Brief Report: 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. (1st May 2023)

• Record Type: Journal Article
• Authors: Cummings, Matthew J.; Bakamutumaho, Barnabas; Jain, Komal; Price, Adam; Owor, Nicholas; Kayiwa, John; Namulondo, Joyce; Byaruhanga, Timothy; Muwanga, Moses; Nsereko, Christopher; Nayiga, Irene; Kyebambe, Stephen; Che, Xiaoyu; Sameroff, Stephen; Tokarz, Rafal; Wong, Wai; Postler, Thomas S.; Larsen, Michelle H.; Lipkin, W. Ian; Lutwama, Julius J.; O'Donnell, Max R.
• Is Part Of: Journal of acquired immune deficiency syndromes. Volume 93:Number 1(2023)
• Page Start: 79
• Page End: 85
• Publication Date: 2023-05-01
• Subjects: tuberculosis -- lipoarabinomannan -- HIV -- biomarkers -- Uganda; AIDS (Disease) -- Periodicals; Acquired Immunodeficiency Syndrome -- Periodicals; AIDS (Disease); Periodicals; 616.9792005
• DOI: 10.1097/QAI.0000000000003159
• Languages: English
• ISSNs: 1525-4135

Abstract

Abstract : Supplemental Digital Content is Available in the Text. Abstract : 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.