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| ID | Type | Description | Link |
|---|---|---|---|
| BIVA studies | Other Identifier | Imperial College London |
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| Name | Class |
|---|---|
| London School of Hygiene and Tropical Medicine | OTHER |
| University of Liverpool | OTHER |
| University of Newcastle Upon-Tyne | OTHER |
| Erasmus Medical Center |
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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.
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.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| 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. |
| |
| 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. |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Validation of biomarker | Diagnostic Test |
|
| 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 |
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Inclusion Criteria:
Exclusion Criteria:
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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,
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| Name | Affiliation | Role |
|---|---|---|
| Michael Levin | Imperial College London | Study Chair |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Imperial College London | London | W2 1PG | United Kingdom |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 37597512 | Result | 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. | |
| 34036552 |
| Label | URL |
|---|---|
| publications and conference proceedings pertaining to PERFORM - BIVA studies | View source |
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| ID | Title | Description |
|---|---|---|
| FG000 | BIVA Studies | A minimum of 3,000 children will be recruited to the BIVA-ED 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. Validation of biomarker |
| FG001 | Control Children Without Fever or Suspicion of Infection | Children attending hospital for reasons other than for investigation of febrile illness or suspicion of infection |
| Title | Milestones | Reasons Not Completed | ||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study |
|
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| ID | Title | Description |
|---|---|---|
| BG000 | BIVA Studies | A minimum of 3,000 children will be recruited to the BIVA-ED 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. Validation of biomarker |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Customized | Participants excluded from age analysis if data missing or incomplete |
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | |||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Primary | Number of Participants With Clinically-assigned Retrospective Phenotype | Clinically-assigned retrospective phenotype, according to the cause of illness | Number of children with definite bacterial illness assessed by positive blood culture and/or positive culture of sample from sterile site | Posted | Count of Participants | Participants | Participants were monitored for outcome throughout their stay in hospital, and received follow-up review at 10 days |
|
Participants were monitored for adverse outcomes throughout their stay in hospital and monitored upto follow up period of 10 days
Observational study; outcome (death)
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | BIVA Studies | A minimum of 3,000 children will be recruited to the BIVA-ED 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. Validation of biomarker |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Sepsis syndrome | Blood and lymphatic system disorders | Systematic Assessment |
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| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Dr J Herberg | Imperial College London | 0207 594 3900 | j.herberg@imperial.ac.uk |
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| Type | Includes Protocol | Includes SAP | Includes ICF | Document Label | Document Date | Document Uploaded Date | Document File Name |
|---|---|---|---|---|---|---|---|
| Prot_SAP | Yes | Yes | No | Study Protocol and Statistical Analysis Plan | Jun 1, 2016 | Feb 3, 2022 | Prot_SAP_000.pdf |
| ICF | No | No | Yes | Informed Consent Form | Jun 3, 2016 | Feb 3, 2022 | ICF_001.pdf |
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| ID | Term |
|---|---|
| D005334 | Fever |
| D007239 | Infections |
| D007249 | Inflammation |
| ID | Term |
|---|---|
| D001832 | Body Temperature Changes |
| D012816 | Signs and Symptoms |
| D013568 | Pathological Conditions, Signs and Symptoms |
| D010335 | Pathologic Processes |
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| OTHER |
| Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA) | OTHER |
| National and Kapodistrian University of Athens | OTHER |
| Stichting Katholieke Universiteit | OTHER |
| University of Graz | OTHER |
| University of Ljubljana | OTHER |
| Riga Stradins University | OTHER |
| Medical Research Council Unit, The Gambia | OTHER |
| Ludwig-Maximilians - University of Munich | OTHER |
| University of Bern | OTHER |
| University of Oxford | OTHER |
| University Hospital, Paris | OTHER |
| University of Santiago de Compostela | OTHER |
| Servicio Gallego de Salud | OTHER_GOV |
| BioMérieux | INDUSTRY |
| Micropathology Ltd, University of Warwick | INDUSTRY |
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blood, urine, nasopharyngeal aspirate/throat swab, stool
| Derived |
| 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. |
| BG001 | Controls for BIVA Studies | 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. Where data was incomplete, patients were not included in the analysis - therefore the number analysed is not always 1290 |
| BG002 | Total | Total of all reporting groups |
| Median |
| Inter-Quartile Range |
| years |
|
| Sex: Female, Male | Participants excluded from sex analysis if data missing or incomplete | Count of Participants | Participants |
|
| Race/Ethnicity, Customized | Participants excluded from race/ethnicity analysis if data missing or incomplete | Count of Participants | Participants |
|
| Co-morbidities leading to increased infection risk, BIVA studies | Participants excluded from Co-morbidities leading to increased infection risk, BIVA studies analysis if data missing or incomplete | Number | participants |
|
| OG001 | Controls for BIVA Studies | 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. Where data was incomplete, patients were not included in the analysis - therefore the number analysed is not always 1290 |
|
|
| 50 |
| 5,957 |
| 120 |
| 5,957 |
| 0 |
| 5,957 |
| EG001 | Healthy Controls | Children attending hospital for reasons other than investigation of febrile illness or suspicion of infection | 0 | 1,290 | 0 | 1,290 | 0 | 1,290 |
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| Mandinka |
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| unknown |
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| Roma European |
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| Mixed |
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| FULA |
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| Gambian |
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| Arabian Peninsula/Arab Middle East |
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| West Asian |
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| WOLOF |
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| North African |
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| East Asian |
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| other |
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| Serahule |
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| Afro-Carribean |
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| South East Asian |
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| Native South American |
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| Other African |
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| Other EU |
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| Other Asian |
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| South Asian Nepal |
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| Jewish |
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| South Asian Indian, Pakistani, Bangladeshi |
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| Subsaharan Africa |
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| Turkish |
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