Sepsis is defined as dysregulated host response to infection that leads to life-threatening organ dysfunction. Biomarkers characterising the dysregulated host response in sepsis are lacking. We aimed to develop host gene expression signatures to predict organ dysfunction in children with bacterial or viral infection. This cohort study was done in emergency departments and intensive care units of four hospitals in Queensland, Australia, and recruited children aged 1 month to 17 years who, upon admission, underwent a diagnostic test, including blood cultures, for suspected sepsis. Whole-blood RNA sequencing of blood was performed with Illumina NovaSeq (San Diego, CA, USA). Samples with completed phenotyping, monitoring, and RNA extraction by March 31, 2020, were included in the discovery cohort; samples collected or completed thereafter and by Oct 27, 2021, constituted the Rapid Paediatric Infection Diagnosis in Sepsis (RAPIDS) internal validation cohort. An external validation cohort was assembled from RNA sequencing gene expression count data from the observational European Childhood Life-threatening Infectious Disease Study (EUCLIDS), which recruited children with severe infection in nine European countries between 2012 and 2016. Feature selection approaches were applied to derive novel gene signatures for disease class (bacterial viral infection) and disease severity (presence absence of organ dysfunction 24 h post-sampling). The primary endpoint was the presence of organ dysfunction 24 h after blood sampling in the presence of confirmed bacterial versus viral infection. Gene signature performance is reported as area under the receiver operating characteristic curves (AUCs) and 95% CI. Between Sept 25, 2017, and Oct 27, 2021, 907 patients were enrolled. Blood samples from 595 patients were included in the discovery cohort, and samples from 312 children were included in the RAPIDS validation cohort. We derived a ten-gene disease class signature that achieved an AUC of 94·1% (95% CI 90·6–97·7) in distinguishing bacterial from viral infections in the RAPIDS validation cohort. A ten-gene disease severity signature achieved an AUC of 82·2% (95% CI 76·3–88·1) in predicting organ dysfunction within 24 h of sampling in the RAPIDS validation cohort. Used in tandem, the disease class and disease severity signatures predicted organ dysfunction within 24 h of sampling with an AUC of 90·5% (95% CI 83·3–97·6) for patients with predicted bacterial infection and 94·7% (87·8–100·0) for patients with predicted viral infection. In the external EUCLIDS validation dataset (n=362), the disease class and disease severity predicted organ dysfunction at time of sampling with an AUC of 70·1% (95% CI 44·1–96·2) for patients with predicted bacterial infection and 69·6% (53·1–86·0) for patients with predicted viral infection. In children evaluated for sepsis, novel host transcriptomic signatures specific for bacterial and viral infection can identify dysregulated host response leading to organ dysfunction. Australian Government Medical Research Future Fund Genomic Health Futures Mission, Children's Hospital Foundation Queensland, Brisbane Diamantina Health Partners, Emergency Medicine Foundation, Gold Coast Hospital Foundation, Far North Queensland Foundation, Townsville Hospital and Health Services SERTA Grant, and Australian Infectious Diseases Research Centre.

中文翻译：

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宿主基因表达特征可识别脓毒症儿童的感染类型和器官功能障碍：一项多中心队列研究

脓毒症被定义为宿主对感染的反应失调，导致危及生命的器官功能障碍。缺乏表征脓毒症宿主反应失调的生物标志物。我们的目的是开发宿主基因表达特征来预测细菌或病毒感染儿童的器官功能障碍。这项队列研究是在澳大利亚昆士兰州四家医院的急诊科和重症监护室进行的，招募了 1 个月至 17 岁的儿童，他们在入院时接受了疑似败血症的诊断测试，包括血培养。使用 Illumina NovaSeq（美国加利福尼亚州圣地亚哥）对血液进行全血 RNA 测序。截至 2020 年 3 月 31 日，已完成表型分析、监测和 RNA 提取的样本均纳入发现队列；此后至 2021 年 10 月 27 日收集或完成的样本构成了败血症儿科感染快速诊断 (RAPIDS) 内部验证队列。外部验证队列是根据欧洲儿童危及生命的传染病观察研究 (EUCLIDS) 的 RNA 测序基因表达计数数据组装而成，该研究在 2012 年至 2016 年间招募了九个欧洲国家的严重感染儿童。疾病类别（细菌病毒感染）和疾病严重程度（采样后 24 小时是否存在器官功能障碍）的新基因特征。主要终点是在确认存在细菌与病毒感染的情况下采血后 24 小时是否存在器官功能障碍。基因特征性能以接受者操作特征曲线 (AUC) 和 95% CI 下的面积报告。 2017年9月25日至2021年10月27日期间，共有907名患者入组。来自 595 名患者的血液样本被纳入发现队列，来自 312 名儿童的样本被纳入 RAPIDS 验证队列。我们得出了一个十基因疾病类别特征，在 RAPIDS 验证队列中区分细菌和病毒感染时，其 AUC 为 94·1% (95% CI 90·6–97·7)。在 RAPIDS 验证队列中，在采样 24 小时内预测器官功能障碍时，十基因疾病严重程度特征的 AUC 达到 82·2%（95% CI 76·3–88·1）。疾病类别和疾病严重程度特征串联使用，可在采样后 24 小时内预测器官功能障碍，预测细菌感染患者的 AUC 为 90·5% (95% CI 83·3–97·6)，而预测细菌感染的患者为 94·7% (87·8–100·0) 对于预测有病毒感染的患者。在外部 EUCLIDS 验证数据集中 (n=362)，疾病类别和疾病严重程度预测采样时的器官功能障碍，对于预测细菌性的患者，AUC 为 70·1% (95% CI 44·1–96·2)感染，预测病毒感染的患者为 69·6% (53·1–86·0)。在评估败血症的儿童中，针对细菌和病毒感染的新型宿主转录组特征可以识别导致器官功能障碍的失调宿主反应。澳大利亚政府医学研究未来基金基因组健康未来使命、昆士兰儿童医院基金会、布里斯班 Diamantina Health Partners、急诊医学基金会、黄金海岸医院基金会、远北昆士兰基金会、汤斯维尔医院和卫生服务 SERTA 补助金以及澳大利亚传染病研究中心。