Unsupervised Classification of the Host Response Identifies Dominant Pathobiological Signatures of Sepsis in Sub-Saharan Africa

<b>Rationale:</b> The global burden of sepsis is concentrated in sub-Saharan Africa, where inciting pathogens are diverse and HIV coinfection is a major driver of poor outcomes. Biological heterogeneity inherent to sepsis in this setting is poorly defined. <b>Objectives:</b> 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). <b>Methods:</b> We analyzed two prospective cohorts of adults hospitalized with sepsis (severe infection with quick Sepsis-related Organ Failure Assessment score ⩾1) at disparate settings in Uganda (discovery cohort [Entebbe, urban], <i>n</i> = 242; validation cohort [Tororo, rural], <i>n</i> = 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. <b>Measurements and Main Results:</b> 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 costimulation and exhaustion, and endothelial barrier dysfunction. A five-protein classifier (area under the receiver operating characteristic curve, 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. <b>Conclusions:</b> We identified prognostically enriched pathobiological signatures among patients with sepsis 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.