Changes in the behaviour of monocyte subsets in acute post-traumatic sepsis patients.

Trauma remains a major public health problem worldwide, marked as the fourth leading cause of death among all diseases. Trauma patients who survived at initial stages in the Emergency Department (ED), have significantly higher chances of mortality due to sepsis associated complications in the ICU at the later stage. There is paucity of literature regarding the role of circulating monocytes subsets and development of sepsis complications following trauma haemorrhagic shock (THS). The study was conducted to investigate the circulating level of monocyte subsets (Classical, Inflammatory, and Patrolling) and its functions in patients with acute post-traumatic sepsis. A total 72, THS patients and 30 age matched healthy controls were recruited. Blood samples were collected at different time points on days 1, 7, and 14 to measure the serum levels of cytokines by Cytometric bead assay (CBA), for the immunophenotyping of monocytes subsets, and also for the cell sorting of monocytes subsets for the functional studies. The circulating levels of monocytes subsets were found to be significantly differs among THS patients, who developed sepsis when compared with others who did not. The levels of patrolling monocytes were elevated in THS patients who developed sepsis and showed negative correlation with Sequential organ failure assessment (SOFA) score on days 7 and 14. Classical monocytes responded strongly to bacterial TLR-agonist (LPS) and produced anti-inflammatory cytokines, whereas patrolling monocytes responded with viral TLR agonist TLR-7/8 (R848) and produced inflammatory cytokines in post-traumatic sepsis patients. In conclusion, this study shows disparity in the behaviour of monocytes subsets in patients with acute post-traumatic sepsis.

Estrogen as a Safe Therapeutic Adjunct in Reducing the Inflammatory Storm in Trauma Hemorrhagic Shock Patients.

ABSTRACT: Trauma is a major cause of death and disability throughout the world. It is a leading cause of death with or without sepsis in about 50% of patients. Limited therapeutic options are available besides definitive care with a mortality benefit. Preclinical studies have demonstrated the mortality benefit of estrogen in trauma hemorrhagic shock (THS). Based on encouraging results from preclinical studies, we hypothesized that early administration of estrogen in male THS patients may reduce the inflammatory storm, prevent sepsis-associated problems, and subsequently reduce mortality. The authors studied the safety of early administration of estrogen as a therapeutic adjunct in the emergency department (ED) and its effects on the inflammatory storm, prevention of sepsis, and mortality during the intensive care unit stay. Forty THS patients were recruited. THS patients were divided into experimental and placebo control groups based on the estrogen administration in the ED. Serum levels of cytokines and immune cells were measured at different time points on days 0, 3, 7, and 14 in both groups of THS patients. The experimental group received intravenous estrogen (25 mg) at a single time point in the ED beside standard of care as per advanced trauma life support guidelines. Patients did not develop any major or minor adverse events and showed favorable clinical outcomes in the experimental group. The levels of T regulatory cells, monocytes, and systemic cytokines significantly reduced and showed a balanced inflammatory response in THS patients who received estrogen.In conclusion, this preliminary study showed that intravenous estrogen therapy is safe and reduced the inflammatory insult due to trauma hemorrhagic shock. It may protect THS patients from sepsis-associated complications. Future clinical trials are required to study the efficacy and mechanistic pathway.

Clinical relevance of single nucleotide polymorphisms within the 13 cytokine genes in North Indian trauma hemorrhagic shock patients.

INTRODUCTION: The susceptibility to adverse outcome from critical injury (occurrence of sepsis, septic shock, organ dysfunction/failure, and mortality) varies dramatically due to different degrees of inflammatory response. We assessed the relationship of the genotype distribution of various cytokine gene polymorphisms (CGP) with regard to the development of sepsis, organ dysfunction or mortality in severely injured patients. METHOD: Observational, hospital-based cohort study of 114 severely injured North Indian patients from New Delhi admitted to the Emergency Department (ED) of Trauma Centre, AIIMS. Patients were monitored from day first to discharge or death, measuring SOFA score, sepsis and septic shock occurrences up to one month. We have analyzed 13 cytokine genes, including the SNPs of structural and regulatory regions at 22 positions. RESULTS: Sequence-specific primer based PCR indicated that eight polymorphic loci IL-1α /-889, IL-1ß/-511, IL-1R (pstI 1970), TGF-ß/ code 10, TNF-α/-308, TNF-α/-238, IL-6/+565 and IL-10/-1082, out of 22 SNPs are significantly associated with sepsis morbidity and outcome. Theses SNPs might be used as risk determinants of the outcome. Patients with IL-10 (-1082A/A) genotypes were found significantly higher in post traumatic sepsis patients and had a significantly higher risk to developed sepsis complication (p < 0.05, OR = 0.86, C.I = 0.08-8.8).In case of TNF-α (-308) position, GA and GG genotype patients have a significantly lower risk of poor outcome (p < 0.05, OR = 0.25, C.I = 0.01-1.3) and (p < 0.05, OR = 0.22, C.I = 0.01-0.5) in comparison to AA genotype. In this study, two polymorphisms (IL-1ß (-511) and IL-1R) were significantly associated with the development of MOF and mortality, where as IL-1α (-889) polymorphism associated with susceptibility for sepsis. The distribution of haplotypes of TGF-ß and IL-6 were also associated with sepsis susceptibility and outcome. CONCLUSION: In conclusion, we have found that the alternations in the genotype and allele frequency of IL-1ß (-511C/T), TNF-α (-308 G/A), TNF-α (-238 G/A) and IL-10 (-1082 G/A) genes are associated with an higher risk of sepsis development in trauma patients and outcomes.