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  微生物与感染  2024, Vol. 19 Issue (5): 314-320      DOI: 10.3969/j.issn.1673-6184.2024.05.007
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脑膜炎败血伊丽莎白菌感染临床特征及机制的研究进展
王雨彤 , 王馨瑜 , 林诺 , 方波 , 张可盈 , 孙桂芹     
浙江中医药大学医学技术与信息工程学院,浙江 杭州 310053
摘要:脑膜炎败血伊丽莎白菌(Elizabethkingia meningoseptica,EM)可引起脑膜炎、败血症、肺部感染、眼部感染、导管相关血流感染和手术部位感染,是医院内感染的重要病原菌之一。EM的感染机制包括侵入宿主细胞、产蛋白酶、生物膜等,EM可产生相关毒力因子使免疫系统受损。此外,EM携带多个耐药基因对临床常用抗菌药物具有耐药性。本文通过对EM的感染类型、临床特征及感染机制等方面进行综述,旨在为EM感染的检测和治疗提供参考。
关键词脑膜炎败血伊丽莎白菌    感染    临床特征    感染机制    
Research progress on the clinical characteristics and mechanism of Elizabethkingia meningoseptica infection
WANG Yutong , WANG Xinyu , LIN Nuo , FANG Bo , ZHANG Keying , SUN Guiqin     
School of Medical Technology and Information Engineering, Zhejiang Chinese Medical University, Hangzhou 310053, Zhejiang Province, China
Abstract: Elizabethkingia meningoseptica (EM) can cause meningitis, sepsis, lung infection, eye infection, catheter-related bloodstream infection and surgical site infection. EM is one of the important pathogens of nosocomial infection. The infection mechanisms of EM include invasion of host cells, production of proteases, biofilms, etc, and EM can produce related virulence factors to damage the immune system. In addition, EM carries multiple drug resistance genes and is resistant to commonly used antibiotics in clinical practice. This article reviews the infection types, clinical features and infection mechanisms of EM, which would provide a reference for the diagnosis and clinical treatment of EM infection.
Keywords: Elizabethkingia meningoseptica    Infection    Clinical characteristic    Infection mechanism    

脑膜炎败血伊丽莎白菌(Elizabethkingia meningoseptica,EM)是一种非发酵的革兰氏阴性杆菌,无鞭毛、芽孢以及荚膜。该菌为一种条件致病菌,免疫力低下、患有多种基础疾病、多次接受手术以及长期服用抗菌药物等都能增加EM菌感染的概率[1]。EM可引起多部位感染,如脑膜炎、败血症、肺部感染等,发病者多有发热、呼吸困难、意识不清、昏迷等症状,严重者可导致死亡。

EM广泛存在于水、土壤、医疗设备等环境,是引发医院内感染的重要病原体,其感染率呈上升趋势[2]。EM菌能够通过入侵宿主细胞、产生酶类、产生毒力因子等导致机体感染[3]。本研究收集整理国内外EM感染的相关研究,针对感染类型、临床特征及感染机制作综述,旨在为EM感染临床诊治提供依据。

1 EM感染类型及临床特征 1.1 脑膜炎

EM主要感染免疫功能低下的人群,如新生儿和老年人[4]。新生儿的皮肤和黏膜屏障功能较弱,非特异性免疫力低,且新生儿的免疫器官发育不全,免疫细胞与免疫球蛋白的数量与功能等生理性偏低,特异性免疫力低下[5]。米芋枚等[6]通过对213例0~14岁化脓性脑膜炎患儿进行病原体分离培养,其中64例革兰氏阴性菌感染中检出EM 2例(3.13%)。目前研究表明EM感染的大多数新生儿为早产儿和极低出生体重儿[7]。张寅英[8]通过对国内外报道的118例新生儿脑膜炎病例进行汇总,其中早产儿42例,低体重儿55例。EM脑膜炎患儿常出现发热、嗜睡、呼吸暂停、癫痫发作、喂养不耐受等非特异性症状[9-10],部分患儿发病后精神、食欲等一般情况尚可,此表现可与其他细菌性脑膜炎相鉴别诊断[11]。EM也可感染免疫力正常的婴儿,出现呼吸急促、意识模糊等临床表现[12]。Bayrak等[13]报道了1例患有遗传性疾病Bardet-Biedl综合征患者,该患者先天性免疫功能低下、多器官功能障碍,感染EM后引起菌血症,出现高热伴寒战的临床表现。当老年人患有糖尿病、高血压等基础疾病时[14],免疫力降低,极易感染EM引起脑膜炎,临床常表现为乏力、低血压、心跳过速等症状[15]。EM也可通过侵入性操作感染免疫力正常的成年人引起脑膜炎[16]

