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1、在临床实践中学习和认识肺曲霉病的临床多样性Understanding Clinical Diversity of Pulmonary Aspergillosis,陈 佰 义 中国医科大学第一医院感染病科/医院感染管理办公室辽宁省感染性疾病医疗中心/国家卫计委细菌真菌感染诊治培训基地,某女，39岁，住院号：615293入院日期:2007年1月13日 主诉:以咳嗽、气短16天，发热8天为来诊。从事钢管销售工作；既往健康。无工业、有机毒物及粉尘接触史；无宠物、家禽、家畜接触史；无明确过敏史；无长期糖皮质激素用药史；无冶游史及输血史。,呼吸困难、发热、咳嗽、黄痰、肺浸润、空腔变,临 床 经 过,入院前
2、16天无诱因出现呼吸困难（气短），活动轻度受限（上楼气短明显），干咳,无发热；在当地诊所应用阿奇霉素、双黄连等药物治疗8天无效发病8天后出现发热，体温达38.6，无寒战；气短、咳嗽加重，咳黄白色粘痰（80100毫升日）。遂行肺CT检查（如下）,入院前8天1月5日,讨论1根据肺部CT，您最可能(单选)给出的影像学诊断是,1、双肺炎症2、间质性肺疾病3、病毒性肺炎4、外源性过敏性肺泡炎(EAA)5、嗜酸细胞性肺炎(EP)6、隐源性机化性肺炎(COP)7、肺血管炎8、肺曲霉病,临 床 经 过,按社区获得性肺炎(CAP)治疗 红霉素(?)0.9 日一次 静滴2天 头孢哌酮舒巴坦(?)2.0 日二次 静
3、滴4天肺CT复查:沿支气管走行广泛分布云雾状阴影，可见片状阴影，呈实变倾向。,1月5日（发病8天）1月12日（发病15天）,加用莫西沙星(拜复乐)(?)0.4 日一次 静滴 2天体温波动在3738.9之间气短、咳嗽伴声嘶黄白色痰，痰量约5060毫升转至我院就诊,入 院 检 查,T 39 P 110次/分 R 24次/分 Bp 140/70mmHg呼吸稍促，口唇无发绀，声音嘶哑，咽充血，平卧位双肺中下部可闻及中等量湿啰音，心率:110次分，律整,血气分析：(未吸氧)pH 7.49 PaO2 58mmHg PaCO232.2mmHg HCO3-25.7mmol/L SaO2 92.5%；氧和指数:
4、276血常规：WBC 16.3 G/L;S 0.83;L 0.15;M 0.02 RBC 4.22*1012/L;HGB 132g/L;PLT 332*109/L尿常规:比重：1.015;PRO+;GLU;BLD+;LEU+;KET肝功:ALT 87U/L;ALP 180U/L;GGT 154U/L;TBIL 12.3mol/L肾功：BUN 2.7mmol/L;Cr 75mol/L心肌酶谱：LDH 888U/L；AST 49U/L；CK 163U/L血离子:K2.7mmol/L;Na+137mmol/L;Cl-97 mmol/L,临床表现及影像学变化特点 1.既往健康 2.咳嗽、气短，继而（8
5、天后）发热、大量黄白痰 3.双肺广泛分布云雾状阴影，且呈实变倾向 4.I 型呼吸衰竭（血气分析提示）5.当地医院抗感染治疗无效,临床思维诊断与鉴别诊断,重症社区获得性肺炎？,临床思维诊断与鉴别诊断,感染性肺疾病 非典型病原体肺炎 金黄色葡萄球菌肺炎 病毒性肺炎 结核病,非感染性肺疾病 外源性过敏性肺泡炎 嗜酸细胞性肺炎 原发性血管炎 免疫性肺泡出血 隐源性机化性肺炎（COP）,痰查嗜酸细胞计数：3 嗜酸细胞计数：50106L-不支持嗜酸细胞性肺炎诊断ANCA:阴性-结合临床表现、不支持ANCA相关血管炎诊断,痰培养及血培养(二次)均未见致病菌生长痰涂片查菌：G、G球菌口咽部正常菌群痰查抗酸杆菌
6、：阴性、需要重复支原体抗体:1:80(+)-不能确定、治疗中复查军团菌抗体:阴性治疗中复查结明试验（）：-不能除外假阳性可能,Cryptogenic Organizing Pneumonia,肺炎链球菌-最常见、可选-内酰胺、呼吸氟喹诺酮流感嗜血杆菌-COPD、可选酶抑制剂、头孢菌素、氟喹诺酮需氧革兰阴性杆菌-患者无ESBLs细菌感染的危险因素金匍菌-多发生流感后、无MRSA危险因素/不必糖肽类/恶唑烷酮肺炎支原体/衣原体-大环内酯类、氟喹诺酮嗜肺军团菌-大环内酯类、氟喹诺酮,经验性抗感染治疗-评估病原体/评估耐药性-拟诊为CAP的经验性抗感染治疗方案,治疗方案 莫西沙星（拜复乐）400mg
7、Qd 静滴哌拉西林/他唑巴坦(特治星)4.5 Q8h 静滴覆盖不能绝对除外耐药的G-细菌双鼻导管吸氧(2Lmin)同时给予安噻吗、安溴索等对症治疗,入院72小时内，病人多次出现喘息、气短加重，双肺满布哮鸣音；临床呈现支气管痉挛表现；常规氨茶碱24小时 1.0 静滴，症状可逐渐缓解。,临床思维诊断与鉴别诊断,治疗72小时病情无缓解 体温波动在3738.6之间 咳嗽、气短症状无缓解 痰量约80100毫升日，棕黄色痰为主 双肺可闻及散在干鸣音及少许湿罗音,首先分析病情未能控制的原因：非感染性疾病？无依据 耐药菌株感染？MRSA/ESBL?无依据 未能有效覆盖可能的致病微生物！真菌？其次判断病情进展的
8、程度，努力寻找病因学证据,肺HRCT（1月17日，入院72小时）痰培养药敏 痰涂片查菌血气分析（2Lmin）pH 7.39，PaO2 66 mmHg，PaCO2 44 mmHg，SaO2 93%，氧合指数：228,临床思维诊断与鉴别诊断,讨论2根据肺部CT，您最可能(单选)给出的影像学诊断是,1、支扩并感染2、金葡菌肺炎3、肺结核病4、军团菌病5、肺曲霉病,金黄色葡萄球菌肺炎肺结核 军团菌肺炎肺曲霉菌病病史 有基础疾患及诱因 有结核病接触史 有受污染水源 宿主免疫状态低下 或肺外结核病史接触史及职业接触史症状 多急骤起病、高热、隐匿起病，发热、发热、肌痛、相对 干咳、呼吸困难、寒战、胸痛、痰脓
