PDF(Pubmed)
Abstract：
One of five global deaths are attributable to sepsis. Hyperferritinemic sepsis (> 500 ng/mL) is associated with increased mortality in single-center studies. Our pediatric research network\'s objective was to obtain rationale for designing anti-inflammatory clinical trials targeting hyperferritinemic sepsis.
We assessed differences in 32 cytokines, immune depression (low whole blood ex vivo TNF response to endotoxin) and thrombotic microangiopathy (low ADAMTS13 activity) biomarkers, seven viral DNAemias, and macrophage activation syndrome (MAS) defined by combined hepatobiliary dysfunction and disseminated intravascular coagulation, and mortality in 117 children with hyperferritinemic sepsis (ferritin level > 500 ng/mL) compared to 280 children with sepsis without hyperferritinemia. Causal inference analysis of these 41 variables, MAS, and mortality was performed.
Mortality was increased in children with hyperferritinemic sepsis (27/117, 23% vs 16/280, 5.7%; Odds Ratio = 4.85, 95% CI [2.55-9.60]; z = 4.728; P-value < 0.0001). Hyperferritinemic sepsis had higher C-reactive protein, sCD163, IL-22, IL-18, IL-18 binding protein, MIG/CXCL9, IL-1β, IL-6, IL-8, IL-10, IL-17a, IFN-γ, IP10/CXCL10, MCP-1/CCL2, MIP-1α, MIP-1β, TNF, MCP-3, IL-2RA (sCD25), IL-16, M-CSF, and SCF levels; lower ADAMTS13 activity, sFasL, whole blood ex vivo TNF response to endotoxin, and TRAIL levels; more Adenovirus, BK virus, and multiple virus DNAemias; and more MAS (P-value < 0.05). Among these variables, only MCP-1/CCL2 (the monocyte chemoattractant protein), MAS, and ferritin levels were directly causally associated with mortality. MCP-1/CCL2 and hyperferritinemia showed direct causal association with depressed ex vivo whole blood TNF response to endotoxin. MCP-1/CCL2 was a mediator of MAS. MCP-1/CCL2 and MAS were mediators of hyperferritinemia.
These findings establish hyperferritinemic sepsis as a high-risk condition characterized by increased cytokinemia, viral DNAemia, thrombotic microangiopathy, immune depression, macrophage activation syndrome, and death. The causal analysis provides rationale for designing anti-inflammatory trials that reduce macrophage activation to improve survival and enhance infection clearance in pediatric hyperferritinemic sepsis.
We assessed differences in 32 cytokines, immune depression (low whole blood ex vivo TNF response to endotoxin) and thrombotic microangiopathy (low ADAMTS13 activity) biomarkers, seven viral DNAemias, and macrophage activation syndrome (MAS) defined by combined hepatobiliary dysfunction and disseminated intravascular coagulation, and mortality in 117 children with hyperferritinemic sepsis (ferritin level > 500 ng/mL) compared to 280 children with sepsis without hyperferritinemia. Causal inference analysis of these 41 variables, MAS, and mortality was performed.
Mortality was increased in children with hyperferritinemic sepsis (27/117, 23% vs 16/280, 5.7%; Odds Ratio = 4.85, 95% CI [2.55-9.60]; z = 4.728; P-value < 0.0001). Hyperferritinemic sepsis had higher C-reactive protein, sCD163, IL-22, IL-18, IL-18 binding protein, MIG/CXCL9, IL-1β, IL-6, IL-8, IL-10, IL-17a, IFN-γ, IP10/CXCL10, MCP-1/CCL2, MIP-1α, MIP-1β, TNF, MCP-3, IL-2RA (sCD25), IL-16, M-CSF, and SCF levels; lower ADAMTS13 activity, sFasL, whole blood ex vivo TNF response to endotoxin, and TRAIL levels; more Adenovirus, BK virus, and multiple virus DNAemias; and more MAS (P-value < 0.05). Among these variables, only MCP-1/CCL2 (the monocyte chemoattractant protein), MAS, and ferritin levels were directly causally associated with mortality. MCP-1/CCL2 and hyperferritinemia showed direct causal association with depressed ex vivo whole blood TNF response to endotoxin. MCP-1/CCL2 was a mediator of MAS. MCP-1/CCL2 and MAS were mediators of hyperferritinemia.
These findings establish hyperferritinemic sepsis as a high-risk condition characterized by increased cytokinemia, viral DNAemia, thrombotic microangiopathy, immune depression, macrophage activation syndrome, and death. The causal analysis provides rationale for designing anti-inflammatory trials that reduce macrophage activation to improve survival and enhance infection clearance in pediatric hyperferritinemic sepsis.
