Characterizing pediatric supermassive transfusion and the contributing injury patterns in the combat environment.

BACKGROUND: Trauma is the leading cause of pediatric mortality in the United States. Often, these patients require supermassive transfusion (SMT), which we define as receipt of >80 mL/kg blood products, double the proposed volume for standard pediatric massive transfusion (MT). Evaluating the blood volumes, injury patterns, clinical findings, and prehospital interventions predictive for SMT are critical to reducing pediatric mortality. We describe the pediatric casualties, injury patterns, and clinical findings that comprise SMT. METHODS: We retrospectively analyzed pediatric trauma data from the Department of Defense Trauma Registry from January 2007-2016. We stratified patients into two cohorts based on blood products received in the first 24 h after injury: 1) those who received 40-80 mL/kg (MT), or 2) those who received >80 mL/kg (SMT). We evaluated demographics, injury patterns, prehospital interventions, and clinical findings. RESULTS: Our original dataset included 3439 pediatric casualties. We identified 536 patients who met inclusion parameters (receipt of ≥40 mL/kg of blood products [whole blood, packed red blood cells, fresh frozen plasma, platelets, or cryoprecipitate]). The MT cohort included 271 patients (50.6%), and the SMT cohort comprised 265 patients (49.4%). Survival to discharge was significantly lower (78% for SMT, 86% for MT; p < 0.011) in the SMT cohort. Multivariable analysis of injury patterns revealed serious injuries (Abbreviated Injury Scale 3-6) to the extremities (OR 2.13, 95% CI 1.45-3.12) and abdomen (OR 1.65, 1.08-2.53) were associated with SMT. Wound dressings (41% versus 29%; p = 0.003), tourniquets (23% vs 12%; p = 0.001), and IO access (17% vs 10%; p = 0.013) were more common in the SMT group. Age-adjusted hypotension was significantly higher in the SMT group (41%, n = 100 vs 23%, n = 59; p < 0.001) with no statistical difference detected in tachycardia (87%, n = 223 vs 87%, n = 228; p = 0.932). CONCLUSIONS: Our research demonstrates that pediatric SMT patients are at increased risk of mortality. Our study highlights the seriousness of extremity injuries in pediatric trauma patients, identifying associations between severe injuries to the extremities and abdomen with the receipt of SMT. Prehospital interventions of wound dressing, tourniquets, and IO access were more frequent in the SMT cohort. Our research determined that hypotension was associated with SMT, but tachycardia was not a reliable predictor of SMT over MT.

Sprouty2 positively regulates T cell function and airway inflammation through regulation of CSK and LCK kinases.

The function of Sprouty2 (Spry2) in T cells is unknown. Using 2 different (inducible and T cell-targeted) knockout mouse strains, we found that Spry2 positively regulated extracellular signal-regulated kinase 1/2 (ERK1/2) signaling by modulating the activity of LCK. Spry2-/- CD4+ T cells were unable to activate LCK, proliferate, differentiate into T helper cells, or produce cytokines. Spry2 deficiency abrogated type 2 inflammation and airway hyperreactivity in a murine model of asthma. Spry2 expression was higher in blood and airway CD4+ T cells from patients with asthma, and Spry2 knockdown impaired human T cell proliferation and cytokine production. Spry2 deficiency up-regulated the lipid raft protein caveolin-1, enhanced its interaction with CSK, and increased CSK interaction with LCK, culminating in augmented inhibitory phosphorylation of LCK. Knockdown of CSK or dislodgment of caveolin-1-bound CSK restored ERK1/2 activation in Spry2-/- T cells, suggesting an essential role for Spry2 in LCK activation and T cell function.

PD-L2 Regulates B-1 Cell Antibody Production against Phosphorylcholine through an IL-5-Dependent Mechanism.

B-1 cells produce natural Abs which provide an integral first line of defense against pathogens while also performing important homeostatic housekeeping functions. In this study, we demonstrate that programmed cell death 1 ligand 2 (PD-L2) regulates the production of natural Abs against phosphorylcholine (PC). Naive PD-L2-deficient (PD-L2-/-) mice produced significantly more PC-reactive IgM and IgA. This afforded PD-L2-/- mice with selectively enhanced protection against PC-expressing nontypeable Haemophilus influenzae, but not PC-negative nontypeable Haemophilus influenzae, relative to wild-type mice. PD-L2-/- mice had significantly increased PC-specific CD138+ splenic plasmablasts bearing a B-1a phenotype, and produced PC-reactive Abs largely of the T15 Id. Importantly, PC-reactive B-1 cells expressed PD-L2 and irradiated chimeras demonstrated that B cell-intrinsic PD-L2 expression regulated PC-specific Ab production. In addition to increased PC-specific IgM, naive PD-L2-/- mice and irradiated chimeras reconstituted with PD-L2-/- B cells had significantly higher levels of IL-5, a potent stimulator of B-1 cell Ab production. PD-L2 mAb blockade of wild-type B-1 cells in culture significantly increased CD138 and Blimp1 expression and PC-specific IgM, but did not affect proliferation. PD-L2 mAb blockade significantly increased IL-5+ T cells in culture. Both IL-5 neutralization and STAT5 inhibition blunted the effects of PD-L2 mAb blockade on B-1 cells. Thus, B-1 cell-intrinsic PD-L2 expression inhibits IL-5 production by T cells and thereby limits natural Ab production by B-1 cells. These findings have broad implications for the development of therapeutic strategies aimed at altering natural Ab levels critical for protection against infectious disease, autoimmunity, allergy, cancer, and atherosclerosis.