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
2、床 经 过,入院前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
3、天头孢哌酮舒巴坦(?) 2.0 日二次 静滴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 H
4、CO3- 25.7mmol/L SaO2 92.5%； 氧和指数: 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
5、; 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A
6、NCA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：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
7、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 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
8、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
9、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
10、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
11、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 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
12、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、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 gra
13、in） 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 materials Ventilation and Air conditioning systemsmarijuana 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 Aspergill
14、us hyphae,Immune dysfunction,Frequency of aspergillosis,Immune hyperactivity,Frequency of aspergillosis,Subacute IA,Aspergilloma Chronic 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 progre
15、ssion,Degree of immunocompromise,Risk of acquisition (and pace of progression),Normal immunity, high inoculum,HIV infection,Chronic leukaemia,Short course glucocorticoids,Acute respiratory infection, ie influenza,Temporary neutropenia,Long term glucocorticoids etc,Solid organ transplant + rejection
16、+ CMV,AIDS,Leukemia and profound neutropenia,Allogeneic stem cell transplant + GVHD,Relapsed/uncontrolled leukemia,5%,10%,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
17、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 aspergillomain 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
18、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 ABPA EAA Bronchialasthma with aspergillus sensitization,Simple (single) aspergilloma,Patient RKHaempotysis, nil else Positive Aspergillus antibodies in bloodLobectomy,
19、Simple (single) aspergilloma,Patient NMPositive Aspergillus antibodies in bloodLobectomy,August 2006 May 2009Community acquired New cough pneumonia requiring ICU care,Aspergilloma,4 years later,Bilateral pulmonary cavities in the upper lungs surrounded by circumferential pleural thickening and conta
20、ining aspergillomas,Pulmonary Aspergillosis,免疫功能正常 Normal immunity真菌球 或 空腔内 曲菌球fungal ball or aspergillomain 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 immuno
21、compromised慢性空腔性肺曲霉病+/- 曲菌球 Chronic cavitary pulmonary aspergillosis +/- fungal ball,免疫能亢进hypersensitivity ABPA EAA Bronchialasthma with 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
22、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) Atelectasis Lucency (air trapping),Central Bronchiectasis Mucoid Impaction,Gotway MB et al. Journal of Computer Assisted Tomography; 26(2):159-173,Criteria for d
23、iagnosis 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 Aspergillosis,免疫功能正常 Normal immunity真菌球 或 空腔内 曲菌球fungal ball or aspergillomain a pre-existing cavity,Exposure of the lung by Aspergillus,免疫缺陷-严重severe
24、 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 ABPA EAA Bronchialasthma with aspergillus sensitization,气道侵袭性病变(airway in
25、vasive 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 -Airway-invasive,Presence of Aspergillus organisms deep to airway basement membrane. Most commonly in neutropenic patients and AIDS patients Cli
26、nical manifestations include -Acute tracheobronchitis (可以发生在正常人群)normal radiologic findings/ tracheal or bronchial wall thickening-Bronchiolitiscentrilobular nodules and branching linear or nodular areas of increased attenuation having a “tree-in-bud“ appearance.-bronchopneumoniaperibronchial areas
27、of consolidation，rarely, lobar consolidation,Tait, Thorax 1993;48: 1285,Pseudomembranous Aspergillus tracheobronchitis,Wheezing 4 days before death,immunocompromised,Pseudomembranous Aspergillus tracheobronchitis with IPA in COPD,Bulpa Eur Resp J 2007;30:782,Invasive bronchiolar aspergillosis in a p
28、atient undergone bone marrow transplantation.-Thin-section CT shows peripheral branching structures associated with focal areas of consolidation -can also be seen in TB, MAC , viral, mycoplasma pneumonia. -aspergillus bronchopneumonia radiology indistinguishable from those of other bronchopneumonias
29、,Bronchopneumonia aspergillosis, (a) Conventional CT scan through the upper lungs shows a segmental area of consolidation in the right upper lobe with visible air bronchogram.,(b) Photograph of the corresponding autopsy specimen shows segmental consolidation,(c) High-power photomicrograph of a small
30、 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-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
31、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, 10-15% allogeneic BMT patients,Unequivocal Halo sign surrounding a nodule,Herbrecht, Denning et al, NEJM 2002;347:408-15.,Hal
32、o 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(1):70-73,Pulmonary nodules a useful feature if invasive pulmonary aspergillosis,CT features in 235 CTs in patients with
33、IPAMacronodule (1cm) 221 (94%) Halo 143 (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%) Pleural effusion 25 (11%) Air crescent sign 24 (10%) Non-specific ground glass 21 (9%),Brain Abscess
34、(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 aspergillomain 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 mode
35、rate 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 ABPA EAA Bronchialasthma with aspergillus sensitization,Chronic Necrotizing (Semi-invasive) Aspergillosis,Fungus is intermediate. No vascular invasion. Tissue necrosis and destructio
36、n. 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 debilitating illness Advanced age. Alcoholism, Malnutrition. DM, COPD. Prolonged steroid
37、therapy Radiation therapy. Inactive TB. Pneumoconiosis. Sarcoidosis.,Symptoms Often insidious and include chronic cough, sputum production, fever, and constitutional symptoms. Hemoptysis has been reported in 15% of affected patients . May manifest with chronic bronchitis and recurrent episodes of mi
38、ld 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 progress slowly over months or years.,Chronic Necrotizing (Semi-inva
39、sive) 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 aspergillosis,Chronic Necrotizing Aspergillosis in DM patient 15 mont
40、h 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 aspergilloma in a pre-existing cavity,Exposure of the lung by Aspergillus,Acute IA,Chronic cavitary pulmonary
41、aspergillosis +/- fungal ball,Chronic fibrosing pulmonary aspergillosis+/- fungal ball,Allergy,ABPA EAA,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,Signs and symptoms,Cultures/ histopathology
42、,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 for Aspergillosis The importance of
43、 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,Invasive aspergillosis C
44、urrent first-line treatment guidelines,Walsh TJ, et al. Clin Infect Dis 2008;46:32760. Prentice AG, et al. . http:/ Maertens J et al. Bone Marrow Transplantation 2011; 46:70918 Bohme A et al. Ann Hematol 2009;88:97110 Thursky KA, et al. Intern Med J 2008;38:496520.,Diversity of Pulmonary Aspergillos
45、is,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 ）
46、Chronic cavitary (necrotizing) pulmonary-semi-invasiveChronic fibrosing pulmonary aspergillosisChronic invasive sinusitis Maxillary (sinus) aspergilloma,AllergicAllergic 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
47、 sinusitis,Immune status,Immune dysfunction,Frequency of aspergillosis,Immune hyperactivity,Frequency of aspergillosis,Subacute IA,Aspergilloma Chronic 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,Invasiveaspergillosis,Chronic pulmonary,Allergicaspergillosis,.,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,
