Neonatal Enterocolitis Research Articles

Gut mucosal injury in neonates is marked by macrophage infiltration in contrast to pleomorphic infiltrates in adult: evidence from an animal model

Necrotizing enterocolitis (NEC) is an inflammatory bowel necrosis of premature infants. In tissue samples of NEC, we identified numerous macrophages and a few neutrophils but not many lymphocytes. We hypothesized that these pathoanatomic characteristics of NEC represent a common tissue injury response of the gastrointestinal tract to a variety of insults at a specific stage of gut development. To evaluate developmental changes in mucosal inflammatory response, we used trinitrobenzene sulfonic acid (TNBS)-induced inflammation as a nonspecific insult and compared mucosal injury in newborn vs. adult mice. Enterocolitis was induced in 10-day-old pups and adult mice (n = 25 animals per group) by administering TNBS by gavage and enema. Leukocyte populations were enumerated in human NEC and in murine TNBS-enterocolitis using quantitative immunofluorescence. Chemokine expression was measured using quantitative polymerase chain reaction, immunoblots, and immunohistochemistry. Macrophage recruitment was investigated ex vivo using intestinal tissue-conditioned media and bone marrow-derived macrophages in a microchemotaxis assay. Similar to human NEC, TNBS enterocolitis in pups was marked by a macrophage-rich leukocyte infiltrate in affected tissue. In contrast, TNBS-enterocolitis in adult mice was associated with pleomorphic leukocyte infiltrates. Macrophage precursors were recruited to murine neonatal gastrointestinal tract by the chemokine CXCL5, a known chemoattractant for myeloid cells. We also demonstrated increased expression of CXCL5 in surgically resected tissue samples of human NEC, indicating that a similar pathway was active in NEC. We concluded that gut mucosal injury in the murine neonate is marked by a macrophage-rich leukocyte infiltrate, which contrasts with the pleomorphic leukocyte infiltrates in adult mice. In murine neonatal enterocolitis, macrophages were recruited to the inflamed gut mucosa by the chemokine CXCL5, indicating that CXCL5 and its cognate receptor CXCR2 merit further investigation as potential therapeutic targets in NEC.

Probiotics

Mr. Lomangino has disclosed that he has been a consultant to the Foundation for Informed Medical Decision Making. He also has disclosed that probiotics are not approved by the FDA for prevention of necrotizing enterocolitis in preterm neonates.

Effect of routine probiotic, Lactobacillus reuteri DSM 17938, use on rates of necrotizing enterocolitis in neonates with birthweight < 1000 grams: a sequential analysis

Effect of routine probiotic, Lactobacillus reuteri DSM 17938, use on rates of necrotizing enterocolitis in neonates with birthweight < 1000 grams: a sequential analysis

Transfusion-Related Acute Gut Injury: Necrotizing Enterocolitis in Very Low Birth Weight Neonates after Packed Red Blood Cell Transfusion

Transfusion-Related Acute Gut Injury: Necrotizing Enterocolitis in Very Low Birth Weight Neonates after Packed Red Blood Cell Transfusion

Probiotics for Preventing Necrotizing Enterocolitis in Preterm Neonates- a Meta-Analysis Perspective

Probiotics for Preventing Necrotizing Enterocolitis in Preterm Neonates- a Meta-Analysis Perspective

Macrophage Migration Inhibitory Factor -173 G/C Polymorphism is Not Associated with An Increased Risk of Necrotizing Enterocolitis in Preterm Neonates in NICU

Background: Necrotizing Enterocolitis (NEC) is a leading cause of morbidity and mortality among preterm neonates. To identify subsets of neonates at high risk of NEC is a challenge. Local pro-inflammatory response of the host could be of relevance in the still unclear pathogenesis of NEC. Macrophage migration inhibitory factor (MIF) is a pro-inflammatory cytokine, implicated in the pathophysiology of inflammatory bowel diseases, such as chronic colitis and gastric inflammation. The MIF promoter contains a functionally relevant single nucleotide polymorphism (SNP) G/C at position -173. The MIF -173 C allele is associated with higher MIF expression in vitro.

