PERFORM
Research type
Research Study
Full title
Personalised Risk assessment in Febrile illness to Optimise Real-life Management across the European Union (PERFORM)
IRAS ID
209035
Contact name
Michael Levin
Contact email
Sponsor organisation
Imperial College London
Duration of Study in the UK
4 years, 11 months, 30 days
Research summary
Research Summary
Childhood fever is a prevalent problem although most children who visit hospital improve without treatment, but a minority require treatment, and a few will have severe disease. We want to improve the diagnosis and management of febrile children by developing tests which identify the need for antibiotics, and the presence of severe illnesses, so that antibiotic treatment can be initiated promptly and only when required. Judicious and prudent use of antibiotics will reduce the likelihood of developing resistant organisms and save treatment costs in the NHS.
There are two parts to recruitment in this study; the first is to assess the management and outcome of children who seek medical treatment in hospital (MOFICHE study). We will collect data from febrile children in 50,000 hospital visits in 9 European countries and the Gambia. The data will be used to model management strategies for febrile children and enable a cost-effectiveness analysis.
In the second part of the study we will prospectively recruit four groups of febrile children presenting to hospital. In these observational studies, we will recruit patients and take research samples for validation of the accuracy of the aforesaid biomarkers, in combination with clinical phenotypic markers and host genetic markers (BIV-studies).
In order to capture the full spectrum of febrile conditions, any febrile child from newborn to age 18 presenting to hospital will be eligible for recruitment. The study will take place in hospitals within the European Union and will last 5 years. Our approach will be as ‘light touch’ and pragmatic as possible, in order both to facilitate recruitment as comprehensively as possible, whilst ensuring the minimum impact on children taking part in the study
Summary of Results
PERFORM; Personalised Risk Assessment in febrile illness to optimise Real-life Management across the European Union (PERFORM) Sponsor; Imperial College London Chief Investigator and Global Co-ordinator: Professor M Levin
REC: London-Central Research Ethics Committee ref: 16/LO/1684We would like to thank the children and young people who participated in this study as well as their parents, guardians and other carers. We would also like to thank London-Central Research Ethics Committee, the Confidentiality Advisory Group and the Health Research Authority for their review and approval.
Who carried out the research? The PERFORM consortium which comprised Hospitals and Universities in 10 European countries, Taiwan, The Gambia and Nepal.
What was the study design? There were two parts to the study;
1. An observational study of patient management and outcome for febrile children presenting to the emergency department at hospitals in EUROPE (Management and Outcome of Fever in children in Europe (MOFICHE).2. A prospective, observational study which recruited children with infectious and inflammatory conditions. Research samples and data were taken in order to discover and validate biomarker findings (Biomarker Validation Studies (BIVA)).
Where and when the study took place. Children were recruited in hospitals in 10 European countries as well as Taiwan, The Gambia and Nepal between 2016 and 2020.
Who participated in the study? Newborn babies up to 18 years were included.
What public involvement was in the study? 38000 children with fever attending emergency departments in European countries and The Gambia were included in MOFICHE (see below) and over 7000 children who presented to hospital with a fever or who were suspected of having an infection or an inflammatory illness were recruited into BIVA (see below). Children who were not suspected of having an infection were recruited as controls. Children were recruited to one or both studies.
1. Management and Outcome of Fever in children in Europe (MOFICHE)
Why was the research needed? Fever is the most frequent reason for a child to attend the paediatric emergency department (ED). Most febrile children suffer from a self-limiting illness which do not require antibiotics although antibiotic prescription rates in febrile children remain high and there is marked variation between countries. This study was needed to investigate the nature and cause of variations in the organisation of hospital management practices and outcomes for febrile children in the ED in 10 European countries.
What was the purpose of the research? Evaluation of the management of febrile illness in children in different European countries including hospital admission, antibiotic prescription and investigations, identification of clinical and vital sign variables that predict severe disease. Also collection of data for cost-effectiveness will provide evidence for European and international health systems to adopt new management strategies for febrile children.
