Abstract
Tuberculous meningitis (TBM) is the most severe form of Mycobacterium tuberculosis (Mtb) infection in humans and is a public health concern worldwide. We evaluated the performance of GeneXpert MTB/RIF (GeneXpert) for the diagnosis of TBM. In addition, genetic diversity and drug susceptibility profiling of Mtb strains isolated from TBM patients were also investigated. A total of 293 TBM suspected cerebrospinal fluid (CSF) samples were collected and subjected to GeneXpert and Mycobacterial Growth Indicator Tube (MGIT 960) culture, respectively. Sensitivity and specificity of GeneXpert was 72.7% and 98.5%, respectively by using MGIT 960 as a gold standard (GeneXpert (n = 20, 6.8%) vs MGIT 960 (n = 22, 7.5%)). All Mtb positive cultures were subjected to 24-locus Mycobacterial Interspersed Repetitive Unit Variable Number Tandem Repeat (MIRU-VNTR) typing, Line probe assay (LPA) and MGIT 960- Drug Susceptibility Testing (DST). The rpoB gene was amplified and sequenced for selected isolates. Among our TBM patients, East African Indian (EAI) lineage (n = 16, 72.7%) was most predominant followed by Beijing (n = 3, 13.6%), S-family (n = 2, 9.1%) and Delhi/CAS (n = 1, 4.5%). Three Mtb strains were found to be Isoniazid (INH) resistant by MGIT 960; however LPA revealed that two strains were INH resistant and one strain was multi drug resistant (MDR) (Resistant to Isoniazid and Rifampicin (RIF)). We identified rifampicin resistant isolate with the mutation D516F in rifampicin resistance-determining region (RRDR) and observed discordant results between LPA, GeneXpert and MGIT 960. In addition, GeneXpert showing false RIF resistance was identified (no mutation in RRDR). We conclude that GeneXpert is useful for the diagnostic confirmation of TBM; however a GeneXpert negative sample should be subjected to MGIT 960 culture or LPA to rule out TBM. EAI lineage was the most predominant among TBM patients in South India and associated with drug resistance. The discordance between GeneXpert, MGIT 960 and LPA with respect to rifampicin resistance has to be ruled out to avoid TB treatment failure or relapse.
Highlights
Tuberculous meningitis (TBM) is the most severe form of extra pulmonary TB (EPTB) affecting the central nervous system (CNS) and it accounts for 1–5% of tuberculosis cases
Several studies have reported that GeneXpert is a useful diagnostic test to rule out TBM cases from cerebrospinal fluid (CSF) samples [22, 23]
We compared the diagnostic performance of GeneXpert for detecting Mycobacterium tuberculosis (Mtb) in CSF samples by using MGIT 960 as a gold standard
Summary
Tuberculous meningitis (TBM) is the most severe form of extra pulmonary TB (EPTB) affecting the central nervous system (CNS) and it accounts for 1–5% of tuberculosis cases. TBM diagnosis is based on a combination of clinical findings, various laboratory testing using CSF, and imaging findings. For TBM diagnosis, Ziehl–Neelsen (ZN) staining for Mtb is the most commonly available test, but without expert microscopists ZN staining has become insensitive and culture takes minimum two to three weeks to provide results with 30–60% sensitivity. A recent study from Donovan et al reported that GeneXpert Ultra was not superior to GeneXpert for TBM diagnosis in both HIV-uninfected and HIV-infected adults [6]. This attracted our interest to validate the diagnostic performance of GeneXpert for the diagnosis of TBM by using Mycobacterial Growth Indicator Tube (MGIT 960) as a gold standard
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