TY - JOUR
T1 - Brief Report
T2 - Detection of Urine Lipoarabinomannan Is Associated with Proinflammatory Innate Immune Activation, Impaired Host Defense, and Organ Dysfunction in Adults with Severe HIV-Associated Tuberculosis in Uganda
AU - Cummings, Matthew J.
AU - Bakamutumaho, Barnabas
AU - Jain, Komal
AU - Price, Adam
AU - Owor, Nicholas
AU - Kayiwa, John
AU - Namulondo, Joyce
AU - Byaruhanga, Timothy
AU - Muwanga, Moses
AU - Nsereko, Christopher
AU - Nayiga, Irene
AU - Kyebambe, Stephen
AU - Che, Xiaoyu
AU - Sameroff, Stephen
AU - Tokarz, Rafal
AU - Wong, Wai
AU - Postler, Thomas S.
AU - Larsen, Michelle H.
AU - Lipkin, W. Ian
AU - Lutwama, Julius J.
AU - O'Donnell, Max R.
N1 - Publisher Copyright:
© Copyright 2023 Wolters Kluwer Health, Inc. All rights reserved.
PY - 2023/5/1
Y1 - 2023/5/1
N2 - Background:The immunopathology of disseminated HIV-associated tuberculosis (HIV/TB), a leading cause of critical illness and death among persons living with HIV in sub-Saharan Africa, is incompletely understood. Reflective of hematogenously disseminated TB, detection of lipoarabinomannan (LAM) in urine is associated with greater bacillary burden and poor outcomes in adults with HIV/TB.Methods:We determined the relationship between detection of urine TB-LAM, organ dysfunction, and host immune responses in a prospective cohort of adults hospitalized with severe HIV/TB in Uganda. Generalized additive models were used to analyze the association between urine TB-LAM grade and concentrations of 14 soluble immune mediators. Whole-blood RNA-sequencing data were used to compare transcriptional profiles between patients with high- vs. low-grade TB-LAM results.Results:Among 157 hospitalized persons living with HIV, 40 (25.5%) had positive urine TB-LAM testing. Higher TB-LAM grade was associated with more severe physiologic derangement, organ dysfunction, and shock. Adjusted generalized additive models showed that higher TB-LAM grade was significantly associated with higher concentrations of mediators reflecting proinflammatory innate and T-cell activation and chemotaxis (IL-8, MIF, MIP-1β/CCL4, and sIL-2Ra/sCD25). Transcriptionally, patients with higher TB-LAM grades demonstrated multifaceted impairment of antibacterial defense including reduced expression of genes encoding cytotoxic and autophagy-related proteins and impaired cross-talk between innate and cell-mediated immune effectors.Conclusions:Our findings add to emerging data suggesting pathobiological relationships between LAM, TB dissemination, innate cell activation, and evasion of host immunity in severe HIV/TB. Further translational studies are needed to elucidate the role for immunomodulatory therapies, in addition to optimized anti-TB treatment, in this often critically ill population.
AB - Background:The immunopathology of disseminated HIV-associated tuberculosis (HIV/TB), a leading cause of critical illness and death among persons living with HIV in sub-Saharan Africa, is incompletely understood. Reflective of hematogenously disseminated TB, detection of lipoarabinomannan (LAM) in urine is associated with greater bacillary burden and poor outcomes in adults with HIV/TB.Methods:We determined the relationship between detection of urine TB-LAM, organ dysfunction, and host immune responses in a prospective cohort of adults hospitalized with severe HIV/TB in Uganda. Generalized additive models were used to analyze the association between urine TB-LAM grade and concentrations of 14 soluble immune mediators. Whole-blood RNA-sequencing data were used to compare transcriptional profiles between patients with high- vs. low-grade TB-LAM results.Results:Among 157 hospitalized persons living with HIV, 40 (25.5%) had positive urine TB-LAM testing. Higher TB-LAM grade was associated with more severe physiologic derangement, organ dysfunction, and shock. Adjusted generalized additive models showed that higher TB-LAM grade was significantly associated with higher concentrations of mediators reflecting proinflammatory innate and T-cell activation and chemotaxis (IL-8, MIF, MIP-1β/CCL4, and sIL-2Ra/sCD25). Transcriptionally, patients with higher TB-LAM grades demonstrated multifaceted impairment of antibacterial defense including reduced expression of genes encoding cytotoxic and autophagy-related proteins and impaired cross-talk between innate and cell-mediated immune effectors.Conclusions:Our findings add to emerging data suggesting pathobiological relationships between LAM, TB dissemination, innate cell activation, and evasion of host immunity in severe HIV/TB. Further translational studies are needed to elucidate the role for immunomodulatory therapies, in addition to optimized anti-TB treatment, in this often critically ill population.
KW - HIV
KW - Uganda
KW - biomarkers
KW - lipoarabinomannan
KW - tuberculosis
UR - http://www.scopus.com/inward/record.url?scp=85152172483&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85152172483&partnerID=8YFLogxK
U2 - 10.1097/QAI.0000000000003159
DO - 10.1097/QAI.0000000000003159
M3 - Article
C2 - 36701194
AN - SCOPUS:85152172483
SN - 1525-4135
VL - 93
SP - 79
EP - 85
JO - Journal of Acquired Immune Deficiency Syndromes
JF - Journal of Acquired Immune Deficiency Syndromes
IS - 1
ER -