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

Autor:	Cummings MJ; Columbia University Medical Center, Division of Pulmonary, Allergy, and Critical Care Medicine , New York, New York, United States; mjc2244@columbia.edu., Lutwama JJ; Uganda Virus Research Institute, National Influenza Center, Entebbe, Uganda., Owor N; Uganda Virus Research Institute, National Influenza Center, Entebbe, Uganda., Tomoiaga AS; Manhattan College, Riverdale, New York, United States., Ross JE; Columbia University Medical Center, New York, New York, United States., Muwanga M; Entebbe General Hospital, Ministry of Health, Entebbe, Wakiso, Uganda., Nsereko C; Entebbe General Hospital, Entebbe, Wakiso, Uganda., Nayiga I; Entebbe General Hospital, Entebbe, Wakiso, Uganda., Kyebambe S; Entebbe General Hospital, Entebbe, Wakiso, Uganda., Shinyale J; Entebbe General Hospital, Ministry of Health, Entebbe, Wakiso, Uganda., Ochar T; Tororo General Hospital, Tororo, Uganda., Kiwubeyi M; Tororo General Hospital, Tororo, Uganda., Nankwanga R; Tororo General Hospital, Tororo, Uganda., Nie K; Icahn School of Medicine at Mount Sinai, New York, New York, United States., Xie H; Icahn School of Medicine at Mount Sinai, New York, New York, United States., Miake-Lye S; Icahn School of Medicine at Mount Sinai, New York, New York, United States., Villagomez B; Icahn School of Medicine at Mount Sinai, New York, New York, United States., Qi J; Icahn School of Medicine at Mount Sinai, New York, New York, United States., Reynolds SJ; National Institutes of Health, Laboratory of Immunoregulation, Bethesda, United States., Nakibuuka MC; Rakai Health Sciences Program, Kalisizo, Central Region, Uganda., Lu X; Columbia University Medical Center, New York, New York, United States., Kayiwa J; Uganda Virus Research Institute, National Influenza Center, Entebbe, Uganda., Haumba M; Uganda Virus Research Institute, National Influenza Center, Entebbe, Uganda., Nakaseegu J; Uganda Virus Research Institute, National Influenza Center, Entebbe, Uganda., Che X; Columbia University Mailman School of Public Health, New York, New York, United States., Wayengera M; Makerere University CHS, Kampala, Uganda., Ghosh S; Columbia University Vagelos College of Physicians and Surgeons, New York, New York, United States., Kim-Schulze S; Icahn School of Medicine at Mount Sinai, Human Immune Monitoring Center (HIMC), Hess Center for Science and Medicine, New York, New York, United States., Lipkin WI; Columbia University Mailman School of Public Health, New York, New York, United States., Bakamutumaho B; Uganda Virus Research Institute, National Influenza Center, Entebbe, Uganda., O'Donnell MR; Columbia University Medical Center, Department of Medicine, New York, New York, United States.
Jazyk:	angličtina
Zdroj:	American journal of respiratory and critical care medicine [Am J Respir Crit Care Med] 2024 Nov 08. Date of Electronic Publication: 2024 Nov 08.
DOI:	10.1164/rccm.202407-1394OC
Abstrakt:	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.
Databáze:	MEDLINE
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