Polymicrobial sepsis alters the adaptive immune response and induces T cell suppression and Th2 immune polarization. We identify a GR-1+CD11b+ population whose numbers dramatically increase and remain elevated in the spleen, lymph nodes, and bone marrow during polymicrobial sepsis. Phenotypically, these cells are heterogeneous, immature, predominantly myeloid progenitors that express interleukin 10 and several other cytokines and chemokines. Splenic GR-1+ cells effectively suppress antigen-specific CD8+ T cell interferon (IFN) γ production but only modestly suppress antigen-specific and nonspecific CD4+ T cell proliferation. GR-1+ cell depletion in vivo prevents both the sepsis-induced augmentation of Th2 cell–dependent and depression of Th1 cell–dependent antibody production. Signaling through MyD88, but not Toll-like receptor 4, TIR domain–containing adaptor-inducing IFN-β, or the IFN-α/β receptor, is required for complete GR-1+CD11b+ expansion. GR-1+CD11b+ cells contribute to sepsis-induced T cell suppression and preferential Th2 polarization.

Purpose of the review Although infection rates have modestly decreased in the neonatal intensive care unit (NICU) as a result of ongoing quality improvement measures, neonatal sepsis remains a frequent and devastating problem among hospitalized preterm neonates. Despite multiple attempts to address this unmet need, there have been minimal advances in clinical management, outcomes, and accuracy of diagnostic testing options over the last three decades. One strong contributor to a lack of medical progress is a variable case definition of disease. The inability to agree on a precise definition greatly reduces the likelihood of aligning findings from epidemiologists, clinicians, and researchers, which, in turn, severely hinders progress towards improving outcomes. Recent findings Pediatric consensus definitions for sepsis are not accurate in term infants and are not appropriate for preterm infants. In contrast to the defined multi-stage criteria for other devastating diseases encountered in the NICU (e.g., bronchopulmonary dysplasia), there is significant variability in the criteria used by investigators to substantiate the diagnosis of neonatal sepsis. Summary The lack of an accepted consensus definition for neonatal sepsis impedes our efforts towards improved diagnostic and prognostic options as well as accurate outcomes information for this vulnerable population.

Objective To review the accuracy of the pediatric consensus definition of sepsis in term neonates and to determine the definition of neonatal sepsis used. Study selection The review focused primarily on pediatric literature relevant to the topic of interest. Conclusions Neonatal sepsis is variably defined based on a number of clinical and laboratory criteria that make the study of this common and devastating condition very difficult. Diagnostic challenges and uncertain disease epidemiology necessarily result from a variable definition of disease. In 2005, intensivists caring for children recognized that as new drugs became available, children would be increasingly studied and thus, pediatric-specific consensus definitions were needed. Pediatric sepsis criteria are not accurate for term neonates and have not been examined in preterm neonates for whom the developmental stage influences aberrations associated with host immune response. Thus, specific consensus definitions for both term and preterm neonates are needed. Such definitions are critical for the interpretation of observational studies, future training of scientists and practitioners, and implementation of clinical trials in neonates.

Neonatal septic shock is a devastating condition associated with high morbidity and mortality. Definitions for the sepsis continuum and treatment algorithms specific for premature neonates are needed to improve studies of septic shock and assess benefit from clinical interventions. Unique features of the immature immune system and pathophysiologic responses to sepsis, particularly those of extremely preterm infants, necessitate that clinical trials consider them as a separate group. Keen clinical suspicion and knowledge of risk factors will help to identify those neonates at greatest risk for development of septic shock. Genomic and proteomic approaches, particularly those that use very small sample volumes, will increase our understanding of the pathophysiology and direct the development of novel agents for prevention and treatment of severe sepsis and shock in the neonate. Although at present antimicrobial therapy and supportive care remain the foundation of treatment, in the future immunomodulatory agents are likely to improve outcomes for this vulnerable population.

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...