9、性 咳嗽、咳痰和咯血 缓脉及肺外表现胸痛、发热 及全身中毒症状X线 多发性小叶性炎症浸 肺炎部陈旧点状、条 早期为单侧受累，胸膜为基底的楔形影，润影，早期可有空洞 索状阴影，节断性或 后进展为双侧、多 内有空洞；晕轮征或 形成，后可出现蜂窝 大叶性、干酪性肺炎 叶性病灶，空洞少 新月体征 状或肺气囊肿改变 及多发性空洞 见实验室 血细胞增高。中性 痰菌多阳性 血清直接荧光抗体 半乳甘露聚糖测定检查 细胞比例增加，阳性；间接免疫荧 增高，组织培养及 从无菌体液或 光抗体滴度4倍 组织病理 分离出 器官中分离出金葡 增高，呼吸道标本 该菌 菌 中分离出该菌 不支持 不支持 不支持 不支持,临床思维
10、诊断与鉴别诊断,支扩并感染,金葡菌肺炎,肺结核病,军团菌病肺炎(空腔罕见),肺曲霉病,讨论3结合临床，您最可能(单选)给出的影像学诊断是,1、支扩并感染2、金葡菌肺炎3、肺结核病4、军团菌病5、肺曲霉病,既往健康起病以气短、干咳为首发症状，一周后出现发热，大量粘液痰，后期出现棕色痰双肺多发病灶，呈进行性加重伴空洞形成经验性系统抗感染治疗无效,气短、干咳、支气管痉挛变应原？发热、坏死性肺炎侵袭性病原体即可作为 变应原又可作为 侵袭性病原体,？,临床思维诊断与鉴别诊断,真菌/曲霉？,痰真菌培养药敏 痰查孢子菌丝血1,3-D 葡聚糖停用哌拉西林他唑巴坦、莫西沙星抗曲霉菌药物治疗 伏立康唑、两性霉素
11、B、卡泊芬净、伊曲康唑,临床思维考虑肺曲霉病可能性大,治疗期间，患者支气管痉挛症状明显，且血清IgE（755 mg/ml)增高，考虑存在曲霉菌所致的变态反应应用甲基强的松龙60毫克/日，分三次静滴对症治疗。,血1,3-D 葡聚糖：19.46 pg/ml(正常值：10 pg/ml）痰真菌培养:烟曲霉菌生长（三次）痰查孢子菌丝：阴性,抗真菌治疗前后对比,1月17日 1月25日,抗真菌治疗三周 2月7日,抗真菌治疗四周 2月14日,血气分析（未吸氧）pH 7.39，PaO2 69 mmHg，PaCO2 46 mmHg SaO2 93%，氧合指数：328,停药两周 2月28日,停药四周 3月15日,1
12、、变应性支气管肺曲菌病(ABPA)？2、原发性侵袭性肺曲霉菌感染(PIPA)？3、原发性半侵袭性肺曲霉菌病(semi-invasive)？4、肺曲霉病(pulmonary aspergillosis)?,讨论4关于患者最后诊断，您的意见是,曲菌属（Aspergillus）,曲菌属于霉菌，有约2-4 m直径的有隔菌丝环境中无处不在:死树叶（Dead leaves）仓储的谷物（Stored grain）发酵堆肥（Compost piles）枯草（Hay）其它腐败植被（Other decaying vegetation）建筑场所（Construction sights）Fireproofing ma
13、terialsVentilation and Air conditioning systems marijuana通过吸入进入鼻窦和肺脏致病,霉菌,多细胞菌丝和孢子变应原/侵袭性病原体的二元特性,痰涂片标本,Aspergillus fumigatus,Aspergillus niger,KOH-calcofluor mount showing septate Aspergillus hyphae,Immune dysfunction,Frequency of aspergillosis,Immune hyperactivity,Frequency of aspergillosis,Subacu
14、te IA,AspergillomaChronic pulmonary,Interaction of Aspergillus with people-A unique microbial-host interaction,曲霉二元特性及其与宿主的相互作用决定了肺曲霉病的临床多样性,Examples of at-risk patients and pace of progression,Degree of immunocompromise,Risk of acquisition(and pace of progression),Normal immunity,high inoculum,HIV
15、infection,Chronic leukaemia,Short course glucocorticoids,Acute respiratory infection,ie influenza,Temporary neutropenia,Long term glucocorticoids etc,Solid organ transplant+rejection+CMV,AIDS,Leukemia and profound neutropenia,Allogeneic stem cell transplant+GVHD,Relapsed/uncontrolled leukemia,5%,10%
