Browsing by Author "Manyelo, Masilo Charles"
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- ItemEvaluation of host biomarkers for early diagnosis of tuberculosis disease in children(Stellenbosch : Stellenbosch University, 2018-12) Manyelo, Masilo Charles; Chegou, Novel N.; Walzl, Gerhard; Stellenbosch University. Faculty of Medicine and Health Sciences. Dept. of Biomedical Sciences: Molecular Biology and Human Genetics.Background: The diagnosis of tuberculosis (TB) remains a challenge in children. There is an urgent need for new tools for early diagnosis of TB disease in children Objectives: To evaluate the usefulness of a previously described 3-marker cerebrospinal fluid (CSF) biosignature (VEGF, IL-13 and cathelicidin LL-37) and other CSF biomarkers for diagnosis of tuberculous meningitis (TBM), and evaluate the utility of a previously identified adult 7-marker serum protein biosignature (CRP, IFN-γ, IP-10, CFH, Apo-AI, SAA and transthyretin) and other blood biomarkers for diagnosis of pulmonary TB (PTB) and TBM in children. Methods: CSF and serum samples were collected from children with suspected meningitis, whereas serum samples were collected from children with suspected PTB for investigation of biomarkers for the diagnosis of childhood TBM and PTB, respectively. Children in the TBM project were enrolled at the Tygerberg Academic Hospital, whereas those in the PTB study were enrolled at the Red Cross War Memorial Children’s Hospital in Cape Town, South Africa. Children were classified as TBM or no-TBM and PTB or no-PTB, using combination of clinical, radiological and laboratory findings. Using a multiplex platform, the concentrations of 69 host biomarkers were evaluated in CSF and serum samples from children in the TBM study whereas 40 host markers were evaluated in serum samples from children in the PTB study. The diagnostic accuracies of individual biomarkers were assessed by receiver operator characteristics (ROC) curve, whereas the General Discriminant Analysis (GDA) was used to assess the accuracies of combinations between different host biomarkers. Results: Of the 69 host biomarkers evaluated in CSF and serum samples from children in the TBM study, multiple individual host biomarkers showed potential as diagnostic candidates for TBM as ascertained by area under the ROC curve (AUC). The previously described 3-marker CSF biosignature was validated in the project. However, refinement of the biosignature by substitution of IL-13 and cathelicidin LL-37 with two new proteins (MPO and IFN-γ) resulted in a new biosignature with improved accuracy (AUC of 0.97). Furthermore, we identified a 4- marker CSF biosignature (sICAM-1, MPO, CXCL8 and IFN-γ), which also diagnosed TBM with AUC of 0.97. The adult 7-marker serum biosignature, modified by the replacement of transthyretin with NCAM1, diagnosed TBM with AUC of 0.80. However, a childhood TBM-specific serum biosignature (adipsin, Aβ42 and IL-10) diagnosed TBM with AUC of 0.84. The adult signature performed with an AUC of 0.79 in children with PTB, showing no significant difference in the diagnosis of childhood PTB or TBM. However, novel childhood PTB-specific biosignatures performed better than the adult 7-marker signature. Conclusion: The adult 7-marker signature showed potential in the diagnosis of both PTB and TBM in children recruited from a high TB incidence area. We validated a previously established 3- marker CSF biosignature, but a refined signature showed much improved accuracy. The biosignatures identified in this thesis hold potential for development of new diagnostic tools for PTB and TBM in children for possible use at the point-of-care. Our findings require further validation in larger and multi-site studies.