Oral lactoferrin for the treatment of sepsis and necrotizing enterocolitis in neonates

Neonatal sepsis and necrotizing enterocolitis (NEC) cause significant neonatal mortality and morbidity in spite of appropriate antibiotic therapy. Enhancing host defence and modulating inflammation by using lactoferrin as an adjunct to antibiotics in the treatment of sepsis and/or NEC may improve clinical outcomes. The primary objective is to assess safety and efficacy of oral lactoferrin as an adjunct to antibiotics in the treatment of neonates with suspected or confirmed sepsis and/or NEC. Relevant trials in any language were searched in July 2011 in the Cochrane Central Register of Controlled Trials (CENTRAL, The Cochrane Library), MEDLINE, PREMEDLINE, EMBASE, CINAHL, web sites: www.clinicaltrials.gov and www.controlled-trials.com, abstracts from the annual meeting of Pediatric Academic Societies (1990 to July 2011), by contacting authors who have published in this field, from the reference lists of identified clinical trials and in the reviewer's personal files. Randomized or quasi-randomized controlled trials evaluating oral lactoferrin (at any dose or duration) used as an adjunct to antibiotic therapy compared with antibiotic therapy alone (with or without placebo) or other adjuncts to antibiotic therapy to treat neonates at any gestational age up to 44 weeks postmenstrual age with confirmed or suspected sepsis or necrotizing enterocolitis (Bell's Stage II or III). We used the standardized methods of the Cochrane Neonatal Review Group (CNRG) for conducting a systematic review and for assessing the methodological quality of the studies (http://neonatal.cochrane.org/en/index.html). The titles and the abstracts of studies identified by the search strategy were independently assessed by the two review authors and full text version was obtained for assessment if necessary. Forms were designed for trial inclusion/exclusion and data extraction. We did not identify any eligible neonatal trial evaluating lactoferrin for treatment of neonatal sepsis or NEC. Currently there is no evidence to recommend or refute the use of lactoferrin for the treatment of neonatal sepsis or necrotizing enterocolitis as an adjunct to antibiotic therapy. The safety and efficacy of different preparations and doses of lactoferrin need to be established in neonates. Well designed adequately powered randomized multicenter trials are needed to address the efficacy and safety of lactoferrin in the treatment of neonatal sepsis and necrotizing enterocolitis. These trials should evaluate long-term neurodevelopmental and pulmonary outcomes in addition to short-term outcomes.

Different feeding regimens could affect the development of necrotizing enterocolitis in preterm neonates

Nutrition: Different feeding regimens could affect the development of necrotizing enterocolitis in preterm neonates

Cytomegalovirus enterocolitis presenting as abdominal compartment syndrome in a premature neonate

Cytomegalovirus (CMV) enterocolitis is an uncommon intestinal disorder of newborns that is often initially misdiagnosed as necrotizing enterocolitis. We treated a premature twin boy with CMV enterocolitis who presented with abdominal compartment syndrome requiring urgent decompression. All patients with neonatal CMV enterocolitis reported were reviewed. Nine previously reported patients with neonatal CMV enterocolitis presented with abdominal distention and signs of sepsis. At the time of surgery, either perforation or stricture was identified. The current report is the first to present with clinical signs of abdominal compartment syndrome. CMV is a rare cause of neonatal enterocolitis. Surgical intervention is required for bowel perforation, stricture, or abdominal compartment syndrome.

Fetal lipopolysaccharide exposure modulates diet-dependent gut maturation and sensitivity to necrotising enterocolitis in pre-term pigs

Uterine infections during pregnancy predispose to pre-term birth and postnatal morbidity, but it is unknown how prenatal bacterial exposure affects maturation of the immature gut. We hypothesised that a prenatal exposure to gram-negative lipopolysaccharide (LPS) has immunomodulatory effects that improve resistance towards necrotising enterocolitis (NEC) in pre-term neonates. At approximately 85% gestation, pig fetuses were injected intramuscularly with saline or LPS (0·014mg/kg), or intra-amniotically with LPS (0·4mg/kg). Pigs were delivered by caesarean section 3-5d later and fed colostrum (C) or formula (F) for 48h. Gut indices did not differ between pigs injected intramuscularly with saline or LPS, and these groups were therefore pooled into two control groups according to diet (control-F, n 32 and control-C, n 11). Control-F pigs showed reduced villus heights, mucosal structure, gut integrity, digestive enzymes, elevated NEC incidence (38 v. 0%, P<0·05) and several differentially expressed immune-related genes, relative to control-C pigs. Compared with the control-F and control-C groups, values in formula-fed pigs given intra-amniotic LPS formula (n 17) were intermediate for villus height, enzyme activities, intestinal permeability and NEC incidence (18%, P=0·2 relative to control-F), and numbers of differentially expressed immune genes. In conclusion, prenatal exposure of the fetal gut to Gram-negative bacteria may modulate the immediate postnatal response to an enteral diet and colonising bacteria.

