Project Details

Metagenomic and Phage sequencing for infectious and autoimmune diagnosis of febrile coma in Malawian children

Stephen Ray, MBcHB, MPhil, MRCPCH, DTM&H, MRes, PhD

Summary

BACKGROUND: 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. 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. GAP: This study will leverage a uniquely well characterised Malawian febrile coma cohort and biobank with world class laboratory collaboration at The Wilson Lab, The Weill Institute for Neurosciences, UCSF, with cutting-edge molecular neurodiagnostic approaches to identify, for the first time, known and novel infectious and auto-immune causes of febrile coma by applying metagenomic next-generation (mNGS) and autoantibody profiling of the (cerebrospinal) CSF. HYPOTHESIS: We hypothesise a wide range of undiscovered infectious [often antimicrobial resistant] and autoimmune causes underlie a significant proportion of febrile coma cases in Malawian children. METHODS: 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 children); 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 (Euroimmun Autoimmune) and novel (phage immunoprecipitation sequencing assays) autoantibody causes of febrile coma in CSF; 3) Identify whether pathogens and/or autoantibodies identified by sequencing yield insight into new clinical syndromes. RESULTS & IMPACT: 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. Website Link: https://www.paediatrics.ox.ac.uk/About/team/stephen-ray