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.

项目摘要/摘要 MODS期间药物，免疫分析和遗传学的小儿研究（范式） 免疫系统的失败在小儿多器官功能障碍综合征的情况下很常见 （mod），与继发感染，持续器官失败和死亡的高风险有关。 严重时，这被称为“免疫分析”。这种免疫系统故障形式可以定义为 在体内刺激后，全血的全血能力降低了细胞因子肿瘤坏死因子（TNF）-α 与脂多糖。我们已经开发了高度标准化的小体积，易于制作的 该测试的方法用于免疫功能的多中心研究。我们的小组有研究 来自不同诊断组的儿童的免疫分析近二十年，包括败血症，创伤， 心肺旁路和病毒感染，但这些研究受到小样本量的限制。 尽管我们的测试方法已经确定了先天免疫功能的阈值，这强烈预测不利 小儿危重疾病的结果，这些阈值可能因诊断组而有所不同，但没有 在大型独立队列中进行了验证。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的影响 免疫功能尚不清楚。此外，许多小儿重症监护病房中的许多常用药物 （PICU）（例如氢化可的松，镇静剂，镇痛药）具有意外的免疫作用，尽管它们的幅度为 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 针对免疫分析逆转的重病成年人和儿童正在进行中，但目前有 没有针对预防免疫分析的研究，这主要是由于对危险因素缺乏了解。 我们的研究计划的总体目标是减少免疫分析及其相关的发病率 感染，器官衰竭和死亡的风险。范式研究是一项1400个受试者，多中心，前瞻性， 观察性研究以检验中心假设，即儿童免疫分析的风险 使用mod可以预测诊断特异性，特定治疗和宿主特异性因素。目标 范式研究首次实现，包括：确认很大 具有MODS的儿童队列，与死亡有关的TNFα生产能力的阈值 长时间的器官功能障碍和医院感染；识别诊断和ICU疗法 易孕儿童或延长免疫分析；并鉴定候选宿主基因组因素 与诊断或治疗因素无关，可能使儿童诱发或延长免疫分析。 这项工作将通过1）改进靶向临床试验的免疫刺激设计的设计； 2） 避免使患有MOD的儿童进行免疫分析的治疗方案； 3）发展和 在PICU中测试精密中医学方法的免疫护理方法； 4）收集大量数据 TNFα反应足以将测定从研究环境转移到临床实验室。