Red blood cell transfusion, feeding and necrotizing enterocolitis in preterm infants

Preliminary studies suggested an association between red blood cell (RBC) transfusion and necrotizing enterocolitis (NEC) in premature neonates. An advantageous effect of withholding feeds during transfusion has never been studied. We aimed, first, to determine whether preterm infants who developed NEC were more likely to be transfused in the 48 to 72 h before the diagnosis of NEC; second, to test if a strict policy of withholding feeds during transfusion would decrease the incidence of transfusion-associated NEC. The study was conducted in two phases. Phase 1: a retrospective case-control study of premature low-birth weight (<32 weeks and <2500 g) infants who developed NEC over a 6-year period. Phase 2: a comparison study of the incidence of NEC during the 18-months preceding, and the 18 months following the change of practice to withholding feeds during RBC transfusion. In the case-control study (25 infants with NEC and 25 controls), more infants in the NEC group received transfusions in the 48 and 72 h preceding diagnosis (56 vs 20% within 48 h, P=0.019; and 64 vs 24% within 72 h, P=0.01). The total number of transfusions and age of RBCs were not different between the two groups. Implementing the policy of withholding feeds during transfusion was associated with a decrease in the incidence of NEC from 5.3 to 1.3% (P=0.047). Infants who developed NEC frequently received RBC transfusions in the 48 and 72 h preceding presentation of NEC. A strict policy of withholding feeds during transfusion may have a protective effect from NEC.

Necrotizing enterocolitis in neonates undergoing the hybrid approach to complex congenital heart disease*

To investigate the prevalence of necrotizing enterocolitis (NEC) in neonates undergoing the Stage I hybrid procedure for palliation of complex congenital heart disease (CHD). Neonates undergoing the Norwood surgery for hypoplastic left-heart syndrome have the highest risk for NEC of all CHD patients. The hybrid procedure is another palliative option for hypoplastic left-heart syndrome, but NEC in neonates undergoing this procedure has not been reported. Retrospective chart review of 73 neonates who underwent the hybrid procedure for palliation of complex CHD. Demographic, perinatal, perioperative, clinical, and procedural data were collected. NEC was defined as modified Bell's Stage II and above. The cardiothoracic and neonatal intensive care units in a large free-standing children's hospital. All neonates who underwent the hybrid Stage I procedure for the palliation of complex CHD from April 2002 through April 2008. Seventy-three neonates were reviewed and 11.0% (eight of 73) developed NEC. Of the patients with NEC, 37.5% (three of eight) died and two patients required abdominal surgery. Earlier gestational age (< 37 wks), lower maximum dose of prostaglandin infusion, and unexpected readmission to the intensive care unit were statistically associated with NEC (p = .009, 0.02, and 0.04, respectively). No other demographic, perinatal, perioperative, clinical, or procedural variables were associated with the development of NEC in this patient population, including enteral feeding regimens, umbilical artery catheters, inotrope use, and average oxygen saturation and diastolic blood pressure. The prevalence of NEC in patients undergoing the hybrid procedure is comparable to that reported for neonates undergoing the Norwood procedure. Earlier gestational age is a significant risk factor for NEC in patients who undergo the hybrid Stage I procedure. Multidisciplinary approaches to better understand abdominal complications and to develop feeding regimens in neonates undergoing the hybrid approach to complex CHD are needed to improve outcomes and decrease morbidities.

Transfusion-Related Acute Gut Injury: Necrotizing Enterocolitis in Very Low Birth Weight Neonates after Packed Red Blood Cell Transfusion

Transfusion-Related Acute Gut Injury: Necrotizing Enterocolitis in Very Low Birth Weight Neonates after Packed Red Blood Cell Transfusion

Preterm Birth and Necrotizing Enterocolitis Alter Gut Colonization in Pigs

Necrotizing enterocolitis (NEC) in preterm neonates is dependent on bacterial colonization, but it remains unclear whether a particular microbiota or specific pathogens are involved. We hypothesized that gut colonization differs between preterm and term neonates and that overgrowth of Clostridium perfringens predisposes to NEC. By using terminal-RFLP and FISH, we characterized the gut microbiota of preterm, caesarean-delivered, formula-fed pigs (n = 44) with or without NEC and of formula- or colostrum-fed term, and vaginally born pigs (n = 13). A different microbiota with high C. perfringens abundance was observed in preterm pigs with NEC compared with healthy individuals. However, immunization against C. perfringens toxins did not prevent NEC, and C. perfringens inoculation (3.6 × 10 cfu/d) failed to induce NEC (n = 16), whereas prophylactic broad-spectrum antibiotics treatment prevented NEC (n = 24). Colonization in both groups of term pigs differed from preterm pigs and was dominated by Lactobacilli spp. In conclusion, gestational age (GA) and NEC influence neonatal gut colonization, whereas diet has minor effects. C. perfringens is more abundant in pigs with NEC but rather as a consequence than a cause of disease. The general bacterial load and underdeveloped gut immune responses in preterm neonates seem more important for NEC development than specific pathogens.

