重庆地区儿童耐药结核病患者耐药情况及临床特征分析

doi:10.12372/jcp.2024.24e0778

临床儿科杂志 ›› 2024, Vol. 42 ›› Issue (10): 868-875.doi: 10.12372/jcp.2024.24e0778

重庆地区儿童耐药结核病患者耐药情况及临床特征分析

龙晓茹(), 杨汝铃, 张祯祯, 许红梅, 赵瑞秋, 郑改焕

重庆医科大学附属儿童医院感染科国家儿童健康与疾病临床医学研究中心儿童发育疾病研究教育部重点实验室儿童发育重大疾病国家国际科技合作基地儿童感染与免疫罕见病重庆市重点实验室重庆市首批公共卫生重点学科（专科）儿童医疗大数据智能应用重庆市高校工程研究中心（重庆 400014）

收稿日期:2024-07-31 出版日期:2024-10-15 发布日期:2024-10-08
通讯作者: 龙晓茹 E-mail:2387207074 @qq.com
基金资助:
重庆市科卫联合医学科研项目面上项目(2023MSXM051);重庆市自然科学基金面上项目(CSTB2024NSCQ-MSX1048);国家儿童健康与疾病临床医学中心临床医学研究项目(NCRCCH-2020-GP-06);重庆医科大学附属儿童医院杰出青年人才基金项目(RC02017);儿童新发重大传染病病原体实时动态监测机制建立(2022YFC2704904)

Analysis of drug resistance and clinical characteristics of children with drug-resistant tuberculosis in Chongqing

LONG Xiaoru(), YANG Ruling, ZHANG Zhenzhen, XU Hongmei, ZHAO Ruiqiu, ZHENG Gaihuan

Department of Infectious Disease of Children’s Hospital of Chongqing Medical University, National Clinical Research Center for Child Health and Disorders, Ministry of Education Key Laboratory of Child Development and Disorders, China International Science and Technology Cooperation Base of Child Development and Critical Disorders, Chongqing Key Laboratory of Child Rare Diseases in Infection and Immunity, The First Batch of Key Disciplines on Public Health in Chongqing, Chongqing Higher Institution Engineering Research Center of Children's Medical Big Data Intelligent Application, Chongqing 400014, China

Received:2024-07-31 Online:2024-10-15 Published:2024-10-08

摘要/Abstract

摘要：

目的本研究旨在分析重庆地区耐药结核病（DR-TB）患儿的耐药谱、耐药位点及临床特征。方法以2014年1月至2022年12月重庆医科大学附属儿童医院收集的296株结核分枝杆菌（MTB) 菌株及其对应患儿为研究对象。采用比例法药物敏感性试验（DST）检测耐药性，用全基因组测序（WGS) 检测耐药位点。回顾性分析DR-TB患儿的临床特征。结果经比例法DST检测，17.2%（51/296）菌株为DR-TB，WGS未发现新的耐药位点。敏感组240例，耐药组51例。耐药组女性、复治、重症结核病、肺结核合并肺外结核、使用二线药物、治疗失败或死亡比例均高于敏感组，但卡介苗接种率低于敏感组，差异均有统计学意义（P<0.05）。共288例患儿完成胸部CT检查，与敏感组相比，耐药组累及双侧肺部比例更高，累及肺叶数量也更多，更容易累及右下叶，坏死比例也更高，差异均有统计学意义（P<0.05）。与敏感组相比，耐药组患儿抗酸染色涂片≥1次阳性的比例更高，T-SPOT.TB阳性率更低，差异有统计学意义（P<0.05）。结论重庆地区儿童DR-TB比例较高，耐药位点与成人相近。女性、复治、未接种卡介苗可能与DR-TB相关，DR-TB患儿肺野受累更广，更易出现肺坏死、扩散至肺外器官并进展为重症，且治疗失败或死亡比例较高。DR-TB患儿整体病原检测阳性率更高，但免疫学检查阳性率偏低，可能存在免疫功能抑制。

关键词: 结核病, 耐药, 临床特征, 儿童

Abstract:

