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Abstract
BackgroundTuberculosis-associated immune reconstitution inflammatory syndrome (TB-IRIS) remains a poorly understood complication in HIV-TB co-infected patients initiating antiretroviral therapy (ART). The role of the innate immune system in TB-IRIS is becoming increasingly apparent, however the potential involvement in TB-IRIS of a leaky gut and proteins that interfere with TLR stimulation by binding PAMPs has not been investigated before. Here we aimed to investigate the innate nature of the cytokine response in TB-IRIS and to identify novel potential biomarkers.MethodsFrom a large prospective cohort of HIV-TB co-infected patients receiving TB treatment, we compared 40 patients who developed TB-IRIS during the first month of ART with 40 patients matched for age, sex and baseline CD4 count who did not. We analyzed plasma levels of lipopolysaccharide (LPS)-binding protein (LBP), LPS, sCD14, endotoxin-core antibody, intestinal fatty acid-binding protein (I-FABP) and 18 pro-and anti-inflammatory cytokines before and during ART. ResultsWe observed lower baseline levels of IL-6 (p = 0.041), GCSF (p = 0.036) and LBP (p = 0.016) in TB-IRIS patients. At IRIS event, we detected higher levels of LBP, IL-1RA, IL-4, IL-6, IL-7, IL-8, G-CSF (p ≤ 0.032) and lower I-FABP levels (p = 0.013) compared to HIV-TB co-infected controls. Only IL-6 showed an independent effect in multivariate models containing significant cytokines from pre-ART (p = 0.039) and during TB-IRIS (p = 0.034). ConclusionWe report pre-ART IL-6 and LBP levels as well as IL-6, LBP and I-FABP levels during IRIS-event as potential biomarkers in TB-IRIS. Our results show no evidence of the possible contribution of a leaky gut to TB-IRIS and indicate that IL-6 holds a distinct role in the disturbed innate cytokine profile before and during TB-IRIS. Future clinical studies should investigate the importance and clinical relevance of these markers for the diagnosis and treatment of TB-IRIS.
Highlights
Over one third of the 33 million people living with HIV are coinfected with tuberculosis (TB) [1]
All patients with available HIV viral loads showed a significant decrease in HIV viral load upon antiretroviral therapy (ART) and no significant differences at either baseline or IRIS event were observed between the two groups
We analyzed plasma levels of markers of increased intestinal permeability, pathogen associated molecular patterns (PAMPs)-binding proteins as well as pro- and anti-inflammatory cytokines before and during ART in one of the largest Tuberculosis-associated immune reconstitution inflammatory syndrome (TB-IRIS) cohorts described to date
Summary
Over one third of the 33 million people living with HIV are coinfected with tuberculosis (TB) [1]. During successful ART, up to 25% of HIV-TB co-infected patients paradoxically develop worsening symptoms of TB, despite effective initial response to concurrent TB treatment [2]. This complication has been named paradoxical tuberculosis-associated immune reconstitution inflammatory syndrome (TB-IRIS) [3] and may require hospitalization or additional immune suppressive therapy [4]. Tuberculosis-associated immune reconstitution inflammatory syndrome (TB-IRIS) remains a poorly understood complication in HIV-TB co-infected patients initiating antiretroviral therapy (ART). The role of the innate immune system in TB-IRIS is becoming increasingly apparent, the potential involvement in TB-IRIS of a leaky gut and proteins that interfere with TLR stimulation by binding PAMPs has not been investigated before. Future clinical studies should investigate the importance and clinical relevance of these markers for the diagnosis and treatment of TB-IRIS
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