Clinical trial NCT03502993: Personalised Risk Assessment in Febrile Illness to Optimise Real-life Management Across the European Union (PERFORM)
Official title: Personalised Risk Assessment in Febrile Illness to Optimise Real-life Management Across the European Union (PERFORM)
Study type: OBSERVATIONAL
Overall status: COMPLETED
Conditions: Fever
Infection
Inflammation
Keywords: children
Lead sponsor: Imperial College London
Sponsor class: OTHER
Collaborators: name: London School of Hygiene and Tropical Medicine
name: University of Liverpool
name: University of Newcastle Upon-Tyne
name: Erasmus Medical Center
name: Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)
name: National and Kapodistrian University of Athens
name: Stichting Katholieke Universiteit
name: University of Graz
name: University of Ljubljana
name: Riga Stradins University
name: Medical Research Council Unit, The Gambia
name: Ludwig-Maximilians - University of Munich
name: University of Bern
name: University of Oxford
name: University Hospital, Paris
name: University of Santiago de Compostela
name: Servicio Gallego de Salud
name: BioMérieux
name: Micropathology Ltd, University of Warwick
First posted: 2018-04-19
Enrollment: 7247
Sex: ALL
Maximum age (years): 17
Standard ages: CHILD
Accepts healthy volunteers: yes
Observational model: CASE_CONTROL
Time perspective: PROSPECTIVE
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,

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.

Eligibility criteria: 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.

Primary outcomes:
measure: Number of Participants With Clinically-assigned Retrospective Phenotype
timeFrame: Participants were monitored for outcome throughout their stay in hospital, and received follow-up review at 10 days
Secondary outcomes:
Other outcomes:
Locations:
city: London
country: United Kingdom
facility: Imperial College London
Study officials:
affiliation: Imperial College London
name: Michael Levin
role: STUDY_CHAIR
References:
citation: 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.
citation: 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.