Browsing by Author "Davis, Angharad G."

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    Host directed therapies for tuberculous meningitis
    (Wellcome Trust, 2020-07-01) Davis, Angharad G.; Donovan, Joseph; Bremer, Marise; Van Toorn, Ronald; Schoeman, Johan; Dadabhoy, Ariba; Lai, Rachel P. J.; Cresswell, Fiona V.; Boulware, David R.; Wilkinson, Robert J.; Thuong, Nguyen Thuy Thuong; Thwaites, Guy E.; Bahr, Nathan C.; Tuberculous Meningitis International Research Consortium
    ENGLISH ABSTRACT: A dysregulated host immune response significantly contributes to morbidity and mortality in tuberculous meningitis (TBM). Effective host directed therapies (HDTs) are critical to improve survival and clinical outcomes. Currently only one HDT, dexamethasone, is proven to improve mortality. However, there is no evidence dexamethasone reduces morbidity, how it reduces mortality is uncertain, and it has no proven benefit in HIV co-infected individuals. Further research on these aspects of its use, as well as alternative HDTs such as aspirin, thalidomide and other immunomodulatory drugs is needed. Based on new knowledge from pathogenesis studies, repurposed therapeutics which act upon small molecule drug targets may also have a role in TBM. Here we review existing literature investigating HDTs in TBM, and propose new rationale for the use of novel and repurposed drugs. We also discuss host variable responses and evidence to support a personalised approach to HDTs in TBM.
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    Neurocognitive and functional impairment in adult and paediatric tuberculous meningitis [version 1; peer review: 2 approved]
    (F1000Research, 2019) Davis, Angharad G.; Nightingale, Sam; Springer, Priscilla E.; Solomons, Regan; Arenivas, Ana; Wilkinson, Robert J.; Anderson, Suzanne T.; Chow, Felicia C.
    ENGLISH ABSTRACT: In those who survive tuberculous meningitis (TBM), the long-term outcome is uncertain; individuals may suffer neurocognitive, functional and psychiatric impairment, which may significantly affect their ability to lead their lives as they did prior to their diagnosis of TBM. In children who survive, severe illness has occurred at a crucial timepoint in their development, which can lead to behavioural and cognitive delay. The extent and nature of this impairment is poorly understood, particularly in adults. This is in part due to a lack of observational studies in this area but also inconsistent inclusion of outcome measures which can quantify these deficits in clinical studies. This leads to a paucity of appropriate rehabilitative therapies available for these individuals and their caregivers, as well as burden at a socioeconomic level. In this review, we discuss what is known about neurocognitive impairment in TBM, draw on lessons learnt from other neurological infections and discuss currently available and emerging tools to evaluate function and cognition and their value in TBM. We make recommendations on which measures should be used at what timepoints to assess for impairment, with a view to optimising and standardising assessment of neurocognitive and functional impairment in TBM research.
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    Recent Developments in Tuberculous Meningitis Pathogenesis and Diagnostics [version 3; peer review: 3 approved]
    (F1000Research, 2019) Cresswell, Fiona V.; Davis, Angharad G.; Sharma, Kusum; Roy, Robindra Basu; Ganiem, Ahmad Rizal; Kagimu, Enock; Solomons, Regan; Wilkinson, Robert J.; Bahr, Nathan C.; Thuong, Nguyen Thuy Thuong; Tuberculous Meningitis International Research Consortium
    ENGLISH ABSTRACT: 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.