Award Title: MR-PRo-adrenomedullin (MR-proADM) and ImmunoXpert Evaluation of procalcitonin-guided antibiotic duration in Children with Infection for Stratification of Effectiveness (PRECISE)
Funder: Medical Research Council

Abstract: WHAT IS THE PROBLEM?_x000D_
The Department of Health recommends that antibiotics should be given for as short a course as is safe, to prevent antimicrobial resistance. Most hospitals in the NHS use a blood test called C-Reactive Protein (CRP) to monitor the body’s response to infection, but it is not specific for bacterial infection and shows a delayed response to infection. An alternative would be a Procalcitonin (PCT) test which is specific for bacterial infection and responds more quickly than CRP, but is not routinely used in the NHS. We are currently running a randomised, controlled trial (the BATCH trial) to see whether PCT testing to guide how long to give intravenous antibiotics (into a vein) for infection in children, is beneficial. New markers of infection, which measure the body’s response to infection, have been studied, and it is suggested they could provide additional information to help identify which children will benefit from PCT testing to guide antibiotic use._x000D_
 AIM OF THE RESEARCH_x000D_
We will embed a smaller study on the newer markers of the body’s response to infection, into the current randomised controlled trial of PCT testing to guide antibiotic use.  This will help us to identify groups of children in whom PCT testing to guide antibiotic use might be beneficial, harmful or ineffective. This can make it safer for some patients, and in others reduce unnecessary PCT testing, thus saving money, as the PCT test will not be offered to those in whom it will be of no benefit._x000D_
WHAT WILL BE DONE, AND WHO WILL BE INVOLVED?_x000D_
In the current trial, children admitted to hospital with bacterial infection and receiving intravenous antibiotics for more than 48 hours are randomly assigned to one of the two treatment arms; PCT-guided or usual care. Doctors and patients know which treatment arm they are in. Four hospitals enrolling children in the current trial will take part in the new study. Parents will be given information about the study and invited to take part. Additional blood samples will be taken on all children in the study (not just those in the PCT arm) to measure the new markers of the body’s response to infection, so groups with low and high levels of these markers can be determined._x000D_
PATIENT AND PUBLIC INVOLVEMENT_x000D_
A parent member of the BATCH trial team, Mrs Sarah Jones has provided advice on the study. In addition, the Liverpool GenerationR Young Person’s Advisory Group are actively involved in the BATCH trial. The group consists of young people aged between twelve to seventeen year olds, who helped design the consent forms and patient information leaflets for the BATCH trial. Sarah Jones and the public involvement lead for the Liverpool group attend monthly BATCH team meetings and provided advice on the acceptability of additional testing and use of salvaged clinical samples for testing in the BATCH trial._x000D_
HOW WILL THE RESEARCH BENEFIT PATIENTS?_x000D_
If the study shows that PCT-guided management is better than current practice, in certain groups of children with infection treated with intravenous antibiotics but not others, then the test will only be offered to those children who are likely to benefit from it. This will lead to improved safety and quality of patient care and reductions in the spread of antimicrobial resistance. It will also reduce time in hospital, and save costs.

Lay Abstract: BACKGROUND: The host-response to bacterial infection is highly heterogeneous, there is therefore a need for stratified treatment strategies instead of the traditional “one-size-fits-all” approach. A precision medicine approach can improve patient outcomes by identifying endotypes in whom the intervention is likely to be harmful or ineffective. In the PRECISE sub-study, we aim to use an embedded mechanistic study to determine endotypes of endothelial dysfunction (mid-range proadrenomedullin (MR-proADM)) and host immune response (ImmunoXpert score: TRAIL, IP-10 and CRP) in whom a Procalcitonin (PCT)-guided antibiotic algorithm might be a) particularly beneficial, b) ineffective, or c) harmful._x000D_
RESEARCH QUESTION: In children hospitalised with suspected or confirmed bacterial infection, do endothelial dysfunction and a likely viral host immune response profile (as indicated by biomarkers) diminish the effectiveness of a  PCT-guided antibiotic algorithm in reducing intravenous (IV) antibiotic duration, compared to usual care? _x000D_
HYPOTHESIS: In children treated with IV antibiotics for suspected or confirmed bacterial infection; a) persistent endothelial dysfunction will be associated with increased duration of IV antibiotics and a PCT-guided antibiotic algorithm may be harmful, and b) a likely viral or other host immune response will be associated with reduced duration of IV antibiotics and a PCT-guided antibiotic algorithm may be ineffective. (Figure 1)_x000D_
AIM: The aim of the PRECISE sub-study (embedded within the BATCH trial), is to determine if there are specific sub-groups of patients, for whom a PCT-guided antibiotic algorithm may be beneficial, harmful or ineffective._x000D_
STUDY DESIGN: Embedded mechanism of action study within a multi-centre, prospective, individually randomised, un-blinded two-arm RCT comparing PCT-guided antibiotic algorithm versus usual care. Recruitment to the host trial commenced in June 2018._x000D_
PARTICIPANTS: Children aged 72 hours up to <18 years hospitalised with suspected or confirmed bacterial infection._x000D_
PRIMARY OUTCOMES: Time until IV antibiotic therapy is stopped will be the primary (time-to-event) endpoint, same as BATCH trial. Baseline MR-proADM and ImmunoXpert scores will define subgroups for the primary comparison, and serial measurements for additional analyses._x000D_
SECONDARY OUTCOMES: Total duration of antibiotics (oral and IV), time to switch from broad spectrum to narrow spectrum antibiotics, time to discharge from hospital, suspected adverse drug reactions, hospital acquired infection up to Day 28._x000D_
PROJECT TEAM: Carrol (CI), Thomas-Jones (Co-CI), Waldron (BATCH trial manager), Pallman (BATCH statistician), Jones (PPI), and Faust, Patel, Paulus, Bernatoniene, Nabwera (all BATCH co-applicants)._x000D_
TIMETABLE: MONTH 1-12: Sample collection and archiving MONTH 12-15: Measurement of MR-ProADM and ImmunoXpert in plasma samples blinded as to randomisation arm. MONTH 15-18: Data cleaning, statistical analysis, prepare for EME report, dissemination._x000D_
IMPACT AND DISSEMINATION: Our research will lead to earlier and more accurate identification of patients who will benefit from a PCT-guided antibiotic algorithm and those in whom it might cause harm, which means that complications and deaths can be averted. This means shorter stays in hospital, less antibiotic exposure and fewer deaths. The results of the PRECISE sub-study will be disseminated locally, nationally and internationally amongst clinical and lay groups.

Research Activity Codes: 4.2 EVALUATION OF MARKERS AND TECHNOLOGIES
Health Categories: INFECTION