Potential of Host Serum Protein Biomarkers in the Diagnosis of Tuberculous Meningitis in Children

Manyelo, Charles M.; Solomons, Regan; Snyders, Candice; Mutavhatsindi, Hygon; Manngo, Portia M.; Stanley, Kim; Walzl, Gerhard; Chegou, Novel N.

doi:10.3389/fped.2019.00376

Cited by 28 publications

(41 citation statements)

References 36 publications

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Section: Methodsmentioning

confidence: 99%

“…We used existing CSF and serum host protein concentration data from children diagnosed with TBM or “not-TBM”, from previous studies [ 16 , 17 ]. Briefly, in these studies we enrolled participants between November 2016 and November 2017 at Tygerberg Academic Hospital, Cape Town, South Africa [ 16 , 17 ]. Children with suspected TBM are referred from primary care day hospitals, district and secondary level hospitals to our institution to establish the diagnosis of TBM and to treat the complications associated with advanced disease (stage 2 and 3 TBM, e.g.…”

Section: Methodsmentioning

confidence: 99%

“…Finally, a better understanding of the biology of arterial ischemic stroke could contribute to the development of new therapeutic and preventive strategies [ 6 ]. In this analysis, we used data from previous studies [ 16 , 17 ] to assess the difference in levels of CSF and serum proteins among children with suspected meningitis, who were finally diagnosed with a) TBM and stroke, b) TBM without stroke and c) children without TBM, ‘not-TBM’. We further assessed the ability of host proteins and combinations of proteins to indicate stroke among children diagnosed with TBM.…”

Section: Introductionmentioning

confidence: 99%

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Serum and cerebrospinal fluid host proteins indicate stroke in children with tuberculous meningitis

et al. 2021

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Introduction Stroke is a common complication in children with tuberculous meningitis (TBM). Host proteins may give us insight into the mechanisms of stroke in TBM and serve as biomarkers for detection of stroke, however, they have not been widely explored. In this study, we compared the concentrations of cerebrospinal fluid (CSF) and serum proteins between children who had TBM-related stroke and children with TBM without stroke. Methods We collected CSF and serum from 47 children consecutively admitted to the Tygerberg Academic Hospital in Cape Town, South Africa between November 2016, and November 2017, on suspicion of having TBM. A multiplex platform was used to measure the concentrations of 69 host proteins in CSF and serum from all study participants. Results After classification of study participants, 23 (48.9%) out of the 47 study participants were diagnosed with TBM, of which 14 (60.9%) demonstrated radiological arterial ischemic infarction. The levels of lipocalin-2, sRAGE, IP-10/ CXCL10, sVCAM-1, MMP-1, and PDGF-AA in CSF samples and the levels of D-dimer, ADAMTS13, SAA, ferritin, MCP-1/ CCL2, GDF-15 and IL-13 in serum samples were statistically different between children who had TBM-related stroke and children with TBM without stroke. After correcting for multiple testing, only the levels of sVCAM-1, MMP-1, sRAGE, and IP-10/ CXCL10 in CSF were statistically different between the two groups. CSF and serum protein biosignatures indicated stroke in children diagnosed with TBM with up to 100% sensitivity and 88.9% specificity. Conclusion Serum and CSF proteins may serve as biomarkers for identifying individuals with stroke amongst children diagnosed with TBM at admission and may guide us to understand the biology of stroke in TBM. This was a pilot study, and thus further investigations in larger studies are needed.

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Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Serum and cerebrospinal fluid host proteins indicate stroke in children with tuberculous meningitis

et al. 2021

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“…Cut-off values for CRP, IFN-γ, IP-10, CFH, Apo-A1, SAA, adipsin, Aβ42 and IL-10 were >80721.0 ng/ml, <61.5 pg/ml, <57.2 pg/ml, >350185.0 ng/ml, >287512.0 ng/ml, >59894.0 ng/ml, <2393.0 ng/ml, <278.4 pg/ml and <7.0 pg/ml, respectively. Although sample size was small, these biomarkers warrant further exploration 65 .…”

