Trefoil factor 3 as a marker of intestinal cell damage during sepsis.

OBJECTIVE: Gastrointestinal dysfunction or gut failure frequently occurs in seriously ill patients and can be responsible for multi-organ failure. Trefoil factor 3 (TFF3) was characterized for its role in reconstitution of an epithelial barrier after mucosal injury in the jejunum. The aims of our study was an analysis of TFF3 levels dynamics in patients with sepsis and the correlation of TFF3 with severity of sepsis and mortality. METHODS: Prospective observational study, a ten days evaluation period in children aged 0-19 years with systemic inflammatory response syndrome or septic state. Blood tests to determine levels of TFF3 were obtained as long as the patient met the criteria for systemic inflammatory response syndrome or sepsis. RESULTS: Analysis of dynamics revealed steady levels of TFF3 during the 10 day period evaluated. TFF3 levels could not differentiate between various septic conditions in patients until a marked organ dysfunction developed. Higher Area Under Curve was noticed between control group and patients with sepsis. We could not make any strong conclusions based on mortality model. CONCLUSIONS: Levels of TFF3 are elevated in paediatric patients with sepsis through organ dysfunction.

Pancreatic stone protein - a possible biomarker of multiorgan failure and mortality in children sepsis.

Pancreatic stone protein (PSP)/regenerating protein 1-alpha (reg) is associated with inflammation, infection, and other disease-related stimuli. The prognostic value of PSP/reg among critically ill pediatric patients is unknown. The aim of this pilot study was to evaluate PSP/reg in children with systemic inflammatory response syndrome or sepsis. Prospective observational study, a five day evaluation period in children 0-19years old with systemic inflammatory response syndrome or septic state. Blood tests to determine levels of PSP/reg were obtained as long as the patient met the criteria for systemic inflammatory response syndrome or sepsis. PSP/reg levels did not differ between patients with systemic inflammatory response syndrome and septic condition until organ dysfunction signs were present. PSP/reg levels were significantly higher in patients with a PELOD score of 12 or higher or in those with MODS. Patients who died tended to have higher PSP/reg levels.

Multiple gene-to-gene interactions in children with sepsis: a combination of five gene variants predicts outcome of life-threatening sepsis.

INTRODUCTION: The aim of the study was to identify the dependency structure of genetic variants that can influence the outcome for paediatric patients with sepsis. METHODS: We evaluated the role of single nucleotide polymorphisms for five genes: bactericidal permeability increasing protein (BPI; rs5743507), lipopolysaccharide-binding protein (LBP; rs2232618), toll-like receptor 4 (TLR4; rs4986790), heat shock protein 70 (HSP 70; rs2227956), and interleukin 6 (IL-6; rs1800795) in 598 children aged 0 to 19 years that were admitted to a paediatric intensive care unit with fever, systemic inflammatory response syndrome, sepsis, severe sepsis, septic shock, or multiple organ dysfunction syndrome. A control group of 529 healthy individuals was included. Multi-way contingency tables were constructed and statistically evaluated using log-linear models. Typical gene combinations were found for both study groups. RESULTS: Detailed analyses of the five studied gene profiles revealed significant differences in sepsis survival. Stratification into high-risk, intermediate-risk, and low-risk groups of paediatric patients can predict the severity of sepsis. CONCLUSIONS: Analysis of single nucleotide polymorphisms for five genes can be used as a predictor of sepsis outcome in children.

Trefoil factor 2 expression and its significance as a predictor of severity of sepsis in children.

Intestinal injury significantly contributes to critical illness, sepsis and multiorgan failure. TFF2 (Trefoil Factor 2) is expressed and secreted preferentially by gastric mucous neck cells. TFF2 gene expression is promptly increased after gut injury, and its expression profile broadens to include the regenerative epithelia of virtually the entire gastrointestinal tract. The first objective of our study was an analysis of TFF2 levels dynamics in patients with Systemic Inflammatory Response Syndrome (SIRS) or septic condition during a 5-day period after admission. The second objective was to determine optimal cut-off value and quantify diagnostic characteristics of TFF2 between controls and patients with various septic states. The study included 57 children aged 0-19 years, with expected or proven SIRS and septic condition. The degree of severity was evaluated according to PELOD Score (Pediatric Logistic Organ Dysfunction). Blood samples to determine levels of TFF2 factor were taken during the time patient met the criteria of SIRS or sepsis. Control group samples to determine the serum levels of TFF2 were taken from patients undergoing elective surgery. Analysis of TFF2 levels dynamics revealed that TFF2 levels kept steady state during the 5-day period. Significantly higher levels of TFF2 were in patients with Multiple Organ Dysfunction Syndrome (MODS). The difference was noticed also in ROC analysis.

Trefoil factor 1 as a marker of mucosal damage of the gastrointestinal tract in children with sepsis.

Intestinal ischemia and reperfusion is a common pathway for many diseases in children. The objective of our study was an analysis of Trefoil factor 1 levels dynamics in patients with SIRS or septic condition during a 5-day period. Analysis of TFF1 levels dynamics revealed that TFF1 levels kept steady state during the 5-day period. TFF1 levels were similar in patients with SIRS, sepsis and severe sepsis. Significantly higher levels of TFF1 were in patients with septic shock and MODS.