1.2 败血症

EM可侵入血管通过血液循环导致败血症,包括早发性败血症和迟发性败血症,出现低血压、心动过速、高热、畏寒、皮肤瘀斑等症状[17-18]。患有败血症的新生儿也可能同时患有脑膜炎,具有非特异性临床特征,包括抽搐、呼吸窘迫、休克等临床表现,没有脑膜刺激迹象[19]。郑劼等[20]对142例诊断为脓毒败血症的患儿进行分析,在84例细菌感染中检出EM 1例(1.2%)。此外,EM也可引起老年人败血症,吴丽华等[18]报道了1例老年患者血流感染EM,该患者既往有“高血压、痛风、慢性阻塞性肺病”病史多年,主要临床特征为发热、反应迟钝、外周血超敏C反应蛋白、中性粒细胞百分比明显升高,提示EM易感染免疫功能低下者。由于EM在大多数情况下具有多重耐药性,相较于其他细菌引起的败血症较难医治,临床须抗菌药物组合使用。

1.3 肺部感染

EM可定植于呼吸道引发呼吸系统感染[21]。Mohapatra等[22]在181名成年肺炎患者中分离培养得到240株细菌分离株,其中检出肺炎克雷伯菌(36.67%)、鲍曼不动杆菌(22.92%)、铜绿假单胞菌(12.92%)等病原体,EM检出4株占1.67%。闫建慧等[9]通过对海南省某三甲医院67例EM感染病例进行分析,发现临床EM主要分离自呼吸道标本,其中痰液最多(49.25%),其次为肺泡灌洗液(37.31%);EM感染患者的基础疾病主要为呼吸系统疾病(49.25%);多数患者住院时间长,且有侵入性操作,其中有机械通气者占94.03%。EM所致肺部感染多为聚集性感染,可引起支气管气管炎[23]、肺炎等疾病。Esteban等[24]报道1例由于使用呼吸机不当感染EM的病例。郭芳芳等[1]报道了ICU的3例重度肺炎患者,肺泡灌洗液EM检测阳性,在ICU呼吸机和治疗台面检出EM,提示为医院内感染。肺部感染主要临床表现为发热、咳嗽,可伴有脓性痰、呼吸困难、胸痛、乏力、食欲不振、寒战、炎症因子指标升高等[25-26]

1.4 眼部感染

EM可引起眼内炎、角膜炎、脂质性角膜病等眼部疾病[27]。EM引起的眼内炎以外源性为主,即EM通过眼周外部创伤感染[28]。Young等[28]报道了1例金黄色葡萄球菌血症同时伴有EM感染的内源性眼内炎患者,临床表现为眼红肿和疼痛,视力模糊,瞳孔固定,无光感,角膜模糊伴角膜后弹力层(Descemet膜)皱褶,深前房充满垂体细胞和纤维蛋白,B超显示多处玻璃体混浊。眼部手术如角膜移植术后由EM引起的感染性角膜炎临床表现常为视力突然下降[29]。此外,长期局部使用降眼压药物及佩戴隐形眼镜也可能导致感染EM,引发眼部炎症[30]

