Identifying immune correlates of disease severity and novel immune drivers of pathogenicity to target in patients with COVID-19

对感染SARS-CoV-2的反应具有高度的异质性，迄今为止的报告表明，绝大多数患者的症状都很轻微，而有相当一部分患者出现了与高炎症反应相关的危及生命的肺损伤。虽然初步研究表明细胞因子风暴是肺损伤的主要驱动因素，但最近的观察表明，导致严重脉管炎和弥散性血管内凝血的血管病变也可能在新冠肺炎病的病理生理机制中发挥重要作用。无论是致病性还是反应性，考虑到大部分的发病率和死亡率也与高炎症有关，更好地了解差异反应的免疫学基础对于更好地确定治疗靶点是必要的。数十种免疫调节剂正在迅速进入临床试验，并被常规使用，但没有彻底了解哪些炎症途径和细胞类型是最好的靶点，这可能对危重患者有害。其中许多药物正在纽约的西奈山卫生系统内进行测试，纽约是一个受新冠肺炎影响最大的城市。我们建议集中我们的人类免疫监测中心(HIMC)和西奈山癌症免疫监测和分析中心(CIMAC)的大量资源，这两个中心已经建立和验证了平台，以前所未有的深度表征SARS-CoV-2患者在诊断和疾病进展期间的免疫表型，总体目标是建立一种算法来预测疾病严重程度、指导免疫调节策略以及识别疾病的新免疫靶点。

There is a highly heterogeneous response to infection with SARS-CoV-2 with reports to date suggesting the vast majority of patients are minimally symptomatic, while a significant subset developing life-threatening lung injury associated with hyper-inflammatory response. While initial studies suggested that the cytokine storm was the main driver of lung injuries, more recent observation suggest that vascular lesions leading to severe vasculitis and disseminated intravascular coagulation may also significantly contribute to COVID-19 disease pathophysiology. Regardless of whether the hyperinflammation is causative or reactive, given much of the morbidity and mortality is also associated with hyperinflammation, a better understanding of the immunologic underpinnings of differential responsiveness is necessary to better identify therapeutic targets. Dozens of immunomodulatory agents are rapidly going into clinical trials as well as being used routinely, without a thorough understanding for which inflammatory pathways and cell types to best target, which could be detrimental to critically ill patients. Many of these agents are being tested within the Mount Sinai Health System in New York, a city disproportionately affected by COVID-19. We propose to focus the significant resources of our Human Immune Monitoring Center (HIMC) and the Mount Sinai Cancer Immune Monitoring and Analysis Centers (CIMAC), which have well established and validated platforms to characterize to an unprecedented depth the immune phenotype of SARS-CoV-2 patients at diagnosis and during disease progression with the overarching goal to establish an algorithm to predict disease severity and guide immunomodulatory strategies as well as identify novel immune targets of disease.