1、2014 ESCMID曲霉菌病治疗指南-慢性肺曲霉病2014 ESCMID Aspergillus Guideline-Chronic Pulmonary AspergillosisPresent by David W.Denning United KingdomECCMID 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 Present by Da
2、vid Denning ECCMID 10th May 2015 in Barcelona慢性肺曲霉菌病-疾病分类Chronic Pulmonary Aspergillosis-subsetsChronic 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 Fibrosi
3、ng 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 nodulePresent byPresent by David Denning E
4、CCMID 10th May 2015 in Barcelona慢性曲霉菌病临床表现分类Clinical phenotypes of chronic Clinical phenotypes of chronic Aspergillus spp diseasesAspergillus 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 pulmonaryaspergillosis(CNPA)or subacuteInvasive aspergillosis(SAI)慢性空腔性肺曲霉菌病Chron
5、ic cavitary pulmonaryaspergillosis(CCPA)慢性纤维化肺曲霉菌病Chronic fibrosingpulmonary aspergillosis(CFPA)曲霉菌肉芽肿Aspergillus nodule(s)Present by Present by David Denning ECCMID 10th May 2015 in Barcelona不同类型的慢性曲霉菌病Different patterns of CPADifferent patterns of CPA曲霉菌肉芽肿Aspergillus nodule(s)单发曲霉球 Single/simple
6、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)慢性肺曲霉菌病-诊断标准Chronic Pulmonary Aspergillosis Diagnostic criteriaChronic 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 ap
7、pearance 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 aspergil
8、losis(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
9、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 Aspergill
10、us 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 histoplas
11、mosis,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 byPresent by Dav
12、id 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 CPARespiratory specimen diagnosis of CPAPresent byPresent by David Denning ECCMID 10th May 2015 in Barcelona患者人群Population目的Intention干预手段InterventionSoRQoE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 n
13、odularpulmonary infiltrate in Non-immunocompromised patients诊断或排除慢性肺曲霉菌病DiagnosisOrexclusionof CPA确诊或排除其他病原体To documentor Exclude otherpathogens直接镜检发现菌丝Direct microscopy forhyphae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
14、菌PCRAspergillusPCR(respiratory secretion)细菌培养Bacterial cultureAAABCCIIIIIIIIIIIIItUffredi,2003Denning,2003;Horvath,1994Denning,2013;Duddy,2012Horvath,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 CPAAntigen di
15、agnosis of CPAPresent byPresent by David Denning ECCMID 10th May 2015 in Barcelona患者人群Population目的Intention干预手段InterventionSoRQoE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 nodularpulmonary infiltrate in Non-immunocompromised patients诊断或排除慢性肺曲霉菌病DiagnosisOrexclusionof CPA肺泡灌洗液抗原Antigen（BAL）血清
16、学抗原检测Antigen（Serum）痰培抗原检测BCIIIIIzumikawa,2012Izumikawa,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）Nodata慢性肺曲霉菌病-抗体检测Aspergillus antibody diagnosis Aspergillus antibody diagnosis of CPAof CPAPresent byPresent by David Denning ECCMID 10th May 2015 in Barcelona患者人群Population目的
17、Intention干预手段InterventionSoRQoE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 nodularpulmonary infiltrate in Non-immunocompromised patients诊断或排除慢性肺曲霉菌病DiagnosisOrexclusionof CPA曲霉抗体IgGAspergillus IgG antibodyAspergillus IgM antibodyAspergillus IgA antibodyAspergillus IgE antibodyAADDBIIIIIIIIIII
18、IGuitard,2012;Baxter,2012;VanToorenenbergen,2012BTS,1970;Uffredi,2003;Kitasato,2009;Ohba,2012;Baxter,2012Schonheyder1987;Nimomiya,1990;Denning,2003;Agarwal,2012IgG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/CFAspergillus precipitins曲霉沉淀素曲霉抗体IgM曲霉抗体IgA曲霉抗体IgEBrouwer,1988;多数室内测试尚未应用，主要原因是不
19、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 follow up Radiological diagnosis and follow up of CPAof CPAPresent byPresent by David Denning ECCMID 10th May 2015 in Barcelona患者人群Population目的Intention干预手段InterventionSoRQoE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 cavita
20、tion,fungal ball,pleuralthickening and/or upperlobe fibrosis提高临床医师对慢性曲霉菌病的关注Raise suspicion ofCPA for physicians影像报告必须提及慢性肺曲霉菌病的可能性Radiological report mustMention possible CPACT Scan（contrast）AAIIII慢性曲霉菌常被长期误诊并未给予治疗CPA is oftenmissed for yearsand patientsmismanaged.微生物检查结果需要具备血管成像高分辨CT的对照确认Microbiol
21、ogicaltesting requiredfor confirmationHigh quality CTwith vesselvisualisation随访患者及停药Follow up on or offtherapyCT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 chronicpulmonary aspergillosison CXR诊断或排除慢性肺曲霉菌病DiagnosisOrexclusionof CPAPET scanPET扫描DIIICT Scan（low dosage）CT扫描（低剂量）CXRX胸片BIIIBIIIInitial FU a
22、t 3-6 mos andwith change of status初始抗真菌治疗3-6个月并伴有状态的改变AIIExpert radiologyadviceAir-crescent signD 10-20Halo signD 0-5Air-space consolidationD 5-10发病初：两周后：Present byPresent 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）Present byPresent
23、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 byPresent by David Denning ECCMID 10th May 2015 in Barcelonaabcdef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
