| dc.description.abstracteng | Background: Each year, millions of people die from sepsis or its consequences. Sepsis is defined as a life-threatening condition based on a dysregulated immune response to an infection. Thus, investigating the complex pathophysiology of sepsis and improving its diagnosis and treatment are of international significance. Previous studies revealed the fundamental role of negative co-stimulatory T-cell inhibitors like T cell immunoglobulin and mucin domain-containing protein 3 (TIM-3) and lymphocyte-activation gene 3 (LAG-3) in the clinical phenotype and outcome of sepsis. TIM-3 and LAG-3 are specific membrane proteins which, upon interacting with their ligands, can lead to T-cell inhibition and restoration of immune homeostasis during sepsis. This study investigated the impact of the functional single nucleotide polymorphisms (SNPs) TIM-3 rs1036199, TIM-3 rs10515746, LAG-3 rs870849 and LAG-3 rs951818 on the outcome of patients with sepsis.
Methods: A total of 712 patients with sepsis were prospectively enrolled from three intensive care units at the University Medical Center Goettingen since 2012. All patients were genotyped, clinically observed for 28 days, and their survival was assessed 90 days after sepsis onset. The primary outcome was the 28- and 90-day mortality. Disease severity and microbiological findings were secondary endpoints.
Results: Kaplan-Meier survival analysis demonstrated a significantly higher 28-day survival for TIM-3 rs1036199 AA homozygous patients compared to C-allele carriers (82% vs. 73%, p = 0.0099) and TIM-3 rs10515746 CC homozygous patients compared to A-allele carriers (82% vs. 74%, p = 0.0202). Furthermore, there was a significantly higher survival rate among the LAG-3 rs951818 AA homozygous patients at 83 %, compared to C-allele carriers at 76 % (p = 0.0476). The TIM-3 rs1036199 AA and rs10515746 CC genotype remained significant predictors for the 28-day mortality in the multivariate Cox regression analysis after adjusting for relevant confounders like age, BMI, etc. (p = 0.0175, HR 0.6703; p = 0.0310, HR = 0.6958). Additionally, it was observed that individuals with the TIM-3 rs1036199 AA genotype exhibited significantly more infections with gram-positive bacteria and Staphylococcus epidermidis in particular (p = 0.0445, p = 0.0295). Concurrently, a higher incidence of Staphylococcus epidermidis infections was detected in the TIM-3 rs10515746 CC homozygotes (p = 0.0313).
Conclusion: This study is the first to demonstrate a positive impact on the outcome of sepsis in patients with the TIM-3 rs1036199 AA and rs10515746 CC genotype. Further research on the pathophysiological mechanisms of sepsis may be key to early identification of at-risk patients and a more personalized approach to sepsis. | de |