ECCMID曲霉菌指南简介慢性肺曲霉菌病感染.ppt

,单击此处编辑母版标题样式,单击此处编辑母版文本样式,第二级,第三级,第四级,第五级,2019/12/2,#,EFISG,European Society of Clinical Microbiology and Infection Diseases,ESCMID Fungal Infectious Study Group,Only for internal learning or discussion,forbidden for any other purpose,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 10,th,May 2015 in Barcelona,),1,Present by,David Denning,ECCMID 10,th,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),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,2,Present by,David Denning,ECCMID 10,th,May 2015 in Barcelona,慢性曲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,pulmonary aspergillosis(CFPA),曲霉菌肉芽肿,Aspergillus nodule(s),3,Present by,David Denning,ECCMID 10,th,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 pulmonary aspergillosis(CFPA),4,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 microbiological 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,CPA,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).Respiratory 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;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 10,th,May 2015 in Barcelona,5,慢性肺曲霉菌病,-,气道标本的诊断,Respiratory specimen diagnosis of CPA,Present by,David Denning,ECCMID 10,th,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,pathogens,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;,Horvath,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,6,慢性肺曲霉菌病,-,抗原检测,Antigen diagnosis of CPA,Present by,David Denning,ECCMID 10,th,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,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建立研究，但痰液的抗原尚未涉及,Antigen,（,Sputum,）,No,data,7,慢性肺曲霉菌病,-,抗体检测,Aspergillus antibody diagnosis,of CPA,Present by,David Denning,ECCMID 10,th,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,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;,Ohba,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,8,慢性肺曲霉菌病,-,影像学诊断和随访,Radiological diagnosis and follow up of CPA,Present by,David Denning,ECCMID 10,th,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,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,visualisation,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,3-6,个月并伴有状态的改变,A,II,Expert radiology,advice,9,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 5-10,10,肺曲霉菌病,发病初：,两周后：,11,肺曲霉菌病,肺曲菌病,-,多发小结节型,12,肺曲霉菌病,13,Present by,David Denning,ECCMID 10,th,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）,14,Present by,David Denning,ECCMID 10,th,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,15,Present by,David Denning,ECCMID 10,th,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。,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）,16,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,17,肺曲霉菌病,曲菌球,18,Present by,David Denning,ECCMID 10,th,May 2015 in Barcelona,伪肿瘤表现的慢性肺曲霉病患者（手术确认）,19,Present by,David Denning,ECCMID 10,th,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,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 triazole 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;,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,20,Present by,David Denning,ECCMID 10,th,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,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,2014;Kohno,ECCMID 2013,两性霉素,B,脂质体,3mg/kg/d,Liposomal AmB,3mg/kg/d,B,IIa,Newton,2014,21,Present by,David Denning,ECCMID 10,th,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,unwilling 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,22,Present by,David Denning,ECCMID 10,th,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,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,therapy,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,depending,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,23,Present by,David Denning,ECCMID 10,th,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,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,Indications 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,Thoracoplasty 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,24,Present by,David Denning,ECCMID 10,th,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,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,Postlobectomy/,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.,25,Present by,David Denning,ECCMID 10,th,May 2015 in Barcelona,指南修订团队,26,