Personalised Risk assessment in Febrile illness to Optimise Real-life Management across the European Union (PERFORM)

The management of febrile patients is one of the most common and important
problems facing healthcare providers. Distinction between bacterial infections
and trivial viral infection on clinical grounds is unreliable, and as a result
innumerable patients worldwide undergo hospitalization, invasive investigation
and are treated with antibiotics for presumed bacterial infection when, in
fact, they are suffering from a self-resolving viral infection.

With this study we aim to improve diagnosis and management of febrile children
through the development of simple diagnostic tests to discriminate febrile
illnesses in children, including bacterial and viral infection and inflammatory
diseases.

Sophisticated phenotypic, transcriptomic (genomic, proteomic) and bioinformatic
approaches will be used to well characterised large-scale, multi-national
patient cohorts already recruited with EU funding. Our aim is to identify, and
validate promising new discriminators of bacterial and viral infection
including transcriptomic and clinical phenotypic markers. The most accurate
markers distinguishing bacterial and viral infection will be evaluated in
prospective cohorts of patients reflecting the different health care settings
across European countries. By linking sophisticated new genomic and proteomic
approaches to careful clinical phenotyping, and building on pilot data from our
previous studies we will develop a comprehensive management plan for febrile
patients which can be rolled out in healthcare systems across Europe.

This study aims to improve the diagnosis and management of febrile children
across Europe and West Africa through the development of simple diagnostic
tests to discriminate febrile illnesses in children, including bacterial and
viral infection and inflammatory diseases.

The whole project will:
• Assess current management of febrile illness across Europe and West Africa
using quantitative and qualitative methods (including cost-effectiveness
analysis).
• Identify personalized discriminators of bacterial and viral infection and
inflammatory diseases, and diagnostic signatures that distinguish severe and
mild disease, using a combination of clinical phenotypic markers, host genetic
markers, and biomarkers derived using transcriptomic, proteomic, and
bioinformatic approaches.
• Develop simple proof-of-concept personalized tests for application at the
point of care. The new biomarkers will be validated in samples of new
prospective inclusions. This part of the study is described in this protocol.
• Model the impact of the introduction of optimised management strategies for
febrile children, in the varied healthcare settings of Europe, thus providing
the evidence necessary for European and international health systems to adopt
new management strategies for febrile children.
• Investigate if collection and analysis of exhaled air in children with and
without a lower respiratory tract infection using the Aeonose device is
possible and reliable. This might be a useful diagnostic tool to recognize
viral and bacterial VOC patterns at the bedside.

PERFORM consists of 3 parts using clinical data and/or samples of patients:

1. Biomarker discovery using pre-existing sample collections (Biomarkers of
Viral and Bacterial Infection (BIVABI))
The BIVABI study is a retrospective observational study which will use
transcriptomic, proteomic and metabolomic approaches to discover biomarkers
that distinguish the different phenotypes of childhood febrile illness,
including children with infection (viral, bacterial, mycobacterial, other) and
inflammation (including Kawasaki disease, juvenile idiopathic arthritis). For
this part no new patients will be included.

2. Prospective observational study of patient management and outcome, using
large, aggregated datasets and not involving sample collection (Management and
Outcome of Fever in children in Europe (MOFICHE))
MOFICHE is a prospective observational study assessing the management and
outcome of children presenting to Emergency Departments (ED) with fever across
Europe. This study will use large departmental datasets to collect information
on nearly 50,000 febrile episodes in 12 ED*s in 8 European countries. In the
Netherlands we aim to collect 5.000 febrile episodes. This study will use
large-scale, pseudo-anonymized departmental data to safeguard identity of
participants and will not involve consented patient recruitment; nor will it
use patient samples. Data included in MOFICHE will be based on that collected
as part of routine clinical care. No tissue samples will be taken for research
use, and informed consent will not be taken for the MOFICHE study. This
ABR-form contains the WMO-part of the study (BIVA) mentioned below at point 3.

3. Biomarker validation using prospectively recruited patients and patient
samples (Biomarker Validation studies (BIVA))
Prospective, observational studies will recruit a validation group of children
with infectious and inflammatory conditions. Research blood samples will be
taken and analysed in order to validate biomarker findings identified in the
BIVABI discovery study. There are 5 related prospective studies. The BIVA-ED
study will recruit the majority of the children. The other studies will target
harder-to-reach groups who will not be adequately recruited in an ED study, in
order to increase numbers. The studies are:

• Biomarker Validation in Emergency Department (BIVA-ED)
• Biomarker Validation in Paediatric Intensive Care (BIVA-PIC)
• Biomarker Validation in High Risk patients (BIVA-HR)
• Biomarker Validation in Inflammatory patients (BIVA-INF)

Airway device study: exhaled air will be collected and analysed with a portable
Aenose..

Blood samples will be collected during a routine diagnostic blood sampling. It
is possible that a fingerstick blood collection will be changed in a
venapunction. In addition a nasopharyngeal swab or throat swab will be
obtained. When urine of stool is left over, these will also be collected.
It is estimated that in this way the burden for the child is very low and
without any risks.

In the majority of the inclusions there will be only 1 timepoint for blood
collection. But, if at 48-72 hours or at 28 days after the hospital visit or at
discharge a routine diagnostic blood sampling will be done, then we also want
to collect blood for this study. At 48-72 hours and (if necessary) at 28 days
after the hospital visist the parents will be asked by a text message about the
illness/recovery of the child.

Bij kinderen op de PICU worden er nog additionele bloedsamples afgenomen op
t=24h, t=48h en daarna 1x per week met een maximum van 5 research samples.

Airway device study:
The exhaled breath sampling technique is non-invasive, safe and without risks.
The sampling will be tested in 1 visit and will not exceed 10 minutes.