Diagnosis and Management of Febrile Illness using RNA Personalised Molecular Signature Diagnosis

Current management of patients presenting with fever is problematic due to the
difficulty in identifying the relatively small number of patients with severe
and life-threatening bacterial infections or inflammatory diseases amongst the
more common self-limited viral illnesses. The current approach, based on
exclusion of bacterial infection using microbiological cultures, presumptive
treatment with antibiotics while results are awaited, and consideration of
inflammatory conditions only after infection has been treated or excluded,
results in delayed and incorrect diagnosis, excessive use of hospital beds and
resources during prolonged periods of investigation, and inappropriate
administration of antibiotics, contributing to the growing problem of
antimicrobial resistance.
We propose a new Personalised Medicine approach to diagnosis of infectious and
inflammatory diseases, based on individual RNA signatures detected in blood and
will demonstrate the benefit of this approach to individuals and healthcare
systems and its economic viability. The study is mainly focused on the
pediatric population, but because we aim to also use the newly developed test
to diagnose adults and because febrile illness in children often has a
different etiology than in adults, we will include children as well as adults.

Our proposal builds on 12 years of sustained EU funding, a consortium covering
11 European countries and 27
partners (with non-EU sites in African and two Asian populations to provide a
global perspective) and our cuttingedge new research, which has demonstrated
that molecular signatures can be used to diagnose a wide variety of
infectious and inflammatory diseases. In this proposal, we extend this work
beyond state-of-the-art by developing a
novel molecular taxonomy of infectious and inflammatory disease, which will be
used as the basis for
personalised diagnosis by identifying the specific *signature* of each disease
using a novel approach, which we term
*Personalised Molecular Signature Diagnosis (PMSD). This approach uses each
individual patient*s blood gene
expression to identify RNA signatures, which are specific to individual
infectious or inflammatory diseases. In
collaboration with biotechnology and industrial partners, we will develop novel
devices to rapidly detect the set of
gene transcripts required for PMSD, and evaluate their impact on improved
patient diagnosis and treatment. We will
evaluate in a pilot demonstration the effect of the PMSD approach on health
care resource utilization, costs, prediction
of disease severity and outcomes of febrile illness to provide the evidence
base for introduction of PMSD in European
health systems.
We will address the following specific objectives:
1. To establish the European Diagnostic Transcriptomic Library based on data
from over 15,000 patients with
infectious and inflammatory conditions. This curated RNA expression library
will include data on clinical phenotype,
presentation, severity of illness and outcome and will include all ages, sexes,
ethnicities, co-morbidities and include
the wide range of infectious and inflammatory conditions.
2. To use the data in the European Diagnostic Transcriptomic Library to develop
a comprehensive molecular
taxonomy of infectious and inflammatory diseases based on RNA expression.
3. To use novel computational dimensionality reduction techniques, multinomial
variable selection methods and costsensitive approaches to identify a minimal
transcript signature for all common infectious and inflammatory
diseases as the basis for PMSD.
4. To evaluate the diagnostic performance of the transcripts required for PMSD
using a high throughput
transcriptomic approach in an independent validation cohort of patients
presenting with fever and inflammatory
conditions, and including challenging patient subgroups at the extremes of age,
and patients with underlying co
morbidities.
5. To develop test platforms for rapid detection of PMSD transcripts in
collaboration with academic, industrial and
small and medium-sized enterprises (SME) partners, and to compare the detection
performance of these devices to
existing RNA-detection technologies.
6. To select the best performing device for evaluation in a large-scale pilot
demonstration of PMSD as compared
with current diagnostic practices in multiple EU health care settings.
7. To describe current diagnostic practices for febrile patients and
preferences of end-users in multiple EU countries
as well as the economic and societal costs and to assess the acceptability and
likely uptake of PMSD.
8. To use the data from the pilot demonstration and current practice (objective
7) to model the potential clinical and
health economic impact of PMSD in different EU national health care settings,
and determine the impact of PMSD
implementation on health systems across Europe.
9. To disseminate the findings to regional, national and EU policy makers to
demonstrate the benefits of a healthcare
model based on PMSD and advocate for widespread implementation of PM.

DIAMONDS consists of 2 parts using clinical data and/or samples of patients:

DIAMONDS SEARCH
The DIAMONDS consortium will acquire clinical data and RNA samples from
subjects with febrile or inflammatory
disease through prospective recruitment of patients attending at the DIAMONDS
clinical sites (inpatient and outpatient settings), as part of an observational
study. We will supplement new patient recruitment with use of
samples from well-curated collections held by collaborators. In total, an
estimated 5,000 samples from adults and
children will be added to the DIAMONDS sample biobank. The main objective of
this clinical study is to obtain all
necessary RNA samples and clinical data required for the prototype PMSD device
configuration and design.
For the recruiting study, subjects will have samples collected at presentation,
at 48 hours and at convalescence
taken for research, taken at the same blood draw alongside their usual clinical
tests. Other samples for diagnosis
including nasal secretions and urine will be collected as appropriate. Written
consent and assent (if applicable) will
be obtained for all subjects taking part. The prospective data and samples will
be merged with existing RNA
expression library and Biobank from previous studies performed by the
consortium in which future research has
been agreed by participants, parents or guardian (EUCLIDS, PERFORM, EU-TB,
IRIS, GENDRES).

DIAMONDS PILOT DEMONSTRATION
A pilot demonstration study to evaluate the performance and impact of PMSD on
the management of febrile
patients in EU healthcare settings. An observational study will be performed to
evaluate whether introduction of
PMSD tests might influence time to diagnosis, accuracy of diagnosis, resource
use, or inappropriate antibiotic use.
2,000 febrile patients at 8 selected high-enrolling hospitals, reflecting the
spectrum of healthcare settings of the EU
partners will be recruited to test the PMSD platform in real clinical and
diagnostic settings, and results will compare
with the standard of care for the diagnosis of febrile diseases.
Patients will have a single set of samples taken for research, taken at the
same blood draw alongside their usual
clinical tests. Written consent and assent (if applicable) will be obtained for
all subjects taking part.

Blood samples will be collected during a routine diagnostic blood sampling from
a venapunction or central line. Capillary sampling is not possible. In addition
a nasopharyngeal swab or throat swab wil be obtained. When urine or stool
sampling is indicated, this will also be collected if leftover material is
available. It is estimated that this way the burden for the child is very low
and without any risks.

In the majority of the inclusions there will only be one 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
tot collect blood for this study. It is possible that a patient develops
multiple separate episodes of fever during admission or treatment, we would
like to collect additional blood samples from these episodes, as there may be
different underlying causes of fever. In case of early discharge, the patient
or patients caregiver will be contacted after a maximum of 28 days to ask about
the well-being of the patient.
From patients admitted to the ICU additional blood samples will be collected at
t=24; t=48 and once a week after that with a maximum of 5 samples per patient.