Am J Perinatol 2017; 34(07): 648-654
DOI: 10.1055/s-0036-1597133
Original Article
Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.

Are Cytokines Useful Biomarkers to Determine Disease Severity in Neonates with Congenital Diaphragmatic Hernia?

Thomas Schaible
1   Department of Neonatology, University Hospital Mannheim, Mannheim, Germany
,
Janine Reineke
1   Department of Neonatology, University Hospital Mannheim, Mannheim, Germany
,
Ludwig Gortner
2   Department of Neonatology, University Hospital Saarland, Homburg, Germany
,
Dominik Monz
2   Department of Neonatology, University Hospital Saarland, Homburg, Germany
,
Regine Schaffelder
3   Department of Gynaecology, University Hospital Mannheim, Mannheim, Germany
,
Erol Tutdibi
2   Department of Neonatology, University Hospital Saarland, Homburg, Germany
› Author Affiliations
Further Information

Publication History

14 April 2016

25 October 2016

Publication Date:
07 December 2016 (online)

Abstract

Background This study investigates plasma cytokine levels in neonates with the more common left-sided congenital diaphragmatic hernia (CDH) and correlates them with severity of disease indicated by position of the liver. An intrathoracic part of liver is associated with higher need for extracorporeal membrane oxygenation (ECMO) and higher risk for chronic lung disease (CLD).

Methods A total of 28 newborns with CDH were subdivided by their liver position in partially intrathoracic (n = 16) and only abdominal (n = 12) position. Only liver-up patients went on ECMO (n = 9) and developed severe/moderate CLD (n = 5). Controls consisted of 19 healthy matched-term neonates. Laboratory samples were extracted from umbilical cord blood and during the neonatal period.

Results In umbilical cord blood, CDH patients showed decreased IL-8 values while MIP-1a (macrophage inflammatory protein-1) values were increased. Concerning the severity of CDH, we measured significantly higher levels of TGFb2 in CDH patients with liver-up than in liver-down cases and controls (p < 0.006). During the neonatal period, the concentration of IL-10 and vascular endothelial growth factor (VEGF) showed significant deviations in the liver-up group with need for ECMO (p < 0.009).

Conclusion In neonates with CDH, plasma cytokine levels are already altered in utero. TGFb2 may work as an early predictor for severity of disease. VEGF and IL-10 could serve as potential biomarkers predicting the course of disease in CDH.

