器官移植受者侵袭性真菌病临床诊疗技术规范（2019版）

中华医学会器官移植学分会

doi:10.3969/j.issn.1674-7445.2019.03.002

器官移植受者侵袭性真菌病临床诊疗技术规范（2019版）

doi: 10.3969/j.issn.1674-7445.2019.03.002

中华医学会器官移植学分会^,

100039 北京，中国人民解放军总医院第八医学中心器官移植研究所（石炳毅）；广州医科大学第一医院（巨春蓉）

基金项目:

国家自然科学基金 81570680

国家自然科学基金 81571555

详细信息

通讯作者:
石炳毅，Email：shibingyi666@126.com

中图分类号: R617, R519
计量
- 文章访问数: 1021
- HTML全文浏览量: 649
- PDF下载量: 254
- 被引次数: 0
出版历程
- 收稿日期: 2019-02-15
- 网络出版日期: 2021-01-19
- 刊出日期: 2019-05-15

Technical specifcation for clinical diagnosis and treatment for invasive fungal disease in organ transplant recipients (2019 edition)

Branch of Organ Transplantation of Chinese Medical Association^,

摘要

摘要: 为了进一步规范实体器官移植（SOT）受者侵袭性真菌病（IFD）的诊断和治疗，中华医学会器官移植学分会结合近期国内外临床证据，从SOT受者IFD的流行病学特点、诊断、预防、治疗等方面，在2017年版《器官移植受者侵袭性真菌病临床诊疗指南》的基础上制定本规范，以期为器官移植和相关学科的同道提供帮助。
- 侵袭性真菌病 /
- 器官移植 /
- 假丝酵母菌 /
- 曲霉 /
- 隐球菌

HTML全文

图 1 SOT受者肺曲霉病及支气管-肺曲霉病高分辨率CT的不同表现

A图为肺移植术后患者，CT显示片状空腔实变伴有小结节（箭头所示）；B图为心脏移植术后患者，支气管-肺曲霉病，轴向CT显示细支气管周围结节（箭头所示），与支气管-肺曲霉病表现一致，通过气管镜诊断为曲霉感染

Figure 1. Different manifestations of high-resolution CT in SOT recipients with pulmonary aspergillosis and broncho-pulmonary aspergillosis

下载: 全尺寸图片幻灯片

图 2 肾移植受者术后曲霉感染的影像学演变过程

A图示远端支气管实变和结节；B图示小叶中心结节伴有晕轮；C图示数日至数周的治疗后演变成空腔

Figure 2. Imaging evolution of aspergillus infection in recipients after renal transplantation

下载: 全尺寸图片幻灯片

图 3 肺假丝酵母菌病的影像学表现

主要表现为双肺多发结节、斑片状或融合性实变区、磨玻璃样渗出影及光晕征

Figure 3. Imaging performance of pulmonary candidiasis

下载: 全尺寸图片幻灯片

图 4 肾移植术后播散性隐球菌病的影像学表现

A图示肺隐球菌病在CT表现为肺部结节影；B图示脑隐球菌病肉芽肿性病变的头颅MRI表现；C图示脑隐球菌病囊肿样改变的头颅MRI表现

Figure 4. Imaging findings of disseminated cryptococcosis after renal transplantation

下载: 全尺寸图片幻灯片

表 1 常见IFD的病原菌、发生率及患者病死率

Table 1. Pathogenic fungus, incidence and fatality rate of patients with common IFD

病原菌	发病率	常见菌群	起病时间	好发对象	临床表现	病死率
假丝酵母菌	侵袭性假丝酵母菌病全球发病率2%~4%。除肺移植外，侵袭性假丝酵母菌病占IFD的53%~59%	白假丝酵母菌、光滑假丝酵母菌、近平滑假丝酵母菌、热带假丝酵母菌、克柔假丝酵母菌	好发于移植后1个月内	在腹腔SOT中更常见，而少或罕见于心、肺移植	假丝酵母菌血症	移植后1年内侵袭性假丝酵母菌病总的病死率达34%
曲霉	侵袭性曲霉病的发病率为0.1%~3.5%。除肺移植外，侵袭性曲霉病占18%~30%（肺移植后感染比例可达44%~63%）	常见烟曲霉感染，其次为黄曲霉、黑曲霉和土曲霉	一般在移植2~3个月后发病，中位发病时间为移植后6个月	最常见于肺移植	临床一般表现为急性侵袭性肺部感染	病死率高达67%~82%
隐球菌	欧美国家发生侵袭性隐球菌病的比例是0~1.5%。除肺移植外，侵袭性隐球菌病约占8%		典型的晚发型感染，一般起病于移植后16~21个月	肾脏和心脏移植	一半以上受者表现为播散性疾病，累及中枢神经系统，33%会出现真菌血症	病死率为14%~27%

