Sepsis poses a grave threat, especially among children, but treatments are limited owing to heterogeneity among patients. We sought to test the clinical and biological relevance of pediatric septic shock subclasses identified using reproducible approaches. We performed latent profile analyses using clinical, laboratory, and biomarker data from a prospective multi-center pediatric septic shock observational cohort to derive phenotypes and trained a support vector machine model to assign phenotypes in an internal validation set. We established the clinical relevance of phenotypes and tested for their interaction with common sepsis treatments on patient outcomes. We conducted transcriptomic analyses to delineate phenotype-specific biology and inferred underlying cell subpopulations. Finally, we compared whether latent profile phenotypes overlapped with established gene-expression endotypes and compared survival among patients based on an integrated subclassification scheme. Among 1071 pediatric septic shock patients requiring vasoactive support on day 1 included, we identified two phenotypes which we designated as Phenotype 1 (19.5%) and Phenotype 2 (80.5%). Membership in Phenotype 1 was associated with ~ fourfold adjusted odds of complicated course relative to Phenotype 2. Patients belonging to Phenotype 1 were characterized by relatively higher Angiopoietin-2/Tie-2 ratio, Angiopoietin-2, soluble thrombomodulin (sTM), interleukin 8 (IL-8), and intercellular adhesion molecule 1 (ICAM-1) and lower Tie-2 and Angiopoietin-1 concentrations compared to Phenotype 2. We did not identify significant interactions between phenotypes, common treatments, and clinical outcomes. Transcriptomic analysis revealed overexpression of genes implicated in the innate immune response and driven primarily by developing neutrophils among patients designated as Phenotype 1. There was no statistically significant overlap between established gene-expression endotypes, reflective of the host adaptive response, and the newly derived phenotypes, reflective of the host innate response including microvascular endothelial dysfunction. However, an integrated subclassification scheme demonstrated varying survival probabilities when comparing patient endophenotypes. Our research underscores the reproducibility of latent profile analyses to identify pediatric septic shock phenotypes with high prognostic relevance. Pending validation, an integrated subclassification scheme, reflective of the different facets of the host response, holds promise to inform targeted intervention among those critically ill.

中文翻译：

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潜伏性儿科脓毒性休克表型的鉴定和转录组学评估


脓毒症构成严重威胁，尤其是在儿童中，但由于患者之间存在异质性，治疗受到限制。我们试图测试使用可重复方法鉴定的儿科感染性休克亚类的临床和生物学相关性。我们使用来自前瞻性多中心儿科感染性休克观察队列的临床、实验室和生物标志物数据进行潜在概况分析，以得出表型，并训练支持向量机模型以在内部验证集中分配表型。我们确定了表型的临床相关性，并测试了它们与常见脓毒症治疗对患者结局的相互作用。我们进行了转录组学分析，以描绘表型特异性生物学并推断潜在的细胞亚群。最后，我们比较了潜在谱表型是否与已建立的基因表达内型重叠，并根据综合亚分类方案比较了患者之间的生存率。在纳入第 1 天需要血管活性支持的 1071 名儿科脓毒性休克患者中，我们确定了两种表型，我们将其命名为表型 1 （19.5%） 和表型 2 （80.5%）。表型 1 的成员资格与相对于表型 2 的复杂病程的 ~ 四倍调整几率相关。属于表型 1 的患者的特征是血管生成素 2/Tie-2 比率、血管生成素-2 、可溶性血栓调节蛋白 （sTM）、白细胞介素 8 （IL-8） 和细胞间粘附分子 1 （ICAM-1） 相对较高，与表型 2 相比，Tie-2 和血管生成素-1 浓度较低。我们没有发现表型、常见治疗和临床结局之间的显著相互作用。 转录组学分析显示，与先天免疫反应有关的基因过表达，主要由被指定为表型 1 的患者发育中的中性粒细胞驱动。已建立的基因表达内型（反映宿主适应性反应）与新衍生的表型（反映宿主先天反应，包括微血管内皮功能障碍）之间没有统计学意义重叠。然而，在比较患者内表型时，综合亚分类方案表明不同的生存概率。我们的研究强调了潜在概况分析的可重复性，以确定具有高预后相关性的儿科脓毒性休克表型。在等待验证之前，反映宿主反应不同方面的综合子分类方案有望为危重患者的针对性干预提供信息。