PediAtric ReseArch of Drugs, Immunoparalysis and Genetics during MODS (PARADIGM)

项目摘要/摘要 MODS期间药物、免疫麻痹和遗传学的儿科研究(范式) 免疫系统衰竭在儿童多器官功能障碍综合征中很常见 (MODS)，并与继发感染、持续性器官衰竭和死亡的高风险相关。 当病情严重时，称为“免疫麻痹”。这种形式的免疫系统衰竭可以定义为 体外刺激下全血产生细胞因子肿瘤坏死因子-α的能力降低 含脂多糖。我们已经开发出高度标准化、小体积、易于加工的 在多中心免疫功能研究中使用的这种测试的方法。我们小组研究了 近20年来，来自不同诊断组的儿童的免疫麻痹，包括败血症，创伤， 例如体外循环、病毒感染等，但这些研究因样本量较小而受到限制。 尽管我们的测试方法已经确定了先天免疫功能的阈值，这些阈值强烈地预测了 儿科危重疾病的预后，这些阈值可能会因诊断组而异，并且尚未 在一个大型独立队列中进行了验证。众所周知，某些情况和治疗会明显地导致 免疫功能受损(如恶性肿瘤)，但大多数急性和慢性诊断对 免疫功能仍不清楚。此外，儿科重症监护室的许多常用药物 (PICU)(如氢化可的松、镇静剂、止痛剂)具有意想不到的免疫作用，尽管其强度是 不清楚。最后，在这种情况下，宿主基因组对免疫功能的影响尚不清楚。临床试验 在危重成人和儿童中正在进行旨在逆转免疫麻痹的研究，但目前有 没有针对预防免疫麻痹的研究，这主要是由于缺乏对危险因素的了解。 我们研究计划的总体目标是减少免疫麻痹及其相关疾病的发生率 有感染、器官衰竭和死亡的风险。范式研究是一项包含1400个对象、多中心、前瞻性、 对儿童发生免疫麻痹的风险这一中心假设进行的观察性研究 MODS可以从诊断、治疗和宿主特异性因素中预测出来。目标为 首次实现的范式研究结果包括：确认，在很大程度上 MODS儿童队列，与死亡相关的肿瘤坏死因子α生产能力阈值， 长期器官功能障碍和医院感染；诊断和ICU治疗的识别 使儿童倾向于或延长免疫麻痹；以及确定候选宿主基因组因素， 可能使儿童倾向于或延长免疫麻痹，而不受诊断或治疗因素的影响。 这项工作将通过1)免疫刺激定向临床试验的改进设计来推动该领域的发展；2) 避免使患有MODS的儿童容易出现免疫麻痹的治疗方案；3)发展和 在PICU中测试免疫护理的精确医学方法；4)收集关于 肿瘤坏死因子α反应足以将检测从研究环境转移到临床实验室。

Project Summary/Abstract PediAtric ReseArch of Drugs, Immunoparalysis and Genetics during MODS (PARADIGM) Failure of the immune system is common in the setting of pediatric multiple organ dysfunction syndrome (MODS) and is associated with high risks for secondary infection, persistent organ failure, and death. When severe, this is termed “immunoparalysis.” This form of immune system failure can be defined as reduced ability of whole blood to produce the cytokine tumor necrosis factor (TNF)-α upon ex vivo stimulation with lipopolysaccharide. We have developed a highly standardized, small-volume, easy-to-process approach to this testing that is used in multi-center studies of immune function. Our group has studied immunoparalysis for nearly two decades in children from varying diagnostic groups including sepsis, trauma, cardiopulmonary bypass, and viral infections, but these studies have been limited by small sample sizes. Although our testing approach has identified thresholds of innate immune function that strongly predict adverse outcomes from pediatric critical illness, these thresholds may vary by diagnostic group and have not been validated in a large independent cohort. It is well known that certain conditions and treatments overtly result in impaired immune function (e.g. malignancy), but the implications of most acute and chronic diagnoses on immune function remain unclear. In addition, many commonly used drugs in the pediatric intensive care unit (PICU) (e.g. hydrocortisone, sedatives, analgesics) have unintended immune effects, though their magnitude is unclear. Lastly, the influence of the host genome on immune function in this setting is unknown. Clinical trials are ongoing in critically ill adults and children targeting the reversal of immunoparalysis, but there are currently no studies targeting the prevention of immunoparalysis, largely due to a lack of understanding of risk factors. The overall goal of our research program is to reduce the incidence of immunoparalysis and its associated risks for infection, organ failure, and death. The PARADIGM study is a 1400-subject, multi-center, prospective, observational study to test the central hypothesis that the risk for development of immunoparalysis in children with MODS can be predicted from diagnosis-specific, treatment-specific, and host-specific factors. Goals to be achieved for the first time as a result of the PARADIGM study include: confirmation, in a very large cohort of children with MODS, of thresholds of TNFα production capacity that are associated with death, prolonged organ dysfunction, and nosocomial infection; identification of diagnoses and ICU therapies that predispose children to, or prolong, immunoparalysis; and identification of candidate host genomic factors that may predispose children to, or prolong, immunoparalysis independent of diagnostic or treatment factors. This work will advance the field through 1) improved design of targeted clinical trials of immune stimulation; 2) avoidance of treatment regimens that predispose children with MODS to immunoparalysis; 3) development and testing of precision-medicine approaches to immune care in the PICU; 4) collection of a critical mass of data on the TNFα response sufficient to move the assay from the research environment to the clinical laboratory.