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Prof Sanjay Patole, MD, DCH, FRACP, MSc, DrPH Centre for Neonatal Research and Education

Ad vances in necrotising enterocolitis. Prof Sanjay Patole, MD, DCH, FRACP, MSc, DrPH Centre for Neonatal Research and Education KEM Hospital for Women, University of Western Australia, Perth. Necrotising enterocolitis in preterm neonates.

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Prof Sanjay Patole, MD, DCH, FRACP, MSc, DrPH Centre for Neonatal Research and Education

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  1. Advances in necrotising enterocolitis Prof Sanjay Patole, MD, DCH, FRACP, MSc, DrPH Centre for Neonatal Research and Education KEM Hospital for Women, University of Western Australia, Perth

  2. Necrotising enterocolitis in preterm neonates • Significant mortality and mortality including long term NDI • Outcomes are worse, especially in ELBW neonates requiring surgical intervention for NEC. • Health burden of ≥Stage II NEC has not changed significantly despite the advances in neonatal intensive care, and extensive research over decades. • Poorly understood pathogenesis is the main reason for the failure to develop strategies for prevention of NEC.

  3. Pathophysiology of NEC Excessive intestinal inflammation due to an immature innate immune response (TLR4) Lu et al Pathophysiology 2014 Decreased diversity, complexity and stability of gut flora (“dysbiosis”) and delayed colonization by beneficial microbes Intestinal epithelial integrity is controlled by a tightly regulated balance between proliferation and differentiation of epithelium from ISC and cellular loss by apoptosis. It involves various signaling pathways. Kandasamy et al Pathophysiology. 2014

  4. Recent advances in NEC Pathogenesis: TLR, gut microbiome, gut-liver axis, dysbiosis and fat intake, MDF 88, late onset infections, Early detection: Biomarkers, imaging Monitoring: Near-infrared spectroscopy, imaging Treatment: ?Stem cells

  5. Recent advances in NEC Primary prevention:Probiotics, prebiotics, lactoferrin, arginine, standardised slow feeding, oral surfactant, G-CSF, EPO, and relaxin, PGE2 Secondary prevention: ?? Probiotics, pentoxifylline Transfusion associated NEC: Feeding, gut oxygenation, Hb

  6. TLR4 • Expression, localization and signaling of TLR4 in colonic epithelium may be developmentally regulated. • Hydrocortisone may accelerate the TLR development towards an adult type. Meng et al Ped Res 2014 • Prevention of ER stress reduced TLR4-mediated intestinal stem cell (ISC) apoptosis and mucosal disruption. These changes suggest that increased ER stress within the premature bowel predisposes to NEC. Afrazi et al. J Biol Chem. 2014 Apr

  7. Gut ‘dysbiosis’ and NEC • Two fecal microbiota signatures (Clostridium and Klebsiella OTUs) and need for prolonged CPAP oxygen signal increased risk of NEC in pre-symptomatic infants. • These biomarkers will assist development of a screening tool to allow very early diagnosis of NEC. Sim et al Clin Infect Dis. 2014 Oct • NEC is associated with an abundance of strict anaerobes and a decrease in community diversity. Brower-Sinings PLOS ONE 2014

  8. DNA methylation • Pre- and postnatal changes in intestinal DNA methylation may contribute to high NEC sensitivity in preterm neonates. • Optimizing gene methylation changes via environmental stimuli (e.g. diet, nutrition, gut microbiota), may make immature infants more resistant to gut dysfunction. Gao et al BMC Genomics. 2014 Aug

  9. Genomics in NEC vs SIP • The different genome-wide expression profiles suggest that NEC and SIP are likely two different diseases caused by distinct etiology and pathophysiology. • This first comprehensive database of gene expression profiles could help in developing disease-specific diagnostic and prognostic biomarkers and new treatments. Chan et al Ann Surg. 2014 Dec

  10. Lysosomal enzymes: New biomarkers? • Gut ischemia is associated with ↑plasma lysosomal enzymes • Case-control study (15 neonates with NEC vs. 18 controls) • Plasma activities of β-glucosidase (ABG), α-glucosidase (GAA), and galactocerebrosidase (GALC) significantly higher in NEC vs. controls (ABG, p=0.009; GAA, p<0.001; GALC, p<0.001). • GAA and GALC had highest diagnostic value with AUC of 0.91 and 0.87. Benkoe et al Clin Chim Acta. 2015

