Department of Critical Care Medicine, School of Medicine, University of Pittsburgh, Pittsburgh, PA, USA.
Children's Hospital of Pittsburgh of UPMC, Pittsburgh, PA, USA.
Genes Immun. 2019 Jul;20(6):520-526. doi: 10.1038/s41435-018-0030-3. Epub 2018 Jul 6.
Post-hoc subgroup analysis of the negative trial of interleukin-1β receptor antagonist (IL1RA) for septic shock suggested that patients with features of macrophage activation syndrome (MAS) experienced a 50% relative risk reduction for mortality with treatment. Here we seek a genetic basis for this differential response. From 1341 patients enrolled in the ProCESS trial of early goal directed therapy for septic shock, we selected 6 patients with MAS features and the highest ferritin, for whole exome sequencing (mean 24,030.7 ηg/ml, ±SEM 7,411.1). In total 11 rare (minor allele frequency <5%) pathogenic or likely pathogenic variants causal for the monogenic disorders of Familial Hemophagocytic Lymphohistiocytosis, atypical Hemolytic Uremic Syndrome, Familial Mediterranean Fever, and Cryopyrin-associated Periodic Fever were identified. In these conditions, seven of the identified variants are currently targeted with IL1RA and four with anti-C5 antibody. Gene-targeted precision medicine may benefit this subgroup of patients with septic shock and pathogenic immune variation.
对白细胞介素-1β受体拮抗剂（IL1RA）治疗败血症休克的阴性试验进行的事后亚组分析表明，具有巨噬细胞活化综合征（MAS）特征的患者接受治疗后死亡率的相对风险降低了 50%。在这里，我们寻求这种差异反应的遗传基础。从败血症休克早期目标导向治疗的 ProCESS 试验中纳入的 1341 名患者中，我们选择了 6 名具有 MAS 特征和最高铁蛋白的患者进行全外显子组测序（平均 24030.7ηg/ml，±SEM 7411.1）。总共鉴定出了 11 种罕见的（次要等位基因频率 <5%）致病性或可能致病性变异体，这些变异体与家族性噬血细胞性淋巴组织细胞增多症、非典型溶血尿毒综合征、家族性地中海热和 Cryopyrin 相关周期性发热等单基因疾病有关。在这些情况下，目前有七种已确定的变异体被 IL1RA 靶向，四种被抗 C5 抗体靶向。针对特定基因的精准医疗可能会使败血症休克和致病性免疫变异的这组患者受益。
