Every year, hundreds of Malawian children arrive at hospitals with fever and coma, and doctors often cannot tell them apart—or treat them correctly—because the cause remains unknown. This matters because febrile coma kills a high proportion of these children, and the lack of rapid diagnostics forces clinicians to guess at treatment, often using broad-spectrum antibiotics that fuel the antimicrobial resistance crisis in Africa. Meanwhile, autoimmune causes of coma, recently discovered in wealthy countries, have never been tested for in African children. The research will apply metagenomic next-generation sequencing and autoantibody profiling to cerebrospinal fluid from 352 well-characterised Malawian children. It will compare this advanced molecular testing against conventional culture and enhanced molecular methods to identify viral, bacterial, fungal, and parasitic pathogens, as well as antimicrobial resistance genes. It will also search for known and novel autoantibodies that could trigger coma. If successful, the project could deliver clinically actionable diagnoses that directly guide treatment for these children, reduce inappropriate antibiotic use, and uncover new infectious or autoimmune syndromes specific to this neglected population. The findings may also lay groundwork for affordable diagnostic tools suited to low-resource settings.
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Children in sub-Saharan Africa are commonly hospitalised with fever and coma (febrile coma) (1). Febrile coma is associated with high mortality, in part due to a lack of available diagnostics to define the aetiology of febrile coma in these children (2-4). Novel diagnostic tests are urgently needed to address this and guide appropriate antibiotic use amid the antimicrobial resistance crisis in Africa. Furthermore, the explosion of autoantibodies recently identified as autoimmune causes of coma in high income settings are yet to be interrogated in African children. This study will leverage a uniquely well characterised Malawian febrile coma cohort and biobank with world class laboratory collaboration, with cutting-edge molecular neurodiagnostic approaches to identify known and novel infectious and auto-immune causes of febrile coma by applying metagenomic next-generation (mNGS) and autoantibody profiling of the (cerebrospinal) CSF. This study aims to: 1) a) Assess the diagnostic yield of advanced CSF mNGS compared to conventional (culture) and enhanced (molecular) testing for pathogenic (viral, bacterial, fungal, parasitic) diagnosis of febrile coma (n=352) b) Investigate what proportion of pathogens and/or antimicrobial resistance genes identified by CSF mNGS are clinically actionable diagnoses that would influence treatment of these children 2) To identify known and novel autoantibody causes of febrile coma in CSF 3) Identify whether pathogens and/or autoantibodies identified by sequencing yield insight into new clinical syndromes The synergies of this collaboration, that will combine state-of-the-art science with a neglected population, will yield unique insights into aetiologies, improved diagnostics and treatments of febrile coma in African children.
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