16、,15%,20%,25%,Medical ICU,COPD+sepsis,Clinical Picture of Pulmonary Aspergillosis,起病-急性、亚急性、慢性发热-无发热、低热、中等度热、高热咳嗽和咳痰-刺激性干咳、白粘痰、黄粘痰、黄褐色粘痰咯血-无、小量、大量支气管痉挛-严重-免疫功能正常或增高宿主-轻中度-免疫功能一般低下-无支气管痉挛-免疫功能严重低下呼吸衰竭-无-免疫缺陷、严重-免疫正常和增高,Pulmonary Aspergillosis,免疫功能正常 Normal immunity真菌球 或 空腔内 曲菌球 fungal ball or aspergil
17、loma in a pre-existing cavity,Exposure of the lung by Aspergillus,免疫缺陷-严重 severe immuno-compromised侵袭性曲霉病/可以是社区获得 Invasive aspergillosis/community acquired infection,免疫缺陷-轻中度严重mild to moderate immunocompromised慢性空腔性 肺曲霉病+/-曲菌球Chronic cavitary pulmonary aspergillosis+/-fungal ball,免疫能亢进 hypersensitiv
18、ity ABPAEAABronchial asthma with aspergillus sensitization,Simple(single)aspergilloma,Patient RKHaempotysis,nil else Positive Aspergillus antibodies in bloodLobectomy,Simple(single)aspergilloma,Patient NMPositive Aspergillus antibodies in bloodLobectomy,August 2006 May 2009Community acquired New cou
19、gh pneumonia requiring ICU care,Aspergilloma,4 years later,Bilateral pulmonary cavities in the upper lungs surrounded by circumferential pleural thickening and containing aspergillomas,Pulmonary Aspergillosis,免疫功能正常 Normal immunity真菌球 或 空腔内 曲菌球 fungal ball or aspergilloma in a pre-existing cavity,Ex
20、posure of the lung by Aspergillus,免疫缺陷-严重 severe immuno-compromised侵袭性曲霉病/可以是社区获得 Invasive aspergillosis/community acquired infection,免疫缺陷-轻中度严重mild to moderate immunocompromised慢性空腔性 肺曲霉病+/-曲菌球Chronic cavitary pulmonary aspergillosis+/-fungal ball,免疫能亢进 hypersensitivity ABPAEAABronchial asthma with
21、 aspergillus sensitization,Allergic Aspergillosis(Hypersensitivity Pneumonitis),Common HRCT Patterns:Centrilobular Nodules 小叶中心性结节Ground-Glass 磨玻璃影Consolidation 实变Air Trapping 气体陷闭Fibrosis 纤维化,Patel RA et al.Journal of Computer Assisted Tomography;24(6):965-970,Tubular Opacities(Mucoid Impaction)Ate
22、lectasisLucency(air trapping),Central BronchiectasisMucoid Impaction,Gotway MB et al.Journal of Computer Assisted Tomography;26(2):159-173,Criteria for diagnosis of ABPA,主要标准-发作性支气管“哮喘”-外周血嗜酸细胞增加(1000mm3)-皮肤曲菌抗原反应-血清IgE 增高(1000ng/ml)-肺浸润史-中心性支扩,次要标准-痰中检出烟曲菌-曾经咳出棕色痰栓-曲菌抗原 迟发皮肤反应（Arthus 反应）,Pulmonary
23、Aspergillosis,免疫功能正常 Normal immunity真菌球 或 空腔内 曲菌球 fungal ball or aspergilloma in a pre-existing cavity,Exposure of the lung by Aspergillus,免疫缺陷-严重 severe immuno-compromised侵袭性曲霉病/可以是社区获得 Invasive aspergillosis/community acquired infection,免疫缺陷-轻中度严重mild to moderate immunocompromised慢性空腔性 肺曲霉病+/-曲菌球C
