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

识别儿童多系统炎症综合征 (MIS-C) 预后价值的生物标志物特征

• 批准号: 10733688
• 负责人: MICHAEL A LYNES
• 金额: $ 163.76万
• 依托单位: CONNECTICUT CHILDREN'S MEDICAL CENTER
• 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/10733688
• 关键词: 2019-nCoV; Acute Renal Failure with Renal Papillary Necrosis; Acute Respiratory Distress Syndrome; Address; Adipose tissue; Admission activity; Adolescent; Adult; Algorithms; Asthma; Attention; Biological; Biological Markers; Biometry; Biosensor; Black American; Blood; Blood Vessels; COVID-19; COVID-19 outbreak; COVID-19 patient; COVID-19 severity; Cardiac; Child; Childhood; Clinical; Collaborations; Collection; Colombia; Coupled; Detection; Diagnosis; Diagnostic; Disease; Elderly; Enrollment; Environmental Exposure; Epidemiology; Epigenetic Process; Europe; Exhibits; Flow Cytometry; Fluorescence; Genetic; Hispanic Americans; Immune; Immune response; Immunologics; Infection; Inflammatory; Intervention Studies; Laboratories; Machine Learning; Mechanical ventilation; Mind; Molecular; Morbidity - disease rate; Mucocutaneous Lymph Node Syndrome; Mucous Membrane; Multisystem Inflammatory Syndrome in Children; Native Americans; Neurosecretory Systems; Obesity; Outcome; Patient-Focused Outcomes; Patients; Population; Prediction of Response to Therapy; RADx; Reporting; Respiratory distress; Risk; SARS-CoV-2 exposure; SARS-CoV-2 infection; Saliva; Sampling; Severity of illness; Spottings; Symptoms; Syndrome; System; Techniques; Technology; Testing; Thrombosis; United States; United States National Institutes of Health; Viral Pneumonia; Virus; acute infection; arm; biobank; biomarker discovery; biomarker identification; biosignature; care outcomes; cerebrovascular; clinically relevant; cohort; cost; deep learning; diagnostic algorithm; diagnostic value; fighting; gut-brain axis; instrument; microbiome analysis; minority children; mortality; participant enrollment; plasmonics; point of care testing; potential biomarker; prognostic; prognostic algorithm; prognostic signature; prognostic value; programs; response; risk stratification; severe COVID-19; treatment strategy; young adult

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.

项目摘要/摘要 在成人中，SARS-CoV-2感染表现出广泛的临床结果，从无症状到轻微疾病。 严重的病毒性肺炎，呼吸窘迫，急性肾脏损伤，血栓形成障碍，以及严重的心脏疾病， 脑血管和血管并发症。严重感染也可能发生在儿童和年轻人身上。 (&lt；21)，相当大比例的新冠肺炎患儿需要重症监护病房的支持，通常包括 机械通风。此外，最初无症状的SARS-CoV-2感染的儿童和青少年 出现了一种罕见但非常严重的多系统炎症综合征(MIS-C)。流行病学，临床 和实验室预测进展为严重形式的SARS-CoV-2和MISC急性感染 因此，在与新冠肺炎的斗争中，这些人是迫切需要的。如《美国国立卫生研究院快速报告》所定义 加速诊断(RADx)计划，生物标记物发现可以实现风险分层和指导 针对发生并发症和/或严重并发症风险增加的新冠肺炎患者的干预性研究 疾病。为了针对这一发现倡议，在这里，我们将使用一组生物学、免疫学和分子 测试，包括光栅耦合荧光等离子(GCFP)和先进的流式细胞术，以研究 轻、中、重度SARS-CoV-2感染的儿童和青壮年(21岁)。GCFP允许 使用一次性生物传感器芯片，这种芯片可以低成本大规模生产，并以微阵列格式进行定位 极大地提高了多路复用能力。此外，我们将使用类似的生物标记物方法来快速 与其他儿科感染性或炎症性疾病患者的区别 临床表现类似于MISC，最重要的是川崎病。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，并进一步 受环境暴露的影响。考虑到这些因素，我们假设儿童的生物标记物 应对SARS-CoV-2感染的概况能够及时准确地预测新冠肺炎的严重程度 并将有助于指导治疗策略，并预测患者的预后。为了测试这一点 假设，我们将使用非传统的诊断和全面的生物标记物发现来表征 儿童青少年轻、中、重度SARS-CoV-2的临床和实验室研究 感染以及MISC。然后，我们将验证我们新开发的诊断和预测算法以 与包括川崎在内的其他临床表现重叠的炎症性疾病区分开来 疾病，并预测并发症的纵向风险。