Nhung Thi Hong Nguyen

Background: Early diagnosis of tuberculous meningitis (TBM) is critical to favorable outcomes. We investigated whether a 3-gene host response signature in whole blood can distinguish TBM from symptomatic controls in children. Methods: Whole-blood RNA sequencing was performed in children with TBM and controls. Expression of the 3-gene signature, [guanylate-binding protein (GBP5), dual specificity phosphatase 3 (DUSP3) and Krupple-like factor 2 (KLF2)] was quantified and a tuberculosis (TB) score was calculated using (GBP5+DUSP3)/2-KLF2. Discriminatory performance was obtained using receiver-operator characteristic curve analysis against microbiologic and composite reference standards. TB score and 3-gene expression in children were compared against adults with TBM. In parallel, an exploratory transcriptome-wide analysis was performed, applying bootstrapped least absolute shrinkage and selection operator regression to identify additional genes associated with TBM. Results: Forty-two children had TBM and 41 were controls. KLF2 was upregulated in TBM compared to controls ( P = 0.043); while GBP5, DUSP3 and TB score showed no difference. The diagnostic performance of GBP5 alone (area under the curves: 0.64; 95% confidence interval: 0.46–0.83) and TB score (area under the curves: 0.59; 95% confidence interval: 0.41–0.77) was poor against the reference standard of definite TBM. GBP5 in children with TBM was lower than in adults without HIV (median 13.04; interquartile ranges: 11.91–14.29 vs. median 13.72; interquartile ranges: 12.58–14.53, P = 0.036), and expression was nonlinear across the age spectrum; lowest in young children. Exploratory transcriptomic analysis suggests that novel genes may contribute a discriminatory signal. Conclusion: The 3-gene host response signature does not discriminate TBM from controls in children and was much less discriminative compared to adults. An alternative set of pediatric-specific signatures may exist, but further discovery and validation are required.

Tuberculous meningitis (TBM) is the most severe form of tuberculosis, disproportionately affecting vulnerable populations such as young children and people living with human immunodeficiency virus (HIV). Major challenges to accurate and early diagnosis of TBM are the non-specific clinical features which overlap with other infectious syndromes and the lack of adequately sensitive tests to detect Mycobacterium tuberculosis in the cerebrospinal fluid (CSF). Diagnosis is, therefore, still dependent on clinical suspicion along with clinical features, cerebrospinal fluid (CSF) characteristics and, where facilities are available, neuroimaging. Typical neuroimaging features of TBM include hydrocephalus, infarcts, tuberculomas and basal exudates; however, less well described are very rare features such as cytotoxic lesion of the corpus callosum (CLOCC), otherwise known as transient splenic lesion. We describe the first case report of a child with confirmed TBM who had a very rare presentation of CLOCC with complete recovery and present a literature review on the pathophysiology and alternative aetiologies where CLOCC is more commonly seen.

Tuberculous meningitis (TBM) is the most severe form of tuberculosis, disproportionately affecting vulnerable populations such as young children and people living with human immunodeficiency virus (HIV). Major challenges to accurate and early diagnosis of TBM are the non-specific clinical features which overlap with other infectious syndromes and the lack of adequately sensitive tests to detect Mycobacterium Tuberculosis in the cerebrospinal fluid (CSF). Diagnosis is therefore still dependent on clinical suspicion along with clinical features, cerebrospinal fluid (CSF) characteristics and where facilities are available, neuroimaging. Typical neuroimaging features of TBM include hydrocephalus, infarcts, tuberculomas and basal exudates, however less well described are very rare features such as cytotoxic lesion of the corpus callosum (CLOCC) otherwise known as transient splenic lesion. We describe the first case report of a child with confirmed TBM who had a very rare presentation of CLOCC, present a literature review on the pathophysiology and alternative aetiologies where CLOCC is more commonly seen.