To determine risk factors and outcomes of necrotizing enterocolitis (NEC)-associated sepsis in infants with NEC.
A retrospective review comparing demographic and clinical information in infants with ...and without NEC-associated sepsis (defined as positive blood culture at the time of NEC onset).
A total of 209 infants with medical (n = 98) and surgical NEC (n = 111) had a median gestational age of 27 weeks (IQR 25; 30.5) and a median birth weight of 910 g IQR 655; 1138. Fifty of 209 (23.9%) infants had NEC-associated sepsis. Infants with NEC-associated sepsis had lower median GA (26.4 vs. 27.4 weeks; p = 0.01), lower birth weight (745 vs. 930 g; p = 0.009), were more likely mechanically ventilated p < 0.001, received dopamine p < 0.001, had more evidence of acute kidney injury 60% vs. 38.4%, p = 0.01, longer postoperative ileus (16 13.0; 22.0 vs. 12 8; 16 days; p = 0.006), higher levels of C-reactive protein, lower platelet counts, longer hospitalization compared to infants without NEC-associated sepsis. On multivariate regression, cholestasis was an independent risk factor for NEC-associated sepsis (OR 2.94; 95% CI 1.1-8.8, p = 0.038).
NEC-associated sepsis was associated with greater hemodynamic support, acute kidney injury, longer postoperative ileus, and hospitalization on bivariate analysis, and cholestasis was associated with higher odds of sepsis on multi regression analysis.
NEC-associated sepsis was present in 24% of infants with NEC. Gram-positive bacteria, Gram-negative bacteria, and Candida were found in 15.3%, 10.5%, and 2.8% of cases, respectively. Infants with NEC-associated sepsis had a greater inflammatory response (CRP levels), received more blood transfusion before NEC onset, frequently needed assisted ventilation ionotropic support, and had acute kidney injury after NEC onset. NEC infants with Gram-negative sepsis had higher portal venous gas, received more platelet transfusions before NEC onset, and had higher CRP levels and lower median lymphocyte counts at 24 h after NEC onset than those with Gram-positive sepsis.
The objective was to develop non-invasive predictive models for late-onset neonatal sepsis from off-the-shelf medical data and electronic medical records (EMR).
The data used in this study are from ...299 infants admitted to the neonatal intensive care unit in the Monroe Carell Jr. Children's Hospital at Vanderbilt and evaluated for late-onset sepsis. Gold standard diagnostic labels (sepsis negative, culture positive sepsis, culture negative/clinical sepsis) were assigned based on all the laboratory, clinical and microbiology data available in EMR. Only data that were available up to 12 h after phlebotomy for blood culture testing were used to build predictive models using machine learning (ML) algorithms.
We compared sensitivity, specificity, positive predictive value and negative predictive value of sepsis treatment of physicians with the predictions of models generated by ML algorithms.
The treatment sensitivity of all the nine ML algorithms and specificity of eight out of the nine ML algorithms tested exceeded that of the physician when culture-negative sepsis was included. When culture-negative sepsis was excluded both sensitivity and specificity exceeded that of the physician for all the ML algorithms. The top three predictive variables were the hematocrit or packed cell volume, chorioamnionitis and respiratory rate.
Predictive models developed from off-the-shelf and EMR data using ML algorithms exceeded the treatment sensitivity and treatment specificity of clinicians. A prospective study is warranted to assess the clinical utility of the ML algorithms in improving the accuracy of antibiotic use in the management of neonatal sepsis.
Necrotizing enterocolitis (NEC) is the most common gastrointestinal emergency among premature infants. Although a large body of research has focused on understanding its pathogenesis, the exact ...mechanism has not been elucidated. Of particular interest is the potential causative role of infectious culprits in the development of NEC. A variety of reports describe bacterial, viral, and fungal infections occurring in association with NEC; however, no single organism has emerged as being definitively involved in NEC pathogenesis. In this review, the authors summarize the literature on infectious causes of NEC.
