Baoli Cheng

Epidemiology of severe sepsis in critically ill surgical patients in ten university hospitals in China

Objectives:To determine the occurrence rate, outcomes, and the characteristics of severe sepsis in surgical intensive care units in multiple medical centers within China and to assess the cost and resource use of severe sepsis in China. Design and Setting:Prospective, observational study of surgical intensive care unit patients at ten university hospitals in six provinces in China. Patients:All adult admissions in studied intensive care units from December 1, 2004, to November 30, 2005. Interventions:None. Measurements and Main Results:The criteria of severe sepsis were based on the American College of Chest Physicians/Society of Critical Care Medicine Consensus Conference definition. Analysis of data from 3,665 intensive care unit admissions identified 318 (8.68%) cases of severe sepsis, 64.8% of which were men. The median age (interquartile range) of patients with severe sepsis was 64 (47–74) yrs. 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, 20 (6.3%) of which had fungemia. The abdomen was the most common site of infections (72.3%), followed by lung (52.8%). The overall hospital mortality of severe sepsis was 48.7%. Risk factors for hospital mortality included age, chronic comorbidity of malignant neoplasm, Gram-positive bacterial infection, invasive fungal infection, admission Acute Physiology Score, and admission Sequential Organ Failure Assessment score of respiratory dysfunction and cardiovascular dysfunction. The median Therapeutic Intervention Scoring System-28 score was 43 (38–49). The mean hospital cost was

Triggering Receptor Expressed on Myeloid Cells-2 Protects against Polymicrobial Sepsis by Enhancing Bacterial Clearance

11,390 per patient and

Impact of invasive fungal infection on outcomes of severe sepsis: a multicenter matched cohort study in critically ill surgical patients

502 per patient per day. Conclusions:Severe sepsis is a common, expensive, and frequently fatal syndrome in critically ill surgical patients in China. Other than the microbiological patterns, the incidence, mortality, and major characteristics of severe sepsis in Chinese surgical intensive care units are close to those documented in developed countries.

Increased Genomic Copy Number of DEFA1/DEFA3 Is Associated with Susceptibility to Severe Sepsis in Chinese Han Population

RATIONALE Triggering receptor expressed on myeloid cells-2 (TREM-2) is a cell surface receptor primarily expressed on macrophages and monocyte-derived cells. TREM-2 not only functions as a regulator of inflammatory response, but also serves as a phagocytic receptor for bacteria. However, the role of TREM-2 in sepsis remains unknown. OBJECTIVES To investigate whether TREM-2 plays a role in sepsis. METHODS The manner of expression of TREM-2 was evaluated in patients with sepsis and in polymicrobial septic mouse model induced by the cecum ligation and puncture approach. Recombinant mouse TREM-2 was used to block the effect of TREM-2. Bone marrow-derived myeloid cells (BMMCs) that overexpress TREM-2 were administrated into septic mice at various times after cecum ligation and puncture. MEASUREMENTS AND MAIN RESULTS The expression levels of TREM-2 were up-regulated in patients with sepsis and septic mice. The kinetics of TREM-2 expression in polymicrobial sepsis was comparable with that of bacteria burden in peritoneal lavage fluid. Blocking the effect of TREM-2 resulted in markedly increased mortality and bacterial burden in polymicrobial sepsis. Administration of TREM-2-overexpressing BMMCs significantly reduced the mortality, even when it was administered 4 hours after the initiation of sepsis. However, injection of TREM-2-overexpressing BMMCs into LPS-challenged endotoxemia mice did not improve the survival rate. The protective effect of TREM-2 in polymicrobial sepsis was not associated with its antiinflammatory properties, but it enhanced bacterial clearance in vivo. Furthermore, administration of TREM-2-overexpressing BMMCs improved the organ injury. CONCLUSIONS TREM-2 plays an important role in the host defense response to sepsis by enhancing bacterial clearance.

Circulating nucleosomes as a predictor of sepsis and organ dysfunction in critically ill patients