What were the results of the MOFICHE study? This study of 38000 emergency department attendances for febrile children confirmed high rates of antibiotic usage, despite only a small proportion of patients with a definite diagnosis of bacterial infection. Analysis of this cohort has identified clinical features and vital sign-based algorithms that predict the likelihood of serious illness which can be used to identify patients requiring further evaluation, treatment, or admission.2. Biomarker Validation Studies (BIVA)
Why was the BIVA research needed? Children are admitted to hospitals with fever every day. Often they get better without treatment and other times they become very ill. Even with testing and careful examination, it can be difficult for the doctor to make the right diagnosis. This means doctors prescribe antibiotics ‘just in case’. The overuse of antibiotics has made some bacteria resistant to treatment, which means that antibiotics do not work in some infections. This research collected samples which were needed to validate biomarkers for bacterial, viral or inflammatory disease. It was hoped that prediction of bacterial, viral and inflammatory disease using these biomakers could (in the future) facilitate appropriate antibiotic prescription.
What was the purpose of the BIVA study research? This study aimed to discover new, better diagnostic tests for children with fever, by comparing samples collected from children with different types of feverish illness as well as those who do not have a fever. The purpose of the research was to develop a simple test that could identify which children need antibiotics.
What treatments or interventions did the participants take/receive? These were an observational studies, there was no change to standard hospital treatment.
What medical problems (adverse reactions) did the participants have? As this was an observational study, no adverse events were recorded. Out of 7247 children were recruited, 50 patients died.
What happened during the study? Blood and other samples were collected and details of clinical care were recorded during the hospital care.
What were the results of the study? BIVA identified and validated promising ‘signatures’ in blood – genes and other proteins (biomarkers) which could distinguish between bacterial and viral infection. A prototype device designed and manufactured by industry partner BioMérieux, demonstrated an accurate diagnosis of bacterial infection in over 2500 patients.
How has this study helped patients and researchers? The ‘signatures’ discovered in this study can be used in a simple test to identify which sick children would benefit from antibiotic prescription. This includes the prototype device already evaluated by industry partner BioMérieux as well as other platforms designed by other research groups.
What happened to blood and other samples from this study? Blood and other samples collected in this study were analysed using laboratory methods not routinely available in hospital. Proteins and chemicals including genes from blood showed that infections or diseases can be defined by a characteristic ‘signature’ of substances. Genes were analysed to see which are activated in blood in order to understand what type of illness was present. The DNA sequence (the genetic code) of some children was examined to further understanding why children respond differently to infection.
What has happened to any left over samples from this study? We have transferred any left over samples to our DIAMONDS study (see below) if consent is in place for use in future research studies.
Details of any further research planned. The findings from the PERFORM study have been taken forward in the DIAMONDS study (Diagnosis and Management of Febrile Illness using RNA personalised signature Diagnosis). This is multi-national EU funded study which aims to develop a new diagnostic classification of infectious and inflammatory diseases so a minimal set of genes can be selected to distinguish common conditions simultaneously. The outcome of this ‘personalised molecular signature diagnosis’ will be a device which can detect genes for diagnosis informing the need antibiotic prescription.
Where can I learn more about the PERFORM study? Results of this research have been published in scientific journals. Results have also been posted on the project website (https://eur03.safelinks.protection.outlook.com/?url=https%3A%2F%2Fu2790089.ct.sendgrid.net%2Fls%2Fclick%3Fupn%3DXv3JSvJ-2B3M71ppf7N9agbQBkrOGktp9LnGd4HJ-2BJnhuObiIGHbLESzOZvHIjPQ8oLZpY_E1aO2-2BZlVOSJJV-2FajQqskegTd6IRomHYTi-2Fbt8SH3YIr2WvE5YFIoPGVRXFAXjq8U0CdYTAtc1kfV5Eia-2FT0mBy6Mm6Hc8jRwInHUZAvUCLrEu46bzVMAx2vxVPuNz8w-2FYGrn5zj6hAl3L-2BzjuSqqaki6Y7k9dRsHIyejGtncR9FeDpQN7T7rOr5QTXuLLTIJWzRDnMEAmnH5GI9coDagA-3D-3D&data=05%7C01%7Capprovals%40hra.nhs.uk%7Ce06433c932ca48568d0e08da6afb13a6%7C8e1f0acad87d4f20939e36243d574267%7C0%7C0%7C637939923837170502%7CUnknown%7CTWFpbGZsb3d8eyJWIjoiMC4wLjAwMDAiLCJQIjoiV2luMzIiLCJBTiI6Ik1haWwiLCJXVCI6Mn0%3D%7C3000%7C%7C%7C&sdata=yqSwnc54PIVC6fTig%2Fruj9KZT1xCY%2F1aWfoJTIheWaU%3D&reserved=0
REC name
London - Central Research Ethics Committee
REC reference
16/LO/1684
Date of REC Opinion
9 Nov 2016
REC opinion
Further Information Favourable Opinion