TY - JOUR
T1 - HIV infection drives pro-inflammatory immunothrombotic pathway activation and organ dysfunction among adults with sepsis in Uganda
AU - Cummings, Matthew J.
AU - Bakamutumaho, Barnabas
AU - Price, Adam
AU - Owor, Nicholas
AU - Kayiwa, John
AU - Namulondo, Joyce
AU - Byaruhanga, Timothy
AU - Jain, Komal
AU - Postler, Thomas S.
AU - Muwanga, Moses
AU - Nsereko, Christopher
AU - Nayiga, Irene
AU - Kyebambe, Stephen
AU - Che, Xiaoyu
AU - Sameroff, Stephen
AU - Tokarz, Rafal
AU - Shah, Shivang S.
AU - Larsen, Michelle H.
AU - Lipkin, W. Ian
AU - Lutwama, Julius J.
AU - O'Donnell, Max R.
N1 - Publisher Copyright:
© 2022 Wolters Kluwer Health, Inc. All rights reserved.
PY - 2023/2/1
Y1 - 2023/2/1
N2 - Background: The global burden of sepsis is concentrated in high HIV-burden settings in sub-Saharan Africa (SSA). Despite this, little is known about the immunopathology of sepsis in persons with HIV (PWH) in the region. We sought to determine the influence of HIV on host immune responses and organ dysfunction among adults hospitalized with suspected sepsis in Uganda. Design: Prospective cohort study. Methods: We compared organ dysfunction and 30-day outcome profiles of PWH and those without HIV. We quantified 14 soluble immune mediators, reflective of key domains of sepsis immunopathology, and performed whole-blood RNA-sequencing on samples from a subset of patients. We used propensity score methods to match PWH and those without HIV by demographics, illness duration, and clinical severity, and compared immune mediator concentrations and gene expression profiles across propensity score-matched groups. Results: Among 299 patients, 157 (52.5%) were PWH (clinical stage 3 or 4 in 80.3%, 67.7% with known HIV on antiretroviral therapy). PWH presented with more severe physiologic derangement and shock, and had higher 30-day mortality (34.5% vs. 10.2%; P<0.001). Across propensity score-matched groups, PWH exhibited greater pro-inflammatory immune activation, including upregulation of interleukin (IL)-6, IL-8, IL-15, IL-17 and HMGB1 signaling, with concomitant T-cell exhaustion, prothrombotic pathway activation, and angiopoeitin-2-related endothelial dysfunction. Conclusions: Sepsis-related organ dysfunction and mortality in Uganda disproportionately affect PWH, who demonstrate exaggerated activation of multiple immunothrombotic and metabolic pathways implicated in sepsis pathogenesis. Further investigations are needed to refine understanding of sepsis immunopathology in PWH, particularly mechanisms amenable to therapeutic manipulation.
AB - Background: The global burden of sepsis is concentrated in high HIV-burden settings in sub-Saharan Africa (SSA). Despite this, little is known about the immunopathology of sepsis in persons with HIV (PWH) in the region. We sought to determine the influence of HIV on host immune responses and organ dysfunction among adults hospitalized with suspected sepsis in Uganda. Design: Prospective cohort study. Methods: We compared organ dysfunction and 30-day outcome profiles of PWH and those without HIV. We quantified 14 soluble immune mediators, reflective of key domains of sepsis immunopathology, and performed whole-blood RNA-sequencing on samples from a subset of patients. We used propensity score methods to match PWH and those without HIV by demographics, illness duration, and clinical severity, and compared immune mediator concentrations and gene expression profiles across propensity score-matched groups. Results: Among 299 patients, 157 (52.5%) were PWH (clinical stage 3 or 4 in 80.3%, 67.7% with known HIV on antiretroviral therapy). PWH presented with more severe physiologic derangement and shock, and had higher 30-day mortality (34.5% vs. 10.2%; P<0.001). Across propensity score-matched groups, PWH exhibited greater pro-inflammatory immune activation, including upregulation of interleukin (IL)-6, IL-8, IL-15, IL-17 and HMGB1 signaling, with concomitant T-cell exhaustion, prothrombotic pathway activation, and angiopoeitin-2-related endothelial dysfunction. Conclusions: Sepsis-related organ dysfunction and mortality in Uganda disproportionately affect PWH, who demonstrate exaggerated activation of multiple immunothrombotic and metabolic pathways implicated in sepsis pathogenesis. Further investigations are needed to refine understanding of sepsis immunopathology in PWH, particularly mechanisms amenable to therapeutic manipulation.
KW - Africa
KW - HIV
KW - Uganda
KW - biomarkers
KW - high-throughput nucleotide sequencing
KW - sepsis
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U2 - 10.1097/QAD.0000000000003410
DO - 10.1097/QAD.0000000000003410
M3 - Article
C2 - 36355913
AN - SCOPUS:85144588601
SN - 0269-9370
VL - 37
SP - 233
EP - 245
JO - AIDS
JF - AIDS
IS - 2
ER -