  11. Biomarkers: IL8, serum and liver FABP • Serum concentrations of I-FABP, L-FABP and IL-8 were significantly higher in infants with NEC compared with controls. • IL-8 had highest diagnostic value with an AUC of 0.99, followed by L-FABP and I-FABP. • Significant correlation between IL-8 and both FABPs in infants with NEC. Benkoe J Pediatr Surg. 2014

  12. Biomarkers: Fecal Calprotectin, iFABPu • Rapid Fecal Calprotectin (FC) Analysis: Point of care testing for diagnosing early NEC. Bin-Nun et al Am J Perinatol 2014 • Five subjects developing NEC (Stage II: 3, Stage III: 2) • The day before first clinical manifestation of NEC, the iFABPu/uCr >10.2 pg/nmol predicted impending NEC with a sensitivity of 100% and a specificity of 95.6%. • iFABPu/uCr didn’t predict NEC 2 days before first s/o NEC Gollin et al Neonatology. 2014

  13. Probiotics Infants: Start early, single vs multi-strain, alternate days, Formula vs breast milk Maternal suppl.: Temporary colonisation of the infant Significance of maternal secretor status, consumption of HMOs by probiotic strains (? Designer synbiotics) Continued suppl. during stage II may prevent progression to stage III NEC Nutritional benefits while reducing NEC and mortality Safety: Probiotic bacteremia, sepsis, contamination

  14. Prebiotics (1) GOS-FOS reduces suspected NEC, time to full feeds, and hospital stay in preterm VLBW infants < 34 weeks (n=77) NEC: 1 (4.0%) vs. 11 (22.0%),HR: 0.49 (95% CI: 0.29-0.84); p=0.002 TFEF:11 (7-21) vs. 14 (8-36) days; p= 0.02 Hospital stay: 16 [9-45] vs. 25 [11-80] days; p= 0.004 Armanian 2014 Nov (2) Disialyllacto-N-tetraose prevents NEC in neonatal rats. Jantscher-Krenn et al. Gut. 2012

  15. Arginine Two RCTs (N=425); 235 included in the systematic review L-arginine reduced stage II and III NEC by 59% compared with placebo (RR: 0.41, 95% CI: 0.20 to 0.85, NNT=9, p=0.02). All stages of NEC reduced by 60% (RR: 0.40, 95% CI: 0.23 to 0.69, NNT=5, p= 0.001). No significant difference in neurodevelopmental disability at 3 years (RR: 0.65; 95% CI: 0.23-1.83, p=0.41) Mitchell et al 2014

  16. Lactoferrin: Multicentre RCT (n=743) NEC significantly lower with BLF and BLF+LGG BLF: 5/247 (2.0%), BLF+LGG: 0/238 (0%), Controls:14/258 (5.4%) BLF vs Control: RR: 0.37 (95% CI: 0.136-1.005; p=0.055) BLF+LGG vs Control: RR: 0.00; p <0.001 Death and/or NEC significantly lower with both treatments BLF: 4.0%, BLF+LGG:3.8%, Control:10.1% BLF vs Control: RR: 0.39 (95% CI: 0.19-0.80; p=0.008) BLF+LGG vs Control: RR: 0.37; 95% CI: 0.18-0.77; p = 0.006) No adverse effects or intolerances to treatment Manzoni et al 2014

  17. Standardised slow-delayed feeding for ELBW 125 ELBW in SSEF group vs. 294 historical controls Longer time to start feeds, TFEF, TPN and CVL days in SSDF No significant difference in any NEC (5.6% vs 11.2%; p=0.10) or surgical NEC (1.6% vs 4.8%; p=.17) in SSDF vs. controls BW <750 g: NEC (2.1% vs 16.2%; p <.01) or combined NEC/death (12.8% vs 29.5%; p=.03) significantly less in the SSDF group No significant diff. in discharge weight or stay in adjusted analysis Viswanathan JPEN 2014

  18. Oral G-CSF and EPO RCT, N=90, Gestation ≤33 weeks Four groups: 20 each on rhG-CSF, rhEPO, or both, and 30 received distilled water as placebo Test solution given orally at the start of feeds and discontinued when reaching 100 mL/kg/day feeds or after a maximum of 7 days, whichever came first El-Ganzouri et al J Pediatr 2014

