Abstract
Background: Tuberculous meningitis (TBM) is the most severe form of tuberculosis and results in high morbidity and mortality in children. Diagnostic delay contributes to the poor outcome. There is an urgent need for new tools for the rapid diagnosis of TBM, especially in children.Methods: We collected serum samples from children in whom TBM was suspected at a tertiary hospital in Cape Town, South Africa. Children were subsequently classified as having TBM or no TBM using a published uniform research case-definition. Using a multiplex cytokine array platform, we investigated the concentrations of serum biomarkers comprising biomarkers that were previously found to be of value in the diagnosis of adult pulmonary TB (CRP, SAA, CFH, IFN-γ, IP-10, Apo-AI, and transthyretin) plus other potentially useful host biomarkers as diagnostic candidates for TBM.Findings: Out of 47 children included in the study, 23 (48.9%) had a final diagnosis of TBM and six were HIV infected. A modified version of the adult 7-marker biosignature in which transthyretin was replaced by NCAM1, diagnosed TBM in children with AUC of 0.80 (95% CI, 0.67–0.92), sensitivity of 73.9% (95% CI, 51.6–89.8%) and specificity of 66.7% (95% CI, 44.7–84.4%), with the other six proteins in the signature (CRP, IFN-γ, IP-10, CFH, Apo-A1, and SAA) only achieving and AUC of 0.75 (95% CI, 0.61–0.90) when used in combination. A new childhood TBM specific 3-marker biosignature (adipsin, Aβ42, and IL-10) showed potential in the diagnosis of TBM, with AUC of 0.84 (95% CI, 0.73–0.96), sensitivity of 82.6% (95 CI, 61.2–95.0%) and specificity of 75.0% (95% CI, 53.3–90.2%) after leave-one-out cross validation.Conclusion: A previously described adult 7-marker serum protein biosignature showed potential in the diagnosis of TBM in children. However, a smaller childhood TBM-specific 3-marker signature demonstrated improved performance characteristics. Our data indicates that blood-based biomarkers may be useful in the diagnosis of childhood TBM and requires further validation in larger cohort studies.
Highlights
Tuberculosis (TB) is currently one of the top 9 causes of death, ranking above HIV and malaria [1]
A study in South Africa reported that tuberculous meningitis (TBM) is the most common form of bacterial meningitis among children [8]
The aim of the present study was to ascertain whether host biomarkers that have shown potential in the diagnosis of adult pulmonary TB in serum and plasma samples [27, 28] possessed diagnostic potential for childhood TBM
Summary
Tuberculosis (TB) is currently one of the top 9 causes of death, ranking above HIV and malaria [1]. About 20–25% of pediatric TB cases are extra pulmonary TB (EPTB), including tuberculous meningitis (TBM) [3]. Outcomes of TBM in children include death in up to 50% of cases and neurological sequelae in up to 53.9% of survivors [9, 10]. The poor outcomes of TBM are mainly due to delayed diagnosis and late initiation of anti-tuberculosis therapy [11]. The diagnosis of TBM in children is challenging, due to sub-optimal performance of the currently available laboratory diagnostic methods. M. tb culture, the gold standard test for diagnosing TB disease has a relatively high sensitivity (60–70%) for diagnosing TBM in comparison to smear microscopy, its turnaround time is up to 42 days [9]. Tuberculous meningitis (TBM) is the most severe form of tuberculosis and results in high morbidity and mortality in children. There is an urgent need for new tools for the rapid diagnosis of TBM, especially in children
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