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1、肺曲霉菌病诊疗,肺曲霉菌病发病率呈上升趋势,北京协和医院2003年报道IFI发病率是90年代的3.6倍国内临床研究：HSCT患者IFI发病率14%25%1美国尸检研究：异体HSCT患者IFI发生率31%，粒缺患者44%2ICU IFI占医院获得性感染的815%3器官移植后IFI发病率约21%,1.Liu ZY,et al.Chin Med J 2003,83,(5):399-402.3.Chin J Intem Med,2007,46(11):960-966.2.Haematologica.2006 Jul;91(7):986-9.,肺曲霉菌病致病菌分布,移植后发生IFI的患者中念珠菌和曲霉感
2、染占80%血液科侵袭性曲霉感染者较多，发病率40%左右ICU约90%为念珠菌感染，其中白念占40%60%非白念（光滑念、热带念、近平滑念、克柔念等）比例在逐渐增加,血症,曲菌分类,超过185种 约有20种可导致机会性感染A.fumigatus烟曲霉（70%）A.flavus黄曲霉（20%）A.niger黑曲霉（低于10%）A.clavatus棒曲霉 A.glaucus灰绿曲霉 A.nidulans构巢曲霉 A.oryzae米曲霉 A.terreus土曲霉A.ustus焦曲霉A.versicolor花斑曲霉,1、烟曲霉菌,在SDA培养基上菌落生长快，棉花样，开始为白色，2 3天后转为绿色，数日后
3、变为深绿色，呈粉末状。分生孢子头的顶囊烧瓶状，小梗单层，排列成木栅状，布满顶囊表面3/4，顶端有链形分生孢子，分生孢子球形，有小棘，绿色,分生孢子,2、黄曲霉菌,在SDA培养基上菌落生长快，黄色，表面粉末状。分生孢子头顶囊球形或近球形，小梗双层，第一层长，布满顶囊表面，呈放射状排列，黄色，顶端有链形孢子,3、土曲霉菌,在SDA培养基上菌落生长快，小，圆形，淡褐色或褐色。分生孢子头的顶囊半球形，小梗双层，第一层短，第二层长，呈放射状排列，分布顶囊表面2/3，顶端有链形孢子,肿/瘤,侵袭性肺部曲菌感染的困惑,不同地区、不同医疗环境发病率相同吗?没有病理证据的下如何确诊？非肿瘤患者肺曲菌感染临床特点
4、？抗曲菌经验治疗（升阶梯还是降阶梯？）非肿瘤患者肺曲菌感染疗程如何？肺曲霉菌感染的定位？首位？,2011.9卫生部专家培训,+,+,+,结合病原,全程靶向,possible-probable-proven-confirm,广谱抗菌,抗优势菌,河北省306例非肿瘤患者侵袭性肺部真菌感染病原分布,21.1%,43.2%,阎锡新、齐天杰，杨丛丽等，中华医院感染杂志，2012，1）,刘又宁报告肺曲霉菌感染影像学特点,河北省306例侵袭性肺部真菌影像学特点,所入选各病例多有以下改变的2-3种，甚至达5种之多,其中50例为曲霉菌感染,曲霉菌形成空洞性病变70.4%，但只有4例患者形成了典型的“晕轮征”或“
5、空气半月征”；念珠菌有14.4%伴空洞，未见“晕轮征”。,肺部曲菌病常见临床类型,腐生曲菌病(曲菌球)过敏性支气管肺曲菌病肺侵袭性曲菌病(IPA)(acute tracheo-bronchitis,bronchiolitis(毛细支气管炎),bronchopneumonia,obstructing bronchopulmonary aspergillosis)血管侵袭性曲菌病,2008 IDSA指南引述依据之一,Angioinvasive aspergillosis,42-42 year-old man with acute myelogenous leukemia 髓性白血病：halo of
6、 ground-glass attenuation 晕轮征,pulmonary infarction,vascular invasion,Saprophytic aspergillosis(aspergilloma)腐生性曲菌病(曲霉肿),54-year-old man with a54-year-old man with a history of tuberculosis.(a)Linear tomogram(magnified view)shows multiple fungus balls within a cavity in the right upper lobe.(b)Photog
7、raph of the corresponding gross surgical specimen demonstrates multiple irregular fungus balls virtually filling the pulmonary cavity.,腐生性曲菌病(曲霉肿),air crescent sign空气新月征,71-year-old man with residual tuberculosis.Chest computed tomographic(CT)scan(lung window)shows large cavities bilaterally in the
8、upper lobes containing fungus balls of different sizes.,Allergic bronchopulmonary aspergillosis,7-14%激素依赖型哮喘为ABPA,43-year-old asthmatic man.(a,b)Thin-section CT scans show multiple tubular areas of increased attenuation.(c)Photomicrograph demonstrate mucous plugs composed of mucin(d)Photomicrograph
9、Grocot silverstain)clearly shows multiple fungal hyphae.菌丝,Chronic Necrotizing Aspergillosis,Semi-invasive aspergillosis in a 68-year-old man with chronic bronchitis and recurrent episodes of mild hemoptysis.(a)Thin-section CT scan(lung window)shows bilateral rounded areas of consolidation with asso
