RATIONALE The global burden of sepsis is concentrated in sub-Saharan Africa, where inciting pathogens are diverse and HIV co-infection is a major driver of poor outcomes. Biological heterogeneity inherent to sepsis in this setting is poorly defined. OBJECTIVES To identify dominant pathobiological signatures of sepsis in sub-Saharan Africa and their relationship to clinical phenotypes, patient outcomes, and biological classifications of sepsis identified in high-income-countries (HICs). METHODS We analyzed two prospective cohorts of adults hospitalized with sepsis (severe infection with qSOFA score≥1) at disparate settings in Uganda (discovery cohort [Entebbe,urban], N=242; validation cohort [Tororo,rural], N=253). To identify pathobiological signatures in the discovery cohort, we applied unsupervised clustering to 173 soluble proteins reflecting key domains of the host response to severe infection. A random forest-derived classifier was used to predict signature assignment in the validation cohort. MEASUREMENTS AND MAIN RESULTS Two signatures (Uganda Sepsis Signature [USS]-1 and USS-2) were identified in the discovery cohort, distinguished by expression of proteins involved in myeloid cell and inflammasome activation, T cell co-stimulation and exhaustion, and endothelial barrier dysfunction. A five-protein classifier (AUROC 0.97) reproduced two signatures in the validation cohort with similar biological profiles. In both cohorts, USS-2 mapped to a more severe clinical phenotype associated with HIV and related immunosuppression, severe tuberculosis, and increased risk of 30-day mortality. Substantial biological overlap was observed between USS-2 and hyperinflammatory and reactive sepsis phenotypes identified in HICs. CONCLUSIONS We identified prognostically-enriched pathobiological signatures among sepsis patients with diverse infections and high HIV prevalence in Uganda. Globally inclusive investigations are needed to define generalizable and context-specific mechanisms of sepsis pathobiology, with the goal of improving access to precision medicine treatment strategies.

中文翻译：

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宿主反应的无监督分类确定了撒哈拉以南非洲脓毒症的主要病理学特征。


基本原理 脓毒症的全球负担集中在撒哈拉以南非洲，那里的诱发病原体多种多样，HIV 混合感染是不良结果的主要驱动因素。在这种情况下，脓毒症固有的生物学异质性定义不明确。目的 确定撒哈拉以南非洲地区脓毒症的主要病理学特征及其与高收入国家 （HIC） 发现的脓毒症临床表型、患者结局和生物学分类的关系。方法 我们分析了在乌干达不同环境中因脓毒症住院的两个成人前瞻性队列 （qSOFA 评分≥ 评分 1） （发现队列 [恩德培，城市]，N=242;验证队列 [Tororo，农村]，N=253）。为了确定发现队列中的病理生物学特征，我们对 173 种可溶性蛋白进行了无监督聚类，反映了宿主对严重感染反应的关键结构域。使用随机森林衍生的分类器来预测验证队列中的特征分配。测量和主要结果 在发现队列中确定了两个特征 （乌干达脓毒症特征 [USS]-1 和 USS-2），以参与髓细胞和炎性小体活化的蛋白质表达、T 细胞共刺激和耗竭以及内皮屏障功能障碍来区分。五蛋白分类器 （AUROC 0.97） 在验证队列中复制了两个具有相似生物学特征的特征。在这两个队列中，USS-2 映射到与 HIV 和相关免疫抑制、严重结核病和 30 天死亡风险增加相关的更严重的临床表型。在 USS-2 与 HIC 中鉴定的高炎症和反应性脓毒症表型之间观察到实质性的生物学重叠。 结论 我们在乌干达不同感染和 HIV 高患病率的脓毒症患者中确定了预后丰富的病理生物学特征。需要进行全球包容性调查，以确定脓毒症病理生物学的可推广和特定背景机制，以改善获得精准医学治疗策略的机会。