Personalised Risk Assessment in Febrile Illness to Optimise Real-life Management Across the European Union (PERFORM) (PERFORM)

Childhood fever is a prevalent problem. Most febrile children who visit hospital improve without treatment, but a minority require treatment, and a few will have severe disease. The investigators want to improve the diagnosis and management of febrile children by developing tests to distinguish between bacterial and viral disease 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.

The investigators will prospectively recruit acutely febrile children presenting to hospital, collecting research samples for validation of biomarkers, in combination with clinical phenotypic markers and host genetic markers (BIVA-studies).

Any febrile child newborn to under 18 presenting to hospital will be eligible for recruitment. The study will last 5 years.

Study Overview

• Status: Completed
• Conditions: Inflammation; Fever; Infection
• Intervention / Treatment: Diagnostic test: Validation of biomarker

Detailed Description

The problem to be addressed:

Fever is among the commonest symptoms for which parents consult health care providers worldwide. Distinction between life-threatening bacterial infection and viral infection is clinically difficult, and many children worldwide receive unnecessary antibiotic treatment, or undergo invasive investigations and hospitalization, whilst bacterial infection is missed in others.

Objective:

The investigators aim to validate biomarkers that will identify children with bacterial infection, viral infection and inflammatory syndromes, using whole-blood RNA expression, proteomic and metabolomics signatures. The investigators aim to assess how efficacious these biomarkers would be if they formed the basis of a diagnostic test.

Design:

The investigators will use established case-control groups of febrile children presenting to hospital, recruited across Europe as part of previous (and current) ethically-approved studies, to discover signatures of febrile illness. The investigators will validate these signatures in samples prospectively collected from children as part of this observational study.

The investigators will use prospective, observational BIVA studies to recruit febrile children with infectious and inflammatory diseases in order to validate diagnostic biomarkers. The investigators will also recruit non-febrile controls in order to discover and validate disease-specific biomarkers and to understand their biological significance.

STUDY SIZE at least 4000 febrile children;

PROCEDURES;

Informed consent using age appropriate patient/parent/guardian information sheets will be taken from parents (or from children aged 16 and over), assent will be taken from the child under the age of 16 (if appropriate).

Routine clinical and laboratory data and research samples from three timepoints (presentation, 48 hours after presentation, 28 days after admission). If patients present to hospital with fever on subsequent occasions, clinical data will be recorded and further research samples will be taken at those times.

Samples; Blood, urine, stool (in the case of gastroenteritis), nasopharyngeal/throat swab

CONTROLS:

The investigators will collect samples from age-matched control patients will not have had a febrile illness, major trauma or vaccination within the previous three weeks and who are having routine blood sampling for reasons other than investigation of infectious or inflammatory disease.

Control children may include critically ill children without infection or those with healthcare associated infections.

• Study Type: Observational
• Enrollment (Actual): 7247

Contacts and Locations

Study Locations

• United Kingdom
  • London, United Kingdom, W2 1PG
    • Imperial College London

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: No older than 17 years (Child)
• Accepts Healthy Volunteers: Yes

• Sampling Method: Probability Sample

Study Population

Children with fever >38ºC, or a history of fever (within 3 days) who requires a blood test for clinical reasons or consents for research bloods to be taken,

Description

Inclusion Criteria:

• All children <18 years with fever >38ºC, or a history of fever (within 3 days), in whom the attending clinician determines the need for blood sampling or whom parents give consent for bloods taken for research purposes
• All children <18 years suspected of infection, including the full spectrum of disease severity and co-morbidities.
• Afebrile control children who are having blood tests for reasons other than for investigation of infectious or inflammatory illness.

Exclusion Criteria:

• Children from whom parent/legal guardian signed consent is not received
• For healthy control children only: febrile illness or vaccination within the last 3 weeks.

Study Plan

How is the study designed?

