Improving diagnosis of brain infections in Indonesia using novel and established molecular diagnostic tools.

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Brain infections, such as meningitis and encephalitis, are a significant cause of morbidity and mortality in Indonesia, as elsewhere, with considerable costs to families, health care and society.The key step in early patient management is to distinguish bacterial causes, which need immediate antibiotic treatment, from the many clinical mimics, such as viral meningitis, which do not. The gold standard for distinguishing the two is lumbar puncture, followed by microscopy and culture of the cerebrospinal fluid (CSF). However, culture results are often delayed, or inconclusive. Many patients are therefore treated with unnecessary antibiotics until a diagnosis of bacterial meningitis is excluded, contributing to the burden of antimicrobial resistance.In Liverpool, we have developed the TRanscripts to Identify bacterial Meningitis (TRIM) test. It is a host transcript-based diagnostic blood test. We have shown it exhibits high sensitivity (100%), specificity (90%) and negative predictive value (100%) in distinguishing adult bacterial meningitis from mimics (viral meningitis or meningism [where patients have clinical symptoms of meningitis but the number of white blood cells in the CSF is not raised]). A key advantage of the TRIM test is that results can be rapidly available (in under four hours) from sample arrival in the laboratory. As a rapid, accurate and low cost (target cost under £10 per patient) blood test, the TRIM test offers improved rule-out of bacterial brain infections, enhancing patient management and promoting cessation of unnecessary antimicrobial use. In partnership with Universitas Gadjah Mada (UGM), Indonesia, preliminary work assessing the TRIM assay at UGM indicate it maintains high accuracy (100%) in distinguishing bacterial infection from mimics among child and adult Indonesian patients with symptoms/signs of meningitis or encephalitis.Our second diagnostic approach is to use pathogen-specific polymerase chain reaction (PCR) and antibody tests; through these we have increased pathogen detection among children with suspected meningo-encephalitis at UGM by over 30 percent (from 11% to 42%), through a pilot of systematic testing of CSF. In this three year study, we will assess the accuracy of the TRIM test in a larger cohort of Indonesian patients with suspected meningo-encephalitis, recruited through hospitals linked to UGM and Universitas of Indonesia. Alongside, we will increase pathogen detection through pathogen-specific PCR and antibody testing at these sites. To improve our pathogen-specific PCR panel, we will perform next generation sequencing, at the Eijkman Institute, Indonesia, on CSF samples where no pathogen has been detected. Sequence information from identified pathogens will be used to inform PCR test design.Linking with the University of Warwick, we will evaluate the cost-effectiveness of introducing these diagnostic tools into routine clinical care for suspected brain infection patients in Indonesian hospitals.This study will assess and implement novel and established diagnostic tools among Indonesian brain infection patients. In the longer-term, these tools will support more appropriate treatment of brain infections among Indonesian patients, strengthen local research capacity and collaboration between UK and Indonesia.