 
  • References

  • 1 Schaible T, Veit M, Tautz J , et al. Serum cytokine levels in neonates with congenital diaphragmatic hernia. Klin Padiatr 2011; 223 (7) 414-418
  • 2 Schaible T, Büsing KA, Felix JF , et al. Prediction of chronic lung disease, survival and need for ECMO therapy in infants with congenital diaphragmatic hernia: additional value of fetal MRI measurements?. Eur J Radiol 2012; 81 (5) 1076-1082
  • 3 Lusk LA, Wai KC, Moon-Grady AJ, Basta AM, Filly R, Keller RL. Fetal ultrasound markers of severity predict resolution of pulmonary hypertension in congenital diaphragmatic hernia. Am J Obstet Gynecol 2015; 213 (2) 216.e1-216.e8
  • 4 Van Marter LJ. Epidemiology of bronchopulmonary dysplasia. Semin Fetal Neonatal Med 2009; 14 (6) 358-366
  • 5 Zamora IJ, Olutoye OO, Cass DL , et al. Prenatal MRI fetal lung volumes and percent liver herniation predict pulmonary morbidity in congenital diaphragmatic hernia (CDH). J Pediatr Surg 2014; 49 (5) 688-693
  • 6 Brindle ME, Cook EF, Tibboel D, Lally PA, Lally KP ; Congenital Diaphragmatic Hernia Study Group. A clinical prediction rule for the severity of congenital diaphragmatic hernias in newborns. Pediatrics 2014; 134 (2) e413-e419
  • 7 Reiss I, Schaible T, van den Hout L , et al; CDH EURO Consortium. Standardized postnatal management of infants with congenital diaphragmatic hernia in Europe: the CDH EURO Consortium consensus. Neonatology 2010; 98 (4) 354-364
  • 8 Peralta CF, Cavoretto P, Csapo B, Vandecruys H, Nicolaides KH. Assessment of lung area in normal fetuses at 12-32 weeks. Ultrasound Obstet Gynecol 2005; 26 (7) 718-724
  • 9 Rypens F, Metens T, Rocourt N , et al. Fetal lung volume: estimation at MR imaging-initial results. Radiology 2001; 219 (1) 236-241
  • 10 Mohseni-Bod H, Bohn D. Pulmonary hypertension in congenital diaphragmatic hernia. Semin Pediatr Surg 2007; 16 (2) 126-133
  • 11 Jobe AH, Bancalari E. Bronchopulmonary dysplasia. Am J Respir Crit Care Med 2001; 163 (7) 1723-1729
  • 12 Thavasu PW, Longhurst S, Joel SP, Slevin ML, Balkwill FR. Measuring cytokine levels in blood. Importance of anticoagulants, processing, and storage conditions. J Immunol Methods 1992; 153 (1) -2 115-124
  • 13 Fleck S, Bautista G, Keating SM , et al. Fetal production of growth factors and inflammatory mediators predicts pulmonary hypertension in congenital diaphragmatic hernia. Pediatr Res 2013; 74 (3) 290-298
  • 14 Stoiser B, Knapp S, Thalhammer F , et al. Time course of immunological markers in patients with the systemic inflammatory response syndrome: evaluation of sCD14, sVCAM-1, sELAM-1, MIP-1 alpha and TGF-beta 2. Eur J Clin Invest 1998; 28 (8) 672-678
  • 15 Stressig R, Fimmers R, Schaible T , et al. Preferential streaming of the ductus venosus toward the right atrium is associated with a worse outcome despite a higher rate of invasive procedures in human fetuses with left diaphragmatic hernia. Ultraschall Med 2013; 34 (6) 568-572
  • 16 Liu J, Tseu I, Wang J, Tanswell K, Post M. Transforming growth factor beta2, but not beta1 and beta3, is critical for early rat lung branching. Dev Dyn 2000; 217 (4) 343-360
  • 17 Takahashi N, Takahashi K, Kobayashi M, Yada Y, Koike Y, Kono Y. Constitutively high-level expression of TGFβ isoforms in cord blood and its relationship to perinatal findings. Cytokine 2015; 73 (1) 101-107
  • 18 Takahashi H, Shibuya M. The vascular endothelial growth factor (VEGF)/VEGF receptor system and its role under physiological and pathological conditions. Clin Sci (Lond) 2005; 109 (3) 227-241
  • 19 Compernolle V, Brusselmans K, Acker T , et al. Loss of HIF-2alpha and inhibition of VEGF impair fetal lung maturation, whereas treatment with VEGF prevents fatal respiratory distress in premature mice. Nat Med 2002; 8 (7) 702-710
  • 20 Sbragia L, Nassr AC, Gonçalves FL , et al. VEGF receptor expression decreases during lung development in congenital diaphragmatic hernia induced by nitrofen. Braz J Med Biol Res 2014; 47 (2) 171-178
  • 21 Patel N, Moenkemeyer F, Germano S, Cheung MM. Plasma vascular endothelial growth factor A and placental growth factor: novel biomarkers of pulmonary hypertension in congenital diaphragmatic hernia. Am J Physiol Lung Cell Mol Physiol 2015; 308 (4) L378-L383
  • 22 Lassus P, Turanlahti M, Heikkilä P , et al. Pulmonary vascular endothelial growth factor and Flt-1 in fetuses, in acute and chronic lung disease, and in persistent pulmonary hypertension of the newborn. Am J Respir Crit Care Med 2001; 164 (10 Pt 1): 1981-1987
  • 23 Qi Y, Jiang Q, Chen C, Cao Y, Qian L. Circulating endothelial progenitor cells decrease in infants with bronchopulmonary dysplasia and increase after inhaled nitric oxide. PLoS One 2013; 8 (11) e79060
  • 24 Tryzmel J, Miskolci V, Castro-Alcaraz S, Vancurova I, Davidson D. Interleukin-10 inhibits proinflammatory chemokine release by neutrophils of the newborn without suppression of nuclear factor-kappa B. Pediatr Res 2003; 54 (3) 382-386
  • 25 Kotani N, Hashimoto H, Sessler DI , et al. Cardiopulmonary bypass produces greater pulmonary than systemic proinflammatory cytokines. Anesth Analg 2000; 90 (5) 1039-1045