Periodic Reporting for period 3 - PERFORM (Personalised Risk assessment in febrile illness to Optimise Real-life Management across the European Union)
Reporting period: 2019-01-01 to 2020-06-30
PERFORM aims to apply molecular and protein methods to identify gene and protein biomarkers to distinguish bacterial from viral infection. Rather than attempting to identify the causative bacteria, PERFORM aims to identify the pattern of genes and proteins activated in blood by the infection to identify a” signature” distinguishing bacterial from viral infection. We are studying over 4000 children recruited in our previous EU funded grant (EUCLIDS), applying cutting edge gene expression and proteomic methods to identify biomarkers that distinguish bacterial from viral infection. The best performing markers will be validated in a newly recruited cohort of 5000 children. In the final phase, we will translate the most promising biomarkers into simple rapid tests that will be further validated prior to introduction into clinical use.
Patients included in PERFORM have undergone molecular pathogen detection studies undertaken by partner Micropathology Ltd for 22 respiratory viruses(throaty swabs) and 24 bacterial targets, 9 viral and 6 fungal targets in blood. This study provides a new picture of how viruses and bacteria interact in febrile illness.
In order to discover predictive RNA biomarkers of bacterial and viral infection PERFORM has completed RNA sequencing on over 2,000 patients at partner Oxford’s genomic facility.PERFORM has also completed a large scale study to detect protein biomarkers distinguishing bacterial from viral infection. Partners Nijmegen University and Oxford University undertook mass spectrometry analysis using tandem mass spectrometry (Oxford) and glycoprotein identification (Nijmegen). Comparison of patients with bacterial and viral infection has enabled optimal protein biomarkers to be identified and simultaneously screened by Luminex for candidate proteins at the University of Amsterdam.
The data and modelling work package has completed analysis of all protein data and identified candidate biomarkers which are currently undergoing large scale validation. Bioinformatic analysis of the RNA sequencing data on 2,000 patients has identified optimised RNA signatures for final validation in the PERFORM cohort.
Partner BioMerieux has undertaken development of a rapid detection device for the signature distinguishing bacterial from viral infection using the FilmArray platform. Final optimised RNA markers are still awaited, but development of the PERFORM v1.0 FilmArray pouch has provided proof of concept. Development of the PERFORM v2.0 pouch will commence when analysis of the RNA sequence data provides the optimised markers.
Evaluation of the socioeconomic impact of a new diagnostic test to distinguish bacterial infection from viral infection, and how fever is managed in different countries has been conducted by the socioeconomic and cost-effectiveness work package. This work has provided details of how fever in children is managed in different EU countries, and costs associated with current approaches. Modelling of how a rapid diagnostic test will alter current health care costs will provide information to support introduction of new approaches into EU health care systems.
While all components of PERFORM were progressing with the aim of successful completion of the study by the end of 2020, the onset of the COVID-19 pandemic delayed progression of the planned laboratory and clinical work. By July 2020 partner institutions have recommenced laboratory work, but the requirement for social distancing results in partner laboratories working at 20% capacity. The pandemic has thus resulted in a six-month period where completion of the RNA and protein validation studies have been on hold. With restrictions now in place we anticipate further delay before the protein and RNA validation studies are available for modelling on the impact of a test to distinguish bacterial from viral infections.
In summary, while all the proposed work to identify and validate an RNA and protein signature was progressing within the planned timelines, the COVID-19 pandemic will result in an appr have therefore requested a one-year extension due to the interruption caused by the pandemic. With a new end date of December 2021, we anticipate successful completion of PERFORM.