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

Completed

• Conditions: Fever; Inflammation; Infection
• Interventions: Diagnostic Test: Validation of biomarker

• Registration Number: NCT03502993
• Lead Sponsor: Imperial College London

Brief Summary

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.

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.

Basic Information
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Recruitment & Eligibility
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Study & Design
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Trial Locations

Study Timeline

• Study Start: 2016-06-02
• Study First Submitted: 2018-03-27
• Study First Submitted QC: 2018-04-18
• Study First Posted: 2018-04-19
• Primary Completion: 2021-01-25
• Study Completion: 2021-12-31
• Results First Submitted: 2022-02-03
• Status Verified: 2023-10
• Results First Submitted QC: 2023-10-12
• Last Update Submitted: 2023-10-12
• Results First Posted: 2023-10-13
• Last Update Posted: 2023-10-13

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 7247

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.

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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.

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Study & Design

• Study Type: OBSERVATIONAL
• Study Design: Not specified

Arm && Interventions

Group	Intervention	Description
BIVA studies - children with fever and/or suspected infection	Validation of biomarker	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.
BIVA studies - control children without fever or suspicion of infection	Validation of biomarker	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.

Primary Outcome Measures

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

Trial Locations

Locations (1)

Imperial College London; 🇬🇧 London, United Kingdom