Title: Personalised Medicine in Sepsis
Funder: Department of Health and Social Care

Abstract: BackgroundSepsis is a major global healthcare problem with recent estimates of >19 million cases and >5million deaths worldwide each year and costs to the NHS of >2 billion annually. Despite extensive efforts there have been no new treatments developed that have demonstrated clear improvement in outcomes for patients with sepsis. The current main treatment strategies are broad-spectrum antibiotics, fluid resuscitation and adrenergic drugs to maintain cardiovascular support. However, there are problems with these treatments. Delayed or incorrect antibiotics increase mortality but unnecessary antibiotics increase antimicrobial resistance, another major global threat. Adrenergic drugs have serious side-effects, especially at higher doses. It is now recognised that sepsis describes a very heterogeneous group of patients with very different underlying pathophysiological processes and different treatment needs. Therefore, development of novel personalised medicine tools to tailor treatments for individual patients is of paramount importance. Aims To investigate the use of novel diagnostic approaches to provide personalised medicine strategies in sepsis. Specifically I will address the following research questions: Do known functional genetic polymorphisms affect response to common vasopressor and inotropic drugs? Are there sub-phenotypes of sepsis that have different treatment requirements? Can we use rapid point-of-care diagnostics to identify infecting bacteria and improve our antibiotic stewardship? Plan of investigation Using existing collected DNA samples (n=4500) from international large sepsis observational studies and randomised controlled trials (RCT) I will test the effect of known functional polymorphisms of relevant candidate genes on the management of shock. I will test for the effect of genotype on drug dose required to maintain blood pressure, survival and adverse event rates. Within the RCTs I will test for a genotype x drug interaction. I will define sub-phenotypes of sepsis patients in two independent sepsis trials (n=700). I will use transcriptomic, multiplex cytokine and metabolic profiles to stratify the sepsis patients and assess their outcomes, as well as their response to different treatment strategies. Conduct a feasibility trial of a rapid point-of-care diagnostic to sequence bacterial DNA in blood from patients in intensive care. I will compare the new test against current laboratory tests in terms of accuracy and speed. I will assess how this additional information changes clinical practice and explore the route to adoption in the NHS. Design novel trials that more efficiently test new therapies in sepsis and in particular incorporate a stratified medicine approach. Potential benefits to patients and the NHS. Sepsis has profound consequences for individuals, their families and cost to the NHS. If patients survive severe sepsis, they will have a long period of recovery and for some, a long-term disability to contend with. My research is designed to give patients the chance of the best outcome by allowing treatment to be tailored specifically for individual needs. The pharmacogenetic work will allow better selection of different vasopressors and inotropes for different patients and allow blood pressure targets to be optimised for individuals. Combined with the identification of sub-phenotypes of sepsis and testing of rapid point-of-care diagnostics, this programme of research will allow existing and novel treatments to be given to patients most likely to benefit. I will then test these interventions in more efficient trial designs that will speed up the translation of research into better survival rates for patients. Finally rapid pathogen detection at the bedside will allow clinicians to provide better outcomes for patients while still reducing the burden of antimicrobial resistance. These innovative approaches are needed to improve the treatment options for patients, because we have not made significant advances in sepsis treatment using conventional methods in recent decades.

Lay abstract: The overall aim of this research programme is to develop a personalised medicine strategy for patients with sepsis to allow us to treat patients as individuals, selecting the most appropriate treatments for them and improve their outcome. BackgroundSepsis is the body's response to severe infection. It is very common worldwide and has a high death rate. In the UK alone, more than 120,000 patients are admitted to intensive care units (ICU) with sepsis each year and the NHS spends more than 2billion caring for them. Sepsis can be difficult to diagnose initially and can progress to a critical illness very quickly. Patients are very ill once they reach the ICU, but current practice is to treat all patients with a similar regime (antibiotics, intravenous fluid resuscitation and powerful adrenaline-like drugs to support the heart and blood pressure). However, there are problems with these treatments. If antibiotics are delayed or the wrong antibiotics are given while laboratory tests are carried out, then death rates are higher. If doctors use very powerful antibiotics too often, bacteria become resistant to them, and there is a serious concern that soon we will have infections that will become resistant to all antibiotics. The adrenaline-like drugs are very effective at supporting the heart and blood pressure but we know they have serious side-effects in some patients. Aims, Design, Methods It is vital that we provide individual treatment to patients with sepsis to ensure they have the best chance of survival. My research aims to do this through modern technology, specifically: To test if the known differences in our genetic make-up mean patients respond differently to the adrenaline-like drugs used to treat sepsis. I will test this in 4500 DNA samples, already collected from patients with sepsis from international sepsis studies and trials. I will test if, based on these genetic variations, some patients require alternative drugs or different doses of the drugs to support the heart and blood pressure, and if this treatment effects their survival and causes less problems for them. In the samples from the previous drug trials we will be able to test if patients respond differently to these treatments based on their DNA variations. To identify different groups of sepsis patients based on known patterns of gene expression (the type and amount of message that comes from the gene and determines what and how much protein is made), protein levels and chemicals in the blood, and test if these groups respond differently to treatments. I will use 700 blood samples that I have already collected and will examine how these patients respond differently to sepsis and if they respond differently to different treatments. To assess new technology in tests, which can be done rapidly in the ICU, to identify the cause of infection more quickly and therefore target it with the most effective antibiotic. In 500 patients I will compare these new results to current tests, (which usually take 48 hours to be ready) checking the accuracy and speed of the result as well as the potential to improve patient care. I will also explore the best way to use this new test within the NHS. To improve sepsis clinical trials. I will work with experts in trial design to develop new sepsis trials (focusing on new tests to provide the best individual treatment) that are more efficient and cost effective in providing answers about which treatments work best. Patient and public involvement (PPI) I have discussed and sought opinion about this work from ICUsteps (the ICU patient and relative support charity), a former sepsis patient and a relative of a patient who had sepsis. They have confirmed the importance of targeted treatments for sepsis. As in my other trials, PPI will be an integral part of this work. I will invite two PPI representatives with experience of sepsis to be on the steering group, and will also approach charities such as ICUsteps and the UK Sepsis Trust for opinions on specific issues. Dissemination The results of this programme of work will be published in medical journals, presented at major international conferences and published on our webpages, including lay summaries. I will also work with patient groups, the media and science exhibitions to ensure that this cutting-edge research is understood and implemented by as wide an audience as possible.

Research activity codes: 4.2 EVALUATION OF MARKERS AND TECHNOLOGIES;6.1 PHARMACEUTICALS;6.2 CELLULAR AND GENE THERAPIES
Health categories: INFECTION;INFLAMMATORY AND IMMUNE SYSTEM