GM-CSF for Immunomodulation Following Trauma (GIFT) Trial

描述（由申请方提供）：本研究的总体目的是证明粒细胞-巨噬细胞集落刺激因子（GM-CSF）药物治疗可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，是发病率和医疗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是常见的，其特征在于在用细菌脂多糖（LPS）离体刺激后全血产生促炎细胞因子肿瘤坏死因子（TNF）-1的能力降低和单核细胞HLA-DR表达降低。我们已经开发了在我们的实验室中进行高度标准化的、可推广的、当天功能性免疫监测的能力，我们的初步数据显示，体外LPS诱导的TNF 1产生能力< 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，沿着几个小的成人研究，表明GM-CSF可以逆转危重病引起的免疫抑制。GM-CSF是FDA批准用于儿童，副作用低，但从未在严重受伤的儿童中进行过研究。因此，我们提出了一系列的试验，包括一个前瞻性，单中心，随机，双盲，安慰剂对照试验的GM-CSF在严重受伤的儿童筛选严重的先天免疫抑制。本申报资料中概述的研究旨在检验新的中心假设，即GM-CSF免疫调节将通过安全、快速和持续改善先天免疫功能降低高危儿童严重损伤后的医院感染风险。“GM-CSF用于创伤后免疫调节”（GIFT）研究将是研究在任何患者人群中体内使用先天性免疫刺激剂治疗重症疾病诱导的免疫抑制的最大研究。对于本项目的所有目标，我们将筛选严重受伤的儿童（损伤严重度评分> 10的儿童）的先天免疫抑制，其定义为体外LPS诱导的TNF 1产生能力< 600 pg/ml。在GIFT研究中，仅对重度先天免疫抑制的受试者进行进一步评价。对于我们的第一个特定目标，我们将在根据年龄和是否存在严重创伤性脑损伤（TBI）确定的队列中进行一系列剂量递增研究，以确定最低的免疫刺激，安全改善免疫功能的GM-CSF耐受剂量（LITD）（体外LPS诱导的TNF 1产生能力和单核细胞HLA-DR表达）降低到与我们的初步研究中的医院感染无关的水平。我们将继续在Specific Aim 2中使用这些LITD，在该研究中，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试验，用于预防无严重TBI儿童的医院感染。我们还将进行一项单组试验，用于较小的重度TBI儿童人群，也是医院感染风险的结局指标。在具体目标3中，我们将评估先天免疫功能（细胞因子产生能力，抗原呈递能力，迁移，吞噬作用和微生物杀伤）与感染风险，GM-CSF反应性以及相互之间的关系。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科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的任何创伤人群的最大和最全面的免疫功能数据集。 公共卫生相关性：创伤性损伤是美国儿童的一个重要公共卫生问题，医院感染是这一人群发病率和医疗保健费用的主要来源。人们越来越认识到，先天免疫抑制发生在严重损伤后，但它很少被测试，几乎从未治疗过。GM-CSF是FDA批准的药物，具有低毒性特征，成人和儿童数据强烈表明它可有效逆转重症疾病诱导的先天免疫抑制，并有可能降低感染风险。治疗的最佳剂量和持续时间尚不清楚。如果GIFT研究的目标得以实现，重症监护医学领域将通过以下方式得到推进：证明大规模实时免疫功能监测的可行性;明确证明小儿重症损伤后先天免疫抑制的可逆性;提供功能性免疫检测应纳入常规临床实验室设置的强有力证据;为儿科医生和重症监护医生提供了一种通过提高免疫功能来降低危重患儿院内感染率的安全有效的方法。

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. PUBLIC HEALTH RELEVANCE: Traumatic injury is an important public health problem for children in the U.S. and nosocomial infection represents a major source of morbidity and health care costs for this population. It is increasingly recognized that innate immune suppression occurs following critical injury, yet it is rarely tested for and almost never treated. GM-CSF is an FDA-approved drug with a low toxicity profile with adult and pediatric data strongly suggesting that it is effective at reversing critical illness-induced innate immune suppression with the potential to reduce infection risk. The optimal dose and duration of therapy are unknown. If the Aims of the GIFT study are achieved, the field of critical care medicine will be advanced by: demonstrating the feasibility of large- scale, real-time immune function monitoring; definitively demonstrating the reversibility of innate immune suppression after pediatric critical injury; providing strong evidence that functional immune testing should be incorporated into the routine clinical laboratory setting; and providing pediatric surgeons and intensivists with a safe and effective way to reduce the rate of nosocomial infections in critically injured children through improvement in immune function.