Serum metabolic signature differentiates neonatal sepsis from controls and resolves upon recovery.

Sepsis, a life-threatening disorder with multi-organ dysfunction, is a leading cause of neonatal mortality. Current microbiology-based sepsis diagnosis is time-consuming, and identification of deregulated host serum metabolite signatures might be useful to develop early screening tools and host-directed therapeutics. In this multi-institutional study, 500 neonates (41%, female) were classified to culture-positive (CP) or negative sepsis (CN) cases and controls (no sepsis: NS, healthy control: HC) based on their microbial culture and mass spectrometry test results. The neonates were randomly grouped into two discovery sets (I:n=71; II:n=269), a validation set (n=60), and a longitudinally followed-up population (n=100). Serum samples of these neonates were processed and profiled using gas chromatography coupled to either quadrupole or time-of-flight mass spectrometry (GC-MS/-TOF-MS). Deregulated (log2¬case/control ≥±0.58, p<0.05) serum metabolites in sepsis cases were identified from the discovery sets and their predictive accuracy in the validation set was calculated using area under the receiving operator characteristic curve (AUC of ROC). The abundance of these deregulated metabolites was monitored in the longitudinally followed-up neonates (CP:n=29, CN:n=35, and NS:n=36) completing therapeutic intervention. Most of the CP cases were Klebsiella pneumoniae (28.6%) or Acinetobacter baumannii (20.6%) positive. Gestational age (CP: 30.9±1.9 weeks, CN: 30.9±1.8 weeks, HC: 32.3±1.3 weeks, NS: 31.6±1.5 weeks) and birthweight (CP: 1.4±0.3 kg, CN: 1.4±0.4 kg, HC: 1.7±0.3 kg, NS: 1.6±0.3 kg) were lower in sepsis neonates compared to controls. Out of 57 identified serum metabolites, a set of six (1,5-Anhydro-D-sorbitol-Lactic-acid-Malic-acid-Myo-inositol-Phenylalanine-Lysine) were identified as sepsis biosignature. The AUC of ROC of the biosignature to predict CP or CN from HC was 0.97 and from NS was 0.84 and 0.64, respectively. Myo-inositol, malic acid, and 1,5-anhydro-D-sorbitol revert to the HC levels in neonates completing therapeutic intervention. A serum metabolite signature showed a >97% predictive accuracy for sepsis and could further be explored for its diagnostic potential and host-directed therapeutics development.

脓毒症（Sepsis）是一类可危及生命的多器官功能障碍性疾病，亦是新生儿死亡的首要诱因之一。当前基于微生物学的脓毒症诊断流程耗时冗长，而识别失调的宿主血清代谢物特征或可助力开发早期筛查工具与宿主导向治疗药物。本项多中心研究中，研究人员依据微生物培养与质谱检测结果，将500名新生儿（其中41%为女性）划分为培养阳性脓毒症（culture-positive, CP）组、培养阴性脓毒症（culture-negative, CN）组，以及对照组：无脓毒症组（no sepsis, NS）与健康对照组（healthy control, HC）。所有受试者被随机分为两个发现队列（队列I：n=71；队列II：n=269）、一个验证队列（n=60）与一个纵向随访队列（n=100）。研究人员采用气相色谱-四极杆/飞行时间质谱联用技术（GC-MS/-TOF-MS）对上述新生儿的血清样本进行处理与代谢组谱分析。从两个发现队列中筛选出脓毒症病例中失调的血清代谢物（log₂(病例/对照)≥±0.58，p<0.05），并通过受试者工作特征曲线下面积（Area Under Receiver Operating Characteristic Curve, AUC of ROC）计算其在验证队列中的预测效能。对完成治疗干预的纵向随访新生儿（CP组29例、CN组35例、NS组36例）的失调代谢物丰度进行动态监测。多数CP组病例为肺炎克雷伯菌（Klebsiella pneumoniae，28.6%）或鲍氏不动杆菌（Acinetobacter baumannii，20.6%）感染。与对照组相比，脓毒症新生儿的胎龄（CP组：30.9±1.9周，CN组：30.9±1.8周，HC组：32.3±1.3周，NS组：31.6±1.5周）与出生体重（CP组：1.4±0.3 kg，CN组：1.4±0.4 kg，HC组：1.7±0.3 kg，NS组：1.6±0.3 kg）均显著更低。在鉴定出的57种血清代谢物中，6种代谢物（1,5-脱水-D-山梨醇、乳酸、苹果酸、肌醇、苯丙氨酸、赖氨酸）被鉴定为脓毒症生物特征标志物组。该生物特征标志物组从健康对照中区分培养阳性与阴性脓毒症的ROC曲线下面积为0.97；从非脓毒症对照中区分的ROC AUC分别为0.84与0.64。肌醇、苹果酸与1,5-脱水-D-山梨醇的水平在完成治疗干预的新生儿中恢复至健康对照水平。本研究鉴定的血清代谢物特征对脓毒症的预测准确率超过97%，其诊断应用潜力与宿主导向治疗药物开发价值有待进一步探索。