IntroductionFungal infection is increasingly common in critical illness with severe sepsis, but the influence of invasive fungal infection (IFI) on severe sepsis is not well understood. The aim of this study was to investigate the impact that IFI has on the outcomes of critically ill surgical patients with severe sepsis in China by means of matched cohort analysis; we also evaluated the epidemiologic characteristics of IFI in this population.MethodsRecords for all admissions to 10 university hospital surgical intensive care units (ICUs) from December 2004 to November 2005 were reviewed. Patients who met criteria for severe sepsis were included. IFI was identified using established criteria based on microbiologic or histological evidence. A matched cohort study was conducted to analyze the relationship between IFI and outcomes of severe sepsis.ResultsA total of 318 patients with severe sepsis were enrolled during the study period, of whom 90 (28.3%) were identified as having IFI. A total of 100 strains of fungi (58% Candida albicans) were isolated from these patients. Independent risk factors for IFI in patients with severe sepsis included mechanical ventilation (>3 days), Acute Physiology and Chronic Health Evaluation score, coexisting infection with both Gram-positive and Gram-negative bacteria, and urethral catheterization (>3 days). Compared with the control cohort, IFI was associated with increased hospital mortality (P < 0.001), high hospital costs (P = 0.038), and prolonged stay in the ICU (P < 0.001) and hospital (P = 0.020).ConclusionIFI is frequent in patients with severe sepsis in surgical ICUs and is associated with excess risk for hospital mortality, longer ICU and hospital stays, and greater consumption of medical resources.

Lack of association between TREM-1 gene polymorphisms and severe sepsis in a Chinese Han population

Background:Human neutrophil peptides 1–3 are endogenous cationic antimicrobial peptides implicated in host defense against microbes. The genes encoding human neutrophil peptides 1–3 (DEFA1/DEFA3) exhibit copy number variations. This study was designed to determine whether DEFA1/DEFA3 copy number variations conferred susceptibility to infection-induced complications such as severe sepsis. Methods:This case–control study was performed in 179 patients with severe sepsis and 233 healthy blood donors and was replicated in an independent cohort of 112 cases and 118 controls. Plasma levels of human neutrophil peptides 1–3, tumor necrosis factor-&agr;, interleukin-6, and interleukin-10 were detected. Results:The genotype of DEFA1/DEFA3 with more than eight copies was more frequent in patients with severe sepsis than in controls (55.9% vs. 31.3%; P = 1.13 × 10−6, odds ratio 2.77, 95% confidence interval 1.85–4.16). After adjustment for age and gender, logistic regression analysis confirmed the association of the genotype of more than eight copies with an increased risk of severe sepsis (P = 2.25 × 10−5, odds ratio 2.66, 95% confidence interval 1.69–4.19). This established association was replicated in a second age- and gender-matched case–control cohort (P = 0.02, odds ratio 1.90, 95% confidence interval 1.11–3.27). Furthermore, compared with those with fewer copies, the patients carrying more than eight copies of DEFA1/DEFA3 presented significantly lower plasma levels of human neutrophil peptides 1–3, tumor necrosis factor-&agr;, interleukin-6, and interleukin-10 (P = 0.039, 0.017, 0.030, and 0.029, respectively). Conclusions:DEFA1/DEFA3 is an important genetic component participating in host immune response to severe sepsis. A higher copy number of DEFA1/DEFA3 (>8 copies) is significantly associated with the risk of severe sepsis.

Altered melatonin secretion and circadian gene expression with increased proinflammatory cytokine expression in early-stage sepsis patients.

OBJECTIVES 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 with an estimated length of stay in the intensive care unit of more than 48 h, were prospectively enrolled as cohort 1. The second independent cohort (cohort 2) consisted of 91 post-surgery patients. Patients receiving chemotherapy, those with AIDS, those on steroid treatment, and those undergoing transplants were excluded. Levels of circulating nucleosomes within 24h of admission in both cohorts, and for cohort 1 also on days 3, 5, and 7 and a last time-point of ICU discharge or at imminent death, were measured and analyzed for their capacity to predict sepsis. The severity of the inflammatory response and organ dysfunction were assessed by cytokine levels and sepsis scores. RESULTS Nucleosome 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 nucleosome levels to differentiate septic patients from non-septic patients was 0.70 (95% confidence interval (CI) 0.51-0.88) in cohort 1, 0.66 (95% CI 0.55-0.79) in cohort 2, and 0.67 (95% CI 0.55-0.79) in all of the subjects. After multiple logistic regression analysis, circulating nucleosomes remained as an independent predictor of sepsis. Furthermore, the levels of circulating nucleosomes on admission were significantly correlated with the inflammatory response and organ dysfunction in sepsis. Meanwhile, a trend was observed for admission levels of circulating nucleosomes in non-survivors to be higher than those in survivors. CONCLUSIONS The level of circulating nucleosomes in the serum has a predictive value for sepsis and organ dysfunction and may serve as a candidate biomarker for the diagnosis/prognosis of sepsis. Further studies are warranted to confirm the present findings.

