Abstract
PurposeThe application of metagenomic next-generation sequencing (mNGS) in the diagnosis of tuberculous meningitis (TBM) remains poorly characterized. Here, we retrospectively analyzed data from patients with TBM who had taken both mNGS and conventional tests including culture of Mycobacterium tuberculosis (MTB), polymerase chain reaction (PCR) and acid-fast bacillus (AFB) stain, and the sensitivity and specificity of these methods were compared.MethodsWe retrospectively recruited TBM patients admitted to the hospital between December 2015 and October 2018. The first collection of cerebrospinal fluid (CSF) samples underwent both mNGS and conventional tests. In addition, patients with bacterial/cryptococcal meningitis or viral meningoencephalitis were mNGS positive controls, and a patient with auto-immune encephalitis was an mNGS negative control.ResultsTwenty three TBM patients were classified as 12 definite and 11 clinical diagnoses, which were based on clinical manifestations, pathogen evidence, CSF parameters, brain imaging, and treatment response. The mNGS method identified sequences of Mycobacterium tuberculosis complex (MBTC) from 18 samples (18/23, 78.26%). In patients with definite TBM, the sensitivity of mNGS, AFB, PCR, and culture to detect MTB in the first CSF samples were 66.67, 33.33, 25, and 8.33%, respectively. The specificity of each method was 100%. Among the four negative mNGS cases (4/23, 17.39%), three turned out positive by repeated AFB stain. The agreement of mNGS with the total of conventional methods was 44.44% (8/18). Combination of mNGS and conventional methods increased the detection rate to 95.65%. One patient was diagnosed as complex of TBM and cryptococcal meningitis, in which AFB stain and cryptococcal antigen enzyme immunoassay were positive and the DNA of Cryptococcus neoformans was detected by mNGS.ConclusionOur study indicates that mNGS is an alternative method to detect the presence of mycobacterial DNA in CSF samples from patients with TBM and deserves to be applied as a front-line CSF test.
Highlights
Tuberculous meningitis (TBM) is the most devastating manifestation of tuberculosis, with more than half of the patients disabled or died from the disease (Thwaites et al, 2007; Marais et al, 2010)
We retrospectively reviewed 23 cases of TBM with both mNGS and conventional tests performed in cerebrospinal fluid (CSF) samples, trying to illustrate the feasibility of mNGS in the early diagnosis of TBM and evaluate the sensitivity and specificity among all methods. mNGS identified sequences mapping to DNA of Mycobacterium tuberculosis complex (MBTC), including M. tuberculosis, M. africanum, M. bovis, M. canetti, and M. orygis in 18 cases. mNGS had the highest sensitivity in all methods
The present study suggests that mNGS could facilitate the identification of MTB in CSF and might be useful as a routine diagnostic procedure for suspected TBM
Summary
Tuberculous meningitis (TBM) is the most devastating manifestation of tuberculosis, with more than half of the patients disabled or died from the disease (Thwaites et al, 2007; Marais et al, 2010). Diagnosis and prompt treatment have long been recognized as the most important factors to determine the outcome (Thwaites et al, 2013). The early diagnosis of TBM remains challenging. The clinical manifestations of TBM are non-specific and may mimic other meningoencephalitis, which can be caused by infectious pathogens including bacteria, virus, fungi, and parasites, leading to difficulty in the determination of the causative organism, especially in the case of sub-acute or chronic infection (Glaser et al, 2006; Solomon et al, 2007; Venkatesan et al, 2013). Mycobacterial culture is the gold standard for diagnosis of TBM, low detection rate and the turnaround time of 2–4 weeks limit its use as an early diagnostic selection (Colman et al, 2016). Improved techniques capable of detecting infectious pathogens in cerebrospinal fluid (CSF) in a timely manner can help improve the early diagnosis of TBM
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