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The global burden of sepsis is concentrated in sub-Saharan Africa (SSA), where epidemic HIV and unique pathogen diversity challenge the effective management of severe infections. In this context, patient stratification based on biomarkers of a dysregulated host response may identify subgroups more likely to respond to targeted immunomodulatory therapeutics. In a prospective cohort of adults hospitalized with suspected sepsis in Uganda, we applied machine learning methods to develop a prediction model for 30-day mortality that integrates physiology-based risk scores with soluble biomarkers reflective of key domains of sepsis immunopathology. After model evaluation and internal validation, whole-blood RNA sequencing data were analyzed to compare biological pathway enrichment and inferred immune cell profiles between patients assigned differential model-based risks of mortality. Of 260 eligible adults (median age, 32 years; interquartile range, 26–43 years; 59.2% female, 53.9% living with HIV), 62 (23.8%) died by 30 days after hospital discharge. Among 14 biomarkers, soluble tumor necrosis factor receptor 1 (sTNFR1) and angiopoietin 2 (Ang-2) demonstrated the greatest importance for mortality prediction in machine learning models. A clinicomolecular model integrating sTNFR1 and Ang-2 with the Universal Vital Assessment (UVA) risk score optimized 30-day mortality prediction across multiple performance metrics. Patients assigned to the high-risk, UVA-based clinicomolecular subgroup exhibited a transcriptional profile defined by proinflammatory innate immune and necroptotic pathway activation, T-cell exhaustion, and expansion of key immune cell subsets including regulatory and gamma-delta T cells. Clinicomolecular stratification of adults with suspected sepsis in Uganda enhanced 30-day mortality prediction and identified a high-risk subgroup with a therapeutically targetable immunological profile. Further studies are needed to advance pathobiologically informed sepsis management in SSA.
Financial support: This work was supported by the National Center for Advancing Translational Sciences (UL1TR001873 to Columbia University, sub-award to M. R. O.), the National Institute of Allergy and Infectious Diseases (K23AI163364 to M. J. C.), and the MakCHS-Berkeley-Yale Pulmonary Complications of AIDS Research Training (PART) Program (D43TW009607, sub-award to B. B.) from the Fogarty International Center, National Institutes of Health. Additional support was provided by the Stony Wold-Herbert Fund (M. J. C.), the Potts Memorial Foundation (M. J. C.), the Thrasher Research Fund (M. J. C.), the Burroughs Wellcome Fund/American Society of Tropical Medicine and Hygiene (M. J. C.), and the DELTAS Africa Initiative (sub-award to M. J. C. and B. B.; Grant no. 107743).
Disclaimer: The funders had no role in study design, data analysis or interpretation, manuscript preparation, or decision to publish. Each enrolled participant ≥ 18 years or their surrogate provided written informed consent. Study protocols were approved by ethics committees at Columbia University (AAAR1450), the Uganda Virus Research Institute (GC/127/17/02-06/582), and the Uganda National Council for Science and Technology (HS2308). RNA sequencing data analyzed in this study are available in the NIH National Center for Biotechnology Information Sequence Read Archive under BioProject accession no. PRJNA794277. Other de-identified data will be made available to researchers affiliated with an appropriate institution after mutual signing of a data access agreement and obtainment of necessary ethics approvals. All code is available on request from M. J. C., A. P., and K. J.
Authors’ addresses: Matthew J. Cummings, Division of Pulmonary, Allergy, and Critical Care Medicine, Department of Medicine, Vagelos College of Physicians and Surgeons, Columbia University, New York, NY, and Center for Infection and Immunity, Mailman School of Public Health, Columbia University, New York, NY, E-mail: email@example.com. Barnabas Bakamutumaho, Department of Arbovirology, Emerging and Re-emerging Infectious Diseases, Uganda Virus Research Institute, Entebbe, Uganda, and Immunizable Diseases Unit, Uganda Virus Research Institute, Entebbe, Uganda, E-mail: firstname.lastname@example.org. Komal Jain, Adam Price, and Stephen Sameroff, Center for Infection and Immunity, Mailman School of Public Health, Columbia University, New York, NY, E-mails: email@example.com, firstname.lastname@example.org, and email@example.com. Nicholas Owor, John Kayiwa, Joyce Namulondo, Timothy Byaruhanga, and Julius J. Lutwama, Department of Arbovirology, Emerging and Re-emerging Infectious Diseases, Uganda Virus Research Institute, Entebbe, Uganda, E-mails: firstname.lastname@example.org, email@example.com, firstname.lastname@example.org, email@example.com, and firstname.lastname@example.org. Moses Muwanga and Christopher Nsereko, Entebbe General Referral Hospital, Ministry of Health, Entebbe, Uganda, E-mails: email@example.com and firstname.lastname@example.org. W. Ian Lipkin, Center for Infection and Immunity, Mailman School of Public Health, Columbia University, New York, NY, and Department of Pathology and Cell Biology, Vagelos College of Physicians and Surgeons, Columbia University, New York, NY, E-mail: email@example.com. 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, Center for Infection and Immunity, Mailman School of Public Health, Columbia University, New York, NY, and Department of Epidemiology, Mailman School of Public Health, Columbia University, New York, NY, E-mail: firstname.lastname@example.org.