GM-CSF for Immunomodulation Following Trauma (GIFT) Trial

描述（由申请人提供）：本研究的总体目标是证明用药物粒细胞-巨噬细胞集落刺激因子（GM-CSF）治疗可以降低高危、危重损伤儿童的医院感染发生率。到目前为止，创伤性损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，这是发病率和卫生保健费用的重要来源。先天免疫功能受损在成人严重损伤后很常见，其特征是全血在体外细菌脂多糖（LPS）刺激下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表达降低。我们已经开发了在我们的实验室进行高度标准化、可推广、当日功能免疫监测的能力，我们的初步数据显示，体外lps诱导的TNF1生产能力< 600 pg/ml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已被fda批准用于儿童，并且具有低副作用，但从未在严重受伤儿童中进行过研究。因此，我们建议进行一系列试验，包括一项前瞻性、单中心、随机、双盲、安慰剂对照试验，在筛选严重先天免疫抑制的危重损伤儿童中使用GM-CSF。本报告中概述的研究旨在验证一个新的中心假设，即通过安全、快速和持续地改善先天免疫功能，GM-CSF的免疫调节将降低高危儿童严重损伤后医院感染的风险。“创伤后免疫调节GM-CSF”（GIFT）研究将是最大的研究，旨在研究在任何患者群体中使用先天免疫刺激剂治疗危重疾病诱导的免疫抑制。为了这个项目的所有目的，我们将筛选严重受伤的儿童（那些损伤严重程度评分为bbb10的儿童）的先天免疫抑制，其定义为体外lps诱导的TNF1生产能力< 600 pg/ml。只有那些先天免疫严重抑制的受试者才会在GIFT研究中进一步评估。为了我们的第一个特定目标，我们将在年龄和是否存在严重创伤性脑损伤（TBI）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lps诱导的TNF1生产能力和单核细胞HLA-DR表达）提高到我们初步研究中与医院感染无关的水平。我们将在特异性目标2中继续使用这些LITDs，我们将进行一项前瞻性、单中心、随机、双盲、安慰剂对照的GM-CSF预防无严重TBI儿童医院感染的试验。我们还将对较小的严重TBI儿童人群进行单臂试验，同样采用医院感染风险的结局指标。在特异性目标3中，我们将评估五种天然免疫功能（细胞因子生产能力、抗原提呈能力、迁移、吞噬和微生物杀灭）与感染风险、GM-CSF反应性以及彼此之间的关系。我们预计GIFT研究将代表儿科创伤管理的范式转变，因为它将证明免疫刺激在减少儿童严重损伤后感染中的作用，将显示实时免疫功能监测的可行性，并将产生迄今为止研究过的任何创伤人群的最大和最全面的免疫功能数据集。

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.