• Matthew J Cummings, Barnabas Bakamutumaho, Alin S Tomoiaga, Nicholas Owor, Komal Jain, Adam Price, John Kayiwa, Joyce Namulondo, Timothy Byaruhanga, Moses Muwanga, Christopher Nsereko, Irene Nayiga, Stephen Kyebambe, Stephen Sameroff, Xiaoyu Che, Julius J Lutwama, W Ian Lipkin, and Max R O'Donnell.
• Division of Pulmonary, Allergy, and Critical Care Medicine, Department of Medicine, Vagelos College of Physicians and Surgeons, Columbia University, New York, NY.
• Crit. Care Med. 2024 Mar 1; 52 (3): 475482475-482.

ObjectivesIn high-income countries (HICs), sepsis endotypes defined by distinct pathobiological mechanisms, mortality risks, and responses to corticosteroid treatment have been identified using blood transcriptomics. The generalizability of these endotypes to low-income and middle-income countries (LMICs), where the global sepsis burden is concentrated, is unknown. We sought to determine the prevalence, prognostic relevance, and immunopathological features of HIC-derived transcriptomic sepsis endotypes in sub-Saharan Africa.DesignProspective cohort study.SettingPublic referral hospital in Uganda.PatientsAdults ( n = 128) hospitalized with suspected sepsis.InterventionsNone.Measurements And Main ResultsUsing whole-blood RNA sequencing data, we applied 19-gene and 7-gene classifiers derived and validated in HICs (SepstratifieR) to assign patients to one of three sepsis response signatures (SRS). The 19-gene classifier assigned 30 (23.4%), 92 (71.9%), and 6 (4.7%) patients to SRS-1, SRS-2, and SRS-3, respectively, the latter of which is designed to capture individuals transcriptionally closest to health. SRS-1 was defined biologically by proinflammatory innate immune activation and suppressed natural killer-cell, T-cell, and B-cell immunity, whereas SRS-2 was characterized by dampened innate immune activation, preserved lymphocyte immunity, and suppressed transcriptional responses to corticosteroids. Patients assigned to SRS-1 were predominantly (80.0% [24/30]) persons living with HIV with advanced immunosuppression and frequent tuberculosis. Mortality at 30-days differed significantly by endotype and was highest (48.1%) in SRS-1. Agreement between 19-gene and 7-gene SRS assignments was poor (Cohen's kappa 0.11). Patient stratification was suboptimal using the 7-gene classifier with 15.1% (8/53) of individuals assigned to SRS-3 deceased at 30-days.ConclusionsSepsis endotypes derived in HICs share biological and clinical features with those identified in sub-Saharan Africa, with major differences in host-pathogen profiles. Our findings highlight the importance of context-specific sepsis endotyping, the generalizability of conserved biological signatures of critical illness across disparate settings, and opportunities to develop more pathobiologically informed sepsis treatment strategies in LMICs.Copyright © 2023 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.

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