Multidimensional analysis of the host response reveals prognostic and pathogen-driven immune subtypes among adults with sepsis in Uganda

Critical Care

Rafal Tokarz¹  Adam Price¹  Wai Wong¹  Stephen Sameroff¹  W. Ian Lipkin²  Julius J. Lutwama³  John Kayiwa³  Nicholas Owor³  Timothy Byaruhanga³  Joyce Namulondo³  Barnabas Bakamutumaho⁴  Michelle H. Larsen⁵  Shivang S. Shah⁶  Matthew J. Cummings⁷  Max R. O’Donnell⁸  Moses Muwanga⁹  Christopher Nsereko⁹ 

[1] Center for Infection and Immunity, Mailman School of Public Health, Columbia University, New York, NY, USA;Center for Infection and Immunity, Mailman School of Public Health, Columbia University, New York, NY, USA;Department of Pathology and Cell Biology, Vagelos College of Physicians and Surgeons, Columbia University, New York, NY, USA;Department of Epidemiology, Mailman School of Public Health, Columbia University, New York, NY, USA;Department of Arbovirology, Emerging and Re-Emerging Infectious Diseases, Uganda Virus Research Institute, Entebbe, Uganda;Department of Arbovirology, Emerging and Re-Emerging Infectious Diseases, Uganda Virus Research Institute, Entebbe, Uganda;Immunizable Diseases Unit, Uganda Virus Research Institute, Entebbe, Uganda;Department of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, NY, USA;Division of Infectious Diseases, Department of Pediatrics, Vagelos College of Physicians and Surgeons, Columbia University, New York, NY, USA;Division of Pulmonary, Allergy, and Critical Care Medicine, Department of Medicine, Columbia University Vagelos College of Physicians and Surgeons, 622 West 168th St, PH 8E-101, 10032, New York, NY, USA;Center for Infection and Immunity, Mailman School of Public Health, Columbia University, New York, NY, USA;Division of Pulmonary, Allergy, and Critical Care Medicine, Department of Medicine, Columbia University Vagelos College of Physicians and Surgeons, 622 West 168th St, PH 8E-101, 10032, New York, NY, USA;Center for Infection and Immunity, Mailman School of Public Health, Columbia University, New York, NY, USA;Department of Epidemiology, Mailman School of Public Health, Columbia University, New York, NY, USA;Entebbe General Referral Hospital, Ministry of Health, Entebbe, Uganda;

关键词: Sepsis;    Biomarkers;    Tuberculosis;    High-throughput nucleotide sequencing;    Uganda;    Africa;   

DOI  :  10.1186/s13054-022-03907-3

来源: Springer

【 摘 要 】

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.

【 授权许可】

CC BY