Systemic inflammation associated with severe intestinal injury in extremely low gestational age newborns (original) (raw)
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Cytokines associated with necrotizing enterocolitis in extremely-low-birth-weight infants
Pediatric Research, 2014
The goal was to identify cytokines associated with necrotizing enterocolitis (NEC). Based on our earlier reports of decreased tissue expression of transforming growth factor (TGF)-β, we hypothesized that infants with NEC also have low blood TGF-β levels. We further hypothesized that because fetal inflammation increases the risk of NEC, infants who develop NEC have elevated blood cytokine levels in early neonatal period. Methods: Data on 104 extremely-low-birth-weight infants with NEC and 893 without NEC from 17 centers were analyzed. Clinical information was correlated with blood cytokine levels on postnatal day 1 (D1), D3, D7, D14, and D21. results: Male gender, non-Caucasian/non-African American ethnicity, sepsis, lower blood TGF-β and interleukin (IL)-2 levels, and higher IL-8 levels were associated with NEC. The NEC group had lower TGF-β levels than controls since D1. The diagnosis of NEC was associated with elevated IL-1β, IL-6, IL-8, IL-10, monocyte chemoattractant protein-1/CC-motif ligand-2, macrophage inflammatory protein-1β/CC-motif ligand-3, and C-reactive protein. conclusion: Clinical characteristics, such as gender and ethnicity, and low blood TGF-β levels are associated with higher risk of NEC. Infants who developed NEC did not start with high blood levels of inflammatory cytokines, but these rose mainly after the onset of NEC.
Journal of Pediatric Surgery, 2011
Purpose: The aim of this study was to compare the efficacy of serum amyloid A (SAA) with that of Creactive protein (CRP), and procalcitonin (PCT) in diagnosis and follow-up of necrotizing enterocolitis (NEC) in preterm infants. Methods: A total of 152 infants were enrolled into this observational study. The infants were classified into 3 groups: group 1 (58 infants with NEC and sepsis), group 2 (54 infants with only sepsis), and group 3 (40 infants with neither sepsis nor NEC, or control group). The data including whole blood count, CRP, PCT, SAA, and cultures that were obtained at diagnosis (0 hour), at 24 and 48 hours, and at 7 and 10 days were evaluated. Results: A total of 58 infants had a diagnosis of NEC. Mean CRP (7.4 ± 5.2 mg/dL) and SAA (46.2 ± 41.3 mg/dL) values of infants in group 1 at 0 hour were significantly higher than those in groups 2 and 3. Although the area under the curve of CRP was higher at 0 hour in infants with NEC, there were no significant differences between groups with respect to the areas under the curve of SAA, CRP, and PCT at all measurement times. Levels of SAA decreased earlier than CRP and PCT in the follow-up of NEC (mean SAA levels were 45.8 ± 45.2, 21.9 ± 16.6, 10.1 ± 8.3, and 7.9 ± 5.1 mg/dL at evaluation times, respectively). Levels of CRP and SAA of infants with NEC stages II and III were significantly higher than those with only sepsis and/or NEC stage I. Conclusions: Serum amyloid A, CRP, and PCT all are accurate and reliable markers in diagnosis of NEC, in addition to clinical and radiographic findings. Higher CRP and SAA levels might indicate advanced stage of NEC. Serial measurements of SAA, CRP, and PCT, either alone or in combination, can be used safely in the diagnosis and follow-up of NEC.
Nutrients
Necrotizing enterocolitis (NEC), spontaneous intestinal perforation (SIP) and meconium-related ileus (MI) requiring surgical intervention are associated with a high risk of severe short- and long-term complications in very-low-birth-weight (VLBW) infants including poor growth, cholestasis and neurodevelopmental impairment. This retrospective study aimed to identify risk factors for such complications in a cohort of 55 VLBW preterm infants requiring surgery with enterostomy creation due to NEC, SIP or MI. Long-term follow-up was available for 43 (78%) infants. Multiple regression analyses revealed that the duration of inflammation and longitudinal growth determined the risk of cholestasis and neurodevelopmental outcome at 2 years corrected age independent of the aetiology of the intestinal complication. Direct bilirubin increased by 4.9 μmol/L (95%CI 0.26–9.5), 1.4 μmol/L (95%CI 0.6–2.2) and 0.8 μmol/L (95%CI 0.22–1.13) with every day of elevated (Interleukin-6) IL-6, (C-reactive pro...
