Identifying biomarker signatures of prognostic value for Multisystem Inflammatory Syndrome in Children (MIS-C)

项目总结/摘要 在成人中，SARS-CoV-2感染表现出广泛的临床结果，从无症状到轻度疾病， 严重病毒性肺炎、呼吸窘迫、急性肾损伤、血栓性疾病和严重心脏病， 脑血管和血管并发症。严重感染也可发生在儿童和年轻人 （< 21），很大一部分因Covid-19入院的儿童需要ICU支持，通常包括 机械通气此外，最初无症状的SARS-CoV-2感染的儿童和青少年 患有罕见但非常严重的多系统炎症综合征（MIS-C）。流行病学，临床 以及SARS-CoV-2和MIS-C严重急性感染进展的实验室预测因子 因此，在这一人群中抗击新冠肺炎的斗争中迫切需要。根据NIH Rapid 加速诊断（RADx）计划，生物标志物发现可以实现风险分层和指导 针对出现并发症和/或严重风险增加的Covid-19患者的干预性研究 疾病为了瞄准这一发现的主动性，本文中我们将使用一系列生物学、免疫学和分子生物学方法。 测试，包括光栅耦合荧光等离子体（GCFP）和先进的流式细胞术，以研究 患有轻度、中度或重度SARS-CoV-2感染的儿童和年轻人（<21岁）。GCFP允许 使用可以低成本大量生产并以微阵列形式点样的一次性生物传感器芯片， 大大提高了多路复用能力。此外，我们将使用类似的生物标志物方法进行快速检测。 MIS-C患者与其他儿科感染性或炎性疾病患者的区分， 临床表现类似MIS-C，最重要的是川崎。儿童的生物学和免疫学 对SARS-CoV-2暴露的反应可能受到多种因素的影响，包括遗传学，表观遗传学， 以及粘膜/肠-脑轴、脂肪组织和神经内分泌免疫网络的产物，并且进一步 受到环境暴露的影响。考虑到这些因素，我们假设儿童的生物标志物 对SARS-CoV-2感染的反应谱能够及时准确地预测Covid-19的严重程度 和诊断MIS-C，并将有助于指导治疗策略，并预测患者的结果。为了验证这一 假设，我们将使用非传统的诊断和全面的生物标志物发现来表征 轻度、中度和重度SARS-CoV-2儿童和青少年的临床和实验室谱 感染，以及MIS-C。然后，我们将验证我们新开发的诊断和预后算法， 将MIS-C与其他具有重叠临床表现的炎性疾病（包括川崎）区分开来 疾病，并预测并发症的纵向风险。

PROJECT SUMMARY / ABSTRACT In adults, SARS-CoV-2 infection exhibits a wide range of clinical outcomes, from asymptomatic and mild disease to severe viral pneumonia, respiratory distress, acute kidney injury, thrombotic disorders, and serious cardiac, cerebrovascular and vascular complications. Severe infection can also occur both in children and young adults (< 21), and a significant proportion of children admitted with Covid-19 require ICU support, frequently including mechanical ventilation. In addition, children and adolescents with initially asymptomatic SARS-CoV-2 infection have presented with a rare, but very severe multisystem inflammatory syndrome (MIS-C). Epidemiologic, clinical and laboratory predictors of progression towards severe forms of acute infection with SARS-CoV-2 and MIS-C are thus urgently needed in the fight against Covid-19 in this population. As defined in the NIH Rapid Acceleration of Diagnostics (RADx) program, biomarker discovery can enable risk stratification and guide interventional studies to target Covid-19 patients at enhanced risk of developing complications and/or severe disease. To target this discovery initiative, herein we will use a battery of biological, immunological and molecular tests, including Grating-Coupled Fluorescence Plasmonic (GCFP) and advanced flow cytometry, to study children and young adults (<21 years) with mild, moderate or severe SARS-CoV-2 infection. GCFP allows the use of disposable biosensor chips that can be mass-produced at low cost and spotted in microarray format to greatly increase multiplexing capabilities. In addition, we will use a similar biomarker approach for rapid differentiation of patients with MIS-C versus other pediatric infectious or inflammatory conditions where the clinical presentation resembles MIS-C, most importantly Kawasaki disease. A child’s biologic and immunologic response to SARS-CoV-2 exposure is likely influenced by a variety of factors, including genetics, epigenetics and products of the mucosa/gut-brain axis, adipose tissue and neuroendocrine immune network, and further modulated by environmental exposures. With these factors in mind, we hypothesize that a child’s biomarker profile in response to SARS-CoV-2 infection enables a timely and accurate prediction of severity of Covid-19 and diagnosis of MIS-C, and will help guide treatment strategies, and predict patient outcomes. To test this hypothesis, we will use a non-traditional diagnostic and comprehensive biomarker discovery to characterize the clinical and laboratory spectrum of children and adolescents with mild, moderate and severe SARS-CoV-2 infection, as well as MIS-C. We will then validate our newly developed diagnostic and prognostic algorithm to distinguish MIS-C from other inflammatory disorders with overlapping clinical manifestations, including Kawasaki disease, and predict the longitudinal risk of complications.