1、肺隱球菌?。≒C，pulmonary cryptococcosis ）-從一個(gè)病例談起,復(fù)旦大學(xué)附屬華山醫(yī)院北院呼吸科 張有志,病史介紹,患者，女性，47歲 主述：因“反復(fù)咳嗽伴胸痛1月”入院（B院） 現(xiàn)病史：患者于2010.9.5無(wú)明顯誘因出現(xiàn)咳嗽，少量白痰，伴右側(cè)胸痛，陣發(fā)性鈍痛，深吸氣時(shí)明顯，無(wú)放射痛，無(wú)發(fā)熱，無(wú)嘔吐、頭痛，某A院行胸部CT示“右下肺炎”，予以莫西沙星靜滴8天患者咳嗽、胸痛有所緩解，繼續(xù)口服莫西沙星6天，2010.9.27復(fù)查CT無(wú)吸收。于2010.10.12就診B院。 既往：體健。否認(rèn)性病冶游史。家中曾養(yǎng)寵物（鴿子、狗）。 查體：T：37.9 ，淺表淋巴結(jié)不大，右下肺可

2、及濕啰音。 輔助檢查： 血常規(guī)、肝腎功能、D-二聚體正常；ESR：65mm/h，CRP：48mg/L；血?dú)夥治稣?；HIV（-） PPD試驗(yàn)陰性；LA試驗(yàn)、G試驗(yàn)陰性（送至C院檢測(cè)）,2010.9.6 A院CT,2010.9.27 A院CT,病史介紹,A院氣管鏡檢查： 鏡下：未見(jiàn)明顯異常； 右下肺灌洗和刷檢：未見(jiàn)惡性細(xì)胞、TB陰性。,2010.10.12 B院CT引導(dǎo)下經(jīng)皮肺穿刺,病理結(jié)果確診： 肺隱球菌病 上皮樣肉芽腫性病變； 成堆隱球菌,幾點(diǎn)疑問(wèn),真菌病一般都是免疫功能低下的患者 隱球菌如何侵襲到肺的 LA試驗(yàn)陰性 肺隱球菌病CT表現(xiàn)和肺炎一樣,關(guān)于隱球菌,帶厚莢膜的酵母菌（乳膠凝集試驗(yàn)）

3、 腐生菌：土壤、鴿糞、霉?fàn)€蔬菜、水果等 感染部位：中樞神經(jīng)系統(tǒng)、皮膚、肺 感染途徑：吸入呼吸道經(jīng)血行播散到其它部位 分型：17個(gè)種、18個(gè)變種 （新生隱球菌及變種具有致病性）,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，379

4、) pulmonary candidiasis(162 cases，342) pulmonary cryptococcosis(74 cases，156) pneumocystis cafinii pneumonia(23 cases，4.8) pulmonary mucormycosis(10 cases，21) 中華結(jié)核和呼吸雜志，2011,34(2),Epidemiology II,Meta-Analysis of Clinical Manifestations of Pulmonary Cryptococcosis in China Mainland 69.7 % patients h

5、ad no underlying diseases The common underlying diseases were acquired immune deficiency syndrome( AIDS) diabetes malignant tumor 中國(guó)臨床醫(yī)學(xué)，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

6、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 21

7、0 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 D

8、iseases 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. Shan

9、ghai 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 str

10、ucture 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 (Gal

11、XM) ，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 differentia

12、l 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 of

13、 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 l

14、engthening 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 surf

15、ace 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 macrophages

16、 (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. T

17、h1/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 Infect Immun. 2014 Feb;82(2):683-93 3 J Immunol. 2012 Dec 15;189(12):5820-30,My opinion i,Change alveolar microenvironment Abrogation of IL

18、-4 receptor-dependent alternatively activated macrophages is sufficient to confer resistance against pulmonary cryptococcosis despite an ongoing T(h)2 response. Int Immunol. 2013 Aug;25(8):459-70.,Radiology I,Peripherally distributed pulmonary nodules/masses were most commonly seen. Japanese Society

19、 of Chemotherapy and The Japanese Association for Infectious Diseases .J Infect Chemother. 2014 Oct 29 Radiological (computed tomography) findings showed predominantly peripheral findings (85.53%) including nodular masses (55.26%), pneumonic infiltrates (23.68%) and mixed type (21.05%). Shanghai Pul

20、monary Hospital .Eur Respir J. 2012 Nov;40(5):1191-200. 71.8 % patients were characterized by nodular lump shadows; 23.8 % by flake-like infiltrated shadows，and 7.4 % had diffuse mixed lesions Zhongshan Hospital .Chinese Journal of Clinical Medicine， 2013,Radiology II,CT scan findings of 29 immunoco

21、mpetent and 43 immunocompromised patients Pulmonary nodules/masses, either solitary or multiple, were the most common CT finding, present in 65 (90.3%) of the 72 patients Cavitations within nodules/masses were more commonly seen in immunocompromised patients, especially AIDS patients air bronchogram

22、s were more commonly seen in immunocompetent patients Pulmonary cryptococcosis: comparison of CT findings in immunocompetent and immunocompromised patients. Acta Radiol. 2014 Apr 22.,My opinion ii,Molecular/functional radiology,current situation in diagnosis,43.42% (33 / 76) were initially misdiagnosed, often as cancer by false-positive (18)FDG-PET Failure of the cryptococcal se