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1、肺隐球菌病（PC，pulmonary cryptococcosis ） -从一个病例谈起,复旦大学附属华山医院北院呼吸科 张有志,病史介绍,患者，女性，47岁 主述：因“反复咳嗽伴胸痛1月”入院（B院） 现病史：患者于2010.9.5无明显诱因出现咳嗽，少量白痰，伴右侧胸痛，阵发性钝痛，深吸气时明显，无放射痛，无发热，无呕吐、头痛，某A院行胸部CT示“右下肺炎”，予以莫西沙星静滴8天患者咳嗽、胸痛有所缓解，继续口服莫西沙星6天，2010.9.27复查CT无吸收。于2010.10.12就诊B院。 既往：体健。否认性病冶游史。家中曾养宠物（鸽子、狗）。 查体：T：37.9 ，浅表淋巴结不大，右下肺
2、可及湿啰音。 辅助检查： 血常规、肝肾功能、D-二聚体正常；ESR：65mm/h，CRP：48mg/L；血气分析正常；HIV（-） PPD试验阴性；LA试验、G试验阴性（送至C院检测）,2010.9.6 A院CT,2010.9.27 A院CT,病史介绍,A院气管镜检查： 镜下：未见明显异常； 右下肺灌洗和刷检：未见恶性细胞、TB阴性。,2010.10.12 B院 CT引导下经皮肺穿刺,病理结果确诊： 肺隐球菌病 上皮样肉芽肿性病变； 成堆隐球菌,几点疑问,真菌病一般都是免疫功能低下的患者 隐球菌如何侵袭到肺的 LA试验阴性 肺隐球菌病CT表现和肺炎一样,关于隐球菌,带厚荚膜的酵母菌（乳胶凝集试
3、验） 腐生菌：土壤、鸽粪、霉烂蔬菜、水果等 感染部位：中枢神经系统、皮肤、肺 感染途径：吸入呼吸道经血行播散到其它部位 分型：17个种、18个变种 （新生隐球菌及变种具有致病性）,Epidemiology I,A multicentre retrospective study of pulmonary mycosis clinically proven from 1998 to 2007 Totally 474 cases of pulmonary mycosis from 16 centers in10 cities. pulmonary aspergillosis(1 80 cases，3
4、79) pulmonary candidiasis(162 cases，342) pulmonary cryptococcosis(74 cases，156) pneumocystis cafinii pneumonia(23 cases，4.8) pulmonary mucormycosis(10 cases，21) 中华结核和呼吸杂志，2011,34(2),Epidemiology II,Meta-Analysis of Clinical Manifestations of Pulmonary Cryptococcosis in China Mainland 69.7 % patients
5、 had no underlying diseases The common underlying diseases were acquired immune deficiency syndrome( AIDS) diabetes malignant tumor 中国临床医学，2013,20（3）：351-354,Epidemiology III,Retrospective investigation of 151 pulmonary cryptococcosis non-HIV cases between 1977 and 2012 44.4% patients had no UDs. Th
6、e common UDs were diabetes (32.1%) hematologic disease (22.6%) collagen disease (22.6%) Japanese Society of Chemotherapy and The Japanese Association for Infectious Diseases .J Infect Chemother. 2014 Oct 29,Epidemiology IV,219 patients with proven cryptococcosis at 20 hospitals in Taiwan, 1997-2010
7、210 isolates were C. neoformans (95.9%); 9 isolates were C. gattii (4.1%). 15.4% did not have any underlying condition. HIV infection was the most common underlying condition (54/219, 24.6%). Among HIV-negative patients, liver diseases (HBV carrier or cirrhosis) were common (30.2%) Taiwan Infectious
8、 Diseases Study Network for Cryptococcosis. PLoS One. 2013 Apr 17;8(4):e61921.,Epidemiology V,Clinical analysis of 76 patients pathologically diagnosed with pulmonary cryptococcosis. Of 76 patients (54 males and 22 females), 41 (53.95%) were immunocompetent and 35 out of the 41 were asymptomatic. Sh
9、anghai Pulmonary Hospital .Eur Respir J. 2012 Nov;40(5):1191-200.,summary,approximately half of patients had no underlying diseases a significant number of patients were asymptomatic,pathogenesis,The capsule is the most important virulence factor of the fungal pathogen Cryptococcus neoformans. The s
10、tructure Production Of the capsule adhesion of Cryptococcus neoformans to epithelial lung cells protective immune responses against cryptococcosis,The structure of capsule,This structure consists of highly hydrated polysaccharides, including glucuronoxylomannan (GXM)，葡萄糖醛酸木糖甘露聚糖 galactoxylomannan (G
11、alXM) ，半乳糖木糖甘露聚糖 mannoproteins (MPs)，甘露糖蛋白，less than 1% of the capsular weight,Production Of the capsule I,CA/CO2-sensing pathways . 1 Regulation of capsule synthesis by carbon dioxide J Clin Invest， 1985， 76( 2) : 508-516 2 Comparative transcriptome analysis of the CO2 sensing pathway via different
12、ial expression of carbonic anhydrase in Cryptococcus neoformans.Genetics. 2010 Aug;185(4):1207-19.,Production Of the capsule II,cryptococcal polysaccharide synthesis is increased by limitation of ferric iron availability to the cell and by dissolved CO2, and the two effects are additive. Regulation
13、of cryptococcal capsular polysaccharide by iron. J Infect Dis. 1993 Jan;167(1):186-90.,Production Of the capsule III,capsule enlargement in living C. neoformans cells was influenced by Ca(2+) in the culture medium. Eukaryot Cell. 2007 Aug;6(8):1400-10.,Production Of the capsule IV,based on the axial
14、 lengthening of PS molecules. Capsule of Cryptococcus neoformans grows by enlargement of polysaccharide molecules.Proc Natl Acad Sci U S A. 2009 Jan 27;106(4):1228-33. PS，etc capsule?,alveolar microenvironment,adhesion to epithelial lung cells,an adhesion-like interaction between MP on the fungal su
15、rface and the complementary receptor molecules on the epithelial cells. Front Cell Infect Microbiol. 2014 Aug 19;4:106.,Phagocytosis defence,Size of Cryptococcus neoformans. Dynamic changes in the morphology of Cryptococcus neoformans during murine pulmonary infection. GXM against alveolar macrophag
16、es (AM) . Mechanisms of immune evasion in fungal pathogens. 1 Microbiology. 2001 Aug;147(Pt 8):2355-65. 2 Curr Opin Microbiol. 2011 Dec;14(6):668-75.,immune response,SP-D increases susceptibility to C. neoformans infection by promoting C. neoformans-driven pulmonary IL-5 and eosinophil infiltration. Th1/Th2 cytokine imbalance. B cells provide a first line of defense during pulmonary C. neoformans infection in mice 1 Genet Mol Res. 2013 Nov 18;12(4)