24、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）仰卧位胸部仰卧位胸部CT俯卧位胸部俯卧位胸部CTPresent byPresent 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 byPresent by David Denning ECCMID 10th May 2015 in
25、 Barcelona患者人群Population目的Intention干预手段InterventionSoRQoE文献Reference备注Comment慢性肺曲霉病进展期患者CPA patients withprogressive disease控制感染性疾病进展Control ofinfection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 TDMAII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 Oral triazole the
26、rapy for CPA PopulationPopulation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 withTDMAII泊沙康唑起始400mg BIDPosaconazoleStart 400mg BIDBII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;DeBuele,1998,Dupont,1990;Campbell,1991;Tsubura,1997;Denning,2003;Nam,2
27、009;Al-shair,2013Saito,2009;Cadranel,2012,Jain,2006;Sambatakou,2006;Camuset,2007;Philippe,2009;Al-shair,2013Felton,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 byPresent by David Denning ECCMID 10th May 2015 in Barcelona患者人群Population目的Intention干预手段InterventionSoRQoE文献Refe
28、rence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 withprogressivedisease,who fail,are intolerant oftriazoles or havetriazole resistance控制感染性疾病进展Control ofinfection米卡芬净 150mg/dItraconazole Start 200mg BID,adjust with TDMBII慢性肺曲霉菌病-针剂替代治疗Alternative intravenous therapy for Alternative in
29、travenous therapy for CPACPA两性霉素B0.7-1.0 mg/kg/dAmphotericin Bdeoxycholate0.7-1.0mg/kg/dCIII卡泊芬净50-70 mg/dCaspofungin50-70mg/dCIIaKohno,2011;Kohno,EJCMID2013;Saito,2009;Kohno,2011;Kohno,2004;Izumikawa,2007;Yasuda,2009;Nam,2009Denning,2003Kier,2014;KohnoECCMID 2013两性霉素B脂质体3mg/kg/dLiposomal AmB3mg/kg/
30、dBIIaNewton,2014Present byPresent by David Denning ECCMID 10th May 2015 in Barcelona患者人群Population目的Intention干预手段InterventionSoRQoE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 withaspergilloma,unwilling or unableto take oraltherapy,multiazoleresistanceand inoperable控制感染性疾病进展C
31、ontrol ofinfection两性霉素B腔内注射Instillation of amphotericin BDeoxycholate into cavityCII慢性肺曲霉菌病-局部空腔治疗Local cavity therapy for CPALocal cavity therapy for CPAGiron,1998;Kravitz,2013实验性治疗Present byPresent by David Denning ECCMID 10th May 2015 in Barcelona患者人群Population目的Intention干预手段InterventionSoRQoE文献R
32、eference备注Comment慢性肺曲霉病抗真菌治疗CPA patients onAntifungal 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 pulmonaryFibrosis,prevention ofHaemoptysis,improvedquality of life.6个月抗真菌治疗6 mo antifungaltherapyBII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 ther
33、apy for CPADuration of antifungal therapy for CPAAgarwal,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SubacuteIA/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 antifungalTherapy,dependingon status and drug toleranceCII6个月6 moBIIFelton,2010;Camuset,2007;J
34、ain,2006;Cadranel,2012Camuset,2007Cadranel,2012Optimal duration oftherapy inCPA is unknown,Indefinite suppressivetherapy may beAppropriate in selectedpatientsPresent byPresent by David Denning ECCMID 10th May 2015 in Barcelona患者人群Population目的Intention干预手段InterventionSoRQoE文献Reference备注Comment单个/简单曲霉
35、球病Simple/single aspergilloma治愈病预防威胁生命的出血Cure andprevention of lifethreateninghaemoptysis肺叶摘除或其他局部切除Lobectomy or any othersegmental resectionAII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 CPAIndications for surgery in CPADaly,1986;Regnard,2000;Kim,2005;Pratap,2007;Brik,2008;Muniappa
36、n,2014;Farid,2013;Chen,2012;Nacera,2012;Lejay,2011;IDSA 2008图像引导下胸腔镜手术（VATS）Video-assisted thoracicsurgery(VATS)BIIChen,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 tomedical management(including multi-azoleresistance)withantifungal treatmentand/or life-threateningha
37、emoptysis.改善疾病的控制，可能治愈Improved controlof disease,possibly cure谨慎的评估下，肺叶拆除或肺切除Careful risk assessment,followed by lobectomyor pneumonectomy胸腔造瘘下的胸廓成形术，以及皮瓣移植术Thoracoplasty withSimultaneous cavernostomy and muscle transpositionflapAIIC/D IIIKim,2005;Farid,2013(others)Grima,2008 Igai,2012患者需要在具有曲霉病手术经验
38、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 byPresent by David Denning ECCMID 10th May 2015 in Barcelona患者人群Population目的Intention干预手段InterventionSoRQoE文献Reference备注Comment未给予抗真菌治疗的曲霉结节Aspergillus nodule nottreated with antifungaltherapy如果存在多病灶需及早确定疾病进展以及肺癌To identify progressionEarly and/orCa
39、rcinoma of lung ifMultiple 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 Follow up of Aspergillus nodule and after resection surgeryresection surgery肺叶/全肺切除术后Postlobectomy/pneumonectomy早期发现疾病复发To detectrecurrenceearly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-
40、6 mos clinical follow up with(low dose)imaging,Inflammatory markers andAspergillus IgG/precipitins3-6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 3years with inflammatorymarkers and AspergillusIgG/precipitinsAAIIIIIIFarid,2013;Muldoon,2014Farid,2013.Present byPresent by David Denning ECCMID 10th May 2015 in Barcelona指南修订团队
