Inflammatory and prognostic biomarkers associated with pulmonary tuberculosis long-term sequelae after TB treatment in relation to HIV status and lung impairment

Sitoe, Nádia (2023): Inflammatory and prognostic biomarkers associated with pulmonary tuberculosis long-term sequelae after TB treatment in relation to HIV status and lung impairment. Dissertation, LMU München: Faculty of Medicine

Abstract

Background: Monitoring of tuberculosis treatment is challenging, especially in people living with HIV (PLHIV) who often present with paucibacillary tuberculosis. Microbiological methods used for treatment monitoring have reduced sensitivity after TB treatment initiation due to the reduction in bacterial load. MTB culture needs highly skilled personnel and complex infrastructure, limited in Mozambican settings. This thesis aimed to study the dynamics of MTB-specific CD4+ T-cells expressing activation and maturation markers, and plasma levels of neutrophil-based mediators during TB treatment to identify inflammatory and prognostic biomarkers for TB treatment monitoring. Methods: During TB sequel cohort study in Maputo Mozambique, plasma and peripheral blood mononuclear cells from baseline, month 2, and at the end of treatment at month 6 were analyzed from selected tuberculosis patients living with and without HIV. Expression of activation and maturation markers on MTB-specific CD4+ T-cells after stimulation with H37Rv cell lysate, purified protein derivative and early secreted antigenic target 6/ culture filtrate protein 10 antigens, was analyzed by interferon-gamma intra-cellular cytokine staining using flow cytometry. Multiple soluble plasma cytokines were quantified by magnetic Luminex assays, where an additional sample from month 12 visit was added. Results were compared between groups at different time points. Results: Regardless of HIV status, activation markers (CD38, HLA-DR and Ki67) on MTB-specific CD4+ T-cells and plasma levels of MMP-1, MMP-8, MPO and S100A8 were reduced after TB treatment initiation. In contrast, the expression of the T cell maturation marker CD27 did not change over the course of TB treatment. During TB treatment, significantly elevated plasma levels of MMP-8 were detected in TB patients living with HIV, especially those who were naïve for antiretroviral treatment at baseline visit. Conclusion: MTB-specific CD4+ T-cells expressing activation markers and plasma levels of neutrophil-based biomarkers can be used as surrogate markers for microbiological TB treatment outcome.

• Item Type: Theses (Dissertation, LMU Munich)
• Keywords: Tuberculosis, Lung impairment, HIV, TB treatment, Intracellular cytokine staining, Flow cytometry, Luminex
• Subjects: 600 Technology, Medicine; 600 Technology, Medicine > 610 Medical sciences and medicine
• Faculties: Faculty of Medicine
• Language: English
• Date of oral examination: 18. December 2023
• 1. Referee: Geldmacher, Christof
• Signature of the printed copy: 0700/UMD 21572