Diagnosing and predicting risk in children with SARS-CoV-2- related illness

儿童多系统炎性综合征（MIS-C）是一种严重的儿童疾病 在COVID-19大流行期间，但我们对分子发病机制或对治疗的反应知之甚少 对于患有MIS-C的孩子来说。这一行政补充的目标是利用 PreVAIL的合作和专业知识，并评估MIS-C治疗前后的分子特征， 治疗，以更好地了解对不同治疗的反应。因此，该应用程序 响应NOSI NOT-HD-22-003。患有MIS-C的儿童表现为发烧，有些人出现皮疹， 结膜充血，嘴唇红斑，甚至冠状动脉扩张，所有与 川崎。出于这个原因，当第一批病人出现在意大利的重症监护室时， 在英国和美国东海岸，医生们开始使用许多过去常用于治疗的药物。 治疗KD。虽然一些患者单独使用静脉注射免疫球蛋白（IVIG）改善，但超过70%的患者在治疗后出现了症状。 需要类固醇、阿那白滞素（IL-1阻断）和/或英夫利西单抗（TNFα阻断）治疗。因为有 关于这些疗法中哪一种最适合治疗MIS-C的临床平衡，我们的PreVAIL kIds（预测 儿童病毒相关性炎症性疾病的严重程度与实验室诊断和人工 美国加州大学圣地亚哥分校的一个研究小组设计并启动了一项双中心随机临床试验 儿童多系统炎症综合征治疗（MISTIC）比较有效性研究。的 目的是确定哪种联合治疗（IVIG与类固醇，英夫利昔单抗和/或阿那白滞素）最 有效降低MIS-C儿童的发病率和死亡率（NCT 04898231）。本研究共招募了74名 受试者，目前已关闭入组，并正在使用应用的新型贝叶斯联合分期模型进行分析 snsmart设计作为MISTIC的一部分，在IVIG前收集血清、血浆和全血RNA， IVIG或首次随机化治疗后12小时。在这份行政补充文件中，我们将评估 MIS-C治疗前和治疗后的分子特征，通过全血（全血）RNAseq、浆细胞 游离（cf）RNA和血浆蛋白质组学，以更好地了解对不同治疗的反应 对患有MIS-C的儿童进行治疗。我们提出了三个具体目标来实现这一目标。具体目标1 将使用RNAseq分析MIS-C患者IVIG治疗前后的wbRNA谱，以及IVIG治疗后的wbRNA谱。 英夫利昔单抗、阿那白滞素和类固醇治疗。Specific Aim 2将分析CfRNA组织来源谱， MIS-C患者在IVIG治疗前后，以及英夫利昔单抗、阿那白滞素和类固醇治疗后。具体 目的3分析MIS-C患者IVIG治疗前后及英夫利昔单抗治疗后的血浆蛋白质组， 阿那白滞素和类固醇治疗。这两个PreVAIL团队在这个多中心的协同专业知识 该提案提供了一个独特的机会，了解病理生理学和对MIS治疗的反应- C，以及潜在的开发这种急性炎症条件的生物标志物。

Multisystem Inflammatory Syndrome in Children (MIS-C) caused significant morbidity and mortality in children during the COVID-19 pandemic, but we know little about the molecular pathogenesis or response to treatments for children with MIS-C. The goal of this administrative supplement is to harness the strength of collaboration and expertise from PreVAIL and evaluate the molecular signature of MIS-C pre- and post- treatment to better understand the response to different treatments. Therefore, this application is responsive to NOSI NOT-HD-22-003. Children with MIS-C presented with fever and some had rash, conjunctival injection, erythema of the lips, and even coronary artery dilation, all signs associated with Kawasaki disease (KD). For this reason, when the first patients presented to intensive care units in Italy, England and then the East Coast of the United States, physicians reached for many of the therapeutics used to treat KD. While some patients improved with intravenous immunoglobulin (IVIG) alone, more than 70% required treatment with steroids, anakinra (IL-1 blockade) and/or infliximab (TNFα blockade). As there was clinical equipoise as to which of these therapies was best for treating MIS-C, our PreVAIL kIds (Predicting Viral-Associated Inflammatory Disease Severity in Children with Laboratory Diagnostics and Artificial Intelligence Initiative) team at UC San Diego designed and launched a two-site randomized, clinical trial (Multisystem Inflammatory Syndrome Therapies in Children (MISTIC) Comparative Effectiveness Study). The goal was to determine which combination of therapies (IVIG with steroids, infliximab and/or anakinra) was most effective in reducing morbidity and mortality in children with MIS-C (NCT04898231). This study enrolled 74 subjects and is now closed for enrollment and under analysis using a novel Bayesian joint stage model applied to the snSMART design. As part of MISTIC, serum, plasma and whole blood RNA were collected pre-IVIG and 12 hours after IVIG or the first-randomized therapy. In this administrative supplement, we will evaluate the molecular signature of MIS-C pre- and post-treatment through whole blood (wb) RNAseq, plasma cell free (cf) RNA, and plasma proteomics to better understand the response to different treatments administered to children with MIS-C. We propose three specific aims to achieve this goal. Specific Aim 1 will analyze the wbRNA profiles using RNAseq of MIS-C patients before and after IVIG therapy, and after infliximab, anakinra, and steroid treatment. Specific Aim 2 will analyze the cfRNA tissue of origin profile of MIS-C patients before and after IVIG therapy, and after infliximab, anakinra and steroid treatment. Specific Aim 3 will analyze the plasma proteome of MIS-C patients before and after IVIG therapy, and after infliximab, anakinra and steroid treatment. The synergistic expertise of these two PreVAIL teams in this multi-center proposal provides a unique opportunity to understand the pathophysiology and response to treatment of MIS- C, as well as potentially develop biomarkers for this acute, inflammatory condition.