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。
关于隐球菌Ｃｒｙｐｔｏｃｏｃｃｕｓ
• 带厚荚膜的酵母菌（乳胶凝集试验） • 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
• 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):5733-42 2 Inቤተ መጻሕፍቲ ባይዱect Immun. 2014 Feb;82(2):683-93
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.
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. • The common UDs were ➢diabetes (32.1%) ➢hematologic disease (22.6%) ➢collagen disease (22.6%)
➢ 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
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 differential expression of carbonic anhydrase in Cryptococcus neoformans.Genetics. 2010 Aug;185(4):1207-19.
PS，etc alveolar microenvironment
capsule?
adhesion to epithelial lung cells
• an adhesion-like interaction between MP on the fungal surface and the complementary receptor molecules on the epithelial cells.
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
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 (GalXM) ，半乳糖木糖 甘露聚糖 • mannoproteins (MPs)，甘露糖蛋白，less than 1% of the capsular weight
immune response
• SP-D increases susceptibility to C. neoformans infection by promoting C. neoformans-driven pulmonary IL-5 and eosinophil infiltration.
Shanghai 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
Totally 474 cases of pulmonary mycosis from 16 centers in10 cities.
• pulmonary aspergillosis(1 80 cases，37．9％) • pulmonary candidiasis(162 cases，34．2％) • pulmonary cryptococcosis(74 cases，15．6％) • pneumocystis cafinii pneumonia(23 cases，4.8％) • pulmonary mucormycosis(10 cases，2．1％)
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
condition (54/219, 24.6%). • Among HIV-negative patients, liver diseases (HBV
carrier or cirrhosis) were common (30.2%)
Taiwan Infectious Diseases Study Network for Cryptococcosis. PLoS One. 2013 Apr 17;8(4):e61921.
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.
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.
pathogenesis
The capsule is the most important virulence factor of the fungal pathogen Cryptococcus neoformans. • The structure • Production Of the capsule • adhesion of Cryptococcus neoformans to epithelial lung cells • protective immune responses against cryptococcosis
Eukaryot Cell. 2007 Aug;6(8):1400-10.
Production Of the capsule IV
• based on the axial 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.