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Neonatal sepsis is a major cause of childhood mortality. Limited diagnostic tools and mechanistic insights have hampered our abilities to develop prophylactic or therapeutic interventions. Biomarkers in human neonatal sepsis have been repeatedly identified as associated with dysregulation of angiopoietin signaling and altered arachidonic acid metabolism. We here provide the mechanistic evidence in support of the relevance for these observations. Angiopoetin-1 (Ang-1), which promotes vascular integrity, was decreased in blood plasma of human and murine septic newborns. In preclinical models, administration of Ang-1 provided prophylactic protection from septic death. Arachidonic acid metabolism appears to be functionally connected to Ang-1 via reactive oxygen species (ROS) with a direct role of nitric oxide (NO). Strengthening this intersection via oral administration of arachidonic acid and/or the NO donor L-arginine provided prophylactic as well as therapeutic protection from septic death while also increasing plasma Ang-1 levels among septic newborns. Our data highlight that targeting angiogenesis-associated pathways with interventions that increase Ang-1 activity directly or indirectly through ROS/eNOS provide promising avenues to prevent and/or treat severe neonatal sepsis., (© 2024. The Author(s).)

Objectives: The purpose of this study was to characterise neonatal Staphylococcus aureus (SA) sepsis in Western Australia (WA) between 2001 and 2020 at the sole tertiary neonatal intensive care unit (NICU), examine risk factors for sepsis in the cohort, and compare short- and long-term outcomes to control infants without any sepsis., Methods: Retrospective cohort study at the Neonatal Directorate at King Edward Memorial Hospital (KEMH) and Perth Children's Hospital, using electronic databases and patient medical records., Results: The overall incidence of SA sepsis was 0.10 per 1000 live births (62/614207). From 2001 to 2010 the incidence was 0.13/1000 live births, reducing to 0.07/1000 live births from 2011 to 2020. SA was most frequently isolated from endotracheal aspirates, and infants with SA sepsis had longer median duration of ventilatory support than those without any sepsis (31 days vs 18 days respectively, p < 0.001). In our cohort, SA sepsis was associated with worse neurodevelopmental outcomes compared to infants without any sepsis., Conclusions: The incidence of neonatal SA sepsis has reduced over the last 20 years, suggesting potential effectiveness of the preventative interventions implemented. Endotracheal tube (ETT) colonisation and prolonged ventilation may be under-recognised as potential sources of SA infection. Our study suggests SA sepsis may negatively impact neurodevelopmental outcomes., (© 2022. The Author(s).)

Background: Preterm infants are at high risk of infection and have distinct pathogen recognition responses. Suggested mechanisms include soluble mediators that enhance cellular levels of cAMP. The aim of this study was to assess the relationship between blood cAMP concentrations and TLR-mediated cytokine production in infants during the first month of life., Methods: Cord and serial peripheral blood samples (days of life 1-28) were obtained from a cohort of very preterm (<30 weeks' gestational age) and term human infants. Whole-blood concentrations of cAMP and FSL-1 and LPS in vitro stimulated cytokine concentrations were measured by ELISA and multiplex bead assay., Results: cAMP concentrations were higher in cord than in peripheral blood, higher in cord blood of female preterm infants, and lower at Days 1 and 7 in infants exposed to chorioamnionitis, even after adjusting for leukocyte counts. TLR2 and TLR4-mediated TNF-α, IL-1β, IL-6, IL-12p70, and IL-10 production in vitro increased over the first month of life in preterm infants and were positively correlated with leukocyte-adjusted cAMP levels and reduced by exposure to chorioamnionitis., Conclusions: The ontogeny of blood cAMP concentrations and associations with chorioamnionitis and TLR-mediated production of cytokines suggest that this secondary messenger helps shape distinct neonatal pathogen responses in early life.

Sepsis remains a leading cause of morbidity and mortality in the neonatal population, and at present, there is no unified definition of neonatal sepsis. Existing consensus sepsis definitions within paediatrics are not suited for use in the NICU and do not address sepsis in the premature population. Many neonatal research and surveillance networks have criteria for the definition of sepsis within their publications though these vary greatly and there is typically a heavy emphasis on microbiological culture. The concept of organ dysfunction as a diagnostic criterion for sepsis is rarely considered in neonatal literature, and it remains unclear how to most accurately screen neonates for organ dysfunction. Accurately defining and screening for sepsis is important for clinical management, health service design and future research. The progress made by the Sepsis-3 group provides a roadmap of how definitions and screening criteria may be developed. Similar initiatives in neonatology are likely to be more challenging and would need to account for the unique presentation of sepsis in term and premature neonates. The outputs of similar consensus work within neonatology should be twofold: a validated definition of neonatal sepsis and screening criteria to identify at-risk patients earlier in their clinical course. IMPACT: There is currently no consensus definition of neonatal sepsis and the definitions that are currently in use are varied.A consensus definition of neonatal sepsis would benefit clinicians, patients and researchers.Recent progress in adults with publication of Sepsis-3 provides guidance on how a consensus definition and screening criteria for sepsis could be produced in neonatology.We discuss common themes and potential shortcomings in sepsis definitions within neonatology.We highlight the need for a consensus definition of neonatal sepsis and the challenges that this task poses.

