Long-term Quality Of Life And Predictive Value Of Circulating Nucleosomes In Sepsis

Part1Long-term quality of life in severe sepsis survivors:up to6years multicenter study in ChinaObjectives:The present study was undertaken to evaluate the long-term health-related quality of life (including physical functioning; role-physical; bodily pain; general health; vitality; social functioning; role-emotional and mental health) in survivors of severe sepsis up to6years. Additionally, returning to work/school was assessed.Methods:From January2004to December2008,112severe sepsis and112age-, gender-and Charlson comorbidity index-matched non-septic critically ill patients from4university hospital ICUs were enrolled. Totally66(58.9%) severe sepsis and80(71.4%) non-septic critically ill patients survived during the long-term follow-up time. Between August and December2010, a total of75patients, including42survivors of severe sepsis and33critically ill controls completed the face-to-face interview. Meanwhile,126age-and gender-matched community residents were interviewed as community control group.Results:There was no difference in the long-term HRQOL in terms of Short-Form36between severe sepsis and non-septic critically ill survivors. However, when compared with that in community controls, HRQOL in survivors of severe sepsis showed a significantly and clinically meaningful decrease, with a lower physical functioning (P=0.016), vitality (P=0.037), role-emotional (P=0.043), mental health (P=0.038) and mental component score (P=0.042). No difference was found with respect to anxiety or depression between severe sepsis and critical ill control (anxiety:9.52%vs.9.09%; depression:11.90%vs.9.09%). In addition, returning to work at1year and by the time of interview in severe sepsis were similar with that in critical illness (60.5%vs.70.0%, P=0.417,71.1%vs.76.7%, P=0.602). The patients who returned to work/school had better HRQOL in physical and mental domains than the patients who didn't.Conclusions:The HRQOL in severe sepsis was impaired even up to6years after hospital discharge and the employment status was related to the HRQOL. However, no difference was found between severe sepsis and non-septic critically ill survivors in the long-term HRQOL, anxiety, depression, or return to work. Part2Dynamic changes of apoptosis and inflammatory factors in sepsisObjectives:Sepsis is a leading cause of death in critically ill patients, and apoptosis plays a major role in the pathophysiology of sepsis. The aim of this study was to evaluate the apoptosis of spleen tissue and the level of inflammatory factors in sepsis.Methods:Balb/c mice were randomly divided into sepsis group and sham group. In sepsis group, mice received cecal ligation and puncture (CLP) to induce sepsis. In the sham group, the cecum is exteriorized but neither ligated nor punctured. Mice of both groups were sacrificed at12,24,72,168hours after CLP. Spleens and blood were collected from every mouse. Apoptosis was determined by terminal deoxynucleotidyl transferase-mediated dUTP nick-end-labeling (TUNEL). The plasma levels of IL-10, TNF-α,IL-4and IL-β were determined by enzyme-linked immunosorbent assay (ELISA).Results:At12,24,72and168hours, the mortalities were10%,46%,70%and80%, meeting the death rate requirements for sepsis models. Pathological changes were observed in the multiple organs of septic mice.. In the sham group, at168hours, the survival rate was100%. The apoptosis index (AI) of spleen cells significantly increased at12,24,72and168hours after CLP (P<0.001). The plasma level of IL-10. TNF-α, IL-4and IL-1(3were significantly increased12hours after CLP (P<0.001). In addition, the plasma level of TNF-a (P=0.046) and IL-1β (P=0.035) were still significantly increased24hours after surgery in the septic mice than the sham group. The apoptosis index of spleen cells was associated with the plasma level of IL-1β(r=0.976, P=0.024). Conclusions:In the early stage of sepsis, the apoptosis index of spleen cells and the plasma level of IL-10,TNF-α,IL-4and IL-β were significantly increased in the septic mice than the sham controls. The variation tendency of apoptosis index was similar with the plasma level of IL-10,TNF-α,IL-4and IL-β.In addition, the variation tendency of apoptosis index was consistent with the change of IL-1β. Part3Circulating Nucleosomes as a Predictor of Sepsis and Organ Dysfunction in Critically Ⅲ PatientsObjectives:Sepsis is a leading cause of death in critically ill patients, and apoptosis plays a major role in the pathophysiology of sepsis. Elevated levels of circulating nucleosomes released by apoptotic cells have been detected in patients with severe sepsis and septic shock. The aim of this study was to evaluate the diagnostic/prognostic value of circulating nucleosomes in sepsis.Methods:Seventy-four newly admitted patients who were estimated to stay for more than48hours in intensive care unit were prospectively enrolled as Cohort1. The second independent cohort consisted of91post-surgery patients. Patients with chemotherapy, AIDS, steroids treatment, or transplants were excluded. Levels of circulating nucleosomes within24-hour of admission in both of the cohorts, and on the3rd,5th,7th day and a last time-point at ICU discharge or at imminent death in Cohort1were measured and analyzed for the capacity of predicting sepsis. Severity of inflammatory response and organ dysfunction was assessed by cytokine levels and sepsis scores.Results:The nucleosomes levels on admission in septic patients were significantly higher than those in non-septic controls in both of the cohorts. The area under the receiver-operating-characteristic curve for admission nucleosomes levels to differentiate the septic patients from non-septic patients was0.70(95%confidence interval [CI]0.59-0.83) in Cohort1and0.66(95%CI0.51-0.81) in Cohort2, and0.67(95%CI0.55-0.79) in all of the subjects. After multiple logistic regression analysis, circulating nucleosomes remained as an independent predictor for sepsis. Furthermore, the levels of circulating nucleosomes on admission were significantly correlated with the inflammatory response and organ dysfunction in sepsis. Meanwhile, a trend that the admission levels of circulating nucleosomes in non-survivors were higher than those in survivors was observed.Conclusions:Serum circulating nucleosomes has a predictive value for sepsis and organ dysfunction, and may serve as a candidate biomarker for diagnosis/prognosis of sepsis. Further studies are warranted to confirm the present findings. Sepsis, a systemic inflammatory reaction to infections, is associated with substantial morbidity and mortality. During the infection, the innate immune response plays a crucial role in satisfactory host resolution of infection. As we know, neutrophils are important effector cells in the immune system's arsenal against invading pathogens. In addition to the phagocytosis and killing microbes upon phagolysosomal fusion, activated neutrophils release granule proteins and chromatin to form fibres called neutrophil extracellular traps (NETs). NETs are abundant at inflammatory sites and can efficiently bind, engulf, and kill both Gram-positive and Gram-negative bacteria, fungi and parasites extracellularly. Interestingly, some pathogens are captured, but not killed in NETs through DNases damaging the structure of the NETs as well as an antiphagocytic capsule. During sepsis, both neutrophils and platelets are actived, and together they cooperate to fomating NETs, which trapping bacterials in the vasculature and also inducing damage in tissue.