79 Mannose Binding Lectin (MBL) Yy Genotype is Associated with An Increased Risk of Necrotizing Enterocolitis(NEC) in Preterm Neonates in NICU

Background: MBL initiates complement activation and could have a role in the pathogenesis of ischemia-reperfusion pathologies, such as NEC. We investigated the association between MBL2 genotype, the development of NEC and the MBL expression on specimens of bowel tissue in a cohort of preterm neonates in NICU. Material and methods: We determined the MBL2 genotype in 118 preterm neonates admitted in NICU. The exon 1 SNPs 52,54, 57 and SNPs -550 and - 221 of the promoter region of the MBL2 gene were also determined. Immunoistochemical analysis was performed on 16 bowel bioptic paraffin-embedded specimens, collected during surgery in neonates with NEC. Clinical cases and summary results:21/118 neonates developed NEC. The analysis of the polymorphisisms in the promoter region at -221(variant X/Y) showed that the frequency of the YY genotype was 85.7% in the neonates with NEC and 53.6% in the controls(p=0.013). Adjusting for gestational age, the association between YY genotype and the development of NEC was still significant(OR=5.02;p=0.015). MBL was highly expressed in anastomotic healthy tissue, in enterocytes and istiocytes. No MBL staining was detectable in the necrotic bowel tissue. Neonates MBL low and deficient producer showed negligible or weak staining for MBL. Conclusions: YY genotype of the promoter of the MBL2 gene appeared to increase the risk of developing NEC. The epithelial localization of MBL in the bowel is consistent with a role for MBL in developing full-thickness necrosis during NEC.

Does abdominal sonography provide additional information over abdominal plain radiography for diagnosis of necrotizing enterocolitis in neonates?

To explore whether addition of abdominal sonography (AUS) to plain radiography is helpful in the management of premature newborns with necrotizing enterocolitis (NEC). This study is a prospective analysis of 93 premature neonates with NEC who were followed-up in our neonatal intensive care unit between October 2007 and April 2009. Patients were classified into two groups; group I with suspected NEC (stage I) (n=54) and group II with definite NEC (stage≥II) (n=39). Pneumatosis intestinalis (PI) (n=29), free air (n=9), and portal venous gas (PVG) (n=1) were observed in group II on plain radiography. In the same group, echoic free fluid (EFF) (n=9), PVG (n=6), PI (n=5), and focal fluid collection (n=3) were the most prominent sonographic findings. In patients with intestinal perforation, whereas EFF and bowel wall thinning were observed on AUS, free air was not detected on plain radiography as a sign of intestinal perforation. Our results suggest AUS to be superior to plain radiography on early detection of intestinal perforation by demonstrating PVG and EFF collection. Therefore, it may be life-saving by directing the surgeon to perform surgical intervention in the case of clinical deterioration in the course of NEC.