  19. G-CSF and EPO Neonates on oral rhG-CSF and/or rhEPO had better feed tolerance, and reached 75, 100, and 150 mL/kg/day feeds earlier, with weight gain, and shorter stay (p<.05). NEC reduced from 10% to 0% in all treatment groups (p<.05) Shorter NBM duration of NBM for ‘’feed intolerance’’ in both rhG-CSF and rhEPO compared with placebo group neonates (p< .05). Serum G-CSF and EPO levels at D0 and D7 did not differ No adverse effects

  20. Relaxin Relaxin (RLXN), a hormone in breast milk but absent from formula, is a potent vasodilator Hypothesis: Relaxin-supplemented feeds would decrease NEC severity and increase intestinal blood flow in a rat pup model of the illness Matheson J Ped Surg 2014

  21. Relaxin Addition of relaxin to NEC group feeds improved the degree of ileal injury Ileal blood flow was decreased in NEC pups vs. controls but the addition of relaxin to ONE feed increased baseline ileal blood flow in the NEC group compared to NEC alone Addition of relaxin to ALL feeds significantly increased baseline ileal blood flow Matheson J Ped Surg 2014

  22. Oral surfactant protein-A (SP-A) Experimental NEC in newborn Sprague-Dawley rat pups by daily formula feeds and intermittent hypoxia. Purified human SP-A (5 μg/day) administered by oral gavage. After 4 days, surviving pups were sacrificed, and histological examination of distal terminal ileal sections was conducted. Intestinal inflammatory cytokine levels (IL-1β, IFN-γ and TNF-α) assessed by ELISA;TLR4 levels assessed by western analysis

  23. Oral SP-A Treatment with SP-A significantly reduced mortality and assessment of NEC SP-A significantly reduced IL-1β and TNF-α levels, but had little effect on elevated levels of IFN-γ SP-A treatment significantly reduced expression of intestinal TLR4, key in NEC pathogenesis Quintanilla et al JPGN 2014

  24. PGE2 Indomethacin, a non-selective PG inhibitor for closing PDA, is associated with intestinal perforation inducing an NEC-like illness. Aim: Define the contribution of PGE2 and its receptor EP4 to intestinal blood flow regulation in preterm neonates with NEC. Methods: Rat pup model of NEC. At 48hours of age, intestinal laser Doppler blood flow was assessed at baseline and after IP indomethacin, PGE2, EP4 antagonist, or EP4 agonist. K Walker J Pediatr Surg 2014

  25. PGE2 At baseline, NEC pups had lower intestinal blood flow than controls Indomethacin, PG E2 and EP4 agonist increased ileal blood flow, but PGE2 and EP4 agonist increased blood flow the most in NEC pups EP4 antagonist decreased intestinal perfusion in both groups K Walker J Pediatr Surg 2014

  26. Fluroscopy for detecting stricture 56 patients, 51 UGI-SBFT and 85 CE, 25 strictures detected Small bowel (SB) strictures: CE vs. UGI-SBFT had higher sensitivity (0.667 vs 0.00) and similar specificity (0.857 vs 0.833). SB and/or colonic strictures: CE had a sensitivity of 0.667 and a specificity of 0.951. Strictures more likely in symptomatic vs. asymptomatic infants (28% vs 8%, p = 0.002) Contrast enema (CE) is the investigation of choice Wiland et al JPGN 2014

  27. Sonography in NEC Prospective study: 26 consecutive NEC Stage II/III infants At least one abdominal US performed in each patient Surgery at the discretion of the surgeon US showed signs of intestinal necrosis in 5/26 patients, all 5 had laparotomy. The sensitivity, specificity, positive and negative predictive values of US for the detection of bowel necrosis were 100, 95.4, 80.0, and 100%, respectively. Yikilmaz et al. Pediatr Surg Int. 2014

  28. Sonography in NEC Abdominal US can identify those infants with NEC who may need surgery by detecting bowel necrosis (prior to the development of perforation or medical deterioration) with high sensitivity and specificity. Early surgical intervention may improve outcomes Yikilmaz et al. Pediatr Surg Int. 2014

  29. Hepatic blood flow in NEC Aim: To evaluate portal and hepatic vein flow in NEC Methods • Patient (suspected/definite NEC, n=24) vs. controls (n=25) • Daily serial DUS performed after suspecting NEC and continued until the initial day of enteral feeding • Portal blood flow (PBF) and "hepatic blood flow ratio" (RHBF) were calculated Akin et al JMFNM 2014

