New Endotype Discovery Sheds Light on Deadly Sepsis Immune Response

Medical News: A breakthrough discovery in sepsis research is offering new hope in understanding and treating this life-threatening condition. A team of researchers from Greece, Germany, and Italy has uncovered a previously unknown endotype that plays a crucial role in the deadly immune response seen in sepsis patients. Their findings could pave the way for more effective and targeted treatments for sepsis, which affects millions of people worldwide each year.


New Endotype Discovery Sheds Light on Deadly Sepsis Immune Response

Understanding Sepsis and Endotypes
Sepsis is a severe condition that occurs when the body's immune system overreacts to an infection, leading to widespread inflammation, organ failure, and, in many cases, death. Despite advances in medical care, sepsis remains a major cause of mortality in hospitals around the world.
 
Endotypes, or distinct biological subtypes within a disease, are becoming an increasingly important focus in medical research. By identifying specific endotypes, researchers can better understand the underlying mechanisms of a disease, allowing for more personalized treatment approaches.
 
In the case of sepsis, two major endotypes have been previously recognized: macrophage activation-like syndrome (MALS) and sepsis-induced immunoparalysis. However, as covered in various past Medical News reports, a significant number of sepsis patients do not fit neatly into these categories, prompting researchers to continue their search for additional endotypes.
 
The New Endotype: Interferon-Gamma Driven Sepsis
In this new study, scientists identified a third major endotype in sepsis patients, one that is driven by the cytokine interferon-gamma (IFNγ). The endotype, known as IFNγ-driven sepsis (IDS), is characterized by elevated levels of both IFNγ and a specific chemokine called CXCL9, which plays a role in the immune system's response to infection.
 
The study was conducted by a collaboration of institutions, including the 4th Department of Internal Medicine at the National and Kapodistrian University of Athens Medical School, the Hellenic Institute for the Study of Sepsis in Greece, Jena University Hospital in Germany, and the Università Cattolica del Sacro Cuore in Italy. A total of 5,503 sepsis patients from these countries were studied in two separate cohorts: a discovery set and a validation set.
 
The researchers used blood samples taken within the first 24 hours of sepsis diagnosis to measure concentrations of IFNγ and CXCL9, along with other markers such as IP-10, soluble CD163, and ferritin. Based on these measurements, the team defined the new IDS endotype as patients having IFNγ levels greater than 3 pg/ml and CXCL9 levels above 2,200 pg/ml. The study revealed that this endotype is present in approximately 20% of sepsis patients.
 
High Mortality Rates Associated with IDS
One of the key findings of the study was that patients with the IDS en dotype had significantly higher mortality rates compared to other sepsis patients. In the discovery cohort, 43% of IDS patients died within 28 days of their sepsis diagnosis, while the mortality rate in the validation cohort was 40.4%. These figures highlight the deadly nature of this specific immune response in sepsis.
 
Furthermore, the study showed that IDS was an independent risk factor for death, even when other factors such as disease severity, organ dysfunction, and other sepsis endotypes were taken into account. This suggests that the presence of the IDS endotype is a strong predictor of poor outcomes in sepsis patients.
 
The Role of Interferon-Gamma and CXCL9
Interferon-gamma (IFNγ) is a protein that plays a key role in the immune system's response to infections. It is produced by various immune cells, including macrophages and lymphocytes, and helps to activate other immune cells to fight off pathogens. However, when produced in excess, IFNγ can cause harmful inflammation and tissue damage, which is what happens in IDS patients.
 
CXCL9, a chemokine that is produced in response to IFNγ, also contributes to the immune response by recruiting immune cells to the site of infection. However, like IFNγ, elevated levels of CXCL9 can lead to excessive inflammation, further damaging the body's tissues and organs. In the case of sepsis, this can result in multiple organ failure and death.
 
The study's findings indicate that the combination of high IFNγ and CXCL9 levels creates a deadly feedback loop in IDS patients, leading to severe inflammation and increased risk of death. Importantly, the researchers also found that reductions in IFNγ and CXCL9 levels within the first 72 hours of sepsis were associated with better outcomes, suggesting that early intervention to lower these levels could improve survival rates in IDS patients.
 
Implications for Sepsis Treatment
The discovery of the IDS endotype has important implications for the treatment of sepsis. Currently, sepsis treatment is largely focused on controlling the infection and supporting organ function, but this new research suggests that targeting the immune response itself could be a more effective approach for certain patients.
 
By identifying patients with the IDS endotype, doctors may be able to tailor treatments specifically to reduce IFNγ and CXCL9 levels, potentially preventing the deadly inflammatory response seen in these patients. This personalized approach to treatment could help to improve survival rates and reduce the overall burden of sepsis on healthcare systems.
 
The researchers also suggest that future clinical trials of sepsis treatments should take into account the presence of different endotypes, as treatments that work for one endotype may not be effective for others. For example, immunotherapies that suppress IFNγ activity could be beneficial for IDS patients, while other patients may require different types of interventions.
 
Conclusion
This groundbreaking study provides new insights into the immune response that occurs in sepsis and identifies a previously unknown endotype that is associated with significantly higher mortality rates. The discovery of the IDS endotype offers hope for the development of more targeted and effective treatments for sepsis, a condition that continues to claim millions of lives each year.
 
The study findings were published in the peer-reviewed journal: eBioMedicine.
https://www.sciencedirect.com/science/article/pii/S235239642400450X
 
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https://www.thailandmedical.news/news/macrophages-play-a-role-in-causing-endothelial-cell-dysfunction-in-sepsis