Necrotising enterocolitis (NEC) is the most common gastrointestinal emergency in premature infants. Immaturity of gastrointestinal immune regulation may predispose preterm infants to NEC as FOXP3 T ...regulatory cells (Treg) are critical for intestinal immune homoeostasis.
To investigate the hypothesis that abnormal developmental regulation of lamina propria Treg would define premature infants with NEC.
Lamina propria mononuclear cell populations from surgically resected ileum from 18 patients with NEC and 30 gestational age-matched non-NEC surgical controls were prospectively isolated. Polychromatic flow cytometry was performed to phenotype and analyse lamina propria T cell populations. The cytokine gene expression profile in NEC tissue was compared with that of non-NEC controls.
The total number of Treg, CD4, or CD8 T cells in each ileum section was independent of gestational age, age or postmenstrual age and similar between patients with NEC and controls. In contrast, the ratio of Treg to CD4 T cells or Treg to CD8 T cells was significantly lower in NEC ileum than in infants without NEC (medians 2.9% vs 6.6%, p=0.001 and medians 6.6% vs 25.9%, p<0.001, respectively). For any given number of CD4 or CD8 T cells, Treg were, on average, 60% lower in NEC ileum than in controls. NEC tissue cytokine gene expression profiles were characteristic of inhibited Treg development or function. Treg/CD4 and Treg/CD8 ratios recovered between initial resection for NEC and reanastomosis.
The proportion of lamina propria Treg is significantly reduced in the ileum of premature infants with NEC and may contribute to the excessive inflammatory state of this disease.
Bloodstream infection (BSI) among neonatal intensive care unit (NICU) infants is a frequent problem associated with poor outcomes. Monitoring for abnormal heart rate characteristics (HRCs) may ...decrease infant mortality by alerting clinicians to sepsis before it becomes clinically apparent.
HRC scores were acquired using the HRC (HeRO) monitor system from Medical Predictive Science Corporation and entered into the electronic medical record by bedside staff. We retrospectively analysed HRC scores recorded twice daily in the medical record during a 30-month period (1 January 2010 through 30 June 2012) for infants in the NICU at the Monroe Carell Jr. Children's Hospital at Vanderbilt. We identified infants that met Centers for Disease Control criteria for late-onset BSI (>3 days of life) during the study period.
During the study period, we recorded 127 673 HRC scores from 2384 infants. We identified 46 infants with BSI. Although 8% (9701/127 673) of the HRC scores were ≥2 and 1% (1387/127 673) were ≥5, BSI (at any time) was observed in just 5% of patients with HRC scores ≥2, and 9% of patients with HRC scores ≥5. Of infants with BSI, 5/46 (11%) had at least one HRC score ≥5 and 17/46 (37%) had at least one score ≥2 recorded in the 48 h period prior to the evaluation that resulted in the first positive blood culture of the episode.
In our single-centre retrospective study, elevated HRC scores had limited ability to detect BSI. BSI was infrequent at any time during hospitalisation in infants with significantly elevated HRC scores.
Necrotizing enterocolitis (NEC) is a leading cause of morbidity and mortality in premature infants. NEC is believed to occur when intestinal bacteria invade the intestinal epithelial layer, causing ...subsequent inflammation and tissue necrosis. Mucins are produced and secreted by epithelial goblet cells as a key component of the innate immune system and barrier function of the intestinal tract that help protect against bacterial invasion. To better understand the role of mucins in NEC, we quantified the number of mucus-containing small intestinal goblet cells present in infants with NEC and found they had significantly fewer goblet cells and Paneth cells compared with controls. To test whether inflammation has a developmentally dependent effect on intestinal goblet cells, TNF-α was injected into mice at various stages of intestinal development. TNF-α caused a loss of mucus-containing goblet cells only in immature mice and induced Muc2 and Muc3 mRNA upregulation only in mature ileum. Only minimal changes were seen in apoptosis and in expression of markers of goblet cell differentiation. TNF-α increased small intestinal mucus secretion and goblet cell hypersensitivity to prostaglandin E2 (PGE(2)), a known mucus secretagogue produced by macrophages. These TNF-α-induced changes in mucus mRNA levels required TNF receptor 2 (TNFR2), whereas TNF-α-induced loss of mucus-positive goblet cells required TNFR1. Our findings of developmentally dependent TNF-α-induced alterations on intestinal mucus may help explain why NEC is predominantly found in premature infants, and TNF-α-induced alterations of the intestinal innate immune system and barrier functions may play a role in the pathogenesis of NEC itself.
