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  中国感染控制杂志  2023, Vol. 22 Issue (8): 945-952   DOI: 10.12138/j.issn.1671-9638.20234185
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引用本文 [复制中英文]

高姗, 林江, 李芳芳, 等. 急性白血病儿童化学治疗期间脓毒症病原学特点及危险因素[J]. 中国感染控制杂志, 2023, 22(8): 945-952. DOI: 10.12138/j.issn.1671-9638.20234185.
[复制中文]
GAO Shan, LIN Jiang, LI Fang-fang, et al. Pathogenic characteristics and risk factors of sepsis in children with acute leukemia during chemotherapy[J]. Chin J Infect Control, 2023, 22(8): 945-952. DOI: 10.12138/j.issn.1671-9638.20234185.
[复制英文]

作者简介

高姗(1981-), 女(汉族), 河南省郑州市人, 副主任医师, 主要从事医院感染流行病学研究

通信作者

林江  E-mail: 971634624@qq.com

文章历史

收稿日期:2023-03-08
急性白血病儿童化学治疗期间脓毒症病原学特点及危险因素
高姗1 , 林江1 , 李芳芳2 , 向明丽3     
1. 郑州大学第一附属医院医院感染管理科,河南 郑州 450052;
2. 济源市第三人民医院医院感染管理科,河南 济源 454650;
3. 郑州大学第一附属医院小儿内科,河南 郑州 450052
摘要目的 了解急性白血病患儿住院化学治疗(化疗)期间医院感染并发脓毒症情况,探讨其病原学特点和危险因素。方法 选取2021年1月—2022年6月某三级教学医院小儿内科819例急性白血病确诊患儿为研究对象。采用巢式病例对照研究方法,以监测期间出现脓毒症的患儿为病例组,按照1∶2的比例,随机选取同期住院且白血病类型相同的患儿为对照组。比较两组患儿基本资料及研究指标的差异,分析白血病化疗相关脓毒症危险因素,以及血标本病原体分布和药敏情况。结果 819例急性白血病患儿中,发生脓毒症51例,发病率为6.23%。按照1∶2的比例配对,纳入102例患儿为对照组。血标本检出病原体29株,其中革兰阴性菌21株(72.41%),以大肠埃希菌为主;革兰阳性菌8株(27.59%),以缓征链球菌为主。使用糖皮质激素(OR=13.20, 95%CI: 3.42~155.81)、中性粒细胞绝对值<0.1×109/L(OR=38.09,95%CI: 12.06~357.61)、血清清蛋白<35 g/L(OR=7.61,95%CI: 2.11~39.76)为急性白血病化疗患儿发生脓毒症的独立危险因素(均P<0.05)。结论 应加强急性白血病患儿化疗期间的感染监测、防控与随访,尤其对使用糖皮质激素、中性粒细胞绝对值和血清清蛋白水平较低的患儿,以减少医院感染并发脓毒症的发生。
关键词急性白血病    脓毒症    儿童    病原学    危险因素    巢式病例对照研究    
Pathogenic characteristics and risk factors of sepsis in children with acute leukemia during chemotherapy
GAO Shan1 , LIN Jiang1 , LI Fang-fang2 , XIANG Ming-li3     
1. Department of Healthcare-associated Infection Management, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, China;
2. Department of Healthcare-associated Infection Management, The Third People's Hospital of Jiyuan City, Jiyuan 454650, China;
3. Department of Pedia-trics, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, China
Abstract: Objective To investigate the occurrence of healthcare-associated infection (HAI) complicated with sepsis in hospitalized children with acute leukemia during chemotherapy, and explore its pathogenic characteristics and risk factors. Methods From January 2021 to June 2022, 819 children who were diagnosed with acute leukemia in the pediatric department of a tertiary first-class hospital were selected as the study subjects. The nested case-control study method was adopted. Children with sepsis during the monitoring period were in the case group, and children with the same type of leukemia during the same hospitalization period were randomly selected as the control group based on 1∶2 ratio. Differences in basic information and research indicators between two groups of children were compared. Risk factors for sepsis related to leukemia chemotherapy, distribution and antimicrobial susceptibility of pathogens from blood specimens were analyzed. Results Among 819 children with acute leukemia, 51 had sepsis, with an incidence of 6.23%. Paired in a 1∶2 ratio, 102 children were included in the control group. 29 strains of pathogens were isolated from blood specimens, including 21 strains (72.41%) of Gram-negative bacteria (mainly Escherichia coli) and 8 strains (27.59%) of Gram-positive bacteria (mainly Streptococcus midis). Use of glucocorticoids (OR=13.20, 95%CI: 3.42-155.81), absolute neutrophil count < 0.1×109/L (OR=38.09, 95%CI: 12.06-357.61) and serum albumin < 35 g/L (OR=7.61, 95%CI: 2.11-39.76) were independent risk factors for sepsis in children with acute leukemia during chemotherapy (all P < 0.05). Conclusion It is necessary to strengthen the monitoring, prevention and control, and follow-up of the infection in children with acute leukemia during chemotherapy, especially for children who use glucocorticoids, with low absolute neutrophil count and low serum albumin level, so as to reduce the occurrence of HAI-associated-sepsis.
Key words: acute leukemia    sepsis    children    pathogenicity    risk factor    nested case-control study    

