Features of Cytokine Regulation in Multidrug-Resistant Tuberculosis Depending on Severity of Endogenous Intoxication

Abstract

Introduction. Tuberculosis (TB) belongs to interleukin-dependent immunodeficiencies with pronounced changes in cytokine system. Despite significant progress achieved in TB control, the role of some cytokines in the development of its resistant forms remains unclear; the issues of identification of integrated markers of progression of the pathological process in multidrug-resistant tuberculosis (MDR TB) is unsolved; as well as no prognostic determination was made in terms of their role in ensuring the effectiveness of standard programs for tuberculosis chemotherapy. In view of the above, it is necessary to analyze indicators of certain cytokines in the blood serum of patients with MDR TB, depending on the resistance profile, which may reflect the severity of local and systemic nature of the specific inflammation, features of immuno-cytokine regulation in order to improve treatment programs. TB belongs to diseases that are accompanied by endogenous intoxication, i.e. accumulation in the body of end and intermediate products of metabolism in metabolism impaired due to inflammatory response. Pathways of endogenous intoxication development in TB are cytotoxic hypoxia, violation of intracellular homeostasis, massive generation and further resorption of tissue decay products, immuno-cytokine and hormonal imbalance, etc. The objective of this study — to estimate the parameters of endogenous intoxication, to determine the features of cytokine regulation in patients with multidrug resistant pulmonary tuberculosis depending on the resistance profile of mycobacteria and to define their role in the development of systemic inflammatory response. Materials and methods. The study included 116 patients with newly diagnosed pulmonary tuberculosis and preserved sensitivity to antimycobacterials; with MDR TB and diagnosed resistant to at least two first-line agents; tuberculosis patients with enhanced resistance. Clinical, radiological, biochemical, microscopic, microbiological, immune-enzymatic and statistical study methods were used. Results. Pearson correlation analysis between pro- and anti-inflammatory cytokines showed that in patients with MDR TB there is a weak negative correlation between the levels of interleukin (IL)-6 and IL-10, IL-18 and IL-10 (–0.22, p < 0,001; –0.16, p < 0.001). Production of IL-6 and IL-10 in groups of TB patients, independent of resistance, increases in response to increased synthesis of endotoxins of Mycobacterium tuberculosis; growth of endogenous intoxication and cytotoxic hypoxia predetermines the development of their resistance. The imbalance of IL-18 and IL-10 ratio in these patients characterizes the increase in severity of the patient’s state, the spread of inflammatory processes in the lungs and the development of resistance; there is a significant advantage of the Tx-lymphocyte type 2 (humoral), which indicates the development of defect in cell-mediated immune response and prevalence of an ineffective anti-inflammatory immune activation. Conclusions. Comprehensive assessment of integral indices of endogenous intoxication and level of certain pro- and anti-inflammatory cytokines in the blood plasma of patients with MDR TB shows a moderate endogenous intoxication, break down of the cellular component of the immune reactivity due to the formation of conditions for the development of Mycobacterium tuberculosis resistance, with further growth of cytotoxic hypoxia and activation of systemic inflammatory response syndrome. Analysis of plasma concentration of IL-6, IL-10 and IL-18 in patients with multidrug-resistance proved, that their level depends on the nature of Mycobacterium tuberculosis resistance.

Keywords

• tuberculosis
• multidrug-resistance
• interleukins
• endogenous intoxication