Technical specifcation for clinical diagnosis and treatment for invasive fungal disease in organ transplant recipients (2019 edition)
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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。
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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% 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 早期 晚期(移植后>4个月) 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 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 -
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