Infants with intrauterine growth restriction (IUGR) are at increased risk for neonatal and lifelong morbidities affecting multiple organ systems including the intestinal tract. The underlying ...mechanisms for the risk to the intestine remain poorly understood. In this study, we tested the hypothesis that IUGR affects the development of goblet and Paneth cell lineages, thus compromising the innate immunity and barrier functions of the epithelium. Using a mouse model of maternal thromboxane A2-analog infusion to elicit maternal hypertension and resultant IUGR, we tested whether IUGR alters ileal maturation and specifically disrupts mucus-producing goblet and antimicrobial-secreting Paneth cell development. We measured body weights, ileal weights and ileal lengths from birth to postnatal day (P) 56. We also determined the abundance of goblet and Paneth cells and their mRNA products, localization of cellular tight junctions, cell proliferation, and apoptosis to interrogate cellular homeostasis. Comparison of the murine findings with human IUGR ileum allowed us to verify observed changes in the mouse were relevant to clinical IUGR. At P14 IUGR mice had decreased ileal lengths, fewer goblet and Paneth cells, reductions in Paneth cell specific mRNAs, and decreased cell proliferation. These findings positively correlated with severity of IUGR. Furthermore, the decrease in murine Paneth cells was also seen in human IUGR ileum. IUGR disrupts the normal trajectory of ileal development, particularly affecting the composition and secretory products of the epithelial surface of the intestine. We speculate that this abnormal intestinal development may constitute an inherent "first hit", rendering IUGR intestine susceptible to further injury, infection, or inflammation.
Neonatal hypoxic-ischemic encephalopathy is an important cause of death as well as long-term disability in survivors. Erythropoietin has been hypothesized to have neuroprotective effects in infants ...with hypoxic-ischemic encephalopathy, but its effects on neurodevelopmental outcomes when given in conjunction with therapeutic hypothermia are unknown.
In a multicenter, double-blind, randomized, placebo-controlled trial, we assigned 501 infants born at 36 weeks or more of gestation with moderate or severe hypoxic-ischemic encephalopathy to receive erythropoietin or placebo, in conjunction with standard therapeutic hypothermia. Erythropoietin (1000 U per kilogram of body weight) or saline placebo was administered intravenously within 26 hours after birth, as well as at 2, 3, 4, and 7 days of age. The primary outcome was death or neurodevelopmental impairment at 22 to 36 months of age. Neurodevelopmental impairment was defined as cerebral palsy, a Gross Motor Function Classification System level of at least 1 (on a scale of 0 normal to 5 most impaired), or a cognitive score of less than 90 (which corresponds to 0.67 SD below the mean, with higher scores indicating better performance) on the Bayley Scales of Infant and Toddler Development, third edition.
Of 500 infants in the modified intention-to-treat analysis, 257 received erythropoietin and 243 received placebo. The incidence of death or neurodevelopmental impairment was 52.5% in the erythropoietin group and 49.5% in the placebo group (relative risk, 1.03; 95% confidence interval CI, 0.86 to 1.24; P = 0.74). The mean number of serious adverse events per child was higher in the erythropoietin group than in the placebo group (0.86 vs. 0.67; relative risk, 1.26; 95% CI, 1.01 to 1.57).
The administration of erythropoietin to newborns undergoing therapeutic hypothermia for hypoxic-ischemic encephalopathy did not result in a lower risk of death or neurodevelopmental impairment than placebo and was associated with a higher rate of serious adverse events. (Funded by the National Institute of Neurological Disorders and Stroke; ClinicalTrials.gov number, NCT02811263.).