24、hronic cavitary pulmonary aspergillosis+/-fungal ball,免疫能亢进 hypersensitivity ABPAEAABronchial asthma with aspergillus sensitization,气道侵袭性病变(airway invasive disease)气腔侵袭性病变(airspace invasive disease血管侵袭性病变(angioinvasive disease),急性侵袭性肺曲霉菌病Acute Invasive Pulmonary Aspergillosis,肺曲霉病-气道侵袭性Aspergillosis
25、-Airway-invasive,Presence of Aspergillus organisms deep to airway basement membrane.Most commonly in neutropenic patients and AIDS patients Clinical manifestations include-Acute tracheobronchitis(可以发生在正常人群)normal radiologic findings/tracheal or bronchial wall thickening-Bronchiolitis centrilobular n
26、odules and branching linear or nodular areas of increased attenuation having a tree-in-bud“appearance.-bronchopneumonia peribronchial areas of consolidation，rarely,lobar consolidation,Tait,Thorax 1993;48:1285,Pseudomembranous Aspergillus tracheobronchitis,Wheezing 4 days before death,immunocompromis
27、ed,Pseudomembranous Aspergillus tracheobronchitis with IPA in COPD,Bulpa Eur Resp J 2007;30:782,Invasive bronchiolar aspergillosis in a patient undergone bone marrow transplantation.-Thin-section CT shows peripheral branching structures associated with focal areas of consolidation-can also be seen i
28、n TB,MAC,viral,mycoplasma pneumonia.-aspergillus bronchopneumonia radiology indistinguishable from those of other bronchopneumonias,Bronchopneumonia aspergillosis,(a)Conventional CT scan through the upper lungs shows a segmental area of consolidation in the right upper lobe with visible air bronchog
29、ram.,(b)Photograph of the corresponding autopsy specimen shows segmental consolidation,(c)High-power photomicrograph of a small area of consolidation shows tissue necrosis.Scattered Aspergillus organisms can be identified in the necrotic tissue(arrows).,白血病并发侵袭性曲菌病,AIDS病人急性侵袭性曲菌,异体BMT病人急性侵袭性曲菌病,肺曲霉病
30、-气腔侵袭性(肺炎)Aspergillosis-Airspace-invasive(pneumonia),细菌性肺炎 单一形态(时相均一)叶段分布 腺泡结节 空气支气管征 坏死(液-气平)收缩不明显,曲霉菌肺炎 多发病灶/多种征象 肿块伴晕影 大片坏死 空气新月征 组织中小气泡影,肺曲霉病-血管侵袭性Aspergillosis-angioinvasive,感染特点:菌丝侵及血管血栓形成坏死出血性梗塞,Pulmonary Infarct,Invasive pulmonary aspergillosis,IPA,IPA occurs in 7%of acute leukaemia patients
31、,10-15%allogeneic BMT patients,Unequivocal Halo sign surrounding a nodule,Herbrecht,Denning et al,NEJM 2002;347:408-15.,Halo sign,Acute Invasive Pulmonary Aspergillosis,Air Crescent Sign,Air Crescent Sign,Invasive Aspergillosis,Presentation,During Treatment,Ko JP et al.Journal of Thoracic Imaging;17