Classification of infections in intensive care units: a comparison of current definition of hospital-acquired infections and carrier state criterion.

BACKGROUND: The rate of nosocomial infection appears to depend on whether it is calculated using the Center for Disease Control (CDC) or carrier state criteria. The objective of this study was to differentiate between primary endogenous (PE), secondary endogenous (SE) and exogenous (EX) infections, and to compare this classification with CDC criteria for nosocomial infections. METHODS: Children hospitalized for more than 72 h at pediatric intensive care unit during 2004-2005 were enrolled. Children, who had the infection before the admission, and or did not develop an infection within the hospitalization were excluded. Surveillance samples were sampled on admission, and then twice a week. Diagnostic samples were obtained when infection was suspected based on the clinical condition and laboratory findings. Infections were evaluated as PE, SE and EX, and their incidences were compared with CDC criteria for nosocomial infections. RESULTS: One hundred seventy eight patients were enrolled in the study. Forty-four patients (24.7%) develop infection. Twenty-seven patients (61.3%) had PE, 10 patients (22.7%) had SE, and 7 patients (15.9%) had EX infection. Secondary endogenous and EX infections are considered as nosocomial, thus 17 patients (38.6%) had a nosocomial infection. Thirty-one patients (70.5%) met CDC criteria for nosocomial infections. Seventeen patients (55%) were classified as PE, and 14 patients (45%) as SE or EX infections. CONCLUSION: Seventy percent of infections (31 out of 44 patients) met the CDC criteria for nosocomial infections, but only 39% of infections (17 out of 44 patients) were classified as nosocomial based on carrier state classification.

The usefulness of S100B, NSE, GFAP, NF-H, secretagogin and Hsp70 as a predictive biomarker of outcome in children with traumatic brain injury.

BACKGROUND: Predicting the long-term outcome after traumatic brain injury (TBI) is an important component of treatment strategy. Despite dramatically improved emergency management of TBI and apparent clinical recovery, most patients with TBI still may have long-term central nervous system (CNS) impairment. METHODS: Sixty-three patients with TBI were enrolled into the prospective study. Venous blood samples were taken at admission and every 24 h for a maximum of 6 consecutive days. Serum concentrations of the biomarkers S100B, neuron-specific enolase (NSE), GFAP, NF-H, secretagogin and Hsp70 were quantified immuno-luminometrically or by enzyme-linked immunosorbent assay. The outcome was evaluated 6 months after TBI using the Glasgow Outcome Scale (GOS) in all patients. RESULTS: The S100B levels in patients with worse outcome (GOS 4 or death) were already significantly higher at D0 (p < 0.001; p = 0.002). NSE levels were significantly higher in patients who died or had worse outcomes (p < 0.001; p = 0.003). Patients who had worse outcomes (GOS) or died had higher GFAP values (p < 0.001; p < 0.001), but their dynamics were similar over the same period. NF-H grew significantly faster in patients who had a worse GOS or died (p < 0.001; p = 0.001). CONCLUSIONS: Although further prospective study is warranted, these findings suggest that levels of biomarkers correlate with mortality and may be useful as predictors of outcome in children with TBI.

Dynamics of glial fibrillary acidic protein during traumatic brain injury in children.

BACKGROUNDS: Glial fibrillary acidic protein (GFAP) is a monomeric intermediate filament protein found in the astroglial cytoskeleton and is not found outside the central nervous system. It is a brain-specific protein that is released after traumatic brain injury (TBI). METHODS: This prospective study enrolled 59 children who had TBI, as verified by computed tomography. Daily GFAP measurement began at admission (<12 hours after trauma) and continued for 6 days. Blood samples were analyzed for GFAP by enzyme-linked immunosorbent assay. Outcome was assessed using the Glasgow Outcome Scale (GOS) at 6 months after injury. RESULTS: The median serum levels of GFAP at admission were 7.47 ng/mL in patients who died, compared with 0.12 ng/mL in patients who survived (p=0.002). GFAP levels were significantly higher in patients who had a poor outcome 6 months after injury than in those who were alive or had good outcome (p<0.001). The area under the receiver operating characteristic curve for GFAP was 0.833 for day 0 and 0.884 for day 2. CONCLUSIONS: These results suggest that determination of serum levels of GFAP may add to the clinical assessment of the primary damage and prediction of outcome after severe TBI.

Hyperphosphorylated neurofilament NF-H as a predictor of mortality after brain injury in children.

