Improving Diagnosis and Understanding the Pathophysiology of Tuberculous Meningitis

Donovan, Joseph Thomas (2020). Improving Diagnosis and Understanding the Pathophysiology of Tuberculous Meningitis. PhD thesis The Open University.

Abstract

Tuberculous meningitis (TBM) is the most severe form of TB. Current diagnostics are insufficiently sensitive. Processes of excessive neuroinflammation are poorly understood. Detecting raised intracranial pressure is challenging. TBM-associated hyponatraemia is poorly understood. This thesis aims to improve diagnosis of TBM and its complications, and further understand TBM’s complex pathophysiology.

Firstly, I present a prospective randomised evaluation of the diagnostic performance of GeneXpert MTB/RIF (Xpert) against GeneXpert MTB/RIF Ultra (Ultra) in 205 individuals with TBM. Diagnostic sensitivities of Ultra and Xpert against a clinical TBM reference standard were 47.2% (25/53, 95% confidence interval [CI] 34.4-60.3%) and 39.6% (21/53, 95% CI 27.6-53.1%) respectively (p=0.56).

Next, I present data from two randomised trials of adjunctive dexamethasone in clinical TBM (ACT HIV [NCT03092817] and LAST ACT [NCT0310078]). 668 adults with TBM underwent baseline S. stercoralis testing. Active S. stercoralis infection significantly associated with reduced median cerebrospinal fluid (CSF) interferon (IFN)-ɣ, interleukin (IL)-2, and tumour necrosis factor (TNF)-α concentrations (3.51 vs. 5.81pg/mL p=0.01; 5.05 vs. 5.77pg/mL p=0.03; 2.17 vs. 3.58pg/mL p=0.02, respectively), and with reduced neurological complications by 3 months (3.8%[1/26] vs. 30.0%[33/110], respectively, p=0.01). In 107 adults with TBM, higher baseline optic nerve sheath diameter (ONSD) associated with more severe TBM and abnormal brain imaging (abnormal imaging 0.55cm vs. normal imaging 0.50cm, p=0.01). Baseline ONSD was higher in participants who died by 3 months (0.56cm [15/72]) vs. participants who survived (0.52cm [57/72]), p=0.02. Finally, 208 adults with TBM underwent longitudinal testing of plasma sodium, urinary sodium, serum osmolality, or urine osmolality. Baseline plasma sodium significantly associated with higher lumbar CSF opening pressure, and elevated CSF neutrophils. Plasma sodium was significantly lower at all time points after baseline in participants who died by 3 months.

Ultra was not superior to Xpert for TBM diagnosis. However, given this study was powered to detect a 25% improvement in diagnostic sensitivity with Ultra it remains possible that Ultra was more sensitive than Xpert at a lower margin of superiority. S. stercoralis co-infection may modulate the intracerebral inflammatory response to M. tuberculosis. ONSD ultrasound may identify severity and predict death, in TBM. Persistent hyponatraemia associates with poor clinical outcomes.

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