下载: 导出CSV

表 2 不同SOT受者人群发生IFD的危险因素

Table 2. Risk factors of IFD in different SOT recipients

移植器官	发生IFD的危险因素
	假丝酵母菌	曲霉		接合菌
	假丝酵母菌	早期	晚期（移植后＞4个月）	接合菌
肾		移植物功能丧失和血液透析；移植后血液透析；长时间大剂量使用糖皮质激素；巨细胞病毒感染；过度免疫抑制	巨细胞病毒感染；过度免疫抑制
肝	手术时间延长或重复操作；再次移植；假丝酵母菌定植；胆总管空肠吻合术；术中大量输血	再次移植；肾衰竭（尤其是移植后血液透析）；暴发性肝衰竭；手术复杂或再次手术；使用单抗药物	移植后第3个月内泼尼松使用量累计 > 6 g；移植后肾衰竭；移植后血液透析；白细胞减少（< 0.5×10⁹/L）；移植物慢性功能丧失	肾衰竭；排斥反应和过度免疫抑制；糖皮质激素；控制不佳的糖尿病；持续中性粒细胞减少；使用铁螯合剂如去铁胺；镰刀菌病；巨噬细胞功能减退
肺	长时间使用广谱抗生素；中心静脉导管；血液透析	支气管吻合口缺血或支架置换；急性排斥反应；单肺移植；移植前或移植后1年内曲霉定植	移植物慢性功能丧失
心	长时间使用广谱抗生素；中心静脉导管；血液透析	呼吸道曲霉定植；再次手术；移植后血液透析；低丙种球蛋白血症（IgG < 4 g/L）	再入重症监护室；肾移植；急性排斥反应 > 2次
胰腺	空肠内引流；静脉血栓；输血后胰腺炎
小肠	排斥反应或移植物功能丧失；吻合口破裂；多器官联合移植

下载: 导出CSV

表 3 临床诊断IFD的依据

Table 3. Clinical diagnosis basis of IFD

项目	诊断依据
宿主因素	（1）近期发生中性粒细胞缺乏（中性粒细胞计数＜0.5×10⁹/L）并持续10 d以上（2）接受异基因造血干细胞移植（3）应用糖皮质激素超过3周[0.3 mg/（kg·d）以上，变应性支气管肺曲霉病除外] （4）90 d内应用过抗T淋巴细胞制剂（如肿瘤坏死因子-α，多克隆抗淋巴细胞免疫球蛋白、阿仑单抗等）或核苷类似物（5）IFD病史（6）受者同时患有艾滋病或遗传性免疫缺陷（如慢性肉芽肿或联合免疫缺陷病）
临床标准	（1）肺真菌病。CT检查至少存在以下三项之一：①致密、边界清楚的病变，伴或不伴晕征；②空气新月征；③空洞（2）气道真菌病。支气管镜检发现以下表现：气管和支气管溃疡、结节、伪膜、斑块或结痂（3）鼻窦真菌病。至少符合以下一项：①局部出现急性疼痛（包括放射至眼部的疼痛）；②鼻部溃疡伴黑痂；③从鼻窦侵蚀骨质，包括扩散至颅内（4）中枢神经系统真菌病。至少符合以下一项：①影像学检查提示局灶性病变；②MRI或CT检查提示脑膜强化（5）播散性假丝酵母菌病。此前2周内出现假丝酵母菌血症，并伴有以下至少一项：①肝或脾牛眼征；②眼科检查提示进展性视网膜渗出
微生物标准	（1）直接检查（细胞学、直接镜检或培养）：①在痰、支气管肺泡灌洗液、支气管刷取物、窦吸取物中发现至少以下一项提示曲霉感染，即发现真菌成分显示为曲霉或培养提示曲霉；②痰或支气管肺泡灌洗液经培养新型隐球菌阳性或经直接镜检、细胞学检查发现隐球菌（2）间接检查（检测抗原或细胞壁成分）：①曲霉，血浆、血清、支气管肺泡灌洗液或脑脊液检测半乳甘露聚糖抗原阳性；②侵袭性真菌（3）血浆、血清、支气管肺泡灌洗液检测隐球菌荚膜多糖抗原阳性

