Neonates exhibit an increased risk of sepsis mortality compared with adults. We show that in contrast to adults, survival from polymicrobial sepsis in murine neonates does not depend on an intact adaptive immune system and is not improved by T cell-directed adaptive immunotherapy. Furthermore, neonates manifest an attenuated inflammatory and innate response to sepsis, and have functional defects in their peritoneal CD11b ؉ cells. Activation of innate immunity with either a Toll-like receptor 4 (TLR4) or TLR7/8 agonist, but not a TLR3 agonist, increased the magnitude, but abbreviated the early systemic inflammatory response, reduced bacteremia, and improved survival to polymicrobial sepsis. TLR4 agonist pretreatment enhanced peritoneal neutrophil recruitment with increased oxidative burst production, whereas the TLR7/8 agonist also enhanced peritoneal neutrophil recruitment with increased phagocytic ability. These benefits were independent of the adaptive immune system and type I interferon signaling. Improving innate immune function with select TLR agonists may be a useful strategy to prevent neonatal sepsis mortality. IntroductionSepsis causes profound defects in innate and acquired immunity. In septic adults, circulating leukocytes fail to mount an attenuated inflammatory response, monocytes have defective antigen presentation in part due to reduced MHC class II expression, and dendritic cells and lymphocytes exhibit increased apoptosis. [1][2][3][4] These deficiencies contribute to a failure to clear primary pathogens, an increased propensity to develop superinfections, and an inability to mount adaptive immune responses. Considerable progress has been made in understanding the pathogenesis of and identifying potential immunomodulatory therapies for treating sepsis in adult animals. For example, MyD88 and type I interferon signaling pathways 5,6 are important requisites for innate and inflammatory host defense responses to pathogens. 7,8 Stimulating the innate immune system with Toll-like receptor (TLR) agonists improves survival in adult animal models of sepsis. 9,10 Similarly, absence of the adaptive immune system 11 or an inability of B cells to produce antibodies 12 predisposes adult mice to a poor outcome in sepsis. Correction of adaptive immune dysfunction by prevention of lymphocyte apoptosis or treatment with agonistic glucocorticoid-induced tumor necrosis factor (TNF) receptor antibody (anti-GITR) to stimulate effector T-cell function, improves survival in animal models of adult sepsis. 11,13 These studies highlight the importance of both the innate and adaptive immune systems in eliminating invading pathogens in adult mammals. However, the mechanisms of protective immunity in neonates that do not possess a fully intact immune system, and who develop sepsis at increased rates, 14 are less clear.More than 1 million babies die each year worldwide within the first 4 weeks of life from sepsis. 15 Neonatal sepsis mortality is higher than in children and adults, 16,17 peaking in premature infants, where r...

Background Standard venous thromboembolism (VTE) prophylaxis with enoxaparin results in inadequate protection in certain patients, with sub-therapeutic plasma anti-Xa levels associated with elevated VTE rates. We hypothesized that many trauma patients would be sub-therapeutic on the standard prophylactic dose of enoxaparin. Our goal was to adjust the enoxaparin dose to achieve target anti-Xa levels to take advantage of the drug based on its pharmacologic properties. Methods Patients admitted to the trauma service were included if they received at least 3 doses of prophylactic enoxaparin and underwent at least 2 screening venous duplex. Peak plasma anti-Xa levels ≤ 0.2 IU/ml were considered low and the dose was increased by 10mg bid until adequate anti-Xa levels were obtained. A strict screening venous duplex protocol was followed. Patients were excluded if they were diagnosed with a DVT prior to beginning enoxaparin or did not have correctly timed anti-Xa levels. Results Sixty-one trauma patients met inclusion criteria. There were 3 patients diagnosed with VTE (4.9%). Patients had a mean age of 45.9 years and were predominantly male (70.5%). Of the 61 patients, 18 (29.5%) had therapeutic anti-Xa levels on standard enoxaparin 30mg bid. Compared to patients who had therapeutic anti-Xa levels on enoxaparin 30mg bid, the 43 patients (70.5%) who were sub-therapeutic were more likely to be male, have larger body weight, and larger body surface area. There were no significant bleeding events in the group that received an enoxaparin dose adjustment. Conclusions A majority of patients had sub-therapeutic anti-Xa levels while on enoxaparin 30mg bid suggesting inadequate VTE prophylaxis. The need for routine use of a higher dose of prophylactic enoxaparin in trauma patients and the effects of routinely dose adjusting enoxaparin on VTE rates should be the study of future prospective, randomized trials.

Sepsis, the systemic inflammatory response to microbial infection, induces changes in both innate and adaptive immunity that presumably lead to increased susceptibility to secondary infections, multi-organ failure and death. Using a model of murine polymicrobial sepsis whose severity approximates human sepsis, we examined outcomes and defined requirements for survival after secondary Pseudomonas aeruginosa pneumonia or disseminated Listeria monocytogenes infection. We demonstrate that early after sepsis, neutrophil numbers and function are decreased, whereas monocyte recruitment through the CCR2/MCP1 pathway and function are enhanced. Consequently, lethality to Pseudomonas pneumonia is increased early but not late after induction of sepsis. In contrast, lethality to listeriosis, whose eradication is dependent upon monocyte/macrophage phagocytosis, is actually decreased both early and late after sepsis. Adaptive immunity plays little role in these secondary infectious responses. This study demonstrates that sepsis promotes selective early, impaired innate immune responses, primarily in neutrophils, that lead to a pathogen-specific, increased susceptibility to secondary infections.