Objective: To characterize the association of histological chorioamnionitis (HCA) with neurodevelopmental outcomes in children born at <30 weeks gestation., Study Design: This retrospective cohort study included infants born 2006-2012 in whom placental histopathology, neonatal outcomes, and Bayley-III assessment at age 2 years were available. We assessed the association of HCA exposure with cognitive, language, and motor delay with logistic regression models adjusted for gestational age, sex, small for gestational age and brain injury., Results: Of 1353 infants, 985 had histological and neonatal data available, and 708 infants had Bayley-III assessments. HCA-exposed infants were at higher risk of some neonatal adverse outcomes, and stage of HCA correlated with low Apgar score and early-onset sepsis. Exposure to HCA was not associated with neurodevelopmental outcomes in adjusted models including stage of HCA., Conclusions: Exposure to HCA, especially higher stage, was associated with neonatal morbidity but not with adverse neurodevelopmental outcomes at 2 years of age.

Background: Deficiencies in phagocytosis may contribute to the increased susceptibility of infants to early life infections. Data on phagocytosis of the major neonatal pathogens Staphylococcus epidermidis (SE), Staphylococcus aureus (SA), and Escherichia coli (EC) by preterm infant leukocytes are inconsistent., Methods: Cord and <24-h peripheral blood were collected from very preterm (<30.1 wks gestational age (GA)) and term (37-42 wks GA) infants. Monocyte and neutrophil phagocytosis of pHrodo-labeled SE, SA, and EC were analyzed using a small-volume flow cytometry assay, with simultaneous characterization of surface activation marker expression., Results: Preterm infants had lower proportions of monocytes and neutrophils capable of phagocytosis than term infants, but preterm infant phagocytes had higher phagocytic capacity. Phagocytosis was strongly correlated between cord and <24-h peripheral blood. Supplementation with exogenous complement significantly increased phagocytosis of EC but not of SE or SA. Monocyte human leukocyte antigen (HLA)-DR expression was lower in preterm infants but did not correlate with phagocytosis., Conclusion: There is no defect in phagocytosis by monocytes and neutrophils from preterm compared with term infants, although preterm infants possess fewer phagocytes, possibly contributing to susceptibility to bacterial infection. Further investigation into the development of postnatal phagocytic competence is warranted.

Introduction: Staphylococcus epidermidis (SE) rarely causes infection in term infants but is a leading cause of late-onset sepsis in preterm infants. We hypothesized that the innate immune responses to SE in preterm infants are impaired in a gestational age (GA)-dependent manner., Methods: Cord and peripheral blood mononuclear cells (MNCs) were stimulated with SE bacteria, and a range of innate immune responses were assessed, including phagocytosis, intracellular killing, Toll-like receptor (TLR) pathway transcriptional activation, cytokine production, TLR2 and TLR4 expression, and cell signaling., Results: Phagocytosis and intracellular killing of SE bacteria were similar in neonatal and adult monocytes. Cytokine gene expression and protein synthesis increased in a GA-dependent manner, which was confirmed at the single-cell level. These GA-related effects were not associated with differences in expression of TLR2 or TLR4, nor with downstream activation of nuclear factor-κB or mitogen-activated protein kinase pathways., Discussion: The expression of TLRs, phagocytic capacity, and intracellular killing by monocytes develops early in fetal development, whereas the ability to mount a bacteria-induced cytokine response requires further maturation. The functional immaturity of monocyte activation pathways in the preterm infant may underpin their particular susceptibility to sepsis with commensal bacteria.

Newborns and especially preterm infants show a unique susceptibility to severe bacterial infections that cause significant morbidity and mortality. As very few data are available on innate immune functions in human fetuses, we conducted a comprehensive study to investigate the expression of several adhesion molecules essentially involved in migration (CD11a, CD11b, CD11c, CD18, and CD62L). Furthermore, phagocytic activity, generation of respiratory burst products, and production of several proinflammatory cytokines were assessed. Various functions of the fetal innate immune system were demonstrated to be essentially different from those observed in term neonates or adults. Expression of several surface markers was significantly diminished on fetal granulocytes. Furthermore, a significantly reduced phagocytic activity of fetal granulocytes and monocytes was found, contrasted by an enhanced generation of reactive oxygen products. In addition, we demonstrate that significant numbers of fetal monocytes are capable of the production of proinflammatory cytokines in response to stimulation. However, the pattern of cytokine production is different from the more mature individuals: the number of IL-6- and tumor necrosis factor-alpha-positive monocytes were significantly diminished, whereas more IL-8-producing monocytes were found compared with adults. The results of our study add significantly to our understanding of the maturation and impairment of the innate immune response.