FAS(APO), DAMP, and AKT Phosphoproteins Expression Predict the Development of Nosocomial Infection After Pediatric Burn Injury.

Pediatric burn injuries are a leading cause of morbidity with infections being the most common acute complication. Thermal injuries elicit a heightened cytokine response while suppressing immune function; however, the mechanisms leading to this dysfunction are still unknown. Our aim was to identify extracellular proteins and circulating phosphoprotein expression in the plasma after burn injury to predict the development of nosocomial infection (NI). Plasma was collected within 72 hours after injury from sixty-four pediatric burn subjects; of these, eighteen went on to develop a NI. Extracellular damage associated molecular proteins (DAMPs), FAS(APO), and protein kinase b (AKT) signaling phosphoproteins were analyzed. Subjects who went on to develop a NI had elevated high mobility group box 1 (HMGB1), heat shock protein 90 (HSP90), and FAS expression than those who did not develop a NI after injury (NoNI). Concurrently, phosphorylated (p-) AKT and mammalian target of rapamycin (p-mTOR) were elevated in those subjects who went on to develop a NI. Quadratic discriminant analysis revealed distinct differential profiles between NI and NoNI burn subjects using HSP90, FAS, and p-mTOR. The area under the receiver-operator characteristic curves displayed significant ability to distinguish between these two burn subject cohorts. These findings provide insight into predicting the signaling proteins involved in the development of NI in pediatric burn patients. Further these proteins show promise as a diagnostic tool for pediatric burn patients at risk of developing infection while additional investigation may lead to potential therapeutics to prevent NI.

Early detection of soluble CD27, BTLA, and TIM-3 predicts the development of nosocomial infection in pediatric burn patients.

Thermal injury induces concurrent inflammatory and immune dysfunction, which is associated with adverse clinical outcomes. However, these effects in the pediatric population are less studied and there is no standard method to identify those at risk for developing infections. Our goal was to better understand immune dysfunction and identify soluble protein markers following pediatric thermal injury. Further we wanted to determine which early inflammatory, soluble, or immune function markers are most predictive of the development of nosocomial infections (NI) after burn injury. We performed a prospective observational study at a single American Burn Association-verified Pediatric Burn Center. A total of 94 pediatric burn subjects were enrolled and twenty-three of those subjects developed a NI with a median time to diagnosis of 8 days. Whole blood samples, collected within the first 72 hours after injury, were used to compare various markers of inflammation, immune function, and soluble proteins between those who recovered without developing an infection and those who developed a NI after burn injury. Within the first three days of burn injury, innate and adaptive immune function markers (ex vivo lipopolysaccharide-induced tumor necrosis factor alpha production capacity, and ex vivo phytohemagglutinin-induced interleukin-10 production capacity, respectively) were decreased for those subjects who developed a subsequent NI. Further analysis of soluble protein targets associated with these pathways displayed significant increases in soluble CD27, BTLA, and TIM-3 for those who developed a NI. Our findings indicate that suppression of both the innate and adaptive immune function occurs concurrently within the first 72 hours following pediatric thermal injury. At the same time, subjects who developed NI have increased soluble protein biomarkers. Soluble CD27, BTLA, and TIM-3 were highly predictive of the development of subsequent infectious complications. This study identifies early soluble protein makers that are predictive of infection in pediatric burn subjects. These findings should inform future immunomodulatory therapeutic studies.

Spontaneous reversal of stenosis in tissue-engineered vascular grafts.

We developed a tissue-engineered vascular graft (TEVG) for use in children and present results of a U.S. Food and Drug Administration (FDA)-approved clinical trial evaluating this graft in patients with single-ventricle cardiac anomalies. The TEVG was used as a Fontan conduit to connect the inferior vena cava and pulmonary artery, but a high incidence of graft narrowing manifested within the first 6 months, which was treated successfully with angioplasty. To elucidate mechanisms underlying this early stenosis, we used a data-informed, computational model to perform in silico parametric studies of TEVG development. The simulations predicted early stenosis as observed in our clinical trial but suggested further that such narrowing could reverse spontaneously through an inflammation-driven, mechano-mediated mechanism. We tested this unexpected, model-generated hypothesis by implanting TEVGs in an ovine inferior vena cava interposition graft model, which confirmed the prediction that TEVG stenosis resolved spontaneously and was typically well tolerated. These findings have important implications for our translational research because they suggest that angioplasty may be safely avoided in patients with asymptomatic early stenosis, although there will remain a need for appropriate medical monitoring. The simulations further predicted that the degree of reversible narrowing can be mitigated by altering the scaffold design to attenuate early inflammation and increase mechano-sensing by the synthetic cells, thus suggesting a new paradigm for optimizing next-generation TEVGs. We submit that there is considerable translational advantage to combined computational-experimental studies when designing cutting-edge technologies and their clinical management.