OBJECTIVE: The aim of the study was to determine whether serum levels of hyperphosphorylated neurofilament NF-H correlate with severity of brain injury in children. METHODS: Forty-nine patients with traumatic brain injury (TBI) were enrolled into the prospective study. Venous blood samples were taken after admission and every 24 h for a maximum of 6 consecutive days. Serum NF-H concentrations were quantified by enzyme-linked immunosorbent assay. The outcome was evaluated 6 months after TBI using Glasgow Outcome Scale (GOS) in all patients. RESULTS: The quantitative level of pNF-H remained significantly higher in patients with poor outcome (GOS = 1) in comparison with the other patients for the 2nd-4th day (p = 0.027; p = 0.019; p = 0.01). Levels of pNF-H were significantly higher in patients with diffuse axonal injury on initial CT scan (p = 0.004). Normal levels pNF-H in the paediatric population are unknown. Objective ROC analysis was identification of optimal cut-offs of proteins for prediction of GOS = 1. CONCLUSIONS: Although further, prospective study is warranted, these findings suggest that levels of hyperphosphorylated neurofilament NF-H correlate with mortality and may be useful as predictors of outcome in children with TBI.

Interleukin-6 gene variants and the risk of sepsis development in children.

A proinflammatory cytokine interleukin-6 (IL-6) plays an important role in the development, pathogenesis and outcome of SIRS, sepsis and septic shock. We have evaluated the role of the IL-6 gene polymorphisms in pediatric patients. A total of 421 consecutive pediatric patients admitted to the pediatric intensive care unit with fever, systemic inflammatory response syndrome (SIRS), sepsis, severe sepsis, septic shock, or multiple organ distress syndrome (MODS) were studied together with 644 healthy controls. DNA was isolated and two IL-6 gene polymorphisms (G-174>C and G-572>C) were analyzed. The frequencies of both analyzed variants differ significantly between the group of patients and healthy controls (p = 0.02 for G-174>C and p = 0.049 for G-572>C). In addition, genetic analysis of the G-174>C IL-6 gene variant revealed significant differences between the subgroup of febrile patients and subgroup of septic shock (p = 0.0319) and between the subgroup of SIRS and septic shock (p = 0.038). In both cases the negative genotype was CC. No statistically significant differences for the IL-6 gene polymorphism G-572>C were found between the groups of patients with different diagnosis. IL-6 gene polymorphisms G-174>C and G-572>C could be the predictors of risk of development and/or the predictors of the severity of sepsis in children.

Bactericidal permeability increasing protein gene variants in children with sepsis.

OBJECTIVE: To evaluate the role of genetic polymorphisms of the bactericidal permeability increasing protein (BPI) in pediatric patients with sepsis. DESIGN: Prospective, single-center, case-control study at the pediatric intensive care unit (PICU) of a university hospital. PATIENTS: 345 consecutive pediatric patients admitted to the PICU with fever, systemic inflammatory response syndrome (SIRS), sepsis, severe sepsis, septic shock, or multiple organ distress syndrome (MODS). INTERVENTIONS: DNA was isolated and two BPI gene polymorphisms BPI (G545 > C) Taq and BPI (A645[ > G) 216 were studied in patients and compared with healthy controls. MEASUREMENTS AND RESULTS: Genetic analysis of the BPI Taq gene revealed significant differences between healthy controls and the subgroup of febrile patients (p = 0.0243), the subgroup of SIRS and sepsis (p = 0.0101), and the subgroup of severe sepsis, septic shock, and MODS (p = 0.0027), respectively. No statistically significant differences for the BPI 216 gene polymorphism were found between patient and healthy control groups. A statistically significant predisposition to Gram-negative sepsis in patients carrying the BPI Taq GG variant together with the BPI 216 AG or GG variant was revealed (p = 0.0081), and these haplotypes were also associated with death due to sepsis-related complications. CONCLUSION: BPI Taq gene polymorphism is the accurate predictor of the severity of sepsis in children admitted to the PICU.

Modeling effect of the septic condition and trauma on C-reactive protein levels in children with sepsis: a retrospective study.

INTRODUCTION: Sepsis is the main cause of morbidity and mortality in intensive care units and its early diagnosis is not straightforward. Many studies have evaluated the usefulness of various markers of infection, including C-reactive protein (CRP), which is the most accessible and widely used. CRP is of weak diagnostic value because of its low specificity; a better understanding of patterns of CRP levels associated with a particular form of infection may improve its usefulness as a sepsis marker. In the present article, we apply multilevel modeling techniques and mixed linear models to CRP-related data to assess the time course of CRP blood levels in association with clinical outcome in children with different septic conditions. METHODS: We performed a retrospective analysis of 99 patients with systemic inflammatory response syndrome, sepsis, or septic shock who were admitted to the Pediatric Critical Care Unit at the University Hospital, Brno. CRP blood levels were monitored for 10 days following the onset of the septic condition. The effect of different septic conditions and of the surgical or nonsurgical diagnosis on CRP blood levels was statistically analyzed using mixed linear models with a multilevel modeling approach. RESULTS: A significant effect of septic condition and diagnosis on the course of CRP levels was identified. In patients who did not progress to septic shock, CRP blood levels decreased rapidly after reaching peak values - in contrast to the values in patients with septic shock in whom CRP protein levels decreased slowly. Moreover, CRP levels in patients with a surgical diagnosis were higher than in patients with a nonsurgical condition. The magnitude of this additional elevation in surgical patients did not depend on the septic condition. CONCLUSION: Understanding the pattern of change in levels of CRP associated with a particular condition may improve its diagnostic and prognostic value in children with sepsis.