Impact of metagenomics next-generation sequencing on etiological diagnosis and early outcomes in sepsis
Feixiang Xu, Chen Chen, Su Lu, Mingming Xue, Hailin Ding, Yanli Song, Yun Zhang, Keyu Sun, Lunxian Tang, Wei Wang, Meitang Wang, Yan Tang, Dingyu Tan, Chenling Yao, Dongwei Shi, Enqiang Mao, Mian Shao, Youguo Ying, Chunmei Zhou, Lihong Huang, Peng Hu, Zhongshu Kuang, Sanqiang Wang, Qingbian Ma, Si Sun, Dongfeng Guo, Tianwen Gu, Bin Yang, Lin Ma, Chengjin Gao, Xiaoye Lu, Hong Zhang, Ruilan Wang, Chaoyang Tong, Zhenju Song
Abstract
BACKGROUND: Clinical implications of metagenomics next-generation sequencing (mNGS) in sepsis have not been fully evaluated. This study aimed to determine the diagnostic, therapeutic, and prognostic impacts of mNGS in sepsis. METHODS: This multicenter prospective study was conducted at 19 sites in China from 2020 to 2021, and 859 adult patients hospitalized with sepsis were enrolled. The advantages, challenges, knowledge gaps and privacy risks of mNGS were carefully introduced to all participants, and participants chose on their own to either receive conventional microbiological test (CMT) alone (conventional-test-only group, n = 394) or receive mNGS test along with CMT (combined test group, n = 465). For prognostic analysis, the primary endpoint was 28-day mortality. Secondary endpoints included 7-day mortality and average per-day hospital cost. Inverse probability of treatment weighting was used to balance covariates between groups. Concurrent CMT and mNGS results from patients in the combined test group were used for diagnostic analyses. Therapeutic impact of mNGS was evaluated based on subsequent antibiotic adjustment. RESULTS: Compared with composite reference standard, the positive percent agreement of mNGS among infected site samples was significantly higher than that of CMT (92.0% [95% CI, 88.7 to 94.5] vs. 51.1% [95% CI, 45.9 to 56.2], p < 0.001), while the negative percent agreement of mNGS was inferior to that of CMT (39.6% [95% CI, 29.5 to 50.4] vs. 69.2% [95% CI, 58.7 to 78.5], p < 0.001). The mNGS test identified causal microbes in 344 (74.0%) patients, and concomitant antibiotic changes occurred in 136 patients (29.2%). Death by day 7 occurred in 24 of 465 (5.2%) patients in the combined test group and in 34 of 394 (8.6%) patients in the conventional-test-only group (hazard ratio, 0.44 [95% CI, 0.26 to 0.77], p = 0.004). However, no significant difference in 28-day mortality was observed between two study groups (hazard ratio, 0.82 [0.56 to 1.20], p = 0.300). CONCLUSIONS: The mNGS test of infected site samples exhibited 40% higher pathogen detection rate than CMT in patients with sepsis, which led to improved etiological diagnosis and tailored antibiotic therapy. Additional use of mNGS halved the risk of early death in 7 days, but did not improve 28-day survival in patients with sepsis. TRIAL REGISTRATION: chictr.org.cn Identifier: ChiCTR2000031113. Registered 22 March 2020.