GM-CSF for Immunomodulation Following Trauma (GIFT) Trial

描述(申请人提供)：这项研究的总体目标是证明使用药物粒细胞-巨噬细胞集落刺激因子(GM-CSF)治疗可以降低高危、危重伤害儿童的医院感染发生率。到目前为止，创伤仍然是美国新生儿期以外儿童死亡的主要原因。在需要ICU护理的受伤儿童中，医院感染的发生率极高，是发病率和医疗费用的重要来源。成人危重创伤后的先天免疫功能受损是常见的，其特征是在细菌脂多糖(LPS)的体外刺激下，全血产生促炎细胞因子肿瘤坏死因子(TNF)-1的能力降低，单核细胞HLA-DR表达减少。我们已经开发出在我们的实验室进行高度标准化、可推广的、当天的功能免疫监测的能力，我们的初步数据显示，具有体外脂多糖诱导的TNF1生产能力的儿童发生医院感染的风险特别高。我们的儿科初步数据以及几项小型成人研究表明，GM-CSF可以逆转危重疾病引起的免疫抑制。GM-CSF是FDA批准用于儿童的，副作用较低，但从未在严重受伤的儿童中进行过研究。因此，我们提出了一系列试验，包括一项前瞻性、单中心、随机、双盲、安慰剂对照的GM-CSF在严重先天性免疫抑制筛查的严重受伤儿童中的试验。这份意见书中概述的研究旨在检验新的中心假设，即GM-CSF的免疫调节将通过安全、快速和持续的改善先天性免疫功能来降低高危儿童严重损伤后医院感染的风险。“GM-CSF用于创伤后免疫调节”(GIFT)研究将是研究体内使用天然免疫刺激剂在任何患者群体中治疗危重疾病引起的免疫抑制的最大研究。对于这个项目的所有目标，我们将筛选严重受伤的儿童(具有创伤严重程度评分&gt；10)，以体外脂多糖诱导的TNF1生产能力&lt；600 pg/ml来定义先天免疫抑制。只有那些患有严重先天免疫抑制的受试者才会在GIFT研究中得到进一步评估。为了我们的第一个特定目标，我们将在根据年龄和有无严重创伤性脑损伤(TBI)确定的队列中进行一系列剂量递增研究，以确定GM-CSF的最低免疫刺激、耐受剂量(LITD)，该剂量将安全地将免疫功能(体外脂多糖诱导的TNF1生产能力和单核细胞HLA-DR表达)提高到与我们初步研究中的医院感染无关的水平。我们将继续在特定的目标2中使用这些LITD，其中我们将进行一项GM-CSF的前瞻性、单中心、随机、双盲、安慰剂对照试验，用于预防没有严重脑外伤的儿童的医院感染。我们还将对患有严重脑外伤的较小数量的儿童进行单臂试验，也将使用医院感染风险的结果衡量标准。在具体目标3中，我们将评估先天性免疫功能的五项指标(细胞因子生产能力、抗原提呈能力、迁移、吞噬和微生物杀伤)与感染风险、GM-CSF反应性之间的关系，以及它们之间的关系。我们预计GIFT研究将代表儿科创伤管理的范式转变，因为它将展示免疫刺激在减少儿科危重创伤后感染方面的作用，将展示实时免疫功能监测的可行性，并将产生迄今所研究的所有创伤人群中最大和最全面的一组免疫功能数据。

DESCRIPTION (provided by applicant): The overall objective of this study is to demonstrate that treatment with the drug granulocyte- macrophage colony-stimulating factor (GM-CSF) can reduce the incidence of nosocomial infection in high-risk, critically injured children. Traumatic injury remains, by far, the leading cause of death for children outside the neonatal period in the United States. The incidence of nosocomial infection is extremely high in injured children who require ICU care and it represents an important source of morbidity and health care costs. Impairment of innate immune function is common following critical injury in adults and is characterized by a reduced capacity of whole blood to produce the pro-inflammatory cytokine tumor necrosis factor (TNF)-1 upon ex vivo stimulation with bacterial lipopolysaccharide (LPS) and reduced monocyte HLA-DR expression. We have developed the capacity to perform highly standardized, generalizable, same-day functional immune monitoring in our laboratory and our preliminary data show that children with an ex vivo LPS-induced TNF1 production capacity < 600 pg/ml are at particularly high risk for the development of nosocomial infection. Our pediatric preliminary data, along with several small adult studies, suggest that GM-CSF can reverse critical illness-induced immunodepression. GM-CSF is FDA-approved for use in children and has a low side-effect profile, but has never been studied in critically injured children. We therefore propose a series of trials including a prospective, single-center, randomized, double-blind, placebo-controlled trial of GM-CSF in critically injured children screened for severe innate immune suppression. The studies outlined in this submission are designed to test the novel central hypothesis that immunomodulation with GM-CSF will result in reduction in the risk of nosocomial infection after critical injury in high-risk children through safe, rapid, and sustained improvement in innate immune function. The "GM-CSF for Immunomodulation Following Trauma" (GIFT) study will be the largest study to investigate the in vivo use of an innate immunostimulant for the treatment of critical illness-induced immune suppression in any patient population. For all Aims of this project we will screen severely injured children (those with an Injury Severity Score > 10) for innate immune suppression as defined by an ex vivo LPS-induced TNF1 production capacity < 600 pg/ml. Only those subjects with severe innate immune suppression will be further evaluated in the GIFT study. For our first Specific Aim we will perform a series of dose-escalation studies in cohorts determined by age and presence or absence of severe traumatic brain injury (TBI) in order to determine the lowest immunostimulatory, tolerable dose (LITD) of GM-CSF that will safely improve immune function (ex vivo LPS-induced TNF1 production capacity and monocyte HLA-DR expression) to levels that were not associated with nosocomial infection in our preliminary studies. We will go on to use these LITDs in Specific Aim 2 in which we will perform a prospective, single-center, randomized, double-blind, placebo-controlled trial of GM-CSF for the prevention of nosocomial infection in children without severe TBI. We will also perform a single-arm trial for the smaller population of children with severe TBI, also with the outcome measure of nosocomial infection risk. In Specific Aim 3 we will evaluate the relationships between five measures of innate immune function (cytokine production capacity, antigen presenting capacity, migration, phagocytosis, and microbial killing) with infection risk, with GM-CSF responsiveness, and with each other. We anticipate that the GIFT study will represent a paradigm shift in the management of pediatric trauma in that it will demonstrate the role of immune stimulation in reducing infection after pediatric critical injury, will show the feasibility of real-time immune function monitoring, and will yield the largest and most comprehensive set of immune function data of any trauma population yet studied.