Recent attention has focused on the role

Recent attention has focused on the role of vitamin D in infectious (de Haan et al., 2014) and autoimmune disease, including tuberculosis (Yang et al., 2013). In resource-limited settings, which have the largest burden of advanced HIV disease, mycobacteria are the most common pathogen involved in the development of IRIS (Conesa-Botella et al., 2009). Vitamin D deficiency is also prevalent and associated with AIDS progression (Van Den Bout-Van Den Beukel et al., 2008). A recent randomized, placebo-controlled trial of vitamin D supplementation in patients with pulmonary tuberculosis demonstrated more rapid clinical recovery than was seen in placebo recipients, although, further investigation of vitamin D for the prevention or reactivation of tuberculosis infection is needed (Salahuddin et al., 2013). Indeed, mounting evidence indicates a strong role for vitamin D in the regulation of the human immune response (Modlin, 2007) and resolution of TB-induced inflammation (Coussens et al., 2012). Multiple in vitro studies have shown that vitamin D suppresses the stimulation of buy EZ Cap Reagent AG (3\' OMe) (Coussens et al., 2012). Furthermore, a prominent role for monocyte activation in paradoxical TB-IRIS was highlighted recently (Andrade et al., 2014). Biomarkers that indicate monocyte and myeloid cell activation may improve prediction of IRIS and suggest new pathways of exploration for preventive and therapeutic strategies.
Methods
Role of Funding Sources
Results
Discussion In this multicenter, prospective study, we identified biomarkers that were associated with increased IRIS risk when measured immediately prior to ART initiation. Our findings suggest that vitamin D, d-dimer and markers of T cell and monocyte activation (IFNγ, sCD14), may help identify patients at highest risk. Notably, d-dimer and vitamin D were not associated with TB-specific IRIS in a multivariate sub-analysis. This study was not powered for this sub-analysis and may best explain the observed discrepancy. Taken together, our results support a potential role for vitamin D in IRIS pathogenesis and thus, a potential target for intervention. There are limitations to our study. Firstly, patients with severe laboratory abnormalities, mental status changes and CNS infections were not eligible for participation, thus these results may not be generalizable to critically ill patients. Additionally, baseline biomarker measurement allowed for the assessment of IRIS risk prediction but did not allow us to evaluate temporal changes in biomarker levels; an approach that might have improved our understanding of the pathophysiology of IRIS. It is also important to note that IRIS incidence was higher in patients in Mexico compared to those in South Africa. This is likely explained by a higher prevalence of AIDS-defining illnesses among patients in Mexico as reported in our published clinical trial results (79.0% vs. 42.8%; Sierra-Madero et al., 2014). The active form of vitamin D has anti-inflammatory properties and higher vitamin D levels are associated with lower risks of immune-mediated disorders, multiple sclerosis and graft versus host disease (Salzer et al., 2012; von Bahr et al., 2015). In a randomized clinical trial of vitamin D supplementation in patients with TB, a subset of patients with a polymorphism in the vitamin D receptor showed improved infection clearance (Martineau et al., 2011). Most patients with HIV infection in low-resource settings have demonstrable vitamin D deficiency and this deficiency is directly related to the degree of immunosuppression (Aziz et al., 2013). A recent clinical trial of vitamin D supplementation in HIV infection showed a reduction in immune activation, suggesting an anti-inflammatory role (Fabre-Mersseman et al., 2014). Consistent with those results, our study revealed an association between lower vitamin D levels and IRIS risk. In contrast, a recent nested case–control study of TB-IRIS in HIV linked severe vitamin D deficiency with underlying inflammation, irrespective of IRIS status, suggesting that low vitamin D levels represent markers of inflammation, rather than of IRIS itself (Conesa-Botella et al., 2012). This hypothesis may best explain why a trend for significance between TB-IRIS risk and vitamin D was not upheld after multivariate adjustment. However in the same study, while corticosteroid use improved inflammatory cytokine expression, it did not influence vitamin D levels, suggesting that in this setting vitamin D deficiency may not be driven by inflammation but rather may drive it or alternatively, may play an independent role in IRIS pathogenesis (Conesa-Botella et al., 2012).