Pentoxifylline in Preterm Neonates

Sepsis, necrotizing enterocolitis (NEC), and chronic lung disease (CLD) in preterm neonates are associated with significant mortality and morbidity, including long-term neurodevelopmental impairment and socioeconomic burden. Safe and effective drugs for the prevention and treatment of these conditions are urgently needed. Pentoxifylline, a synthetic theobromine derivative, is a non-steroidal immunomodulating agent with unique hemorrheologic effects which has been used in a range of infectious, vascular, and inflammatory conditions in adults and children. The unique properties of pentoxifylline explain its potential benefits in preterm neonates with sepsis, NEC, and CLD, conditions characterized by activation of the inflammatory cytokine cascade, free radical toxicity, and impaired microcirculation. Pentoxifylline has anti-inflammatory properties resulting from inhibition of erythrocyte phosphodiesterase. It lowers blood viscosity and improves microcirculation and tissue perfusion. As a phosphodiesterase inhibitor, pentoxifylline downregulates pro-inflammatory cytokines such as tumor necrosis factor-alpha, interleukin-6, and interferon-gamma. Methylxanthines, including caffeine, theophylline, and theobromine are relatively non-toxic drugs; of these, theobromine is the least toxic. Pentoxifylline-related significant adverse events are thus very rare. Unlike other methylxanthines, pentoxifylline does not have significant cardiac and bronchodilating effects at therapeutic doses. Although it is contraindicated in adults with recent cerebral hemorrhage due to its effect on platelets, red blood cells, and plasma fibrinogen levels, no significant adverse effects including thrombocytopenia and bleeding have been reported in critically ill preterm neonates with sepsis or NEC after treatment with pentoxifylline. Based on data from pilot randomized trials and observational studies, our systematic review suggests that pentoxifylline may reduce mortality and/or morbidity in preterm neonates with sepsis, NEC, and CLD. Results of experimental studies also indicate that pentoxifylline may potentially be beneficial in meconium aspiration syndrome and hypoxic ischemic encephalopathy. Given the substantial burden of sepsis, NEC, and CLD in high-risk preterm neonates, and the findings of this systematic review, pentoxifylline needs to be evaluated urgently as a preventative and therapeutic agent for these conditions in randomized controlled trials that can detect minimal clinically significant effect sizes. Further clinical and experimental studies are also necessary to evaluate whether pentoxifylline is safe and effective in meconium aspiration syndrome and hypoxic ischemic encephalopathy.

Noninvasive evaluation of splanchnic tissue oxygenation using near-infrared spectroscopy in preterm neonates

Background. Diagnosis of necrotizing enterocolitis (NEC) in preterm neonates is challenging. We hypothesized that regional splanchnic oxygen saturation (rsSO2) measured by near-infrared spectroscopy (NIRS) is a biomarker for mesenteric perfusion.Objective. To evaluate feasibility and safety of continuous rsSO2 monitoring in preterm infants in the first 14 days of life.Methods. Preterm neonates ≤30 weeks' gestation had a NIRS sensor placed in the left paraumbilical region within 48 h of birth. rsSO2 was recorded every 30 s. Clinical data including pulse oximetry (SaO2) were recorded. Fractional tissue oxygen extraction (FTOE) was computed as follows: (SaO2 − rsSO2) × 100/SaO2.Results. Of 21 infants enrolled, 2 were excluded because of skin breakdown and missing data. Daily mean rsSO2 values decreased over the first 9 days (p < 0.0001) followed by an increase from day 10 (D10) to D14 (p = 0.0061). rsSO2 was lower and FTOE was higher in infants with feeding intolerance compared to those without feeding intolerance (p = 0.0043). rsSO2 accounted for ≥99.5% of the variance in FTOE. Two neonates with NEC had persistently low rsSO2 with loss of variability preceded or followed by very high rsSO2.Conclusions. We have reported feasibility, safety and ranges for rsSO2 for a small number of preterm infants in the first 2 weeks of life.

New biomarkers to identify septicemia and necrotizing enterocolitis in preterm neonates

Apolipoprotein CII and serum amyloid A (host-response biomarkers) might be useful for the early identification of septicemia and necrotizing enterocoiltis in preterm neonates, a study in Hong Kong has found.

Monogenic autoinflammatory diseases: new insights into clinical aspects and pathogenesis.

The genetic and clinical characterizations of monogenic autoinflammatory syndromes have led to ground breaking insights into the regulation of inflammatory responses to endogenous and exogenous inducers or triggers of inflammation and continue to uncover key inflammatory pathways of the innate immune system. This article summarizes recent progress in the clinical aspects and understanding of the pathogenesis of this growing spectrum of diseases. The understanding of the spectrum of organ manifestations in autoinflammation was expanded by the discovery of two novel monogenic diseases both caused by the absence of an anti-inflammatory signal and added evidence that increased IL-1 signaling can cause aseptic osteolytic bone lesions and that the absence of IL-10 signaling causes inflammatory enterocolitis in neonates. New knock in animal models for TNF-receptor-associated periodic syndrome, and familial Mediterranean fever and cryopyrin-associated periodic syndromes allow insights into the complexity of the dysregulated immune pathways. Exploring 'triggers' of the NLRP3 inflammasome spurred studies of tissue inflammation in diseases including gout and those that previously have not been considered inflammatory in nature such as diabetes, fibrosing lung disease and possibly coronary artery disease. The genetic characterization of a growing number of monogenic autoinflammatory diseases has provided important insights into the phenotypic expression of single gene disorders and the complexity of the dysregulated inflammatory pathways leading to clinical disease. Knowledge obtained from these disorders is pertinent to a number of common disorders and provides new targets for drug development.