Abstract
BackgroundThe global burden of sepsis is concentrated in sub-Saharan Africa, where severe infections disproportionately affect young, HIV-infected adults and high-burden pathogens are unique. In this context, poor understanding of sepsis immunopathology represents a crucial barrier to development of locally-effective treatment strategies. We sought to determine inter-individual immunologic heterogeneity among adults hospitalized with sepsis in a sub-Saharan African setting, and characterize associations between immune subtypes, infecting pathogens, and clinical outcomes.MethodsAmong a prospective observational cohort of 288 adults hospitalized with suspected sepsis in Uganda, we applied machine learning methods to 14 soluble host immune mediators, reflective of key domains of sepsis immunopathology (innate and adaptive immune activation, endothelial dysfunction, fibrinolysis), to identify immune subtypes in randomly-split discovery (N = 201) and internal validation (N = 87) sub-cohorts. In parallel, we applied similar methods to whole-blood RNA-sequencing data from a consecutive subset of patients (N = 128) to identify transcriptional subtypes, which we characterized using biological pathway and immune cell-type deconvolution analyses.ResultsUnsupervised clustering consistently identified two immune subtypes defined by differential activation of pro-inflammatory innate and adaptive immune pathways, with transcriptional evidence of concomitant CD56(-)/CD16( +) NK-cell expansion, T-cell exhaustion, and oxidative-stress and hypoxia-induced metabolic and cell-cycle reprogramming in the hyperinflammatory subtype. Immune subtypes defined by greater pro-inflammatory immune activation, T-cell exhaustion, and metabolic reprogramming were consistently associated with a high-prevalence of severe and often disseminated HIV-associated tuberculosis, as well as more extensive organ dysfunction, worse functional outcomes, and higher 30-day mortality.ConclusionsOur results highlight unique host- and pathogen-driven features of sepsis immunopathology in sub-Saharan Africa, including the importance of severe HIV-associated tuberculosis, and reinforce the need to develop more biologically-informed treatment strategies in the region, particularly those incorporating immunomodulation.
Highlights
The global burden of sepsis is concentrated in sub-Saharan Africa (SSA), where nearly 40% of all sepsis cases occur and up to 65% of all deaths are sepsis-related [1, 2]
Participants Of 301 adult patients enrolled in the RESERVE-U cohort, 288 (96%) and 128 (43%) had serum and wholeblood Ribonucleic acid (RNA) samples available for analysis, respectively, and were included in this study (Additional file 1: Figure E2)
Unsupervised clustering of soluble mediators consistently reveals two immune subtypes among adults with suspected sepsis in Uganda In the discovery and internal validation cohorts, a two cluster model was determined to be optimal based on multiple indices of cluster stability and validity (Fig. 1a, b and Additional file 1: Figure E3AE3B, Tables E2-E3), with clear between-cluster separation across the first principal component of mediator variance (Figs. 1c and Additional file 1: Figure E3C)
Summary
The global burden of sepsis is concentrated in sub-Saharan Africa (SSA), where nearly 40% of all sepsis cases occur and up to 65% of all deaths are sepsis-related [1, 2] In this context, where epidemic HIV, extensive pathogen diversity, and limited critical care capacity challenge effective management of life-threatening infections, clinical trials of sepsis treatment protocols developed in highincome countries (HICs) have repeatedly shown harm [3, 4]. The global burden of sepsis is concentrated in sub-Saharan Africa, where severe infections disproportionately affect young, HIV-infected adults and high-burden pathogens are unique In this context, poor understanding of sepsis immunopathology represents a crucial barrier to development of locally-effective treatment strategies. We sought to determine inter-individual immunologic heterogeneity among adults hospitalized with sepsis in a subSaharan African setting, and characterize associations between immune subtypes, infecting pathogens, and clinical outcomes
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