Patients suffering from ulcerative colitis (UC) exhibit chronic colonic inflammation caused by a dysregulated mucosal immune response and epithelial barrier disruption. Th2 cytokines, including ...IL-13, have been implicated in the pathogenesis of UC. IL-13 induces phosphorylation of STAT6, and we previously demonstrated increased epithelial p-STAT6 in children with UC. In this study, we investigated the role of STAT6 in oxazolone colitis, a murine model of UC, by inducing colitis in STAT6-deficient (STAT6(-/-)) and wild type (WT) mice. We observed increased epithelial cell, T cell, macrophage, and NKT cell STAT6 phosphorylation, as well as increased p-STAT6(+) IL-13-producing NKT cells, in colitic WT mice. Colitis was attenuated in STAT6(-/-) mice, with improvements in weight, colon length, and histopathology. There was decreased induction of the pore-forming tight junction protein claudin-2 in STAT6(-/-) mice. Similarly, short hairpin RNA STAT6 knockdown reduced claudin-2 induction and transepithelial resistance decrease in IL-13-treated human T84 cells. Tissue expression of IL-13, IFN-γ, IL-17, and IL-10 mRNA was similarly induced in WT and STAT6(-/-) colitic mice; however, we observed increased mRNA expression for the Th2-inducing cytokines IL-33 and thymic stromal lymphopoietin in WT mice with colitis, which was abrogated in STAT6(-/-) mice. Mesenteric lymph node cells from STAT6(-/-) mice with colitis exhibited reduced secretion of IL-4, IL-5, IL-13, and IFN-γ. IL-33 augmented mesenteric lymph node cell secretion of IL-5, IL-13, IL-6, and IFN-γ. These data implicate STAT6 in the pathogenesis of colitis in vivo with important roles in altering epithelial barrier function and regulating Th2-inducing cytokine production.
According to recent research, brain injury after premature birth often includes impaired growth of the cerebellum. However, causes of cerebellar injury in this population are poorly understood. In ...this study, we analyzed whether postnatal hyperoxia perturbs white matter development of the cerebellum, and whether cerebellar glial damage can be prevented by minocycline. We used a hyperoxia model in neonatal rats providing 24 h exposure to fourfold increased oxygen concentration (80% O2) from P6 to P7, followed by recovery in room air until P9, P11, P15, P30. Injections with minocycline were performed at the beginning and 12 h into hyperoxia exposure. Hyperoxia induced oxidative stress in the cerebellum at P7 as evidenced by increased nitrotyrosine concentrations. Numbers of proliferating, NG2+Ki67+ oligodendroglial precursor cells were decreased at P7 after hyperoxia and at P11 following recovery in room air. Numbers of mature, CC1+ oligodendrocytes were diminished in recovering hyperoxia rats, and myelin basic protein expression was still decreased at P30. Electron microscopy analysis of myelinated fibers at P30 revealed thinner myelin sheath after hyperoxia. Long‐term injury of the cerebellum by neonatal hyperoxia was confirmed by reduced volumes in MRI measurements at P30. In response to 80% O2, expression of platelet‐derived growth factor (PDGF)‐A was largely reduced in cerebellar tissue and also in cultured cerebellar astrocytes. Treatment with minocycline during hyperoxia prevented oxidative stress, attenuated oligodendroglial injury, and improved astroglial PDGF‐A levels. In conclusion, early hyperoxia causes white matter damage in the cerebellum with astroglial dysfunction being involved, and both can be prevented by treatment with minocycline. Neonatal exposure to hyperoxia causes hypomyelination of the cerebellum. Reduced astroglial growth factor production but not microglial inflammation seems to contribute to oligodendroglial damage, and minocycline rescues oligodendroglia development in the cerebellum after hyperoxia. GLIA 2015;63:1825–1839
Main Points
Neonatal exposure to hyperoxia causes hypomyelination of the cerebellum.
Reduced astroglial growth factor production but not microglial inflammation seems to contribute to oligodendroglial damage, and minocycline rescues oligodendroglia development in the cerebellum after hyperoxia.
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