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Personalised Risk assessment in febrile illness to Optimise Real-life Management across the European Union

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

Paediatric services are faced with how to detect the small number of children with bacterial infections among the more common viral illnesses. Current diagnosis relies on the culture of bacteria but the results may take 48 hours or more to become available, so do not influence the decision on whether to administer antibiotics. In the absence of reliable tests, a large proportion of febrile children are treated with antibiotics when in fact they suffer from viral infections, while others with serious bacterial infections are sent away only to return critically ill.
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.
By month 54 PERFORM completed recruitment of 6,000 patients in 9 European countries, The Gambia and Nepal (www.perform2020.org). All patients have undergone phenotyping to establish whether they had bacterial or viral infection. In addition,38,000 children have been included in the MOFICHE study of febrile children attending Accident & Emergency departments. MOFICHE provides data on resource use, for cost-effectiveness analysis modelling.
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.
PERFORM has set in progress a large RNA expression study to identify the pattern of genes expressed in the blood of children with fever to distinguish bacterial from viral infection. Data so far confirmed that bacterial infection can be distinguished from viral infection with a small number of RNA transcripts. Concurrent proteomic analysis has identified novel protein biomarkers which may improve distinction of bacterial from viral infections. Our observational study of febrile children across European countries provides a unique picture of how children with fever are managed. The expected impact of this action will be identification and development of improved methods to diagnose bacterial infection and distinguish bacterial infection from other causes of fever in children. The work is likely to result in improved models for care of febrile children and ultimately in reduction in unnecessary antibiotic use, contributing to the global effort to reduce anti-microbial resistance.
The PERFORM Clinical Network