Almost all type of pathogens – bacteria, fungi, parasites, and viruses – can aggravate the life-threatening condition, which leads to the body’s immune system overreacting and attacking its own tissues and organs. Sepsis is difficult to diagnose and even more difficult to treat. Duke scientists have discovered a biomarker of the runaway immune response to sepsis that could improve early diagnosis, prognosis, and treatment to save lives.
Facts and Figures:
The 20th century witnessed a remarkable decrease in infectious disease deaths. Although a great deal of the decline was due to improved sanitation, early antibiotics, resuscitation, and supportive hospital care have also played major roles, particularly in improving outcomes in bacteremia and sepsis.
- With sepsis mortality, still up to 5.3 million people each year, there has long been hoping that this therapeutic arsenal could be complemented by host-directed sepsis therapies.
- However, failures in more than 100 clinical trials aimed at modulating the immune response in sepsis have demonstrated that a better understanding of host biology and differences in clinical factors is necessary.
According to a 2012 study, sepsis affects one in four in intensive care units (ICUs) across the country every year. Very few people know the key warning signs.
The study – Indian Intensive Care Case Mix and Practice Patterns (INDICAPS) – based on a sample size of 4,209 patients, including 171 children, admitted to 124 ICUs across 17 states, showed that 26% patients in ICUs contracted sepsis. The mortality rate in patients with sepsis is 42.2%.
People with sepsis are typically treated with a combination of antibiotics and supportive care, treatments that target the pathogens but do nothing to address the runaway immune response that, ironically, proves more deadly than the infection itself.
- Metabolite markers are particularly attractive for this goal because they serve to integrate multiple inputs (transcriptional, translational, and environmental) into an active biomolecule that can have large effects on physiology.
- On the other hand, genetic markers of susceptibility have the advantage of not changing during the course of the disease, making the direction of causation for true genetic associations unambiguous.
- Therefore, an improved understanding of human genetic differences that contribute to regulation of metabolite levels could powerfully couple the larger effect sizes of metabolites to the causality of genetic variants for prioritizing and designing interventions.
Discovery of methylthioadenosine (MTA)
One component of the host response that has received significant interest in characterizing and possibly treating sepsis is the activation of inflammatory caspases.
- Reliable sepsis biomarkers could improve diagnosis, prognosis, and treatment. Integration of human genetics, patient metabolite, and cytokine measurements, and testing in a mouse model demonstrate that the methionine salvage pathway is a regulator of sepsis that can accurately predict prognosis in patients.
- Pathway-based genome-wide association analysis of nontyphoidal Salmonella bacteremia showed a strong enrichment for single-nucleotide polymorphisms near the components of the methionine salvage pathway.
- Measurement of the pathway’s substrate, MTA, in two cohorts of sepsis patients demonstrated increased plasma MTA in non-survivors.
- Plasma MTA was correlated with levels of inflammatory cytokines, indicating that elevated MTA marks a subset of patients with excessive inflammation.
- A machine-learning model combining MTA and other variables yielded approximately 80% accuracy (area under the curve) in predicting death.
- The results demonstrate how combining genetic data, biomolecule measurements, and animal models can shape our understanding of the disease and lead to new biomarkers for patient stratification and potential therapeutic targeting.
MTA thus can predict which patients are most likely to die from the illness.
This could help determine whether patients could benefit from therapies that either enhance or suppress the immune system, paving the way for new treatments.
- Todi, S., Chatterjee, S., Sahu, S., & Bhattacharyya, M. (2010). Epidemiology of severe sepsis in India: an update.Critical Care, 14(S1), P382.
- Wang, L., Ko, E. R., Gilchrist, J. J., Pittman, K. J., Rautanen, A., Pirinen, M., & Salinas, R. E. (2017). Human genetic and metabolite variation reveals that methylthioadenosine is a prognostic biomarker and an inflammatory regulator in sepsis. Science Advances, 3(3), e1602096.
Read more at: https://www.docplexus.in/#/app/posts/68220ab3-c686-4ce5-8831-1808b1e738f7
Copyright 2017 © Docplexus