  30. Hepatic blood flow in NEC Results • PBF and RHBF significantly ↓ in patients vs. controls • Clinical improvement in NEC associated with ↑PBF and RHBF. Cut-off RHBF level for diagnosis of NEC: 0.66. Conclusion • DUS useful for diagnosis and follow-up of NEC by providing quantitative information on hepatic blood flow. • Daily PBF and RoHBF measurements in neonates with NEC may be beneficial to make the decision of starting enteral feeding.Akin et al JMFNM 2014

  31. Abdominal near-infrared spectroscopy (NIS) Background: NIS is a noninvasive method of measuring local tissue oxygenation (StO2). Abdominal StO2 (AStO2) measurements in preterm piglets are directly correlated with changes in intestinal BF and markedly reduced by NEC. Aim: To use NIS to establish normal values for abdominal StO2 in preterm infants and test whether they are reduced in infants who develop NEC Methods: 100 preterm (< 32 weeks) VLBW infants Patel et al Ped Crit Care Med 2014

  32. Abdominal NIS: Results Mean AStO2 in normal preterm infants (n=78) during the first week of life was significantly higher than in those (n=14) who later developed NEC: 77.3% ± 14.4% vs 70.7% ± 19.1%, p = 0.002 AStO2 ≤56% identified those progressing to NEC Sensitivity: 86%, Specificity: 64%, NPV: 96%, PPV: 30% AStO2 ≤56% independently associated with a significantly increased risk of NEC (OR: 14.1; p=0.01). Infants with NEC had significantly more variation in AStO2 during and after feeding in the first 2 weeks of life.

  33. Abdominal sonography in NEC A retrospective study of 95 preterm infants (mean gestation: 28.6 weeks), presenting with NEC and who underwent plain abdominal radiography and sonography, was performed. In uni- and multivariate analyses, radiographic and sonographic findings were correlated with complications ('surgery and/or death' and 'stenosis') Garbi-Goutel et al J Pediatr Surg 2014

  34. Abdominal sonography in NEC Free intraperitoneal air (OR: 8.0; IC, 1.4-44.2), free abdominal fluid (OR 3.5; IC 1.3-9.4), portal venous gas (OR 3.9; IC, 1.2-12.9), and bowel wall thickening (OR 2.8; IC,1.1-7.2) were significantly associated with surgery and/or death. Intramural gas was significantly correlated (OR=11.8; IC, 1.5-95.8) with intestinal stenosis following NEC. None of the x-ray findings were associated with complications. Conclusion: Sonographyreliable for assessing prognosis in NEC

  35. Portal venous blood flow and gut ischemia Aim: Evaluate the utility of portal blood flow and other hemodynamic measurements for early diagnosis of ischemia that may cause NEC Methods: Measured neonatal PBF and hemodynamics in 75 neonates without congenital anomalies. All neonates followed for 1 month after birth. The average gestation and birth weight was 30.5 weeks, and 1,172 g. Kobayashi et al. Eur J Pediatr Surg. 2014

  36. PVBF and gut ischemia PV cross-sectional area and BFV changed over time to maintain a fixed PVBF volume. Seven infants demonstrated a reduction in PVBF before development of abdominal symptoms. Both the cross-sectional area and BFV decreased over time before onset of NEC symptoms. Conclusion: A significant decline in PBF volume may be useful for the early diagnosis of NEC. Kobayashi et al. Eur J Pediatr Surg. 2014

  37. Magnetic resonance imaging (MRI) • The correlation of MRI results with histologic images of the excised ileal tissue samples strongly suggests that MRI can noninvasively identify NEC and assess intestinal injury prior to clinical symptoms in a physiologic rat pup model of NEC. Mustafi et al. NMR Biomed. 2014 Mar

  38. Stem cell therapy Amniotic fluid stem cells prevent development of ascites in a neonatal rat model of NEC. Zani et al. Eur J Pediatr Surg. 2014 Amniotic fluid stem cells improve survival and enhance repair of damaged intestine in NEC via a COX-2 dependent mechanism in rats. Zani et al Gut 2014 Review: Yang et al. Methods Mol Biol. 2014

  39. Thank you!!

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