Investigation of the hyporesponsive endotype to inform a precision medicine approach to sepsis

What is being done?
This research aims to improve the care of patients with sepsis by providing new insights into the nature and drivers of the individual patient sepsis response. Our long-term goal is to help to develop a precision medicine approach to sepsis that allows the right patients to be getting the right treatment at the right time.

Why is this needed?
Sepsis occurs when the body's response to infection is dysregulated and inappropriate. This results in organ failure and sometimes death. Why this happens in some people is unclear and we have no current treatments that target this. Sepsis is the most common reason for admission to medical intensive care units in the UK and has a high mortality of 25-30%. This is a major current problem for the NHS and sepsis is recognised by the WHO as a global health priority.

How will this be done?
In this research we will use our finding that levels of gene activity in blood cells can predict your type of sepsis response. We will study sepsis patients with a hyporesponsive state as these patients have the worse outcomes and may benefit from specific immunomodulatory therapies. Our first objective is to work out how doctors can identify such patients with confidence by measuring biomarkers in the blood. Our second objective is to determine how this response may change over time during the sepsis illness. Our third objective is to understand genetic predisposing factors. Our fourth objective is to understand the nature of white blood cell dysfunction in the hyporesponsive sepsis state. Our fifth objective is to work with doctors undertaking clinical trials to use knowledge of the hyporesponsive state to help develop new treatments for sepsis. We will do this through the UK Genomic Advances in Sepsis study, applying big data (-omics) and clinical experimental medicine approaches.

Where will the work be done?
The work will be undertaken at the University of Oxford, Sanger Institute and Imperial College.

When will the work be carried out?
The work will be undertaken from 2020 to 2024.

The dysregulated host response that characterises the clinical syndrome of sepsis is recognised to be highly heterogeneous. Transcriptomics can be used to define specific sepsis disease endotypes based on gene expression signatures in peripheral blood, and in particular to identify patients with evidence of hyporesponsiveness (including immune cell tolerance and exhaustion) who have the worst outcomes. The ability to distinguish such patients provides a timely opportunity to progress towards a precision medicine approach to managing sepsis. This is important as disease heterogeneity currently limits therapeutic options and is a major contributory factor in the failure of clinical trials that have sought to modulate the host response in sepsis to improve survival. We aim to define this endotype with greater precision by consensus endotyping, determine the most informative RNA biomarkers, and investigate how the endotype evolves during the septic episode. We will investigate genetic drivers contributing to the endotype based on association with gene expression or endotype membership. We will then use single cell -omic approaches to determine the specific cellular drivers of the leukocyte transcriptomic signature, and investigate the nature and extent of cellular dysfunction during the acute septic illness and in survivors. Our final objective will be to assess the impact of knowledge of the hyporesponsive endotype on the design and interpretation of a clinical trial investigating immune stimulation therapy. Our longer-term goal is to enable the development of therapies to modulate the host response in sepsis that can be appropriately timed and targeted to the individual patients most likely to benefit.

A. Beneficiaries of this research
This is translationally focused research with long term goals that will benefit a number of groups. These will include individual patients at risk of or who develop sepsis, through promoting a precision medicine approach and more effective therapeutic interventions; researchers in academia and the pharmaceutical industry though identification, characterisation and application of knowledge of the most severe sepsis disease endotype including in clinical trials; the citizens of the UK through better quality of life and health of the population by improved management of sepsis; and the UK government through reduced health care costs and promoting a healthier, more economically productive workforce.

B1. Potential impacts: patients at risk of or who develop sepsis
Sepsis is a devastating condition with a high mortality rate, which is a current area of unmet need for patients and their families. This research has the potential for very substantial impact through advancing a precision medicine approach to therapy in sepsis. We will do this by enabling the targeting of drugs to the right patients at the right time for maximal benefit by identifying the sepsis response state of the individual patient at that point in their illness. Moreover, the insights gained by this research will inform the development of new or more targeted therapies.

B2. Potential impacts: researchers in academia and industry
We will impact researchers by advancing knowledge of sepsis disease endotypes, together with new insights into drivers and mechanisms of the disease and how we can intervene in a targeted manner. The establishment of a consensus endotype and robust biomarkers is urgently needed given independent reports of overlapping endotypes while understanding of the disease natural history and mechanism is needed to inform development of therapies. The research will also provide impact through proof of concept for future clinical trials in sepsis. This will impact those working in research and the pharmaceutical industry through the ability to conduct rational drug trials in the setting of patient stratification, reducing current heterogeneity in the disease phenotype.

B3. Potential impacts: society, economics and government
Our work is of significant potential societal impact to the citizens of the UK, enhancing the quality of life and health of the population through better patient outcomes in sepsis including reduced mortality and hospital length of stay. There is the opportunity for impact by increasing the effectiveness of the NHS, reducing health care costs and promoting a healthy economically productive population. There is also an important opportunity to promote education and knowledge of sepsis among the public with significant potential impact for early disease recognition.