Multidimensional analysis of the host response reveals prognostic and pathogen-driven immune subtypes among adults with sepsis in Uganda
Abstract Background The 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 deve...
| Main Authors: | , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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BMC
2022-02-01
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| Series: | Critical Care |
| Subjects: | |
| Online Access: | https://doi.org/10.1186/s13054-022-03907-3 |
| _version_ | 1818330471273070592 |
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| author | Matthew J. Cummings Barnabas Bakamutumaho Adam Price Nicholas Owor John Kayiwa Joyce Namulondo Timothy Byaruhanga Moses Muwanga Christopher Nsereko Stephen Sameroff Rafal Tokarz Wai Wong Shivang S. Shah Michelle H. Larsen W. Ian Lipkin Julius J. Lutwama Max R. O’Donnell |
| author_facet | Matthew J. Cummings Barnabas Bakamutumaho Adam Price Nicholas Owor John Kayiwa Joyce Namulondo Timothy Byaruhanga Moses Muwanga Christopher Nsereko Stephen Sameroff Rafal Tokarz Wai Wong Shivang S. Shah Michelle H. Larsen W. Ian Lipkin Julius J. Lutwama Max R. O’Donnell |
| author_sort | Matthew J. Cummings |
| collection | DOAJ |
| description | Abstract Background The 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. Methods Among 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. Results Unsupervised 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. Conclusions Our 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. |
| first_indexed | 2024-12-13T13:04:29Z |
| format | Article |
| id | doaj.art-733096a2fb53498da73010f99b9ffb32 |
| institution | Directory Open Access Journal |
| issn | 1364-8535 |
| language | English |
| last_indexed | 2024-12-13T13:04:29Z |
| publishDate | 2022-02-01 |
| publisher | BMC |
| record_format | Article |
| series | Critical Care |
| spelling | doaj.art-733096a2fb53498da73010f99b9ffb322022-12-21T23:44:52ZengBMCCritical Care1364-85352022-02-0126111510.1186/s13054-022-03907-3Multidimensional analysis of the host response reveals prognostic and pathogen-driven immune subtypes among adults with sepsis in UgandaMatthew J. Cummings0Barnabas Bakamutumaho1Adam Price2Nicholas Owor3John Kayiwa4Joyce Namulondo5Timothy Byaruhanga6Moses Muwanga7Christopher Nsereko8Stephen Sameroff9Rafal Tokarz10Wai Wong11Shivang S. Shah12Michelle H. Larsen13W. Ian Lipkin14Julius J. Lutwama15Max R. O’Donnell16Division of Pulmonary, Allergy, and Critical Care Medicine, Department of Medicine, Columbia University Vagelos College of Physicians and SurgeonsDepartment of Arbovirology, Emerging and Re-Emerging Infectious Diseases, Uganda Virus Research InstituteCenter for Infection and Immunity, Mailman School of Public Health, Columbia UniversityDepartment of Arbovirology, Emerging and Re-Emerging Infectious Diseases, Uganda Virus Research InstituteDepartment of Arbovirology, Emerging and Re-Emerging Infectious Diseases, Uganda Virus Research InstituteDepartment of Arbovirology, Emerging and Re-Emerging Infectious Diseases, Uganda Virus Research InstituteDepartment of Arbovirology, Emerging and Re-Emerging Infectious Diseases, Uganda Virus Research InstituteEntebbe General Referral Hospital, Ministry of HealthEntebbe General Referral Hospital, Ministry of HealthCenter for Infection and Immunity, Mailman School of Public Health, Columbia UniversityCenter for Infection and Immunity, Mailman School of Public Health, Columbia UniversityCenter for Infection and Immunity, Mailman School of Public Health, Columbia UniversityDivision of Infectious Diseases, Department of Pediatrics, Vagelos College of Physicians and Surgeons, Columbia UniversityDepartment of Microbiology and Immunology, Albert Einstein College of MedicineCenter for Infection and Immunity, Mailman School of Public Health, Columbia UniversityDepartment of Arbovirology, Emerging and Re-Emerging Infectious Diseases, Uganda Virus Research InstituteDivision of Pulmonary, Allergy, and Critical Care Medicine, Department of Medicine, Columbia University Vagelos College of Physicians and SurgeonsAbstract Background The 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. Methods Among 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. Results Unsupervised 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. Conclusions Our 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.https://doi.org/10.1186/s13054-022-03907-3SepsisBiomarkersTuberculosisHigh-throughput nucleotide sequencingUgandaAfrica |
| spellingShingle | Matthew J. Cummings Barnabas Bakamutumaho Adam Price Nicholas Owor John Kayiwa Joyce Namulondo Timothy Byaruhanga Moses Muwanga Christopher Nsereko Stephen Sameroff Rafal Tokarz Wai Wong Shivang S. Shah Michelle H. Larsen W. Ian Lipkin Julius J. Lutwama Max R. O’Donnell Multidimensional analysis of the host response reveals prognostic and pathogen-driven immune subtypes among adults with sepsis in Uganda Critical Care Sepsis Biomarkers Tuberculosis High-throughput nucleotide sequencing Uganda Africa |
| title | Multidimensional analysis of the host response reveals prognostic and pathogen-driven immune subtypes among adults with sepsis in Uganda |
| title_full | Multidimensional analysis of the host response reveals prognostic and pathogen-driven immune subtypes among adults with sepsis in Uganda |
| title_fullStr | Multidimensional analysis of the host response reveals prognostic and pathogen-driven immune subtypes among adults with sepsis in Uganda |
| title_full_unstemmed | Multidimensional analysis of the host response reveals prognostic and pathogen-driven immune subtypes among adults with sepsis in Uganda |
| title_short | Multidimensional analysis of the host response reveals prognostic and pathogen-driven immune subtypes among adults with sepsis in Uganda |
| title_sort | multidimensional analysis of the host response reveals prognostic and pathogen driven immune subtypes among adults with sepsis in uganda |
| topic | Sepsis Biomarkers Tuberculosis High-throughput nucleotide sequencing Uganda Africa |
| url | https://doi.org/10.1186/s13054-022-03907-3 |
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