Title: The impact of a single diagnostic test (Metagenomic sequencing) on clinical management of sepsis and meningitis in children.
Funder: Health Education England

Abstract: Research question Can metagenomic sequencing improve the diagnosis of sepsis in children and impact on clinical management and antimicrobial prescribing? Background Sepsis is a life-threatening disease that affects 25,000 children in the UK every year. The condition is caused by excessive immune response to an infection. Identifying the underlying infectious cause of sepsis is key to patient management. However, current routine laboratory investigations frequently fail to provide this information, resulting in widespread broad-spectrum antimicrobial use. This has side-effects for the patient and contributes to the increase in antimicrobial resistance that is seen in our society. Aims and objectives A new diagnostic test that uses metagenomic sequencing to detect the infectious causes of sepsis will be optimised and implemented in the clinical laboratory. The performance of the new test will be compared with current diagnostic tests that are used routinely in the laboratory. The impact on clinical management of patients and antibiotic prescribing will be measured. The health economic benefits of new test, through reduced antimicrobial use, impact on infection prevention and control practice and a shortened patient journey will be analysed. Design of study Blood and cerebrospinal fluid (CSF) samples will be collected from children with suspected septicaemia and / or meningitis at Great Ormond Street Hospital and children's hospitals across the UK. A new metagenomic sequencing assay will be performed on the study samples and the performance compared with routine laboratory tests. Clinical case note review will be used to measure the impact of metagenomic sequencing on patient management and antimicrobial prescribing. The health economic benefits that may arise through reduced antimicrobial use and a shortened patient journey will be analysed. Anticipated Impact and Dissemination The anticipated impact of this study is faster and more accurate diagnosis of the underlying infectious causes of sepsis in children. This in turn will lead to less or narrower spectrum antibiotics being used. The wider societal benefit of this is a reduction in antimicrobial resistance. Outcomes will be shared with the scientific community through peer-reviewed publications and presentations at conferences. Workshops will be hosted for service users to keep them informed of the project's progress, disseminate key findings, and provide education and training. Wider dissemination to patients, the public, and national bodies will be through a variety of media, including an educational film that will include experiences of patients who have given their consent. Social media will be used to reach the widest possible audience, and key stakeholders will be invited to take part in this.

Lay abstract: Aims A new test will be carried out in the clinical laboratory to find the infectious causes of sepsis in children. The results will be compared with current tests. How patient care is managed and how antibiotics are prescribed will be measured Background Sepsis is a life-threatening disease that affects 25,000 children in the UK every year, caused by the body's response to infection. A patient has septicaemia (blood-poisoning) when germs are in the blood-stream. Sepsis can also be caused by infection of other organs in the body, for example meningitis which is an infection of the fluid around the brain and spinal cord (cerebrospinal fluid). Blood samples taken from patients can be tested in the laboratory to find out exactly which germ is causing the infection, and this information is used to decide on the best treatment, normally antibiotics. The most common way to find germs in the laboratory is to grow them on petri dishes. This type of testing can take several days, will not find viruses and doesn't work well if the patient has already been given antibiotics. Another way to identify germs is to look for their genome (DNA). This is done by magnifying tiny amounts of the germ's DNA. However, lots of separate tests are needed to look for all possible causes of an infection and this type of test can't tell which antibiotics will work. Current tests also make it difficult to rule-out infection, therefore many patients receive unnecessary treatment with antibiotics. This produces side-effects for the patient and contributes to an increase in bacteria becoming resistant to antibiotics. Design of study We will use a new test that can look at all DNA in a patient's blood or fluid around the brain and spinal cord (cerebrospinal fluid) sample. Computer programs will be used to find any DNA in the sample that does not belong to the patient, as this is likely to be from the germ causing the infection. The genome of the germ contains information about which antibiotics will treat the infection. If no germ DNA is found then we may be able to use this test to rule-out infection, and stop unnecessary antibiotic treatment. We will collect samples from children who might have septicaemia and / or meningitis at Great Ormond Street Hospital and hospitals across the UK. Following ethical approval at participating centres, we will perform the new test on the study samples, and test them in the usual way. We will use this information to answer the following questions: Did the new test find less, more or the same number of infections in children compared with the old test? Did the new test find infections in children more quickly, more slowly or in about the same time compared with the old test? Did results from the new test change the way patients were looked after, and in particular the antibiotic treatment they received?Patient and Public InvolvementThis summary has been circulated to representative patient groups (GOSH Young Persons' Advisory Group for research(YPAG),Sepsis Trust) and the applicant's professional networks. The views of service users about current and future diagnostic tests and antimicrobial prescribing were surveyed using an online poll. These groups will be involved in the project throughout by providing feedback through surveys, workshops and stakeholder meetings. Dissemination Outcomes will be shared regularly to service users, the wider NHS, stakeholders and representative patient groups using written reports, peer-reviewed publications and workshops. An educational film will be produced and will include experiences of patients who have given their consent. Social media will be used to reach the widest possible audience.

Research activity codes: 4.2 EVALUATION OF MARKERS AND TECHNOLOGIES
Health categories: INFECTION;INFLAMMATORY AND IMMUNE SYSTEM