[Show abstract][Hide abstract] ABSTRACT: Recent studies have demonstrated that mesenchymal stem cells (MSCs) modulate the immune response and reduce lung injury in animal models. Currently, no clinical studies of the effects of MSCs in acute respiratory distress syndrome (ARDS) exist. The objectives of this study were first to examine the possible adverse events after systemic administration of allogeneic adipose-derived MSCs in ARDS patients and second to determine potential efficacy of MSCs on ARDS.
Twelve adult patients meeting the Berlin definition of acute respiratory distress syndrome with a PaO2/FiO2 ratio of < 200 were randomized to receive allogeneic adipose-derived MSCs or placebo in a 1:1 fashion. Patients received one intravenous dose of 1 x 106 cells/kg of body weight or saline. Possible side effects were monitored after treatment. Acute lung injury biomarkers, including IL-6, IL-8 and surfactant protein D (SP-D), were examined to determine the effects of MSCs on lung injury and inflammation.
There were no infusion toxicities or serious adverse events related to MSCs administration and there were no significant differences in the overall number of adverse events between the two groups. Length of hospital stay, ventilator-free days and ICU-free days at day 28 after treatment were similar. There were no changes in biomarkers examined in the placebo group. In the MSCs group, serum SP-D levels at day 5 were significantly lower than those at day 0 (p = 0.027) while the changes in IL-8 levels were not significant. The IL-6 levels at day 5 showed a trend towards lower levels as compared with day 0, but this trend was not statistically significant (p = 0.06).
Administration of allogeneic adipose-derived MSCs appears to be safe and feasible in the treatment of ARDS. However, the clinical effect with the doses of MSCs used is weak, and further optimization of this strategy will probably be required to reach the goal of reduced alveolar epithelial injury in ARDS.Trial registration: Clinical trials.gov, NCT01902082.
Respiratory research 04/2014; 15(1):39. · 3.64 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The present study was undertaken to evaluate the long-term health-related quality of life (HRQOL) as well as the employment status in survivors of severe sepsis up to 6 years afterwards.
From January 2003 to December 2008 a total of 112 severe sepsis and 112 age, gender and Charlson comorbidity index-matched non-septic critically ill patients from 4 university hospital intensive care units (ICU) were enrolled in the study and 126 age and gender-matched community residents were interviewed as the community control group.
A total of 66 (58.9 %) severe sepsis and 80 (71.4 %) non-sepsis critically ill patients survived during the long-term follow-up time. Between August and December 2010 a total of 75 patients including 42 survivors of severe sepsis and 33 critically ill controls completed the face-to-face interview. There were no differences in the long-term HRQOL in terms of Short-Form 36 criteria between severe sepsis and non-sepsis critically ill survivors. However, when compared with the 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 scores (p = 0.042). In addition, the criteria returning to work at 1 year and at the time of interview in severe sepsis survivors were similar with those in critically ill survivors (60.5 % vs. 70.0 %, p = 0.41 and, 71.1 % vs. 76.7 %, p = 0.602).
The HRQOL in survivors of severe sepsis was impaired even up to 6 years after hospital discharge.
[Show abstract][Hide abstract] ABSTRACT: 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 septic patients and in polymicrobial septic mouse model induced by the cecum ligation and puncture (CLP) 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 CLP. Measurements and Main Results: The expression levels of TREM-2 were upregulated in both septic patients and septic mice. The kinetics of TREM-2 expression in polymicrobial sepsis was comparable to 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. On the other hand, 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 lipopolysaccharide-challenged endotoxemia mice did not improve the survival rate. The protective effect of TREM-2 in polymicrobial sepsis was not associated with its anti-inflammatory properties, but it enhanced bacteria 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 via enhancing bacterial clearance.
American Journal of Respiratory and Critical Care Medicine 05/2013; · 11.04 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: 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.
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.
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.
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.
International journal of infectious diseases: IJID: official publication of the International Society for Infectious Diseases 05/2012; 16(7):e558-64. · 2.17 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: 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.
[Show abstract][Hide abstract] ABSTRACT: This study assessed the performance of Sequential Organ Failure Assessment, Logistic Organ Dysfunction Score and Multiple Organ Dysfunction Score in outcome prediction in severe sepsis. A total of 528 consecutive patients with a diagnosis of severe sepsis were enrolled from two surgical intensive care units of university hospitals in China. Clinical and laboratory data of patients were collected and admission and maximum values of each scoring system were calculated. Areas under the receiver operating characteristic curve, which were used to assess discrimination, were 0.80, 0.83 and 0.74 for admission Sequential Organ Failure Assessment, Logistic Organ Dysfunction Score and Multiple Organ Dysfunction Score respectively, and 0.91, 0.93 and 0.86 for corresponding maximum values respectively. Calibration assessed by the Hosmer-Lemeshow statistic was better with admission (chi2 = 18.2) and maximum Logistic Organ Dysfunction Score (chi2 = 19.6) than with admission (chi2 = 98.1) and maximum Multiple Organ Dysfunction Score (chi2 = 30.9). Brier Scores, indicating the overall performance of the scores, were 0.18, 0.17 and 0.22 for admission Sequential Organ Failure Assessment, Logistic Organ Dysfunction Score and Multiple Organ Dysfunction Score respectively, and 0.12, 0.10 and 0.15 for their maximum counterparts respectively. This study found good performance of both admission Sequential Organ Failure Assessment and Logistic Organ Dysfunction Score in severe sepsis, and a slightly weaker performance of admission Multiple Organ Dysfunction Score. Since poor calibration was observed in Logistic Organ Dysfunction Score and Multiple Organ Dysfunction Score, we suggest further study of customisation of these scores in critical illness with severe sepsis.