Necrotizing enterocolitis is associated with neonatal intestinal injury
Journal of Pediatric Surgery, 2011
PURPOSE: We hypothesized that a subset of premature newborns has subclinical, intestinal mucosal compromise that predisposes to the development of necrotizing enterocolitis (NEC) days or weeks later. METHODS: Fifty-five newborns of 23 to 36 weeks' gestational age were identified, and urine was collected over the first 90 hours of life. The urinary concentration of intestinal fatty acid binding protein (iFABP(u)), a sensitive marker for intestinal injury, was determined. The diagnosis of NEC was based upon clinical condition, pathology, and/or imaging findings. RESULTS: Neonatal iFABP(u) exceeded 800 pg/mL in 27 subjects, including 9 of 9 who subsequently developed stage 2 or 3 NEC. This degree of iFABP(u) elevation, but not asphyxia, was significantly associated with the development of NEC (P < .01). CONCLUSION: In this population of premature newborns, there was a substantial incidence of intestinal mucosal compromise. All infants who subsequently developed stage 2 or 3 NEC had an elevated iFABP(u). This finding suggests a model for the pathogenesis of some cases of NEC, whereby perinatal mucosal injury predisposes to further damage when feedings are initiated. In addition, neonatal iFABP(u) assessment may represent a tool to identify infants at the highest risk for NEC and allow for the institution of focused, preventive measures.
ImpactLate-onset sepsis and necrotizing enterocolitis (NEC) in very low birth weight (VLBW, <1500g) premature infants can result in severe morbidity and mortality. Diagnosis is challenging due to overlap with non-infectious conditions, leading to a delayed or unnecessary antibiotic use.In a single-center cohort of VLBW infants, inflammatory biomarkers were elevated at the time of sepsis due to Gram-negative sepsis or NEC, but not other sepsis; compared to times without sepsis or NEC.Physiomarkers of sepsis correlate with some biomarkers of sepsis, and combining their information could help in the early diagnosis of sepsis.BackgroundEarly diagnosis of late-onset sepsis (LOS) and necrotizing enterocolitis (NEC) in VLBW (<1500g) infants is challenging due to non-specific clinical signs. Inflammatory biomarkers increase in response to infection, but non-infectious conditions also cause inflammation in premature infants. Physiomarkers of sepsis exist in cardiorespiratory data and m...
PLoS ONE, 2011
Necrotizing enterocolitis (NEC) is a devastating neonatal intestinal inflammatory disease, occurring primarily in premature infants, causing significant morbidity and mortality. The pathogenesis of NEC is associated with an excessive inflammatory IL-8 response. In this study, we hypothesized that this excessive inflammatory response is related to an immature expression of innate immune response genes. To address this hypothesis, intestinal RNA expression analysis of innate immune response genes was performed after laser capture microdissection of resected ileal epithelium from fetuses, NEC patients and children and confirmed in ex vivo human intestinal xenografts. Changes in mRNA levels of toll-like receptors (TLR)-2 and-4, their signaling molecules and transcription factors (MyD88, TRAF-6 and NFkB1) and negative regulators (SIGIRR, IRAK-M, A-20 and TOLLIP) and the effector IL-8 were characterized by qRT-PCR. The expression of TLR2, TLR4, MyD88, TRAF-6, NFkB1 and IL-8 mRNA was increased while SIGIRR, IRAK-M, A-20 and TOLLIP mRNA were decreased in fetal vs. mature human enterocytes and further altered in NEC enterocytes. Similar changes in mRNA expression were observed in immature, but not mature, human intestinal xenografts. Confirmation of gene expression was also validated with selective protein measurements and with suggested evidence that immature TRL4 enterocyte surface expression was internalized in mature enterocytes. Cortisone, an intestinal maturation factor, treatment corrected the mRNA differences only in the immature intestinal xenograft. Using specific siRNA to attenuate expression of primary fetal enterocyte cultures, both TOLLIP and A-20 were confirmed to be important when knocked down by exhibiting the same excessive inflammatory response seen in the NEC intestine. We conclude that the excessive inflammatory response of the immature intestine, a hallmark of NEC, is due to a developmental immaturity in innate immune response genes.