下载: 导出CSV

表 4 SOT受者靶向预防真菌感染用药

Table 4. Targeted use of drug to prevent fungal infection in SOT recipients

移植器官	靶向人群	抗真菌药选择	疗程
肾脏	不需要
肝脏	高危人群（1）主要因素：①再次行移植手术、暴发性肝衰竭、MELD≥30分；②肾衰竭，需要替代治疗（2）次要因素：①MELD 20~30分、劈离式、活体供者、Roux-en-Y胆总管空肠吻合术；②输血过多（血细胞组分制品≥40 U）；③肾衰竭，不需要替代治疗（肌酐清除率 < 50 mL/min）；④早期再次介入治疗、假丝酵母菌多点定植或感染	存在1个主要或2个次要因素：（1）米卡芬净（2）卡泊芬净（3）两性霉素B脂质体	2~4周或至危险因素去除
胰腺	所有移植受者	氟康唑	1~2周
小肠	所有移植受者高危因素（1）急性排斥反应和初始移植物功能低下（2）血液透析（3）移植后再行剖腹手术、吻合口异常	氟康唑存在高危因素者：（1）两性霉素B脂质体（2）卡泊芬净（3）米卡芬净	3~4周或至吻合口愈合和排斥反应消失存在高危因素者：（1）疗程取决于危险因素是否去除（2）至吻合口愈合和排斥反应消失
肺或心肺	推荐所有移植受者预防或指导性预防用药对象：（1）使用阿伦单抗或抗胸腺细胞球蛋白（2）急性排斥反应（3）单肺移植（4）曲霉定植（移植前或移植后1年内）（5）获得性低丙种球蛋白血症（IgG < 4 g/L）	预防用药：（1）雾化两性霉素B脂质体25 mg至支气管吻合口愈合，每周3次（2）2~6个月为每周1次（3） > 6个月时每2周1次指导性预防用药：负荷剂量25 mg，每周3次，2周后每周1次	预防用药：使用雾化两性霉素B脂质体没有限制，或至少用12个月指导性预防用药：用至危险因素去除
心脏	高危移植受者：（1）急性排斥反应血液透析（2）移植后再次手术（3）气道内曲霉大量定植	伊曲康唑	至少3个月
MELD为终末期肝病模型评分

下载: 导出CSV

参考文献(41)