32、(1):70-73,Pulmonary nodules a useful feature if invasive pulmonary aspergillosis,CT features in 235 CTs in patients with IPAMacronodule(1cm)221(94%)Halo143(60%)Consolidation 71(30%)Macro-nodule,infarct shaped 63(27%)Cavitary lesion 48(20%)Air bronchograms 37(16%)Clusters of small nodules(1cm)25(11%)
33、Pleural effusion 25(11%)Air crescent sign 24(10%)Non-specific ground glass 21(9%),Brain Abscess(单发、多发),内眼炎,皮肤损害,急性侵袭性曲霉病的肺外表现,Pulmonary Aspergillosis,免疫功能正常 Normal immunity真菌球 或 空腔内 曲菌球 fungal ball or aspergilloma in a pre-existing cavity,Exposure of the lung by Aspergillus,免疫缺陷-严重 severe immuno-com
34、promised侵袭性曲霉病/可以是社区获得 Invasive aspergillosis/community acquired infection,免疫缺陷-轻中度严重mild to moderate immunocompromised慢性空腔性 肺曲霉病+/-曲菌球Chronic cavitary pulmonary aspergillosis+/-fungal ball,免疫能亢进 hypersensitivity ABPAEAABronchial asthma with aspergillus sensitization,Chronic Necrotizing(Semi-invasiv
35、e)Aspergillosis,Fungus is intermediate.No vascular invasion.Tissue necrosis and destruction.Granulomatous inflammation similar to that seen in reactivation TB.Usually no previous cavity,vs presence of cavity in non-invasive form.May occur with mild immunosuppression.,Predisposing factors Chronic deb
36、ilitating illnessAdvanced age.Alcoholism,Malnutrition.DM,COPD.Prolonged steroid therapyRadiation therapy.Inactive TB.Pneumoconiosis.Sarcoidosis.,SymptomsOften insidious and include chronic cough,sputum production,fever,and constitutional symptoms.Hemoptysis has been reported in 15%of affected patien
37、ts.May manifest with chronic bronchitis and recurrent episodes of mild hemoptysis.,Radiology Thin-section CT scan shows unilateral/bilateral rounded segmental areas of consolidation with or without cavitation or adjacent pleural thickening,Multiple nodular areas of increased opacity.The findings pro
38、gress slowly over months or years.,Chronic Necrotizing(Semi-invasive)Aspergillosis,56岁男性，慢支和结核病史,双侧慢性浸润伴钙化提示既往结核病(箭).,上叶浸润明显进展,双侧肺实质实变,慢性(半侵袭性)肺曲菌病Chronic semi-invasive pulmonary aspergillosis,慢性半侵袭性曲菌病,曲菌病所致慢性肉芽肿性病变,68岁，男性，“慢支”和反复小量咯血,左上叶圆形实变伴有空腔,慢性半侵袭性（坏死性）肺曲菌病Chronic invasive pulmonary aspergillo
39、sis,Chronic Necrotizing Aspergillosis in DM patient 15 month f/u,Gotway MB et al.Journal of Computer Assisted Tomography;26(2):159-173,肺曲霉病所致空洞,慢性半侵袭性（坏死性）肺曲菌病Chronic invasive pulmonary aspergillosis,pulmonary aspergillosis,fungal ball or aspergillomain a pre-existing cavity,Exposure of the lung by