Journal of Pediatric Surgery, 2007
Background/Purpose: Failure of the gut barrier and endotoxemia have been implicated in sepsis and multiple organ failure (MOF) syndromes in adults. The contributions of endotoxin (ETX) and proinflammatory cytokines (CKs) to the pathophysiology of disease and the outcomes of infants in the neonatal intensive care unit (NICU) are not clear. We measured ETX and CK concentrations in infants who presented with clinical signs of sepsis and/or necrotizing enterocolitis (NEC) to study their impact on MOF and outcomes. Methods: Blood samples from infants with signs of NEC and/or sepsis were collected for culture and determination of complete blood cell counts and concentrations of CKs (interleukin [IL]-1b, tumor necrosis factor [TNF] a, and IL-6) and ETX at the onset of illness. Infants with signs of sepsis but without those of NEC were classified by blood culture results into a confirmed sepsis group (ie, positive culture) or a control group (ie, negative culture). Endotoxin concentrations were determined by chromogenic Limulus amebocyte lysate assay, and CK levels were quantitated by enzyme-linked immunoassay. Data are expressed as mean F SD and as odds ratios (ORs) with 95% confidence intervals (CIs). P values lower than .05 were considered to be significant. Results: There was no demographic or clinical difference among the NEC (n = 27), sepsis (n = 44), and control (n = 56) groups, except that fewer (P = .02) infants in the NEC group (11%) had received maternal milk feedings as compared with infants in the sepsis group (23%) and those in the control group (39%). Endotoxin concentrations were higher (P b .0001) in the NEC group (3.30 F 2.11) as compared with the sepsis group (0.67 F .86) and the control group (0.09 F 0.24). Generalized linear regression analysis using formula feeding, mechanical ventilation, and Gram-negative bacteremia as covariates demonstrated that NEC increased ETX concentrations independently (r = .80; P b .0001). Endotoxemia correlated with higher concentrations of all 3 CKs (P b .0001). There was an inverse
Rapid immune perturbations during sepsis and necrotising enterocolitis in preterm babies
Research Square (Research Square), 2022
Deaths complicated by infection are a major cause of mortality in preterm babies. Here we study the influence of bacterial sepsis and the gut inflammatory disorder necrotising enterocolitis (NEC), frequently associated with bacterial complications, on host immune dysregulation in extremely preterm babies. We identify a peripheral blood immune signature that distinguishes sepsis and NEC from other cases of suspected, though microbiologically unconfirmed, sepsis. Some signature traits could even make this distinction in babies with low or undetectable C-reactive protein, a common clinical test to alert infection. Our analysis incorporates longitudinal single-cell genomic evaluation of peripheral blood immune cells, elucidating amphiregulin as a key differentially expressed gene during sepsis and NEC, which was validated as a plasma analyte that correlated with disease-associated clinical signs. Collectively, signature immune traits provide insight into dysregulated sepsis and NECassociated pathways and highlight candidate markers, pending validation, that could improve diagnostic-led, targeted antibiotic prescribing.
Neonatal Necrotizing Enterocolitis – Inflammation and Intestinal Immaturity
Anti-Inflammatory & Anti-Allergy Agents in Medicinal Chemistry, 2009
Neonatal necrotizing enterocolitis is a devastating inflammatory bowel disease of premature infants. The pathogenesis remains incompletely understood and there is no specific treatment. Efforts are ongoing to understand aspects of intestinal immaturity which contribute to susceptibility to this disease. This review focuses on bacterial colonization patterns, intestinal barrier function, and inflammatory responses of immature enterocytes leading to a unique vulnerability of the preterm gut. In addition the possible therapeutic potential of factors in human milk and probiotic bacteria is discussed.