[1]	中国侵袭性真菌感染工作组.血液病/恶性肿瘤患者侵袭性真菌病的诊断标准与治疗原则(第四次修订版)[J].中华内科杂志, 2013, 52(8):704-709. DOI: 10.3760/cma.j.issn.0578-1426.2013.08.030. Chinese Invasive Fungal Infection Working Group. Diagnosis standard and treatment principle of invasive fungal diseases in patients with hematological malignancy/malignant tumors (fourth revised edition)[J]. Chin J Intern Med, 2013, 52(8):704-709. DOI: 10.3760/cma.j.issn.0578-1426.2013.08.030.
[2]	GROSSI PA, GASPERINA DD, BARCHIESI F, et al. Italian guidelines for diagnosis, prevention, and treatment of invasive fungal infections in solid organ transplant recipients[J]. Transplant Proc, 2011, 43(6):2463-2471. DOI: 10.1016/j.transproceed.2011.06.020.
[3]	中华医学会器官移植学分会.实体器官移植患者侵袭性真菌感染的诊断和治疗指南[J].中华器官移植杂志, 2009, 30(7):440-441.DOI: 10.3760/cma.j.issn.0254-1785.2009.07.016. Branch of Organ Transplantation of Chinese Medical Association. Diagnosis and treatment guideline of invasive fungal infections in solid organ transplant recipients[J]. Chin J Organ Transplant, 2009, 30(7):440-441. DOI: 10.3760/cma.j.issn.0254-1785.2009.07.016.
[4]	中华医学会器官移植学分会.实体器官移植患者侵袭性真菌感染的诊断和治疗指南(续)[J].中华器官移植杂志, 2009, 30(8):503-506.DOI: 10.3760/cma.j.issn.0254-1785.2009.08.017. Branch of Organ Transplantation of Chinese Medical Association. Diagnosis and treatment guideline of invasive fungal infections in solid organ transplant recipients (continue) [J]. Chin J Organ Transplant, 2009, 30(8):503-506. DOI: 10.3760/cma.j.issn.0254-1785.2009.08.017.
[5]	CASTANHEIRA M, MESSER SA, DIETRICH RR, et al. Antifungal susceptibility patterns of a global collection of fungal isolates and polysorbate-80 effect on the susceptibility of the antifungal classes[C]. Philadelphia: Week Meeting of the Infectious Diseases Society of America, 2014: 1454.
[6]	PAPPAS PG, KAUFFMAN CA, ANDES DR, et al. Clinical practice guideline for the management of candidiasis: 2016 update by the Infectious Diseases Society of America[J]. Clin Infect Dis, 2016, 62(4): e1-e50. DOI: 10.1093/cid/civ933.
[7]	PERFECT JR, DISMUKES WE, DROMER F, et al. Clinical practice guidelines for the management of cryptococcal disease: 2010 update by the Infectious Diseases Society of America[J]. Clin Infect Dis, 2010, 50(3):291-322. DOI: 10.1086/649858.
[8]	PATTERSON TF, THOMPSON GR 3RD, DENNING DW, et al. Practice guidelines for the diagnosis and management of aspergillosis: 2016 update by the Infectious Diseases Society of America[J]. Clin Infect Dis, 2016, 63(4):e1-e60. DOI: 10.1093/cid/ciw326.
[9]	GAVALDÀ J, MEIJE Y, FORTÚN J, et al. Invasive fungal infections in solid organ transplant recipients[J]. Clin Microbiol Infect, 2014, 20(Suppl 7):27-48. DOI: 10.1111/1469-0691.12660.
[10]	DE PAUW B, WALSH TJ, DONNELLY JP, et al. Revised definitions of invasive fungal disease from the European Organization for Research and Treatment of Cancer/Invasive Fungal Infections Cooperative Group and the National Institute of Allergy and Infectious Diseases Mycoses Study Group (EORTC/MSG) Consensus Group[J]. Clin Infect Dis, 2008, 46(12):1813-1821. DOI: 10.1086/588660.
[11]	PAPPAS PG, ALEXANDER BD, ANDES DR, et al. Invasive fungal infections among organ transplant recipients: results of the Transplant-Associated Infection Surveillance Network (TRANSNET) [J]. Clin Infect Dis, 2010, 50(8):1101-1111. DOI: 10.1086/651262.
[12]	NEOFYTOS D, FISHMAN JA, HORN D, et al. Epidemiology and outcome of invasive fungal infections in solid organ transplant recipients[J]. Transpl Infect Dis, 2010, 12(3):220-229. DOI: 10.1111/j.1399-3062.2010.00492.x.
