| Part 1 Epidemiological study of severe sepsis Objective:To determine the occurrence rate, outcomes, and the characteristics of severe sepsis in intensive care units in multiple medical centers within China and to assess the cost and resource use of severe sepsis. To investigate the risk factors for hospital mortality of severe sepsis.Methods:The criteria of severe sepsis in present study were based on the American College of Chest Physicians/Society of Critical Care Medicine Consensus Conference definition in 1992 and 2002. A prospective and observational study was conducted in intensive care units at ten university hospitals from December 1, 2004, to November 20, 2005. The statistical analysis was performed with SPSS 16.0 for Windows.Results:From December 1, 2004, to November 20, 2005, a total of 3655 critically ill patients were included in our study. Among these patients, 318 (8.68%) developed severe sepsis, 64.8% of which were men. The median age of patients with severe sepsis was 64 (47-74) years. Microbes had been isolated from 228 (71.7%) patients, including 171 (53.8%) with Gram-negative bacteria and 146 (45.9%) with Gram-positive bacteria. A total of 90 (22.0%) patients had invasive fungal infection. The abdomen was the most common site of infections (72.3%), followed by lung (52.8%), and more than half of the cases (59.1%) had infections in multiple sites. The median of APACHEⅡscore was 19 (14-25), and the median of admission SOFA score was 8 (6-12). The hospital mortality rate of severe sepsis was 48.7%. Risk factors for hospital mortality adopted in the final step of the multivariate Binary-logistic regression included age, chronic comorbidity of malignant neoplasm, Gram-positive bacterial infection, invasive fungal infection, initial Acute Physiology Score, and initial Sequential Organ Failure Assessment score of respiratory dysfunction and cardiovascular dysfunction. Each patient with severe sepsis spend approximately 7.58 (6.71-8.48) hrs each 8-hr nurse shift according to the Therapeutic Intervention Scoring System-28 score. The mean hospital cost was￥92259 per patient and￥4066 per patient per day. The mean daily cost for nonsurvivors was much higher than that for the survivors (￥6577±3491 vs.￥2438±1256, p< 0.001).Conclusion:Severe sepsis is a common, expensive, and frequently fatal syndrome in critically ill patients in China. Other than the microbiological patterns, the incidence, mortality, and major characteristics of severe sepsis in Chinese intensive care units are close to those documented in developed countries. A national data-base for sepsis would be helpful to fulfill longitudinal, large-scale national or international studies in sepsis, to allocate health resource, to improve the outcome of sepsis, to optimize healthcare quality, and to evaluate the effectiveness and efficiency of ICU utilization and care strategies. Part 2 Association study between CNPs within Defensin GeneCluster and severe sepsisObjective:To investigate whether copy number polymorphisms within defensin gene cluster in chromosome 8p22-23 is associated with the incidence and fatal outcome of severe sepsis by case-control association analysis, and to elucidate the mechanism of defensin in the pathophysiology of severe sepsis.Method:Quantitative real-time PCR was performed to study the copy number variation of DEFA1/DEFA3 gene and DEFB4 gene within the defensin gene cluster in 179 patients with severe sepsis and 233 healthy volunteers from Chinese Han people. The association of copy number polymorphisms within the defensin gene cluster with the incidence and fatal outcome of severe sepsis was analyzed by x~2 test or Fisher's exact test. Logistic regression was used to model the effect of copy number on the incidence of severe sepsis when gender and age were included as covariates. The statistical analysis was performed with SPSS 16.0 and GraphPad 3.0 for Windows. P<0.05 was considered statistically different.Results:The severe sepsis group consisted of 106 males (59.2%), with mean age of 59.9±17.5 yrs, among which 91 cases (50.8%) were dead in hospital. And the health controls consisted of 103 males (44.2%), with mean age of 48.2±13.0 yrs. In the controls, copy number of DEFA1/DEFA3 had a range of 2-15 per genome, with a median number of 7 copies. The median copy number of DEFA1/DEFA3 in the patients with severe sepsis was 9 copies per genome (range 4～16 copies), significantly higher than that in the controls (P<0.001). However, there is no significant difference between the copy number of DEFB4 in the control (a range of 2-13, with a median number of 5 copies) and severe sepsis (a range of 2-12, with a median number of 5 copies, P=0.20). Furthermore, there is no significant difference of the copy number of DEFA1/DEFA3 and DEFB4 genes between the survival severe septic patients and non-survivors. Additionally, multi-variables Binary-logistic regression analysis of the CNP adjusted for age and gender confirmed the association of the copy number polymorphism of DEFA1/DEFA3 with the predisposition of severe sepsis in Chinese Han cohort (P<0.05), and the areas under the receiver operating characteristic curves (ROC) was 0.77 (0.72-0.82).Conclusion:Present study first reported the association between copy number polymorphisms within defensin gene cluster and severe sepsis, and demonstrated that the CNP of DEFA1/DEFA3 gene was an independent risk factor for the susceptibility of severe sepsis, while copy number polymorphisms were not association with the fatal outcome of severe sepsis. The DEFB4 gene CNP is neither associated with the susceptibility to severe sepsis or with the fatal outcome of severe sepsis. The logistic regression model combined with age, gender and CNP of DEFA1/DEFA3 gene is powerful to predict the incidence of severe sepsis (ROC area >0.75). These findings indicated that defensin may play an important role in pathophysiology of severe sepsis. Further investigation the molecular mechanism of the association between DEFA1/DEFA3 gene CNPs and the incidence of severe sepsis will help to improve the comprehension of immunomodulation and the discovery of new target for severe sepsis.
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