40、Aspergillus,Acute IA,Chronic cavitary pulmonary aspergillosis+/-fungal ball,Chronic fibrosing pulmonary aspergillosis+/-fungal ball,Allergy,ABPAEAA,OVERLAP syndrome,1,2,3,4,4,Eur Respir Rev 2011;20:121,156174,Difficulties in Establishing a Diagnosis for Invasive Moulds,No disease,Cultures/Antigen,Si
41、gns andsymptoms,Cultures/histopathology,Sequelae,Prophylaxis,Preemptive,Empirical,Treatment,Morbidity/Mortality,Beta-glucan/GM/PCR test?,Fever-driven,Diagnostic-driven,侵袭性曲霉病早期经验治疗(?)的临床思维,急性侵袭性/变应性/重叠综合症-出现呼吸衰竭和/或迁徙病灶/危及生命-可以综合考虑予以经验性治疗亚急性/慢性曲霉病应力争目标治疗-鉴别诊断包括：结核病、奴卡菌病-完全不同的治疗方案.,Treatment Success f
42、or AspergillosisThe importance of early therapy,7-10 days,Nodular Lesion with Halo Sign(N=143),Nodular Lesion without Halo Sign(N=143),Greene R,et al.ECCMID.2003.,52.4%,62.3%,40.9%,29.1%,41.5%,15.8%,Cure%,Aspergillosis:obtaining a diagnosis,CT scan,Galacto-mannan,glucan,PCR,Galactomannan,glucan,PCR,
43、Invasive aspergillosisCurrent first-line treatment guidelines,Walsh TJ,et al.Clin Infect Dis 2008;46:32760.Prentice AG,et al.http:/J et al.Bone Marrow Transplantation 2011;46:70918Bohme A et al.Ann Hematol 2009;88:97110Thursky KA,et al.Intern Med J 2008;38:496520.,Diversity of Pulmonary Aspergillosi
44、s,Persistence without disease-colonization of the airways or nose sinuses,Airways/nasal exposure to airborne Aspergillus,Acute(1 month course)-Invasive aspergillosis/allergic(？)Subacute/chronic necrotising(1-3 months),Chronic aspergillosis(3 months)Aspergilloma（Saprophytic Aspergillosis）Chronic cavi
45、tary(necrotizing)pulmonary-semi-invasive Chronic fibrosing pulmonary aspergillosis Chronic invasive sinusitis Maxillary(sinus)aspergilloma,Allergic Allergic bronchopulmonary(ABPA)急性起病、反复发作 Extrinsic allergic alveolitis(EAA)急性亚急性慢性 Asthma with fungal sensitisation 反复发作 Allergic Aspergillus sinusitis,
46、Immune status,Immune dysfunction,Frequency of aspergillosis,Immune hyperactivity,Frequency of aspergillosis,Subacute IA,AspergillomaChronic pulmonary,曲霉二元特性及其与宿主的相互作用决定了肺曲霉病的临床多样性,不同个体表现不同,Immune dysfunction,Frequency of aspergillosis,Immune hyperactivity,Frequency of aspergillosis,Invasive aspergillosis,Chronic pulmonary,Allergic aspergillosis,.,曲霉二元特性及其与宿主的相互作用决定了肺曲霉病的临床多样性,同一个体随着免疫状态不同而呈现不同表现,