1.5 其他部位感染

EM除上述常见感染部位外,还可致尿道感染[31]、胆道感染[32]、腹膜炎[33]、胰腺炎[34]等。Hagiya等[35]报道了1例腹膜后纤维化患者由EM引起的肾造口术相关尿路感染病例,临床表现为高热,无其他尿路感染特异性症状。李蓉蓉等[32]报道了1例由经内镜逆行胰胆管造影(endoscopic retrograde cholangiopancreatography,ERCP)侵入性操作导致胆道感染EM的患者,临床表现为高热,伴畏寒、寒战,白细胞等炎性指标明显升高。

表 1 EM感染常见类型及临床表现 Tab. 1 Common types and clinical symptoms of em infection
Infection site Diseases caused Clinical manifestation
Brain Meningitis Newborn Fever, lethargy, apnea, seizures, feeding intolerance, tachypnea, confusion
Elders Fatigue, hypotension, tachycardia
Blood Septicemia Newborn Convulsions, respiratory distress, shock
Elders Acute fever, confusion
Lungs Pneumonia Fever, cough, may be accompanied by purulent sputum, dyspnea, chest pain, fatigue, loss of appetite, chills, elevated inflammatory response
Eye Keratitis Eye pain, redness and swelling, drooping of atrial abscess, corneal scarring, decreased vision
Lipid keratopathy Pain, redness, tearing, blurred vision
Endophthalmitis Redness, swelling and pain of the eye, blurred vision, fixed pupil without light, blurred cornea with dm membrane folds, vitreous opacity
2 EM感染的相关机制研究 2.1 黏附与入侵

EM对营养要求较低,广泛存在于自然界的水、土壤、植物及医疗设备(呼吸机、气管插管、加湿器、新生儿培养箱)等,当对有基础疾病或免疫力低下的患者进行侵入性操作时,EM可通过伤口侵入人体,引发肺部、眼部等局部感染[28, 36]。Waleed等[15]报道,EM局部感染后,可扩散进入血液、脑脊液,并在其中生长繁殖,最终导致败血症、脑膜炎等疾病的发生。Lau等[37]进一步研究发现,EM产生的芳基硫酸酯酶有助于细菌侵入宿主大脑内皮细胞,从而穿过血脑屏障引起脑膜炎。EM中含外膜蛋白A(outer membrane protein A,OmpA)和外膜蛋白W(outer membrane protein W,OmpW)[38],可以诱导生物膜的形成,使得EM对一般消毒剂及宿主免疫系统的清除均有一定的抵抗性[39-40]

2.2 毒力因子

1984年,Miyazaki [41]从EM中纯化出了一种弹性蛋白酶,经实验研究发现这种弹性蛋白酶对成年小鼠具有致死毒性,推断此蛋白是新生儿脑膜炎的致病因子之一。Lin等[42]通过对EM 361-97进行全基因组测序和基因组注释,比较基因组分析得出,EM的毒力因子包括脂多糖、内肽酶、镁转运蛋白、热休克蛋白、过氧化氢酶、过氧化物酶、超氧化物歧化酶等,这些毒力因子参与细菌的生物膜形成、脂质的合成和代谢、铁摄取和运输及巨噬细胞感染性等。孙桂芹[43]研究发现,EM菌产生的N-糖苷酶F[peptide-N4-(N-acetyl-β-D-glucosaminyl) asparigineamidase, PNGase F]能够协同内毒素脂多糖,促进炎症因子IL-6、TNF-α、INF-γ等快速升高,加重小鼠的肺部炎症反应。Sun等[44]在EM临床分离株中还发现了EM的第2个N-糖苷酶(peptide: N-glycosidase F-Ⅱ, PNGase F-Ⅱ),推测该种酶是EM的毒力因子之一。