摘要：
背景：全球5例死亡中有1例归因于脓毒症。在单中心研究中,高铁蛋白血症性败血症(>500ng/mL)与死亡率增加相关。我们的儿科研究网络的目标是获得设计针对高铁蛋白血症性败血症的抗炎临床试验的理论基础。
方法：我们评估了32种细胞因子的差异，免疫抑制（低全血体内TNF对内毒素的反应）和血栓性微血管病（低ADAMTS13活性）生物标志物，七个病毒DNA，和巨噬细胞活化综合征（MAS）定义为合并肝胆功能障碍和弥散性血管内凝血，117例高铁蛋白血症（铁蛋白水平>500ng/mL）患儿的死亡率与280例不高铁蛋白血症的脓毒症患儿的死亡率相比。对这41个变量进行因果推断分析，MAS,和死亡率。
结果：高铁蛋白血症患儿的死亡率增加（27/117，23％vs16/280，5.7％；赔率=4.85，95％CI[2.55-9.60]；z=4.728；P值<0.0001）。高铁蛋白败血症有较高的C反应蛋白，sCD163,IL-22,IL-18,IL-18结合蛋白,MIG/CXCL9,IL-1β,IL-6,IL-8,IL-10,IL-17a,IFN-γ，IP10/CXCL10,MCP-1/CCL2,MIP-1α,MIP-1β,TNF,MCP-3，IL-2RA（sCD25），IL-16,M-CSF,和SCF水平；较低的ADAMTS13活性，sFasL,全血离体TNF对内毒素的反应，和TRAIL水平；更多的腺病毒，BK病毒,和多种病毒DNA；和更多的MAS（P值<0.05）。在这些变量中，只有MCP-1/CCL2（单核细胞趋化蛋白），MAS,和铁蛋白水平与死亡率直接相关。MCP-1/CCL2和高铁蛋白血症与离体全血TNF对内毒素的反应降低直接因果关系。MCP-1/CCL2是MAS的介导因子。MCP-1/CCL2和MAS是高铁蛋白血症的介质。
结论：这些发现将高铁蛋白血症性败血症确定为以细胞因子血症增加为特征的高危疾病。病毒性DNA血症，血栓性微血管病,免疫抑制,巨噬细胞活化综合征,和死亡。因果分析为设计抗炎试验提供了理论基础，该试验可减少巨噬细胞活化，以提高小儿高铁蛋白血症性败血症的生存率和提高感染清除。
方法：我们评估了32种细胞因子的差异，免疫抑制（低全血体内TNF对内毒素的反应）和血栓性微血管病（低ADAMTS13活性）生物标志物，七个病毒DNA，和巨噬细胞活化综合征（MAS）定义为合并肝胆功能障碍和弥散性血管内凝血，117例高铁蛋白血症（铁蛋白水平>500ng/mL）患儿的死亡率与280例不高铁蛋白血症的脓毒症患儿的死亡率相比。对这41个变量进行因果推断分析，MAS,和死亡率。
结果：高铁蛋白血症患儿的死亡率增加（27/117，23％vs16/280，5.7％；赔率=4.85，95％CI[2.55-9.60]；z=4.728；P值<0.0001）。高铁蛋白败血症有较高的C反应蛋白，sCD163,IL-22,IL-18,IL-18结合蛋白,MIG/CXCL9,IL-1β,IL-6,IL-8,IL-10,IL-17a,IFN-γ，IP10/CXCL10,MCP-1/CCL2,MIP-1α,MIP-1β,TNF,MCP-3，IL-2RA（sCD25），IL-16,M-CSF,和SCF水平；较低的ADAMTS13活性，sFasL,全血离体TNF对内毒素的反应，和TRAIL水平；更多的腺病毒，BK病毒,和多种病毒DNA；和更多的MAS（P值<0.05）。在这些变量中，只有MCP-1/CCL2（单核细胞趋化蛋白），MAS,和铁蛋白水平与死亡率直接相关。MCP-1/CCL2和高铁蛋白血症与离体全血TNF对内毒素的反应降低直接因果关系。MCP-1/CCL2是MAS的介导因子。MCP-1/CCL2和MAS是高铁蛋白血症的介质。
结论：这些发现将高铁蛋白血症性败血症确定为以细胞因子血症增加为特征的高危疾病。病毒性DNA血症，血栓性微血管病,免疫抑制,巨噬细胞活化综合征,和死亡。因果分析为设计抗炎试验提供了理论基础，该试验可减少巨噬细胞活化，以提高小儿高铁蛋白血症性败血症的生存率和提高感染清除。