Objective Our study was to analyze the drug resistance spectrum, drug resistance sites, and clinical characteristics of children with drug-resistant tuberculosis (DR-TB) in Chongqing. Methods A total of 296 Mycobacterium tuberculosis (MTB) strains were isolated from pediatric patients of Children's Hospital of Chongqing Medical University from January 2014 to December 2022. These isolates were tested for anti-TB drugs with phenotypic drug susceptibility test (DST), and their potential genotypic resistance mutations were identified with whole genome sequencing (WGS). The clinical characteristics of DR-TB patients were analyzed retrospectively. Results According to phenotypic DST, 17.2% (51/296) of the strains were DR-TB, and no new gene mutations associated with drug resistance were detected by WGS. There were 240 patients in the drug-sensitive group and 51 in the drug-resistant group. Compared with the drug-sensitive group, the proportion of female, retreatment, severe tuberculosis, pulmonary tuberculosis combined with extrapulmonary tuberculosis, second-line drug use, treatment failure or death was higher, but the BCG vaccination rate was lower in the drug-resistant group, and the differences were statistically significant (P<0.05). A total of 288 children completed chest CT examination. Compared with the drug-sensitive group, the drug-resistant group involved a higher proportion of both lungs, involved more lobes, more likely to involve the lower right lobe, and had a higher percentage of necrosis, and the differences were all statistically significant (P<0.05). Compared with the drug-sensitive group, the proportion of positive acid-fast staining smear ≥1 times was higher, and the positive rate of T-SPOT.TB was lower in the drug-resistant group, with statistical significance (P<0.05). Conclusions The proportion of DR-TB in children in Chongqing is relatively high, and the gene mutations associated with drug resistance are similar to those in adults. Female, retreatment, and no BCG vaccination may be associated with DR-TB. Children with DR-TB have a wider range of lung involvement, are more likely to experience lung necrosis, and have a higher risk of lung lesions spreading to extra-pulmonary organs and progressing to severe disease, with higher rates of treatment failure or death. The overall positive rate of pathogen detection was higher in DR-TB children, but the positive rate of immunological examination was lower, suggesting that the children may have immune suppression.

Key words: tuberculosis, drug-resistant, clinical feature, child

龙晓茹, 杨汝铃, 张祯祯, 许红梅, 赵瑞秋, 郑改焕. 重庆地区儿童耐药结核病患者耐药情况及临床特征分析[J]. 临床儿科杂志, 2024, 42(10): 868-875.

LONG Xiaoru, YANG Ruling, ZHANG Zhenzhen, XU Hongmei, ZHAO Ruiqiu, ZHENG Gaihuan. Analysis of drug resistance and clinical characteristics of children with drug-resistant tuberculosis in Chongqing[J]. Journal of Clinical Pediatrics, 2024, 42(10): 868-875.

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参考文献 30

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药物	耐药菌株数	耐药相关突变位点	突变率 [n(%)]
异烟肼	37	katG Ser315Thr	28(75.7)
		katG Ser140Asn	0(0.0)
		ahpC-54C>T	0(0.0)
		fabG1-15C>T和inhA Ile194Thr	1(2.7)
		fabG1-15C>T	1(2.7)
丙硫异烟胺	5	ethA Gln347*	0(0.0)
		ethA 140_140del	1(20.0)
		ethA 938_939insT	1(20.0)
		fabG1-15C>T	1(20.0)
		fabG1-15C>T和inhA Ile194Thr	1(20.0)
利福平	19	rpoB Leu430Pro	1(5.3)
		rpoB Asp435Ala和Leu452Pro	1(5.3)
		rpoB Asp435Tyr和Asn437Asp	2(10.5)
		rpoB His445Asn	1(5.3)
		rpoB His445Asp	1(5.3)
		rpoB His445Leu	0(0.0)
		rpoB His445Tyr	1(5.3)
		rpoB Ser450Leu	10(52.6)
		rpoB Ser450Leu和rpoC Leu527Val	1(5.3)
利福喷丁	23	rpoB Leu430Pro	0(0.0)
		rpoB Asp435Ala和Leu452Pro	1(4.3)
		rpoB Asp435Tyr和Asn437Asp	2(8.7)
		rpoB His445Asn	1(4.3)
		rpoB His445Asp	1(4.3)
		rpoB His445Leu	1(4.3)
		rpoB His445Tyr	1(4.3)
		rpoB Ser450Leu	12(52.2)
		rpoB Ser450Leu和rpoC Leu527Val	1(4.3)
乙胺丁醇	21	embB Met306Val	5(23.8)
		embB Met306Ile	1(4.8)
		embB Met306Leu和embA -12C>T	1(4.8)
		embB Ala356Val	0(0.0)
		embB Ser380Asn	0(0.0)
		embB Gly406Ala	1(4.8)
		embB Gly406Asp	1(4.8)
		embB Gly406Ser	0(0.0)
		embB Gln497Arg	1(4.8)
左氧氟沙星	9	gyrA Ala90Val	2(22.2)
		gyrA Ala90Val和Ser91Pro	1(11.1)
		gyrA Asp94Gly	5(55.6)
		gyrB Asn499Asp	0(0.0)
		gyrB Thr500Asn	0(0.0)
		gyrB Glu501Asp	0(0.0)
莫西沙星	12	gyrA Ala90Val	3(25.0)
		gyrA Ala90Val和Ser91Pro	1(8.3)
		gyrA Asp94Gly	6(50.0)
		gyrB Asn499Asp	0(0.0)
		gyrB Thr500Asn	0(0.0)
		gyrB Glu501Asp	1(8.3)
阿米卡星	3	rrs 1401a>g	3(100)

