Pediatric Acute Liver Failure (PALF) TReatment for ImmUne Mediated PathopHysiology (TRIUMPH)

项目总结 儿童急性肝功能衰竭(PALF)是一种罕见的破坏性疾病，估计有250人受到影响 每年在北美的儿童，造成约15%的死亡和肝脏需求 移植(LT)占额外的20%-30%。在大多数情况下，肝脏的特定原因 受伤的情况永远无法确定。最近在这些患者中进行的研究支持这样的理论 这些患者中有许多人的肝脏损伤与日常免疫反应异常有关 感染或暴露在环境中。最近的研究表明，T淋巴细胞是一种 炎症过程的核心驱动因素。护理PALF患者的医生正在寻找 平息这种T细胞反应的疗法，抑制炎症级联，并允许患者 剩下的肝细胞需要愈合和再生。儿童免疫异常的临床体会 与其他疾病状态相关的反应，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。 拟议的研究网络的目标是支持免疫抑制的治疗试验。 使用大剂量皮质类固醇或马抗胸腺细胞球蛋白逆转有害作用 PALF患儿的炎性免疫反应以防止进一步的疾病进展和 降低这一人群的死亡率和LT。我们提出了一个双盲，三臂，随机， 大剂量甲基强的松龙或马抗胸腺细胞球蛋白的安慰剂对照试验。我们 将检验这样一种假设，即接受肝移植的患者的存活率将显著提高 免疫抑制治疗与接受安慰剂治疗的患者相比。我们还将确定 PALF患者免疫抑制治疗的安全性和风险之间的平衡 副作用和治疗效益。我们的结果将不仅包括临床终点，如 作为患者的生存时间，疾病和不良健康事件的解决时间，也是衡量 患者报告了疾病康复期间的结果。试验参与者将提供 血液和肝脏样本将接受检查，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。样品将存储在 一个储存库，用于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 an abnormal 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 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 proposed research network 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 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 will be significantly higher in patients receiving immunosuppressive therapy as compared to patients that receive placebo. 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.