Pediatric Acute Liver Failure Immune Response Network (PALF IRN): Treatment for Immune Mediated Pathophysiology (TRIUMPH)

项目摘要 儿童急性肝功能衰竭(PALF)是一种罕见的破坏性疾病，估计每年影响250名儿童 在北美，导致约15%的人死亡，在美国需要肝移植(LT) 额外增加20%-30%。在大多数情况下，肝损伤的具体原因从未确定。近期 在这些患者中进行的研究支持这样的理论，即这些患者中的许多人的肝损伤与 对日常感染或环境暴露的高度炎症免疫反应。研究表明， 最近发现T淋巴细胞是炎症过程的中心驱动力。护理PALF的医生 患者正在寻找治疗方法，以平息这种T细胞反应，抑制炎症级联反应，并允许 患者剩余的肝细胞需要愈合和再生。异常儿童的临床体会 与其他疾病状态相关的高炎性免疫反应，如系统性青少年特发性 关节炎和获得性再生障碍性贫血已经证明，大剂量皮质类固醇和马抗 胸腺细胞球蛋白可以抑制免疫反应，逆转进行性组织损伤。的目标是 儿科急性肝功能衰竭免疫反应网络(PALF IRN)将支持一项治疗试验 使用大剂量皮质类固醇或马抗胸腺细胞球蛋白进行免疫抑制治疗以逆转有害 PALF患儿的炎性免疫反应可防止疾病的进一步发展和减少 这一人群的死亡率和LT。我们建议对免疫介导的病理生理进行治疗。 凯旋试验，一项大剂量甲基强的松龙的双盲、三臂、随机、安慰剂对照试验 或者马抗胸腺细胞球蛋白。我们将检验这样一种假设，即在出生后21天，用自体肝脏存活 与接受免疫抑制治疗的患者相比，接受免疫抑制治疗的患者随机化程度明显更高 单独接受支持性护理的患者。我们还将确定免疫抑制治疗的安全性 并确定副作用风险和治疗收益之间的平衡。我们的结果将是 包括临床终点，如患者存活率、疾病解决时间和不良健康状况 这些指标不仅包括患者报告的事件，还包括患者报告的疾病康复结果。试验参与者 将提供血液和肝脏样本进行检查，以更好地了解它们的免疫反应， 尤其是循环和肝脏中的T淋巴细胞。样本将存储在储存库中，以 支持未来探索这种罕见疾病的新方面的研究。

Project Summary Pediatric Acute Liver Failure (PALF) is a rare, devastating condition that affects an estimated 250 children per year in North America, causing death in approximately 15% and the need for liver transplantation (LT) in an additional 20-30%. In the majority of cases, a specific cause of the liver injury is never determined. Recent research conducted in these patients supports the theory that many of these patients have liver injury related to a hyperinflammatory immune response to everyday infections or environmental exposures. Studies have recently implicated T lymphocytes as the central drivers of the inflammatory process. Physicians caring for PALF patients are searching for therapies that quiet this T cell response, dampen the inflammatory cascade and allow the patient’s remaining liver cells to heal and regenerate. Clinical experience in children with abnormal hyperinflammatory immune responses associated with other disease states such as Systemic Juvenile Idiopathic Arthritis and Acquired Aplastic Anemia has demonstrated that both high dose corticosteroids and equine anti- thymocyte globulin can suppress immune responses and reverse progressive tissue damage. The goal of the Pediatric Acute Liver Failure Immune Response Network (PALF IRN) is to support a treatment trial of immunosuppressive therapy using high dose corticosteroids or equine anti-thymocyte globulin to reverse harmful inflammatory immune responses in children with PALF to prevent further disease progression and reduce mortality and LT in this population. We propose the TReatment for ImmUne Mediated PathopHysiology (TRIUMPH) trial, a double-blind, three arm, randomized, placebo controlled trial of high dose methylprednisolone or equine anti-thymocyte globulin. We will test the hypothesis that survival with native liver at 21 days post randomization will be significantly higher in patients receiving immunosuppressive therapy as compared to patients that receive supportive care alone. We will also determine the safety of immunosuppressive therapy in PALF patients and define the balance between risk of side-effects and treatment benefit. Our outcomes will include not only clinical end-points such as patient survival, time to resolution of disease and adverse health events, but also measures of patient reported outcomes during rehabilitation from the illness. Trial participants will provide blood and liver samples that will be examined to better understand their immune responses, especially that of T lymphocytes, in both the circulation and in the liver. Samples will be stored in a repository to support future studies exploring new aspects of this rare disease.