Immune response in sepsis mapped in new study

The immune response in people with sepsis, which changes over time, has been mapped in a new study, which could pave the way for more targeted treatments for this life-threatening condition.

Dr Yasmeen Ghnewa, Lecturer in Immunology in the Department of Bioscience at the University of East London (UEL), contributed to an international study led by King's College London that could help identify treatments targeting specific immune changes at the most appropriate stage of a patient's illness.

Sepsis is a life-threatening condition that occurs when there is misfiring of the immune response to infection. In sepsis, there is failure of the vital organs, and it can be fatal even when treated quickly. It’s estimated that there are over 160 million cases and about 21 million deaths from sepsis worldwide each year.

Current treatments for sepsis focus on treating the underlying infection with antimicrobials and providing supportive care for failing vital organs. Despite efforts to treat the misfiring immune system, none have been successful at achieving improved outcomes for patients.

In the new study, published today in Immunity, researchers sought a more detailed understanding of the immune response mechanisms that change over time in patients with sepsis. 

They analysed blood samples collected at four different timepoints (between admission to and discharge from critical care) from critically ill patients with sepsis at Guy’s and St Thomas’ NHS Foundation Trust. To build a detailed picture of the immune response, called an ‘immune profile,’ the researchers looked at multiple layers of immune response information in the blood samples, including data on immune cells, gene expression and protein expression analyses that are changing.

Dr Ghnewa played a key role in establishing and optimising the flow cytometry methods used in the study. Flow cytometry is a sophisticated laboratory technique that uses lasers and fluorescent markers to identify and measure different types of immune cells. She processed patient samples, performed the analyses and helped ensure the quality and reproducibility of the data. The resulting immune cell profiles provided important insights into how the immune response changes during sepsis and recovery.

Using machine learning approaches, they then combined these layers of information to generate a more comprehensive immune profile for the first time in patients with sepsis. 

The analyses revealed an immune trajectory that had three distinct, temporal immune states (referred to as STImS) between admission and recovery, with each state involving different immune cell activity, and immune response programmes. 

Importantly, these sepsis immune states didn’t match to the clinical stage of sepsis. For example, the 'early’ immune state (STImS1) was not the same as the early clinical stage of sepsis, which is often the day a clinician diagnoses sepsis.
The researchers say these findings could have important implications when considering how best to treat sepsis patients – specifically with what treatments and when.

Dr Matthew Fish, former PhD student at King’s College London and lead author of the paper, said: 
 

The main aim of this work was to build a profile of sepsis immune responses over time. When people are admitted to hospital with sepsis, they are usually classed as having ‘early’ sepsis – but our findings show that this isn’t necessarily the case – their immune system may already be at stages of the immune response. Knowing exactly what is happening to a patient’s immune system during sepsis could identify which treatments are likely to work best.”

The authors say the next step for this work is to understand what causes changes in the immune system between onset of infection to the development of sepsis.  Understanding these changes could help identify new treatment targets and approaches to reduce either the progression to sepsis or the severity of sepsis, with the potential to improve outcomes and make a difference to lives of millions affected by serious infections worldwide