Sepsis Clinical Trial
Official title:
Validation of Molecular and Protein Biomarkers in Sepsis
Background:
Sepsis (blood poisoning) is a clinical syndrome characterised by a dysregulated host response
to infection causing life-threatening organ dysfunction which results in admission to an
intensive care unit. It typically shows an initial harmful inflammation resulting from the
immune system's overreaction to a severe infection. It is a major healthcare problem,
affecting millions of people worldwide. In the UK, it kills over 37,000 people/year, costing
the NHS £2.5 billion a year, and is increasing in incidence. Despite extensive efforts to
tackle this burden, at present, however, there are no specific and effective therapies for
this illness.
Sepsis is a potentially life-threatening condition caused by a severe infection. When someone
develops sepsis, inflammation occurs not just at the site of the infection but throughout the
whole body. This widespread inflammation can be very harmful. It is known that similar
responses occur in other conditions, not relating to infection.
The investigators are recruiting patients with severe infections causing organ failure (also
known as severe sepsis/ septicaemia and septic shock) and also patients where widespread
inflammation, not related to infection, causes organ failure. In this study the investigators
hope to find out whether certain groups of genetic and blood based protein markers of sepsis
can forewarn the clinicians to this condition and also highlight patients who are responding
well to the treatment.
Although it is known that the majority of the patients suffering from sepsis will survive
their ICU stay and leave the hospital alive, there is insufficient data how these patients do
on a longer term, i.e. after some time at home. To date there is little information on the
ability of the observed genetic and blood based protein markers to predict the functional
status of the patients surviving these conditions.
Sepsis, defined as life threatening organ failure resulting from a dysregulated host response
to infection, remains a leading cause of death in critically ill patients and has been
included as a health priority in a 2017 WHO resolution. Diagnosis of this disorder is
challenging because the clinical signs and symptoms of systemic inflammation in sepsis
overlap with those of non-infectious critical conditions i.e. severe inflammatory response
syndrome (SIRS) e.g. cardiac arrest and burns. Early and accurate diagnosis of sepsis is
critical for improving patient outcomes and reducing antibiotic usage. Delays in antibiotic
administration are associated with worse outcomes; however paradoxically, indiscriminate
prescription of antibiotics to patients without bacterial infections increases both rates of
morbidity and antimicrobial resistance. The rate of inappropriate antibiotic prescriptions in
the hospital setting is estimated at 30 to 50% and would be decreased by access to improved
diagnostic tests.
There is currently no gold standard laboratory test that can broadly determine the presence
and type of infection. Although new polymerase chain reaction (PCR)-based molecular
diagnostics can profile pathogens directly from blood culture, they suffer from sensitivity
issues due to dependence on sufficient numbers of pathogens in the blood sample. They are
also limited to detection of a discrete range of pathogens. As a result, there is a growing
focus on molecular diagnostics that profile the host immune response. Current sepsis
groupings are based on clinical criteria such as the presence of shock, infection source, or
organ failure, but such groupings may not represent the underlying biology driving the host
response. They have also failed to adequately match patients for novel interventions. If the
heterogeneity of sepsis truly reflects heterogeneity in the host response, characterisation
of these underlying host response types will be fundamental to enabling precision sepsis
therapeutics.
In a previous multi-centre, clinical-temporal study in three cohorts of patients admitted to
the intensive clinical care unit (ICU); (i) out of hospital cardiac arrest (n=36 - SIRS
group)) (ii) pulmonary sepsis (n=84) (iii) abdominal sepsis (n=64) and 30 healthy controls,
validated potential host immune biomarkers. Using 202 samples from these cohorts, the
investigators derived a set of gene biomarkers which can identify patients with severe
inflammation and discriminate sepsis from non-infected inflammation across a broad range of
clinical conditions. Other biomarkers have been identified for use for other purposes e.g.
prognosis/severity. Our patent arising from this work has been filed and entered PCT stage.
From these patented markers a parsimonious set of 17 genes has been further delineated, which
are under further evaluation. A sub-panel of two gene entities has been identified that can
accurately detect severe inflammation using receiver operating characteristic/area under the
curve (ROC) analysis with a value of approximately 0.98. A panel of three/four gene entities
has been identified for discrimination of SIRS from all sepsis types (ROC 0.89-0.92), all
depending on sensitivity or specificity range settings.
Better diagnostics for sepsis-driven inflammation are needed in both inpatient and outpatient
settings. In low-acuity outpatient settings, contributing circa 80% of total UK antibiotic
use, a simple diagnostic to discriminate a septic inflammatory process from an innocuous,
self-limiting condition, would assist in appropriate antimicrobial use, appropriate triage,
avoiding further investigations, and appropriate escalation / admissions. In higher-acuity
settings, causes of non-infectious inflammation are important to exclude; a decision model
for antibiotic prescription should include a non-infected, non-healthy cause. A reliable
diagnostic, such as ours, needs to distinguish all three presentations: non-infected
inflammation, sepsis, and relative health. It will represent a major step-change in provision
of diagnostic/stratification capability, vastly improve decision and patient management
pathways and potentially reducing antibiotic overuse in the acute medical and critical-care
environment.
These biomarkers once validated in an independent cohort via qPCR for mRNA and their
commensurate proteins, together with an accompanied easy-to-use, clinically oriented scoring
system will represent a complete data package which can be rolled out internally, subject to
the appropriate further accreditation and/or leveraged for development of point-of-care
devices by commercial partners. This latter option could prove useful for dissemination of
the test to other patent-appropriate global territories.
There is an urgent need to validate these findings in several ways; Using an independent
patient cohort, where laboratory scientists are blinded to the clinical phenotypes of the
recruited patients and clinicians are not aware of the gene expression data.
Using a bioinformatics approach to validate the results in already published datasets
This project will use different approaches to validate these novel SIRS or sepsis-associated
biomarkers identified by Artificial Neural Network (ANN) and parametric data mining of
previously published datasets and further validated previously from a previous well
characterised clinical cohort;
1. Public Health England laboratories will assess biomarker mRNA expression using a qPCR
approach, with RNA purified from patient and control whole blood
2. Public Health England and Cardiff laboratories will assess protein biomarkers using
ELISA assays
3. Proteomic analysis of blood by external collaborators
Further data analysis will be conducted using ROC curve analysis and arithmetic algorithms
and/or other statistical/bioinformatics methods. Assessment of specificity and sensitivity
and positive and negative predictive values using well established methods will also be
conducted to evaluate the performance of the biomarker panels in discriminating patient
control and disease groups.
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