2.3 影响宿主免疫

EM可分泌外膜囊泡(outer membrane vesicles,OMV)[45],包含复杂的成分如外膜蛋白、脂多糖(lipopolysaccharide, LPS)以及其他免疫刺激分子(脂蛋白、肽聚糖等)[46],可以刺激宿主产生免疫应答,诱导宿主产生炎性反应,若细菌存在于脑脊液中,则可能诱发脑膜炎。基于OMV自身的抗原特性,Yang等[45]评估了利用亚胺培南诱导的EM OMV作为疫苗的免疫原性和对机体的保护作用,认为OMV可以制成疫苗诱导并增强人体的特异性体液免疫,产生持久的抗体反应,其有助于通过补体依赖的细胞毒性作用和增强吞噬细胞活性来清除人体内的细菌。此外,Yang等[45]还通过EM OMV皮下免疫诱导体液免疫反应,证明了OMV可促进树突状细胞成熟,这与先前Watkins等[47]报道一致。

2.4 耐药性

EM对临床常用于治疗革兰氏阴性菌的抗菌药物耐药性较高[48],例如对β-内酰胺类、氨基糖苷类、四环素类等耐药率较高,且EM的耐药性存在一定的地区差异[4]。张丹等[14]研究发现,EM对哌拉西林及其含酶抑制剂的耐药率低于40%,对左氧氟沙星、米诺环素、多西环素表现出较高的敏感性,敏感率在70%以上。

Breurec等[49]报道EM基因组中包含至少17个抗菌药物耐药基因。已有研究表明,伊丽莎白菌属细菌金属-β-内酰胺酶基因blablaBblaGOB编码金属-β-内酰胺酶,可水解β-内酰胺环,使大多数β-内酰胺抗菌药物(如碳青霉烯类和氨曲南、氨基糖苷类药物和氯霉素等)失活[50-52]

3 展望

EM作为临床感染率不高的细菌,偶或出现局部爆发的可能。EM的感染通常与中央静脉感染、不当使用抗菌药物、长期住院或长时间化疗等因素有关[53-54]。患者感染EM后可能会出现一系列症状,包括但不限于脑膜炎、败血症、肺部眼部感染等,由于这些症状可能对患者的健康造成严重威胁,因此须引起足够重视。尽管近年来EM的检测诊断取得了显著进展,但有关EM的基础研究仍相对不足,例如EM的病原学研究、免疫学研究、流行病学研究、引起多部位感染的机制、形成生物膜的机制等。

除了常规检测方法以外,目前针对EM感染的临床诊断方法还包括高通量测序技术[55]、质谱技术[56]及拉曼光谱[57]等,这些新技术将为EM临床诊断提供新的检测手段。此外,EM近乎天然的多耐药性给临床治疗带来了困扰。临床治疗EM感染的重点聚焦于个体化抗菌治疗[58],通过分离培养、不同药物的敏感性检测,从而选择适合患者个体的抗菌药物进行治疗。国内外研究数据显示,对EM菌敏感性较高的药物包括米诺环素、替加环素、左氧氟沙星、哌拉西林-他唑巴坦、头孢哌酮-舒巴坦钠[59]。临床除了选择上述EM敏感的抗菌药物外,也可选择万古霉素用于治疗[60]。需要注意的是,当EM与其他病原体混合感染时,临床治疗抗菌药物的选择,如联合万古霉素与环丙沙星、利唑唑胺或利福平[61]等,哌拉西林/他唑巴坦与甲氧苄啶/磺胺甲恶唑或氟喹诺酮类药物联合的治疗方案有效且死亡率较低[62],但上述组合仍须进一步的临床研究来确定其疗效,以期为临床治疗提供帮助。

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文章信息

王雨彤, 王馨瑜, 林诺, 方波, 张可盈, 孙桂芹
WANG Yutong, WANG Xinyu, LIN Nuo, FANG Bo, ZHANG Keying, SUN Guiqin
脑膜炎败血伊丽莎白菌感染临床特征及机制的研究进展
Research progress on the clinical characteristics and mechanism of Elizabethkingia meningoseptica infection
微生物与感染, 2024, 19(5): 314-320.
Journal of Microbes and Infections, 2024, 19(5): 314-320.
通信作者
孙桂芹
E-mail:sunguiqin2001@163.com

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