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

项目概要/摘要 多器官功能障碍综合征的药物、免疫和遗传学研究 免疫系统衰竭在小儿多器官功能障碍综合征中很常见 （MODS），并且与继发感染、持续性器官衰竭和死亡的高风险相关。 当严重时，这被称为“免疫麻痹”。这种形式的免疫系统故障可以定义为 离体刺激后全血产生细胞因子肿瘤坏死因子（TNF）-α的能力降低 与脂多糖。我们开发了一种标准化程度高、批量小、易于加工的 该方法用于免疫功能的多中心研究。我们小组研究了 免疫麻痹在不同诊断组的儿童中持续了近二十年，包括败血症，创伤， 体外循环和病毒感染，但这些研究受到样本量小的限制。 尽管我们的测试方法已经确定了先天免疫功能的阈值， 从儿科危重病的结果，这些阈值可能会有所不同的诊断组，并没有被 在大型独立队列中验证。众所周知，某些条件和治疗明显导致 免疫功能受损（例如恶性肿瘤），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）（例如氢化可的松，镇静剂，镇痛剂）具有非预期的免疫效应，尽管其程度 不清楚最后，在这种情况下，宿主基因组对免疫功能的影响是未知的。临床试验 正在重症成人和儿童中进行，目标是逆转免疫麻痹，但目前 没有针对预防免疫麻痹的研究，主要是由于缺乏对风险因素的了解。 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。 感染、器官衰竭和死亡的风险。PARADIGM研究是一项1400例受试者、多中心、前瞻性、 一项观察性研究，旨在检验儿童发生免疫麻痹的风险 可以从诊断特异性、治疗特异性和宿主特异性因素预测MODS的发生。目标来 作为PARADIGM研究的结果，首次实现的目标包括：确认，在一个非常大的 MODS儿童队列，TNFα产生能力与死亡相关的阈值， 长期器官功能障碍和医院感染;确定诊断和ICU治疗， 使儿童易患或延长免疫麻痹;以及鉴定候选宿主基因组因子， 可能使儿童易患或延长免疫麻痹，与诊断或治疗因素无关。 这项工作将通过1）改进免疫刺激的靶向临床试验的设计; 2） 避免治疗方案，使MODS儿童易患免疫瘫痪; 3）发展和 测试PICU中免疫护理的精确医学方法; 4）收集关于以下方面的临界质量数据： TNFα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.