Using data collected in observational studies and clinical trials we are scanning the genomes of patients with sepsis to identify genetic variations, called single nucleotide polymorphisms (SNPs), that put patients at higher risk of poor outcomes from sepsis and septic shock. We predict that identification of these variants will allow us to identify biological pathways that we could target with current or novel treatments in those patients most at risk.

We have worked as part of the Genomic Advances in Sepsis (GAinS) consortium since in its inception. This group has analysed the RNA signatures, also known as the transcriptome, of patients with sepsis to define two patient groups. These Sepsis Response Signatures (SRS) are characterised by features suggestive of immune dysfunction in the SRS1 group compared to SRS2 and patients in the SRS1 group had worse outcomes than those in SRS2. More recently we have categorised patients from the Effect of Early Vasopressin vs Norepinephrine on Kidney Failure in Patients with Septic Shock (VANISH) randomized trail into one of these two groups based on measurements of RNA taken at entry into the study. Importantly, we found that those patients who were in the SRS2 group who were randomised to receive corticosteroids as part of the trial had worse outcomes than those patients in this group who received placebo. This finding suggests that being able to identify which RNA group a patients with septic shock is in could be used to determine which treatments thety are most likely to respond to. Ongoing work is aimed at understanding the biological mechanisms that underpin the SRS corticosteroid interaction and identifying ways that RNA profiles can be measured in the clinical environment.

Proteins involved in inflammation, known as cytokines, are important mediators in the development of sepsis and its complications. We are currently analysing panels of these proteins to understand what they can tell us about how patients respond differently to sepsis and its treatments. Trajectory analysis of cytokines measured during the VANISH trial have identified proteins that could be used to track response to steroids treatment and how combinations of drugs could be used to modify the circulating levels of these proteins and potentially improve outcomes from sepsis.

Metabonomics is the study of metabolic profiles or fingerprints measured in samples of bodily fluids collected from patients. These profiles can, not only give us insight into complex cellular processes, but also the impact of environmental factors such as diseases and treatments. Our group is exploring how we can use metabolic profiles measured in samples from patients with septic shock collected during clinical trials to better understand the pathophysiology of sepsis, identify groups of patients who may need specific treatments and track response to treatment and the initial infective insult. Our work has identified fatty acid metabolites that are involved in inflammation that are associated with organ failure and predict patients most at risk of death from septic shock.

Funders

• National Institute for Health Research (NIHR)
• NIHR Imperial Biomedical Research Centre
• Medical Research Council
• UK Intensive Care Society Research Prioritisation Award
• European Institute of Innovation & Technology (EIT) Health

Industry links

• BioMerieux 

• Genomic Advances in Sepsis (GAinS) consortium
• Knight Group, Wellcome Centre for Human Genetics, Oxford
• Davenport Laboratory, Wellcome Sanger Institute, Cambridge
• Imperial Centre for Antimicrobial Optimisation (CAMO)
• Imperial College MRC-NIHR National Phenome Centre

Internal

• Dr Beatriz Jimenez
• Dr Gonçalo Correia

External

• Prof. Julian Knight
• Dr Emma Davenport
• Dr Katie Burnham

Ms Humma Hussain

We are leading, in collaboration with the biotechnology company bioMérieux, on the IMmune Profiling of ICU pAtients to address Chronic Critical illness and ensure healThy ageing (IMPACCT) study. This study is testing the ability of a device that can profile patients’ RNA on the Intensive Care Unit in order to rapidly identify those patients with sepsis who are at highest risk of developing complications such as secondary infection and death. More details can be found here. 

Rautanen, A. et al. Genome-wide association study of survival from sepsis due to pneumonia: An observational cohort study. The Lancet Respiratory Medicine 3, 53–60 (2015).

Davenport, E. E. et al. Genomic landscape of the individual host response and outcomes in sepsis: A prospective cohort study. The Lancet Respiratory Medicine 4, 259–271 (2016).

Burnham KL, Davenport EE, Radhakrishnan J, Humburg P, Gordon AC, Hutton P, Svoren-Jabalera E, Garrard C, Hill AVS, Hinds CJ, Knight JC. Shared and distinct aspects of the sepsis transcriptomic response to fecal peritonitis and pneumonia. Am J Respir Crit Care Med 2017;196:328–339.

Antcliffe, D. B. et al. Transcriptomic signatures in sepsis and a differential response to steroids from the VaNISH randomized trial. American Journal of Respiratory and Critical Care Medicine 199, 980–986 (2019).

Antcliffe DB, Santhakumaran S, Orme RML, Ward JK, Al-Beidh F, ODea K, Perkins GD, Singer M, McAuley DF, Mason AJ, Cross M, Ashby D, Gordon AC. Levosimendan in septic shock in patients with biochemical evidence of cardiac dysfunction: a subgroup analysis of the LeoPARDS randomised trial. Intensive Care Medicine 2019; 45: 1392-1400

Antcliffe D, Jimenez B, Veselkov K, Homes E, Gordon AC. Metabolic Profiling in Patients with Pneumonia on Intensive Care. EBioMedicine 2017; 18:244-253.

Antcliffe DB, Wolfer A, O’Dea K, Takata M, Holmes E, Gordon AC. Profiling inflammatory markers in patients with pneumonia on intensive care. Scientific Reports 2018; 8(1):14736

Jones T, Janani L, Gordon A, Al-Beidh F, Antcliffe DB. A novel role for cytochrome P450 epoxygenase metabolites in septic shock, Critical Care Explorations 2022, 21;4(1):e0622