Early diagnosis of neonatal infections using urine metabolomics

 描述(由申请人提供)：坏死性小肠结肠炎(NEC)、尿路感染(UTIs)和败血症是发生在出生前几周极低出生体重儿(&lt；1500克)的条件。所有这三种情况在一定程度上都是由于不寻常的微生物定植。 NEC、尿路感染和脓毒症的最初临床症状是非特异性的，它们是重叠的。因此，每种情况的诊断往往依赖于密切观察和临床敏锐。一旦诊断被怀疑，实验室确认可能会耗费时间，并浪费治疗特定疾病的机会。在确认疾病之前，可疑婴儿经常接受广谱预防性抗生素治疗，这可能会产生意想不到的负面后果。早期评估风险并区分NEC、UTI和脓毒症的非侵入性测试将改善结果，并可能减少全球范围内不必要的抗生素暴露。为了实现这一长期目标，我们的目标是了解生命早期的生化特征--生物标记物--在健康的新生儿和被诊断患有各种疾病的新生儿之间存在差异。由于NEC、尿路感染和败血症都发生在生物代谢失调和人类新陈代谢的交界处，我们将重点放在尿代谢产物作为动态平衡的指标上。我们开发了一种从废旧尿布中提取尿液的方案，使用高分辨率质谱仪识别代谢物，并应用统计工具将代谢物与疾病状态相关联。因为我们能够从废物中获得必要的生物分子信息，我们准备在一个中心研究大量早产儿。这种研究设计消除了多中心研究中经常存在的变量，包括微生物暴露和污染，并使加快样本采集成为可能。在这个项目的第一年，我们将收集和分析1200个尿布样本。据我们所知，以前没有对早产儿进行大规模的单中心尿液研究，因为很难获得从这一人群收集尿液的同意。我们将使用高效液相色谱高分辨质谱仪对无症状婴幼儿和患病婴幼儿尿液中的生物分子进行检测，并用统计学方法得出有意义的相关性。随着我们发现尿液成分的差异，我们将验证这些差异是否为生物标志物。这些生物标志物将通过为诊断开发提供起点，使全球早产儿NEC、尿路感染和脓毒症的早期风险评估和区分成为可能。在收集这些数据的过程中，我们还将了解胎龄和出生时体重、性别、食物、药物和分娩期间母体药物对产后新生儿代谢的影响。

 DESCRIPTION (provided by applicant): Necrotizing enterocolitis (NEC), urinary tract infections (UTIs), and sepsis are conditions that occur in very low birth weight infants (<1500g) in the first weeks of life. All three conditions are due in part to unusual microbial colonization. The initial clinical symptoms of NEC, UTIs, and sepsis are non-specific and they overlap. Diagnosis of each condition therefore often relies upon close observation paired with clinical acumen. Once diagnosis is suspected, laboratory confirmation can be time-consuming, and opportunities for treating specific conditions are wasted. Prior to confirmation of disease, infant under suspicion frequently receive broad-spectrum prophylactic antibiotic treatment that can have unintended negative consequences. A non-invasive test that assesses risk early and differentiates between NEC, UTIs, and sepsis will improve outcomes and may reduce unnecessary antibiotic exposure worldwide. To achieve this long- term goal, we aim to develop an understanding of the biochemical characteristics-biomarkers-that differ early in life between newborns that will be healthy and those that will be diagnosed with each condition. Because NEC, UTIs, and sepsis all occur at the intersection between dysbiosis and human metabolism, we focus upon urinary metabolic products as indicators of homeostasis. We have developed a protocol for extracting urine from waste diapers, identifying metabolites using high-resolution mass spectrometry, and applying statistical tools to correlate metabolites with disease states. Because we are able to obtain the necessary biomolecular information from a waste product, we are poised to study a large population of preterm newborns at a single center. This study design eliminates variables often present in multi-center studies, including microbial exposure and contamination, and makes it possible to accelerate sample acquisition. We will collect and analyze 1200 diaper samples in year one of this project. To our knowledge, no previous large-scale single-center urine-based study of preterm babies exists because of difficulty obtaining consent to collect urine from this population. We will use liquid chromatography high-resolution mass spectrometry to measure the biological molecules in urine from asymptomatic infants and infants who become ill with the study conditions, and statistical methods to draw meaningful correlations. As we uncover differences in the composition of urine, we will validate these differences as biomarkers. These biomarkers will enable earlier risk assessment and differentiation for NEC, UTIs, and sepsis in preterm infants worldwide by providing a starting point for diagnostic development. In the process of collecting these data, we will also learn about how gestational age and weight at birth, gender, food, pharmaceuticals, and maternal medications during birth impact neonatal metabolism post-partum.