Design Details

• Observational Models: Case-Control
• Time Perspectives: Prospective

Number of groups / cohorts

2

Cohorts and Interventions

Group / Cohort	Intervention / Treatment
BIVA studies - children with fever and/or suspected infection; A minimum of 3,000 children will be recruited to the BIVA-ED (Biomarker Validation in Emergency Department) study, in order to capture sufficient children with confirmed bacterial infection. Additional children with less common febrile illnesses will also be recruited: 500 critically ill (BIVA-PIC); 200 at high-risk of bacterial illness through primary or secondary immunodeficiency (BIVA-HR); 150 with an inflammatory diagnosis, whose initial presentation is difficult to discriminate from bacterial infection (BIVA-INF). Samples collected from recruits in the BIVA studies will be used for the validation of biomarkers (clinical, proteomic and transcriptomic biomarkers) for diagnosis of febrile illness, including markers of bacterial and viral infection (confirmed by culture and/or molecular microbiology) and inflammatory conditions.	Diagnostic test: Validation of biomarker
BIVA studies - control children without fever or suspicion of infection; Afebrile children <18 years (16 years depending in the setting) of age who are having blood tests for reasons other than for investigation of infectious or inflammatory illness or whom parents give consent for bloods taken for research purposes. Controls may have a range of clinical presentations including co-morbidities without infection. One set of samples will be taken from controls, no follow up data or samples taken.	Diagnostic test: Validation of biomarker

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Participants With Clinically-assigned Retrospective Phenotype	Clinically-assigned retrospective phenotype, according to the cause of illness	Participants were monitored for outcome throughout their stay in hospital, and received follow-up review at 10 days

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
MOFICHE study accessed the records	Number of prescriptions of broad spectrum antibiotics versus the number of prescription of narrow spectrum antibiotics (dose in 24 hours)	throughout the study one year
BIVA study assessment of the ability of biomarker tests to predict disease severity	Assessment of the ability of biomarker tests to predict disease severity	throughout the study 3 years

Collaborators and Investigators

• Sponsor: Imperial College London
• Collaborators: London School of Hygiene and Tropical Medicine; Erasmus Medical Center; University of Oxford; Ludwig-Maximilians - University of Munich; Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA); University of Bern; National and Kapodistrian University of Athens; University of Liverpool; Medical Research Council Unit, The Gambia; University of Newcastle Upon-Tyne; University of Santiago de Compostela; University of Ljubljana; University Hospital, Paris; BioMérieux; University of Graz; Stichting Katholieke Universiteit; Servizo Galego de Saúde; Riga Stradins University; Micropathology Ltd, University of Warwick
• Investigators: Study Chair: Michael Levin, Imperial College London

Publications and helpful links

General Publications

• Hartman SJF, Upadhyay PJ, Hagedoorn NN, Mathot RAA, Moll HA, van der Flier M, Schreuder MF, Bruggemann RJ, Knibbe CA, de Wildt SN. Current Ceftriaxone Dose Recommendations are Adequate for Most Critically Ill Children: Results of a Population Pharmacokinetic Modeling and Simulation Study. Clin Pharmacokinet. 2021 Oct;60(10):1361-1372. doi: 10.1007/s40262-021-01035-9. Epub 2021 May 26.
• Habgood-Coote D, Wilson C, Shimizu C, Barendregt AM, Philipsen R, Galassini R, Calle IR, Workman L, Agyeman PKA, Ferwerda G, Anderson ST, van den Berg JM, Emonts M, Carrol ED, Fink CG, de Groot R, Hibberd ML, Kanegaye J, Nicol MP, Paulus S, Pollard AJ, Salas A, Secka F, Schlapbach LJ, Tremoulet AH, Walther M, Zenz W; Pediatric Emergency Medicine Kawasaki Disease Research Group (PEMKDRG); UK Kawasaki Genetics consortium; GENDRES consortium; EUCLIDS consortium; PERFORM consortium; Van der Flier M, Zar HJ, Kuijpers T, Burns JC, Martinon-Torres F, Wright VJ, Coin LJM, Cunnington AJ, Herberg JA, Levin M, Kaforou M. Diagnosis of childhood febrile illness using a multi-class blood RNA molecular signature. Med. 2023 Sep 8;4(9):635-654.e5. doi: 10.1016/j.medj.2023.06.007. Epub 2023 Aug 18.

Helpful Links

• publications and conference proceedings pertaining to PERFORM - BIVA studies

Study record dates

Study Major Dates

• Study Start (Actual): June 2, 2016
• Primary Completion (Actual): January 25, 2021
• Study Completion (Actual): December 31, 2021

Study Registration Dates

• First Submitted: March 27, 2018
• First Submitted That Met QC Criteria: April 18, 2018
• First Posted (Actual): April 19, 2018

Study Record Updates

• Last Update Posted (Actual): October 13, 2023
• Last Update Submitted That Met QC Criteria: October 12, 2023
• Last Verified: October 1, 2023

More Information

Terms related to this study

• Keywords: children
• Additional Relevant MeSH Terms: Pathologic Processes; Inflammation; Anti-Infective Agents; Anti-Bacterial Agents
• Other Study ID Numbers: REC ref: 16/LO/1684; BIVA studies (Other Identifier: Imperial College London)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No