[13]	蒋进发, 魏思东, 张宇, 等.肝脏移植术后侵袭性真菌感染的临床特点分析[J].中华医院感染学杂志, 2014, 24(8):1998-2000.DOI: 10.11816/cn.ni.2014-135058. JIANG JF, WEI SD, ZHANG Y, et al. The clinical characteristics of invasive fungal infections after liver transplantation[J]. Chin J Nosocomiol, 2014, 24(8):1998-2000. DOI: 10.11816/cn.ni.2014-135058.
[14]	ZICKER M, COLOMBO AL, FERRAZ-NETO BH, et al.Epidemiology of fungal infections in liver transplant recipients: a six-year study of a large Brazilian liver transplantation centre[J]. Mem Inst Oswaldo Cruz, 2011, 106(3):339-345. doi: 10.1590/S0074-02762011000300014
[15]	LORTHOLARY O, GANGNEUX JP, SITBON K, et al.Epidemiological trends in invasive aspergillosis in France: the SAIF network (2005-2007) [J]. Clin Microbiol Infect, 2011, 17(12):1882-1889. DOI: 10.1111/j.1469-0691.2011.03548.x.
[16]	MUÑOZ P, CERÓN I, VALERIO M, et al. Invasive aspergillosis among heart transplant recipients: a 24-year perspective[J]. J Heart Lung Transplant, 2014, 33(3):278-288. DOI: 10.1016/j.healun.2013.11.003.
[17]	BODRO M, SABÉ N, GOMILA A, et al. Risk factors, clinical characteristics, and outcomes of invasive fungal infections in solid organ transplant recipients[J]. Transplant Proc, 2012, 44(9):2682-2685. DOI: 10.1016/j.transproceed.2012.09.059.
[18]	FORTÚN J, MARTÍN-DÁVILA P, MORENO S, et al. Risk factors for invasive aspergillosis in liver transplant recipients[J]. Liver Transpl, 2002, 8(11):1065-1070. doi: 10.1053/jlts.2002.36239
[19]	FISHMAN JA, ISSA NC. Infection in organ transplantation: risk factors and evolving patterns of infection[J]. Infect Dis Clin North Am, 2010, 24(2):273-283. DOI: 10.1016/j.idc.2010.01.005.
[20]	FORTÚN J, MEIJE Y, FRESCO G, et al. Aspergillosis. clinical forms and treatment[J]. Enferm Infecc Microbiol Clin, 2012, 30(4):201-208. DOI: 10.1016/j.eimc.2011.12.005.
[21]	MONFORTE V, ROMAN A, GAVALDA J, et al. Nebulized amphotericin B prophylaxis for aspergillus infection in lung transplantation: study of risk factors[J]. J Heart Lung Transplant, 2001, 20(12):1274-1281. doi: 10.1016/S1053-2498(01)00364-3
[22]	MUÑOZ P, RODRÍGUEZ C, BOUZA E, et al. Risk factors of invasive aspergillosis after heart transplantation: protective role of oral itraconazole prophylaxis[J]. Am J Transplant, 2004, 4(4):636-643. doi: 10.1111/ajt.2004.4.issue-4
[23]	RUIZ-CAMPS I, AGUADO JM, ALMIRANTE B, et al. Guidelines for the prevention of invasive mould diseases caused by filamentous fungi by the Spanish Society of Infectious Diseases and Clinical Microbiology (SEIMC) [J].Clin Microbiol Infect, 2011, 17 (Suppl 2):1-24. DOI: 10.1111/j.1469-0691.2011.03477.x.
[24]	GAVALDÀ J, VIDAL E, LUMBRERAS C. Infection prevention in solid organ transplantation[J]. Enferm Infecc Microbiol Clin, 2012, 30 (Suppl 2):27-33. DOI: 10.1016/S0213-005X(12)70079-4.
[25]	GAVALDÀ J, MEIJE Y, LEN Ó, et al. Invasive fungal infection in solid organ transplant[J]. Enferm Infecc Microbiol Clin, 2012, 30(10):645-653. DOI: 10.1016/j.eimc.2012.09.004.
[26]	SALIBA F, DELVART V, ICHAÏ P, et al. Fungal infections after liver transplantation: outcomes and risk factors revisited in the MELD era[J]. Clin Transplant, 2013, 27(4): E454-E461. DOI: 10.1111/ctr.12129.
