Recent Developments in Tuberculous Meningitis Pathogenesis and Diagnostics

Abstract

The pathogenesis of Tuberculous meningitis (TBM) is poorly understood, but contemporary molecular biology technologies have allowed for recent improvements in our understanding of TBM. For instance, neutrophils appear to play a significant role in the immunopathogenesis of TBM, and either a paucity or an excess of inflammation can be detrimental in TBM. Further, severity of HIV-associated immunosuppression is an important determinant of inflammatory response; patients with the advanced immunosuppression (CD4+ T-cell count of <150 cells/μL) having higher CSF neutrophils, greater CSF cytokine concentrations and higher mortality than those with CD4+ T-cell counts > 150 cells/μL. Host genetics may also influence outcomes with LT4AH genotype predicting inflammatory phenotype, steroid responsiveness and survival in Vietnamese adults with TBM. Whist in Indonesia, CSF tryptophan level was a predictor of survival, suggesting tryptophan metabolism may be important in TBM pathogenesis. These varying responses mean that we must consider whether a "one-size-fits-all" approach to anti-bacillary or immunomodulatory treatment in TBM is truly the best way forward. Of course, to allow for proper treatment, early and rapid diagnosis of TBM must occur. Diagnosis has always been a challenge but the field of TB diagnosis is evolving, with sensitivities of at least 70% now possible in less than two hours with GeneXpert MTB/Rif Ultra. In addition, advanced molecular techniques such as CRISPR-MTB and metagenomic next generation sequencing may hold promise for TBM diagnosis. Host-based biomarkers and signatures are being further evaluated in childhood and adult TBM as adjunctive biomarkers as even with improved molecular assays, cases are still missed. A better grasp of host and pathogen behaviour may lead to improved diagnostics, targeted immunotherapy, and possibly biomarker-based, patient-specific treatment regimens.

Keywords: HIV; TB; TBM; Tuberculous meningitis; diagnostics; pathogenesis.

Figure 1.. Illustrative summary of the pathogenesis of tuberculous meningitis (TBM).

Reproduced with permission from author and Journal of Leukocyte Biology . A: Mycobacterium tuberculosis bacilli (M.tb) disseminate from the primary site of infection in the lung to seed the brain. The bacilli traverse the blood brain barrier (BBB) and blood cerebrospinal fluid barrier (BCSFB) through various virulence factors that enable the invasion of and migration through cerebral vascular endothelial cells, or are carried into the CNS by infected peripheral innate immune cells. B: In the CNS antigen recognition and internalization by microglia, neurons and astrocytes occurs, mediated by numerous host genetic factors. C: The resulting immune response stimulates the release of proinflammatory cytokines and chemokines and other immune mediators that contribute to the breakdown of the BBB and the influx of innate and adaptive immune cells from the periphery. D: A prolific inflammatory response ensues. The inflammatory exudate in the basal cisterns contributes to cerebral vascular pathology and the development of hydrocephalus and raised intracranial pressure. Vasogenic edema due to an influx of proteins through the leaky BBB, and cytotoxic edema as a result of cellular damage contribute to the raised pressure. The overall decrease in cerebral blood flow puts the brain at risk of ischemia, infarction and poor patient outcomes. In some cases the infection is controlled in discrete tuberculomas or abscesses, which may resolve with treatment and time.

Figure 2.. Kaplan-Meier survival curves stratified by LTA4H genotype.

Figures A and B show survival in 763 patients with tuberculous meningitis in Vietnam , with human immunodeficiency virus (HIV) infection ( A), and without HIV infection ( B). In HIV-infected patients, case-fatality rates were 34.8% (16 of 46) in those with TT genotype, 42.1% (61 of 145) in CT genotype, and 38.8% (52 of 134) in CC genotype. In HIV-uninfected patients, case-fatality rates were 7.1% (3 of 42) in TT, 21.4% (40 of 187) in CT, and 18.7% (39 of 209) in CC. Figures C and D show survival in 375 patients with tuberculous meningitis in Indonesia . These patients are HIV-uninfected with severe (GCS ≤ 13) ( C) or milder (GCS 14–15) disease ( D). In a recessive model, TT genotype versus CT/TT combined had HR 0.81 (95% CI 0.41-1.62, p = .550) in severe and 0.31 (95% CI 0.04-2.25, p = .156) in milder disease.

Figure 3.. Outcomes of the host – M. tuberculosis interaction depicted by the basic parabola of the damage-response framework.

On the left side of the parabola, shaded in blue, the immune system fails to limit mycobacterial growth and invasion which results in host damage. On the right side, shaded in red, the immune response is excessive and the resultant inflammation and host-damage. The proportion of the parabola lying below the black line represents disease latency, which is not associated with clinically evident host damage. On the blue side therapeutic interventions could be targeted at stimulating an immune response, whilst on the red side therapeutic interventions could aim to dampen immune response.

Figure 4.. Novel Host and Pathogen biomarkers for diagnosis of tuberculous meningitis ^– .

LAM = lipoarabinomannan, RNA = riboneucleic acid, VOC = volatile organic chemicals, IGRA = inferferon gamma resease assay, DLL1 = delta-like ligand 1, VDBP = vitamin d binding protein, ADA = adenosine deaminase. * This image focuses only on novel host or TB biomarkers for diagnosis of TBM and does not incorporate traditional tools such as culture or AFB smear, or newer nucleic acid amplification tests in use commonly such as GeneXpert or GeneXpert Ultra, or experimental techniques such as metagenomic next generation sequencing.