Section: Tbm Diagnosticsmentioning

confidence: 96%

Recent Developments in Tuberculous Meningitis Pathogenesis and Diagnostics

et al. 2020

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The pathogenesis of Tuberculous meningitis (TBM) is poorly understood, but contemporary molecular biology technologies have allowed for recent improvements in our understanding of TBM. For instance, neutrophils appear to play a significant role in the immunopathogenesis of TBM, and either a paucity or an excess of inflammation can be detrimental in TBM. Further, severity of HIV-associated immunosuppression is an important determinant of inflammatory response; patients with the advanced immunosuppression (CD4+ T-cell count of <150 cells/μL) having higher CSF neutrophils, greater CSF cytokine concentrations and higher mortality than those with CD4+ T-cell counts > 150 cells/μL. Host genetics may also influence outcomes with LT4AH genotype predicting inflammatory phenotype, steroid responsiveness and survival in Vietnamese adults with TBM. Whist in Indonesia, CSF tryptophan level was a predictor of survival, suggesting tryptophan metabolism may be important in TBM pathogenesis. These varying responses mean that we must consider whether a “one-size-fits-all” approach to anti-bacillary or immunomodulatory treatment in TBM is truly the best way forward. Of course, to allow for proper treatment, early and rapid diagnosis of TBM must occur. Diagnosis has always been a challenge but the field of TB diagnosis is evolving, with sensitivities of at least 70% now possible in less than two hours with GeneXpert MTB/Rif Ultra. In addition, advanced molecular techniques such as CRISPR-MTB and metagenomic next generation sequencing may hold promise for TBM diagnosis. Host-based biomarkers and signatures are being further evaluated in childhood and adult TBM as adjunctive biomarkers as even with improved molecular assays, cases are still missed. A better grasp of host and pathogen behaviour may lead to improved diagnostics, targeted immunotherapy, and possibly biomarker-based, patient-specific treatment regimens.

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“…Over the past few years, the search for host biomarker(s) or biosignatures has gained increased attention in attempts to develop companion diagnostic platforms ( 8 – 20 ). Although expensive and resource-demanding, genome-wide analyses of transcriptomes offer unbiased identification of genes and immunologic pathways relevant for the understanding of TB pathogenesis, and risk of progression to disease ( 21 – 23 ).…”

Section: Introductionmentioning

confidence: 99%

Host Blood RNA Transcript and Protein Signatures for Sputum-Independent Diagnostics of Tuberculosis in Adults

et al. 2021

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To achieve the ambitious targets for tuberculosis (TB) prevention, care, and control stated by the End TB Strategy, new health care strategies, diagnostic tools are warranted. Host-derived biosignatures are explored for their TB diagnostic potential in accordance with the WHO target product profiles (TPPs) for point-of-care (POC) testing. We aimed to identify sputum-independent TB diagnostic signatures in newly diagnosed adult pulmonary-TB (PTB) patients recruited in the context of a prospective household contact cohort study conducted in Andhra Pradesh, India. Whole-blood mRNA samples from 158 subjects (PTB, n = 109; age-matched household controls, n = 49) were examined by dual-color Reverse-Transcriptase Multiplex Ligation-dependent Probe-Amplification (dcRT-MLPA) for the expression of 198 pre-defined genes and a Mesoscale discovery assay for the concentration of 18 cytokines/chemokines in TB-antigen stimulated QuantiFERON supernatants. To identify signatures, we applied a two-step approach; in the first step, univariate filtering was used to identify and shortlist potentially predictive biomarkers; this step may be seen as removing redundant biomarkers. In the second step, a logistic regression approach was used such that group membership (PTB vs. household controls) became the binary response in a Lasso regression model. We identified an 11-gene signature that distinguished PTB from household controls with AUCs of ≥0.98 (95% CIs: 0.94–1.00), and a 4-protein signature (IFNγ, GMCSF, IL7 and IL15) that differentiated PTB from household controls with AUCs of ≥0.87 (95% CIs: 0.75–1.00), in our discovery cohort. Subsequently, we evaluated the performance of the 11-gene signature in two external validation data sets viz, an independent cohort at the Glenfield Hospital, University Hospitals of Leicester NHS Trust, Leicester, UK (GSE107994 data set), and the Catalysis treatment response cohort (GSE89403 data set) from South Africa. The 11-gene signature validated and distinguished PTB from healthy and asymptomatic M. tuberculosis infected household controls in the GSE107994 data set, with an AUC of 0.95 (95% CI: 0.91–0.98) and 0.94 (95% CI: 0.89–0.98). More interestingly in the GSE89403 data set, the 11-gene signature distinguished PTB from household controls and patients with other lung diseases with an AUC of 0.93 (95% CI: 0.87–0.99) and 0.73 (95% CI: 0.56–0.89). These criteria meet the WHO TTP benchmarks for a non–sputum-based triage test for TB diagnosis. We suggest that further validation is required before clinical implementation of the 11-gene signature we have identified markers will be possible.

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Potential of Host Serum Protein Biomarkers in the Diagnosis of Tuberculous Meningitis in Children

Cited by 28 publications

References 36 publications

Serum and cerebrospinal fluid host proteins indicate stroke in children with tuberculous meningitis

Serum and cerebrospinal fluid host proteins indicate stroke in children with tuberculous meningitis

Recent Developments in Tuberculous Meningitis Pathogenesis and Diagnostics

Host Blood RNA Transcript and Protein Signatures for Sputum-Independent Diagnostics of Tuberculosis in Adults

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