流感相关性侵袭性肺曲霉病和COVID-19相关性肺曲霉病的可能病理机制
4. 侵袭性曲霉病宿主因素
长时间中性粒细胞缺乏:近期发生中性粒细胞缺乏(中性粒细胞计数<0.5×109/L),并持续超过10 d。
罹患血液恶性肿瘤患者:血液恶性肿瘤或接受异基因造血干细胞移植。
接受免疫抑制剂治疗或靶向治疗:既往90 d内接受T细胞免疫抑制剂治疗,如:环孢素、TNF-α阻滞剂、特定的单克隆抗体(如阿仑单抗),或核苷类似物;接受B细胞免疫抑制剂治疗,如布鲁顿酪氨酸激酶抑制剂(如依鲁替尼)。
实体器官移植受者及难治性GVHD患者:实体器官移植受者;累及肠、肺或肝的Ⅲ级或Ⅳ级GVHD,且对一线皮质类固醇治疗无效。
遗传性严重免疫缺陷患者:遗传性严重免疫缺陷(如慢性肉芽肿、STAT3缺陷或严重联合免疫缺陷)。
失代偿肝硬化患者。
HIV感染患者。
慢性呼吸道病变:慢性气道病变(COPD,支气管扩张)。
重症病毒性肺炎:重症流感(或其他严重病毒性肺炎,如COVID-19感染)。
侵袭性曲霉病和毛霉病危险因素/宿主人群[10-15]
注:红色区域为侵袭性曲霉病危险因素;黄色区域为毛霉病危险因素,橙色区域为侵袭性曲霉病和侵袭性毛霉病混合危险因素。
危险因素的叠加增加了COVID-19患者罹患毛霉病风险。Seidel等[16]对德国6家教学医院2020年3月至2021年6月期间的COVID-19感染患者进行了回顾,在13例COVID-19并发毛霉病的患者中,5例为免疫抑制宿主(白血病或器官移植),3例患者伴有于毛霉病相关的高危因素(糖尿病),多数患者接受了糖皮质激素治疗(84.6%)。13例患者基础疾病状态和治疗过程如下图所示。
注:左图可见锐角分支曲霉菌丝,右图可见直角分支毛霉菌丝。
一项亚洲侵袭性霉菌感染流行病学研究中,155例罹患侵袭性霉菌感染中,最常见的致病霉菌病原菌为曲霉菌(81%,含8%混合感染中包含的曲霉菌)和毛霉菌(10%),多数患者侵袭性霉菌感染累及肺部(78.7%,122/155)[17]。在另外两项重症患者的曲霉菌和毛霉菌流行病学研究中,肺部同为主要累及器官[20,21]。
1. 侵袭性霉菌感染的临床表现和微生物证据
侵袭性霉菌病的诊断标准[10]:
(1)确诊:
(2)临床诊断:
2. 侵袭性肺曲霉病和肺毛霉病影像学表现[22]
结节:CT下表现为清晰或不清晰圆形或不规则阴影,直径可达30 mm,小结节≤3 mm,大结节3~30 mm。
团块:直径>30 mm的团块阴影,不考虑轮廓,边界或密度特征。
实变:密度均匀的肺实质高密度影,其中血管和气道壁边界模糊,可以表现为空气支气管征。
空气支气管征:在呼气状态下不透明肺部背景(高衰减)下可见支气管内气腔(低衰减)。
树芽征:表示类似于发芽树的小叶分支结构。该类型表示细支气管内或周围支气管病变,包括黏液嵌塞和细支气管炎症。此种情况多数表现为外周病变与大气道病变相关。
晕征:肺结节或团块影周围围绕着一圈晕轮状磨玻璃影。
反晕征:病灶中心表现为磨玻璃影周围围绕着厚度不均匀的环状实变。
低密度征:肺结节或团块影中心呈现低密度衰减。
空气新月征:含结节(<30 mm)或团块影(> 30 mm)空腔内形成新月形区域。
3. 侵袭性肺曲霉病与肺毛霉病的影像学差异
4. 非血液恶性肿瘤/非粒细胞缺乏侵袭性肺曲霉病患者肺部影像学表现缺乏特异性
5. 培养和(荧光染色)直接镜检诊断侵袭性霉菌感染
国际指南对于培养和镜检在霉菌感染诊断中的推荐[14, 27]
6. BALF-GM试验诊断侵袭性霉菌感染
7. GM试验诊断侵袭性霉菌感染
ESCMID-ECMM-ERS曲霉病指南中推荐GM试验抗原检测用于侵袭性曲霉病的诊断,对应不同人群指南在标本选择上给予了区别推荐。由于受限于血清GM试验的敏感性,对于接受抗霉菌预防治疗患者,非粒细胞缺乏患者,ICU患者和实体器官移植患者指南更倾向于选择支气管肺泡灌洗液标本进行侵袭性肺曲霉病的诊断。
8. PCR诊断侵袭性霉菌感染
9. NGS诊断侵袭性霉菌感染
注:VITAL研究中曲霉合并毛霉菌属真菌感染患者接受艾沙康唑初始或挽救治疗42天时临床结局。
艾沙康唑安全性好,肝胆异常不良事件发生率显著低于伏立康唑。SECURE研究中对接受伏立康唑治疗(n=259)和艾沙康唑治疗(n=257)的药物相关不良反应进行了比较,艾沙康唑药物相关不良事件发生率显著低于伏立康唑(42% vs 60%,P<0.001)。其中艾沙康唑组肝胆异常发生率显著低于伏立康唑组(9% vs 16%,P=0.016)。该研究还发现,艾沙康唑组眼部不良事件发生率显著低于伏立康唑组(15% vs 27%,P=0.002)。
艾沙康唑较其他广谱三唑类药物QTc间期延长发生率显著降低。Van Matre等[35]开展的一项单中心回顾性队列研究比较了伏立康唑、泊沙康唑和艾沙康唑治疗侵袭性真菌病的疗效和安全性,共纳入100例患者,接受艾沙康唑治疗组相较于其他两组QTc延长的发生率显著降低(P=0.037)。
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作者简介
崔俊昌 教授
主任医师,教授,博士生导师
解放军总医院呼吸与危重症医学部呼吸感染科主任
全军传染病学专业委员会委员
中国老年医学学会呼吸病学分会感染学组委员
中国药学会药物临床评价专业委员会委员
主要研究领域为呼吸道感染及抗感染药物合理应用
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