Abstract
BackgroundThe World Health Organization recommends GeneXpert MTB/RIF Ultra (Xpert Ultra), a fully automated polymerase chain reaction (PCR) assay, as the initial tuberculous meningitis (TBM) diagnostic test. The assay’s PCR cycle threshold (Ct) values represent the number of PCR cycles required for probe signal to be detected (low Ct value = high bacillary load) and may approximate tuberculosis (TB) bacillary load. We measured the relationship between cerebrospinal fluid (CSF) TB bacillary load with mortality. MethodsWe prospectively enrolled 102 human immunodeficiency virus (HIV)–positive Ugandans with probable or definite TBM from April 2015 to August 2019. Xpert Ultra Ct tertiles and semi-quantitative categories were separately analyzed as predictors of 2-week mortality. We investigated associations between Ct and baseline clinical and CSF parameters. ResultsSubjects with Ct values in the low tertile (ie, high bacillary load) had 57% 2-week mortality—worse than the intermediate (17%) and high (25%) Ct tertiles and Xpert Ultra–negative (30%) probable TBM cases (P = .01). In contrast, the reported semi-quantitative Xpert Ultra categorization was less precise; with the medium to low category trending toward worse 2-week survival (42%) compared with very low (28%), trace (26%), and negative (30%) categories (P = .48). Ct tertile was significantly associated with baseline CSF lactate (P = .03). ConclusionsHigh CSF TB bacillary load, as measured by Xpert Ultra Ct tertile, is associated with an almost 2-fold higher 2-week mortality in HIV-associated TBM and is a better predictor than the reported Xpert Ultra semi-quantitative category. Xpert Ultra Ct values could identify TBM patients at increased risk of death who may benefit from enhanced supportive care.
Highlights
The World Health Organization recommends GeneXpert MTB/RIF Ultra (Xpert Ultra), a fully automated polymerase chain reaction (PCR) assay, as the initial tuberculous meningitis (TBM) diagnostic test
TBM has a devastating impact, with approximately 40% in-hospital mortality and up to 60% of survivors left with neurological disability [6, 7]
With the introduction of the new, more sensitive Xpert Ultra, and in a population of predominantly human immunodeficiency virus (HIV)-positive persons in Uganda with TBM, we examined whether cerebrospinal fluid (CSF) TB bacillary load was associated with clinical outcome and CSF biochemical or cellular parameters
Summary
We prospectively enrolled 102 human immunodeficiency virus (HIV)–positive Ugandans with probable or definite TBM from April 2015 to August 2019. We prospectively evaluated adults aged ≥18 years suspected to have meningitis presenting to Mulago National Referral Hospital and Mbarara Regional Referral Hospital in Uganda between April 2015 and August 2019 as part of the screening process for 2 clinical trials (XXX [ASTRO-CM]: NCT01802385 and High-Dose Intravenous and Oral Rifampicin to ImproveSurvival of Adult Tuberculous Meningitis [RifT]: ISRCTN42218549). Subjects with probable or definite TBM as defined by the consensus uniform clinical case definition were included. Definite TBM includes any CSF positivity by microscopy, culture, or PCR. Probable TBM cases have negative CSF TB microbiology but reach a score of >12 points or >10 points with or without brain imaging, respectively, based on clinical, radiological, and CSF criteria and evidence of confirmed TB in another anatomical location [15].
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