The Utility of a Three-gene Host Response to Discriminate Tuberculous Meningitis From Other Infections in Children.
Huynh J., Le NHT., Le Nguyen BH., Hoang HT., La Ngoc V., Ensor S., Phan KQN., Tran NHT., Pham TN., Dang Do TA., Tram TTB., Vu DTM., Dinh Do V., Griffiths A., Anderson S., Gibb D., Ha DMT., Tung TH., Qui ND., Nhung NHT., Thwaites GE., Thuong NTT., SURE trial team None.
BackgroundEarly 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.MethodsWhole-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 microbiological 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.ResultsForty-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.ConclusionThe 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.