10、ciated cavitation in both upper lobes.(b)Photograph of an autopsy specimen from the left upper lobe shows an irregular cavitary lesion with regular margins and a dark brown appearance caused by necrotic material and Aspergillus infection.,Necrotizing bronchial aspergillosis,54-year-old man who prese
11、nted with cough and sputum production.(a)Chest CT scan(mediastinal window)obtained at the level of the carina shows a thickened,narrowed right main bronchus with associated right upper lobe collapse.(b)Bronchoscopic image shows elevated,whitish mucosal lesions in the right main bronchus(arrow).(c)Hi
12、gh-power photomicrograph(original magnification,400;hematoxylineosin stain)of a biopsy specimen from the right upper lobe reveals massive Aspergillus hyphae invading the bronchial epithelium。,Airway-invasive Aspergillosis,Invasive bronchiolar aspergillosis in a patient who had undergone bone marrowt
13、ransplantation.(a)Thin-section CT scan(lung window)shows peripheral branchingstructures associated with focal areas of consolidation in the right lower lobe.(b)Photograph of the corresponding autopsy specimen shows multiple yellowish acinar nodules.(c)High-power photomicrograph of a lung biopsy spec
14、imen demonstrates complete destruction of the bronchiolar wall by Aspergillus infection.,支气管壁被曲菌完全破坏,制霉菌素,两性霉素B(1958),灰黄霉素,5-FC,咪康唑,酮康唑,氟康唑,伊曲康唑,L-AmB ABCD ABLC,特比萘芬,粪壳菌素,药物数量,肺曲霉菌感染治疗-抗真菌药物与治疗指南,AF,Maertens J.BMC Infectious Diseases 2010,10:182,明显好于恶性肿瘤/血液病的有效率56%-60%,根据MIC确定抗菌药物效能,烟曲霉,2010年中国研究者发表
15、的一项研究检测了常用抗真菌药物（卡泊芬净、伏立康唑、伊曲康唑、泊沙康唑和两性霉素B）对中国临床常见曲霉菌的体外药敏值。该研究显示伏立康唑、伊曲康唑对烟曲霉、黄曲霉仍然有效；卡泊芬净的MIC90值最低。,伊曲康唑对黑曲霉niger耐药，两性霉素B对flavus.terrus 耐药,伏立康唑明显优于两性霉素B,Kobayashi et al：Japanese Journal of Chemotherapy,54(4):308,2006,光滑念珠菌（50）,白色念珠菌（氟康唑敏感)（100）,念珠菌属 spp,米卡芬净,两性霉素 B,氟康唑,伊曲康唑,伏立康唑,克柔念珠菌（50）,光滑念珠菌（氟康唑
16、耐药t）（30）,热带念珠菌（50）,近平滑念珠菌（50）,0.015（g/mL）,0.06,0.25,1,4,16,64,64,32,8,2,0.5,0.12,0.03,抗真菌药物对念珠菌MIC90值的比较,米卡芬净对念珠菌属有很强的杀菌活性 除对近平滑念珠菌外，其MIC最低,氟康唑对非白念珠菌的耐药已很严重 尤其对光滑与克柔,新三唑类对念珠菌抗菌活性很好 伏立康唑对近平滑杀菌活性最强,抗真菌药物对曲霉菌MIC90值的比较,土曲霉（50）,烟曲霉（100）,黄曲霉（50）,曲霉菌属 spp,0.015（g/mL）,0.06,0.25,1,4,16,64,64,32,8,2,0.5,0.12,
17、0.03,黑曲霉（50）,Kobayashi et al：Japanese Journal of Chemotherapy,54(4):308,2006,米卡芬净,两性霉素B,氟康唑,伊曲康唑,伏立康唑,氟康唑对曲霉完全无效,其它三唑类对曲霉有广谱活性,米卡芬净对曲霉MIC最小,体外研究念珠菌、曲霉菌抗菌活性比较,研究共检测了各抗真菌药物对全球10,637株念珠菌、1,415株曲霉菌的体外抗菌活性MIC90值(g/ml),Rev Iberoam Micol.2003;20(4):121-36.中国真菌学杂志2009;2:78-81.,棘白菌素对氟康唑耐药的念珠菌体外药物敏感性的研究结果显示：米
18、卡芬净对59株耐药白念珠菌的MIC均值为0.06g/mL对8株耐药光滑念珠菌的MIC均值为0.063g/mL,下列真菌可能天然耐药,重症患者，存在IFI高危因素，临床拟诊，真菌感染而先期使用氟康唑的结果：不能降低IFI发生率（是预防还是安慰？）非白念感染比例增加（是抢先还是诱导？）药物毒副作用,“预防使用”的分寸如何把握？,氟康唑与安慰剂的区别？,26个医学中心参加的随机、双盲、多中心、安慰剂对照的临床试验270例持续发热（38.3），广谱抗生素治疗4天仍无效的成年患者重症患者治疗组：氟康唑800 mg/天(iv)，n=133；对照组：安慰剂，n=137；平均治疗12天,Ann Intern Med.2008;149:83-90.,P=0.78,治疗成功率（体温下降）,性价比,不同深部抗真菌药物的价格比（以北京地区价格为例）,治疗深部真菌感染的广谱抗真菌药物中伊曲康唑具最优的性价比,总 结,当前真菌感染趋势曲霉菌感染在增加侵袭性曲霉感染导致的死亡率增加经验性抗真菌治疗应覆盖曲菌，经验治疗首选伊曲康唑，并推荐序贯治疗临床诊断或确诊重症肺曲霉菌感染首选棘白霉素类或伏立康唑，或伊曲康唑已有重要器官损伤首选棘白霉素类，无条件可用两性霉素B。,