Nuclear factor-κB mediated lipopolysaccharide-induced mRNA expression of hepcidin in human peripheral blood leukocytes

Triggering receptor expressed on myeloid cells-1 (TREM-1) is a cell surface receptor expressed on neutrophils and monocytes. TREM-1 acts to amplify inflammation and serves as a critical mediator of inflammatory response in the context of sepsis. Blocking of TREM-1 can protect against sepsis in mice. To date, the predisposition of TREM-1 gene polymorphisms to sepsis has not been reported. This study was designed to investigate whether TREM-1 genomic variations were associated with the development of severe sepsis. Three common polymorphisms (rs7768162, rs9471535, and rs2234237) within the TREM-1 gene were detected in 175 patients with severe sepsis and in 139 healthy control subjects. Neither allelic frequencies nor genotype distributions of the assayed single nucleotide polymorphisms were found to be significantly different between patients and controls as well as between surviving and nonsurviving patients in different models of inheritance. The distributions of estimated haplotype patterns were also comparable between the defined groups. The present findings suggest that the three studied polymorphisms within the TREM-1 gene may not play a major role in the predisposition to severe sepsis in a Chinese Han cohort. Further replication studies with large sample size to achieve sufficient power (80%) to dismiss these polymorphisms as candidate markers for severe sepsis are warranted.

Sphingosine 1-phosphate Receptor 2 Signaling Suppresses Macrophage Phagocytosis and Impairs Host Defense against Sepsis.

Inflammatory and immune responses, as well as melatonin secretion, are affected by circadian regulation. Abnormal circadian rhythm of melatonin release has been reported to be associated with the later stages of sepsis; however, its role in the early stages of sepsis is unclear. We studied 11 septic and 11 non-septic patients in our intensive care unit (ICU). Peripheral blood was drawn at 4-h intervals on the first day, beginning at 2:00 p.m., over a total period of 24 h. Plasma levels of melatonin, tumor necrosis factor α (TNF-α) and interleukin 6 (IL-6) were measured by radioimmunoassay or enzyme-linked immunosorbent assay (ELISA). Messenger RNA levels of circadian genes Cry-1 and Per-2 were analyzed using quantitative real-time PCR. Results show the circadian rhythm of melatonin secretion was altered in the early stages of sepsis. The melatonin secretion acrophase occurred earlier in septic patients at 6:00 p.m., compared with at 2:00 a.m. in non-septic ICU patients. Compared with the non-septic group, both Cry-1 and Per-2 expression were significantly decreased while TNF-α and IL-6 expression were significantly increased in septic patients [TNF-α, 64.1 (43.6-89.1) vs. 11.4 (10.4-12.5) ng/ml; IL-6, 41.2 (35.7-50.8) vs. 19.1 (16-136.7) ng/ml; median (range), both P=0.04]. The peak concentrations of TNF-α and IL-6 were shown to be in concordance with the rhythm of melatonin secretion. The circadian rhythm of melatonin secretion and circadian gene expression were altered in the early stages of sepsis, which likely led to the changes in pro-inflammatory cytokine release. These findings shed light on the potential link between circadian rhythm and the progression of early-stage sepsis.

Dexmedetomidine Versus Propofol Sedation Improves Sublingual Microcirculation After Cardiac Surgery: A Randomized Controlled Trial.

Hepcidin is a known key modulator of iron homeostasis and an innate immune molecule secreted by the liver. The transcriptional mechanism of hepcidin in hepatocytes during inflammation is mediated via the IL-6/STAT3 pathway. Recently, hepcidin demonstrated an anti-inflammatory function in endotoxic mice, and a TLR4-dependent inducible expression of hepcidin was detected in myeloid cells. In this study, we explored the expression and signaling mechanism regulating hepcidin mRNA expression in peripheral blood leukocytes. The mRNA levels of hepcidin in peripheral blood leukocytes from patients with severe sepsis (n = 14) was significantly higher than those in healthy controls (n = 16;0.286 ± 0.065 vs 0.068 ± 0.025; P < 0.05). Ex vivo studies found hepcidin mRNA can be highly induced by challenge of 100 ng/ml LPS or 20 ng/ml TNF-α in peripheral blood leukocytes rather than IL-6, IL-1 and IFN-γ. Anti-TNF-α antibody significantly decreased the levels of hepcidin mRNA induced by LPS. Inhibitor of nuclear factor (NF)-κB rather than that of STAT3 completely abolished the inducibility of hepcidin mRNA in PBMCs and neutrophils. These results indicate that hepcidin mRNA expression in peripheral blood leukocytes induced by LPS depends on NF-κB, and TNF-α may be a key mediator in this procedure.