Immune cell characteristics and cytokine responses in adult HIV-negative tuberculous meningitis: an observational cohort study

Abstract

Immunopathology contributes to high mortality in tuberculous meningitis (TBM) but little is known about the blood and cerebrospinal fluid (CSF) immune response. We prospectively characterised the immune response of 160 TBM suspects in an Indonesian cohort, including 67 HIV-negative probable or definite TBM cases. TBM patients presented with severe disease and 38% died in 6 months. Blood from TBM patients analysed by flow cytometry showed lower αβT and γδT cells, NK cells and MAIT cells compared to 26 pulmonary tuberculosis patients (2.4-4-fold, all p < 0.05) and 27 healthy controls (2.7-7.6-fold, p < 0.001), but higher neutrophils and classical monocytes (2.3-3.0-fold, p < 0.001). CSF leukocyte activation was higher than in blood (1.8-9-fold). CSF of TBM patients showed a predominance of αβT and NK cells, associated with better survival. Cytokine production after ex-vivo stimulation of whole blood showed a much broader range in TBM compared to both control groups (p < 0.001). Among TBM patients, high ex-vivo production of TNF-α, IL-6 and IL-10 correlated with fever, lymphocyte count and monocyte HLA-DR expression (all p < 0.05). TBM patients show a strong myeloid blood response, with a broad variation in immune function. This may influence the response to adjuvant treatment and should be considered in future trials of host-directed therapy.

Thalidomide and Phosphodiesterase 4 Inhibitors as Host Directed Therapeutics for Tuberculous Meningitis: Insights From the Rabbit Model

“…In addition, immune-suppression such as that seen in HIV-infection is associated with a significantly higher frequency of Mtb dissemination from the lungs to extrapulmonary sites, including the CNS (Dube et al, 1992;Thwaites et al, 2005;Marais et al, 2010;Ducomble et al, 2013;Heemskerk et al, 2016). A recent meta-analysis of the global TBM burden has reported about a 40% mortality rate within 6 months of TBM diagnosis with progressively deteriorating disease (van Laarhoven et al, 2019).…”

Recent Developments in Tuberculous Meningitis Pathogenesis and Diagnostics

“…Flow-cytometry on blood in a subset of 160 HIV-negative adults with TBM showed lower αβT and γδT cells, NK cells and MAIT cells in TBM subjects compared to 26 pulmonary TB adults (2.4 to 4-fold, all p < 0.05) and 27 healthy controls (2.7-7.6-fold, p < 0.001), but higher neutrophils and classical monocytes (2.3 - 3.0-fold, p < 0.001). CSF flow cytometry of TBM patients showed a predominance of αβT and NK cells, associated with better survival, as well as the presence of MAIT cells, previously undescribed in CSF 20 . Indonesian HIV-negative TBM patients showed a strong myeloid blood response and a remarkably broad lymphoid CSF response including innate lymphocytes, however there was little correlation between blood and CSF compartments 20 .…”

“…CSF flow cytometry of TBM patients showed a predominance of αβT and NK cells, associated with better survival, as well as the presence of MAIT cells, previously undescribed in CSF 20 . Indonesian HIV-negative TBM patients showed a strong myeloid blood response and a remarkably broad lymphoid CSF response including innate lymphocytes, however there was little correlation between blood and CSF compartments 20 .…”

Recent Developments in Tuberculous Meningitis Pathogenesis and Diagnostics

“…Flow-cytometry on blood in a subset of 160 HIV-negative adults with TBM showed lower αβT and γδT cells, NK cells and MAIT cells in TBM subjects compared to 26 pulmonary TB adults (2.4 to 4-fold, all p < 0.05) and 27 healthy controls (2.7-7.6-fold, p < 0.001), but higher neutrophils and classical monocytes (2.3 -3.0-fold, p < 0.001). CSF flow cytometry of TBM patients showed a predominance of αβT and NK cells, associated with better survival, as well as the presence of MAIT cells, previously undescribed in CSF 17 . Indonesian HIV-negative TBM patients showed a strong myeloid blood response and a remarkably broad lymphoid CSF response including innate lymphocytes, however there was little correlation between blood and CSF compartments 17 .…”

“…CSF flow cytometry of TBM patients showed a predominance of αβT and NK cells, associated with better survival, as well as the presence of MAIT cells, previously undescribed in CSF 17 . Indonesian HIV-negative TBM patients showed a strong myeloid blood response and a remarkably broad lymphoid CSF response including innate lymphocytes, however there was little correlation between blood and CSF compartments 17 .…”