Zhang Ying, Zhao Ruiqiu, Zhang Zhenzhen, Liu Quanbo, Zhang Aihua, Ren Qiaoli, Li Siyuan, Long Xiaoru, Xu Hongmei
Department of Infection, 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, Chongqing Key Laboratory of Child Infection and Immunity, The Children's Hospital of Chongqing Medical University, Chongqing, People's Republic of China.
Infect Drug Resist. 2021 Oct 24;14:4375-4393. doi: 10.2147/IDR.S331890. eCollection 2021.
Pediatric tuberculosis (TB) is one of the top ten causes of death in children. Our study was to analyze influencing factors of multidrug-resistant tuberculosis (MDR-TB) and validation of whole-genome sequencing (WGS) used in children with drug-resistant TB (DR-TB).
All (Mtb) strains were isolated from patients aged below 18 years old of Children's Hospital of Chongqing Medical University, China. A total of 208 isolates were tested for eight anti-TB drugs with phenotypic drug susceptibility test (DST) and for genetic prediction of the susceptible profile with WGS. The patients corresponding to each strain were grouped according to drug resistance and genotype. Influencing factors of MDR-TB and DR-TB were analyzed.
According to the phenotypic DST and WGS, 82.2% of strains were susceptible to all eight drugs, and 6.3% were MDR-TB. Using the phenotypic DSTs as the gold standard, the kappa value of WGS to predict isoniazid, rifampin, ethambutol, rifapentine, prothionamide, levofloxacin, moxifloxacin and amikacin was 0.84, 0.89, 0.59, 0.86, 0.89, 0.82, 0.88 and 1.00, respectively. There was significant difference in the distribution of severe TB, diagnosis, treatment and outcome between MDR and drug-susceptible group (P<0.05). The distribution of severe TB and treatment between DR and drug-susceptible group was statistically different (P<0.05). The results of binary logistic regression showed that Calmette-Guérin bacillus (BCG) vaccine is the protective factor for MDR-TB (OR=0.19), and MDR-TB is the risk factor for PTB and EPTB (OR=17.98).
The BCG vaccine is a protective factor for MDR-TB, and MDR-TB might not be confined to pulmonary infection, spreading to extrapulmonary organs in children. MDR-TB had more severe cases and a lower recovery rate than drug-susceptible TB. WGS could provide an accurate prediction of drug susceptibility test results for anti-TB drugs, which are needed for the diagnosis and precise treatment of TB in children.
儿童结核病是儿童十大死因之一。本研究旨在分析耐多药结核病（MDR-TB）的影响因素，并验证全基因组测序（WGS）在耐药结核病（DR-TB）儿童中的应用。
所有结核分枝杆菌（Mtb）菌株均分离自中国重庆医科大学附属儿童医院18岁以下患者。共208株菌株进行了8种抗结核药物的表型药敏试验（DST）以及WGS对药敏谱的基因预测。将每种菌株对应的患者按耐药性和基因型分组。分析MDR-TB和DR-TB的影响因素。
根据表型DST和WGS，82.2%的菌株对所有8种药物敏感，6.3%为MDR-TB。以表型DST为金标准，WGS预测异烟肼、利福平、乙胺丁醇、利福喷汀、丙硫异烟胺、左氧氟沙星、莫西沙星和阿米卡星的kappa值分别为0.84、0.89、0.59、0.86、0.89、0.82、0.88和1.00。MDR组与药物敏感组在重症结核病的分布、诊断、治疗及转归方面存在显著差异（P<0.05）。DR组与药物敏感组在重症结核病的分布及治疗方面存在统计学差异（P<0.05）。二元logistic回归结果显示，卡介苗（BCG）疫苗是MDR-TB的保护因素（OR=0.19），而MDR-TB是肺结核（PTB）和肺外结核（EPTB）的危险因素（OR=17.98）。
卡介苗疫苗是MDR-TB的保护因素，且MDR-TB可能不限于肺部感染，在儿童中可扩散至肺外器官。MDR-TB比药物敏感结核病的病情更严重，治愈率更低。WGS可为抗结核药物的药敏试验结果提供准确预测，这对儿童结核病的诊断和精准治疗是必要的。
