Multiparametric mapping of Covid-19 immune responses in Kidney transplant recipients

摘要 截至2020年5月，全球已报告超过500万例COVID-19确诊病例，其中超过40万例 相关死亡。大约5-20%的患者发展为危重病，主要表现为急性 呼吸窘迫综合征当这种情况发生时，估计死亡率在40%左右，高达80% 在呼吸机患者中。一些早期的报道描述了过度炎症反应的发展， 所谓的“细胞因子风暴”，与临床状况的迅速恶化密切相关， mortality. 早期报告肾移植受者，谁是在高风险，由于慢性免疫抑制和 其他合并症，描绘了一幅令人担忧的画面。在一个36例患者的系列中，39%需要 机械通气，21%需要肾脏替代治疗，28%死亡。在11名患者中， 插管，64%死亡。然而，仍然存在理解疾病自然过程、具体的 风险因素，识别生物标志物，以及COVID-19对移植物/患者生存的潜在影响， 脆弱的KTR为了填补这一信息空白，我们提出了一个全面的观察分析， 在2个医疗中心的COVID 19感染的KTR中的流行病学因素和免疫测定结果 纽约市的COVID 19感染中心（曼哈顿的西奈山医院和 布朗克斯）。我们假设特定的受体临床特征会影响COVID-19的临床病程 KTR中的受体免疫抑制改变了COVID-19 KTR发展的能力 保护性抗COVID-19体液和细胞介导的免疫，导致发病率， 这些人的死亡。 我们将通过以下方式检验这一假设：1）在一个大型KTR数据集中检查COVID-19严重程度的风险因素， 来自普通人群的COVID-19个体（目标1）; 2）通过表征COVID-19反应性 从COVID-19 KTR连续收集的样本中的体液和细胞免疫应答（目的2）;以及3）通过 全面评估COVID-19 KTR的DNA和系列血清、RNA和PBMC，以确定 疾病机制和结果的潜在信息生物标志物（目标3）。 由于该疾病的高发病率、社区传播率， 高死亡率和缺乏明显有效的治疗选择。我们的研究将是第一批 确定肾移植中COVID-19的风险因素、预测因素和致病机制， 适用于其他移植器官的接受者，以及由于以下原因而慢性免疫抑制的个体： 自身免疫性疾病

Abstract As of May 2020, over five million confirmed cases of COVID-19 have been reported globally with over 400,000 associated deaths. Around 5-20% of patients develop critical illness, which predominantly manifests as acute respiratory distress syndrome. When this develops, the estimated mortality is around 40%, and as high as 80% in ventilated patients. Several early reports describe the development of an excessive inflammatory response, the so-called `cytokine storm', which is strongly associated with rapid deterioration in clinical condition and mortality. Early reports of kidney transplant recipients, who are at high risk due to chronic immunosuppression and additional comorbid diseases, portray a concerning picture. In one series of 36 patients, 39% required mechanical ventilation, 21% required renal replacement therapy, and 28% died. Of the 11 patients that were intubated, 64% died. However, there is still an unmet need of understanding disease natural course, specific risk factors, identifying biomarkers, as well as potential impact of COVID-19 on graft/patient survival in vulnerable KTRs. To fill this information gap, we propose a comprehensive observational analysis of epidemiological factors and immunological assay results in COVID19-infected KTRs at 2 medical centers at the epicenter of COVID19 infection in NYC (Mount Sinai Hospital in Manhattan and Montefiore Hospital in the Bronx). We hypothesize that specific recipient clinical characteristics affect COVID-19 clinical course and that recipient immunosuppression in KTRs alters the ability of COVID-19 KTRs to develop protective anti-COVID-19 humoral and cell-mediated immunity that contributes to the morbidity and mortality of these individuals. We will test this hypothesis by 1) examining risk factors of COVID-19 severity in a large dataset of KTRs and individuals from the general population with COVID-19 (aim 1); 2) by characterizing the COVID-19 reactive humoral and cellular immune response in serially collected samples from COVID-19 KTRs (aim 2); and 3) by comprehensive assessment of DNA and serial serum, RNA, and PBMC from COVID-19 KTRs to identify disease mechanisms and potentially informative biomarkers for outcomes (aim 3). The proposed work is significant because of the high incidence of the disease, rate of community transmission, high mortality, and absence of clearly effective therapeutic options. Our studies will be amongst the first to define risk factors, predictors, and pathogenic mechanisms of COVID-19 in Kidney transplantation and may apply to recipients of other transplanted organs, as well as to individuals on chronic immunosuppression due to autoimmune diseases.