项目	敏感组(n=240)	耐药组(n=51)	统计量	P
男性[n(%)]	126(52.5)	14(27.5)	χ²=10.57	0.001
年龄[n(%)]			χ²=0.37	0.947
0~4岁	75(31.2)	18(35.3)
5~9岁	42(17.5)	8(15.7)
10~14岁	105(43.8)	21(41.2)
15~18岁	18(7.5)	4(7.8)
民族[n(%)]			χ²=0.75	0.386
汉族	211(87.9)	47(92.2)
少数民族	29(12.1)	4(7.8)
居住地[n(%)]			χ²=0.07	0.788
城市	80(33.3)	18(35.3)
农村	160(66.7)	33(64.7)
治疗状态[n(%)]			χ²=10.85	0.001
初治	238(99.2)	46(90.2)
复治	2(0.8)	5(9.8)
有结核病接触史[n(%)]	89(37.1)	25(49.0)	χ²=2.52	0.113
有卡介苗接种史[n(%)]	191(79.6)	30(58.8)	χ²=9.92	0.002
有效治疗前症状持续时长[M(P₂₅~P₇₅)]/d	29.1(15.9~60.0)	18.9(10.8~46.8)	Z=0.10	0.923
住院次数[M(P₂₅~P₇₅)]/次	1.0(1.0~4.0)	2.0(1.0~5.3)	Z=0.24	0.817
重症结核病[n(%)]	150(62.5)	44(86.3)	χ²=10.70	0.001
诊断[n(%)]			χ²=7.29	0.026
肺结核	119(49.5)	16(31.4)
肺外结核	3(1.3)	0(0.0)
肺结核合并肺外结核	118(49.2)	35(68.6)
治疗用药[n(%)]			χ²=48.25	<0.001
一线药物	177(73.8)	27(52.9)
一线加二线药物	59(24.5)	10(19.6)
二线药物	4(1.7)	14(27.5)
治疗结局[n(%)]			χ²=6.77	0.009
治愈或治疗完成	229(95.4)	43(84.3)
治疗失败或死亡	11(4.6)	8(15.7)

项目	敏感组(n=237)	耐药组(n=51)	χ²值	P
病变位置			7.96	0.019
左侧	37(15.6)	2(3.9)
右侧	70(29.5)	11(21.6)
双侧	130(54.9)	38(74.5)
累及肺叶数量			11.54	0.021
1叶	40(16.9)	3(5.9)
2叶	54(22.8)	6(11.8)
3叶	38(16.0)	7(13.7)
4叶	22(9.3)	9(17.6)
5叶	83(35.0)	26(51.0)
累及肺叶部位
左上叶	151(63.7)	36(70.6)	0.87	0.351
左下叶	163(68.8)	32(62.7)	0.70	0.403
右上叶	175(73.8)	39(76.5)	0.15	0.696
右中叶	154(65.0)	40(78.4)	3.46	0.063
右下叶	157(66.2)	42(82.4)	5.10	0.024
病变类型
树芽征	7(3.0)	2(3.9)	0.12	0.726
实变	52(21.9)	10(19.6)	0.14	0.713
钙化	56(23.6)	10(19.6)	0.38	0.535
坏死	6(2.5)	7(13.7)	9.20	0.002
空洞	45(19.0)	7(13.7)	0.79	0.376
肺不张	40(16.9)	11(21.6)	0.63	0.426
粟粒性病变	31(13.1)	7(13.7)	0.02	0.902
结节影	55(23.2)	8(15.7)	1.39	0.239
支气管充气征	22(9.3)	9(17.6)	3.06	0.080
支气管扩张	31(13.1)	12(23.5)	3.61	0.058
支气管狭窄	37(15.6)	13(25.5)	2.86	0.091
淋巴结病变	181(76.4)	41(80.4)	0.38	0.535
胸膜病变	74(21.2)	15(29.4)	0.07	0.799
胸腔积液	63(26.6)	13(25.5)	0.03	0.872

项目	敏感组(n=240)	耐药组(n=51)	χ²值	P
抗酸染色涂片			5.50	0.019
≥1次阳性	68(28.3)	23(45.1)
全部阴性	172(71.7)	28(54.9)
TST			7.55	0.056
阴性	87(36.2)	27(52.9)
一般阳性	25(10.4)	1(2.0)
中度阳性	39(16.3)	5(9.8)
强阳性	89(37.1)	18(35.3)
T-SPOT.TB阳性	222(92.5)	42(82.4)	4.40	0.036
Xpert MTB/RIF			3.61	0.058
≥1次阳性	150(62.5)	39(76.5)
全部阴性	90(37.5)	12(23.5)
TB-DNA			0.76	0.384
≥1次阳性	81(33.8)	14(27.5)
全部阴性	159(66.2)	37(72.5)

重庆地区儿童耐药结核病患者耐药情况及临床特征分析

Analysis of drug resistance and clinical characteristics of children with drug-resistant tuberculosis in Chongqing

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