Division of Critical Care Medicine, Department of Pediatrics, University of Michigan, C.S. Mott Children's Hospital, Ann Arbor, MI.
Division of Critical Care Medicine, Department of Pediatrics, Nationwide Children's Hospital, Columbus, OH.
Pediatr Crit Care Med. 2022 Feb 1;23(2):79-88. doi: 10.1097/PCC.0000000000002860.
Sepsis-induced immunoparalysis represents a pathologic downregulation of leukocyte function shown to be associated with adverse outcomes, although its mechanisms remain poorly understood. Our goal was to compare genome-wide gene expression profiles of immunoparalyzed and nonimmunoparalyzed children with sepsis to identify genes and pathways associated with immunoparalysis.
Prospective observational study.
Twenty-six children with lower respiratory tract infection meeting criteria for sepsis, severe sepsis, or septic shock admitted to the PICU.
Two tertiary care PICUs.
None.
Innate immune function was assayed ex vivo by measuring release of tumor necrosis factor-α from whole blood after incubation with lipopolysaccharide for 4 hours. Immunoparalysis was defined as a tumor necrosis factor-α production capacity less than 200 pg/mL. Ten of the 26 children were immunoparalyzed. There were 17 significant differentially expressed genes when comparing genome-wide gene expression profiles of immunoparalyzed and nonimmunoparalyzed children (false discovery rate < 0.05). Nine genes showed increased expression in immunoparalyzed children (+1.5- to +8.8-fold change). Several of these dampen the immune system. Eight showed decreased expression in immunoparalyzed children (-1.7- to -3.9-fold change), several of which are involved in early regulation and activation of immune function. Functional annotation clustering using differentially expressed genes with p value of less than 0.05 showed three clusters related to immunity with significant enrichment scores (2.2-4.5); the most significant gene ontology terms in these clusters were antigen processing and presentation and negative regulation of interleukin-6 production. Network analysis identified potential protein interactions that may be involved in the development of immunoparalysis in children.
In this exploratory analysis, immunoparalyzed children with sepsis showed increased expression of genes that dampen the immune system and decreased expression of genes involved in regulation and activation of the immune system. Analysis also implicated other proteins as potentially having as yet unidentified roles in the development of immunoparalysis.
脓毒症引起的免疫麻痹代表白细胞功能的病理性下调，已知其与不良预后相关，但其机制仍不清楚。我们的目标是比较免疫麻痹和非免疫麻痹脓毒症儿童的全基因组基因表达谱，以确定与免疫麻痹相关的基因和途径。
前瞻性观察性研究。
26 名符合脓毒症、严重脓毒症或感染性休克标准的下呼吸道感染患儿，收入儿科重症监护病房。
两个三级儿童重症监护病房。
无。
通过测量脂多糖孵育 4 小时后全血中肿瘤坏死因子-α的释放来体外测定固有免疫功能。免疫麻痹定义为肿瘤坏死因子-α产生能力小于 200pg/mL。26 名患儿中有 10 名发生免疫麻痹。比较免疫麻痹和非免疫麻痹患儿的全基因组基因表达谱，有 17 个基因差异表达显著（假发现率<0.05）。免疫麻痹患儿有 9 个基因表达增加（+1.5 至+8.8 倍变化）。其中一些基因抑制免疫系统。免疫麻痹患儿有 8 个基因表达减少（-1.7 至-3.9 倍变化），其中一些基因参与免疫功能的早期调节和激活。使用差异表达基因的 p 值<0.05 的功能注释聚类显示，有三个与免疫相关的聚类具有显著的富集分数（2.2-4.5）；这些聚类中最显著的基因本体术语是抗原加工和呈递以及白细胞介素-6产生的负调节。网络分析确定了可能参与儿童免疫麻痹发展的潜在蛋白质相互作用。
在这项探索性分析中，脓毒症免疫麻痹患儿表现出抑制免疫系统的基因表达增加，以及参与免疫系统调节和激活的基因表达减少。分析还表明，其他蛋白质可能在免疫麻痹的发展中具有尚未确定的作用。
