PET扫描,D,III,CT Scan（low dosage）,CT扫描（低剂量）,CXR,X胸片,B,III,B,III,Initial FU at 3 - 6 mos and with change of status,初始抗真菌治疗3
22、-6个月并伴有状态的改变,A,II,Expert radiology advice,肺曲霉菌病,侵袭性肺曲菌病的影像变化：,Air-crescent sign D 10 -20,Halo sign D 0-5,Air-space consolidation D 5-10,肺曲霉菌病,发病初：,两周后：,肺曲霉菌病,肺曲菌病-多发小结节型,肺曲霉菌病,Present by David Denning,ECCMID 10th May 2015 in Barcelona,慢性肺曲霉菌表现为腔内曲霉球充满空腔。胸膜的增厚，临近软组织空腔壁可能难以辨别。注意胸膜外脂肪组织的高衰减（如箭头所示）,Pres
23、ent by David Denning,ECCMID 10th May 2015 in Barcelona,所示为一位长期吸烟的慢性肺曲霉菌病患者。真菌球（蓝色箭头所示）几乎填满了肺气肿所形成的肺大泡 a)纵隔窗视角 b）肺窗视角 c-e）逐层扫描冠状成形和X线胸片呈现进行性的增厚。注意因为感染炎性介质导致的右锁骨下静脉的差异。尽管冠状面成形清晰的说明了病变，但从胸片影像的阴影上分析却难得多,Present by David Denning,ECCMID 10th May 2015 in Barcelona,a,b,c,d,e,f,一位有长期吸烟史，堪萨斯分枝杆菌感染，营养不良和肝硬化患者。
24、 患者数度咳血，在给予长期伏立康唑治疗的同时给予动脉栓塞治疗。 双侧曲霉球几乎填满了整个空腔（a-d中星形标记）。 注意（e-f）中左肺的小空腔和不规则空腔壁。相对于胸膜增厚（黄色箭头标注）和肺泡实变（蓝色箭头标注），曲霉球表现为较弱地衰减。 全身性动脉肥大（红色箭头标注）,肺曲霉菌病,曲菌球随体位的变化：,仰卧位胸部CT,俯卧位胸部CT,肺曲霉菌病,曲菌球,Present by David Denning,ECCMID 10th May 2015 in Barcelona,伪肿瘤表现的慢性肺曲霉病患者（手术确认）,Present by David Denning,ECCMID 10th Ma
25、y 2015 in Barcelona,患者人群 Population,目的 Intention,干预手段 Intervention,SoR,QoE,文献 Reference,备注 Comment,慢性肺曲霉病进展期患者,CPA patients with progressive disease,控制感染性疾病进展,Control of infection,伊曲康唑起始200mg BID，通过血药浓度检测调整剂量,Itraconazole Start 200mg BID, adjust with TDM,A,II,无治疗药物对照研究数据,慢性肺曲霉菌病-三唑类药物治疗 Oral triazol
26、e therapy for CPA Population,伏立康唑起始150-250mg BID，通过血药浓度检测调整剂量,Voriconazole Start 150-250mg BID, adjust with TDM,A,II,泊沙康唑起始400mg BID,Posaconazole Start 400mg BID,B,II,伏立康唑更适合用于半侵袭性曲霉菌病（SIA）/慢性坏死性肺曲霉菌病（CNPA）以及伴有真菌球的患者以减少耐药的风险,Agarwal, 2013; De Buele, 1998, Dupont, 1990; Campbell, 1991; Tsubura, 1997;
27、 Denning, 2003; Nam, 2009; Al-shair, 2013,Saito, 2009; Cadranel, 2012, Jain, 2006; Sambatakou, 2006; Camuset, 2007; Philippe, 2009; Al-shair, 2013,Felton, 2010;,应用伏立康唑，伊曲康唑时或权衡利弊使用泊沙康唑时需要血药浓度检测 目标浓度来自于侵袭性曲霉菌病，PK/PD和预防研究数据,Present by David Denning,ECCMID 10th May 2015 in Barcelona,患者人群 Population,目的
28、Intention,干预手段 Intervention,SoR,QoE,文献 Reference,备注 Comment,慢性肺曲霉病进展期患者（初始治疗失败，三唑类药物不耐受，或三唑类药物耐药）,CPA patients with progressive disease, who fail, are intolerant of triazoles or have triazole resistance,控制感染性疾病进展,Control of infection,米卡芬净 150mg/d,Itraconazole Start 200mg BID, adjust with TDM,B,II,慢性
29、肺曲霉菌病-针剂替代治疗 Alternative intravenous therapy for CPA,两性霉素B 0.7-1.0 mg/kg/d,Amphotericin B deoxycholate 0.7-1.0mg/kg/d,C,III,卡泊芬净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,
30、 2014; Kohno ECCMID 2013,两性霉素B脂质体 3mg/kg/d,Liposomal AmB 3mg/kg/d,B,IIa,Newton, 2014,Present by David Denning,ECCMID 10th May 2015 in Barcelona,患者人群 Population,目的 Intention,干预手段 Intervention,SoR,QoE,文献 Reference,备注 Comment,伴有曲霉球的慢性肺曲霉病患者，不愿意或不能给予口服治疗，唑类药物多耐药以及不能手术治疗患者,CPA with aspergilloma, unwillin
