Identification of transcriptomic sepsis endotypes in sub-Saharan Africa: derivation, validation, and global alignment in two Ugandan cohorts

Purpose Sub-Saharan Africa carries the highest global burden of critical illness, yet transcriptomic sepsis endotypes have not been defined in the region. Their clinical relevance and alignment with endotypes identified in high-income countries (HICs) remain unknown. Methods We analyzed data from tw...

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Published in:Intensive care medicine Vol. 51; no. 9; pp. 1573 - 1586
Main Authors: Cummings, Matthew J., Lutwama, Julius J., Tomoiaga, Alin S., Zhao, Meng, Owor, Nicholas, Lu, Xuan, Eliku, Peter James, Ross, Jesse E., Nsereko, Christopher, Nayiga, Irene, Kyebambe, Stephen, Nsubuga, John Bosco, Shinyale, Joseph, Asasira, Ignatius, Kiyingi, Tonny, Ochar, Thomas, Kiwubeyi, Moses, Nankwanga, Rittah, Reynolds, Steven J., Nakibuuka, Martina Cathy, Kayiwa, John, Haumba, Mercy, Nakaseegu, Joweria, Che, Xiaoyu, Nie, Kai, Kim-Schulze, Seunghee, Ghosh, Sankar, Lipkin, W. Ian, O’Donnell, Max R., Bakamutumaho, Barnabas
Format: Journal Article
Language:English
Published: Berlin/Heidelberg Springer Berlin Heidelberg 01.09.2025
Springer Nature B.V
Subjects:
Accuracy
Adult
Africa South of the Sahara
Alignment
Anesthesiology
Bacterial infections
Cell activation
Classification
Clustering
Cohort Studies
Critical Care Medicine
Critical Illness
Cytometry
Emergency Medicine
Enrollments
Epidemiology
Female
Gene expression
HIV
Human immunodeficiency virus
Humans
Immune response
Intensive
Leukocytes (neutrophilic)
Lymphocytes
Malaria
Male
Medicine
Medicine & Public Health
Middle Aged
Mortality
Original
Pain Medicine
Pediatrics
Physiology
Pneumology/Respiratory System
Prospective Studies
Proteins
Regression analysis
Ribonucleic acid
RNA
Sepsis
Sepsis - classification
Sepsis - genetics
Sepsis - mortality
Transcriptome - genetics
Transcriptomics
Tuberculosis
Uganda - epidemiology
Africa South of the Sahara
Uganda
Africa
Sepsis
Precision medicine
HIV
High-throughput nucleotide sequencing
Africa
ISSN:0342-4642, 1432-1238, 1432-1238
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Summary:Purpose Sub-Saharan Africa carries the highest global burden of critical illness, yet transcriptomic sepsis endotypes have not been defined in the region. Their clinical relevance and alignment with endotypes identified in high-income countries (HICs) remain unknown. Methods We analyzed data from two prospective observational cohorts of critically ill adults with sepsis in Uganda (discovery cohort [Tororo, rural], N = 243; validation cohort [Entebbe, urban], N = 112). Unsupervised clustering of whole-blood RNAseq data was used to identify endotypes in the discovery cohort. A random forest classifier was used to predict endotype assignment in the validation cohort. Differential gene expression, pathway enrichment, and digital cytometry were used to define endotype pathobiology and determine overlap with HIC-derived endotypes. Results Two endotypes—Uganda Sepsis Endotypes 1 (USE-1) and 2 (USE-2)—were identified in the discovery cohort. USE-2, marked by neutrophil-driven innate immune activation and lymphocyte suppression, was associated with greater physiological severity and higher mortality (41.3% vs. 22.0%; absolute difference 19.3%, 95% CI 7.6–30.9%), irrespective of HIV, tuberculosis, or malaria infection. A 13-gene classifier (misclassification rate 1.43%) replicated two endotypes in the validation cohort with similar biological and clinical profiles. USE-2 showed strong transcriptional overlap with SRS1 and inflammopathic endotypes but only modest concordance in patient-level assignments. Overlap with Mars1 was variable. Conclusions We identified two transcriptomic sepsis endotypes in Uganda that reflect inter-individual differences in targetable pathobiology and confer prognostic enrichment across high-burden infections. Divergence from HIC-derived endotypes highlights the need for sepsis classifications that are both globally relevant and locally responsive.
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ISSN:0342-4642
1432-1238
1432-1238
DOI:10.1007/s00134-025-08047-0