Genetic Signature Provides Early Prediction of Sepsis and Organ Failure

Dr R.E.W. (Bob) Hancock, OC, OBC, FRSC {Canada Research Chair and Professor, Department of Microbiology and Immunology,UBC} Director, Centre for Microbial Diseases and Immunity Research University of British Columbia, Vancouver, British Columbia,  CanadaMedicalResearch.com Interview with:
Dr R.E.W. (Bob) Hancock, OC, OBC, FRSC
{Canada Research Chair and Professor, Department of Microbiology and Immunology,UBC}
Director, Centre for Microbial Diseases and Immunity Research
University of British Columbia,
Vancouver, British Columbia,  Canada

MedicalResearch: What is the background for this study? What are the main findings?

Dr. Hancock: We wanted to understand how patients transitioned from the hyperinflammatory phase (cytokine storm) of sepsis to the hypoinflammatory (immunosuppressive) phase of sepsis (inability to respond appropriately to infections). About 15% of patients die in this first phase and 20% in the second phase, making sepsis one of the most deadly syndromes (35% overall mortality, 5 million deaths [8.3% of all deaths] annually worldwide). We hypothesized that immunosuppression was characterized by a state termed endotoxin tolerance a cellular amnesia (termed cellular reprogramming) in which cells fail to respond to microbial cues.

Overall we found that an Endotoxin Tolerance gene signature is significantly associated with the subsequent development of confirmed sepsis and new organ dysfunction in patients who had suspected sepsis. All 620 sepsis patients in retrospective and new analyses presented with an expression profile strongly associated with the endotoxin tolerance signature (p<0.01; AUC 96.1%). This occurred in fact very early in sepsis and in a new clinical study we found that the signature could be detected already in the emergency ward at first clinical  presentation and 24-48 hours prior to definitive diagnosis. Importantly, this signature further differentiated between suspected sepsis patients who did, or did not, go on to develop confirmed sepsis, and predicted the development of organ dysfunction.

MedicalResearch: What should clinicians and patients take away from your report?

Dr. Hancock: Severe sepsis and associated organ failure can be diagnosed very early on and accurately  in sepsis, despite the described extreme heterogeneity of this disease. The finding of an endotoxin tolerance profile in patients at first clinical presentation and up to day 3 has profound implications to understanding the mechanism underlying sepsis and might suggest that we need to alter the cellular reprogramming of immune cells (especially macrophages) rather than treating the hyperinflammatory phase (the latter has led to more than 30 failed clinical trials for immunosuppressive agents).

MedicalResearch: What recommendations do you have for future research as a result of this study?

Dr. Hancock: We need to confirm these findings in larger clinical trials and develop the final test format for clinical usage using MassTag PCR. We are interested in finding out if unlocking the endotoxin tolerant cells (presumably M2 macrophages) to produce M1 (normal anti-infective) macrophages can provide benefit to sepsis patients.

 

Citation:
Endotoxin Tolerance Signature Predicts Sepsis and Organ Dysfunction at Initial Clinical Presentation

Pena, Olga M. et al.

EBioMedicine Received: July 5, 2014; Received in revised form: October 6, 2014; Accepted: October 7, 2014; Published Online: October 22, 2014

DOI: http://dx.doi.org/10.1016/j.ebiom.2014.10.003