急性白血病(acute leukemia)是儿童常见的恶性肿瘤之一,由于疾病自身特点及化学治疗(化疗)药物的应用,白血病患儿存在不同程度的免疫功能缺陷,较易导致医院感染的发生[1-2]。感染导致的脓毒症及脓毒性休克已成为儿童白血病长期的生存障碍之一[3]。本文在日常医院感染目标性监测的基础上,通过巢式病例对照研究,探讨急性白血病患儿化疗期间发生医院感染并发脓毒症的临床特点及其相关危险因素,以便为儿童急性白血病相关脓毒症的有效防控提供依据。

1 对象与方法 1.1 研究对象

选取2021年1月—2022年6月某三级医院小儿内科急性白血病确诊患儿为研究对象,开展医院感染前瞻性监测。纳入标准:符合《实用小儿血液病学》[4]急性白血病的诊断标准;年龄1~14岁;无意识障碍,主要器官无严重功能障碍,病情稳定,无代谢性疾病;住院时长>48 h;住院期间实施化疗;征得患儿或监护人同意,监护人签署知情同意书。排除标准:急症患儿;有认知障碍、精神病史、无法进行正常语言交流且无监护人陪护者。

1.2 研究方法

采用巢式病例对照研究方法,以监测期间临床诊断为脓毒症的急性白血病患儿为病例组,按照1∶2的比例,以住院时间(±7 d)为配对条件,随机选取未发生脓毒症、白血病类型相同的患儿为对照组,排除社区感染、使用抗菌药物,以及资料不完整的患儿。收集研究对象病原学及临床资料,包括年龄、性别、疾病危险度、白血病类型、既往住院情况和感染情况、化疗方案、骨髓移植、侵入性操作(手术、穿刺、留置导管)、糖皮质激素使用、层流床使用及入院时骨髓原始细胞比例、白细胞水平、中性粒细胞绝对值、血清清蛋白等指标。分析脓毒症病原体分布及药敏情况;比较两组患儿基本资料和研究指标的差异。随访所有纳入研究的患儿直至出现脓毒症、死亡等结局或研究时间终点(2022年6月30日)。病例诊断由医院感染管理专职人员和临床医生依据诊断标准、结合检验结果进行医院感染和脓毒症的判断。

1.3 诊断标准

参照《中国脓毒症/脓毒性休克急诊治疗指南(2018)》[5],对于感染或疑似感染的患者,当脓毒症相关序贯器官衰竭[sequential(sepsis-related)organ failure assessment, SOFA]评分较基线上升≥2分,诊断为脓毒症。依据国家卫生部《医院感染诊断标准(试行)》[6]进行医院感染的判定。

1.4 血培养方法

按照《临床微生物实验室血培养操作规范》WS/T 503—2017[7],疑似感染患儿均采集至少双套培养(2瓶需氧,必要时加厌氧,总采血量4~20 mL),留置静脉导管患儿同时抽取导管内和外周静脉血送检,未留置静脉导管患儿同时抽取双侧不同部位外周静脉血送检。

1.5 多重耐药菌定义

指对临床使用的三类或三类以上抗菌药物同时呈现耐药的细菌[8]