Anaesthesia and intensive care 01/2011; 39(1):55-60. · 1.40 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Alpha 7 nicotinic acetylcholine receptor, a kind of ligand-gated ion channel mainly expressed in macrophages, plays a crucial role in improving survival in sepsis via suppressing proinflammatory cytokines. The predisposition of genomic polymorphisms within alpha 7 nicotinic acetylcholine receptor gene (CHRNA7) to sepsis has not been investigated. The current association study was performed to analyse six common genetic variations within 5'-upstream region of CHRNA7 gene in 229 patients with severe sepsis and 267 controls. Neither allelic frequencies nor genotype distributions were significantly different between patients and controls, as well as between surviving and nonsurviving patients. The frequencies of estimated haplotypes were also comparable between above defined groups. The present study suggests that genomic polymorphisms in the 5'-upstream region of CHRNA7 gene may not be a major risk factor for severe sepsis in Chinese Han population.
International Journal of Immunogenetics 10/2010; 37(5):361-5. · 1.36 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: 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.
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-alpha, interleukin-6, and interleukin-10 were detected.
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 x 10, 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 x 10, 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-alpha, interleukin-6, and interleukin-10 (P = 0.039, 0.017, 0.030, and 0.029, respectively).
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.
[Show abstract][Hide abstract] ABSTRACT: Pediatric Risk of Mortality (PRISM), Pediatric Index of Mortality (PIM) and PIM2 could be applicable to the subset of term neonates has not been well investigated. The purpose of this study is to access and compare the performance of these scoring systems in predicting mortality probability in term Chinese neonates with critical illness. PRISM, PIM and PIM2 scores were calculated prospectively during a 1-year period on 243 neonates admitted to the neonatal intensive care unit (NICU) in the Children's Hospital of Zhejiang University in China. Of these, 36 neonates (14.81%) died in the NICU, while the mortality rates estimated by PRISM, PIM and PIM2 were 16.19, 14.58 and 11.12%, respectively. The area under the receiver-operating characteristic (ROC) curve [95% confidence intervals (CIs)] were 0.834 (0.767-0.902), 0.851 (0.786-0.916) and 0.854 (0.790-0.918) for PRISM, PIM and PIM2, respectively. The Hosmer-Lemeshow test gave a chi-square of 1.35 (p = 0.930) for PRISM, 1.03 (p = 0.960) for PIM and 4.58 (p = 0.469) for PIM2. The standardized mortality rates (SMRs) (95% CI) using PRISM, PIM and PIM2 were 0.92 (0.79-1.08), 1.02 (0.88-1.20) and 1.33 (1.13-1.62), respectively. Although PRISM, PIM and PIM2 have displayed good discrimination and calibration in the present setting, PIM is considered as the most accurate and appropriate tool for predicting mortality in the studied NICU.
Journal of Tropical Pediatrics 12/2009; 56(4):235-41. · 1.01 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Gelsolin is an actin-binding plasma protein that is part of an 'actin-scavenging' system. Studies suggest that plasma gelsolin may play a crucial role in the pathophysiology of sepsis. Little is known about the course of plasma gelsolin levels over time in patients with severe sepsis. The aim of the study was to investigate plasma gelsolin levels in severe septic patients and to determine whether these levels predict the severity or clinical outcome of severe sepsis.
Ninety-one patients who were diagnosed with severe sepsis at admission to a surgical intensive care unit were enrolled, and admission plasma gelsolin levels were recorded. Plasma gelsolin levels were recorded daily in 23 of these patients. Daily plasma gelsolin levels were recorded in an additional 15 nonseptic critically ill patients. Fifteen volunteers served as healthy control individuals. Plasma gelsolin levels were measured using an enzyme-linked immunosorbent assay. Concentrations of IL-6, IL-10 and tumour necrosis factor (TNF)-alpha were also measured on intensive care unit admission.
The admission gelsolin levels were significantly decreased in severe sepsis (20.6 +/- 11.7 mg/l) compared with nonseptic critically ill patients (52.3 +/- 20.3 mg/l; P < 0.001) and healthy control individuals (126.8 +/- 32.0 mg/l; P < 0.001). Severe septic patients had increased IL-6 levels compared with nonseptic critically ill patients (20.0 +/- 10.7 pg/ml versus 11.4 +/- 13.9 pg/ml; P = 0.048), whereas no significant difference in IL-10 or TNF-alpha levels was observed (IL-10: 97.9 +/- 181.5 pg/ml versus 47.4 +/- 91.5 pg/ml, respectively [P = 0.425]; TNF-alpha: 14.2 +/- 13.9 pg/ml versus 6.9 +/- 5.3 pg/ml, respectively; P = 0.132). Survivors of severe sepsis exhibited substantial recovery of their depressed plasma gelsolin levels, whereas gelsolin levels in nonsurvivors remained at or below their depleted admission levels.
Plasma gelsolin may be a valuable marker for severe sepsis. Recovery of depleted plasma gelsolin levels correlated with clinical improvement. The prognostic role of plasma gelsolin in critical illness requires further investigation in a large cohort.
Critical care (London, England) 08/2008; 12(4):R106. · 4.72 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: 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.
Human Immunology 04/2008; 69(3):220-6. · 2.30 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: 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.
Prospective, observational study of surgical intensive care unit patients at ten university hospitals in six provinces in China.
All adult admissions in studied intensive care units from December 1, 2004, to November 30, 2005.
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 $11,390 per patient and $502 per patient per day.
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.
Critical Care Medicine 12/2007; 35(11):2538-46. · 6.12 Impact Factor