Personalised Medicine in Sepsis

Background Sepsis 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.