31、g or unable to take oral therapy, multiazole resistance and inoperable,控制感染性疾病进展,Control of infection,两性霉素B腔内注射,Instillation of amphotericin B Deoxycholate into cavity,C,II,慢性肺曲霉菌病-局部空腔治疗 Local cavity therapy for CPA,Giron, 1998; Kravitz, 2013,实验性治疗,Present by David Denning,ECCMID 10th May 2015 in B
32、arcelona,患者人群 Population,目的 Intention,干预手段 Intervention,SoR,QoE,文献 Reference,备注 Comment,慢性肺曲霉病抗真菌治疗,CPA patients on Antifungal therapy,控制感染性疾病进展，组织肺纤维化，预防出血，改善甚或质量,Control of infection, arrest of pulmonary Fibrosis, prevention of Haemoptysis, improved quality of life.,6个月抗真菌治疗,6 mo antifungal therap
33、y,B,II,治疗慢性肺曲霉菌病的最佳疗程尚未知晓；在部分患者中长期哦抑制治疗可能是恰当的,慢性肺曲霉菌病-抗真菌治疗疗程 Duration of antifungal therapy for CPA,Agarwal, 2013: Yoshida, 2012; Nam, 2010: Felton, 2010; Camuset, 2007: Jain, 2006: Cadranel, 2012,亚急性肺曲霉菌病/慢性坏死性肺曲霉菌病,Subacute IA/CNPA,治愈,Cure,长疗程抗真菌治疗，疗程取决于患者状态和药物耐受性,Long term antifungal Therapy, de
34、pending on status and drug tolerance,C,II,6个月,6 mo,B,II,Felton, 2010; Camuset, 2007; Jain, 2006; Cadranel, 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
35、2015 in Barcelona,患者人群 Population,目的 Intention,干预手段 Intervention,SoR,QoE,文献 Reference,备注 Comment,单个/简单曲霉球病,Simple/single aspergilloma,治愈病预防威胁生命的出血,Cure and prevention of lifethreatening haemoptysis,肺叶摘除或其他局部切除,Lobectomy or any other segmental resection,A,II,患者需要严格的手风险评估：手术评估=风险/获益,慢性肺曲霉菌病-手术指证 Indic
36、ations for surgery in CPA,Daly, 1986; Regnard, 2000; Kim, 2005; Pratap, 2007; Brik, 2008; Muniappan, 2014; Farid, 2013; Chen, 2012; Nacera, 2012; Lejay, 2011; IDSA 2008,图像引导下胸腔镜手术（VATS）,Video-assisted thoracic surgery (VATS),B,II,Chen, 2014; Muniappan, 2014.,抗真菌治疗下慢性空腔性肺曲霉菌病复发（包括多重三唑类耐药），伴有/不伴威胁生命的出
37、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 of disease, possibly cure,谨慎的评估下，肺叶拆除或肺切除,Careful risk assessment, followed by lobectomy or pneumonectomy,胸腔造瘘下的胸廓成形术，以及皮瓣移植术,Thorac
38、oplasty with Simultaneous cavernostomy and muscle transposition flap,A,II,C/D,III,Kim, 2005; Farid, 2013 (others),Grima, 2008 Igai , 2012,患者需要在具有曲霉病手术经验的中心进行,可以考虑转化为胸廓切开术,前期的栓塞可视为延期手术的指证,需要具有经验的手术团队,Present by David Denning,ECCMID 10th May 2015 in Barcelona,患者人群 Population,目的 Intention,干预手段 Interven
39、tion,SoR,QoE,文献 Reference,备注 Comment,未给予抗真菌治疗的曲霉结节,Aspergillus nodule not treated with antifungal therapy,如果存在多病灶需及早确定疾病进展以及肺癌,To identify progression Early and/or Carcinoma of lung if Multiple lesions,如单个结节切除无需随访,曲霉结节和术后随访 Follow up of Aspergillus nodule and after resection surgery,肺叶/全肺切除术后,Postlo
40、bectomy/ pneumonect omy,早期发现疾病复发,To detect recurrence early,无预测复发的评估,如曲霉抗体IgG持续升高需要充分的再评估,3-6个月的低剂量影像随访；炎性标记物和曲霉抗原及沉淀素随访,3-6 mos clinical follow up with (low dose) imaging, Inflammatory markers and Aspergillus IgG/precipitins,3-6个月的炎性标记物和曲霉抗原及沉淀素随访，其后3年内随访周期为每半年,3-6 mos then 6 monthly for 3 years with inflammatory markers and Aspergillus IgG/precipitins,A,A,III,III,Farid, 2013; Muldoon, 2014,Farid, 2013.,Present by David Denning,ECCMID 10th May 2015 in Barcelona,指南修订团队,
