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

诊断和预测患有 SARS-CoV-2 相关疾病的儿童的风险

• 批准号: 10849054
• 负责人: JANE C BURNS
• 金额: $ 41.09万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-01-01 至 2024-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10849054
• 关键词: 2019-nCoV; Acute; Address; Administrative Supplement; Aftercare; Artificial Intelligence; Biological Markers; COVID-19 pandemic; Case Study; Child; Clinical; Collaborations; Combined Modality Therapy; Coronary artery; Diagnosis; Diagnostic; England; Enrollment; Equipoise; Erythema; Exanthema; Fever; Functional disorder; Goals; Hour; Immunoglobulin Therapy; Inflammatory; Injections; Intensive Care Units; Interleukin-1; Intravenous Immunoglobulins; Italy; Joints; Laboratories; Lip structure; Modeling; Molecular; Molecular Profiling; Morbidity - disease rate; Mucocutaneous Lymph Node Syndrome; Multisystem Inflammatory Syndrome in Children; Pathogenesis; Patients; Physicians; Plasma; Plasma Cells; Proteome; Proteomics; RNA; Randomized; Serum; Severity of illness; Site; Steroids; Syndrome; System; TNF gene; Therapeutic Uses; Tissues; United States; Viral; Whole Blood; anakinra; comparative effectiveness study; design; improved; inflammatory marker; infliximab; mortality; novel; pandemic disease; pediatric patients; randomized, clinical trials; response; risk prediction; transcriptome sequencing; treatment response

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.

儿童多系统炎症综合征（MIS-C）引起儿童的显着发病率和死亡率 在19日期的大流行期间，我们对分子发病机理或对治疗的反应知之甚少 适用于MIS-C的孩子。这种行政补充的目的是利用 盛行的协作和专业知识，并评估MIS-C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，此应用程序是 响应NOSI NOT-HD-22-003。 MIS-C的儿童发烧，有些儿童出现了皮疹， 结膜注射，嘴唇的红斑，甚至是冠状动脉词典，所有符号 川崎病（KD）。因此，当第一批患者出现在意大利的重症监护病房时 英格兰，然后是美国东海岸，医生到达了许多曾经的治疗剂 对待KD。虽然单独使用静脉免疫球蛋白（IVIG）改善了一些患者，但超过70％ 所需的类固醇，Anakinra（IL-1阻断）和/或英夫利昔单抗（TNFα阻滞）的治疗。就像是 这些疗法中的哪种最适合治疗MIS-C，我们的流行儿童（预测） 具有实验室诊断儿童的病毒相关炎症性疾病严重程度 圣地亚哥分校的情报倡议）团队设计并启动了一个两个站点随机的临床试验 （儿童的多系统炎症综合征疗法（模拟）比较有效性研究）。这 目标是确定最多的疗法（IVIG与类固醇，英夫利昔单抗和/或Anakinra）的组合是最多的 有效降低MIS-C儿童的发病率和死亡率（NCT04898231）。这项研究注册了74 受试者，现在使用新型的贝叶斯关节阶段模型进行了关闭，以供入学和分析 到SNSMART设计。作为模拟的一部分 IVIG或首次递送治疗后12小时。在此行政补充中，我们将评估 通过全血（WB）RNASEQ，血浆细胞进行MIS-C的分子特征 免费（CF）RNA和血浆蛋白质组学，以更好地了解对不同疗法的反应 管理MIS-C的儿童。我们提出了三个实现这一目标的特定目标。具体目标1 将使用IVIG治疗前后的MIS-C患者的RNASEQ分析WBRNA谱，之后 英夫利昔单抗，anakinra和类固醇治疗。特定的目标2将分析cFRNA组织的原点谱的组织 IVIG治疗前后的MIS-C患者以及英夫利昔单抗，Anakinra和类固醇治疗后。具体的 AIM 3将分析IVIG治疗前后MIS-C患者的血浆蛋白质组，以及在英夫利昔单抗之后， Anakinra和类固醇治疗。这两个盛行的团队在这个多中心中的协同专业知识 提案提供了一个独特的机会，可以理解病理生理学和对错误治疗的反应 C，以及可能为这种急性炎症状况而发展的生物标志物。

项目成果

Evaluation of Autoantibody Binding to Cardiac Tissue in Multisystem Inflammatory Syndrome in Children and COVID-19 Vaccination-Induced Myocarditis.

• DOI: 10.1001/jamanetworkopen.2023.14291
• 发表时间: 2023-05-01
• 期刊: JAMA NETWORK OPEN
• 影响因子: 13.8
• 作者: Patel, Harsita;Sintou, Amalia;Chowdhury, Rasheda A.;Rothery, Stephen;Iacob, Alma Octavia;Prasad, Sanjay;Rainer, Peter P.;Martinon-Torres, Federico;Sancho-Shimizu, Vanessa;Shimizu, Chisato;Dummer, Kirsten;Tremoulet, Adriana H.;Burns, Jane C.;Sattler, Susanne;Levin, Michael
• 通讯作者: Levin, Michael