Systemic lymphocyte trafficking markers in TB and TB/HIV co-infections.
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Background. Several studies demonstrate that immune inflammation and trafficking of immune cells to affected tissues plays a major role in the pathogenesis of tuberculosis (TB) and human immunodeficiency virus (HIV) infections; however, characterization of soluble markers of lymphocyte trafficking and inflammation in the context of TB and TB/HIV co-infection remains to be elucidated. Here we sought to evaluate the role of specific lymphocyte trafficking and inflammatory markers as predictors of TB disease. Methods. The presented study was performed on stored plasma samples from TB Recurrence upon Treatment with HAART (TRuTH) and Improving Recurrence Success (IMPRESS) cohorts. TB recurrent cases (n = 37) were matched to controls (n = 103) on study arm in the original trial and antiretroviral therapy (ART) start date. A subset of cases was followed longitudinally at: preTB, active TB and postTB/cure timepoints. In IMPRESS a subset of HIV infected (n = 41) and HIV uninfected (n = 37) individuals were sampled at active TB disease and post TB/cure. Plasma concentrations of soluble mucosal addressin cell adhesion molecule (sMAdCAM), soluble intracellular adhesion molecule (sICAM), soluble vascular adhesion molecule (sVCAM), lipopolysaccharide binding protein (LBP) and transforming growth factor – beta (TGF-β) were measured using enzyme-linked immunosorbent assays (ELISAs) and Multiplex assays. Results. Two analytes were associated with increased rate of TB recurrence in the univariate model: square root transformed (sqrt) sICAM (odds ratio [OR] 1.047. 95% confidence interval [CI] 1.014 – 1.081, p = 0.005) and sqrtLBP (OR 3.283, 95% CI 1.018 – 10.588, p = 0.047) and the multivariable model. Longitudinal analysis showed reduced levels of LBP, sMAdCAM and sVCAM and an increase in levels of TGF- β3 during the entire follow-up. In IMPRESS data, trends of increased plasma LBP from active TB to post TB/cure in HIV infected individuals and trends of reduced plasma LBP in HIV uninfected individuals post treatment were observed. Conclusion. The TRuTH data demonstrates that plasma levels of sICAM and LBP can act as predictors of TB recurrence in HIV infected individuals receiving ART treatment. A decrease of plasma LBP levels from active TB to treatment completion in HIV uninfected individuals likely suggests that active TB and associated inflammatory changes are associated with gut inflammation and dysbiosis.