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

MODS 期间的药物、免疫麻痹和遗传学儿科研究 (PARADIGM)

• 批准号: 10394894
• 负责人: MARK W HALL
• 金额: $ 61.96万
• 依托单位: RESEARCH INST NATIONWIDE CHILDREN'S HOSP
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-05-01 至 2024-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10394894
• 关键词: Acute; Address; Adult; Analgesics; Biological Assay; Cardiopulmonary Bypass; Caring; Cessation of life; Child; Childhood; Chronic; Clinical; Clinical Management; Clinical Pharmacology; Clinical Trials; Collection; Critical Care; Critical Illness; Critically ill children; DNA; Data; Data Set; Development; Diagnosis; Diagnostic; Diagnostic Factor; Drug Exposure; Drug usage; Environment; Epigenetic Process; Failure; Functional disorder; Funding; Future; Generations; Genes; Genetic; Genome; Genomics; Goals; Hydrocortisone; Immune; Immune System Diseases; Immune system; Immunization; Immunologic Markers; Immunologic Monitoring; Impairment; Incidence; Inflammatory Response; Intrinsic factor; Knowledge; Laboratories; Lipopolysaccharides; Malignant Neoplasms; Messenger RNA; Modeling; Morbidity - disease rate; Multicenter Studies; Multiple Organ Failure; Nosocomial Infections; Observational Study; Opioid; Organ; Organ failure; Outcome; Patients; Pediatric Intensive Care Units; Pediatric Research; Pharmaceutical Preparations; Plasma; Population; Predictive Factor; Prevention; Prevention approach; Principal Investigator; Process; Production; Regulation; Research; Risk; Risk Factors; Sample Size; Sepsis; Standardization; Statistical Models; TNF gene; Testing; Time; Trauma; Treatment Factor; Treatment Protocols; Validation; Virus Diseases; Whole Blood; Work; adverse outcome; base; candidate identification; cohort; cytokine; design; genetic variant; high risk; immune function; immunoregulation; improved; improved outcome; infection risk; innate immune function; mortality; mortality risk; pharmacometrics; precision medicine; preservation; prevent; programs; prospective; response; secondary infection; sedative; severe injury; treatment strategy

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.

项目概要/摘要 MODS 期间的药物、免疫麻痹和遗传学儿科研究 (PARADIGM) 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。 当严重时，这被称为“免疫麻痹”。这种形式的免疫系统衰竭可以定义为 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 我们开发了一种高度标准化、体积小、易于加工的产品。 我们的小组研究了用于免疫功能多中心研究的这种测试方法。 近二十年来，来自不同诊断组（包括脓毒症、创伤、 体外循环和病毒感染，但这些研究受到样本量较小的限制。 尽管我们的测试方法已经确定了先天免疫功能的阈值，可以强烈预测不良反应 儿科危重疾病的结果，这些阈值可能因诊断组而异，并且尚未得到证实 众所周知，某些条件和治疗会明显导致结果。 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的影响 此外，儿科重症监护病房常用的药物很多。 (PICU)（例如氢化可的松、镇静剂、镇痛药）具有意想不到的免疫作用，尽管其严重程度是 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。 正在针对危重成人和儿童进行针对逆转免疫麻痹的治疗，但目前有 没有针对预防免疫麻痹的研究，很大程度上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 PARADIGM 研究是一项包含 1400 名受试者的多中心前瞻性研究。 观察性研究，检验儿童发生免疫麻痹风险的中心假设 MODS 的目标可以根据诊断特异性、治疗特异性和宿主特异性因素进行预测。 PARADIGM 研究的结果首次实现的目标包括：在一个非常大的范围内进行确认 患有 MODS 的儿童队列，与死亡相关的 TNFα 产生能力阈值， 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；并鉴定候选宿主基因组因素 可能使儿童易于或延长免疫麻痹的时间，与诊断或治疗因素无关。 这项工作将通过 1) 改进免疫刺激靶向临床试验的设计 2) 推动该领域的发展； 避免使患有 MODS 的儿童容易出现免疫麻痹的治疗方案 3) 发育和 测试儿科重症监护病房 (PICU) 中免疫护理的精准医学方法；4) 收集大量有关的数据； TNFα 反应足以将测定从研究环境转移到临床实验室。