Abstract
Background The diagnosis of tuberculous meningitis (TBM) especially in children is challenging. New tests are urgently needed for the diagnosis of the disease, especially in resource-limited settings. Methods We collected cerebrospinal fluid (CSF) samples from children presenting with symptoms requiring investigation for meningitis at a tertiary hospital in Cape Town, South Africa. Children were later classified as TBM or no TBM using published case definitions. Using a multiplex platform, we investigated the concentrations of biomarkers comprising a previously established 3-marker biosignature (VEGF, IL-13, and LL-37) and other potentially useful host biomarkers as diagnostic candidates for TBM. Findings Out of 47 children, age, 3 months to 13 years, 23 were diagnosed with TBM and six (16%) were HIV-infected. We validated the previously identified CSF biosignature (sensitivity of 95.7% (95% CI, 79.0-99.2%) and specificity of 37.5% (95% CI, 21.2-57.3%)). However, substitution of IL-13 and LL-37 with IFN-γ and MPO, respectively, resulted in improved accuracy (area under the ROC curve (AUC) = 0.97, 95% CI, 0.92-1.00, up to 91.3% (21/23) sensitivity and up to 100% (24/24) specificity). An alternative four-marker biosignature (sICAM-1, MPO, CXCL8, and IFN-γ) also showed potential, with an AUC of 0.97. Conclusion We validated a previously identified CSF biosignature and showed that refinement of this biosignature by incorporation of other biomarkers diagnosed TBM with high accuracy. Incorporation of these biomarkers into a point-of-care or bedside diagnostic test platform may result in the improved management of TBM in children.
Highlights
Tuberculosis (TB) remains a global health problem and was responsible for the deaths of estimated 1.6 million people in 2017 [1]
In addition to the three biomarkers that comprised our previous 3-marker model [15] (IL-13, VEGF, and cathelicidin LL-37), we evaluated the concentrations of 66 other candidate biomarkers including markers that were previously investigated in adult TB studies [16, 17, 19, 20] and other proteins which have not been previously investigated in the TB field, including complement factors and other proteins, as possible diagnostic biomarkers for tuberculous meningitis (TBM) by ELISA or the Luminex platform
As we were interested in validating the diagnostic accuracy of the previously established 3-marker cerebrospinal fluid (CSF) biosignature (VEGF, IL-13, and cathelicidin LL-37), we first looked at the utility of individual analytes comprising this signature, followed by the evaluation of combinations between different biomarkers comprising the signature
Summary
Tuberculosis (TB) remains a global health problem and was responsible for the deaths of estimated 1.6 million people in 2017 [1]. It is well established that diagnosing pulmonary TB disease in children is challenging, especially in resource-constrained settings [3]. TBM frequently results in a poor outcome due to nonspecific symptoms and signs [4] The limitations of both the most widely used diagnostic test for TB (smear microscopy) [5] and the culture gold standard test are well publicised [3, 5]. We validated a previously identified CSF biosignature and showed that refinement of this biosignature by incorporation of other biomarkers diagnosed TBM with high accuracy Incorporation of these biomarkers into a point-of-care or bedside diagnostic test platform may result in the improved management of TBM in children
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