Translating metagenomics into clinical practice of complex paediatric neurological presentations

Abstract

Background Atypical or complex paediatric neurological presentations are common clinical conundrums and often remain undiagnosed despite extensive investigations. This is particularly pronounced in immunocompromised patients. Here we show that clinical metagenomics (CMg) is a valuable adjunct diagnostic tool to be used by neuro-infection multidisciplinary teams (MDTs). Methods We included patients referred to the Great Ormond Street Hospital neuro-infection MDT in whom diagnostic uncertainty remained, despite a standardised comprehensive set of investigations, and who were referred for untargeted CMg on brain tissue and/or cerebrospinal fluid (CSF). In a retrospective review, two clinicians independently assessed whether CMg in conjunction with the MDT resulted in a change of management. Findings 60 undiagnosed patients met the inclusion criteria. We detected the causative pathogen by CMg in 14/60 (23%), with 12/36 patients known to be immunocompromised. CMg results, even when negative, informed patient care, resulting in changes in clinical management in 42/57 (74%). Six patients had unexpected findings of pathogens not identified on prior samples. In four patients, the pathogen was found solely in the brain biopsy and was absent from all other specimens, including CSF. Interpretation CMg is particularly useful when conventional diagnostic techniques for meningoencephalitis are exhausted and proved to be an important diagnostic tool for immunocompromised patients. CMg provided increased reassurance against an infective aetiology prior to recommending immunosuppressive or immunomodulatory treatment. Specialised MDTs should advocate for early brain biopsies and routine CMg in an experienced laboratory for undiagnosed complex neurological cases affecting immunocompromised patients. Funding: the authors declare no funding