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

在新冠肺炎大流行之后，儿童多系统炎症综合征(MISC)已演变为一种 暴露在SARS-CoV-2中的儿童面临新的威胁。管理信息系统C的出现是如此之新，发展如此之快 目前还没有诊断测试来识别这些患者，也没有工具来预测疾病 进步。通过在美国建立的、有资金支持的多中心财团(魅力：特征 MIS-C及其与川崎病的关系由PCORI资助)和英国(钻石)，我们将收集 支持拟议研究的临床数据和样本。首先，我们将生成文字记录、蛋白质和 来自新冠肺炎、MISC和其他发热性疾病儿童的抗体数据集。接下来，我们将使用这些 设计测试数据以区分有发展为严重新冠肺炎或MISC风险的儿童和诊断 测试以将这些情况与儿童发烧的其他原因区分开来。延续我们已有的 与哥伦比亚大学合作，我们将确定针对所有已知人类的抗体谱系 并确定先前存在的针对其他冠状病毒的抗体可能如何塑造免疫 SARS-CoV-2急性感染和MIS-C的反应头两年(R61)将建立在 联合团队在MIS-C和SARS-CoV-2中发现独特的蛋白质组和转录模式 感染患者和相关临床参数与冠状病毒抗原的抗体反应 多肽阵列。这项工作将利用已经储存的血浆、血清和RNA样本，这些样本来自患有 新冠肺炎、MISC、川崎病等炎症性条件。严格的去/不去标准有 已经建立，并将决定进展到R33阶段。最后两年(R33)将重点放在 平台开发以及多中心和两国测试验证，以诊断和预测 基于适体技术的SARS-CoV-2感染或MIS-C儿童，侧向流动蛋白检测， 与商业合作伙伴进行服务点RNA或抗体分析。未识别的临床和分子数据 将存放在RADx-RAD中心，以便利数据共享。这类研究中的许多潜在障碍 已经克服了：a)IRB批准的患者招募数据和样本正在进行中，b)临床 样本已被储存，c)已产生关于RNAseq、适体蛋白质组学的强大初步数据， 和冠状病毒抗体反应，以及d)两个团队在以前的合作和 生产力。这些调查团队在这项多中心提案中的协同专业知识提供了 为患有SARS谱系的儿童创造诊断和预后工具的独特机会- 冠状病毒2型疾病。 1

In the wake of COVID-19 pandemic, Multisystem Inflammatory Syndrome in Children (MIS-C) has evolved as a new threat to children exposed to SARS-CoV-2. The emergence of MIS-C is so new and so rapidly evolving that there are currently no diagnostic tests to identify these patients nor are there tools to predict disease progression. Through established, funded, multi-center consortia in the U.S. (CHARMS: Characterization of MIS-C and its Relationship to Kawasaki Disease funded by PCORI) and the UK (DIAMONDS), we will collect clinical data and samples to support the proposed studies. First, we will generate transcript, protein and antibody datasets from children with COVID-19, MIS-C, and with other febrile illnesses. Next, we will use these data to devise tests to distinguish children at risk of progression to severe COVID-19 or MIS-C and diagnostic tests to distinguish these conditions from other causes of fever in children. Continuing our established collaboration with Columbia University, we will define the antibody repertoire against all known human coronaviruses and determine how pre-existing antibody to other coronaviruses may shape the immune response in acute SARS-CoV-2 infection and MIS-C. The first two years (R61) will build on the expertise of the assembled teams to discover unique proteomic and transcriptomic patterns in MIS-C and SARS-CoV-2- infected patients and relate clinical parameters to the antibody response to coronaviral antigens profiled on peptide arrays. This work will leverage already banked plasma, serum, and RNA samples from children with COVID-19, MIS-C, Kawasaki disease and other inflammatory conditions. Rigorous Go/NoGo criteria have been established and will determine progression to the R33 phase. The final two years (R33) will focus on platform development and multicenter and bi-national test validation to diagnose and predict severity in children with SARS-CoV-2 infection or MIS-C based on aptamer technology, lateral-flow protein detection, point-of-service RNA or antibody profiling with commercial partners. De-identified clinical and molecular data will be deposited in the RADx-rad hub to facilitate data sharing. Many potential hurdles in this type of research have already been overcome: a) IRB-approved patient recruitment for data and samples is on-going, b) clinical samples have been banked, c) strong preliminary data has been generated on RNAseq, aptamer proteomics, and coronaviral antibody responses, and d) the teams have a strong track record of previous collaboration and productivity. The synergistic expertise of these investigative teams in this multi-center proposal provides a unique opportunity to create diagnostic and prognostic tools for children suffering from the spectrum of SARS- CoV-2 illnesses. 1