[27]	AGUADO JM, RUIZ-CAMPS I, MUÑOZ P, et al. Guidelines for the treatment of invasive candidiasis and other yeasts. Spanish Society of Infectious Diseases and Clinical Microbiology (SEIMC). 2010 update[J]. Enferm Infecc Microbiol Clin, 2011, 29(5):345-361. DOI: 10.1016/j.eimc.2011.01.008.
[28]	AGUADO JM, VARO E, USETTI P, et al. Safety of anidulafungin in solid organ transplant recipients[J]. Liver Transpl, 2012, 18(6):680-685. DOI: 10.1002/lt.23410.
[29]	SUN HY, CACCIARELLI TV, SINGH N. Micafungin versus amphotericin B lipid complex for the prevention of invasive fungal infections in high-risk liver transplant recipients[J]. Transplantation, 2013, 96(6):573-578. DOI: 10.1097/TP.0b013e31829d674f.
[30]	SALIBA F, FISCHER L, PASCHER A, et al. Micafungin as antifungal prophylaxis in high-risk liver transplantation: randomised multicentre trial [C]. Vienna: 16th Congress of the European Society for Organ Transplantation, 2013: 217.
[31]	SALIBA F, FISCHER L, PASCHER A, et al. Efficacy and safety of micafungin as antifungal prophylaxis in high-risk liver transplantation [C]. Denver: 53rd International Congress on Antimicrobial Agents and Chemotherapy (ICAAC), 2013: 810.
[32]	SAN-JUAN R, AGUADO JM, LUMBRERAS C, et al. Universal prophylaxis with fluconazole for the prevention of early invasive fungal infection in low-risk liver transplant recipients[J]. Transplantation, 2011, 92(3):346-350. DOI: 10.1097/TP.0b013e3182247bb4.
[33]	MONFORTE V, LÓPEZ-SÁNCHEZ A, ZURBANO F, et al. Prophylaxis with nebulized liposomal amphotericin B for aspergillus infection in lung transplant patients does not cause changes in the lipid content of pulmonary surfactant[J]. J Heart Lung Transplant, 2013, 32(3):313-319. DOI: 10.1016/j.healun.2012.11.013.
[34]	LUONG ML, HOSSEINI-MOGHADDAM SM, SINGER LG, et al. Risk factors for voriconazole hepatotoxicity at 12 weeks in lung transplant recipients[J]. Am J Transplant, 2012, 12(7):1929-1935. DOI: 10.1111/j.1600-6143.2012.04042.x.
[35]	SINGER JP, BOKER A, METCHNIKOFF C, et al. High cumulative dose exposure to voriconazole is associated with cutaneous squamous cell carcinoma in lung transplant recipients[J]. J Heart Lung Transplant, 2012, 31(7):694-699. DOI: 10.1016/j.healun.2012.02.033.
[36]	ZWALD FO, SPRATT M, LEMOS BD, et al. Duration of voriconazole exposure: an independent risk factor for skin cancer after lung transplantation[J]. Dermatol Surg, 2012, 38(8):1369-1374. DOI: 10.1111/j.1524-4725.2012.02418.x.
[37]	EPAULARD O, VILLIER C, RAVAUD P, et al. A multistep voriconazole-related phototoxic pathway may lead to skin carcinoma: results from a French nationwide study[J]. Clin Infect Dis, 2013, 57(12): e182-e188. DOI: 10.1093/cid/cit600.
[38]	CORNELY OA, BASSETTI M, CALANDRA T, et al. ESCMID* guideline for the diagnosis and management of Candida diseases 2012: non-neutropenic adult patients[J]. Clin Microbiol Infect, 2012, 18 (Suppl 7):19-37. DOI: 10.1111/1469-0691.12039.
[39]	NETT JE, ANDES DR. Antifungal agents: spectrum of activity, pharmacology, and clinical indications[J]. Infect Dis Clin North Am, 2016, 30(1):51-83. DOI: 10.1016/j.idc.2015.10.012.
[40]	SHOHAM S, MARR KA. Invasive fungal infections in solid organ transplant recipients[J]. Future Microbiol, 2012, 7(5):639-655. DOI: 10.2217/fmb.12.28.
[41]	CHAU MM, KONG DC, VAN HAL SJ, et al. Consensus guidelines for optimising antifungal drug delivery and monitoring to avoid toxicity and improve outcomes in patients with haematological malignancy, 2014[J]. Intern Med J, 2014, 44(12b):1364-1388. DOI: 10.1111/imj.12600.