1.6 统计学方法

应用SPSS 24.0统计学软件进行数据处理。符合正态分布的计量资料以均数±标准差(x±s)表示,两组独立、正态、方差齐资料的组间比较采用t检验;计数资料采用频数、百分比表示,组间比较采用χ2检验或Fisher确切概率法;多因素分析采用非条件二元logistic回归分析法。以P≤0.05表示差异具有统计学意义。

2 结果 2.1 患儿基本情况

研究期间,共有1 023例急性白血病患儿在该科住院治疗,排除未实施化疗患儿160例、未同意参与调查患儿29例、急症患儿15例,最终有819例急性白血病患儿符合要求纳入本研究。819例患儿中,发生脓毒症51例,发病率为6.23%。其中,男性27例(52.94%),女性24例(47.06%);平均年龄(8.41±4.11)岁;急性淋巴细胞白血病35例(68.63%)、急性髓系白血病16例(31.37%);46例(90.20%)感染部位明确者,分别为血液29例(56.86%),呼吸道15例(29.42%),肛周及皮肤各1例(分别占2.00%),未明确感染部位者5例(9.80%)。

以监测期间临床诊断为脓毒症的51例急性白血病患儿为病例组,按照配对条件选取102例患儿为对照组。

2.2 病原体分布

51例急性白血病脓毒症患儿血标本共检出病原体29株。其中革兰阴性(G-)菌21株(72.41%),革兰阳性(G+)菌8株(27.59%)。G-菌以大肠埃希菌(27.59%)、肺炎克雷伯菌(17.24%)居多;G+菌以链球菌为主,以缓征链球菌(13.79%)居多。见表 1

表 1 儿童急性白血病脓毒症血标本病原体分布 Table 1 Distribution of pathogens from blood specimens of acute leukemia children complicated with sepsis
2.3 病原体耐药情况

检出G-菌中,肠杆菌目细菌(大肠埃希菌及肺炎克雷伯菌)未发现对替加环素、黏菌素耐药的菌株。大肠埃希菌对氨苄西林、头孢呋辛、环丙沙星、左氧氟沙星、多西环素的耐药率>80%;肺炎克雷伯菌对氨苄西林、头孢唑林、妥布霉素、环丙沙星、多西环素、米诺环素、复方磺胺甲唑的耐药率≥80%。8株大肠埃希菌、5株肺炎克雷伯菌至少对3类抗菌药物耐药,符合多重耐药菌的定义。检出G+菌中,链球菌属未发现对美罗培南、万古霉素、利奈唑胺耐药的菌株。缓征链球菌对青霉素G、红霉素、克林霉素的耐药率达到100%;4株缓征链球菌均为多重耐药菌。

2.4 单因素分析

病例组与对照组在年龄、住院时长、化疗阶段、中心静脉置管、使用糖皮质激素、白细胞计数、中性粒细胞绝对值、血清清蛋白水平方面比较,差异均有统计学意义(均P<0.05)。见表 2

表 2 儿童急性白血病合并脓毒症影响因素的单因素分析 Table 2 Univariate analysis on influencing factors for acute leukemia children complicated with sepsis
2.5 多因素分析

将急性白血病儿童是否发生脓毒症作为因变量,对单因素分析中有统计学差异或临界的因素进行赋值,见表 3。二元logistic多因素回归分析结果显示,按年龄进行调整后,使用糖皮质激素(OR=13.20,95%CI: 3.42~155.81)、中性粒细胞绝对值< 0.1×109/L(OR=38.09,95%CI: 12.06~357.61)、血清清蛋白<35 g/L(OR=7.61,95%CI: 2.11~39.76)为急性白血病儿童化疗期间发生脓毒症的独立危险因素(均P<0.05),见表 4

表 3 儿童急性白血病合并脓毒症危险因素的变量赋值 Table 3 Variable assignment of risk factors for acute leukemia children complicated with sepsis

表 4 儿童急性白血病合并脓毒症危险因素的多因素分析 Table 4 Multivariate analysis on risk factors for acute leukemia children complicated with sepsis
3 讨论

