المفاهيم الأساسية
Mortality from tuberculous meningitis is associated with increased neutrophil activation and decreased T and B cell activation pathways. A four-gene host response signature in blood can predict early mortality from tuberculous meningitis.
الملخص
The study used whole blood RNA sequencing to investigate the transcriptional profiles associated with mortality in 281 Vietnamese adults with tuberculous meningitis (TBM), 295 with pulmonary tuberculosis (PTB), and 30 healthy controls.
Key findings:
TBM mortality was associated with increased activation of inflammatory and innate immune response pathways, particularly those involving neutrophil activation, and decreased activation of adaptive immunity pathways involving T and B cell responses.
Specific gene modules and hub genes were identified that were strongly associated with TBM mortality. These included upregulation of genes involved in acute inflammation and neutrophil activation (e.g. MCEMP1, FCAR), and downregulation of genes involved in T and B cell signaling (e.g. NELL2, TRABD2A, PLCG1, CD247).
The association of these pathways and hub genes with mortality differed somewhat between HIV-positive and HIV-negative TBM. In HIV-positive TBM, mortality was associated with increased angiogenesis, while in HIV-negative TBM it was associated with increased TNF signaling and decreased extracellular matrix organization.
A four-gene host response signature in blood (MCEMP1, NELL2, ZNF354C, CD4) was highly predictive of three-month mortality in both HIV-negative and HIV-positive TBM, with an AUC of 0.80 and 0.86 respectively.
These findings provide novel insights into the pathogenesis of TBM and identify potential prognostic biomarkers that could help guide treatment of this lethal disease.
الإحصائيات
"Mortality was associated with higher peripheral blood neutrophil counts and lower lymphocyte counts."
"Overall three-month mortality rate was 21.7% (61/281) for TBM, 16.4% (34/207) in HIV-negative and 36.5% (27/74) in HIV-positive TBM."
اقتباسات
"Mortality and morbidity from tuberculous meningitis (TBM) are frequent and strongly associated with the inflammatory response to Mycobacterium tuberculosis infection."
"The poor outcomes from TBM are strongly associated with the inflammatory response, with both a paucity and an excess of inflammation linked to death from TBM."
"Host-based peripheral blood gene expression analysis has been used to identify active or progressive pulmonary TB and in pulmonary TB treatment monitoring, but has yet to be applied to TBM."