脓毒症是儿童急性白血病化疗期间常见合并症之一,极易造成患儿预后不佳。本研究发现,急性白血病患儿化疗期间医院感染导致的脓毒症发病率达到6.23%;近年来文献[9-10]报道儿童急性白血病合并脓毒症发病率也维持在较高水平。一旦造成脓毒症或脓毒性休克,则大大增加了死亡风险[11]。因此,在急性白血病患儿化疗期间,应注重医院感染及脓毒症的监测,分析危险因素,以利于早期、个体化干预。

本研究发现,儿童急性白血病脓毒症血标本病原体以大肠埃希菌、肺炎克雷伯菌等肠杆菌为主,与文献[12]报道一致。这可能是由于化疗过程中口腔和下呼吸道的微生物通过炎症病变的黏膜转移到血液中而造成[13]。因此,化疗期间应重视患者黏膜保护,加强口腔护理[14]。另外,本研究发现脓毒症相关病原体均为多重耐药菌。所以,在临床诊疗、护理中,应采取一系列措施,如提高医务人员手卫生依从性,严格落实接触隔离措施,规范合理使用抗菌药物,以有效控制多重耐药菌在急性白血病患儿中的传播[15-16]

本研究中,化疗诱导缓解期发生脓毒症的概率相对维持治疗期较高,可能与该阶段白血病细胞大量浸润导致机体抵抗力下降,加之糖皮质激素持续使用引发严重骨髓抑制和粒细胞缺乏等有关[17],提示该时期可能是脓毒症的高发阶段。另外,与未留置中心静脉导管急性白血病患儿相比,留置该类型导管患儿脓毒症的发病率明显升高,与其他文献[9, 18]报道的结果一致。因此,应密切观察患儿感染征象,规范血管导管置管和维护操作,预防感染发生[19]

多因素分析结果显示,中性粒细胞绝对值<0.1×109/L的急性白血病患儿发生脓毒症的风险更高。以往研究中,中性粒细胞绝对值低于0.1×109/L且粒细胞缺乏持续时间超过7 d被认为是脓毒症发生的高危因素[20]。由于中性粒细胞产生于骨髓造血细胞,具有免疫作用,一旦缺乏,则较易引发医院感染[21]。急性白血病患者本身骨髓造血功能有缺陷,中性粒细胞的数量和质量均较低;化疗又会进一步影响骨髓造血功能,导致中性粒细胞数量、质量及其功能恶化,机体将难以对抗致病菌侵袭而易诱发感染[22-23]。因此,建议在患儿化疗后,可根据中性粒细胞水平或缺乏持续时间,积极预防性抗感染治疗及粒细胞集落刺激因子的支持治疗[9]

急性白血病患儿在化疗诱导缓解期间,常使用左旋门冬酰胺酶;为避免该药引起的胰腺炎,临床往往建议6周内低脂饮食,但这有可能导致营养不良[24]。一般而言,患者营养状况越差,发生医院感染的风险越高[25-26]。本研究中,血清清蛋白低于35 g/L是急性白血病患儿发生脓毒症的独立危险因素,与其他报道结论一致[27-28]。这可能与清蛋白水平降低会使机体正常酶的数量和活性下降,造成机体免疫力降低,增加感染风险有关[29]。因此,建议尽早给与急性白血病患儿营养支持,尽快改善其营养状况,以预防医院感染。

糖皮质激素,如地塞米松或泼尼松等,除杀灭肿瘤细胞之外,还将抑制免疫应答,破坏淋巴细胞和干扰补体参与免疫反应,从而引发感染[30-32]。本研究中,糖皮质激素的使用可能会明显增加急性白血病患儿发生脓毒症的风险。因此,建议应关注急性白血病患儿糖皮质激素的规范应用,加强日常护理,树立安全注射意识,以降低外源性感染的发生风险。

综上所述,应加强急性白血病患儿化疗期间,特别是诱导缓解期的监测与随访,密切关注留置中心静脉导管、使用糖皮质激素治疗、中性粒细胞绝对值和血清清蛋白水平较低的患儿;病区的管理中,注重各项感染防控措施的有效落实,强化无菌观念,加强环境的清洁与消毒、医务人员手卫生等,落实急性白血病患儿的保护性隔离措施,尽量缩短住院时长,有效阻断多重耐药菌的传播等,从而减少医院感染导致的脓毒症发生。

利益冲突:所有作者均声明不存在利益冲突。

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